The present invention relates to stable pharmaceutical compositions comprising Nateglinide.
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.
Presently Nateglinide oral tablets are available in 60mg or 120mg strengths and are marketed by Novartis under the trade name STARLIX.
Nateglinide is disclosed in Japanese Patent Application Laid Open No. 63-54321 (equivalent to EP-A-196222 and US 4,816,484) and in J. Med. Chem. 32, 1436. The Japanese application describes how the compound may be crystallized from aqueous methanol to yield crystals having a melting point of 129.degree. to 130.degree. C. These crystals were in a crystalline form and were known as "B-type" crystals.
The known B-type crystals suffer from problems of instability, especially when subjected to mechanical grinding. The instability results in conversion of the B-type crystals into other forms. US Pat. No 5,463,116 discloses a method of producing a crystalline form of Nateglinide having improved stability (H Type) i.e. having an enhanced stability to grinding which is thus said to be more suitable for use in medicines than those of the B-type.
US Pat. No 6,559,188 describe compositions of Nateglinide or a pharmaceutically acceptable salt thereof, which is capable of being granulated without the need for pulverization after the granulation step. All the examples given in this patent make use of lactose and microcrystalline cellulose as filler. The concentration of lactose being 34 to 46% w/w and microcrystalline cellulose 17 to 23% w/w, the total concentration of filler ranging from 50-70% w/w.
In the present invention pharmaceutical compositions comprising Nateglinide Form B, and prepared by pulverizing after the granulation, were found to be stable. Further it was seen that pharmaceutical compositions which were prepared by using lactose or microcrystalline cellulose alone, as filler did not show comparable dissolution profiles to that of STARLIX. It was however seen that when lactose and microcrystalline cellulose were used in combination as filler in a specific concentration, a dissolution profile comparable with STARLIX was obtained.
Hence in one aspect it provides a process of preparation of stable pharmaceutical composition comprising Nateglinide Form B wherein the process comprises a step of pulverization.
In another aspect it provides a process of preparation of stable pharmaceutical composition comprising Nateglinide Form B wherein the process comprises a step of pulverization after the granulation step.
In another aspect it provides a process of preparation of stable pharmaceutical composition comprising Nateglinide Form B or a pharmaceutically acceptable salt thereof and at least one other antidiabetic compound wherein the process comprises a step of pulverization after the granulation step.
In another aspect it provides a process of preparation of stable pharmaceutical composition comprising Nateglinide Form B wherein the composition is used for the preparation of a medicament for the prevention, delay of progression or treatment of metabolic disorders, in particular of type 2 diabetes mellitus or a disease or condition associated with diabetes mellitus and the process comprises a step of pulverization.
In another aspect it provides a stable pharmaceutical composition comprising Nateglinide Form B and a combination of lactose and microcrystalline cellulose as filler; wherein lactose is present in concentration of 46% to 70% w/w and microcrystalline cellulose is present in a concentration of 8% to 17% w/w of the total weight of
pharmaceutical composition, and is prepared by a process which comprises a step of pulverization.
In another aspect it provides a stable pharmaceutical composition comprising Nateglinide Form B; at least one other antidiabetic compound and a combination of lactose and microcrystalline cellulose as filler; wherein lactose is present in concentration of 46% to 70% w/w and microcrystalline cellulose is present in a concentration of 8% to 17% w/w of the total weight of pharmaceutical composition, and is prepared by a process which comprises a step of pulverization.
In another aspect it provides a stable pharmaceutical composition comprising Nateglinide Form B and a combination of lactose and microcrystalline cellulose as filler; wherein lactose is present in concentration of 46% to 70% w/w and microcrystalline cellulose is present in a concentration of 8% to 17% w/w of the total weight of pharmaceutical composition, and is prepared by a process which comprises a step of pulverization, the composition being used for the preparation of a medicament for the prevention, delay of progression or treatment of metabolic disorders, in particular of type 2 diabetes mellitus or a disease or condition associated with diabetes mellitus.
