DESC:FIELD OF THE INVENTION
The present invention relates to a novel sustained release composition of Clindamycin or its pharmaceutical acceptable salts.
BACKGROUND OF THE INVENTION
Clindamycin is a broad-spectrum antibiotic and antiparasitic agent. It is a semi-synthetic derivative of Lincomycin, a natural lincosamide isolated from Streptomyces lincolnensis. Clindamycin reserved for the treatment of serious infections caused by susceptible anaerobic bacteria, such as those occurring in the abdomen, gastrointestinal tract, lower respiratory tract, on the skin, and in the genitourinary area. Clindamycin acts by inhibiting bacterial protein synthesis at the level of the 50S ribosome. As a result, it exerts a prolonged post- antibiotic effect.
Clindamycin is approved by US FDA as Immediate Release capsule under the brand name Cleocin HCl® for the treatment of serious infections caused by susceptible anaerobic bacteria. Cleocin HCl® is also indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci.

The biological half-life of clindamycin is about 2.9 hours, thus necessitating frequent administration of every six hours (3–4 times a day) to maintain constant therapeutic drug levels. This frequent administration could affect the compliance, thus the efficacy of the antibiotic.

Immediate release compositions provide the drug to the patient in a manner that result in a rapid rise of the plasma drug concentration followed by a rapid decline. This sharp rise in drug concentration can result in side effects and make multiple daily administration of the drug necessary in order to maintain a therapeutic level of the drug in the body.

The need for a sustained release dosage form for drugs taken chronically such as Clindamycin Hydrochloride is self-evident. Patient compliance is greatly improved with sustained release dosage forms that are taken, for example, once or twice a day. Also, there are significant clinical advantages such as better therapeutic efficacy as well as reduced side effects with sustained-release dosage forms.

It is recognized that sustained-release preparation is advantageous to improve patient compliance, especially for elderly patients as frequent administration can be reduced by maintaining a constant plasma drug concentration over a prolonged period of time.

The drug is freely soluble in water, and hence judicious selection of release-controlling excipients is necessary to achieve a constant in vivo rate of the drug.

In the prior art, various methods are disclosed to prepare a sustained/extended release composition of the clindamycin.
US 2004/0137156 discloses a method of preparing a compressed coated tablet of Clindamycin Hydrochloride, wherein tablet is coated at least twice with a coating solution comprising a water-insoluble coating polymer and a water-soluble pore former and cured after at least the first coating step.
US 2003/0129236 discloses multiple-pulsed delivery of at least two fractions of clindamycin to a subject, one in an immediate-release form (within about 30 minutes of oral administration) and the other in an extended-release form (about 4 hours to 15 hours after oral administration).
US 2003/0133982 discloses zero-order sustained release solid dosage forms suitable for administration of water-soluble drug (Clindamycin Hydrochloride), which comprises a matrix core comprising ethylcellulose and the active agent and a hydrophobic polymer coating encasing the entire matrix core.
US 2004/0228915 discloses extended release multiparticulate tablet, comprising: a plurality of particulates, each comprising: a core comprising clindamycin and a core binder, a release rate controlling polymer coating covering the core, and a binder-dispersing agent overcoating the release rate controlling polymer coating.
CN106389389 A discloses a process for the preparation of method of clindamycin chitosan sustained-release microspheres.

