counterfeit-resistant dosage form for oxidation-sensitive opioids, their manufacturing process, and

专利摘要:
FALSIFICATION-RESISTANT DOSAGE FORM FOR OXIDATION-SENSITIVE OPIOIDS, THEIR MANUFACTURING PROCESS, AND PACKAGING.The present invention relates to a thermoformed pharmaceutical dosage form having a tensile strength of at least 300 N, said dosage form comprising:- an opioid (A),- a physiologically acceptable free acid (B) in an amount of 0.001 to 5.0% by weight, based on the total weight of the pharmaceutical dosage form, and- a polyalkylene oxide (C) having an average molecular weight Mw of at least 200,000 g / mol.
公开号:BR112012001466A2
申请号:R112012001466-8
申请日:2010-07-21
公开日:2020-08-11
发明作者:Anja Geissler；Ulrike Bertram；Kornelia Grießmann；Johannes Bartholomäus
申请人:Grünenthal GmbH；
IPC主号:

专利说明:

Invention Patent Descriptive Report for "FORM OF
FALSIFICATION-RESISTANT DOSING FOR OXIDATION-SENSITIVE OPIOIDS, THEIR MANUFACTURING PROCESS, AND PACKAGING. "The present invention relates to a pharmaceutical dosage form that contains an opioid with improved dosage stability. Many pharmaceutically active compounds have potential violated and are thus advantageously provided in counterfeit-resistant pharmaceutical dosage forms. Prominent examples of such pharmaceutically active compounds are opioids. Violators are known to crush conventional pills, which contain opioids, to destroy the "microencapsulation" with release over time and then ingest the resulting powder orally, intranasally, rectally, or by injection. Various concepts for preventing drug violation have been developed. One concept is based on the mechanical properties of the forms dosage systems, particularly increased resistance to breakage (crush resistance) . The main advantage of such pharmaceutical dosage forms is that fragmentation, particularly spraying, by conventional means, such as grinding in a mortar or fracturing by means of a hammer, is impossible or at least substantially prevented. Such pharmaceutical dosage forms are useful to prevent drug violation of the pharmacologically active compound contained herein, as they cannot be sprayed by conventional means and, therefore, cannot be administered in a sprayed form, for example, nasally. The mechanical properties, in particular, the high breaking strength of these pharmaceutical dosage forms make them resistant to counterfeiting. In relation to such counterfeit-resistant pharmaceutical dosage forms, for example, WO 2005/016313, WO 2005/016314, wo 2005/063214, wo 2005/102286, wo 2006/002883, wo 2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099, and WO
2008/107149. A problem in the manufacture of pharmaceutical dosage forms. that contain opioids, such as oxymorphone, hydromorphone, and oxycodone,
. it is its sensitivity to oxidative degradation and decomposition.
The 5 "oxidation can be caused by molecular oxygen or by radicals or peroxides generated by compounds that come in close proximity with these oxidation-sensitive opioids.
Pharmaceutical excipients, such as, for example, polyethylene glycols, can cause or catalyze oxidative degradation, for example, in the course of the process to manufacture pharmaceutical dosage forms.
In addition, molecular oxygen can generate said radicals or peroxides. . Typically, decomposition is monitored in standard storage stability tests, for example, under accelerated storage conditions, such as 40 ° C / 75% relative humidity.
Under these 15 conditions, degradation and decomposition proceed faster than under ambient conditions.
Drug approving authorities, such as CHMP and FDA, and international harmonization unions, such as ICH, have established standard storage stability thresholds that must be achieved to obtain a proven pharmaceutical dosage form.
Particular problems arise when the oxidation-sensitive opioid needs to be exposed to high temperatures during the manufacturing process, such as hot melt extrusion, film coating and the like.
Under these conditions, opioids are even more sensitive to oxidation.
For example, several known processes for the manufacture of pharmaceutical dosage forms having an increased breaking strength require that a pharmaceutical composition containing the active ingredient be subjected to a specific amount of pressure at a specific elevated temperature over a specific period of time.
Depending on the constituents of the pharmaceutical composition and their quantities, temperature, pressure and time can be varied within certain limits.
However, if the minimum requirements are not met
made, the breaking strength of the resulting pharmaceutical dosage form will be very low.
As a result, some conventional processes for the manufacturer. cation of pharmaceutical dosage forms, particularly for 5 "pharmaceutical dosage forms having an increased resistance to breakage, require comparatively severe process conditions and, thus, are thus far not applicable for oxidation sensitive opioids. In particular, the rupture of the chain of pharmaceutical excipients such as polyethylene oxide during hot melt extrusion risks the formation of free radicals, 10 thereby also increasing oxidative stress. Lower dosages of oxidation-sensitive opioids often show a higher percentage oxidative degradation and decomposition than higher dosages. Thus, with regard to storage stability, pharmaceutical dosage forms containing 15 smaller dosages of oxidation-sensitive opioids need particular attention. The effect of oxidation mechanisms and chemical interactions on the stability of polymer systems for A9-tetrahydrocannabino | a-morph (a non-opioid) produced by a hot fusion method is described 20 in M. Munjal and another, J. Pharm. Sciences, 95 (11), 2006, 2473-85. The study demonstrated for this highly unstable drug a complex nature of interactions including compatibility of excipient drug, use of antioxidants, cross-linking in polymeric matrices, microenvironment pH, and moisture effect. 25 K.C. Waterman and another, Pharm. Develop. Tech. 7 (1), 2002, 1-32 review the stabilization of pharmaceutical products until oxidative degradation. Several methods for reducing oxidation are recommended. The authors conclude that, in the end, each drug presents a unique situation. WO 2008/107149 describes oral dosage forms having an increased break resistance that can contain redox stabilizers such as complexing agents, for example, EDTA. WO 2008/086804 refers to controlled release compositions
containing a matrix composition comprising a) polymer or a mixture of polymers, b) an active drug substance and optionally C) one or more pharmaceutically acceptable excipients, i.e., without
. Sudden release of dose ("dose dumping ') induced by alcohol and have excellent 5" properties in relation to the avoidance of drug violation.
Preferably, the composition is resistant to isolating and / or dissolving the active drug substance from the composition by crushing, melting and / or extracting e-tanol, whereby the composition is resistant to drug violation.
Citric acid can be present as a flavoring agent.
Example 2 relates to a composition containing 7% by weight of citric acid.
WO 2008/148798 describes a pro-release composition. prolonged in layers for prolonged effect and a way to ensure the prolonged effect, for example, administration once a day is to ensure the ideal absorption of the active substance through the gastrointestinal tract, 15 that is, from the stomach to the straight.
There is no general concept to successfully suppress oxidative degradation of drugs sensitive to oxidation in pharmaceutical dosage forms.
The individual complex oxidation mechanisms that are relevant to a particular drug as well as the plurality of possible factors that have an influence on the oxidation processes require extensive investigations in each particular case taking into account the particular circumstances.
It is also known that the other ingredients in pharmaceutical dosage forms can show stability problems when they are exposed to severe process conditions.
For example, high molecular weight polyethylene oxide tends to degrade in hot melt extrusion.
Polymer degradation, however, can result in an uncontrolled release profile, particularly when the active ingredient is embedded in a polyethylene oxide matrix, and could be another cause for oxidative degradation of the active ingredient by radicals.
When adding the appropriate excipients to stabilize high molecular weight polyethylene oxide, such as a-tocopherol, it must be taken into account that the said excipients in turn can have a detrimental effect on the stability of other ingredients of the pharmaceutical dosage, for example, of the $ pharmacologically active compound.
It is an object of the present invention to provide dosage forms. 5 "counterfeit-resistant pharmaceutical gemstones containing opioids, particularly oxidation-sensitive opioids, which have advantages over the prior art pharmaceutical dosage forms.
Pharmaceutical dosage forms must have improved dosage stability, so that they can contain oxidation-sensitive opioids even at comparatively low doses.
In addition, it should be possible to prepare pharmaceutical dosage forms by conventional processes under conventional conditions such as elevated temperature and pressure (for example, during hot melt extrusion thermoforming). of the patent claims.
The invention relates to a thermoformed pharmaceutical dosage form having a breaking strength of at least 300 N and comprising - an opioid (A), 20 - a free physiologically acceptable acid (B) in an amount of 0.001 at 5.0 ° /) by weight, based on the total weight of the pharmaceutical dosage form, and - a polyalkylene oxide (C) having an average molecular weight Mw of at least 200,000 g / mol. 25 It has been surprisingly discovered that certain morphinan talis derivatives such as oxymorphone are oxidatively degraded to N-oxides (for example, oxymorphone-N-oxide, N-oxides in general are often said to be toxic and possibly carcinogenic) in the manufacture and storage of corresponding dosage forms and that the formation of said N-oxides and other decomposition products can be suppressed by the presence of suitable amounts of acid (B) in the pharmaceutical dosage forms according to the invention.
While not intended to be bound by any theory, the acid-stabilizing effect (B) can correlate with 4 the pKa value of oxidation-sensitive opioids.
The pKA value of oxymorph-
. na is 8.3. Conventional oxymorphone formulations, which are 5 "resistant to counterfeiting due to their increased breaking strength, but which do not show desired shelf life, provide a pH value of about 7.5 when dispersed in water.
Under these conditions, a considerable amount of the oxymorphone is present as a free base (i.e., it is not protonated), which may be more sensitive with respect to oxidation than the (protonated) salt form. This concept is also supported by the fact that in the absence of acid (B), the dosage forms tend to have a yellowish beige color, while the presence of acid (B) leads to whiter, for example, tablets colorless, the presence of acid (B) can decrease the pH value within the dosage form, thereby improving resistance with respect to oxidative degradation.
It has surprisingly been found that pharmaceutical excipients that are conventionally used to improve resistance with respect to oxidative degradation, particularly certain antioxidants, for example, a-tocopherol, can be counterproductive and preferably to deter instead of improving resistance. of the drug with respect to oxidative degradation.
In addition, there is experimental evidence that, surprisingly, acid (B) is also capable of stabilizing high molecular weight polyalkylene oxides against degradation, such as polyalkylene (C) oxides having an average molecular weight Mw at least 200,000 g / mol.
The pharmaceutical dosage form according to the invention is thermoformed, preferably by extrusion, although also other thermoforming methods can be used to manufacture a pharmaceutical dosage form according to the invention such as temperature press molding. elevation or heating of tablets that were manufactured by conventional compression in a first stage and then heated above the softening temperature of the polymer in the tablet in a second stage to form hard tablets.
In this regard, thermoforming means forming, or molding, a mass 0 after the application of heat.
In a preferred embodiment, the dosage form
. The pharmaceutical gem is thermoformed by hot melt extrusion. 5 "Preferably, the pharmaceutical dosage form is a monolithic mass.
The pharmaceutical dosage form is preferably prepared by hot melt extrusion.
The melt-extruded filaments are preferably cut into monoliths, which are then preferably formed into tablets.
In this regard, the term "tablets" 10 should preferably not be understood as dosage forms being made by compressing powder or granules (compressi), but preferably - as molded extrudates.
The pharmaceutical dosage form according to the invention contains, as component (A), an opioid (A), preferably an oxidation-sensitive opioid (A), more preferably oxymorphone or oxycodone.
For the purpose of the specification, the term opioid (A) also includes the free base and the physiologically acceptable salt thereof.
According to the ATC Index, opioids are divided into natural opium alkaloids, derivatives of phenylpiperidine, derivatives of different propylamine, derivatives of benzomorph, derivatives of oripavine, derivatives of morphinan and others.
Examples of natural opium alkaloids are morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, papaveretum, and codeine.
Other opioids (A) are, for example, e-tilmorphine, hydrocodone, oxymorphone, and their physiologically acceptable derivatives or compounds, preferably their salts and solvates, preferably their hydrochlorides, physiologically acceptable enantiomers , stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, preferably esters, ethers or amides. Other preferred opioids (A) include N- (1-methyl-2-piperidinoethyl) -N- (2-pyridyl) propionamide, (1 R, 2R) -3- (3-dimethylamino-1-ethyl-2 -methyl-propyl) phenol, (1 R, 2R, 4S) -2- (dimethylamino) methyl-4- (p-fluorobenzyloxy) -1- (m-methoxy-
phenyl) cyclohexanol, (1 R, 2R) -3- (2-dimethyl | aminomethi | -cic | o-hexi |) hay |, (1S, 2S) -3- (3-dimethylamino-1-ethyl | -2 -meti | -propi |) hay |, (2R, 3R) -1-dimethylamino-3 (3-metho-. xiphenyl) -2-methyl-pentan-3-hi, (1 RS, 3RS, 6RS) -6 -dimethylaminomethyl-1- (3-methoxy-
. phenyl) -cyclohexane-1,3-diol, preferably as a racemate, 3- (2-dimethylaminomethylF1-hydroxy-scyllohexyl) phenyl 2- (4-isobutyl-5-nyl) propionate, 2- ( 3- (2-dimethylaminomethyl) 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl, 2- (4-isobutyl-phenyl) propionate 6-methoxy-naphthalen-2-yl) propionate 3- (2-dimethylaminomethyl-cyloxy-1-enyl) -phenyl, 2- (6-methoxy-naphthalen-2-yl) propionate, 3- (2-dimethylaminomethyl acid ester) 2- (6-methoxy-naphthalen-2-yl) propionate -1-hydroxy-cyl-he-10 xyl) -phenyl (RR-SS) -2-acetoxy-4-trifluoromethyl-benzoic, 3- (2-dimethi | aminomethi | -1-hydroxy-cycl | -hexi |) -phenyl (RR-SS) -2-hydroxy-4-trifluoromethyl-benzoic, 3- (2-dimethylaminometik1-hydroxy-cyclohexyl) -phenyl (RR-SS) -4- acid ester chloro-2-hydroxy-benzoic, 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl (RR-SS) -2-hydroxy-4-methyl-benzoic acid ester, 15 3- (2-dimethi | aminomethi | -1-hydroxy-cic | o-hexj |) -pheni | (RR-SS) -2-hydroxy-4-methoxy-benzoic, 3- (2-dimethi | aminomethi | -1-hydroxy-cjc | o-hexi |) -pheni acid ester | (RR-SS) -2-hydroxy-5-nitro-benzoic, 3- (2-dimethylaminometik1- hydroxy-cyclohexyl) -phenyl (RR-SS) -2 ', 4'-difluoro-3- hydroxy-biphenyl-4-carboxylic, 1,1- (3-dimethyl | amino-3-phenyl | pentamethyl | en) -6-Huoro-1, 3,4,9-tetrahydropyric-20 no [3,4 -b] indole, in particular its hemicitrate; 1,1- [3-dimethylamino-3- (2-tienyl) pentamethyl] -1,3,4,9-tetrahydropyran [3,4-b] indole, in particular its citric; and 1,1- [3-dimethyl | amino-3- (2-thieni |) pentamethyl | en] -1, 3,4,9-tetrahydropyric [3,4-b] -6-fluoro- indole, in particular its hemicitrate, and corresponding stereoisomeric compounds, in each case the corresponding derivatives 25 thereof, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, for example, esters, ethers or amides, and in each case the physiologically acceptable compounds thereof, in particular their salts and solvates, for example, hydrochlorides. 30 Preferred opioids (A) are of general formula (I)
lN /, R, ', (I)
IR, O / "O" d: "R 'where R1 is -H, -OH or -OC1-6-a | chi | a; R2 is -H or -C1-6-a1 here | a; 5 R3 is- Hou-OHeR4é-H; orR3eR4joint is = O; and ---- is an optional double bond; or the physiologically acceptable salts thereof.The particularly preferred opioids (A) include oxymorphone, oxycodone, hydromorphone, and the physiologically acceptable salts thereof The content of opioid (A) in the pharmaceutical dosage form is not limited, preferably its content is within the range of 0.01 to 80 ° /) by weight, more preferably 0.1 to 50 ° /) by weight , even more preferably from 1 to 25 ° /) by weight, based on the total weight of the pharmaceutical dosage form In a preferred embodiment, the opioid content (A) is within the range of 7 ± 6 ° /) by weight, more preferably 7 ± 5 ° /) by weight, even more preferably 5 ± 4 ° /) by weight, 7 ± 4 ° /) by weight or 9 ± 4 ° /) in weight, more preferably 5 ± 3 ° /) in weight, 7 ± 3 ° /) in weight or 9 ± 3 ° /) in weight, eemparticu | ar5 ± 2 ° /) weight, 7 ± 2 ° / weight or 9 ± 2 ° / time, with based on the total weight of the pharmaceutical dosage form. In another preferred embodiment, the opioid content (A) is within the range of 11 ± 10 ° / by weight, more preferably 11 ± 9 ° /) by weight, even more preferably 9 ± 6 ° /) weight, 11 ± 6 ° /) weight, 13 ± 6 ° / weight or 15 ± 6 ° /) by weight, more preferably 11 ± 4 ° /) by weight, 13 ± 4 ° /) by weight or 15 ± 4 ° /) weight, and emparticu ar11 ± 2 ° / weight, 13 ± 2 ° / weight or 15 ± 2 ° /) by weight, based on the total weight of the pharmaceutical dosage form. In another preferred embodiment, the opioid content (A) is within the range of 20 ± 6 ° /) by weight, more preferably 20 ± 5 ° /) by weight, even more preferred.
preferably 20 ± 4 ° /) by weight, more preferably 20 ± 3 ° /) by weight, and in particular 20 ± 2 ° /) by weight, based on the total weight of the dosage form. pharmaceutical gem.
