WO2014102832A2 - Dispersion solide de chlorhydrate de saxagliptine - Google Patents

Dispersion solide de chlorhydrate de saxagliptine Download PDF

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Publication number
WO2014102832A2
WO2014102832A2 PCT/IN2013/000816 IN2013000816W WO2014102832A2 WO 2014102832 A2 WO2014102832 A2 WO 2014102832A2 IN 2013000816 W IN2013000816 W IN 2013000816W WO 2014102832 A2 WO2014102832 A2 WO 2014102832A2
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WO
WIPO (PCT)
Prior art keywords
solid dispersion
saxagliptin hydrochloride
pharmaceutically acceptable
amorphous
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2013/000816
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English (en)
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WO2014102832A3 (fr
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Kesireddy Subash Chander Reddy
Bandi Vamsi Krishna
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Hetero Research Foundation
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Hetero Research Foundation
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Publication date
Application filed by Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2014102832A2 publication Critical patent/WO2014102832A2/fr
Publication of WO2014102832A3 publication Critical patent/WO2014102832A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention provides a novel amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • Saxagliptin chemically (l.S',3iS',55)-2-[(25)-2-amino-2-(3-hydroxy-l-adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and has the structure formula:
  • Saxagliptin hydrochloride is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.
  • the generic name saxagliptin hydrochloride is marketed by BRISTOL MYERS SQUIBB under the brand name Onglyza®.
  • Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice.
  • polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules.
  • Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
  • Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (1R).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • 1R Infrared spectrometry
  • Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
  • Saxagliptin and its hydrochloride can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • an object of the present invention is to provide a novel amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention provides amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier.
  • the present invention there is provided a process for the preparation of amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier, which comprises:
  • compositions comprising a therapeutically effective amount of amorphous solid dispersion of saxagliptin hydrochloride along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
  • Figure 1 is a powder X-ray diffractogram patterns of amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier.
  • Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper- ⁇ radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.
  • room temperature refers to temperature at about 25 to 35°C.
  • amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier is provided.
  • the powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier is shown in figure 1.
  • the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
  • the said pharmaceutically acceptable carriers are used to facilitate the presence of an amorphous saxagliptin hydrochloride.
  • solid dispersion refers to a composition prepared by dissolving or dispersing a substituted saxagliptin hydrochloride in an organic solvent or mixture of organic solvents with one or more pharmaceutically acceptable carriers and converting the solution or dispersion to a solid form.
  • a process for the preparation of amorphous solid dispersion of saxagliptin hydrochloride in combination with, a pharmaceutically acceptable carrier which comprises:
  • Saxagliptin hydrochloride used in step (a) may preferably be saxagliptin hydrochloride obtained by the known process.
  • the solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide and methanol.
  • the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus or hydroxypropyl methylcellulose.
  • the solvent may be removed from the solution in step (b) by known methods, for example, distillation or spray drying.
  • the distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure.
  • the distillation may preferably be carried out until the solvent is almost completely distilled off.
  • reduced pressure refers to a pressure of less than 100 mmHg.
  • spray drying refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.
  • compositions comprising a therapeutically effective amount of amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier and along with pharmaceutically acceptable excipients, and at least one pharmaceutically acceptable excipient.
  • amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
  • the present invention provides a pharmaceutical composition containing said solid dispersion along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or luricants.
  • pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or luricants.
  • binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
  • diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof.
  • Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, and polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate and sorbitan monol
  • disintegrants include low-substituted hydroxypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.
  • lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
  • Coloring agents include any FDA approved colors for oral use.
  • the invention will now be further described by the following examples, which are illustrative rather than limiting.
  • Example 2 The separated solid was filtered and then dried at 30 to 35°C for 5 hours to obtain a solid.
