Pharmaceutical composition and its preparation process

专利摘要:
PHARMACEUTICAL COMPOSITION. The present invention relates to an oral pharmaceutical composition comprising coated particles of a complex of at least one active agent with an ion exchange resin, wherein said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material. The invention also relates to a process for preparing the oral pharmaceutical composition.
公开号:BR112013025519B1
申请号:R112013025519-6
申请日:2012-04-05
公开日:2022-02-01
发明作者:Ljiljana Sovic Brkicic；Cvjetko Brkicic；Zdravko Dokuzovic
申请人:Ljiljana Sovic Brkicic；Cvjetko Brkicic；
IPC主号:

专利说明:

[001] The present invention relates to oral pharmaceutical compositions that provide a controlled and site-specific drug delivery. Background of the Invention
[002] The controlled release of active agents is an important aspect in the oral administration of any drug. It is particularly important for the oral administration of active agents that have narrow therapeutic windows. An example of such active agents is levodopa, the drug of choice in the treatment of Parkinson's disease.
[003] Parkinson's disease (PD) is one of the most common neurodegenerative diseases, typically affecting older people. Several classes of drugs have been used in the treatment of Parkinson's disease with varying degrees of success.
[004] The prevalence of diagnosed PD in the population over the age of 55 is around 1.4% and increases with age. In addition, signs of Parkinson's disease in the elderly are estimated to be present in 30% of the population over the age of 65 years. Although PD is considered a multisystem disease, it is primarily a movement disorder caused by a continuous long-term degeneration of dopaminergic neurons that are located in the compact part of the midbrain substantia nigra. PD becomes symptomatic only after the degeneration of about 60-80% of these dopaminergic neurons, or after the loss of about 90% of striatal dopamine. Dopamine, which is produced within the substantia nigra, reaches the striatum via the nigrostriatal tract and is released normally at striatal synapses. Striatal dopamine deficiency, due to degeneration of dopaminergic neurons in the substantia nigra, is considered to be the cause of PD. However, dopamine itself is not absorbed from the gastrointestinal tract and cannot pass through the blood-brain barrier.
[005] Drugs comprising the natural dopamine-metabolic precursor levodopa currently provide the most effective treatment of PD. Levodopa is able to cross the blood-brain barrier in the basal ganglia, where it is decarboxylated by the enzyme aromatic L-amino acid decarboxylase (AADC) to form dopamine, thereby replacing the missing neurotransmitter. However, AADC is also present in the intestinal wall, liver, kidney, and brain capillaries, and peripheral decarboxylation resulting from levodopa and the formation of levodopa metabolites causes a number of side effects such as nausea, vomiting, dysrhythmias. heart failure and postural hypotension. Peripheral decarboxylation of levodopa can be prevented primarily by the additional administration of a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which cannot itself pass the blood-brain barrier. Levodopa combined with carbidopa or benserazide is now the treatment of choice when levodopa is indicated. Solid dosage forms that contain a combination of levodopa and carbidopa are known and used in the treatment of PD and other movement disorders. For example, a quick-release oral tablet that contains levodopa and carbidopa together with cellulose, magnesium stearate and starch is marketed under the name SINEMET®. However, even levodopa/carbidopa combination therapy is usually associated with severe side effects such as dyskinesias and psychiatric disorders.
[006] Furthermore, currently available preparations are only effective for a relatively short period and can even be harmful under certain conditions. The use of immediate-release levodopa preparations results in peak blood levels with blood levels of levodopa that are initially too high and then soon too low to be effective. Furthermore, only about 5% of the dose of levodopa administered in this way reaches the brain.
[007] Involuntary movements (dyskinesias) in the form of orofacial or limb decora or dystonia are common side effects of levodopa that often limit possible dosage. Other side effects of levodopa include orthostatic hypotension, nightmares, hallucinations, and occasionally toxic delirium. Hallucinations and delirium are more common in elderly patients with dementia. In some patients, the drug cannot reduce parkinsonism without producing some degree of dyskinesia or other side effects.
[008] These side effects tend to occur at lower doses as treatment continues, and so-called "wear and tear" and "on-off" phenomena have emerged as major problems in the long-term treatment of Parkinson's with levodopa. After 2 to 5 years of treatment, >50% of patients begin to experience fluctuations in their response to levodopa. In most of these patients the benefit of each dose becomes shorter (the "wear and tear" effect) and some patients switch unpredictably between mobility and immobility (the "on-off" effect). The "on" periods are usually associated with elevated or high plasma concentrations of levodopa and often include abnormal involuntary movements, ie, dyskinesias, and uncontrollable hyperactivity. "Off" periods were correlated with decreased or low plasma levodopa levels and bradykinetic episodes. Alternations between "on" and "off" periods can occur many times a day. Traditionally, such alternations have been managed by keeping individual doses of levodopa as low as possible and by using dosing intervals as short as possible every 1 to 2 hours.
[009] A number of techniques are generally known for formulating oral pharmaceutical compositions to control the release behavior of the pharmaceutically active agent.
[0010] The U.S. Patent No. 4,221,778 describes sustained-release pharmaceutical preparations that contain an ion exchange resin that has a pharmaceutically active drug adsorbed thereto to provide a drug/resin complex wherein at least a portion of the complex is treated with a solvating agent and provided with a diffusion barrier coating. The U.S. Patents 4,847,077, U.S. 4,859,461, U.S. 4,859,462 and U.S. 4,959,219 describe similar preparations that use different solvating agents and plasticizers.
[0011] The U.S. Patent 6,001,392 describes a controlled-release dextrope suspension for oral administration that comprises a mixture of coated and uncoated cation exchange resins onto which dextromethorphan has been loaded, in which about 30% of the drug/resin complexes are coated. with a mixture of ethyl cellulose or ethyl cellulose latex with plasticizers and water-dispersible polymers.
[0012] The U.S. Patent No. 4,361,545 describes orally administrable solid pharmaceutical compositions for the slow, zero-order release of drugs that have a water solubility of about 1/5-1/500 (weight/weight) which comprises a combination of a surface-controlling compound that has a water solubility of about 1/1-1/40 (weight/weight), an erosion controlling compound that has a water solubility of about 1/1-1/10 (weight/weight), an activator surface and a surfactant.
[0013] WO 94/06416 A1 describes a pharmaceutical tablet consisting of a first layer containing one or more drugs with immediate or controlled release formulation, a second layer containing one or more drugs, the same or different from those of the first layer , with a slow release formulation, and a low permeability barrier type layer overlying said second layer or, alternatively, placed between the first and second layers.
[0014] Efforts have also been made to obtain controlled-release oral dosage combinations of levodopa and carbidopa.
[0015] U.S. Patents 4,832,957, U.S. 4,900,755 and US4,983,400 describe a matrix or monolithic drug delivery system that contains carbidopa and levodopa as active agents in which the drugs are dispersed uniformly in a polymer vehicle at a concentration that is greater than one or the other. drug solubility in the polymer vehicle. The preferred carrier is a combination of the water soluble polymer hydroxypropyl cellulose of the copolymer and the less water soluble polyvinyl acetate and crotonic acid. Another preferred vehicle is polymethyl methacrylate.
[0016] The U.S. Patent 2003/0224045 A1 describes a pharmaceutical dosage form comprising immediate-release and controlled-release components comprising a combination of carbidopa and levodopa for the treatment of diseases associated with depleted amounts of dopamine in a patient's brain tissue.
[0017] WO 01/01984 A1 describes pharmaceutical compositions comprising levodopa, carbidopa and entacapone, and in particular an oral solid composition comprising pharmacologically effective amounts of levodopa, carbidopa and entacapone wherein a substantial amount of carbidopa is separated from entacapone and/or of levodopa.
[0018] WO 99/17745 A1 describes a monolithic controlled delivery system for oral administration comprising a disintegration layer, an erosion layer and a swelling layer, two of which are external and one of which is intermediate, each layer containing one or more drugs, such as levodopa and/or carbidopa.
[0019] A controlled-release solid oral dosage formulation comprising levodopa and carbidopa in a vehicle of hydroxypropyl cellulose polymer and copolymer of polyvinyl acetate and crotonic acid is marketed under the name SINEMET® CR.
[0020] Existing controlled-release formulations comprising levodopa/carbidopa suffer from a number of disadvantages. In particular, such preparations typically exhibit delayed start-up. For example, the peak effect of commercially available SINEMET® CR tablets has been shown to occur one hour later than that of conventional SINEMET® tablets. In addition, the bioavailability of existing controlled-release formulations is low. At the same time, the clinical response to controlled-release tablets was found to be less reliable and less predictable compared to conventional formulations. Existing controlled-release formulations of levodopa suffer from inadequate inter- and intra-patient reproducibility of blood levels. This is particularly problematic in the case of levodopa, where the dosage has to be frequently increased over time to maintain effectiveness, which further contributes to the development of long-term side effects.
[0021] In particular, it has been found that existing controlled-release formulations of levodopa do not provide a comparable favorable effect with continuous administration of levodopa such as by intravenous infusion. On the other hand, it has been found that the intravenous infusion of levodopa, in addition to being much less convenient for the patient, often causes sclerosis of the peripheral veins.
[0022] The U.S. Patent 2008/0051459 A1 describes a duodenal pump with intestinal administration of a composition comprising levodopa and optionally carbidopa continuously for a period of more than 16 hours. The obvious disadvantage of this method of administering the levodopa/carbidopa drug is a need for a patient to maintain permanent duodenal or jejunal intubation, which is cumbersome, painful, and susceptible to infections.
[0023] Therefore, an objective of the present invention is to overcome the disadvantages of the prior art and to provide an oral delivery system that allows controlled and site-specific delivery of drugs, and in particular drugs with narrow therapeutic windows such as levodopa. and other drugs used in the treatment of Parkinson's disease and other movement disorders to achieve maximum absorption, bioavailability, and optimal blood levels. Description of the Invention
[0024] In one aspect, the invention relates to an oral pharmaceutical composition comprising coated particles of a complex of at least one active agent with an ion exchange resin, wherein said particles are coated with a bioadhesive coating layer. comprising at least one bioadhesive material.
[0025] The composition according to the invention comprises at least one active agent. It should be understood that an active agent is generally present in the composition in a therapeutically effective amount. The term "therapeutically effective amount" refers to an amount or proportion of active agent that is sufficient to bring about an appreciable biological response when administered to a patient.
[0026] All pharmacologically active agents are generally suitable for use in the composition of the invention. Preferred classes of active agents include antiparkinsonians, antiepileptics, antipsychotics, antidepressants, narcotics, antihypertensives, antioxidants, antineoplastics, cytostatics, gastrointestinal drugs, and musculoskeletal drugs.
