Controlled release pharmaceutical composition with resistance against the influence of ethanol employing a coating comprising neutral vinyl polymers and excipients

Abstract

The invention relates to a controlled release pharmaceutical composition, comprising a core, comprising a pharmaceutical active ingredient, whereby the core is coated by an ethanol resistance conferring coating layer which has the effect of conferring the release profile of the pharmaceutical active ingredient to be resistant against the influence of ethanol, whereby the ethanol resistance conferring coating layer comprises at least 70% by weight of a mixture of a polymeric portion a) and an excipients portion b), with the polymeric portion a) is consisting of a water insoluble essentially neutral vinyl polymer or vinyl copolymer and the excipients portion b) is consisting of the excipients b1) 100 to 250% by weight of a non-porous inert lubricant, b2) 1 to 35% by weight of a cellulosic compound, b3) 0.1 to 25% by weight of an emulsifier and additionally or alternatively to b3), b4) 0.1 to 30% by weight of a plasticizer whereby the excipients of the excipients portion b) are each calculated on the dry weight of the polymer portion a).

Claims

1. A controlled release pharmaceutical composition, comprising a core comprising a pharmaceutical active ingredient, wherein: the core is coated with an ethanol resistance conferring coating layer, which confers ethanol resistance to a release profile of the pharmaceutical active ingredient under in-vitro conditions at pH 1.2 and/or at pH 6.8 in a buffered medium; wherein ethanol resistance means that the release profile is not accelerated by more than 20% and is not delayed by more than 20% under the influence of a 40% ethanol-containing medium in comparison to a release profile of a medium without ethanol; the coating layer comprises at least 70% by weight of a mixture of a polymeric portion a) and an excipients portion b); the polymeric portion a) comprises 60 to 99% by weight of a water insoluble, essentially neutral vinyl polymer or copolymer; and the excipients portion b) comprises: b1) 100 to 250% by weight of a non-porous inert lubricant; b2) 1 to 35% by weight of a cellulosic compound; b3) 0.1 to 25% by weight of an emulsifier; and additionally or alternatively to b3), b4) 0.1 to 30% by weight of a plasticizer, wherein the percent (%) by weight of each excipient is based on the dry weight of the polymeric portion a).

2. The controlled release pharmaceutical composition of claim 1, wherein the core is a pellet, the core having no coating between it and the ethanol resistance conferring coating.

3. The controlled release pharmaceutical composition of claim 2, wherein the core further comprises a neutral carrier pellet on top of which the pharmaceutical active ingredient is bound in a binder.

4. The controlled release pharmaceutical composition of claim 2, wherein the core further comprises a polymeric matrix in which the pharmaceutical active ingredient is bound.

5. The controlled release pharmaceutical composition of claim 2, wherein the core further comprises a pellet consisting of a crystallized active ingredient.

6. The controlled release pharmaceutical composition of claim 1, wherein the core is a coated pellet, which is coated with the ethanol resistance conferring coating.

7. The controlled release pharmaceutical composition of claim 6, wherein the coated pellet is a sustained release pharmaceutical formulation.

8. The controlled release pharmaceutical composition of claim 6, wherein the coated pellet is an enteric coated pharmaceutical formulation.

9. The controlled release pharmaceutical composition of claim 1, wherein the coating layer comprises up to 20% by weight of at least one further pharmaceutical excipient, which is different from the polymers of the polymeric portion a) and different from the excipients of the excipients portion b).

10. The controlled release pharmaceutical composition of claim 1, wherein the water insoluble, essentially neutral vinyl polymer or copolymer is a copolymer comprising free-radical polymerized units of more than 95% and up to 100% by weight of 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.

11. The controlled release pharmaceutical composition of claim 1, wherein the water insoluble, essentially neutral polymer or copolymer is a polyvinyl acetate type polymer or a polyvinyl acetate type copolymer.

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

13. The controlled release pharmaceutical composition of claim 12, wherein the non-porous inert lubricant is talc.

14. The controlled release pharmaceutical composition of claim 12, wherein the non-porous inert lubricant is Ca- or Mg-stearate.

15. The controlled release pharmaceutical composition of claim 1, wherein the cellulosic compound is a water soluble cellulose derivative.

16. The controlled release pharmaceutical composition of claim 15, wherein the cellulosic compound is hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium-carboxymethylcellulose or methyl cellulose.

17. The controlled release pharmaceutical composition of claim 1, wherein the emulsifier is present and is a non-ionic emulsifier.

