WO2022228735A1 - Pharmaceutical composition comprising a combination of sitagliptin and metformin and method of preparation thereof - Google Patents

Pharmaceutical composition comprising a combination of sitagliptin and metformin and method of preparation thereof Download PDF

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Publication number
WO2022228735A1
WO2022228735A1 PCT/EP2022/025189 EP2022025189W WO2022228735A1 WO 2022228735 A1 WO2022228735 A1 WO 2022228735A1 EP 2022025189 W EP2022025189 W EP 2022025189W WO 2022228735 A1 WO2022228735 A1 WO 2022228735A1
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Prior art keywords
sitagliptin
weight
metformin
pharmaceutical composition
acceptable salt
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PCT/EP2022/025189
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French (fr)
Inventor
Evangelos Karavas
Efthymios Koutris
Vasiliki SAMARA
Ioanna Koutri
Anastasia Kalaskani
Andreas KAKOURIS
Manolis FOUSTERIS
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Pharmathen S.A.
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Publication of WO2022228735A1 publication Critical patent/WO2022228735A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a stable pharmaceutical composition for oral administration comprising in a single dosage form a therapeutically effective quantity of a dipeptidyl peptidase 4 (DPP -4) inhibitor such as Sitagliptin or pharmaceutical acceptable salt thereof and a biguanide with antihyperglycemic effect such as Metformin or pharmaceutically acceptable salt thereof, and a method for the preparation thereof.
  • DPP -4 dipeptidyl peptidase 4
  • Diabetes mellitus is a condition defined by persistently high levels of sugar (glucose) in the blood.
  • Glucose is a small, simple sugar that serves as a primary fuel for energy production, especially for the brain, muscles and several other body organs and tissues.
  • Glucose also serves as a building block for larger structural molecules of the body, such as glycoproteins and glycolipids.
  • the human body tightly regulates glucose levels. Abnormally high or low levels result in serious, potentially life-threatening complications such as cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes, cognitive impairment.
  • Type 2 diabetes is the most common form of diabetes. It was once called adult-onset diabetes because it typically begins in middle or older age. But more and more teens and young adults are also developing it now a day due to increased obesity.
  • Dipepidyl peptidase-4 (DPP -4) inhibitors represent a class of agents that are being developed for the treatment or improvement in glycemic control in type 2 diabetes.
  • DPP -4 inhibitors include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin.
  • Sitagliptin works to competitively inhibit the enzyme DPP -4 resulting in driving blood glucose levels towards normal and tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia), which is seen with some other oral hypoglycemic agents.
  • Sitagliptin Hydrochloride Monohydrate 7-[(3R)-3-Amino- 1 -oxo-4-(2, 4, 5-trifluorophenyl) butyl] -5, 6, 7, 8- tetrahydro -3- (trifluoromethyl)- 1,2,4-triazo lo[ 4,3-a. ]pyrazine hydrochloride monohydrate.
  • the molecular formula is C16H16CIF6N5O H2O corresponding to a molecular weight of 461.79.
  • Sitagliptin Hydrochloride exhibits polymorphism.
  • the polymorph used in the present invention matches with API HCL Form III (as per USV Ltd WO 2012/025944 A3 patent) and HCL crystalline form stated to WO 2012/147092 A2 (as per Cadila Healthcare Ltd).
  • the characteristic peaks of Sitagliptin Hydrochloride Monohydrate are the following: 6.6°, 8.0°, 13.7°, 16.0°, 18.0° and 27.0° 2Q ⁇ 0.2° 2Q.
  • Metformin is a biguanide with antihyperglycaemic effect, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
  • Metformin hydrochloride 3-(diaminomethylidene)-l,l- dimethylguanidine hydrochloride.
  • the molecular formula is C 4 H 12 CIN 5 corresponding to a molecular weight of 165.6. It is a white or almost white crystalline powder which is freely soluble in water, slightly soluble in alcohol (96%), practically insoluble in acetone and in methylene chloride.
  • Metformin Hydrochloride exhibits polymorphism.
  • the polymorph used for the development of current pharmaceutical product described herein matches with API Form A (as per Scott .L. Childs et al, Crystal growth & design, 441-449, Vol.4, No.3, 2004).
  • the characteristic peaks of Metformin Hydrochloride are the following: 12.3°, 13.8°, 17.7°, 22.4°, 24.6°, 25.4°, 31.3° and 37.2° 2Q.
  • Combination products are known to offer several advantages. First, the concentrations of the active ingredients (APIs) are consistently maintained within an optimal therapeutic range for both APIs. Secondly, combination products have been shown to improve patient compliance. Finally, combination products have more advantages for the treatment of Type 2 diabetes as it has been shown that single treatment along with diet and exercise fails quickly. In the present invention, it has been surprisingly observed that an unexpected and synergistic therapeutic benefit can be obtained in the treatment of type-2 diabetes with a combination therapy comprising Metformin and Sitagliptin.
  • EP-B-2477660 discloses a pharmaceutical composition comprising Metformin and Sitagliptin or Vildagliptin in combination with a lubricant wherein the lubricant is polyethylene glycol or mixtures of polyethylene glycol with one or more other lubricants and comprises more than 10% by weight of the total weight of the composition.
  • US-A-2019/099368 discloses a chewable dosage form having a matrix comprising: a combination of Metformin HC1 and Sitagliptin or salt thereof; fully or partially pregelatinized starch, a texture modifying gum; a lubricant, an emulsifier, a flavoring agent; and a sweetener.
  • the main object of the present invention is to provide a pharmaceutical composition comprising a fixed dose combination of Sitagliptin or a pharmaceutically acceptable salt thereof and Metformin or pharmaceutically acceptable salt thereof which overcomes the deficiencies of the prior art.
  • the composition of the present invention is an immediate release composition intended for oral administration.
  • a further object of the present invention is to provide a pharmaceutical composition which is bioavailable and has acceptable pharmacotechnical properties.
  • a major object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients in order to achieve the appropriate dissolution profile and stability for the finished dosage form.
  • Said dosage form affords predictable and reproducible drug release rates in order to achieve better treatment to a patient.
  • a further approach of the present invention is to provide a method for the preparation of a stable combined solid dosage formulation for oral administration containing Sitagliptin and Metformin which results in longer shelf-life of the product.
