Claims:1. An immediate release composition comprising Sitagliptin hydrochloride and/or solvate and one or more pharmaceutical excipient(s), wherein the composition is prepared by wet granulation.
2. An immediate release composition as claimed in claim 1 wherein the composition is selected from bead, granules, tablets and capsules.
3. An immediate release composition as claimed in claim 1 comprising Sitagliptin hydrochloride is in the form of anhydrous or monohydrate.
4. An immediate release composition as claimed in claim 1 wherein the pharmaceutical excipient is selected from diluents, disintegrants, binders, lubricants, surfactants, glidants, sweeteners, anti-tacking agents, coloring agents and flavoring agents.
5. An immediate release composition as claimed in claim 1 wherein the wet granulation is carried out by using suitable solvent(s) selected form water, methanol, ethanol, isopropyl alcohol, acetone and mixtures thereof

6. An immediate release composition as claimed in claim 1 optionally comprising an antidiabetic agent selected from metformin, buformin, acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide, glimepride, gliplizide, gliclazide, chlorpropamide, tolbutamide, phenformin, alogliptin, linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, saroglitazar, englitazone, darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, cangliflozin, dapagliflozin, remogliflozin and sergliflozin.
7. An immediate release composition as claimed in claim 1 characterized in that the composition is stabilized by suitable packaging configuration which prevents moisture absorption.
8. An immediate release composition as claimed in claim 7 wherein the moisture barrier is selected from PVC coated with PVDC / PE or Alu/Alu.
9. An immediate release composition as claimed in claim 1 wherein the composition is stable for 6 months at 40°C and 75% relative humidity.
10. An immediate release composition as claimed in claim 1 wherein the composition is administered orally. , Description:FIELD OF THE INVENTION

The present invention relates to an immediate release composition of Sitagliptin hydrochloride prepared by wet granulation process.

BACKGROUND OF THE INVENTION

Sitagliptin is a dipeptidyl peptidase IV inhibitor used in the treatment and prevention of Type 2 diabetes, also known as non-insulin dependent diabetes mellitus.

United States Patent number 6699871 (assigned to Merck & Co., referred to herein as ‘871) describes a class of beta-amino tetrahydrotriazolo –[4,3-a] pyrazines, which are potent inhibitors of DDP-IV useful in the treatment of type 2 diabetes. Specifically disclosed herein is Sitagliptin which is chemically (2R)-4-oxo-4-[3-(trifluromethyl)-5,6–dihyro[1,2,4]-triazolo [4,3-a] pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine. Sitagliptin is currently marketed in the form of film coated tablets wherein sitagliptin is in the form of the phosphate monohydrate salt. It is indicated to improve glycaemic control for adult patients with type 2 diabetes mellitus, It is indicated as monotherapy in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance. It is also indicated as dual oral therapy in combination with: metformin - when diet and exercise plus metformin alone do not provide adequate control; a sulphonylurea - when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate control and when metformin is inappropriate due to contraindications or intolerance; a peroxisome proliferator-activated receptor gamma (PPARy) agonist (i.e. a thiazolidinedione) when use of a PPARY agonist is appropriate and when diet and exercise plus the PPARY agonist alone do not provide adequate control. It is indicated as triple oral

therapy in combination with a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate control; a PPARy agonist and metformin when use of a PPARy agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate control. Sitagliptin is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate control.

PCT publication WO2005/072530 (assigned to Merck & Co., referred to herein as ‘530) teaches various crystalline salts of Sitagliptin namely hydrochloride, tartrate, benzenesulfonate, p-toluenesulfonate and 10-camphorsulfonate. It further exemplifies Sitagliptin 100 mg tablets prepared by the process of direct compression of crystalline salts and excipients such as mannitol, croscarmellose sodium, microcrystalline cellulose and magnesium stearate. However, as Sitagliptin is known to be sticky direct compression may not provide uniform distribution of the active ingredient. The present invention prepares tablets by wet granulation of Sitagliptin or its pharmaceutically acceptable salts and/or solvates.

