AU2011253881A1

AU2011253881A1 - Extended release formulation

Info

Publication number: AU2011253881A1
Application number: AU2011253881A
Authority: AU
Inventors: John C. Clark; John V. Lamer; Deborah Marie Sherman; Stephen A. White
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 1996-03-25
Filing date: 2011-12-07
Publication date: 2012-01-12

Abstract

A method and an extended release formulation for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises 5 administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.

Description

AUSTRALIA Patents Act COMPLETE SPECIFICATION (ORIGINAL) Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Wyeth LLC Actual Inventor(s): John V. Lamer, Deborah Marie Sherman, John C. Clark, Stephen A. White Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: EXTENDED RELEASE FORMULATION Our Ref: 930747 POF Code: 474101/499548 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): - 1- 2 EXTENDED RELEASE FORMULATION 5 The present application is a divisional application from Australian Patent Application 2010214740, which in turn is a divisional application of Australian Patent Application 2007201828, which in turn is a divisional of Australian Patent Application 2003259586, which in turn is a divisional of Australian Patent Application 65442/00, which in turn is a divisional of Australian Patent 727653, the entire disclosure of each 10 of these earlier applications is incorporated herein by reference. Background of the invention Extended release drug formulations are conventionally produced as compressed tablets by hydrogel tablet technology. To produce these sustained 15 release tablet drug dosage forms, the active ingredient is conventionally compounded with cellulose ethers such as methyl cellulose, ethyl cellulose or hydroxypropylmethylcellulose with or without other excipients and the resulting mixture is pressed into tablets. When the tablets are orally administered, the cellulose ethers in the tablets swell upon hydration from moisture in the digestive system, 20 thereby limiting exposure of the active ingredient to moisture. As the cellulose ethers are gradually leached away by moisture, water more deeply penetrates the gel matrix and the active ingredient slowly dissolves and diffuses through the gel, making it available for absorption by the body. An example of such a sustained release dosage form of the analgesic/antiinflammatory drug etodolac (Lodine*) appears in US patent 25 4,966,768. Where the production of tablets is not feasible, it is conventional in the drug industry to prepare encapsulated drug formulations which provide extended or sustained release properties. In this situation, the extended release capsule dosage forms may be formulated by mixing the drug with one or more binding agents to form 30 a uniform mixture which is then moistened with water or a solvent such as ethanol to form an extrudable plastic mass from which small diameter, typically 1 mm, cylinders of drug/matrix are extruded, chopped into appropriate lengths and transformed into spheroids using standard spheronization equipment. The spheroids, after drying, may then be film-coated to retard dissolution. Gelatin capsules are filled with the film- 3 coated spheroids in the quantity needed to obtain the desired therapeutic effect. Spheroids releasing the drug at different rates may be combined in a gelatin capsule to obtain desired release rates and blood levels. US patent 4,138,475 discloses a sustained release pharmaceutical composition consisting of a hard gelatin capsule 5 filled with film-coated spheroids comprised of propanolol in admixture with microcrystalline cellulose wherein the film coating is composed of ethyl cellulose, optionally with hydroxypropylmethylcellulose and/or a plasticizer. Venlafaxine, 1-[2-(dimethylamino)-1-(4-methoxyphenypethyl)ethy cyclohexanol, is an important drug in the neuropharmacological arsenal used for 10 treatment of depression. Venlafaxine and the acid addition salts thereof are disclosed in US patent 4,535,186. Venlafaxine hydrochloride is presently administered to adults in compressed tablet form in doses ranging from 75 to 350 mg/day, in divided doses two or three times a day. In therapeutic dosing with venlafaxine hydrochloride tablets, rapid dissolution results in a rapid increase in blood plasma levels of the active 15 compound shortly after administration followed by a decrease in blood plasma levels over several hours as the active compound is eliminated or metabolized, until sub therapeutic plasma levels are approached after about twelve hours following administration, thus requiring additional dosing with the drug. With the plural daily dosing regimen, the most common side effect is nausea, experienced by about 45% 20 of patients under treatment with venlafaxine hydrochloride. Vomiting also occurs in about 17% of the patients. The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge 25 in Australia as at the priority date of any of the claims. Brief Description of the Invention In accordance with this invention there is provided an extended release (ER), 30 encapsulated formulation containing venlafaxine hydrochloride as the active drug component, which provides in a single dose, a therapeutic blood serum level over a twenty four hour period.