[0027] Examples of suitable active agents include ondansetron, granisetron, tropisetron, dolasetron, palonosetron, aprepitant, sulfasalazine, doxazosin, atenolol, bisoprolol, hydrochlorothiazide, carvedilol, amlodipine, felodipine, nifedipine, verapamil, diltiazem, enalapril, lisinopril, ramipril, quinapril , cilazapril, fosinopril, trandolapril, losartan, valsartan, simvastatin, lovastatin, fluvastatin, atorvastatin, rosuvastatin, gemfibrozil, fenofibrate, cholestyramine, oxybutynin, propiverine, solifenacin, trospium, darifenacin, sildenafil, phentolamine, tamsulosin, finasteride, cyclophos-clorambuphamide , melphalan, busulfan, lomustin, temozolomide, methotrexate, mercaptopurine, thioguanine, cladribine, fludarabine, cytarabine, 5-fluorouracil, gemcitabine, capecitabine, vinblastine, vincristine, vindesine, etoposide, paclitaxel, docetaxel, actinomycin D, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, mitomycin, cisplatin, carboplatin, oxaliplatin, procarbazine, rituximab, trastuzumab, cetuximab, bevacizumab, sunitinib, sorafenib, dasatinib, lapatinib, nilotinib, temsirolimus, amsacrine, asparaginase, urea hydroxyl, estramustine, topotecan, irinotecan, imatinib, bortezomib, erlotinib, anagrelide, tamoxide, megestrol, flutamide, megestrol, amide , nilutamide, bicalutamide, anastrazole, letrozole, exemestane, mycophenolate mofetil, sirolimus, everolimus, cyclosporine, tacrolimus, azathioprine, etidronic acid (eg sodium etidronate), clodronic acid (eg sodium clodronate), pamidronic acid (eg e.g. sodium pamidronate), alendronic acid (eg sodium alendronate), tiludronic acid (eg sodium tiludronate), ibandronic acid (eg sodium ibandronate), risedronic acid (eg risedronate sodium) , zoledronic acid (eg, zoledronate sodium), morphine, hydromorphone, oxycodone, pethidine, fentanyl, pentazocine, buprenorphine, tramadol, acetyl salicylic acid, met amizole, paracetamol, sumatriptan, methyl phenobarbital, phenobarbital, primidone, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, vigabatrin, progabid, tiagabine, sulthiam, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, fenturide, levetiracetam, zonisamide, pregaba-lin, stiripentol, lacosamide, beclamide, trihexyphenidyl, biperiden, levodopa, carbidopa, benserazide, entacapone, amantadine, bromocriptine, pergolide, dihydroergocriptine, ropinirole, pramipexole, cabergoline, apomorphine, pyribedil, rotigotine, selegiline, rasagiline, tolcapone, entacapone, budipine, levomepromazine, chlorpromazine, promazine, fluphenazine, perazine, haloperidol, sertindole, ziprazidone, zuclo-pentixol, clozapine, olanzapine, quetiapine, loxapine, sulpiride, amisulpride, lithium (e.g. lithium carbonate ), protipendil, risperidone, clothiapine, mosapramine, zotepine, aripiprazole, paliperidone, diazepam, alprazolam, meprobamate, flurazepam, nitrazepam, midazo lam, zolpidem, clomipramine, amitriptyline, maprotiline, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidon, escitalopram, mirtazapine, venlafaxine, methyl phenidate, modafinil, neostigmine, pyridostigmine, disulfiram, naloxone, methadone, riluzole, abacavir, acyclovir , atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, desipramine, diphenhydramine, disopyramide, doxepin, doxycycline, ephedrine, ergonovine, ethambutol, glucose, imipramine, ketorolac, ketoprofen, labetalol, levofloxacin, metoprolol, metronidazole, minocycline, misoprostol , phenazone, phenylalanine, prednisolone, primaquine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, zidovudine, codeine, dextromethorphan, hydrocodone, hydralazine, metaproterenol, phenyl propanol amine and pseudoephedrine.
[0028] The composition of the invention is particularly suitable for active agents belonging to class I of the Biopharmaceutics Classification System (BCS). BCS class I active agents are characterized by the fact that they exhibit high permeability and high solubility. Examples of BCS class I active agents include abacavir, acyclovir, amitriptyline, atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, cyclophosphamide, desipramine, diazepam, diltiazem, diphenhydramine, disopyramide, doxepin, doxycycline, enalapril, ephedrine, ergonovine , ethambutol, fluoxetine, glucose, imipramine, ketorolac, ketoprofen, labetalol, levodopa, levofloxacin, metoprolol, metronidazole, midazolam, minocycline, misoprostol, nifedipine, paracetamol, pethidine, phenazone, phenobarbital, phenylalanine, prednisolone, primaquine, promazine, propranolol, quinidine , risperidone, rosiglitazone, salicylic acid, theophylline, verapamil and zidovudine.
[0029] Active agents that have short biological half-lives on the order of up to about 8 hours are also preferred. Examples include codeine, dextromethorphan, doxepin, ephedrine, hydrocodone, hydralazine, metaproterenol, morphine, levodopa, carbidopa, benserazide, entacapone, phenylpropanolamine, pseudoephedrine and verapamil.
[0030] Levodopa, carbidopa, benserazide, entacapone and mixtures thereof are particularly preferred.
[0031] The composition of the invention may comprise a combination of two or more active agents. Preferred combinations of active agents include bisoprolol/hydrochlorothiazide, verapamil/trandolapril, amlodipine/atorvastatin, tramadol/paracetamol, beclamide/trihexyphenidyl, buprenorphine/naloxone, levodopa/carbidopa, levodopa/benserazide and levodopa/carbidopa/entacapone.
[0032] Unless otherwise indicated, all references to active agents herein are intended to include their pharmaceutically acceptable salts and solvates. Such references also lend themselves to including crystalline and amorphous forms. As used herein, the term "pharmaceutically acceptable" refers to materials that are suitable for use in humans and animals without excessive toxicity, consistent with a reasonable risk/benefit ratio.
[0033] The composition of the invention comprises particles coated with a complex of at least one active agent with an ion exchange resin.
[0034] Suitable ion exchange resins are typically water-insoluble and comprise a pharmacologically inert organic or inorganic matrix that contains covalently bonded functional groups that are ionic or can be ionized under appropriate pH conditions. Examples of organic matrices include synthetic matrices (e.g. polymers or copolymers of acrylic acid, methacrylic acid, styrene sulfonate or divinyl benzene sulfonate) and partially synthetic matrices (e.g. cellulose or modified dextran). Examples of inorganic matrices include silica gel modified by the addition of ionic groups. Covalently bonded ionic groups can be strongly acidic (eg sulfonic acid groups), weakly acidic (eg carboxylic acid groups), strongly basic (eg quaternary ammonium groups), weakly basic (eg primary amine groups) or a combination of acidic and basic groups. Ion exchange resins suitable for ion exchange chromatography or water deionization are also normally suitable for use in the present invention. Such ion exchange resins are described, for example, by HF Walton, "Principles of Ion Exchange" in E. Heftmann (Ed.), "Chromatography: A laboratory handbook of chromatographic and electrophoretic methods", 3rd ed., Van Nostrand , New York, 1975, pages 312-343. Suitable ion exchange resins typically have exchange capacities below about 6 meq/g (milliequivalents per gram) and in particular below about 5.5 meq/g dry resin (acid or free base form).
[0035] The ion exchange resin is preferably selected from the group consisting of polymers and copolymers of acrylic acid, methacrylic acid and styrene modified with ionic groups, cellulose modified with ionic groups, dextran modified with ionic groups and silica gel modified with ionic groups. Suitable ionic groups include sulfonate groups, tertiary amine groups and quaternary ammonium groups. Polymers and copolymers of styrene sulfonate, styryl methyl trimethyl ammonium and dimethyl amino methyl styrene salts are particularly preferred.
[0036] It is also preferred that the ion exchange resin be cross-linked with a cross-linking agent. Suitable cross-linking agents are generally known in the state of the art. Preferred crosslinking agents are divinyl and polyvinyl compounds, and more preferably divinyl benzene. The ion exchange resin is preferably crosslinked to an extent from about 3 to about 20% by weight, in particular from about 4 to about 16% by weight, more preferably from about 6 to about 10% by weight. % by weight, and even more preferably about 8% by weight based on the total weight of the dry resin (acid or free base form).
[0037] It is particularly preferred that the ion exchange resin is a crosslinked sulfonated copolymer of styrene and divinyl benzene, which is preferably crosslinked to an extent of about 8% by weight based on the total weight of the dry resin (H+ form ). This ion exchange resin typically has an ion exchange capacity of about 4.5 to 5.5 meq/g dry resin (H+ form). Another preferred ion exchange resin is a crosslinked copolymer of styrene functionalized with quaternary ammonium and divinyl benzene groups, which is preferably crosslinked to an extent of about 8% by weight based on the total weight of the dry resin ( H+). This ion exchange resin typically has an ion exchange capacity of about 3 to 4 meq/g dry resin (H+ form).
[0038] The ion exchange resin preferably has an average particle size in the range of about 10 to about 1000 μm, in particular in the range of about 20 to about 250 μm, and more preferably in the range of 25 at about 200 μm. The ion exchange resin can be in the form of irregularly shaped particles that have an average particle size in the range of about 40 to about 250 μm, or spherical particles that have an average particle size in the range of about 45 µm. at about 150 μm.
[0039] It is also preferred that the complex of at least one active agent with the ion exchange resin comprises the active agent(s) in an amount of about 5 to 80% by weight, in particular from 10 to 70 % by weight, more preferably from 20 to 60% by weight, and most preferably from 30 to 50% by weight, based on the total weight of the complex.
[0040] The average particle size of the complex of at least one active agent with the ion exchange resin is preferably from about 10 to 3000 μm, in particular from about 30 to 2000 μm, and even more preferably from about from 50 to 1,000 μm. It is also preferred that at least about 85%, in particular at least about 95%, and even more preferably at least about 98% by volume of the particles have an average particle size within these preferred ranges. As used herein, the term average particle size refers to average volume. Particle size can be determined by means of sieve analysis or laser diffraction analysis as is generally known in the prior art. Sieve analysis is typically performed on a dry powder sample. Laser diffraction analysis can be performed using a sample as a dry powder or it can be suspended in an inert liquid vehicle such as purified water, for example when using a Malvern Mastersizer Apparatus MS 2000 instrument.
[0041] The coated particles also comprise a bioadhesive coating layer comprising at least one bioadhesive material. The term "bioadhesive" generally refers to a material which can impart adhesion of particles to a biological surface (e.g. tissue and/or cell) and in particular to a mucous membrane.
[0042] Suitable bioadhesive materials generally include modified and unmodified homopolymers, copolymers and natural or synthetic hydrophilic hydrogels. Examples include polycarboxylates, hyaluronan, chitosan, alginates such as sodium alginate, pectin, xanthan gum, poloxamers, cellulose derivatives, polyvinyl acetate and polyvinyl pyrrolidone. Preferred are modified and unmodified synthetic polycarboxylate polymers that typically have a weight average molecular weight of at least about 10,000 Daltons, preferably at least about 50,000 Daltons, more preferably at least about 100,000 Daltons, even more preferably at least about 1,000,000 Daltons, and most preferably about 1,000,000 to about 10,000,000 Daltons. Modifications may include cross-linking, neutralization, hydrolysis and total or partial esterification.
[0043] Preferred bioadhesive materials include optionally crosslinked ecopolymer polymers of acrylic acid or alkyl acrylic acids, in particular optionally crosslinked copolymers of acrylic acid or methacrylic acid with (C10-C30) alkyl acrylate. Suitable crosslinkers include vinyl and allyl ethers of polyalcohols, in particular allyl sucrose, allyl pentaerythritol and divinyl glycol. Acrylic acid homopolymers crosslinked with allyl sucrose or allyl pentaerythritol and copolymers of acrylic acid and alkyl acrylate (C10C30) crosslinked with allyl pentaerythritol are particularly preferred.
[0044] It is also preferred that the bioadhesive coating layer is present in an amount of from 1 to 30% by weight, in particular from 2 to 10% by weight and more preferably from 3 to 7% by weight based on the combined weight of the complex, an optionally present release-modifying coating layer and the bioadhesive coating layer.