Ortega E et al. Drug Res (Stuttg). 2017 Jan;67(1):32-37 discloses the extended-release formulation containing clindamycin, Hydroxypropyl methylcellulose and poloxamer or acrylic acid polymer in the ratio of 1: 0.04: 0.5 respectively.
The composition disclosed in the art used either specialized technologies or processes, like coating and curing or special excipients, like water-insoluble coating polymer. Further these processes are time consuming, requires costly equipment and/or excipients.
Still there is unmet need of a simple, economical, cost-effective method to develop the sustained release once or twice a day composition of Clindamycin.
The inventors of the present invention have developed a simple and economical composition of Clindamycin with minimum use of excipients to maintain the plasma concentration of clindamycin for at least 12- hours period.
OBJECTIVE OF THE INVENTION
The principal object of the invention is to provide a once or twice a day sustained release pharmaceutical composition comprising Clindamycin, water soluble release controlling polymer(s) and process of preparing the same using simple techniques like wet granulation.
SUMMARY OF THE INVENTION
The present invention provides a sustained release pharmaceutical composition comprising Clindamycin or its pharmaceutically acceptable salts.
The present invention provides a sustained release pharmaceutical composition comprising Clindamycin or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.
In one of the embodiments, present invention provides a sustained release pharmaceutical composition comprising Clindamycin or its pharmaceutically acceptable salts, water soluble release controlling polymers and pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 50 to 90% w/w of Clindamycin, 5 to 50% w/w of water soluble release controlling polymers and 0 to 10% of pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin, 5 to 30% w/w of water soluble release controlling polymers and 0 to 10% of pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 50 to 90% w/w of Clindamycin Hydrochloride, 5 to 50% w/w of water soluble release controlling polymers and 0 to 10% w/w of pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymers and 0 to 10% w/w of pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of Hydroxypropylmethyl cellulose and 0 to 10% w/w of pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymers and 0 to 10% w/w of pharmaceutically acceptable excipients, wherein said composition is prepared by wet granulation method.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of hydroxypropylmethyl cellulose and 0 to 10% w/w of pharmaceutically acceptable excipients, wherein said composition is prepared by wet granulation method.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin, 5 to 30% w/w of water soluble release controlling polymer, 0.1 to 3% w/w of binder, 0.5 to 10% w/w of diluent, 0 to 1 % w/w of glidant, 0 to 2 % w/w of lubricant and 0 to 2 % w/w of disintegrant.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymer, 0.1 to 3% of binder, 0.5 to 10% w/w of diluent, 0 to 1 % w/w glidant, 0 to 2 % w/w of lubricant and 0 to 2 % w/w of disintegrant.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymer, 0.1 to 3% of binder, 0.5 to 10% w/w of diluent, 0 to 1 % w/w glidant, 0 to 2 % w/w of lubricant and 0 to 2 % w/w of disintegrant, wherein said composition is prepared by wet granulation method.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymer, 0.1 to 3% of binder, 0.5 to 10% w/w of diluent, 0 to 1 % w/w glidant, 0 to 2 % w/w of lubricant and 0 to 2 % w/w of disintegrant.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymer, 0.1 to 3% of binder, 0.5 to 10% w/w of diluent, 0 to 1 % w/w glidant, 0 to 2 % w/w of lubricant and 0 to 2 % w/w of disintegrant wherein said composition is prepared by wet granulation method.
In yet another embodiment, the present invention provides a stable, sustained release pharmaceutical composition comprising Clindamycin or its pharmaceutically acceptable salts.
In yet another embodiment, present invention provides a stable, sustained release pharmaceutical composition comprising Clindamycin or its pharmaceutically acceptable salts, water soluble release controlling polymers and pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a stable sustained release composition of Clindamycin Hydrochloride wherein the stability of the composition is determined by evaluating total impurities, assay and dissolution profile at initial and at 6 months at accelerated condition such as at 40oC/75% RH (Relative Humidity).
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising Clindamycin or its pharmaceutically acceptable salts, water soluble release controlling polymers and pharmaceutically acceptable excipients, which exhibits an in vitro dissolution profile substantially corresponding to the following pattern when tested according to United States Pharmacopoeia dissolution test (900 ml of 0.1N HCl for 1 and 2 hours followed by pH 6.8 Phosphate buffer using USP apparatus II with paddle speed at 50 rpm and temperature 37°C:
• after 1 hour, not more than about 30% of the total Clindamycin or its pharmaceutically acceptable salts is released
• after 4 hour, not more than about 60% of the total Clindamycin or its pharmaceutically acceptable salts is released
• after 6 hour, not more than about 75% of the total Clindamycin or its pharmaceutically acceptable salts is released
• after 8 hour, not more than about 90% of the total Clindamycin or its pharmaceutically acceptable salts is released.
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 present invention provides a sustained release pharmaceutical composition comprising Clindamycin or its pharmaceutically acceptable salts. More specifically, the compositions of the present invention do not contain water insoluble release controlling polymers. Also, excipients used in the present compositions are of low cost, the manufacturing process is simple and less time consuming.
