pharmaceutical composition in unit dosage form formulated for sublingual administration and use of s

专利摘要:
"pharmaceutical composition in unit dosage form formulated for sublingual administration and use of said composition". The present invention relates to sublingual film formulations of dopamine agonists and methods of treating parkinson's disease, tremors, restless legs syndrome, sexual dysfunction, and depressive disorders therewith. In one aspect, the invention features a pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein the unit dosage form is a film including one or more disintegrants (e.g., materials that favor disintegration or rapid dissolution by virtue of of its solubility in water, such as hydrolyzed starches, sugars, and glycerin, which can play a dual role as a plasticizer and a disintegrant) and a plasticizing agent, the film having a first moiety including apomorphine hydrochloride ("apomorphine hydrochloride" ), and a second portion including pH neutralizing agent.
公开号:BR112013015204A2
申请号:R112013015204
申请日:2011-12-16
公开日:2019-10-01
发明作者:John Giovinazzo Anthony；Clinton Koons Michael；John Bryson Nathan；David Barnhart Scott
申请人:Arx Llc；Cynapsus Therapeutics Inc；
IPC主号:

专利说明:

Descriptive Report of the Invention Patent for PHARMACEUTICAL COMPOSITION IN FORM OF DOSAGE UNIT FORMULATED FOR SUBLINGUAL ADMINISTRATION AND USE OF THAT COMPOSITION.
Background of the Invention
The present invention relates to compositions including a dopamine agonist formulated for sublingual administration and the use of similar compositions for the treatment of Parkinson's disease.
Parkinson's disease (PD) is a progressive degenerative disease of the central nervous system. The risk of developing Parkinson's disease increases with age, and the affected individuals are usually adults over 40. Parkinson's disease occurs in all parts of the world, and affects more than 1.5 million individuals in the United States alone.
Although the primary cause of Parkinson's disease is not known, it is characterized by degeneration of the dopaminergic neurons of the substantia nigra. The substantia nigra is a portion of the lower brain, or brain stem, that helps control voluntary movements. The lack of dopamine in the brain caused by the loss of these neurons is believed to cause observable disease symptoms.
The symptoms of Parkinson's disease vary from patient to patient. The most common symptom is a lack of movement and stiffness, characterized by an increase in the stiffness of voluntary skeletal muscles. Additional symptoms include tremor at rest, bradykinesia (slow movement), lack of balance, and trouble walking. Common secondary symptoms include depression, sleep disturbance, dizziness, stooped posture, dementia, problems with speech, breathing, and swallowing. The symptoms become progressively worse over time and finally result in death.
A variety of therapeutic treatments are available for Parkinson's disease. Possibly the best known therapeutic treatment is levodopa, a precursor to dopamine. Although administration of levodopa can result in dramatic improvement in symptoms, patients can experience serious side effects, including
2/89 nausea and vomiting. Concomitant administration of carbidopa with levodopa is a significant improvement, with the addition of carbidopa inhibiting the metabolism of levodopa in the intestine, liver and other tissues, thereby allowing more levodopa to reach the brain. Other dopamine agonists, such as bromocriptine, pergolide, pramipexole, and andropinirole are also used to treat Parkinson's disease, and can be administered to patients with Parkinson's disease who alone or in combination with levodopa.
Many patients develop involuntary choreiform movements which are the result of excessive activation of dopamine receptors. These movements generally affect the face and the limbs and can become very serious. The referred movements disappear if the dose of dopamine precursor (eg, levodopa) or dopamine agonist is reduced, but this typically causes the stiffness to return. In addition, the margin between beneficial and unwanted effects appears to become progressively narrower as the chemotherapy treatment period extends.
An additional complication of long-term chemotherapy treatment with dopamine agonists is the development of rapid fluctuations in the clinical state where the patient suddenly alternates between mobility and immobility for periods ranging from a few minutes to a few hours. Fluctuations are of several general types. Wearing off phenomena are deteriorations in the relief provided by a dose of levodopa before the next dose takes effect (Van Laar T., CNS Drugs, 17: 475 (2003)). As they are related to a patient's dose schedule, the periods referred to are often relatively predictable (Dewey RB Jr., Neurology, 62 (suppl 4): S3-S7 (2004)). In contrast, on-off phenomena are sudden transitions from an on period of levodopa benefit to an off period of akinesia, stiffness, and tremor that occur and, minutes or even seconds, (Swope DM., Neurology, 62 (suppl 4 ): S27-S31 (2004)) with no discernible relationship to a patient's dose schedule. Two other phenomena are the effect on retar
3/89 given, in which the effects of levodopa are substantially delayed, and dose failure (also known as the no effect or missed dose), in which no effect occurs. These various off states can produce an abrupt loss of mobility such that the patient may suddenly stop while walking or be unable to get up from a chair on which he or she has normally sat a few moments before.
Subcutaneous injections of apomorphine have proven effective in treating on-ofF fluctuations in Parkinson's disease within 5 to 15 minutes, and last for 45 to 90 minutes. Tests have shown a consistent reversal of off-period akinesia, a reduction in daily needs for and consequently a reduction in the amount of on-time dyskinesias. The advantages over other dopamine agonists include a rapid onset of action and a lower incidence of psychological complications. For rescue therapy in patients with onoff fluctuations, apomorphine also has the advantage over other dopamine agonists that it has a relatively short half-life.
Numerous formulations and routes of administration for apomorphine have been studied and apomorphine therapy has been seen to be impaired by several complications. For example, oral administration of apomorphine tablets has required high doses to obtain the necessary therapeutic effect because apomorphine administered in this way undergoes extensive metabolism in the small intestine and / or, after absorption, in the liver; sublingual administration of apomorphine tablets caused severe stomatitis in prolonged use with ulceration of the oral mucosa in half of the treated patients (see Deffond et al., J. Neurol. Neurosurg. Psychiatry 56: 101 (1993)); and intranasal administration produced a transient nasal block, a burning sensation and a swollen nose and lips (see Koller et al., Neurology 62: S22 (2004)). Although subcutaneous injections of apomorphine have proven effective, a needle injection is difficult for patients with Parkinson's due to impaired motor function. In addition, a common side effect of subcutaneous injection is the development of nodules, which often become infected, requiring treatment.
4/89 thiobiotic or surgical debridement (see Prietz et al., J. Neurol. Neurosurg. Psychiatry 65: 709 (1998)).
There is a need for new formulations of dopamine agonists which are safe, effective, and easy for a Parkinson's patient to use.
Summary of the Invention
The invention features sublingual formulations including a dopamine agonist, or a salt thereof. The formulations can be useful for the treatment of Parkinson's disease, tremors, restless legs syndrome, sexual dysfunction, and depressive disorders with them.
In one aspect, the invention features a pharmaceutical composition in the form of a dosage unit formulated for sublingual administration, wherein the dosage unit form is a film including one or more disintegrants (for example, materials that favor disintegration or rapid dissolution in by virtue of its solubility in water, such as hydrolyzed starches, sugars, and glycerin, which can play a dual role as a plasticizer and a disintegrant) and a plasticizer, the film having a first portion including apomorphine hydrochloride, and a second portion including pH neutralizing agent, wherein the dosage unit form includes from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and the agent neutralizing agent is present in an amount sufficient to produce a solution having a pH of between 3.0 and 6.0, preferably between 4.5 and 6.5, (for example, a p H between 2.5 and 4.5, 3.0 and 6.0, 3.5 and 6.5,
4.5 and 6.5, or 5.0 and 6.0) when the dosage unit form is placed in un buffered water at pH 7 (for example, the pH observed within 5 minutes of placing the unit form dosage in 1, 5, or 10 mL of unbuffered water). The film can include from 1 to 50% (by weight / weight) (for example, 1 ± 0.75%, 2 ± 1.5%, 3 ± 0.5%, 5 ± 2%, 7.5 ± 2.5%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5% , or 50 ± 5% (by weight / weight) of one or more disintegrants. In some embodiments, the dosage unit form additionally includes
5/89 a high molecular weight polymer having an average molecular weight of more than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. In other embodiments, the dosage unit form additionally includes a low molecular weight polymer having an average molecular weight of from 5 KD to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. The pH neutralizing agent can be an organic base (for example, pyridoxine, meglumine, or any organic base described here, in this patent application) or an inorganic base (for example, magnesium hydroxide, sodium bicarbonate, or a base inorganic substance described here, in this patent application). In particular embodiments, the dosage unit form includes 35 ± 5% (by weight / weight) of disintegrant, from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and pyridoxine present in an amount sufficient to produce a solution having a pH of between 4.5 and 6.5 when the dosage unit form is placed in water not buffered at pH 7.
In a related aspect, the invention features a pharmaceutical composition in the form of a dosage unit formulated for sublingual administration, wherein the dosage unit form is a film including: (i) apomorphine hydrochloride; (ii) a low molecular weight polymer having an average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) a high molecular weight polymer having an average molecular weight of more than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose, wherein the dosage unit form includes the from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride.
The invention additionally features a pharmaceutical composition in the form of a dosage unit formulated for administration
6/89 sublingual, wherein the dosage unit form is a bilayer film having a first layer and a second layer, the second layer including a pH neutralizing agent and the first layer including: (i) apomorphine hydrochloride; (ii) a low molecular weight polymer having an average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) a high molecular weight polymer having an average molecular weight of more than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose, wherein the dosage unit form includes the from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and the pH neutralizing agent is present in an amount sufficient to produce a solution having a pH of between 3.0 and 6.0, preferably between 4.5 and 6.5, (for example, a pH of between 2.5 and 4.5, 3.0 and 6.0, 3.5 and 6.5 , 4,5 and 6,5, or 5,0 and 6,0) when the dosage unit form is placed in un buffered water at pH 7 (for example, the pH observed within 5 minutes of placing the form of dosing unit in 1, 5, or 10 mL of unbuffered water). The pH neutralizing agent can be an organic base (for example, pyridoxine, meglumine, or any organic base described here, in this patent application) or an inorganic base (for example, magnesium hydroxide, sodium bicarbonate, or a base inorganic substance described here, in this patent application). In particular embodiments, the unit dosage form includes an antioxidant, 1 ± 0.5% (by weight / weight) of glycerol monoestereate, 35 ± 5% (by weight / weight) of disintegrant, from 0.5 up to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine and pyridoxine hydrochloride present in an amount sufficient to produce a solution having a pH between 4.5 and 6.5 when the form dosing unit is placed in water not buffered at pH 7.
In an embodiment of any of the above dosage unit forms, the dosage unit form can include from 0.2
7/89 to 5% (by weight / weight) eg 0.5 ± 0.25%, 0.75 ± 0.25%, 1 ± 0.5%,
1.5 ± 0.5%, 2 ± 0.5%, 2.5 + 0.5%, 3 ± 0.5%, 3.5 ± 0.5%, 4 ± 0.5%, or 5 ± 0.5% (by weight / weight)) of a permeation enhancer (for example, an ionic surfactant, non-ionic surfactant, polysorbate, tocopherol derivatives, poloxamer, monoglyceride, diglyceride, fatty acid, fatty alcohol, mixtures thereof , or any permeation enhancer described here, in this patent application). In particular embodiments, the permeation enhancer is glycerol monostearate. In another embodiment of any of the above dosage unit forms, the dosage unit form can include an antioxidant (for example, from 0.05 to 2.5% (by weight / weight) (for example, 0 , 05 ± 0.025%, 0.1 ± 0.075%, 0.3 ± 0.1%, 0.5 ± 0.25%, 0.75 ± 0.25%, 1 ± 0.5%, 1.5 ± 0.5%, 2 ± 0.5%, or 2.5 ± 0.5% (by weight / weight)) of metabisulfite, or any antioxidant described here, in this patent application. above dosage form, the dosage unit form can additionally include from 3 to 18% (by weight / weight) (e.g. 3 to 12%, 3 ± 1%, 5 ± 2%, 7.5 ± 2 , 5%, 10 ± 3%, 12 ± 3%, 15 ± 3%, or 18 ± 3% (by weight / weight)) of plasticizer, such as a polyol (for example, sorbitol, mannitol, maltitol, xylitol , glycerol, propylene glycol, or polyethylene glycol), oleic acid, or triacetin In particular embodiments of the above dosage unit forms, the dosage unit form may include flow from 1 to 50% (by weight / weight) (for example, 1 ± 0.75%, 2 ± 1.5%, 3 ± 0.5%, 5 ± 2%, 7.5 ± 2, 5%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, or 50 ± 5% (by weight / weight) of hydrolyzed starch. The hydrolyzed starch can be a dextrin, a maltodextrin, or any hydrolyzed starch described herein, in this patent application. In yet another embodiment of any of the dosage unit forms of the invention, the dosage unit form can have a sublingual bioavailability of more than 40% (for example, a sublingual bioavailability of from 40 to 70%, 45 to 85%, 55 to 95%, 65 to 100%, 70 to 100%, 70 to 99%, 75 to 100%, 75 to 99%, or 80 to 99%). In particular modalities, any of the forms of unity of the
8/89 message described here, in this patent application, can have a T _max of from 10 to 25 minutes (for example, 9 ± 3, 10 ± 3, 11 ± 3, 12 ± 3, 13 + 3, 14 ± 3, 15 ± 3, 16 ± 3, 17 ± 3, 18 ± 3, 20 ± 3, 22 ± 3, 24 ± 3, or 25 ± 3 minutes). In yet another embodiment of any of the above dosage unit forms, the dosage unit form, after sublingual administration to a subject, produces an average circulating apomorphine concentration of at least 3 ng / mL within a period of a from 5 to 15 minutes after administration. For example, the dosage unit form can produce an average circulating concentration of from 3 to 6 ng / mL within 7 to 10 minutes, from 5 to 10 ng / mL within 5 to 10 minutes, from from 7 to 12 ng / mL within 5 to 10 minutes, from 10 to 16 ng / mL within 5 to 10 minutes, from 3 to 6 ng / mL within 7 to 15 minutes, from 5 up to 10 ng / mL within 7 to 15 minutes, from 7 to 12 ng / mL within 7 to 15 minutes, from 10 to 16 ng / mL within 7 to 15 minutes, from 3 to 6 ng / mL within 15 to 20 minutes, from 5 to 10 ng / mL within 15 to 20 minutes, from 7 to 12 ng / mL within 15 to 20 minutes, or from 10 to 16 ng / mL within 15 to 20 minutes after administration. In an embodiment of any of the above dosage unit forms, the dosage unit form when administered sublingually to a subject is non-irritating (for example, non-irritating using the test of Example 7). In a particular embodiment of any of the above dosage unit forms, the dosage unit form is an individual film packaged in aluminum foil coated with sealed plastic, where the dosage unit form is stable for a period of at least 2 months, 4 months, or 6 months at 40 ° C (for example, colorless using the test described in Example 8).
The invention features a pharmaceutical composition in unit dosage form formulated for sublingual administration, the unit dosage form having a first portion including an acid addition salt from a dopamine agonist, and a second portion including a neutralizing agent. pH, where the dopamine agonist is selected
9/89 between bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, and acid addition salts thereof. In particular embodiments, the dosage unit form is a lozenge, a pill, a pill, a film, or a tape.
The invention features a pharmaceutical composition in unit dosage form formulated for sublingual administration, in which the unit dosage form is a film including: (i) from 10 to 75% (by weight / weight) (for example, 30 to 75%, 10 ± 5%, 15 ± 5%, 20 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5%, 65 ± 5%, 70 + 5%, or 75 ± 5% (by weight / weight)) of dopamine agonist, or an acid addition salt thereof; (ii) from 0.5 to 16% (by weight / weight) (for example, 0.5 to 10%, 0.5 ± 0.1%, 1 ± 0.5%, 2 ± 0.75 %, 3 ± 1%, 5 ± 1%, 6 ± 2%, 7 ± 3%, 8 ± 3%, 9 ± 3%, 12 ± 3%, or 16 ± 3% (by weight / weight)) a low molecular weight polymer having an average molecular weight of from 5 KDa to 50 KDa (e.g. 5 ± 3, 8 ± 3, 10 ± 3, 15 ± 5, 18 ± 5, 22 ± 6, 28 ± 6, 34 ± 8, 44 ± 8, or 50 ± 10 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) from 4 to 35% (by weight / weight) (for example, 4 to 20%, 4 ± 2%, 5 ± 2.5%, 7.5 ± 3%, 10 ± 3.5 %, 14 ± 5%, 18 ± 5%, 20 ± 6%, 25 ± 6%, 30 ± 6%, or 35 ± 6% (by weight / weight)) of a high molecular weight polymer having a molecular weight average weight of more than 60 KDa (for example, 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. In some embodiments, the film has a surface coated with a pH neutralizing agent (for example, a coating or powder of an inorganic or organic base). In still other embodiments, the unit dosage form when placed in 1 ml_ of water not buffered at pH 7 results in a solution having a pH of between 2.5 and 6.5, preferably between 4.5 and 6.5, (for example, a pH of between 2.5 and 4.5, 3.0 and 6.0,
3.5 and 6.5, 4.5 and 6.5, or 5.0 and 6.0), and has a sublingual bioavailability of
10/89 more than 40% (for example, a sublingual bioavailability of from 40 to 70%, 45 to 85%, 55 to 95%, 65 to 100%, 70 to 100%, 70 to 99%, 75 to 100%, 75 to 99%, or 80 to 99%). In particular modalities, the dopamine agonist is selected from apomorphine, an apomorphine prodrug, bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, and acid addition salts thereof.
In a related aspect, the invention features a pharmaceutical composition in the form of a dosage unit formulated for sublingual administration, wherein the dosage unit form is a bilayer film having a first layer and a second layer, the first layer including: (i ) from 10 to 75% (by weight / weight) (e.g., 30 to 75%, 10 ± 5%, 15 ± 5%, 20 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5%, 65 ± 5%, 70 ± 5%, or 75 ± 5% (by weight / weight)) dopamine agonist, or an acid addition salt thereof; (ii) from 0.5 to 16% (by weight / weight) (for example, 0.5 to 10%, 0.5 ± 0.1%, 1 ± 0.5%, 2 ± 0.75 %, 3 ± 1%, 5 ± 1%, 6 ± 2%, 7 ± 3%, 8 ± 3%, 9 ± 3%, 12 ± 3%, or 16 ± 3% (by weight / weight)) a low molecular weight polymer having an average molecular weight of from 5 KDa to 50 KDa (e.g. 5 ± 3, 8 ± 3, 10 ± 3, 15 ± 5, 18 ± 5, 22 ± 6, 28 ± 6, 34 ± 8, 44 ± 8, or 50 ± 10 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) from 4 to 35% (by weight / weight) (for example, 4 to 20%, 4 ± 2%, 5 ± 2.5%, 7.5 ± 3%, 10 ± 3.5 %, 14 ± 5%, 18 ± 5%, 20 ± 6%, 25 ± 6%, 30 ± 6%, or 35 ± 6% (by weight / weight)) of a high molecular weight polymer having a molecular weight average weight of more than 60 KDa (for example, 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose, and wherein the second layer includes a pH neutralizing agent and from 15 to 50% (by weight / weight) (for example, 15 ± 5%, 20 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ±
11/89
5%, or 50 ± 5% (by weight / weight)) of a high molecular weight polymer having an average weight molecular weight of more than 60 KDa (for example, 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa at 120 KDa, 100 KDa at 300 KDa, 220 KDa at 500 KDa, or 400 KDa at 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. In some embodiments, the second layer includes from 6 to 65% (by weight / weight) (for example, 10 to 50%, 6 ± 2%, 8 ± 2%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5%, or 65 ± 5% (by weight / weight) of pH neutralizing agent. In particular embodiments, the dosage unit form is a three-layer film including two outer layers of dopamine agonist, and an inner layer of pH neutralization. In particular modalities, the dopamine agonist is selected from apomorphine, an apomorphine prodrug, bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, and acid addition salts thereof. In particular embodiments, the dosage unit form includes an antioxidant, 1 ± 0.5% glycerol monostearate, 35 ± 5% (by weight / weight) of hydrolyzed starch, and 4 ± 2% (by weight / weight) pyridoxine , wherein the first layer includes 10 ± 5% (by weight / weight) of apomorphine hydrochloride, 2 ± 0.75% (by weight / weight) of a low molecular weight polymer having an average weight molecular weight from from 5 KDa to 50 KDa, and 30 ± 6% (by weight / weight) of a high molecular weight polymer having an average molecular weight of more than 60 KDa.
