WO2023242854A1 - Dual release bilayer composition comprising metformin and dpp-iv inhibitors - Google Patents
Dual release bilayer composition comprising metformin and dpp-iv inhibitors Download PDFInfo
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- WO2023242854A1 WO2023242854A1 PCT/IN2022/050684 IN2022050684W WO2023242854A1 WO 2023242854 A1 WO2023242854 A1 WO 2023242854A1 IN 2022050684 W IN2022050684 W IN 2022050684W WO 2023242854 A1 WO2023242854 A1 WO 2023242854A1
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
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- 229960002458 gemigliptin Drugs 0.000 description 1
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- 229960004666 glucagon Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
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- 239000005556 hormone Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 239000007942 layered tablet Substances 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 229960004937 saxagliptin Drugs 0.000 description 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
- 108010033693 saxagliptin Proteins 0.000 description 1
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- 235000010413 sodium alginate Nutrition 0.000 description 1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229940052016 turmeric extract Drugs 0.000 description 1
- 235000020240 turmeric extract Nutrition 0.000 description 1
- 239000008513 turmeric extract Substances 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940057977 zinc stearate Drugs 0.000 description 1
Classifications
-
- 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
- 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
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
Definitions
- the present invention relates to the field of pharmaceutical composition for the treatment of diabetic disorders.
- the present invention relates to a stable, extended-release, oral composition of metformin and a Dipeptidyl peptidase (DPP)-IV inhibitor in the form of bilayer tablets.
- DPP Dipeptidyl peptidase
- Controlled release oral dosage forms are widely used for numerous therapies and offer better patient compliance, maintain uniform dosage levels, and reduce dose frequency as well as side effects.
- an immediate dissolution of the dose needs to be released in the shortest time possible to provide rapid onset of action, followed by extended drug release to maintain the therapeutic effects.
- many approaches such as bilayer tablets, multilayer tablets, multi-particulate systems and monolithic matrix tablets have been applied.
- bilayer tablet technology has been attracting the most attention in recent times among tablet manufacturers.
- Bi-layered tablets prevent chemical incompatibilities between the formulation components, including drug-drug and drug-excipient interaction, by physical separation.
- bilayer technologies also provide pre- determined release profiles by combining layers with different release profiles.
- US 20070172525 and US 20080064701 discloses pharmaceutical composition comprising a DPP-4 inhibitor and a slow-release form of metformin.
- W02009111200 discloses a formulation comprising an inner core 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.
- W02009099734 discloses pharmaceutical composition
- HPMC extended-release excipient
- the tablet core is then coated with immediate release polymer comprising sitagliptin.
- US20090105265 discloses a fixed-dose combination (FDC) of metformin and sitagliptin.
- the application discloses use of surfactants in the composition to achieve desired dissolution profile.
- US20100330177 discloses a fixed-dose combination of metformin and sitagliptin.
- the application discloses use of glidant as excipient.
- W02014170770 discloses pharmaceutical composition of sitagliptin and metformin which is devoid of glidant or surface-active agents.
- WO2011098483 teaches the use of a hydroxypropyl methyl cellulose (HPMC) as the rate controlling polymer in both the metformin and sitagliptin layer.
- HPMC hydroxypropyl methyl cellulose
- the present invention provides consistent in- vitro extended release of metformin which further ensures steady plasma concentrations throughout the shelf life of the composition. Furthermore, said extended-release compositions are bioequivalent to the reference compositions known in the art.
- the primary objective of the present invention is to provide a pharmaceutical composition comprising a fixed dose combination (FDC) of metformin and a DPP-IV inhibitor for the treatment of diabetes and process of preparation thereof.
- Metformin may be in the form of a pharmaceutically acceptable salt, wherein metformin hydrochloride (HC1) is preferred.
- a preferred DPP-IV inhibitor is sitagliptin or a pharmaceutically acceptable salt thereof, wherein sitagliptin phosphate monohydrate is being preferred.
- Another objective of the present invention is to provide a stable extended-release oral composition of metformin hydrochloride and sitagliptin phosphate monohydrate.
- the pharmaceutical formulation is in the form of a tablet, and in particular, a bilayer tablet.
- Another objective of the present invention is to provide bilayer tablet with extended-release layer of metformin and immediate release layer of sitagliptin, wherein extended-release layer of the formulation comprises combination of two rate controlling polymers to achieve desired release profile and process of preparation thereof.
- the present invention provides a dual release pharmaceutical composition comprising fixed dose combination (FDC) of metformin and a DPP-IV inhibitor, which has improved stability and dissolution rate and the process of preparation of the pharmaceutical composition thereof.
- FDC fixed dose combination
- the present invention provides a bilayer tablet comprising an extended-release layer comprising metformin or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients; and an immediate release layer comprising a DPP-IV inhibitor with one or more pharmaceutically acceptable excipients, wherein DPP-IV inhibitor is sitagliptin or pharmaceutically acceptable salt thereof.
- the present invention provides a dual release bilayer tablet composition in a single unit dosage form comprising: a) An extended release (ER) layer comprising metformin or a pharmaceutically acceptable salt thereof and one or more rate-controlling polymers wherein rate controlling substances are selected from the group consisting of one or more of ionic and non-ionic polymers. b) An immediate release (IR layer) comprising sitagliptin or a pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients.
- ER extended release
- IR layer an immediate release comprising sitagliptin or a pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients.
- composition refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
- pharmaceutically acceptable excipient refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
- bilayer tablet refers to novel drug delivery having two different layers which are compressed together to form a unitary dosage form. Each layer may have different active agents and excipients with same or different release profiles.
- immediate release refers to rapid release of drug after administration to achieve rapid absorption of the drug.
- extended release refers to slow release of active agent over a prolonged period.
- DPP-IV inhibitor or “Dipeptidyl peptidase 4 inhibitors” refers oral antihyperglycemic agents also known as gliptins which are used to inhibit the enzyme Dipeptidyl peptidase IV (DPP IV). These enzymes are responsible for controlling the action of insulinstimulating hormones, glucagon-like peptide (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP). Therefore, inhibition of DPP-IV enzymes causes increase in GLP-1 and GIP levels which inhibits glucagon levels and leads to increase in insulin secretions.
- GLP-1 glucagon-like peptide
- GIP glucose-dependent insulinotropic polypeptide
- the drugs include sitagliptin, vildagliptin, saxagliptin, linagliptin, Gemigliptin, Denagliptin, Alogliptin, Anagliptin, and a pharmaceutically acceptable salt thereof.
- the term “dual release” refers to release the active agents either immediately or in an extended or sustained or modified manner.
- the term “rate controlling polymers” refers to additives which controls the release of active agents from dosage form over a long time and maintain plasma concentration of drug within desired range.