  • a further aspect of the present invention relates to a pharmaceutical formulation comprising Sitagliptin and Metformin as active ingredients, wherein croscarmellose sodium is included in product formula and formulation is stable for 6months without any issue at assay & related substances of both active ingredients.
  • a pharmaceutical composition for oral administration comprising in a single dosage form a combination of Sitagliptin hydrochloride monohydrate and Metformin hydrochloride as active ingredients wherein the required Sitagliptin amount is dispensed in external phase (extragranularly) of product formula after drying and sizing step of wet granules.
  • a process for the preparation of a stable, solid dosage form for oral administration comprising a DPP -4 inhibitor such as Sitagliptin or pharmaceutical acceptable salt thereof and a biguanide with antihyperglycemic effect such as Metformin or pharmaceutically acceptable salt thereof wherein the composition comprises croscarmellose in external phase of product formula, which comprises the following steps: a) pre-mixing of binder with Metformin drug substance b) dispensing an aqueous solvent in the premixed blend of drug substance from previous step to form granular mass, wherein the granular mass is processed as following: c) drying the granular mass of step (b) until the water content level is well below acceptable limits, d) sizing the granular mass through a sieve of appropriate mesh size, e) mixing granular mass of previous step with Sitagliptin, a diluent and a disintegrant, f) adding glidant and blending to form a DPP -4 inhibitor such as Sitagliptin
  • a pharmaceutical composition comprising an active ingredient (e.g. Sitagliptin and Metformin) is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
  • an active ingredient e.g. Sitagliptin and Metformin
  • the wording excipient and/or API dispensed in the external phase or extragranular excipient has the meaning of an excipient added during manufacturing process after wet granulation and drying phase.
  • the wording excipient and/or API dispensed in the internal phase or intragranular excipient has the opposite meaning i.e. the wet granulated and dried mass.
  • the expression by weight refers to by weight of the total weight of the composition, unless otherwise stated.
  • the primary goal of the present invention is to develop an immediate release fixed dose combination composition
  • an immediate release fixed dose combination composition comprising Sitagliptin or a pharmaceutical acceptable salt thereof and Metformin or a pharmaceutically acceptable salt thereof that is simple to manufacture, bioavailable, cost effective, stable and possesses good pharmacotechnical properties when compared to the reference product.
  • the properties of the drug or drugs, its dosage forms and the economics of the operation will determine selection of the best process for tableting.
  • wet granulation and direct compression are used in developing a tablet.
  • the dry granulation method may be used when one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted. The method consists of blending, slugging the ingredients, dry screening, lubrication and compression.
  • the wet granulation method is used to convert a powder mixture 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 damp mass is then screened 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.
  • powders do not have sufficient adhesive or cohesive properties to form hard, strong granules.
  • a binder is usually required to bond the powder particles together due to the poor cohesive properties of most powders. Heat and moisture sensitive drugs cannot usually be manufactured using wet granulation.
  • the size and shape of the resulting tablet should be considered since an easy oral administration to a patient is required, as well as an easy tablet manufacturing process which meets all the herein described requirements.
  • the high-dose Sitagliptin and Metformin tablets have to meet all the herein listed requirements with preferably a limited number and amount of pharmaceutical excipients to reduce the size of the tablet.
  • Granulation liquids that are typically used include water, ethanol and isopropanol, either alone or in combination. Water is the preferred granulation liquid for the present invention.
  • the main objective of the present invention is to develop a robust and stable immediate release film-coated tablet comprising a fixed dose combination of Sitagliptin and Metformin in two strengths 50/850mg and 50/1000mg respectively.
  • the excipients were selected to enhance dissolution, physicochemical properties and stability of drug substances in the finished dosage form and thus were subjected to compatibility study with the APIs.
  • the preferred formulation of this invention comprises Sitagliptin and Metformin as the active ingredients, one or more binders, diluents, a disintegrant and optionally a lubricant.
  • the excipients have been carefully selected after many optimization steps.
  • Binder excipients are formulated to act as an adhesive, to literally “bind together” powders, granules and other dry ingredients to impart to the product the necessary mechanical strength. Binders are added to create a more effective and predictable granule formation.
  • Examples of pharmaceutically acceptable binders include, but are not limited to, starches; polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose hydroxylethyl cellulose, hydroxylpropylmethyl cellulose; sucrose; dextrose; com syrup; polysaccharides; and gelatin.
  • the binder may be present in an amount from about 5% to about 40% by weight of the composition.
  • Povidone also known as polyvinylpyrrolidone is the preferred binder in the present invention. It is used in a variety of manufacturing processes such as a dry binder for direct compression, as a granulating agent, as a retarding and as a film-forming agent as well as in taste-masking applications. Povidone is an excellent binder in wet granulation for the production of tablets and granules, since it is readily soluble in all the usual solvents. It can then be added either as a solution during granulation, or dry to the other ingredients, in which case the solvent is added alone during granulation.
  • the preferred concentration of povidone in the present invention is from 5 to 10% w/w of the total weight of the tablet and more preferably from 6 to 8% w/w of the total weight of the tablet.
  • composition of the present invention may also contain diluents and fillers.
  • pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • the filler and/or diluent may be present in an amount from about 8% to about 40% by weight of the composition.
  • the preferred diluent in the present invention is microcrystalline cellulose and is used in an amount from 8 to 15% w/w of the total weight of the tablet and more preferably from 8 to 10% w/w of the total weight of the tablet.
  • Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration.
  • One, two, three or more disintegrants can be selected.
  • pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross- linked polymers, e.g., cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium or croscarmellose); soy polysaccharides; and guar gum, sodium starch glycolate.
  • the preferred disintegrant in the present invention is croscarmellose sodium.
  • the disintegrant may be present in an amount from about 0% to about 2%, more preferably from about 0.1% to about 1% of the total weight of the tablet.
  • Surfactants are materials that lower the surface tension between two liquids or between a liquid and a solid.
  • Surfactants can be selected from sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate, sulphosuccinates such as sodium dioctyl sulphosuccinate, partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, partial fatty acid esters of sorbitan such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylenesorbitan such as polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers (Pluronic®) or ethoxylated triglycerides.
  • sodium lauryl sulphate is employed as a surfactant in the present invention.
  • sodium lauryl sulphate is employed as
  • Lubricants or glidants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Such glidants are commonly included in the final tablet mix in amounts usually less than 1% by weight.