The invention features a pharmaceutical composition in unit dosage form formulated for sublingual administration, in which the unit dosage form is a film including: (i) from 10 to 75% (by weight / weight) (for example, 30 to 75%, 10 ± 5%, 15 ± 5%, 20 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5%, 65 ± 5%, 70 ± 5%, or 75 ± 5% (by weight / weight)) of apomorphine, an apomorphine prodrug, or an acid addition salt thereof; (ii) from 0.5 to 16% (by weight / weight) (for example, 0.5 to 10%, 0.5 ± 0.1%, 1 ±
12/89
0.5%, 2 ± 0.75%, 3 ± 1%, 5 ± 1%, 6 ± 2%, 7 ± 3%, 8 ± 3%, 9 ± 3%, 12 ± 3%, or 16 ± 3% (by weight / weight)) of a low molecular weight polymer having an average weight molecular weight from 5 KDa to 50 KDa (for example, 5 ± 3, 8 ± 3, 10 ± 3, 15 ± 5 , 18 ± 5, 22 ± 6, 28 ± 6, 34 ± 8, 44 ± 8, or 50 ± 10 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) from 4 to 35% (by weight I weight) (for example, 4 to 20%, 4 ± 2%, 5 ± 2.5%, 7.5 ± 3%, 10 ± 3.5 %, 14 ± 5%, 18 ± 5%, 20 ± 6%, 25 ± 6%, 30 ± 6%, or 35 ± 6% (by weight / weight)) of a high molecular weight polymer having a molecular weight average weight of more than 60 KDa (for example, 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. In some embodiments, the film has a surface coated with a pH neutralizing agent (for example, a coating or powder of an inorganic or organic base). In still other embodiments, the dosage unit form when placed in 1 mL of water not buffered at pH 7 results in a solution having a pH of between 2.5 and 6.5, preferably between 4.5 and 6.5, (for example, a pH of between 2.5 and 4.5, 3.0 and 6.0, 3.5 and 6.5, 4.5 and 6.5, or 5.0 and 6.0), and has a sublingual bioavailability of more than 40% (for example, a sublingual bioavailability of from 40 to 70%, 45 to 85%, 55 to 95%, 65 to 100%, 70 to 100%, 70 to 99% , 75 to 100%, 75 to 99%, or 80 to 99%).
In a related aspect, the invention features a pharmaceutical composition in the form of a dosage unit formulated for sublingual administration, wherein the dosage unit form is a bilayer film having a first layer and a second layer, the first layer including: (i ) from 10 to 75% (by weight / weight) (e.g., 30 to 75%, 10 ± 5%, 15 ± 5%, 20 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5%, 65 ± 5%, 70 ± 5%, or 75 ± 5% (by weight / weight)) apomorphine, an apomorphine prodrug, or an acid addition salt thereof; (ii) from 0.5 to 16% (by weight / weight)
13/89 (e.g. 0.5 to 10%, 0.5 ± 0.1%, 1 ± 0.5%, 2 ± 0.75%, 3 ± 1%, 5 ± 1%, 6 ± 2 %, 7 ± 3%, 8 ± 3%, 9 ± 3%, 12 ± 3%, or 16 ± 3% (by weight / weight)) of a low molecular weight polymer having an average weight molecular weight from from 5 KDa to 50 KDa (e.g. 5 ± 3, 8 ± 3%, 10 ± 3, 15 ± 5, 18 ± 5, 22 ± 6, 28 ± 6, 34 ± 8, 44 ± 8, or 50 ± 10 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) from 4 to 35% (by weight / weight) (for example, 4 to 20%, 4 ± 2%, 5 ± 2.5%, 7.5 ± 3%, 10 ± 3.5 %, 14 ± 5%, 18 ± 5%, 20 ± 6%, 25 ± 6%, 30 ± 6%, or 35 ± 6% (by weight / weight)) of a high molecular weight polymer having a molecular weight average weight of more than 60 KDa (for example, 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose, and wherein the second layer includes a pH neutralizing agent and from 15 to 50% (by weight / weight) (for example, 15 ± 5%, 20 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, or 50 ± 5% (by weight / weight)) of a high polymer molecular weight having an average molecular weight of more than 60 KDa (for example, 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa at 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. In some embodiments, the second layer includes from 6 to 65% (by weight / weight) (for example, 10 to 50%, 6 ± 2%, 8 ± 2%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5%, or 65 ± 5% (by weight / weight) of pH neutralizing agent. In particular embodiments, the dosage unit form is a three-layer film including two outer layers of apomorphine, and an inner layer of pH neutralization.
In some embodiments of the above aspects, the film additionally includes from 3 to 18% (by weight / weight) (for example, 3 to 12%, 3 ± 1%, 5 ± 2%, 7.5 ± 2.5 %, 10 ± 3%, 12 ± 3%, 15 ± 3%, or 18 ± 3% (by weight
14/89 / weight)) of plasticizer, such as a polyol (e.g., sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, or polyethylene glycol), oleic acid, or triacetin.
In particular embodiments of the above aspects, the film, or a film layer, additionally includes from 1 to 50% (by weight / weight) (for example, 1 ± 0.75%, 2 ± 1.5%, 3 ± 0.5%, 5 ± 2%, 7.5 ± 2.5%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, or 50 ± 5% (by weight / weight)) of hydrolyzed starch. The hydrolyzed starch can be a dextrin, a maltodextrin, or any hydrolyzed starch described herein, in this patent application.
The films of the invention can include an antioxidant. For example, films, or a layer of a bilayer film can include from 0.05 to 2.5% (by weight / weight) (for example, 0.05 ± 0.025%, 0.1 ± 0.075%, 0.3 ± 0.1%, 0.5 ± 0.25%, 0.75 ± 0.25%, 1 ± 0.5%, 1.5 ± 0.5%, 2 ± 0.5%, or 2.5 ± 0.5% (by weight / weight) of metabisulfite, or any antioxidant described herein, in this patent application.
The films of the invention can have a T _max of from 10 to 25 minutes (for example, 9 ± 3, 10 ± 3, 11 ± 3, 12 ± 3, 13 ± 3, 14 ± 3, 15 ± 3, 16 ± 3, 17 ± 3, 18 ± 3, 20 ± 3, 22 ± 3, 24 ± 3, or 25 ± 3 minutes).
The films of the invention can include from 0.2 to 5% (by weight / weight) for example, 0.5 ± 0.25%, 0.75 ± 0.25%, 1 ± 0.5%, 1 , 5 ± 0.5%, 2 ± 0.5%, 2.5 ± 0.5%, 3 ± 0.5%, 3.5 ± 0.5%, 4 ± 0.5%, or 5 ± 0.5% (by weight / weight)) of a permeation enhancer (for example, an ionic surfactant, nonionic surfactant, polysorbate, tocopherol derivatives, poloxamer, monoglyceride, diglyceride, fatty acid, fatty alcohol, mixtures thereof, or any permeation enhancer described here, in this patent application). In particular embodiments, the permeation enhancer is glycerol monostearate.
The films of the invention can include a low molecular weight polymer selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose. For example, hydroxypropyl methylcellulose can have about 20% to about 35% methoxy substitution and about 5% to about
15/89 of 15% hydroxypropyl substitution.
The films of the invention can include a high molecular weight polymer selected from hydroxypropyl methyl cellulose and hydroxyethyl cellulose. For example, the high molecular weight polymer can be hydroxypropyl methyl cellulose having about 20% to about 35% methoxy substitution and about 5% to about 15% hydroxypropyl substitution. The high molecular weight polymer may be a hydroxyethyl cellulose having an average molecular weight of from 60 KDa to 1,000 KDa (for example, 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa at 300 KDa, 220 KDa at 500 KDa, or 400 KDa at 800 KDa).
In particular embodiments, the first layer is separated from the second layer by a barrier (for example, a third layer).
For films of the invention including a pH neutralizing agent, in some embodiments the pH neutralizing agent is an inorganic base (for example, aluminum hydroxide, aluminosilicates, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide , calcium carbonate, iron carbonate, magnesium carbonate, zinc carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, sodium phosphate monobasic potassium, dibasic potassium phosphate, tribasic potassium phosphate, mixtures thereof, and any inorganic base described here, in this patent application). In still other embodiments, the pH neutralizing agent is an organic base (for example, acetate salts, citrate salts, stearate salts, laurate salts, proprionate salts, lactate salts, succinate salts, oxalate salts , tartrate salts, glycolate salts, galacturonate salts, glucuronate salts, alginate salts, sorbate salts, caprylate salts, carboxymethyl cellulose, polyacrylate, and mixtures thereof and amines, such as pyridoxine, meglumine, lysine, Eudragit E, diethanolamine, glycine, citrate, acetate, histidine, N-methyl glucamine, and tris (hydroxymethyl) aminomethane, mixtures thereof, or any organic base described herein, in this patent application). In particular modalities, the base has a pKa of from
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2.5 to 9.5 (for example, a pKa of 2 ± 0.5, 2.5 ± 1, 3 ± 1.5, 4 ± 2, 5 ± 2, 6 ± 2, 7 ± 1, or a pKa of from 4.5 to 8.5).
In a related aspect, the invention features a kit including: (i) a monolayer film of the invention; (ii) a pH neutralizing agent; and (iii) instructions for administering the first film and the pH neutralizing agent simultaneously to a subject.
Sublingual formulations can include dopamine agonist particles having an effective particle size from 0.5 pm to 50 pm (e.g., an effective particle size from 1 pm to 10 pm, 1 pm to 9 pm pm, from 1 pm to 8 pm, from 1 pm to 7 pm, from 1 pm to 6 pm, from 1 pm to 5 pm, from 2 pm to 10 pm, from 3 pm to 10 pm, from 4 pm to 10 pm, from 2 pm to 7 pm, 2 pm to 6 pm, 0.5 pm to 25 pm, 0.5 pm to 20 pm, or from 5 pm to 12 pm). In particular embodiments, the formulations include dopamine agonist particles containing apomorphine, an apomorphine prodrug, bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, or particles formed from their addition salts. .
Sublingual formulations can include dopamine agonist particles having an effective particle size from 10 pm to 100 pm (for example, an effective particle size from 10 pm to 90 pm, from 10 pm to 80 pm, from 10 pm to 70 pm, from 10 pm to 60 pm, from 10 pm to 50 pm, from 20 pm to 100 pm, from 30 pm to 100 pm, from from 40 pm to 100 pm, from 20 pm to 70 pm, or from 20 pm to 60 pm). In particular embodiments, the formulations include particles of dopamine agonists containing apomorphine, an apomorphine prodrug, bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, or particles formed from their addition salts of acid.
In some other embodiments, sublingual formulations can include dopamine agonist particles having an effective particle size from 20 nm to pm (for example, a
17/89 effective particle from 20 nm to pm, from 40 nm to 1 pm, from 60 nm to 1 pm, from 80 nm to 1 pm, from 100 nm to pm, at from 20 nm to 800 nm, from 20 nm to 700 nm, from 50 nm to 700 nm, from 40 nm to 800 nm, from 60 nm to 800 nm, from 100 nm to 800 nm, from 60 nm to 700 nm, from 60 nm to 600 nm, from 100 nm to 600 nm, from 150 nm to 800 nm, or from 150 nm to 600 nm). In particular embodiments, the formulations include dopamine agonist particles containing apomorphine, an apomorphine prodrug, bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, or particles formed from their addition salts. .
Sublingual formulations can include apomorphine particles having an effective particle size from 0.5 pm to 50 pm (for example, an effective particle size from 1 pm to 10 pm, from 1 pm to 9 pm, from 1 pm to 8 pm, from 1 pm to 7 pm, from 1 pm to 6 pm, from 1 pm to 5 pm, from 2 pm to 10 pm, from from 3 pm to 10 pm, from 4 pm to 10 pm, from pm to 7 pm, from 2 pm to 6 pm, from 0.5 pm to 25 pm, from 0.5 pm until 20 pm, or from 5 pm to 12 pm).
Sublingual formulations can include apomorphine particles having an effective particle size from 10 pm to 100 pm (e.g., an effective particle size from 10 pm to 90 pm, from 10 pm to 80 pm , from 10 pm to 70 pm, from 10 pm to 60 pm, from 10 pm to 50 pm, from 20 pm to 100 pm, from 30 pm to 100 pm, from 40 pm to 100 pm, from 20 pm to 70 pm, or from 20 pm to 60 pm).
In some other embodiments, sublingual formulations may include apomorphine particles having an effective particle size from 20 nm to pm (for example, an effective particle size from 20 nm to pm, from 40 nm until 1 pm, from 60 nm to 1 pm, from 80 nm to 1 pm, from 100 nm to 1 pm, from 20 nm to 800 nm, from 20 nm to 700 nm, at from 50 nm to
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700 nm, from 40 nm to 800 nm, from 60 nm to 800 nm, from 100 nm to 800 nm, from 60 nm to 700 nm, from 60 nm to 600 nm, from from 100 nm to 600 nm, from 150 nm to 800 nm, or from 150 nm to 600 nm).
In another aspect, the invention features a pharmaceutical composition in the form of a dosage unit formulated for sublingual administration, the dosage unit form including from 2 to 60 mg of an apomorphine prodrug (for example, from 2 to 15 mg). mg, 10 to 50 mg, 12 to 30 mg, 20 to 50 mg, 15 to 30 mg, or 35 10 to 50 mg of an apomorphine prodrug) in the form of apomorphine particles having a size of effective particle from 10 pm to 100 pm (for example, effective particle size from 10 pm to 90 pm, from 10 pm to 80 pm, from 10 pm to 70 pm, from from 10 pm to 60 pm, from 10 pm to 50 pm, from 20 pm to 100 pm, from 30 pm to 100 pm, from 40 pm to 100 pm, from 20 pm to 70 pm, or from 20 pm to 60 pm). The unit dosage form can be a lozenge, a pill, a tablet, a film, or a tape including the apomorphine prodrug in its free base form. In still other embodiments, the dosage unit form is a film formulation described here, in this patent application.
In yet another aspect, the invention features a pharmaceutical composition in the form of a dosage unit formulated for sublingual administration, the dosage unit form including particles of dopamine agonists having an effective particle size from 10 25 pm to 100 pm (eg effective particle size from 10 pm to 90 pm, from 10 pm to 80 pm, from 10 pm to 70 pm, from 10 pm to 60 pm, from 10 pm to 50 pm, from 20 pm to 100 pm, from 30 pm to 100 pm, from 40 pm to 100 pm, from 20 pm to 70 pm, or from 20 pm to 60 pm ). The dosage unit form can be a lozenge, a pill, a tablet, a film, or a tape including the dopamine agonist in its free base form. In still other modalities, the dosage unit form is a
19/89 film formulation described here, in this patent application. In particular embodiments, the formulations include particles of dopamine agonists containing apomorphine, an apomorphine prodrug, bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, or particles formed from their addition salts of acid.
In some embodiments, the sublingual formulation includes apomorphine particles and the apomorphine particles include an apomorphine acid addition salt or an apomorphine prodrug. The acid addition salt can be apomorphine hydrochloride or any acid addition salt described herein, in this patent application. Alternatively, the acid addition salt may be the hydrochloride salt of an apomorphine prodrug or any other acid addition salt described herein, in this patent application.
In an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in a unit dosage form including from 0.1 to 100 mg or from 2 to 60 mg of apomorphine, an apomorphine prodrug, or a salt of addition of acid from them (for example, from 0.5 to 5 mg, from 4 to 10 mg, from 6 to 15 mg, from 8 to 20 mg, from 10 to 25 mg, from 12 to 30 mg, from 20 to 35 mg, 25 to 40 mg, or 30 to 40 mg of apomorphine, an apomorphine prodrug, or an acid addition salt thereof). For example, each dosage unit form can contain 1 ± 0.5 mg, 3 ± 1 mg, 4 ± 1 mg, 5 ± 1 mg, 8 ± 2 mg, 10 ± 3 mg, 12 ± 3 mg, 15 ± 3 mg, 22 ± 4 mg, 27 ± 4 mg, 30 ± 5 mg, 35 ± 5 mg, 40 + 5 mg, 45 ± 5 mg, 50 ± 5 mg, 55 + 5 mg, or 60 ± 5 mg of apomorphine , an apomorphine prodrug, or an acid addition salt thereof.
In another embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in a unit dosage form including a ropinirole acid addition salt. In particular embodiments, the pharmaceutical composition includes the ropinirole hydrochloride salt.
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In another embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is a film including a solid solution of a dopamine agonist acid addition salt (for example, a solid apomorphine solution, an apomorphine prodrug, bromocriptine, bromocriptine , dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, or an acid addition salt thereof).
In one embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in a unit dosage form including from 0.1 to 100 mg or 0.1 to 40 mg of ropinirole, or an acid addition salt of same (for example, from 0.1 to 2 mg, from 1 to 5 mg, from 4 to 10 mg, from 6 to 15 mg, from 8 to 20 mg, from 10 to 25 mg, from 12 to 30 mg , from 20 to 35 mg, from 25 to 40 mg, or from 30 to 40 mg of ropinirole, or an acid addition salt thereof). For example, each dosage unit form can contain 0.5 ± 0.25 mg, 3 ± 1 mg, 4 ± 1 mg, 5 ± 1 mg, 8 ± 2 mg, 10 ± 3 mg, 12 ± 3 mg, 15 ± 3 mg, 22 ± 4 mg, 27 ± 4 mg, 30 ± 5 mg, 35 ± 5 mg, or 40 ± 5 mg, of ropinirole, or an acid addition salt thereof.
In an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in a unit dosage form including from 0.1 to 100 mg or 0.2 to 20 mg of bromocriptine, or an acid addition salt of it (for example, from 0.2 to 2 mg, from 0.5 to 3 mg, from 1 to 4 mg, from 3 to 7 mg, from 6 to 11 mg, from 9 to 15 mg, from 13 up to 18 mg, or 16 to 20 mg of bromocriptine, or an acid addition salt thereof). For example, each dosage unit form can contain 0.2 ± 0.1 mg, 0.5 ± 0.25 mg, 1 ± 0.5 mg, 2 ± 0.5 mg, 3 ± 1 mg, 4 ± 1.5 mg, 6 ± 2 mg, 10 ± 3 mg, 14 ± 3 mg, 18 ± 3 mg, or 20 ± 5 mg of bromocriptine, or an acid addition salt thereof.
In an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in a unit dosage form including from 0.1 to 100 mg or from 2 to 20 mg of bromocriptine, or an acid addition salt of the same (for example, from
21/89 from 0.2 to 2 mg, from 0.5 to 3 mg, from 1 to 4 mg, from 3 to 7 mg, from 6 to 11 mg, from 9 to 15 mg, from 13 to 18 mg, or 16 to 20 mg of bromocriptine, or an acid addition salt thereof). For example, each dosage unit form can contain 0.2 ± 0.1 mg, 0.5 ± 0.25 mg, 1 ± 0.5 mg, 2 ± 0.5 mg, 3 ± 1 mg, 4 ± 1.5 mg, 6 ± 2 mg, 10 ± 3 mg, 14 ± 3 mg, 18 ± 3 mg, or 20 ± 5 mg of bromocriptine, or an acid addition salt thereof.
