Patent Application
20080057118
In an aspect, the present invention relates to modified release pharmaceutical compositions of valproic acid compound-coated particles which can be compressed into tablets or filled into capsules without affecting the desired release profile. The invention further relates to processes for preparing the compositions of the invention and their methods of use, treatment and administration.
Another aspect of the present invention includes modified release pharmaceutical compositions comprising a valproic acid compound along with at least one modified release polymer, with or without other pharmaceutically acceptable excipients.
Valproic acid compounds that are useful in the present invention include valproic acid and pharmaceutically acceptable salts, amides, esters, and prodrugs of valproic acid. Partial salts, such as divalproex sodium, are included within the scope of useful compounds.
Suitable pharmaceutically acceptable basic addition salts include, but are not limited to, valproic acid compounds having cations that are alkali metals, alkaline earth metals, and transition metals such as lithium, sodium, potassium, calcium, magnesium, aluminum, and the like, and ammonium and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamile, triethylamine, diethylamine, ethylamine, and the like. Representative organic amines useful for the formation of base addition salts with valproic acid include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
In accordance with the invention, pharmacologically inert cores comprise, without limitation thereto, pellets, beads, particles or nonpareil seeds that may be water-soluble or water-insoluble and organic or inorganic.
The inert cores generally have a particle size in the range of 100 to 850 μm, or about 150 to 300 μm, and comprise water-insoluble inert materials, such as glass particles or silicon dioxide, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate, microcrystalline cellulose (including Celphere™ microcrystalline cellulose spheres sold by Asahi Kasei Chemicals Corporation, Tokyo, Japan), cellulose derivatives, or soluble inert materials such as sugar spheres having sugars like sucrose, dextrose, lactose, anhydrous lactose, spray-dried lactose, lactose monohydrate, or mannitol, starches, sorbitol, or insoluble inert plastic materials, i.e., spherical or nearly spherical core beads of polyvinylchloride, polystyrene or any other pharmaceutically acceptable insoluble synthetic polymeric material, and the like, and mixtures thereof.
In one embodiment of the present invention, the cores may be produced by any mechanical means, including extrusion spheronization, optionally using a binder during the granulation process.
In one aspect of the present invention, the cores have a defined size and shape, and enough strength to withstand fluidizing processes, thereby being resistant to attrition.
In one of the embodiments of the present invention, the cores are optionally seal coated to increase the strength of the core to withstand fluidizing processes. The seal coating helps to increase the mechanical strength of the cores by forming a tough insoluble coating on the surface and hence prevents material from shaving off during the fluidization process due to attrition. Useful seal coatings comprise pharmaceutically acceptable polymers, such as hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, polyvinylpyrrolidone, cellulose acetate, waxes such as polyethylene glycol, methacrylic acid copolymers like poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (Eudragit™ RL), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (Eudragit™ RS), and the like, and mixtures thereof.
In another embodiment of the present invention, the cores are coated with a first layer comprising of an active substance and subsequent layers comprising modified release polymer.
In an embodiment of the present invention, the active substance may be either dissolved or dispersed or suspended in a liquid, optionally containing a pharmaceutically acceptable binder, and may then be applied onto the cores.
In an embodiment of the present invention, the active substance may be either dissolved or dispersed or suspended in a solvent, optionally containing a pharmaceutically acceptable binder and a modified release polymer, and may then be applied onto the cores.
Examples of pharmaceutically acceptable binders include, but are not limited to, acacia, cellulose derivatives, gelatin, glucose, polyvinylpyrrolidone, sodium alginate and alginate derivatives, sorbitol, starch, hydrophilic cellulose excipients such as methylcellulose, hydroxypropyl methylcellulose and carboxymethylcellulose, xanthan gum, etc., and mixtures thereof.
In another embodiment of the present invention, a process to prepare the modified release divalproex sodium coated particle composition comprises:
In one embodiment of the present invention, the active compound is applied on the core using fluidized bed technology with Wurster or top spray or side spray techniques, from a dispersion or suspension or solution of the active compound, with or without a polymer, in a solvent system.
An aspect of the invention includes stable pharmaceutical compositions of a valproic acid compound, wherein a modified release coating provides stability to the composition by acting as a moisture barrier coating.
