PH-dependent controlled release pharmaceutical opioid composition with resistance against the influence of ethanol

Abstract

The invention relates to a pH-dependent controlled release pharmaceutical composition, comprising a core, and an opioid, wherein the core is coated at least by one coating layer, controlling the release of the pharmaceutical composition, wherein the coating layer comprises a polymer mixture of i) 40-95% by weight, based on dry weight of the polymer mixture, of at least one water insoluble essentially neutral vinyl polymer, and ii) 5-60% by weight, based on dry weight of the polymer mixture, of at least one anionic polymer or copolymer, which is insoluble in a buffered medium below pH 4.0 and soluble at least in the range from pH 7.0 to pH 8.0, characterized in that the coating layer further comprises 110 to 250% by weight of a non-porous inert lubricant, 1 to 35% by weight of a neutral cellulosic compound and 1 to 25% by weight of an emulsifier, each calculated on dry weight of the polymer mixture.

Claims

1. A pH-dependent controlled release pharmaceutical composition, comprising a core, comprising at least one pharmaceutical active ingredient, which is an opioid, wherein the core is coated by at least one coating layer, controlling release of the pharmaceutical composition, wherein the at least one coating layer comprises: (A) a polymer mixture of (Ai) 40-95% by weight, based on a dry weight of the polymer mixture, of at least one water insoluble essentially neutral vinyl polymer or copolymer, and (Aii) 5-60% by weight, based on the dry weight of the polymer mixture, of at least one anionic polymer or copolymer, which is insoluble in a buffered medium below pH 4.0 and soluble at least in a pH range from 7.0 to 8.0; (B) 110 to 250% by weight of a non-porous inert lubricant; (C) 1 to 35% by weight of at least one neutral cellulosic compound; and (D) 1 to 25% by weight of at least one emulsifier, wherein (B) through (D) are calculated on the dry weight of the polymer mixture, and wherein the at least one active ingredient is released to a degree of 75% or less after 12 hours in simulated gastric fluid pH 1.2 for a first 2 hours and in buffered medium pH 6.8for a remaining time with or without an addition of 40% ethanol (v/v) in the media.

2. The controlled release pharmaceutical composition of claim 1, wherein the non-porous inert lubricant (B) is a layered silica component, a pigment, or a stearate compound.

3. The controlled release pharmaceutical composition of claim 1, wherein the non-porous inert lubricant (B) is talc.

4. The controlled release pharmaceutical composition of claim 1, wherein the non-porous inert lubricant (B) is Ca- or Mg-stearate.

5. The controlled release pharmaceutical composition of claim 1, wherein the water insoluble essentially neutral vinyl polymer (Ai) is a copolymer comprising free-radical polymerized units of more than 95 up to 100% by weight of at least one C.sub.1- to C.sub.4-alkyl ester of acrylic or of methacrylic acid, and less than 5% by weight of acrylic or methacrylic acid.

6. The controlled release pharmaceutical composition of claim 1, wherein the water insoluble essentially neutral polymer (Ai) is a polyvinyl acetate polymer or copolymer.

7. The controlled release pharmaceutical composition of claim 1, wherein the water soluble anionic polymer (Aii) is a (meth)acrylate copolymer comprising free-radical polymerized units of 25 to 95% by weight at least one C.sub.1- to C.sub.4-alkyl ester of acrylic or of methacrylic acid, and 5 to 75% by weight at least one (meth)acrylate monomer comprising an anionic group.

8. The controlled release pharmaceutical composition of claim 7, wherein the water soluble anionic polymer (Aii) comprises free-radical polymerized units of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate, and 5 to 15% by weight of methacrylic acid.

9. The controlled release pharmaceutical composition of claim 1, wherein the neutral cellulosic compound (C) is hydroxypropylmethylcellulose.

10. The controlled release pharmaceutical composition of claim 1, wherein the emulsifier (D) is a nonionic emulsifier.

11. The controlled release pharmaceutical composition of claim 10, wherein the non-ionic emulsifier is a polyoxyethylene derivative of a sorbitan ester.

12. The controlled release pharmaceutical composition of claim 10, wherein the non-ionic emulsifier is a polyethoxy sorbitan monooleate.

13. The controlled release pharmaceutical composition of claim 1, having, under in-vitro conditions according to USP paddle, 100 rpm, buffered at pH 1.2 for a first two hours or pH 6.8 (European Pharmacopoeia) for a remaining time respectively in a medium with and without addition of 40% (v/v) ethanol, the following properties: when the at least one pharmaceutical active ingredient is released to a degree of less than 20% without the addition of 40% (v/v) ethanol, a difference in a release rate with the addition of 40% (v/v) ethanol is not more than plus or minus 15% of a corresponding release rate without 40% (v/v) ethanol; and when the at least one pharmaceutical active ingredient is released to a degree of 20-80% without the addition of 40% (v/v) ethanol, the difference in the release rate with the addition of 40% (v/v) ethanol is not more than plus or minus 30% of the corresponding release rate without 40% (v/v) ethanol.

