WO2009105049A1

WO2009105049A1 - Oral tablet compositions containing nateglinide and surfactan ph adjusting agent

Info

Publication number: WO2009105049A1
Application number: PCT/TR2009/000029
Authority: WO
Inventors: Inan Sahin; Serap Odabasi; Nur Tasar; Pelin Sari; Selda Koluman
Original assignee: BILIM ILAC SANAYI VE TICARET AS
Current assignee: BILIM ILAC SANAYI VE TICARET AS
Priority date: 2008-02-22
Filing date: 2009-02-20
Publication date: 2009-08-27
Anticipated expiration: 2010-08-22
Also published as: TR200801178A2; EP2257278A1

Abstract

This invention is about pharmaceutical preparations containing Nateglinide and surfactant: pH adjusting agent system and their preperation processes. An oral solid composition comprising; a) Nateglinide or pharmaceutically acceptable salts thereof; and b) At least one pharmaceutically acceptable surfactant-pH adjusting agent system that is produced with the steps of the mixing of nateglinide, one or more filler, disintegrant, binder and glidant, granulation with the surfactant: pH adjusting agent system, drying, milling, lubrication, tabletting and film coating.

Description

DESCRIPTION

ORAL TABLET COMPOSITIONS CONTAINING NATEGLINIDE AND SURFACTANT- pH ADJUSTING AGENT

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising nateglinide in combination with a surfactant-pH adjusting agent system, and process for their preparation.

BACKROUND OF THE INVENTION

Nateglinide is indicated as monotherapy to lower blood glucose in patients with Type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM) whose hyperglycemia cannot be adequately controlled by diet and physical exercise and who. have not been chronically treated with other anti-diabetic agents.

Nateglinide is an amino acid (phenylalanine) derivative, which is chemically and pharmacologically distinct from other antidiabetic agents. Nateglinide is a rapid, short-acting oral insulin secretagogue.

Its effect is dependent on functioning beta cells in the pancreas islets. Nateglinide- induced insulin secretion by pancreatic beta cells is glucose-sensitive, such that less insulin is secreted as glucose levels fall. Conversely, the coadministration of food or a glucose infusion results in an enhancement of insulin secretion.

Presently nateglinide oral tablets ara available in 60mg, 120mg and 180mg strengths are marketed by Novartis under the trand name Starlix®.

Starlix® is also indicated for use in combination with metformin. In patients whose hyperglycemia is inadequately controlled with metformin, Starlix may be added to, but not substituted for, metformin.

Nateglinide is known that N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine of the following formula:

Nateglinide is a white powder with a molecular weight of 317.43. It is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water.

Antidiabetics are decreasing either a post prandial blood glucose level or fasting blood glucose level to make it close to normal level. As antidiabetics for decreasing a post prandial blood glucose level to make it close to a normal level, nateglinide has been developed, and it is discribed in, for example, Japanese Patent Publication No. 15,221/1992 or Japanese Patent Laid-Open No.194,696/1998. Further, antidiabetics for decreasing a fasting blood glucose level to make it close to a normal level are dicribed in, for example, Kondo Nobuo, Nippon Rinsho, vol. 55,1997, extra ed., p.159 and the like. In recent years, for treating diabetes, it has been considered important that both a post prandial glucose level and a fasting blood glucose level are decreased to make them close to normal levels.

The various crystalline forms are related to each other in that drying of one form may result in a transformation to another form, namely nateglinide Form A, B, D, E, F, G, H, I, J, K, L, M₁ N, Q, S, T, V, Z, α, β, Ω, θ, _Y and δ.

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 crystalized from aqueous methanol to yield crystals having a melting point of 129⁰C to 13O⁰C. These crystals are in a crystalline form known as ^λB-Type' crystals. The known B-Type crystals suffer from problems of instability, especially when subjected to pulvarization. The insatability results in conversion of the B- Type crystals into other forms. US 5,463,116 discloses a method of producing a crystalline form of nateglinide having improved stability ( H-Type) to pulverization, and is thus said to be more suitable for use in doage forms than those of the B-Type.