In an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in unit dosage form including from 0.1 to 100 mg or from 0.5 to 30 mg of dihydroergocriptine, or an acid addition salt of it (for example, from 0.5 to 5 mg, from 4 to 10 mg, from 6 to 15 mg, from 8 to 12 mg, from 10 to 15 mg, from 15 to 25 mg, or from 20 to 30 mg of dihydroergocriptine, or an acid addition salt thereof). For example, each dosage unit form can contain 1 ± 0.5 mg, 3 ± 1 mg, 4 ± 1 mg, 5 ± 1 mg, 8 ± 2 mg, 10 ± 3 mg, 12 ± 3 mg, 15 ± 3 mg, 22 ± 4 mg, 27 ± 4 mg, or 30 ± 5 mg of dihydroergocriptine, or an acid addition salt thereof.
In an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in unit dosage form including from 0.1 to 100 mg or from 0.05 to 10 mg of lisuride, or an acid addition salt of it (for example, from 0.05 to 0.5 mg, from 0.4 to 1 mg, from 0.8 to 1.5 mg, from 1 to 2 mg, from 1.5 to 3 mg, 2.5 to 5 mg, or 5 to 10 mg of lisuride, or an acid addition salt thereof). For example, each dosage unit form may contain 0.1 ± 0.05 mg, 0.3 ± 0.1 mg, 0.4 ± 0.1 mg, 0.5 ± 0.1 mg, 1 ± 0 , 5 mg, 2 + 1 mg, 3 ± 1 mg, 5 ± 2 mg, 7 ± 2 mg, 9 ± 2 mg, or 10 + 2 mg of lisuride, or an acid addition salt thereof.
In an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in a unit dosage form including from 0.1 to 100 mg or 0.5 to 75 mg of pyribedyl, or an acid addition salt of the same (for example, from 0.5 to 5 mg, 4 to 10 mg, 6 to 15 mg, 8 to 12 mg, 10 to 15 mg, 15 to 25 mg, 20 to 30 mg, 35 to 45 mg , 40 to 50 mg, or 50 to 75 mg of pyribedyl,
22/89 or an acid addition salt thereof). For example, each dosage unit form can contain 1 ± 0.5 mg, 3 ± 1 mg, 4 ± 1 mg, 5 ± 1 mg, 8 ± mg, 10 ± 3 mg, 12 ± 3 mg, 15 ± 3 mg, 22 ± 4 mg, 27 ± 4 mg, 30 ± 5 mg, 40 ± 10 mg, 50 ± 10 mg, or 75 ± 20 mg of pyribedyl, or an acid addition salt thereof.
In an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in unit dosage form including from 0.1 to 100 mg or from 0.05 to 10 mg of pergolide, or an acid addition salt of it (for example, from 0.05 to 0.5 mg, from 0.4 to 1 mg, from 0.8 to 1.5 mg, from 1 to 2 mg, from 1.5 to 3 mg, 2.5 to 5 mg, or 5 to 10 mg of pergolide, or an acid addition salt thereof). For example, each dosage unit form can contain 0.1 ± 0.05 mg, 0.3 ± 0.1 mg, 0.4 ± 0.1 mg, 0.5 ± 0.1 mg, 1 ± 0 , 5 mg, 2 ± 1 mg, 3 ± 1 mg, 5 ± 2 mg, 7 ± 2 mg, 9 ± 2 mg, or 10 ± 2 mg of pergolide, or an acid addition salt thereof.
In an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in a unit dosage form including from 0.1 to 100 mg or from 0.1 to 20 mg of pramipexole, or an acid addition salt of it (for example, from 0.1 to 0.5 mg, from 0.2 to 2 mg, from 0.5 to 3 mg, from 1 to 4 mg, from 3 to 7 mg, from 6 to 11 mg, 9 to 15 mg, 13 to 18 mg, or 16 to 20 mg pramipexole, or an acid addition salt thereof). For example, each dosage unit form can contain 0.2 ± 0.1 mg, 0.5 ± 0.25 mg, 1 ± 0.5 mg, 2 ± 0.5 mg, 3 ± 1 mg, 4 ± 1.5 mg, 6 ± 2 mg, 10 ± 3 mg, 14 ± mg, 18 ± 3 mg, or 20 ± 5 mg of pramipexole, or an acid addition salt thereof.
In an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in unit dosage form including from 0.1 to 100 mg or from 0.1 to 20 mg of rotigotine, or an acid addition salt of it (for example, from 0.1 to 0.5 mg, from 0.2 to 2 mg, from 0.5 to 3 mg, from 1 to 4 mg, from 3 to 7 mg, from 6 to 11 mg, 9 to 15 mg, 13 to 18 mg, or 16 to 20 mg
23/89 rotigotine, or an acid addition salt thereof). For example, each dosage unit form can contain 0.2 ± 0.1 mg, 0.5 ± 0.25 mg, 1 ± 0.5 mg, 2 ± 0.5 mg, 3 ± 1 mg, 4 ± 1.5 mg, 6 ± 2 mg, 10 ± 3 mg, 14 ± 3 mg, 18 ± 3 mg, or 20 ± 5 mg of rotigotine, or an acid addition salt thereof.
In a particular embodiment of any of the above pharmaceutical compositions, the unit dosage form when administered sublingually to a subject is non-irritating.
In yet another embodiment of any of the above pharmaceutical compositions in which the dopamine agonist is selected from apomorphine, an apomorphine prodrug, or a salt thereof, after sublingual administration to a subject in unit dosage form produces a mean concentration of circulating apomorphine of at least 3 ng / mL within a period of from 5 to 15 minutes after administration. For example, the dosage unit form can produce an average circulating concentration of from 3 to 6 ng / mL within 7 to 10 minutes, from 5 to 10 ng / mL within 5 to 10 minutes, from from 7 to 12 ng / mL within 5 to 10 minutes, from 10 to 16 ng / mL within 5 to 10 minutes, from 3 to 6 ng / mL within 7 to 15 minutes, from 5 up to 10 ng / mL within 7 to 15 minutes, from 7 to 12 ng / mL within 7 to 15 minutes, from 10 to 16 ng / mL within 7 to 15 minutes, from 3 to 6 ng / mL within 15 to 20 minutes, from 5 to 10 ng / mL within 15 to 20 minutes, from 7 to 12 ng / mL within 15 to 20 minutes, or from 10 to 16 ng / mL within 15 to 20 minutes after administration.
In another embodiment of any of the above pharmaceutical compositions, the unit dosage form when placed in 1 ml of water not buffered at pH 7 results in a solution having a pH of between 2.5 and 8.0, preferably between 4, 5 and 6.5, (for example, a pH of between 2.5 and 4.5, 3.0 and 6.5, 3.5 and 7.5, 4.5 and 8.0, or 6.5 and 8.0). For example, the films of the invention may include a neutralizing layer that controls the pH of the dissolved pharmaceutical composition and produces a pre-set pH value 24/89 after dissolution.
In another embodiment of any of the above pharmaceutical compositions, the dosage unit form has a sublingual bioavailability of more than 40% (for example, a sublingual bioavailability of from 40 to 70%, from 45 to 85%, from 55 95%, 65 to 100%, 70 to 100%, 70 to 99%, 75 to 100%, 75 to 99%, or 80 to 99%).
The invention further presents a method for treating movement disorders, such as Parkinson's disease, restless legs syndrome, or tremor, in a subject by sublingually administering a pharmaceutical composition of the invention to the subject in an amount effective to treat the subject .
The invention also features a method of relieving dyskinesia in a subject afflicted with Parkinson's disease by sublingually administering a pharmaceutical composition of the invention to the subject in an amount effective to alleviate dyskinesia.
The invention also features a method of relieving akinesia in a subject afflicted with Parkinson's disease by sublingually administering a pharmaceutical composition of the invention to the subject in an amount effective to relieve akinesia.
The invention features a method of treating sexual dysfunction in a subject by sublingually administering a pharmaceutical composition of the invention to the subject in an amount effective to treat the subject.
The invention also features a method for treating a depressive disorder in a subject by sublingually administering a pharmaceutical composition of the invention to the subject in an amount effective to treat the subject.
In an embodiment of any of the above methods, the method additionally includes administering an effective amount of an anti-emetic agent (for example, nicotine, lobeline sulfate, pipamazine, oxypendil hydrochloride, ondansetron, buclizine hydrochloride, hydrochloride hydrochloride cyclizine, dimenhydrinate, eacopolamine, metopimazine, benzaui hydrochloride 25/89 namine, or diphenidol hydrochloride).
The invention features a method method for preparing a bilayer film having a first layer and a second layer, the method including:
(i) formation of a first viscous solution by mixing an aqueous solution including a volatile organic solvent with (a) from 30 to 75% (by weight / weight) (for example, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5%, 65 ± 5%, 70 ± 5%, or 75 ± 5% (by weight / weight)) of dopamine agonist , or an acid addition salt of the same (for example, apomorphine, an apomorphine prodrug, bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, or an acid addition salt of the same ); (b) from 0.5 to 16% (by weight / weight) (for example, 0.5 to 10%, 0.5 ± 0.1%, 1 ± 0.5%, 2 ± 0.75 %, 3 ± 1%, 5 ± 1%, 6 ± 2%, 7 ± 3%, 8 ± 3%, 9 ± 3%, 12 ± 3%, or 16 ± 3% (by weight / weight)) a low molecular weight polymer having an average molecular weight from 5 KDa to 50 KDa (for example, 5 ± 3, 8 ± 3%, 10 ± 3, 15 ± 5, 18 ± 5, 22 ± 6, 28 ± 6, 34 ± 8, 44 ± 8, or 50 ± 10 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; (c) from 4 to 35% (by weight / weight) (for example, 4 to 20%, 4 ± 2%, 5 ± 2.5%,
7.5 ± 3%, 10 ± 3.5%, 14 ± 5%, 18 ± 5%, 20 ± 6%, 25 ± 6%, 30 ± 6%, or 35 ± 6% (by weight / weight) ) of a high molecular weight polymer having an average molecular weight of more than 60 KDa (for example, 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; (d) from 3 to 18% (by weight / weight) (for example, 3 to 12%, 3 ± 1%, 5 ± 2%, 7.5 ± 2.5%, 10 ± 3%, 12 ± 3%, 15 ± 3%, or 18 ± 3% (by weight / weight)) of a plasticizer; and (e) from 1 to 50% (by weight / weight) (for example, 1 ± 0.75%, 2 + 1.5%, 3 ± 0.5%, 5 ± 2%, 7.5 ± 2.5%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5% , or 50 ± 5% (by weight / weight)) of hydrolyzed starch;
26/89 (ii) melting the first viscous solution onto an inert support, and drying the solution to form a first film layer;
(iii) formation of a second viscous solution by mixing an aqueous solution including a volatile organic solvent with (a) from 15 to 50% (by weight / weight) (for example, 15 ± 5%, 20 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, or 50 ± 5% (by weight / weight)) of a high molecular weight polymer having an average weight molecular weight of more than 60 KDa (eg 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; (b) from 6 to 65% (by weight / weight) (for example, 10 to 50%, 6 ± 2%, 8 ± 2%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5%, or 65 ± 5% (by weight / weight)) of pH neutralizing agent; (c) from 3 to 18% (by weight / weight) (for example, 3 to 12%, 3 ± 1%, 5 ± 2%, 7.5 ± 2.5%, 10 ± 3%, 12 ± 3%, 15 ± 3%, or 18 ± 3% (by weight / weight)) of a plasticizer; and (d) from 1 to 50% (by weight / weight) (for example, 1 ± 0.75%, 2 ± 1.5%, 3 ± 0.5%, 5 ± 2%,
7.5 ± 2.5%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, or 50 ± 5% (by weight / weight)) of hydrolyzed starch;
(iv) melting the second viscous solution on an inert support, and drying the solution to form a second layer of film;
(v) contacting the faces of the first film layer and the second film layer with a volatile organic solvent, pressing the faces together in such a way that the volatile organic solvent is sandwiched between the first film layer and the second film layer, and drying the layers to form a bilayer film.
The invention features a method for preparing a bilayer film having a first layer and a second layer, the method including:
(i) formation of a first viscous solution by mixing an aqueous solution including a volatile organic solvent with (a) from 30
27/89 to 75% (by weight / weight) (e.g. 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5% , 65 + 5%, 70 ± 5%, or 75 ± 5% (by weight / weight)) of apomorphine, an apomorphine prodrug, or an acid addition salt thereof; (b) from 0.5 to 16% (by weight / weight) (for example, 0.5 to 10%, 0.5 ± 0.1%, 1 ± 0.5%, 2 ± 0.75 %, 3 ± 1%, 5 ± 1%, 6 ± 2%, 7 ± 3%, 8 ± 3%, 9 ± 3%, 12 ± 3%, or 16 ± 3% (by weight / weight)) a low molecular weight polymer having an average molecular weight from 5 KDa to 50 KDa (for example, 5 ± 3, 8 ± 3%, 10 ± 3, 15 ± 5, 18 ± 5, 22 ± 6, 28 ± 6, 34 ± 8, 44 ± 8, or 50 ± 10 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; (c) from 4 to 35% (by weight / weight) (for example, 4 to 20%, 4 ± 2%, 5 ± 2.5%, 7.5 ± 3%, 10 ± 3.5% , 14 ± 5%, 18 ± 5%, 20 ± 6%, 25 ± 6%, 30 ± 6%, or 35 ± 6% (by weight / weight)) of a high molecular weight polymer having a weight molecular weight average of more than 60 KDa (for example, 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80 KDa to 120 KDa, 100 KDa to 300 KDa, 220 KDa to 500 KDa, or 400 KDa to 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; (d) from 3 to 18% (by weight / weight) (for example, 3 to 12%, 3 ± 1%, 5 ± 2%, 7.5 ± 2.5%, 10 ± 3%, 12 ± 3%, 15 ± 3%, or 18 ± 3% (by weight / weight)) of a plasticizer; and (e) from 1 to 50% (by weight / weight) (for example, 1 ± 0.75%, 2 ± 1.5%, 3 ± 0.5%, 5 ± 2%, 7.5 ± 2.5%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5% , or 50 ± 5% (by weight / weight)) of hydrolyzed starch;
(ii) melting the first viscous solution onto an inert support, and drying the solution to form a first film layer;
(iii) formation of a second viscous solution by mixing an aqueous solution including a volatile organic solvent with (a) from 15 to 50% (by weight / weight) (for example, 15 ± 5%, 20 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, or 50 ± 5% (by weight / weight)) of a high molecular weight polymer having an average weight molecular weight of more than 60 KDa (e.g. 60 KDa to 500 KDa, 60 KDa to 1,000 KDa, 80
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KDa at 120 KDa, 100 KDa at 300 KDa, 220 KDa at 500 KDa, or 400 KDa at 800 KDa) selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; (b) from 6 to 65% (by weight I weight) (for example, 10 to 50%, 6 ± 2%, 8 ± 2%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, 50 ± 5%, 55 ± 5%, 60 ± 5%, or 65 ± 5% (by weight / weight)) of pH neutralizing agent; (c) from 3 to 18% (by weight I weight) (for example, 3 to 12%, 3 ± 1%, 5 ± 2%, 7.5 ± 2.5%, 10 ± 3%, 12 ± 3%, 15 ± 3%, or 18 ± 3% (by weight / weight)) of a plasticizer; and (d) from 1 to 50% (by weight / weight) (for example, 1 ± 0.75%, 2 ± 1.5%, 3 ± 0.5%, 5 ± 2%,
7.5 ± 2.5%, 10 ± 2%, 14 ± 3%, 18 ± 4%, 22 ± 5%, 25 ± 5%, 30 ± 5%, 35 ± 5%, 40 ± 5%, 45 ± 5%, or 50 ± 5% (by weight / weight)) of hydrolyzed starch;
(iv) melting the second viscous solution on an inert support, and drying the solution to form a second layer of film;
(v) contacting the faces of the first film layer and the second film layer with a volatile organic solvent, pressing the faces together in such a way that the volatile organic solvent is sandwiched between the first film layer and the second film layer, and drying the layers to form a bilayer film.
The volatile organic solvent (for example, an organic solvent having between 20 ° C and 80 ° C) can include acetone, ethanol, isopropyl alcohol, diethyl ether, butanol, propanol, ethyl acetate, or combinations thereof.
In some embodiments of the method, the plasticizer is a polyol (for example, sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, or polyethylene glycol), oleic acid, or triacetin. In particular embodiments of the method, the hydrolyzed starch is a dextrin or a maltodextrin. The method can be used to produce any bilayer film of the invention described here, in this patent application.
In still other modalities of the method, the dopamine agonist is apomorphine or apomorphine prodrug. For example, the apomorphine or apomorphine prodrug can be an apomorphine acid addition salt, such as apomorphine hydrochloride. Apomorphine hydrochloride
29/89 can be crushed to produce material having an effective particle size from 0.5 pm to 50 pm (for example, an effective particle size from 1 pm to 10 pm, 1 pm to 9 pm , from 1 pm to 8 pm, from 1 pm to 7 pm, from 1 pm to 6 pm, from 1 pm to 5 pm, from 2 pm to 10 pm, from 3 pm until 10 pm, from 4 pm until 10 pm, from 2 pm until 7 pm, 2 pm until 6 pm, 0.5 pm until 25 pm, 0.5 pm until 20 pm, or from 5 pm to 12 pm) before adding apomorphine hydrochloride to this mixture from step (i).
In an embodiment of any of the above methods and compositions in which the dopamine agonist includes apomorphine or apomorphine prodrug, apomorphine, apomorphine prodrug, or the salt thereof is a racemic mixture of R and S isomers, or enriched in R isomer (that is, the ratio of R isomer to S isomer for all apomorphine in the composition, or all apomorphine being administered, is from 5: 1 to 1,000: 1, from 10: 1 to 10,000: 1 , or from 100: 1 to 100,000: 1, or for all apomorphine isomers in the composition is at least 98% R isomer, 99% R isomer, 99.5% R isomer, 99.9 % R isomer, or is free of any observable amount of S isomer.
The term administration or administering refers to a method for administering a sublingual dosage of dopamine agonist to a patient.
As used herein, in this patent application, the term apomorphine particle refers to microparticles or nanoparticles containing apomorphine, an apomorphine prodrug, or salts thereof.
As used herein, in this patent application, the term dopamine agonist particle refers to microparticles or nanoparticles containing a dopamine agonist (e.g., apomorphine, an apomorphine prodrug, bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pyribedyl, pergolide, pergolide pramipexole, rotigotine, ropinirole, or an acid addition salt thereof).
As used here, in this patent application, the term
Average circulating concentration refers to the mean plasma concentration of apomorphine at time t observed for a group of subjects after sublingual administration of a particular dosage unit form of the invention. For example, among 20 subjects, the mean circulating apomorphine concentration 10 minutes after sublingual administration of the dosage unit form may be at least 3 ng / mL, 5 ng / mL, 7 ng / mL, 9 ng / mL, 11 ng / mL, 13 ng / mL, or 15 ng / mL, depending on the amount of apomorphine in the dosage unit.
Depressive disorder means any psychological or psychiatric disorder associated with symptoms of depressed mood. Treatable depressive disorders can be characterized by an inhibition or reduction of dopaminergic function in the nucleus accumbens, for example, major depression, dysthymia, bipolar disorder (manic depression), and post-traumatic stress disorder.
As used herein, in this patent application, the terms effective particle size and particle size are used interchangeably and refer to a mixture of particles having a distribution in which 50% of the particles are below and 50% of the particles are above of a defined measure. Effective particle size refers to the volume-weighted average diameter as measured by a laser / light scattering method or equivalent, where 50% of the particles, by volume, have a smaller diameter, while 50% by volume has a larger diameter. Effective particle size can be measured by conventional particle size measurement techniques known to those skilled in the art. The techniques referred to include, for example, fractionation of sedimentation field flow, photon correlation spectroscopy, light scattering (for example, with a Microtrac UPA 150), laser diffraction, and disk centrifugation.