14. The controlled release pharmaceutical composition of claim 1, wherein the opioid is at least one selected from the group consisting of morphine, codeine and thebaine, diamorphine (heroin), oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine, methadone, levomethadyl acetate hydrochloride (LAAM), pethidine (meperidine), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine or phenazocine, hydromorphine, hydrocodone, oxymorphone, oxycodone, buprenorphine, hydromorphone, levorphanol, tramadol, tilidine, sufentanil, pentozocine, nalbuphine, meptazinol, meperidine, fentanyl, a pharmaceutically acceptable salt thereof, a free base form thereof, and a free acid form thereof.

15. The controlled release pharmaceutical composition of claim 1, in the form of at least one pellet comprised in a multiparticulate pharmaceutical form.

16. The controlled release pharmaceutical composition of claim 1, further comprising: at least one selected from the group consisting of a sub coat and a top coat.

17. The controlled release pharmaceutical composition of claim 1, in the form of at least one coated pellet with an overall average diameter in a range of from 100 to 5000 μm.

18. The controlled release pharmaceutical composition of claim 17, wherein the at least one coated pellet has an overall average diameter in a range between 100 to 700 μm.

19. The controlled release pharmaceutical composition of claim 17, wherein the at least one coated pellet has an overall average diameter in a range between 1400 to 5000 μm.

20. The controlled release pharmaceutical composition of claim 19, wherein the coating layer is present in an amount of at least 50% by weight calculated on a weight of core.

21. The controlled release pharmaceutical composition of claim 1, wherein component (C) comprises a hydroxypropylmethyl cellulose and component (D) comprises a polyoxyethylene sorbitan monoleate.

Description

DETAILS OF THE INVENTION

(1) The invention is concerned with

(2) A pH-dependent controlled release pharmaceutical composition, comprising a core, comprising at least one pharmaceutical active ingredient, which is an opioid, wherein the core is coated at least by one coating layer, controlling the release of the pharmaceutical composition, wherein the coating layer comprises a polymer mixture of i) 40-95, preferably 60-95, most preferably 70 -90% by weight of at least one water insoluble essentially neutral vinyl polymer or copolymer, based on dry weight of the polymer mixture, and ii) 5-60, preferably 5-40, most preferably 10-30% by weight, based on dry weight of the polymer mixture, of at least one anionic polymer or copolymer, which is insoluble in a buffered medium below pH 4.0 and soluble at least in the range from pH 7.0 to pH 8.0. characterized in that the coating layer further comprises, essentially contains or contains 110 to 250, preferably 140-220% by weight of a non-porous inert lubricant, 1 to 35% by weight, preferably 2-30% by weight, most preferred 5-25% by weight of at least one neutral cellulosic compound and 1 to 25% by weight, preferably 5-20% by weight, most preferred 5-15% by weight of at least one emulsifier each calculated on the dry weight of the polymer mixture.
Release profiles for opioids

(3) The invention provides a controlled release pharmaceutical composition for opioids, where the active ingredient is released to a degree of 75% or less preferably to a degree of 50-75%, most preferred to a degree of 55-70%, after 12 hours in simulated gastric fluid pH 1.2 (USP) for the first 2 hours and in buffered medium pH 6.8 (USP) for the remaining time with or without the addition of 40% ethanol (v/v) in the media.

(4) The Core

(5) In a manner known per se, active ingredient-containing cores or pellet cores form the basis for the coatings of vinyl (co)polymers. Pelletizing can be carried out on active ingredient-free spheres (nonpareills) or core-free pellets, pellet cores, can be produced. First, a rounded, active ingredient-containing substrate with or without a core is produced. By means of a fluidized bed process, liquid can be applied to placebo pellets or other suitable carrier materials, the solvent or suspending agent being evaporated. According to the preparation process, a drying step can be added. The spraying step and subsequently drying may be repeated several times until the intended amount of pharmaceutical active ingredient is fully applied.

(6) The active ingredient is as a rule brought into an organic solvent or into water and mixed. In order to guarantee the satisfactory sprayability of the mixture, it is usually necessary to formulate a mixture with relatively low viscosity.

(7) In addition to the active ingredient, the dispersion can contain further pharmaceutical excipients: binders, such as polyvinylpyrrolidone (PVP), moisture retention agents, disintegration promoters, lubricants, disintegrants, (meth)acrylates, starch and its derivatives, sugar solubilizers or others.

(8) Appropriate application processes are known, for example, from Bauer, Lehmann, Osterwald, Rothgang “Uberzogene Arzneiformen” [Coated Pharmaceutical Forms] Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, Chap. 7, pp. 165-196.

(9) Details are furthermore known to the person skilled in the art from textbooks. See, for example: Voigt, R. (1984): Lehrbuch der pharmazeutischen Technologie [Textbook of Pharmaceutical Technology]; Verlag Chemie Weinheim—Beerfield Beach/Florida—Basle. Sucker, H., Fuchs, P., Speiser, P.: Pharmazeutische Technologie [Pharmaceutical Technology], George Thieme Verlag Stuttgart (1991), in particular chapters 15 and 16, pp. 626 -642. Gennaro, A., R. (Editor), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton Pa. (1985), Chapter 88, pp. 1567-1573. List, P. H. (1982): Arzneiformenlehre [Pharmaceutical Form Theory], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart.