  • the solid obtained was dissolved in methylene chloride (3000 ml) at room temperature. The solution was then cooled to 0 to 5°C and then added hydrochloric acid (1 1%) in ethyl acetate (50 ml). The reaction mass was stirred for 3 hours at 0 to 5°C and filtered. The solid obtained was dried to obtain 50 gm of saxagliptin hydrochloride.
  • Example 2 Example 2:
  • a mixture of saxagliptin hydrochloride (50 gm) and copovidone (100 gm) was dissolved in methanol (450 ml) at room temperature. The solution was filtered through hy-flow bed and the solvent was distilled off under reduced pressure at below 50°C and then dried to obtain 142 gm of amorphous saxagliptin hydrochloride solid dispersion with copovidone.
  • a mixture of saxagliptin hydrochloride (50 gm) and copovidone (150 gm) was dissolved in methanol (600 ml) at room temperature. The solution was filtered through hy-flow bed and the solvent was distilled off under reduced pressure at below 50°C and then dried to obtain 190 gm of amorphous saxagliptin hydrochloride solid dispersion with copovidone.
  • Example 2 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with copovidone.
  • Example 2 Preparation of amorphous saxagliptin hydrochloride solid dispersion with copovidone Example 2 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with copovidone.
  • Example 2 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with copovidone.
  • Example 8 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with copovidone.
  • Example 2 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with copovidone.
  • Example 9 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with hydroxypropyl methylcellulose.
  • Example 11 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with hydroxypropyl methylcellulose.
  • Example 9 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with hydroxypropyl methylcellulose.
  • Example 9 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with hydroxypropyl methylcellulose.
  • Example 13
  • Example 9 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous saxagliptin hydrochloride solid dispersion with hydroxypropyl methylcellulose.
  • Example 14 Preparation of amorphous saxagliptin hydrochloride solid dispersion with soluplus Example 14 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous saxagiiptin hydrochloride solid dispersion with soluplus.
  • Example 14 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous saxagiiptin hydrochloride solid dispersion with soluplus.
  • Example 14 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous saxagiiptin hydrochloride solid dispersion with soluplus.
  • Example 14 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous saxagiiptin hydrochloride solid dispersion with soluplus.
  • the separated solid was filtered and then dried at 30 to 35°C for 5 hours to obtain a solid.
  • the solid obtained was dissolved in methylene chloride (3000 ml) at room temperature. The solution was then cooled to 0 to 5°C and then added hydrochloric acid (1 1%) in ethyl acetate (50 ml). The reaction mass was stirred for 3 hours at 0 to 5°C and then added copovidone (50 gm) and methanol (300 ml) at room temperature. The solution was filtered through hy-flow bed and the solvent was distilled off under reduced pressure at below 50°C. The solid obtained was dried to obtain 95 gm of amorphous saxagliptin hydrochloride solid dispersion with copovidone.
  • Example 22 Preparation of amorphous saxagliptin hydrochloride solid dispersion with hydroxypropyl methylcellulose
  • [(3S,5R,7S)-3-hydroxyadamantan-l-yl]-2-oxoethyl]carbamate 100 gm was dissolved in isopropyl alcohol (100 ml) and water (100 ml) and then added concentrated hydrochloric acid (35 ml) at room temperature. The contents were heated to 65°C and stirred for 1 hour. Water (200 ml) was added to the solution at 65°C and then cooled to room temperature. To the reaction mass was added methylene chloride (600 ml), sodium hydroxide (10N, 30 gm) and water (20 ml) at room temperature.
  • the pH of the reaction mass was adjusted to 9.0 to 9.5 with potassium carbonate solution (24%) and then added water (20 ml) and sodium chloride (125 gm). The reaction mass was stirred for 45 minutes and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrated to obtain a residual mass. To the residual mass was added ethyl acetate (170 ml) and then cooled to 10 to 15°C. Water (170 ml) was added to the reaction mixture slowly and stirred for 3 hours at 10 to 15°C. The separated solid was filtered and then dried at 30 to 35°C for 5 hours to obtain a solid. The solid obtained was dissolved in methylene chloride (3000 ml) at room temperature.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une nouvelle dispersion solide amorphe de chlorhydrate de saxagliptine associée à un excipient pharmaceutiquement acceptable. Elle concerne un procédé de préparation et des compositions pharmaceutiques comprenant cette dispersion.
PCT/IN2013/000816 2012-12-31 2013-12-30 Dispersion solide de chlorhydrate de saxagliptine Ceased WO2014102832A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN5537/CHE/2012 2012-12-31
IN5537CH2012 2012-12-31

Publications (2)

Publication Number Publication Date
WO2014102832A2 true WO2014102832A2 (fr) 2014-07-03
WO2014102832A3 WO2014102832A3 (fr) 2015-03-19

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Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20090696A1 (es) * 2007-04-20 2009-06-20 Bristol Myers Squibb Co Formas cristalinas de saxagliptina y procesos para preparar las mismas
CN102379869A (zh) * 2010-08-31 2012-03-21 林飞 包含沙格列汀的口服制剂及其应用
EP2608788A1 (fr) * 2010-10-04 2013-07-03 Assia Chemical Industries Ltd. Polymorphes de chlorhydrate de saxagliptine et leurs procédés de préparation
WO2013136343A1 (fr) * 2012-03-12 2013-09-19 Mylan Laboratories Ltd. Chlorhydrate de saxagliptine amorphe
WO2013171766A2 (fr) * 2012-05-15 2013-11-21 Hetero Research Foundation Dispersion solide de saxagliptine

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