4 Through administration of the venlafaxine formulation of this invention, there is provided a method for obtaining a flattened drug plasma concentration to time profile, thereby affording a tighter plasma therapeutic range control than can be obtained with multiple daily dosing. In other words, this invention provides a method for eliminating 5 the sharp peaks and troughs (hills and valleys) in blood plasma drug levels induced by multiple daily dosing with conventional immediate release venlafaxine hydrochloride tablets. In essence, the plasma levels of venlafaxine hydrochloride rise, after administration of the extended release formulations of this invention, for between about five to about eight hours (optimally about six hours) and then begin to fall 10 through a protracted, substantially linear decrease from the peak plasma level for the remainder of the twenty four hour period, maintaining at least a threshold therapeutic level of the drug during the entire twenty-four period. In contrast, the conventional immediate release venlafaxine hydrochloride tablets give peak blood plasma levels in 2 to 4 hours. Hence, in accordance with the use aspect of this invention, there is 15 provided a method for moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilization of multiple daily tablet dosing with venlafaxine hydrochloride which comprises administering to a patient in need of treatment with venlafaxine hydrochloride, a one-a-day, extended release formulation of venlafaxine hydrochloride. 20 The use of the one-a-day venlafaxine hydrochloride formulations of this invention reduces by adaptation, the level of nausea and incidence of emesis that attend the administration of multiple daily dosing. In clinical trials of venlafaxine hydrochloride ER, the probability of developing nausea in the course of the trials was greatly reduced after the first week. Venlafaxine ER showed a statistically significant 25 improvement over conventional venlafaxine hydrochloride tablets in two eight-week and one 12 week clinical studies. Thus, in accordance with this use aspect of the invention there is provided a method for reducing the level of nausea and incidence of emesis attending the administration of venlafaxine hydrochloride which comprises dosing a patient in need of treatment with venlafaxine hydrochloride with an extended 30 release formulation of venlafaxine hydrochloride once a day in a therapeutically effective amount.

5 Detailed Description of the Invention 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride is polymorphic. Of the forms isolated and characterized to date, Form I is considered to 5 be the kinetic product of crystallization which can be converted to Form 11 upon heating in the crystallization solvent. Forms I and 11 cannot be distinguished by their melting points but do exhibit some differences in their infrared spectra and X-ray diffraction patterns. Any of the polymorphic forms such as Form I or Form 11 may be used in the formulations of the present invention. 10 The extended release formulations are comprised of 1-[2-20(dimethylamino) 1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride in admixture with microcrystalline cellulose and hydroxypropylmethylcellulose. Formed as beads or spheroids, the drug containing formulation is coated with a mixture of ethyl cellulose and hydroxypropylmethyl cellulose to provide the desired level of coating, generally 15 from about two to about twelve percent on a weight/weight basis of final product or more preferably from about five to about ten percent (w/w), with best results obtained at from about 6 to about 8 percent (w/w). More specifically, the extended release spheroid formulations of this invention comprise from about 30 to 40 percent venlafaxine hydrochloride, from about 50 to 20 about 70 percent microcrystalline cellulose, NF, from about 0.25 to about 1 percent hydroxypropylmethylcellulose, USP, and from about 5 to about 10 percent film coating, all on a weight/weight basis. And preferably, the spheroid formulations contain about 35 percent venlafaxine hydrochloride, about 55 to 60 percent microcrystalline cellulose NF (Avicel*PH101), about one half percent hydroxypropyl 25 methylcellulose 2208 USP (K3, Dow, which has a viscosity of 3 cps for 2% aqueous solutions, a methoxy content of 19-24% and a hydroxypropoxy content of 4-13%), and from about 6 to 8 percent film coating. The film coating is comprised of 80 to 90 percent of ethyl cellulose, NF and 10 to 20 percent hydroxypropyl methylcellulose (2910), USP on a weight/weight basis. 30 Preferably the ethyl cellulose has a ethoxy content of 44.0-51% and a viscosity of 50 cps for a 5% aqueous solution and the hydroxypropylmethylcellulose is USP 2910 having a viscosity of 6 cps at 2% aqueous solution with a methoxy content of 28-30% and a hydroxypropoxy content of 7-12%. The ethyl cellulose used hererin is Aqualon HG 2834.