Solvents that can be used in processing include aqueous materials like water, alcohols like ethanol and isopropyl alcohol, hydro-alcoholic mixtures, organic solvents like acetone, methylene chloride and the like, and mixtures thereof.
When preparing the pharmaceutical preparation according to an embodiment of the invention it has surprisingly been found that the use of a solvent mixture of isopropyl alcohol and methylene chloride gives improved processability, by way of reducing agglomerate formation during drug loading. The ratio of isopropyl alcohol to methylene chloride may be varied from about 5:95 to 75:25 parts by volume, or about 15:85 to 30:75 parts by volume.
In one embodiment of the present invention, an optional seal coating may be applied between the drug loaded core and the modified release coating. The total amount of sealing layer contained in the drug-loaded particles may be varied depending on the desired release rate of the active compound.
In another embodiment of the present invention, drug-loaded cores are coated with a modified release polymer. Examples of suitable modified release polymers include but are not limited to ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose (different grades such as Methocel K 4M, Type 2208, Methocel E 4M Type 2910 supplied by Colorcon Asia Private Limited), hydroxypropyl cellulose, hydroxypropyl methyl pthalate, cellulose acetate pthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, Eudragit™ RL, Eudragit™ RS, polyvinylpyrrolidone, polyalkylene glycols such as polyethylene glycol, and cellulose derivatives such as hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, propyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxymethylcellulose, carboxymethylethylcellulose, methyl-hydroxypropylcellulose, vinyl acetate copolymers, polysaccharides (such as alginate, xanthan gum and the like), polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof, acrylates such as methacrylates and acrylic acid copolymers; high molecular weight polyvinylalcohols; waxes like fatty acids and glycerides, and mixtures thereof.
Proprietary coating formulations like Acryl Eze®, Surelease® and Kollidon SR® may also be used.
Plasticizers may be added to the polymeric solutions or suspensions in order to improve the processability or modify the drug release characteristics. Examples of plasticizers that may be used include but are not limited to citrate esters, acetylated monoglycerides, diacetylated monoglycerides, glycerine triacetate, triethyl citrate, acetyl triethyl citrate, tributyl citrate, polyethylene glycol, propylene glycol and mixtures thereof.
In addition to the above excipients, processing aids such as stearic acid or its derivatives may be used in the coating process to prevent agglomeration of the coating particles during the process of coating or after the coating.
In an embodiment of the present invention, the final dosage form comprises a large number of inert cores, which are layered with divalproex, dispersed or suspended or dissolved with a polymer in a solvent system.
In embodiments of the present invention, the final dosage form comprises a plurality of modified release particles and one or more pharmaceutically acceptable excipients compressed into a tablet. In other embodiments, a final dosage form of the present invention comprises a plurality of modified release particles filled into a hard gelatin capsule, with or without one or more pharmaceutically acceptable excipients. When coated particles are processed into tablets or capsules, the coated particles are further processed with any of the following described pharmaceutically acceptable excipients.
In another embodiment of the present invention, the final dosage form comprises an extended release composition comprising divalproex sodium mixed with at least one release modifying polymer, with or without one or more pharmaceutically acceptable excipients, compressed into a tablet, which optionally may be film coated.
In an embodiment, the invention includes extended release pharmaceutical compositions comprising divalproex sodium, wherein the modified release polymer is in a concentration range of more than about 50 percent by weight of the total composition.
The pharmaceutically acceptable excipients which may be used for further processing coated particles or which may be used to prepare the extended release compositions include the following.
Various useful diluents include but are not limited to starches, lactose, mannitol, Pearlitol™ SD 200, cellulose derivatives, confectioners sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle products), Pharmatose™ (available from DMV) and others. Different grades of starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™ PH 101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.
Various useful binders include but are not limited to hydroxypropylcellulose (Klucel™-LF), hydroxypropyl methylcellulose or hypromellose (Methocel™), polyvinylpyrrolidone or povidone (PVP-K25, PVP-K29, PVP-K30, PVP-K90), plasdone S 630 (copovidone), powdered acacia, gelatin, guar gum, carbomer (e.g. carbopol), methylcellulose, polymethacrylates, and starch.