18. The controlled release pharmaceutical composition of claim 17, wherein the emulsifier is polyoxyethylene derivative of a sorbitan ester or a sorbitan ether.

19. The controlled release pharmaceutical composition of claim 17, wherein the emulsifier is a polyethoxy sorbitan monooleate.

20. The controlled release pharmaceutical composition of claim 1, wherein the pharmaceutical active ingredient has a solubility in ethanol which is classified as slightly soluble according to the USP Pharmacopeia references tables.

21. The controlled release pharmaceutical composition of claim 1, wherein the pharmaceutical active ingredient is an opioid or an opioid antagonist.

22. The controlled release pharmaceutical composition of claim 21, wherein the pharmaceutical active ingredient is morphine or naloxone or a pharmaceutically acceptable salt thereof.

23. The controlled release pharmaceutical composition of claim 1, wherein the pharmaceutical active ingredient has solubility in ethanol which is classified as sparingly soluble according to the USP Pharmacopeia references tables.

24. The controlled release pharmaceutical composition of claim 23, wherein the pharmaceutical active ingredient is metoprolol or a pharmaceutically acceptable salt thereof.

25. The controlled release pharmaceutical composition of claim 1, wherein the controlled release pharmaceutical composition is in at least one form selected from the group consisting of a pellet contained in a multiparticulate pharmaceutical form, a compressed tablet, a capsule, a sachet, an effervescent tablet, a reconstitutable powder.

26. The controlled release pharmaceutical composition of claim 1, further comprising a top coat.

27. The controlled release pharmaceutical composition of claim 1, wherein the coating layer comprises at least 3.0% by weight of the polymeric portion a) based on the weight of the core.

28. The controlled release pharmaceutical composition of claim 1, wherein the core has an average diameter of 100 to 5000 μm.

29. The controlled release pharmaceutical composition of claim 28, wherein: the core has an average diameter in the range of 100 to 700 μm; and the amount of a polymer dry substance of the polymer portion a) is from 15 to 200% by weight based on the weight of the core.

30. The controlled release pharmaceutical composition of claim 28, wherein: the core has an average diameter in the range of above 700 and up to 1400 μm; and the amount of a polymer dry substance of the polymer portion a) is from 10 to 150% by weight based on the weight of the core.

31. The controlled release pharmaceutical composition of claim 28, wherein: the core has an average diameter in the range of above 1400 and up to 5000 μm; and the amount of a polymer dry substance of the polymer portion a) is from 5 to 100% by weight based on the weight of the core.

32. The controlled release pharmaceutical composition of claim 1, wherein the core is an uncoated or a coated tablet.

33. A process for preparing the controlled release pharmaceutical composition of claim 1, comprising coating an uncoated or a coated core comprising the pharmaceutical active ingredient with the coating layer by a spray process or by fluidized bed spray coating.

34. A method of conferring ethanol resistance to a pharmaceutical composition, comprising coating a core comprising a pharmaceutical active ingredient with the coating layer of claim 1, wherein the ethanol resistance reduces the risk of enhanced or reduced release of the pharmaceutical active ingredient after oral ingestion by simultaneous or subsequent consumption of ethanol.

35. The controlled release pharmaceutical composition of claim 1, wherein component b3) is present.

36. The controlled release pharmaceutical composition of claim 35, wherein component b1) comprises talc, component b2) comprises a hydroxypropylmethylcellulose, and component b3) comprises a polyethylene glycol sorbitan monooleate.

Description

EXAMPLES

(1) Model Drug

(2) Studies are conducted using metoprolol succinate and naloxone hydrocloride, as a model drug.

(3) Dissolution Studies

(4) Coated pellets are tested according to USP 32-NF27, 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.

(5) Dissolution Parameters:

(6) Naloxone Hydrochloride

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

(8) RPM: 100/min.

(9) Temperature: 37.5±0.5° C.

(10) Dissolution volume: 500 ml.

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

(12) Mode of detection: HPLC

(13) Metoprolol Succinate

(14) Apparatus: USP Type-II (Paddle)

(15) RPM: 100/min.

(16) Temperature: 37.5±0.5° C.

(17) Dissolution volume: 900 ml.