6 Other equivalents of the hydroxypropylmethylcelluloses 2208 and 2910 USP and ethyl cellulose, NF, having the same chemical and physical characteristics as the proprietary products named above may be substituted in the formulation without changing the inventive concept. 5 It was completely unexpected that an extended release formulation containing venlafaxine hydrochloride could be obtained because the hydrochloride of venlafaxine proved to be extremely water soluble. Numerous attempts to produce extended release tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping 10 problems) or dissolved too rapidly in dissolution studies. Typically, the tablets prepared as hydrogel sustained release formulations gave 40-50% dissolution at 2 hrs, 60-70% dissolution at 4 hrs and 85-100% dissolution at 8 hrs. Numerous spheroid formulations were prepared using different grades of microcrystalline cellulose and hydroxypropyl methylcellulose, different ratios of 15 venlafaxine hydrochloride and filler, different binders such as polyvinylpyrrolidone, methylc;ellulose, water, and polyethylene glycol of different molecular weight ranges in order to find a formulation which would provide a suitable granulation mix which could be extruded properly. In the extrusion process, heat buildup occurred which dried out the extrudate so much that it was difficult to convert the extruded cylinders into 20 spheroids. Addition of hydroxypropylmethylcellulose 2208 to the venlafaxine hydrochloride microcrystalline cellulose mix made production of spheroids practical. The following examples are presented to illustrate applicant's solution to the problem of preparation of the extended release drug containing formulations of this invention. 25 30

Claims

1. An encapsulated, extended release formulation of venlafaxine hydrochloride 5 comprising a hard gelatin capsule containing a therapeutically effective amount of spheroids comprised of venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropyl methylcellulose coated with ethyl cellulose and hydroxypropylmethylcellulose. 10 2. An extended release formulation according to claim 1 wherein the spheroids are composed of about 37.3% by weight of venlafaxine hydrochloride, about 0.5% by weight of hydroxypropylmethylcellulose 2208, and about 62.17% by weight of microcrystalline cellulose. 15 3. A composition according to claim 1 wherein the film coating is comprised of ethyl cellulose (4.81% of total weight) and hydroxypropylmethylcellulose (0.85% of total weight).

4. A composition according to claim 1 wherein the film coating is comprised of ethyl 20 cellulose (4.04% of total weight) and hydroxypropylmethylcellulose (0.714% of total weight).

5. A composition according to claim 1 wherein the film coating is comprised of ethyl cellulose (2.48% of total weight) and hydroxypropylmethylcellulose (0.437% of 25 total weight).

6. A film coating composition which is composed of ethyl cellulose (85% of total weight), having a 44.0-51.0% content of ethoxy groups, and hydroxypropylmethylcellulose (15% of total weight) having a methoxy content of 30 28.0-30.0% and a hydroxypropoxy group content of 7.0-12.0%.

