Field of the invention

The technical field of the present invention relates to modified release dosage form of p-blocker. The present invention also relates to a process for the preparation of modified release dosage form of p-blocker.

Background of the invention

p-blockers are widely used for the treatment of hypertension and cardiovascular diseases. Various P-blockers are available in the market include propranolol, metoprolol, carvedilol, atenolol, betaxolol, acebutolol, bisoprolol, labetalol, nadolol, pindolol, sotalol and timolol as immediate release or sustained release dosage forms. However, sustained release formulations are desirable as they can achieve better control of hypertension for a longer period of time compared to immediate release formulations, which require multiple dosings daily.

Propranolol chemically known as 1 -(Isopropyl amino)-3-( 1 -naphthyloxy)-2-propanol, is commercially available as 60 mg, 80 mg, 120 mg and 160 mg extended-release capsules under the trade name Inderal® LA (Wyeth) and 80 and 120 mg extended-release capsules under the trade name Innopran® XL (Reliant Pharms) and is indicated for the management of hypertension, angina pectoris and migraine.

Numerous techniques are known in the prior art for preparing sustained or controlled release dosage forms of p-blockers such as matrix based systems as disclosed in US 4,138,475, US 4,428,926, US 4,522,804, US 4,556,678, US 6,465,014, US 2006/0182806, US 2007/0202162, encapsulating plurality of beads/pellets with various diffusion barriers as disclosed in US 4,898,737, film coating onto the surface of core as disclosed in US 4,248,856, drug layering or pelltization as disclosed in US 4,927,640, US 4,957,745, US 5,149,542, US 6,500,454, US 7,022,342, US 7,314,640, US 2004/0126427, US 2006/0099259, WO 2005/084636 and WO 2005/123045 which are discussed in brief below.

US 4,138,475 discloses sustained release composition containing film-coated spheroids comprising propranolol and microcrystalline cellulose.

US 4,248,856 discloses sustained release composition comprising compressed core containing propranolol and cellulose polymers and seal coating surrounding the core and then sugar coating over the seal coated core.

US 4,428,926 discloses dosage form comprising a matrix core containing propranolol and a coating containing polyvinyl alcohol and polyethylene glycol.

US 4,522,804 discloses constant order release rate formulation comprising propranolol, microcrystalline cellulose, hydrogenated vegetable oil, acrylic acid polymer, silicon dioxide and lubricant.
US 4,556,678 discloses sustained release tablet comprising propranolol, hydroxypropylmethylcellulose, hydroxypropyl cellulose and lubricant.

US 4,898,737 discloses controlled release pellet comprising a core of propranolol, organic acid and a polymer and multi-layer membrane surrounding said core.

US 4,927,640 and US 4,957,745 disclose controlled release preparation comprising a plurality of beads coated with metoprolol, permeable polymeric membrane surrounding [each said bead, wherein the coating consisting , essentially of ethylcellulose or a mixture of ethylcellulose and hydroxypropylmethylcellulose.

US 5,149,542 discloses composition comprising inert material, drug layer over the inert material and a coating membrane comprising a mixture of stearic acid and ethylcellulose or of paraffin and methacrylic acid copolymers applied upon drug layer.

US 6,465,014 discloses a sustained release composition comprising drug, sodium alginate and propylene glycol alginate.

US 6,500,454 discloses dosage form comprising timed, sustained release beads comprising a core particle comprising propranolol a first membrane comprising ethylcellulose,and a second outer membrane comprising a mixture of ethylcellulose and an enteric polymer.

US 7,022,342 discloses controlled release dosage form comprising a core consisting of propranolol, sugar spheres, microcrystalline cellulose and ethylcellulose and coating consisting of a mixture of ethylcellulose, hydroxypropylmethylcelliilose, acetyl tributyl citrate and talc over the core.

US 7,314,640 disclose a controlled release pellet comprising water swellable inert core, a drug layer comprising metoprolol succinate, binder and surfactant applied on to the inert core and a controlled release coating surrounding the drug layer.

US 2004/0126427 discloses extended release pharmaceutical multiparticulate dosage form comprising immediate release (IR) beads and sustained release beads, wherein said IR beads comprise a core particle comprising a nonpareil seed coated with propranolol in a polymeric binder and SR beads comprise a core particle comprising a non-pareil seed coated with propranolol in a polymeric binder and a membrane comprising a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer.