  • the glidant component may be hydrophobic or hydrophilic. One, two, three or more glidants can be selected. Examples of pharmaceutically acceptable glidants include, but are not limited to, colloidal silica dioxide, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, sodium stearyl fumarate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • the glidant may be present in an amount preferably from about 0.1% to about 5% by weight of the composition and most preferably from about 0.1% to about 2% by weight of the composition.
  • Sodium stearyl fumarate is the preferred glidant in the present invention. It reduces the friction between the die wall and tablet mix during the compression and ejection of the tablets. It helps prevent adhesion of tablets to the punches and dies. It is stable and does not polymerize within the tableting mix and it has a higher degree of API compatibility than the most commonly used magnesium stearate.
  • the pharmaceutical composition of the present invention is obtained by wet granulation of the Metformin granules in the presence of a binder, drying and subsequent addition of a disintegrant, a diluent and Sitagliptin and optionally one or more further pharmaceutically acceptable excipients.
  • the tablet as described in the present invention comprises as active ingredients, i) between 1 to 35%, preferably between 1.5 to 25% of Sitaglitptin or a pharmaceutically acceptable salt thereof, ii) between 65 to 98.5%, preferably between 75 to 98.5% of Metformin or a pharmaceutically acceptable salt thereof. iii) not less than 5% by weight binder, 0% to 1% by weight disintegrant, not less than 8% by weight diluent, 0% to 2% by weight glidant.
  • the scope of present invention is the preparation of an oral solid dosage form comprising Sitagliptin and Metformin (as HCL salts) drug substances and exhibiting an immediate drug release profile at aqueous medium.
  • the pharmaceutical composition shall be bioequivalent to reference product as per acceptance criteria indicated for generic products and be stable under different storage conditions.
  • Formulation trial 1 is shown in Table 1 below. Povidone was selected as a binder, sodium lauryl sulphate was selected as a surfactant, microcrystalline cellulose was selected as diluent/filler and sodium stearyl fumarate as a lubricant/glidant. Both Sitagliptin and Metformin (as HCL salts) are dispensed in wet granules as described in manufacturing process. Table 1: Qualitative and quantitative Formulation trial 1.
  • the manufacturing process comprises the following steps: pre-mixing of povidone with Sitagliptin and Metformin, - dissolution of sodium lauryl sulfate in purified water and dispensing of aqueous preparation in the premixed blend of APIs of step (a) to form granular mass: further wherein the granular mass is processed as following: a) drying the granular mass of previous step at 40°C until the water content level is well below acceptable limits, b) sizing the granular mass through a sieve of appropriate mesh size, c) mixing granular mass of previous step with microcrystalline cellulose, d) adding glidant (sodium stearyl fumarate) and blending to form a final blend, e) compression of final blend, f) coating of compressed tablets with appropriate coloring agent.
  • pre-mixing of povidone with Sitagliptin and Metformin - dissolution of sodium lauryl sulfate in purified water and dispensing of aqueous preparation in
  • the physicochemical characteristics of Formulation trial 1 were determined by recording the in vitro dissolution profile in Buffer 0.025M NaCl for 45min at 75 rpm (USP II) in comparison to reference product. An immediate drug release profile was recorded for reference product with % drug release more than 85% at 15min. The results are shown in Table 2 below and show the dissolution of both APIs separately for the 50mg/1000mg strength tablet.
  • an alternative manufacturing process comprising of Sitagliptin dispensed at external phase was also evaluated as following: a) pre-mixing of binder (povidone) with Metformin drug substance b) dispensing aqueous solvent (purified water) in the premixed blend of drug substance of step (a) to form granular mass: further wherein the granular mass is processed as following: c) drying the granular mass of step (b) until the water content level is well below acceptable limits, d) sizing the granular mass through a sieve of appropriate mesh size, e) mixing granular mass of step (d) with Sitagliptin, diluent (microcrystalline cellulose) and disintegrant (croscarmellose sodium), f) adding glidant and blending to form a final blend, g) compression of final blend, h) coating of compressed tablets with
  • Table 8A Dissolution profile for Sitagliptin for trial 3
  • Table 8B Dissolution profile for Metformin for trial 3
  • Sitagliptin API dispensing at external phase of product formula does not significantly impact the drug release of APIs as well as the physicochemical characteristics of coated tablets (i.e. disintegration & uniformity of dosage units).
  • significantly lower related substances levels (unknown related substances) were recorded for Sitagliptin HCL API compared to Formulation Trial 2.
  • Sitagliptin HCL API is selected to be dispensed in external phase of current product formula rather than in wet granules.
  • Different levels of diluent (microcrystalline cellulose-MCC) and binder (povidone) were also evaluated within the context of current invention as per following formulation trials Sitagliptin/Metformin 50/1000mg fc tabs.
  • both povidone and microcrystalline cellulose content impact the drug release rate as well as hardness and disintegration. More particularly, higher results at early time interval of dissolution testing (5min) were recorded when lower diluent & binder content was applied to product formula. However, lower disintegration and hardness were recorded compared to reference product. Additionally, the drug release at early time interval was suppressed at higher binder content level which is also reflected on disintegration results. Tablets hardness was slightly increased under higher MCC content. Considering the current results, the medium level is proposed for both diluent and binder ingredients for current product formula.
  • the manufacturing process for preparing the preferred composition of the present invention comprises of the following steps: a) pre-mixing of binder (povidone) with Metformin drug substance b) dispensing an aqueous solvent (purified water) in the premixed blend of drug substance of step (a) to form granular mass: further wherein the granular mass is processed as following: c) drying the granular mass of step (b) until the water content level is well below acceptable limits, d) sizing the granular mass through a sieve of appropriate mesh size, e) mixing granular mass of step (d) with Sitagliptin, diluent (microcrystalline cellulose) and disintegrant (croscarmellose sodium), f) adding glidant and blending to form a final blend, g) compression of final blend, h) coating of compressed tablets with appropriate coloring agent.