Preferably, the total amount of opioid (A) that is contained. 5 "taken in the pharmaceutical dosage form is within the range of 0.01 to 200 mg, more preferably from 0.1 to 190 mg, even more preferably from 1.0 to 180 mg, even more preferably from 1.5 to 160 mg, more preferably 2.0 to 100 mg in particular from 2.5 to 80 mg.
In a preferred embodiment, opioid (A) is contained in the pharmaceutical dosage form in an amount of 7.5 ± 5 mg, 10 ± 5 mg, 20 ± 5mg, 30 ± 5mg, 40 ± 5mg, 50 ± 5mg, 60 ± 5mg, 70 ± 5mg, 80 ± "5mg, 90 ± 5mg, 100 ± 5mg, 110 ± 5mg, 120 ± 5mg, 130 ± 5.140 ± 5mg, 150 ± 5 mg, or 160 ± 5 mg.
In another preferred embodiment, opioid (A) is contained in the pharmaceutical dosage form in an amount of 5 ± 15 2.5mg, 7.5 ± 2.5mg, 10 ± 2.5mg, 15 ± 2.5mg, 20 ± 2.5mg, 25 ± 2.5mg, 30 ± 2.5mg, 35 ± 2.5mg, 40 ± 2.5mg, 45 ± 2.5mg, 50 ± 2.5mg, 55 ± 2.5mg, 60 ± 2, 5mg, 65 ± 2.5mg, 70 ± 2.5mg, 75 ± 2.5mg, 80 ± 2.5mg, 85 ± 2.5mg, 90 ± 2.5mg, 95 ± 2.5mg, 100 ± 2.5mg , 105 ± 2.5mg, 110 ± 2.5mg, 115 ± 2.5mg, 120 ± 2.5mg, 125 ± 2.5mg, 130 ± 2.5mg, 135 ± 2.5mg, 140 20 ± 2.5mg, 145 ± 2.5mg, 150 ± 2.5mg, 155 ± 2.5mg, or 160 ± 2.5mg.
In a particularly preferred embodiment, opioid (A) is oxymorphone, preferably its HCl salt, and the pharmaceutical dosage form is adapted for administration twice a day.
In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of 5 to 40 mg.
In another particularly preferred embodiment, opioid (A) is oxymorphone, preferably its HCI, and the pharmaceutical dosage form is adapted for administration once a day.
In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of 10 to 80 mg. 30 In another particularly preferred embodiment, opioid (A) is oxycodone, preferably its HCl salt, and the pharmaceutical dosage form is adapted for administration twice a day.
In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of 5 to 80 mg.
In another particularly pre- modality. wound, opioid (A) is oxycodone, preferably its HCl, and the donor form
. Pharmaceutical message is adapted for administration once a day.
In this 5 "embodiment, opioid (A) is preferably contained in a pharmaceutical, dosage form in an amount of 10 to 320 mg.
In yet another particularly preferred embodiment, opioid (A) is hydromorphone, preferably its HCl, and the pharmaceutical dosage form is adapted for administration twice a day.
In this mode, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of 2 to 52 mg.
In another particularly preferred embodiment, opioid (A) is hydromorphone, preferably its HCl, and the pharmaceutical dosage form is adapted for administration once a day.
In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of 4 to 104 mg.
The pharmaceutical dosage form according to the invention is characterized by excellent storage in stability.
Preferably, after storage for 4 weeks at 40 ° C and 75 ° / o relative humidity, the opioid content (A) rises to at least 98.0%, more preferably at least 20 to 98.5%, even more preferably at least 99.0%, even more preferably at least 99.2%, more preferably at least 99.4% and in particular at least 99.6%, of its original content prior to storage.
Suitable methods for measuring the content of opioid (A) in pharmaceutical dosage form are known to those skilled in the art.
In this respect, Eur.
Ph. Or USP, especially reverse phase HPLC analysis.
Preferably, the pharmaceutical dosage form is stored in preferably sealed, closed containers, preferably as described in the experimental section, more preferably being equipped with an oxygen scavenger, in particular with an oxygen scavenger which is effective even in low relative humidity.
The pharmaceutical dosage form according to the invention contains, as component (B), a physiologically acceptable free acid in an amount of 0.001 to 5.0 ° /) by weight, based on the total weight of the pharmaceutical dosage form .
The acid (B) can be organic or inorganic, II. liquid or solid.
Solid acids are preferred, particularly acids
. organic or inorganic crystals. 5 "Acid (B) is free. This means that the acidic functional groups of acid (B) are not all together constituents of an opio- salt of (A). If opioid (A) is present as a salt of an acid, for example, as hydrochloride, the pharmaceutical dosage form according to the invention preferably contains as component (B) another chemically different acid which is not present as a constituent of the opioid salt ( In other words, monoacids that form an opioid salt (A) should not be considered as free acids (B) in the sense of the present invention.
When acid (B) has more than a single acidic functional group (for example, phosphoric functional acid), acid (B) 15 may be present as a constituent of an opioid salt (A), with the proviso that at least one of the acidic functional groups of acid (B) is not involved in the formation of the salt, that is, it is free.
Preferably, however, each and every functional acid group (B) is not involved in the formation of a salt with opioid (A). It is also possible, however, that the free acid (B) and the acid that forms a salt with opioid (A) are identical.
Under these circumstances, acid (B) is preferably present in molar excess compared to opioid (A). In a preferred embodiment, the acid (B) contains at least one acidic functional group (for example, -CO2H, -SO3H, -PO3H2, -OH and si-25) having a PKa value within the range of 2.00 ± 1.50, more preferably 2.00 ± 1.25, even more preferably 2.00 ± 1.00, even more preferably 2.00 ± 0.75, more preferably 2.00 ± 0.50 and in particular 2.00 ± 0.25. In another preferred embodiment, acid (B) contains at least one acidic functional group having a PKÁ value within the range of 2.25 ± 1.50, more preferably 2.25 ± 1.25, even more preferably 2.25 ± 1.00, even more preferably 2.25 ± 0.75, more preferably 2.25 ± 0.50 and in particular 2.25 ± 0.25. In another preferred embodiment, acid (B) contains V
13/65 has at least one acidic functional group having a PR value within the range of 2.50 ± 1.50, more preferably 2.50 ± 1.25, even more preferred. 2.50 ± 1.00, even more preferably 2.50 ± 0.75, more preferably
. 2.50 ± 0.50 and in particular 2.50 ± 0.25. In another pre-wound form, acid (B) contains at least one acidic functional group having a PR value within the range of 2.75 ± 1.50, more preferably 2.75 ± 1.25, <even more preferably 2.75 ± 1.00, even more preferably 2.75 ± 0.75, more preferably 2.75 ± 0.50 and in particular 2.75 ± 0.25 In another preferred embodiment, acid (B) contains at least one acidic functional group 10 having a pKa value within the range of 3.00 ± 1.50, more preferably 3.00 ± 1.25, even more preferably 3.00 ± 1.00, even more preferable - approximately 3.00 ± 0.75, more preferably 3.00 ± 0.50 and in particular 3.00 ± 0.25 In yet another preferred embodiment, acid (B) contains at least one acidic functional group having a PKa value within the range of 3.25 ± 15 1.50, more preferably 3.25 ± 1.25, even more preferably 3.25 ± 1.00, even more preferably 3.25 ± 0.75, most preferably 3 , 25 ± 0.50 and in particular 3.25 ± 0.25 In yet another preferred embodiment, the acid (B) contains at least one acidic functional group having a pKA value within the range of 20 4.50 ± 1.50, more preferably 4.50 ± 1.25, even more preferably 4.50 ± 1.00, still more preferably 4.50 ± 0.75, more preferably 4.50 ± 0.50 and in particular 4.50 ± 0.25. In yet another preferred embodiment, acid (B) contains at least one acidic functional group having a PKa value within the range of 4.75 ± 1.50, more preferably 4.75 ± 1.25, even 25 most preferably 4.75 ± 1.00, even more preferably 4.75 ± 0.75, more preferably 4.75 ± 0.50 and in particular 4.75 ± 0.25. In yet another preferred embodiment, acid (B) contains at least one acidic functional group having a PI value (a within the range of 5.00 ± 1.50, more preferably 5.00 ± 1.25, even more preferably 5.00 ± 1.00, even more preferably 5.00 ± 0.75, more preferably 5.00 ± 0.50 and in particular 5.00 ± 0.25, preferably acid (B) it is an organic or sulfonic carboxylic acid, particularly a carboxylic acid.
Multicarboxylic acids and / or hydroxy carboxylic acids are especially preferred. q
In the case of multicarboxylic acids, the partial salts of the same should also be considered as multicarboxylic acids, for example "the partial sodium, potassium or ammonium salts.
For example, citric acid is a multicarboxylic acid having three carboxyl groups.
Since there is at least one protonated carboxyl group (for example, sodium dihydrogen citrate or disodium hydrogen citrate), the salt should be considered as a multicarboxylic acid.
Preferably, however, all the carboxyl groups of the multicarboxylic acids are protonated.
Preferably, acid (B) is of low molecular weight, that is, unpolymerized.
Typically, the molecular weight of acid (B) is below 500 g / mol.
Examples of acids include saturated and unsaturated monocarboxylic acids, saturated and unsaturated bicarboxylic acids, tricarboxylic acids, γ-hydroxy acids and γ-hydroxy acids of monocarboxylic acids, γ-hydroxy acids and Î ± -hydroxy acids of carboxylic acids, γ-hydroxy acids and - hydroxy acids of tricarboxylic acids, keto acids, α-keto acids, β-keto acids, polycarboxylic acids, polyhydroxy monocarboxylic acids, 20 of polyhydroxy carboxylic acids, polyhydroxy tricarboxylic acids.
Preferably, acid (B) is selected from the group consisting of benzenesulfonic acid, citric acid, a-glycoeptonic acid, D-glyconic acid, glycolic acid, lactic acid, lactic acid, malonic acid, mandelic acid, propionic acid, succinic acid , tartaric acid (d, I, or dl), tonic acid (toluenesulfonic acid), valeric acid, palmitic acid, pamacic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, glutamic acid, 4 -chlorobenzenesulfonic acid, ethanedisulfonic acid, ethyl succinic acid, fumaric acid, galactaric acid (MUC-30 CO), D-glucuronic acid, 2-oxo-glutaric acid, glycerophosphoric acid, hippuric acid, isethionic acid (ethanolsulfonic acid), lactobionic, maleic acid, maleinic acid, 1,5-naphthalene-disulfonic acid, 2-naphthalene-
sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecyl sulphate, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, oleic acid,
P undecylenic acid, ascorbic acid, (") -phorphic acid, d-camphorsulfonic acid., Dichloroacetic acid, ethanesulfonic acid, formic acid, meta-5" oursulfonic acid, nicotinic acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharin, salicylic acid, gentisic acid, and / or 4- acid. acetamidobenzoic. The acid content (B) is within the range of 0.001 to 5.0 ° /) by weight, preferably from 0.005 to 2.5 ° /) by weight, more preferably from 0.01 to 10 2.0 ° 6 in weight, even more preferably from 0.05 to 1.5 ° /) by weight, more preferably from 0.1 to 1.0 ° /) by weight and in particular from 0.2 to 0.9 ° /) by weight , based on the total weight of the pharmaceutical dosage form. Preferably, acid (B) is a multi-carboxylic acid. More preferably, the multicarboxylic acid is selected from the group consisting of citric acid, maleic acid and fumaric acid. Citric acid is particularly preferred. Multicarboxylic acid, preferably citric acid, can be present in its anhydrous form or as a solvate and hydrate, respectively, for example, as monohydrate. 20 In a preferred embodiment, the content of acid (B), preferably citric acid, is within the range of 0.2 ± 0.18 ° / 0 by weight, more preferably 0.2 ± 0.15 ° /) by weight, even more preferably 0.2 ± 0.12 ° /) by weight, even more preferably 0.2 ± 0.09 ° /) by weight, more preferably 0.2 ± 0.06 ° / ) by weight, and in particular 0.2 ± 0.03 ° /) by weight, based on the total weight of the pharmaceutical dosage form. In another preferred embodiment, the content of acid (B), preferably citric acid, is within the range of 0.3 ± 0.18 ° /) by weight, more preferably 0.3 ± 0.15 ° / ) by weight, even more preferably 0.3 ± 0.12 ° /) by weight, even more preferably 0.3 ± 0.09 ° /) by weight, more preferably 30 ± 0.3 ± 0.06 ° / ) by weight, and in particular 0.3 ± 0.03 ° / 0 by weight, based on the total weight! pharmaceutical dosage form. In yet another preferred embodiment, the acid content (B), preferably
preferably citric acid, is within the range of 0.4 ± 0.18 ° /) by weight, more preferably 0.4 ± 0.15 ° /) by weight, even more preferably 0.4 ± 0.12 m
° /) by weight, even more preferably 0.4 ± 0.09 ° /) by weight, more preferably
. 0.4 ± 0.06 ° /) by weight, and in particular 0.4 ± 0.03 ° /) by weight, with 5 "basis on the total weight of the pharmaceutical dosage form.
In yet another preferred embodiment, the acid content (B), preferably. preferably citric acid, is within the range of 0.5 ± 0.18 ° /) by weight, more preferably 0.5 ± 0.15 ° /) by weight, even more preferably 0.5 ± 0.12 ° /) by weight, even more preferably 0.5 ± 0.09 ° / 0 by weight, more preferably 0.5 ± 0.06 ° /) by weight, and in particular 0.5 ± 0.03 ° /) by weight, based on the total weight of the pharmaceutical dosage form.
