A PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS OF NATEGLINIDE
Technical Field of the Invention
The present invention relates to a stable dosage form of Nateglinide with enhanced dissolution profile and a process of preparation thereof.
Background of the Invention
Nateglinide is an amino acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. It is widely indicated as monotherapy to lower blood glucose in patients with Type 2 diabetes. It is also indicated for use in combination with Metformin.
Nateglinide is insoluble in water. This physical property creates unpredictable dissolution rates, which lead to absorption problems.
U.S. Patent No. 5,463,116 describes a method for producing a crystalline form of Nateglinide having improved stability over the B-type crystals. B-type crystals suffer from problems of instability especially when subjected to mechanical grinding or pulverization. This instability results in the conversion of B-type crystals into other forms.
U.S. Patant No. 6,559,188 describes compositions of Nateglinide or a pharmaceutically acceptable salt thereof wherein lactose and microcrystalline cellulose are used as fillers alone or in combination. The final formulation is formed without a pulverization step.
The most common approach used to address the problem of poor solubility is by reducing the drug's particle size or micronizing the drug to a size of few microns. These strategies increase the effective surface area of nateglinide and thus improving the solubility. Dosage forms containing micronized drug particles exhibit enhanced solubility and consequently an improved bioavailability. Highly micronized drug particles possess poor flow properties and increased chances of re-agglomeration during processing. In few cases, re-agglomeration of micronized drug particles may be so problematic that the essential concept of enhancing the solubility by increasing the effective surface area is defeated.
In the present invention we have found that when Nateglinide is co-sifted and/or co-milled with pharmaceutical inert carriers, these inert carriers give a "cushioning effect" to Nateglinide, which leads to stable dosage forms with an enhanced dissolution profile. Finely milled particles possess a high surface energy and charge on them. A pharmaceutical inert carrier helps in neutralizing the surface charge by providing a layer between two particles and thereby separating them. This separation of particles leads to an increase in surface area and improved dissolution.
Summary of the Invention
Detailed Description of the Invention
The term 'Nateglinide' as used herein includes Nateglinide base as well as pharmaceutically acceptable salts thereof, in crystalline or amorphous form. In particular, the composition comprises the B- or H-type crystal modification of Nateglinide, more particularly the B-type with a particle size of d90
The term "pharmaceutically inert carrier" refers to a substance, which is physiologically acceptable and compatible with the drug and other excipients in the dosage form and has a large surface area for drug particle adsorption. By virtue of such adsorption, the effective surface area exposed to the dissolution media is increased many fold, which thereby increases the rate of dissolution. Such adsorption of the drug on the carrier surface also prevents the re-agglomeration of drug particles due to neutralization of surface charges on the drug particles generated during milling, by an inert carrier. Carriers also help in the wetting of a drug. These carriers improve the uptake of water by capillary action, thereby enhancing the drug's dissolution rate. Further, these carriers also form a layer around the drug which provides a "cushioning effect". Due to this layer around the drug, the drug remains stable even upon the application of external stress. The ratio of Nateglinide to the pharmaceutically inert carriers may be in the range of about 10: 1 to about 1:2.
Suitable pharmaceutically inert carrier include one or more of silicate derivatives such as, magnesium silicate, colloidal silicon dioxide, magnesium trisilicate, magnesium aluminium silicate; cellulose derivatives such as, microcrystalline cellulose, carboxymethylcellulose; and clays such as, veegum, bentonite and mixtures thereof. For
example, colloidal silicon dioxide may be used alone or in combination with other cellulose derivatives.
The process of co-milling of Nateglinide and pharmaceutically inert carriers may be carried out in one or more conventional milling instruments including air jet mill, multi mill, ball mill or any other method of particle attrition. For example, the process of co-milling Nateglinide with colloidal silicon dioxide may be carried out in an accelerated air-jet mill.
The process of co-sifting Nateglinide with colloidal silicon dioxide may be carried out by mixing and co sifting repeatedly till a uniform mixture is formed.
The co-sifted and/or co-milled mixture of Nateglinide and pharmaceutically inert carriers may be further processed with pharmaceutically acceptable excipients into various dosage forms including one or more of tablets, capsules, and pills. These dosage forms, may be made by one or more of comminuting, mixing, granulation, melting, sizing, filling, drying, molding, immersing, coating, and compressing.
Pharmaceutical compositions of Nateglinide may be prepared by the process of blending co-sifted and/or co-milled mixtures with one or more pharmaceutically acceptable excipients; wet granulating the blend with a granulating fluid or solution/dispersion of pharmaceutically acceptable excipients in the granulating fluid; drying and sizing the granules; and compressing the granules into tablets or filling into capsules.
Pharmaceutical compositions of Nateglinide may also be prepared by the process of blending the co-sifted and/or co-milled mixture with one or more pharmaceutically acceptable excipients; dry granulating the blend with a roller compactor or slugging; drying and sizing the granules; and compressing the granules into tablets or filling into capsules.
Pharmaceutical compositions of Nateglinide Form B, which have a particle size of d90 <45um, may be prepared by the process of blending the co-sifted and/or co-milled mixture with one or more pharmaceutically acceptable excipients; and compressing the blend into tablets or filling into capsules.
The term 'pharmaceutically acceptable excipient' refers to ingredients of the composition, excluding the active drug substance.
Suitable pharmaceutically acceptable excipients include one or more of fillers, binders, disintegrants, lubricants, glidants, and colors.
Suitable fillers include one or more of corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized, and sucrose.
Suitable binders include one or more of methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullutan, pregelatinized starch, agar, tragacanth, sodium alginate, and propylene glycol.
Suitable disintegrants include one or more of starch, croscarmellose sodium, crospovidone, and sodium starch glycolate.
Suitable lubricants and glidants include one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, and white beeswax.
Suitable coloring agents include one or more FDA approved colors for oral use.
The tablets prepared by the present invention may be coated with one or more additional layers of film forming agents and/or pharmaceutically acceptable excipients.
The coating layers over the tablet may be applied as a solution/ dispersion of coating ingredients using any conventional technique known in the prior art including spray coating in a conventional coating pan, fluidized bed processor; and dip coating.
Suitable solvents used for preparing a solution/dispersion of the coating ingredients include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.
Suitable film forming agents include one or more of ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; Waxes, such as, polyethylene glycol; methacrylic acid polymers, such as, Eudragit ® RL and RS; and mixture thereof. Commercially available coating compositions marketed under various trade names, such as Opadry® may also be used for coating.
The following examples are illustrative of the invention, and are not to be construed as limiting the invention.
EXAMPLE 1-2

