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High Drug Load Pharmaceuticl Composition Of Verapamil Prepared By Extrusion And Spheronization

Abstract: The present invention relates to a high drug load- pharmaceutical composition comprising an effective amount of Verapamil or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof in combination with suitable excipients. The invention also relates to a process for preparation of a high drug load pharmaceutical composition comprising an effective amount of Verapamil

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Patent Information

Application #
Filing Date
19 March 2015
Publication Number
06/2019
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

JUBILANT GENERICS LIMITED
PLOT 1A, SECTOR 16A, NOIDA-201 301, UP, INDIA.

Inventors

1. NITHIYANANDAM, RAVIKUMAR
CF-04 GKS RESIDENCY, 55-A GOVINDASWAMY LAYOUT, ASHOK NAGAR, CHETTY STREET, COIMBATORE-641 001, TAMIL NADU, INDIA.
2. GAT, GANESH VINAYAK
61/5 UNITED WESTERN CHS, GODAVARI KARVENAGAR-411052, PUNE, INDIA.
3. NAKHAT, PREMCHAND DALICHANDJI
GURUKRUPA MEDICALS AND ELECTRONIC LOHI (BAZAR), TQ. DARWHA, DIST. YAVATMAL-445 210, MAHARASHTRA, INDIA.
4. BHARDWAJ, VINEET
79, SHARDA N IKETAN, PITAMPURA - 11034, NEW DELHI, INDIA.
5. NA
NA
6. NA
NA
7. NA
NA
8. KUMAR, DINESH
1073/1, SECTOR-39B, CHANDIGARH-160036, INDIA.
9. BALI, VIKAS
HOUSE NO. 319, SECTOR 23, HOUSING BOARD COLONY, N.I.T, FARIDABAD-121005, HARYANA, INDIA.