Water-soluble drugs can easily dissolve in water or the gastrointestinal environment and tend to be released from the formulation at once, thus being rapidly absorbed, resulting in a rapid increase in drug blood level.
When a water-soluble and short half-life drug is also a high-dose drug (for example, a drug that requires daily doses above 500 mg), the development of sustained-release oral formulations becomes even more difficult.
Clindamycin Hydrochloride is freely water soluble, has shorter half life and high dose drug (600 mg Clindamycin base). The challenge was to develop the sustained release composition of the Clindamycin Hydrochloride using water soluble polymer(s) and to maintain the appropriate size of the composition which can be easily swallowed.
Inventors of the present invention met the challenge by using Matrix technology which is simple and less time consuming process to develop sustained release composition of Clindamycin Hydrochloride with minimum use of excipients.
Unless otherwise indicated, this disclosure uses the following definitions.
As used herein the term “Clindamycin” refers to Clindamycin or its pharmaceutically acceptable salts (Hydrochloride or Phosphate), solvates, prodrugs, hydrates, enantiomers or polymorphs thereof.
The term “sustained release” includes, inter alia, extended release, delayed release, modified release, controlled release, prolonged release, programmed release or their combination, but not immediate release.
The term “% w/w” refers to % by weight of total pharmaceutical composition.
The term "comprising" means that the various components, ingredients, or steps, conjointly employed in practicing the present invention. Accordingly, the term "comprising" encompasses the more restrictive terms "consisting essentially of" and "consisting of".
The term "pharmaceutical composition" means that, pellets, beads, granules, tablets, capsules, microcapsules, tablets in capsules.
The term “stable,” as used herein, refers to chemical stability, wherein the total amount of impurities in the pharmaceutical composition remains less than about 2.0%, particularly less than about 1.5% upon storage of the composition for a period of at least 6 months at accelerated conditions.
The pharmaceutical compositions according to the present invention, includes therapeutically effective amount of Clindamycin or its pharmaceutically acceptable salts, water soluble release controlling polymer, and one or more pharmaceutically acceptable excipients selected from group consisting of diluents, binders, disintegrants, glidants and lubricants or any other excipients known in the art.
All excipients can be used at levels well known to the persons skilled in the art.
Water soluble release controlling polymers are selected from but are not limited to hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carbopols available under various grades like carbopol 71G, 934P, 971P etc., poloxamer and combinations thereof.
Hydroxypropyl methylcellulose (HPMC) or hypromellose refers to soluble methylcellulose ethers. HPMC is used as a matrix material. HPMC polymers for preparing hydrophilic matrix systems are available in various viscosity grades.
Hydroxypropyl methylcellulose available under various trade names such as METHOCEL K4M, METHOCEL K15M, METHOCEL K100M, METHOCEL E4M, Methocel K100LV, METHOCEL E50LV, METHOCEL E5, METHOCEL E15LV METHOCEL K15M CR, METHOCEL K100M CR, METHOCEL K100 LV CR and METHOCEL K4M Premium.
Diluents or fillers are selected from, but are not limited to, carbohydrates, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate or combination thereof.
Binders are selected from, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose, celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, polyvinylpyrrolidone or combination thereof.
Lubricants are selected from, but are not limited to, those conventionally known in the art such as magnesium stearate, aluminium stearate or calcium stearate or zinc stearate, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid or combinations thereof.
Glidants are selected from, but are not limited to, silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide or combinations thereof.
Disintegrants are selected from but are not limited to alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate and starches or combinations thereof.
The pharmaceutical composition may optionally be coated using coating agents, plasticizers, opacifier, colouring agent and suitable solvents known to one of ordinary skill in the art.
Through selection and combination of excipients, compositions can be provided exhibiting improved performance with respect to, among other properties, stability, compatibility of drug and excipients, safety, dissolution profile, disintegration profile and/or other pharmacokinetic, chemical and/or physical properties. Where the composition is formulated as a tablet, the combination of excipients selected provides tablets that can exhibit improvement, among other properties, in dissolution profile, hardness, crushing strength, and/or friability.
In yet another embodiment, present invention provides a stable, sustained release pharmaceutical composition comprising Clindamycin or its pharmaceutically acceptable salts, water soluble release controlling polymers and pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a stable sustained release composition of Clindamycin Hydrochloride wherein the stability of the composition is determined by evaluating total impurities, assay and dissolution profile at initial and at 6 months at accelerated condition such as at 25oC/60% Relative humidity (RH), 30oC/65% RH and 40oC/75% RH.
The total amount of impurities in the Clindamycin Hydrochloride pharmaceutical composition remains less than about 2.0%, particularly less than about 1.5% upon storage of the composition for a period of at least 6 months at accelerated conditions.
Further, there is no significant changes in the assay or dissolution of Clindamycin Hydrochloride pharmaceutical composition upon storage of the composition for a period of at least 6 months at accelerated conditions.
