PHARMACEUTICAL COMPOSITIONS FOR EXTENDED RELEASE
INTRODUCTION TO THE INVENTION
The present invention relates to pharmaceutical compositions for the extended release of drug substances, processes for preparing the same and methods of use and treatment.
Beta-adrenergic receptor blocking agents cause a reduction of cardiac inotropism and chronotropism. Beta-adrenergic receptor blocking agents include, but are not limited to, the drugs atenolol, betaxolol, acebutolol, bisoprolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol.
Metoprolol succinate is chemically (±) 1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt), with the structural Formula I. It is useful in the treatment of hypertension, angina pectoris and heart failure. It is commercially available in extended release tablets under the brand name TOPROL-XL™, manufactured by AstraZeneca.

Formula I Propranolol is a beta-adrenergic receptor-blocking agent and has the chemical name 1-(lsopropyl amino)-3-(1-naphthyloxy)-2-propanol, with the structural Formula II. It is used as antihypertensive. It is commercially available in the form of the hydrochloride salt as 60 mg, 80 mg, 120 mg and 160 mg sustained-release capsules under the trade name INDERAL™ LA, manufactured by Wyeth-Ayerst.


U.S. Patent Application Publication No. 2005/0008701 discloses a controlled release pellet comprising an inert core that is water-soluble or water swellable layered with a beta adrenergic blocking agent and a controlled release coating surrounding the drug layer. The patent application claims the controlled release coating comprising of a water-insoluble or slightly water permeable polymer.
U.S. Patent Application Publication No. 2004/0126427 discloses an extended release pharmaceutical multi-particulate dosage form comprising immediate release (IR) beads and sustained release (SR) beads or SR beads without IR beads, wherein said SR and IR beads comprise a core particle comprising propranolol or a pharmaceutical^ acceptable salt. Also the dosage form comprise of sustained release membrane comprising a water insoluble polymer or a combination of a water insoluble polymer and a water-soluble polymer. The patent also discloses the dissolution profile of the dosage form.
U.S. Patent No. 6,500,454 describes a pharmaceutical dosage form comprising timed-sustained release (TSR) beads, wherein said TSR beads comprise a core particle comprising propranolol or a pharmaceutical^ acceptable salt thereof, a first membrane comprising ethylcellulose surrounding said core to sustain drug release and a second outer membrane comprising a mixture of ethylcellulose and an enteric polymer.
Hence, there is a need for pharmaceutical compositions for the extended release of beta-blockers comprising more than one portion, wherein each portion has different release pattern and combining the portions so as to give consistent dissolution profile required for once or twice a day administration.

Thus, the development of pharmaceutical compositions as described in context of the present invention would be a significant improvement in the field of clinical practice.
SUMMARY OF THE INVENTION
An embodiment of the present invention relates to pharmaceutical compositions for the extended release of beta-blockers or their pharmaceutical^ acceptable salts, solvates, enantiomers, polymorphs or mixtures thereof, processes for preparing the same and methods of use and treatment.
In an aspect, the present invention relates to pharmaceutical compositions for the extended release of beta-blockers comprising more than one portion, wherein each portion has a different release pattern.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical compositions for the extended release of drug substances, such as beta-blockers or their pharmaceutically acceptable salts, solvates, enantiomers, polymorphs or mixtures thereof, processes for preparing the same and methods of use and treatment.
An embodiment of the present invention relates to pharmaceutical compositions for the extended release of beta-blockers comprising more than one portion, wherein each portion has a different release pattern.
In the present invention different release patterns of each portion of composition is achieved by means of formulating the active substance using matrix or reservoir or combination of matrix-reservoir principles and each portion further may be presented as monolithic or as multi particulate compositions.
Matrix portions of compositions of the present invention may be prepared by direct blending, dry granulation or wet granulation of active substance with one or more rate controlling substances and they are filled into capsules or

compressed as tablets or layered on to inert beads and further such beads are filled into capsules or compressed as tablets.
Reservoir portions of compositions of the present invention may be prepared by coating the powders or granules or pellets or tablets or cores with one or more rate controlling substances and they may be filled into capsules.
The pellets or cores that can be used include but are not limited to: water-soluble beads such as sugar spheres, lactose and the like; and water-insoluble beads such as microcrystalline cellulose, silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like. Active substance may be layered on to the inert core or mixed with core forming materials and made as drug containing core.
Matrix-reservoir portions of compositions of the present invention may be prepared by first preparing the matrix portion as mentioned in the previous paragraphs and subsequently coating the matrix composition with one or more rate controlling substances.
Rate and extent of release of active substance from the portion of the composition depends on the type and amount of rate controlling substance used, the type of composition used and the process used to prepare the composition.
Two or more different compositions having different release patterns are selected to prepare the final composition.
Ratios of active substance to the rate controlling substance may vary from 1:50 to 50:1, or 1:25 to 25:1.
Rate controlling substances that can be included are but not limited to: hydrophilic substances such as carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC); homopolymers or copolymers of N-vinylpyrrolidone; vinyl and acrylic polymers; polyacrylic acid and the like; hydrophobic substances such as celluloses like ethyl cellulose, low substituted hydroxyl propyl cellulose (L-HPC), cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate; polyalkyl methacrylates; polyalkyl