[0045] The coated particles optionally comprise a release-modifying coating layer that is placed between the complex and the bioadhesive layer and comprises at least one release-modifying material. In certain embodiments, in particular if the active agent(s) belong to class II or IV of the Biopharmaceutics Classification System (BCS), where the active agents are characterized by having a low solubility, the The composition may consist exclusively of particles that do not comprise a release-modifying coating layer. Preferably, at least a portion of the coated particles comprises the release-modifying coating layer. The release-modifying material is preferably selected from delayed-release materials and/or controlled-release materials.
[0046] Suitable delayed release materials typically have zero or limited solubility or erodibility in a first environment, while being soluble and/or erodible in a second environment. Examples of suitable delayed release materials include anionic cellulose derivatives, anionic vinyl resins, anionic acrylic resins and combinations thereof. Preferred anionic cellulose derivatives include cellulose ethers, cellulose esters and cellulose ester-ethers, in particular alkyl celluloses, hydroxy alkyl celluloses, hydroxy alkyl alkyl celluloses and acyl celluloses, which are esterified with di- or tricarboxylic acids. Cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate and hydroxypropyl methyl cellulose acetate succinate are particularly preferred. Preferred anionic vinyl resins include polyvinyl esters which are esterified with di- or tricarboxylic acids. Polyvinyl acetate phthalate is particularly preferred. Preferred anionic acrylic resins include polymers and copolymers of acrylic acid or alkyl acrylic acid, in particular copolymers of acrylic or methacrylic acid with alkyl acrylates or alkyl methacrylates. Poly(methacrylic acid-co-ethyl acrylate) and poly(methacrylic acid-co-methyl methacrylate) are particularly preferred. Most preferred as delayed release materials are cellulose acetate fatalate, polyvinyl acetate phthalate, 1:1 poly(methacrylic acid-ethyl co-acrylate), hydroxypropyl methyl cellulose acetate succinate, poly( 1:1 methacrylic acid-methyl co-methacrylate), 1:2 poly(methacrylic acid-methyl co-methacrylate) and combinations thereof, and even more preferably cellulose acetate phthalate, methyl acetate phthalate polyvinyl, pooli(methrylic acid-ethyl co-acrylate) 1:1, hydroxypropyl methyl cellulose acetate succinate and combinations thereof.
[0047] Suitable controlled release materials generally include natural and synthetic film-forming materials that have diffusion barrier properties. Such materials generally must be water insoluble and permeable to water and the active agent. However, it may be desirable to incorporate a water-soluble substance, such as methyl cellulose, to alter the permeability of the coating, or to incorporate an acid-insoluble, base-soluble substance to act as an enteric coating. Examples of suitable controlled release materials are also described by R.C. Rowe in "Materials used in Pharmaceutical Formulation", A.T. Florence (Ed.), Blackwell Scientific Publications, Oxford, 1984, pages 1-36. Examples of suitable controlled release materials include cellulose derivatives such as cellulose ethers and cellulose esters, (meth)acrylic resins such as acrylate and methacrylate polymers and copolymers, vinyl resins such as vinyl pyrrolidone polymers and copolymers, acetate of vinyl and vinyl chloride, shellac, zein, rosin esters, silicone elastomers and mixtures thereof. Preferred cellulose derivatives include alkyl celluloses, hydroxy alkyl celluloses, hydroxy alkyl alkyl celluloses and acyl celluloses, in particular ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and cellulose acetate. Preferred (meth)acrylic resins include copolymers of acrylate and methacrylate which optionally comprise quaternary amine functional groups, in particular poly(ethyl acrylate-co-methyl methacrylate) and poly(ethyl acrylate-co-methyl chloride). trimethyl ammonium ethyl methacrylate), more particularly poly(ethyl acrylate-co-methyl methacrylate) 2:1, poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonium methacrylate ethyl chloride) 1:2:0.1 and poly(ethyl acrylate-methyl co-methacrylate-trimethyl ammonium ethyl methacrylate co-chloride) 1:2:0.2. Preferred vinyl resins include polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate) and mixtures thereof. Ethyl cellulose, methyl cellulose and mixtures thereof are particularly preferred. More preferably, the controlled release coating comprises a water-based ethyl cellulose latex or a pseudolatex plasticized with dibutyl sebacate or vegetable oils.
[0048] The release-modifying coating layer is preferably present in an amount of from about 5 to about 70% by weight, in particular from about 10 to about 60% by weight, and more preferably from about 20% by weight. to about 50% by weight, based on the combined weight of the complex and release-modifying coating layer. Variations in the amount of release-modifying material and/or the use of mixtures of coated and uncoated particles can be employed to selectively modify the dissolution profile as desired. It is preferred that about 20 to about 80%, more preferably about 30 to about 70%, and even more preferably about 40 to about 60% of the particles comprise a release-modifying coating layer.
[0049] According to a preferred embodiment, the composition comprises at least two groups of coated particles which differ in the amount and/or composition of the release-modifying material and/or which comprise different active agents.
[0050] In one embodiment, the composition comprises a first group of coated particles that comprises a release-modifying layer and a second group of coated particles that have no release-modifying layer or that have a release-modifying layer with a minor amount of release modifier material. In another embodiment, the composition comprises two groups of coated particles that comprise release-modifying layers that differ in composition of the release-modifying material. In these embodiments, particles that have no release-modifying layer or that have a release-modifying layer with a smaller amount of release-modifying material will exhibit a faster release of the active agent. Similarly, groups of particles that differ in release-modifying material composition will exhibit different release behaviors.
[0051] When the composition comprises at least two different groups of coated particles, the active agent(s) of those groups of particles may be the same or different. When the active agent(s) is(are) the same, the combination of different groups of coated particles that exhibit different release behavior can be used to adapt the overall profile of the active agent release. When the active agent(s) is(are) different, different active agents can be provided according to different release profiles, e.g. an active agent can be released more quickly and/ or earlier than another active agent.
[0052] It should be appreciated that these and other embodiments may also be combined to obtain compositions comprising any number of different groups of coated particles. For example, a composition according to the invention may comprise a first group of coated particles comprising a first active agent or combination of active agents and a release-modifying layer, a second group of coated particles comprising the same active agent or combination of active agents without a release-modifying layer and a third group of coated particles comprising a different active agent or a combination of active agents.
[0053] The coated particles optionally comprise an enteric coating layer which is placed over the bioadhesive layer and comprises at least one enteric coating material. The enteric coating layer is preferably placed directly on top of the bioadhesive layer, i.e. without another layer between the bioadhesive layer and the enteric coating layer. Suitable enteric coating materials are generally known in the art. Typically, they are substantially resistant to gastric juices to primarily prevent the release of the active agent in the stomach and thereby promote enteric release. Examples of suitable enteric coating materials include anionic cellulose derivatives, anionic vinyl resins, anionic acrylic resins.
[0054] Preferred anionic cellulose derivatives include cellulose ethers, cellulose esters and cellulose ester-ethers, such as alkyl celluloses, hydroxy alkyl celluloses, hydroxy alkyl alkyl celluloses or acyl celluloses, which are esterified with di- or tricarboxylic acids such as phthalic acid, hexahydrophthalic acid, trimellitic acid or succinic acid and their pharmaceutically acceptable salts. Cellulose ether phthalates, cellulose ester phthalates, cellulose ester ether phthalates and their pharmaceutically acceptable salts are preferred. Particularly preferred are cellulose acetate phthalate, cellulose diacetate phthalate, cellulose triacetate phthalate, methyl cellulose phthalate, hydroxypropyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, acetate hexahydrophthalate of cellulose, hydroxypropyl methyl cellulose hexahydrophthalate and pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts include alkali metal, alkaline earth metal and ammonium salts, in particular sodium cellulose acetate phthalate, calcium cellulose acetate phthalate and ammonium hydroxypropyl methyl cellulose phthalate.
[0055] Preferred anionic vinyl resins include polyvinyl esters which are esterified with di- or tricarboxylic acids such as phthalic acid, hexahydrophthalic acid, trimellitic acid or succinic acid and their pharmaceutically acceptable salts. Polyvinyl acetate phthalate is particularly preferred. Even more preferred are mixtures of anionic vinyl resins with phthalate plasticizers such as dialkyl phthalates, for example diethyl phthalate or dibutyl phthalate, alkyl aryl phthalates or diaryl phthalates.
[0056] Preferred anionic acrylic resins include polymers and copolymers of acrylic acid or alkylacrylic acid, and in particular copolymers of acrylic or methacrylic acid with alkyl acrylates or alkyl methacrylates. Examples include poly(methacrylic acid-co-ethyl methacrylate), poly(methacrylic acid-co-methylmethacrylate) and combinations thereof, preferably poly(methacrylic acid-co-methylmethacrylate) 50:50 , poly(methacrylic acid-co-methyl methacrylate) 30:70, poly(methacrylic acid-co-methacrylic acid-co-methacrylate-dimethylamino ethyl acrylate-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate-ethyl acrylate) ), and combinations thereof, and most preferably poly(methacrylic acid-co-methyl methacrylate) 50:50 which has an average molecular weight of about 135,000 g/mol, poly(methacrylic acid-co-methacrylate of methyl) 30:70 which has an average molecular weight of about 135,000 g/mol, the poly(methacrylic acid-dimethylamino ethyl co-methacrylate-ethyl acrylate) which has an average molecular weight of about 750,000 g/mol , poly(methacrylic acid-methyl co-methacrylate-ethyl acrylate) which has an average molecular weight of about 1,000,000 g/mol and combinations of the smos.
[0057] Other suitable enteric coating materials include: (a) keratin, sandarac-tolu keratin, salol (phenyl salicylate), salol beta-naphthyl benzoate and acetotanin, salol with Peru balsam, salol with tolu, salol with gum mastic , salol and stearic acid, and salol and shellac; (b) formalized protein, formalized gelatin, and formalized cross-linked ion exchange resins gelatin; (c) myristic acid-hydrogenadol castor oil-cholesterol, stearic acid-mutton tallow, stearic acid-tolu balm, and stearic acid-castor oil; (d) shellac, ammoniated shellac, ammoniated shellac-salol, wool fat shellac, cetyl alcohol shellac, tolu balsam-stearic acid shellac, and n-butyl stearate shellac; (e) abietic acid, methyl abictate, benzoin, tolu balm, sandarac, tolu mastic, and cetyl alcohol mastic.
[0058] The presence and nature of an enteric coating can be chosen according to the desired site of active agent release. If the active agent is to be released into the stomach, the particles will generally not comprise an enteric coating layer.
[0059] If the active agent is to be released into the duodenum, the enteric coating material is preferably chosen to dissolve at a pH in the range of about 5.0-6.0 and in particular of about 5.5-6 ,0. Particles comprising such an enteric coating are particularly preferred when the active agent is levodopa. Suitable enteric coating materials include poly(methacrylic acid-ethyl co-acrylate) and in particular poly(methacrylic acid-ethyl co-acrylate) 1:1.
[0060] If the active agent is to be released into the ileum, the enteric coating material is preferably chosen to dissolve at a pH in the range of about 6.0 to 7.0 and in particular from about 6.0 to 6.5. Suitable enteric coating materials include poly(methacrylic acid-co-methylmethacrylate) and in particular poly(methacrylic acid-co-methylmethacrylate) 1:1.
[0061] If the active agent is to be released into the colon, the enteric coating material is preferably chosen to dissolve at a pH in the range of about 6.5 to 7.5 and in particular above 7.0. Suitable enteric coating materials include poly(methacrylic acid-co-methyl methacrylate) and poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) and in particular poly(methyl acrylate-co-methacrylate). methyl methacrylate-co-methacrylic acid) 1:2 and the poly(methyl acrylate-co-methacrylate-co-methacrylic acid) 7:3:1.