Teva patent application ( WO2004067496) provides for a novel crystalline forms of nateglinide, denominated pure Form-U. Crystalline Form-U does not have any significant amounts of bound solvents, and is an anhydrate. As used herein, the term 'anhydrate' refers to having a a bound solvate level of less than about 2 % is measured by LOD (Loss on drying). The characterization of this anhydrate shows that it is stable towards grinding.

As used herein the term Torm U' is utilised interchangeable with ^Λpure Form U' both referring to the novel form lacking a XRPD peak. The Form U described in crystallization examples of the priority applications is pure Form U despite Figure 1 showing the XRPD of the impure form. Form U polymorphically stable when stored for a period of at least about 6 months 40⁰C / 75 % RH, or about 25°C / 60 % RH. In addition, Form U is polymorphically stable at least 6 months when stored at a temperature of about 55°C.

Nateglinide-containing preparations can not show the fast-acting short duration effect in decreasing blood glucose level ( fast-acting hypoglycemic agent), which is characteristic of nateglinide. In order to express the potential medical properties of nateglinide characterized by the quick action and short duration, this drug should be of immediate-release property.

The pharmacokinetic features of nateglinide may be attributable to its rapid intestinal absorbtion. Because nateglinide is an anionic compound with pKa 3.1, it exists predominantly in ionized form at the intestinal physiological pH of 6.5. Moreover, its chloroform/water partition coefficient is reported to be 0.2 at pH 6.8 (British Journal of Pharmacology, 137(3), 391-399,2002) indicating that it is scarcely lipophilic. These physicochemical features are incompatible with rapid absorbtion by passive diffusion, suggesting that nateglinide absorbed via a specific transport system(s) in the intestine.

Additionally, based on absorbtion studies in Caco-2 Cells, the transport of nateglinide from the mucosal to serosal side of the Caco-2 Cell monolayer appears to be a passive difussion process and that there appears to be an 'absorbtion window' when the pH is the range of 5.5 to 7.0. Also, the relatively poor solubility of nateglinide in acidic pH and considerably higher solubility at higher pH. (e.g., pH 6.8 phosphate buffer) or when surfactants are added to acidic media.

Dosage forms containing micronized drug particles exhibit enhanced solubility and consequently an improved bioavability. 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 solubility by increasing the effective surface area is defeated. To improve the nateglinide poor solubility, the most common approach is micronizing the particles to a few microns.

Nateglinide is poorly water soluble subtances and therefore capsules filled with nateglinide drug subtances powder of its low disintegrating ability. As a result, such nateglinide-containing preparations cannot show the fast-acting and short duration effect in decreasing blood glucose level (fast-acting hypoglycemic agent), which is characteristic of nateglinide. In order to show the characteristic efficacy of nateglinide, the drug needs to be released rapidly from preparations and so improvement on a preparation has been required. Rapid disintegration may be of paramount significance in eliminating the erratic absorbtion behavior releated to co-administration with food, and may help eliciting a more benificial therapeutic effect.

The physical properties of nateglinide create unpredictable dissolution rates and lead to absorption problems. The use of surfactants in pharmaceutical formulations to assist in disintegration and dissolution of drug material is well known. Lachman et al. in Theory and Practice of Industrial Pharmacy, second edition, page 108-9, discloses the use of surface active agents or surfactants in almost every dosage form including liquids, semi-solids and solids. The surfactants play an important role in the absorption and efficacy of certain drugs. It leads to a surprising and unexpected discovery of use of surfactants to enhance the solubility and dissolution of solid dose oral formulations of poorly soluble drugs like nateglinide.

THE AIM OF THE INVENTION

The aim of invention of oral tablet compositions containing Nateglinide and surfactant- pH adjusting agent system;

- To enhance the solubility and dissolution of solid dose oral formulations of poorly soluble drugs like nateglinide.

- To eliminate disintegration problem of tablets containing Nateglinide

- To provide the absorbtion of nateglinide via a specific transport system(s) in the intestine.

