WO2016178240A1 - Formulation pharmaceutique lyophilisée de rifabutine et procédé de préparation associé - Google Patents

Formulation pharmaceutique lyophilisée de rifabutine et procédé de préparation associé Download PDF

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Publication number
WO2016178240A1
WO2016178240A1 PCT/IN2015/000348 IN2015000348W WO2016178240A1 WO 2016178240 A1 WO2016178240 A1 WO 2016178240A1 IN 2015000348 W IN2015000348 W IN 2015000348W WO 2016178240 A1 WO2016178240 A1 WO 2016178240A1
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WO
WIPO (PCT)
Prior art keywords
polysorbate
pharmaceutical formulation
rifabutin
agent
active
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/IN2015/000348
Other languages
English (en)
Inventor
Mitesh Natavarlal Patel
Mafatlal Tribhovandas DAVE
Pranavkumar Jayesh Choksi
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.)
Gufic Biosciences Ltd
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Gufic Biosciences Ltd
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Filing date
Publication date
Application filed by Gufic Biosciences Ltd filed Critical Gufic Biosciences Ltd
Priority to EA201792417A priority Critical patent/EA201792417A1/ru
Priority to EP15891266.7A priority patent/EP3291798A4/fr
Publication of WO2016178240A1 publication Critical patent/WO2016178240A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to freeze dried pharmaceutical formulation of Rifabutin along with a suitable Solubilizing agent and Bulking agent for parenteral administration.
  • the pharmaceutical formulation provides sufficient solubilization and stabilization of Rifabutin thus improving the shelf life and reduces the likelihood of precipitation during storage.
  • the invention further relates to a process of preparation of freeze dried pharmaceutical formulation of Rifabutin.
  • Rifabutin is second line anti tubercular drug used in treatment of tuberculosis. It is related to Rifampin in structure and mechanism of action but it is less active against Mycobacterium tuberculosis and more active against Mycobacterium avium complex (MAC). Majority of M.tuberculosis isolates resistant to R are cross resistant to Rifabutin. Thus it is not an option for treatment of Multidrug-resistant tuberculosis (MDR-TB). The only place of Rifabutin in the treatment of TB is as 's' substitute for 'R' to minimize drug interaction due to strong enzyme inducing property of R. This is especially needed in HIV co-infected patients of TB who receive a protease inhibitor and/or a non-nucleoside reverse transcriptase inhibitor whose metabolism is markedly induced by R-rendering them ineffective.
  • MDR-TB Multidrug-resistant tuberculosis
  • Rifabutin The primary indication of Rifabutin is for prophylaxis and treatment of MAC infection in HIV-AIDS patients.
  • Rifabutin alone 300mg/day is an alternative to Azithromycin / Clarithromycin; while for treatment of MAC infection, it is combined with two or three other anti-MAC drugs.
  • Gastrointestinal intolerance, rashes, granulocytopenia, myalgia, and uveitis have been reported with Rifabutin. Reactions similar to those caused by R can also occur.
  • Oral bioavailability of Rifabutin is low (about 20%), but t1 ⁇ 2 is much longer (730hrs.).
  • Rifabutin may be administered orally as once a day at a dose ranging from 150 mg to 300mg (5mg/kg). The bioavailability of Rifabutin after oral administration as well as intravenous administration is very less and at about 20%.
  • Rifabutin is l',4-didehydro-l-deoxy-l,4-dihydro-5'-(2- methylpropyl)-l-oxorifamycin XIV (Chemical Abstracts Service, 9th Collective Index) or (9S, 12E, 14S, 15R, 16S, 17R, 18R, 19R,20S,21 S,22E, 24Z)-6, 16, 18,20-tetrahydroxy- 1 '- isobutyl- 14-methoxy-7,9, 15,17,19,21 ,25-heptamethyl-spiro [9,4-
  • Rifabutin has a molecular formula of C4 6 H 62 N 4 0i l, a molec :
  • Rifabutin is a red-violet powder soluble in chloroform and methanol, sparingly soluble in ethanol, and very slightly soluble in water (0.19 mg/mL). Its log P value (the base 10 logarithm of the partition coefficient between n-octanol and water) is 3.2 (n- octanol/water).
  • Parenteral drug preparation of Rifabutin for therapy of human and animal infectious diseases is disclosed in RU Patent No. 2481109. The excipients mentioned in Patent No. RU2481 109 along with chelating agent and antioxidant, however, it is experienced that « product is not soluble to the concentration mentioned in the patent.
  • Rifabutin is sensitive to chemical degradation which limits the shelf-life of solutions in water as liquid injection and being insoluble in water is extremely dangerous to administer in parenteral state.
  • Chinese Patent Publication No.CN1775214 includes main medicine, medicinal organic co-solvent, alkaline antioxidant, surfactant and sodium hydroxide for pH adjustment. This mass composition may lead to degradation or less stable due to undesirable reaction.
  • the present invention provide freeze dried pharmaceutical formulation of Rifabutin or pharmaceutically acceptable salt thereof along with a suitable solubilising and bulking agent for parenteral administration.
  • the solubility of Rifabutin is increased by adding solubilizing agents selected from Polysorbate derivatives such as Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80.
