The present invention relates to rapidly disintegrating pharmaceutical compositions of 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.
It is known that Nateglinide exhibits an excellent effect of lowering the blood sugar level when it is taken orally, and is thus usable as a medicine for diabetes.
However, it was found that when Nateglinide is orally taken before or after a meal for the purpose of preventing the blood sugar level after the meal from rising, the bioavailability of the compound is lowered.
Prior art patent US 6,143,323 discloses that a tablet composition containing Nateglinide and a low substituted hydroxypropylcellulose are rapidly disintegrated in the stomach after the administration and are absorbed without being influenced by food.
US 6,641,841 describes a process of preparing a tablet comprising nateglinide and a disintegrant selected from group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and croscarmellose sodium.

The object of the present invention is to provide a tablet composition that is rapidly absorbed without being influenced by the meals and without impairing the essential properties of Nateglinide contained therein, which has an effect of lowering the blood sugar level and only a short effect-lasting time.
The present invention relates to a tablet composition containing Nateglinide as the active ingredient and sodium starch glycolate and crospovidone as disintegrating aids.
Hence in one aspect it provides a rapidly disintegrating pharmaceutical composition comprising Nateglinide in a free or pharmaceutically acceptable salt form and a disintegrant selected from sodium starch glycolate, crospovidone or mixtures thereof.
In another aspect it provides a rapidly disintegrating pharmaceutical composition comprising Nateglinide in a free or pharmaceutically acceptable salt form and a disintegrant selected from sodium starch glycolate, crospovidone or mixtures thereof and filler.
In another aspect it provides a rapidly disintegrating pharmaceutical composition comprising Nateglinide in a free or pharmaceutically acceptable salt form and a disintegrant selected from sodium starch glycolate, crospovidone or mixtures thereof and a filler selected from lactose, microcrystalline cellulose or both.
In another aspect it provides a rapidly disintegrating pharmaceutical composition comprising Nateglinide in a free or pharmaceutically acceptable salt form, a disintegrant selected from sodium starch glycolate, crospovidone or mixtures thereof and polyvinylpyrrolidone as a binder.

In another aspect it provides a rapidly disintegrating pharmaceutical composition comprising Nateglinide in a free or pharmaceutically acceptable salt form, a disintegrant selected from sodium starch glycolate, crospovidone or mixtures thereof and at least one other antidiabetic compound.
In another aspect it provides a rapidly disintegrating pharmaceutical composition comprising Nateglinide in a free or pharmaceutically acceptable salt form, a disintegrant selected from sodium starch glycolate, crospovidone or mixtures thereof and at least one other antidiabetic compound selected from the group consisting of glitazones, sulfonyl urea derivatives and metformin in each case in free form or in form of a pharmaceutically acceptable salt thereof.
In another aspect it provides a rapidly disintegrating pharmaceutical composition comprising Nateglinide in a free or pharmaceutically acceptable salt form and a disintegrant selected from sodium starch glycolate, crospovidone or mixtures thereof, 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.
The rapidly disintegrating pharmaceutical composition as described herein may include other pharmaceutically acceptable excipients in addition to Nateglinide and a disintegrant.
The term 'Nateglinide' as used herein includes Nateglinide in a free or pharmaceutically acceptable salt form selected from 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 particularly 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 dosage range of the nateglinide depends upon factors known to the person skilled in the art including species of the warm-blooded animal, body weight and age, the nature and severity of the condition to be treated, and the mode of administration to be employed. Unless stated otherwise herein, Nateglinide is preferably divided and administered from one to four times per day.
Nateglinide is preferably administered to the warm-blooded animal in a dosage range of about 5 to 1200, more preferably 10 to 1000 and most preferably 25 to 800 mg/day, especially when the warm-blooded animal is a human of about 70 kg body weight.
Disintegrants used in the present invention are sodium starch glycolate and crospovidone or mixtures thereof.
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 fillers, binders, surfactants, lubricants, glidants, colors and the like.
The fillers can be selected from the group comprising of corn starch, lactose, white sugar, sucrose, 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 the like.
Examples of binders include polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose, gelatin, gum Arabic, ethyl cellulose, polyvinyl

alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Examples of surfactants include sodium lauryl sulphate, polysorbate 80, polaxomer 407 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.
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 otherwise, 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 dry composition.
The disintegrant can be present in an amount of about 2% to about 40% (w/w), and most preferably about 5% to about 30% (w/w), by weight based on the total weight of the dry composition.

