MANDAOGADE PRASHANT MANOHAR (IN)
KADAM VINAYAK DINKAR (IN)
JAIN GIRISH KUMAR (IN)
MANDAOGADE PRASHANT MANOHAR (IN)
KADAM VINAYAK DINKAR (IN)
| US20050136107A1 |
We claim:
1. An extended release pharmaceutical composition comprising two layers wherein the first layer comprises of a) a therapeutically effective amount of clarithromycin or a pharmaceutically acceptable salt, solvate or derivatives thereof along with at least one rate controlling hydrophilic polymer having high viscosity and other suitable pharmaceutical excipients and b) the second layer comprises of a therapeutically effective amount of clarithromycin or a pharmaceutically acceptable salt, solvate or derivatives thereof along with at least one rate controlling hydrophilic polymer having low viscosity and other suitable pharmaceutical excipients.
2. A pharmaceutical composition of claim 1 , wherein the clarithromycin comprises between about 100 mg to about 1000 mg.
3. A pharmaceutical composition of claim 1, wherein the hydrophilic rate-controlling polymers comprises of polyvinylpyrrolidone, cellulose ethers, cellulose acetate, , methacrylic acid and its derivatives, vinyl acetate copolymers, vinyl ether / maleic anhydride copolymers, polyvinyl alcohol, cellulose acetate phthalates, polyvinyl acetate phthalates, polysaccharides and carbohydrate gums like xanthan gum, cross- linked polyethylene oxide, maleic anhydride / methyl vinyl ether copolymers and derivatives, solvates and mixtures thereof.
4. A pharmaceutical composition of claim 3, wherein the most preferred polymers are cellulose ethers and derivatives comprising one or more of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose and derivatives and mixtures thereof. , 5. A pharmaceutical composition of claim 1, further comprising one or more pharmaceutically acceptable excipients.
6. A pharmaceutical composition of claim 1, wherein the composition comprises a once a day formulation.
7. A pharmaceutical composition of claim 1, wherein the dosage form comprises a bilayer tablet.
8. A pharmaceutical composition of claim 1, wherein the composition is prepared by process comprising blending clarithromycin with the rate-controlling polymer and pharmaceutically acceptable excipients, granulating the blend and drying the granules and blending with lubricants and blending the same with the second layer prepared in similar manner and compressing two granule layers into a bilayer tablet.
9. The pharmaceutical composition of claim 8 as a bilayer tablet is optionally coated using suitable coating polymers. 10. Use of the pharmaceutical composition as claimed in claim 1, in the manufacture of a medicament for the treatment of bacterial diseases and related disorders. |
EXTENDED RELEASE FORMULATIONS
FIELD OF INVENTION
The present invention relates to an extended release solid pharmaceutical composition of poor to moderately soluble drugs. More preferably the pharmaceutical composition relates to an oral dosage form comprising the drug added in two granule layers, one granule layer comprising of drug and at least one rate controlling hydrophilic polymer and the said polymer having a viscosity in the range of about 100-100,000 cps; another granule layer comprising of drug with at least one rate controlling hydrophilic polymer having a viscosity in the range of about 50-100,000 cps and higher. These two granule layers are finally compressed together to yield a bilayer tablet. Suitable drugs for incorporation into the said extended release solid pharmaceutical composition include any human or veterinary drug that has poor to moderate solubility. The invention specifically includes erythromycin and/or its salts, solvates and derivatives thereof and more particularly the pharmaceutical composition comprising clarithromycin.
BACKGROUND OF THE INVENTION
Oral solid dosage forms are the preferred route for many drugs and are still the most widely used formulations for new and existing modified release (MR) products. Over many years, approaches and technologies in the area of modified release oral drug delivery have been developed to extend the release of drug over a number of hours, an effect accomplished either by combining the drug with release-retardant materials to form a matrix core, or applying release- modifying film coatings to cores containing the drug. Over the last decade, the approach to modified release oral drug delivery systems has changed from a mere line extension to a clinically superior approach for marketed drugs as well as for new chemical entities. The benefits offered by modified release systems include reduced dosing frequency with improved patient compliance, better and more uniform clinical effects with lower incidence of side effects and with possible enhanced bioavailability. The rational design of modified release systems, where biological, physicochemical and physicomechanical
considerations have been taken into account during formulation of MR dosage form, may eliminate the risk of 'dose dumping' in vivo.
