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 |