- To provide the nateglinide-containing preparations show the fast-acting short duration effect in decreasing blood glucose level ( fast-acting hypoglycemic agent), which is characteristic of nateglinide.

DEFINITION OF FIGURES

Figures are given below to explain well of the invention of oral tablet compositions containing Nateglinide and surfactant-pH adjusting Agent.

Figure 1- XRPD diagram of Form U

Figure 2- Dissolution profile of Example 5 and referance product in 0.01N HCI (containing % 0.5 SLS) dissoluion media. Figure 3- Dissolution profile of Example 5 and referance product in pH 4.5 (containing

% 0.25 SLS) dissoluion media. Figure 4- Dissolution profile of Example 5 and referance product in pH 6.8 (containing

% 0.1 SLS) dissoluion media.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a tablet composition containing nateglinide as the active ingredient and a surfactant-pH adjusting agent system.

The composition may further include one or more pharmaceutically acceptable excipients including filler, binder, disintegrant, surfactant, pH adjusting agent, lubricant, glidant coloring agent and film forming agents.

The filler may be one or more of corn starch, lactose, mannitol, maltodextrin, sucrose, sugar compressible, sorbitol, calcium carbonate, magnesium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulphate, microcrystalline cellulose, silificied microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose and mixtures thereof.

The binder may be one or more of polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pregelatinezed starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof.

The disintegrant may be one or more of crospovidone, copovidone, sodium starch glycolate, croscarmellose sodium, polacrilin potassium, starch derivates, hydroxypropyl cellulose and mixtures thereof.

The surfactant may be one or more of sodium lauryl sulphate, potassium dodecyl sulphonate, sodium dodecyl benzene sulphonate, sodium salt of lauryl polyoxyethylene sulphate, lauryl polyoxyethylene oxide sulphate, lauryl polyethylene oxide sulphonate, dioctyl ester of sodium sulphosuccinic acid or sodium lauryl sulphonate, polysorbate derivates, nonyl phenol polyoxyethylene ether, tridecyl alcohol poyoxyethylene ether, dodecyl mercaptane polyoxyethylene thioether, the lauric ester of polyetylene glycol, the lauric ester of sorbitan polyoxyethylene ether or tertiary alkyl amine oxide, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, stearyl trimethyl ammonium chloride, cetyl prydinium chloride, cetyl trimethyl ammonium bromide, stearyl amine salts, stearyl dimethyl amine hydrochloride, alkyl phenoxyetoxyethyl dimethyl ammonium chloride, decyl pridinium bromide, pyridinium chloride derivative of the acetyl amino ethyl esters of lauric acids, lauryl trimethyl ammonium chloride, decyl amine acetate, lauryl dimethyl ethyl ammonium chloride, the lactic acid and sitric acid and other acids salts of stearyl-1-amidoimidazoline with methyl chloride, benzyl chlorid, chloro acetic acid, and mixtures thereof.

The pH adjusting agent may be one or more of acetic acid, ammonia solution, monoethanole amine, diethanoleamine, triethanoleamine meglumine, sodium citrate, citric acid, hhdrochloric acid, lactic acid, phospharic acid, propionic acid, sulphiric acid, tartaric acid, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium hydroxide and mixtures thereof.

The lubricant may be one or more of, calcium stearate, glycerin mono stearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, magnesium stearate, medium-chain triglycerides, myristic acid, sodium stearyl fumarate, stearic acid, talc, zinc stearate and mixtures thereof.

The glidant may be one or more of calcium silicate, collidal silicon dioxide, silicon dioxide, magnesium silicate, magnesium trisilicate, talc and mixtures thereof.

The film forming agents may be one or more of ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymetyhl cellulose, hyroxyethyl cellulose, hydroxypropylmethyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; waxes such as polyethylene glycol; methacrylic acid polymers marketed such as trade names Eudragit® E and S; and the like and mixture thereof. Alternatively; coomercial available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.

