Sustained-release donepezil formulation

Abstract

A sustained-release formulation for an acetylcholinesterase inhibitor, comprising an acetylcholinesterase inhibitor and at least two gel-forming polymers, and methods of manufacture thereof. The acetylcholinesterase inhibitor preferably comprises donepezil.

Claims

1. A sustained-release formulation comprising an acetylcholinesterase inhibitor, wherein the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt thereof, wherein the release rate of the acetylcholinesterase inhibitor is controlled by two non-ionic gel-forming polymers which are a combination of a low viscosity grade hydroxypropyl methylcellulose polymer (low viscosity grade HPMC polymer) and a high viscosity grade hydroxypropyl methylcellulose polymer (high viscosity grade HPMC polymer), the formulation comprising: (a) donepezil or a pharmaceutically acceptable salt thereof in a concentration of about 10% (w/w) of the total formulation; (b) the low viscosity grade HPMC polymer in a concentration in the range of from about 11% to about 19% (w/w) of the total formulation; (c) the high viscosity grade HPMC polymer in a concentration in the range of from about 3% to about 5% (w/w) of the total formulation; and (d) at least one excipient selected from the group consisting of a filler, a binder, a disintegrant, and a glidant.

2. The formulation of claim 1, wherein the pharmaceutically acceptable salt of donepezil is donepezil hydrochloride.

3. The formulation of claim 1, wherein the filler is selected from the group consisting of lactose, glucose, fructose, sucrose, dicalcium phosphate, a sugar alcohol, corn starch, potato starch, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, poly(methacrylic acid, methyl methacrylate) 1:1, poly(methacrylic acid, ethyl acrylate) 1:1, alginic acid, sodium alginate, and a mixture thereof.

4. The formulation of claim 1, wherein the binder is selected from the group consisting of polyvinyl pyrrolidone, a copolymer of polyvinyl pyrrolidone and polyvinyl acetate, low molecular weight hydroxypropyl cellulose, low molecular weight carboxy methyl cellulose, ethylcellulose, gelatin, polyethylene oxide, acacia, dextrin, magnesium aluminum silicate, starch, polymethacrylate, hydroxvpropyl methylcellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, poly(methacrylic acid, methyl methacrylate) 1:1, poly(methacrylic acid, ethyl acrylate) 1:1, alginic acid, sodium alginate, and a mixture thereof.

5. The formulation of claim 1, wherein the disintegrant is selected from the group consisting of low-substituted carboxymethyl cellulose sodium, crospovidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, microcrystalline cellulose, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, magnesium silicate, aluminum silicate, and a mixture thereof.

6. The formulation of claim 1, wherein the glidant comprises at least one of silicone dioxide and magnesium stearate.

7. The formulation of claim 1, wherein the low viscosity grade HPMC polymer is HPMC K100 and the high viscosity grade HPMC polymer is HPMC K100M.

8. The formulation of claim 1, wherein the low viscosity grade HPMC polymer is HPMC K100 and the high viscosity grade HPMC polymer is HPMC K15M.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the accumulative dissolution test results of formulations of Examples I-VIII comprising a combination of anionic gel-forming polymer (Carbopol) and non-ionic gel-forming polymer (HPMC) as release-controlling agents;

(2) FIG. 2 shows the accumulative dissolution test results for the formulations of Examples IX and X; and

(3) FIG. 3 shows the accumulative dissolution test results for the formulations of Examples XI-XVIII.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(4) The present invention is of a sustained-release formulation, comprising an acetylcholinesterase inhibitor and at least two gel-forming polymers.

(5) The combination of gel-forming polymers used in embodiments of the present invention was found to improve the dissolution profile of acetylcholinesterase inhibitors such as donepezil, thereby reducing the sharp blood plasma increase which occurs with the standard commercial formulation. The polymer combination was found to rapidly form a gel of a suitable consistency to retard the release rate, providing slower, smoother release over a longer time period.