In yet another preferred embodiment, the content of acid (B), preferably citric acid, is within the range of 0.6 ± 0.18 ° /) by weight, more preferably 0.6 ± 0.15 ° /) by weight, even more preferably 0.6 ± 0.12 ° /) by weight, even more preferably 0.6 ± 0.09 ° /) by weight, more preferably 0.6 ± 0.06 ° /) by weight, and in particular 0.6 ± 0.03 ° /) by weight, based on the total weight of the pharmaceutical dosage form.
In yet another preferred embodiment, the content of acid (B), preferably citric acid, is within the range of 0.7 ± 0.18 ° /) by weight, plus 20 preferably 0.7 ± 0.15 ° / ) by weight, even more preferably 0.7 ± 0.12 ° /) by weight, even more preferably 0.7 ± 0.09 ° /) by weight, more preferably 0.7 ± 0.06 ° /) by weight, and in particular 0.7 ± 0.03 ° /) by weight, based on the total weight of the pharmaceutical dosage form.
In yet another preferred embodiment, the content of acid (B), preferably citric acid, is within the range of 0.8 ± 0.18 ° /) by weight, more preferably 0.8 ± 0.15 ° / ) by weight, even more preferably 0.8 ± 0.12 ° /) by weight, even more preferably 0.8 ± 0.09 ° /) by weight, more preferably 0.8 ± 0.06 ° /) by weight, and in particular 0.8 ± 0.03 ° /) by weight, based on the total weight of the pharmaceutical dosage form. In yet another preferred embodiment, the content of acid (B), preferably citric acid, is within the range of 0.85 ± 0.18 ° /) by weight, more preferably 0.85 ± 0.15 ° / 0 by weight, even more preferably 0.85 ±
0.12% by weight, even more preferably 0.85 ± 0.09 ° /) by weight, more preferably 0.85 + 0.06 ° /) by weight, and in particular 0.85 ± 0.03 ° /) ) in »weight, based on the total weight of the pharmaceutical dosage form.
. In yet another preferred embodiment, the content of acid (B), preferably 5 "citric acid, is within the range of 0.9 ± 0.18 ° /) by weight, more preferably 0.9 ± 0.15 ° /) by weight, even more preferably 0.9 ± 0.12 ° /) by weight, even more preferably 0.9 ± 0.09 ° /) by weight, more preferably 0.9 + 0.06 ° /) by weight, and in particular 0.9 ± 0.03 ° /) by weight, based on the total weight of the pharmaceutical dosage form 10 In another preferred embodiment, the acid content (B), preferably citric acid, is within the range of 1.0 ± 0.18 ° /) by weight, more preferably 1.0 ± 0.15 ° /) by weight, even more preferably 1.0 ± 0.12 ° / ) by weight, even more preferably 1.0 ± 0.09 ° /) by weight, more preferably 1.0 ± 0.06 ° /) by weight, and in particular 1.0 ± 0.03 ° /) by weight, based on the total weight of the pharmaceutical dosage form The pharmaceutical dosage form according to the invention comprises, as component (C), a polyalkylene oxide (C) having a weight molecular weight Mw of at least 200,000 g / mol, preferably at least 500,000 g / mol, more preferably at least 750,000 20 g / mol, even more preferably at least 1,000,000 g / mol, most preferably at least 2,000 .000 g / mol and in particular within the range of from 500,000 to 15,000,000 g / mol. Preferably, the polyalkylene oxide is selected from the group consisting of polymethylene oxide, polyethylene oxide and polypropylene oxide, in the copolymers and mixtures thereof. Polyalkylene oxide (C) can comprise a single polyalkylene oxide having a particular average molecular weight, or a mixture (combination) of different polymers, such as two, three, four, or five polymers, for example, polymers of same chemical nature, but different average molecular weight, polymers of different chemical nature, but the same average molecular weight, or polymers of different chemical nature as well as different molecular weight.
For the purpose of the specification, a polyalkylene glycol has a molecular weight of up to 20,000 g / mol while a polyalkylene oxide has b a molecular weight of greater than 20,000 g / mol.
In a modality
- wound, the average weight over all the molecular weights of all 5 "polyalkylene oxides that are contained in the pharmaceutical dosage form is at least 200,000 g / mol.
Thus, polyalkylene glycols, if any, are preferably not taken into account when determining the average molecular weight of polyalkylene oxide (C). Preferably, the content of p-alkylene oxide (C) is within the range of 20 to 99 ° /) by weight, more preferably 25 to 95 ° /) by weight, even more preferably from 30 to 90 ° /) by weight , even more preferably from 30 to 85 ° /) by weight, more preferably from 30 to 80 ° /) by weight and in particular from 30 to 75 ° /) by weight, based on the total weight of the pharmaceutical dosage form .
In a preferred embodiment, the polyalkylene oxide content is at least 20 ° /) by weight, more preferably at least 25 ° /) by weight, even more preferably at least 30 ° /) by weight, even more preferably at least 35 ° /) by weight and in particular at least 40 ° /) by weight.
In a preferred embodiment, the total content of polyalkylene oxide (C) is within the range of 25 ± 20 ° /) by weight, more preferably 25 ± 15 ° /) by weight, more preferably 25 ± 10 ° / ) by weight, and in particular 25 ± 5 ° /) by weight.
In another preferred embodiment, the total content of polyalkylene oxide (C) is within the range of 35 ± 20 ° /) by weight, more preferably 35 ± 15 ° /) by weight, more preferably 35 ± 10 ° /) by weight, and in particular 35 ± 5 ° /) by weight.
In yet another preferred embodiment, the total content of polyalkylene oxide (C) is within the range of 45 ± 20 ° /) by weight, more preferably 45 ± 15 ° /) by weight, more preferably 45 ± 10 ° / ) by weight, and in particular 45 ± 5 ° /) by weight.
In yet another preferred embodiment, the total content of polyalkylene oxide (C) is within the range of 55 ± 20 ° /) by weight, 30 more preferably 55 ± 15 ° /) by weight, more preferably 55 ± 10 ° /) by weight, and in particular 55 ± 5 ° /) by weight.
In another preferred embodiment, the total content of polyalkylene oxide (C) is within the range of 65 ± 20
° /) by weight, more preferably 65 ± 15 ° /) by weight, more preferably 65 ± 10 ° /) by weight, and in particular 65 ± 5 ° /) by weight.
In yet another preferred embodiment, the total content of polyalkylene oxide (C) is within the
- range of 75 ± 20 ° /) by weight, more preferably 75 ± 15 ° /) by weight, plus 5 "preferably 75 ± 10 ° / 0 by weight, and in particular 75 + 5 ° / by weight.
In
Yet another preferred embodiment, the total content of polyalkylene oxide (C) is within the range of 80 ± 15 ° /) by weight, more preferably 80 ± 10 ° /) by weight, and more preferably 80 ± 5 ° / ) by weight.
In a preferred embodiment, the polyalkylene oxide (C) is homogeneously distributed in the pharmaceutical dosage form according to the invention.
Preferably, polyalkylene oxide (C) forms a matrix in which the opioid (A) is embedded.
In a particularly preferred embodiment, the opioid (A) and polyalkylene oxide (C) are intimately homogeneously distributed in the pharmaceutical dosage form so that the pharmaceutical dosage form does not contain any segment where opioid (A) is. present in the absence of po | ia | chiene oxide (C) or where poHalkylene oxide (C) is present in the absence of opioid (A). When the pharmaceutical dosage form is film coated, the polyalkylene oxide (C) is preferably homogeneously distributed in the core of the pharmaceutical dosage form, that is, the film coating preferably does not contain polyalkylene oxide (C ). However, the film coating as such can certainly contain one or more polymers, which, however, preferably differ from the polyalkylene oxide (C) contained in the core. 25 Polyalkylene oxide (C) can be combined with one or more different polymers selected from the group consisting of polyalkylene oxide, preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyvinylpyrrolidone, poly (alkyl) acrylate, poly (hydroxy fatty acids), such as, for example, poly (3-hydroxybutyrate-co-3-hydroxyvalerate) ( Biopo | ®), poly (hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol,
liesteramide, polyethylene succinate, polylactone, polyglichide, polyurethane,
polyamide, polylactide, polyacetal (eg, polysaccharides optionally with modified side chains), polyacid / glycohyde, polylactone, »polyglycolide, polyiorto.ester, polyanhydride, polyethylene blocking polymers. polybutylene glycol and terephthalate (Polyactive "), polyanhydride (PoIyfeprosan), 5" copolymers thereof, blocking copolymers thereof, and mixtures of at least two of the established polymers, or other polymers with the above characteristics. Preferably, the molecular weight dispersion MJM, of polyalkylene oxide (C) is within the range of 2.5 ± 2.0, more preferably - 10 2.5 ± 1.5, even more preferably 2.5 ± 1.0, even more preferably 2.5 ± 0.8, more preferably 2.5 ± 0.6, and in particular 2.5 ± 0.4. "Polyalkylene oxide (C) preferably has a viscosity at 25 ° C of 30 to 17.6 Pa.s (17,600 CP), more preferably from 0.055 to 17.6 Pa s (55 to 17,600 CP), still more preferably from 0.6 to 17.6 Pa s 15 (600 to 17.600 cP) and most preferably from 4.5 to 17.6 Pas (4.500 to 17.600 CP), measured in a 5 ° aqueous solution) by weight using a viscosity - Brookfield RVF model (spindle no. 2 / rotary speed 2 rpm); from 0.4 to 4.0 Pa s (400 to 4,000 CP), more preferably 4.0 to 0.8 Pa s (400 to 800 cP ) or 2.0 to 4.0 Pa s (2,000 to 4,000 CP), measured in an aqueous solution at 220 ° /) by weight using the established viscometer (spindle no. 1 or 3 / rotary speed 10 rpm); or from 1.65 to 10.0 Pa s (1.650 to 10,000 cP), more preferably 1.65 to 5.5 Pa (1.650 to 5.550 OcP), 5.5 to 7.5 Pa (5.50 to 7.500 CP) or 1.65 to 10 , 0 Pa s (7,500 to 10,000 CP), measured in an aqueous solution at 1 ° /) by weight using the established viscometer (spindle no. 2 / speed of rotation 2 rpm). according to the invention polyalkylene oxide (C) having an average molecular weight of at least
200,000 g / mol is combined with at least one other polymer, preferably, but not necessarily, also having a molecular weight of 30 average weight (Mw) of at least 200,000 g / mol, selected from the group consisting of polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, poly (hydroxy fatty acids), polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene succinate, polylactone, polyglycolide, polyurethane, po | , polylacid, polylactide / gly-. colloid, polyLactone, polyglycolide, polyLoester, polyanhydride, polymers of
. blocking of polyethylene glycol and polybutylene terephthalate, polyanhydride, poly-5 "ketal, cellulose esters, cellulose ethers and cups thereof.
Cellulose esters and cellulose ethers are particularly preferred, for &
for example, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose hydroxypropyl | methyl | cellulose, carboxymethylcellulose, and the like. In a preferred embodiment, the other said polymer is neither a polyalkylene oxide nor a polyalkene.
However, the pharmaceutical dosage form can contain polyalkylene glycol, for example, as a plasticizer, but then the pharmaceutical dosage form is preferably a ternary mixture of polymers: polyalkylene oxide 15 (C) + another polymer + plasticizer .
In a particularly preferred embodiment, another said polymer is a hydrophilic cellulose ester or cellulose ether, preferably hydroxypropylmethyl (HPMC), hydroxypropylcellulose (HPC) or hydroxyethylcellulose (HEC), preferably having a viscosity average (preferably measured by capillary viscometry or rotary viscometry) from 1,000 to 150,000 mPas, more preferably from 3,000 to 150,000. In a preferred embodiment, the average viscosity is within the range of 110,000 ± 50,000 mPas, more preferably 110,000 ± 40,000 mPas, even more preferably 110,000 ± 30,000 mPas, more preferably 110,000 ± 20,000 25 mPas, and in particular 100,000 ± 10,000 mPas.
In a preferred embodiment the relative weight ratio of said polyalkylene oxide (C) and another said polymer is within the range of 20: 1 to 1:20, more preferably 10: 1 to 1:10, even more preferably from 7: 1 to 1: 5, even more preferably from 5: 1 to 1: 1, more preferably 30 from 4: 1 to 1.5: 1 and in particular 3: 1 to 2: 1. In a preferred embodiment, the relative weight ratio of said polyalkylene oxide (C) and another referenced polymer is within the range of 10: 1 to 5: 1, more preferably 8: 1 to
5: 1, more preferably 7: 1 to 5: 1. Preferably, the content of said other polymer is from 0.5% to 25% by weight, more preferably from 1.0 to 20% by weight, even more. preferably at 2.0 to 22.5 ° /) by weight, even more preferably at 3.0 to 5 "20 ° /) by weight and more preferably at 4.0 to 17.5 ° /) by weight and in particular -
W to 5.0 to 15 ° / wt, based on the total weight of the pharmaceutical dosage form. In a preferred embodiment, the other polymer is a cellulose ester or cellulose ether, preferably HPMC, having a content within the range of 10 ± 8 ° /) by weight, more preferably 10 ± 6 ° /) by weight, still - most preferably 10 ± 5 ° /) by weight, even more preferably 10 ± 4 ° /) by weight, more preferably 10 ± 3 ° /) by weight, and in particular 10 ± 2 ° /) by weight, based on in the total weight of the pharmaceutical dosage form. In another preferred embodiment, the other polymer is a cellulose ester 15 or cellulose ether, preferably HPMC, having a content within the range of 14 ± 8 ° /) by weight, more preferably 14 ± 6 ° /) in weight, even more preferably 14 ± 5 ° /) by weight, even more preferably 14 ± 4 ° /) by weight, more preferably 14 ± 3 ° /) by weight, and in particular 14 ± 2 ° /) by weight, with based on the total weight of the pharmaceutical dosage form. All polymers are preferably used as powders. They can be soluble in water. In addition to opioid (A), acid (B) and polyalkylene oxide (C), the pharmaceutical dosage form according to the invention can contain 25 other substituents, such as conventional pharmaceutical excipients. Preferably, the pharmaceutical dosage form comprises an antioxidant. Suitable antioxidants include ascorbic acid, α-tocopherol (vitamin E), butylhydroxyanisol, butylhydroxytoluene, ascorbic acid salts (vitamin C), ascorbic palmitate, monothioglycerine, coniferyl benzoate, nordihydroguaiaretic acid, esters of acid of ga // us, phosphoric acid, and derivatives thereof, such as vitamin E succinate or vitamin E palmitate and / or sodium bisulfide, more preferably butyl-
hydroxytoluene (BHT) or butylhydroxyanisol (BHA) and / or a-tocopherol.
Preferably, the antioxidant content is within the range of * 0.001 to 5.0 ° /) by weight, more preferably from 0.002 to 2.5 ° /) by weight,
· More preferably 0.003 to 1.5 ° /) by weight, even more preferably 5 "0.005 to 1.0 ° /) by weight, even more preferably 0.01 to 0.5 ° /) by weight,
More preferably, 0.05 to 0.4 ° /) by weight and in particular 0.1 to 0.3 ° /) by weight, based on the total weight of the pharmaceutical dosage form.
A particularly preferred antioxidant is a-tocopherol.
It has surprisingly been found that a-tocopherol stabilizes polyalkyl-1O oxide in and simultaneously destabilizes certain opioids (A), such as oxymorphine.
Thus, in a preferred embodiment, the content of α-tocopherol is balanced between sufficient stability of polyoxide oxide on the one hand and sufficient stability of opioid (A) on the other hand.
