Description
STABLE PHARMACEUTICAL COMPOSITIONS COMPRISING PULVERIZED GRANULES OF NATEGLINIDE OF FORM B
Technical Field
[1] The present invention relates to stable pharmaceutical compositions comprising
nateglinide and processes for making them.
Background Art
[2] 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 60 mg or 120 mg strengths and are marketed by Novartis under the trade name STARLIX®.
[3] 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 °C to 130 °C. These crystals were described as being in a crystalline form and were known as 'B-type1 crystals.
[4] The known B-type (also known as Form B) crystals suffer from problems of in-
stability, especially when subjected to mechanical grinding. The instability results in conversion of the B-type crystals into other polymorphic forms. U.S. Patent No 5,463,116 discloses a method of producing a crystalline form (H type or Form H) of nateglinide having improved stability, 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.
[5] U.S. Patent No. 6,559,188 describes compositions of nateglinide which are capable
of being granulated without the need for pulverization after the granulation step. All of the examples given in this patent make use of lactose and microcrystalline cellulose as filler. The concentration of lactose is disclosed as being 34 to 46% w/w and micro-crystalline cellulose as being 17 to 23% w/w, the total concentration of filler ranging from 50-70% w/w.
[6] In the present invention pharmaceutical compositions comprising nateglinide of
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 either 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 range, a dissolution profile comparable with STARLIX® was obtained.
Summary of the Invention
[7] In one general aspect there is provided a process for the preparation of a stable
pharmaceutical composition comprising Nateglinide Form B. The process includes a step of pulverization,
[8] Embodiments of the process may include one or more of the following features. For
example, the step of pulverization may be carried out after a granulation step. The granulation step may be carried out in a fluidized bed drier. The step of pulverization may be carried out in a conventional milling instrument, the conventional milling instrument including one or more of an air jet mill, a multi mill and a ball mill.
[9] The granulation step may be carried out by wet granulation or dry granulation.
[10] The wet granulation process may include blending nateglinide, fillers, surfactant
and disintegrant; granulating the blend with a binder solution; drying the granules; pulverizing; lubricating and compressing the lubricated granules. Alternatively, the wet granulation process may include blending nateglinide, fillers, surfactant, disintegrant and binder, granulating the blend with a solvent; drying the granules; pulverizing; lu­bricating and compressing the lubricated granules.
[11] The dry granulation process may include blending nateglinide, fillers, surfactant,
disintegrant and binder; compacting or slugging the blend; breaking the slugs to make granules; pulverizing; lubricating and compressing the lubricated granules.
[12] The composition may further include one or more pharmaceutically acceptable
excipients selected from filler, binder, disintegrant, surfactant, lubricant, coloring agent, and flavoring agent. The filler may be a combination of lactose in the range of 46% to 70% w/w and macrocrystalline cellulose in the range of 8% to 17% w/w of the total weight of the pharmaceutical composition, The binder may be one or more of polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof. The disintegrant may be one or more of crospovidone, sodium starch glycolate, croscarmellose sodium, starch and mixtures thereof. The surfactant may be one or more of sodium lauryl sulphate, poloxamer, Polysorbate 80 and mixtures thereof. The lubricant may be one or more of magnesium stearate, stearic acid, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and mixtures thereof.
[13] In another general aspect there is provided a process for the preparation of a stable
pharmaceutical composition comprising nateglinide Form B, a filler which is a combination of lactose in the range of 46% to 70% w/w and microcrystalline cellulose in the range of 8% to 17% w/w of the total weight of the pharmaceutical composition, and optionally one or more pharmaceutically acceptable excipients comprising binder,
disintegrant, surfactant and lubricant, wherein the process comprises
[14] a) blending nateglinide, filler, surfactant and disintegrant;
[15] b) granulating the blend with a binder solution;
[16] c) drying the granules;
[17] d) pulverizing the granules;
[18] e) adding a lubricant to the blend of step (d); and
[19] f) compressing the blend into tablets.
[20] Embodiments of the process may include one or more of the embodiments
described above.
[21] In another general aspect there is provided a stable pharmaceutical composition
comprising nateglinide Form B and a combination of lactose and microcrystalline cellulose as filler, wherein the lactose is present in a concentration of 46% to 70% w/w and the 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.
[22] Embodiments of the process may include one or more of the following features or
those described above. For example, the composition may further include one or more pharmaceutically acceptable excipients selected from binder, disintegrant, surfactant, lubricant, coloring and flavoring agent. The composition may be in the form of a tablet, a coated tablet or a capsule.
[23] In another general aspect there is provided a medicament for the prevention, delay