Eudragit® E is the trade name of dimethylamino methacrylate-notralized methacrylate copolymer. Eudragit® S is the trade name of methacrylicacid copolymer ( Type A, USP/NF)

Opadry® is generally containing film forming agents such as; hydroxypropylmethyl cellulose, propylene glycol, polyvinyl alcohol, ethyl cellulose, methyl cellulose and additionaly color pigments, plasticizer and antiadherent materials.

Suitable coloring agents include on or more FDA approved colors for oral use. The compositions of nateglinide may be prepared by processes known in the prior art including mixing, granulation, melting, sieving, filling, dryig, molding, immersing, coating, compressing, extrusion-spheronization, etc.

The oral solid composition of nateglinide may be prepared by processes, for example, wet granulation, dry granulation or direct compression and may be in the form of tablets or capsules.

The processes of direct compression may include preparing a blend of nateglinide, surfactant, filler, disintegrant, binder, lubricant and glidant; and compressing the blend into a tablet.

The process of dry granulation may be carried out by slugging or roller compaction. The composition of nateglinide may be prepared by the process of blending nateglinide, surfactant, filler, disintegrant and binder; compacting or slugging the blend; breaking the slugs to make granules; lubricating and compressing the lubricated granules.

The process of wet granulation may be carried out by blending nateglinide, surfactant, pH adjusting agent, filler and disintegrant; and granulating the blend with a solution/dispersion of the binder. Alternatively, nateglinide, filler, disintegrant, binder and glidant; and the granulating the blend wtih a solution/disoersion of the surfactant and pH adjusting agent. The granules are dried and may be mixed with other excipients like disintegrant, lubricant, glidants, extra-granular filler and coloring agents and compressed with a suitable punches into tablets. The granulation may also be carried out in a fluidized bed-dryer and siezing may be done by milling or pulverizing.

The tablets prepared by the present invention may be considered may be coated one or more additional layers of 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 pan processor; and dip coating. Suitable solvents used for preparing a solution/dispersion of the coating ingredients includes methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.

The term 'nateglinide' as used herein includes nateglinide in a free or pharmaceutically salt form, in crystalline or amorphous form. For example, the nateglinide may be the-U type crystal modification. The active ingredients or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or solvates thereof. The amount of nateglinide to be used may vary from about 5% to 70% (w/w), and in particular, from about 15% to about 40% (w/w) of the total pharmaceutical composition.

The term "filler' or is a bulking agent, providing a quantity of material which can accurately be formed into a tablet. Fillers fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. By increasing the bulk volume, the final product has the proper volume for patient handling. The amount of filler to be used may vary from about %15-%90 (w/w).

The term 'binder' are used in pharmaceutical solid formulations to add cohesiveness to poweders, thereby providing the necessary bonding to form granules, which under compaction form a cohesive mass or compact referred to as a tablet. The formation of granules aids in the conversion of powders-of widely varying particle sizes-to granules, which may more uniformly flow from the hopper to the feed system, and uniformly fill the die cavity. The amount of binder to be used may vary from about % 0,5 to about %10 (w/w). And in particular from about 0,5 % to about 5 % (w/w), of the total pharmaceutical composition.

The term ^λdisintegrants' as used herein includes a substance that facilitate the breakup of a tablet after administration. Disintegrating agents may be added prior to granulation or during the lubrication step prior to compression or at borh processing steps. The amount of disintegrant to be used may vary from about % 0,5 to about %10 (w/w).

The term 'surfactans' as used herein includes a substance that lowers the surface tension of the medium in which it is dissolved, and/or the interfacial tension with other phases, and, accordingly, is positively adsorbed at the liquid/vapor and/or at other interfaces. Suitable surfactans include one or more of anionic, noionic, cationic and mixtures thereof.

The nonionic surfactans have a hydrophobic/hydrophilic balance wherein there is neither a negative nor a positive charge in either part of the molecule, thus giving it the nonionic terminology. The amount of surfactant to be used may vary from about % 0,5 to about %10 (w/w). And in particular from about 0,5 % to about 3 % (w/w), of the total pharmaceutical composition.