[0062] It is also preferred that the enteric coating layer is present in an amount of from 1 to 80% by weight, in particular from 10 to 60% by weight, and more preferably from 30 to 50% by weight, based on weight. total coated particles.
[0063] It has surprisingly been found that the oral pharmaceutical composition according to the invention provides a reproducible, site-specific and controlled release of active agents whereby the active agents are initially released rapidly, to have a rapid onset of action, and then slowly and substantially continuously over an extended period of time, for example, over a period of 1 to 10 hours, to provide blood levels that fall within the therapeutic window. These superior properties reduce the total daily dose required as well as the number of daily doses, thereby reducing both short-term and long-term side effects.
[0064] Without wishing to be bound by any particular theory, it is believed that the bioadhesive material provides retention of the multiplicity of coated particles by adhering to a biological surface at the desired site of absorption of the active agent, such as a desired site within the gastrointestinal tract of a patient. The rate of release of the active agent from its complex with the ion exchange resin depends in particular on the ionic intensity of the surrounding fluid at the particular absorption site, which is relatively constant intra- and inter-patients. An uncontrolled and irregular release of the active agent, for example throughout the patient's gastrointestinal tract, is thereby prevented.
[0065] The composition preferably exhibits a release of active agent characterized in that the total amount of active agent released is not greater than 60% by weight after 2 hours, not greater than 70% by weight after 4 hours and not greater than 90% by weight after 8 hours (USP method #2, paddle rotation speed 50 rpm, 37 °C, dissolution medium 0-1 h: 500 ml 0.1 N HCl, 1- 12 h: buffer mixture [500 ml of 0.1 N HCl + 500 ml of phosphate buffer], pH 6.25, ion intensity 0.075).
[0066] It is particularly preferable for the composition to exhibit a zero-order, pseudo-zero-order, first-order, or pseudo-first-order release profile. A "zero-order" release profile characterizes the release profile of a dosage form that releases a constant amount of drug per unit time. A "pseudo-zero-order" release profile is one that approximates a zero-order release profile. A "first-order" release profile characterizes the release profile of a dosage form that releases a constant percentage of an initial drug load per unit time. A "pseudo-first-order" release profile is one that approximates a first-order release profile.
[0067] The average particle size of the coated particles is preferably from about 20 to about 5000 µm, in particular from about 50 to about 4000 µm, and more preferably from about 70 to about 3000 µm. It is also preferred that at least about 85%, in particular at least about 95%, and more preferably at least about 98% by volume of the particles have an average particle size within these preferred ranges.
[0068] Coated particles typically have a specific gravity (SG) that is higher than the specific gravity of duodenal fluids (SG = 1.008 - 1.03) or intestinal fluids (SG = 1.007 - 1.009). As used herein, the term "specific gravity" refers to the ratio of particle density to water density at 4°C. Preferably, the coated particles have a specific gravity in the range from 1.1 to 2.0, and more preferably from 1.2 to 1.8. The specific gravity of the coated particles can be calculated from the displacement volume of water (ΔV) resulting from adding a sample to water at 4°C, where the mass of the sample (m) and the density of water at 4° C (PH2O) are according to the following formula: SG = (m/ΔV)/pH2O.
[0069] The coated particles according to the invention typically exhibit a large specific surface area. As used herein, the term "specific surface area" typically means surface area BET. BET surface areas can be determined by calculating nitrogen desorption data obtained on a BET FlowSorb II 2300 instrument (Micromeritics Instrument Corp., USA) using a mixture of 30% by volume nitrogen and 70% by volume helium at 77°K. Preferably, the coated particles exhibit a specific surface area in the range of about 3,000 to 20,000 m 2 /m 3 . In another embodiment, the coated particles exhibit a specific surface area in the range of about 1 to 200 m 2 /g.
[0070] In one embodiment, the oral pharmaceutical composition according to the invention comprises coated particles of a complex of at least one active agent with an ion exchange resin, (i) wherein said particles are coated with a coating layer bioadhesive which comprises at least one bioadhesive material and (ii) the coated particles also comprise an enteric coating layer which is placed, preferably directly, over the bioadhesive layer and comprises at least one enteric coating material.
[0071] In another embodiment, the oral pharmaceutical composition according to the invention comprises coated particles of a complex of at least one active agent with an ion exchange resin, (i) wherein said particles are coated wherein with a bioadhesive coating layer comprising at least one bioadhesive material and (ii) at least a portion of the coated particles also comprising a release modifying coating layer which is placed between the complex and the bioadhesive layer and comprising at least one release modifying material .
[0072] According to a preferred embodiment, the oral pharmaceutical composition according to the invention comprises coated particles of a complex of at least one active agent with an ion exchange resin, (i) wherein said particles are coated wherein with a bioadhesive coating layer comprising at least one bioadhesive material and (ii) the coated particles also comprise an enteric coating layer which is placed over the bioadhesive layer and comprises at least one enteric coating material and (iii) at least one part of the coated particles also comprises a release-modifying coating layer which is placed between the complex and the bioadhesive layer and comprises at least one release-modifying material.
[0073] According to a particularly preferred embodiment, the coated particles comprise: (a) 1 to 50% by weight, in particular 5 to 40% by weight and preferably 10 to 20% by weight of at least one active agent; (b) 1 to 50% by weight, in particular 10 to 35% by weight and preferably 15 to 25% by weight of the ion exchange resin; (c) 0 to 50% by weight, in particular 1 to 50% by weight, preferably 10 to 40% by weight and more preferably 15 to 30% by weight of the release-modifying material; (d) 0.5 to 30% by weight, in particular 1 to 10% by weight and preferably 2 to 8% by weight of the bioadhesive material; and (e) 0 to 80% by weight, in particular 1 to 80% by weight, preferably 10 to 60% by weight and more preferably 30 to 50% by weight of the enteric coating material;
[0074] based on the total weight of the coated particles.
[0075] The composition may further comprise at least one active agent, or a pharmaceutically acceptable salt or solvate thereof, outside the coated particles to provide an immediate burst of the active agent. The active agent(s) may be identical or different from the active agent(s) contained in the coated particles. The active agent(s) may optionally be combined or coated with an enteric material.
[0076] The composition according to the invention is particularly suitable for active agents that have narrow therapeutic windows such as levodopa, carbidopa, benserazide and/or entacapone.
[0077] In a particularly preferred embodiment, the composition comprises levodopa and carbidopa or benserazide in a ratio of from 20:1 to 1:1, preferably from 15:1 to 2:1, and more preferably from 10:1 to 4: 1.
[0078] In the final formulation, in addition to the coated particles in the various forms defined above, other suitable substances can be mixed. Such other substances may be bonded to the ion exchange resin, and coated with some or all of the above defined coating layers as necessary to obtain the desired dissolution profile, or may be in their native free solid or liquid form.
[0079] The composition of the invention may further comprise excipients. Suitable types of excipients include adsorbents, antioxidants, acidifying agent, alkalizing agent, buffering agents, coloring agents, flavoring agents, sweetening agents, anti-adherents, binders, diluents, direct compression excipients, disintegrants, glidants, lubricants, opacifiers and/or agents. of polishing.
[0080] The term "antioxidant" generally refers to an excipient used to inhibit oxidation and thereby prevent deterioration of active agents by oxidative processes. Suitable antioxidants include ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxy toluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate and sodium metabisulfite.
[0081] The term "sweetening agent" generally refers to an excipient used to sweeten a pharmaceutical composition. Suitable sweetening agents include aspartame, dextrose, glycerin, mannitol, sodium saccharin, sorbitol and sucrose.
[0082] The term "colorant" generally refers to an excipient used to impart a color to a pharmaceutical composition. Suitable dyes include FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, other F.D. & C., caramel, red ferric oxide, and natural coloring agents such as grape skin extract, beetroot powder, beta-carotene, annatto, carmine, turmeric or paprika. The amount of dye used will vary as desired.
[0083] The term "flavoring" generally refers to an excipient used to impart a pleasant taste and also often a pleasant odor to a pharmaceutical composition. Suitable flavors generally include synthetic flavor oils, aromatic flavor compounds, natural oils, extracts from whole plants or parts thereof such as leaves, flowers, fruits or combinations thereof. Examples include cinnamon oil, wintergreen oil, peppermint oil, clove oil, laurel oil, anise oil, eucalyptus oil, thymus oil, cedar leaf, nutmeg oil, sage oil, bitter almond oil and cassia oil. Other useful flavorings include vanilla, citrus oils such as lemon, orange, grapefruit, lime or grapefruit oils, and fruit essences such as apple, pear, peach, strawberry, raspberry essence. , cherry, plum, pineapple or apricot. Flavors that have been found to be particularly useful include the commercially available orange, grape, cherry and chewing gum flavors and mixtures thereof. The amount of flavoring can depend on a number of factors, including the desired organoleptic effect, and can be adapted as necessary by those skilled in the art. Particularly preferred flavors are grape and cherry flavors and citrus flavors such as orange flavor.
[0084] Plasticizers can also be included in the pharmaceutical composition to modify the properties and characteristics of the polymers used in the coating layers or core of the composition. The term "plasticizer" generally refers to a compound used to plasticize or soften a component, such as a polymer or a binder, of the pharmaceutical composition. Suitable plasticizers generally include low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, polypropylene glycols, multi-block polymers , single block polymers, low molecular weight polyethylene glycol, citrate ester type plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers may also preferably include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other polyethylene glycol compounds, monopropylene glycol monoisopropyl ether, monoethyl ether of propylene glycol, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, acetyl tributyl citrate, more preferably triethyl citrate, dibutyl sebacate, citrate of acetyl triethyl, tributyl citrate and allyl glycolate. All such plasticizers are generally commercially available. It is also contemplated that a combination of plasticizers may be used in the present formulation. PEG-based plasticizers are commercially available or can be obtained by a variety of methods, as disclosed in "Poly(etylene glycol) Chemistry: Biotechnical and Biomedical Applications" (J.M. Harris, Ed.; Plenum Press, NY).
[0085] The compositions of the invention may also include oils, for example fixed oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and most preferably olive oil, fatty acids such as oleic acid, stearic acid and isostearic acid, esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Other optional ingredients include alcohols such as ethanol, isopropanol, hexadecanol, glycerol and propylene glycol, glycerol ketals such as 2,2-dimethyl-1,3-dioxolan-4-methanol, ethers such as poly (ethylene glycol) 450, petroleum hydrocarbons such as mineral oil and petrolatum, water or mixtures thereof with or without the addition of a pharmaceutically appropriate surface-active agent, suspending agent or emulsifying agent.