- the rate controlling polymers used in present invention can be ionic and non-ionic polymers.
- dissolution refers to the process in which solid particles form solution when enter to systemic circulation.
- plasma concentration refers to the measurement of amount of active agent in a given volume of blood plasma.
- the present invention relates to a bilayer pharmaceutical composition with dual drug release profile comprising an extended-release layer of metformin admixed with a combination of ionic and non-ionic release controlling polymers and immediate release layer comprising a DPP- IV inhibitor.
- the present invention provides a bilayer tablet composition comprising:
- the present invention provides a bilayer tablet composition exhibiting dual drug release profile comprising:
- the present invention provides an extended layer comprising metformin or pharmaceutical acceptable salt thereof, wherein metformin hydrochloride (HC1) is preferred.
- metformin hydrochloride is present in an amount from 40 to 90 wt.%, based on the total weight of the entire composition, and preferably in an amount of from 50 to 80 wt.%, with correspondence to a therapeutically effective amount ranging from 200 mg to 1500 mg and preferably from 500 to 1000 mg in each unit formulation form, but not limited thereto.
- the present invention provides extended layer of metformin with combination of ionic and non-ionic polymers.
- the metformin extended-release layer comprises two controlled release polymers in the ratio of 1 : 15 to 15:1 based on total weight of the entire composition.
- the ionic polymers that can be used in the present invention include both anionic and cationic polymers.
- Exemplary anionic polymers include, for example, sodium carboxymethylcellulose (Na CMC); sodium alginate; polymers of acrylic acid or carbomers (e.g., CARBOPOL® 934, 940, 974P NF, ACRYPOL® 940, 934P, 971P, 912G); enteric polymers such as polyvinyl acetate phthalate (PVAP), methacrylic acid copolymers (e.g., EUDRAGIT® LI 00, L 30D 55, A, and FS 30D), and hypromellose acetate succinate (AQUAT HPMCAS); and xanthan gum.
- Exemplary cationic polymers include, for example, dimethylaminoethyl methacrylate copolymer (e.g., EUDRAGIT® E 100).
- ionic polymer is present in an amount preferably from about 1 to 4 wt.% based on the total weight of the entire composition.
- ionic polymer is an anionic polymer selected from carbomer (ACRYPOL® 912G) present in a range 1 to 2 wt.% based on the total weight of the entire composition.
- non-ionic polymers include, hydroxypropylcellulose (HPC) and polyethylene oxide (PEO), Povidone (PVP: polyvinyl pyrrolidone), polyvinyl alcohol, copolymer of PVP and polyvinyl acetate, HPMC (hydroxypropyl methylcellulose), hydroxy ethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate (PHEMA), water soluble nonionic polymethacrylates and their copolymers, modified cellulose, modified polysaccharides, nonionic gums, nonionic polysaccharides, and/or combinations thereof.
- HPMC hydroxypropyl methylcellulose
- PHEMA polyhydroxyethylmethacrylate
- water soluble nonionic polymethacrylates and their copolymers modified cellulose, modified polysaccharides, nonionic gums, nonionic polysaccharides, and/or combinations thereof
- non-ionic polymer is present in an amount preferably from about 10 to 30 wt.% based on the total weight of the entire composition.
- nonionic polymer is HPMC (hydroxypropyl methylcellulose) present in a range 10 to 20 wt.% based on the total weight of the entire composition.
- the extended layer may further comprise pharmaceutically acceptable additives wherein the pharmaceutically acceptable additive may be selected from the group consisting of aqueous binder, lubricant and anti-adherent and combinations thereof.
- the present invention provides an immediate release layer comprising a DPP-IV inhibitor.
- the DPP-IV inhibitor is sitagliptin or pharmaceutical acceptable salt thereof.
- DPP-IV inhibitor is Sitagliptin phosphate monohydrate.
- the immediate layer according to the present invention, sitagliptin phosphate monohydrate is present in an amount of 2 to 20 wt.%, based on the total weight of the entire composition, with correspondence to a therapeutically effective amount ranging from 50 mg to 200 mg and preferably from 50 mg to 100 mg in each unit formulation form, but not limited thereto.
- the present invention provides an immediate layer, which may further comprise pharmaceutically acceptable additives wherein the pharmaceutically acceptable additives may be selected from the group consisting of diluent, disintegrant, colorant, aqueous binder, anti-adherent, lubricant, and combinations thereof.
- aqueous binder used in present invention are selected from group consisted of, but are not limited to corn starch, polyvinyl pyrrolidone (PVP K12, KI 7, K25, K30, K60, K90, or KI 20), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives like hydroxymethylcellutose, hydroxyethylcellulose, hydroxypropyl-cellulose and hydroxypropylmethylcellulose, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth and combinations thereof.
- aqueous binder is present in an amount preferably from about 0.05 to 4 wt.% based on the total weight of entire composition.
- Examples of lubricant used in present invention are selected from calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc and combinations thereof.
- lubricant is present in an amount preferably from about 0.05 to 0.5 wt.% based on the total weight of entire composition.
- diluent used in present invention are selected from cellulose derivatives, such as microcrystalline cellulose or wood cellulose, lactose, lactose anhydrous, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, com starch, modified com starch and combinations thereof.
- diluent is present in an amount preferably from about 1 to 10 wt.% based on the total weight of entire composition.
- disintegrant used in present invention are selected from croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, com starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and combinations thereof.
- disintegrant is present in an amount preferably from about 0.1 to 2 wt.% based on the total weight of entire composition.
- colorant used in present invention are selected from tar dyes, turmeric extract, caramel, carotene solution, 0-carotene, copper chlorophyll, and riboflavin.
- the colorants can be selected from among food or pharmaceutically-acceptable ingredients such as FD&C lakes, titanium dioxide and dyes, pigments such as red or yellow iron oxide.
- colorant is present in an amount preferably from about 0.01 to 0.1 wt.% based on the total weight of entire composition.
- anti-adherent agents used in present invention are selected from starch, cellulose, talc, colloidal silicon dioxide, magnesium stearate or combinations thereof.
- the metformin extended-release layer having extended-release characteristics.
- the extended layer releases metformin 25% to 35% in 1 hour, 60% to 70% in 3 hours and 90%-100% in 10 hours.
- sitagliptin immediate release layer is having immediate release characteristics.
- the immediate layer releases 85% of drug in 30 minutes.
- the bilayer tablet composition of present invention is intended for the treatment of diabetes mellitus, preferably type 2 diabetes mellitus.