  • Table 12A Dissolution results of Sitagliptin API, Optimum Formulation Trial
  • Table 12B Dissolution results of Metformin API, Optimum Formulation Trial
  • Table 14A Dissolution profile for Sitagliptin at zero time and 6 months for Optimum Formulation Trial
  • Table 14B Dissolution profile for Metformin at zero time and 6 months for Optimum Formulation Trial
  • Sitagliptin HCL API Based on X-ray analysis of Sitagliptin HCL API, it seems that material matches to crystalline polymorph Form III (as per USV Ltd WO 2012/025944 A3 patent) and HCL crystalline form stated to WO 2012/147092 A2 (as per Cadila Healthcare Ltd). Additionally, Metformin HCL API matches to Form A (as per Scott L.Childs et al, Crystal growth & design, 441-449, Vol.4, No.3, 2004). Considering stability results, it can be stated that crystalline form of Sitagliptin HCL and Metformin HCL API remains stable in finished product even under storage of 6m at accelerated conditions.

Abstract

The present invention relates to a solid pharmaceutical composition comprising a fixed dose combination of Sitagliptin or a pharmaceutically acceptable salt thereof and Metformin or a pharmaceutically acceptable salt thereof, for oral administration and a process for the preparation thereof. The pharmaceutical composition of the present invention is to be used for the treatment of Type 2 diabetes.

Description

PHARMACEUTICAL COMPOSITION COMPRISING A COMBINATION OF SITAGLIPTIN AND METFORMIN AND METHOD OF PREPARATION THEREOF
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition for oral administration comprising in a single dosage form a therapeutically effective quantity of a dipeptidyl peptidase 4 (DPP -4) inhibitor such as Sitagliptin or pharmaceutical acceptable salt thereof and a biguanide with antihyperglycemic effect such as Metformin or pharmaceutically acceptable salt thereof, and a method for the preparation thereof.
BACKROUND OF THE INVENTION
Diabetes mellitus is a condition defined by persistently high levels of sugar (glucose) in the blood. Glucose is a small, simple sugar that serves as a primary fuel for energy production, especially for the brain, muscles and several other body organs and tissues. Glucose also serves as a building block for larger structural molecules of the body, such as glycoproteins and glycolipids. The human body tightly regulates glucose levels. Abnormally high or low levels result in serious, potentially life-threatening complications such as cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes, cognitive impairment.
Type 2 diabetes is the most common form of diabetes. It was once called adult-onset diabetes because it typically begins in middle or older age. But more and more teens and young adults are also developing it now a day due to increased obesity.
Dipepidyl peptidase-4 (DPP -4) inhibitors represent a class of agents that are being developed for the treatment or improvement in glycemic control in type 2 diabetes. Examples of DPP -4 inhibitors include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. Among them, Sitagliptin, works to competitively inhibit the enzyme DPP -4 resulting in driving blood glucose levels towards normal and tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia), which is seen with some other oral hypoglycemic agents.
The chemical name of Sitagliptin Hydrochloride Monohydrate is 7-[(3R)-3-Amino- 1 -oxo-4-(2, 4, 5-trifluorophenyl) butyl] -5, 6, 7, 8- tetrahydro -3- (trifluoromethyl)- 1,2,4-triazo lo[ 4,3-a. ]pyrazine hydrochloride monohydrate. The molecular formula is C16H16CIF6N5O H2O corresponding to a molecular weight of 461.79. It is a white to off-white powder which is freely soluble in water, 0.1N HC1, 4.5 pH acetate buffer, 6.8 pH phosphate buffer, 7.4 pH phosphate buffer, 9.4 pH buffer and methanol at room temperature (25°C), sparingly soluble in ethanol and acetonitrile, slightly soluble in isopropyl alcohol, very slightly soluble in ethyl acetate and practically insoluble in dichloromethane, n-heptane and toluene.
Sitagliptin Hydrochloride (Monohydrate) exhibits polymorphism. The polymorph used in the present invention matches with API HCL Form III (as per USV Ltd WO 2012/025944 A3 patent) and HCL crystalline form stated to WO 2012/147092 A2 (as per Cadila Healthcare Ltd). The characteristic peaks of Sitagliptin Hydrochloride Monohydrate are the following: 6.6°, 8.0°, 13.7°, 16.0°, 18.0° and 27.0° 2Q ± 0.2° 2Q.
Metformin is a biguanide with antihyperglycaemic effect, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
The chemical name of Metformin hydrochloride is 3-(diaminomethylidene)-l,l- dimethylguanidine hydrochloride. The molecular formula is C4H12CIN5 corresponding to a molecular weight of 165.6. It is a white or almost white crystalline powder which is freely soluble in water, slightly soluble in alcohol (96%), practically insoluble in acetone and in methylene chloride.
Metformin Hydrochloride exhibits polymorphism. The polymorph used for the development of current pharmaceutical product described herein matches with API Form A (as per Scott .L. Childs et al, Crystal growth & design, 441-449, Vol.4, No.3, 2004). The characteristic peaks of Metformin Hydrochloride are the following: 12.3°, 13.8°, 17.7°, 22.4°, 24.6°, 25.4°, 31.3° and 37.2° 2Q.
Combination products are known to offer several advantages. First, the concentrations of the active ingredients (APIs) are consistently maintained within an optimal therapeutic range for both APIs. Secondly, combination products have been shown to improve patient compliance. Finally, combination products have more advantages for the treatment of Type 2 diabetes as it has been shown that single treatment along with diet and exercise fails quickly. In the present invention, it has been surprisingly observed that an unexpected and synergistic therapeutic benefit can be obtained in the treatment of type-2 diabetes with a combination therapy comprising Metformin and Sitagliptin.
EP-B-2477660 discloses a pharmaceutical composition comprising Metformin and Sitagliptin or Vildagliptin in combination with a lubricant wherein the lubricant is polyethylene glycol or mixtures of polyethylene glycol with one or more other lubricants and comprises more than 10% by weight of the total weight of the composition.
US-A-2019/099368 discloses a chewable dosage form having a matrix comprising: a combination of Metformin HC1 and Sitagliptin or salt thereof; fully or partially pregelatinized starch, a texture modifying gum; a lubricant, an emulsifier, a flavoring agent; and a sweetener.
Although each of the patents above represents an attempt to overcome the stability problems associated with pharmaceutical compositions comprising Sitagliptin and Metformin in a single dosage form, there still exists a need for a stable pharmaceutical composition which provides a stable performance under long-term and accelerated conditions.
SUMMARY OF THE INVENTION
The main object of the present invention is to provide a pharmaceutical composition comprising a fixed dose combination of Sitagliptin or a pharmaceutically acceptable salt thereof and Metformin or pharmaceutically acceptable salt thereof which overcomes the deficiencies of the prior art. The composition of the present invention is an immediate release composition intended for oral administration.