US 2006/0099259 discloses composition comprising a core comprising propranolol disposed on an inert core and a coating comprising of ethylcellulose and polyvinylpyrrolidone or ethylcellulose and hydroxypropylmethylcellulose disposed on the core.
US 2006/0182806 discloses extended-release pharmaceutical composition comprising a core comprising propranolol and coating comprising at least one water-soluble polymer and at least one water-insoluble polymer being applied on to the core.

US 2007/0082050 discloses a modified release dosage formulation comprising propranolol, a release-modifying coat comprising a mixture of a water-impermeable polymer and a water-swellable polymer applied over the core.

US 2007/0202162 discloses composition comprising a plurality of particles comprising propranolol and at least one pharmaceutical excipient, a fraction of particles being coated to obtain an extended propranolol release profile and another fraction of particles being coated to obtain a different extended propranolol release profile.

US 2008/0187579 discloses formulation comprising sustained release particles having an inner core bead comprising propranolol, an intermediate coating substantially surrounding said inner core bead, and an outer pH independent polymer coating substantially surrounding said intermediate coating.

WO 2005/084636 discloses an oral controlled-release pharmaceutical composition comprising water soluble, water swellable or water-insoluble inert core; drug layer comprising metoprolol; and polymeric coatings surrounding the drug layer.

WO 2005/123045 discloses a compressed tablet of a pharmaceutical compound which comprises uncoated pellets containing a pharmaceutical compound, said pellets being dispersed in a matrix which comprises said pellets and a swellable polymer.

WO 2008/126098 discloses an extended release formulation comprising: a polymer coated spheroid core comprising propranolol hydrochloride and one or more pharmaceutically acceptable excipients, wherein said core is essentially free of extended release polymers.

The above prior art references discloses controlled release formulations of (3-blockers using different techniques. However, there exists a need for better approaches which could be easily manufactured. Hence, the inventors of present invention have endeavored to develop efficient and cost effective method of preparation of drug formulations which provide a rapid onset and a prolonged action of (3-blocker with the presence of both sustained release and initial quick release coat on the same core.

Objective of the invention

Accordingly, the main objective of the present invention is to provide modified release dosage form of p- blocker.

Yet another objective of the present invention is to provide modified release dosage form of p- blocker in such a way that it will comply with the reference product in terms of in vivo parameters like Cmax, tmax, AUC and in vitro parameters like dissolution etc.

Yet another objective of the present invention is to provide process for the preparation of modified release dosage form of p- blocker.

Summary of the invention

Accordingly, the main embodiment of the present invention is to provide a modified release oral dosage form comprising:

(a) core comprising a p-blocker and at least one pharmaceutical excipient,

(b) modified release coating surrounding the core comprising an effective
amount of modified release polymer and

(c) an immediate release coating layer over the modified release coat comprising
p-blocker, wherein the p-blocker present in the core and coating is same.

Detailed description of the invention

In one embodiment, the core may be in the form of spheroids/granules/minitablets/tablet.
The dosage form of the present invention provides an initial quick release of p-blocker and later sustained release of p-blocker from the polymer coated core.

In another embodiment, p-blocker include propranolol, metoprolol, metoprolol, carvedilol, atenolol, betaxolol, acebutolol, bisoprolol fumarate, labetalol, nadolol, pindolol, and sotalol and their pharmaceutically acceptable salts thereof.

The pharmaceutical excipient used in the core of the present invention is selected from diluent, binder and lubricant.

In another embodiment, the core comprising p-blocker can be prepared either by extrusion-spheronisation or by granulation.

Suitable diluents used according to the present invention are selected from sucrose, dextrose, lactose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose and the like or combination thereof. The amount of diluent may range from about 30% to 45% w/w.

Suitable binders used according to the present invention are selected from the group comprising of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pregelatinized starch and the like.

Suitable lubricants used according to the present invention are selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like.