Various techniques have been reported in the literature of modified ^ release systems for drugs having limited solubility. Among these, erosion of the matrix is the dominant mechanism controlling the release of water-insoluble drugs. Typically such extended release formulations allow once a day dosing.
Various prior art formulations disclose compositions arid manufacturing procedures for the formulation of controlled release dosage forms incorporating poor to moderately soluble drugs, including sustained release once a day dosage form of Clarithromycin.
US Patent No. 6,010,718 (Abbott Laboratories) describes formulations containing 5%-50% by weight of total polymer. It discloses formulations containing 10%-20% by weight of rate controlling polymer in the formulation in addition to other excipients. The rate-controlling polymer is a hydrophilic water-soluble polymer, preferably cellulose polymers.
US Patent No. 5,705,190 (Abbott Laboratories) describes controlled release compositions for poorly soluble basic drugs comprising a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid to facilitate dissolution of the basic drug at a higher pH. The examples disclosed herein describe formulations containing 10-20% w/w of rate controlling polymer.
US Patent No. 4,389,393 (Forest Laboratories, Inc.) describes sustained release therapeutic composition using less than about one third of the weight of the solid unit dosage form of a carrier base material constituted of hydroxypropyl methyl cellulose or a mixture of one or more hydroxypropyl methylcelluloses, with up to 30% by weight of certain other rate controlling polymers. The invention as described discloses sustained release solid dosage forms containing as little as 5 to about 30 weight percent of hydroxypropyl methylcellulose delivered desired results.
US Patent No. 6,673,369 (Ranbaxy Laboratories Limited) relates to a controlled release pharmaceutical composition comprising a pharmaceutically effective amount of at least one drug having a water solubility of less than one part per 30 parts and from about 0.1 to about
4.5% w/w, of one or more of rate controlling cellulose ether polymers. It describes the formulations comprising clarithromycin tablets containing about 10 % to 90 % of the clarithromycin in the compositions. The key limitation of the invention disclosed in the'369 patent is the use of high viscosity cellulosic ether polymer and these polymers have a viscosity of at least about 4,000 cps.
US Application 20050136107 (Novartis) describes an extended release clarithromycin composition comprising clarithromycin along with a polymer component in the concentration of about greater than 50 percent of total composition and the said polymer component comprises at least one hydrophilic polymer and the said polymer component has a viscosity of less than about 50 cps. The examples of the said application illustrate hydroxypropylmethyl cellulose (HPMC) as the preferred hydrophilic polymer. The viscosity of HPMC described in the examples is about 3 to about 20 cps.
US Application 20050064034 (Andrx) describes an extended release clarithromycin composition comprising clarithromycin along with at least one hydrophilic polymer having a viscosity of less than 50 cps and the second polymer having a viscosity of greater than 200 cps and wherein each polymer is independently present in an amount less than 5% or more than 50% by weight of the composition.
Despite the availability of different technologies for modified release formulations containing poorly soluble drugs, there is a clinical need for better modified release preparations with simple, stable, easily manufactured compositions giving improved patient compliance, better and more uniform clinical effects and possible enhanced bioavailability. This need is particularly more important for systems using low viscosity polymers. To this end, the present invention reports the extended release compositions of drugs having poor or moderate solubility using combination of suitable polymers with drug.
SUMMARY OF THE INVENTION
The present invention provides an extended release solid pharmaceutical composition of poor to moderately soluble drugs. The said extended release solid pharmaceutical composition comprises of clarithromycin as the preferred drug, added in two granule layers,
one granule layer comprising of drug and at least one rate controlling hydrophilic polymer and the said polymer having a viscosity in the range of about 100 -100,000 cps; another granule layer comprising of drag with at least one rate controlling hydrophilic polymer having a viscosity in the range of about 50-100,000 cps, These two granule layers are finally compressed together to yield a bilayer tablet.
Accordingly, it is an object of the present invention to provide a pharmaceutical composition for the time-specific delivery of poorly and moderately soluble drugs.
It is further object of the present invention to provide an extended release formulation to be administered once daily of drugs with poor water solubility.
The present invention, therefore also provides a pharmaceutical formulation comprising at least one poorly or moderately soluble pharmaceutically active agent alongwith suitable pharmaceutical excipients, particularly, diluents, binders, lubricants and rate controlling polymers.