- the present invention provides a bilayer pharmaceutical composition, which comprises: a. Granules of metformin hydrochloride as extended-release layer admixed with combination of ionic and non-ionic release controlling polymers, wherein the release controlling polymers are present in the ratio of 1 : 15 to 15:1 based on total weight of bilayer composition; b. Granules of sitagliptin phosphate monohydrate as immediate release layer; wherein granules of each layer are compressed to form bilayer tablet composition.
- the present invention relates to an improvement in bilayer tablet technology and provides a method of producing a bilayer pharmaceutical tablet comprising the steps of:
- step (iii) admixing the aqueous solution of step (ii) with the dry-powder blend of step (i) to form granules by wet granulation; (iv) drying the granules with fluidized bed dryer to obtain dry granules of appropriate size; and
- step (iii) admixing the aqueous solution of step (ii) with the dry-powder blend of step (i) to form granules by wet granulation;
- step (c) compressing the extended release (ER) layer of step (a) and the immediate release (IR) layer of step (b) to form a bilayer tablet;
- the pharmaceutically acceptable excipients are selected from a group consisting of an aqueous-binder present in a range of 0.05 to 4 wt.%; a lubricant present in a range of 0.05 to 0.5 wt.%; a diluent present in a range of 1 to 10 wt.%; a disintegrant present in a range of 0.1 to 2 wt.%; a colorant present in a range of 0.01 to 0.1 wt.%; and an anti-adherent present in a range of 0.02 to 0.2 wt.%, by weight of the total composition.
- the bilayer tablet comprises an extended-release (ER) layer and an immediate release (IR) layer of the dual-release composition.
- a unit formulation of the bilayer tablet comprises a therapeutically effective amount of metformin hydrochloride in a range of 200-1500 mg and sitagliptin phosphate monohydrate in a range of 50-200 mg.
- the rate-controlling polymers comprise either hydrophilic or hydrophobic polymers and are present in a range of 0.001-50% by weight of the composition.
- the extended-release granules obtained from step (i) and immediate release granules obtained from step (ii) are compressed together to form a bilayer tablet composition. Once the granules are compressed to form tablet, the tablet are optionally film coated. The optional film coat can be INSTACOAT.
- solvents examples include ethanol, methyl alcohol, n-butyl alcohol, acetonitrile, purified water, acetone, isopropyl ketone, isopropyl alcohol, methylene chloride, ethyl acetate, chloroform, dichloromethane, or combinations thereof.
- solvent used in immediate release is Isopropyl alcohol and in extended release is Isopropyl alcohol and purified water.
- Example 1 Composition 1 - Formula for Sitagliptin 100 mg & Metformin hydrochloride 1000 mg (extended release) tablets
- Example 2 Composition 2- Sitagliptin 100 mg & Metformin hydrochloride 500 mg (Extended
- Example 3 Composition 3 - Sitagliptin 50 mg & Metformin hydrochloride 500 mg (Extended
- Example 4 Composition 4 - Sitagliptin 50 mg & Metformin hydrochloride 1000 mg (Extended
- ER metformin hydrochloride granules Preparation of extended-release (ER) metformin hydrochloride granules: a. All the raw materials were dispensed under reverse laminar air flow (RLAF). b. After dispensing, the weight of each ingredient was individually checked and metformin hydrochloride was sifted with sieve no. 40, and excipients HPMC K200M and Acrypol 912G were sifted with sieve no. 40, with the help of Vibro sifter. c. After sifting, the ingredients were dry mixed with rapid mixer granulator (RMG) with the following process parameters: Slow speed impeller with chopper off for 10 minutes. d. Wet granulation: Binder with solvent was mixed in a rapid mixer granulator (RMG) with the following process parameters:
- Lubrication The lubricant materials magnesium stearate, colloidal silicon dioxide and Acrypol were sifted and mixed with dried granules in an octagonal blender for 10 minutes and 3 minutes after addition of magnesium stearate.
- IR immediate release
- RLAF reverse laminar air flow
- the weight of each ingredient was individually checked and Sitagliptin phosphate monohydrate was sifted with sieve no. 40, and excipients lactose, microcrystalline cellulose and crospovidone were sifted with sieve no. 40 and colorant iron oxide was geometrically mixed with lactose with sieve no. 80.
- RMG Rapid mixer granulator
- Wet granulation Binder with solvent were mixed in a rapid with Rapid mixer granulator (RMG) with following process parameters:
- Slow speed g. Lubrication The dried granules were weighed and lubricated with sifted colloidal silicon dioxide, magnesium stearate and crospovidone in an octagonal blender for 10 minutes and 3 minutes after addition of magnesium stearate.
- the compressed bilayer tablets were film coated with INSTACOAT, methylene chloride and isopropyl alcohol.
- Example 6 Drug release / Dissolution profile of the pharmaceutical composition
- the composition comprising sitagliptin phosphate monohydrate and metformin hydrochloride in a bilayer tablet was found to show efficient dissolution profile for 1 st hour (between 25-50%), 3 rd hour (between 45-75%) and 10 th hour (not less than 80%).
- the composition comprising sitagliptin phosphate monohydrate and metformin hydrochloride in a bilayer tablet was found to show efficient stability for initial period and time period of 3 months.
- the weight in mg for sitagliptin phosphate monohydrate was found to be not less than 90 mg and not more than 110 mg; and for metformin hydrochloride was found to be not less than 900 mg and not more than 1100 mg.
- the study was a randomized, single dose, two treatment and two-way complete crossover design with at least a washout period of 7 days between the two dosing sessions.
- volunteers received either of the test preparation of one FDC tablet or reference preparation of one JANUMET XR tablet, only on the study day at a fixed time.
- Table 5 Comparison of the pharmacokinetic parameters [0074] Sitagliptin & Metformin were detected in plasma from 0.5 to 72 hrs for both the preparations. Peak plasma levels were achieved for Sitagliptin between 3.5 to 4.5 hrs and for Metformin between 3.5 to 6.0 hrs. The mean peak plasma levels of Sitagliptin and Metformin with Reference preparation, on the study day ranged between 250.24- 379.73 ng/ml and 1044.00- 1583.45 ng/ml. respectively while for the Test preparation, ranged between 241.54 329.05 ng/ml and 1013.51 - 1547.87 ng/ml respectively.
- Test preparation FDC Tablet Containing Sitagliptin Phosphate Monohydrate IP eq. to Sitagliptin IP lOOmg + Metformin Hydrochloride IP (as sustained release) lOOOmg is bioequivalent with the Reference preparation, one JANUMET XR tablet (each tablet contains Sitagliptin Phosphate Monohydrate IP eq. to Sitagliptin 100mg+ Metformin Hydrochloride IP 1000 mg (as extended- release form).