PCT publication WO2007/078726 (assigned to Merck & Co., referred to herein as ‘726) exemplifies pharmaceutical composition by wet granulation of sitagliptin phosphate and metformin together. The present invention provides immediate release composition of sitagliptin hydrochloride by the wet granulation process.

PCT publication WO2015/114152 (assigned to Galenicum Health S.L., referred to herein as ‘152) suggests dry granulation of sitagliptin hydrochloride. Dry granulation is a tedious process and needs more time in commercial scale. It also requires strict process controls for compaction force, granule flow and the like. The present invention prepares tablets by wet granulation of Sitagliptin or its pharmaceutically acceptable salts and/or solvates.

OBJECT OF THE INVENTION

The object of the present invention is to provide immediate release composition of Sitagliptin hydrochloride prepared by wet granulation for oral administration.

Another object of the present invention is to provide immediate release composition of Sitagliptin hydrochloride prepared by wet granulation for oral administration which are stable.

SUMMARY OF THE INVENTION

An immediate release composition comprising Sitagliptin hydrochloride and/or solvate and one or more pharmaceutical excipient(s), wherein the composition is prepared by wet granulation.

DESCRIPTION OF THE INVENTION

Immediate release compositions of sitagliptin are found useful to treat human with type II diabetes.

According to one embodiment of the present invention is an immediate release composition of Sitagliptin hydrochloride prepared by the process of wet granulation of active ingredient and/or solvate and one or more pharmaceutical excipient(s).

The amount of active ingredient sitagliptin present in the composition according to the present invention can be 1-300 mg, preferably 5-200 mg and most preferably 10-100 mg of sitagliptin.
It is preferred that the composition according to the present invention comprises 1 to 50 wt% , preferably 10 to 40 wt% more preferably 20 to 40 wt% of sitagliptin based on the total weight of the composition.

The composition may be selected from beads, granules, tablets and capsules.

The composition may comprise sitagliptin hydrochloride selected from anhydrous or monohydrate.

The composition of the present invention is administered orally.

The pharmaceutical excipient used in the composition of the present invention may be selected from diluents, disintegrants, binders, lubricants, surfactants, glidants, sweeteners, anti-tacking agents, coloring agents and flavoring agents.
The diluents may be selected from microcrystalline cellulose, lactose (anhydrous and monohydrate), combinations of crystalline cellulose with lactose (brand names - Cellactose, Tabletosse), guar gum, silicified cellulose, corn starch, maize starch, starch derivatives such as prege1atinized starch, calcium hydrogen phosphate in anhydrous and hydrated form, sugar, fructose, dextrates, sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, lactiol, and/ or other sugars such as saccharose, raffinose, trehalose, fructose or mixtures thereof, calcium carbonate, calcium lactate and/or mixtures thereof.

The diluent may be in an amount of 10 to 99 weight%, preferably 25 to 90 weight% of the weight of the composition.

The pharmaceutical composition according to the invention preferably comprises one or more diluents selected from the group consisting of microcrystalline cellulose, lactose monohydrate, mannitol and mixtures thereof. Furthermore, it is preferred that the pharmaceutical composition according to the invention comprises 10 to 99 wt.-%, more preferably 25 to 90 wt.-%, most preferably 40 to 70 wt % of diluent, based on the total weight of the pharmaceutical composition.

The disintegrants may be selected from crospovidone, starch, starch derivatives such as pregelatinised starch and sodium starch glycollate, microcrystalline cellulose, carboxymethylcellulose sodium (CMC-Na, croscarmellose sodium) or calcium (CMC-Ca), cross-linked CMC-Na, polacrilin potassium, low substituted hydroxypropyl cellulose and/or mixtures thereof and can be present in an amount of 1 to 50 weight%. preferably 2 to 45 weight% based on the weight composition. Preferably, the composition of the present invention comprises croscarmellose sodium as disintergant.

The binders may be selected from polyvinylpyrrolidone, microcrystalline cellulose, cellulose ether, hydroxyethy1 cellulose, hydroxypropy1 cellulose, hydroxypropy1 methylcellulose, corn starch, maize starch, pregelatinised starch, polymethacry1ate, or mixtures thereof. The binder can be present in a range of 0.5 to 25 weight%, preferably 1 to 20 weight% on the weight of the
composition.

