WO2024096839A1 - A pharmaceutical composition comprising solid dispersion of empagliflozin - Google Patents
A pharmaceutical composition comprising solid dispersion of empagliflozin Download PDFInfo
- Publication number
- WO2024096839A1 WO2024096839A1 PCT/TR2023/051218 TR2023051218W WO2024096839A1 WO 2024096839 A1 WO2024096839 A1 WO 2024096839A1 TR 2023051218 W TR2023051218 W TR 2023051218W WO 2024096839 A1 WO2024096839 A1 WO 2024096839A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- composition according
- empagliflozin
- solid dispersion
- sodium
- Prior art date
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- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 title claims abstract description 86
- 229960003345 empagliflozin Drugs 0.000 title claims abstract description 85
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 76
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 55
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 75
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 10
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- 238000013265 extended release Methods 0.000 description 2
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- 150000003839 salts Chemical class 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
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- 229920000148 Polycarbophil calcium Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
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- 229940124639 Selective inhibitor Drugs 0.000 description 1
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
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- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
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- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000012776 robust process Methods 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
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- 229920002554 vinyl polymer Polymers 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 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
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising i) a solid dispersion consisting of Empagliflozin and silicon dioxide and ii) at least one pharmaceutically acceptable excipient.
- the said pharmaceutical composition has a desirable pharmacokinetic characteristic, favorable storage stability and comparative dissolution properties.
- the invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of hyperglycaemia.
- Empagliflozin is a selective inhibitor of sodium/glucose co-transporter-2 (SGLT2) and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2DM).
- the sodium glucose cotransporter 2 (SGLT-2) is a low-affinity, high-capacity, active sodium glucose symporter expressed at the apical membrane of epithelial cells lining the proximal renal tubule.
- SLGT-2 is responsible for reabsorbing the majority of the glucose filtered at the glomerulus. In other words, SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood. Inhibition of SGLT-2 by i Empagliflozin decreases glucose reabsorption and promotes urinary glucose excretion. Urinary glucose loss is the primary mechanism by which Empagliflozin lowers blood glucose.
- Empagliflozin is marketed as mono Empagliflozin, in combination with metformin, in combination with linagliptin and in combination with linagliptin and metformin by Boehringer Ingelheim. These marketed products are approved in the form of film coated tablet. These tablets contain Empagliflozin in the strengths of 5 mg, 10 mg, 12.5 mg, 25 mg.
- Jardiance® is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
- Jardiance is indicated in adults for the treatment of symptomatic chronic heart failure.
- Empagliflozin is a white to yellowish non-hygroscopic crystalline solid, very slightly soluble in water (pH 1 -7.4), slightly soluble in acetonitrile and ethanol, sparingly soluble in methanol, and practically insoluble in toluene. It is very slightly soluble in aqueous media between pH 1 -7.5 but has low intestinal permeability and thus it is classified as BCS Class III compound based on Biopharmaceutical Classification System. According to EPAR, particle size was not found to be critical for dissolution, but since coarser API dissolves slightly more slowly and therefore the drug substance is milled and particle size is tightly controlled.
- An amorphous form generally has better solubility and bioavailability than corresponding crystalline form of the same compound and that may be the reason, in particular cases, to use amorphous form of the said compound while targeting to obtain a formulation with better stability, solubility and compressibility etc.
- WO 2005/092877 discloses glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture.
- WO 2006/117359 A1 discloses stable a crystalline form of Empagliflozin and a pharmaceutical composition or medicament comprising the crystalline form. Additional crystalline forms of Empagliflozin are disclosed in WO 2006/117360 A1 (EP 1888551 B1) and WO 2011/039107A1 (EP 2483286 B1). In particular, the said patent discloses the crystalline Form-I and Form-ll and process for preparation thereof.
- WO 2016169534 discloses novel forms of amorphous Empagliflozin, processes for preparing the same and the use thereof in dosage forms. These solid forms of amorphous Empagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous Empagliflozin.
- CN 111214450 B discloses solid dispersion comprising Empagliflozin, a carrier material and other pharmaceutically acceptable auxiliary materials, and is characterized in that the carrier material consists of poloxamer and mannitol and a preparation process thereof.
- KR 10-2330597 B1 covers a pharmaceutical formulation comprising amorphous Empagliflozin or a hydrate thereof and polycarbophil and optionally containing one or more excipients selected from the group consisting of magnesium alumino metasilicate or nonporous colloidal silica.
- WO 2021123165 A1 provides solid pharmaceutical dosage forms and methods for making the same, wherein the pharmaceutical dosage forms comprise Empagliflozin in the form of an amorphous solid solution with at least one polymer wherein the at least one polymer is selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, cellulose ether, dextrin, gum arabicum, pullulan, poly(meth)acrylate, and mixtures thereof.
- IN 201711026696 discloses a pharmaceutical composition comprising amorphous Empagliflozin along with one or more pharmaceutically acceptable excipients.
- IN 201741011748 discloses solid dispersion of Empagliflozin and processes for the preparation of the same wherein solid dispersion comprises HPMC, Co-povidone, HPC and prepared by hot-melt extrusion method.