In a preferred embodiment, the α-tocopherol content is within the range of 0.2 + 0.18 ° /) by weight, more preferably 0.2 ± 0.15 ° /) by weight, even more preferably 0, 2 ± 0.12 ° /) by weight, even more preferably 0.2 ± 0.09 ° /) by weight, more preferably 0.2 ± 0.06 ° /) by weight, and in particular 0.2 ± 0.03 ° /) by weight, based on the total weight of the pharmaceutical dosage form. 20 In a preferred embodiment, the relative weight ratio of acid (B), preferably citric acid, and the antioxidant, preferably a-tocopherol, is within the range of 10: 1 to 1:10, more preferably 8: 1 to 1: 8, even more preferably from 6: 1 to 1: 6, even more preferably from 5: 1 to 1: 4, more preferably from 4: 1 to 1: 3 and in particular from 3: 1 to 1: 2. The pharmaceutical dosage form according to the invention may also contain a semi-synthetic or synthetic, natural wax.
Synthetic waxes with a softening point of at least 50 ° C, more preferably 60 ° C are preferred.
Carnauba wax and beeswax are particularly preferred, especially carnauba wax. Preferably, the opioid release profile (A) is delayed by the matrix.
Preferably, the opioid (A) is embedded in a matrix comprising the polyoxide, said matrix controlling the release of the opioid (A) from the pharmaceutical dosage form.
Physiologically acceptable materials that are known for example. The person skilled in the art can be used as supplementary matrix materials.
Polymers, particularly preferably 5 "cellulose esters, cellulose ethers and / or acrylic resins are preferably used as hydrophilic matrix materials.
Ethylcellulose, hydroxypropylmethylcellu-. lose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, poly (meth) acrylic acid and / or derivatives thereof, such as the salts, amides or esters thereof, are very particularly preferably used as matrix materials.
Matrix materials prepared from hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, corresponding fatty alcohols or esters or ethers or mixtures thereof are also preferred.
Mono- or diglycerides of C12-C30 fatty acids and / or C12-C30 fatty alcohols and / or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.
It is possible to use mixtures of the hydrophobic and hydrophilic materials set out above as matrix materials.
Preferably, the relative weight ratio of the polyalkylene oxide to the opioid (A) is at least 0.5: 1, more preferably at least 20 1: 1, at least 2: 1, at least 3: 1, at least least 4: 1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1 or at least 9: 1; even more preferably at least 10: 1 or at least 15: 1, even more preferably at least 20: 1, more preferably at least 30: 1 and in particular at least 40: 1. In a preferred embodiment, the relative weight ratio of polyalkylene oxide to opioid (A) is within the range of 3: 1 to 50: 1, more preferably 3: 1 to 40: 1 and in particular 3: 1 to 30: 1. The pharmaceutical dosage form according to the invention preferably contains a plasticizer.
The plasticizer improves the processability of polyalkylene oxide.
A preferred polystyrene is polyalkylene 30 glycol, type polyethylene glycol, triacetin, fatty acids, fatty acid esters, waxes and / or microcrystalline waxes.
Particularly preferred plasticizers are polyethylene glycols, such as PEG 6000.
Preferably, the content of the plasticizer is within the range of 0.1 to 25 ° /) by weight, more preferably from 0.5 to 22.5 ° /) by weight, even more
N preferably 1.0 to 20 ° /) by weight, even more preferably 2.5 to 17.5 ° /) by weight, more preferably from 5.0 to 15 ° /) by weight and in particular '5' 7 , 5 to 12.5 ° /) by weight, based on the total weight of the pharmaceutical dosage form In a preferred embodiment, the plasticizer is a polyalkylene glycol having a content within the range of 10 ± 8 ° /) by weight, more preferably 10 ± 6 ° /) by weight, even more preferably 10 ± 5 ° /) by weight, 10 even more preferably 10 ± 4 ° /) by weight, more preferably 10 ± 3 ° /) in weight, and in particular 10 ± 2 ° /) by weight, based on the total weight of the pharmaceutical dosage form In another preferred embodiment, the plasticizer is a polyalkylene glycol having a content within the range of 15 ± 8 ° /) in weight, more preferably 15 ± 6 ° /) by weight, even more preferably 15 ± 5 ° /) by weight, even more preferably 15 ± 4 ° /) by weight, more preferably 15 ± 3 ° /) by weight , and in particular 15 ± 2 ° /) by weight, based on the weight total amount of the pharmaceutical dosage form. In a preferred embodiment, the relative weight ratio of the polyalkylene oxide to the polyalkylene glycol is within the range of 4.2 ± 2: 1, more preferably 4.2 ± 1.5: 1, even more preferably 4 , 2 ± 1: 1, even more preferably 4.2 ± 0.5: 1, more preferably 4.2 ± 0.2: 1, and in particular 4.2 ± 0.1: 1. This relationship meets the requirements high relative polyalkylene oxide content and good extrudability. 25 During the manufacture of the slice dosage forms that are obtained by cutting the extruded filament, the weight of the slices determines the weight of the resulting dosage form. The pronounced variation in weight of these slices results in a concordant weight deviation of dosage forms from the target weight. The weight variation of the slices depends on the surface properties of the extruded filament. A filament with a completely smooth surface allows the generation of slices with a low weight variation. On the contrary, a waxy filament or shark skin
slices with a greater variation in weight, thereby increasing the number of refuse. 0 It has recently been surprisingly discovered that the surface properties of the extruded filament can be activated by the 5 "weight ratio of po | ia | chi | eno oxide: po | ia | chi [en glycol.
The preferred compositions from Xj to X32 of the pharmaceutical dosage form according to the invention are summarized in the tables here below: ° /) by weight XXX opioid (A) (for example, HCI of oxy- 1.50 ± 1.50 ± 1.50 ± 1.50 ± morphone) 1.25 1.00 0.75 0.50 acid (B) (for example, citric acid) 0.5 ± 0.30 0.5 ± 0.25 0, 5 ± 0.20 0.5 ± 0.15 pohalguilene oxide (C) 77 ± 22 77 ± 20 77 ± 15 77 ± 10 cellulose ester or ether (for example 12 ± 10 12 ± 7.5 12 ± 5 12 ± 2.5 plo, HPMC) plasticizer (for example, PEG) 10 ± 7.5 10 ± 5 10 ± 2.5 10 ± 1.0 antioxidant (for example, a-0.2 ± 0.12 0, 2 ± 0.1 0.2 ± 0.05 0.2 ± 0.03 tocopherol) ° /) by weight XXX opioid (A) (e.g. ± 2.33 ± morphone) 1.25 1.00 0.75 0.50 acid (B) (for example, citric acid) 0.85 ± 0.85 ± 0.85 ± 0.85 ± 0.60 0 , 50 0.25 0.15 po | ia | chiene (C) oxide 70 ± 25 70 ± 20 70 ± 15 70 ± 10 cellulose ester or ether (for example 10 ± 9.5 10 ± 7, 5 10 ± 5 10 ± 2.5 plo, HPMC) plasticizer (eg PEG) 16.6 ± 7.5 16.6 ± 5 16.6 ± 2.5 16.6 ± 1.0 antioxidant (eg, a-tocofe- 0.2 ± 0.12 0.2 ± 0.1 0.2 ± 0.05 0.2 ± 0.03 roll) 10 ° /) by weight X9 l X10 I Xjj X12 opioid (A) .- (for example, HCl oxy- 3.50 ± [3.50 ± I 3.50 ± 3.50 ± morphone) 1.25 1.00 0.75 0.50 acid (B) (e.g. citric acid) 0.85 ± 0.85 ± 0.85 ± 0.85 ±
0.60 0.50 0.25 0.15 polyalkylene oxide (C) 69 ± 30 69 ± 20 69 ± 15 69 ± 10
"cellulose ester or ether (eg 10 ± 9.5 10 ± 7.5 10 ± 5 10 ± 2.5
. plo, HPMC) plasticizer (for example, PEG) 16.4 ± 7.5 16.4 ± 5 16.4 ± 2.5 16.4 ± 1.0 antioxidant (for example, a-tocopherol) 0.2 ± 0.12 0.2 ± 0.1 0.2 ± 0.05 0.2 ± 0.03
° /) by weight X13 X14 X15 X16 opioid (A) (eg oxy- 4.65 ± 4.65 ± 4.65 ± 4.65 ± morphone HCl) 1.25 1.00 0.75 0, 50 acid (B) (eg citric acid) 0.85 ± 0.85 ± 0.85 ± 0.85 ±
0.60 0.50 0.25 0.15 polyalkylene oxide (C) 68 ± 30 68 ± 20 68 ± 15 68 ± 10 cellulose ester or ether (for example 10 ± 9.5 10 ± 7.5 10 ± 5 10 ± 2.5 plo, HPMC)
plasticizer (eg PEG) 16.2 ± 7.5 16.2 ± 5 16.2 ± 2.5 16.2 ± 1.0 antioxidant (for example, α-stub- 0.2 ± 0.12 0 , 2 ± 0.1 0.2 ± 0.05 0.2 ± 0.03 ferol)
° /) by weight X17 X18 X19 X20 opioid (A) (eg oxy-6.98 ± 6.98 ± 6.98 ± 6.98 ± 6.9 ± morphone HCl) 1.25 1.00 0.75 0, 50 acid (B) (eg citric acid) 0.85 ± 0.85 ± 0.85 ± 0.85 ± 0.60 0.50 0.25 0.15 polyalkylene oxide (C) 66 ± 30 66 ± 20 66 ± 15 66 ± 10 cellulose ester or ether (eg 10 ± 9.5 10 ± 7.5 10 ± 5 10 ± 2.5 µl, HPMC)
plasticizer (for example, PEG) 15.8 ± 7.5 15.8 ± 5 15.8 ± 2.5 15.8 ± 1.0 antioxidant (for example, a-toco- 0.2 ± 0.12 0 , 2 ± 0.1 0.2 ± 0.05 0.2 ± 0.03 ferol)
° /) Yl weight X21 X22 X23 X24 opioid (A) (for example, HCl of 9.30 ± 9.30 ± 9.30 ± 9.30 ± oxymorphone) 1.25 1.00 0.75 0.50
P acid (B) (eg citric acid) 0.85 ± 0.85 ± 0.85 ± 0.85 ± 0.60 0.50 0.25 0.15 polyalkylene oxide (C) 64 ± 30 64 ± 20 64 ± 15 64 ± 10 cellulose ester or ether (for example 10 ± 9.5 10 ± 7.5 10 ± 5 10 ± 2.5 plo, HPMC) plasticizer (for example, PEG) 15.3 ± 7.5 15.3 ± 5 15.3 ± 2.5 15.3 ± 1.0 antioxidant (for example, a-tocofe- 0.2 ± 0.12 0.2 ± 0.1 0.2 ± 0 , 05 0,2 ± 0,03 rol) ° /) by weight X25 X26 X27 X28 opioid (A) (for example, HCl of 13,95 ± 13,95 ± 13,95 ± 13,95 ± oximorfone) 1, 25 1.00 0.75 0.50 acid (B) (eg, 0.85 ± 0.60 0.85 ± 0.50 0.85 ± 0.25 0.85 ± 0.15 citric acid) oxide polyalkylene (C) 60 ± 30 60 ± 20 60 ± 15 60 ± 10 cellulose ester or ether (for 10 ± 9.5 10 ± 7.5 10 ± 5 10 ± 2.5 example, HPMC) plasticizer (for example , PEG) 13.9 ± 7.5 13.9 ± 5 13.9 ± 2.5 13.9 ± 1.0 antioxidant (e.g., a- 0.2 ± 0.12 0.2 ± 0.1 0.2 ± 0.05 0.2 ± 0.03 tocopherol) ° /) by weight I X29 I X30 X31 X32 opioid (A) (for example, HCI of I 18.60 ± I 18.60 ± 18.60 ± 18.60 ± oxymorphone) I 1.25 I 1.00 0.75 0.50 acid (B) (for example, acid I 0.85 ± 0.60 I 0.85 ± 0.50 0.85 ± 0.25 0.85 ± 0.15 citric) polyalkylene oxide (C) I 57 ± 30 I 57 ± 20 57 ± 15 57 ± 10 cellulose ester or ether (per J_10 ± 9) 10 ± 7.5 10 ± 5 10 ± 2.5 example, HPMC)
pIastifying (eg PEG) 13.6 ± 7.5 13.6 ± 5 13.6 ± 2.5 13.6 ± 1.0 antioxidant (for example, a- 0.2 ± 0.12 0.2 ± 0.1 0.2 ± 0.05 0.2 ± 0.03 tocopherol)
"In a preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 100 ± 75 mg, more preferably 100 ± 50 mg, more preferably 100 ± 25 mg.
In another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 5 200 ± 75 mg, more preferably 200 ± 50 mg, more preferably 200 ± 25 mg.
In another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 250 ± 75 mg, more preferably 250 ± 50 mg, more preferably 250 ± 25 mg.
In yet another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 300 ± 75 mg, more preferably 300 ± 50 mg, more preferably 300 ± 25 mg.
In yet another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 400 ± 75 mg, more preferably 400 ± 50 mg, more preferably 400 ± 25 mg.
In a preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 500 ± 250 mg, more preferably 500 ± 200 mg, more preferably 500 ± 150 mg.
In another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 750 ± 250 mg, more preferably 750 ± 200 mg, more preferably 750 ± 150 mg.
In another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 1000 ± 250 mg, more preferably 1000 ± 200 mg, more preferably 1000 ± 150 mg.
In yet another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 1250 ± 250 mg, more preferably 1250 ± 200 mg, more preferably 1250 ± 150 mg.