In another aspect it provides a stable pharmaceutical composition comprising Nateglinide Form B; at least one other antidiabetic compound and a combination of lactose and microcrystalline cellulose as filler; wherein lactose is present in concentration of 46% to 70% w/w and microcrystalline cellulose is present in a concentration of 8% to 17% w/w of the total weight of pharmaceutical composition, and is prepared by a process which comprises a step of pulverization, the composition being used for the preparation of a medicament for the prevention, delay of progression or treatment of metabolic disorders, in particular of type 2 diabetes mellitus or a disease or condition associated with diabetes mellitus.
In another aspect it provides a process of preparation of stable pharmaceutical composition comprising Nateglinide Form B wherein the process comprises a step of pulverization which is carried out in conventional milling instruments such as air jet mill, multi mill, or ball mill.
In another aspect it provides a stable pharmaceutical composition comprising Nateglinide Form B; at least one other antidiabetic compound and a combination of lactose and microcrystalline cellulose as filler; wherein lactose is present in concentration of 46% to 70% w/w and microcrystalline cellulose is present in a concentration of 8% to 17% w/w of the total weight of pharmaceutical composition, and is prepared by a process which comprises a step of pulverization which is carried out in conventional milling instruments such as air jet mill, multi mill, or ball mill.
The pharmaceutical compositions as described herein may include other pharmaceutically acceptable excipients in addition to Nateglinide and filler.
The term 'Nateglinide' as used herein includes Nateglinide in a free or pharmaceutically acceptable salt form such as an acid addition salt, for example as a sodium salt or as a maleate. In particular, the composition comprises the B- or H-type crystal modification of Nateglinide, more preferably the B-type. The active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
The fillers can be selected from the group comprising 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, sucrose, and the like. In particular lactose, microcrystalline cellulose, mannitol or dicalcium phosphate can be used. When combination of lactose and microcrystalline cellulose is used lactose may be present in concentration of more than 46% to 70% w/w and microcrystalline cellulose may be present in a concentration of 8% to 17% w/w of the total weight of pharmaceutical composition.
The term 'other pharmaceutically acceptable excipient' refers to ingredients of the composition, excluding the active drug substance.
Examples of other pharmaceutically acceptable excipients as used herein include binders, disintegrants, lubricants, surfactants, glidants, colors and the like.
Examples of binders include methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Examples of disintegrants include starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Examples of lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like.
Examples of surfactants include sodium lauryl sulphate, poloxamer, Polysorbate 80 and the like.
The coloring agents of the present invention may be selected from any FDA approved colors for oral use.
Nateglinide or pharmaceutically acceptable salt thereof may be present in any amount which is sufficient to elicit a therapeutic effect and, where applicable, may be present either substantially in the form of one optically pure enantiomer or as a mixture, racemic or othenwise, of enantiomers.
Nateglinide can be present in an amount of about 5% to about 70% (w/w), and most preferably about 15% to about 40% (w/w), based on the total weight of the pharmaceutical composition.
The total concentration of filler may vary from 40-80% w/w of the total weight of the pharmaceutical composition. When lactose and microcrystalline cellulose are used in combination lactose may be present in a concentration range of 46% to 70% w/w, more
preferably in the range of 46% to 55% w/w, and microcrystalline cellulose may be present in a concentration range of 8% to 17% w/w more preferably in the range of 9% to 13% w/w of the pharmaceutical composition.
The stable pharmaceutical composition can be prepared by processes known in the prior art selected from wet granulation or dry granulation and may be in the form of tablet or capsule. Pulverization can be carried out in conventional milling instruments such as air jet mill, multi mill, ball mill or by any other method of particle attrition.
In one of the embodiments nateglinide tablet may be prepared by blending nateglinide, fillers, surfactant and disintegrant; granulating the blend with a binder solution; drying the granules; pulverizing; lubricating and compressing the lubricated granules.