In another embodiment, the present invention provides a sustained release pharmaceutical composition comprising Clindamycin or its pharmaceutically acceptable salts, water soluble release controlling polymers and pharmaceutically acceptable excipients which exhibits an in vitro dissolution profile substantially corresponding to the following pattern when tested according to United States Pharmacopoeia dissolution test (900 ml of 0.1N HCl for 1 and 2 hours followed by pH 6.8 Phosphate buffer using USP apparatus II with paddle speed at 50 rpm and temperature 37°C:
• after 1 hour, not more than about 30% of the total Clindamycin or its pharmaceutically acceptable salts is released
• after 4 hour, not more than about 60% of the total Clindamycin or its pharmaceutically acceptable salts is released
• after 6 hour, not more than about 75% of the total Clindamycin or its pharmaceutically acceptable salts is released
• after 8 hour, not more than about 90% of the total Clindamycin or its pharmaceutically acceptable salts is released.
In another embodiment, the present invention provides a sustained release pharmaceutical composition comprising Clindamycin Hydrochloride, water soluble release controlling polymers and pharmaceutically acceptable excipients which exhibits an in vitro dissolution profile substantially corresponding to the following pattern when tested according to United States Pharmacopoeia dissolution test (900 ml of 0.1N HCl for 1 and 2 hours followed by pH 6.8 Phosphate buffer using USP apparatus II with paddle speed at 50 rpm and temperature 37°C):
• after 1 hour, not more than about 30% of the total Clindamycin Hydrochloride is released
• after 4 hour, not more than about 60% of the total Clindamycin Hydrochloride is released
• after 6 hour, not more than about 75% of the total Clindamycin Hydrochloride is released
• after 8 hour, not more than about 90% of the total Clindamycin Hydrochloride is released.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising Clindamycin Hydrochloride, water soluble release controlling polymers and pharmaceutically acceptable excipients which exhibits an in vitro dissolution profile substantially corresponding to the following pattern:
• after 1 hour, not more than about 20% of the total Clindamycin Hydrochloride is released
• after 4 hour, not more than about 50% of the total Clindamycin Hydrochloride is released
• after 6 hour, not more than about 65% of the total Clindamycin Hydrochloride is released
• after 8 hour, not more than about 75% of the total Clindamycin Hydrochloride is released.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising Clindamycin Hydrochloride, water soluble release controlling polymer and pharmaceutically acceptable excipients wherein, pharmaceutically acceptable excipients are selected from group consisting of diluents, binders, disintegrants, glidants and lubricants or any other excipients known in the art.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising Clindamycin Hydrochloride, water soluble release controlling polymer selected from hydroxypropylmethyl celluloses and carbopol, diluents selected from microcrystalline cellulose and lactose, binders selected from polyvinyl pyrrolidone and hydroxypropyl methyl cellulose, glidants selected from silicon dioxide and talc and lubricants selected from Magnesium Stearate and sodium stearyl fumarate and any other excipients known in the art.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 50 to 90% w/w of Clindamycin, 5 to 50% w/w of water soluble release controlling polymers and 0 to 10% w/w of pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 50 to 90% w/w of Clindamycin Hydrochloride, 5 to 50% w/w of water soluble release controlling polymers and 0 to 10% w/w of pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin, 5 to 30% w/w of water soluble release controlling polymer and 0 to 10% w/w of pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymer and 0 to 10% w/w of pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymer and 0 to 10% w/w of pharmaceutically acceptable excipients, wherein said composition is prepared by wet granulation method.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymer, 0.1 to 3% w/w of binder, 0.5 to 10% w/w of diluent, 0 to 1 % w/w of glidant, 0 to 2 % w/w of lubricant and 0 to 2 % w/w of disintegrant.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymer, 0.1 to 3% w/w of binder, 0.5 to 10% w/w of diluent, 0 to 1 % w/w of glidant, 0 to 2 % w/w of lubricant and 0 to 2 % w/w of disintegrant, wherein said composition is prepared by wet granulation method.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of hydroxypropylmethyl cellulose, 0.1 to 3% w/w of polyvinyl pyrrolidone, 0.5 to 10% w/w of microcrystalline cellulose, 0 to 1 % w/w silicon dioxide, 0 to 2 % w/w of magnesium stearate.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of hydroxypropylmethyl cellulose, 0.1 to 3% of polyvinyl pyrrolidone, 0.5 to 10% w/w of microcrystalline cellulose, 0 to 1 % w/w silicon dioxide, 0 to 2 % w/w of magnesium stearate, wherein said composition is prepared by wet granulation method.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of hydroxypropylmethyl cellulose, 0.1 to 3% of polyvinyl pyrrolidone, 0.5 to 10% w/w of microcrystalline cellulose, 0 to 1 % w/w silicon dioxide, 0 to 2 % w/w of magnesium stearate, wherein said composition is prepared by wet granulation method.
In yet another embodiment, the present invention provides a sustained release pharmaceutical composition comprising 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of hydroxypropylmethyl cellulose, 0.5 to 10% w/w of microcrystalline cellulose, 0 to 1 % w/w silicon dioxide, 0 to 2 % w/w of magnesium stearate, wherein said composition is prepared by wet granulation method.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the stable, sustained release composition of Clindamycin or its pharmaceutical acceptable salts. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES
Following examples are provided for illustration and should not be considered for limiting the scope of invention.