- CN 106880595 A discloses solid dispersion of amorphous Empagliflozin and its preparation method.
- the solid dispersion comprises amorphous Empagliflozin and at least one of the pharmaceutically acceptable excipients.
- CN 106692069 A discloses solid dispersion comprising Empagliflozin, povidone and lubricant wherein lubricant is selected from talc, magnesium stearate, silicon dioxide, sodium stearyl fumarate, and sodium lauryl sulfate.
- WO 2016051368 discloses a solid dispersion of amorphous Empagliflozin and a cyclodextrin.
- WO 2017203457 A1 discloses amorphous solid dispersion of Empagliflozin and one or more pharmaceutically acceptable carrier wherein the carrier is HPMC phthalate, methyl cellulose, ethyl cellulose, Soluplus®, hydroxypropyl cellulose, L-hydroxypropyl cellulose, HPMC, HPMC-As, Eudragit® E-100, microcrystalline cellulose.
- the carrier is HPMC phthalate, methyl cellulose, ethyl cellulose, Soluplus®, hydroxypropyl cellulose, L-hydroxypropyl cellulose, HPMC, HPMC-As, Eudragit® E-100, microcrystalline cellulose.
- a pharmaceutical composition comprising solid dispersion consisting of Empagliflozin and silicon dioxide not only provides storage stable composition but also provides a composition with similar dissolution profile when compared to the reference product Jardiance® tablet.
- a main object of the present invention is to provide a pharmaceutical composition comprising a stable solid dispersion of Empagliflozin.
- Another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a solid dispersion consisting of Empagliflozin and silicon dioxide.
- Yet another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide.
- Yet another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
- Yet another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
- Yet another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein said pharmaceutical composition is tablet.
- Yet another object of the present invention is to provide a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin, which remains stable during manufacturing and stability.
- Yet another object of the present invention is to provide a pharmaceutical composition above mentioned solid dispersion of Empagliflozin, which overcomes the problems of the prior art.
- Yet another object of the invention is to provide a commercially scalable, cost effective, environment friendly and robust process for the preparation of a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% based on the total weight of the composition.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein silicon dioxide is in amount of about from 1 wt% to 15 wt% based on the total weight of the composition.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and silicon dioxide is in amount of about from 1 wt% to 15 wt% based on the total weight of the composition.
- the present invention provides a tablet composition
- a tablet composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and silicon dioxide is in amount of about from 1 wt% to 15 wt%. based on the total weight of the composition.
- the present invention provides a tablet composition
- a tablet composition comprising: i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and silicon dioxide is in amount of about from 1 wt% to 15 wt% based on the total weight of the composition.
- the present invention provides a tablet comprising: a) 1 wt% to 20 wt% of Empagliflozin, b) 1 wt% to 15 wt% of silicon dioxide, c) 30 wt% to 80 wt% of one or more of diluents, d) 0 wt% to 10 wt% of one or more surfactant, e) 1 wt% to 20 wt% of one or more of disintegrants, f) 1 wt% to 15 wt% of one or more binders, and g) 0.1 wt% to 5 wt% of one or more lubricant based on the total weight of the composition.
- the present invention provides a pharmaceutical composition of any of the above aspects, wherein the said composition remains stable after storage for 3 months at 40°C and 75% relative humidity (RH).
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising solid dispersion of Empagliflozin as mentioned herein above, which is prepared by solvent evaporation.
- the present invention discloses a use of such pharmaceutical composition as medicament in the treatment of hyperglycemia.
- Figure 1 XRPD pattern of solid dispersion of Empagliflozin and Silicon dioxide prepared according to Example 1.
- Figure-2 An overlay of XRPD patterns of Empagliflozin composition (prepared according to Example-3) before (as numbered 3) and after (as numbered 2) storage at 40° C/75% RH for 3 months along with placebo (as numbered 1).
- Figure-3 Graph showing the in vivo results of Empagliflozin of Example-3 vis-a-vis reference drug in fasting condition (Jardiance®).
- % used in this specification means the percentage by weight unless otherwise stipulated.
- composition means pharmaceutical composition includes, without limitation, capsule, tablet, caplet, powder, pellet, granules liquid dispersion, bead, solution, suspension, emulsion etc.
- Empagliflozin ' as used in the present invention includes, but is not limited to, Empagliflozin per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
- solid dispersion refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components.
- solid dispersion refers to stable solid dispersions comprising amorphous drug substance and carrier like silicon dioxide.
- solid dispersion as used herein also refers to stable solid dispersions comprising amorphous drug substance and carrier like silicon dioxide with or without another adsorbent/absorbent.
- amorphous drug substance it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.
- stable or “stability” means that the pharmaceutical dosage form is physically and chemically stable
- chemically stable means that the pharmaceutical dosage form when stored at 40 °C and 75 % relative humidity for 3 or 6 months, each of the degradation impurity and total impurities remain within ICH limit.
- physically stable as used herein means that X-ray powder diffraction pattern (XRPD) of the pharmaceutical dosage form according to the invention when stored at 40 °C and 75 % relative humidity for 1 or 3 months in a closed vial does not exhibit detectable X- ray diffractions characteristic of the crystalline form of Empagliflozin.