The release of p-blocker from the core is effectively controlled by using suitable modified release polymers such as methylcellulose, ethylcellulose (commercially available as Surelease®, Ethocel®), hydroxypropylcellulose (Klucel®), carboxymethylcellulose and its salts (Nymcel®), hydroxypropylmethylcellulose (Methocel®), polyvinylalcohols, polyoxyethylene glycols, polyethylene oxide, povidone (Kollidon®, Plasdone®), copolymers of polyvinyl alcohol and polyvinyl pyrrolidone (Kollicoat ), acrylic acid copolymers (Eudragit®), carbopol, xanthan gum, alginates and its salts and the like or combination thereof. The amount of polymer may range from about 2% to about 20% w/w.

The quantity of coating to be applied on the core to give the desired release characteristics depend on the type of polymer and amount of polymer build up on the core. The amount of modified release coat applied onto the cores ranges from about 80 % into about 98% preferably 88% to about 95% and the amount of immediate release coat ranges from 2% to about 20% based on the percentage of drug present in the core and immediate release portion.

In another embodiment, immediate release layer comprising p-blocker further comprises one or more of binder, plasticizer and solubilizer.

Suitable solubilizing agent of the present invention is selected from anionic or non-ionic surfactants such as sodium lauryl sulphate, polyethylene-propylene glycol copolymer (Poloxamer), polyoxyethylene stearates (Macrogol-stearate), polysorbates, propylene glycol, polyvinyl alcohol and the like or mixtures thereof Suitable plasticizers used according to the present invention are selected from diethyl phthalate, di butyl phthalate, cetyl alcohol, polyethylene glycol-4000, triethyl citrate, triacetin, propylene glycol and the like.

In another embodiment, there is provided a process for the preparation of a modified release oral dosage form comprising:

(a) core comprising a p-blocker and at least one pharmaceutical excipient,

(b) modified release coating surrounding the core comprising an effective
amount of modified release polymer and

(c) an immediate release coating layer over the modified release coat comprising
p-blocker, wherein the p-blocker present in the core and coating is same, comprising the steps of:

(i) granulating p-blocker and diluent,

(ii) extruding the granulated mixture to obtain extrudates,

(iii) spheronizing the extrudates to obtain spherical cores,

(iv) drying the spheroid cores,

(v) preparing the solution/dispersion of modified release polymer in a solvent,

(vi) coating the spheroid cores with solution/dispersion of step (v) and curing the
coated spheroids,

(vii) preparing the solution/dispersion of p-blocker in a solvent,

(viii) coating the polymer coated cores with solution/dispersion of step

(vii) and

(ix) filling the spheroids in capsules or compressing into tablets.

In yet another embodiment, there is provided an alternate process for the preparation of a modified release oral dosage form comprising:

(a) core comprising a p-blocker and at least one pharmaceutical excipient,

(b) modified release coating surrounding the core comprising an effective
amount of modified release polymer and

(c) an immediate release coating layer over the modified release coat comprising
p-blocker, wherein the p-blocker present in the core and coating is same,
comprising the steps of:

(i) granulating p-blocker and diluent, (ii) drying the granules of step (i),

(iii) lubricating the dried granules of step (ii),

(iv) compressing the lubricated granules of step (iii) using 4 mm SC punches
into minitablets,

(v) preparing the solution/dispersion of modified release polymer in a solvent,

(vi) coating the tablets of step (iv) with solution/dispersion of step (v),

(vii) preparing the solution/dispersion of p-blocker in a solvent,

(viii) coating the polymer coated tablets with solution/dispersion of step (vii) and
(ix) filling the tablets of step (viii) in capsules.

The coating layers over the core may be applied as solution/dispersion of coating ingredients.

Suitable solvents used according to present invention include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water, and the like or combination thereof.
In a preferred embodiment, modified release dosage form comprises:

(a) core comprising propranolol hydrochloride and at least one pharmaceutical
excipient,

(b) modified release coating surrounding the core comprising an effective
amount of modified release polymer and

(c) an immediate release coating layer over the modified release coat comprising propranolol hydrochloride.

The amount of propranolol present in the core may range from about 20% to about 90% w/w and the amount of propranolol present in second layer may range from about 0.5% to about 20% w/w.