As used herein, in this patent application, the term apomorphine prodrug refers to esters of apomorphine and glycosides of formula (I):
31/89
R ¹ -
n-ch ₃
O
R ²
R ² d), and acid addition salts thereof. In formula I, each R ¹ and R ² urn is independently H, C (O) -R3, C (O) -O-R3, or a glycoside of a monosaccharide or oligosaccharide; or R ¹ and R ² combine with the oxygen atoms to which they are attached to form a cyclic acetal, a cyclic ketal, a cyclic carbonate (i.e., -C (O) -OC (O) -), or a glycoside of orthoester; and R3 is a cyclic, straight chain or branched hydrocarbon of 1 to 12 carbon atoms, which is optionally saturated (i.e., a C1-12 alkyl), includes one or more carbon-carbon double bonds (i.e., a C2-12 alkenyl), and / or includes one or more carbonocarbon triple bonds (i.e., a C2-12 alkynyl). For example, apomorphine glycosides can be glycosides of straight or branched glycosidic moieties containing 1 to 20 glycosidic units. Apomorphine glycosides and orthoester glycosides can be synthesized as described in International Patent Publication No. WO / 2003/080074. Apomorphine esters, cyclic acetals, and cyclic ketals can be synthesized using methods analogous to those described in United States Patent No. 4,687,773, Borgman et al., J. Med. Chem., 19: 717 (1976), and in International Patent Publication No. WO / 2005/099702. The above patent publications are hereby incorporated by reference. Apomorphine carbonate esters can be prepared as described in Atkinson et al., J. Pharma. Know. 65: 1685 (1976), and in Campbell et a)., Neuropharmacology 21: 953 (1982). Apomorphine prodrugs which can be used in the dosage unit forms of the invention include, without limitation, 0.0'diacetylapomorphine, Ο, Ο'-dipropionylapomorphine, O, O'-di-isobutyrylapomorphine, O, O'-dipivaloylapomorphine , Ο, Ο'-dibenzoylapomorphine, apomorphine carbonate, apomorphine diethyl carbonate, apomorphine methylene aceta, apomorphine
32/89 ethyl acetal, apomorphine dimethyl acetal, and acid addition salts thereof.
As used herein, in this patent application, the term non-irritant refers to pharmaceutical compositions of the invention which, using the irritation test described in Example 7, either: (i) after administration the unshaven cheek exhibits irritation that is equal a or less than that observed for a non-buffered acidic control film that produces a local pH of less than 3 after administration to, and dissolution in, a cheek pouch; and / or (ii) after administration the shaved cheek has a curing time that is equal to or less than that observed for an un-buffered acidic control film that produces a local pH of less than 3 after administration to, and dissolution in, a jugal bag.
As used herein, in this patent application, pH neutralizing agent refers to any basic component present in the dosage unit forms of the invention. PH neutralizing agents which can be used in unit dosage forms of the invention include organic bases (eg, amines), inorganic bases (eg, oxides, hydroxides, carbonates, or phosphates), and mixtures thereof . The pH neutralizing agent is typically present in an amount sufficient to produce a solution having a pH of between 2.5 and 8.0, preferably between 4.5 and 6.5, when the dosage unit form is placed in 1 mL of water not buffered at pH 7.
As used herein, in this patent application, sexual dysfunction refers to disorders of orgasm, response time, ejaculation, nociception, congestive arousal and erection, vasculogenic dysfunction, or desire. In males, the form of sexual dysfunction is typically erectile dysfunction, the inability to obtain and sustain an erection sufficient for intercourse. Females can also have sexual arousal and orgasm dysfunctions that increase with age and are associated with the presence of vascular risk factors and the onset of menopause. Some of the vascular and muscular mechanisms that contribute to penile erection in males are believed to involve similar vasculogenic factors in reactions
33/89 female genitals. Female sexual dysfunction includes a failure to obtain or maintain sexual lubrication-swelling sexual arousal reactions until sexual activity is complete.
As used here, in this patent application, the term sublingual bioavailability refers to the average sublingual bioavailability of dopamine agonist formulated as described here, in this patent application, and administered sublingually in a study of 5 or more rabbits compared to 100 % bioavailability for a dopamine agonist administered subcutaneously. Sublingual bioavailability can be determined from a pharmacokinetic study as described in Example 2.
As used here, in this patent application, the term Tmax refers to the average time, after sublingual administration of a dopamine agonist formulated as described, for maximum circulating concentration in a study of 5 or more rabbits. AT _ma x can be determined from a pharmacokinetic study as described in Example 2.
As used herein, in this patent application, the term treat refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. To prevent disease, it refers to prophylactic treatment of a patient who is not yet ill, but who is susceptible, or is otherwise at risk, to prophylactic a particular disease. To treat illness or use for therapeutic treatment refers to administering treatment to a patient who is already suffering from a disease to improve the disease and improve the patient's condition. Thus, in the claims and modalities, treating is the administration to a subject for either therapeutic or prophylactic purposes.
Other features and advantages of the invention will be apparent from the Detailed Description, the Drawings, and the Claims that follow.
Brief Description of Drawings
Figure 1 is a graph representing the pharmacokinetic profile
34/89 for films A, B, and C compared to apomorphine administered subcutaneously (see Examples 1 and 2).
Figure 2 is a graph representing the pharmacokinetic profile for films D and E compared to apomorphine administered subcutaneously (see Examples 1 and 2).
Figure 3 is a graph representing the pharmacokinetic profile for films F, G, and H compared to apomorphine administered subcutaneously (see Examples 1 and 2).
Figure 4 is a graph representing the pharmacokinetic profile for films J and K compared to apomorphine administered subcutaneously (see Examples 1 and 2).
Detailed Description
The invention features sublingual formulations of dopamine agonists. The formulations can be useful for the treatment of Parkinson's disease, restless legs syndrome, tremors (among other movement disorders), sexual dysfunction, and depressive disorders with them. The films can be a single layer or a bilayer (for example, a dosage unit form having a first layer including an apomorphine acid addition salt, or an apomorphine prodrug, and a second layer including a neutralizing agent). pH).
Fluctuations in motor disability and dyskinesias are a major problem in the long-term treatment of Parkinson's disease. In the later stages of Parkinson's disease, many patients develop severe off-episodes where, despite continuing to take their medication, they experience periods when they lose the ability to move (for example, patients develop bradykinesia (delayed movement) or akinesia (disability) to move)). These off episodes typically occur 3 to 4 times a day.
Apomorphine has a rapid onset of action which is ideal for use as a rescue therapy for intractable off-periods in Parkinson's disease. Other dopamine agonists may also be useful.
Using the sublingual formulations of the invention, a subject
35/89 suffering from the effects of Parkinson's disease in the middle or later stage may be able to recognize the onset of their symptoms "off" and be able to administer a sublingual dose of a formulation of the invention to alleviate the dyskinesia associated with referred off episodes. Sublingual formulations are easy for a subject with impaired motor skills to administer and may release a Parkinson's patient from the need for a caregiver, who may otherwise be required to administer an injectable apomorphine dosage form at the start of an off episode.
The sublingual formulations of the invention can increase the bioavailability of the dopamine agonist, prolong the stability, in some cases, of the dopamine agonist, and / or increase the safety and efficacy of dopamine agonist therapy. The formulations can produce a rapid uptake of the dopamine agonist in the subject, allowing episodes of dyskinesia to be self-treated. In addition, the convenience with which these sublingual formulations can be self-administered provides a significant advantage for critically ill patients, such as those with mid-stage or later stage Parkinson's disease.
The pharmaceutical compositions of the invention can provide a solid oral dosage form of rapid dissolution and rapid absorption that includes (i) an acid salt form of a dopamine agonist and (ii) a pH modifying agent. Typically, the acid addition salt has high water solubility, which helps to achieve rapid dissolution, a prerequisite for rapid absorption. Passive transcellular absorption is the primary absorption route for dopamine agonists in the sublingual cavity. Passive absorption by partition of the neutral, free or non-ionized form of the dopamine agonist occurs within tissues and across cell membranes and is therefore partially determined by the 2 key factors: (i) the abundance of the neutral species of dopamine agonist a which is guided by a balance of the ionized form (saline form) and the non-ionized form which is a function of the local pH and the pKa of the dopami agonist
36/89 na; and (ii) the lipophilicity of the neutral dopamine agonist species. The inclusion of the pH modifying agent helps to maintain a pH and favor the deprotonation of the ionized form (saline form), thereby increasing the fraction of non-ionized species and increasing the absorption rate.
Another benefit of the formulations of the invention is that they can be non-irritating at the site of administration. Irritation during sublingual or nasal release of a dopamine agonist is believed to result in some cases of absorption of the neutral form of the dopamine agonist in the absence of a pH modifier. The passive trans-cellular absorption of the neutral species from the natural balance of ionized and non-ionized species causes a shift in the same equilibrium to reconstitute the solution concentration of the neural dopamine agonist species. In theory, a similar shift can lead to depletion of the agonist from the solution, resulting in the release of the acid and a reduction in local pH. The lower pH in turn can cause local irritation, especially in the case of chronic administration, of repeated dosing.
Additional details on how to produce and use the sublingual formulations of the invention are provided below and in the Examples.
Dopamine agonists
Dopamine agonists which can be used in the compositions and methods of the invention include, without limitation, ergotamine and non-ergotamine dopamine agonists, such as apomorphine, bromocriptine, bromocriptine, dihydroergocriptine, lisuride, pyribedyl, pergolide, pramipexole, rotigotine, ropinirole, and acid addition salts thereof. Dopamine agonists can be formulated as described in the Examples.
Monolayer and bilayer films
The films of the invention are not dissimilar to the films used, for example, to produce Listerine® PocketPak® mouthwashes.
Films can include one layer, two layers, or more. If in two layers, the layer adapted to adhere to mucosal tissue can be referred to as the adhesive layer. With two layers, the outer layer can be less adhesive or non-adhesive, and can provide pro
37/89 protection against mechanical agitation, such as agitation by a user's tongue. The components of the outer layer may themselves be less dissolvable than the components of an adhesive layer. However, in the aggregate, the film must dissolve due to the fact that it will transition to fully dissolved parts or parts that will be carried by normal cleaning processes on the mucosa tissue in question. By forming two layers, diffusion or the formation process itself can provide a gradient in quantities of components in the transition between the two layers. The two layers can be used to separate the components (for example, an acidic layer containing dopamine agonist and a buffered pH neutralization layer), which together can enhance absorption, reduce irritation, and / or increase agonist stability dopamine, but which may otherwise be incompatible in some formulations that require long-term stability (i.e., shelf life). The two layers of bilayer components can be laminated together using combinations of water, heat, solvent and mixed aqueous, organic or aqueous-organic solutions containing either or a combination of one or more polymers, one or more low molecular weight sugars, one or more stabilizers, one or more flavors, one or more sweeteners, one or more permeation enhancers or other desirable agent.
Alternatively, the dosage unit form of the invention can be a monolayer film which is an acidic layer containing dopamine agonist which is coated with or impregnated with a particulate base. The particulate base can be incorporated into the monolayer film using the methods described in International Patent Publication No. WO / 2009/052421, United States Patent Publication No. 20060210610, each of which is incorporated here, by reference. The film of the invention may include an effervescent particulate (ie, a particulate carbonate base) or disintegrant (for example, materials that favor disintegration or rapid dissolution due to its solubility in water, such as hydrolyzed starches, sugars, and glycerin ,
38/89 which can play a dual role as a plasticizer and a disintegrant). The effervescent films referred to can be prepared as described in United States Patent Publication No. 20010006677, incorporated herein, by reference.
The polymers used in the films of the invention can be polymers that affect the hydration rate or the mucosal adhesion properties of an adhesive layer. The said polymers can be, for example, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC, such as Pharmacoat 606 ™, Shin-Etsu Chemical Company Ltd., Japan), hydroxyethyl cellulose (HEC, commercially available from Hercules Incorporated, Aquaion Division under the trade name NATROSOL ™), and methyl cellulose, optionally in a mixture with other polymers, such as polyoxyethylene / polyoxypropylene polymers, copolymers or block copolymers, polyvinylpyrrolidone polymers or derivatives, and / or gums. The average molecular weight of the polymer can be selected based on the produced expansion and dissolution profile.
The films of the invention may include combinations of one or more low molecular weight polymers (for example, those from about 5 KDa to about 50 KDa) and high molecular weight polymers (for example, those from about 5 KDa to 60 KDa to about 500 KDa) in order to obtain desirable dissolution properties and mechanical strength. For example, a combination of hydroxypropyl cellulose (for example, Klucel, grade JF, Hercules Inc., Aquaion Division) and hydroxypropyl methylcellulose (for example, Methocel, grades E5, E50, E4M, and SG A16M from Dow Chemical) can be used . These water-soluble cellulose-derived polymers have molecular weights of about 140,000; 30,000; 90,000; 400,000; and more than about 100,000 daltons, respectively. The molecular weights of water-soluble polymers can be determined as described in Keary, Carbohydrate Polymers 45: 293 (2001), which is incorporated here, by reference.
Mixtures of less soluble and / or less swellable polymers with more soluble or more swellable polymers can help the transition from
39/89 film to a sufficiently dissolved form. For example, the film may include carbamer, polyethylene oxide, ethyl cellulose, titanium oxide and dye (such as F, D and C blue lake dye). Often the film is formed using a pharmaceutically suitable solvent such as ethanol, water, mixtures, or the like. The solvents referred to are typically largely evaporated before use. Optionally, the films comprise a combination of more than one polymer or more than one molecular weight of a given set of polymers in order to control the rate of hydration, physical properties and mechanical properties.
The film of the invention can optionally be a multilaminate product including a monolayer or bilayer of the invention affixed to an outer layer of additional slow dissolution. A similar multilaminate film would be placed with this slowly dissolving layer away from the mucosal layer, in such a way as to create a barrier layer and provide directional release of the dopamine agonist into the mucosa, increasing the rate of uptake.
Basic Layers
The multilayer films of the invention can include a film formed from a basic polymer. Polyamines which can be used in the dosage unit forms of the invention include homo and copolymers of dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, dimethylaminopropyl acrylate, dimethylaminpropyl methacrylate, or another acrylate with similar amino functionality, chitosan or a partially hydrolyzed substantially basic choline in a partially hydrolyzed basic form. , homo and co polymers of polyethylimine, polylysine, polyvinylimidazole, or polyvinylamine. In some embodiments, the polyamine is Eudragit E100.
Other Components
Plasticizers, penetration enhancers, flavoring agents, preservatives, odorants, coloring agents, and the like can be included in the dosage unit forms of the invention.
Plasticizers will generally modify the feel, the softness, the flexibility (in a non-moistened state) of the unit's shape.
40/89 message of the invention. Penetration enhancers, in some cases, can act as plasticizers. Examples of plasticizers include, without limitation, glycerol, propylene glycol, fatty acid esters, such as glyceryl oleate, polyalcohols, sorbitan esters, citric acid esters, polyethylene glycol (eg, PEG 400), polyvinyl alcohol, polyvinyl methyl ether , triacetin; mannitol, xylitol, and sorbitol. The plasticizer can be present in any suitable range, including, for example, about 0.5% to 30%, 10% to 20%, or 15% to 18% by weight of the dry film.
Permeation enhancers can be used to increase the permeability of the dopamine agonist in the mucous membrane in the dosage unit forms of the invention. One or more permeation boosters can be used to modulate the absorption rate in the mucosa of the dopamine agonist. Any effective permeation enhancers can be used including, for example, ionic surfactants, non-ionic surfactants, bile salts, such as sodium cholate, sodium glycocholate, sodium glycodesoxycholate, taurodeoxycholate, sodium deoxycholate, sodium kenocolate lithocolate, kenodesoxycholate, ursocolate, ursodeoxy-cholate, hyodeoxycolate, dehydrocholate, glycoquenocolate, tauroquenocolate, and tauroquenodeoxycholate; sodium dodecyl sulfate (SDS), dimethyl sulfoxide (DMSO), N-lauroyl sacrcosine, sorbitan monolaurate, stearyl methacrylate, Ndodecylazacycloheptan-2-one, N-dodecyl-2-pyrrolidinone, N-dodecyl-2-2piperidinone -nonyl) -1,3-dioxolane, N- (2-methoxymethyl) dodecylamine, Ndodecylethanolamine, N-dodecyl-N- (2-methoxymethyl) acetamide, 1-Ndodecyl-2-pyrrolidone-5-carboxylic acid, acetic acid 2-pentyl-2-oxo-pyrrolidine, 2-dodecyl-2-oxo-1-pyrrolidine acetic acid, 2-dodecyl-2oxo-1-pyrrolidine acetic acid, 1-azacylioheptan-2-one-dodecylacetic acid, menthol , propylene glycol, glycerol monostearate, sorbitol monolaurate, glycerol dilaurate, tocopherol acetate, phosphatidyl choline, glycerol, polyethylene glycol, monoglycerides, such as glycerol monostearate, glycerol monohydrate, glycerol and triglycerides, diglycerides and diglycerides , such as glycerol succinyl caprylate lecithin, tween surfactants, surfactant s of sorbitan, sodium lauryl sulfate; salts, acids and others
41/89 derivatives of saturated and unsaturated fatty acids, fatty alcohols, surfactants, bile salt analogs, bile salt derivatives, or similar synthetic permeation enhancers as described in United States Patent No. 4,746,508, which is incorporated herein , by reference.
A sweetener, flavoring and / or odorant can be added to the dosage unit forms of the invention to make them more palatable. At least one odorant or flavoring agent composition can be used. Any effective aroma or odor can be processed. Flavoring agents can be natural, artificial, or a mixture thereof. The flavoring agent provides a flavor that will help to reduce the undesirable taste of the active ingredient. In one embodiment, the flavoring agent may provide the aroma of mint, menthol, lemon honey, orange, lemon lime, grape, blueberry, vanilla berry, bubble gum, or cherry. The flavoring agent can be a natural or artificial sweetener, such as sucrose, Magnasweet ™, sucralose, xylitol, sodium saccharin, cyclamate, aspartame, acesulfame, and salts thereof.
Apomorphine is susceptible to oxidative degradation. To minimize oxidative degradation it is desirable that the formulations of the invention contain one or more antioxidants. Antioxidants that can be used in the films of the invention can be selected from thiols (for example, aurothioglucose, dihydrolipoic acid, propylthiouracil, thioredoxin, glutathione, cysteine, cystine, cystamine, thiodipropionic acid), sulfoximines (for example, butionine-sulphoximines, homo-cysteine-sulfoximine, butionin-sulfones, and penta-, hexa- and hepta-thionine-sulfoximine), metal chelators (for example, α-hydroxy-fatty acids, palmitic acid, phytic acid, lactoferrin, citric acid, lactic acid , and succinic acid, malic acid, humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA, and DTPA and salts thereof), sodium metabisulfite, sodium thiosulfate, vitamins and vitamin derivatives (for example, vitamin E, vitamin C, ascorbyl palmitate, ascorbyl phosphate Mg, and ascorbyl acetate), phenols (eg, butylhydroxytoluene, butylhydroxyanisole, ubiquinol, nordihydroguaiaretic acid, trihydroxy
42/89 butyrophenone), benzoates (e.g., coniferyl benzoate), uric acid, mannose, propyl gaiate, selenium (e.g., selenium-methionine), stilbenes (e.g., stybene oxide and stybene transoxide), and combinations thereof. The total amount of antioxidant included in the films can be from 0.001% to 3% by weight, preferably 0.01% to 1% by weight, in particular 0.05% to 0.5% by weight, based on the total weight of the formulation. Other dopamine agonists may also benefit from including antioxidants in the formulations of the invention.
The films of the invention can include from 1 to 50% (by weight / weight) of one or more hydrolyzed starches. Various hydrolyzed starches can be used including maltrodextrins with an ED greater than 10 and dry glucose syrups which have an ED above 20. Suitable hydrolyzed starch products are commercially available from Grain Processing Corporation of Muscatine, Iowa, under trade names such as MALTRIN M200®, MALTRIN 180®, and MALTRIN 250®. MALTRIN M200® is a hydrolyzed starch product having an ED of 20, and MALTRIN 180® is a hydrolyzed starch product having an ED of 18. Equivalent dextrose (DE) is the relative sweetness of sugars, oligosaccharides, or combinations compared to dextrose , both expressed as a percentage. For example, a maltodextrin with an ED of 10 would be 10% as sweet as dextrose (ED = 100), while sucrose, with an ED of 120, would be 1.2 times as sweet as dextrose. For solutions made from starch, it is an estimate of the percentage of reducing sugars present in the total starch product. The DE describes the degree of conversion of starch to dextrose: Starch is close to 0, glucose / dextrose is 100 (percentage), dextrins vary between 1 and 13, and maltodextrins vary between 3 and 20. DE gives an indication of the degree polymerization medium (DP) for starch sugars. The rule of thumb is DE * DP = 120.