A further object of the present invention is to provide a pharmaceutical composition which is bioavailable and has acceptable pharmacotechnical properties.
It is another object of the present invention to provide a stable combination of Sitagliptin and Metformin in a single dosage form to increase patient compliance and thus treatment success.
A major object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients in order to achieve the appropriate dissolution profile and stability for the finished dosage form. Said dosage form affords predictable and reproducible drug release rates in order to achieve better treatment to a patient.
A further approach of the present invention is to provide a method for the preparation of a stable combined solid dosage formulation for oral administration containing Sitagliptin and Metformin which results in longer shelf-life of the product.
A further aspect of the present invention relates to a pharmaceutical formulation comprising Sitagliptin and Metformin as active ingredients, wherein croscarmellose sodium is included in product formula and formulation is stable for 6months without any issue at assay & related substances of both active ingredients.
In accordance with the above objects of the present invention a pharmaceutical composition for oral administration is provided comprising in a single dosage form a combination of Sitagliptin hydrochloride monohydrate and Metformin hydrochloride as active ingredients wherein the required Sitagliptin amount is dispensed in external phase (extragranularly) of product formula after drying and sizing step of wet granules.
According to another embodiment of the present invention, a process for the preparation of a stable, solid dosage form for oral administration, comprising a DPP -4 inhibitor such as Sitagliptin or pharmaceutical acceptable salt thereof and a biguanide with antihyperglycemic effect such as Metformin or pharmaceutically acceptable salt thereof wherein the composition comprises croscarmellose in external phase of product formula, is provided, which comprises the following steps: a) pre-mixing of binder with Metformin drug substance b) dispensing an aqueous solvent in the premixed blend of drug substance from previous step to form granular mass, wherein the granular mass is processed as following: c) drying the granular mass of step (b) until the water content level is well below acceptable limits, d) sizing the granular mass through a sieve of appropriate mesh size, e) mixing granular mass of previous step with Sitagliptin, a diluent and a disintegrant, f) adding glidant and blending to form a final blend, g) compression of final blend, h) coating of compressed tablets. Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient (e.g. Sitagliptin and Metformin) is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
In the present invention the wording excipient and/or API dispensed in the external phase or extragranular excipient has the meaning of an excipient added during manufacturing process after wet granulation and drying phase. The wording excipient and/or API dispensed in the internal phase or intragranular excipient has the opposite meaning i.e. the wet granulated and dried mass. Also, the expression by weight refers to by weight of the total weight of the composition, unless otherwise stated.
The primary goal of the present invention is to develop an immediate release fixed dose combination composition comprising Sitagliptin or a pharmaceutical acceptable salt thereof and Metformin or a pharmaceutically acceptable salt thereof that is simple to manufacture, bioavailable, cost effective, stable and possesses good pharmacotechnical properties when compared to the reference product.
There are three commercially important processes for making compressed tablets: wet granulation, direct compression and dry granulation (slugging or roller compaction). The method of preparation 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 few 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(s), behavior of the mixture during processing and the properties of the final tablets. Pre-formulation studies are done to determine the chemical and physical compatibility of the active component with proposed excipients.
The properties of the drug or drugs, its dosage forms and the economics of the operation will determine selection of the best process for tableting. Generally, both wet granulation and direct compression are used in developing a tablet. The dry granulation method may be used when one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted. The method consists of blending, slugging the ingredients, dry screening, lubrication and compression.
The wet granulation method is used to convert a powder mixture 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 damp mass is then screened 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. In general, powders do not have sufficient adhesive or cohesive properties to form hard, strong granules. A binder is usually required to bond the powder particles together due to the poor cohesive properties of most powders. Heat and moisture sensitive drugs cannot usually be manufactured using wet granulation.
As there is an important amount of Metformin present in the formulation of the invention, the size and shape of the resulting tablet should be considered since an easy oral administration to a patient is required, as well as an easy tablet manufacturing process which meets all the herein described requirements. Thus, there is a need in the industry for techniques and pharmaceutical formulations which will allow preparation of high-dose Sitagliptin and Metformin combination tablets. The high-dose Sitagliptin and Metformin tablets have to meet all the herein listed requirements with preferably a limited number and amount of pharmaceutical excipients to reduce the size of the tablet. Because of the above wet granulation was chosen as the preferred manufacturing process of the present invention. Granulation liquids that are typically used include water, ethanol and isopropanol, either alone or in combination. Water is the preferred granulation liquid for the present invention.
The main objective of the present invention is to develop a robust and stable immediate release film-coated tablet comprising a fixed dose combination of Sitagliptin and Metformin in two strengths 50/850mg and 50/1000mg respectively. The excipients were selected to enhance dissolution, physicochemical properties and stability of drug substances in the finished dosage form and thus were subjected to compatibility study with the APIs. The preferred formulation of this invention comprises Sitagliptin and Metformin as the active ingredients, one or more binders, diluents, a disintegrant and optionally a lubricant. The excipients have been carefully selected after many optimization steps.
Binder excipients are formulated to act as an adhesive, to literally “bind together” powders, granules and other dry ingredients to impart to the product the necessary mechanical strength. Binders are added to create a more effective and predictable granule formation. Examples of pharmaceutically acceptable binders include, but are not limited to, starches; polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose hydroxylethyl cellulose, hydroxylpropylmethyl cellulose; sucrose; dextrose; com syrup; polysaccharides; and gelatin. The binder may be present in an amount from about 5% to about 40% by weight of the composition.
Povidone also known as polyvinylpyrrolidone is the preferred binder in the present invention. It is used in a variety of manufacturing processes such as a dry binder for direct compression, as a granulating agent, as a retarding and as a film-forming agent as well as in taste-masking applications. Povidone is an excellent binder in wet granulation for the production of tablets and granules, since it is readily soluble in all the usual solvents. It can then be added either as a solution during granulation, or dry to the other ingredients, in which case the solvent is added alone during granulation. The preferred concentration of povidone in the present invention is from 5 to 10% w/w of the total weight of the tablet and more preferably from 6 to 8% w/w of the total weight of the tablet.
The composition of the present invention may also contain diluents and fillers. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent may be present in an amount from about 8% to about 40% by weight of the composition. The preferred diluent in the present invention is microcrystalline cellulose and is used in an amount from 8 to 15% w/w of the total weight of the tablet and more preferably from 8 to 10% w/w of the total weight of the tablet.
Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. One, two, three or more disintegrants can be selected. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross- linked polymers, e.g., cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium or croscarmellose); soy polysaccharides; and guar gum, sodium starch glycolate. The preferred disintegrant in the present invention is croscarmellose sodium. The disintegrant may be present in an amount from about 0% to about 2%, more preferably from about 0.1% to about 1% of the total weight of the tablet.
Surfactants are materials that lower the surface tension between two liquids or between a liquid and a solid. Surfactants can be selected from sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate, sulphosuccinates such as sodium dioctyl sulphosuccinate, partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, partial fatty acid esters of sorbitan such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylenesorbitan such as polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers (Pluronic®) or ethoxylated triglycerides. Preferably, sodium lauryl sulphate is employed as a surfactant in the present invention. Preferably in a concentration of 0.1 to 5% of the total weight of the tablet.
Lubricants or glidants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Such glidants are commonly included in the final tablet mix in amounts usually less than 1% by weight. The glidant component may be hydrophobic or hydrophilic. One, two, three or more glidants can be selected. Examples of pharmaceutically acceptable glidants include, but are not limited to, colloidal silica dioxide, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, sodium stearyl fumarate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. The glidant may be present in an amount preferably from about 0.1% to about 5% by weight of the composition and most preferably from about 0.1% to about 2% by weight of the composition.
Sodium stearyl fumarate is the preferred glidant in the present invention. It reduces the friction between the die wall and tablet mix during the compression and ejection of the tablets. It helps prevent adhesion of tablets to the punches and dies. It is stable and does not polymerize within the tableting mix and it has a higher degree of API compatibility than the most commonly used magnesium stearate. The pharmaceutical composition of the present invention is obtained by wet granulation of the Metformin granules in the presence of a binder, drying and subsequent addition of a disintegrant, a diluent and Sitagliptin and optionally one or more further pharmaceutically acceptable excipients.
The tablet as described in the present invention comprises as active ingredients, i) between 1 to 35%, preferably between 1.5 to 25% of Sitaglitptin or a pharmaceutically acceptable salt thereof, ii) between 65 to 98.5%, preferably between 75 to 98.5% of Metformin or a pharmaceutically acceptable salt thereof. iii) not less than 5% by weight binder, 0% to 1% by weight disintegrant, not less than 8% by weight diluent, 0% to 2% by weight glidant.
The following Examples illustrate aspects of the present invention but are not in any way limiting the scope of invention.
EXAMPLES
Example 1
The scope of present invention is the preparation of an oral solid dosage form comprising Sitagliptin and Metformin (as HCL salts) drug substances and exhibiting an immediate drug release profile at aqueous medium. Also, the pharmaceutical composition shall be bioequivalent to reference product as per acceptance criteria indicated for generic products and be stable under different storage conditions.
Formulation trial 1 is shown in Table 1 below. Povidone was selected as a binder, sodium lauryl sulphate was selected as a surfactant, microcrystalline cellulose was selected as diluent/filler and sodium stearyl fumarate as a lubricant/glidant. Both Sitagliptin and Metformin (as HCL salts) are dispensed in wet granules as described in manufacturing process. Table 1: Qualitative and quantitative Formulation trial 1.
Figure imgf000011_0001
The manufacturing process comprises the following steps: pre-mixing of povidone with Sitagliptin and Metformin, - dissolution of sodium lauryl sulfate in purified water and dispensing of aqueous preparation in the premixed blend of APIs of step (a) to form granular mass: further wherein the granular mass is processed as following: a) drying the granular mass of previous step at 40°C until the water content level is well below acceptable limits, b) sizing the granular mass through a sieve of appropriate mesh size, c) mixing granular mass of previous step with microcrystalline cellulose, d) adding glidant (sodium stearyl fumarate) and blending to form a final blend, e) compression of final blend, f) coating of compressed tablets with appropriate coloring agent.
The physicochemical characteristics of Formulation trial 1 were determined by recording the in vitro dissolution profile in Buffer 0.025M NaCl for 45min at 75 rpm (USP II) in comparison to reference product. An immediate drug release profile was recorded for reference product with % drug release more than 85% at 15min. The results are shown in Table 2 below and show the dissolution of both APIs separately for the 50mg/1000mg strength tablet.
Table 2: Dissolution profile for Sitagliptin & Metformin for trial 1
Figure imgf000012_0002
It is obvious from the dissolution results that a suppressed dissolution profile is recorded for formulation Trial 1 at early time intervals for both drug substances against reference product. Thus, the formulation development focuses on product formula and dissolution rate will be closely monitored through appropriate time specifications (Tiomin
Figure imgf000012_0001
Example 2
Considering the dissolution results of formulation Trial 1, the addition of a disintegrant was also evaluated within the context of current invention. A Design of Experiment (DoE) series was performed to evaluate the levels of disintegrant and surfactant. A 22 full factorial DoE was performed to evaluate the impact of amount of sodium lauryl sulfate and croscarmellose dispensed in product formula on CQAs of drug product. The highest strength product formula (Sitagliptin/Metformin 50/1000mg fc tabs) is evaluated along current optimization study and different levels for sodium lauryl sulfate (SLS), dispensed in wet granulation, and croscarmellose sodium, dispensed in external phase, were analyzed.
Amount of sodium lauryl sulfate (SLS) dispensed in wet granulation: HIGH level (13.0mg/tab), MEDIUM level (6.5mg/tab), LOW level (O.Omg/tab). Amount of croscarmellose dispensed in external phase: HIGH level (20.0mg/tab), MEDIUM level (13.0mg/tab), LOW level (6.5mg/tab)
According to Analysis of Variance (ANOVA) results for dissolution croscarmellose affects the drug release at early time intervals whereas no significant effect is recorded at later time intervals. More specifically, in-vitro drug release at 5min was enhanced at higher croscarmellose content levels, wherein a similar release profile to reference product was recorded under LOW level (6.5mg/tab). SLS does not impact the drug release of either drug substance.