In another preferred embodiment, modified release dosage form comprises:

(a) core comprising about 25% to 75% w/w of propranolol hydrochloride and 30% to about 45% w/w of diluent selected from macrocrystalline cellulose, sucrose;

(b) modified release coating surrounding the core comprising about 2% to about 20% w/w of modified release polymer selected from ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose or combination thereof; and

(c) an immediate release coating layer over the modified release coat comprising about 0.5%o to about 20% w/w of propranolol hydrochloride and binder selected from hydroxypropylmethylcellulose, pregelatinized starch.

The modified release dosage form prepared according to present invention exhibits the following dissolution profile when measured in a type 1 dissolution apparatus (Basket) at 100 rpm, at a temperature of 37± 0.5°C, in 900 ml of pH 1.2 buffer solution for 1.5 hours, followed by 900 ml of pH 6.8 phosphate buffer:

i. not more than about 30% of total propranolol is released after 1.5 hours of measurement;

ii. not more than about 50% of total propranolol is released after 4 hours of measurement;

iii. from about 55 to about 80% of total propranolol is released after 8 hours of measurement,

iv. from about 70 to about 95% of total propranolol is released after 14 hours of measurement, and

v. not less than about 81 to about 110% of total propranolol is released after 24 hours of measurement.

In yet another embodiment, the modified release dosage form of the present invention may be in the form of tablet or capsule.

In yet another embodiment, the present invention also provides method of treating hypertension, angina, and migraine by administering modified release dosage form prepared according to present invention,

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1: Propranolol hydrochloride Modified Release capsules

The processing steps involved in manufacturing propranolol modified release
capsules as given in example 1 are given below:

(i) propranolol and microcrystalline cellulose was sifted and blended,
(ii) granulated the blended material of step (i) with water,

(ii) the granulated mixture was extruded to obtain extrudates,

(iii) the extrudates were then spheronised to obtain spherical cores,

(iv) the spheroid cores were dried,

(v) a solution/dispersion of ethylcellulose and hydroxypropylmethylcellulose in
a mixture of isopropyl alcohol, dichloromethane and water was prepared,

(vi) the spheroid cores of step (iv) were coated with the solution / dispersion of
step (v),

(vii) propranolol hydrochloride was dissolved in a mixture of isopropyl alcohol
and water,

(viii) hydroxypropylmethylcellulose was dispersed in step (vii) solution,

(ix) polymer coated spheroids of step (vi) was then coated with dispersion of
step (viii) and

(x) the spheroids of step (ix) were then filled in capsules.

Example 2: Propranolol hydrochloride Modified Release capsules
The processing steps involved in manufacturing propranolol modified release
capsules as given in example 2 are given below:

(i) propranolol and microcrystalline cellulose was sifted and blended,

(ii) granulated the blended material of step (i) with water,

(iii) the granules obtained in step (ii) were dried,

(iv) lubricated the granules of step (iii) with magnesium stearate,

(v) the lubricated blend was compressed using 4 mm SC punches into
minitablets,

(vi) a solution/dispersion of ethylcellulose and hydroxypropylmethylcellulose in
a mixture of isopropyl alcohol and dichloromethane was prepared,

(vii) the tablets of step (v) were coated with the solution / dispersion of step (vi),

(viii) propranolol hydrochloride was dissolved in a mixture of isopropyl alcohol
and water,

(ix) hydroxypropylmethylcellulose was dispersed in step (viii) solution,

(x) polymer coated tablets of step (vii) was then coated with dispersion of step

(ix) and

(xi) the tablets of step (x) were then filled in capsules.

The compositions described in example 3-8 were prepared using the procedure similar to the one described in example 2.

Example 3: PropranoloPhvdrochloride Modified Release capsules

Example 4: Propranolol hydrochloride Modified Release capsules

Example 5: Propranolol hydrochloride Modified Release capsules

Example 6: Propranolol hydrochloride Modified Release capsules

Example 7: Propranolol hydrochloride Modified Release capsules

Example 8: Propranolol hydrochloride Modified Release capsules

The dissolution profile of the modified release capsules of propranolol prepared according to the present invention was carried out in 900 ml of pH 1.2 buffer solution for 1.5 hours, followed by 900 ml of pH 6.8 phosphate buffer as medium according to the procedure described in the USP, Apparatus USP I,

Basket, @ 100 rpm speed. The release profile (% of drug released in hours) is given in tables 1-2.