In some embodiments, the various components (for example, plasticizers, penetration enhancers, flavoring flavoring agents, preservatives, odorants, coloring agents, particulate base, and dopamine agonist particles) included in unit dosage forms
43/89 of the invention can be combined and incorporated into a first portion that is acidic and includes the dopamine agonist, or combined and incorporated into a second portion that includes a pH neutralizing component, or the components can be divided between the two portions. In some cases it may be desirable to minimize the interaction between the acidic portion of the dosage unit form and the basic portion of the dosage unit form including a barrier between the two. For example, a barrier can be included in the dosage unit forms of the invention as a third layer interposed between the acidic layer and the base layer of a multilayer sublingual dosage form. Alternatively, the barrier may be a rapidly dissolving layer on the surface of a particulate component in the form of a dosage unit, such as a particulate base coated on, or embedded within, an acidic portion of the dosage unit form. In yet another approach, the barrier may be a rapidly dissolving layer on the surface of dopamine agonist particles in the form of a dosage unit, which additionally includes a basic portion. These approaches can be used to ensure that the acidic portion containing dopamine agonist of the unit dosage form is not neutralized prior to administration to a subject.
Dopamine agonist particles
The pharmaceutical formulations described herein, in this patent application, can include dopamine agonist particles having an effective particle size from about 1 micron to about 10 microns. The starting dopamine agonist composition may be predominantly crystalline, predominantly amorphous, or a mixture thereof, and may include unmodified dopamine agonist.
In an alternative approach, the pharmaceutical formulations described herein, in this patent application, can include particles of dopamine agonists having an effective particle size of less than about 1 micron (i.e., nanoparticulate formulations). The starting dopamine agonist composition can be predominantly crystalline,
44/89 predominantly amorphous, or a mixture thereof, and may include unmodified dopamine agonist.
These dopamine agonist particles can be produced using any method known in the art to obtain the desired particle sizes. Useful methods include, for example, grinding, homogenization, supercritical fluid fracture, or precipitation techniques. Exemplary methods are described in United States Patent Nos. 4,540,602; 5,145,684; 5,518,187; 5,718,388; 5,862,999; 5,665,331; 5,662,883; 5,560,932; 5,543,133; 5,534,270; and 5,510,118; 5,470,583, each of which is specifically incorporated by reference.
Grinding to obtain particles of submicron dopamine agonists
In one approach, the dopamine agonist, or a salt thereof, is ground to obtain micron or submicron sized particles. The grinding process can be a dry process, for example, a dry roller grinding process, or a wet process, i.e. wet grinding. A wet grinding process is described in United States Patent Nos. 4,540,602, 5,145,684, 6,976,647 and EPO patent publication No. 498,482, the disclosures of which are hereby incorporated by reference. In this way, the wet grinding process can be practiced in combination with a liquid dispersion medium and dispersing or wetting agents as described in these publications. Useful liquid dispersion media include safflower oil, ethanol, n-butanol, hexane, or glycol, among other liquids selected from known organic pharmaceutical excipients (see U.S. Patent Nos. 4,540,602 and 5,145,684), and may be present in an amount of 2.0 to 70%, 3 to 50%, or 5 to 25% by weight based on the total weight of the dopamine agonist in the formulation.
The grinding media for the particle size reduction step can be selected from rigid media, typically spherical in shape, although non-spherical grinding media can also be used. The grinding media can preferably have a measure
45/89 particle average from 1 mm to about 500 microns. For fine grinding, the particles of the grinding media can have an average particle size from about 0.05 to about 0.6 mm. Smaller sized grinding media will result in smaller sized dopamine agonist particles compared to the same conditions using larger sized grinding media. When selecting the material, grinding media with higher density, for example, video (2.6 g / cm ³ ), zirconium silicate (3.7 g / cm ³ ), and zirconium (5.4 g / cm ³⁾ ) and 95% zirconium oxide stabilized with yttrium, can be used for more efficient grinding. Alternatively, polymeric grinding media can be used. Polymeric resins suitable for use here, in this patent application, are chemically and physically inert, substantially free of metals, solvent and monomers, and of sufficient hardness and friability to allow them to avoid being ground or crushed during crushing. Suitable polymeric resins include, without limitation, cross-linked polystyrenes, such as divinylbenzene cross-linked polystyrene, styrene copolymers, polycarbonates, polyacetals, such as Delrin ™, vinyl chloride polymers and copolymers, polyurethanes, polyamides, poly (tetrafluoro), for example, poly (tetrafluoro), for example, poly (tetrafluoro). , Teflon ™, and other fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and esters such as cellulose acetate, polyhydroxymethacrylate, polyhydroxyethyl acrylate, and polymers containing silicone such as polysiloxanes.
Shredding can take place in any suitable shredding mill. Suitable mills include an air jet mill, a roller mill, a ball mill, an attractor mill, a vibrating mill, a planetary mill, a sand mill and a bead mill. A high-energy media mill is preferred when small particles are desired. The mill can contain a rotating shaft.
The preferred proportions of the grinding media, dopamine agonist, the optional liquid dispersion medium, and the dispersing agents, wetting agents or stabilizers of various particles present in the grinding vessel can vary within wide limits and depend, for
46/89 example, the size and density of the grinding media, the type of mill selected, the grinding time, etc. The process can be carried out in a continuous, batch or semi-batch mode. In high-energy media mills, it may be desirable to fill 80 to 95% of the grinding chamber volume with grinding media. On the other hand, in roller mills, it is often desirable to leave the grinding vessel half filled with air, the remaining volume comprising the grinding media and liquid dispersion media, if present. This allows a cascade effect inside the vessel on the cylinders which allows efficient grinding. However, when defoaming is a problem during wet grinding, the vessel can be completely filled with the liquid dispersion medium or an anti-defoaming agent can be added to the liquid dispersion.
The friction time can vary widely and depends essentially on the mechanical means and on the selected permanence conditions, on the desired initial and final particle size, among other factors. For roller mills, processing times from several days to weeks may be required. On the other hand, milling durations of less than about 2 gardens are generally required using high-energy media mills. After friction is completed, the grinding medium is separated from the ground dopamine agonist particulate product (either in the form of a dry or liquid dispersion) using conventional separation techniques, such as by filtration, or by sieving through a screen. mesh.
To produce dopamine agonist particles having an effective particle size of less than about 1 micron, the grinding media can be produced from beads having a measurement ranging from 0.05 mm to 4 mm. For example, high energy grinding of dopamine agonist with 0.4 mm yttrium stabilized zirconium oxide beads for a grinding time of 25 minutes up to 1.5 hours in recirculation mode at 1200 to 3000 RPM. In another approach, high energy grinding of dopamine agonist can be used with 0.1 mm zirconium oxide balls for a lifetime of
47/89 2-hour grinding maintenance in batch mode. The grinding concentration can be from about 10% to about 30% dopamine agonist by weight compared to the weight of the grinding sludge, which can contain a wetting and / or dispersing agent to coat the initial suspension so that a uniform feed rate can be applied in continuous grinding mode. Alternatively, batch grinding mode is used with some grinding media containing an agent to adjust the viscosity and / or provide a wetting effect so that the dopamine agonist is well dispersed between the grinding media.
Microprecipitation to Obtain Dopamine Agonist Nanoparticles
Dopamine agonist particles can also be prepared by homogeneous nucleation and precipitation in the presence of a wetting agent or a dispersing agent using methods analogous to those described in United States Patent Nos. 5,560,932 and 5,665,331, which are specifically incorporated by reference. A similar method can include the steps of: (1) dispersing the dopamine agonist in a suitable liquid medium; (2) adding the mixture from step (1) to a mixture including at least one dispersing agent or a wetting agent such that at the appropriate temperature, the dopamine agonist is dissolved; and (3) precipitation of the formulation from step (2) using an appropriate antisolvent. The method can be followed by removing any formed salt, if present, by dialysis or filtration and concentrating the dispersion by conventional means. In one embodiment, the particles of dopamine agonists are present in an essentially pure form and dispersed in a suitable liquid dispersion medium. In this approach the particles of dopamine agonists are a distinct phase within the resulting mixture. Useful dispersing agents, wetting agents, solvents, and anti-solvents can be determined experimentally.
Homogenization to Obtain Dopamine Agonist Nanoparticles
Particles of dopamine agonists can also be prepared
48/89 by means of high pressure homogenization (see United States Patent No. 5,510,118). In this approach dopamine agonist particles are dispersed in a liquid dispersion medium and subjected to repeated homogenization to reduce the particle size of the dopamine agonist particles to the desired average effective particle size. The dopamine agonist particles can be reduced in size in the presence of at least one or more dispersing agents or wetting agents. Alternatively, dopamine agonist particles can be contacted with one or more dispersing agents or wetting agents, either before or after friction. Other materials, such as a diluent, can be added to the dopamine agonist / dispersing agent mixture before, during, or after the size reduction process. For example, unprocessed dopamine agonist can be added to a liquid medium in which it is essentially insoluble to form a premix (i.e., about 0.1 to 60% by weight / weight of dopamine agonist and about 20 to 60% by weight / weight of dispersing agents or wetting agents). The apparent viscosity of the premix suspension is preferably less than about 1000 centipoise. The premix can then be transferred to a microfluidizer and circulated continuously at low pressures, and then at maximum capacity (i.e., 3,000 to 30,000 psi) until the desired particle size reduction is achieved. The resulting dopamine agonist particle dispersion can be spray coated onto a sublingual pharmaceutical formulation of the invention using techniques well known in the art.
Grinding with Simethicone
Foaming during nano-sizing can present formulation problems and can have negative consequences for particle size reduction. For example, high levels of foam or air bubbles in the mill can cause a dramatic increase in viscosity making the grinding process inoperable. Even a very low level of air presence can dramatically reduce grinding efficiency
It is possible to obtain the desired particle size. This may be due to the resulting air in the mill dampening the grinding balls and limiting the grinding efficiency. The air can also form a microemulsion with the ground ingredients which presents many problems with respect to the release of a precise dose and palatability. The addition of a small amount of simethicone is a very effective anti-foaming agent which minimizes grinding variability or special handling techniques to avoid introducing air into the grinding process.
The Use of Wetting and Dispersing Agents
The dopamine agonist particles can be prepared using one or more wetting and / or dispersing agents, which are, for example, adsorbed on the surface of the dopamine agonist particle. The particles of dopamine agonists can be contacted with wetting and / or dispersing agents either before, during or after the size reduction. Generally, wetting and / or dispersing agents fall into two categories: nonionic agents and ionic agents. The most common non-ionic agents are excipients which are contained in classes known as binders, fillers, surfactants and wetting agents. Limited examples of non-ionic surface stabilizers are hydroxypropyl methyl cellulose, polyvinylpyrrolidone, Plasdone, polyvinyl alcohol, Pluronics, Tweens and polyethylene glycols (PEGs). Ionic agents are typically organic molecules carrying an ionic bond such that the molecule is loaded into the formulation, such as salts of long chain sulfonic acid (for example, sodium lauryl sulfate and sodium dioctyl sulfosuccinate).
Excipients, such as wetting and dispersing agents, can be applied to the surface of the dopamine agonist nanoparticulate through spray drying, spray granulation, or spray stratification process. These procedures are well known to those skilled in the art. It is also common to add additional excipients prior to solvent removal in the nanoparticulate suspension to assist in dispersing the solid composition in medium
50/89 in which the solid composition will be exposed (e.g., saliva) to further prevent agglomeration and / or growth of the particle size of the small particles of dopamine agonists. An example of a similar additional excipient is a redispersing agent. Suitable redispersing agents include, without limitation, sugars, polyethylene glycols, urea and quarternary ammonium salts.
Therapy
Typical examples of treatable diseases and conditions using the sublingual formulations of the invention are as listed above, and include, but are not limited to, Parkinson's disease, sexual dysfunction, and depressive disorders, such as major depression and bipolar disorder.
The sublingual formulations of the invention include rapidly disintegrating or dissolving dosage forms, also known as fast dissolving, fast melting, and rapid disintegrating dosage forms. These dosage forms quickly dissolve or disintegrate in the patient's mouth without chewing or without the need for water within a short time. Due to their ease of administration, the mentioned compositions are particularly useful for the specific needs of patients with impaired motor skills. Sublingual formulations can be in the form of a dosage unit in the form of, for example, a lozenge, a pill, a tablet, a film, or a tape. Alternatively, sublingual formulations can be prepared in non-unit dosage forms, such as a gel.
The dopamine agonist can be administered in its free base form or as a pharmaceutically acceptable salt, such as some non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry. Examples of acid addition salts include organic acids such as acetic, glucuronic, citric, lactic, pamoic, maleic, citric, malic, maleic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic or the like; polymeric acids such as tannic acid,
51/89 carboxymethyl cellulose, alginic acid, polyaclate, and copolymers of acrylate, methacrylate, and / or derivatives of carboxymethyl polymers; and inorganic derivative such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or the like. Metal complexes include calcium, zinc, iron, and the like. In some cases the formulation of the invention includes the hydrochloride salt of a dopamine agonist.
The formulations can be administered to patients in therapeutically effective amounts. For example, an amount is administered which prevents, reduces, or eliminates the symptoms of Parkinson's disease, sexual dysfunction, or depression, respectively. Typical dose ranges are from about 0.5 mg to about 30 mg of apomorphine, or a salt thereof, administered up to five times a day. Typical dose ranges are from about 0.2 mg to about 20 mg of bromocriptine, or a salt thereof, administered up to five times a day. Typical dose ranges are from about 0.2 mg to about 20 mg of bromocriptine, or a salt thereof, administered up to five times a day. Typical dose ranges are from about 0.3 mg to about 30 mg of dihydroergocriptine, or a salt thereof, administered up to five times a day. Typical dose ranges are from about 0.05 mg to about 10 mg of lisuride, or a salt thereof, administered up to five times a day. Typical dose ranges are from about 0.5 mg to about 75 mg of pyribedyl, or a salt thereof, administered up to five times a day. Typical dose ranges are from about 0.05 mg to about 10 mg of pergolide, or a salt thereof, administered up to five times a day. Typical dose ranges are from about 0.1 mg to about 20 mg of pramipexole, or a salt thereof, administered up to five times a day. Typical dose ranges are from about 0.1 mg to about 20 mg of rotigotine, or a salt thereof, administered up to five times a day. Typical dose ranges are from about 0.1 mg to about 40 mg of rotigotine, or a salt thereof, administered up to five times a day. It is likely that the exemplary dosage of dopamine agonist to be administered depends on variables such as the type and extent of the condition, health status
52/89 the patient in particular, the dopamine agonist in particular being administered, and the sublingual formulation in particular being used.
Potential adverse effects can be ameliorated by administering apomorphine, or an apomorphine prodrug, in combination with an anti-emetic agent, such as nicotine, lobeline sulfate, pipamazine, oxipendil hydrochloride, ondansetron, buclizine hydrochloride, cyclizine hydrochloride, dimenhydrinate, scopolamine, metopimazine, benzauinamine hydrochloride or diphenidol hydrochloride. In some cases, it may be desirable to incorporate the antiemetic into the sublingual formulation for simultaneous administration in combination with apomorphine, or apomorphine prodrug.
The following examples are published in order to give people with regular knowledge of the art a complete disclosure and description of how the methods and compounds claimed here, in this patent application, are carried out, produced, and evaluated, and are intended to are purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.
EXAMPLE 1 - Monolayer and bilayer films
Films A to H, J, K, and L were prepared as described below. Films A to H were prepared using a solid particle of apomorphine hydrochloride having an effective particle size in the range of 125 pm to 250 pm. Films J, K, and L were prepared using a solid particle of apomorphine hydrochloride which was processed to produce an effective particle size of about 8 pm. For Films J, K, and L, apomorphine hydrochloride was ground using a Jet-Pulverizer 2 Micron-Master cyclone discharge mill with a stainless steel coating. Nitrogen was used as the process gas at a pressure of 100 PSI and a temperature of 25 to 45 ° C. Apomorphine hydrochloride was fed to the mill using a vibrating V-channel feeder and recovered in an integrated bottom collector to reduce the material loss associated with a dust bag collector. The design of this grinding unit is described in United States Patent No. 3,559,895.
Movie A.
53/89
Film A is a monolayer film containing the components and amounts listed in Table A. Film A was prepared first by mixing sodium metabisulfite, disodium EDTA, propylene glycol, maltodextrin, and sucralose with water, and stirring the mixture. Acetone and menthol were added to this solution, and the mixture was stirred. Apomorphine hydrochloride was added, with stirring, forming a clear solution. Hypromellose was added slowly with stirring until a viscous, clear and uniform liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry film was clear in appearance.
Table A.
liquid on dry film film
1st. PHARMACOCINETIC STUDY dry volume
Component__________________ mg / 100mg mg / 100mg mg
Water 39.8794 acetone 39.8247 sodium metabisulphite 0.1693 0.8342 0.5422 Disodium EDTA 0.1693 0.8342 0.5422 Apomorphine HCI 4.6845 23.0810 15.0027 menthol 1.1400 5.6169 3.6510 propylene glycol 2.2899 11.2826 7.3337 maltodextrin M180 3.6340 17.9051 11.6383 sucralose 0.5526 2.7227 1.7698 Methocel E50 4.3210 21.2900 13.8385 Methocel E5 3.3353 16.4334 10.6817 Total mass, mg 100.0000 100.0000 65,0000
Movie B.
Film B is a monolayer film containing the components and amounts listed in Table B. Film B was prepared first by mixing sodium metabisulfite, disodium EDTA, glycerin, maltodextrin, and sucralose with water, and stirring the mixture. Acetone and menthol were acres
54/89 to this solution, and the mixture was stirred. Apomorphine hydrochloride was added and stirred, forming an opaque dispersion. Hypromellose was added slowly with stirring until a viscous, opaque and uniform liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry film was an opaque white color.
Table B.
liquid volume dry film dry film
Component_________ mg / 100mg mg / 100mg mg
Water 33.3333 acetone 33.3333 sodium metabisulphite 0.3280 0.9841 0.2460 Disodium EDTA 0.3337 1.0130 0.2533 Apomorphine HCI 20.0000 60.0000 15.0000 menthol 3.0565 9.1694 2.2924 glycerin 1.7945 5.3835 1.3459 Maltrin M180 0.8548 2.5644 0.6411 sucralose 1.0613 3.1838 0.7959 Methocel E50 2.2696 6.8087 1.7022 Methocel E5 3.6310 10.8931 2.7233 Total mass, mg 100.0000 100.0000 25.0000 Theoretical solids content,% 33.3334
Movie C.
Film C is a bilayer film formed from an apomorphine layer containing the components and quantities listed in Table C1 and a neutralizing layer containing the components and quantities listed in Table C2.
The apomorphine C1 layer was prepared first by mixing 15 sodium metabisulfite, disodium EDTA, glycerin, maltodextrin, and sucralose with water, and stirring the mixture. Acetone and menthol were added to this solution, and the mixture was stirred. Apomorphine hydrochloride was a55 / 89 grown and agitated, forming an opaque dispersion. Hypromellose was added slowly with stirring until a viscous, opaque and uniform liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry film was an opaque white color.