(18) Mode of detection: online UV-VIS

(19) Dissolution Medium 1:

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

(21) Dissolution Medium 2:

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

(23) Dissolution Medium 3:

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

(25) Dissolution Medium 4:

(26) Phosphate buffered saline pH 6.8 (European Pharmacopoeia=EP) with 40% (v/v) ethanol

(27) Polymeric Portion a): Water Insoluble, Essentially Neutral Vinyl Copolymer

(28) EUDRAGIT® NE is used as water insoluble, essentially neutral vinyl copolymer (polymeric portion a)). EUDRAGIT® NE is composed of free-radically polymerized units of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.

(29) Excipients Portion b)

(30) Non-Porous Inert Lubricant b1):

(31) Talc Pharma: Talc with a mean particle size determined by laser diffraction 19.3 μm (10 μm determined by sedimentation)

(32) Talc Pharma M: Talc with a mean particle size determined by laser diffraction 10.5 μm (4.7 μm determined by sedimentation)

(33) Cellulosic Compound b2): Hydroxypropylmethylcellulose

(34) Emulsifier b3): Polysorbat 80

(35) Preparation of Uncoated Cores Comprising the Active Ingredient

(36) Sugar spheres (non-pareilles) of 1700-2000 microns are loaded with metoprolol succinate or naloxone hydrochlorid in a fluidised bed processor using bottom spray.

(37) Naloxone Hydrochloride

(38) Polyvinyl pyrrolidone (Kollidon® K25) is used as a binder. 900 g of non-pareilles cores are coated with 270 g metoprolol succinate bound in 80 g binder (Kollidon® K25).

(39) Metoprolol Succinate

(40) Polyvinyl pyrrolidone (Kollidon® K25) is used as a binder. 900 g of non-pareilles cores are coated with 90 g metoprolol succinate bound in 4.5 g binder (Kollidon® K25). Further 120 g Talc and 30 g silicium dioxide are used as lubricants on the cores.

(41) Drug Layering

(42) Polyvinyl pyrrolidone (Kollidon® K25) and the active ingredient is dissolved in water while gentle stirring. Lubricants are dispersed in water applying high shear forces. The lubricant suspension is poured into the Polyvinyl pyrrolidone (Kollidon® K25) solution applying gentle stirring. Stirring is continued through the entire coating process.

(43) Coating of the Cores with the Ethanol Resistance Conferring Coating Layer

(44) Coating Suspension Preparation:

(45) The non-porous inert lubricant, the emulsifier and the cellulosic compound (excipient portion b)) are dissolved or dispersed in water applying high shear forces. The lubricant suspension is poured into the EUDRAGIT® NE dispersion applying gentle stirring. Stirring is continued through the entire coating process.

(46) Coating Process:

(47) 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. Atomizing pressure was 1.5 to 2.2 bar at a nozzle diameter of 1.2 mm. After coating the pellets are fluidised at ca. 40° C. and ca. 45% r.h. for a half hour in a fluid bed processor. The coated pellets are having an average diameter of about 2600-3000 μm.

(48) The resulting coated cores comprising the active ingredient were tested in the corresponding dissolution media at pH 1.2 and/or pH 6.8 without and with 40% (v/v) ethanol. The results are shown in tables 1-2 and 2-2. Release values in bold figures were used for the calculation of the arithmetic average as discussed before under “Resistance against the influence of ethanol”.

(49) Discussion of the Examples

(50) Examples 1 to 3 compared to examples 4 to 6 show the influence of the type of talc. Comparative example C1 show that no ethanol resistance is achieved with talc alone but without the cellulosic compound (HPMC=hydroxypropylmethylcellulose) and without the emulsifier (Polysorbat 80). Comparative example C2 is without the cellulosic compound (HPMC). Comparative example C3 is without the emulsifier (Polysorbat 80). In both cases no ethanol resistance is observed. Ethanol resistance according to the invention is found in the examples 1 to 9. The examples 2 and 6 show an acceleration of less than 10% in the medium with ethanol.

