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WO2011101862A1 - Formulation stabilisée de la forme polymorphe iii du fluconazole - Google Patents

Formulation stabilisée de la forme polymorphe iii du fluconazole Download PDF

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Publication number
WO2011101862A1
WO2011101862A1 PCT/IN2011/000084 IN2011000084W WO2011101862A1 WO 2011101862 A1 WO2011101862 A1 WO 2011101862A1 IN 2011000084 W IN2011000084 W IN 2011000084W WO 2011101862 A1 WO2011101862 A1 WO 2011101862A1
Authority
WO
WIPO (PCT)
Prior art keywords
fluconazole
polymorph iii
pharmaceutical composition
oral pharmaceutical
stabilized
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/IN2011/000084
Other languages
English (en)
Inventor
Nandan Mohan Chandavarkar
Kour Chand Jindal
Shailesh Sharad Kulkarni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
FDC Ltd
Original Assignee
FDC Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by FDC Ltd filed Critical FDC Ltd
Publication of WO2011101862A1 publication Critical patent/WO2011101862A1/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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present inverftion relates to stabilized formulation of Fluconazole polymorph III and method of stabilizing the formulation containing Fluconazole polymorph III.
  • Fluconazole is a triazole antifungal antibiotic used to prevent and treat a variety of fungal and yeast infections. Fluconazole is used to treat infections caused by fungus, which can invade any part of the body including the mouth, throat, esophagus, lungs, bladder, genital area, and the blood. Fluconazole is also used to prevent fungal infection in people with weak immune systems caused by cancer treatment, bone marrow transplant, or diseases such as AIDS.
  • Fluconazole is designated chemically as 2,4-difluoro-a,al-bis(lH-l,2,4-triazoI-l- ylmethyl) benzyl alcohol.
  • the molecular structure of Fluconazole is represented as:
  • Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Polymorphs of a pharmaceutical solid may have different physical and solid state chemical properties. The most stable polymorphic form of a drug substance is often used because it has the lowest potential for conversion from one polymorphic form to another.
  • Fluconazole the fifst of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration and as a powder for oral suspension. Fluconazole exists in different polymorphic forms like I, II, III and hydrate.
  • US patent 4404216 discloses 2-(2,4-Difluorophenyl)-l,3-bis(lH-l,2,4-triazol-l- yl)propan-2-ol (fluconazole) and its pharmaceutically acceptable acid addition salts. This particular bis-triazole derivative and its salts are useful for treating fungal infections in animals, including humans. This patent further discloses methods for preparing these compounds and pharmaceutical composition using pharmaceutical acceptable carrier.
  • GB patent 2270521 discloses crystalline monohydrate form of fluconazole, which is useful for pharmaceutical formulation as an antifungal agent and is less bitter than the non-hydrated compound. Crystalline monohydrate form of fluconazole was synthesized from anhydrous fluconazole.
  • US patent 7094904 discloses process for the synthesis of monohydrate and crystal modifications I and II of fluconazole. The process discloses hydrolyzing silyl ether of following formula to form fluconazole monohydrate.
  • fluconazole polymorph III has best bioavailability. Hence fluconazole polymorph III is most preferred among these polymorphs.
  • fluconazole polymorph III API is susceptible to absorb moisture; hence during formulation the atmospheric moisture or the moisture present in the pharmaceutical excipients is enough to slowly convert polymorph III to hydrated form. It was also found by the current inventors that when Polymorph III is exposed to high humidity or when its formulation is prepared using aqueous process, polymorph III gets converted to hydrated form. Since fluconazole polymorph III has more bioavailability over the other known forms, keeping the polymorph III intact during its shelf life is necessary to achieve maximum therapeutic benefit of the antifungal activity. Therefore, it is necessary to stabilize polymorph III even during formulation process to make it stable during its storage.
  • the present invention therefore provides an improved stabilized formulation of fluconazole polymorph III by using non aqueous process having advantage over the conventional processes which would otherwise convert fluconazole polymorph III into its hydrated form.
  • the formulation of the present invention encompasses solid dosage forms like tablets, capsules, granules, powders and pellets.
  • main objective of the present invention is to provide stable oral dosage forms of fluconazole polymorph III and at least one pharmaceutically acceptable excipient stabilized by non-aqueous process.
  • Another objective of the present invention is to provide said formulations having maximum therapeutic benefit of antifungal activity by retaining polymorphic form of fluconazole polymorph III during its storage.
  • Yet another objective of the present invention is to provide a process for preparing the said oral dosage formulations comprising fluconazole polymorph III. Summary of the invention:
  • the invention discloses a stabilized pharmaceutical composition comprising fluconazole polymorph III and a process for preparing the same.