(10) Pellet cores can be rounded by processes such as rotor agglomeration, precipitation or spray processes, in particular ultrasonic vortex spray processes, to give still uncoated cores or pellet cores of defined size, e.g. 50 to 2500 μm. This has the advantage that the entire core volume is available for active ingredient loading. The active ingredient loading can thereby again be increased in relation to the embodiment having an inert core.

(11) A process of direct compaction may be used to produce cores for minitablets.

(12) Besides the pharmaceutical active ingredient, the core may comprise further pharmaceutical excipients: binders such as cellulose and derivatives thereof, polyvinyl-pyrrolidone (PVP), humectants, disintegration promoters, lubricants, disintegrants, starch and derivatives thereof, sugar solubilizers or others.

(13) Coating layer controlling the release of the pharmaceutical composition

(14) The core is coated at least by one, preferably by one or more preferably by only one coating layer, controlling the release of the pharmaceutical composition. The coating layer conveys the effect of resistance of the release profile against ethanol containing aqueous media. The coating layer, controlling the release of the pharmaceutical composition may also be called an outer coating layer because it surrounds the core.

(15) The (outer) coating layer controls the release of the pharmaceutical composition. The coating layer conveys the effect the resistance of the release profile against ethanol containing aqueous media.

(16) In case of incompatibilities between ingredients of the core and ingredients of the coating an insulating sub coat may be applied between the core and the (outer) coating layer.

(17) The coating layer, controlling the release of the pharmaceutical composition, may be further covered with a non-functional, preferably water soluble top coat that has essentially no influence on the release characteristics.

(18) After preparation of the active ingredient-containing cores or pellet cores, these are provided in spray processes with the coating layer, such that coated cores or coated pellets respectively are obtained. The coating is prepared by means of spray application from organic solution, or preferably from aqueous dispersions. For implementation, it is crucial here that uniform, pore-free coatings result. As a rule, the coated pellets are additionally subsequently dried for a few minutes after the spray application before the conditioning process is begun. As a rule, the polymer coatings contain pharmaceutically customary excipients such as, for example, release agents or plasticizers.

(19) The coating layer, controlling the release of the pharmaceutical composition, may be present in an amount of at least 30% by weight calculated on the weight of core. The coating is preferably present in an amount of 60-250, more preferably 75-180% by weight, calculated on the weight of core.

(20) The average thickness of the coating layer may be in range of about 10-1000, preferably in the range of 50-500 μm.

(21) Coated Pellets

(22) The controlled release pharmaceutical composition may preferably be present in the form of coated pellets, minitablets or tablets with an overall average diameter from 100-5000 μm, preferably 100 to 2000, most preferably 300 to 1000 μm.

(23) The controlled release pharmaceutical composition according to the invention may be present in the form of coated pellets with an overall average diameter in the range between 100 to 700 μm preferably above 200 μm or above 500 μm or in the range between 250 and 400 μm.

(24) The controlled release pharmaceutical composition according to the invention may be present in the form of minitablets or tablets with an overall average diameter in the range between 1400 to 5000 μm, preferably 1500 to 4000, most preferably 1800 to 3500 μm.

(25) When the coated pellets have an overall average diameter in the range between 100 to 700 μm, preferably above 200 μm or above 500 μm or in the range between 250 and 400 μm the coating layer should be present in an amount of at least 100% by weight calculated on the weight of core.

(26) When the coated pellets have an overall average diameter in the range between 1400 to 5000 μm, preferably above 2000 μm or above 2500 μm or in the range between 2500 and 3500 μm, the coating layer should be present in an amount of at least 50% by weight, at least 100% by weight, at least 140% by weight, calculated on the weight of core.

(27) Mini tablets

(28) The controlled release pharmaceutical composition may preferably be present in the form of coated mini tablets, where the mini tablets have an average diameter from 1 to 5 mm.

(29) Water insoluble essentially neutral vinyl polymers or copolymers

(30) Water-insoluble essentially neutral vinyl polymers or copolymers are understood to mean those polymers or copolymers which are water-insoluble over the entire pH range of 1 to 14 and only swellable in water.

(31) A Vinyl polymer originates from the polymerization of monomers with vinyl groups such like (meth)acrylic monomers.

(32) Essentially neutral is meant in the sense in that the polymers, if at all, may contain only small amounts of ionic groups. Even if small amounts of ionic groups are present the physical-chemical behaviour of such polymers is almost the same as the physical-chemical of polymers without any ionic groups. Essentially neutral is especially meant in the sense in that the polymers contain less than 5, less than 4, less than 3, less than 2 or less than 1% by weight of monomer residues with anionic or cationic side groups. Preferably the water-insoluble neutral vinyl polymers or copolymers do not contain any cationic groups. Most preferably the water-insoluble essentially neutral vinyl polymers or copolymers do not contain any ionic groups at all and thus are neutral water-insoluble vinyl polymers (100% neutral).

(33) Especially water insoluble (meth)acrylic polymers composed of 5 or 10% by weight of monomer residues containing cationic quaternary ammonium groups, e. g. of the type Eudragit® RS or Eudragit® RL, are not suitable for the purposes of the present invention since the resulting pharmaceutical compositions are not sufficiently resistant against the influence of 40% ethanol.