The term ^λpH adjusting agent' as used herein includes a substance that adjust the pH of pharmaceutical forms to intended use. Also they have the function of solubility enhancing activity by increasing or decreasing the pH of the medium which can be site of action and/or buffer solutions. The term 'lubricants' as used herein includes a substance that reduce the friction arising at the interface of tablet and the die wall during compression and ejection. The amount of lubricant to be used may vary from about % 0,25 to about %5 (w/w). And in particular from about 0,25 % to about 2 % (w/w), of the total pharmaceutical composition.

The term ^vglidants' as used herein includes a substance that improves flow characteristics of the granulation, Gidants can improve the flow of granulations from hoppers into feed mechanism and ultimately into the die cavity. The amount of disintegrant to be used may vary from about % 0,25 to about %8 (w/w). And in particular from about 0,25 % to about %5 (w/w), of the total pharmaceutical composition.

In the NDA rewiev (New Drug Application) of Novartis Pharmaceuticals published in FDA documents, the dissolution method (USP, Apparatus II, paddle, 75rpm, Ph 6.8 phosphate buffer, 1000ml) found to be unsatisfactory for the following reasons

- Lack of discrimination between samples manufactured with varying process parameters

- The dissolution of the tablet appears to be due to an erosive process rather than disintegration based on visual inspection-despite the high solubility of the nateglinide drug substance in the pH 6.8 phosphate buffer

The absorbtion window of nateglinide ( pH 5.5 to 7.0) and the ionization of the drug in the intestinal phsiological pH 6.5 make the dissolution behavior of nateglinide in alkaline pH, more important for the in-vivo bioavability.

In the present invention we have found that when nateglinide is used with a combination of surfactant-pH adjusting system in a tablet formulation, the dissolution propeties of nateglinide in alkaline pH improve, and there is no lack of discrimination between samples manufactured with varying process parameters and also the dissolution of tablets apperars to be disintegration based on visiual inspection.

Also we have found that micronized nateglinide particles exhibit enhanced solubility by increasing the effective surface area. Highly micronized nateglinide particles possess poor flow properties and increased chances of re-agglomeration during processing. We have found the optimal particle size distrubition of micronized nateglinide that does not have any negative effect on solubility and process.

The following examples are illustrative of the invention, and are not to be construed as limiting the invention. EXAMPLE 1

* Concentration may be adjusted to maintain constant tablet weight based on the quantity of nateglinide potency.

PROCEDURE

1. Nateglinide (d₉o<15Oμm), lactose, polyvinylpyrrolidone, croscarmellose sodium, colloidal silicon dioxide are passed through a screen and than mixed in a high shear blender to give a uniform dry mixture.

2. Deionized water are added slowly to the dry mixture of Step 1 under fast mixing in a high shear mixer granulator and the bulk is then granulated.

3. The wet granules are dried in a drying oven/fludized bed dryer, passed through a screen.

4. The extragranular croscarmellose sodium, microcrystalline cellulose, talc are mixed and blended with the granules 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. EXAMPLE 2

PROCEDURE

1. Nateglinide (d₉₀<150μm), lactose, polyvinylpyrrolidone, croscarmellose sodium, colloidal silicon dioxide are passed through a screen and than mixed in a high shear blender to give a uniform dry mixture.

2. Deionized water, polysorbate 80 and meglumine are added slowly to the dry mixture of Step 1 under fast mixing in a high shear mixer granulator and the bulk is then granulated.

5. The magnesium stearate is passed through a screen, blended with the blend of step 4 and the total mixture is compressed into tablets. EXAMPLE 3

PROCEDURE

1. Nateglinide (dgo<15Oμm), lactose, polyvinylpyrrolidone, croscarmellose sodium, colloidal silicon dioxide are passed through a screen and than mixed in a high shear blender to give a uniform dry mixture.

5. The magnesium stearate is passed through a screen, blended with the blend of step 4 and the total mixture is compressed into tablets. EXAMPLE 4

PROCEDURE

1. Nateglinide (dg_O<15Oμm), lactose, polyvinylpyrrolidone, croscarmellose sodium, colloidal silicon dioxide are passed through a screen and than mixed in a high shear blender to give a uniform dry mixture.