[0086] Soaps and synthetic detergents can be used as surfactants and as vehicles for detergent compositions. Suitable soaps include alkali, ammonium and triethanol amine salts of fatty acids. Suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkyl amine acetates, anionic detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and glyceride sulfates and sulphosinates. Preferred detergents include amphoteric detergents such as alkyl beta-aminopropionates and 2-alkyl imidazoline quaternary ammonium salts and mixtures thereof, and more preferably nonionic detergents such as fatty amine oxides, fatty acid alkanolamides and poly(oxyethylene)-block-poly(oxypropylene) copolymers.
[0087] Several other components can be added to the composition to optimize a desired release profile of the active agent including glyceryl monostearate, nylon, cellulose acetate butyrate, d,1-poly(lactic) acid, 1,6-hexane diamine, diethylene triamine, starches, derivatized starches, acetylated monoglycerides, gelatin coacervates, poly(styrene-co-maleic acid), glucose, castor wax, stearyl alcohol, glycerol palmitostearate, polyethylene, polyvinyl, polyvinyl chloride, 1,3-butylene glycol dimethacrylate, ethylene glycol dimethacrylate and methacrylate hydrogels.
[0088] It should be understood that compounds used in the pharmaceutical formulation technique may serve a variety of functions or purposes. Thus, if a compound named herein is mentioned only once or is used herein to define more than one term, its purpose or function should not be interpreted as being limited solely to that purpose(s) or function(s). ) named.
[0089] The pharmaceutical composition of the invention may take any shape or form known in the art of pharmaceutical sciences. In particular, it can be a bar, a plate, a rotation paraboloid, a rotation ellipsoid or the like. Preferably, the composition is in the form of a capsule, such as a hard or soft gelatin or vegetable capsule, a tablet, caplet, coated capsule, pill, sphere, powder or liquid suspension such as an unhydrated suspension with olive oil, glycerin, polyethylene glycol or another suitable nonionic vehicle. More preferably, the composition is in the form of a capsule. The final form of the composition may also include markings, cuts, grooves, letters and/or numerals on the surface for decoration, identification and/or other purposes. The dosage form may include a topcoat to provide the desired gloss, color, taste, or other aesthetic characteristics. Suitable materials for preparing the topcoat are generally known in the state of the art.
[0090] Other preferred embodiments of the composition according to the invention are represented by oral formulations, in particular hard vegetable capsules, which comprise: 1) Levodopa/carbidopa at a weight ratio of 4:1, in particular 50 mg of levodopa /12.5 mg decarbidopa, where arbidopa is in the immediate release form of the native powder, and levodopa is in the form of ion exchange resin/drug particles coated with bioadhesive and enteric coating layers. 2) Levodopa/carbidopa at a weight ratio of 4:1, in particular 100 mg levodopa/25 mg carbidopa, where carbidopa is in the immediate-release form of the native powder, and levodopa is in the form of a mixture of ion exchange resin/drug resin particles coated with bioadhesive and enteric layers and ion exchange resin/drug particles coated with bioadhesive and enteric release control coating layers.3) Levodopa/carbidopa at a ratio of 4:1 weight, in particular 200 mg levodopa/50 mg carbidopa, where carbidopa is in the immediate release form of the native powder, and levodopa is in the form of a mixture of ion exchange resin particles /drug coated with bioadhesive and enteric layers and ion exchange resin particles / drug coated with bioadhesive and enteric release control coating layers.4) Levodopa/entacapone/carbidopa at a weight ratio of 5-25:20 :1-5, in particular 50-250 mg of levodopa, 200 mg entacapone, 10-50 mg carbidopa, wherein the levodopa is in the form of a mixture of bioadhesive and enteric coated ion exchange resin/drug resin particles and ion exchange resin/drug particles coated with bioadhesive and enteric release control coating layers, and entacapone and carbidopa are in the form of drug/ion exchange resin particles coated with bioadhesive and enteric coating layers or in native powder form.
[0091] Alternatively, in the above modalities, carbidopa can be replaced by benserazide.
[0092] The oral pharmaceutical composition of the present invention can be prepared by methods generally known in the state of the art. A typical process for preparing the composition comprises the steps of: (i) contacting an active agent with an ion exchange resin to obtain an active agent/ion exchange resin complex; (ii) optionally, coating the complex of step (i) with a coating layer comprising a release-modifying material; (iii) coating the complex of step (i) or the coated complex of step (ii) with a coating layer comprising a bioadhesive material ; and (iv) optionally coating the coated complex of step (iii) with a coating layer comprising an enteric coating material.
[0093] In step (i), the active agent is preferably mixed with an aqueous suspension of the resin, and the resulting complex is washed and dried. Adsorption of the active agent onto the resin can be detected by measuring a change in pH of the reaction medium, or by measuring a change in the concentration of counterions and/or active agent. The complex is typically washed with an alcohol such as ethanol and/or water to ensure removal of any unbound active agent. The complexes are normally air dried on trays at room temperature or at an elevated temperature. The binding can be carried out, for example, as a batch or column process, as is known in the prior art.
[0094] The binding of the active agent to the resin can generally follow one of four general types of reaction. In the case of binding a basic active agent to a cation exchange resin they are: (a) resin (salt form, e.g. Na+ form) plus active agent (salt form), (b) resin (salt form, e.g. Na+ form) plus active agent (free base), (c) resin (H+ form) plus active agent (salt form), and (d) resin (H+ form) ) plus the active agent (free base). In the case of binding an acidic active agent to an anion exchange resin they are: (a) resin (salt form, e.g. Cl- form) plus active agent (salt form), (b) resin (salt form, eg Cl- form) plus active agent (free acid), (c) resin (OH- form) plus active agent (salt form); and (d) resin (OH- form) plus active agent (free acid). All of these reactions with the exception of (d) involve the by-products formed by the counterions competing with the active agent for binding sites on the resin, thereby reducing the amount of active agent binding at equilibrium. Thus, for both acidic and basic active agents, the truly stoichiometric binding of the active agent to the resin is only effected through reaction (d).
[0095] In steps (ii) to (iv), conventional coating solvents and coating procedures, such as fluidized bed coating or spray coating, can be employed to coat the particles. Fluid bed coating techniques are taught, for example, in U.S. Patents. 3,089,824, U.S. 3,117,027 and U.S. 3,253,944. The coating is normally applied to the active agent and ion exchange resin complex, but may alternatively be applied to the resin prior to complexing with the active agent. The coating mixture is typically applied as a solution, a dispersion or an emulsion in a coating solvent. Examples of suitable coating solvents include methanol, ethanol, isopropanol, isobutanol, n-butyl acetate, ethyl acetate, acetone, methyl ethyl ketone, hexane, methyl isobutyl ketone, tetrachloride of carbon, methylene chloride, ethylene chloride, ethylene trichloro, tetrahydrofuran, 2-nitropropane, toluene, xylene, mixtures thereof, such as a mixture of methylene chloride and acetone. Methanol, ethanol, isopropanol, isobutanol, n-butyl acetate and ethyl acetate are preferred.
[0096] The invention will be further illustrated by the following examples. Brief Description of the Drawings
[0097] Fig. 1 shows the release of 500 mg levodopa from the resin and levodopa drug complex obtained in Example 1A dispersed in deionized water at room temperature under stirring with a magnetic stirrer. NaCl was added as follows: 9 min: 200 mg; 36 min: 700 mg; 52 min: 1200 mg; 61 min: 3300 mg.
[0098] Fig. 2 shows the dissolution profile of coated LDRC obtained in Example 1B-1 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, pH 5.5, ion intensity 0.075).
[0099] Fig. 3 shows the dissolution profile of coated LDRC obtained in Example 1B-3 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, pH 5.5, ion intensity 0.075).
[00100] Fig. 4 shows the dissolution profiles of coated LDRC obtained in Examples 1B-2 through 1B-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, pH 6.0, ion intensity 0.075) .
[00101] Fig. 5 shows the dissolution profile of coated LDRC obtained in Example 1C-3 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, pH 6.0, ion intensity 0.075).
[00102] Fig. 6 shows the dissolution profile of coated LDRC obtained in example 1C-5 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, pH 6.0, ion intensity 0.075).
[00103] Fig. 7 shows the dissolution profiles of coated LDRC obtained in Examples 1D-2 through 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, dissolution medium 0-1 hour: 0.1 N HCl, 1-12 hours: phosphate buffer pH 6.25, ion intensity 0.075).
[00104] Fig. 8 shows the dissolution profiles of coated LDRC obtained in Examples 1D-1 and 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, dissolution medium 0-1 hour: 0.1 N HCl, 1-12 hours: phosphate buffer pH 6.25, ion intensity 0.075).
[00105] Fig. 9 shows the dissolution profiles of uncoated ropinirole drug resin complex (RoDRC) obtained in Example 2A and coated RoDRC obtained in Example 2D before and after sieving (USP method #2, paddle rotation speed 75 rpm, 37 °C, dissolution medium 0-1 hour: 500 ml of 0.1 N HCl, 1-10 hours: buffer mixture [500 ml of 0.1 N HCl + 500 ml of phosphate buffer], pH 5.6 , ionic intensity 0.075).
[00106] Fig. 10 shows the dissolution profile of coated alendronate drug resin complex (AlDRC) obtained in Example 3D (USP method #2, paddle rotation speed 75 rpm, 37°C, dissolution medium 1000 ml 0.1 M NaCl ).
[00107] Fig. 11 shows the dissolution profile of coated risperidone drug resin complex (RiDRC) obtained in Example 4D (USP method #2, paddle rotation speed 75 rpm, 37°C, dissolution medium 0-1 hour: 500 ml of 0.1 N HCl, 1-12 hours: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ion intensity 0.075).
[00108] Fig. 12 shows the dissolution profile of coated olanzapine drug resin complex (OzDRC) obtained in Example 5D (USP method #2, paddle rotation speed 75 rpm, 37°C, dissolution medium 0-1 hour: 500 ml of 0.1 N HCl, 1-12 hours: buffer mixture [500 ml of 0.1 N HCl + 500 ml of phosphate buffer], pH 5.6, ion intensity 0.075; 10 g of NaCl was added after 10 ,5 hours). Examples
[00109] Levodopa release was measured spectrophotometrically at 280 nm. Example 1A) Preparation of Levodopa Drug Resin Complex (LDRC)
[00110] 400 g of a sodium polystyrene sulfonate cation exchange resin cross-linked with divinyl benzene (125-400 mesh) was mixed with 1200 ml of deionized water under slow stirring for 1 hour. The resin was placed to settle and the water was decanted. Diluted HCl was prepared by adding 300 ml of concentrated HCl to 1200 ml of deionized water and mixing. The resin was mixed with 250 ml of the diluted HCl for 30 minutes and then placed to sediment, the supernatant was decanted, and this step was repeated until all the diluted HCl had been used. The resin was washed by being mixed with 500 ml of deionized water for 10 minutes, allowing the resin to settle, the supernatant was decanted and this step was repeated 8 times or until the supernatant was neutral on litmus paper.
[00111] A mixture of 300 ml of ethanol and 300 ml of deionized water was added to the resin and 250 g of levodopa was added and treated with the resin for 4 hours under mixing for 1 minute every 30 minutes. The resin was allowed to settle overnight and then the supernatant was decanted. The resin was washed by mixing it with 300 ml of a water/ethanol mixture (3:2), the resin was placed to sediment, the supernatant was decanted and this step was repeated until no crystals of levodopa were visible under a microscope. after having evaporated the supernatant. The complex obtained from the drug levodopa resin was dried in an oven at 60°C. Moisture content (LOD [loss on drying]): 5 ± 0.5% by weight, Levodopa content (HPLC): 40 ± 1% by weight. The obtained complex was found to be stable against exposure to air at room temperature for at least 6 months.
[00112] The ionic binding of levodopa in the complex was tested by adding increasing amounts of electrolyte (NaCl) to a slurry of LDRC in deionized water. Levodopa release is shown in Fig. 1.B) Coating with a deliberation modifying coating layer

