EP4045048A1

EP4045048A1 - Oral formulations comprising sitagliptin hci monohydrate with improved pharmaceutical characteristics

Info

Publication number: EP4045048A1
Application number: EP19949416.2A
Authority: EP
Inventors: Ersin Yildirim; Bayram Kanik; Fatma ÖZTÜRK; Tansel AKTA; Celil ÜNLÜ
Original assignee: Santa Farma Ilac Sanayi A S; Santa Farma Ilac Sanayi AS
Current assignee: Santa Farma Ilac Sanayi A S; Santa Farma Ilac Sanayi AS
Priority date: 2019-10-14
Filing date: 2019-10-14
Publication date: 2022-08-24
Also published as: WO2021076066A1; EP4045048A4

Abstract

An oral pharmaceutical formulation in the form of an immediate release tablet comprising sitagliptin hydrochloride, preferably monohydrate manufactured by using wet granulation method wherein croscarmellose sodium and dibasic calcium phosphate are used both in intragranular and extragranular phases. The total amount ratio of croscarmellose sodium used in intragranular and extragranular phases to the total amount of composition is between 1:5 and 5:1, preferably between 1:2 and 2:1, more preferably 1:2.5 and, the amount of ratio of dibasic calcium phosphate in intragranular to the amount of ratio of dibasic calcium phosphate in extragranular phases is 1:5, preferably 1:2, more preferably 1:1.

Description

ORAL FORMULATIONS COMPRISING SITAGLIPTIN HCI MONOHYDRATE WITH IMPROVED PHARMACEUTICAL CHARACTERISTICS

FIELD OF INVENTION

The present invention relates to a pharmaceutical composition, comprising sitagliptin hydrochloride monohydrate, wherein the pharmaceutical composition is in an oral solid dosage form with improved pharmaceutical characteristics.

STATE OF ART

Sitagliptin, the chemical name of which is (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazol[4,3- a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine, is a member of a class of antihyperglycemic agents called dipeptidyl peptidase 4 (DPP-IV) inhibitors which improve blood glucose control in type 2 diabetes patients by increasing the concentrations of incretin hormones.

Incretin hormones, including glucagon-like peptide- 1 (GLP-1) and glucose dependent insulinotropic peptide (GIP), are released by the intestine throughout the day and their concentrations increase in response to food intake. The activity of GLP-1 and of GIP is limited by the DPP-IV enzyme which quickly hydrolyzes incretins and transforms them into inactive products. Sitagliptin prevents this incretin hydrolysis by DPP-IV, so plasma concentrations of active forms of GLP-1 and GIP increase. As a result, sitagliptin increases insulin release and reduces the concentration of glucagon in a glucose dependent manner. The empirical formula of sitagliptin is C16H15F6N50 and the compound has a molecular weight of 407.3 g/mol. The structural formula of sitagliptin is shown in the Formula I.

Formula i

Molecular weight of Sitagliptin hydrochloride is 443.77 g/mole, and molecular weight of Sitagliptin hydrochloride monohydrate is 461.77 mg/mole. Sitagliptin base and its pharmaceutically acceptable acid addition salts first have been described in EP1412357. In particular, Example 7 at the EP1412357 discloses the preparation of sitagliptin base and its pharmaceutically acceptable salt thereof, particularly hydrochloride salt. Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median T_max) occurring 1 to 4 hours after the administration. The absolute bioavailability of sitagliptin is approximately 87%. Since co administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, it may be administered with or without food. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%). Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.

Sitagliptin was first commercially authorized in EU by the European Medicines Agency on 20.03.2007. The medicinal product is currently marketed in the form of film coated tablets under the trade name of Januvia^® in the strengths of 100 mg, 50 mg, and 25 mg per tablet.

Combination product of sitagliptin and its acceptable salt there of with metformin HCI was first commercially authorized in EU by the European Medicines Agency on 16.07.2008. The medicinal product is currently marketed in the form of film coated tablets under the trade name of Janumet^® in the strengths of 50 mg/500 mg, 50 mg/850 mg and 50 mg/1000 mg per tablet.

The marketed originator products comprise phosphate monohydrate salt of sitagliptin as active substance.

Likewise, in relation to the marketed medicinal product, a subsequent EP 1654263 specifically protects the dihydrogen phosphate salt of the dipeptidyl peptidase-IV inhibitor sitagliptin and crystalline hydrates thereof, in particular a crystalline monohydrate.