Table 01.
liquid volume dry film dry film
Component________ mg / IQOmg mg / 100mg mg
Water 33.3333 acetone 33.3333 sodium metabisulphite 0.3280 0.9841 0.2460 Disodium EDTA 0.3337 1.0130 0.2533 Apomorphine HCI 20.0000 60.0000 15.0000 menthol 3.0565 9.1694 2.2924 glycerin 1.7945 5.3835 1.3459 Maltrin M180 0.8548 2.5644 0.6411 sucralose 1.0613 3.1838 0.7959 Methocel E50 2.2696 6.8087 1.7022 Methocel E5 3.6310 10.8931 2.7233 Total mass, mg 100.0000 100.0000 25.0000 Theoretical solids content,% 33.3334
The C2 neutralizing layer was prepared by slowly adding sodium carboxymethyl cellulose to water with stirring until a viscous, clear and uniform liquid was produced. Tribasic sodium phosphate, dibasic sodium phosphate, sodium metabisulfite, disodium EDTA, glycerin, and maltodextrin were then all added, and the mixture was stirred. Acetone was added to this solution, and the mixture was stirred, until a clear, uniform, viscous liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The dry layer
The resulting 56/89 was clear-cut.
Table C2.
liquid by volume dry film moviedry Component mg / 100 mg mg / 100 mg mg
Water 70.0000- I L 1 acetone 10,0000 *tribasic sodium phosphate (Na ₃ PO ₄ ) 3.3480 16,7400 1.6740 dibasic sodium diphosphate (Na ₂ HPO ₄ ) 0.5580 2.7900 0.2790 sodium metabisulphite 0.2158 1.0792 0.1079 Disodium EDTA 0.1835 0.9174 0.0917 glycerin 1.9256 9.6280 0.9628 Maltrin M180 5.2000 26,0000 2.6000 sodium CMC, 7L2P 8.5691 42.8454 4.2845 Total mass, mg 100.0000 100.0000 10,0000 Theoretical solids content,% 20.0000
The apomorphine layer and the neutralizing layer were laminated together by applying an ethanol spray between them. This bilayer construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from inert supports, cut into unit dose films of a predetermined size (22 mm χ 22 mm), and packed in individual aluminum packages. The resulting dry bilayer film was an opaque white color.
Film D.
Film D is a bilayer film formed from an apomorphine layer containing the components and quantities listed in Table D1 and a neutralizing layer containing the components and quantities listed in Table D2.
The apomorphine layer D1 was prepared by slowly adding hydroxyethyl cellulose and hypromellose to the water with stirring until a viscous, clear and uniform liquid was produced. Sodium metabisulfite, disodium EDTA, glycerin, maltodextrin, and sucralose were then all
57/89 added, and the mixture was stirred. Acetone and menthol were then added to this solution, and the mixture was stirred. Apomorphine hydrochloride was then added and the mixture was stirred, forming an opaque dispersion. The resulting mixture was placed under vacuum to eliminate 5 air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry layer was an opaque white color.
Table D1.liquid by volume dry film dry film Component mg / 100 mg mg / 100 mg mg
Water 38.6792 acetone 14,1509 sodium metabisulphite 0.4688 0.9939 0.4290 Disodium EDTA 0.4643 0.9843 0.4249 Apomorphine HCI 16.3912 34.7494 15.0000 menthol 2.550 5.3105 2.2924 glycerin 4.3386 9.1978 3.9703 Maltrin M180 19.2072 40.7194 17.5770 sucralose 0.8698 1.8439 0.7959 Natrosol 250 G 1.2332 2.6145 1.1286 Natrosol 250 L 1.2332 2.6145 1.1286 Methocel E5 0.4558 0.9718 0.4195 Total mass, mg 100.0000 100.0000 43.1662 Theoretical solids content,% 47.1698
The neutralizing layer D2 was prepared by slowly adding hydroxyethyl cellulose to the water with stirring until a viscous, clear and uniform liquid was produced. Tribasic sodium phosphate, dibasic sodium phosphate, sodium metabisulfite, disodium EDTA, glycerin, and maltodextrin were then all added, and the mixture was stirred. Acetone was added to this solution, and the mixture was stirred, until a clear, uniform, viscous liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer
58/89 on an inert support, and dried in an oven. The resulting dry layer was clear in appearance.
Table D2.liquid on filmdry filmdry volumeComponent mg / 100mg mg / 100mg mg Water 79.6754 acetone 5.8157 tribasic sodium phosphate (Na ₃ PO ₄ ) 2.4339 16.7751 1.6775 dibasic sodium diphosphate (Na ₂ HPO ₄ ) 0.4056 2.7959 0.2796 sodium metabisulphite 0.1255 0.8652 0.0865 Disodium EDTA 0.1067 0.7355 0.0735 glycerin 1,1199 7.7186 0.7719 Maltrin M180 5.2342 36.0756 3.6076 Natrosol 250 G 3,3887 23.3562 2.3356 Natrosol 250 L 1.6944 11.6781 1.1678 Total mass, mg 100.0000 100.0000 10,0000 Theoretical solids content,% 20.2179
The apomorphine layer and the neutralizing layer were layered together by applying an ethanol spray between them. This bilayered construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from inert supports, cut into unit dose films of a predetermined size (22 mm χ 22 mm), and packed in individual aluminum packages. The resulting dry film bilayer was an opaque white color.
E. Movie
Film E is a bilayer film formed from an apomorphine layer containing the components and quantities listed in Table E1 and a neutralizing layer containing the components and quantities listed in Table E2.
The apomorphine E1 layer was prepared by slowly adding hydroxyethyl cellulose and hypromellose to the water with stirring until it was
59/89 produced a viscous, clear and uniform liquid. Sodium metabisulfite, disodium EDTA, glycerin, maltodextrin, and sucralose were then all added, and the mixture was stirred. Acetone and menthol were added to this solution, and the mixture was stirred. Apomorphine hydrochloride was then added with stirring, forming an opaque dispersion. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry layer was an opaque white color.
Table E1.
liquid by volume dry film dry film Component mg / 100 mg mg / 100 mg mg
Water 38.6792 acetone 14,1509 sodium metabisulphite 0.4688 0.9939 0.4290 Disodium EDTA 0.4643 0.9843 0.4249 Apomorphine HCI 16.3912 34.7494 15.0000 menthol 2.550 5.3105 2.2924 glycerin 4.3386 9.1978 3.9703 Maltrin M180 19.2072 40.7194 17.5770 sucralose 0.8698 1.8439 0.7959 Natrosol 250 G 1.2332 2.6145 1.1286 Natrosoi 250 L 1.2332 2.6145 1.1286 Methocel E5 0.4558 0.9718 0.4195 Total mass, mg 100.0000 100.0000 43.1662 Theoretical solids content,% 47.1698
The neutralizing layer E2 was prepared by slowly adding hydroxyethyl cellulose to the water with stirring until a viscous, clear and uniform liquid was produced. Meglumine, sodium metabisulfite, disodium EDTA, glycerin, and maltodextrin were then all added, and the mixture was stirred. Acetone was added to this solution, and the mixture was stirred, until a viscous, clear and uniform liquid was produced
60/89 me. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry layer was clear in appearance.
Table E2.
dry liquid volume dry film
Component__________ mg / IQOmg mg / 100mg ____ mg
Water 85.8172 acetone 1.7129 meglumine 5.1388 41.2092 10.3023 sodium metabisulphite 0.0370 0.2965 0.0741 Disodium EDTA 0.0314 0.2520 0.0630 glycerin 1.0963 8.7913 2.1978 Maltrin M180 0.6852 5.4946 1.3736 Natrosol 250 G 2.7407 21.9782 5.4946 Natrosol 250 L 2.7407 21.9782 5.4946 Total mass, mg 100.0000 100,0000 25,0000 Theoretical solids content,% 12.4699
The apomorphine layer and the neutralizing layer were laminated together by applying an ethanol spray between them. This bilayered construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from inert supports, cut into unit dose films of a predetermined size (22 mm χ 22 mm), and packaged in individual aluminum packages. The resulting dry bilayer film was an opaque white color.
Film F.
Film F is a bilayer film formed from an apomorphine layer containing the components and quantities listed in Table F1 and a neutralizing layer containing the components and quantities listed in Table F2.
The F1 apomorphine layer was prepared by slowly adding hydroxyethyl cellulose and hypromellose to the water with stirring until it was
61/89 a viscous, clear and uniform liquid is produced. Sodium metabisulfite, disodium EDTA, glycerin, maltodextrin, and sucralose were then all added, and the mixture was stirred. Acetone and menthol were added to this solution, and the mixture was stirred. Apomorphine hydrochloride was increased with agitation, forming an opaque dispersion. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry layer was an opaque white color.
Table F1.
liquid in dry film dry film volume
Component___________ mg / 100mg mg / 100mg mg
Water 55,2012 acetone 6.8337 sodium metabisulphite 0.3984 1.0495 0.2860 Disodium EDTA 0.3984 1.0495 0.2860 Apomorphine HCI 20.8956 55.0389 15.0000 menthol 2.6361 6.9436 1.8924 glycerin 2.7861 7.3385 2.0000 Maltrin M180 3.4423 9.0671 2.4711 sucralose 0.8302 2.1867 0.5959 Natrosol 250 L 6.1328 16.1539 4.4025 Methocel E5 0.4451 1.1723 0.3195 Total mass, mg 100.0000 100.0000 27.2534 Theoretical solids content,% 37.9651
The neutralizing layer F2 was prepared by slowly adding hydroxyethyl cellulose to the water slowly with stirring until a viscous, clear and uniform liquid was produced. Meglumine, sodium metabisulfite, disodium EDTA, glycerin, and maltodextrin were then all added, and the mixture was stirred. Acetone was added to this solution, and the mixture was stirred, until a viscous, clear and uniform liquid was produced. The resulting mixture was placed under vacuum to eliminate bubbles
62/89 of air, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry layer was clear in appearance.
Table F2.
liquid volume dry film dry film
Component__________ mg / IQOmg mg / 100mg mg
Water 60.8111 acetone 6.1425 meglumine 19.6561 59.4803 9.9630 sodium metabisulphite 0.1326 0.4012 0.0672 Disodium EDTA 0.1127 0.3410 0.0571 glycerin 1.4742 4.4610 0.7472 Maltrin M180 4.9140 14.8701 2.4907 Natrosol 250 L 6.7568 20.4464 3.4248 Total mass, mg 100.0000 100.0000 16.7500 Theoretical solids content,% 33.0464
The apomorphine layer and the neutralizing layer were laminated together by applying an ethanol spray between them. This bilayered construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from inert supports, cut into unit dose films of a predetermined size (22 mm χ 22 mm), and packed in individual aluminum packages. The resulting dry bilayer film was an opaque white color.
Movie G.
Film G is a bilayer film formed from an apomorphine layer containing the components and quantities listed in Table G1 and a neutralizing layer containing the components and quantities listed in Table G2.
The G1 apomorphine layer was prepared by slowly adding hydroxyethyl cellulose and hypromellose to the water with stirring until a viscous, clear and uniform liquid was produced. Sodium metabisulfite, disodium EDTA, glycerin, maltodextrin, and sucralose were then all added, and the mixture was stirred. Acetone and menthol were added
63/89 to this solution, and the mixture was stirred. Apomorphine hydrochloride was added with stirring, forming an opaque dispersion. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting drying bed 5 was an opaque white color.
Table G1.
liquid in dry film dry film volume
Component____________ mg / 100mg mg / 100mg mg
Water 55,2012 --- „---_—--- --- acetone 6.8337 sodium metabisulphite 0.3984 1.0495 0.2860 Disodium EDTA 0.3984 1.0495 0.2860 Apomorphine HCI 20.8956 55.0389 15.0000 menthol 2.6361 6.9436 1.8924 glycerin 2.7861 7.3385 2.0000 Maltrin M180 3.4423 9.0671 2.4711 sucralose 0.8302 2.1867 0.5959 Natrosol 250 L 6.1328 16.1539 4.4025 Methocel E5 0.4451 1.1723 0.3195 Total mass, mg 100.0000 100.0000 27.2534 Theoretical solids content,% 37.9651
The neutralizing layer G2 was prepared by slowly adding hydroxyethyl cellulose to the water with stirring until a viscous, clear and uniform liquid was produced. Sodium citrate, sodium metabisulfite, 10 disodium EDTA, glycerin, and maltodextrin were all added, and the mixture was stirred. Acetone was added to this solution, and the mixture was stirred, until a viscous, clear and uniform liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry layer was clear in appearance.
64/89
Table G2.
liquid in dry film dry film volume
Component___________ mg / 100mg mg / 100 mg____mg
Water 68.5434 acetone 8.2782> - ' sodium citrate 4.9669 21.4291 5.0358 sodium metabisulphite 0.1778 0.7709 0.1812 Disodium EDTA 0.1519 0.6553 0.1540 glycerin 1.9868 8.5716 2.0143 Maltrin M180 8.2782 35.7152 8.3931 Natrosol 250 L 7.6159 32.8579 7.7216 Total mass, mg 100.0000 100.0000 23.5000 Theoretical solids content,% 23.1784
The apomorphine layer and the neutralizing layer were laminated together by applying an ethanol spray between them. This bilayer construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from inert supports, cut into unit dose films of a predetermined size (22 mm χ 22 mm), and packed in individual aluminum packages. The resulting dry bilayer film was an opaque white color.
H. Movie
Film H is a bilayer film formed from an apomorphine layer containing the components and quantities listed in Table H1 and a neutralizing layer containing the components and quantities listed in Table H2.
The apomorphine layer H1 was prepared by slowly adding hydroxyethyl cellulose and hypromellose to the water with stirring until a viscous, clear and uniform liquid was produced. Sodium metabisulfite, disodium EDTA, glycerin, maltodextrin, and sucralose were then all added, and the mixture was stirred. Acetone and menthol were added to this solution, and the mixture was stirred. Apomorphine hydrochloride was the
65/89 increased with agitation, forming an opaque dispersion. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry layer was an opaque white color.
Table H1.
liquid in dry film dry film volume
Component ______________ mg / 100 mg mg / 100 mg______mg
Water 55,2012 acetone 6.8337 sodium metabisulphite 0.3984 1.0495 0.2860 Disodium EDTA 0.3984 1.0495 0.2860 Apomorphine HCI 20.8956 55.0389 15.0000 menthol 2.6361 6.9436 1.8924 glycerin 2.7861 7.3385 2.0000 Maltrin M180 3.4423 9.0671 2.4711 sucralose 0.8302 2.1867 0.5959 Natrosol 250 L 6.1328 16.1539 4.4025 Methocel E5 0.4451 1.1723 0.3195 Total mass, mg 100.0000 100.0000 27.2534 Theoretical solids content,% 37.9651
The neutralizing layer H2 was prepared by slowly adding hydroxyethyl cellulose to the water with stirring until a viscous, clear and uniform liquid was produced. Meglumine, sodium citrate, sodium metabisulfite, disodium EDTA, glycerin, and maltodextrin were then all added, and the mixture was stirred. Acetone was added to this solution, and the mixture was stirred, until a clear, uniform, viscous liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven. The resulting dry layer was clear.
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Table H2.
liquid in dry film dry film volume
Component___________ mg / IQOmg mg / 100mg ____mg
Water 60.2192 acetone 6.0828 meglumine 14.4769 42.9608 5.0049 sodium citrate 5.9611 17.6897 2.0609 sodium metabisulphite 0.1313 0.3896 0.0454 Disodium EDTA 0.1116 0.3312 0.0386 glycerin 1.4599 4.3322 0.5047 Maltrin M180 4.8662 14.4406 1.6823 Natrosol 250 L 6.6910 19.8558 2.3132 Total mass, mg 100.0000 100.0000 11.6500 Theoretical solids content,% 33.6980
The apomorphine layer and the neutralizing layer were laminated together by applying an ethanol spray between them. This bilayered construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from inert supports, cut into unit dose films of a predetermined size (22 mm χ 22 mm), and packed in individual aluminum packages. The resulting dry bilayer film was an opaque white color.
Movie J
Film J is a bilayer film formed from an apomorphine layer containing components and quantities listed in Table J1 and a neutralizing layer containing the components and quantities listed in Table J2.
The apomorphine layer J1 was prepared by adding hydro15 xiethyl cellulose and hypromellose to the water slowly while stirring until a viscous, clear and uniform liquid was produced. Sodium metabisulfite, disodium EDTA dihydrate, glycerin, maltodextrin, and sucralose were then added, and the mixture was stirred. Acetone, monostearate
67/89 glyceryl and menthol were then added to the solution, and the mixture was stirred. Apomorphine hydrochloride was then added, with stirring, forming an opaque dispersion. The resulting mixture was placed under vacuum to eliminate air bubbles. The viscous liquid was then melted as a uniform layer on an inert support and dried in an oven.
The resulting dry layer was an opaque white color.
Table J1
Component liquid by volume in mg / 100 mg dry film in mg / 100 mg dry filmin mg Water 36.9736 acetone 14.2616 sodium metabisulphite 0.4555 0.9332 0.4179 Disodium EDTA, dihydrate 0.4714 0.9667 0.4329 Apomorphine HCI 16.3345 33.4966 15.0000 menthol 2.4973 5.1211 2.2933 glyceryl monostearate 0.4770 0.9781 0.4380 glycerin 4.4518 9,1292 4.0881 maltodextrin M180 18.6597 38.2647 17,1352 sucralose 0.8512 1.7454 0.7816 Natrosol 250 L 4.1082 8.4245 3.7725 Methocel E5 0.4558 0.9405 0.4212 Total mass, mg 100.0000 100.0000 44.7807 Theoretical solids content 48.7%
Table J2 net in
Component volume in mg / 100 mg dry film in mg / 100 mg dry filmin mg Water 60.68455 acetone 6.2112569 meglumine 19.594899 59.1916 9,9146 sodium metabisulphite 0.13395251 0.4215 0.0706
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ComponentDisodium EDTA, dihydrate liquid by volume in mg / 100 mg 0.1164038 dry film in mg / 100 mg 0.3516 dry filmin mg0.0589 glycerin 1.6141056 4.8758 0.8167 maltodextrin M180 4.8965322 14.7913 2.4775 Natrosol 250 L 6.7427278 20.3682 3.4117 Total mass, mg 100.0000 100.0000 16.7500 Theoretical solids content,% 33,1042
The neutralizing layer J2 was prepared by adding hydroxyethyl cellulose to the water slowly with stirring until a viscous, clear and uniform liquid was produced. Meglumine, sodium metabisulfite, disodium EDTA dihydrate, glycerin, and maltodextrin were then added, and the mixture was stirred. Acetone was added to this solution, and the mixture was stirred, until a clear, uniform, viscous liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles. The viscous liquid was then melted as a uniform layer on an inert support and dried in an oven. The resulting dry layer was clear in appearance.
The separated apomorphine hydrochloride layer and the neturalizing layer were laminated together by applying an ethanol spray between them. This bilayered construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from the inert supports, cut into unit dose films of a predetermined size (22 mm x 22 mm), and subsequently packed into individual aluminum packages. The resulting dry bilayer film was an opaque white color.
Movie K
Film K is a bilayer film formed from an apomorphine layer containing components and quantities listed in Table K1 and a neutralizing layer containing the components and quantities listed in Table K2.
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The apomorphine K1 layer was prepared by adding hydroxyethyl cellulose and hypromellose to the water slowly while stirring until a viscous, clear and uniform liquid was produced. Sodium metabisulfite, disodium EDTA dihydrate, glycerin, maltodextrin, and sucralose were then added, and the mixture was stirred. Acetone, glyceryl monostearate and menthol were then added to the solution, and the mixture was stirred. Apomorphine hydrochloride was then added, with stirring, forming an opaque dispersion. The resulting mixture was placed under vacuum to eliminate air bubbles. The viscous liquid was then melted 10 as a uniform layer on an inert support and dried in an oven.
The resulting dry layer was an opaque white color.