Example 1: Clindamycin Hydrochloride sustained release tablets:
Table 1
S.NO Ingredients %w/w
Intra-granular
1 Clindamycin Hydrochloride 80.08
2 Microcrystalline cellulose 1.14
3 Hydroxypropylmethyl cellulose (METHOCEL K100M CR) 5.78
Binder
4 Polyvinyl pyrrolidone 0.67
5 Purified water
Extra-granular
6 Hydroxypropylmethyl cellulose (METHOCEL K100M CR) 10.77
7 Colloidal silicon dioxide 0.56
8 Magnesium stearate 1
Tablet weight 100

Manufacturing procedure:
1. Clindamycin Hydrochloride, microcrystalline cellulose & hydroxypropylmethyl cellulose (METHOCEL K100M CR) were sifted through #40 mesh and dry mixed in Rapid mixture granulator.
2. Polyvinyl pyrrolidone was dissolved in purified water to produce a binder solution.
3. The dry mix of step (1) is granulated with the binder solution of step (2) and granules then dried.
4. The dried granules of step (3) were mixed with hydroxypropylmethyl cellulose (METHOCEL K100M CR) and colloidal silicon dioxide for 15 min.
5. Magnesium stearate was added to blend of step (4) and mixed for 5 min.
6. Blend of step (5) was compressed into tablets.