of progression or treatment of metabolic disorders, the medicament comprising nateglinide Form B, a combination of lactose and microcrystalline cellulose as filler, and optionally another anti-diabetic compound, wherein the lactose is present in a con­centration of 46% to 70% w/w and the microcrystalline cellulose is present in a con­centration of 8% to 17% w/w of the total weight of the pharmaceutical composition and the medicament is prepared by a process which comprises a step of pulverization.
[24] Embodiments of the medicament may include one or more of the following features
or those described above. For example, the metabolic disorder may be type 2 diabetes mellitus or a disease or condition associated with diabetes mellitus.
[25] The details of one or more embodiments of the inventions are set forth in the de-
scription below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Description Of Drawings
[261 Figure 1 depicts super-imposed X-Ray Diffraction (XRD) patterns of nateglinide
Form-H, nateglinide Form-B and an exemplary nateglinide tablet formulation. Detailed Description of the Invention
[27] The term 'Nateglinide' as used herein includes nateglinide in a free or pharma-
ceutically 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 the pharmaceutically acceptable salt thereof may also be used in the form of a hydrate or may include other solvents used for crystallization. Nateglinide may be present either substantially in the form of one optically pure enantiomer or as a mixture, racemic or otherwise, of enantiomers. Nateglinide may be administered to a 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. 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 composition.
[28] Stable, as used herein, refers to little or no evidence of conversion of nateglinide
from Form B to Form H, for example, as observed by X-ray diffraction, infrared spectroscopy, or Raman spectroscopy measurements.
[29] Filler, as described herein, may be selected from the group comprising 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, starch, starch pregelatinized, sucrose, colloidal silicon dioxide and the like. In particular lactose, microcrystalline cellulose, mannitol or dicalcium phosphate can be used. When a combination of lactose and microcrystalline cellulose is used, lactose may be present in a concentration of 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.
[30] 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.
[31] The pharmaceutical compositions as described herein may include other pharma-
ceutically acceptable excipients in addition to nateglinide and a filler. Examples of other pharmaceutically acceptable excipients as used herein include binders, dis-integrants, lubricants, surfactants, glidants, colors and the like.
[32] 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.
[33] Examples of disintegrants include starch, croscarmellose sodium, crospovidone,
sodium starch glycolatc and the like.
[34] 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.
[35] Examples of surfactants include sodium lauryl sulphate, poloxamer, Polysorbate 80
and the like.
[36] The coloring agents as described herein may be selected from any FDA approved
colors for oral use.
[37] The stable pharmaceutical composition can be prepared by processes known in the
art selected from wet granulation or dry granulation and may be in the form of a 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.
[38] In one of the embodiments natcglinide tablets may be prepared by blending
nateglinide, fillers, surfactant and disintegrant; granulating the blend with a binder solution; drying the granules; pulverizing the dried granules; lubricating; and compressing the lubricated granules.
[39] In another embodiment nateglinide tablets may be prepared by blending nateglinide,
fillers, surfactant, disintegrant and binder; granulating the blend with a solvent; drying the granules; pulverizing the dried granules; lubricating; and compressing the lubricated granules.
[40] In another embodiment nateglinide tablets may be prepared by blending nateglinide,
fillers, surfactant, disintegrant and binder; compacting or slugging the blend; breaking the slugs to make granules; pulverizing the dried granules; lubricating; and compressing the lubricated granules.
[41] The tablets may optionally be coated with film forming agents and/or pharma-
ceutically acceptable excipients. Particularly suitable for use are commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry and Eudragit®. The coating layers over the tablet may be applied as solution/dispersion of coating ingredients using conventional techniques known in the art selected from spray coating in a conventional coating pan or fluidized bed processor, dip coating, and the like.
[42] The following examples are illustrative of the invention, and are not intended to be
construed as limiting the invention.
EXAMPLE 1[44] [45]
PROCEDURE:
Nateglinide, lactose, a pan of the 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).
Polyvinylpyrrolidone is dissolved in the remaining quantity of purified water
till a clear solution is formed, this solution is added slowly to the premix of
Step 2, and the bulk is then granulated.
The wet granules are dried in a fluid bed drier, passed through a screen, and
then subjected to a pulverization step.
The remaining part of the colloidal silicon dioxide and the crospovidone are
mixed, passed through a screen, and blended with the granules of step 4.
The magnesium stearate is passed through a screen, blended with the blend of
step 5, and the total mixture is compressed into tablets.
EXAMPLE 2