In another embodiment nateglinide tablet may be prepared by blending nateglinide, fillers, surfactant, disintegrant and binder; granulating the blend with a solvent; drying the granules; pulverizing; lubricating and compressing the lubricated granules.
In another embodiment nateglinide tablet may be prepared by blending nateglinide, fillers, surfactant, disintegrant and binder; compacting or slugging the blend; breaking/ pulverizing the slugs to make granules; lubricating and compressing the lubricated granules.
The tablets prepared by the present invention may be coated with one or more additional layers comprising film forming agents and/or pharmaceutically acceptable excipients.
The coating layers over the tablet may be applied as solution/ dispersion of coating ingredients using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating and the like.
Example of solvents used for preparing a solution/dispersion of the coating ingredients include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like and mixtures thereof.
Example of film forming agents include 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 the like and mixture thereof. Alternatively, commercially available coating compositions comprising film-forming polymers 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

Ingredient Example 1 (wt/tablet) mg
Nateglinide 120
Lactose 399
Polyvinylpyrrolidone 12
Sodium starch glycolate 67.3
Colloidal silicon dioxide 14
Sodium lauryl sulphate 24
Purified water q.s
Crospovidone 39.7
Colloidal silicon dioxide 12.8
Magnesium stearate 11.2
PROCEDURE:
1. Nateglinide, lactose, a part of colloidal silicon dioxide and sodium starch glycolate are mixed in a high shear blender to give a uniform dry mixture.
2. Sodium lauryl sulphate is dissolved in about 50% of the purified water and is added slowly to the dry mixture of Step 1 under fast mixing In a rapid mixer granulator (RMG).
3. Polyvinylpyrrolidone is dissolved in remaining quantity of purified water till a clear solution is formed, and this solution is added slowly to the premix of Step 2 and the bulk is then granulated.
4. The wet granules are dried in a fluid bed drier, passed through a screen and then subjected to a pulverization step.
5. The remaining part of colloidal silicon dioxide and crospovidone are mixed, passed through a screen and blended with the granules of step 4.
6. The magnesium stearate is passed through a screen, blended with the blend of step 5 and total mixture is compressed to tablets.
EXAMPLE 2

Ingredient Example 2 (wt/tablet) mg
Nateglinide 120
Microcrystalline cellulose 399
Polyvinylpyrrolidone 12
Sodium starch glycolate 67.3
Colloidal silicon dioxide 14
Sodium lauryl sulphate 24
Purified water q.s
Crospovidone 39.7
Colloidal silicon dioxide 12.8
Magnesium stearate 11.2
PROCEDURE:
1. Nateglinide, microcrystalline cellulose, a part of colloidal silicon dioxide and sodium starch glycolate are mixed in a high shear blender to give a uniform dry mixture.
2. Sodium lauryl sulphate is dissolved in about 50% of the purified water and is added slowly to the dry mixture of Step 1 under fast mixing in a rapid mixer granulator (RMG).
3. Polyvinylpyrrolidone is dissolved in remaining quantity of purified water till a clear solution is formed, and this solution is added slowly to the premix of Step 2 and the bulk is then granulated.
4. The wet granules are dried in a fluid bed drier, passed through a screen and then subjected to a pulverization step.
5. The remaining part of colloidal silicon dioxide and crospovidone are mixed, passed through a screen and blended with the granules of step 4.
6. The magnesium stearate is passed through a screen, blended with the blend of step 5 and total mixture is compressed to tablets.
EXAMPLE 3

Ingredient Example 3 (wt/tablet) mg
Nateglinide 120
Lactose 325
Microcrystalline cellulose 86
Polyvinylpyrrolidone 12
Sodium starch glycolate 67.3
Colloidal silicon dioxide 14
Poloxamer 12
Purified Water q.s.