According to the ANOVA results for disintegration, higher disintegration results were recorded at lower croscarmellose levels for either sodium lauryl sulfate amount. Disintegration results well above 9 min similarly to reference product were recorded at LOW croscarmellose content (6.5mg/tab, equiv. to 0.5%wt). Additionally, as per statistical analysis SLS does not significantly affect the disintegration of tablets. Overall, considering the analytical results recorded along current Design of Experiments (DoE), the low drug release levels along the early time intervals of in-vitro dissolution were counterfeited at low level of croscarmellose content at either sodium lauryl sulfate level. The Medium/High croscarmellose content enhanced significantly the %drug dissolved at 5min unlikely to reference product profile. Similar disintegration results to reference product were recorded at low level of croscarmellose.
Taken together the data led to the development of the Formulation trial 2 as shown in table 3 below. Table 3. Qualitative and quantitative Formulation trial 2.
Figure imgf000013_0001
The physicochemical properties as well as in-vitro drug release profile of Sitagliptin/Metformin 50/850mg & 50/1000mg fc tablets are summarized below. Table 4. Physicochemical characteristics of Formulation trial 2.
Figure imgf000014_0001
Table 5A: Dissolution profile for Sitagliptin for trial 2
Figure imgf000014_0002
Table 5B: Dissolution profile for Metformin for trial 2
Figure imgf000014_0003
Table 6. Assay and related substances for Formulation trial 2
Figure imgf000015_0001
Based on the above results, similar dissolution profile and physicochemical characteristics were recorded for both APIs in relation to the reference product. However, higher related substances levels were recorded for Sitagliptin HCL API compared to reference product for both known and unknown substances. Therefore, further optimization is needed.
Example 3
Following the optimization of formulation variables and considering the related substances levels recorded at Formulation Trial 2, the current invention also focuses on manufacturing process of finished product. More particularly, an alternative manufacturing process comprising of Sitagliptin dispensed at external phase was also evaluated as following: a) pre-mixing of binder (povidone) with Metformin drug substance b) dispensing aqueous solvent (purified water) in the premixed blend of drug substance of step (a) to form granular mass: further wherein the granular mass is processed as following: c) drying the granular mass of step (b) until the water content level is well below acceptable limits, d) sizing the granular mass through a sieve of appropriate mesh size, e) mixing granular mass of step (d) with Sitagliptin, diluent (microcrystalline cellulose) and disintegrant (croscarmellose sodium), f) adding glidant and blending to form a final blend, g) compression of final blend, h) coating of compressed tablets with appropriate coloring agent.
The same punch and compression force were also applied to current Formulation Trial (Trial 3) and the tablets were analyzed in terms of drug release, assay & related substances. The results are summarized in the following tables.
Table 7: Physicochemical characteristics of Formulation Trial 3.
Figure imgf000016_0001
Table 8A: Dissolution profile for Sitagliptin for trial 3
Figure imgf000016_0002
Table 8B: Dissolution profile for Metformin for trial 3
Figure imgf000017_0001
Table 9: Assay & related substances of Sitagliptin/Metformin 50/1000mg fc tabs, Formulation Trial 3
Figure imgf000017_0002
Based on the results, the Sitagliptin API dispensing at external phase of product formula does not significantly impact the drug release of APIs as well as the physicochemical characteristics of coated tablets (i.e. disintegration & uniformity of dosage units). However, significantly lower related substances levels (unknown related substances) were recorded for Sitagliptin HCL API compared to Formulation Trial 2. Considering the current results, Sitagliptin HCL API is selected to be dispensed in external phase of current product formula rather than in wet granules. Different levels of diluent (microcrystalline cellulose-MCC) and binder (povidone) were also evaluated within the context of current invention as per following formulation trials Sitagliptin/Metformin 50/1000mg fc tabs. Three alternative amount levels were investigated: Low level- 60.0 mg/tab for povidone & 100.0 mg/tab for MCC. Medium level- 91.0 mg/tab for povidone & 119.8 mg/tab for MCC. High level- 120.0 mg/tab for povidone & 140.0 mg/tab for
MCC.
Based on formulation trials results, both povidone and microcrystalline cellulose content impact the drug release rate as well as hardness and disintegration. More particularly, higher results at early time interval of dissolution testing (5min) were recorded when lower diluent & binder content was applied to product formula. However, lower disintegration and hardness were recorded compared to reference product. Additionally, the drug release at early time interval was suppressed at higher binder content level which is also reflected on disintegration results. Tablets hardness was slightly increased under higher MCC content. Considering the current results, the medium level is proposed for both diluent and binder ingredients for current product formula.
Overall, considering the experimental formulation trials prepared along the current invention and the relevant responses recorded, the qualitative/quantitative formula of the preferred pharmaceutical composition of the present invention is stated in Table 10 below.
Table 10: Qualitative/Quantitative Formu a of Optimum Formulation Trial.
Figure imgf000018_0001
The manufacturing process for preparing the preferred composition of the present invention comprises of the following steps: a) pre-mixing of binder (povidone) with Metformin drug substance b) dispensing an aqueous solvent (purified water) in the premixed blend of drug substance of step (a) to form granular mass: further wherein the granular mass is processed as following: c) drying the granular mass of step (b) until the water content level is well below acceptable limits, d) sizing the granular mass through a sieve of appropriate mesh size, e) mixing granular mass of step (d) with Sitagliptin, diluent (microcrystalline cellulose) and disintegrant (croscarmellose sodium), f) adding glidant and blending to form a final blend, g) compression of final blend, h) coating of compressed tablets with appropriate coloring agent.
The disintegration, hardness as well as dissolution profile of the preferred composition of the present invention (Optimum formulation Trial) are stated in tables below.
Table 11 : Disintegration & Hardness results for Optimum Formulation Trial
Figure imgf000019_0001
Table 12A: Dissolution results of Sitagliptin API, Optimum Formulation Trial
Figure imgf000019_0002
Table 12B: Dissolution results of Metformin API, Optimum Formulation Trial
Figure imgf000020_0001
Since the scope of current pharmaceutical preparations was to investigate the bioavailability of generic drug product, a bioequivalence study was conducted on healthy fed subjects to determine the bioavailability of the test product (Optimum Formulation Trial 50/1000mg film coated tablets) versus Janumet® 50/1000mg film coated tablets/MSD (Reference). The results indicated that the 90% Confidence Interval (Cl) for AUCO-t, based on log-transformed data, was 101.5% (geometric mean value) and 101.7% for Cmax for Sitagliptin and 104.3% (geometric mean value) for AUC0- t and 104.2% for Cmax for Metformin. Based on in-vivo studies results, it seems that generic product meets the bioequivalence criteria. Thus, both in vivo & in vitro results confirmed the non inferiority of generic product against the marketed product.