7. An extended release formulation of venlafaxine hydrochloride for once daily administration which comprises spheroids containing 37.3% venlafaxine,

62.17% microcrystalline cellulose and 0.5% hydroxypropylmethylcellulose type 8 2208, coated with a quantity of a mixture comprised of 85% ethyl cellulose type HG 2834 and 15% hydroxypropylmethylcellulose type 2910 sufficient to give coated spheroids having a dissolution profile which gives the desired release rate over a 24 hour period. 5 8. An extended release formulation of venlafaxine hydrochloride according to claim 7 which provides lower peak serum levels of up to 150 ng/ml and extended therapeutically effective plasma levels over a twenty-four hour period. 10 9. A method for providing a therapeutic blood plasma concentration of venlafaxine over a twenty-four hour period with diminished incidences of nausea and emesis which comprises administering orally to a patient in need thereof, an encapsulated, extended release formulation that provides a peak blood plasma level of venlafaxine in from about four to about hours, said formulation 15 containing venlafaxine hydrochloride as the active ingredient. 10. A method for eliminating the troughs and peaks of drug concentration in a patients blood plasma attending the therapeutic metabolism of plural daily doses of which comprises administering orally to a patient in need thereof, an 20 encapsulated, extended release formulation that provides a peak blood plasma level of venlafaxine in from about four to about eight hours, said formulation containing venlafaxine hydrochloride as the active ingredient. 11. A method for providing a therapeutic blood plasma concentration of venlafaxine 25 over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration. 30 12. A method for moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilization of multiple daily dosing with venlafaxine hydrochloride, which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour 9 period with a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration. 13. A method of reducing the level of nausea and the incidence of emesis in a 5 patient in need of venlafaxine which comprises administering orally to said patient, a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period and a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration. 10 14. A method for treating depression in a patient in need of such treatment, which comprises administering orally to said patient, a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma 15 level of venlafaxine in from about 4 to 8 hours after administration. 15. A method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that 20 provides a therapeutic blood plasma concentration of venlafaxine over the 24 hour period with a peak blood plasma level of no more than 150 ng/ml. 16. A method of moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilisation of multiple daily dosing with venlafaxine 25 hydrochloride, which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of no more than 150 ng/ml. 30 17. A method of reducing the level of nausea and the incidence of emesis in a patient in need of venlafaxine by administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic 10 blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of no more than 150 ng/ml. 18. A method for treating depression in a patient in need of such treatment, said 5 method including the steps of administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of no more than 150 ng/ml. 10 19. A method according to any one of claims 11 to 14 wherein the formulation provides a peak blood plasma level of venlafaxine of no more than 150 ng/ml. 20. A method according to any one of claims 15 to 17 wherein the formulation provides peak blood plasma level of venlafaxine in from about 4 to 8 hours after 15 administration. 21. A method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride 20 formulation having a dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 37*C as follows: Time Average % Venlafaxine HCI released (hours) 2 Less than 30 25 4 30-55 8 55-80 12 65-90 24 Greater than 80 30 22. A method for moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilisation of multiple daily dosing with venlafaxine hydrochloride, which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour 11 period, having a dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 370C as follows: Time Average % Venlafaxine HCI released (hours) 5 2 Less than 30 4 30-55 8 55-80 12 65-90 24 Greater than 80 10 23. A method of reducing the level of nausea and the incidence of emesis in a patient in need of venlafaxine by administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period, having a 15 dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 370C as follows: Time Average % Venlafaxine HCI released (hours) 2 Less than 30 20 4 30-55 8 55-80 12 65-90 24 Greater than 80 25 24. A method for treating depression in a patient in need of such treatment, which comprises administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period, having a dissolution profile in 30 USP Apparatus 1 (basket) at 100 rpm in purified water at 370C as follows: 12 Time Average % Venlafaxine HCI released (hours) 2 Less than 30 4 30-55 5 8 55-80 12 65-90 24 Greater than 80 10 25. A method according to any one of claims 11 to 24, wherein the formulation of venlafaxine hydrochloride is an extended release formulation that is administered as a single daily dosing formulation. 