In the state of art there are many patents/patent applications which are summarized below. WO2015114152 relates to stable pharmaceutical composition in the form of immediate release tablets comprising sitagliptin hydrochloride monohydrate wherein the pharmaceutical composition is prepared by dry granulation. A compacted granulate comprising sitagliptin HCI monohydrate has a particle size volume distribution with a D90 between 150 and 450 microns, when measured by laser diffraction analysis.

W02012131005 relates to stable pharmaceutical compositions comprising amorphous sitagliptin in a stable and readily bioavailable form. The amorphous sitagliptin has been prepared from a solution comprising sitagliptin and a crystallization inhibitor, wherein the sitagliptin is sitagliptin hydrochloride and the crystallization inhibitor is polyvinylpyrrolidone, and wherein the composition further comprises a pharmaceutically acceptable excipient which is microcrystalline cellulose.

EP2578208 relates to formulation comprising DPP-IV inhibitor with at least one binding dry granulation excipient which is polycarbophil by using briquette pressing or compression between rollers. EP1852108 relates to solid pharmaceutical compositions comprising as an active ingredient a

DPP IV inhibitor compound with an amino group or a salt thereof, a first diluent, a second diluent, a binder, a disintegrant and a lubricant by using wet granulation manufacturing method.

W02006078593 relates to a compressed pharmaceutical tablet comprising DPP-IV inhibitor formulations manufactured by using direct compression method wherein DPP-IV inhibitor is in free form or in acid addition salt form, at least 60% or 80%, and the particle size distribution in the tablet is less than 250 pm.

TR2011/08763 relates to a pharmaceutical formulation comprising DPP-IV inhibitor and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer manufactured by using hot-melt granulation method.

TR2016/10368 relates to a pharmaceutical film tablet formulation comprising 31-32% w/w of sitagliptin phosphate anhydrous as active ingredient wherein the auxiliary agents are microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, sodium stearyl fumarate, magnesium stearate and coating material wherein the tablet is obtained by direct compression method. Moreover, 14 to 16% w/w microcrystalline cellulose is used as diluent agent.

W02006033848 relates to a pharmaceutical compositions comprising amorphous sitagliptin phosphate prepared by a direct compression process. However, despite great efforts the present inventors have not been able to prepare stable pharmaceutical composition according to W02006033848 because the amorphous sitagliptin phosphate in the tablets crystallized.

W02016016770 relates to a novel modified release pharmaceutical composition of sitagliptin or pharmaceutically acceptable salt thereof and one or more rate controlling excipients, wherein the composition provides mean plasma concentration of sitagliptin in the range of about 100 nM to about 850 nM over a period of at least 24 hours after once daily oral administration to a subject.

W02009111200 relates to a pharmaceutical formulations comprising an inner core tablet composition comprising metformin hydrochloride. The inner core is coated with a sustained- release polymer and further comprises a coating comprising an immediate release composition of sitagliptin. When dissolving such tablets, firstly the sitagliptin from the immediate release coating is released. After dissolution of the immediate release coating, the sustained-release of the metformin hydrochloride starts

W02008113000 relates to a pharmaceutical composition for treating diabetes consisting of a slow release core comprising metformin or a pharmaceutically acceptable salt thereof as a first active ingredient and optionally one pharmaceutically acceptable excipient and an immediate release layer comprising a dipeptidyl peptidase IV inhibitor or a pharmaceutically acceptable salt thereof as a second active ingredient.

W02009099734 relates to a pharmaceutical compositions providing an extended release of metformin and an immediate release of sitagliptin. The tablet core is comprised of metformin and an extended release excipient (HPMC). The tablet core is then coated with immediate release polymer comprising sitagliptin

EP2356985 relates to a pharmaceutical composition comprising at least two separate compartments, wherein one compartment contains a composition comprising metformin or a pharmaceutically acceptable salt thereof and wherein another compartment contains a composition comprising sitagliptin or a pharmaceutically acceptable salt thereof, wherein at least one of the compartments represents an extended release composition, and wherein none of said two compartments represents a coating.

WO2013110085 relates to a multi-layer oral dosage form includes a first layer with a therapeutically effective amount of metformin or a pharmaceutically acceptable salt thereof and a hydrophobic rate controlling excipient. A second layer with a therapeutically effect amount of sitagliptin or a pharmaceutically acceptable salt thereof.