Under the scope of the evaluation of the related substances profile & assay of finished product, Sitagliptin/Metformin 50/1000mg film coated tablets, with qualitative/quantitative formula of Optimum Formulation Trial, were loaded into stability chambers and monitored with a fit-for- purpose HPLC analytical method. Stability data (related substances & assay analysis) upon storage at zero time & 6 months under long term (25°C ± 2°C/60%±5%RH) and accelerated storage conditions (40°C±2°C/75%±5%RH) are summarized in Table 13 below. The in-vitro dissolution results under stability conditions are summarized in Table 14. The nature of container closure system is PVC/PE/PVDC -aluminum blister. Table 13: Stability results (related substances & assay) of Optimum Formulation trial
Figure imgf000021_0001
Table 14A. Dissolution profile for Sitagliptin at zero time and 6 months for Optimum Formulation Trial
Figure imgf000021_0002
Table 14B. Dissolution profile for Metformin at zero time and 6 months for Optimum Formulation Trial
Figure imgf000022_0001
Based on the stability results it can be stated that Optimum Formulation Trial is stable since no significant shift of dissolution rate was recorded even under accelerated storage conditions for 6 months. In addition, assay and related substances after 6 months stability at long-term and accelerated storage conditions are well within the acceptance criteria. Finally, X-ray diffraction analysis of crystalline form of Sitagliptin HCL and Metformin HCL showed that both APIs remain stable in finished product even under storage of 6m at accelerated conditions.
Based on X-ray analysis of Sitagliptin HCL API, it seems that material matches to crystalline polymorph Form III (as per USV Ltd WO 2012/025944 A3 patent) and HCL crystalline form stated to WO 2012/147092 A2 (as per Cadila Healthcare Ltd). Additionally, Metformin HCL API matches to Form A (as per Scott L.Childs et al, Crystal growth & design, 441-449, Vol.4, No.3, 2004). Considering stability results, it can be stated that crystalline form of Sitagliptin HCL and Metformin HCL API remains stable in finished product even under storage of 6m at accelerated conditions.
Overall, the preferred pharmaceutical composition of current invention (Optimum Formulation Trial) is considered stable since no significant change on drug release, assay, related substances and API crystalline form were recorded under 6-month stability at long-term and accelerated storage conditions.
While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

1. A pharmaceutical composition for oral administration comprising in a single dosage form 1% to 6% by weight of Sitagliptin or pharmaceutical acceptable salt thereof, 1% to 80% by weight Metformin or pharmaceutical acceptable salt thereof, not less than 5% by weight binder, 0% to 1% by weight disintegrant, not less than 8% by weight diluent, 0% to 2% by weight glidant.
2. The pharmaceutical composition according to claim 1 comprising Metformin hydrochloride and Sitagliptin hydrochloride monohydrate.
3. The pharmaceutical composition according to claim 1, wherein the disintegrant is croscarmellose sodium.
4. The pharmaceutical composition according to claim 1, wherein the binder is povidone, the diluent is microcrystalline cellulose and the glidant is sodium stearyl fumarate.
5. The pharmaceutical composition according to claim 1, wherein Sitagliptin or pharmaceutical acceptable salt thereof & disintegrant are added extragranularly.
6. The pharmaceutical composition according to claim 1, wherein no less than 25% of the drug substances is released at 5min time interval, when subjected to an in-vitro dissolution testing using USP II (paddle method) at a rotation speed of 75rpm in a 900mL aqueous dissolution medium at Buffer 0.025M NaCl.
7. A process for the preparation of a stable pharmaceutical composition for oral administration comprising in a single dosage form a combination of a therapeutically effective quantity of Sitagliptin or pharmaceutical acceptable salt thereof and Metformin or pharmaceutical acceptable salt thereof, which comprises the following steps: a) pre-mixing of not less than 5% by weight of a binder with Metformin or pharmaceutical acceptable salt thereof, b) dispensing an aqueous solvent in the premixed blend of drug substance of step (a) to form granular mass, c) drying the granular mass of step (b), d) sizing the granular mass through a sieve of appropriate mesh size, e) mixing granular mass of step (d) with Sitagliptin or pharmaceutical acceptable salt, not less than 8% by weight diluent and 0% to 1% by weight disintegrant, f) adding 0% to 2% by weight glidant and blending to form a final blend, g) compressing the final blend, h) optionally coating of compressed tablets with appropriate coloring agent.
8. The process according to claim 7 wherein the disintegrant is croscarmellose sodium, the binder is povidone, the diluent is microcrystalline cellulose and the glidant is sodium stearyl fumarate.
9. The process according to claim 7 comprising 1% to 80% by weight Metformin hydrochloride and 1% to 6% by weight Sitagliptin hydrochloride monohydrate.
PCT/EP2022/025189 2021-04-27 2022-04-27 Pharmaceutical composition comprising a combination of sitagliptin and metformin and method of preparation thereof WO2022228735A1 (en)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2007078726A2 (en) * 2005-12-16 2007-07-12 Merck & Co., Inc. Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin
WO2012025944A2 (en) 2010-08-27 2012-03-01 Usv Limited Sitagliptin, salts and polymorphs thereof
WO2012147092A2 (en) 2011-03-03 2012-11-01 Cadila Healthcare Limited Novel salts of dpp-iv inhibitor
EP2477660B1 (en) 2009-09-15 2015-02-11 ratiopharm GmbH Pharmaceutical composition comprising active agents metformin and sitagliptin or vildagliptin
US20190099368A1 (en) 2017-09-29 2019-04-04 Merck Sharp & Dohme Corp. Chewable dosage forms containing sitagliptin and metformin

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007078726A2 (en) * 2005-12-16 2007-07-12 Merck & Co., Inc. Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin
EP2477660B1 (en) 2009-09-15 2015-02-11 ratiopharm GmbH Pharmaceutical composition comprising active agents metformin and sitagliptin or vildagliptin
WO2012025944A2 (en) 2010-08-27 2012-03-01 Usv Limited Sitagliptin, salts and polymorphs thereof
WO2012147092A2 (en) 2011-03-03 2012-11-01 Cadila Healthcare Limited Novel salts of dpp-iv inhibitor
US20190099368A1 (en) 2017-09-29 2019-04-04 Merck Sharp & Dohme Corp. Chewable dosage forms containing sitagliptin and metformin

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