In a preferred embodiment, the pharmaceutical dosage form according to the invention has a total density within the range of 1.19 ± 0.30 g / cm 3, more preferably 1.19 ± 0.25 g / cm 3, even more preferably 1.19 ± 0.20 g / cm3, even more preferably 1.19 ± 0.15 g / cm3,
more preferably 1.19 ± 0.10 g / cm ', and in particular 1.19 ± 0.05 g / cm'. Preferably, the total density of the pharmaceutical dosage form of 0 according to the invention is 1.17 ± 0.02 g / cm ', 1.19 ± 0.02 g / cm' or 1.21 ± 0.02 - g / cm3. The methods for measuring the density of a dosage form are 5 "known to a person skilled in the art. The total density of a
The dosage form can, for example, be determined using the mercury porosimetry method or the helium pycnometer method as described in Ph. Eur. Preferably, the pharmaceutical dosage form according to the invention is adapted for administration oral. It is also possible, however, to administer the pharmaceutical dosage form through different routines and, thus, the pharmaceutical dosage form can alternatively be adapted for buccal, lingual, rectal or vaginal administration. Implants are also possible. In a preferred embodiment, the pharmaceutical dosage form according to the invention is adapted for administration once a day. In another preferred embodiment, the pharmaceutical dosage form according to the invention is adapted for administration twice a day. In yet another preferred embodiment, the pharmaceutical dosage form according to the invention is adapted for administration three times a day. For the purpose of the specification, "twice a day" means equal or almost equal time intervals, that is, about every 12 hours, or different time intervals, for example, 8 and 16 hours or 10 and 14 hours, between individual administrations. 25 For the purpose of the specification, "three times a day" means equal or almost equal time intervals, that is, about every 8 hours, or different time intervals, for example, 6, 6 and 12 hours; or 7.7 and 10 hours, between individual administrations. Preferably, the pharmaceutical dosage form according to the invention causes a delayed or prolonged release at least partially of opioid (A). Controlled or prolonged release is understood according to the invention preferably to mean a release profile in which the opioid (A) is for a relatively long period with a frequency
The reduced absorption with the objective of extended therapeutic action. Preferably, the meaning of the term "prolonged release" is in accordance with the 5 "European standard on the nomenclature of the release profile of pharmaceutical dosage forms (CHMP). This is obtained in particular with peroral administration. The term "delayed or prolonged release at least partially" encompasses, according to the invention, any pharmaceutical dosage form that ensures the modified release of the opioids (A) 10 contained herein. Pharmaceutical dosage forms preferably comprise dosage forms coated or uncoated pharmaceutical products, which are produced with specific auxiliary substances, by particular processes or by a combination of the two possible options for proposing to change the release rate or release site.15 In the case of pharmaceutical dosage forms according to the invention, the release time profile of a controlled release form can be modified, for example, as follows: release extended, repeated action release, prolonged release and sustained release. For the purpose of the "controlled release" specification it preferably means a product in which the release of active compound over time is controlled by the type and composition of the formulation. For the purpose of the "extended release" specification it preferably means a product in which the release of active compound is delayed for a finite delay time, after which the release is unimpeded. For the purpose of the specification "Repeated release action" preferably means a product in which a first portion of active compound is initially released, followed by at least another portion of active compound being released subsequently. For the purpose of the "prolonged release" specification, it preferably means a product in which the rate of release of active compound from the formulation after administration has been reduced over time, to maintain therapeutic activity, reduce toxic effects, or for some other purpose. For the purpose of the "sustained release" specification preferable
Reasonably means a way of formulating a drug so that it is released into the body stably, over a long period of time, and thereby reducing the frequency of dosing. For other details, - reference can be made, for example, to K.H. Bauer, Lehrbuch der Pharma- 5 "zeutischen Technologie, 6" edition, WVG Stuttgart, 1999; and Eur. Ph.
e The pharmaceutical dosage form according to the invention can comprise one or more opioids (A) at least in part in another controlled release form, in which the controlled release can be obtained with the aid of known conventional materials and processes 10 by the person skilled in the art, for example, by soaking the substance in a controlled release matrix or by applying one or more controlled release coatings. The release of the substance must, however, be controlled in such a way that the addition of controlled release materials does not impair the required breaking strength. The controlled release 15 of the pharmaceutical dosage form according to the invention is preferably obtained by soaking the substance in a matrix. Preferably, the polyalkylene oxide (C) serves as such a matrix. Auxiliary substances that act as parent materials control release. The matrix materials can, for example, be gel-forming materials, hydrophilic from which the release proceeds mainly by diffusion, or hydrophobic materials, from which the release proceeds mainly by diffusion of the pores in the matrix . Preferably, the release profile is substantially controlled by the matrix, preferably by soaking the opioid (A) in a matrix comprising polyalkylene oxide (C) and optionally, other matrix materials. Preferably, the release profile is not osmotically regulated. Preferably, the release kinetics is not zero order. Preferably, under physiological conditions the pharmaceutical dosage form according to the invention released after 30 minutes from 0.1 to 30 75%, after 240 minutes from 0.5 to 95 ° /), after 480 minutes from 1.0 to 100 % and after 720 minutes of 2.5 to 100% of the opioid (A). Other preferred release profiles from R1 to R6 are summarized in the table below [all data
T ° /) by weight of oE! Ioide released $ A) j: l in £ o _Jr,) r, Jr, __j &) r,) r, 8 | 60 minu-jo - 30 | 0 -50 | 0 - 50 | 15 -25 | 20- 30 | 20-50 "| tos" | 120 mi-jo -40 jo -75 | 0 -75 | 25 -40 | 35- 50 | 40 - 75. jnutos | 240 mi- | 3 - 55 | 3 -95 j1o -95 | 40 -70 j55 -75 | 60 - 95 nutos j480 mi-j10-65 | 10-100 j35-100 j60-90 | 80 -95 | 80 - 100 - nutes | 720 mi- | 20 - 75 | 20 - 100 | 55 - 100 | 70 - 100 I 90 - 100 I 90 - 100 nutes | 960 mi- | 30 - 88 j30-100 j70-100 |> 80 j95-100 I nutos | 1440 j50-100 j50-100 |> 90 minutes | 2160 |> 80 |> 80 I minutes I Other preferred release profiles from R1 to R6 are summarized in the table below [all data in ° / ) by weight of released opioid
INÈ time R, R, R, R, q R ,, R ,, | 30 minu-j17.5 ± 7.5 j17.5 ± 6.5 | 17.5 ± 5.5 | 17.5 ± 4, 5 | 17.5 ± 3.5 | 17.5 ± 2.5 | tOS | 60 minu-j27.0 ± 8.0 | 27.0 ± 7.0 j27.0 ± 6.0 | 27.0 ± 5.0 | 27.0 ± 4.0 | 27.0 ± 3, 0 | tOS | 120 mi-j41.5 ± 9.5 | 41.5 ± 8.5 | 41.5 ± 7.5 | 41.5 ± 6.5 | 41.5 ± 5.5 | 41.5 ± 4 , 5 | nutos | 240 mi-j64.5 ± j64.5 ± j64.5 ± | 64.5 ± 9.5 | 64.5 ± 8.5 | 64.5 ± 7.5 | nutes 12.5 11.5 10.5 | 480 mi-j88.0 ± j88.0 ± j88.0 ± | 88.0 ± 9.0 | 88.0 ± 8.0 | 88.0 ± 7.0 | jnutos | 12.0 | 11.0 | I0, O
| 720 mi- | 96.0 ± 9.0 | 96.0 ± 8.0 | 96.0 ± 7.0 | 96.0 ± 6, ¶96.0 ± 5.0 | 96.0 ± 4, 0j nutos | 840 mi-j97.5 ± 7.5 j97.5 ± 6.5 | 97.5 ± 5.5 | 97.5 ± 4.5 | 97.5 ± 3.5i97.5 ± 2.5 | nutos
P Preferably, the release profile of the far- dosage form. The pharmaceutical product according to the present invention is stable in storage, preferably in storage at elevated temperature, for example, 37 ° C, for 3 months in sealed containers. In this respect, "stable" 5 means that by comparing the initial release profile with the release profile after storage, at any given time the release profiles deviate from each other by no more than 20%, more preferably not more than 15%, even more preferably not more than 10 ° / 0, even more preferably not more than 7.5%, more preferably not more than 5. ° / 0 and in not more than 2.5%. Preferably, under in vitro conditions the pharmaceutical dosage form released after 0.5 hour from 1.0 to 35 ° /) by weight, after 1 hour from 5.0 to 45 ° /) by weight, after 2 hours of 10 to 60 ° /) by weight, after 4 hours at least 15 ° /) by weight, after 6 hours at least 20 ° /) by weight, after 8 hours at least 25 ° /) by weight and after 12 hours at least 30 ° /) by weight of the opioid (A) that was originally contained in the pharmaceutical dosage form. Suitable in vitro conditions are known to those skilled in the art. In this regard, for example, Eur. Ph. Preferably, the release profile is measured under the following conditions: Paddle apparatus equipped with a perforator, 50 rpm, 37 ± 5 ° C, 900 mL of simulated intestinal fluid pH 6.8 (phosphate buffer) or pH 4.5. In a preferred mode, the rotary speed of the blade is increased to 100 rpm. In a preferred embodiment, after preferably oral administration of the pharmaceutical dosage form according to the invention, in vivo the average peak of the plasma level (Cmaj is above the average reached after tm ,, 4.0 ± 2.5 hours , more preferably after tm, 4.0 ± 2.0 hours, even more preferably after tm, 4.0 ± 1.5 hours, more preferably after tma, 4.0 ± 1.0 hours and in particular after t ,,,,, 4.0 ± 0.5 hours.
In another preferred mode, after preferably oral administration of the do- form. pharmaceutical message according to the invention, in vivo the average peak level
- plasma (Cmax) is about the average reached after tm ,, 5.0 ± 2.5 hours, plus 5 'preferably after tm ,, 5.0 ± 2.0 hours, even more preferably after tm ,, 5, 0 ± 1.5 hours, more preferably after tm, 5.0 ± 1.0 hours and in pairs. after tm ,, 5.0 ± 0.5 hours.
In yet another preferred embodiment, after preferably oral administration of the pharmaceutical dosage form according to the invention, in vivo the average peak plasma level (Cmax) is above the average achieved after tm 6.0 6.0 ± 2 , 5 hours, more preferably after tm, 6.0 ± 2.0 hours, even more preferably after tm, 6.0 ± 1.5 hours, more preferably after tm, 6.0 ± 1.0 hours and in particular after tm, 6.0 ± 0.5 hours.
In a preferred embodiment, the mean value for t1 / 2 after preferably oral administration of the pharmaceutical dosage form according to the invention in vivo is 4.0 ± 2.5 hours, more preferably 4.0 ± 2 , 0 hours, even more preferably 4.0 ± 1.5 hours, more preferably 4.0 ± 1.0 hours, and in particular 4.0 ± 0.5 hours.
In another preferred embodiment, the mean value for t1 / 2 after preferably oral administration of the pharmaceutical dosage form according to the invention in vivo is preferably 5.0 ± 2.5 hours, more preferably 5, 0 ± 2.0 hours, even more preferably 5.0 ± 1.5 hours, more preferably 5.0 ± 1.0 hours, and in particular 5.0 ± 0.5 hours.
In yet another preferred embodiment, the mean value for t1 / 2 after preferably oral administration of the pharmaceutical dosage form according to the invention in vivo is preferably 6.0 ± 2.5 hours, more preferably 6.0 ± 2 , 0 hours, even more preferably 6.0 + 1.5 hours, more preferably 6.0 ± 1.0 hours, and in particular 6.0 ± 0.5 hours.
Preferably, the pharmaceutical dosage form according to the invention contains a coating, preferably a film coating.
Suitable coating materials are known to the person skilled in the art.
Suitable coating materials are commercially available, for example, under the trademarks Opa-dry® and Eudragit®. 0
Examples of suitable materials include cellulose esters
- if and cellulose ethers, such as methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carbimethylcellulose (Na-CMC), ethylcellulose (EC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP); poly (meth) acrylates, such as aminoalkylmethacrylate copolymers, methylacrylate methyl methacrylate copolymers, methacrylacetic acid methyl methacrylate copolymers, methylacrylate and methylacrylate vinyl polymers, such as polyvinylpyrrolidone, polyvinylacetatophthalate, polyvinyl alcohol, polyvinylacetate, and natural film formers such as shellac.
In a particularly preferred embodiment, the coating is water-soluble.
In a preferred embodiment, the coating is based on polyvinyl alcohol, such as the hydrolyzed polyvinyl alcohol portion, and additionally contains polyethylene glycol, such as macrogol 3350, and / or pigments.
In another preferred embodiment, the coating is hydroxypropyl based, preferably type 2910 having a viscosity of 3 to 15 mPas. 20 The coating of the pharmaceutical dosage form can increase its storage stability.
The coating can be resistant to gastric juices and dissolve as a function of the pH value of the release environment.
By means of this coating, it is possible to ensure that the pharmaceutical dosage form according to the invention passes through the undissolved stomach and the active compound is released into the intestines.
The coating that is resistant to gastric juices preferably dissolves at a pH value between 5 and 7.5. The corresponding materials and methods for delayed release of active compound and for the application of coatings that are resistant to gastric juices are known to the person skilled in the art, for example, "Coated Pharmaceutical dosage forms - Fundamentals, Manufacturing Techniques , Biopharmaceutical Aspects, Test Methods and Raw Materials "by Kurt H.
Bauer, K.
Lehmann, Hermann P.
Osterwald, Rothgang, Gerhart, 1 "edition, 1998, Medpharm Scientific Publishers. * In a preferred embodiment, the pharmaceutical dosage form
- according to the invention does not contain any substance that irritates the 5 "nasal passages and / or pharynx, that is, substances that, when administered through the nasal passages and / or pharynx, cause a physical reaction that is so unpleasant to the patient that he / she does not want or cannot continue the administration, for example, burning, or physiologically opposes the absorption of the corresponding active compound, for example, 10 due to nasal discharge or sneezing.
Other examples of substances that irritate the nasal passages and / or pharynx are those that cause burning, itching, the desire to sneeze, increased secretion formation or a combination of at least two of these stimuli.
The corresponding substances and the quantities of them that should conventionally be used are known to the person skilled in the art.
Some of the substances that irritate the nasal passages and / or pharynx are, consequently, based on one or more constituents or one or more plant parts of a substance of a hot substance drug.
The corresponding hot substance drugs are known to themselves 20 by the person skilled in the art and are described, for example, in the "Pharmazeutische Biologie - Drogen und ihre lnhaltsstoffe" by Prof.
Dr.
Hildebert Wagner, 2 "revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 and following.
The corresponding description hereby introduced as a reference and is deemed to be part of the description. The pharmaceutical dosage form according to the invention, moreover, preferably does not contain any opioid antagonist (A), preferably no antagonist against physicotropic substances, in particular no opioid antagonist (A). Suitable antagonists for a given opioid (A) are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of physiologically compounds corresponding acceptable amounts, in particular in the form of salts or solvates thereof.
The pharmaceutical dosage form according to the invention preferably does not contain any antagonists * selected from the group comprising naloxone, naltrexone, nalmefene,
- nalide, nalmexone, nalorphine or nalufine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular. in the form of a base, a salt or a solvate; and in neuroleptics, for example, a compound selected from the group comprising haloperil, promethazine, fluphenazine, perphenazine, Ievomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixin, zuclopentixol, flupentixol, protipendone, 10, zotepine, melamine, zotepone, benzoin, melamine, zotepone, 10% and bromperidol.
The pharmaceutical dosage form according to the invention, moreover, preferably does not contain any emetics.
Emetics are known to the person skilled in the art and can be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of salts or solvates thereof.
The pharmaceutical dosage form according to the invention preferably does not contain any emetic based on one or more constituents of ipecacuanha root (ipecac), for example, based on the constituent of e-20 methyl, as they are, for example, described in "Pharmazeutische Biologie - Drogen und ihre lnhaltsstoffe" by Prof.
Dr.
Hildebert Wagner, 2 "revised edition, Gustav Fischer Verlag, Stuttgart, New York, 1982. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the description.
The pharmaceutical dosage form according to the invention preferably also does not contain any apo-morphine as an emetic.
Finally, the pharmaceutical dosage form according to the invention preferably also contains no bitter substances.
Bitter substances and effective amounts for use can be found in US-2003/0064099 A1, the corresponding description of which should be deemed to be the description of this application and is hereby introduced as a reference.
Examples of bitter substances are aromatic oils, such as peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit flavoring substances, lemon flavoring substances (Iemons), oranges, lemons (Iimes) , grapefruit or mixtures of
- same, and / or denatonium benzoate. "The pharmaceutical dosage form according to the invention, therefore, preferably does not contain any substance that irritates the nasal passages and / or pharynx, nor antagonists to the opioid (A), nor emetics, nor bitter substances.
The pharmaceutical dosage form according to the invention is preferably adapted for oral administration.
Typically, the pharmaceutical dosage form according to the invention takes the form of a tablet.
Preferably, the pharmaceutical dosage form is neither a film form nor multiple particles. The pharmaceutical dosage form according to the invention is preferably resistant to counterfeiting.
Preferably, resistance to counterfeiting is obtained based on the mechanical properties of the pharmaceutical dosage form so that fragmentation is avoided or at least substantially prevented.
According to the invention, the term fragmentation means spraying the pharmaceutical dosage form using conventional means generally available to a violator, for example, a pestle and mortar, a hammer, a mallet or other conventional means for spraying under the action of force.
In this way, resistance to counterfeiting preferably means that spraying of the pharmaceutical dosage form using conventional means is avoided or at least substantially prevented.