W02014170770 relates to a solid oral pharmaceutical composition comprising sitagliptin or a salt thereof, metformin or a salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is devoid of glidant and/or surface active agent.

Sitagliptin is indicated for adult patients with type 2 diabetes mellitus, to improve glycaemic control. 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 indicated as dual oral therapy in combination with: metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control; a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic 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 glycaemic 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 glycaemic 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 glycaemic 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 glycaemic control.

Different manufacturing methods for solid formulations comprising sitagliptin and its acceptable salts are explained in the prior art documents stated above. Especially, sitagliptin phosphate is defined as the active substance.

In accordance with the prior arts, there is a need for a solid pharmaceutical formulation comprising sitagliptin HCI, particularly monohydrate. Further, the inventors of the present invention have surprisingly succeeded in formulating an immediate release dosage form of sitagliptin with improved pharmaceutical characteristics by using wet granulation method.

SUMMARY OF INVENTION The object of this invention is to develop a immediate release oral pharmaceutical formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof, which has DPP-IV inhibition, glycemic controlling properties, to provide additional advantages to the relevant technique.

The present invention relates to an immediate release solid oral composition comprising sitagliptin and one or more acceptable excipients manufactured by using optimised wet granulation process.

Another object of the present invention is related to an oral dosage form composition for the treatment of of diabetes mellitus type 2, also known as non-insulin dependent diabetes mellitus. Another object of the present invention is a pharmaceutical composition comprising only sitagliptin as active substance. In another embodiment, pharmaceutical composition is the combination of sitagliptin and metformin.

Another object of the present invention is to provide a preparation method of a pharmaceutical composition of sitagliptin wherein the pharmaceutical compositions herein disclosed can be manufactured into solid dosage forms, such as tablets having good stability and the desired dissolution profiles.

In a preferred embodiment present invention, the active agent is sitagliptin hydrochloride monohydrate. In another preferred embodiment, the active agent is crystalline sitagliptin hydrochloride. Preferably, the active agent is sitagliptin hydrochloride monohydrate. Another object of the present invention is to provide a pharmaceutical compositions containing sitagliptin HCI monohydrate by using wet granulation process wherein provided for the manufacture of tablets containg the active ingredient, fillers, diluents, disintegrants, solubilizers, and lubricants etc. In another object of the present invention is provide a pharmaceutical compositions containing sitagliptin wherein the total weight of the sitagliptin HCI is less than 30% w/w by total tablet weight.

In another object of the present invention is provide a pharmaceutical composition containing sitagliptin HCI with optimized amounts of excipients and manufactured by using wet granulation method.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a solid oral dosage form comprising sitagliptin and optimized amounts of pharmaceutically acceptable excipients manufactured by using the most proper manufacturing method.

In the prior art documents, formulations comprising sitagliptin and its pharmaceutically acceptable excipients are mostly manufactured by the methods like direct compression and dry granulation.

Direct compression and dry granulation (slugging or roller compaction) and type of excipients are selected to give the tablet formulation the desired physical characteristics that allow for the rapid compression of the tablets. After compression, the tablets must have a number of additional attributes, such as appearance, hardness, disintegrating ability and an acceptable dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the drug, behavior of the mixture during processing and the properties of the final tablets. Preformulation studies are done to determine the chemical and physical compatibility of the active component with proposed excipients.

Dry granulation is usually described as a method of controlled crushing of precompacted powders densified by either slugging or passing the material between two counter-rotating rolls. More specifically, powdered components that may contain very fine particles are typically mixed prior to being compacted to yield hard slugs which are then ground and sieved before the addition of other ingredients and final compression to form tablets. Because substantially no liquids are used in the dry granulation process, the issues related to wet granulation are avoided. Although dry granulation would in many cases appear to be the best way to produce products such as tablets containing APIs, it has been relatively little used because of the challenges in producing the desired kind of granules as well as managing the granulated material in the manufacturing process.

Direct compression is generally considered to be the simplest and the most economical process for producing tablets. However, it may only be applied to materials that do not need to be granulated before tableting. Direct compression requires only two principal steps; i.e., the mixing of all the ingredients and the compression of this mixture. However, direct compression is applicable to only a relatively small number of substances as the ingredients of the tablets often need to be processed by some granulation technique to make them compressible and/or for improving their homogenity and flowability.

