WO2008126098A1

WO2008126098A1 - Extended release pharmaceutical formulation of propranolol hydrochloride

Info

Publication number: WO2008126098A1
Application number: PCT/IN2007/000244
Authority: WO
Inventors: Nagesh Nagaraju; Satya Sankar Sahoo; Balaram Mondal; Gour Mukherji
Original assignee: Jubilant Organosys Limited
Priority date: 2007-04-12
Filing date: 2007-06-18
Publication date: 2008-10-23

Abstract

Disclosed herein an extended release pharmaceutical formulation of the propranolol hydrochloride comprising a core and an extended release coating on said core wherein said core comprising said propranolol hydrochloride and one ore more pharmaceutically acceptable excipients and coating comprising extended release polymers in an amount of about 1 to about 5% by weight based on the total weight of the core.

Description

EXTENDED RELEASE PHARMACEUTICAL FORMULATION OF PROPRANOLOL HYDROCHLORIDE

Field of the Invention This invention, in general relates to a pharmaceutical formulation of Propranolol salts. More particularly, the present invention provides an extended release pharmaceutical formulation of Propranolol hydrochloride and a process for preparing the same.

Background of the Invention Propranolol [l-(isopropyl amino)-3-(l-naphthyloxy)-2-propanol] is a beta-adrenergic blocking agent and as such is a competitive inhibitor of the effects of catecholamines at beta-adrenergic receptor sites. Propranolol and its pharmaceutically acceptable salts are described in US patent 3,337,628. Propranolol hydrochloride is mainly used in the treatment of the hypertension, cardiac arrhythmias and angina pectoris because of its β- adrenergic blocking activity. Propranolol hydrochloride is also used in the treatment of migraine and anxiety. It will be appreciated by those skilled in the art that extended release formulation in the form of capsules, tablets or any other convenient dosage forms are preferred over conventional formulations because of the ability of the former to maintain effective blood levels over extended period of time, for optimal therapy.

Extended release formulations reduce the frequency of dosing thereby resulting in better patient compliance. They also minimize the severity and frequency of adverse effects of an active pharmaceutical agent, as they maintain the constant blood levels and avoid crests and troughs associated with treatment with the conventional immediate release formulations. In order to avoid the problem of blood level fluctuations associated with the conventional immediate release formulations and for better patient compliance, Wyeth pharmaceuticals Inc, have marketed its propranolol extended release capsules "Inderal LA^®" to be administered once a day.

In its US Patent No. 4,13.8,475; Wyeth has discloses a composition for the extended release formulation containing 5 to 15 % by weight of extended release polymer. The specification and examples of the said patent suggests that the preferred formulations are obtaining by coating one or more extended release polymers in an amount of 9- 10% by weight.

US Application No. 2006/0099258 discloses a controlled-release propranolol formulation comprise a core -comprising a pharmaceutically acceptable propranolol salt and a sugar sphere and a coating disposed on the core, wherein the coating is done by 10 to 17 % by weight of the control release polymer.

A major drawback of propranolol is because of its extensive metabolism, little unchanged active material reaches the systemic circulation after oral administration. Additionally, plasma levels of propranolol show a large patient-to-patient variation. ,

Achieving extended release of the drug by coating the enteric coating materials as described in US Pat No. 4,248,856 allows the tablet to pass unchanged through the stomach and disintegrate in^x the intestinal tract but such enteric-coated tablets often suffer from the disadvantage¹ of not providing a uniform and constant drug release. Further, the enteric coating materials are more susceptible to hydrolysis or become soluble at a pH greater than 5. In certain instances, plasticizers are used in such coatings so as to minimize the hardening of particular coating thereby increasing the amount of the coating materials in the formulation.

The extended release of the drug can also be achieved by use of hydrogels as described in US Pat No. 7,189,414, wherein the hydrogels have the character to form gels that have the ability to expand or contract in response to a specific stimulus, such as light, temperature or pH\_v Typically, such hydrogels will precipitate in solution or collapse with concomitant expulsion of gel pore contents. In some cases, these processes are reversible. The swelling property exhibited by said hydrogel disrupts the continuity of the tablet structure and thus, allows the different components to enter into solution or into suspension.