- similarity factor refers to one way of comparing dissolution profiles of two different products (Multisource Pharmaceutical Products: Guidelines on Registration Requirements to establish Interchangeability, Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland).
- This model independent mathematical approach compares the dissolution profile of the two products: test and reference (or two strengths, or pre- and post-approved products from the same manufacturer). Tests are recommended to be performed under the same test conditions.
- the dissolution time points for both the profiles should be the same, for example for immediate release products e.g. 10, 15, 30, 45, 60 minutes and for extended release products, e.g., 1 , 2, 3, 5 and 8 hours.
- a present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
- a present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
- a composition of the present invention comprises active ingredient Empagliflozin in the amount from 1 wt% to 20 wt% based on the total weight of the composition.
- a composition of the present invention comprises silicon dioxide in amount from 1 wt% to 15 wt% based on the total weight of the composition.
- a composition of the present invention comprises solid dispersion consisting of Empagliflozin and silicon dioxide in amount from 5 wt% to 20 wt% based on the total weight of the composition.
- a pharmaceutical composition of the present invention further comprises one or more pharmaceutically acceptable excipients.
- the excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
- the pharmaceutical excipient can be selected from excipient can be selected from diluent, binder, disintegrant, surfactant and lubricant.
- Diluent includes, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, and mixtures thereof.
- diluent is microcrystalline cellulose and lactose monohydrate.
- the amount of diluent is preferably from about 30 wt% to about 80 wt%, more preferably from about 50 wt% to about 80 wt% based on the total weight of the pharmaceutical composition.
- Disintegrant includes, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, starch, pregelatinized starch, sodium alginate and mixtures thereof.
- the amount of the disintegrant is preferably from about 1 wt% to about 20 wt%, more preferably from about 1 wt% to about 15 wt% based on the total weight of the pharmaceutical composition.
- Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, dextran, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, pullulan, gums, synthetic resins and mixtures thereof.
- L-HPC low substituted hydroxypropyl cellulose
- the amount of the binder is preferably from about 1 wt% to about 15 wt%, more preferably from about 1 wt% to about 10 wt% based on the total weight of the pharmaceutical composition.
- Surfactant includes, but are not limited to, poloxamer, polysorbates, d-alpha tocopheryl glycol 1000 succinate, polyoxy-35-castor oil, polyoxy-40-hydrogenated castor oil, labrosol, propylene glycol and mixtures thereof.
- the amount of the surfactant is preferably from about 0 wt% to about 10 wt%, more preferably from about 0 wt% to about 5 wt% based on the total weight of the pharmaceutical composition.
- Lubricant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, com starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, and mixtures thereof.
- metallic stearates such as magnesium stearate, calcium stearate, zinc stearate
- stearic acid hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate
- polyethylene glycols com starch
- sodium stearyl fumarate sodium benzoate
- mineral oil talc
- waxes DL-leucine
- the amount of one or more lubricant is preferably from about 0.1 wt% to about 5 wt%, more preferably from about 0.2 wt% to about 3 wt% based on the total weight of the pharmaceutical composition.
- the pharmaceutical composition includes, but are not limited to, capsules powder, tablet, minitablet, micro-tablet, granule, or pellet, pill, lozenge, solution, suspension, emulsion and the like wherein the composition can be further film coated.
- the pharmaceutical composition is in the form of a tablet.
- the pharmaceutical composition is in the form of a film coated tablet.
- the pharmaceutical composition of the present invention may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique.
- the film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients.
- a suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof.
- a preferred film- forming polymer is hydroxypropyl methyl cellulose.
- Other suitable film- forming polymers which are known in the art may also be used.
- the film coating may also contain opacifiers like titanium dioxide, flow aids like talc and pigment like iron oxide yellow.
- Release of the pharmaceutical composition includes, but are not limited to, immediate release, extended release, sustained release, zero order release and the like.
- the pharmaceutical composition has immediate release.
- a process to obtain solid dispersion of the present invention includes, but is not limited to, solvent evaporation method, fusion method, kneading method, melting method, spray drying method, co-grinding method, lyophilization technique, hot melt extrusion, melt agglomeration, supercritical fluid (SCF) technology and the like.
- the solid dispersion of the present invention is prepared by dissolving Empagliflozin in a suitable solvent with or without additional ingredients and sprayed onto silicon dioxide particles via the use of suitable technology like fluid bed technology.
- suitable solvent used for dissolving Empagliflozin includes, but is not limited to, purified water, ethanol, methanol, isopropanol, acetone, N, N-dimethylformamide etc.
- the pharmaceutical composition of the present invention can be obtained by using known conventional methods i.e. granulation or direct compression.
- the process to obtain granulate includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation, slugging, roller compaction.
- the pharmaceutical composition in accordance with the present invention may be used as a medicament.
- the pharmaceutical composition typically may be used in the treatment of hyperglycemia.
- composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.
- Example 1 Preparation of solid dispersion of Empagliflozin and silicon dioxide
- Example 2 A pharmaceutical composition comprising solid dispersion of Empagliflozin and silicon dioxide Table-1
- Microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose and croscarmellose sodium were sieved through a suitable mesh size.