Preferably, the mechanical properties of the pharmaceutical dosage form according to the invention, particularly its resistance to breakage, substantially rely on the presence and spatial distribution of polyalkylene oxide (C), although its mere presence is typically is not sufficient to obtain these properties.
The advantageous mechanical properties of the pharmaceutical dosage form according to the invention may not automatically be obtained simply by processing the opioid (A), acid (B), polyalkylene oxide (C), and optionally with other excipients via conventional methods for the preparation of
"pharmaceutical dosage forms.
In fact, generally suitable apparatus must be selected for preparation and the parameters for critical processing must be adjusted, particularly pressure / strength, temperature and time.
Thus, even if conventional devices are used, process protocols must generally be adapted to meet the required criteria. The pharmaceutical dosage form according to the invention has a breaking strength of at least 300 N, preferably at least 400 N, more preferably at least 500 N, even more preferably at least 750 N, even more preferably at least 1000 N, more preferably at least 1250 N and in particular at least 15 1500 N.
The "break resistance" (crush resistance) of a pharmaceutical dosage form is known to the person skilled in the art.
In this regard, for example, W.A.
Ritschel, Tablette matrix, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann and 20 others, Pharmaceutical dosage forms: Tablets, Volume 2, Healthcare information; 2nd edition, 1990; and Encyclopedia of Pharmaceutical Technology, Hemalthcare Information; 1 edition.
For the purpose of the specification, the breaking strength is preferably defined as the amount of force that is required to break the pharmaceutical dosage form (= breaking strength). Consequently, for the purpose of the specification, the pharmaceutical dosage form preferably does not have the desired break strength when it breaks, that is, it is fractured into at least two independent parts that are separated from one another.
In another preferred modality, however, the pharmaceutical dosage form is considered to be broken if the strength decreases by 25% (threshold value) of the highest strength measured during measurement (see below).
The pharmaceutical dosage forms according to the invention are distinguished from conventional pharmaceutical dosage forms in which, due to their breaking strength, they cannot be sprayed
"by applying force with conventional means, such as, for example, 5" a pestle and mortar, a hammer, a mallet or other usual means for. spraying, in particular devices developed for this purpose (tablet crushers). In this regard, "spraying" means breaking into small particles that would immediately release the pharmacologically active compound (A) in a suitable medium.
The avoidance of spraying virtually excludes oral or parenteral abuse, particularly intravenous or nasal abuse.
Conventional tablets typically have a breaking strength well below 200 N in any extension direction.
The break strength of conventional round tablets can be estimated according to the following empirical formula: Break Resistance [in N] = 10 x Diameter of the Tablet [in mm]. Thus, according to said empirical formula, a round tablet having a breaking strength of at least 300 N would require a diameter of at least 30 mm.
Such a tablet, however, could not be swallowed.
The above empirical formula preferably does not apply to the pharmaceutical dosage forms of the invention, which are unconventional but preferably special.
In addition, the actual average chewing force is about 220 N (cf., for example, P.A.
Proeschel et al., J Dent Res, 2002, 81 (7), 464- 468). This means that conventional tablets having a resistance to break well below 200 N can be crushed in spontaneous chewing, while pharmaceutical dosage forms according to the invention cannot.
Furthermore, during the application of a gravitational acceleration of about 9.81 m / s2, 300 N correspond to a gravitational force.
Greater than 30 kg, that is, the pharmaceutical dosage forms according to the invention can preferably support a weight greater than 30 kg without being sprayed.
Methods for measuring the breaking strength of a pharmaceutical dosage form are known to those skilled in the art. The 4 suitable devices are commercially available.
- For example, the breaking strength (crush resistance 5 "tO) can be measured according to Eur. Ph. 5,0, 2,9,8 or 6,0, 2,09,08 and" Resistance to Crushing of Tablets ". The test is designed to determine, under defined conditions, the crush strength of tablets, measured by the force necessary to break them by crushing. The apparatus consists of two jaws facing each other, one of which moves 10 in direction to one another. The flat surfaces of the jaws are perpendicular to the direction of movement. The crushing surfaces of the jaws are flat or larger than the contact zone with the tablet. The apparatus is calibrated using a system with an accuracy of 1 Newton.The tablet is placed between the jaws, taking into account, when applicable, the shape, the break mark and the inscription, for each measurement the tablet is oriented in the same way with respect to the direction of application of the force (and the extension direction in which the resistance breakage must be measured). The measurement is carried out without 10 tablets, taking care that all fragments have been removed before each determination. The result is expressed as mean, minimum and maximum values of the measured forces, all expressed in Newton. A similar description of the breaking strength (breaking strength) can be found at USP. The breaking strength can alternatively be measured according to the method described here, where it is established that the breaking strength is the force required to cause a tablet to fail (i.e., break) in a specific pin. The tablets are usually placed between two rolls, one of which moves to apply sufficient force to the tablet to cause fracture. For round, conventional tablets (circular cross section), loading occurs across its diameter (sometimes referred to as diametrical loading), and the fracture occurs in the plane. The breaking strength of pills is generally called hardness in the pharmaceutical literature; however, the use of this term is misleading.
In material science, the term hardness refers to the resistance of a surface to penetration or indentation by a small probe.
The term resis-. crushing resistance is also used to describe the strength of
"tablets to the application of a compressive load.
Although this 5 "term describes the true nature of the test more precisely than the hardness, it does indicate that the pills are actually crushed during the test, which is often not the case.
Alternatively, the breaking strength (crush strength) can be measured according to WO 2005/016313, WO 10 2005/016314, and WO 2006/082099, which can be considered as a modification of the method described in Eur.
Ph.
The apparatus used for the measurement is preferably a material tester "Zwick Z 2.5", Fm ,, = 2.5 KN with a maximum extraction of 1150 mm, which must be increased with a column and a spindle, a clearance less than 100 mm and a speed of 15 test adjustable between 0.1 and 800 mm / minutes together with soRvvare test-Control.
The measurement is performed using a pressure piston with inserts screwed to it and a cylinder (10 mm diameter), a force transducer, Fm ,,. 1 KN, diameter = 8 mm, class 0.5 of 10 N, class 1 of 2 N for lSO 7500-1, with manufacturer's M test certificate according to DIN 20 55350-18 (total force of Zwick Fm ,, = 1 , 45 KN) (the whole apparatus of Zwick Gm-bH & Co.
KG, Ulm, Germany) with Dispatch No. BTC-FR 2.5 TH.
D09 for the tester, Dispatch No. BTC-LC 0050N.
POl for the force transducer, Dispatch No. BO 70000 S06 for the centering device.
In a preferred embodiment of the invention, the breaking strength is measured by means of a breaking strength tester, for example, Sotax®, type HTIOO or type HTI (Allschwil, Switzerland). Both So- tax® HTIOO and Sotax® HTI can measure the breaking strength according to two different measuring principles: constant speed (where the test jaw is moved at a constant speed adjustable from 5 to 30 200 mm / minute) or constant force (where the test jaw increases the force linearly, adjustable from 5 to 100 N / sec). In principle, both measuring principles are suitable for measuring the breaking strength of the
pharmaceutical dosage form according to the invention. Preferably, the breaking strength is measured at a constant speed, preferably at a constant speed of 120 mm / minute.
. In a preferred embodiment, the pharmaceutical dosage form is considered to be broken if it is broken into at least two separate slices. The pharmaceutical dosage form according to the invention preferably has mechanical strength over a wide range of temperature, in addition to a breaking strength (crushing resistance), optionally also sufficient hardness, impact resistance, impact elasticity, tensile strength and / or modulus of elasticity, optionally also at low temperatures ( for example, below -24 ° C, below -40 ° C or in liquid nitrogen), to make it virtually impossible to spray it by spontaneous chewing, grinding in a mortar, crushing, etc. Thus, preferably the comparatively high breaking strength of the pharmaceutical dosage form according to the invention is maintained even at low or very low temperatures, for example, when the pharmaceutical dosage form is initiated cooled to increase its fragility, for example, for temperatures below -25 ° C, 20 below -40 ° C or in liquid nitrogen. The pharmaceutical dosage form according to the invention is characterized by a certain degree of resistance to breakage. This does not mean that the pharmaceutical dosage form must also have a degree of hardness. Hardness and resistance to breaking are different properties. 25 Therefore, resistance to counterfeiting of the pharmaceutical dosage form does not necessarily depend on the hardness of the pharmaceutical dosage form. For example, due to their breaking strength, impact resistance, elasticity module and tensile strength, respectively, the pharmaceutical dosage form can preferably be deformed, for example, plastically, when exercising a external force, for example, using a hammer, but it cannot be sprayed, that is, crushed into a high number of fragments. In other words, the pharmaceutical dosage form according to
According to the invention, it is characterized by a certain degree of resistance to rupture, but not necessarily by a certain degree of shape stability. ^ Therefore, in the meaning of the specification, a pharmaceutical dosage form that is deformed when exposed to a force in a particular extension direction, but which does not break (plastic deformation or. Plastic flow) should preferably be considered to have the desired break resistance in that extension direction.
A particularly preferred embodiment of the invention relates to a counterfeit-resistant pharmaceutical form and dosage having a breaking strength of at least 300 N and being thermoformed by hot melt extrusion, said pharmaceutical dosage form comprising
- an opioid (A) selected from the group consisting of oxymorphone, oxydoctor, hydromorphone, and their physiologically acceptable salts; 15 - a physiologically acceptable multicarboxylic acid (B), preferably citric acid, in which the acid content (B) is within the range of 0.001 to 5.0 ° /) by weight, based on the total weight of the pharmaceutical dosage form ;
- an antioxidant, in which the antioxidant content, preferably α-tocopherol, is within the range of 0.001 to 5.0 ° /) by weight, based on the total weight of the pharmaceutical dosage form; and
- a polyalkylene oxide (C) having an average molecular weight Mw of at least 200,000 g / mol; where - the opioid (A) is embedded in a matrix comprising polyalkylene oxide (C), said matrix controlling the release of opioid (A) from the pharmaceutical dosage form; and
- after storage for 4 weeks at 40 ° C and 75% relative humidity, the opioid content (A) rises to at least 98.0% of its original content before storage. The pharmaceutical dosage form according to the invention can be produced by different processes, the particularly preferred ones of which are explained in more detail below.
Several suitable processes
have already been described in the prior art.
In this regard, for example, WO 2005/016313, WO 2005/016314, VVO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097 , and WO 2006/082099. "The present invention also relates to pharmaceutical dosage forms that are obtainable by any of the processes described below.
In general, the process for producing the pharmaceutical dosage form according to the invention preferably comprises the following steps: (a) mixing all the ingredients; (b) optionally preforming the mixture obtained from step (a), preferably by applying heat and / or force to the mixture obtained from step (a), the amount of heat supplied is preferably not sufficient to heat the polyalkylene oxide (C) to its softening point; (C) harden the mixture by applying heat and force, it is possible to supply the heat during and / or before applying force and the amount of heat provided is sufficient to heat the po | ia | chi | C) at least until its softening point; (d) optionally, singling out the hardened mixture; (e) optionally, modeling the pharmaceutical dosage form; and (f) optionally, providing a film coating.
Heat can be supplied directly, for example, by contact using hot gas such as hot air, or with the aid of ultrasound.
The force can be applied and / or the pharmaceutical dosage form can be modeled, for example, by forming tablets directly or with the aid of a suitable extruder, particularly by means of a screw extruder equipped with two screws (screw extruder double) or by means of a planetary gear extruder.
The final model of the pharmaceutical dosage form can be provided during the hardening of the mixture by applying heat and strength (step (C)) or in a subsequent step (step (e)). In both cases, mixing
All components are preferably in the plasticized state, that is, preferably, the modeling is carried out at a temperature at least above the softening point of the polyethylene oxide (C). However, extrusion at lower temperatures, for example, room temperature, is also 5 "possible and may be preferred.
Modeling can be carried out, for example, by means of a tablet forming press comprising die and die punch and punches of the appropriate model.
A particularly preferred process for making the pharmaceutical dosage form of the invention involves hot melt extrusion.
In this process, the pharmaceutical dosage form according to the invention is produced by thermoforming with the aid of an extruder, preferably without any discoloration resulting from the observable of the extrudate.
It has surprisingly been found that acid (B) is able to suppress discoloration.
In the absence of acid (B), the extrudate tends to develop a beige to yellowish color, while in the presence of acid (B) the extrudates are substantially colorless, that is, white.
This process is characterized by the fact that a) all components are mixed, b) the resulting mixture is heated in the extruder at least to the point of softening of the polyalkylene oxide (C) and extruded through the extruder outlet hole by application of strength, C) the extrudate still made of plastic is singularized and formed in the form of pharmaceutical dosage or d) the singularized and optionally reheated extrudate is formed in the pharmaceutical dosage form.
The mixing of the components according to the process step a) can also proceed in the extruder.
The components can also be mixed in a mixer known to the person skilled in the art.
The mixer can, for example, be a cylinder mixer, agitation mixer, shear mixer or compulsory mixer.
Before mixing with the residual components, polyalkylene oxide (C) is preferably supplied according to the invention with an antioxidant, preferably α-tocopherol. This can be done by mixing the two components, polyalkylene oxide (C) and the antioxidant, preferably by dissolving or suspending the antioxidant in a highly volatile solution and homogeneously mixing this solution. or suspension with polyalkylene oxide (C) and removing the solvent by drying, preferably under an atmosphere of inert gas.
The mixture, preferably melted, which has been heated in the extruder at least to the point of softening of polyalkylene oxide (C) is extruded from the extruder through a die with at least one hole.
The process according to the invention requires the use of suitable extruders, preferably screw extruders.
Screw extruders that are equipped with two screws (twin screw extruders) are particularly preferred.
The extrusion is preferably carried out in such a way that the expansion of the filament due to the extrusion is not more than 3Õ ° / o, that is, when using a matrix with a hole having a diameter of, for example, 6 mm, the extruded filament should have a diameter of no more than 8 mm.
More preferably, the expansion of the filament is not more than 25%, even more preferably not more than 20%, more preferably not more than 15% and in particular not more than 10%. Preferably, the extrusion is carried out in the absence of water, that is, water is not added.
However, traces of water (for example, caused by atmospheric humidity) may be present.
The extruder preferably comprises at least two temperature zones, with heating of the mixture at least to the point of softening of the polyalkylene oxide (C) proceeding in the first zone, which is downstream of a feed zone, and optionally mix zone. ture.
The productivity of the mixture is preferably from 1.0 kg to 15 kg / hour.
In a preferred embodiment, productivity is 1 to 3.5 kg / hour.
In another preferred mode, productivity is 4 to 15 kg / hour.
In a preferred embodiment, the inlet pressure of the matrix is within the range of 2.5 to 10 MPa (25 to 100 bar). The matrix inlet pressure can be adjusted, among others, by matrix geometry, temperature profile and extrusion speed. 5 "The matrix geometry or the hole geometry is freely selectable.
The die or holes can therefore have a round, elongated or oval cross section, where the round cross section preferably has a diameter of 0.1 mm to 15 mm and the elongated cross section preferably has a maximum longitudinal extension of 21 mm and a cross section of 10 mm.
Preferably, the die or holes have a round cross section.
The housing of the extruder used according to the invention can be heated and cooled.
The corresponding temperature control, that is, heating or cooling, is such that the mixture to be extruded has at least an average temperature (product temperature) corresponding to the softening temperature of the po | ia | chi | C) and does not rise above the temperature at which the opioid (A) to be processed can be damaged.