[00113] Levodopa drug resin complex (LDRC) was fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus and dried in place to 45-50°C. The product was sieved through a 40 mesh stainless steel screen. Microscopic examination revealed uniformly coated particles with moderate agglomeration. The coated products obtained in Examples 1B-2 to 1B-4 were further cured for 2 hours at 60°C.
[00114] The dissolution profiles of coated LDRC obtained in Examples 1B-1 and 1B-3 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, pH 5.5, ion intensity 0.075 ) are shown in Figs. 2 and 3. The dissolution profiles of coated LDRC obtained in Examples 1B-2 through 1B-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, pH 6.0, ion intensity 0.075) are shown in Fig. 4.C) Coating with a layer of bioadhesive coating
* High molecular weight polymer of cross-linked acrylic acid with allyl ethers and pentaerythritol
[00115] Levodopa drug resin complex (LDRC) was fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus and dried in place at 50°C. The product was sieved through a 40 mesh stainless steel screen. Microscopic examination revealed uniformly coated particles with moderate agglomeration.
[00116] The dissolution profiles of coated LDRC obtained in Examples 1C-3 and 1C-5 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, pH 6.0, ion intensity 0.075) are shown in Figs. 5 and 6.D) Coating with an enteric coating layer

* Commercially available methacrylic acid copolymer with dispersing agents formulated for easy dispersion in water
[00117] Levodopa drug resin complex (LDRC) was fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus and dried in place at 55°C. The product was sieved through a 40 mesh stainless steel screen. Microscopic examination revealed uniformly coated particles with moderate agglomeration.
[00118] The dissolution profiles of coated LDRC obtained in Examples 1D-2 to 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, dissolution medium 0-1 hour: 0.1 N HCl, 1-12 hours: phosphate buffer pH 6.25, ion strength 0.075) are shown in Fig. 7. The dissolution profiles of coated LDRC obtained in Examples 1D-1 and 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37°C, dissolution medium 0-1 hour: 0 .1 N HCl, 1-12 hours: phosphate buffer pH 6.25, ion strength 0.075) are shown in Fig. 8.E) Hard gelatine capsules comprising levodopa and carbidopa