(Table Removed)
* Particle size d90 = 46 um ** Particle size d90 = 22 urn PROCEDURE:
1. Colloidal silicon dioxide and Nateglinide are co-sifted by mixing repeatedly till a
uniform mixture is formed.
2. The co-sifted mixture of step 1 along with microcrystalline cellulose, lactose
monohydrate and a part of Croscarmellose sodium are mixed in a high shear mixer and
granulated using aqueous solutions that include sodium lauryl sulphate and polyvinyl
pyrrolidone.
3. The wet granules are dried in a fluid bed drier, passed through a screen and then
milled.
4. The colloidal silicon dioxide and the rest of the croscarmellose sodium are mixed,
passed through a screen and blended with the mixture of step 3.
5. The magnesium stearate is passed through a screen, blended with the blend of step 4
and the resulting mixture is compressed to tablets.
EXAMPLE 3-4

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• Particle size d90 = 27|j,m PROCEDURE:
• ** Particle size d90 = 8jam
1. Colloidal silicon dioxide and Nateglinide are co-sifted repeatedly and mixed
together in a low shear blender.
2. The co-sifted mixture of step 1 along with microcrystalline cellulose, lactose
monohydrate and a part of sodium starch glycolate are mixed in a high shear mixer
and granulated using aqueous solutions containing sodium lauryl sulphate and
polyvinyl pyrrolidone.
3. The wet granules are dried in a fluid bed drier, passed through a screen and milled.
4. The colloidal silicon dioxide and the rest of the sodium starch glycolate are mixed,
passed through a screen and blended with the mixture of step 3.
5. The magnesium stearate is passed through a screen, blended with the blend of step
4 and the total mixture is compressed into tablets.
Comparative In vitro dissolution study
The In vitro release profile of nateglinide from tablets as per Examples 1-4 were studied in 1000 ml, 0.01 N HC1, with 0.5% SLS (pH-1.2), using USP apparatus - II, at 50 rpm. The results are listed in Table 1.
Table 1

(Table Removed)
Table 1 indicates that compositions having Nateglinide particle size d 90 <45um show a better dissolution profile as compared to the compositions having particle size d90, > 45 um.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

WE CLAIM:
1. A process for the preparation of an oral pharmaceutical composition of
nateglinide, the process comprising:
a. co-milling/co-sifting nateglinide and one or more pharmaceutically
inert carriers selected from one or more of silicate derivatives,
cellulose derivatives and clays to form a blend;
b. granulating the blend to form granules;
c. drying and sizing the granules; and
d. compressing the granules into tablets or filling into capsules.
2. The process according to claim 1, wherein the silicate derivatives
comprise one or more of colloidal silicon dioxide, magnesium silicate,
magnesium trisilicate, magnesium and aluminum silicate.
3. The process according to claim 1, wherein the cellulose derivatives comprise one or more of microcrystalline cellulose and carboxymethylcellulose.
4. The process according to claim 1, wherein the clays comprise one or more of veegum, bentonite and mixtures thereof.
5. The process according to claim 1, wherein the ratio of nateglinide to the pharmaceutically inert carrier comprises a range from about 10: 1 to about 1:2.

6. The process according to claim 1, wherein the nateglinide has a particle
size of dgo <45 urn.
7. The process according to claim 1, further comprising mixing one or more
pharmaceutically acceptable excipients with the co-milled/co-sifted blend
prior to granulation.
8. The process according to claim 7, wherein the one or more
pharmaceutically acceptable excipients comprise fillers, binders,
disintegrants, surfactants, lubricants, colorings and flavoring agents.
9. The process according to claim 1, wherein the co-milling is done with an air jet mill, a multi mill, or a ball mill.
10. An oral pharmaceutical composition prepared according to the process of claim 1 comprising:
a. nateglinide or pharmaceutically acceptable salts thereof; and
b. colloidal silicon dioxide, wherein the nateglinide or a
pharmaceutically acceptable salt thereof has a particle size of dgo < 45
urn.