Various useful disintegrants include but are not limited to carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxy methylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (FMC-Asahi Chemical Industry Co., Ltd.), crospovidone, examples of commercially available crospovidone products including but not limited to crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, XI-10, and INF-10 [manufactured by ISP Inc. (USA)], and low-substituted hydroxypropylcellulose. Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starch.
Various glidants or antisticking agents include but are not limited to talc, silica derivatives, colloidal silicon dioxide and the like, and mixtures thereof.
Various lubricants that can be used include but are not limited to stearic acid and stearic acid derivatives such as magnesium stearate, calcium stearate, zinc stearate, sucrose esters of fatty acid, polyethylene glycol, talc, sodium stearyl fumarate, zinc stearate, castor oils, and waxes.
Optionally, compressed tablets may be film coated using many of the same excipients as are used for seal coating. Several ready mixed coating materials are available, including those sold as OPADRY™ (supplied by Colorcon), for example Opadry grey 20A57646. These products require only mixing with a liquid, prior to application.
An opacifier like titianium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating. Antiadhesives or antisticking agents are frequently used in the film coating process to avoid sticking effects during film formation and drying.
Suitable polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol), waxes (e.g., carnauba wax, candelilla wax and white wax), acetylated monoglycerides, diacetylated monoglycerides, vanillin, etc.
In an embodiment, the invention includes compositions, which are formulated into solid oral dosage forms such as tablets, capsules, granules, etc.
In an embodiment the invention includes dosage forms, which are prepared by direct compression or dry granulation or wet granulation.
Equipment suitable for processing the pharmaceutical compositions of the present invention includes mechanical sifters, blenders, roller compacters, compression machines, rotating bowls or coating pans, fluid bed coaters with Wurster technology or top spray technology, etc.
In an embodiment, the invention includes processes to prepare extended release pharmaceutical compositions comprising divalproex sodium, comprising:
The dosage forms prepared according to the present invention can be subjected to an in vitro dissolution evaluation, such as according to Test 711 “Dissolution” in United States Pharmacopoeia 24, United States Pharmacopeial Convention, Inc., Rockville, Md., 1999 (“USP”), to determine the rate at which the active substance is released from the dosage forms, and the content of active substance can be determined in solutions by high performance liquid chromatography. The pharmaceutical dosage forms of the present invention are intended for oral administration to a patient in need thereof.
In an embodiment, the invention includes the use of packaging materials such as containers and lids of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, and blisters or strips composed of aluminum or high-density polypropylene, polyvinyl chloride, polyvinyl dichloride, etc.
The following examples illustrate certain specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.
A. Seal Coating:
B. Drug Loading:
C. Modified Release Coating:
Coating Parameters:
The in vitro release profile of the product of Example 1 in comparison with a commercial product was determined using the USP procedure with the following parameters:
Media: pH 7.5 phosphate buffer.
Volume: 500 ml.
Apparatus: USP apparatus II (Paddle).
Speed: 50 rpm.
Bioavailability of the Example 1 product (“T”) was compared with the commercial product (“R”) using 34 human subjects in a 2-way crossover single dose fasted and fed state study, giving the following results:
Excess quantities were taken in order to compensate for processing losses. Manufacturing process: similar to that described in Example 1, with a capsule fill weight of 250 mg.
The in vitro release profile of the product of Example 2 in comparison with a commercial product was determined using the USP procedure with the following parameters:
Media: pH 1.2 (0.08N) HCl for 2 hours followed by pH 7.5 phosphate buffer.
Volume: 900 ml.
Apparatus: USP apparatus II (Paddle).
Speed: 50 rpm.
Bioavailability of the Example 2 product (“T”) was compared with the commercial product (“R”) using 14 human subjects in a 2-way crossover single dose fasted state study, giving the following results:
A. Drug Layering:
C. Modified Release Coating:
D. Delayed Release Coating:
A. Drug Layering:
B. Modified Release Coating:
C. Delayed Release Coating:
A. Drug Layering:
B. Modified Release Coating:
C. Delayed Release Coating:
1. Divalproex sodium was deagglomerated in a rapid mixer granulator at high impeller and chopper speeds for about 20 minutes.
2. Microcrystalline cellulose (Avicel PH112), pregelatinized starch (Starch 1500 LM) and silicon dioxide (Syloid 244 FP) were sifted through a #40 ASTM mesh sieve.