The most important solid pharmaceutical composition example is explained in EP 1654263 patent which is dihydrogen phosphate salt monohydrate that is used in the marketed medicinal product. According the examples given in EP1654263 patent document, the manufacturing process of the sitagliptin comprising formulations is direct compression and roller compaction process.

In a preferred embodiment of the present invention is to provide a pharmaceutical compositions containing sitagliptin HCI monohydrate by using wet granulation process wherein provided for the manufacture of tablets containing the active ingredient, fillers, diluents, disintegrants and lubricants selected as to be the most suitable ones with respect to the intended form of administration.

In a preferred embodiment, suitable fillers and/or diluents may comprise but not limited to dibasic calcium phosphate dihydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. The most preferred fillers and/or diluents are dibasic calcium phosphate dihydrate and microcrystalline cellulose.

In a preferred embodiment, the pharmaceutical composition comprises at least a disintegrant, preferably, it is selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof. More preferably, the disintegrant is croscarmellose sodium.

In a preferred embodiment, the pharmaceutical composition comprises at least a lubricant, preferably, it is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. More preferably, the lubricant is sodium stearyl fumarate, magnesium stearate or a mixture thereof, preferably is a mixture thereof.

Ingredients of composition and manufacturing method were designed to be similar with the example given in the relevant patent which is Formulation I is presented below. Formulation I: Formulation for Drug product manufactured by using direct compression method

In this embodiment of the present invention, a solid dosage form was composed of sitagliptin HCI monohydrate wherein detailed manufacturing steps are as presented below:

1. Sitagliptin hydrochloride monohydrate, Microcrystalline cellulose PH 102 and Dibasic calcium phosphate were screened through a proper sieve and stirred.

2. Croscarmellose sodium was screened through a proper sieve and then added to the powder blend prepared in Step 1 and stirred.

3. Sodium stearyl fumarate was screened through a proper sieve and added to the powder blend prepared in Step 2 and stirred. 4. Magnesium stearate was screened through a proper sieve and is added to the powder granulation prepared in Step 3 and are stirred to obtain a uniform final blend.

After getting final blend, the next step was considered as tablet compression. However, it is observed that the flowability of final blend was not suitable for the compression. Direct compression of powder requires materials exhibiting good flowability, compactibility and compressibility. The active substance used in the formulation of present invention is sitagliptin HCI monohydrate. The flowability of this substance is not good regarding its physical appearance tend to show segregation.

Further, dry granulation method is not performed with the current formulation due to poor flowability and segregation characteristic of drug substance. Moreover, wet granulation is more effective in comparison with the same quantum of the dry powder binder.

Thus, the manufacturing process of the sitagliptin was changed from direct compression to wet granulation because improving bonds between powder particles.

The wet granulation method is used to convert a powder blend into granules having suitable flow and cohesive properties for tableting. The procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation. The granulating fluid can be used alone or as a solvent containing binder or granulating agent. The choice of the granulating fluid depends greatly on the properties of the materials to be granulated. The damp mass is then shifted through a suitable screen and dried by tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill. The overall process includes weighing, dry powder blending, wet granulating, drying, milling, blending lubrication and compression.

According to Handbook of Pharmaceutical Excipients, povidone is used in a variety of pharmaceutical formulations and it is primarily used in solid-dosage forms. A binder is determined to be used as the same with originator product Janumet formulation; povidone. In tablet compression process, povidone solutions are used as binders in wet-granulation processes or povidone is added to powder blends in the dry form and granulated in situ by the addition of water, alcohol, or hydroalcoholic solutions. Based on this information, Povidone K30 was used as a binder at the wet granulation process. Small quantitative adjustments on the previous formulation and addition of povidone and sufficient amount of deionised water were done according to manufacturing method modification. Formulation II: Formulation for Drug product manufactured by using wet granulation method

2. Povidone K30 was dissolved in sufficient quantity of water and added to the intragranular phase prepared in Step 1 to perform granulation process.

3. The granules prepared in Step 2 were dried in fluid bed dryer and shifted through a proper sieve.

4. Croscarmellose sodium was screened through a proper sieve and added to the granules prepared in Step 3 and stirred.

5. Sodium stearyl fumarate was screened through a proper sieve and added to the granules prepared in Step 4 and stirred.

6. Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step 5 and stirred to obtain a uniform final blend.