Specification

FIELD OF THE INVENTION Present invention in general relates to high drug load, controlled release pharmaceutical compositions comprising Verapamil or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof in combination with suitable excipients. In particular, the present invention provides a high drug load, controlled release solid oral pharmaceutical composition comprising Verapamil and process f-or preparing the same. BACKGROUND OF THE INVENTION Verapamil is a calcium channel blocker or calcium ion antagonist and is indicated for treatment of hypertension, angina pectoris and cardiac arrhythmia. Verapamil Hydrochloride is chemically described as Benzeneacetonitrile, a-[3-[[2- (3,4-d imethoxyphenyl)-ethyl]methylamino ]propyl]-3,4-d imethoxy-a-( 1-methylethyl), monohydrochloride and is represented by the following formula: Verapamil Hydrochloride is marketed in US as extended release tablets and capsules under the brand names CALAN SR®, COVERA-HS®, VERELAN® and VERELAN PM®. Inactive ingredients in the VERELAN® capsules are fumaric acid, talc, sugar spheres, povidone, shellac, gelatin, FD&C red #40, yellow iron oxide, titanium dioxide, methylparaben, propylparaben, silicon dioxide, and sodium Iaury! sulfate. In addition, the Verelan 240 mg and 360 mg capsules contain FD&C blue# I and D&C red #28; and the Verelan 180 mg capsule contains black iron oxide. 2 Synthesis ofVerapamil was first described in US Patent number 3261859. Various controlled release formulations ofVerapamil have been described in the prior art. US Patent No. 4863742 discloses controlled absorption pellet formulation of Verapamil for oral administration. The formulation .comprises a core of a powder mixture containing Verapamil or a pharmaceutically acceptable salt thereof, an organic acid and a polymeric material. The core comprises layers of powder mixture and polymeric material superimposed one upon the other. Powder layering over cores is a time consuming process and is also susceptible to generation of dust which may act as potential health hazard. US Patent No. 4808413 discloses a modified release formulation in the form of an extruded-spheronized beadlet from which medicament is released at a controlled rate. The beadlet comprises a medicament, a non-lipophilic non-fat binder and an organic carboxylic acid to facilitate spheronization, to impart hardness to the beadlet and aid in obtaining a desired narrow particle size distribution ofbeadlets. Examples provided in the specification involve ACE inhibitors (Captopril, Lisinopril, Fosinopril and Zofenopril), Calcium channel blockers (Diltiazem and Nifedipine) and ~-blocker (Nadolol). US Patent No. 4859469 discloses galenic forms of Verapamil chlorhydrate having sustained release property. The galenic forms comprise microgranules containing Verapamil chlorhydrate and at least one wetting agent. Example I and 2 disclose formulation of microgranules comprising Verapamil Hydrochloride by Extrusion and spheronisation which are coated with a microporous membrane. The invention relates to microgranules having diameter between 0.05 mm and 3 mm which are coated with a microporous membrane comprising Eudgratit E30D and L30D polymer. 3 IPO DELHI 18-63-2916 US Patent No. 5350584 discloses a process for the production of microcrystalline cellulose free multiparticulate. The multiparticulates comprise a medicament and a charged resin, and are prepared by extrusion and spheronisation. Use of resins as excipient in pharmaceutical formulation poses additional challenges to formulation scientist. Examples provided in the specification involve Simvastatin and Lovastatin. However, there is no teaching with respect to working example involving.extrusion and ·spheronisation of Verapamil. US Patent No. 5049394 discloses extrusion and spheronisation method for preparing a pharmaceutical composition in the form of a bead having a diameter of0.5 to 1.5 mm. Examples provided in the specification involve Erythromcyin. However, the specification is sileAt with respect to working example involving extrusion and spheronisation of Verapamil. US Patent No. 6355273 discloses a process comprising extrusion and spheronisation for the preparation of pharmaceutical compositions in form of polymeric microparticles. The microparticles comprise a drug and a cross-linked amphiphilic polymer. Examples provided in the specification involve Nifedipine and Nicardipine. However, the specification is silent with respect to working example involving extrusion and spheronisation ofVerapamil. Verapamil Hydrochloride should be stored at room temperature & protected from light. The drug has a very short plasma half-life