Example 2: Clindamycin Hydrochloride sustained release tablets:
Table 2
S.NO Ingredients %w/w
Intra-granular
1 Clindamycin Hydrochloride 72.07
2 Microcrystalline cellulose 0.73
3 Hydroxypropylmethyl cellulose (METHOCEL K100LVCR) 16.2
Binder
4 Polyvinyl pyrrolidone 0.6
5 Purified water
Extra-granular
6 Hydroxypropylmethyl cellulose (METHOCEL K100M CR) 9
7 Colloidal silicon dioxide 0.5
8 Magnesium stearate 0.9
Tablet weight 100

Manufacturing procedure:
1. Clindamycin Hydrochloride, microcrystalline cellulose & hydroxypropylmethyl cellulose (METHOCEL K100LV CR) were sifted with through #40 mesh and dry mixed in Rapid mixture granulator.
2. Polyvinyl pyrrolidone was dissolved in purified water to produce a binder solution.
3. The dry mix of step (1) is granulated with the binder solution of step (2) and granules then dried.
4. The dried granules of step (3) were mixed with hydroxypropylmethyl cellulose (METHOCEL K100M CR) and colloidal silicon dioxide for 15 min.
5. Magnesium stearate was added to blend of step (4) and mixed for 5 min.
6. Blend of step (5) then compressed into tablets.

Example 3: Clindamycin Hydrochloride sustained release tablets:
Table 3
S.NO Ingredients %w/w
Intra-granular
1 Clindamycin Hydrochloride 72.07
2 Microcrystalline cellulose 7.13
Binder
3 Hydroxypropylmethyl cellulose (METHOCEL K100LV CR) 0.3
4 Purified water
Extra-granular
5 Hydroxypropylmethyl cellulose (METHOCEL E5) 5
6 Hydroxypropylmethyl cellulose (METHOCEL K100M CR) 15
7 Magnesium stearate 0.5
Tablet weight 100

Manufacturing procedure:
1. Clindamycin Hydrochloride & microcrystalline cellulose were sifted with through #40 mesh and dry mixed in Rapid mixture granulator.
2. Hydroxypropylmethyl cellulose (METHOCEL K100LV CR) was dissolved in purified water to produce binder solution.
3. The dry mix of step (1) is granulated with the binder solution of step (2) and granules then dried.
4. The dried granules of step (3) were mixed with hydroxypropylmethyl cellulose (METHOCEL K100M CR) and hydroxypropylmethyl cellulose (METHOCEL E5) for 15 min.
5. Magnesium stearate was added to blend of step (4) and mixed for 5 min.
6. Blend of step (5) then compressed into tablets.

Example 4: Clindamycin Hydrochloride sustained release tablets:
Table 4
S.NO Ingredients %w/w
Intra-granular
1 Clindamycin Hydrochloride 72.07
2 Microcrystalline cellulose 0.73
3 Hydroxypropylmethyl cellulose (METHOCEL K100LV CR) 19.4
Binder
4 Purified water
Extra-granular
5 Hydroxypropylmethyl cellulose (METHOCEL K100M CR) 7.3
6 Magnesium stearate 0.5
Tablet weight 100

Manufacturing procedure:
1. Clindamycin Hydrochloride, microcrystalline cellulose & hydroxypropylmethyl cellulose (METHOCEL K100LV CR) were sifted with through #40 mesh and further dry mixed in Rapid mixture granulator.
2. The dry mix of step (1) is granulated with purified water and granules then dried.
3. The dried granules of step (2) were mixed with hydroxypropylmethyl cellulose (METHOCEL K100M CR) for 15 min.
4. Magnesium stearate was added to blend of step (3) and mixed for 5 min.
5. Blend of step (4) was then compressed into tablets

Example 5: Clindamycin Hydrochloride sustained release tablets:
Table 5
S.NO Ingredients %w/w
Intra-granular
1 Clindamycin Hydrochloride 71.258
2 Microcrystalline cellulose 0.748
3 Hydroxypropylmethyl cellulose (METHOCEL K100LVCR) 17
Binder
4 Polyvinyl pyrrolidone 0.6
5 Purified water
Extra-granular
6 Hydroxypropylmethyl cellulose (METHOCEL K100M CR) 9
7 Colloidal silicon dioxide 0.5
8 Magnesium stearate 0.9
Tablet weight 100

Manufacturing procedure:
1. Clindamycin Hydrochloride, microcrystalline cellulose & hydroxypropylmethyl cellulose (METHOCEL K100LV CR) were sifted with through #40 mesh and dry mixed in Rapid mixture granulator.
2. Polyvinyl pyrrolidone was dissolved in purified water to produce a binder solution.
3. The dry mix of step (1) is granulated with the binder solution of step (2) and granules then dried.
4. The dried granules of step (3) were mixed with hydroxypropylmethyl cellulose (METHOCEL K100M CR) and colloidal silicon dioxide for 15 min.
5. Magnesium stearate was added to blend of step (4) and mixed for 5 min.
6. Blend of step (5) then compressed into tablets.