[00119] One or more resin complexes of the levodopa drug were dry blended with carbidopa and magnesium stearate or talc as indicated. The mixture obtained was filled into hard gelatine capsules. F) A tablet comprising levodopa and carbidopa

[00120] Levodopa drug resin complex was dry blended with carbidopa and excipients as indicated. The obtained mixture was compressed into tablets.Examples 2-51) Preparation of drug resin complexes (DRCs) 2A) Preparation of ropinirole drug resin complex (RoDRC)
[00121] 100 g of sodium polystyrene sulfonate cation exchange resin cross-linked with divinyl benzene (125-400 mesh) was added to 500 ml of deionized deaerated water and mixed occasionally under argon for 1 hour. The resulting slurry was transferred to a 250 ml glass column and washed with 200 ml of de-aerated deionized water. 40 g of ropinirole hydrochloride was dissolved in 300 ml of deionized deaerated water and passed through the column at a rate of 10 ml per minute. The column was washed with 1000 ml of deionized deaerated water. The complex obtained from the drug resin was removed from the column and dried first on filter paper and then in vacuum on silica to a moisture content of 5% by weight.
[00122] The dissolution profile of the uncoated complex obtained from ropinirole drug resin (RoDRC; USP Method #2, paddle rotation speed 75 rpm, 37°C, dissolution medium 0-1 hour: 0.1 N HCl , 110 hours: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ion intensity 0.075) is shown in Fig. 9.3A) Preparation of alendronate drug resin complex (AlDRC)
[00123] 50 g of cholestyramine anion exchange resin (Cl- form, 99% < 100 μ, 56% < 50 μ) was washed with 5 x 200 ml of deaerated water. The final portion of the water was decanted after 5 hours. 300 ml of deaerated water and 16.25 g of alendronate sodium were added to the resin. The resulting slurry was mixed at room temperature for 60 minutes, centrifuged, and the solvent was decanted. This was repeated three more times until a total of 65 g of alendronate sodium had been used. The complex obtained from the drug resin was washed with 3 liters of water and dried first on filter paper and then in a vacuum on silica until a moisture content of 5% by weight.4A) Preparation of the drug resin complex risperidone (RiDRC )
[00124] 100 g of the divinyl benzene crosslinked polystyrene sulfonate cation exchange resin (H+ form) was washed with 500 ml of deionized deaerated water for 30 minutes. The water was decanted and the resin was washed with 300 ml of 96% ethanol. 100 g of risperidone was added to 300 ml of 96% ethanol. The slurry was heated to 60°C, added to the resin and mixed for 12 hours under argon. The solvent was decanted and the resin was washed with 5 x 250 ml of 96% ethanol. The last portion of the ethanol was left to stand overnight under argon. The ethanol was decanted and the complex obtained from the drug resin was dried first on filter paper and then in vacuum on silica to a moisture content of 5% by weight.5A) Preparation of olanzapine drug resin complex (OzDRC)
[00125] 100 g of the divinyl benzene crosslinked polystyrene sulfonate cation exchange resin (H+ form) was washed with 500 ml of 96% deaerated ethanol. Ethanol was decanted. 80 g of olanzapine was dispersed in 500 ml of 96% deaerated ethanol at 40°C and added to the resin. The resulting slurry was mixed for 5 hours at 40°C under argon and then allowed to stand overnight at room temperature. The solvent was decanted and the complex obtained from the olanzapine drug resin was washed with 10 x 500 ml of deaerated 96% ethanol. The complex obtained from the drug resin was first dried on filter paper and then vacuum dried on silica to a moisture content of 5% by weight.8) Coating with a release-modifying coating layer28) RoDRC coating with a layer of release modifier coating