- step-3 The obtained blend in step-3 was compressed into tablet.
- Example 3 A pharmaceutical composition comprising solid dispersion of Empagliflozin and silicon dioxide
- Microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, poloxamer and croscarmellose sodium were sieved through a suitable mesh size.
- step-3 The obtained blend in step-3 was compressed into tablet.
- Example 4 Dissolution Data of Example 2 & 3 at pH 6.8 phosphate buffer 900 ml
- Example 5 In vivo analysis of Empagliflozin composition of Example-3 and reference product in fasting conditions
- Example-3 The tablets prepared in Example-3, were placed in PVC/ aluminum blisters, and stored for 3 months under conditions of 40°C/75% RH.
- XRPD pattern of Empagliflozin composition (of Example-3) were checked before (as numbered 3) and after the storage (as numbered 2) at 40° C/75% RH for 3 months along with its placebo (as numbered 1), which are depicted in Figure-2. It is evident from the given figure-2 that amorphous Empagliflozin remained stable i.e. in amorphous form even after 3 months under conditions of 40°C/75% RH.
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Abstract
The present invention relates to a pharmaceutical composition comprising i) a solid dispersion consisting of Empagliflozin and silicon dioxide and ii) at least one pharmaceutically acceptable excipient. The said pharmaceutical composition has desirable pharmacokinetic characteristics, favorable storage stability and comparative dissolution properties. The invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of hyperglycaemia.
Description
A PHARMACEUTICAL COMPOSITION COMPRISING SOLID DISPERSION OF EMPAGLIFLOZIN
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising i) a solid dispersion consisting of Empagliflozin and silicon dioxide and ii) at least one pharmaceutically acceptable excipient. The said pharmaceutical composition has a desirable pharmacokinetic characteristic, favorable storage stability and comparative dissolution properties. The invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of hyperglycaemia.
BACKGROUND OF THE INVENTION
Empagliflozin is chemically known as (1 S)-1 ,5-anhydro-1-(4-chloro-3-{4-[(3S)- tetrahydrofuran-3-yloxy] benzyl} pheny l)-D-glucitol , having the following formula (I),
Empagliflozin is a selective inhibitor of sodium/glucose co-transporter-2 (SGLT2) and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2DM). The sodium glucose cotransporter 2 (SGLT-2) is a low-affinity, high-capacity, active sodium glucose symporter expressed at the apical membrane of epithelial cells lining the proximal renal tubule. SLGT-2 is responsible for reabsorbing the majority of the glucose filtered at the glomerulus. In other words, SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood. Inhibition of SGLT-2 by i
Empagliflozin decreases glucose reabsorption and promotes urinary glucose excretion. Urinary glucose loss is the primary mechanism by which Empagliflozin lowers blood glucose.
Empagliflozin is marketed as mono Empagliflozin, in combination with metformin, in combination with linagliptin and in combination with linagliptin and metformin by Boehringer Ingelheim. These marketed products are approved in the form of film coated tablet. These tablets contain Empagliflozin in the strengths of 5 mg, 10 mg, 12.5 mg, 25 mg.
Firstly, Empagliflozin is marketed under the brand name Jardiance® in Europe since 2014.
Jardiance® is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
- as monotherapy when metformin is considered inappropriate due to intolerance
- in addition to other medicinal products for the treatment of diabetes.
Jardiance is indicated in adults for the treatment of symptomatic chronic heart failure.
According to European Public Assessment Report (EPAR), Empagliflozin is a white to yellowish non-hygroscopic crystalline solid, very slightly soluble in water (pH 1 -7.4), slightly soluble in acetonitrile and ethanol, sparingly soluble in methanol, and practically insoluble in toluene. It is very slightly soluble in aqueous media between pH 1 -7.5 but has low intestinal permeability and thus it is classified as BCS Class III compound based on Biopharmaceutical Classification System. According to EPAR, particle size was not found to be critical for dissolution, but since coarser API dissolves slightly more slowly and therefore the drug substance is milled and particle size is tightly controlled.
This latter characteristic i.e. low permeability is the factor limiting oral bioavailability of many such kind of compounds. To address such problem, numerous techniques are
known in the art such as particle size reduction, nanosuspension technology, using surfactant, salt formation, pH adjustment, hydrotrophy, solid dispersion, etc. Solid dispersion is one of the techniques explored in the art to improve the dissolution and bioavailability of compound like Empagliflozin.
At the same time, while exploring solid dispersion technique, it is important to understand that alteration in polymorphic form of the compound also affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). It is known that crystalline solids normally require a significant amount of energy for dissolution due to their highly organized lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non -crystal line form. That may be the reason that why amorphous forms in a number of drugs exhibit different dissolution characteristics and, in some cases, different bioavailability patterns as compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003- 2007).
An amorphous form generally has better solubility and bioavailability than corresponding crystalline form of the same compound and that may be the reason, in particular cases, to use amorphous form of the said compound while targeting to obtain a formulation with better stability, solubility and compressibility etc.