acrylates; polyvinyl acetate (PVA); chitosan; crosslinked vinylpyrrolidone polymers; hydrogenated castor oil and the like. Other classes of rate controlling substances or their mixtures in various ratios as required are also within the purview of this invention without limitation.
According to the present invention, the ratio of the hydrophilic to hydrophobic rate controlling substance can range from 1:5 to 5:1, or from 1:3 to 3:1, or from 1:2 to 2:1.
In the present invention during the preparation of matrix or reservoir compositions or during converting these portions into final formulation, one or more pharmaceutical^ acceptable excipients may optionally be used. These pharmaceutical^ acceptable excipients may include but are not limited to diluents such as microcrystalline cellulose (MCC), silicified MCC (e.g. Prosolv™ HD 90), microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like; binders such as acacia, guar gum, alginic acid, dextrin, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methylcellulose (e.g. METHOCEL®), carboxymethylcellulose sodium, povidone (various grades of KOLLIDON®, PLASDONE®) starch and the like; disintegrants such as carboxymethyl cellulose sodium (e.g. Ac-Di-Sol®, Primellose®), crospovidone (e.g. Kollidon®, Polyplasdone®), povidone K-30, polacrilin potassium, starch, pregelatinized starch, sodium starch glycolate (e.g. Explotab®) and the like; surfactants which can include anionic surfactants such as chenodeoxycholic acid, 1-octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxycholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium cholate hydrate, sodium lauryl sulfate (SLS) and sodium dodecyl sulfate (SDS); cationic surfactants such as cetylpyridinium chloride monohydrate and hexadecyltrimethylammonium bromide; nonionic surfactants such as N-decanoyl-N-methylglucamine, octyl a-D-glucopyranoside, n-Dodecyl b-D-maltoside (DDM), polyoxyethylene sorbitan esters like polysorbates and the

like; plasticizers such as acetyltributyl citrate, phosphate esters, phthalate esters, amides, mineral oils, fatty acids and esters, glycerin, triacetin or sugars, fatty alcohols, polyethylene glycol, ethers of polyethylene glycol, fatty alcohols such as cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol and the like.
Solvents that may be used in granulation or layering or coating include but are not limited to: aqueous solvents such as water; organic volatile solvents such as acetaldehyde, acetone, benzene, carbon disulphide, carbon tetrachloride, 1,2 dichloroethane, dichloromethane, N, n-dimethylformamide, 1,4-dioxane, epichlorhydrin, ethyl acetate, ethanol, ethyl ether, ethylene glycol, 2-ethoxyethanol (acetate), formaldehyde, isopropanolol, methanol, methyl n-butyl ketone, methyl ethyl ketone, 2-methoxyethanol (acetate), perchloroethylene, toluene, 1,1,1-trichloroethane, trichloroethylene; and the like.
In an embodiment, water is used along with one or more organic volatile solvents in the coating, which gives a consistent dissolution profile thus providing batch-to-batch reproducibility.
Further, water along with one or more organic volatile solvents can be used in various ratios as required within the purview of this invention without limitation.
Pharmaceutical compositions of the present invention may further include other ingredients, such as but not limited to pharmaceutical^ acceptable glidants, lubricants, opacifiers, colorants and other commonly used excipients.
In one embodiment of the invention, beta-blocker compositions having two or more portions wherein each portion has different release pattern are prepared by mixing a beta-blocker with suitable pharmaceutical excipient and a solvent or solvent mixture or solvent containing binder to form a dough-like mass and this mass is extruded to get small particles that are further rounded using a spheronizer, rounded particles are dried using suitable techniques at a desired temperature, then dried particles are milled and sifted through a desired mesh sieve. Part of a fraction retained between two sieves is further coated with a solvent dispersion of rate controlling substances with or without a plasticizer

using techniques known in the art; other parts of a fraction retained between two sieves are coated with a solvent dispersion with different concentrations of coating materials to get varied coating buildup. These coated fractions are mixed in a specific ratio and filled into capsules to get the desired release profile.
In another embodiment of the invention, propranolol hydrochloride compositions having two portions wherein each portion has different release pattern are prepared by mixing propranolol with microcrystalline cellulose and water to make a dough-like mass and this mass is extruded to get small particles that are further rounded using a spheronizer, rounded particles are dried using a fluid bed drier at a temperature of about 60°C, dried particles are sifted through an ASTM 14 mesh sieve and an ASTM 20 mesh sieve. Part of the fraction retained between these two sieves is further coated with an organic solvent dispersion of hydroxypropyl methylcellulose, ethyl cellulose and acetyl tributyl citrate in a fluid bed processor, and another part of the fraction retained between the two sieves is coated with an organic solvent dispersion having a different concentration of coating materials to get additional coating buildup. These two fractions are mixed in a predetermined ratio and filled into hard gelatin capsules to get a product having the desired release profile.
The pharmaceutical compositions of the present invention can also be manufactured as described below. The granules or cores can be prepared by sifting the active and excipients through the desired mesh size sieve and then mixed using a rapid mixer granulator, planetary mixer, mass mixer, ribbon mixer, fluid bed processor or any other suitable device. The blend can be granulated by dry or wet granulation. In wet granulation, the granulate can be dried using a tray drier, fluid bed drier, rotary cone vacuum drier and the like. The dried granulate particles are sieved and then mixed with lubricants and disintegrants and compressed into tablets or filled into capsules.
Further, the manufacture of granules may be done by direct compression with the use of directly compressible excipients using a suitable device, such as a multi-station rotary machine to form compressed slugs or by roller compaction