  • the invention discloses a composition wherein the fluconazole polymorph III not only retains its polymorphic form but also stable on normal storage conditions and is therefore having maximum therapeutic benefit of antifungal activity.
  • the process employed is non-aqueous in order to avoid transformation of polymorph III into hydrated form.
  • the present invention provides oral dosage forms comprising fluconazole polymorph III and at least one pharmaceutically acceptable excipient.
  • the formulations of the current invention comprising fluconazole polymorph III, which was stabilized using non-aqueous process so as to retain the polymorphic form during the storage and thus posses improved bioavailability.
  • the present invention provides stabilized oral pharmaceutical composition comprising
  • the composition is prepared using non-aqueous process.
  • the non-aqueous process involves use of non-aqueous solvents selected from methylene chloride, isopropyl alcohol, ethanol, methanol or acetone.
  • the amount of fluconazole polymorph III is present in the range of 30 to 80% by weight of total formulation.
  • oral pharmaceutical compositions according to the invention encompass the dosage forms including tablets, capsules, granules, powders and pellets.
  • Suitable diluent(s) used in the pharmaceutical composition of the present invention is selected from the group consisting of cellulose derivatives such as microcrystalline cellulose, powdered cellulose, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, kaolin, magnesium oxide, magnesium carbonate, lactose, glucose, fructose, mannitol, dextrates, maltitol, sorbitol and xylitol.
  • cellulose derivatives such as microcrystalline cellulose, powdered cellulose, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, kaolin, magnesium oxide, magnesium carbonate, lactose, glucose, fructose, mannitol, dextrates, maltitol, sorbitol and xylitol.
  • Binders used in the pharmaceutical composition of the present invention is selected from the group consisting of cellulose derivatives such as Hydroxypropyl methylcellulose, Hydroxypropyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose, ethyl cellulose, gums such as guar gum, gum acacia, xanthan gum and tragacanth gum, Povidone, acrylate polymers, gelatin, starch and pregelatinized starch.
  • Disintegrant(s) is selected from group consisting of but not limited to croscarmellose sodium, crospovidone, starch, pregelatinized starch and sodium starch glycolate.
  • Lubricant(s) is selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, stearic acid, talc, zinc stearate, hydrogenated vegetable oil, glyceryl behenate and colloidal silicon dioxide.
  • compositions of the present invention further comprise at least one excipient such as glidant, sweetener, surfactant, flavor and colorant.
  • the pharmaceutical composition of the invention is in solid oral dosage form containing fluconazole polymorph III in conventional pharmaceutical dosages.
  • an oral solid formulation of fluconazole is prepared by granulation method using top spray granulation or by high/low shear granulation process.
  • X-ray powder diffraction was performed to illustrate the crystal behaviour of fluconazole polymorph III and hydrated form in API and formulations. Description of X-ray powder diffraction patterns are as shown in Table 1.
  • Figure 3 Fluconazole Polymorph III API after exposure in open condition to high humidity of 84%RH at 25°C for 10 days.
  • Figure 4 Fluconazole Tablets using Polymorph III API prepared by simple mixing of excipient and compression (Example 1) , after exposure in open condition to high humidity of 75%RH at 40°C for 10 days.
  • Figure 5 Fluconazole Tablets using Polymorph III API prepared by Example No. 2 after exposure in open condition to high humidity of 75%RH at 40°C for 10 days.
  • Figure 6 Fluconazole Tablets using Polymorph III API prepared by Example No. 3 before exposure to high humidity/temperature conditions.
  • Figure 7 Fluconazole Tablets using Polymorph III API prepared by Example No. 3, in aluminum strip pack after exposure to high humidity of 75%RH at 40°C for 3 months.
  • Figure 8 Fluconazole Tablets using Polymorph III API prepared by Example No. 4 before exposure to high humidity/temperature conditions.
  • Figure 9 Fluconazole Tablets using Polymorph III API prepared by Example No. 4, in cold form blister pack after exposure to high humidity of 75%RH at 40°C for 6 months.
  • step 2 Mixing ingredients of step 1 in a suitable mixer.
  • step 3 Dissolving ethyl cellulose in Methylene Chloride, and granulating dry mix in step 2.
  • step 7 Drying the wet mass in step 3 till LOD of the granules step is below 3%
  • step 6 Drying the wet mass in step 6 till LOD of the granules step is below 3%
  • step 3 and step 6 Passing the granules of step 3 and step 6 through sieve no. 30 (ASTM, 600 microns) and mixing these granules in a suitable blender.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une formulation stabilisée de la forme polymorphe III du fluconazole, et une méthode de stabilisation de la formulation contenant la forme polymorphe III du fluconazole.
PCT/IN2011/000084 2010-02-17 2011-02-04 Formulation stabilisée de la forme polymorphe iii du fluconazole Ceased WO2011101862A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN437MU2010 2010-02-17
IN437/MUM/2010 2010-02-17