As propranolol hydrochloride is highly soluble in water, a high amount of extended release polymer is required to achieve an extended once daily formulation. The use of high amount of extended release polymer in the pharmaceutical formulation for achieving such result has a possibility of producing toxic effects on the long-term therapy. Further, the high amount of said polymers makes the process tedious increasing the processing time, thereby elevating the production cost. Due to the high solubility and first pass effect of propranolol hydrochloride, it is very difficult to formulate a meaningful extended release formulation of propranolol hydrochloride. Because of the above-mentioned problems very few extended release formulations of propranolol hydrochloride has been approved by US-FDA.

Therefore by the aforementioned facts, there exists a need for an extended release pharmaceutical formulation of propranolol hydrochloride avoiding the drawbacks associated with the prior arts. Accordingly the present invention provides a pharmaceutical formulation with a desired extended release formulation comprising propranolol hydrochloride using a low amount of extended release polymers.

Summary of the Invention

In accordance with principal aspect of the present invention there is provided an extended release pharmaceutical formulation comprising propranolol hydrochloride or its other pharmaceutically acceptable salts wherein said formulation provides a desired extended release of the drug, lowering the incidence of possible toxic effects of the polymers when used in a long term therapy.

In accordance with another aspect of the present invention there is provided a cost efficient process to .prepare an extended release pharmaceutical formulation comprising propranolol hydrochloride or its other pharmaceutically acceptable salts.

It is yet another aspect of the present invention to provide an extended release pharmaceutical formulation of propranolol hydrochloride comprising a core containing propranolol hydrochloride and one or more pharmaceutically acceptable excipients, and an extended release coating over said core comprising extended release polymers in an amount of about 1 % to about 5 % by weight based on the total weight of the core, wherein said core is essentially free of rate controlling polymer. It is still another aspect of the present invention to provide an extended release pharmaceutical formulation of propranolol hydrochloride comprising a core and an extended release coating on said core wherein the formulation exhibits desired dissolution profile and pharmacokinetic result of the propranolol hydrochloride, thereby providing the desired extended release pharmaceutical formulation.

It is yet another aspect of the present invention to provide an extended release pharmaceutical formulation of propranolol hydrochloride comprising a core and an extended release coating on said core comprising extended release polymers in an amount of about 1 % to about 5 % by weight based on the total weight of the core thereby lowering the incidence of possible toxic effects of the polymers when used in a long term therapy.

It is still another aspect of the present invention to provide an extended release pharmaceutical formulation of the propranolol hydrochloride comprising a core containing propranolol hydrochloride and one or more pharmaceutically acceptable excipients and an extended release coating on said core wherein said pharmaceutically acceptable excipients comprising diluents in an amount of about 20% to about 60% and binders in an amount of about 0.5% to about 5%.

It is further aspect of the present invention to provide an extended release pharmaceutical formulation of the propranolol hydrochloride suitable for once a- day dosing of the propranolol ' hydrochloride in the treatment of various clinical indications like hypertension, angina pectoris, migraine, hypertrophic subaortic stenosis.

It is another aspect of the present invention to provide a cost efficient process for preparing an extended release pharmaceutical formulation of the propranolol hydrochloride comprising a core and an extended release coating on said core wherein said coating comprises of extended release polymers in an amount of about 1 % to about 5 % by weight based on the total weight of the core wherein the low amount of said extended release polymers minimizes the production cost by lowering the processing time and solvents quantity used for dissolving or dispersing the coating materials.

It is yet another aspect of the invention to provide a cost efficient process for preparing an extended release pharmaceutical formulation of the propranolol hydrochloride comprising a core and an extended release coating on said core wherein said core in the form of spheroids and wherein said spheroids prepared by extrusion- spheronization or drug layering on NPS (non pareil seeds).