Many attempts have been made in the art to improve the solubility of Empagliflozin and one of them is preparing an amorphous form. However, amorphous Empagliflozin alone is highly unstable and recrystallizes virtually immediately, which poses a great challenge while developing a composition with amorphous form of Empagliflozin.
WO 2005/092877 discloses glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture.
WO 2006/117359 A1 (EP 1888552 B1) discloses stable a crystalline form of Empagliflozin and a pharmaceutical composition or medicament comprising the crystalline form. Additional crystalline forms of Empagliflozin are disclosed in WO 2006/117360 A1 (EP 1888551 B1) and WO 2011/039107A1 (EP 2483286 B1). In particular, the said patent discloses the crystalline Form-I and Form-ll and process for preparation thereof.
WO 2016169534 discloses novel forms of amorphous Empagliflozin, processes for preparing the same and the use thereof in dosage forms. These solid forms of amorphous Empagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous Empagliflozin.
CN 111214450 B discloses solid dispersion comprising Empagliflozin, a carrier material and other pharmaceutically acceptable auxiliary materials, and is characterized in that the carrier material consists of poloxamer and mannitol and a preparation process thereof.
KR 10-2330597 B1 covers a pharmaceutical formulation comprising amorphous Empagliflozin or a hydrate thereof and polycarbophil and optionally containing one or more excipients selected from the group consisting of magnesium alumino metasilicate or nonporous colloidal silica.
WO 2021123165 A1 provides solid pharmaceutical dosage forms and methods for making the same, wherein the pharmaceutical dosage forms comprise Empagliflozin in the form of an amorphous solid solution with at least one polymer wherein the at least one polymer is selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, cellulose ether, dextrin, gum arabicum, pullulan, poly(meth)acrylate, and mixtures thereof.
IN 201711026696 discloses a pharmaceutical composition comprising amorphous Empagliflozin along with one or more pharmaceutically acceptable excipients.
IN 201741011748 discloses solid dispersion of Empagliflozin and processes for the preparation of the same wherein solid dispersion comprises HPMC, Co-povidone, HPC and prepared by hot-melt extrusion method.
CN 106880595 A discloses solid dispersion of amorphous Empagliflozin and its preparation method. The solid dispersion comprises amorphous Empagliflozin and at least one of the pharmaceutically acceptable excipients.
CN 106692069 A discloses solid dispersion comprising Empagliflozin, povidone and lubricant wherein lubricant is selected from talc, magnesium stearate, silicon dioxide, sodium stearyl fumarate, and sodium lauryl sulfate.
WO 2016051368 discloses a solid dispersion of amorphous Empagliflozin and a cyclodextrin.
WO 2017203457 A1 discloses amorphous solid dispersion of Empagliflozin and one or more pharmaceutically acceptable carrier wherein the carrier is HPMC phthalate, methyl cellulose, ethyl cellulose, Soluplus®, hydroxypropyl cellulose, L-hydroxypropyl cellulose, HPMC, HPMC-As, Eudragit® E-100, microcrystalline cellulose.
IN 4964/CHE/2014 discloses amorphous solid dispersion of Empagliflozin with polyvinyl pyrrolidinone.
There still exist a need for pharmaceutical compositions comprising Empagliflozin, which are physically and chemically stable, have improved dissolution profile and are prepared by an economically viable process, which is also suitable on a commercial scale.
The inventors of the present invention have surprisingly found that a pharmaceutical composition comprising solid dispersion consisting of Empagliflozin and silicon dioxide
not only provides storage stable composition but also provides a composition with similar dissolution profile when compared to the reference product Jardiance® tablet.
OBJECT OF THE INVENTION
A main object of the present invention is to provide a pharmaceutical composition comprising a stable solid dispersion of Empagliflozin.
Another object of the present invention is to provide a pharmaceutical composition comprising a solid dispersion consisting of Empagliflozin and silicon dioxide.
Yet another object of the present invention is to provide a pharmaceutical composition comprising a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide.
Yet another object of the present invention is to provide a pharmaceutical composition comprising i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
Yet another object of the present invention is to provide a pharmaceutical composition comprising i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
Yet another object of the present invention is to provide a pharmaceutical composition comprising i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein said pharmaceutical composition is tablet.
Yet another object of the present invention is to provide a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin, Metformin and at least one pharmaceutically acceptable excipient.
Yet another object of the present invention is to provide a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin, Linagliptin and at least one pharmaceutically acceptable excipient.
Yet another object of the present invention is to provide a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin, which remains stable during manufacturing and stability.
Yet another object of the present invention is to provide a pharmaceutical composition above mentioned solid dispersion of Empagliflozin, which overcomes the problems of the prior art.
Yet another object of the invention is to provide a commercially scalable, cost effective, environment friendly and robust process for the preparation of a pharmaceutical composition comprising above mentioned solid dispersion of Empagliflozin.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
In another aspect, the present invention provides a pharmaceutical composition comprising:
i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% based on the total weight of the composition.
In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein silicon dioxide is in amount of about from 1 wt% to 15 wt% based on the total weight of the composition.
In another aspect, the present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and silicon dioxide is in amount of about from 1 wt% to 15 wt% based on the total weight of the composition.