Abstract
The present invention relates to a stable, extended-release, oral composition of metformin and a Dipeptidyl peptidase (DPP)-IV inhibitor in the form of bilayer tablets. The dual-release composition comprising an extended release (ER) layer comprising metformin or a pharmaceutically acceptable salt thereof, and one or more rate-controlling polymers; and an immediate release (IR layer) comprising a DPP-IV inhibitor, along with pharmaceutically acceptable excipients. The composition finds application in treating diabetic disorders.
Description
DUAL RELEASE BILAYER COMPOSITION COMPRISING METFORMIN AND DPP-IV INHIBITORS
FIELD OF INVENTION:
[001] The present invention relates to the field of pharmaceutical composition for the treatment of diabetic disorders. Particularly, the present invention relates to a stable, extended-release, oral composition of metformin and a Dipeptidyl peptidase (DPP)-IV inhibitor in the form of bilayer tablets.
BACKGROUND OF THE INVENTION:
[002] Numerous studies have been conducted to address the formulation and drug release systems of combination of antidiabetic drugs and attempts have been made to achieve the combination formulation having desired dissolution profile.
[003] Controlled release oral dosage forms are widely used for numerous therapies and offer better patient compliance, maintain uniform dosage levels, and reduce dose frequency as well as side effects. In certain disease conditions, an immediate dissolution of the dose needs to be released in the shortest time possible to provide rapid onset of action, followed by extended drug release to maintain the therapeutic effects. To obtain this dual drug release concept, many approaches, such as bilayer tablets, multilayer tablets, multi-particulate systems and monolithic matrix tablets have been applied.
[004] Among the existing technologies, bilayer tablet technology has been attracting the most attention in recent times among tablet manufacturers. Bi-layered tablets prevent chemical incompatibilities between the formulation components, including drug-drug and drug-excipient interaction, by physical separation. Furthermore, bilayer technologies also provide pre- determined release profiles by combining layers with different release profiles.
[005] US 20070172525 and US 20080064701 discloses pharmaceutical composition comprising a DPP-4 inhibitor and a slow-release form of metformin. W02009111200 discloses a formulation comprising an inner core 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.
[006] W02009099734 discloses pharmaceutical composition comprising a tablet core of metformin and an extended-release excipient (HPMC). The tablet core is then coated with immediate release polymer comprising sitagliptin.
[007] US20090105265 discloses a fixed-dose combination (FDC) of metformin and sitagliptin. The application discloses use of surfactants in the composition to achieve desired dissolution profile.
[008] US20100330177 discloses a fixed-dose combination of metformin and sitagliptin. The application discloses use of glidant as excipient. W02014170770 discloses pharmaceutical composition of sitagliptin and metformin which is devoid of glidant or surface-active agents. WO2011098483 teaches the use of a hydroxypropyl methyl cellulose (HPMC) as the rate controlling polymer in both the metformin and sitagliptin layer.
[009] Various types of formulations have been suggested in the prior art for fixed-dose combination of metformin and sitagliptin composition. The prior art in the broad sense teaches the preparation of compositions wherein sitagliptin is coated over a metformin core or is in the form of bilayer tablets. The release controlling polymer taught in the prior art is a non-ionic polymer which is primarily HPMC. HPMC is not thought itself to be affected by changes in pH, however, the release rates of drugs from HPMC matrices are affected by the pH of the dissolution fluid. Although the influences of formulation variables on release rates have been investigated, but the effect of pH on drug release has largely been ignored. [Mitchell, K.; Ford, J. L.; Armstrong, D. J.; Elliott, P. N. C, Rostron, C; Hogan, J. E. Int. J. Pharm. 1990, 66, 233 -242 .
[0010] Incorporation of ionic polymers, in cellulosic non-ionic release controlling matrixes is attractive for developing a pH-independent release profile for weakly basic drugs. When formulated with HPMC matrixes alone, these drugs were found to lead to a pH-dependent drug release profile that exhibits a higher release in acidic pH and a lower release in basic pH because
of the pH-dependent solubility of the drug. The incorporation of anionic polymers in release controlling matrix can influence drug release in basic media by lowering the micro-environmental pH and can also retard the drug release in acidic media by forming an insoluble mass that acts as a barrier to drug diffusion.
[0011] Thus, there still exists a need for an alternate, improved, and stable fixed-dose combination (FDC) formulation of metformin and sitagliptin. The present invention addresses this problem by providing a simplified technology in which HPMC is mixed with an ionic release controlling polymer. The mixing of the HPMC with an ionic polymer result in an optimized and strong release controlling matrix to achieve the desired release profile. Combining ionic release controlling polymers with HPMC produces a synergistic increase in viscosity of the matrix because of a stronger hydrogen bonding between the ionic polymer and HPMC. This stronger cross-link between the two polymers results in a more rigid structure through which drug diffusion can occur. The net result of this interaction is increased consistency of drug release profile versus HPMC matrix alone.
[0012] Therefore, the present invention provides consistent in- vitro extended release of metformin which further ensures steady plasma concentrations throughout the shelf life of the composition. Furthermore, said extended-release compositions are bioequivalent to the reference compositions known in the art.
OBJECTIVES OF THE INVENTION:
[0013] The primary objective of the present invention is to provide a pharmaceutical composition comprising a fixed dose combination (FDC) of metformin and a DPP-IV inhibitor for the treatment of diabetes and process of preparation thereof. Metformin may be in the form of a pharmaceutically acceptable salt, wherein metformin hydrochloride (HC1) is preferred. A preferred DPP-IV inhibitor is sitagliptin or a pharmaceutically acceptable salt thereof, wherein sitagliptin phosphate monohydrate is being preferred.
[0014] Another objective of the present invention is to provide a stable extended-release oral composition of metformin hydrochloride and sitagliptin phosphate monohydrate. In some
embodiments, the pharmaceutical formulation is in the form of a tablet, and in particular, a bilayer tablet.
[0015] Another objective of the present invention is to provide bilayer tablet with extended-release layer of metformin and immediate release layer of sitagliptin, wherein extended-release layer of the formulation comprises combination of two rate controlling polymers to achieve desired release profile and process of preparation thereof.
SUMMARY OF THE INVENTION:
[0016] The present invention provides a dual release pharmaceutical composition comprising fixed dose combination (FDC) of metformin and a DPP-IV inhibitor, which has improved stability and dissolution rate and the process of preparation of the pharmaceutical composition thereof. In one general aspect, the present invention provides a bilayer tablet comprising an extended-release layer comprising metformin or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients; and an immediate release layer comprising a DPP-IV inhibitor with one or more pharmaceutically acceptable excipients, wherein DPP-IV inhibitor is sitagliptin or pharmaceutically acceptable salt thereof.