Another aspect of the present invention is an extended release, solid pharmaceutical composition adapted for oral administration of once a day dosage regimen. This composition comprises of atleast one poorly or moderately soluble pharmaceutically active agent together with suitable pharmaceutically acceptable carriers or excipients thereof.
Yet, another aspect of the present invention is the use of combination of rate controlling polymers preferably in two layers having specific viscosity in the range of about 50-100,000 cps and higher and the second polymer with a viscosity in the range of about 100-100,000 cps. In other words, the invention provides an extended release, solid pharmaceutical composition comprising at least one poorly or moderately soluble pharmaceutically active agent together with rate controlling hydrophilic polymers in combination, added in two layers. The present formulation provides obvious benefits with respect to small tablets, which are easier to administer thus ensuring better patient compliance.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates dissolution profile of Clarithromycin from Clarithromycin extended release tablets (Example-1) in 0.3M Phosphate Buffer of pH 6, 900 ml, Apparatus 2, 75 rpm
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an extended release solid oral pharmaceutical composition suitable for poor to moderately soluble drugs. These drugs can be formulated into an extended release composition by manufacturing the composition in two granule layers, one granule layer comprising of drug and at least one rate controlling hydrophilic polymer and the said polymer having a viscosity in the range of about 100-100,000 cps; another granule layer comprising of drug with at least one rate controlling hydrophilic polymer and the said polymer having a viscosity in the range of about 50-100,000 cps and higher. These two granule layers are finally compressed together to yield a bilayer tablet.
The said medicament according to the present invention comprises a formulation substantially as herein described, and in particular a tablet formulation, typically an extended release tablet formulation substantially as hereinafter further described.
Suitably, a formulation according to the present invention provides an extended release tablet dosage form comprising at least one poorly water-soluble drug together with one or more hydrophilic polymers in suitable amounts within the formulation.
Suitably in pharmaceutical products or formulations according to present invention, the poorly or moderately soluble drug preferably is an erythromycin derivative, most preferably clarithromycin or its salts, solvates or derivatives thereof.
The drugs used in accordance with the present invention may be present at a dosage range of about 50-1500 mg. Clarithromycin, in particular, is known to be soluble in stomach (pH 1.2) and fairly soluble in the upper region of small intestine (pH 5.0). The solubility of this drug decreases in the lower intestine where the pH is alkaline (pH 6-8), leading to poor absorption in the region.
In a preferred embodiment of the present invention, a time-specific controlled release or sustained release formulation comprises of at lease one pharmaceutically active agent having pH-dependent solubility, which may be formulated so that the release of the drug being held significantly pH-independent throughout the environment of the gastro-intestinal tract.
hi another embodiment of the present invention, a time-specific controlled release or sustained release formulation comprises a pharmaceutically active agents (poorly soluble) alongwith suitable excipients, i.e. one or more hydrophilic polymers, hi particular, the present invention provides extended release tablet formulations comprising an extended release source of at least one poorly soluble active agent. A preferred active for use in tablet according to the present invention is clarithromycin. As such in a formulation according to the present invention, clarithromycin after oral administration can be released in a sustained manner independent of pH. It has been seen that tablets according to the present invention produce relatively uniform blood levels of clarithromycin over extended periods of therapy, suitably with oral administration at intervals of about 12-18 hours. An extended release is thus achieved by formulation substantially as hereinbefore described.
A tablet according to the present invention comprises a combination of materials, including one or more suitable diluents, polymers, binders and lubricants. The above materials are combined with poorly soluble active, such as clarithromycin in the following proportions, to achieve the beneficial steady or extended or sustained release characteristics of the present invention:
(a) 10 to 90 weight % one or more poorly soluble actives (in particular clarithromycin);
(b) 50 and above weight % one or more hydrophilic polymers (preferably having viscosity in the range of 50-100,000cps);
(c) Binders, lubricants, colorants in specific amounts, manufactured in two layers and compressed as bilayer tablet.
Suitable pharmaceutical excipients employed in a pharmaceutical formulation according to the present invention, may include any suitable pharmaceutically acceptable diluents, disintegrants, lubricants and suitable polymers.
Pharmaceutically acceptable diluents employed in a pharmaceutical formulation according to the present invention, may be, microcrystalline cellulose, powdered cellulose, lactose, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, mannitol, kaolin, sucrose derivatives and starch. A preffered diluent employed in pharmaceutical formulation according to the present invention comprises lactose and derivatives thereof.