(51) TABLE-US-00003 TABLE 1-2 Example No. 1 2 3 4 5 6 Drug pellets Naloxone Naloxone Naloxone Naloxone Naloxone Naloxone Polymeric portion a) [wt. %/core] EUDRAGIT NE 40 30 20 40 30 20 Excipient portion b) b1) Talc Pharma [wt. %/polymeric portion 210 210 210 a)] b1) Talc Pharma M [wt. %/polymeric 210 210 210 portion a)] b2) HPMC [wt. %/polymeric portion a)] 20 20 20 20 20 20 b3) Polysorbat 80 [wt. %/polymeric portion 10 10 10 10 10 10 a)] Total weight gain [wt. %/core] 136 102 68 136 102 68 Active release without/with 40% EtOH [v/v]  1 h (pH 1.2) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  2 h (pH 1.2) 0.0 0.0 0.0 0.0 0.0 6.3 0.0 0.0 0.0 2.7 11.5 25.2  3 h (pH 6.8) 0.0 0.0 2.7 3.1 3.6 17.6 0.0 0.0 4.9 18.2 38.2 45.3  4 h (pH 6.8) 2.6 0.0 5.6 11.1 16.6 37.7 3.2 15.2 23.3 37.1 59.0 60.0  5 h (pH 6.8) 5.4 0.0 15.7 19.2 34.7 54.5 12.2 30.4 40.0 50.7 74.1 72.6  6 h (pH 6.8) 13.0 4.0 26.1 24.4 47.5 66.2 23.7 42.4 53.6 62.6 83.6 82.1  8 h (pH 6.8) 30.4 15.8 47.2 58.9 66.9 82.8 43.2 62.3 73.4 80.6 94.1 93.6 10 h (pH 6.8) 45.9 28.8 64.8 77.1 78.8 95.6 59.4 77.7 84.9 91.0 97.7 99.0 12 h (pH 6.8) 58.3 40.2 76.1 85.2 87.1 100.0 71.9 87.0 91.5 96.6 100.0 100.0 16 h (pH 6.8) 75.9 59.1 92.6 94.8 94.9 100.0 86.5 95.9 97.1 98.8 100.0 100.0 20 h (pH 6.8) 86.5 71.7 99.4 97.5 98.3 100.0 93.2 98.3 98.5 98.9 100.0 100.0 24 h (pH 6.8) 92.7 79.3 99.5 98.2 99.7 100.0 96.9 99.3 99.3 99.1 100.0 100.0 Arithmetic average (bold figures) −15.1 +7.0 +18.4 +17.9 +10.2 +5.1 n for calculation 5 5 5 5 4 4 Ethanol resistance yes yes yes yes yes yes

(52) TABLE-US-00004 TABLE 2-2 Example No. C1 7 8 9 C2 C3 Drug pellets Metoprolol Metoprolol Metoprolol Naloxone Metoprolol Naloxone succinate succinate succinate succinate Polymeric portion a) [wt. %/core] EUDRAGIT NE 8 10 20 20 50 12 Excipient portion b) b1) Talc Pharma [wt. %/polymeric 200 200 200 200 portion a)] b1) Talc Pharma M [wt. %/polymeric 200 210 portion a)] b2) HPMC [wt. %/polymeric portion a)] 20 20 10 10 b3) Polysorbat 80 [wt. %/polymeric 10 10 10 10 portion a)] Total weight gain [wt. %/core] 24 33 66 64 155 38.4 Active release without/with 40% EtOH [v/v]  1 h (pH 1.2) 5.8 78.1 10.8 20.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  2 h (pH 1.2) 19.4 97.1 63.1 77.9 0.0 0.0 0.0 13.4 2.4 11.5 0.0 18.4  3 h (pH 6.8) 36.7 100.0 79.9 92.0 21.8 35.3 5.9 33.4 7.5 30.5 1.8 40.3  4 h (pH 6.8) 56.7 100.0 91.5 97.5 41.4 61.1 22.6 47.7 15.6 51.2 4.7 53.5  5 h (pH 6.8) 72.0 100.0 95.5 100.0 57.3 73.2 40.6 60.5 26.5 66.2 8.5 66.1  6 h (pH 6.8) 83.0 97.4 100.0 68.6 80.3 54.4 72.2 40.0 76.6 12.9 78.4  8 h (pH 6.8) 93.7 83.5 87.4 75.5 89.9 61.8 87.9 22.3 88.9 10 h (pH 6.8) 91.4 93.0 86.9 96.2 84.2 92.9 36.9 94.3 12 h (pH 6.8) 95.5 96.9 93.6 98.0 93.8 96.7 50.5 94.9 16 h (pH 6.8) 98.9 99.9 98.1 99.9 69.8 94.9 20 h (pH 6.8) 99.7 98.9 83.3 94.3 24 h (pH 6.8) 87.2 93.2 Arithmetic average (bold figures) +53.1 +12.3 +15.2 +19.3 +34.5 +51.8 n for calculation 4 3 4 4 4 5 Ethanol resistance no yes yes yes no no