(6) The gel formed by the combination of gel-forming polymers provides controlled release, such that when the formulation is ingested and comes into contact with the gastrointestinal fluids, the polymers nearest the surface hydrate to form a viscous gel layer. Because of the high viscosity, the viscous layer dissolves away only gradually, exposing the material below to the same process. The mass thus dissolves away only slowly, thereby slowly releasing the active ingredient into the gastrointestinal fluids. The combination of at least two gel-forming polymers enables properties of the resultant gel, such as viscosity, to be manipulated in order to provide the desired release profile.

(7) According to some embodiments, the combination of at least two gel-forming polymers may comprise a combination of at least one non-ionic gel-forming polymer and at least one anionic gel-forming polymer; a combination of two different non-ionic gel-forming polymers; or a combination of non-ionic gel-forming polymers of the same chemistry, but having different solubilities and/or viscosities and/or molecular weight (for example a combination of hydroxyproplyl methylcellulose of different viscosity grades, such as HPMC K100 and HPMC K15M or HPMC K100M). Non-limiting examples of anionic gel forming polymers which are suitable for use in embodiments of the present invention include sodium carboxymethylcellulose (Na CMC), carboxymethyl cellulose (CMC), anionic polysaccharides such as sodium alginate, alginic acid, pectin, polyglucuronic acid (poly-alpha- and -beta-1,4-glucuronic acid), polygalacturonic acid (pectic acid), chondroitin sulfate, carrageenan, furcellaran, anionic gums such as xanthan gum, polymers of acrylic acid or carbomers (Carbopol® 934, 940, 974P NF), Carbopol® copolymers, a Pemulen® polymer, polycarbophil, and others.

(8) Non-limiting examples of suitable non-ionic gel-forming polymers include Povidone (PVP: polyvinyl pyrrolidone), polyvinyl alcohol, copolymer of PVP and polyvinyl acetate, HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate (PHEMA), water soluble nonionic polymethacrylates and their copolymers, modified cellulose, modified polysaccharides, nonionic gums, nonionic polysaccharides and/or mixtures thereof.

(9) In some embodiments, the at least two gel-forming polymers comprise at least two of HPMC K100, HPMC K15M and HPMC K100M as non-ionic gel-forming polymers.

(10) Optionally and preferably, a concentration of HPMC K100 is in the range of from about 1% to about 30% (w/w) of the total formulation; a concentration of HPMC K15M is in the range of from about 1% to about 20% (w/w) of the total formulation; and a concentration of HPMC K100M is in the range of form about 1% to about 10% (w/w) of the total formulation.

(11) More preferably, a concentration of HPMC K100 is in the range of from about 11% to about 19%; a concentration of HPMC K15M is in the range of from about 3% to about 5%, and a concentration of HPMC K100M is in the range of from about 1% to about 5%.

(12) In some embodiments, the at least two gel-forming polymers comprise HPMC K100 and HPMC K100M.

(13) In some embodiments, the at least two gel-forming polymers comprise HPMC K100 and HPMC K15M

(14) In some embodiments, the at least two gel-forming polymers comprise Carbopol as anionic gel-forming polymer and at least one of HPMC K100, and HPMC K100M as non-ionic gel-forming polymers.

(15) Optionally and preferably, a concentration of Carbopol is in a range of from about 1% to about 20% (w/w) of the total formulation, more preferably from about 2% to about 15%, and most preferably, around 4.5%. Also preferably, a concentration of HPMC K100 in such embodiments is in the range of from about 1% to about 30%, more preferably from about 5% to about 15%, and most preferably about 13.6%. Also preferably, a concentration of HPMC K100M in such embodiments is in the range of from about 1% to about 10%, more preferably from about 1% to about 5%.

(16) In some embodiments, the at least two gel-forming polymers comprise Carbopol and HPMC K100.

(17) In some embodiments, the at least two gel-forming polymers comprise Carbopol, HPMC K100 and HPMC K100M.

(18) In some embodiments, the at least two gel-forming polymers comprise alginic acid as anionic gel-forming polymer, and at least one of HPMC K100 and HPMC K15M as non-ionic gel forming polymers.