Crospovidone 39.7
Colloidal silicon dioxide 12.8
Magnesium stearate 11.2
PROCEDURE:
1. Nateglinide along with lactose, microcrystalline cellulose, a part of colloidal silicon dioxide and sodium starch glycolate are mixed in a high shear blender to give a uniform dry mixture.
2. Poloxamer is dissolved in about 50% of the purified water and is added slowly to the dry mixture of Step 1 under fast mixing in a rapid mixer granulator (RMG).
3. Polyvinylpyrrolidone is dissolved in remaining quantity of purified water till a clear solution is formed, and this solution is added slowly to the premix of Step 2 and the bulk is then granulated.
4. The wet granules are dried in a fluid bed drier, passed through a screen and then subjected to a pulverization step.
5. The remaining part of colloidal silicon dioxide and crospovidone are mixed, passed through a screen and blended with the granules of step 4.
6. The magnesium stearate is passed through a screen, blended with the blend of step 5 and total mixture is compressed to tablets.
EXAMPLE 4

Ingredient Example 4 (wt/tablet) mg
Nateglinide 120
Lactose 325
Microcrystalline cellulose 74
Polyvinylpyrrolidone 12
Sodium starch glycolate 67.3
Colloidal silicon dioxide 14.0
Sodium lauryl sulphate 24
Purified Water q.s.
Crospovidone 39.7
Colloidal silicon dioxide 12.8
Magnesium stearate 11.2
PROCEDURE:
1. Nateglinide, lactose, microcrystalline cellulose, a part of colloidal silicon dioxide and sodium starch glycolate are mixed in a high shear blender to give a uniform dry mixture.
2. Sodium lauryl sulphate is dissolved in about 50% of the purified water and is added slowly to the dry mixture of Step 1 under fast mixing in a rapid mixer granulator (RMG).
3. Polyvinylpyrrolidone is dissolved in remaining quantity of purified water till a clear solution is formed, and this solution is added slowly to the premix of Step 2 and the bulk is then granulated.
4. The wet granules are dried in a fluid bed drier, passed through a screen and then subjected to a pulverization step.
5. The remaining part of colloidal silicon dioxide and crospovidone are mixed, passed through a screen and blended with the granules of step 4.
6. The magnesium stearate is passed through a screen, blended with the blend of step 5 and total mixture is compressed to tablets.
Comparative In vitro dissolution study
In vitro release of nateglinide from tablets as per composition of Example 1-4 was studied in 1000 ml, 0.01 N HCI, with 0.5% SLS (pH-1.2), using USP apparatus - II, at 50 rpm. The results are listed in Table 1.
Table 1: In vitro release of nateglinide from tablets

(TABLE REMOVED)

Table 1 clearly indicates that pharmaceutical compositions comprising combination of lactose (46 to 70%w/w) and microcrystalline cellulose (8 to 17% w/w) as filler show a comparable dissolution profile to that of STARLIX, and a better dissolution profile as compared to compositions comprising a single filler.
Stability data
Figure 1 clearly indicates that pharmaceutical compositions prepared as per the details given in example 4 remain stable, and there is no conversion of Form B to Form H.
Further, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed invention and be so described as a negative limitation. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

WE CLAIM:
1. A process for preparation of stable pharmaceutical composition comprising Nateglinide Form B, wherein the process comprises a step of pulverization.
2. The process for preparation of stable pharmaceutical composition according to claim 1, wherein pulverization is carried out after the granulation step.
3. The process for preparation of stable pharmaceutical composition according to claim 1, wherein pulverization is carried out in conventional milling instruments such as air jet mill, multi mill or ball mill.
4. The process for preparation of stable pharmaceutical composition according to claim 2, wherein granulation is carried out in fluidized bed drier.
5. The process for preparation of stable pharmaceutical composition according to claim 1, wherein the composition comprises of other pharmaceutically acceptable excipients selected from a group consisting of filler, binder, disintegrant, surfactant, lubricant, coloring and flavoring agent.