In- Vitro Dissolution Data:
The sustained release tablets of Clindamycin Hydrochloride prepared as per the example 1-5 were subjected to dissolution studies in 900 ml of 0.1N HCl for 1 and 2 hours followed by pH 6.8 Phosphate buffer using USP apparatus II with paddle speed at 50 rpm and temperature 37°C. The % of Clindamycin Hydrochloride released into the solution at each time point was determined by a HPLC assay and it is presented in Table 5
Table 5
Time (hr) Drug released (%)
Example 1 Example 2 Example 3 Example 4 Example 5
1 hr- pH 1.2 17.8 23.8 18.5 28.5 19
2 hr- pH 1.2 28.9 35.4 28.8 33.3 30
3 hr- pH 6.8 39.2 50.3 39.2 44.7 42
4 hr- pH 6.8 - 59 45.1 52.2 49
6 hr- pH 6.8 - 74.1 58.5 65.4 61
8 hr- pH 6.8 - 86.3 69.2 75.8 72
10 hr- pH 6.8 75.4 96.3 76.2 85.2 81
12 hr- pH 6.8 104.3 83.5 92.8 89
18 hr- pH 6.8 90.9 - - -

It is evident from the dissolution data that a sustained release tablet prepared with water soluble release controlling polymer like hydroxypropyl methyl cellulose provides sustained release of a Clindamycin Hydrochloride for at least 12 hours.
Stability of Composition
The stability of Clindamycin Hydrochloride Sustained release tablets of example 5 stored at 400C/75% relative humidity (RH), 250C/60% (RH), 300C/65% (RH) was determined at periodic intervals over a 6-month period by determining the impurity levels and dissolution.
Impurity levels and assay were determined by HPLC method using lnertsil ODS 3V, 250x4.6mm, 5µm column (at 25oC) with PDA or UV/PDA detector and the data is presented in table 6 as a percentage of specific impurity:
Dissolution studies are carried out in 900 ml of 0.1N HCl for 1 and 2 hours followed by pH 6.8 Phosphate buffer using USP apparatus II with paddle speed at 50 rpm and temperature 37°C. Table 7 provides a dissolution data for example 5 at 6 months’ storage at accelerated conditions.
Table 6 Impurity Data (Stability)
Name of the Impurity Percentage of Impurity
250C/60% (RH) Percentage of Impurity 300C/65% (RH) Percentage of Impurity
400C/75% (RH)
Initial 6 Month Initial 6 Month Initial 6 Month
Clindamycin B 0.422 0.559 0.422 0.556 0.422 0.543
7- Epiclindamycin 0.317 0.411 0.317 0.405 0.317 0..410
Lincomycin 0.002 0.017 0.002 0.032 0.002 0.120
Any Individual Impurity 0.007
0.014 0.007
0.016 0.007
0.006
Total Impurities 0.754 1.001 0.754 1.013 0.754 1.079
Assay 95.6 106.2 95.6 106.8 95.6 103.5

Table 7: Dissolution data (stability)
Time (hr) Drug released (%)
Initial 250C/60% (RH)
6 Month 300C/65% (RH) (RH)
6 Month 400C/75% (RH)
6 Month
1 hr- pH 1.2 19 20 19 23
2 hr- pH 1.2 30 31 29 33
3 hr- pH 6.8 42 44 41 44
4 hr- pH 6.8 49 49 45 51
6 hr- pH 6.8 61 61 56 64
8 hr- pH 6.8 72 72 68 75
10 hr- pH 6.8 81 81 75 86
12 hr- pH 6.8 89 88 85 94