[0017] In another aspect, the present invention provides a dual release bilayer tablet composition in a single unit dosage form comprising: a) An extended release (ER) layer comprising metformin or a pharmaceutically acceptable salt thereof and one or more rate-controlling polymers wherein rate controlling substances are selected from the group consisting of one or more of ionic and non-ionic polymers. b) An immediate release (IR layer) comprising sitagliptin or a pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients.
DETAILED DESCRIPTION OF THE INVENTION:
[0018] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such
compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
[0019] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
[0020] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
[0021] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
[0022] Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
[0023] The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
[0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
[0025] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
[0026] The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
[0027] The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
[0028] The term “bilayer tablet” refers to novel drug delivery having two different layers which are compressed together to form a unitary dosage form. Each layer may have different active agents and excipients with same or different release profiles.
[0029] The term "immediate release" refers to rapid release of drug after administration to achieve rapid absorption of the drug.
[0030] The term “extended release” refers to slow release of active agent over a prolonged period.
[0031] The term “DPP-IV inhibitor” or “Dipeptidyl peptidase 4 inhibitors” refers oral antihyperglycemic agents also known as gliptins which are used to inhibit the enzyme Dipeptidyl peptidase IV (DPP IV). These enzymes are responsible for controlling the action of insulinstimulating hormones, glucagon-like peptide (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP). Therefore, inhibition of DPP-IV enzymes causes increase in GLP-1 and GIP levels which inhibits glucagon levels and leads to increase in insulin secretions. The drugs include sitagliptin, vildagliptin, saxagliptin, linagliptin, Gemigliptin, Denagliptin, Alogliptin, Anagliptin, and a pharmaceutically acceptable salt thereof.
[0032] The term “dual release” refers to release the active agents either immediately or in an extended or sustained or modified manner.
[0033] The term “rate controlling polymers” refers to additives which controls the release of active agents from dosage form over a long time and maintain plasma concentration of drug within desired range. The rate controlling polymers used in present invention can be ionic and non-ionic polymers.
[0034] The term “dissolution” refers to the process in which solid particles form solution when enter to systemic circulation.
[0035] The term “plasma concentration” refers to the measurement of amount of active agent in a given volume of blood plasma.
[0036] The present invention relates to a bilayer pharmaceutical composition with dual drug release profile comprising an extended-release layer of metformin admixed with a combination of ionic and non-ionic release controlling polymers and immediate release layer comprising a DPP- IV inhibitor.
[0037] In one embodiment, the present invention provides a bilayer tablet composition comprising:
(a) an extended layer comprising metformin or a pharmaceutically acceptable salt thereof; and
(b) an immediate layer comprising a DPP-IV inhibitor, wherein the DPP-IV inhibitor is sitagliptin and pharmaceutical acceptable salt thereof.
[0038] In one embodiment, the present invention provides a bilayer tablet composition exhibiting dual drug release profile comprising:
(a) an extended layer comprising metformin, or a pharmaceutically acceptable salt thereof admixed with a combination of ionic and non-ionic release controlling polymers; and
(b) an immediate layer comprising DPP-IV inhibitor wherein DPP-IV inhibitor is Sitagliptin and pharmaceutical acceptable salt thereof.
[0039] The present invention provides an extended layer comprising metformin or pharmaceutical acceptable salt thereof, wherein metformin hydrochloride (HC1) is preferred. In the extended layer according to the present invention, metformin hydrochloride is present in an amount from 40 to 90
wt.%, based on the total weight of the entire composition, and preferably in an amount of from 50 to 80 wt.%, with correspondence to a therapeutically effective amount ranging from 200 mg to 1500 mg and preferably from 500 to 1000 mg in each unit formulation form, but not limited thereto.
[0040] In one embodiment, the present invention provides extended layer of metformin with combination of ionic and non-ionic polymers.
[0041] In a preferred embodiment, the metformin extended-release layer comprises two controlled release polymers in the ratio of 1 : 15 to 15:1 based on total weight of the entire composition.
[0042] In another embodiment, the ionic polymers that can be used in the present invention include both anionic and cationic polymers. Exemplary anionic polymers include, for example, sodium carboxymethylcellulose (Na CMC); sodium alginate; polymers of acrylic acid or carbomers (e.g., CARBOPOL® 934, 940, 974P NF, ACRYPOL® 940, 934P, 971P, 912G); enteric polymers such as polyvinyl acetate phthalate (PVAP), methacrylic acid copolymers (e.g., EUDRAGIT® LI 00, L 30D 55, A, and FS 30D), and hypromellose acetate succinate (AQUAT HPMCAS); and xanthan gum. Exemplary cationic polymers include, for example, dimethylaminoethyl methacrylate copolymer (e.g., EUDRAGIT® E 100).
[0043] In an embodiment, ionic polymer is present in an amount preferably from about 1 to 4 wt.% based on the total weight of the entire composition. In most preferred embodiment, ionic polymer is an anionic polymer selected from carbomer (ACRYPOL® 912G) present in a range 1 to 2 wt.% based on the total weight of the entire composition.
[0044] In another embodiment, examples of non-ionic polymers include, hydroxypropylcellulose (HPC) and polyethylene oxide (PEO), Povidone (PVP: polyvinyl pyrrolidone), polyvinyl alcohol, copolymer of PVP and polyvinyl acetate, HPMC (hydroxypropyl methylcellulose), hydroxy ethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate (PHEMA), water soluble nonionic polymethacrylates and their
copolymers, modified cellulose, modified polysaccharides, nonionic gums, nonionic polysaccharides, and/or combinations thereof.
[0045] In an embodiment, non-ionic polymer is present in an amount preferably from about 10 to 30 wt.% based on the total weight of the entire composition. In most preferred embodiment, nonionic polymer is HPMC (hydroxypropyl methylcellulose) present in a range 10 to 20 wt.% based on the total weight of the entire composition.
[0046] In one embodiment, the extended layer may further comprise pharmaceutically acceptable additives wherein the pharmaceutically acceptable additive may be selected from the group consisting of aqueous binder, lubricant and anti-adherent and combinations thereof.
[0047] The present invention provides an immediate release layer comprising a DPP-IV inhibitor. In an embodiment of present invention, the DPP-IV inhibitor is sitagliptin or pharmaceutical acceptable salt thereof. In most preferred embodiment DPP-IV inhibitor is Sitagliptin phosphate monohydrate. The immediate layer according to the present invention, sitagliptin phosphate monohydrate is present in an amount of 2 to 20 wt.%, based on the total weight of the entire composition, with correspondence to a therapeutically effective amount ranging from 50 mg to 200 mg and preferably from 50 mg to 100 mg in each unit formulation form, but not limited thereto.
[0048] In a preferred embodiment, the present invention provides an immediate layer, which may further comprise pharmaceutically acceptable additives wherein the pharmaceutically acceptable additives may be selected from the group consisting of diluent, disintegrant, colorant, aqueous binder, anti-adherent, lubricant, and combinations thereof.