period (2 to 4 hours). This requires several daily administrations of Verapamil Hydrochloride at an interval of 6 hours only. Verapamil Hydrochloride is a drug having bitter taste. Typically, prescribed daily dosages of Verapamil Hydrochloride for the treatment of hypertension are high, e.g. 120- 480 mg in adults. Thus, there is a need for an oral dosage form which not only masks the bitter taste of Verapamil Hydrochloride, but also provides the prescribed daily dosage of the drug in a manner which is convenient to administer. The present 4 invention provides a controlled release pharmaceutical composition of Verapamil Hydrochloride capable of providing high drug load of the drug to the patient in a convenient manner. Pharmaceutical art is a highly unpredictable art. An approach that works under a particular condition may not work under another set of conditions. In the present case, none of the prior arts discloses a simple, reproducible, and cost-effective process for preparing controlled release pharmaceuticar composition capable of delivering high drug load of Verapamil Hydrochloride. The present inventors developed a simple, reproducible, and cost-effective process for preparing pharmaceutical composition capable of delivering high drug load of Verapamil Hydrochloride in controlled and convenient manner. Pharmaceutical compositions prepared according to the process of the present invention enable the amount of additive to be reduced significantly. Further, the pharmaceutical compositions prepared according to the manufacturing process of the present invention possess desirable formulation characteristics. SUMMARY OF THE INVENTION One embodiment of the present invention relates to high drug load, controlled release pharmaceutical compositions comprising a pharmacologically effective amount of Verapamil or its pharmaceutically acceptable salt present in an amount of from about 30% to about 80% by weight, preferably more than 40% by weight. In particular, the amount ofVerapamil or its pharmaceutically acceptable salt may vary from about 60% to about 80% by weight, based on the total weight of the composition. In another embodiment, the present invention provides a process for the preparation of high drug load, controlled release pharmaceutical compositions comprising from about 30% to about 80% by weight ofVerapamil Hydrochloride based on the total weight of the composition. 5 Another embodiment of the present invention includes a high drug load, controlled release solid oral pharmaceutical composition comprising from about 30% to about 80% by weight of Verapamil Hydrochloride based on the total weight of the composition wherein the composition is prepared by extrusion and spheronization. ln yet another embodiment, the process used for the manutacture of the pharmaceutical composition of the present invention involves dry blending drug and excipients, wet granulation (aqueous or non-aqueous) of the mass, extrusion through a screen of defined mesh size to compact the wet mass into cylindrical strands. The cylindrical strands are placed in a spheronizer wherein the cylindrical strands break up to form spheres. The spheres, thus obtained, may be optionally ~oated. In yet another embodiment of the invention, the high drug load, controlled release pharmaceutical composition comprises about I 00 to about 500 mg of Verapamil Hydrochloride. Another embodiment of the present invention encompasses a high drug load, controlled release pharmaceutical composition comprising from ahout 30% to about 80% by weight ofVerapamil Hydrochloride based on the total weight ofthe composition and a· pharmaceutically acceptable excipient selected from at least one of diluent, binder, disintegrant, surfactant, lubricant, and glidant. In another embodiment, the high drug load pharmaceutical composition of the present invention includes particle size of Yerapamil Hydrochloride, wherein D9o is less than about 100 J.lm. In another embodiment, the present invention relates to a spheronized beadlet l comprising from about 30% to about 80% by weight of Yerapamil Hydrochloride, optionally from about 0% to about 5% by weight of an organic acid, and from about 6 0% to about 10% by weight of a binder, and from about 0% to about 20% by weight of plasticizer. In yet another embodiment, the present invention relates to a high drug load pharmaceutical composition comprising spheronized beadlet of Verapamil Hydrochlodde and an enteric coating disposed thereon. In another embodiment, the spheronized beadlets used for the pharmaceutical composition have bulk density above 0.6g/cm3. In another embodiment, the beadlets present in the pharmaceutical