(34) In general, only one or one type of water-insoluble essentially neutral vinyl polymer or copolymer is present in the pharmaceutical composition. However, it is also possible, if appropriate, for two or more water-insoluble polymers or copolymers or types of such polymers or copolymers to be present alongside one another or in a mixture.

(35) Water insoluble vinyl polymers of the type of poly vinyl actetate

(36) Suitable water insoluble polymers are of the type of polyvinyl acetate polymers or copolymers derived thereof.

(37) Examples of water insoluble poly vinyl acetate type polymers or copolymers are polyvinyl acetate (PVAc, Kollicoat), vinylacetate-vinylpyrrolidon-copolymer (Kollidon® VA64).

(38) Water insoluble (meth)acrylic copolymers

(39) Among the Water insoluble (meth)acrylic copolymers neutral or essentially neutral methacrylate copolymers are suitable for purposes of the present invention.

(40) Neutral (meth)acrylate copolymers (EUDRAGIT® NE type)

(41) Neutral or essentially neutral methacrylate copolymers consist at least to an extent of more than 95% by weight, in particular to an extent of at least 98% by weight, preferably to an extent of at least 99% by weight, in particular to an extent of at least 99% by weight, more preferably to an extent of 100% by weight, of (meth)acrylate monomers with neutral radicals, especially C.sub.1- to C.sub.4-alkyl radicals.

(42) Suitable (meth)acrylate monomers with neutral radicals are, for example, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. Preference is given to methyl methacrylate, ethyl acrylate and methyl acrylate.

(43) Methacrylate monomers with anionic radicals, for example acrylic acid and/or methacrylic acid, may be present in small amounts of less than 5% by weight, preferably not more than 2% by weight, more preferably not more than 1 or 0.05 to 1% by weight.

(44) Suitable examples are neutral or virtually neutral (meth)acrylate copolymers composed of 20 to 40% by weight of ethyl acrylate, 60 to 80% by weight of methyl methacrylate and 0 to less than 5% by weight, preferably 0 to 2 or 0.05 to 1% by weight of acrylic acid or methacrylic acid (EUDRAGIT® NE).

(45) EUDRAGIT® NE and Eudragit® NM are copolymers composed of free-radically polymerized units of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.

(46) A suitable water insoluble polymer is a copolymer composed of free-radical polymerized units of more than 95 up to 100% by weight C.sub.1- to C.sub.4-alkyl esters of acrylic or of methacrylic acid and less than 5% by weight of acrylic or methacrylic acid.

(47) Water soluble anionic polymers

(48) A water soluble anionic polymer in the sense of the present invention is a polymer which is insoluble below pH 5.0 and soluble at least in the range from pH 7.0 to pH 8.0, preferably in the range from pH 6.0 to 8.0, most preferably soluble in the range from 5.5 to 8.0 in a suitable buffered medium, preferably a buffered medium according to USP or European Pharmacopoeia standards. Most of the polymers which are soluble in the range from pH 7.0 to pH 8.0 in a suitable buffered aqueous medium are not soluble in pure water or demineralised water.

(49) Water soluble anionic cellulose derivatives

(50) Anionic cellulose derivates are based on a natural cellulose chain and chemically modified with anionic compounds. The polymer may by partially or totally neutralized, preferably with alkali ions. Examples of anionic cellulose derivatives are cellulose acetate phthalate (CAP), hydroxy propyl methyl cellulose phthalate (HPMCP), carboxy methyl cellulose (CMC), hydroxyl propyl methyl cellulose acetate succinate (HPMCAS) or cellulose acetate succinate (CAS).

(51) Water soluble anionic (meth)acrylate copolymers

(52) A suitable water soluble anionic (meth)acrylate copolymer is composed of free-radical polymerized units of 25 to 95, preferably 40 to 95, in particular 60 to 40, % by weight free-radical polymerized C.sub.1- to C.sub.4-alkyl esters of acrylic or of methacrylic acid and 75 to 5, preferably 60 to 5, in particular 40 to 60, % by weight (meth)acrylate monomers having an anionic group.

(53) The proportions mentioned normally add up to 100% by weight. However it is also possible in addition, without this leading to an impairment or alteration of the essential properties of the invention, for small amounts in the region of up to 10 or 0 to 10, for example 1 to 5, % by weight of further monomers capable of vinylic copolymerization, such as, for example, hydroxyethyl methacrylate or hydroxyethyl acrylate, to be present. However, it is preferred that no further monomers capable of vinylic copolymerization are present. It is generally preferred that no further monomers except from those explicitly mentioned are present in the water soluble anionic (meth)acrylate copolymers.

(54) C.sub.1- to C.sub.4-alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.

(55) A (meth)acrylate monomer having an anionic group is, for example, acrylic acid, with preference for methacrylic acid.

(56) Suitable anionic (meth)acrylate copolymers are those composed of 40 to 60% by weight methacrylic acid and 60 to 40% by weight methyl methacrylate or 60 to 40% by weight ethyl acrylate (EUDRAGIT® L or EUDRAGIT® L 100-55 types).

(57) EUDRAGIT® L is a copolymer of 50% by weight methyl methacrylate and 50% by weight methacrylic acid. The pH of the start of the specific active ingredient release in intestinal juice or simulated intestinal fluid can be stated to be pH 6.0.