(19) In some embodiments, the at least two gel-forming polymers comprise alginic acid and HPMC K15M.

(20) In some embodiments, the at least two gel-forming polymers comprise alginic acid, HPMC K15M and HPMC K100.

(21) Optionally and preferably, in embodiments comprising HPMC K100, HPMC K15M, and alginic acid, a concentration of alginic acid is in the range of from about 1% to about 30%, more preferably from about 10% to about 20%, and most preferably about 15%. Also optionally, in such embodiments a concentration of HPMC K100 is preferably in the range of from about 1% to about 30%, more preferably from about 11.1% to about 13.3%, most preferably around 12%. Also optionally, in such embodiments a concentration of HPMC K15M is in the range of from about 1% to about 15%, more preferably from about 3.8% to about 4.8%, and most preferably about 4%.

(22) According to some embodiments of the present invention, the acetylcholinesterase inhibitor is a reversible inhibitor comprising a piperidine derivative. Preferably, the acetylcholinesterase inhibitor is donepezil. Optionally and preferably, a concentration of donepezil is in the range of about 10% (w/w) of the total formulation.

(23) The formulation of the present invention may optionally comprise at least one excipient, such as a filler, a binder, a disintegrant, and a glidant.

(24) Examples of suitable fillers include but are not limited to lactose, glucose, fructose, sucrose, dicalcium phosphate, sugar alcohols also known as “sugar polyol” such as sorbitol, manitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates (a blend of several sugar alcohols), corn starch, potato starch, sodium carboxymethycellulose, ethylcellulose and cellulose acetate, enteric polymers, or a mixture thereof.

(25) According to some embodiments, the filler comprises lactose.

(26) Examples of suitable binders include but are not limited to water-soluble, hydrophilic polymers, such as Povidone (PVP: polyvinyl pyrrolidone), copovidone (a copolymer of polyvinyl pyrrolidone and polyvinyl acetate), low molecular weight HPC (hydroxypropyl cellulose) low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxy methyl cellulose, ethylcellulose, gelatin, polyethylene oxide, acacia, dextrin, magnesium aluminum silicate, starch, and polymethacrylates such as Eudragit NE 30D, Eudragit RL, Eudragit RS, Eudragit E, polyvinyl acetate, and enteric polymers, or mixtures thereof.

(27) Examples of suitable enteric polymers for use as fillers or binders in the formulation of the present invention include hydroxypropyl methylcellulose acetate succinate (also known as hypromellose acetate succinate), cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, ethyl acrylate) 1:1, alginic acid, and sodium alginate.

(28) In some embodiments, the binder comprises Povidone, ethylcellulose and HPC. Optionally and preferably, ethylcellulose is present at a concentration of about 25% (w/w) of total formulation, HPC is present at a concentration of from about 3% to about 4% (w/w) of total formulation, and Povidone is present at a concentration of from about 11% to about 13% (w/w) of total formulation.

(29) Examples of suitable disintegrants include but are not limited to low-substituted carboxymethyl cellulose sodium, crospovidone (cross-linked polyvinyl pyrrolidone), sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose (Croscarmellose), pregelatinized starch (starch 1500), microcrystalline cellulose, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, and magnesium or aluminum silicate.

(30) According to some embodiments, the disintegrant comprises microcrystalline cellulose, optionally at a concentration in the range of from about 6% to about 13% (w/w) of total formulation.

(31) Examples of suitable glidants include but are not limited to magnesium, silicon dioxide, talc, starch, and titanium dioxide.

(32) According to some embodiments, the glidant comprises silicon dioxide and magnesium stearate. Optionally and preferably, silicon dioxide is present at a concentration in the range of from about 0.1% to about 0.6% (w/w) of total formulation, and magnesium stearate is present at a concentration in the range of from about 0.5% to about 0.6% (w/w) of total formulation.

(33) According to some embodiments, any of the formulations of the present invention optionally and preferably comprise a tablet for oral administration. The tablet is optionally formed by granulating the active ingredient with the optional excipients and compressing the granulation into tablets, as described in detail in the Examples section below.