The lubricants may be selected from stearic acid, magnesium stearate, magnesium palmitate, magnesium oleate, magnesium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, glyceryl behanate, macrogols and/or mixtures thereof and can be present in a range of 0.1 to 10 weight%, preferably 0.5 to 5 weight% based on the weight of
the composition. Preferably, the pharmaceutical composition comprises a lubricant selected from the group consisting of magnesium stearate and sodium stearyl fumarate.

The surfactants may be selected from anionic surfactants such as sodium lauryl sulfate and docusate sodium, cationic surfactants such as cetrimide, ampholytic surfactants such as N-dodecyl-N,N-dimethylbetaine, non-ionic surfactants such as sorbitan fatty acid esters (e.g. Spans® ), polysorbates (e.g.polyoxyethylene alkyl ethers, poloxamers, mediumchain triglycerides, polyoxylglycerides, polyoxyethylene castor oil derivates (e. g. Cremophor ® ) and/or mixtures thereof & can be present in a range of 0.1 to 10 weight%, preferably 0.5 to 5 weight% based on the weight of the composition.

The glidants may be selected from colloidal silicon dioxide, talc, stearic acid, palmitic acid, polyethylene glycol, carnauba wax and/ or mixtures thereof and can be present in a range of 0.1 to 10 weight%, preferably 0.5 to 5 weight% based on the weight of the composition.

The sweetener can be selected from acesulfame K, sucralose, alitame, aspartame, saccharin sodium, dipotassium glycyrrhizinate, thaumatin and the like.

The coloring agents may be selected from natural pigments and inorganic materials.

The flavoring agents may be selected from natural or synthetic materials, such as orange, spearmint, strawberry and cream flavour and the like.

The immediate release composition of the present invention may be prepared by wet granulation of sitagliptin hydrochloride and/or its solvate and one or more pharmaceutical excipients wherein wet granulation may be carried out using suitable solvent(s) selected from water, methanol, ethanol, isopropyl alcohol, acetone and mixtures thereof.

The wet granulation process may be carried out with suitable solvent(s) on
(a) sitagliptin hydrochloride and/or its solvate followed by addition of extragranular excipients; or
(b) mixture of sitagliptin hydrochloride and/or its solvate and one or more excipients.

The granulated mass may be dried and used as granules or converted into beads or mixed with additional excipients and filled in sachets.

The granulated mass may be optionally dried and mixed with additional excipients prior to formation of beads or compression into tablets.

The term “immediate release” as described herein refers to release of the active ingredient immediately on reaching the stomach. The immediate release composition of the present invention may be film coated which provides improved surface smoothness and color, increased chemical and physical stability of Sitagliptin due to reduced permeability of oxygen and/ or water vapor, less disintegration of the solid composition in acidic medium resulting in decreased gastrointestinal side effects, and easier swallowing of tablet.

The film coating materials may be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, povidone and copovidone, graft copolymers of polyethyleneglycol and polyvinyl alcohol (Kollicoat IR) , shellac, polymers of methacrylic acid or methacrylic acid esters, methacrylic acid-methyl acrylate copolymers, polyvinyl alcohol, plasticizers such as propylene glycol, polyethylene glycol, glycerol triacetate, triethyl citrate, antitacking agents such as talc, glycerol monostearate, magnesium stearate and colorants or pigments such as titanium dioxide or iron oxide.

The immediate release composition of the present invention may optionally comprise an antidiabetic agent selected from metformin, buformin, acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide, glimepride, gliplizide, gliclazide, chlorpropamide, tolbutamide, phenformin, alogliptin, linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, saroglitazar, englitazone, darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, cangliflozin, dapagliflozin, remogliflozin, sergliflozin and the like.

The invention also relates to a packaged pharmaceutical composition comprising the composition described above packaged in a blister made of single or multiple polymer and/or aluminum layers such as PVC coated with PVDC/PE or Alu/Alu for stabilization. The packaging prevents moisture absorption. Typically the packaged composition is packaged with an atmosphere having a reduced oxygen concentration such as below 15 vol%, preferably below 10 vol%, more preferably below 5 vol% oxygen. The composition may be packaged with a nitrogen atmosphere.