Preferably, the temperature of the mixture to be extruded is adjusted below 180 ° C, preferably below 150 ° C, but at least for the softening temperature of polyalkylene oxide (C). Typical extrusion temperatures are 120 ° C and 130 ° C.
In a preferred embodiment, the torque of the extruder is within the range of 30 to 95%. The torque of the extruder can be adjusted, among others, by matrix geometry, temperature profile and extrusion speed.
After the extrusion of the melted mixture and optional cooling of the extruded filament or extruded filaments, the extrudates are preferably singularized.
This singularization can preferably be accomplished by cutting the extrudates by means of rotating or rotating knives, waterjet cutters, wires, blades or with the aid of laser cutters.
Preferably, the intermediate or final storage of the optionally singularized extrudate or the final model of the pharmaceutical dosage form according to the invention is carried out under an oxygen-free atmosphere which can be obtained, for example, by means of oxygen recoverers. The singularized extrudate can be formed by pressing 5 "tablets to give the final model to the pharmaceutical dosage form.
r The application of force in the extruder on the at least plasticized mixture is adjusted by controlling the rotating speed of the transmission device in the extruder and the geometry of the extruder and dimensioning the outlet orifice in such a way that the pressure necessary to extrude the mixture plasticized is built into the extruder, preferably immediately before extrusion. The extrusion parameters that, for each particular composition, are necessary to give rise to a pharmaceutical dosage form with desired mechanical properties, can be established by simple, preliminary tests. For example, but not limiting, extrusion can be carried out using a twin screw extruder type ZSE 18 or ZSE27 (Leistritz, Nürnberg, Germany), screw diameters of 18 or 27 mm. Screws having eccentric ends can be used. A heatable die with a round hole having a diameter of 7, 8, or 9 mm can be used. The extrusion parameters can be adjusted, for example, to the following values: screw rotation speed: 120 Upm; release rate 2 kg / hour for a ZSE 18 or 8 kg / hour for a ZSE27; product temperature: in front of the matrix 125 ° C and behind the matrix 135 ° C; and jacket temperature: 110 ° C. Preferably, extrusion is carried out by means of twin screw extruders or planetary gear extruders, twin screw extruders (corrective or counter-rotating) being particularly preferred. The pharmaceutical dosage form according to the invention is preferably produced by thermoforming with the aid of an extruder without any consequent discoloration observable from the extrudates. The process for preparing the pharmaceutical dosage form
according to the invention is preferably carried out continuously. Preferably, the process involves the extrusion of a homogeneous mixture of all components. It is particularly advantageous if the intermediate thus obtained, for example, the filament obtained by extrusion, has 5 "uniform properties. Uniform density is particularly desired,
W uniform distribution, uniform distribution of the active compound, uniform mechanical properties, uniform porosity, uniform appearance of the surface, etc. Only under these circumstances can the uniformity of pharmacological properties, such as the stability of the release profile, be so insured and the amount of waste can be kept low. Another aspect of the invention relates to the package containing a pharmaceutical dosage form according to the invention and an oxygen recoverer. Suitable packages include blister packs and bottles, such as glass bottles or bottles made from thermoplastic polymers. Suitable oxygen recoverers are known to those skilled in the art. The oxygen stove can be any stove known in the art to recover oxygen. Both organic and inorganic oxygen recoverers can be used. In one embodiment, the oxygen reclaimer is any metal complex showing oxygen recovery activity. Examples include complexes containing one or more aluminum, aluminum ferrosilicon, antimony, beryllium, calcium silicone, cerium, cobalt, gallium, hafnium, iron, magnesium alloy, nickel catalyst, selenium, silicone, silver, estron - estrus, titanium, zinc, and / or zirconium. In yet another modality, one or more elements of Group IA of the periodic table and their alloys and compounds can be used as oxygen recoverers. Examples of group IA elements include cesium, lithium, potassium, sodium. Other examples of inorganic oxygen scavengers include one or more of sodium azide (NaNj, sodium sulfide (Na2SO3), hydrazine, and hydroxylamine. In one embodiment, the oxygen scavenger is an organic compound.
Examples include one or more of the polyterpenes, ascorbic acid, polycarboxylic amino acid, cyclohexanedione, tetramethyl piperidone, and heterocyclic compounds with amino groups substituted by N.
Oxygen recoverers and their application in 5 "pharmaceutical packaging are known to those skilled in the art. In a preferred embodiment, the oxygen recoverer is selected from the group consisting of oxidizable organic polymers catalyzed by metal and antioxidants.
Particularly preferred are those oxygen scavengers that are able to function in a dry environment below 60% relative humidity, preferably below 3 ° / 0 relative humidity and that are combined with a desiccant.
Examples of commercially available oxygen scavengers meeting these requirements include Pharmakeep "KDIO and KD20. It has surprisingly been found that storage stability of the pharmaceutical dosage form can be increased by keeping the oxygen content of the atmosphere within the package low.
Methods for packaging pharmaceutical dosage forms and applying suitable oxygen scavengers are known to those skilled in the art.
In this regard, for example, D.A.
Dean, Pharmaceutical Packaging Technology, Taylor & Francis, 1st edition; F.A.
Paine et al., Packaging Pharmaceutical and Healthcare Products, Springer, 1 "edition; and O.G.
Piringer et al., Plastic Packaging: Interactions with Food and Pharmaceuticals, Wiley-VCH, 2 "edition.
When packaging is concerned, round bottles made of polyolefins, preferably HDPE, are preferred.
The wall thickness of the bottle is preferably at least 0.25 mm, more preferably at least 0.5 mm, otherwise the bottle may collapse.
When the lid of the packaging is concerned, the packaging is preferably selected by induction or heat with an aluminum foil.
It was surprisingly discovered that by selecting an appropriate packaging model and sealing, the vacuum that is produced by the effect of the oxygen stove (underpressure of about 20,000 Pa = 2 N / cm2) can
to be handled without causing the packaging to collapse.
Induction sealing (for example, 3 seconds of energy) is preferred.
When sealing a 75 ml bottle having an opening with a diameter of 1 inch with 5 "aluminum foil, an underpressure of 20,000 Pa due to oxygen recovery. Results in a force of about 10 N corresponding to the force which is exercised by a weight of 1 kg.
The mechanical stability of the seal can be tested by introducing an appropriate amount of oxygen recoverer into the bottle, sealing it and waiting for a sufficient period of time, for example, 2 days, so that the oxygen is recovered and an underpressure of around 20,000 Pa was developed.
Alternatively, the bottle can be sealed without any oxygen recoverer inside and a weight of 1 kg can be placed on the aluminum sheet externally, thereby simulating the force.
Another aspect of the invention relates to the use of an opioid (A) for the manufacture of the pharmaceutical dosage form as described above for the treatment of pain.
Another aspect of the invention relates to the use of a pharmaceutical dosage form as described above to avoid to prevent or prevent abuse of the opioid (A) contained herein.
Another aspect of the invention relates to the use of a pharmaceutical dosage form as described above to prevent or prevent the unintended o-verdose of the opioid (A) contained herein.
In this regard, the invention also relates to the use of an opioid (A) as described above and / or a polyalkylene oxide (C) as described above for the manufacture of the pharmaceutical dosage form according to the invention. for the prophylaxis and / or treatment of a disorder, thereby preventing an overdose of opioid (A), particularly due to the combination of the pharmaceutical dosage form by mechanical reaction.
In addition, the invention relates to a method for the prophylaxis and / or treatment of a disorder comprising administering the pharmaceutical dosage form according to the invention, thereby preventing an overdose of the opioid (A), particularly due to the fragmentation of the pharmaceutical dosage form by mechanical action.
Preferably, the mechanical action is selected from the group consisting of chewing, grinding in a 5 "mortar, grinding, and using apparatus for spraying conventional pharmaceutical dosage forms.
The following examples also illustrate the invention, but should not be construed as limiting its scope.
Example 1 The tablets were prepared by hot-melt extrusion of various homogeneous constituent mixtures under the same extrusion conditions, as follows: Extruder type: Leistritz Extruder ZSE18PH 40D equipped with high-shear screws and a 9 mm die diameter productivity: 1.0 kg / h speed of revolution: 100 rpm barrel temperature: 100 ° C extruded temperature: 120 ° extruded CO was cut into 325 mg slices containing about 5 mg of oxymorphone hydrochloride.
The individual constituents of the extruded mixtures, as well as the total amount of decomposition products before and after storage under accelerated storage conditions, are summarized in the table below: constituent decomposition products (° / 0 by weight) other ingredient (° / 0 eg (° / 0 by weight) weight) (A) PEO PEG HPMC a-toc. ONO 'ONO' È Z '
A, 1.5 | 76.9 | 10.0 | 10.0 | 1.5 1 / 0.06 0.58 0.41 1.93 A, 1.5 | 77.5 | 10.0 | 10 , 0 | 1.0 1 / 0.09 0.49 0.58 1.81 A, 1.5 | 78.0 | 10.0 | 10.0 I 0.5 1 / 0.08 0.36 0 , 56 1.64 A, 1.5 | 78.3 | 10.0 | 10.0 | 0.2 1 / 0.08 0.26 0.63 1.51 A5 1.5 [78 »0Mj0) 0A -j '0.07 0.17 0.81 1.69
| B, 1.5 76.9 10.0 10.0 1.5 / 0.06 0.58 0.41 1.93 | B, 1.5 40.0 10.0 46.9 1.5 / 0.09 0.55 0.64 1.76 | B, 1.5 50.0 10.0 36.9 1.5 / 0.00 0.52 0.29 1.64 | B, 1.5 50 , 0 36.9 10.0 1.5 / 0.11 0.76 0.36 1.74
W | C, 1.5 76.9 10.0 10.0 1.5 / 0.06 0.58 0.41 1.93 jc, 1.5 76.9 / 10.0 1.5 10.00 of Lutrof F68 0.05 0.53 0.65 1.83 | C, 1.5 50.0 10.0 10.0 1.5 26.90 mannitol 0.08 0.82 0.39 2.72 lc, 1.5 76.9 / 10.0 1.5 10.00 camaúba wax 0.12 0.53 0.39 1.03 D, 1.5 76.9 10.0 10.0 1.5 / 0.06 0.58 0.41 1.93 D, 1.5 76.8 10.0 10.0 1.5 0.10 fumaric acid 0.05 0.48 0.52 1.70 D, 1, 5 76.8 10.0 10.0 1.5 0.10 Na-EDTA 0.07 0.51 0.48 1.77 D, 1.5 76.8 10.0 10.0 1.5 0, 10 citric acid 0.07 0.48 0.37 1.45 E, 1.5 76.9 10.0 10.0 1.5 / 0.06 0.58 0.41 1.93 E, 1.5 76.8 10.0 10.0 1.5 0.10 cithco acid 0.07 0.48 0.37 1.45 E, 1.5 76.7 10.0 10.0 1.5 0.20 acid citric 0.00 0.40 0.20 1.13 E, 1.5 76.4 10.0 10.0 1.5 0.50 citric acid 0.00 0.06 0.12 0.17 (A) : oxymorphone hydrochloride PEO: polyethylene oxide Mw 7 mio g / mol PEG: polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa * s 5 a-toc. : a-tocopherol oNo: oxymorphone-N-oxide (mixture) E: sum of all impurities 1: after extrusion, before storage 2 · after storage, amber glass bottles, plastic cap, 4. weeks, 40 ° C, 75% relative humidity. Decomposition products were analyzed by HPLC-UV.
The elution peak for oxymorphone-N-oxide would not be sufficiently separate from a peak of an unknown degradation product (called "UK 0.83"). In this way, both peaks were integrated together. It is evident from a comparison of examples from A1 to A5 that the oxymorphone-N-oxide content before storage (ONO1) is not substantially changed when the antioxidant α-tocopherol content is decreased by 1.5 ° /) by weight to 1.0 ° /) by weight, 0.5 ° / 0 by weight, 0.2 ° /) by weight and up to 0 ° /) by weight.
In storage (ONO2), however, the o-xymorphone-N-oxide content is proportional to the a-tocopherol content. This is more surprising because oxymorphone-N-oxide is an oxidation product and someone would expect antioxidants to generally suppress rather than support the formation of oxidation products.
However, the complete omission of antioxidant (a-tocopherol) has disadvantages.
It could be shown by viscosity measurements that highly molecular polyethylene oxide is degraded in extrusion and / or storage in the absence of antioxidant.
It was surprisingly discovered that about 0.2 ° /) by weight of α-tocopherol is sufficient to stabilize the polyethylene oxide; higher levels of a-tocopherol do not result in higher viscosities of polyalkylene oxide and, therefore, do not prevent more pronounced PEO from degradation.
In this way, the antioxidant content (a-tocopherol) is preferably balanced so that, on the one hand, high molecular weight polyethylene oxide is sufficiently stabilized and that, on the other hand, the unwanted formation of oxymorphone-N-oxide is kept low during storage.
In addition, it is evident from a comparison of examples from B1 to B4 and examples from Cj to C4 that the partial replacement of high molecular weight polyethylene oxide or the total replacement of polyethylene glycol with an alternative non-plasticizer results in a substantial decrease in the content of unwanted oxymorphone-N-oxide. This is surprising because one would expect polyethylene oxide and polyethylene glycol to be potential peroxide vehicles and that their reduction would result in a reduction in oxidation from oxymorphone to oxymorphone-N-oxide.
Furthermore, it is also evident from a comparison of examples of D1aD5andE1aE4 that the addition of physiologically acceptable acids, particularly citric acid, leads to a reduction in the formation of oxymorphone-N-oxide.
This effect is more pronounced when the amount of acid is increased.
At a concentration of 0.1 ° /) in small
so, the effect is comparatively weak, but at a concentration of 0.2 ° /) in weight the effect is stronger and is also enhanced when the citric acid concentration is decreased. Not only is the amount of oxymorphone-N-oxide decreased, but so is the total amount of decomposition products. position, particularly those with high HPLC retention times.
, Example 2 The tablets that were manufactured in analogy to the example A1, B1, Cj, D1 and E1 above were packaged in different packaging materials and stored at 40 ° C and 75 ° /) relative humidity. The decomposition products before and after storage under accelerated storage conditions are summarized in the table below: 7 "T" -, -, - mi HDPE amber glass | amber glass, amber glass closed +, e- | j :::: d: mba: closed I Before Ç with open cuperador sheet of Ii "argon; | desiccant I da- aluminum oxygen 7 I maze- ê4 8 4 8 4 8 jj4 8 4 8 l nage! Se-se-se-se- | se-se-se-se- 0 f; ma- ma- ma- ma- ma- ma- ma- ma- ma- ma- ma- ma - ê%,,.,: 0 nas nas nas nas nas I nas nas nas; 324, 325, 323, 337, 325, 322, I 321, 322, 324, 324, | 323,64 t I Mg i 05 57 56 25 23 65 I 27 69 62 30; mg mg mg mg mg mg_j mg mg mg mg_ I tr I content 92.5 94.6 92.5 ;;; or- I 96.30 g, ° i | 92.9 qo /, 0 ° /, 89.4 0 ° /, 93.7 0 ° /, 88.5 0 ° /, 96.7 0 ° /, I 0 ° /, 94.8j94.6 Oq / o 0 ° /, qo /, Purity I! I 97.9 98.3 98.0 ê I / $ 97.7 96.7 98.0 94.5 99.1 98.6 I 98.5 8 ° /, 6 ° /, 4% I 99,18 ° o $ /; x ;; or-! 0 ° 0 0 ° /, 3% 0 ° /, 0% 2 ° /, I 9%
ET "'d" I /! 91.5 90.8 93.5 79.9 94.5 93.6j90.5 88.2 93.5 92.1 a-stump | 1% | 91.69 ° / 9% 1 ° /, 4 ° /, 2 ° /, 2% II 6 ° 0 / 3q / o 1 ° / 0 8% and ol I%
oximor-)) r) rr phona-N- oxide UK.