In another aspect, the present invention provides a tablet composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and silicon dioxide is in amount of about from 1 wt% to 15 wt%. based on the total weight of the composition.
In another aspect, the present invention provides a tablet composition comprising: i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient, wherein Empagliflozin is in amount of about from 1 wt% to 20 wt% and silicon dioxide is in amount of about from 1 wt% to 15 wt% based on the total weight of the composition.
In another aspect, the present invention provides a tablet comprising: a) 1 wt% to 20 wt% of Empagliflozin, b) 1 wt% to 15 wt% of silicon dioxide, c) 30 wt% to 80 wt% of one or more of diluents, d) 0 wt% to 10 wt% of one or more surfactant, e) 1 wt% to 20 wt% of one or more of disintegrants, f) 1 wt% to 15 wt% of one or more binders, and g) 0.1 wt% to 5 wt% of one or more lubricant based on the total weight of the composition.
In another aspect, the present invention provides a pharmaceutical composition of any of the above aspects, wherein the said composition remains stable after storage for 3 months at 40°C and 75% relative humidity (RH).
In another aspect, the present invention provides a pharmaceutical composition comprising solid dispersion of Empagliflozin as mentioned herein above, which is prepared by solvent evaporation.
In another aspect, the present invention discloses a use of such pharmaceutical composition as medicament in the treatment of hyperglycemia.
The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : XRPD pattern of solid dispersion of Empagliflozin and Silicon dioxide prepared according to Example 1.
Figure-2: An overlay of XRPD patterns of Empagliflozin composition (prepared according to Example-3) before (as numbered 3) and after (as numbered 2) storage at 40° C/75% RH for 3 months along with placebo (as numbered 1).
Figure-3: Graph showing the in vivo results of Empagliflozin of Example-3 vis-a-vis reference drug in fasting condition (Jardiance®).
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention will now be more specifically illustrated as hereunder.
The term % used in this specification means the percentage by weight unless otherwise stipulated.
The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range.
The term “composition” as used in the present invention means pharmaceutical composition includes, without limitation, capsule, tablet, caplet, powder, pellet, granules liquid dispersion, bead, solution, suspension, emulsion etc.
The term ' Empagliflozin ' as used in the present invention includes, but is not limited to, Empagliflozin per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
The term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term "solid dispersion" as used herein, refers to stable solid dispersions comprising amorphous drug substance and carrier like silicon dioxide. Further the term "solid dispersion" as used herein also refers to stable solid dispersions comprising amorphous drug substance and carrier like silicon dioxide with or without another adsorbent/absorbent. By "amorphous drug substance," it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.
The term "stable" or "stability" means that the pharmaceutical dosage form is physically and chemically stable, whereas "chemically stable" means that the pharmaceutical dosage form when stored at 40 °C and 75 % relative humidity for 3 or 6 months, each of the degradation impurity and total impurities remain within ICH limit. The term "physically stable" as used herein means that X-ray powder diffraction pattern (XRPD) of the pharmaceutical dosage form according to the invention when stored at 40 °C and 75 % relative humidity for 1 or 3 months in a closed vial does not exhibit detectable X- ray diffractions characteristic of the crystalline form of Empagliflozin.
The term "similarity factor" or f2 factor as used herein refers to one way of comparing dissolution profiles of two different products (Multisource Pharmaceutical Products: Guidelines on Registration Requirements to establish Interchangeability, Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland). This model independent mathematical approach compares the dissolution profile of the two products: test and reference (or two strengths, or pre- and post-approved products from the same manufacturer). Tests are recommended to be performed under the same test conditions. The dissolution time points for both the profiles should be the same, for example for immediate release products e.g. 10, 15, 30, 45, 60 minutes and for extended release products, e.g., 1 , 2, 3,
5 and 8 hours. Only one time point should be considered after 85% dissolution of the reference product. An f2 value of 50 or greater (50-100) ensures sameness or equivalence of the two curves, and thus the performance of the two products. The similarity factor f2 should be computed using the equation: f2 =50 log {[l+(l/n) t=1 n (Rt - Tt )2 ]-0-5 100} where Rt and Tt are the cumulative percentage of the drug dissolved at each of the selected n time points of the comparator (reference) and (test) product respectively .
In general embodiment, a present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
In one embodiment, a present invention provides a pharmaceutical composition comprising: i) a solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide, and ii) at least one pharmaceutically acceptable excipient.
In one embodiment, a composition of the present invention comprises active ingredient Empagliflozin in the amount from 1 wt% to 20 wt% based on the total weight of the composition.
In one embodiment, a composition of the present invention comprises silicon dioxide in amount from 1 wt% to 15 wt% based on the total weight of the composition.
In one embodiment, a composition of the present invention comprises solid dispersion consisting of Empagliflozin and silicon dioxide in amount from 5 wt% to 20 wt% based on the total weight of the composition.
In another embodiment, a pharmaceutical composition of the present invention further comprises one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients. The pharmaceutical excipient can be selected from excipient can be selected from diluent, binder, disintegrant, surfactant and lubricant.
Diluent includes, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, and mixtures thereof. Preferably, diluent is microcrystalline cellulose and lactose monohydrate.