Table K1 liquid in volume in mg / dry film on dry film
Component_____________ 100 mg mg / 100 mg in mg
Water 36.9736 acetone 14.2616 sodium metabisulphite 0.4555 0.9332 0.4179 Disodium EDTA, dihydrate 0.4714 0.9667 0.4329 Apomorphine HCI 16.3345 33.4966 15.0000 menthol 2.4973 5.1211 2.2933 glyceryl monostearate 0.4770 0.9781 0.4380 glycerin 4.4518 9,1292 4.0881 maltodextrin M180 18.6597 38.2647 17,1352 sucralose 0.8512 1.7454 0.7816 Natrosol 250 L 4.1082 8.4245 3.7725 Methocel E5 0.4558 0.9405 0.4212 Total mass, mg 100.0000 100.0000 44.7807 Theoretical solids content 48.7%
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Table K2 liquid by volume on dry film on dry film
Component_____________ mg / 100 mg mg / 100 mg in mg
Water 60.7040 acetone 6.2195 Pyridoxine HCI 19.6039 59.2684 9.9275 sodium hydroxide 3.3010 9,9800 1.6716 sodium metabisulphite 0.1356 0.4100 0.0687 Disodium EDTA, dihydrate 0.1205 0.3642 0.0610 glycerin 1.6617 5.0238 0.8415 maltodextrin M180 1.5089 4.5619 0.7641 Natrosol 250 L 6.7449 20.3918 3.4156 Total mass, mg 100.0000 100.0000 16.7500 Theoretical solids content,% 33.0765------- liiiMí
The neutralizing layer K2 was prepared by adding hydroxyethyl cellulose to the water slowly with stirring until a viscous, clear and uniform liquid was produced. Sodium hydroxide, pyridoxine HCI, sodium meta5 bisulfite, disodium EDTA dihydrate, glycerin, and maltodextrin were then added, and the mixture was stirred. Acetone was added to this solution, and the mixture was stirred, until a clear, uniform, viscous liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles. The viscous liquid was then melted 10 as a uniform layer on an inert support and dried in an oven.
The resulting dry layer was clear in appearance.
The separated apomorphine hydrochloride layer and the neturalizing layer were laminated together by applying an ethanol spray between them. This bilayer construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from the inert supports, cut into unit dose films of a predetermined size (22 mm x 22 mm), and subsequently packed into individual aluminum packages. The resulting dry bilayer film was white o71 / 89 paca.
Film L (To be added, MgOH ₂ neutralizing agent)
Film L
Film L is a bilayer film formed from an apomorphine layer containing the components and quantities listed in Table L1 and a neutralizing layer containing the components and quantities listed in Table L2.
The L1 apomorphine layer was prepared by adding hydroxyethyl cellulose and hypromellose to the water slowly while stirring until a viscous, clear and uniform liquid was produced. Sodium metabisulfite, disodium EDTA dihydrate, glycerin, maltodextrin, and sucralose were then added, and the mixture was stirred. Acetone, glyceryl monostearate and menthol were then added to the solution, and the mixture was stirred. Apomorphine hydrochloride was then added, with stirring, forming an opaque dispersion. The resulting mixture was placed under vacuum to eliminate air bubbles. The viscous liquid was then melted as a uniform layer on an inert support and dried in an oven. The resulting dry layer was an opaque white color.
Table L1 liquid in volume on dry film on dry film ______Component______ mg / 100 mg mg / 100 mg in mg
Water 36.9736 acetone 14.2616 sodium metabisulphite 0.4555 0.9332 0.4179 Disodium EDTA, dihydrate 0.4714 0.9667 0.4329 Apomorphine HCI 16.3345 33.4966 15.0000 menthol 2.4973 5.1211 2.2933 glyceryl monostearate 0.4770 0.9781 0.4380 glycerin 4.4518 9,1292 4.0881
72/89 net in
Componentmaltodextrin M180 volume in mg / 100 mg 18.6597 dry film in mg / 100 mg 38.2647 dry filmin mg17,1352 sucralose 0.8512 1.7454 0.7816 Natrosol 250 L 4.1082 8.4245 3.7725 Methocel E5 0.4558 0.9405 0.4212 Total mass, mg 100.0000 100.0000 44.7807 Theoretical solids content 48.7%
Table L2
liquid by volume on dry film on dry filmComponent mg / 100 mg mg / 100 mg in mg Water 60.6845 acetone 6.2113 magnesium hydroxide 2.5949 7.8386 1.6000 sodium metabisulphite 0.1395 0.4215 0.0860 Disodium EDTA, dihydrate 0.1164 0.3516 0.0718 glycerin 2.6141 7.8966 1.6118 maltodextrin M180 13.8965 41.9782 8.5685 Natrosol 250 L PHARM 13.7427 41.5136 8.4737 Total mass, mg 100.0000 100.0000 20.4119 Theoretical solids content,% 33,1042
The L2 neutralizing layer was prepared by adding hydroxyethyl cellulose to the water slowly with stirring until a viscous, clear and uniform liquid was produced. Sodium metabisulfite, disodium EDTA dihydrate, glycerin, maltodextrin, and magnesium hydroxide were all added, and the mixture was stirred. Acetone was added to this solution, and the mixture was stirred, until a viscous, opaque and uniform dispersion was produced. The resulting mixture was placed under vacuum to eliminate air bubbles. The viscous liquid was then melted as a uniform layer on an inert support and dried in an oven. The dry layer
73/89 result was a translucent white appearance.
The separate apomorphine hydrochloride layer and the pH adjustment layer were laminated together by applying an ethanol spray between them. This bilayered construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from the inert supports, cut into unit dose films of a predetermined size (22 mm χ 22 mm), and subsequently packed in individual aluminum packages. The resulting dry bilayer film was an opaque white color.
EXAMPLE 2 - Pharmacokinetics
The food was removed from the animals for a minimum of 12 hours before the start of the study and four hours post-dose. Before dosing, the animals were weighed and assigned to experimental groups, stratified according to body weight. Animals showing poor or irregular appetite before the study were excluded. For sublingual administration of the test article, the animals were placed inside an induction chamber and anesthetized with isoflurane using a face mask. The test article was placed under the tongue and the animals' mouths were closed, while also being kept under anesthesia. Five minutes after administration, the animal was released. Blood samples were collected pre-dosing, and in 10 minutes, in 20 minutes, in 30 minutes, in 1 hour, in 2 hours, and in 4 hours after the administration of the test article through a percutaneous catheter in the auricular artery. Blood samples were stabilized and kept cold until analysis. Bioassays were performed using C18RPHPLC-MS. The pharmacokinetic parameters for various formulations were calculated using a non-compartmental (trapezoid) model and are provided in Table 1 and Table 2 below.
Table 1. Pharmacokinetics of films A, B, C, D, and E.
Pharmacokinetic values inj sc ^a THE B Ç D AND Administered dose (mg / kg) 0.5 0.28 0.28 0.28 0.28 0.28 N = 6 5 5 5 5 5 Cmax (ng / mL) 331 116 117 39 104 166
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Pharmacokinetic values inj sc ^a THE B Ç D AND Tmax (minutes) 25 20 32 10 35 32 AUCinf (ng / mL »minute) 17828 10142 8150 1107 8707 11967 Bioavailability (%) ^b 100 96 77 10 87 109
^a Value of literature.
^b Relative to 100% bioavailability for administration by subcutaneous injection.
Table 2. Pharmacokinetics of films F, G, H, J, and K.
Pharmacokinetic values inj sc ^a F G H J ..... k .......- Administered dose (mg / kg) 0.5 0.28 0.28 0.28 0.28 0.28 N = ^b 6 4 5 5 8 8 Cmax (ng / mL) 331 94 132 91 107 100 Tmax (minutes) 25 25 40 28 13 14 AUCinf (ng / ml_ * minute) 17828 6210 9511 6285 5019 5680 Bioavailability (%) ^c 100 61 82 66 57 65
^a Value of literature.
^b Number of rabbits tested (for Film F, 5 rabbits were dosed, but one data point was rejected as a discrepancy (> 2 standard deviations from the mean).
^c Relative to 100% bioavailability for administration by subcutaneous injection.
Film A (the only film that includes propylene glycol) incorporates apomorphine hydrochloride dissolved in the monolayer in high concentration, and presents rapid dissolution and rapid initial uptake. Preliminary stability suggests less stability than that observed for Film B (a monolayer glycerol formulation that includes crystalline apomorphine hydrochloride).
Film C combines the apomorphine layer of Film B with a pH neutralization layer containing carboxymethyl cellulose and inorganic phosphate as a base. Five minutes after dosing in the rabbit with Film C, a large portion of the film was recovered. Analysis showed that it was the undissolved apomorphine layer. It was determined that ca
75/89 apomorphine layer does not dissolve well in phosphate buffer, which explains the low AUC and C _ma x observed for this formulation. The rapid T _max observed for Film C appears to be an artifact of the low dissolution of the apomorphine layer.
Films D and E are designed to dissolve more quickly including a large portion of hydrolyzed starch as a disintegrant. In the case of Film E, the phosphate was replaced with an organic base (meglumine) to minimize interference with the dissolution of the apomorphine layer. Film D showed slower uptake and greater variability10 from (rabbit to rabbit) than Films A or B. Film E was superior to Film D, but showed slower uptake than Movies A and B.
In Films F, G, and H, the amount of apomorphine hydrochloride in the apomorphine layer was increased to 55% (by weight / weight). Films F, G, and H use an organic base (ie, meglumine for Film 15 F; citrate for Film G, and a mixture of meglumine and citrate for Film H).
Film F showed a lower AUC and C _max , slightly smaller T _max , and less variability.
In contrast, Film G showed high values of AUC and 20 C _max , but a longer T _max and greater variability than Film F.
Film H performed similarly to Film F.
To assess the impact of water on pharmacokinetic parameters, 200 pl of water was added to the rabbit's mouth after dosing with Film H. It was observed that AUC and C _ma x increased, but T _max also increased. Water did not help to accelerate absorption at initial time points.
Mineral (inorganic) pH neutralizers appear to lead to lower C _ma x, higher T _max and greater variability. Citrate appears to be better tolerated than phosphate. Meglumin seems to provide better results.
Films E, F, H, J, and K have pharmacokinetic parameters closer to a subcutaneous injection (best peak shape) after dose adjustment (that is, using higher amounts of
76/89 apomorphine), with Films J and K showing the fastest T _max values and pharmacokinetic values closest to those observed for subcutaneous injection of apomorphine hydrochloride.
All bilayers have around the same initial absorption rate (ie 40 ng / ml in the blood in 10 minutes after dosing).
It has been observed that monolayers have a faster initial onset of absorption. This is surprising given the fact that the drug is protonated (see Example 6). As the neutral apomorphine has a much higher permeability rate than the protonated form, it can be concluded that the absorption of the monolayer is accompanied by the release of the hydrochloride salt by the apomorphine and into the tissue. As HCI is a potential irritant when left un-buffered (saliva is un-buffered), increasing the pH can prevent any tissue irritation and therefore the use of a pH neutralizer (ie up to a pH of 2.5 to 5 may be desired) , 5).
All measurements were made with the sublingual film placed against the bottom of the mouth (not on the lower part of the tongue) and with a layer of apomorphine in direct contact with the tissues.
EXAMPLE 3 - Crushed apomorphine dispersed in bilayer film.
Using methods analogous to those described in Example 1, a powder crushed with apomorphine hydrochloride jet (D95 <20 pm) is added, along with the other components of the apomorphine layer, to a mixture of ethanol and ethyl acetate to create a dispersion homogeneous. The mixture is spread over a thin plastic coating and dried to produce a film. This film can be administered as is or combined with a neutralizing layer as for Example 1. It is also contemplated the addition of jet-grounded pH neutralizing agent to the neutralizing layer either for inclusion with apomorphine (ie, to produce a single layer in which both active apomorphine hydrochloride and a neutralizing agent are dispersed as solid agents within a single layer) or to a neutralizing layer (i.e., to form a bilayer film).
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EXAMPLE 4 - Dosage Forms including permeation enhancers
Using methods analogous to those described in Example 1, from 0.2 to 2% (by weight / weight) of permeation enhancer is included in the apomorphine layer of either film A to H, or, optionally, in both layers of the bilayer film. The permeation enhancer can be glycerol monostearate, or any permeation enhancer described here, in this patent application.
EXAMPLE 5 - Permability Studies
Freshly collected oral tissues were obtained from pigs and the mucous membranes were carefully isolated. The mucous membranes prepared with an approximate measurement of 4 cm ² were mounted between donor and recipient chambers of Franz diffusion cells with an available diffusion area of 1.77 cm ² . The test treatments and controls were performed in quadruplicate. The recipient compartment, which contained an action bar, was filled with 8 ml of KRB buffer, pH 7.4 containing 1% BSA. Franz cells were placed in an acceptance / agitation block. The temperature was adjusted to 37 ° C in order to maintain the fabric surface temperature at 32 ° C; the agitation rate was adjusted to 400 rpm. Two milliliters of compound formulated at different pHs were added to the donor chambers, completely covering the exposed mucosa. All dosing solutions contained 0.1% sodium dithionite, 0.2% DMSO and 5% propylene glycol or glycerin. The donor compartment was covered with Parafilm to minimize evaporation. An aliquot (~ 0.5 mL) was removed from the receiving compartment at 2, 60, 90, and 120 min and replaced with an equal volume of buffer heated to 37 ° C. The sampling time points of the donor compartment were 0, 60, 90 and 120 min. The samples were diluted with 0.5 mL (1: 1) of 10% aqueous ascorbic acid. The concentration of each analyzed was quantified by LC MS / MS (Annex I). The entire study was carried out in the dark with yellow light, and glass vials and syringes were used for sampling. The apparent permeability coefficient (Papp), the total amount of flow and the percentage
The recovery rate for control and test compounds was calculated as follows:
Papp = (dCr / crt) · Vr / (A · CO)
Normalized Papp = (dCr / dt) · Vr / (A · Starting Cd + Final Cd) / 2)
Flow = (w / Cr / cê) · Vr / (A)
Recovery Percentage = 100 · ((Vr · Cr final) + (Vd · Final CD)) / (Vd • CO)
In the above equations, dC _r / cê is the slope of the cumulative concentration of the receiver compartment versus time, pM-min-1; A is the area of the diffusional surface of the exposed skin membrane, 1.77 cm ² ; V _r is the volume of the receiving compartment, 8.0 mL; V _d is the volume of the donor compartment, 2.0 mL; C _r is the cumulative concentration of the receiving compartment in μΜ; Co is the donor concentration at 0 minutes of incubation, μΜ; C _r fmai θ the concentration of the receptor at the end of the incubation period, μΜ; Initial C _d is the donor concentration at the beginning of the incubation period (interval), pM. C _d fmai θ the donor concentration at the end of the incubation period (interval), pM. The results are tabulated below ._____________________
Tested treatment Papp pH 6.4 0.071 pH 6.8 0.054 pH 7.4 0.185 pH 8.0 0.556 pH 8.0 + 1% glycerin monostearate 2.34 pH 8.0 + 1% magnesium stearate 0.3 pH 8.0 + 1% tocopherol acetate 0.98
Glycerin monostearate and tocopherol acetate increase the apparent rate of permeability through excised oral tissue, while magnesium stearate delays permeation.
EXAMPLE 6 - Ropinerol bilayer film.
A bilayer film is formed from a ropinerol containing the components and quantities listed in Table R1 and a neutralizing layer containing the components and quantities listed in Table R2.
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The API R1 layer is prepared by slowly adding hydroxyethyl cellulose and hypromellose to the water with stirring until a viscous, clear and uniform liquid is produced. Disodium EDTA, glycerin, maltodextrin, and sucralose are then all added, and the mixture is stirred.
Acetone and menthol are added to this solution, and the mixture is stirred. Ropinerol hydrochloride is then added with stirring, forming an opaque dispersion. The resulting mixture is placed under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven.
10 Table R1. liquid by volume dry film dry film Component mg / 100 mg mg / 100 mg mg
Water 38.6792 Acetone 14,1509 Disodium EDTA 0.4643 0.9843 0.4249 Ropinerol HCI 16.3912 34.7494 15.0000 menthol 2.550 5.3105 2.2924 glycerin 4.3386 9.1978 3.9703 Maltrin M180 19.2072 40.7194 17.5770 sucralose 0.8698 1.8439 0.7959 Natrosol 250 G 1.2332 2.6145 1.1286 Natrosol 250 L 1.2332 2.6145 1.1286 Methocel E5 0.4558 0.9718 0.4195 Total mass, mg 100.0000 100.0000 43.1662 Theoretical solids content,% 47.1698
The neutralizing layer R2 is prepared by slowly adding hydroxyethyl cellulose to the water with stirring until a viscous, clear and uniform liquid is produced. Pyridoxine, disodium EDTA, glycerin, and maltodextrin are then all added, and the mixture is stirred. Aceto15 na is added to this solution, and the mixture was stirred, until a viscous, clear and uniform liquid was produced. The resulting mixture is placed
80/89 under vacuum to eliminate air bubbles, melted as a uniform layer on an inert support, and dried in an oven.
Table R2.
liquid volume dry film dry film
Component mg / 100 mg mg / 100 mg mg
Water 85.8172 acetone 1.7129 pyridoxine 5.1388 41.2092 10.3023 sodium metabisulphite 0.0370 0.2965 0.0741 Disodium EDTA 0.0314 0.2520 0.0630 glycerin 1.0963 8.7913 2.1978 Maltrin M180 0.6852 5.4946 1.3736 Natrosol 250 G 2.7407 21.9782 5.4946 Natrosol 250 L 2.7407 21.9782 5.4946 Total mass, mg 100.0000 100.0000 25.0000 Theoretical solids content,% 12.4699
The dopamine agonist layer (ropinerol) and the neutralizing layer were laminated together by applying an ethanol spray between them. This bilayered construction, sandwiched between two inert supports, was dried in an oven. The dry bilayer was removed from the inert supports, cut into unit dose films of a predetermined size and packed in individual aluminum packages. The resulting dry bi-layer film was an opaque white color.
EXAMPLE 7 - Irritation Test (General Method).
On Day 1, Adult Golden Syrian hamsters (approximately 8 weeks old and 100 grams), divided into 36 controls (18 / sex) and 30 treated with test articles (15 / sex), are anesthetized. Approximately 1 cm ² of the left buccal pouch is scraped by hand scraping with a scalpel to remove the supernatural layer of tissue without bleeding. On Day 2, test articles are applied to the cheek pouches on both sides, scraped and not, at 9 am, 1 pm and 5 pm (three times a day). Dosing is continued for a total of
81/89 days (that is, until Day 29). Control animals are treated similarly but with a control film applied to the cheek bags of both cheeks. The control film is formulated as described above in the examples, but (i) without any dopamine agonist, (ii) without a pH neutralizing agent, and (iii) with sufficient acid (for example, succinic acid, acetic acid, or an inorganic acid) to produce a pH of less than 3 after administration to, and dissolution into, an animal's cheek pouch. Systemic signs, body weight and food consumption are recorded daily. The cheeks are everted, cleaned of food by washing with distilled water and gauze, and examined for signs of irritation before the first dose on Days 1, 2, 3, 4, 8, 14, & 21 and before the necropsy on Day 29. Necropsies are recorded on Day 2: 3 controls / sex; Day 5: 5 controls and 5 treated animals / sex; Day 29: 5 controls and 5 treated animals / sex; Day 43: 5 controls and 5 animals treated / sex with examination of macroscopic signs and histopathology of the yoke bags. Each animal can be monitored for both for the extent of irritation after administration. For shaved animals, animals can be monitored for the amount of time required to observe cheek healing while receiving treatment.
The compositions of the invention can be non-irritating (for example, performing equal to, or better than, a placebo formulation free of an active acid addition salt) as determined using the test described above.
EXAMPLE 8 - Stability of packaged films including apomorphine hydrochloride.
Films (see Example 1) were individually wrapped in aluminum sheets coated with plastic and heat sealed to eliminate any contact with air or light. The films were tested for stability by placing the packed films in an oven at 40 ° C. After 2 months the color of the films was observed for any change in color that would indicate oxidation of apomorphine to a quinone type product, which are blue to green (see Rehse Achives des Pharmazie 1969, 7, 488).