(34) The present invention thus further provides a method for manufacturing a sustained-release formulation comprising an acetylcholinesterase inhibitor and at least two gel-forming polymers, the method comprising mixing the acetylcholinesterase inhibitor with optional excipients and a solvent to form a wet granulate; mixing the wet granulate with at least two gel-forming polymers, and optional excipients and compressing the mixture to form tablets.

(35) Any of the formulations of the present invention may be used for treating a condition related to decreased cortical acetylcholine, such as, for example, Alzheimer's disease.

(36) According to some embodiments, there is provided a method of increasing cortical acetylcholine, the method comprising administration of any of the formulations of the present invention.

(37) According to some embodiments, there is provided a method of treating a condition related to decreased cortical acetylcholine, such as, for example, Alzheimer's disease, the method comprising administration of any of the formulations of the present invention.

(38) As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

(39) The formulations, methods or uses of the present invention may optionally further comprise one or more additional active ingredient for the treatment of Alzheimer's disease, such as, for example, an acetylcholinesterase inhibitor (including galantamine and/or rivastigmine) and/or an N-methyl-d-aspartate (NMDA) receptor antagonist (including memantine).

(40) According to some embodiments, an additional active ingredient may be co-administered either with the formulation of the present invention, either as a single dosage form or in separate dosage forms, either concurrently or sequentially, wherein the additional active ingredient is administered either before or after the composition of the present invention.

(41) The principles and operation of the compositions and methods according to the present invention may be better understood with reference to the accompanying descriptions.

(42) Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

(43) Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.

(44) Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

EXAMPLES

(45) Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion.

Examples I-VIIIA

(46) Examples I-VIIIA are based on a combination of an anionic gel-forming polymer (Carbopol) and a non-ionic gel-forming polymer (HPMC) as release-controlling agents.

(47) TABLE-US-00001 I II III IV V VI VII VIII VIIA Materials mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab Donepezil HCl 20.00 20.00 20.00 20.00 20.00 24.6 24.6 24.6 24.6 Lactose 72.00 72.00 72.00 72.00 72.00 126.05 126.05 126.05 126.05 Ethylcellulose 50.00 50.00 50.00 50.00 50.00 Hydroxypropyl 8.00 8.00 8.00 8.00 8.00 9.20 9.20 9.20 9.20 Cellulose Povidone K-30 3.45 3.45 3.45 3.45 Total dry gran. 150.00 150.00 150.00 150.00 150.00 163.30 163.30 163.30 163.30 Microcrystalline 27.50 33.30 22.5 21.0 cellulose Lactose 29.00 9.00 9.00 9.00 9.00 Carbopol 10.00 10.00 20.00 30.00 20.00 6.90 9.60 10.4 19.7 HPMC-K100 10.00 30.00 20.00 10.00 10.00 29.90 31.20 31.2 23.2 HPMC-K100M 10.00 Colloidal silicon 1.20 1.30 1.3 1.4 dioxide Mg stearate 1 1 1 1 1 1.2 1.3 1.3 1.4 Total 200.00 200.00 200.00 200.00 200.00 230.00 240.00 230.00 230.00
Methods of Preparation

(48) For Examples I-V, Donepezil hydrochloride (Luna Chemicals), lactose (DMV Fonterra Excipients), Ethylcellulose (Hercules) and hydroxypropyl cellulose (Hercules) were mixed together in a mortar. A suitable amount of purified water was added to the mixture and wet granulation was carried out. The granules thus obtained were dried in an oven and then sieved to obtain the desired granulate size.

(49) Granulate was mixed with lactose, HPMC (Colorcon), Carbopol (Lubrizol) and magnesium stearate (Merck) and then compressed into tablets comprising 20 mg Donepezil hydrochloride using a single punch tabletting machine.

(50) For Examples VI-VIIIA, Donepezil hydrochloride (Neuland), lactose (DMV Fonterra Excipients), and hydroxypropyl cellulose (Hercules) were mixed in a V-processor. An aqueous solution of Kollidone in purified water was added to the mixture and wet granulation was carried out. The resulting granulate was further dried in a V-processor. Dried granules were milled using Glatt milling machine.