2. Deionized water, polysorbate 80 and meglumine are added slowly to the dry mixture of Step 1 under fast mixing in a high shear mixer granulator and the- bulk is then granulated.

5. The magnesium stearate is passed through a screen, blended with the blend of step 4 and the total mixture is compressed into tablets. EXAMPLE 5

PROCEDURE

1. Nateglinide (dg₀<150μm), lactose, polyvinylpyrrolidone, croscarmellose sodium, colloidal silicon dioxide are passed through a screen and than mixed in a high shear blender to give a uniform dry mixture,

2. Deionized water ,polysorbate 80 and meglumine are added slowly to the dry mixture of Step 1 under fast mixing in a high shear mixer granulator and the bulk is then granulated.

5. The magnesium stearate is passed through a screen, blended with the blend of step 4 and the total mixture is compressed into tablets. EXAMPLE 6

PROCEDURE

5. The magnesium stearate is passed through a screen, blended with the blend of step 4 and the total mixture is compressed into tablets. EXAMPLE 7

PROCEDURE

5. The magnesium stearate is passed through a screen, blended with the blend of step 4 and the total mixture is compressed into tablets. EXAMPLE 8

PROCEDURE

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 Dissolut

The in vitro release of nateglinide from tablets as per the compositions of examples studied with the methods mentioned below;

1) Method for 0.01 N HCl

Apparatus : USP Paddle

Dissolution media : 0.01N HCI (including 0.5 % SLS)

Volume : 1000 ml

Time : 60 minute

Speed : 50 rpm

Temperature : 37 ± 0.5 ⁰C

Choromotographic Conditions :

Method UPLC

Dedector PDA

Column Acquity UPLC C18, 50*2.1 mm,1.7μm

Column Temperature 3O⁰C

Flow rate 0.400 mL / min.

Wave Length 210 nm

Enjection volume l μL

Enjection Technique Partial loop with needle overfill (PLUNO)

Loop 2 μL

Data Collection Rate 10 point / sec.

Enjection time 2 min.

Weak Needle Wash Water R: Methanol R (80.20)

Strong Needle Wash Water R: Methanol R (20.80)

Seal Wash Water R: Methanol R (10.90)

Solvent Dissolution media

Mobil Phase 450.0 mL pH 2.5 buffer and 550.0 mL Acetonitril R are mixed and degased by filtering through 0.20 μm filter. 2) Method for pH 4.5

Apparatus USP Paddle

Dissolution media pH 4.5 acetate buffer (including 0.25 % SLS)

Volume 1000 ml

Time 60 minute

Speed 50 rpm

Temperature 37 + 0.5 ⁰C

Chromatographic Conditions :

Method UPLC

Dedector PDA

Column Acquity UPLC C18, 50*2.1 mm,1.7μm

Column Temperature 3O⁰C

Flow rate 0.400 mL / min.

Wave Length 210 nm

Enjection volume l μL

Enjection Technique Partial loop with needle overfill (PLUNO)

Loop 2 μL

Data Collection Rate 10 point / sec.

Enjection time 2 min.

Weak Needle Wash Water R : Methanol R (80:20)

Strong Needle Wash Water R : Methanol R (20:80)

Seal Wash Water R : Methanol R (10:90)

Solvent Dissolution media

Mobil Phase 450.0 mL pH 2.5 buffer and 550.0 mL Acetonitril R are mixed and degased by filtering through 0.20 μm filter. 3) Method for pH 6.8

Apparatus USP Paddle

Dissolution media pH 6.8 phosphate buffer (including 0.1 % SLS)

Volume 1000 ml

Time 60 minute

Speed 50 rpm

Temperature 37 ± 0.5 ⁰C

Chromatographic Conditions :

Method UPLC

Dedector PDA

Column Acquity UPLC C18, 50*2.1 mm,1.7μm

Column Temperature 3O⁰C

Flow rate 0.400 mL / min.