to form slugs, which are passed through a multimill, fluid energy mill, ball mill, colloid mill, roller mill, hammer mill and the like, equipped with a suitable screen. The milled slugs are then lubricated and compressed into tablets or pellets and are coated with a rate controlling substance. Coated pellets are further filled into capsules or compressed as tablets or minitablets, which are optionally further coated and then are filled into capsules.
The pharmaceutical compositions as disclosed in context of the present invention are used in the treatment of hypertension.
The following examples will further illustrate certain aspects and embodiments of the invention in greater detail and are not intended to limit the scope of the invention.
EXAMPLES
Example 1
Compositions for propranolol extended release capsules


Manufacturing process for portion A:
a) Core preparation
1. Propranolol hydrochloride and Avicel were sifted through an ASTM 20# mesh sieve.
2. The mixture of step 1 was loaded to rapid mixer granulator and mixed for 10 minutes.
3. The blend of step 2 was granulated with water to form a wet mass.
4. The wet mass of step 3 was extruded using 1 mm roller.
5. The extruded mass was spheronized for 10 minutes at 750 rpm.
6. The pellets obtained of step 5 were dried in fluid bed dryer at 60°C till loss on drying (LOD) at 105 °C was less than 1.5 % w/w.
7. The pellets were segregated having a size between an ASTM 14# mesh sieve and an ASTM 20# mesh sieve.
b) Extended release coating preparation
8. Isopropyl alcohol and methylene chloride were mixed together.
9. Ethyl cellulose, HPMC and acetyl tributyl citrate were added to step 8 solvent mixtures with stirring for 20 minutes to get a clear polymer solution.
10. The core pellets of step 7 were loaded in a fluid bed processor and coated with the solution of step 9 to a desired weight build-up of 3-8% w/w.
Similarly, cores of portion B were prepared similar to the cores of portion A; these cores are coated in the same manner in step 10 except that the coating buildup was 7-17% w/w.

c) Blending and capsule filling
11. A dissolution test was performed on Portion A and Portion B pellets separately to calculate the proportion of each part to be mixed together to get a desired dissolution profile.
12. A 37.5 : 62.5 ratio of Portion A and Portion B was blended in a double cone blender for 10 minutes.
13. Finally, the blend of step 12 was filled into hard gelatin capsules.
Example 2 Dissolution study of Example 1
• Medium and duration of study: pH 1.2 buffer for 1.5 hours followed by pH 6.8 phosphate buffer up to 24 hours
• Apparatus: USP 1 (Basket type)
• Volume: 900 ml
• rpm: 100

Example 3 Compositions for propranolol extended release capsules


Manufacturing process:
Same as Examplel except for not using acetyl tributyl citrate. Also, after the step 7 of Examplel, 40 kg of pellets were taken which were equivalent to 24 kg of propranolol hydrochloride and were further processed as per Example 1.
Two batches A and B were prepared using the composition of Example 3 and their % drug release showed variability over a 24 hour time period.
Dissolution profile:
• Medium and duration of study: pH 1.2 buffer for 1.5 hours followed by pH 6.8 phosphate buffer up to 24 hours
• Apparatus: USP 1 (Basket type)
• Volume: 900 ml
• rpm: 100

I _l I I I
Example 4 Compositions for propranolol extended release capsules

Manufacturing process:
Same as Example 3 except for the use of water in the coating solvent mixture.

Two batches C and D were prepared using the composition of Example 4 and their % drug release showed less variability over a 24 hour time period as compared to Example 3, which does not contain water in its coating composition.
Dissolution profile:
• Medium and duration of study: pH 1.2 buffer for 1.5 hours followed by pH 6.8 phosphate buffer up to 24 hours
• Apparatus: USP 1 (Basket type)

• Volume: 900 ml
• rpm: 100

Claims
1. A pharmaceutical dosage form having particles comprising a drug substance and a coating, where a coating on at least one portion of particles has a greater thickness than a coating on another portion of particles.
2. The pharmaceutical dosage form of claim 1, wherein a coating is formed from a composition comprising: a hydrophilic substance, a hydrophobic substance, or a mixture thereof; an organic solvent; and water.
3. The pharmaceutical dosage form of claim 1, wherein a coating is formed from a composition comprising a hydrophilic substance, a hydrophobic substance, an organic solvent, and water.