(51) Granulate was mixed with microcrystalline cellulose (FMC), HPMC (Colorcon), Carbopol (Lubrizol), collodial silicon dioxide (Cabot) and magnesium stearate (Merck) and then a KORSCH tabletting machine was used to form tablets, containing 20-23 mg Donepezil hydrochloride.

(52) For Example VIII, tablets were then coated with OPADRY (Colorcon) in TAI-coater.

(53) Dissolution Studies

(54) The release profile of Donepezil hydrochloride from Donepezil hydrochloride 20 mg tablets of Examples 1-VII was determined by inserting six Donepezil hydrochloride tablets of each formulation into individual dissolution vessels, each containing 750 ml of 0.1 M hydrochloric acid.

(55) After 1 hour, the dissolution medium was changed by adding 250 ml of 0.2 M sodium phosphate. The pH was then adjusted to 6.8±0.05. The samples were continuously stirred with a VanKel paddle stirrer at 50 rpm.

(56) Determination of the release was carried out using an automatic dissolution station. Samples were automatically drawn from each dissolution vessel through an appropriate filter into a flow cell. Samples analysis was performed automatically using a Cary UV system.

(57) The percentage of release-controlling agents in each of the Examples tested is shown below:

(58) TABLE-US-00002 HPMC HPMC Example K100 Carbopol K100M I 5 5 0 II 15 5 0 III 10 10 0 IV 5 15 0 V 5 10 1 VI 13 3 0 VII 13 4 0 VIII 13.6 4.5 0 VIIIA 10.1 8.6 0

(59) The accumulative dissolution test results of different formulations comprising a combination of anionic gel-forming polymer (Carbopol) and non-ionic gel-forming polymer (HPMC) as release-controlling agents are shown in FIG. 1 and in Table 1 below:

(60) TABLE-US-00003 TABLE 1 Example Example Time, h Example I Example II Example III Example IV Example V Example VI Example VII VIII VIIIA 0 0 0 0 0 0 0 0 0 1 55.93 25.39 23.42 18.46 15.24 28.97 31.36 23.10 18.26 2 69.59 37.04 30.43 26.71 19.47 39.43 44.27 33.87 20.50 3 77.14 50.30 38.99 30.09 22.69 52.10 56.52 44.90 25.10 4 80.66 61.41 49.64 35.17 27.05 75.17 67.75 60.23 31.38 5 83.28 71.04 61.12 40.65 31.65 92.66 78.00 77.75 39.75 6 85.06 79.11 72.87 48.38 38.22 99.50 87.62 90.00 50.67 8 87.16 92.23 94.24 64.43 55.91 99.82 98.89 98.30 70.65 10 91.73 98.90 100.00 78.86 72.22 99.86 99.32 98.30 86.50 12 97.94 91.36 85.05 99.82 99.52 98.30 97.93 14 98.48 96.75 95.04 100 99.82 98.30 100.83

Examples IX and X

(61) Examples IX and X are based on a combination of an anionic gel-forming polymer (alginic acid) and non-ionic gel-forming polymer (HPMC) as release controlling agents.

(62) TABLE-US-00004 Example IX Example X Materials mg/tab % mg/tab % Donepezil HCl 24.60 9.84% 24.60 9.84% Lactose 126.05 50.42% 126.05 50.42% HPC L 9.20 3.68% 9.20 3.68% Povidone K-30 3.45 1.38% 3.45 1.38% Total dry gran. 163.30 65.32% 163.3 57.30% Avicel PH102 34.1 13.64% 32.5 11.40% HPMC K100 31.7 11.12% HPMC K15M 12.1 4.84% 11.4 4.00% Alginic acid 37.5 15.00% 42.7 14.98% Colloidal silicon 1.5 0.60% 1.7 0.60% dioxide Mg Stearate 1.5 0.60% 1.7 0.60% Total 250.00 100.00% 285.00 100.00%

(63) Tablets were prepared as described for Examples VI and VII above, with alginic acid used in place of Carbopol.