Wave Length 210 nm

Enjection volume 1 Im¬

Enjection Technique partial loop with needle overfill (PLUNO)

Loop 2 μL

Data Collection Rate 10 point / sec.

Enjection time 2 min.

Weak Needle Wash Water R : Methanol R (80:20)

Strong Needle Wash Water R : Methanol R (20:80)

Seal Wash Water R : Methanol R (10:90)

Solvent Dissolution media

Mobil Phase 450.0 mL pH 2.3 buffer and 550.0 mL Acetonitril R are mixed and degased by filtering through 0.20 μm filter.

The in vitro release of nateglinide from tablets as per the compositions of examples in 0.01 N HCI were given in Table 1.

The in vitro release of nateglinide from tablets as per the compositions of examples in pH 4.5 were given in Table 2.

The in vitro release of nateglinide from tablets as per the compositions of examples in pH 6.8 were given in Table 3. Table 1. The in vitro release of nateglinide from tablets as per the compositions of examples in 0.01 N HCI

K>

Table 2. The in vitro release of nateglinide from tablets as per the compositions of examples in pH 4.5

Table 3. The in vitro release of nateglinide from tablets as per the compositions of examples in pH 6.8

Related formulation, as compared taoiets containing surfactant- pH adjusting agent system (1:1-3.8) dissolution profiles, it is found that combination of surfactant-pH adjusting system in a tablet formulation, the dissolution propeties of nateglinide in alkaline pH improve, and disssolution rate is more discrimitive compared referance product (Starlix®) especially in pH 6.8 and the dissolution of the tablet appears to be due to an erosive process rather than disintegration based on visual inspection.

Related formulation, as compared tablets containing surfactant- pH adjusting agent system (1:1-3.8) dissolution profiles, it is found that combination of surfactant-pH adjusting system in a tablet formulation, the best result obtained with .Example 5 (polysorbate- meglumine 1:1.5). Dissolution is beter formulations containing polysorbate-meglumine 1:1- 1:3.8 than Example 1.

Similarity factor [f₂) used for comparing dissolution profiles is given below.

Dissolution profiles is compared using the above similarity factor. R_t and T_t is the % dissolved drug in a time point of the Reference Product and the Test Product. The dissolution profile can be expected as similar when the {f₂) result is between 50 to 100.

Similarity factor (f₂) results of Example 5 and referance product are given below.

Dissolution profile of Example 5 and referance product in 0.01N HCI dissoluion media is given in Figure 2.

Dissolution profile of Example 5 and referance product in pH 4.5 dissoluion media is given in Figure 3.

Dissolution profile of Example 5 and referance product in pH 6,8 dissoluion media is given in Figure 4.

Claims

1. An oral solid composition comprising; a) Nateglinide or pharmaceutically acceptable salts thereof; and b) At least one pharmaceutically acceptable surfactant-pH adjusting agent system,

2. The oral solid composition of claim I₇ wherein the nateglinide comprises an amount of from about the 15 % w/w to about 70% w/w of the composition.

3. The oral solid composition of claim 1, wherein the nateglinide comprises Form U type crystal modification.

4. The oral solid composition of claim 1, wherein the surfactant comprises one or more of anionic, nonionic, cationic, and mixtures thereof.

5. The oral solid composition of claim 4, wherein the surfactant is one or more nonionic surfactant; polysorbate 80, nonyl phenol polyoxyethylene ether, lauric ester of polyethylene glycol, tridecyl alcohol polyoxyethylene ether, dodecyl mercaptan polyoxyethylene thioether, and mixtures thereof.

6. The oral solid composition of claim 5, wherein the surfactant is polysorbate 80.

7. The oral solid composition of claim 6, wherein the polysorbate 80 comprises an amount of 0.5% w/w to about 1.5 % w/w of the composition.

8. The oral solid composition of claim 1, wherein the pH adjusting agent comprises one or more acidifying or alkalizing agent, and mixtures thereof.