The amount of diluent is preferably from about 30 wt% to about 80 wt%, more preferably from about 50 wt% to about 80 wt% based on the total weight of the pharmaceutical composition.
Disintegrant includes, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, starch, pregelatinized starch, sodium alginate and mixtures thereof.
The amount of the disintegrant is preferably from about 1 wt% to about 20 wt%, more preferably from about 1 wt% to about 15 wt% based on the total weight of the pharmaceutical composition.
Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, dextran, ethyl
cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, pullulan, gums, synthetic resins and mixtures thereof.
The amount of the binder is preferably from about 1 wt% to about 15 wt%, more preferably from about 1 wt% to about 10 wt% based on the total weight of the pharmaceutical composition.
Surfactant includes, but are not limited to, poloxamer, polysorbates, d-alpha tocopheryl glycol 1000 succinate, polyoxy-35-castor oil, polyoxy-40-hydrogenated castor oil, labrosol, propylene glycol and mixtures thereof.
The amount of the surfactant is preferably from about 0 wt% to about 10 wt%, more preferably from about 0 wt% to about 5 wt% based on the total weight of the pharmaceutical composition.
Lubricant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, com starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, and mixtures thereof.
The amount of one or more lubricant is preferably from about 0.1 wt% to about 5 wt%, more preferably from about 0.2 wt% to about 3 wt% based on the total weight of the pharmaceutical composition.
The pharmaceutical composition includes, but are not limited to, capsules powder, tablet, minitablet, micro-tablet, granule, or pellet, pill, lozenge, solution, suspension, emulsion and the like wherein the composition can be further film coated. Preferably, the pharmaceutical composition is in the form of a tablet. Most preferably, the pharmaceutical composition is in the form of a film coated tablet.
The pharmaceutical composition of the present invention may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique. The film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients. A suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof. A preferred film- forming polymer is hydroxypropyl methyl cellulose. Other suitable film- forming polymers which are known in the art may also be used. The film coating may also contain opacifiers like titanium dioxide, flow aids like talc and pigment like iron oxide yellow.
Release of the pharmaceutical composition includes, but are not limited to, immediate release, extended release, sustained release, zero order release and the like. Preferably, the pharmaceutical composition has immediate release.
In one embodiment, a process to obtain solid dispersion of the present invention includes, but is not limited to, solvent evaporation method, fusion method, kneading method, melting method, spray drying method, co-grinding method, lyophilization technique, hot melt extrusion, melt agglomeration, supercritical fluid (SCF) technology and the like.
In one embodiment, the solid dispersion of the present invention is prepared by dissolving Empagliflozin in a suitable solvent with or without additional ingredients and sprayed onto silicon dioxide particles via the use of suitable technology like fluid bed technology.
Suitable solvent used for dissolving Empagliflozin includes, but is not limited to, purified water, ethanol, methanol, isopropanol, acetone, N, N-dimethylformamide etc.
The pharmaceutical composition of the present invention can be obtained by using known conventional methods i.e. granulation or direct compression. The process to obtain granulate includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation, slugging, roller compaction.
The pharmaceutical composition in accordance with the present invention may be used as a medicament. The pharmaceutical composition typically may be used in the treatment of hyperglycemia.
Moreover, the pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.
The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.
Examples:
Example 1 : Preparation of solid dispersion of Empagliflozin and silicon dioxide
Empagliflozin (25 mg) was dissolved in N, N-dimethyl formamide (35 mg). Silicon dioxide (31.50 mg) was loaded to granulator and obtained solution of Empagliflozin was added to the granulator and mixed. The obtained mixture was dried till the residual solvent content found to be within the acceptable limit to get the solid dispersion of Empagliflozin and silicon dioxide (56.50 mg). XRPD pattern is depicted in Fig.-1.
Example 2: A pharmaceutical composition comprising solid dispersion of Empagliflozin and silicon dioxide
Table-1
Process For The Preparation:
1. Microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose and croscarmellose sodium were sieved through a suitable mesh size.
2. Solid dispersion obtained as per Example-1 and blend obtained in step-1 were added into the container and mixed.
3. Magnesium stearate was sieved through a suitable mesh and added into the container at step-2 and mixed.
4. The obtained blend in step-3 was compressed into tablet.
Example 3: A pharmaceutical composition comprising solid dispersion of Empagliflozin and silicon dioxide
Table-2
Process For The Preparation:
1. Microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, poloxamer and croscarmellose sodium were sieved through a suitable mesh size.
2. Solid dispersion obtained as per Example-1 and blend obtained in step-1 were added into the container and mixed.
3. Magnesium stearate was sieved through a suitable mesh and added into the container at step-2 and mixed.
4. The obtained blend in step-3 was compressed into tablet.
Example 4: Dissolution Data of Example 2 & 3 at pH 6.8 phosphate buffer 900 ml
50 rpm with USP apparatus II at 37°C
Table-3
Dissolution of test products of Example-2 & Example-3 and reference product Jardiance® 25 mg were performed using standard USP apparatus II, paddles, at 50 rpm in 900 ml at pH=6.8. The drug release was determined by using an HPLC method. From the above dissolution data given in table-4, it is evident that f2 is more than 50, which establishes sameness or equivalence both products i.e. test products (of Example-2 & Example-3) and reference product in terms of its dissolution and performance.