Claims:

1. A modified release oral dosage form comprising:

(a) core comprising a p-blocker and at least one pharmaceutical excipient,

(b) modified release coating surrounding the core comprising an effective
amount of modified release polymer and

(c) an immediate release coating layer over the modified release coat comprising
P-blocker, wherein the p-blocker present in the core and coating is same.

2. The dosage form of claim 1, wherein the p-blocker is selected from propranolol, metoprolol, metoprolol, carvedilol, atenolol, betaxolol, acebutolol, bisoprolol fumarate, labetalol, nadolol, pindolol, and sotalol and their pharmaceutically acceptable salts thereof.

3. The dosage form of claim 1, wherein the excipient is selected from diluent, binder and lubricant.

4. The dosage form of claim 3, wherein the diluent is selected from sucrose, dextrose, lactose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose.

5. The dosage form of claim 1, wherein the modified release polymer is selected from methylcellulose, ethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and its salts, hydroxypropylmethylcellulose, polyvinylalcohols, polyoxyethylene glycols, polyethylene oxide, povidone, copolymers of polyvinyl alcohol and polyvinyl pyrrolidone, acrylic acid copolymers, carbopol, xanthan gum, alginates and its salts or combination thereof.

6. A modified release dosage form comprising:

(a) core comprising propranolol hydrochloride and at least one pharmaceutical
excipient,

(b) modified release coating surrounding the core comprising an effective
amount of modified release polymer and

(c) an immediate release coating layer over the modified release coat comprising propranolol hydrochloride.

7. A modified release dosage form comprising:
(a) core comprising about 25% to 75% w/w of propranolol hydrochloride and 30% to about 45% w/w of diluent selected from microcrystalline cellulose, sucrose;

(b) modified release coating surrounding the core comprising about 2% to about 20% w/w of modified release polymer selected from ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose or combination thereof; and

(c) an immediate release coating layer over the modified release coat comprising about 0.5% to about 20% w/w of propranolol hydrochloride and binder selected from hydroxypropylmethylcellulose, pregelatinized starch.

8. A process for the| preparation of a modified release oral dosage form
comprising:

(a) core comprising a p-blocker and at least one pharmaceutical excipient,

(b) modified release coating surrounding the core comprising an effective
amount of modified release polymer and

(c) an immediate release coating layer over the modified release coat comprising
p-blocker, wherein the p-blocker present in the core and coating is same,
comprising the steps of:

(i) granulating p-blocker and diluent,

(ii) extruding the granulated mixture to obtain extrudates,

(iii) spheronizing the extrudates to obtain spherical cores,

(iv) drying the spheroid cores,

(v) preparing the solution/dispersion of modified release polymer in a solvent,

(vi) coating the spheroid cores with solution/dispersion of step (v) and curing the
coated spheroids,

(vii) preparing the solution/dispersion of p-blocker in a solvent,

(viii) coating the polymer coated cores with solution/dispersion of step (vii) and (ix) filling the spheroids in capsules or compressing into tablets.

9. A process for the preparation of a modified release oral dosage form
comprising:

(a) core comprising a p-blocker and at least one pharmaceutical excipient,

(b) modified release coating surrounding the core comprising an effective
amount of modified release polymer and

(c) an immediate release coating layer over the modified release coat comprising
p-blocker, wherein the p-blocker present in the core and coating is same,
comprising the steps of:

(i) granulating p-blocker and diluent,

(ii) drying the granules of step (i),

(iii) lubricating the dried granules of step (ii),

(iv) compressing the lubricated granules of step (iii) into minitablets ,

(v) preparing the solution/dispersion of modified release polymer in a solvent,

(vi) coating the tablets of step (iv) with solution/dispersion of step (v),

(vii) preparing the solution/dispersion of p-blocker in a solvent,

(viii) coating the polymer coated tablets with solution/dispersion of step (vii) and

(ix) filling the tablets of step (viii) in capsules.

10. The dosage form according to previous claim(s) wherein the solvent is
selected from methylene chloride, isopropyl alcohol, acetone, methanol, ethanol,
water or combination thereof.