[46]

[47] [48]
PROCEDURE:
Nateglinide, microcrystalline cellulose, a part of the colloidal silicon dioxide,
and sodium starch glycolate are mixed in a high shear blender to give a
uniform dry mixture.
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).
Polyvinylpyrrolidone is dissolved in the remaining quantity of purified water
till a clear solution is formed, this solution is added slowly to the premix of
Step 2, and the bulk is then granulated.
The wet granules are dried in a fluid bed drier, passed through a screen, and
then subjected to a pulverization step.
The remaining part of the colloidal silicon dioxide and the crospovidone are
mixed, passed through a screen, and blended with the granules of step 4.
The magnesium stearate is passed through a screen, blended with the blend of
step 5, and the total mixture is compressed into tablets.
EXAMPLE 3

[49]

[50] [51]PROCEDURE:
Nateglinide along with lactose, microcrystalline cellulose, a part of the
colloidal silicon dioxide, and sodium starch glycolate are mixed in a high
shear blender to give a uniform dry mixture.
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).
Polyvinylpyrrolidone is dissolved in the remaining quantity of purified water
till a clear solution is formed, this solution is added slowly to the premix of
Step 2, and the bulk is then granulated.
The wet granules are dried in a fluid bed drier, passed through a screen, and
then subjected to a pulverization step.
The remaining part of the colloidal silicon dioxide and crospovidone are
mixed, passed through a screen, and blended with the granules of step 4.
The magnesium stearate is passed through a screen, blended with the blend of
step 5, and the total mixture is compressed into tablets.
EXAMPLE 4

[53] [54]
[55] [56]
[57] [58]
PROCEDURE:
1.
Nateglinide, lactose, microcrystalline cellulose, a part of the 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 the 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 the colloidal silicon dioxide and the crospovidone are
6.
mixed, passed through a screen, and blended with the granules of step 4.
The magnesium stearate is passed through a screen, blended with the blend of
step 5, and the total mixture is compressed into tablets. Comparative//? vitro dissolution study
In vitro release of nateglinide from tablets prepared according to the compositions of Examples 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

[59] Table 1 clearly indicates that pharmaceutical compositions comprising combination
of lactose (at 46 to 70% w/w) and microcrystalline cellulose (at 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
[60] Figure 1 depicts super-imposed X-Ray Diffraction (XRD) patterns of nateglinide
Form-H, nateglinide Form-B and tablets made according to the formulation of Example 4. 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 nateglinide to Form H nateglinide.
[61] While the present invention has been described in terms of its specific em-
bodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. 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:
A process for the preparation of a stable pharmaceutical composition comprising
Nateglinide Form B and one or more pharmaceutically acceptable excipients selected
from filler, binder, disintegrant. surfactant, lubricant, coloring agent, and flavoring
agent as herein described, wherein the process comprises a step of pulverization.
The process for the preparation of a stable pharmaceutical composition according to
claim 1, wherein the step of pulverization is carried out after a granulation step.
The process for the preparation of a stable pharmaceutical composition according to
claim 1, wherein the step of pulverization is carried out in a conventional milling
instrument, the conventional milling instrument comprising one or more of an air jet
mill, a multi mill and a ball mill.
The process for the preparation of a stable pharmaceutical composition according to
claim 2, wherein the granulation step is carried out in a fluidized bed drier.
The process for the preparation of a stable pharmaceutical composition according to
claim 1, wherein the granulation step is carried out by wet granulation or dry
granulation.
The process for the preparation of a stable pharmaceutical composition according to
claim 5, wherein the wet granulation process comprises blending nateglinide, fillers,
surfactant and disintegrant; granulating the blend with a binder solution; drying the
granules; pulverizing; lubricating and compressing the lubricated granules.
The process for the preparation of a stable pharmaceutical composition according to
claim 5, wherein the wet granulation process comprises blending nateglinide, fillers,
surfactant, disintegrant and binder; granulating the blend with a solvent; drying the
granules; pulverizing; lubricating and compressing the lubricated granules.
The process for the preparation of a stable pharmaceutical composition according to
claim 5, wherein the dry granulation process comprises blending nateglinide, fillers,
surfactant, disintegrant and binder; compacting or slugging the blend; breaking the
compacts or slugs to make granules; pulverizing; lubricating and compressing the
lubricated granules.
The process for the preparation of a stable pharmaceutical composition according to
claim 1 wherein the process comprises a) blending nateglinide Form B, a filler which
is a combination of lactose in the range of 46 % to 70 % w/w and microcrystalline
cellulose in the range of 8 % to 17 % w/w of the total weight of the pharmaceutical
composition, surfactant and disintegrant; b) granulating the blend with a binder
solution; c) drying the granules; d) pulverizing the granules; e) adding a lubricant to
the blend of step (d); and f) compressing the blend into tablets.
A process for the preparation of stable pharmaceutical composition of nateglinide
Form B substantially described and exemplified herein.