26. A method according to any one of claims 11 to 25 wherein the formulation 15 provides a peak blood plasma level of venlafaxine from 5-8 hours after administration. 27. A method according to any one of claims 11 to 26 wherein the formulation provides a peak blood plasma level of venlafaxine at about 6 hours. 20 28. A method according to any one of claims 11 to 27 wherein the formulation of venlafaxine hydrochloride contains a therapeutically effective amount of spheroid core comprising venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose, the spheroid core being coated with a 25 coating comprising ethyl cellulose and hydroxypropylmethylcellulose. 29. A method according to claim 28 wherein the coated spheroid core comprises 30%-40% venlafaxine hydrochloride, 50%-70% microcrystalline cellulose, 0.25%-1% hydroxypropylmethylcellulose and 5%-10% of a film coating 30 comprising ethyl cellulose and hydroxypropylmethylcellulose, all on a weight to weight basis.. 13 30. A method according to claim 28 or 22 wherein the coated spheroid core comprises 35% venlafaxine hydrochloride, 55%-60% microcrystalline cellulose, 0.5% hydroxypropylmethylcellulose and from about 6%-8% of the film coating. 5 31. A method according to any one of claims 28 to 30 wherein the film coating the spheroids comprises about 80-90% by weight of ethyl cellulose and 10-20% by weight of hydroxypropylmethylcellulose. 32. A method according to any one of claims 28 to 31 wherein the film coating the 10 spheroids comprises 85-90% by weight of ethyl cellulose and 10-15% by weight of hydroxypropylmethylcellulose. 33. A method according to any one of claims 28 to 32 wherein the ethyl cellulose is ethyl cellulose NF and includes 44%-51% ethoxy content, and the 15 hydroxypropylmethylcellulose includes 28%-30% methoxy content and 7%-12% hydroxypropoxy content. 34. A method according to any one of claims 28 to 33 wherein the ethyl cellulose is Aqualon HG 2834 and the hydroxypropylmethylcellulose is type 2208 or 2910 20 USP. 35. A method according to any one of claims 28 to 34 wherein microcrystalline cellulose is microcrystalline cellulose NF. 25 36. A method according to any one of claims 28 to 35 wherein the hydroxymethylcellulose has a viscosity of 3cps for 2% aqueous solution, a methoxy content of 19% to 24% and a hydroxypropoxy content of 4% to 13%. 37. A method according to any one of claims 11 to 27 wherein the formulation of 30 venlafaxine hydrochloride contains a therapeutically effective amount of a spheroid core comprising venlafaxine hydrochloride and a microcrystalline cellulose, the spheroid core being substantially free of hydroxypropylmethylcellulose. 14 38. A method according to claim 37 wherein the spheroid core comprises 30%-40% by weight of venlafaxine hydrochloride. 39. A method according to claim 37 wherein the spheroid core comprises 6%-29% 5 by weight of venlafaxine hydrochloride. 40. A method according to any one of claims 37 to 39 wherein the spheroid core is coated with a coating comprising ethylcellulose and hydroxypropylmethylcellulose. 10 41. A method according to claim 40 wherein the coating is comprised of 80%-90% of ethylcellulose and 10%-20% hydroxypropylmethylcellulose on a weight to weight basis. 15 42. A method according to claim 40 or 41 wherein the coating of the spheroid core comprises from 2%-12% by weight of the formulation of venlafaxine hydrochloride. 43. A method for providing a therapeutic blood plasma concentration of venlafaxine 20 over a twenty-four hour period with diminished incidences of nausea and emesis which comprises administering orally to a patient in need thereof, an encapsulated, extended release formulation that provides a peak blood plasma level of venlafaxine in from about four to about eight hours, said formulation containing venlafaxine hydrochloride as the active ingredient. 25 44. A method for eliminating the troughs and peaks of drug concentration in a patients blood plasma attending the therapeutic metabolism of plural daily doses of which comprises administering orally to a patient in need thereof, an encapsulated, extended release formulation that provides a peak blood plasma 30 level of venlafaxine in from about four to about eight hours, said formulation containing venlafaxine hydrochloride as the active ingredient. 15 45. A method according to any one of claims 11 to 26 wherein the formulation is an encapsulated formulation. 46. A method according to any one of claims 11 to 24 substantially as hereinbefore 5 described with reference to any one of the Examples. 47. An extended release formulation according to claim 1, substantially as hereinbefore described with reference to any one of the Examples. 10 15 20 25