The solid dose formulation can be prepared by processes known in the prior art selected from wet granulation, dry granulation or direct compression and may be in the form of tablet or capsule.
In one of the embodiments nateglinide tablet may be prepared by blending nateglinide, filler, surfactant and disintegrant; granulating the blend with a binder solution; drying the granules; sizing; lubricating and compressing the lubricated granules.
In another embodiment nateglinide tablet may be prepared by blending nateglinide, disintegrant, surfactant and binder; granulating the blend with a solvent; drying the granules; sizing; lubricating and compressing the lubricated granules.
Granulation may be carried out in fluidized bed dryer, or a top spray granulator or a rapid mixer granulator of the conventional type and sizing can be done by milling or pulverization.
In another embodiment nateglinide tablet may be prepared by blending nateglinide, filler, disintegrant, surfactant and binder; compacting or slugging the blend; breaking the slugs to make granules; lubricating and compressing the lubricated granules.
In another embodiment nateglinide tablet may be prepared by blending nateglinide, filler, disintegrant, surfactant, binder and lubricant followed by compressing.
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 selected from 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 selected from polyethylene glycol; methacrylic acid polymers selected from Eudragit ® RL and RS; and the like and mixture thereof. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, selected from 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 1-3

Ingredient ... Quantity(wt/tablet) mg
Example 1 Example 2 Example 3
Nateglinide 120 120 120
Lactose 325 325 325
Microcrystalline cellulose 86 86 86
Polyvinylpyrrolidone 12 12 12
Sodium starch glycolate 25 46.5 40.5
Colloidal silicon dioxide 28 28 28
Sodium lauryl sulphate 12 12 24
Purified water q.s q.s q.s
Sodium starch glycolate 23 46.5 40.5
Colloidal silicon dioxide 12.8 12.8 12.8
Magnesium stearate 11.2 11.2 11.2
PROCEDURE:
1. Nateglinide and colloidal silicon dioxide are sifted together.
2. Lactose, microcrystalline cellulose, a part of sodium starch glycolate along with
nateglinide-colloidal silicon dioxide blend are mixed in a high shear blender to
give a uniform dry mixture.
3. Sodium lauryl sulphate is dissolved in about 50% of the purified water and is
added slowly to the dry mixture of Step 2 under fast mixing in a rapid mixer
granulator (RMG).
4. 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 3 and
the bulk is thus granulated.
5. The wet granules are dried in a fluid bed drier, passed through a screen and then
subjected to sizing.
6. The remaining part of sodium starch glycolate and colloidal silicon dioxide are
mixed, passed through a screen and blended with the granules of step 5.

7. The magnesium stearate is passed through a screen, blended with the blend of step 6 and the total mixture is compressed to tablets.
Example 4

Ingredient Quantity (wt/tablet) mg
Nateglinide 120
Lactose 325
Microcrystalline cellulose 86
Polyvinylpyrrolidone 12
Crospovidone 25
Colloidal silicon dioxide 28
Sodium lauryl sulphate 12
Purified water q.s
Crospovidone 23
Colloidal silicon dioxide 12.8
Magnesium stearate 11.2
PROCEDURE:
1. Nateglinide and colloidal silicon dioxide are sifted together.
2. Lactose, microcrystalline cellulose, a part of crospovidone along with
nateglinide-colloidal silicon dioxide blend are mixed in a high shear blender to
give a uniform dry mixture.
3. Sodium lauryl sulphate is dissolved in about 50% of the purified water and is
added slowly to the dry mixture of Step 2 under fast mixing in a rapid mixer
granulator (RMG).
4. 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 3 and
and the bulk is thus granulated.
5. The wet granules are dried in a fluid bed drier, passed through a screen and then
subjected to sizing.

6 The remaining part of crospovidone and colloidal silicon dioxide are mixed, passed through a screen and blended with the granules of step 5.
7. The magnesium stearate is passed through a screen, blended with the blend of step 6 and the total mixture is compressed to tablets.
Example 5

Ingredient Quantity (wt/tablet) mg
Nateglinide 120
Lactose 325
Microcrystalline cellulose 74
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 and colloidal silicon dioxide are sifted together.
2. Lactose, microcrystalline cellulose, sodium starch glycolate along with
nateglinide-colloidal silicon dioxide blend are mixed in a high shear blender to
give a uniform dry mixture.

3. Sodium lauryl sulphate is dissolved in about 50% of the purified water and is
added slowly to the dry mixture of Step 2 under fast mixing in a rapid mixer
granulator (RMG).
4. 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 3 and
the bulk is thus granulated.

5. The wet granules are dried in a fluid bed drier, passed through a screen and then
subjected to sizing.
6. Crospovidone and colloidal silicon dioxide are mixed, passed through a screen
and blended with the granules of step 5.
7. The magnesium stearate is passed through a screen, blended with the
blend of step 6 and the total mixture is compressed to tablets.
Table 1: DISINTEGRATION TIME

Disintegration Time (min)
STARLIX 6
Example 1 6
Example 2 3
Example 3 4
Example 4 6
Example 5 7
Table 1 clearly indicates that compositions containing crospovidone or sodium starch glycolate as disintegrant show a disintegration time comparable to STARLIX.
While there has been shown and described what are the preferred embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made without departing from the scope of the invention as it is defined by the appended claims.