(58) EUDRAGIT® L 100-55 is a copolymer of 50% by weight ethyl acrylate and 50% by weight methacrylic acid. EUDRAGIT® L 30 D-55 is a dispersion comprising 30% by weight EUDRAGIT® L 100-55. The pH of the start of the specific active ingredient release in intestinal juice or simulated intestinal fluid can be stated to be pH 5.5.

(59) Likewise suitable are anionic (meth)acrylate copolymers composed of 20 to 40% by weight methacrylic acid and 80 to 60% by weight methyl methacrylate (EUDRAGIT® S type). The pH of the start of the specific active ingredient release in intestinal juice or simulated intestinal fluid can be stated to be pH 7.0.

(60) Suitable (meth)acrylate copolymers are those consisting of 10 to 30% by weight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid (EUDRAGIT® FS type). The pH at the start of the specific active ingredient release in intestinal juice or simulated intestinal fluid can be stated to be pH 7.0.

(61) EUDRAGIT® FS is a copolymer polymerized out of 25% by weight methyl methacrylate, 65% by weight methyl acrylate and 10% by weight methacrylic acid. EUDRAGIT® FS 30 D is a dispersion comprising 30% by weight EUDRAGIT® FS.

(62) Additionally suitable is a copolymer composed of 20 to 34% by weight methacrylic acid and/or acrylic acid, 20 to 69% by weight methyl acrylate and 0 to 40% by weight ethyl acrylate and/or where appropriate 0 to 10% by weight further monomers capable of vinylic copolymerization,
with the proviso that the glass transition temperature of the copolymer according to ISO 11357-2, subsection 3.3.3, is not more than 60° C. This (meth)acrylate copolymer is particularly suitable, because of its good elongation at break properties, for compressing pellets to tablets.

(63) Additionally suitable is a copolymer composed of 20 to 33% by weight methacrylic acid and/or acrylic acid, 5 to 30% by weight methyl acrylate and 20 to 40% by weight ethyl acrylate and more than 10 to 30% by weight butyl methacrylate and where appropriate 0 to 10% by weight further monomers capable of vinylic copolymerization, where the proportions of the monomers add up to 100% by weight,
with the proviso that the glass transition temperature of the copolymer according to ISO 11357-2, subsection 3.3.3 (midpoint temperature T.sub.mg), is 55 to 70° C. Copolymers of this type are particularly suitable, because of its good mechanical properties, for compressing pellets to tablets.

(64) The abovementioned copolymer is composed in particular of free-radical polymerized units of 20 to 33, preferably 25 to 32, particularly preferably 28 to 31% by weight methacrylic acid or acrylic acid, with preference for methacrylic acid, 5 to 30, preferably 10 to 28, particularly preferably 15 to 25% by weight methyl acrylate, 20 to 40, preferably 25 to 35, particularly preferably 18 to 22% by weight ethyl acrylate, and more than 10 to 30, preferably 15 to 25, particularly preferably 18 to 22% by weight butyl methacrylate,
where the monomer composition is chosen, so that the glass transition temperature of the copolymer is from 55 to 70° C., preferably 59 to 66, particularly preferably 60 to 65° C.

(65) Glass transition temperature means in this connection in particular the midpoint temperature T.sub.mg according to ISO 11357-2, subsection 3.3.3. Measurement takes place without added plasticizer, with residual monomer contents (REMO) of less than 100 ppm, with a heating rate of 10° C/min and under a nitrogen atmosphere.

(66) The copolymer preferably consists essentially to exclusively of 90, 95 or 99 to 100% by weight of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the ranges of amounts indicated above.

(67) However, it is possible, without this necessarily leading to an impairment of the essential properties, for small amounts in the range from 0 to 10, e.g. 1 to 5% by weight of further monomers capable of vinylic copolymerization additionally to be present, such as, for example, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinylmalonic acid, styrene, vinyl alcohol, vinyl acetate and/or derivatives thereof.

(68) Preparation of anionic (meth)acrylate copolymers

(69) The anionic (meth)acrylate copolymers can be prepared in a manner known per se by free-radical polymerization of the monomers (see, for example, EP 0 704 207 A2 and EP 0 704 208 A2). The copolymer according to the invention can be prepared in a manner known per se by free-radical emulsion polymerization in aqueous phase in the presence of, preferably, anionic emulsifiers, for example by the process described in DE-C 2 135 073.

(70) The copolymer can be prepared by conventional processes of free-radical polymerization continuously or discontinuously (batch processes) in the presence of free-radical forming initiators and, where appropriate, regulators to adjust the molecular weight undiluted, in solution, by bead polymerization or in emulsion. The average molecular weight Mw (weight average, determined for example by measuring the solution viscosity) may be for example in the range from 80 000 to 1 000 000 (g/mol). Emulsion polymerization in aqueous phase in the presence of water-soluble initiators and (preferably anionic) emulsifiers is preferred.

(71) In the case of bulk polymerization, the copolymer can be obtained in solid form by crushing, extrusion, granulation or hot cut.