It is still another object of the present invention to provide a process for preparation of an extended release pharmaceutical formulation of the propranolol hydrochloride comprising the steps of blending the propranolol hydrochloride and one or more diluents in a suitable blending equipment; granulating the resultant blend with aqueous / non aqueous solution of binder; subjecting the granulated wet mass to form an extrudate; spheronizing the extrudate to form spheroids or spheroids; drying the spheroids; coating the spheroids with extended release coating wherein coating comprises of extended release polymers in an amount of about 1 % to about 5 % by weight based on the total weight of the core, and filling the coated spheroids in a suitable size capsule.

Brief Description of the Drawings

The accompanying drawings, which are included to provide a further understanding of the invention and constitute a part of this specification

Figure 1 is a graph illustrating the release over time of propranolol into the bloodstream for formulation of Example 2 (Test formulation), denoted by symbol •; and release over time of propranolol into the bloodstream for Inderal LA® (Reference formulation), denoted by symbol D.

Figure 2 illustrates the concentration of the 4-hydroxypropranolol in the bloodstream with respect to time from formulation of Example 2 (Test formulation), denoted by symbol •; and concentration of the 4-hydroxypropranolol in bloodstream with respect to time from Inderal LA® (Reference formualtion), denoted by symbol α. Detailed Description of the Invention

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The term "extended release polymer" as used herein means a single polymer or copolymer or a combination of one or more polymers, which extend the release of the propranolol hydrochloride of the formulation provided by the present invention over an extended period of time, i.e. 24 hours, and includes controlled release and sustain release wherein said extended release polymers are used only in the coating of the extended release formulation in an amount ranging from about 1 to 5% by weight based on the total weight of the core.

The term "dissolution profile" as used herein denotes the cumulative amount of propranolol hydrochloride released as a function of time. The dissolution profile is characterized by the test conditions selected such as apparatus type i.e. USP type I or USP type II, formulation, temperature, pH and volume of the dissolution medium.

As used herein "bioequivalent" denotes that the formulation of the present invention when tested in normal healthy individuals results in Cmax and AUC, which are within the interval of 80-125%, when compared with Inderal LA^®, a marketed product.

As used herein "about" means leverage to the numerical range endpoint and can be considered ±10% to the end point values.

The present invention provides an extended release pharmaceutical formulation of the propranolol hydrochloride domprising a core comprising propranolol hydrochloride, a diluent and a binder and an extended release coating on the said core wherein the coating comprises of extended release polymers in an amount of from about 1 to about 5% by weight based on the total weight of the core. More preferably the coating comprises from about 2 to about 4 % by weight of the extended release polymers. Said coating surrounds the core.

Applicants have surprisingly found that the pharmaceutical formulation comprising a core containing propranolol hydrochloride, a diluent and a binder and an extended release coating comprises about 1 to about 5% by weight based on the total weight of the core is able to extend the release of the drug from the core for about 24 hours and able to produce an desired extended release of the drug.

The desired release of the drug from the formulation exhibits no significant difference in the dissolution profiles and the pharmacokinetic results when compared with that of the marketed product "Inderal LA , thus bioequivalent to the marketed product.

The present invention necessarily avoids the use of any extended release polymers in the core of the formulation thereby preventing any control of drug release from the core.

Core

Core of the formulation of the invention is comprised of propranolol hydrochloride, diluent, and binder. The propranolol hydrochloride is used in an amount from about

15 % to about 15 % by weight based on the total weight of the core. Preferably, propranolol hydrochloride is^used in an amount from about 20 % to about 60 % by weight based on the total weight of the core. The amount of propranolol hydrochloride in the formulation of the invention varies from 50 to 200 mg, preferably from about 60 to 160 mg. The core of the formulation of the invention is

, preferably in the form of spheroids.

Suitable diluent is used in an amount from about 20 % to about 60 % by weight based on the total weight of the core. Selective diluent is characterized by non-swelling property or less swelling property in acidic and aqueous medium. Preferably, from about 30 % to 40 % by weight based on the total weight of the core. The unlimited examples of diluents include microcrystalline cellulose, powdered cellulose, dibasic calcium phosphate, starch, lactose and mannitol and combinations thereof. Most preferably the diluent is microcrystalline cellulose. Microcrystalline cellulose is insoluble in dilute acids and water, but soluble in alkaline solutions with slight swelling.