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The results are provided in Table 3.
Table 3.
Movie 1 month at 40 ° C 2 months at 40 ° C THE Colorless to light beige Blue B Colorless to light beige Colorless to light beige Ç Colorless to light beige Colorless to light beige D Not testedAND colorless Light blue F Not testedG colorless Light blue H Not testedJ colorless Light blue K colorless colorless
EXAMPLE 9 - Studies of tissue histology.
Animals (8 per group) were dosed 3 times with either Bilayer Film J or Bilayer Film K (7 mm disc, 1.1 mg of apomorphine hydrochloride prepared according to Example 1) with an interval of 2 hours between dosing . With each dose administered, 500 pl of water was added to the sublingual region immediately after administering the dose to simulate salivation. Approximately 4 hours after the last dose, the animals were sacrificed, the tongue and the adjacent sublingual tissue were harvested and immediately fixed by placing in 10% formalin. The tissues were processed and embedded in paraffin, sectioned and stained with hematoxylin and eosin (H&E). Three sections of the tongue and sublingual tissues were thinned and processed. Slides were produced from each animal's slide tissue to include sections on the right, midline and left to ensure that the dose application site was examined microscopically. The resulting slides were examined.
There were no macroscopic observations (that is, there was no evidence of irritation) due to the test article. In all slides, there were no microscopic findings in any group regarding the application of
83/89 bilayer test strips. There is no evidence of local irritation related to multidose application of the tape according to the procedure.
EXAMPLE 10 - Bilayer films prepared for clinical tests.
Placebo (M-film) and API (N-film) bilayer films were prepared as described below for use in clinical trials.
Placebo Film (M1)
The placebo film is a bilayer film formed without apomorphine and contains the components and quantities listed in Table M1 and a neutralizing layer containing the components and quantities listed in Table M2.
The apomorphine M1 layer was prepared by combining acetone, glyceryl monostearate, and menthol with stirring until a clear and uniform solution was produced. Water was added, and the mixture was stirred. Then hypromellose was added to this solution slowly with stirring until a clear and uniform liquid was produced. Sodium metabisulfite and disodium EDTA dihydrate were then added, with stirring until a uniform liquid was produced. Hydroxyethyl cellulose was added to this solution slowly with stirring until a viscous, clear and uniform liquid was produced. Glycerin, maltodextrin, and sucralose were then added with stirring until a clear, uniform, viscous liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles. The viscous liquid was then melted as a uniform layer on an inert support and dried in an oven. The resulting dry layer was clear / cloudy.
Table M1 liquid by volume on dry film on dry film Component mg / 100 mg mg / 100 mg in mg
Water 60.9548Ι · | ·· ί | · Η8θ ^ ΒΒ; acetone 11.0307 sodium metabisulphite 0.5522 1.9710 0.4820
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ComponentDisodium EDTA, dihydrate liquid by volume in mg / 100 mg0.5555 dry film in mg / 100 mg1.9830 dry film in mg0.4849 menthol 2.3072 8.2357 2.0140 glycerin 1.8994 6,7800 1.6580 glyceryl monostearate 0.3333 1.1933 0.2918 maltodextrin M180 9.9469 35,5063 8.6829 sucralose 1.4189 5.0647 1.2385 Natrosol 250 L 10,5069 37.5053 9.1717 Methocel E5 0.4932 1.7606 0.4305 Total mass, mg 100.0000 100.0000 24.4544 Theoretical solids content,% 28.0145
Table M2
liquid around dry film fire in mg / in mg / dry film Component 100 mg 100 mg in mg
Water 59.1217 acetone 10.7182 Pyridoxine HCI 2.4449 8.1065 1.6800 sodium hydroxide 0.4886 1.6201 0.3258 sodium metabisulphite 0.5571 1.8471 0.3714 Disodium EDTA, dihydrate 0.5589 1.8531 0.3726 menthol 2.3341 7.7390 1.5561 glycerin 1.6712 5.5412 1,1142 glyceryl monostearate 0.3180 1.0544 0.2120 maltodextrin M180 10.0977 33.4803 6.7320 sucralose 1.3778 4.5684 0.9186 Natrosol 250 L 10.3118 34.1900 6.8747 Total mass, mg 100.0000 100.0000 20,1074 Theoretical solids content,% 30,1601
The M2 neutralizing layer was prepared by combining acetone, glyceryl monostearate, and menthol to form a mixture. The mixture was
85/89 stirred until a clear and uniform solution was produced. Water was added, and the mixture was stirred. Sodium hydroxide, pyridoxine HCI, sodium metabisulfite, and disodium EDTA dihydrate were then added with stirring until a clear, uniform liquid was produced. Hydroxyethyl cellulose was added to this solution slowly with stirring until a viscous, clear and uniform liquid was produced. Glycerin, maltodextrin, and sucralose were then added with stirring until a clear, uniform, viscous liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles. The resulting viscous liquid was melted as a uniform layer on a separate dry placebo layer (film M1) against an inert support, and dried in an oven. The resulting dry bilayer was removed from the inert support, cut into unit dose films of a predetermined size (22 mm x 22 mm), and subsequently packed into individual aluminum packs. The resulting dry bilayer film was clear / cloudy.
Film N (API bilayer film for test studies)
Film N is a bilayer film formed from an apomorphine layer containing the components and quantities listed in Table N1 and a neutralizing layer containing the components and quantities listed in Table N2.
The apomorphine layer N1 was prepared by combining acetone, glyceryl monostearate, and menthol with stirring until a clear and uniform solution was produced. Apomorphine hydrochloride (crushed to an effective particle size of about 8 pm using a Micron-Master 2 cyclone discharge mill with stainless steel coating as described in Example 1) was added with stirring, forming an opaque dispersion . Water was added, and the mixture was stirred. Hypromellose was added to this solution slowly with stirring until a clear and uniform liquid was produced. Sodium metabisulfite and disodium EDTA dihydrate were then added with stirring until a uniform liquid was produced. Hydroxyethyl cellulose was added to this solution slowly with stirring until a viscous, clear and uniform liquid was produced. Glycerin, maltodextrin, and sucralose were then added with stirring until a clear, uniform, viscous liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles. The viscous liquid was then melted as a uniform layer on an inert support and dried in an oven. The resulting dry layer was clear / cloudy.
Table N1 liquid by volume on dry film on dry film
Component mg / 100 mg mg / 100 mg in mg
Water 58.6167 acetone 10.6170 sodium metabisulphite 0.5322 1.7297 0.4230 Disodium EDTA, dihydrate 0.5325 1.7309 0.4233 Apomorphine HCI 3.7743 12.2677 3.0000 menthol 2,2274 7.2397 1.7704 glycerin 1.8489 6,0096 1.4696 glyceryl monostearate 0.3171 1.0306 0.2520 maltodextrin M180 9.5753 31.1228 7.6109 sucralose 1.3674 4.4444 1.0869 Natrosol 250 L 10,1139 32.8735 8.0390 Methocel E5 0.4777 1.5511 0.3793 Total mass, mg 100.0000 100.0000 24.4544 Theoretical solids content,% 30.7662
Table N2 liquid in dry film volume in mg / 100 dry film in
Component mg / 100 mg mg mg
Water 59.1217 acetone 10.7182 Pyridoxine HCI 2.4449 8.1065 1.6800 sodium hydroxide 0.4886 1.6201 0.3258 sodium metabisulphite 0.5571 1.8471 0.3714
87/89
ComponentDisodium EDTA, dihydrate liquid by volume in mg / 100 mg0.5589 dry film in mg / 100 mg1.8531 dry film in mg0.3726 menthol 2.3341 7.7390 1.5561 glycerin 1.6712 5.5412 1,1142 glyceryl monostearate 0.3180 1.0544 0.2120 maltodextrin M180 10.0977 33.4803 6.7320 sucralose 1.3778 4.5684 0.9186 Natrosol 250 L 10.3118 34.1900 6.8747 Total mass, mg 100.0000 100.0000 20,1074 Theoretical solids content,% 30,1601
The neutralizing layer 02 was prepared by combining acetone, glyceryl monostearate, and menthol to form a mixture. The mixture was stirred until a clear and uniform solution was produced. Water was added, and the mixture was stirred. Sodium hydroxide, pyridoxine HCI, sodium metabisulfite, and disodium EDTA dihydrate were then added with stirring until a clear, uniform liquid was produced. Hydroxyethyl cellulose was added to this solution slowly with stirring until a viscous, clear and uniform liquid was produced. Glycerin, maltodextrin, and sucralose were then added with stirring until a clear, uniform, viscous liquid was produced. The resulting mixture was placed under vacuum to eliminate air bubbles. The resulting viscous liquid was melted as a uniform layer on a dry layer containing separate Apomorphine HCl (film 01) against an inert support, and dried in an oven. The resulting dry bilayer was removed from the inert support, cut into unit dose films of a predetermined size (22 mm x 22 mm), and subsequently packed into individual aluminum packs. The resulting dry bilayer film was clear / cloudy.
When a 3 mg, 22 mm χ 22 mm unit is placed in 10 mL of pure milliQ water with a stir bar, a pH of between 4.5 and 6.5 is measured.
88/89
EXAMPLE 11 - Study of Phase I.
A single-center phase I study in 15 healthy subjects was designed to assess the pharmacokinetics, safety and tolerability of a single dose of a single dose of N film administered in a crossover schedule. 15 healthy male volunteers are previously treated with an anti-emetic (10 mg domperidone) for three days. On the first day, 12 subjects receive a dose equivalent to 3 mg of apomorphine hydrochloride formulated as film N with the drug layer facing downwards towards the floor of the mouth. 3 subjects receive the placebo film M. Blood samples (5 ml) are taken from all subjects before dosing, and at 10, 20, 30, 45, 60, 90, 120, 180, 240 minutes post-dose. The blood is immediately centrifuged to recover the plasma, which is then stored on dry ice. After a 24-hour wear period, the same individuals are dosed a second time with the same test product and placed on the floor of the mouth but with the drug layer oriented upwards towards the bottom of the tongue.
Assessments include parmacokinetic determination and local tolerance.
Other Modalities
All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application were specifically and individually indicated to be incorporated by reference.
Although the invention has been described in connection with specific modalities thereof, it will be understood that it is capable of additional modifications and that this requirement is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including the reported deviations from the present discovery that are within known or usual practice within the art to which the invention relates and that can be applied to essential characteristics
89/89 stipulated above, and which follow within the scope of the claims.
This application claims benefit of and priority for United States Provisional Patent Application No. 61 / 423,858, filed on December 16, 2010, and for United States Provisional Patent Application
United States No. 61 / 483,864, filed May 9, 2011, each of which is incorporated by reference here, in this patent application, in its entirety.
Other modalities are within the claims.

权利要求:
Claims (32)
[1]
1. Pharmaceutical composition in unit dosage form formulated for sublingual administration, characterized by the fact that the said unit dosage form is a film comprising 30 ± 5% (by weight / weight) of one or more disintegrants and a plasticizing agent, the said film having a first portion comprising apomorphine hydrochloride ("apomorphine hydrochloride") and a second portion comprising pH neutralizing agent, wherein said unit dosage form comprises from 0.5 to 5 mg, from 4 to 10 mg, or 8 to 20 mg of apomorphine hydrochloride and said pH neutralizing agent is present in an amount sufficient to produce a solution having a pH of between 3.0 and 6.5 when said unit dosage form is placed in non-buffered water at pH 7.
[2]
2. Pharmaceutical composition according to claim 1, characterized in that said unit dosage form further comprises a high molecular weight polymer having an average molecular weight of more than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose.
[3]
Pharmaceutical composition according to claim 1 or 2, characterized in that the said unit dosage form further comprises a low molecular weight polymer having an average molecular weight of 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose.
[4]
4. Pharmaceutical composition in unit dosage form formulated for sublingual administration, characterized by the fact that the said unit dosage form is a film comprising:
(i) apomorphine hydrochloride;
(ii) a low molecular weight polymer having an average molecular weight from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl
2/7 cellulose, and methyl cellulose; and (iii) a high molecular weight polymer having an average molecular weight of more than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and said methyl cellulose, wherein said unit dosage form comprises 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride.
[5]
5. Pharmaceutical composition in unit dosage form formulated for sublingual administration, characterized by the fact that said dosage unit form is a bilayer film having a first layer and a second layer, said second layer comprising a pH neutralizing agent and said first layer comprising:
(i) apomorphine hydrochloride;
(ii) a low molecular weight polymer having an average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) a high molecular weight polymer having an average molecular weight of more than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose, wherein said unit dosage form comprises the from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and the pH neutralizing agent referred to is present in an amount sufficient to produce a solution having a pH between 3.0 and 6.5 when said unit dosage form is placed in non-buffered water at pH 7.
[6]
Pharmaceutical composition according to any one of claims 1 to 3 or 5, characterized in that the said pH neutralizing agent is meglumine, pyridoxine, or magnesium hydroxide.
3/7
[7]
Pharmaceutical composition according to any one of claims 1 to 3, 5, and 6, characterized in that said pH neutralizing agent is an organic base having a pKa of 5 ± 2.
[8]
Pharmaceutical composition according to claim 7, characterized in that said pH neutralizing agent is pyridoxine.
[9]
9. Pharmaceutical composition in unit dosage form formulated for sublingual administration, characterized by the fact that the said unit dosage form is a film comprising:
(A) a first layer comprising:
(i) 10 to 75% (w / w) of apomorphine hydrochloride;
(ii) from 0.5 to 10% (w / w) of a low molecular weight polymer having an average molecular weight by weight of about 5 KDa to 50 KDa, selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) from 4 to 35% (w / w) of a high molecular weight polymer having an average molecular weight in excess of 60 KDa, selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose , and methyl cellulose, and (B) a second layer comprising:
(iv) from 6 to 65% (w / w) of a pH neutralizing agent, which is an organic base that has a pKa of 5 ± 2, and (v) from 15 to 50% (w / w) of a high molecular weight polymer having an average molecular weight in excess of 60 KDa, selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose, wherein said first layer comprises from 2 to 60 mg of apomorphine hydrochloride, in which, after sublingual administration to individuals, the said dosage unit form produces an average circulation concentration of 3 to 6 ng / ml within a period of 7 to 20 minutes, and in which the said unit dosage form, when placed
4/7 in 1 ml of non-buffered water at pH 7 results in a solution with a pH of 4.5 to 6.5.
[10]
Pharmaceutical composition according to claim 9, characterized in that said low molecular weight polymer is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl or cellulose.
[11]
Pharmaceutical composition according to claim 10, characterized in that said hydroxypropylmethylcellulose has about 20% to about 35% substitution of methoxy and about 5% to about 15% substitution of hydroxypropyl.
[12]
Pharmaceutical composition according to claim 9, characterized in that said high molecular weight polymer is hydroxypropylmethylcellulose or hydroxyethylcellulose.
[13]
Pharmaceutical composition according to claim 12, characterized in that said high molecular weight polymer is hydroxypropylmethylcellulose with about 20% to about 35% methoxy substitution and about 5% to about 15% of hydroxypropyl substitution.
[14]
Pharmaceutical composition according to claim 12, characterized in that said high molecular weight polymer is hydroxyethylcellulose with an average molecular weight by weight from 60 KDa to 1,000 KDa.
[15]
15. Pharmaceutical composition in unit dosage form formulated for sublingual administration, characterized by the fact that said unit dosage form is a film comprising a first layer and a second layer, in which the first layer comprises from 2 to 60 mg of apomorphine hydrochloride and wherein the second layer comprises 25 ± 5% to 65 ± 5% (w / w) of pyridoxine.
[16]
Pharmaceutical composition according to claim 15, characterized in that said film comprises carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose.
[17]
Pharmaceutical composition according to claim 15
5/7 or 16, characterized by the fact that the second layer comprises 65 ± 5% (w / w) of a pH neutralizing agent, which is pyridoxine.
[18]
Pharmaceutical composition according to any one of claims 15 to 17, characterized by the fact that pyridoxine is present in an amount such that a dosage unit form placed in 1 ml of water not buffered at pH 7 results in a value of pH between 2.5 and 8.0.
[19]
Pharmaceutical composition according to any one of claims 9 to 18, characterized in that said unit dosage form comprises from 12 ± 3 mg of apomorphine hydrochloride; or said unit dosage form comprises from 22 ± 4 mg of apomorphine hydrochloride; or said unit dosage form comprises 30 ± 5 mg of apomorphine hydrochloride; or said unit dosage form comprises 35 ± 5 mg of apomorphine hydrochloride.
[20]
Pharmaceutical composition according to any one of claims 4 to 19, characterized in that said film further comprises from 3 to 12% (w / w) of plasticizer.
[21]
Pharmaceutical composition according to any one of claims 1 to 3 and 20, characterized in that said plasticizer is a polyol, oleic acid, or triacetin.
[22]
22. Pharmaceutical composition according to claim 21, characterized in that said plasticizer is a polyol selected from sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, and polyethylene glycol.
[23]
Pharmaceutical composition according to any one of claims 1 to 22, characterized in that the said pharmaceutical composition further comprises from 1 to 50% (by weight / weight) of hydrolyzed starch.
[24]
24. The pharmaceutical composition according to claim 23,
6/7 characterized by the fact that said hydrolyzed starch is a dextrin or a maltodextrin.
[25]
25. Pharmaceutical composition according to any one of claims 1 to 24, characterized in that said pharmaceutical composition further comprises an antioxidant.
[26]
26. Pharmaceutical composition according to claim 25, characterized in that said drug additionally comprises from 0.05 to 2.5% (w / w) of metabisulfite.
[27]
27. Pharmaceutical composition according to any one of claims 1 to 26, characterized in that it additionally comprises 1 ± 0.5% (w / w) of permeation enhancer.
[28]
28. Pharmaceutical composition according to claim 27, characterized in that said permeation enhancer is glycerol monostearate.
[29]
29. Pharmaceutical composition according to any one of claims 1 to 28, characterized in that said pharmaceutical composition has a sublingual bioavailability of more than 40%; or it has a T _max of from 10 to 25 minutes; or after sublingual administration to an individual, said unit dosage form produces an average circulating apomorphine concentration of at least 3 ng / ml within a period of 5 to 15 minutes; or said unit dosage form when administered sublingually to an individual is non-irritating.
[30]
Pharmaceutical composition according to any one of claims 1 to 29, characterized in that said unit dosage form is an individual film packaged in an aluminum foil coated with sealed plastic, wherein said unit dosage form is stable for a period of at least 2 months at 40 ^Q C.
[31]
31. Use of a pharmaceutical composition as defined in any of claims 1 to 30, characterized by the fact that it is in a method for treating Parkinson's disease in an individual, said method
7/7 all comprising sublingual administration of said pharmaceutical composition in an amount effective to treat said individual.
[32]
32. Invention, in any form of its embodiments or in any applicable category of claim, for example, product, processes
5 so or use encompassed by the material initially described, revealed or illustrated in the present patent application.

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法律状态:
2019-11-05| B25A| Requested transfer of rights approved|Owner name: CYNAPSUS THERAPEUTICS, INC. (CA) |

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2019-11-12| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-11-26| B25A| Requested transfer of rights approved|Owner name: PROJECT PEGASUS SUB ACQUISITION ULC (CA) |

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2019-12-17| B25A| Requested transfer of rights approved|Owner name: SUNOVION CNS DEVELOPMENT CANADA ULC (CA) |

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2020-01-07| B25A| Requested transfer of rights approved|Owner name: SUNOVION PHARMACEUTICALS INC. (US) |

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2020-06-30| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-11-17| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-12-15| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-07-27| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2021-10-05| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-12-28| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US42385810P| true| 2010-12-16|2010-12-16|

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US201161483864P| true| 2011-05-09|2011-05-09|

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PCT/US2011/065665|WO2012083269A1|2010-12-16|2011-12-16|Sublingual films|

---