(72) The (meth)acrylate copolymers are obtained in a manner known per se by free-radical bulk, solution, bead or emulsion polymerization. They must be brought before processing to the particle size range of the invention by suitable grinding, drying or spraying processes. This can take place by simple crushing of extruded and cooled pellets or hot cut.

(73) The use of powders may be advantageous especially on mixture with other powders or liquids. Suitable apparatuses for producing powders are familiar to the skilled person, e.g. air jet mills, pinned disc mills, compartment mills. It is possible where appropriate to include appropriate sieving steps. A suitable mill for industrial large quantities is, for example, an opposed jet mill (Multi No. 4200) operated with a gauge pressure of about 6 bar.

(74) Partial neutralization

(75) The anionic polymers may be partially or fully neutralized by bases. Bases suitable are those expressly mentioned in EP 0 088 951 A2 or WO 2004/096185 or derivable there from. In particular: sodium hydroxide solution, potassium hydroxide solution (KOH), ammonium hydroxide or organic bases such as, for example, triethanolamine, sodium carbonate, potassium carbonate, sodium bicarbonate, trisodium phosphate, trisodium citrate or ammonia or physiologically tolerated amines such as triethanolamine or tris(hydroxymethyl)aminomethane. Further suitable cationic, organic bases are basic amino acids histidine, arginine and/or lysine.

(76) Multiparticulate pharmaceutical forms

(77) The controlled release pharmaceutical composition according to the invention may have the form of pellets, which are contained in a multiparticulate pharmaceutical form, for instance in the form of a compressed tablet, capsules, sachets, effervescent tablets or reconstitutable powders.

(78) Top Coat and Sub Coats

(79) The controlled release pharmaceutical composition according to the invention may be further coated with a sub coat and/or a top coat.

(80) A sub coat may be located between the core and the coating layer controlling the release of the pharmaceutical active substance (controlling layer). A sub coat may have the function to separate substances of the core from substances of the controlling layer which may be incompatible with each other. The sub coat has essentially no influence on the release characteristics. A sub coat is preferably essentially water-soluble, for instance it may consist of substances like hydroxyl propyl methyl cellulose (HPMC) as a film former. The average thickness of the sub coat layer is very thin, for example not more than 15 μm, preferably not more than 10 μm.

(81) A top coat is also preferably essentially water soluble. A top coat may have the function of colouring the pharmaceutical form or protecting from environmental influences for instance from moisture during storage. The top coat may consist out of a binder, for instance a water soluble polymer like a polysaccharide or HPMC, or a sugar compound like saccharose. The top coat may further contain pharmaceutical excipients like pigments or lubricants in small amounts. The topcoat has essentially no influence on the release characteristics.

(82) The expressions sub coat and top coat is well known to the person skilled in the art.

(83) Process for producing a pharmaceutical form according to the invention

(84) The controlled release pharmaceutical composition according to the invention may be produced in a manner known per se by pharmaceutically customary processes such as direct compression, compression of dry, wet or sintered granules and subsequent rounding off, wet or dry granulation or direct pelleting or by binding powders (powder layering) onto active ingredient-free beads or neutral cores (nonpareilles) or active ingredient-containing particles and by applying the polymer coating in a spray process or by fluidized bed granulation.

(85) Excipients/Customary additives

(86) The core may further contain, beside the pharmaceutical active ingredient, excipients or customary additives respectively in a manner known to the person skilled in the art. The further excipients are not critical for the invention.

(87) The coating layer may also, beside the polymer mixture, the non-porous inert lubricant, the neutral cellulosic compound and the emulsifier as essential ingredients, further contain excipients or customary additives respectively in a manner known to the person skilled in the art. However if excipients are contained in the coating layer they are always different from the essential ingredients, which are the polymers of polymer mixture, the non-porous inert lubricant, the neutral cellulosic compound and the emulsifier. In contrast the essential ingredients, which are the polymers of polymer mixture, the non-porous inert lubricant, the neutral cellulosic compound and the emulsifier, the further excipients are not critical for the invention. The further excipients do not contribute to the beneficial inventive effects. Preferably the amount of further excipients in the coating layer is less than 5% by weight, more preferably less than 2% by weight calculated on the dry weight of the total coating layer. Most preferably there are no further excipients in the coating layer.

(88) Excipients or customary additives respectively shall be added only at amounts which do not negatively influence the function of the core or the outer coating layer according to the invention as disclosed in here. As a guide line excipients or customary additives may be for instance used in a way similar or identical as in the working examples disclosed in here.

(89) Excipients customary in pharmacy, occasionally also referred to as customary additives, are added to the formulation of the invention, preferably during production of the granules or powders. It is, of course, always necessary for all the excipients or customary additives employed to be toxicologically acceptable and usable in particular in medicaments without a risk for patients.

(90) The amounts employed and the use of excipients customary in pharmacy for medicament coatings or layerings are familiar to the skilled worker. Examples of possible excipients or additives customary in pharmacy are release agents, pigments, stabilizers, antioxidants, pore formers, penetration promoters, gloss agents, aromatizing substances or flavourings. They serve as processing aids and are intended to ensure a reliable and reproducible production process and good long-term storage stability or they achieve additional advantageous properties in the pharmaceutical form. They are added to the polymer preparations before processing and may influence the permeability of the coatings, it being possible to utilize this where appropriate as additional control parameter.

