Patent Application
20170119678
This patent application claims priority to Indian patent application number 3040/CHE/2014, filed on Jun. 23, 2014, the contents of which are incorporated by reference herein in their entirety.
The present invention relates to solid oral dosage forms of carvedilol or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to extended release compositions of carvedilol phosphate.
Carvedilol phosphate, a nonselective β-adrenergic blocking agent with al-blocking activity is chemically described as (2RS)-1(9H-Carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy) ethyl]amino]propan-2-olphosphate salt (1:1) hemihydrate. It is a racemic mixture with the following structure:
In the United States, Carvedilol phosphate is available as extended release capsules containing 10 mg, 20 mg, 40 mg, 80 mg carvedilol phosphate with trade name Coreg®CR by SB Pharmco.
U.S. Pat. Nos. 4,503,067 and 5,071,868, assigned to Boehringer, disclose carvedilol and its salts.
U.S. Pat. No. 6,022,562, assigned to Flamel Technologies, disclose reservoir type microcapsules comprising drug coated with a coating comprising film forming polymer, nitrogen-containing polymer, plasticizer, surface-active and/or lubricating agent.
U.S. Pat. No. 8,101,209, assigned to Flamel Technologies, claims delayed and controlled release microparticles coated with at least one hydrophilic polymer A carrying groups that are ionized at neutral pH, and at least one hydrophobic compound B.
U.S. Patent Application Publication No. 2005/0175695, assigned to GlaxoSmithKline, claims microparticle composition comprising a mixture of rapidly releasing microparticles and at least two types of controlled release microparticles.
U.S. Patent Application Publication No. 2010/0021549, assigned to Flamel Technologies, describes reservoir-type microparticles of carvedilol non-covalently combined, at least in part, with nanoparticles of at least one polyamino acid polymer, abbreviated to “POM”.
U.S. Patent Application Publication No. 2009/0220611, assigned to Flamel Technologies, describes microparticles comprising drug, coating film A and different coating film B comprising hydrophilic polymer bearing group that is ionized at neutral pH with two different triggering mechanisms of drug.
U.S. Patent Application Publication No. 2012/0245212, assigned to TSH Biopharm, disclose controlled release formulation comprising two or more subunits wherein at least one of said subunits is an immediate release carvedilol subunit and at least one of said subunits is a slow release carvedilol subunit.
There remains a need to develop alternative extended release compositions of carvedilol phosphate using simple techniques. Accordingly, inventors of the present invention have developed compositions of carvedilol phosphate that were found to be comparable with marketed Coreg CR® capsules.
The present invention relates to solid oral dosage forms comprising carvedilol phosphate and one or more pharmaceutically acceptable excipients.
The present invention particularly relates to extended release matrix compositions of carvedilol and one or more pharmaceutically acceptable excipients.
One embodiment of the present invention relates to extended release matrix composition and its dosage forms comprising carvedilol phosphate, polyethylene oxide, polyacrylic acid and one or more pharmaceutically acceptable excipients.
Another embodiment of this invention relates to extended release capsule dosage form suitable for once-daily administration comprising a plurality of mini-tablets comprising carvedilol phosphate having particle size d90 from 1 μm to 10 μm, polyethylene oxide, polyacrylic acid and one or more pharmaceutically acceptable excipients.
Yet another embodiment of the present invention provides the use of carvedilol phosphate compositions for the treatment of at least one of hypertension, heart failure and left ventricular dysfunction following myocardial infarction in a patient in need thereof.
The present invention relates to solid dosage forms comprising carvedilol phosphate and one or more pharmaceutically acceptable excipients.
The term “carvedilol” as used herein according to the present invention includes carvedilol in the form of free base or a pharmaceutically acceptable salt thereof preferably, carvedilol phosphate.
As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus for example, reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure so forth.
The term “excipient” means a pharmacologically inactive component such as a diluent, a binder, a disintegrant, a glidant, a lubricant, etc of a pharmaceutical product. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human pharmaceutical use. Reference to an excipient includes both one and more than one such excipients.
By the term “solid dosage form” or “dosage form” or “composition” as used herein refers to a solid dosage form suitable for oral administration, such as a tablet, capsule, mini-tablets, spheroids, pellets, granules, pills and the like meant for extended release.
The term “extended release” used herein refer to a dosage form that provides gradual release of carvedilol phosphate over an extended period of time.
The term “poly acrylic acid” as used herein is synonymous to “carbomer” or “carbopol”.
One embodiment of the present invention relates to extended release matrix composition and its dosage forms comprising carvedilol phosphate, polyethylene oxide, polyacrylic acid and one or more pharmaceutically acceptable excipients.
Polyethylene oxide used according to the present invention is present in an amount of from about 5% w/w to about 50% w/w based on total weight of the composition, preferably from about 10% w/w to about 40% w/w.