[0049] Examples of aqueous binder used in present invention are selected from group consisted of, but are not limited to corn starch, polyvinyl pyrrolidone (PVP K12, KI 7, K25, K30, K60, K90, or KI 20), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives like hydroxymethylcellutose, hydroxyethylcellulose, hydroxypropyl-cellulose and hydroxypropylmethylcellulose, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and
gum tragacanth and combinations thereof. In an embodiment, aqueous binder is present in an amount preferably from about 0.05 to 4 wt.% based on the total weight of entire composition.
[0050] Examples of lubricant used in present invention are selected from calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc and combinations thereof. In an embodiment, lubricant is present in an amount preferably from about 0.05 to 0.5 wt.% based on the total weight of entire composition.
[0051] Examples of diluent used in present invention are selected from cellulose derivatives, such as microcrystalline cellulose or wood cellulose, lactose, lactose anhydrous, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, com starch, modified com starch and combinations thereof. In an embodiment, diluent is present in an amount preferably from about 1 to 10 wt.% based on the total weight of entire composition.
[0052] Examples of disintegrant used in present invention are selected from croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, com starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and combinations thereof. In an embodiment, disintegrant is present in an amount preferably from about 0.1 to 2 wt.% based on the total weight of entire composition.
[0053] Examples of colorant used in present invention are selected from tar dyes, turmeric extract, caramel, carotene solution, 0-carotene, copper chlorophyll, and riboflavin. Also the colorants can be selected from among food or pharmaceutically-acceptable ingredients such as FD&C lakes, titanium dioxide and dyes, pigments such as red or yellow iron oxide. In an embodiment, colorant is present in an amount preferably from about 0.01 to 0.1 wt.% based on the total weight of entire composition.
[0054] Examples of anti-adherent agents used in present invention are selected from starch, cellulose, talc, colloidal silicon dioxide, magnesium stearate or combinations thereof. In an
embodiment anti-adherent present in an amount preferably from about 0.02 to 0.2 wt.% based on the total weight of entire composition.
[0055] In an embodiment, the metformin extended-release layer having extended-release characteristics. The extended layer releases metformin 25% to 35% in 1 hour, 60% to 70% in 3 hours and 90%-100% in 10 hours.
[0056] In an embodiment, sitagliptin immediate release layer is having immediate release characteristics. The immediate layer releases 85% of drug in 30 minutes.
[0057] In one embodiment, the bilayer tablet composition of present invention is intended for the treatment of diabetes mellitus, preferably type 2 diabetes mellitus.
[0058] In another embodiment, the present invention provides a bilayer pharmaceutical composition, which comprises: a. Granules of metformin hydrochloride as extended-release layer admixed with combination of ionic and non-ionic release controlling polymers, wherein the release controlling polymers are present in the ratio of 1 : 15 to 15:1 based on total weight of bilayer composition; b. Granules of sitagliptin phosphate monohydrate as immediate release layer; wherein granules of each layer are compressed to form bilayer tablet composition.
[0059] In an embodiment, the present invention relates to an improvement in bilayer tablet technology and provides a method of producing a bilayer pharmaceutical tablet comprising the steps of:
(a) preparing an extended release (ER) layer:
(i) preparing a dry-powder blend of metformin hydrochloride along with pharmaceutically acceptable excipients;
(ii) preparing an aqueous solution of a binder with a solvent, wherein the solvent is isopropyl alcohol;
(iii) admixing the aqueous solution of step (ii) with the dry-powder blend of step (i) to form granules by wet granulation;
(iv) drying the granules with fluidized bed dryer to obtain dry granules of appropriate size; and
(v) lubricating the dry granules;
(b) preparing an immediate release (IR) layer:
(i) preparing a dry-powder blend of sitagliptin phosphate monohydrate along with pharmaceutically acceptable excipients;
(ii) preparing an aqueous solution of a binder with a solvent, wherein the solvent is isopropyl alcohol and purified water;
(iii) admixing the aqueous solution of step (ii) with the dry-powder blend of step (i) to form granules by wet granulation;
(iv) air drying the granules followed by dry screening to obtain dry granules of appropriate size; and
(v) lubricating the dry granules
(c) compressing the extended release (ER) layer of step (a) and the immediate release (IR) layer of step (b) to form a bilayer tablet; and
(d) coating the bilayer tablet with transparent aqueous and non-aqueous coating.
[0060] In yet another embodiment, the pharmaceutically acceptable excipients are selected from a group consisting of an aqueous-binder present in a range of 0.05 to 4 wt.%; a lubricant present in a range of 0.05 to 0.5 wt.%; a diluent present in a range of 1 to 10 wt.%; a disintegrant present in a range of 0.1 to 2 wt.%; a colorant present in a range of 0.01 to 0.1 wt.%; and an anti-adherent present in a range of 0.02 to 0.2 wt.%, by weight of the total composition.
[0061] In a further embodiment, the bilayer tablet comprises an extended-release (ER) layer and an immediate release (IR) layer of the dual-release composition. Further, a unit formulation of the bilayer tablet comprises a therapeutically effective amount of metformin hydrochloride in a range of 200-1500 mg and sitagliptin phosphate monohydrate in a range of 50-200 mg.
[0062] In another embodiment, the rate-controlling polymers comprise either hydrophilic or hydrophobic polymers and are present in a range of 0.001-50% by weight of the composition.
[0063] In yet another embodiment, the extended-release granules obtained from step (i) and immediate release granules obtained from step (ii) are compressed together to form a bilayer tablet composition. Once the granules are compressed to form tablet, the tablet are optionally film coated. The optional film coat can be INSTACOAT.
[0064] Examples of solvents that can be used in the present invention for granulation include ethanol, methyl alcohol, n-butyl alcohol, acetonitrile, purified water, acetone, isopropyl ketone, isopropyl alcohol, methylene chloride, ethyl acetate, chloroform, dichloromethane, or combinations thereof. In most preferred embodiments solvent used in immediate release is Isopropyl alcohol and in extended release is Isopropyl alcohol and purified water.