9. The oral solid composition of claim 8, wherein the pH adjusting agent comprises one or more alkalizing agent; ammonia solution, monoethanoleamine, diethanoleamine, triethanoleamine, meglumine, sodium citrate, potassium carbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium hydroxide, and mixtures thereof. lO.The oral solid composition of claim 9, wherein the pH adjusting agent is meglumine. ll.The oral solid composition of claim 10, wherein the meglumine comprises an amount of 1.0 % w/w to about 1.9 % w/w of the composition.

12.The oral solid composition of claim 1, wherein the surfactant-pH adjusting agent system is polysorbate 80:meglumine mixture.

13.The oral solid composition of claim 12, wherein the polysorbate 80:meg!umine system comprises a ratio of 1 : 3.8.

14,The oral solid composition of claim 1, wherein the composition comprises one or more pharmaceutically acceptable excipients comprising fillers, binders, disintegrants, surfactants, pH adjusting agents, lubricants, glidants and coating agents.

15.The oral solid composition of claim 14, wherein the filler comprises one or more of corn starch, lactose, mannitol, maltodextrin, sucrose, sugar compressible, sorbitol, calcium carbonate, magnesium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulphate, microcrystalline cellulose, silificied microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose and mixtures thereof. lβ.The oral solid composition of claim 15, wherein the fillers are lactose and microcrystalline cellulose.

17.The oral solid composition of claim 14, wherein the binder comprises one or more of polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pregelatinezed starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof.

18-The oral solid composition of claim 17, wherein the binder is polyvinylpyrrolidone. lθ.The oral solid composition of claim 14, wherein the disintegrant comprises one or more of crospovidone, copovidone, sodium starch glycolate, croscarmellose sodium, polacrilin potassium, starch derivates, hydroxypropyl cellulose, and mixtures thereof.

2O.The oral solid composition of claim 19, wherein the disintegrant is croscarmellose sodium.

21.The oral solid composition of claim 14, wherein the lubricant comprises one or more of calcium stearate, glycerin mono stearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, magnesium stearate, medium-chain triglycerides, myristic acid, palmitic acid, sodium stearyl fumarate, stearic acid, talc, zinc stearate and mixtures thereof.

22.The oral solid composition of claim 21, wherein the lubricant is magnesium stearate.

23.The oral solid composition of claim 14, wherein the glidant comprises one or more of calcium silicate, collidal silicon dioxide, silicon dioxide, magnesium silicate, magnesium trisilicate, talc and mixtures thereof. 24,The oral solid composition of claim 23, wherein the glidant is collida! silicon dioxide and talc.

25.The oral solid composition of claim 14, wherein the film forming agents may be one or more of ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymetyhl cellulose, hyroxyethyl cellulose, hydroxypropylmethy! phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; waxes such as polyethylene glycol; dimethylamino methacrylate- notralized methacrylate copolymer, methacrylicacid copolymer ( Type A, USP/NF) and mixtures thereof.

26.The oral solid composition of claim 25, wherein the film forming agents may be one or more hydroxypropylmethyl cellulose, propylene glycol, polyvinyl alcohol, ethyl cellulose, methyl cellulose and additionaly color pigments, plasticizer and antiadherent materials and mixtures thereof.

27.The oral solid composition of claim 26, wherein the solution/dispersion of film coating solvent is distilled water.

28.The process of claim l,comprisinig; blending nateglinide with one or more of filler, disintegrant, binder and glidant to form a blend; granulation with surfactantipH adjusting agent system, drying, pulverizing, lubricating, compressed the granulation into tablets; and film coating with a coating agent.

29.The process of claim 28, comprising; granulation of blend wherein the granulation liquid is water.

30.Comprising a mixture of polysorbate: meglumine system and water as granulation agent.

31.The process of claim 30, where in there is no conversion of Form U of nateglinide to any other polymorphic form during processing of the Form U of nateglinide.

32.An oral solid composition comprising; a) Nateglinide or pharmaceutically acceptable salts thereof; and b) At least one pharmaceutically acceptable surfactant-pH adjusting agent system, wherein the nateglinide has a particle size of d₉₀<150μm