Example 5: In vivo analysis of Empagliflozin composition of Example-3 and reference product in fasting conditions
Empagliflozin film coated tablets of Example-3 were compared with reference product Jardiance® film coated tablet under fasting conditions.
Table-4
Example 6: Stability Result of Empagliflozin composition prepared according to
Example 3
The tablets prepared in Example-3, were placed in PVC/ aluminum blisters, and stored for 3 months under conditions of 40°C/75% RH. XRPD pattern of Empagliflozin composition (of Example-3) were checked before (as numbered 3) and after the storage (as numbered 2) at 40° C/75% RH for 3 months along with its placebo (as numbered 1), which are depicted in Figure-2. It is evident from the given figure-2 that amorphous Empagliflozin remained stable i.e. in amorphous form even after 3 months under conditions of 40°C/75% RH.
Claims
1. A pharmaceutical composition comprising: a) a solid dispersion consisting of Empagliflozin and silicon dioxide, and b) at least one pharmaceutically acceptable excipient.
2. The pharmaceutical composition according to claim 1 , wherein solid dispersion consisting of an amorphous Empagliflozin and silicon dioxide.
3. The pharmaceutical composition according to claim 1 , wherein Empagliflozin is present in an amount from 1 % to 20 % by weight based on the total weight of the composition.
4. The pharmaceutical composition according to claim 1 , wherein silicon dioxide is present in an amount from 1 % to 15 % by weight based on the total weight of the composition
5. The pharmaceutical composition according to claim 1 , wherein at least one pharmaceutically acceptable excipient is selected from the group comprising of diluent, binder, disintegrant, surfactant and lubricant.
6. The pharmaceutical composition according to claim 5, wherein diluent is selected from lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide and mixtures thereof.
7. The pharmaceutical composition according to claim 5 or claim 6, wherein diluent is microcrystalline cellulose and lactose monohydrate.
8. The pharmaceutical composition according to claim 5, wherein binder is selected from carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, low-
substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, dextran, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, pullulan, gums, synthetic resins and mixture thereof.
9. The pharmaceutical composition according to claim 5 or 8, wherein binder is hydroxypropyl cellulose or low-substituted hydroxypropyl cellulose.
10. The pharmaceutical composition according to claim 5, wherein disintegrant is selected from sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, starch, pregelatinized starch, sodium alginate and mixtures thereof.
11. The pharmaceutical composition according to claim 5 or claim 10, wherein disintegrant is croscarmellose sodium.
12. The pharmaceutical composition according to claim 5, wherein lubricant is selected from magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, com starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate and mixtures thereof.
13. The pharmaceutical composition according to claim 5, wherein surfactant is selected from poloxamer, polysorbates, d-alpha tocopheryl glycol 1000 succinate, polyoxy-35-castor oil, polyoxy-40-hydrogenated castor oil, labrosol, ethanol, propylene glycol and mixtures thereof.
14. The pharmaceutical composition according to claim 5 or claim 13, wherein surfactant is poloxamer.
15. The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is selected from capsule, tablet, caplet, powder, pellet, granule, liquid dispersion, bead, solution, suspension and emulsion.
16. The pharmaceutical composition according to claim 1 or claim 15, wherein pharmaceutical composition is tablet.
17. The pharmaceutical composition according to any of claim 1 to 16 remains stable for 3 months at 40 °C and 75 % RH.
18. A pharmaceutical composition according to any of claim 1 to claim 17 further contains one or more additional active substance.
19. A pharmaceutical composition according to any of claim 1 to claim 18 is useful in the treatment of hyperglycemia.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2022/016500 | 2022-11-01 | ||
| TR2022016500 | 2022-11-01 |
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| WO2024096839A1 true WO2024096839A1 (en) | 2024-05-10 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111214450A (en) * | 2020-04-23 | 2020-06-02 | 上海翰森生物医药科技有限公司 | Empagliflozin tablet and preparation process thereof |
| CN112716966A (en) * | 2021-02-03 | 2021-04-30 | 浙江诺得药业有限公司 | Empagliflozin pharmaceutical composition and preparation method thereof |
| WO2021210929A1 (en) * | 2020-04-17 | 2021-10-21 | 보령제약 주식회사 | Novel pharmaceutical formulation having improved stability comprising amorphous empagliflozin |
-
2023
- 2023-10-30 WO PCT/TR2023/051218 patent/WO2024096839A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021210929A1 (en) * | 2020-04-17 | 2021-10-21 | 보령제약 주식회사 | Novel pharmaceutical formulation having improved stability comprising amorphous empagliflozin |
| CN111214450A (en) * | 2020-04-23 | 2020-06-02 | 上海翰森生物医药科技有限公司 | Empagliflozin tablet and preparation process thereof |
| CN112716966A (en) * | 2021-02-03 | 2021-04-30 | 浙江诺得药业有限公司 | Empagliflozin pharmaceutical composition and preparation method thereof |
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