Suitable binder of the present invention is used in amount from about 0.5 % to about 5 % by weight based on the total weight of the core wherein said amount is used in a manner that does not affect the hydration of the core. Preferably, from about 1 % to about 3 % by weight based on the total weight of the core. Suitable examples of binders include polyvinylpyrrolidone, polyvinylalcohol, hydroxypropyl methylcellulose starch paste, hydroxypropylcellulose and combinations thereof. The preferred binder is hydroxypropylcellulose (HPC).

i HPC chemically is partially substituted poly (hydroxypropyl) ether of cellulose. HPC is commercially available _y from Aqualon under the brand name Klucel^®. Klucel is available in different viscosity grades, which is graded in terms of its molecular weight. Various Grades of Klucel commercially available are Klucel EF, Klucel LF, Klucel JF, Klucel GF, and Klucel MF. Klucel EF having molecular weight of about 80,000 is the preferred HPC for the formulation of the invention. A 2 % aqueous solution of Klucel EF has a viscosity of 7mPas.

Core in the form of spheroids can be preferably produced by extrusion- spheronization or drug layering on NPS (non pareil seeds). i The core of the formulation of the present invention can be prepared by blending propranolol hydrochloride « with diluents and subsequently, granulation with an aqueous or non - aqueous bύider solution followed by extrusion — spheronization. Alternatively the core can be formed by spraying a solution or a suspension of propranolol hydrochloride and binder in a suitable aqueous / non-aqueous solvent on the inert sugar spheres or any other suitable types of non-pareil seeds. The spraying can be carried out in fluid bed processor or any other suitable equipment. The blending and granulation can be carried out in high shear granulators like RMG or any other granulating equipment.

The preferred process for the preparation of core is extrusion- spheronization.

Preferred process for the preparation of core by extrusion- spheronization comprises the steps of blending propranolol hydrochloride with one or more diluent in a suitable blending equipment, granulating the resultant blend with aqueous / non aqueous solution of binder, passing the granulated wet mass to form an extrudate, spheronizing the extrudate to form spheroids and drying the so formed spheroids.

Extended release coating

The extended release coating is mainly comprises of extended release polymers, which extend the release of propranolol hydrochloride from the core, and optionally other pharmaceutically acceptable excipients, which helps in coating process and improves quality of the coating. The extended release coating comprises extended release polymers in an amount of from about 1 to about 5% by weight based on the total weight of the core. More preferably, extended release coating comprises extended release polymers in an amount of from about 2 to 4 % by weight based on the total weight of the core. '

The extended release polymers of the present invention are selected from one or more of non-enteric film forming materials, which are capable of substantially, protecting the core during its passage from the stomach to the intestines and also providing the required extended release of propanol hydrochloride from core. Non-enteric film forming materials useful for this purpose includes a water-soluble polymer and one a water insoluble water permeable polymer.

The suitable examples of water -insoluble, water permeable polymers include but are not limited to, ethyl cellulose, propyl cellulose, and copolymers of methacrylates, acrylates and methacrylic acid. The amount of water -insoluble, water permeable polymer in the extended release coating is from about 50% to about 80% by weight based on the total weight of the extended release coating formulation, preferably, from about 55 % to about 78 % by weight based on the total weight of the extended release coating formulation. The preferred water -insoluble, water permeable polymer for use in the extended- release coating of the invention is ethyl cellulose. Ethyl cellulose is non -ionic, pH insensitive, film forming, cellulose ether, insoluble in water but soluble in polar "organic solvents. It is available in a wide range of viscosities and ethoxyl contents from Aqualon, USA. For example ethyl cellulose is available as TlO, N7, NlO, N14, N22, N50, and NlOO types. The preferred ethyl cellulose for the extended release coating is N50, which has a viscosity in the range of 40- 52 cps (based on 5% solution of ethyl cellulose in 80/20 mixture of toluene/ethanol). Ethoxyl content of N50 type of ethyl cellulose lies in the range of 48-0 to 49.5% by weight.