(91) Pigments:

(92) As already stated pigments may be used in the coating layer in the function as non-porous inert lubricants to promote resistance against the influence of ethanol. If pigments are additionally added as excipients which do not contribute to the invention they may be added to a top coat onto the coating layer to give some coloring. The pigments to be used in the function as non-porous inert lubricants in the coating layer or as excipients which do not contribute to the invention are generally of course non-toxic and suitable for pharmaceutical purposes. Concerning this, see also, for example: Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmittel, Harald, Boldt Verlag K G, Boppard (1978); Deutsche Lebensmittelrundschau 74, No. 4, p. 156 (1978); Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980.

(93) Examples of pigments are orange yellow, cochineal red lake, coloured pigments based on alumina or azo dyes, sulphonic acid dyes, orange yellow S (E110, C.I. 15985, FD&C Yellow 6), indigo carmine (E132, C.I. 73015, FD&C Blue 2), tartrazine (E 102, C.I. 19140, FD&C Yellow 5), Ponceau 4R (E 125, C.I. 16255, FD&C Cochineal Red A), quinoline yellow (E 104, C.I. 47005, FD&C Yellow 10), erythrosine (E127, C.I. 45430, FD&C Red 3), azorubine (E 122, C.I. 14720, FD&C Carmoisine), amaranth (E 123, C.I. 16185, FD&C Red 2), acid brilliant green (E 142, C.I. 44090, FD&C Green S).

(94) The E numbers indicated for the pigments relate to an EU numbering. Concerning this, see also “Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmittel, Harald Boldt Verlag KG, Boppard (1978); Deutsche Lebensmittelrundschau 74, No. 4, p. 156 (1978); Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980. The FD&C numbers relate to the approval in food, drugs and cosmetics by the U.S. food and drug administration (FDA) described in: U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors: Code of Federal Regulations—Title 21 Color Additive Regulations Part 82, Listing of Certified Provisionally Listed Colors and Specifications (CFR 21 Part 82).

(95) Plasticizers Further additives may also be plasticizers. Plasticizers may be favourably added to the coating layer. The usual amounts are between 0 and 50 , preferably 5 to 20, % by weight based on the polymer mixture of the layer coating layer. Preferably there are essentially no or no plasticizers added to the coating layer.

(96) Plasticizers may influence the functionality of the polymer layer, depending on the type (lipophilic or hydrophilic) and added amount. Plasticizers achieve through physical interaction with the polymers a reduction in the glass transition temperature and promote film formation, depending on the added amount. Suitable substances usually have a molecular weight of between 100 and 20 000 and comprise one or more hydrophilic groups in the molecule, e.g. hydroxyl, ester or amino groups.

(97) Examples of suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethylene glycols 200 to 12 000. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and dibutyl sebacate (DBS). Mention should additionally be made of esters which are usually liquid at room temperature, such as citrates, phthalates, sebacates or castor oil. Esters of citric acid and sebacinic acid are preferably used.

(98) Addition of the plasticizers to the formulation can be carried out in a known manner, directly, in aqueous solution or after thermal pre-treatment of the mixture. It is also possible to employ mixtures of plasticizers.

(99) Addition of a neutral cellulosic compound in the coating

(100) The coating layer further contains 1 to 35% by weight, preferably 2-30% by weight, most preferred 5-25% by weight, calculated on dry weight of the polymer mixture (compounds i) and ii)), of at least one neutral cellulosic compound. The neutral cellulosic compound is a neural derivative of cellulose and may be preferably an ethyl ether or a methyl ether of cellulose. Most preferred the neutral cellulosic compounds are hydroxyethyl cellulose or hydroxypropylmethyl cellulose (HPMC).

(101) Addition of emulsifiers in the coating

(102) The inventors have found that the addition of one or more emulsifiers in the coating seems to improve the resistance of the pharmaceutical composition indirectly. It is supposed that the presence of a detergent in the spraying suspension promotes the film forming process to become more complete. A more complete film seems to be more resistant against the influence of ethanol than a film which was formed without the presence of a certain amount of an emulsifier in the coating. A film which was formed without the presence of certain amounts of an emulsifier in the coating is supposed to be a little more porous than a film which was formed in the presence of the emulsifier. Therefore the action of an emulsifier in the film forming process although not really understood may be similar but not identical to the effect of curing processes applied to coated pellets. It is further surprising that there seems to no negative influence or changes of the release profile itself neither when ethanol is present in the medium or not.

(103) The controlled release pharmaceutical composition according to the present invention may further therefore contain 2 to 20% by weight, preferably 5 to 15% by weight, calculated on dry weight of the polymer mixture (compounds i) and ii)), of at least one emulsifier, preferably a nonionic emulsifier.

(104) Preferably the emulsifier is a polyoxyethylene derivative of a sorbitan ester.

(105) Most preferred the detergent is polyoxyethylene sorbitan monooleate (polyethylene glycol sobitan monooleate, CAS registry number 9005-65-6, for instance Tween® 80).