Polyethylene oxide used according to the present invention has a molecular weight ranging from about 10,00,000 to about 70,00,000 daltons, preferably from 40,00,000 to 70,00,000 daltons. For example, polyox grades such as WSR N-12K, WSR N-60K, WSR-301, WSR coagulant and WSR-303 (commercially available from Dow Chemical Company) can be used.
Polyacrylic acid used according to the present invention is present in an amount of from about 1% w/w to about 10% w/w preferably, from about 3% w/w to about 7% w/w selected from one or more of polyacrylic acids having viscosity ranging from 4000 to 60000 cps in 0.5% w/v solution at pH 7.5 (as per USP32-NF27) preferably from 4000 to 40000 cps.
Polyacrylic acid used according to the present invention is a combination of low and high viscosity carbopols in a ratio of from 1:0.5 to 1:5 preferably from 1:1 to 1:3. For example, carbomer grades such as carbomer 934, carbopol 974P (carbomer 934P), carbopol 971P (carbomer 941), carbomer 1342 are useful in the present invention.
Polyethylene oxide and polyacrylic acid according to the present invention are present in a ratio of from 1:0.1 to 1:1, preferably from 1:0.125 to 1:0.5.
The composition according to present invention may further comprise excipients selected from one or more of diluents, binders, disintegrants, glidants and lubricants.
Diluents: Various useful diluents include but are not limited to microcrystalline cellulose, microtine cellulose, powdered cellulose, lactose anhydrous, lactose monohydrate, dibasic calcium phosphate, tribasic calcium phosphate, starch, pregelatinized starch, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, dextrates, dextrin, dextrose, kaolin, maltodextrin, mannitol, xylitol and sorbitol and the like and combinations thereof.
Binders: Various useful binders include but are not limited to hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, pregelatinized starch, powdered acacia, gelatin, guar gum, carbomers and the like and combinations thereof.
Disintegrants: Various useful disintegrants include but are not limited to sodium starch glycolate, croscarmellose sodium, crospovidone, and the like and combinations thereof. Preferred superdisintegrant is sodium starch glycolate.
Glidants: Various useful glidants include but are not limited to colloidal silicon dioxide, other forms of silicon dioxide, such as aggregated silicates and hydrated silica, magnesium silicate, magnesium trisilicate, talc, and the like and combinations thereof.
Lubricants: Various useful lubricants include but are not limited to talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, fumaric acid, palmitic acid, sodium stearyl fumarate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols, and the like and combinations thereof.
Lubricants according to the present invention are used in an amount of from 0.5% w/w to 15% w/w based on total weight of the composition.
The composition according to the present invention is in the form of a tablet, mini-tablets, caplets, pellets, or a capsule, preferably mini-tablets.
Another embodiment of this invention relates to extended release capsule dosage form suitable for once-daily administration comprising a plurality of mini-tablets comprising carvedilol phosphate having particle size d90 from 1 μm to 10 μm, polyethylene oxide, polyacrylic acid and one or more pharmaceutically acceptable excipients.
Compositions of the present invention are prepared by direct compression technique comprising the steps of blending carvedilol phosphate, polymers and one or more other pharmaceutically acceptable excipients, compressing the blend to obtain tablets, preferably mini-tablets.
The mini-tablets according to the present invention have a diameter less than 5 mm and concavity less than 0.6 mm.
Alternatively the compositions of the present invention are prepared by wet granulation technique.
Wet granulation process comprise the steps of: (i) co-sifting and blending carvedilol phosphate along with desired intragranular excipients to form a dry mix, (ii) granulating the dry mix of step (i) using a suitable solvent(s) or a binder solution to form granules followed by drying, (iii) blending the granules of step (ii) with extragranular excipients, (iv) lubricating blend of step (iii) using suitable lubricant(s) and finally compressing the lubricated granules of step (iv) into tablets/mini-tablets of desired dimensions or filled into capsules.
The tablets or mini-tablets prepared according to the present invention are optionally coated with a film coating.
The plurality of mini-tablets prepared according to the present invention are preferably filled into capsules in an amount that shows efficacy therapeutically in a patient in need thereof.
Yet another embodiment of the present invention provides the use of carvedilol phosphate compositions for the treatment of at least one of hypertension, heart failure and left ventricular dysfunction following myocardial infarction in a patient in need thereof.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.
Comparative dissolution profile was established between marketed Coreg CR capsules and capsules of the present invention with the following attributes.
Dissolution medium: 0.1 N HCl
| Number | Date | Country | Kind |
|---|---|---|---|
| 3040/CHE/2014 | Jun 2014 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IN2015/000233 | 6/8/2015 | WO | 00 |