Water-soluble polymer is used in an amount from about 20% to about 50 % by weight based on the total weight of the extended release coating formulation, preferably, from about 22 % to about 45 % by weight based on the total weight of the extended release coating composition. Water-soluble polymer used for the extended release coating is selected from the group comprising hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, polyvinyl alcohol, hydroxyethyl methylcellulose and sodium carboxy methylcellulose. A combination of water-soluble polymer may be used. The more preferred water-soluble polymers include hydroxypropyl methylcellulose and hydroxypropyl cellulose. The most preferred water-soluble polymer is hydroxypropyl cellulose. Hydroxypropyl methylcellulose used in the extended release coating is available in different viscosity grades such as those available under the brand name Methocel® available. The preferred ones are those having viscosity 5 to 50 cps when determined on the basis of 2 % by weight aqueous solutions. Examples of such grades are Methocel E5 (5cps), Methocel El 5 (15cps) and Methocel F50 LV (50cps). Similarly low viscosity hydroxypropyl methylcellulose is commercially available from Shin-Etsu chemical company, Japan under the brand name Pharmacoat 603 (3 cps), Pharmacoat 606(6cps), Pharmacoat 615(15cps).

The extended release coating of the present invention may optionally contain plasticizers, colorants and polar or non-polar organic solvents to dissolve or disperse the polymers. Examples of such solvents include water and isopropyl alcohol. Suitable examples of plasticzers and colorants are all those known to the person skilled in the art. Low amount of the coating materials reduces the quantity of solvents for dissolving or dispersing the polymers, thereby reducing the production i cost.

Extended release coating of spheroids can be carried in any suitable coating equipment but preferably coating is carried in fluid bed processor fitted with a Wurster apparatus of suitable size. The coated spheroids are filled into suitable size capsules. i The formulation of the present invention are prepared as a solid dosage form suitable for oral administration of propranolol hydrochloride for once a day dosing, for the treatment of various USFDA approved indications like hypertension, cardiac arrhythmias, angina pectoris and migraine. Preferred solid dosage form include spheroids or spheroids filled in a capsule.

The following non-limiting examples illustrate further aspects of the invention.

Example 1 to 4

The presented examples describe an extended release formulation of propranolol hydrochloride made using different percentages of extended release coating.

Table 1.1

Formulation of exl to ex 4 are presented in table 1.1

*Evaporates while processing,

Procedure: (Example 1 to 4) 1. Propranolol hydrochloride & macrocrystalline cellulose were sifted through a suitable size sieve and blended together.

2. The blend of step (1) was granulated with the aqueous solution of hydroxypropyl cellulqse.

3. Wet mass of step (2) was extruded through radial extruder.

4. Cylindrical extrudate of step (3) were spheronized with the help of spheronizer to produce spheroids.

5. The content of step (4) was dried in a suitable drier.

6. The dried spheroids were coated with the above-mentioned extended release coating formulation in fluid bed processor.

Dissolution study

In- vitro dissolution study of the above mentioned formulation (ex.l- 4) and Inderal^® LA was carried according to¹ United States Pharmacopoeia dissolution test method for propranolol hydrochloride extended release capsules. The conditions of experiment are as follows:

Apparatus: USP Type I, Basket type@ lOOrpm,

Dissolution Media: 900 ml of pH1.2 buffer for 1.5 hours followed by testing in 900ml of pH 6.8 at 4,8,14, 24 hrs.

Temperature of dissolution Media: 37⁰C.

Table 1.2

Results of dissolution study

The dissolution results for the formulation of example 2 with only 3.39 % of the extended release coating polymers were able to control the release of the highly soluble propranolol hydrochloride over an extended period of time and the dissolution profile substantially corresponds to that of Inderal^® LA.

Pharmacokinetic study

The pharmaceutical formulation of example 2, was subjected to bioavailability studies against extended release formulation of propranolol hydrochloride 160 mg, commercially available from Wyeth Pharma under the brand name "Inderal^® LA".