3. Step 2 materials were added to step 1 and dry mixed at a high Impeller speed with the chopper off, for 15 minutes.
4. Povidone K30 was dissolved in isopropyl alcohol with stirring to obtain a clear solution.
5. Dry mixture of step 3 was granulated using the binder solution of step 4.
6. The wet granules were milled in a comminuting mill without any sieve with knife forward and medium speed.
7. The wet milled granules were dried in a fluid bed granulator at 50° C. until a LOD (loss on drying) was less than 1.5% w/w at 80° C.
8. Dried granules of step 7 were sifted through a #16 mesh sieve.
9. The extragranular excipients pregelatinized starch (Starch 1500 LM, silicon dioxide (Syloid 244 FP) and talc were passed through a ASTM 40# mesh sieve.
10. Loaded the granules of step 8 and ingredients of step 9 into a double cone blender, then blended for about 7 minutes.
11. Final blend was compressed to obtain tablets using 23×9.5 mm oval shaped plain/plain punches.
12. The tablets were coated using a coating solution (hypromellose 5 cps dissolved in isopropyl alcohol-methylene chloride (70:30) along with diacetylated monoglycerides) until a weight build up of about 2.5-3.5% w/w was obtained.
13. The barrier coated tablets were coated using the enteric coating dispersion (hypromellose phthalate dissolved/dispersed in isopropyl alcohol-acetone (65:35) along with diacetylated monoglycerides and pigments) until a weight build up of about 6-8% w/w, based on the tablet weight, was obtained.
14. The enteric-coated tablets were polished with the diacetylated monoglycerides and vanillin, dissolved in isopropyl alcohol.
15. The polished tablets were imprinted with identifying information using a tablet imprinting machine with Opacode Black S-1-8152HV. Final tablet weight was 991.5 mg.
Medium: 1 hour in (pH 1.2) 0.08N HCl, followed by 7.5 pH phosphate buffer.
Volume: 900 ml.
Apparatus: USP Type II (Paddle), 50 RPM.
1. Divalproex sodium was deagglomerated in a rapid mixer granulator by mixing at impeller and chopper high speed for about 20 minutes.
2. Hypromellose (Methocel K4M, Type 2208), hypromellose (Methocel E4M, Type 2910) and colloidal silicon dioxide (Aerosil 200, first quantity) were sifted together through a ASTM #30 mesh sieve in a mechanical sifter.
3. Step 2 and step 3 ingredients were mixed together in a rapid mixer granulator for about 20 minutes at impeller high speed and chopper off.
4. Dry mix of step 3 was roll compacted using a roller compactor to obtain slugs and the slugs were sifted through a ASTM #14 mesh sieve in a mechanical sifter.
5. The slugs were milled through a 4 mm screen using a comminuting mill with knives forward and slow speed. Sifted the milled slugs through a ASTM #40 mesh sieve. The material retained on a ASTM #40 mesh sieve was taken for further processing.
6. Colloidal silicon dioxide (Aerosil 200, second quantity) was sifted through a ASTM #16 mesh sieve. The sifted colloidal silicon dioxide was blended with the sifted and milled slugs of step 5 for 10 minutes in a double cone blender.
7. The final blend was compressed into tablets using 23×9.5 mm oval shaped plain/plain punches.
8. The tablets were coated using the Opadry and hypromellose dispersion prepared in isopropyl alcohol-methylene chloride (70:30) until a weight build up of about 1.5-2.5% w/w was obtained. Final tablet weight was 1275 mg.
Media: 0.1 N HCl, 500 ml for 45 minutes, followed by 0.05 M phosphate buffer+75 mM sodium lauryl sulfate (pH 5.5), 900 ml.
Apparatus: USP apparatus II (Paddle).
Speed: 100 rpm.
Bioavailability of the Example 7 product (“T”) was compared with a commercial product (“R”) using 34 human subjects in a 2-way crossover single dose fasted and fed state study, giving the following results:
| Number | Date | Country | Kind |
|---|---|---|---|
| 1594/CHE/2006 | Sep 2006 | IN | national |
| Number | Date | Country | |
|---|---|---|---|
| 60870005 | Dec 2006 | US |