(64) Release profiles were determined as described above for Examples I-VII. The accumulative dissolution test results for the formulations of Examples IX and X are shown in FIG. 2 and in Table 2 below:

(65) TABLE-US-00005 TABLE 2 Time, h Example IX Example X 0 0 0 1 71.1 30.2 2 93.9 41.0 3 98.3 50.3 4 99.5 59.8 5 100.0 71.8 6 100.0 83.7 8 100.0 97.9 10 100.0 99.6 12 100.0 99.9 14 100.0 100.0

Examples XI-XX

(66) Examples XI to XVIII are based on a combination of two non-ionic gel-forming polymers (HPMC), of different viscosities, as release controlling agents.

(67) TABLE-US-00006 XI XII XIII XIV XV XVI XVII XVIII XIX XX Materials mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab Donepezil 20 20 21.39 21.39 21.39 24.6 24.6 24.6 24.6 24.6 HCl Lactose 122 122 98.75 98.75 98.75 126.05 126.05 126.05 126.05 126.05 HPC L 8 8 8 8 8 9.2 9.2 9.2 9.2 9.2 Povidone K- 3.45 3.45 3.45 3.45 3.45 30 Total dry 150.00 150.00 128.14 128.14 128.14 163.30 163.30 163.30 163.30 163.30 gran. Microcrystall. 20 25.4 35 19.1 15.9 21.6 Cellulose Lactise 9 9 30.86 30.86 10.86 HPMC K100 30 34 38 30 36 37.5 37 45.0 46.9 45.0 HPMC 10 6 12.5 12.1 10.0 11.3 7.5 K15M HPMC 2 10 4 K100M Povidone K- 10 10 10 10 30 Aerosil 1.3 1.3 1.3 1.3 Mg Stearate 1 1 1 1 1 1.3 1.3 1.3 1.3 1.3 Total 200.00 200.00 200.00 200.00 200.00 250.00 250.00 250.00 250.00 250.00

(68) Tablets for Examples XI-XIV were prepared as described for Examples I-V above; Examples XV-XX were prepared as described for Examples VI-VIII above;

(69) Release profiles were determined as described above for Examples I-VIII.

(70) The percentage of release-controlling agents in each of the Examples tested is shown below:

(71) TABLE-US-00007 HPMC HPMC HPMC Form. K100 K15M K100M XI 15 5 0 XII 17 3 0 XIII 19 0 1 XIV 15 0 5 XV 18 0 2 XVI 15 5 0 XVII 14.8 4.8 0 XVIII 18 4 0 XIX 18.9 4.5 0 XX 18 3 0

(72) The accumulative dissolution test results for the formulations of Examples XI-XX are shown in Table 3 below; results for Examples XI-XVIII are further shown in FIG. 3.

(73) TABLE-US-00008 TABLE 3 Time, h XI XII XIII XIV XV XVI XVII XVIII XIX XX 0 0 0 0 0 0 0 0 0 0 0 1 20.95 29.19 46.91 36.49 29.36 22.76 29.49 17.59 18.42 19.88 2 36.76 52.24 62.37 50.13 43.79 34.54 40.06 29.07 30.30 33.33 3 49.97 68.87 76.58 60.05 54.87 44.15 50.63 40.22 39.58 43.67 4 61.39 87.29 84.06 67.25 63.79 52.06 59.13 49.15 47.3 53.17 5 71.92 94.75 92.36 73.50 72.00 58.92 65.14 57.85 54.42 62.62 6 81.83 97.87 98.18 79.49 79.25 65.33 70.02 66.25 61.35 72.13 8 94.77 99.26 99.79 89.70 90.47 79.34 78.55 84.11 75.00 92.40 10 98.37 99.78 99.84 96.13 96.45 93.38 87.45 93.2 88.37 100.22 12 99.12 99.37 99.90 98.64 98.90 98.60 93.74 96.42 96.58 101.62 14 99.18 99.43 99.90 99.60 98.90 100 97.70 97.48 99.27 101.48

(74) It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

(75) Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.