0.83 - Sum of oximor-: 0.64 j1.16 (0.55 j2.63 (0.09! 0.12 |! 0.37 I 0 phono-N- 0.09 ° / ot; Wo I% | Q / OIQ / O | O / j IO / j | IQ / O oxide and 0 UK $ # THE AND
0.83 I Part 1 | l | 10.77 | 0.46 | 0.34 I principle /, 0 /, 0 /,; 0.38 0.43 0.45 2.15 0.16 0.18 0.32 I al- 0.13% Ç, | QO Q / OO / jO / JO / jO / QQ / OI known à ¢ I cit t 1.94 1.55 1.88 I Sum to I of 0.73%! 2) 22 3.21 1.88 5.44 0.82 0.95 1.33 ° /, 0 /, 0 /, impure- $ ° /, ° /, O / q ° /,% ° /, 0 /,
Ô% k 'E ,,! ,,, HDPE bottles had a volume of 75 ml. The oxygen scavenger was Pharmakeep "KD20 (Mitsubishi, Japan).
It has been surprisingly found that the inclusion of an oxygen recoverer in the package results in another stabilization of the dosage form 5 so that the formation of decomposition products is limited to extremely low values.
Example 3: The tablets were manufactured as described in example 1, packaged in 75 ml volume HDPE bottles together with an oxygen stove combined with a desiccant (Pharmakeep 20 KD), closed with a plastic cap with induction seal.
The individual constituents of the extruded mixtures, the total amount of decomposition products before and after storage under accelerated storage conditions are summarized in the table below: I decomposition products -II constituents (° / 0 by weight) · I,,, I (° / 0 by weight) - (A) PEO PEG HPMC a toc. Citric acid ONO 'ONO' ONO 'E' Z 'E' F, 1.5 73.8 10.0 14.0 0.2 0.5 na na na na na 0.05 l £ 2j1, sL77 & j10.0 10.0 0.2_L 0ndAndAndAnd jo, 05 j0.1o _J (A): oxymorphone hydrochloride 5 PEO: polyethylene oxide Mw 7 mio g / mol PEG: polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa * s a-toc. : a-tocopherol oNO: oxymorphone-N-oxide (mixture) E: sum of all impurities 1: after extrusion, before storage 2 · after storage, HDPE bottles, plastic cap with se-. induction loops, oxygen recovery, 4 weeks, 40 ° C, 75% relative humidity 3; after storage, HDPE bottles, plastic cap with induction seal, oxygen recovery, 8 weeks, 40 ° C, 75% relative humidity The results show that the product's purity is very high after manufacture and that the product has stable storage for two weeks under accelerated conditions of 40 ° C / 75 ° /) relative humidity.
Example 4: The tablets were manufactured as described in example 1, but cut into 215 mg slices representing 5 mg or 40 mg of oxymorphone HCI, after forming the tablets were coated with about 6.5 mg each. Opadry coating | conventional polyvinyl alcohol as the film-forming excipient, packaged in 75 ml bottles of HDPE by volume with an
genius combined with a desiccant (Pharmakeep 20 KD), closed with the plastic cap with induction seal.
The individual constituents of the extruded mixtures, the total amount of decomposition products before and after storage under 5 "accelerated storage conditions are summarized in the table below:
constituent decomposition products (° / 0 by weight) ex. (° / 0 by weight) (A) PEO PEG HPMC a-toc.
Citric acid ONO 'ONO' Ê E '
G, 2.33 70.0 16.63 10.0 0.2 0.84 na na na na
G, 18.6 56.8 13.56 10.0 0.2 0.84 nd nd 0.05 0.05
(A): oxymorphone hydrochloride
PEO: polyethylene oxide Mw 7 mio g / mol
PEG: polyethylene glycol 6000
HPMC: hypromellose 100,000 Pa * s a-toc. : a-tocopherol oNo: oxymorphone-N-oxide (mixture)
Z: sum of all impurities 1: after extrusion, before storage
2; after storage, HDPE bottles, plastic cap with
induction loop, oxygen recovery, 1 month, 40 ° C, 75% relative humidity
va Example 5: The most preferred dosage form according to example 3 is also suitable for stabilizing oxycodone. This could be demonstrated by a formulation containing 80 mg of oxycodone HCl manufactured analogous to example 1, but the extrudate was cut_in_fati.as_d.e_4.0O_mg: constituent decomposition products (° / 0 by weight) ex. (° / 0 by weight) (A) PEO PEG HPMC a-toc.
ONO 'ONO' Z 'E' citric acid
| HJ20 | 54.3 | 15; iO | 0.2 | 0.5 | 0.06 | 0.07 | 0.22; OJ3 (A): oxycodone PEO: polyethylene oxide Mw 7 mio g / mol
PEG: polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa * s a-toc. : a-tocopherol oNo: oxycodone-N-oxide (cleanness D "E) 5" '- after extrusion, before storage. '· After storage, amber glass bottles, plastic cap, -. oxygen recovery with desiccant (Pharmakeep 20KD) 1 month, 40 ° C, 75% relative humidity Example 6: A three-way, randomized, single-dose crossover study (40 mg oxymorphone HCl, example 4 tablets) , with 1 week between treatments, subjects were fasted overnight and meals were taken 4 and 10 hours after dosing.
No water was given for ± 1 hour of dosing.
All tablets were taken with 240 mL of water (example T). PK samples were considered for oxymorphone and pre-dose of 6-OH-oxymorphone and for 48 hours after dosing.
Bioequivalence was compared with Opana ER® (reference R). The results are summarized in the tables below: Treatment Average SD CV T 2147 989 46% Cmax [g / mL] R 2671 1163 44% T 38695 13836 36% AUCT [g * h / mL] R 38171 14652 38 ° 6 T 42575 15836 37O / j AUC [g * h / mL] R 41296 15242 37o / o
Estimated Point T / R Lower Limit 9Ó ° / o Cl Upper Limit 9Õ ° / o CI
C ,,,, 79.37 71.69 87.87 AUCT 101.98 95.17 109.29 AUC 102.24 95.48 109.48 CI = confidence interval
It is evident that the dosage forms according to the invention having an increased breaking strength are bioequivalent to conventional dosage forms (Opana ER®).
Example 7 5 "The tablets were prepared under identical conditions by. Hot melt extrusion of two mixtures of homogeneous constituents he | 2: | 2 Oxymorphone HCl [° / 0] 11.1 11.1 PEO [° / 0] 68, 2 63.2 PEG [° / 0] 10.0 15.0 HPMC Shin Etsu [%] 10.0 10.0 a-tocopherol [° / 0] 0.2 0.2 Citric acid, anhydrous [° / 0 0.5 0.5 Weight of Imal 360 360 I PEO: PEG I 6.82: 1 | 4.21: 1 I under the following identical extrusion conditions: extruder type: Leistritz Extruder type Micro 27 GL 40 D equipped with medium shear spindles and an 8 mm diameter die productivity: 10 kg / h revolution speed: 120 rpm manufacturing time: 30 minutes warmer heating zone temperature: 100 ° C matrix temperature: 130 ° C The extrudate was cut into 360 mg slices containing about 40 mg oxymorphone hydrochloride.100 slices were weighed individually and the standard weight change was calculated.The composition slices h (PEO: PEG = 6.82: 1) showed a standard change 2.3 ° /), while the composition slices | 2 (PEO: PEG = 4.21: 1) showed a standard change of 1.6 ° /) only. It is evident from these comparative tests that, surprisingly, the processability of the extruded mass can be employed.
adjusted by adjusting the PEO to PEG ratio. Example 8 To investigate whether multicarboxylic acids other than citric acid can also hinder the formation of oxymorphone-N-oxide, compounds containing maleic acid or fumaric acid were manufactured as - described in example 1. For comparison, tablets containing salt Inorganic NaH2PO4 were also manufactured. The samples were stored in open dishes at 40 ° C and 75% relative humidity for 4 weeks.
The individual constituents of the extruded mixtures as well as the total amount of decomposition products before and after storage under accelerated storage conditions are summarized in the table below: I constituent decomposition products (° / 0 by weight) I other ingredient (° / 0 in l / eg, I | (% in, weight)! Weight) (a) peo peg hpmc ja-toc. ono 'Jono' Jf '_k' j, 1.5 76.0 10.0 10.0 j1.5 I Maleinic acid 1.0 ° /) jnd! nd | q, 20 | 0.22 J, 1.5 76.0 10.0 10.0 | 1.5 fumaric acid 1.0 ° /) jnd I nd | q, 17 | 0.3d j, 1, 5 76.0 10.0 10.0 j1.5 I NaH2PO, 1.0 ° /) * jnd | q, 18 jo, 06 jo, 75 (A): oxymorphone hydrochloride PEO: polyethylene oxide Mw 7 mio g / mol PEG: polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa * s a-toc. : a-tocopherol * NaH2PO4: Used in the form of 1.3% of the oNO dihydrate: oxymorphone-N-oxide (mixture) E: sum of all impurities; maleinic acid, fumaric acid and related compounds subtracted from the sum of impurities 1: after extrusion, before storage 2 · after storage, open plate, 4 weeks, 40 ° C, 75 ° / o um-. relative quality In the case of maleinic and fumaric acid of these compounds to maleinic acid, another related compound was detected during the purity test as impurities (up to about 4 ° / o). Their values were subtracted from the sum of impurities.
It is evident from a comparison of examples J1 and J2 with A1 and B1 that the presence of maleinic and fumaric acid protected -oxymorphone totally against N-oxide oxidation and, to a large extent, against other degradation, although the samples were stored in open dishes and in closed bottles.
These results are comparable to those obtained with citric acid (example 1, D4 and E2-E4). Samples containing
NaH2PO4 (J3) showed formation of N-oxide and other degradation when compared to formulations without any acidic compound (Ai and Bi), but to a lesser extent than multicarboxylic acids like citric, maleinic and fumaric acid.
Example 9 To investigate whether the presence of citric acid also protects oxidation-sensitive opioids other than oxymorphone against N-oxidation, tablets containing oxycodone hydrochloride were manufactured as described in example 1. For comparison, tablets containing smaller amounts of a-tocopherol were also manufactured.
The samples were stored in open dishes at 40 ° C and 75% relative humidity for 4 weeks.
The individual constituents of the extruded mixtures as well as the total amount of decomposition products before and after storage under accelerated storage conditions are summarized in the table.
below: constituent decomposition products (° / 0 by weight) other ingredient (° / 0 eg (° / 0 by weight) weight) (A) PEO PEG HPMC a-toc. oNo1 I ONO2 Ê Z2
K, 1.5 77.0 10.0 10.0 1.5 / 0.05 | Q, 58 0.31 1.63
K, 1.5 78.3 10.0 10.0 0.2 / 0.05! 0.28 0.58 0.69
K, 1.5 76.0 10.0 10.0 1.5 Citric acid 1.0 nd) nd 0.19 0.22
K, 1.5 77.3 10.0 10.0 0.2 Citric acid 1.0 nd I nd 0.18 0.23
(A): oxycodone hydrochloride PEO: polyethylene oxide Mw 7 mio g / mol PEG: polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa * s 5. a-toc. : a-tocopherol. oNo: oxycodone-N-oxide Z: sum of all impurities 1 · after extrusion, before storage. 2 · after storage, open plate, 4 weeks, 40 ° C, 75 ° /). These results show that citric acid completely protected oxycodone against N-oxide oxidation and, to a large extent, against other degradation, although the samples were stored in open dishes rather than in closed bottles.
The reduction in the amount of a-tocopherol resulted in reduced degradation, when the formulations were used without containing citric acid.
These results are comparable to those obtained with oxymorphone.

权利要求:
Claims (17)
[1]
1. Thermoformed pharmaceutical dosage form, characterized by the fact that it has a breaking strength of at least 300 N and comprising: 5 - an opioid (A), - a physiologically acceptable free acid (B) in an amount of 0.001 to 5.0% by weight, based on the total weight of the pharmaceutical dosage form, and - a polyalkylene oxide (C) having an average weight molecular weight 10 Mw of at least 500,000 g / mol.
[2]
2. Pharmaceutical dosage form according to claim 1, characterized by the fact that acid (B) is a multicarboxylic acid.
[3]
3. Pharmaceutical dosage form, according to claim 2, characterized by the fact that multicarboxylic acid is selected from the group consisting of maleic acid, fumaric acid, glutaric acid, malonic acid and citric acid.
[4]
4. Pharmaceutical dosage form according to any of claims 1 to 3, characterized by the fact that the content of acid (B) is within the range of 0.005 to 2.5% by weight, based on the total weight of the pharmaceutical dosage form.
[5]
Pharmaceutical dosage form according to any one of claims 1 to 4, characterized by the fact that it comprises a polyalkylene glycol, in which the relative weight ratio of polyalkylene oxide to polyalkylene glycol is within the range of 4.2 ± 2: 1.
[6]
Pharmaceutical dosage form according to any one of claims 1 to 5, characterized in that it comprises an antioxidant.
[7]
7. Pharmaceutical dosage form, according to claim 6, characterized by the fact that the antioxidant is a-tocopherol.
[8]
8. Pharmaceutical dosage form, according to claim 6 or 7, characterized by the fact that the antioxidant content is within the range of 0.001 to 5.0% by weight, based on the total weight of the dosage form -
pharmaceutical gem.
[9]
9. Pharmaceutical dosage form according to any one of claims 1 to 8, characterized by the fact that after storage for 4 weeks at 40 ° C and 75% relative humidity, the opioid content (A ) amounts to at least 98.0% of its original content before storage.
[10]
1O. Pharmaceutical dosage form according to any of claims 1 to 9, characterized by the fact that the opioid (A) is embedded in a matrix comprising polyalkylene oxide (C), said matrix controlling the release of the opioid from the pharmaceutical dosage form.
[11]
11. Pharmaceutical dosage form according to any one of claims 1 to 10, characterized by the fact that opioid (A) is selected from the group consisting of oxymorphone, oxycodone, hydromorphine, and their physiologically acceptable salts.
[12]
Pharmaceutical dosage form according to any one of claims 1 to 11, characterized in that the relative weight ratio of polyalkylene oxide (C) to opioid (A) is at least 1: 1.
[13]
Pharmaceutical dosage form according to any one of claims 1 to 12, characterized in that it is adapted for administration once a day or twice a day.
[14]
14. Pharmaceutical dosage form according to any one of the preceding claims, which has a tensile strength of at least 500 N.
[15]
15. Packaging, characterized by the fact that it contains a pharmaceutical dosage form, as defined in any of claims 1 to 14, and an oxygen reclaimer.
[16]
16. Process for the manufacture of a pharmaceutical dosage form, as defined in any one of claims 1 to 14, characterized by the fact that it comprises the steps of: (a) mixing all the components of the mixture; (b) heating the resulting mixture in the extruder, at least, to the point of softening of the polyalkylene oxide (C) and extruding through the exit hole of the extruder by applying force; (c) singularize and form the extrudate still made of plastic in the form of pharmaceutical dosage or (d) form the extrudate singularized and optionally reheated in the form of pharmaceutical dosage.
[17]
17. Invention, characterized by any of its embodiments or categories of claim encompassed by the material initially revealed in the patent application or in its examples presented here.

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法律状态:
2020-08-25| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-09-01| 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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2020-10-20| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 10A ANUIDADE. |

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2020-12-15| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-02-09| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2598 DE 20-10-2020 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |

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2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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