6. The process for preparation of stable pharmaceutical composition according to claim 5, wherein filler is a combination of lactose in the range of 46% to 70% w/w and microcrystalline cellulose is in the range of 8% to 17% w/w of the total weight of the pharmaceutical composition.
7. The process for preparation of stable pharmaceutical composition according to claim 6, by wet granulation or dry granulation.
8. The process for preparation of stable pharmaceutical composition according to claim 7, by blending nateglinide, fillers, surfactant and disintegrant; granulating the blend with a binder solution; drying the granules; pulverizing; lubricating and compressing the lubricated granules.
9. The process for preparation of stable pharmaceutical composition according to claim 7, by blending nateglinide, fillers, surfactant, disintegrant and binder; granulating the blend with a solvent; drying the granules; pulverizing; lubricating and compressing the lubricated granules.
10. The process for preparation of stable pharmaceutical composition according to claim 7, by blending nateglinide, fillers, surfactant, disintegrant and binder; compacting or slugging the blend; breaking/pulverizing the slugs to make granules; lubricating and compressing the lubricated granules.
11. A stable pharmaceutical composition comprising Nateglinide Form B, and a combination of lactose and microcrystalline cellulose as filler; wherein lactose is present in a concentration of 46% to 70% w/w and microcrystalline cellulose is present in a concentration of 8% to 17% w/w of the total weight of the pharmaceutical composition and is prepared by a process which comprises a step of pulverization.
12. The stable pharmaceutical composition according to claim 11, wherein lactose is present in a concentration of 46% to 55% w/w.
13. The stable pharmaceutical composition according to claim 11, wherein microcrystalline cellulose is present in a concentration of 9% to 13% w/w.
14.The stable pharmaceutical composition according to claim 11, wherein in addition to Nateglinide and fillers, it comprises of other pharmaceutically
acceptable excipients selected from a group consisting of binder, disintegrant, surfactant, lubricant, coloring and flavoring agent.
15. The pharmaceutical composition according to claim 14 wherein binder is selected from polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof.
16. The pharmaceutical composition according to claim 15 wherein binder is polyvinylpyrrolidone.
17. The pharmaceutical composition according to claim 14 wherein disintegrant is selected from crospovidone, sodium starch glycolate, croscarmellose sodium, starch and mixtures thereof.
18. The pharmaceutical composition according to claim 17 wherein disintegrant is sodium starch glycolate.
19. The pharmaceutical composition according to claim 17 wherein disintegrant is crospovidone.
20. The pharmaceutical composition according to claim 14 wherein surfactant is selected from sodium lauryl sulphate, poloxamer, Polysorbate 80 and mixtures thereof.
21. The pharmaceutical composition according to claim 20 wherein surfactant is sodium lauryl sulphate.
22. The pharmaceutical composition according to claim 20 wherein surfactant is poloxamer.
23. The pharmaceutical composition according to claim 14 wherein lubricant is selected from magnesium stearate, stearic acid, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and mixtures thereof.
24. The pharmaceutical composition according to claim 23 wherein lubricant is magnesium stearate.
25. The pharmaceutical composition according to claim 11 wherein it is in the form of a tablet.
26. The pharmaceutical composition according to claim 11 wherein it is in the form of a capsule.
27. The pharmaceutical composition according to claim 25 wherein the tablet is further coated with one or more functional and/or non-functional layers.
28. A medicament for the prevention, delay of progression or treatment of metabolic disorders, in particular of type 2 diabetes mellitus or a disease or condition associated with diabetes mellitus comprising Nateglinide Form B, and a combination of lactose and microcrystalline cellulose as filler; wherein lactose is present in a concentration of 46% to 70% w/w and microcrystalline cellulose is present in a concentration of 8% to 17% w/w of the total weight of the pharmaceutical composition and is prepared by a process which comprises a step of pulverization.
29. A process for preparation of stable pharmaceutical composition comprising Nateglinide Form B, wherein the process comprises a step of pulverization as described and illustrated herein.