Based on the above stability data, it can be concluded that Clindamycin Hydrochloride Sustained release tablets as per the present invention are stable as there is no significant increase in impurities and no significant change of drug release and no significant change in assay from initial values up to 6 months storage at accelerated conditions.
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 the invention. ,CLAIMS:1. A stable, sustained release composition comprising, Clindamycin or its pharmaceutically acceptable salts, water soluble release controlling polymers and pharmaceutically acceptable excipients.
2. The stable, sustained release composition as claimed in claim 1, comprising, 50 to 90% w/w of Clindamycin or its pharmaceutically acceptable salts, 5 to 50% w/w of water soluble release controlling polymers and 0 to 10% of pharmaceutically acceptable excipients.
3. The stable, sustained release composition as claimed in claim 1, comprising, 70 to 90% w/w of Clindamycin or its pharmaceutically acceptable salts, 5 to 30% w/w of water soluble release controlling polymers and 0 to 10% of pharmaceutically acceptable excipients.
4. The stable, sustained release composition as claimed in claim 1, wherein, water soluble release controlling polymers are selected from but are not limited to hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, Carbopols available under various grades like Carbopol 71G, 934P, 971P etc., Poloxamer and combinations thereof.
5. The stable, sustained release composition as claimed in claim 1, wherein, pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, disintegrants, glidants and lubricants.
6. The stable, sustained release composition as claimed in claim 1, comprising, 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of water soluble release controlling polymer, 0.1 to 3% w/w of binder, 0.5 to 10% w/w of diluent, 0 to 1 % w/w of glidant, 0 to 2 % w/w of lubricant and 0 to 2 % w/w of disintegrant, wherein said composition is prepared by wet granulation method.
7. The stable, sustained release composition as claimed in claim 1 comprising, 70 to 90% w/w of Clindamycin Hydrochloride, 5 to 30% w/w of hydroxypropyl methyl cellulose, 0.1 to 3% of polyvinyl pyrrolidone, 0.5 to 10% w/w of microcrystalline cellulose, 0 to 1 % w/w silicon dioxide, 0 to 2 % w/w of magnesium stearate, wherein said composition is prepared by wet granulation method.
8. A stable, sustained release composition of Clindamycin or its pharmaceutically acceptable salts with water soluble release controlling polymers and pharmaceutically acceptable excipients, wherein total amount of impurities in the composition remains less than about 2.0%, particularly less than about 1.5% upon storage of the composition for a period of at least 6 months at accelerated conditions.
9. A stable, sustained release composition of Clindamycin or its pharmaceutically acceptable salts with water soluble release controlling polymers and pharmaceutically acceptable excipients, which exhibits an in vitro dissolution profile substantially corresponding to the following pattern, when tested according to United States Pharmacopoeia dissolution test (900 ml of 0.1N HCl for 1 and 2 hours followed by pH 6.8 Phosphate buffer using USP apparatus II with paddle speed at 50 rpm and temperature 37°C:
• after 1 hour, not more than about 30% of the total Clindamycin or its pharmaceutically acceptable salts is released,
• after 4 hour, not more than about 60% of the total Clindamycin or its pharmaceutically acceptable salts is released,
• after 6 hour, not more than about 75% of the total Clindamycin or its pharmaceutically acceptable salts is released,
• after 8 hour, not more than about 90% of the total Clindamycin or its pharmaceutically acceptable salts is released.
10. A stable, sustained release composition of Clindamycin Hydrochloride with water soluble release controlling polymers and pharmaceutically acceptable excipients, which exhibits an in vitro dissolution profile substantially corresponding to the following pattern when tested according to United States Pharmacopoeia dissolution test (900 ml of 0.1N HCl for 1 and 2 hours followed by pH 6.8 Phosphate buffer using USP apparatus II with paddle speed at 50 rpm and temperature 37°C:
• after 1 hour, not more than about 20% of the total Clindamycin Hydrochloride is released,
• after 4 hour, not more than about 50% of the total Clindamycin Hydrochloride is released,
• after 6 hour, not more than about 65% of the total Clindamycin Hydrochloride is released,
• after 8 hour, not more than about 75% of the total Clindamycin Hydrochloride is released.