The immediate release compositions were packaged in blister packaging and stored at 40°C / 75% relative humidity.

The immediate release compositions according to the present invention packaged in blister packaging do not degrade and are found to be stable as it prevents moisture absorption for 6 months at 40°C / 75% relative humidity.

The term stable defined herein is composition with % impurities of less than 0.2% by weight of Sitagliptin when tested in conventional manner after storage for 6 months at 40°C and 75% relative humidity. The content of sitagliptin and its degradation products in the composition was evaluated by HPLC.

The immediate release composition of the present invention is for oral administration.

The immediate release composition of the present invention may preferably comprise
(a) 1 to 50 weight% sitagliptin hydrochloride;
(b) 25 to 90 weight% diluents;
(c) 2 to 45 weight% disintegrants;
(d) 1 to 20 weight% binders;
(e) optionally glidants, sweeteners, flavoring agents, coloring agents;
(f) optionally an antidiabetic agent;
(g) optionally film coated; and
(h) packaged in PVC coated with PVDC/PE or Alu/Alu
wherein the weight % is on the weight of the composition and the composition is prepared by wet granulation and is stable for 6 months at 40°C / 75% relative humidity.

The immediate release composition of the present invention is bioequivalent to the reference product.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.

EXAMPLES

Example 1: Product of the present invention :

Sr. No. Ingredients % weight by weight Typical composition mg
1. Sitagliptin Hydrochloride equivalent to Sitagliptin 20-35 108.950
2. Cellulose, Microcrystalline 25 - 35 110.050
3. Calcium Hydrogen Phosphate 5-15 46.000
4. Croscarmellose Sodium 3-12 34.000
5. Povidone 1-7 18.000
6. Solvent* Qs Qs
7. Sodium Stearyl Fumarate 0.1-2 2.000
8. Magnesium Stearate 0.1-2 1.000
9. Opadry II beige (85F570014) 2-5 10.000

* Ethanol, Methanol, Acetone, Isopropyl alcohol, Dichloromethane

Process:

1. Co-sift Sitagliptin Hydrochloride, Calcium Hydrogen Phosphate Anhydrous, Cellulose, Microcrystalline and Croscarmellose Sodium and charge to granulator
2. Prepare the binder solution by dissolving povidone in solvent
3. Granulate step-1 by using step-2 and dry the wet granules
4. Lubricate the dried and sized granules with lubricants
5. Compress the blend to form tablets and coat

Example 2 : Comparison of dissolution profile :

Time points (Min.) Januvia 100 mg Product of the present invention
0 0 0
5 68 72
10 85 87
15 92 91
20 95 93
30 97 96
45 98 97

Example 3 : Bioequivalence studies

Parameters Geometric LSM T/R Ratio(%)
(90% Confidence Interval)
Treatment T Treatment R T vs R
AUC0-t (ng*hr/mL) 4695.91 4693.99 100.0411 ( 96.9930,103.1850 )
AUC0-inf (ng*hr/mL) 4856.69 4796.45 101.2559 ( 99.1658,103.3902 )
Cmax (ng/mL) 510.20 476.03 107.1794 ( 98.7648,116.3108 )

Example 4 : Stability studies

Sitagliptin Film Coated Tablets 100 mg prepared in Example 1
Pack details: PVDC PACK (250 Micron PVC/ 60 GSM PVDC, White opaque)

Condition: 40°C/75%RH
Parameters Initial 3M 6M
Appearance* Complies Complies Complies
Assay (%) 99.8 98.4 98.3
Water content (%) 4.9 5.7 5.0
Disintegration time 1 min 20 sec 1 min 09 sec 1 min 50 sec
Dissolution (%) 99 100 100
Related Substances (By HPLC)
Unspecified Impurities (%) 0 BLQ** BLQ**
Total Impurities (%) 0 0 0

*Appearance: Beige coloured, round, biconvex, film coated tablet debossed with ‘100’ on one side and plain on other side.
** BLQ: Below limit of quantification.

Stability data of Sitagliptin Film Coated Tablets 100 mg in PVDC Pack at 40ºC/75% RH condition was found to be satisfactory up to 6 months