A randomized, open label, two sequence, two treatment, two period, single dose,

1 crossover bioavailability on propranolol hydrochloride oral extended release formulation (capsule filled with coated spheroids, test formulation [TF]) of example 2 administered once daily with "Inderal^® LA" 160 mg (reference formulation [RF]) in overnight fasting 12 healthy, adult, male human subjects. The results of study in terms of pharmacokinetic parameters are summarized in table 2 below. The US-FDA approved testing centre carried out the study.

Table2 Pharmacokinetic results \

The data mentioned above shows that formulation of present invention (example 2) containing only 3.39 % of the extended release coating polymers can unexpectedly and surprisingly produce a bioequivalent formulation [as stipulated by the US FDA (Health and Medicine Regulatory Agency of USA) guidelines on bioequivalence] to "Inderal^® LA", which is made by using substantially higher quantities of extended release coating.

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations, would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

Claims

We Claim:

1. An extended release pharmaceutical formulation of propranolol hydrochloride comprising: a core comprising propranolol hydrochloride and one or more pharmaceutically acceptable excipients, wherein said core is essentially free of rate controlling polymer; and an extended release coating layer coated over said core comprising extended release polymers in an amount of about 1 % to about 5 % by weight based on the total weight of the core.

2. The pharmaceutical formulation according to claim 1, wherein said propranolol hydrochloride is used in an amount of from about 15 % to about 75 % by weight based on the total weight of the core.

3. The pharmaceutical formulation according claim 2, wherein said propranolol hydrochloride is preferably used in an amount from about 20 % to about 60 % by weight based on the total weight of the core.

4. The pharmaceutical formulation according to claim 1, wherein said pharmaceutically acceptable excipients are selected from diluents and binders.

5. The pharmaceutical formulation according claim 4, wherein said diluent is selected from the group comprising microcrystalline cellulose, powdered cellulose, dibasic calcium phosphate, starch, lactose or mannitol.

6. The pharmaceutical formulation according claim 5, wherein said diluent is preferably microcrystalline cellulose.

7. The pharmaceutical formulation according claim 4, wherein said diluent is used in an amount of about 20 % to about 60 % by weight based on the total weight of the core.

8. The pharmaceutical formulation according claim 4, wherein said binder is selected ; from the group comprising of polyvinylpyrrolidone, polyvinylalcohol, hydroxypropyl methylcellulose starch paste or hydroxypropylcellulose.

9. The pharmaceutical formulation according claim 8, wherein said binder is preferably hydroxypropylcellulose.

10. The pharmaceutical formulation according claim 4, wherein said binder is used in an amount of about 0.5 % to about 5 % by weight based on the total weight of the core.

11. The pharmaceutical formulation according claim 1, wherein said extended release coating comprises from about 50 % to about 78 % by weight of water insoluble, water permeable polymers and about 22 % to about 50% by weight of water soluble polymers.

12. The pharmaceutical formulation according claim 11, wherein said water insoluble, water permeable polymer is ethyl cellulose.

13. The pharmaceutical formulation according claim 11, wherein said water-soluble polymer is hydroxy propyl methylcellulose.

14. The pharmaceutical formulation according claim 1, wherein said extended release polymers are preferably used in an amount of from about 2.5 % to about 4 % by weight based on the total weight of the core.

15. The pharmaceutical formulation according claim 1, wherein said formulation is in the form of spheroids filled into capsules.

16. The pharmaceutical formulation according claim 1, wherein said formulation is prepared by a process comprising: blending the propranolol hydrochloride and one or more diluent in suitable blending equipment; granulating the resultant blend with aqueous / non aqueous solution of binder; subjecting the granulated wet mass to form an extrudate; spheronizing the extrudate to form spheroids; drying the so formed spheroids; coating the spheroids with extended release coating wherein said coating comprises of extended release polymers in an amount of from about 1 % to about 5 % by weight based on the total weight of the core; filling the coated spheroids in a suitable size capsule.