composition have tapped density above 0.7g/cm3. In another embodiment, pharmaceutical compositions of the present invention are placed inside capsule shell of size No. 00 to size No.4. In further embodiment, the present invention includes method of using the high drug load, enteric coated pharmaceutical composition comprising spheronized beadlet of Yerapamil Hydrochloride in the treatment of hypertension. Another embodiment of the present invention includes method of using the high drug load, pharmaceutical composition comprising Yerapamil Hydrochloride in the treatment of hypertension. DETAILED DESCRIPTION OF THE INVENTION The present invention can be more readily understood by reading the following detailed description ofthe invention and study of the included eMmples. 7 18. As used herein, the term "composition", as in pharmaceutical composition, is intended to encompass a drug product comprising Verapamil or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with "formulation" and "dosage form". Pharmaceutical compositions of the invention include, but are not limited to, granules, pellets, spheronized beadlets, tablets, capsules, sachets, powders and the like. Preferably, the pharmaceutical composition refers to tablets and capsules. More preferably, the pharmaceutical composition refers to hard gelatin capsules filled with beadlets. Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition or formulation. "Controlled release composition" as used herein means a pharmaceutical composition which releases the drug substance at a slower rate than from an immediate release composition. The term "Controlled release composition" is used herein interchangeably with prolonged release composition, extended release composition, modified· release composition, sustained release composition, retard release composition. Similarly, the material used to modify the said release of the drug from composition are termed herein as extended release material, modified release material, sustained release material and the like, all having the same meaning. The term "High drug load" as used herein, refers to more than 29% by weight of Verapamil Hydrochloride based on the total weight of the composition. Preferably the amount of Verapamil or its pharmaceutically acceptable salt is more than 40% by weight. In particular, the amount ofVerapamil or its pharmaceutically acceptable salt 8 may vary from about 60% to about 80% by weight, based on the total weight of the composition The term "Bulk density" as used herein, refers to the ratio of the mass of an untapped sample and its volume including the contribution of the interparticulate void volume. Bulk density indicates mass of a material that can be filled in per unit volume. Preferably, beadlets used for the pharmaceutical composition have bulk density above 0.6g/cm3. The term "Tapped density" as used herein, refers to the ratio of the mass of a tapped powder sample and its volume. Tapped density of beadlets is determined using Electro lab tap density tester (Model ETD 1 020) where tapping is done at a rate of 500 to 1250 strokes per minute (Spm). Preferably, beadlets present in the pharmaceutical composition have tapped density above 0.7g/cm3. The present invention relates to high drug load pharmaceutical composition of Verapamil or its pharmaceutically acceptable esters, salts, esters, solvates, polymorphs, enantiomers or mixtures thereof. Preferably, salt of Verapamil is Verapamil Hydrochloride. In another embodiment the high drug load pharmaccut:~~l composition of the present invention includes particle size of Verapamil or its salt, wherein D9o is less than about 100 ~m. Another embodiment of the present invention includes a process for preparing high drug load, controlled release solid oral pharmaceutical compositions comprising Verapamil Hydrochloride wherein, the composition is prepared by extrusion and spheronization. Any pharmaceutically acceptable solvent can be used for producing wet mass for extrusion. Suitable solvent for producing wet mass include water, esters 9 such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane and combinations thereof. Preferably, the solvent used is water. One embodiment of the invention encompasses a high drug load, controlled release pharmact:ulical composition comprising Verapamil or a salt thereof and a pharmaceutically acceptable excipient selected from at least one of diluent, binder, disintegrant, surfactant, lubricant, organic acid and gl;dant, wherein composition is prepared by extrusion and spheronization. Diluents are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to calcium carbonate (BarcroftTM, CaiCarb ™, CalciPure™, Destab™, MagGran™, Millicarb™, Pharma- CarbTM, Precarb™, SturcaJTM, Yivapres CaTM), calcium phosphate, dibasic anhydrous (ATAB ™, Di-Cafos A-N™, Emcompress AnhydrousTM, FujicalinTM), calcium phosphate, dibasic dihydrate (Cafos™, CalipharmTM, CalstarTM, Di-Cafos'~'M, Emcompress™), calcium phosphate tribasic (Tri-Cafos™, TRI-CAL WG™, TRITAB ™), calcium sulphate (Destab™, Drierite™, Snow WhiteTM, Cai-TabTM, CompactroJTM, USG Terra Alba™), cellulose powdered (ArboceJTM, ElcemaTM, Sanacet™, Solka-Floc™), silicified microcrystailine cellulose (ProSoJvTM), cellulose acetate, compressible sugar (Di-Pac™), confectioner's sugar, dextraies (CandexTM, Emdex™), dextrin (AvedexTM, Caloreen™, Crystal Gum™, Primogran WTM), dextrose (Caridex™, DextrofinTM, Lycadex PF™, Roferose™, Tab fine 0-IOQTM), fructose (AdvantoseTM, FructamyJTM, Fructofin™, Krystar™), kaolin (LionTM, Sim 9QTM), lactitol (Finlac ACXTM, Finlac DC™, Finlac MCX™), lactose (Aero Flo 20TM, Aero Ho 65™, AnhydroxTM, CapsuLae™, Fast-Flo™, FlowLac™, GranuLac™, lnhaLacTM, LactochemTM, Lactoha"ieTM, Lactopress™, MicrofmeTM, MicrotoseTM, PharmatoseTM, Prisma LacTM, RespitoseTM, SacheLac™, SorboLacTM, Super-Tab™, TablettoseTM, Wyndale™, ZeparoxTM), magnesium carbonate, magnesium oxide (MagGran MQTM), 10 ..... ""iP .. ;!=~ II'""' .t ! .. tJ• ':Y· maltodextrin (C*Dry MD™, Glucidex™, GlucodryTM, Lycatab DSHTM, Maldex'~'M, Maitagran™, Maltrin™, Maltrin QD™, Paselli MD 10 PH™, Star-DriTM), maltose (Advantose I 00™), mannitol (Mannogem™, PearlitoJTM), microcrystailine cellulose (Avice! PH™, Celex™, Celphere™, Ceolus KG™, EmcoceJTM, Ethispheres'~'M, Fibrocel™, Pharmacel™, Tabulose™, Vivapur™), polydextrose (LitesseTM), simethicone (Dow Corning <..)_7- 2243 LVA ™, Cow Coming Q7-25871'M, Sentry Simethicone™), sodium alginate (KelcosoJTM, KeltoneTM, ProtanaJTM), sodium chloride (Aiberger™), sorbitol (Liponec 70-NC™, Liponic 76-NCv, MeritoJTM, Neosorb™, Sorbifm™, Sorbitol Instant™, Sorbogem™), starch (Aytex PTM, Flufiex W™, Instant Pure-Cote™, Melojei'TM, Meritena Paygel 55™, Perfectamyl D6PHTM, Pure-Bind™, Pure- Cote™, Pure-Dent™, Pure-Gel™, Pure-SetTM, Purity 21 ™, Purity 826™, Tablet White™), pregelatinized starch (lnstastarch™, Lycatab C™, Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab ST 200TM, Spress B820™, Starch 1500 G™, Tablitz™, Unipure LDTM, Unipure WG220TM), sucrose, trehalose and xylitol (Klinit™, Xylite™, XylitabTM, XylisorbTM, XylitoloTM), or mixtures thereof The amount of diluent(s) may vary within a range of from about 20% to about 80% by weight based on the total weight of the composition. Binders impart cohesiveness to formulation. Various useful binders include, but are not limited to acacia, alginic acid (Kelacid™, Protacid™, Satialgine J-18TM), carbomer (Acritamer™, Carbopol™, Pemulen™, Ultrez™), carboxymethylcellulose sodium (Akucell™, Aquasorb™, Blanose™, Finnftx™, Nymcel™, TyloseTM), ceratonia (Meyprofleur™), cottonseed oil, dextrin (A vedex™, CaloreenTM, Crystal GumTM, Primogran W™), dextrose (Caridex™, DextrofmT:vt, Lycedex PfTM, RoferoseTM, Tabftne D-100™), gelatin (Cryogel™, lnstagel™, SolugeiTM), guar gum (Galactosol™, Meprogat™, Meyprodor™, 5 Meyprofm™, MeyproguarTM), hydrogenated vegetable oil type 1 (Akoftne™, LubritabTM, SterotexTM, Dynasan P[omicron]O™, Softisan 154™, Hydrocote™, Lipovol™, HS-K™, Sterotex HMTM), hydroxyethyl cellulose (Alcoramnosan™, CellosizeTM, ldroramnosanTM, 11 03 ~ -v· •. ,.a:\. . .- £f··I.:.J.::, Liporamnosan™, Natrosol™, Tylose PH A ™), hydroxyethyhnethyl cellulose (Culmina!™, Tylopur MH™, Tylopur MHB™, Tylose MBTM, Tyiose MH™, Tylose 10 MHB™), hydroxypropyl cellulose (Kiucel™, Methocel'~'M, Nissa HPCTM), low substituted hydroxypropyl cellulose, hypromellose (Benecel MHPC'~'M, Methocel'~'M, " MetoloseTM, Pharmacoaf'"M, Spectracel 6'~'M, Spectracel JSTM, TylopurTivl), magnesium aluminium silicate (Carrisorb™,_Gelsorb™, MagnabiteTM, NeusilinTM, PharmsorbTM, Veegum™), maltodextrin

Documents

Application Documents

# Name Date
1 752-DEL-2015-Form-5-(19-03-2015).pdf 2015-03-19
2 752-DEL-2015-Form-3-(19-03-2015).pdf 2015-03-19
3 752-DEL-2015-Form-2-(19-03-2015).pdf 2015-03-19
4 752-DEL-2015-Form-1-(19-03-2015).pdf 2015-03-19
5 752-DEL-2015-Description (Provisional)-(19-03-2015).pdf 2015-03-19
6 752-DEL-2015-Correspondence Others-(19-03-2015).pdf 2015-03-19
7 752-del-2015-GPA-(07-08-2015).pdf 2015-08-07
8 752-del-2015-GPA-(18-03-2016).pdf 2016-03-18
9 752-del-2015-Form-5-(18-03-2016).pdf 2016-03-18
10 752-del-2015-Form-3-(18-03-2016).pdf 2016-03-18
11 752-del-2015-Form-2-(18-03-2016).pdf 2016-03-18
12 752-del-2015-Form-1-(18-03-2016).pdf 2016-03-18
13 752-del-2015-Correspondence Others-(18-03-2016).pdf 2016-03-18