Publications (1)

Publication Number Publication Date
WO2011101862A1 true WO2011101862A1 (fr) 2011-08-25

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ID=44280226

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2011/000084 Ceased WO2011101862A1 (fr) 2010-02-17 2011-02-04 Formulation stabilisée de la forme polymorphe iii du fluconazole

Country Status (1)

Country Link
WO (1) WO2011101862A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107935947A (zh) * 2018-01-04 2018-04-20 苏州天马药业有限公司 一种氟康唑晶型ⅲ的制备方法
CN109806235A (zh) * 2019-03-13 2019-05-28 悦康药业集团上海制药有限公司 一种氟康唑片及其制备方法
CN112023056A (zh) * 2019-09-05 2020-12-04 杭州百诚医药科技股份有限公司 一种氟康唑药物组合物及其制备方法
CN112137972A (zh) * 2020-09-16 2020-12-29 石家庄四药有限公司 一种氟康唑片剂组合物、片剂及制备方法
CN112778679A (zh) * 2020-12-31 2021-05-11 苏州市新广益电子有限公司 一种高强度、高热稳定性的聚4-甲基-1-戊烯微孔膜及其制备方法
CN116251067A (zh) * 2023-04-23 2023-06-13 淄博市中心医院 一种氟康唑片、制备方法及用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4404216A (en) 1981-06-06 1983-09-13 Pfizer Inc. Antifungal 1,3-bis-triazolyl-2-propanol derivative
GB2270521A (en) 1992-09-09 1994-03-16 Pfizer Crystalline monohydrate of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
US20050118265A1 (en) * 2003-11-28 2005-06-02 Anandi Krishnan Antifungal oral dosage forms and the methods for preparation
US7094904B2 (en) 2001-03-23 2006-08-22 Richter Gedeon Vegyeszeti Gyar Rt. Process for preparing monohydrate and crystal modifications of fluconazole

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4404216A (en) 1981-06-06 1983-09-13 Pfizer Inc. Antifungal 1,3-bis-triazolyl-2-propanol derivative
GB2270521A (en) 1992-09-09 1994-03-16 Pfizer Crystalline monohydrate of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
US7094904B2 (en) 2001-03-23 2006-08-22 Richter Gedeon Vegyeszeti Gyar Rt. Process for preparing monohydrate and crystal modifications of fluconazole
US20050118265A1 (en) * 2003-11-28 2005-06-02 Anandi Krishnan Antifungal oral dosage forms and the methods for preparation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ACTA POLONIAE PHARMACEUTICA - DRUG RESEARCH, vol. 66, no. 2, 2009, pages 115 - 122
CAIRA MINO R ET AL: "Preparation and crystal characterization of a polymorph, a monohydrate, and an ethyl acetate solvate of the antifungal fluconazole.", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 93, no. 3, March 2004 (2004-03-01), pages 601 - 611, XP002653534, ISSN: 0022-3549 *
JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 93, 2004, pages 601 - 611
THE JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 84, no. 12, December 1995 (1995-12-01), pages 1438 - 41

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107935947A (zh) * 2018-01-04 2018-04-20 苏州天马药业有限公司 一种氟康唑晶型ⅲ的制备方法
CN109806235A (zh) * 2019-03-13 2019-05-28 悦康药业集团上海制药有限公司 一种氟康唑片及其制备方法
CN112023056A (zh) * 2019-09-05 2020-12-04 杭州百诚医药科技股份有限公司 一种氟康唑药物组合物及其制备方法
CN112023056B (zh) * 2019-09-05 2023-05-23 杭州百诚医药科技股份有限公司 一种氟康唑药物组合物及其制备方法
CN112137972A (zh) * 2020-09-16 2020-12-29 石家庄四药有限公司 一种氟康唑片剂组合物、片剂及制备方法
CN112778679A (zh) * 2020-12-31 2021-05-11 苏州市新广益电子有限公司 一种高强度、高热稳定性的聚4-甲基-1-戊烯微孔膜及其制备方法
CN112778679B (zh) * 2020-12-31 2023-09-29 苏州市新广益电子股份有限公司 一种高强度、高热稳定性的聚4-甲基-1-戊烯微孔膜及其制备方法
CN116251067A (zh) * 2023-04-23 2023-06-13 淄博市中心医院 一种氟康唑片、制备方法及用途
CN116251067B (zh) * 2023-04-23 2024-06-07 淄博市中心医院 一种氟康唑片、制备方法及用途

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