EXAMPLES:
[0065] The present invention is illustrated below by reference to the following non-limiting examples. Further, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
Example 1: Composition 1 - Formula for Sitagliptin 100 mg & Metformin hydrochloride 1000 mg (extended release) tablets
Table 1 : Composition 1
Example 2: Composition 2- Sitagliptin 100 mg & Metformin hydrochloride 500 mg (Extended
Release) Tablets
Table 2: Composition 2
Example 3: Composition 3 - Sitagliptin 50 mg & Metformin hydrochloride 500 mg (Extended
Release)
Table 3: Composition 3
Example 4: Composition 4 - Sitagliptin 50 mg & Metformin hydrochloride 1000 mg (Extended
Release)
Table 4: Composition 4
Example 5: Manufacturing process
[0066] To prepare a bilayer tablet composition of the present invention following steps were performed: i. Preparation of extended-release (ER) metformin hydrochloride granules: a. All the raw materials were dispensed under reverse laminar air flow (RLAF). b. After dispensing, the weight of each ingredient was individually checked and metformin hydrochloride was sifted with sieve no. 40, and excipients HPMC K200M and Acrypol 912G were sifted with sieve no. 40, with the help of Vibro sifter. c. After sifting, the ingredients were dry mixed with rapid mixer granulator (RMG) with the following process parameters: Slow speed impeller with chopper off for 10 minutes.
d. Wet granulation: Binder with solvent was mixed in a rapid mixer granulator (RMG) with the following process parameters:
Time: 2-5 minutes slow speed
Mixing: Impeller and chopper at fast speed or till to get the desired Ampere load. e. Wet Milling: The granules were milled in multi-mill with the following process parameters:
Slow speed and 8.0 mm screen f. Drying: After milling the wet mass was dried with the help of fluidized bed dryer (FBD) having following process parameters:
Inlet Temperature: 45-55°C
Outlet temperature: 35-45°C
Time: 10 minutes (air dry) + with intermittent raking & till to get the LOD 1.0- 2.0% w/w at 105°C.
After drying the binder was dry screened with multi mill and Vibro sifter. g. Lubrication: The lubricant materials magnesium stearate, colloidal silicon dioxide and Acrypol were sifted and mixed with dried granules in an octagonal blender for 10 minutes and 3 minutes after addition of magnesium stearate.
After lubrication, the granules were weighed and send for Quality Control (QC) testing. ii. Preparation of immediate release (IR) granules: a. All the raw materials were dispensed under reverse laminar air flow (RLAF). b. After dispensing, the weight of each ingredient was individually checked and Sitagliptin phosphate monohydrate was sifted with sieve no. 40, and excipients lactose, microcrystalline cellulose and crospovidone were sifted with sieve no. 40 and colorant iron oxide was geometrically mixed with lactose with sieve no. 80. c. After sifting, the ingredients were dry mixed with the help of Rapid mixer granulator (RMG) for 10 minutes. d. Wet granulation: Binder with solvent were mixed in a rapid with Rapid mixer granulator (RMG) with following process parameters:
Time: 2-5 minutes slow speed
Mixing: impeller and chopper at fast speed or till to get the desired ampere load.
e. Wet Milling: The granules were milled in multi-mill with following process parameters:
Slow speed and 8.0 mm screen f. Drying: After milling the wet mass was air dried for 10-15 minutes and dried with following process parameters:
Inlet Temperature: 50-60°C
Outlet temperature: 35-45°C till to get the LOD 1.5% to 2.5% w/w at 105°C
After drying the binder was dry screened with multi mill and Vibro sifter with following process parameters:
Sifting: 20#
1.5 mm screen
Re-sifting: 20#
Slow speed g. Lubrication: The dried granules were weighed and lubricated with sifted colloidal silicon dioxide, magnesium stearate and crospovidone in an octagonal blender for 10 minutes and 3 minutes after addition of magnesium stearate.
After lubrication, the granules were weighed and send for quality control (QC) testing. iii. Compression:
After preparation of extended release (ER) and immediate release (IR) granules, these granules were compressed to form a bilayer tablet with help of tablet compression machine having punch size: 17.50*8.50 mm, oval, concave, both upper & lower punches plain. The compressed bilayer tablets were examined with in-process check such as average weight, uniformity, length, width, thickness and hardness and friability. iv. Coating:
The compressed bilayer tablets were film coated with INSTACOAT, methylene chloride and isopropyl alcohol.
Example 6: Drug release / Dissolution profile of the pharmaceutical composition
[0066] The dissolution profile was conducted for Composition 1 -Formula for Sitagliptin 100 mg & Metformin hydrochloride 1000 mg (extended release) tablets and Composition 3-Formula for Sitagliptin 50 mg & Metformin hydrochloride 500 mg (Extended Release) tablets. This was
performed in multiple batches. The composition comprising sitagliptin phosphate monohydrate and metformin hydrochloride in a bilayer tablet was found to show efficient dissolution profile for 1st hour (between 25-50%), 3rd hour (between 45-75%) and 10th hour (not less than 80%).
Example 7: Stability study of the pharmaceutical composition
[0067] The stability profile was conducted for Composition 1 -Formula for Sitagliptin 100 mg & Metformin hydrochloride 1000 mg (extended release) tablets and Composition 3 -Formula for Sitagliptin 50 mg & Metformin hydrochloride 500 mg (Extended Release) tablets. This was performed in multiple batches. The composition comprising sitagliptin phosphate monohydrate and metformin hydrochloride in a bilayer tablet was found to show efficient stability for initial period and time period of 3 months. In the bilayer tablet, the weight in mg for sitagliptin phosphate monohydrate was found to be not less than 90 mg and not more than 110 mg; and for metformin hydrochloride was found to be not less than 900 mg and not more than 1100 mg.
Example 8: Bioequivalence study of the pharmaceutical composition
[0068] The study evaluated the pharmacokinetic parameters and compared the bioequivalence of FDC bilayer tablet containing sitagliptin phosphate monohydrate IP equivalent to sitagliptin IP 100 mg + metformin hydrochloride IP (as sustained release) 1000 mg with one JANUMET XR tablet in 24 healthy adult male volunteers.
Subjects:
[0069] Adult, healthy male volunteers with mean age 30.77 ± 5.34 years and mean weight 60.54 ±5.13 kg.
Study:
[0070] The study was a randomized, single dose, two treatment and two-way complete crossover design with at least a washout period of 7 days between the two dosing sessions. In each dosing session, volunteers received either of the test preparation of one FDC tablet or reference preparation of one JANUMET XR tablet, only on the study day at a fixed time.
Analysis:
[0071] Samples were analyzed by liquid chromatography with tandem mass spectrometry (LCMS/MS) after extracting the drug from plasma and injecting it on the LCMS/MS column for chromatographic analysis.
Discussion:
[0072] Plasma levels of sitagliptin and metformin for every volunteer at each time point were plotted to obtain time-plasma concentration curves for the study preparations. The mean parameters of bioavailability for this single dose study were - Cmax (Maximum Plasma Concentration)
Tmax (Time to Maximum Plasma Concentration)
AUCo-t (The area under plasma concentration time curve) ONATA
AUCo-inf (The area under plasma concentration time curve 0 to infinity) ti/2 (Elimination half-life)
Kei (Elimination rate constant)
[0073] Based on comparison of the (AUCo) for Sitagliptin & Metformin, after single dose administration, the relative bioavailabilities of Sitagliptin & Metformin of the Test preparation are 98.56% and 95.91% respectively in comparison with the Reference preparation, as disclosed in Table 5.