7. Tablet compression was performed with the final blend in Step 6.

The flowability of final blend was good that leads tablet compression process to be achieved. Tablets obtained were subjected to routine analytical tests like disintegration which is the indication of dissolution release profile of the final product. Tablet should be disintegrated with the test performed explained in USP<701> Disintegration monograph, within the acceptance criteria of disintegration time of maximum 15 minutes for core tablet. The result was about 18 minutes which means that this formulation does not meet the specification. Disintegration time is directly affects the dissolution release profile. Based on this information, lower the disintegration time leads to high dissolution profile. Within this correlation, formulation is redesigned.

Wet granulation method let the powder prior to compression has better flowability. This means that the wet granulation method is the proper manufacturing method. However, it needs some adjustments to shorten the disintegration time with value of 18 minutes.

Disintegration refers to the mechanical break up of a compressed tablet into small granules upon ingestion and therefore it is characterised by the breakdown of the interparticulate bonds, which were forged during the compaction of the tablet. The interparticulate bonds in the formulation II was maintained with the binder povidone K30. Therefore, next formulation is redesigned comprising no binder.

To be able to achieve binding effect in the formulation without using a binder, amounts of Microcrystalline cellulose PH 102, Dibasic calcium phosphate, Croscarmellose sodium and deionised water were justified during manufacturing process to be performed successfully. These quantitative adjustments were directly affected tablet weight. In addition, particle size distribution of the granules was decreased by using smaller porous sieves to be wetted the granules more easily due to reach of expended surface area.

Formulation III: Modified Formulation for Drug product manufactured by using wet granulation method In this embodiment of the present invention, a solid dosage form was composed of sitagliptin HCI monohydrate wherein detailed manufacturing steps are as presented below:

1. Sitagliptin hydrochloride monohydrate, Microcrystalline cellulose PH 102, specified amount of Croscarmellose sodium and Dibasic calcium phosphate were screened through a proper sieve and stirred.

2. Sufficient quantity of water was added to the intragranular phase prepared in Step 1 to perform granulation process.

4. Remaining amount of Croscarmellose sodium was screened through a proper sieve and added to the granules prepared in Step 3 and stirred.

7. Tablet compression was performed with the final blend in Step 6.

It was observed that;

Flowability of the granules were good Granulation was not successful as it was expected At first disintegration test was performed on tablets obtained according to USP<701> Disintegration test to define whether the problem was resolved or not.

The result was between 7-8 minutes which is under acceptance criteria of maximum 15 minutes. It was understood that the modifications made were gave the opportunity to decrease the disintegration time. Tablets were subjected to in vitro dissolution study. The conditions of dissolution study are set by US FDA, based on the information available dissolution media is water. Other conditions are defined as; Volume of dissolution media is 900 ml, temperature of study is 37°C±0.5, rotation speed is 100 rpm, apparatus is paddle and the duration of dissolution study is 30 minutes. Table I: The results of dissolution study conducted on tablets obtained with Formulation III by using modified wet granulation method

As shown in Table I in which the comparative dissolution results of Formulation III and Reference drug product (Januvia ), release profile of reference drug product is faster than proposed formulation.

An improvement was needed in the formulation by using the same manufacturing method. Therefore, Formulation III was redesigned by doing modifications stated below along with the reasons.

Amount of Croscarmellose sodium was increased. The function of Croscarmellose sodium is disintegrant in the formulation, therefore it directly affects the disintegration time and dissolution release profile of drug product in solid dosage form. With increase in concentration of disintegrant, disintegration time decreases.

The specified amount of Croscarmellose was used in intragranular phase prior to granulation process (intragranular phase). Remaining amount was used after the granulation process (ex tragranular phase).

This method can be more effective. If both intragranular and extragranular methods are used, extragranular portion break the tablet into granules and the granules further disintegrate by intragranular portion to release the drug substance into solution.

Specified amount of dibasic calcium phosphate was remained unchanged and half amount of it was used in intragranular phase prior to granulation process (intragranular phase). Remaining amount was used after the granulation process (extragranular phase).