A tablet formulation according to the present invention may include one or more hydrophillic pharmaceutically acceptable polymers, which provide additional support to the composition against any disruptive effect and controls the release of clarithromycin. The pharmaceutically acceptable polymers, in addition to their influence in controlling drug release, also provide mechanical support to the solid composition and help to maintain the physical integrity of the composition. The artisan may further select appropriate polymers, which provide the desired effect. Various polymers as appropriate for such formulations include, water soluble or water swellable polymers like polyvinylpyrrolidone, cellulose ethers, vinyl acetate copolymers, polyvinyl alcohol, polysaccharides and carbohydrate gums like xanthan gum, cross-linked polyethylene oxide, maleic anhydride / methyl vinyl ether copolymers and derivatives, solvates and mixtures thereof.
The most desired polymers for use according to the present invention include cellulose acetate, cellulose acetate phthalates, methacrylic acids, vinyl ether / maleic anhydride copolymers, polyvinyl acetate phthalates and shellac. The most preferred polymer is hydroxypropyl methylcellulose and derivatives thereof.
The present invention further comprises of other pharmaceutically acceptable excipients. The examples of suitable excipients for the present invention include talc, polyvinyl pyrrolidone, lactose, silicon dioxide (Aerosil ® ) and the like.
A tablet formulation according to the present invention may also include pharmaceutically acceptable lubricants and glidants. The artisan can select appropriate lubricants and glidants to prevent picking and sticking of the tablets to the compression tooling. Examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, calcium silicate, magnesium silicate and colloidal silicone dioxide. The most preferred pharmaceutical lubricant and glidant is magnesium stearate and talc.
The present invention further comprises a process of preparing a pharmaceutical product, or a pharmaceutical formulation, or a medicament substantially as hereinbefore described.
Suitably such a process comprises providing at least one poorly soluble drug. This drug may be formulated into an extended release composition by manufacturing the composition in two granule layers, one granule layer comprising of drug and at least one rate controlling hydrophilic polymer in the concentration of preferably about 0.1-20 % by weight of total composition and the said polymer having a viscosity in the range of about 100-100,000 cps; another granule layer comprising of drug with at least one rate controlling hydrophilic polymer in the concentration of preferably about 40-60% by weight of total composition and the said polymer having a viscosity in the range of about 50-150 cps along with other pharmaceutical excipients as hereinbefore described. These two granule layers are finally compressed together to yield a bilayer tablet.
The present invention will now be further illustrated by the following examples, which do not limit the scope of the invention in any way.
EXAMPLES Example-1
Extended release tablets were prepared using the following materials in the stated quantities:
Procedure:
1. Mix ingredients no. 1-3 in RMG
2. Dissolve Povidone K-30 in purified water
3. Granulate the blend of step 1 using binder solution of step 2 in suitable granulator
4. Dry the granules, size and lubricate using ingredients 5-7
5. Mix the ingredients 8-14
6. Compress the blend of step 4 and 5 to get the bilayered tablet
7. Prepare aqueous dispersion of Opadry and coat the tablets to achieve desired coat build up. The dissolution profile in pH 6.0 phosphate buffer at 75 rpm using USP apparatus 2 is as shown in figure- 1.
Example-2
Extended release tablets were prepared using the following materials in the stated quantities:
Procedure:
1. Mix ingredients no. 1-3 in RMG
2. Dissolve Povidone K-30 in purified water
3. Granulate the blend of step 1 using binder solution of step 2 in suitable granulator
4. Dry the granules, size and lubricate using ingredients 5-10
5. Mix the ingredients 11-13
6. Granulate the blend of step 5 using binder solution in suitable granulator and dry the granules
7. Compress the blend of step 4 and 6 to get the bilayered tablet
8. Prepare aqueous dispersion of Opadry and coat the tablets to achieve desired coat build up.
Example-3
Extended release tablets were prepared using the following materials in the stated quantities:
Procedure:
1. Mix ingredients no. 1-3 in RMG
2. Dissolve Povidone K-30 in purified water
3. Granulate the blend of step 1 using binder solution of step 2 in suitable granulator
4. Dry the granules, size and lubricate using ingredients 5-10
5. Mix the ingredients 11-13
6. Granulate the blend of step 5 using binder solution in suitable granulator and dry the granules
7. Compress the blend of step 4 and 6 to get the bilayered tablet
8. Prepare aqueous dispersion of Opadry and coat the tablets to achieve desired coat build up.