[00126] The drug resin complex Ropinirole (RoDRC) was fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus analogous to that of Example 1B.38) AlDRC coating with a release-modifying coating layer
[00127] 25 g of ethyl cellulose was mixed thoroughly with 30 ml of 99% ethanol and 0.5 g of glycerin g used as a plasticizer. The obtained mixture was added to 40 g of the alendronate drug resin complex prepared in Example 3A and mixed until the mixture was homogeneous. The wet mass was forced through a 425 μ sieve and dried at 60°C for 2 hours. The granulate obtained was sieved through a sieve of 425 μ.C) Coating with a layer of bioadhesive coating
* High molecular weight polymer of cross-linked acrylic acid with allyl ethers and pentaerythritol
[00128] The drug resin complexes were fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus analogous to that of Example 1C.D) Coating with an enteric coating layer

* Commercially available methacrylic acid copolymer with dispersing agents formulated for easy dispersion in water
[00129] The drug resin complexes were fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus analogous to that of Example 1D.
[00130] The dissolution profiles of the ropinirole drug resin coated complexes obtained in Example 2D before and after sieving in phosphate buffer (USP method #2, paddle rotation speed 75 rpm, 37°C, dissolution medium 0 -1 hour: 500 ml of 0.1 N HCl, 1-10 hours: buffer mixture [500 ml of 0.1 N HCl + 500 ml of phosphate buffer], pH 5.6, ion intensity 0.075) are shown in Fig. 9.
[00131] The dissolution profiles of the drug resin coated complexes obtained in Examples 3D, 4D and 5D are shown in Figs. 10 to 12.

权利要求:
Claims (22)
[0001]
1. Oral pharmaceutical composition, characterized in that it comprises coated particles of a complex of at least one active agent with an ion exchange resin, wherein said particles are coated with a bioadhesive coating layer comprising at least one material bioadhesive and further comprises an enteric coating layer which is positioned above the bioadhesive layer and comprises at least one enteric coating material, wherein the bioadhesive material is selected from the group consisting of optionally cross-linked homopolymers of acrylic acid or an alkylacrylic acid and copolymers optionally crosslinked of acrylic acid or methacrylic acid with a (C10-C30) alkyl acrylate.
[0002]
2. Composition according to claim 1, characterized in that at least a part of the coated particles also comprises a release-modifying coating layer that is placed between the complex and the bioadhesive layer and comprises at least one modifier material. of release.
[0003]
Composition according to claim 1 or 2, characterized in that the bioadhesive material has a weight average molecular weight of at least about 10,000 Daltons, preferably at least about 50,000 Daltons, more preferably at least about about 50,000 Daltons. 100,000 Daltons, even more preferably at least about 1,000,000 Daltons, and most preferably about 1,000,000 to about 10,000,000 Daltons.
[0004]
4. Composition according to any one of claims 1 to 3, characterized in that the enteric coating material is selected from the group consisting of anionic cellulose derivatives, anionic vinyl resins and anionic acrylic resins.
[0005]
5. Composition according to claim 4, characterized in that the enteric coating material is selected from the group consisting of cellulose acetate phthalate, cellulose diacetate phthalate, cellulose triacetate phthalate, methyl cellulose phthalate, phthalate of hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate hexahydrophthalate, hydroxypropyl methyl cellulose hexahydrophthalate and the pharmaceutically acceptable salts thereof, polyvinyl acetate phthalate, poly(methacrylic acid-co-acrylate) of ethyl and poly(methacrylic acid-co-methyl methacrylate).
[0006]
6. Composition according to any one of claims 2 to 5, characterized in that the release-modifying material is selected from delayed-release materials and/or controlled-release materials.
[0007]
7. Composition according to claim 6, characterized in that the release-modifying material is selected from the group consisting of ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, cellulose acetate phthalate, trimellitate cellulose acetate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, poly(methacrylic acid-ethyl co-acrylate, poly(methacrylic acid-methyl methacrylate), polyvinyl chloride, methyl acetate phthalate polyvinyl, poly(vinyl pyrrolidone-co-vinyl acetate), silicone elastomers, shellac, zein, rosin esters and mixtures thereof.
[0008]
8. Composition according to claim 7, characterized in that the release-modifying material is selected from the group consisting of methyl cellulose, ethyl cellulose and mixtures thereof.
[0009]
9. Composition according to any one of claims 2 to 8, characterized in that it comprises at least two groups of coated particles that differ in the amount and/or composition of the release-modifying material.
[0010]
10. Composition according to any one of claims 1 to 9, characterized in that the ion exchange resin is selected from the group consisting of polymers and copolymers of acrylic acid, methacrylic acid and styrene modified with ionic groups, cellulose modified with ionic groups, dextran modified with ionic groups and silica gel modified with ionic groups, wherein said ionic groups are selected from sulfonate groups, tertiary amine groups and quaternary ammonium groups.
[0011]
11. Composition according to claim 10, characterized in that the ion exchange resin is a crosslinked sulfonated copolymer of styrene and divinyl benzene.
[0012]
12. Composition according to any one of claims 1 to 11, characterized in that the average particle size of the particles of the active agent complex with the ion exchange resin is preferably from about 10 to about 3,000 µm, in particular from about 30 to about 2000 µm, and more preferably from about 50 to about 1000 µm.
[0013]
Composition according to any one of claims 1 to 12, characterized in that the average particle size of the coated particles is preferably from about 20 to about 5,000 μm, in particular from about 50 to about 4000 µm, and more preferably from about 70 to about 3000 µm.
[0014]
14. Composition according to any one of claims 1 to 13, characterized in that the coated particles have a specific gravity in the range from 1.1 to 2.0, and preferably from 1.2 to 1.8.
[0015]
15. Composition according to any one of claims 1 to 14, characterized in that the coated particles exhibit a specific surface area in the range of about 1 to 200 m2/g.
[0016]
16. Composition according to claim 1, characterized in that the active agent is selected from the group consisting of levodopa, carbidopa, benserazide, entacapone and mixtures thereof.
[0017]
17. Composition according to claim 1, characterized in that the active agent is selected from the group consisting of alendronate, olanzapine, risperidone and ropinirole.
[0018]
18. Composition according to any one of claims 1 to 17, characterized in that it comprises at least two groups of coated particles that comprise different active agents.
[0019]
19. Composition according to any one of claims 1 to 18, characterized in that it further comprises an active agent, or a pharmaceutically acceptable salt or solvate thereof, outside the coated particles.
[0020]
20. Composition according to any one of claims 1 to 19, characterized in that it comprises levodopa and carbidopa or benserazide in a ratio of 20:1 to 1:1, preferably 15:1 to 2:1, and more preferably from 10:1 to 4:1.
[0021]
Composition according to any one of claims 1 to 20, characterized in that the coated particles comprise (a) 1 to 50% by weight, in particular 5 to 40% by weight and preferably 10 to 20% by weight. weight of at least one said active agent; (b) 1 to 50% by weight, in particular 10 to 35% by weight and preferably 15 to 25% by weight of said ion exchange resin; (c) 0 to 50 % by weight, in particular 1 to 50% by weight, preferably 10 to 40% by weight and more preferably 15 to 30% by weight of said release-modifying material; (d) 0.5 to 30% by weight, in particular 1 to 10% by weight and preferably 2 to 8% by weight of said bioadhesive material; and (e) 1 to 80% by weight, in particular 1 to 80% by weight, preferably 10 to 60% by weight and more preferably 30 to 50% by weight of said enteric coating material; based on the total weight of the coated particles.
[0022]
22. Process for preparing a composition as defined in any one of claims 1 to 21, characterized in that said process comprises the steps of: (i) contacting an active agent with an ion exchange resin to obtain an active agent/ion exchange resin complex; (ii) optionally, coating the complex from step (i) with a coating layer comprising a release-modifying material; (iii) coating the complex from step (i) or the complex coated from step (ii) with a coating layer comprising a bioadhesive material; and (iv) coating the coated complex of step (iii) with a coating layer comprising an enteric coating material.

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CN111840240A|2020-05-29|2020-10-30|仁和堂药业有限公司|Finasteride preparation and application thereof|

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CN111840255B|2020-07-31|2022-03-01|北京丰帆生物医药科技有限公司|Verapamil temperature-sensitive slow-release preparation and preparation method and application thereof|

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CN112190573A|2020-11-17|2021-01-08|四川大学华西医院|Combined medicine for treating liver cancer|

法律状态:
2018-03-27| B15K| Others concerning applications: alteration of classification|Ipc: A61K 9/20 (2006.01), A61K 9/50 (2006.01), A61K 31/ |

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-10-01| 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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2020-08-11| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-09-08| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-08-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-08-10| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2021-08-17| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-11-16| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2022-02-01| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/04/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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EP11161398A|EP2508174A1|2011-04-06|2011-04-06|Pharmaceutical composition|

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EP11161398.0|2011-04-06|

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PCT/EP2012/056366|WO2012136816A2|2011-04-06|2012-04-05|Pharmaceutical composition|

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