(106) Improved Storage stability

(107) Surprisingly there is no influence on the storage stability when either the cellulosic compound or the emulsifier is used alone in the pharmaceutical composition. In this case the storage stability remains acceptable, which means there is still room for improvement. However when the cellulosic compound and the emulsifier are used together the storage stability becomes much better and can be called excellent.

(108) Use

(109) The pH-dependent controlled release pharmaceutical composition according to the invention may be used to reduce the risk of enhanced release of the included pharmaceutical active ingredient after oral ingestion by simultaneous or subsequent consumption of ethanol containing drinks (misuse).

(110) The pH-dependent controlled release pharmaceutical composition according to the invention may be used to reduce the risk of abuse of the included pharmaceutical active ingredient by in-vitro extraction using ethanol containing media before oral ingestion.

Examples

(111) Methods

(112) Model drug

(113) Studies are conducted using naloxone, an opioid antagonist, as a model drug for opioids. Opioids may be used in this kind of examples in the same way.

(114) Dissolution studies

(115) Coated pellets are tested according to USP 28-NF23, General Chapter <711>, Dissolution, for the first two hours in simulated gastric fluid pH 1.2 and then in buffered medium at pH 6.8.

(116) Dissolution parameters:

(117) Apparatus: USP Type-I (Basket)

(118) RPM: 100/min.

(119) Temperature: 37.5 ±0.5° C.

(120) Dissolution volume: 500 ml.

(121) Withdrawal volume: 5 ml withdrawn manually using pipette, without replenishment of the medium.

(122) Mode of detection: HPLC

(123) Dissolution medium 1:

(124) Simulated gastric fluid pH 1.2 (European Pharmacopoeia=EP)

(125) Dissolution medium 2:

(126) Simulated gastric fluid pH 1.2 (European Pharmacopoeia=EP) with 40% (v/v) ethanol

(127) Dissolution medium 3:

(128) Phosphate buffered saline pH 6.8 (European Pharmacopoeia=EP)

(129) Dissolution medium 4:

(130) Phosphate buffered saline pH 6.8, EP with 40% v/v ethanol-0.9 g of KH.sub.2PO.sub.4, 1.8 g of K.sub.2HPO.sub.4, 7.65 g of NaCI with 540 ml D.M. water and 360 ml of alcohol.

(131) Copolymers

(132) EUDRAGIT® NE is a copolymer composed of free-radically polymerized units of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.

(133) EUDRAGIT® FS is a copolymer composed of free-radically polymerized units of 25% by weight methyl methacrylate, 65% by weight methyl acrylate and 10% by weight methacrylic acid.

(134) Formulation details

(135) Cores (sugar sphere, non-pareilles) of 1700-2000 microns are loaded with naloxone in a fluidised bed processor using bottom spray. Polyvinyl pyrrolidone (Kollidon® K25) is used as a binder. 900 g of non-pareilles cores are coated with 270 g naloxone bound in 80 g binder (Kollidon® K25).

(136) Coating suspension preparation:

(137) EUDRAGIT® dispersions are mixed in a suitable vessel applying gentle stirring. Lubricants and different polymers are dissolved or dispersed in water applying high shear forces.

(138) The lubricant suspension is poured into the EUDRAGIT® dispersion applying gentle stirring. Stirring is continued through the entire coating process.

(139) Coating process:

(140) Drug layered pellets are coated with different coating suspensions in a fluidized bed apparatus under appropriate conditions, i. e. a spray rate of approximately 10-20 g / min coating suspension per kg cores and a bed temperature of approximately 25-28° C. After coating the pellets are fluidised at 50° C. for one hour in a fluid bed processor. Micronized talc is used as an excipient. The coated pellets are having an average diameter of about 3000 μm.

(141) Storage stability The storage stability is considered to be acceptable, when the deviation of the release profile before and after storage is expressed by a similarity f.sub.2-value of 50 or more but less than 60. The storage stability is considered to be good, when the deviation of the release profile before and after storage is expressed by an f.sub.2-value of 60 to 100.

(142) TABLE-US-00001 TABLE 1 Examples Example C1 C2 C3 C4 C5 6 Coating Polymer 85 85 85 100 85 85 mixture 15 15 15 — 15 15 EUDRAGIT ® NE/ EUDRAGIT ® FS [wt. %/ wt. %] Talc [wt. % / 200 100 200 200 200 200 polymer mixture]* HPMC — — — 20 20 20 [wt. %/ polymer mixture]* Tween ® — — 10 10 — 10 80 [wt. %/ polymer mixture]* Active ingredient release without/ with 40% EtOH (v/v) 2 hours  5/15 20/55 0/0 0/0 20/40 0/0 (pH 1,2) 6 hours 25/50  80/100 10/25 30/70 50/70 20/25 (pH 6,8) 12 hours  80/100 100/100 60/90 80/90 90/10 70/70 (pH 6,8) 24 hours 100/100 100/100 100/100 100/100 100/100 100/100 (pH 6,8) Rating Ethanol yes no yes no yes yes resistance = or < 75% no no no no no yes release after 12 h Storage accept- no accept- good accept- good stability able able able (40° C./ 75% r.h., closed), 6 month C1-C5: Comparative examples, Example 6 according to the invention EtOH = ethanol/r.h. = relative humidity HMPC = Hydroxypropylmethyl cellulose