Table 5: Comparison of the pharmacokinetic parameters
[0074] Sitagliptin & Metformin were detected in plasma from 0.5 to 72 hrs for both the preparations. Peak plasma levels were achieved for Sitagliptin between 3.5 to 4.5 hrs and for Metformin between 3.5 to 6.0 hrs. The mean peak plasma levels of Sitagliptin and Metformin with Reference preparation, on the study day ranged between 250.24- 379.73 ng/ml and 1044.00- 1583.45 ng/ml. respectively while for the Test preparation, ranged between 241.54 329.05 ng/ml and 1013.51 - 1547.87 ng/ml respectively.
Conclusion:
[0075] Based on the pharmacokinetic parameters studied, it can be concluded that the Test preparation, FDC Tablet Containing Sitagliptin Phosphate Monohydrate IP eq. to Sitagliptin IP lOOmg + Metformin Hydrochloride IP (as sustained release) lOOOmg is bioequivalent with the Reference preparation, one JANUMET XR tablet (each tablet contains Sitagliptin Phosphate Monohydrate IP eq. to Sitagliptin 100mg+ Metformin Hydrochloride IP 1000 mg (as extended- release form).
Claims
1. A dual-release composition comprising: an extended release (ER) layer comprising metformin or a pharmaceutically acceptable salt thereof, and one or more rate-controlling polymers; and an immediate release (IR) layer comprising a DPP-IV inhibitor, along with pharmaceutically acceptable excipients.
2. The composition as claimed in claim 1 , wherein the extended release (ER) layer comprises metformin hydrochloride in a range of 40-90 wt.% by weight of the total composition.
3. The composition as claimed in claim 1, wherein the DPP-IV inhibitor comprises sitagliptin or a pharmaceutically acceptable salt thereof.
4. The composition as claimed in claim 3, wherein the DPP-IV inhibitor comprises sitagliptin phosphate monohydrate in a range of 2-20 wt.% by weight of the total composition.
5. The composition as claimed in claim 1, wherein the one or more rate-controlling polymers comprise either hydrophilic or hydrophobic polymers and are present in a range of 0.001-50% by weight of the total composition.
6. The composition as claimed in claim 1, wherein the one or more rate-controlling polymers comprise an ionic release-controlling polymer and a non-ionic release-controlling polymer.
7. The composition as claimed in claim 6, wherein the ionic release-controlling polymer and the non-ionic release-controlling polymer are present in a ratio in a range of 1 : 15 to 15 : 1 by weight of the total composition.
8. The composition as claimed in claim 7, wherein the ionic release-controlling polymer comprises an anionic polymer selected from carbomer in a range 1 to 2 wt.% by weight of the total composition.
9. The composition as claimed in claim 7, wherein the non-ionic release-controlling polymer is hydroxypropyl methylcellulose (HPMC) in a range 10 to 20 wt.% by weight of the total composition.
10. The composition as claimed in claim 1, wherein extended release (ER) layer releases metformin hydrochloride in a range of 25-35% in 1 hour, 60-70% in 3 hours, and 90-100% in 10 hours.
11. The composition as claimed in claim 1, wherein immediate release (IR) layer releases sitagliptin phosphate monohydrate in a range of 85-100% in 30 minutes.
12. The composition as claimed in claim 1, wherein the composition finds application for treating diabetes mellitus, preferably type II diabetes mellitus.
13. A process for preparation of the dual-release composition as claimed in claim 1, the process comprising:
(a) preparing an extended release (ER) layer:
(i) preparing a dry-powder blend of metformin hydrochloride along with pharmaceutically acceptable excipients;
(ii) preparing an aqueous solution of a binder with a solvent, wherein the solvent comprises isopropyl alcohol;
(iii) admixing the aqueous solution of step (ii) with the dry-powder blend of step (i) to form granules by wet granulation;
(iv) drying the granules with fluidized bed dryer to obtain dry granules of appropriate size; and
(v) lubricating the dry granules;
(b) preparing an immediate release (IR) layer:
(i) preparing a dry-powder blend of sitagliptin phosphate monohydrate along with pharmaceutically acceptable excipients;
(ii) preparing an aqueous solution of a binder with a solvent, wherein the solvent comprises isopropyl alcohol and purified water;
(iii) admixing the aqueous solution of step (ii) with the dry-powder blend of step (i) to form granules by wet granulation;
(iv) air drying the granules followed by dry screening to obtain dry granules of appropriate size; and
(v) lubricating the dry granules
(c) compressing the extended release (ER) layer of step (a) and the immediate release (IR) layer of step (b) to form a bilayer tablet; and
(d) coating the bilayer tablet with a transparent aqueous or non-aqueous coating.
14. The composition as claimed in claim 13, wherein the bilayer tablet comprises aqueous coating when purified water is used as the solvent.
15. The composition as claimed in claim 13, wherein the bilayer tablet comprises non-aqueous coating when isopropyl alcohol is used as the solvent.
16. The composition as claimed in any of the preceding claims, wherein the pharmaceutically acceptable excipients are selected from a group consisting of an aqueous-binder present in a range of 0.05 to 4 wt.%; a lubricant present in a range of 0.05 to 0.5 wt.%; a diluent present in a range of 1 to 10 wt.%; a disintegrant present in a range of 0.1 to 2 wt.%; a colorant present in a range of 0.01 to 0.1 wt.%; and an anti-adherent present in a range of 0.02 to 0.2 wt.%, by weight of the total composition.
17. The composition as claimed in any of the preceding claims, wherein the bilayer tablet comprises an extended-release (ER) layer and an immediate release (IR) layer of the dualrelease composition.
18. The composition as claimed in claim 17, wherein a unit formulation of the bilayer tablet comprises a therapeutically effective amount of metformin hydrochloride in a range of 200- 1500 mg and sitagliptin phosphate monohydrate in a range of 50-200 mg.
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| Application Number | Priority Date | Filing Date | Title |
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| IN202211034152 | 2022-06-14 | ||
| IN202211034152 | 2022-06-14 |
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| WO2023242854A1 true WO2023242854A1 (en) | 2023-12-21 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2713361A1 (en) * | 2008-02-05 | 2009-08-13 | Merck Sharp & Dohme Corp. | Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor |
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- 2022-07-28 WO PCT/IN2022/050684 patent/WO2023242854A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2713361A1 (en) * | 2008-02-05 | 2009-08-13 | Merck Sharp & Dohme Corp. | Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor |
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