Dibasic calcium phosphate is a water insoluble functional filler, diluent and improves flow and compressibility for all powder blends. - Amounts of other excipients were adjusted by keeping constant the final weight. Formulation IV: Finally modified Formulation for Drug product manufactured by using wet granulation method

1. Sitagliptin hydrochloride monohydrate, Microcrystalline cellulose PH 102, specified amount of Croscarmellose sodium and specified amount of Dibasic calcium phosphate were screened through a proper sieve and stirred.

4. Remaining amounts of Croscarmellose sodium and Dibasic calcium phosphate were screened through a proper sieve and added to the granules prepared in Step 3 and stirred.

7. Tablet compression was performed with the final blend in Step 6.

8. Compressed tablets were coated with a defined coating agent.

The total amount ratio of Croscarmellose sodium to total pharmaceutical composition is between 1:5 to 5:1, preferably between 1:1 to 1:5, more preferably 1:2.5 by using wet granulation process comprising no binder. In addition, the amount of ratio of dibasic calcium phosphate in intragranular to the amount of ratio of dibasic calcium phosphate in extragranular phases is 1:5, preferably 1:2, more preferably 1:1.

It was observed that; - Flowability of the granules were better

Granulation process were performed successfully

Tablets were subjected to disintegration time, friability, in vitro dissolution profile analysis.

Disintegration time was found between 2-3 minutes.

Friability result was 0.15%. This test was performed according to USP <1216> Tablet Friability monograph.

Table II: The results of dissolution study conducted on tablets obtained with Formulation IV by using modified wet granulation method

Based on the results of disintegration time, friability and dissolution profile analysis both disintegration time and dissolution profile study results were improved and more similar to originator product authorized by EMA and FDA.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. An oral pharmaceutical formulation in the form of an immediate release tablet comprising sitagliptin hydrochloride, preferably monohydrate manufactured by using wet granulation method wherein croscarmellose sodium and dibasic calcium phosphate are used both in intragranular and extragranular phases and,

-the total amount ratio of croscarmellose sodium used in intragranular and extragranular phases to the total amount of composition is between 1:5 and 5:1, preferably between 1:2 and 2:1, more preferably 1:2.5 and,

- the amount of ratio of dibasic calcium phosphate in intragranular to the amount of ratio of dibasic calcium phosphate in extragranular phases is 1:5, preferably 1:2, more preferably 1:1.

2. An oral pharmaceutical composition according to claim 1, wherein filler/diluent is selected from the group dibasic calcium phosphate dihydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof, preferably dibasic calcium phosphate dihydrate and microcrystalline cellulose.

3. An oral pharmaceutical composition according to claim 1, wherein disintegrant is selected from the group croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof, preferably croscarmellose sodium.

4. An oral pharmaceutical composition according to claim 1, wherein lubricant is selected from the group sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof, preferably sodium stearyl fumarate, magnesium stearate or a mixture thereof..

5. The pharmaceutical formulation according to claim 1, wherein no binder in the form of powder and/or dispersed in a solvent is used.

6. An oral pharmaceutical composition according to claim 1 wherein the formulation in w/w % is as stated below:

Sitagliptin HCI monohydrate 15 - 25

Microcrystalline cellulose 20 - 30

Dibasic calcium phosphate 40 - 50 Croscarmellose sodium 0.1 - 4 Sodium stearyl fumarate 0.1 - 4 Magnesium stearate 0.1 - 2 Deionised water Quantity sufficient

7. An oral pharmaceutical composition according to claim 1 wherein manufacturing process comprises the following steps: a. Sitagliptin hydrochloride monohydrate, Microcrystalline cellulose PH 102, specified amount of Croscarmellose sodium and specified amount of Dibasic calcium phosphate were screened through a proper sieve and stirred. b. Sufficient quantity of water was added to the intragranular phase prepared in Step a to perform granulation process. c. The granules prepared in Step b were dried in fluid bed dryer and screened through a proper sieve. d. Remaining amounts of Croscarmellose sodium and Dibasic calcium phosphate were screened through a proper sieve and added to the granules prepared in Step c and stirred. e. Sodium stearyl fumarate was screened through a proper sieve and added to the granules prepared in Step d and stirred. f. Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step e and stirred to obtain a uniform final blend. g. Tablet compression was performed with the final blend in Step f. h. Compressed tablets were coated with a defined coating agent.

8. An oral pharmaceutical composition according to claim 1 wherein the pharmaceutical formulation further comprises metformin.