  • the solubilizing agent is present in the ratio of 1 :1 to 1 :20, preferably 1 : 18, more preferably 1 : 17 by weight of the active.
  • the Structure of lyophilized Rifabutin cake is formed by adding bulking agents selected from Mannitol, Sucrose, Lactose, Trehalose and mono and di-saccharides derivatives, cyclodextrins and the like.
  • the Bulking agent is present in the ratio of 1 :1 to 1 :20, preferably 1 : 15, more preferably 1 :12.5 by weight of the active.
  • the present invention provides a method for increasing solubility of Rifabutin in an aqueous solution.
  • the present invention provides a process for preparation of freeze dried pharmaceutical formulation of Rifabutin.
  • Rifabutin is red-violet powder with a pKa of 3.2 and is insoluble in water.
  • the solubility of Rifabutin decreases further strongly when the pH is below 4.
  • the present invention discloses a freeze dried pharmaceutical formulation for parenteral administration comprising;
  • pH of said formulation is in the range of 5 to 8.
  • Rifabutin or a pharmaceutically acceptable salt is present in the formulation in an amount from lmg to lOOmg/vial; more preferably 60mg/vial and 80mg/vial.
  • the solubility of Rifabutin is increased using a suitable solubilizing agent where Rifabutin can be maintained in a dissolved state in the aqueous solution thereby preventing crystallization or crystalline growth of Rifabutin.
  • the solubilizing agent is selected from Polysorbate derivatives such as Polysorbate 20 (Polyoxyethylene (20) sorbitan monolaurate); Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate); Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) and Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate).
  • the solubilizing agent is present in the ratio of 1 : 1 to 1 :20, preferably 1 : 18, more preferably 1 : 17 by weight of the active.
  • the ' Structure of lyophilized Rifabutin is formed by addition of bulking agents selected from Mannitol, Sucrose, Lactose, Trehalose and mono and di-saccharides derivatives, cyclodextrins and the like.
  • the Bulking agent is present in the ratio of 1 :1 to 1 :20, preferably 1 :15, more preferably 1 : 12.5 by weight of the active.
  • the freeze dried pharmaceutical formulation of the present invention optionally comprises acidifying agent and buffering agent.
  • the acidifying agent is selected from glacial acetic acid, citric acid, Ortho-phosphoric acid, Succinic acid and the like.
  • the acidifying agent is present in the ratio of 1 : 0.166 by weight of the active.
  • the buffering agent is selected from dibasic sodium phosphate, disodium hydrogen orthophosphate, Trisodium citrate, Sodium hydroxide and the like.
  • the buffering agent is present in the ratio of 1 : 0.32 by weight of the active.
  • Such formulation after freeze drying is chemically and physically stable over an extended period of time and is suitable for intended pharmaceutical use after reconstitution with water for injection, sodium chloride injection or 5% dextrose injection which is represented in the examples below.
  • the aqueous intravenous formulation of the present invention may also comprise a physiologically and pharmaceutically acceptable compound effective to render the aqueous intravenous formulation isotonic, i.e. to have an osmotic pressure corresponding to that of a 0.9% solution of sodium chloride.
  • a physiologically and pharmaceutically acceptable compound effective to render the aqueous intravenous formulation isotonic, i.e. to have an osmotic pressure corresponding to that of a 0.9% solution of sodium chloride.
  • chloride salts such as NaCl
  • saccharide such as sorbitol, mannitol and dextrose/glucose.
  • the preparation of isotonic solutions is well known for one skilled in the art.
  • the diluents suitable for the purpose of present invention include 5% Dextrose, 5% Glucose, Ringers solution, Lactated Ringers solution, saline solution and half normal saline.
  • the present invention provides a method of increasing solubility of Rifabutin in an aqueous solution comprising the step of combining Rifabutin aqueous solution with a solubilising agent and an acidifying agent. Alternately, adding solublizing agent and an acidifying agent to the aqueous solution of Rifabutin.
  • the solubilizing agent being the pharmaceutically acceptable solubilizing agent selected from Polysorbatederivatives such as Polysorbate 20, Polysorbate 40, Polysorbate 60, and Polysorbate 80.
  • the present invention provides a method of increasing solubility of Rifabutin in an aqueous solution comprising, adding 10% solution of Polysorbate 80 as solubilizing agent, Mannitol as bulking agent, 5% solution of glacial acetic acid as acidifying agent and dibasic sodium phosphate as buffering agent to the aqueous solution of Rifabutin.
  • the invention provides a process for preparation of pharmaceutical formulation, in particular for intravenous infusion, comprising Rifabutin or a pharmaceutically acceptable salt thereof as the active ingredient, along with pharmaceutically acceptable solubilizing agent and bulking agent.
  • Rifabutin or pharmaceutically acceptable salt thereof initially is solubilized in an aqueous solution containing solubilizing agent, preferably in the ratio 1 :17 followed by addition of bulking agent such as Mannitol 300 mg to 800 mg, more preferably 750 mg to an acceptable level of rangejhetween 6.0- 8.0 followed by filtration from 0.22 micron filter paper.
  • the filtrate.ii nen freeze dried to render it sterile and filling 10 ml quantity of filter solution in sterile glass container of 20 ml vial size.
  • the formulation of the current invention is meant for administration via the IV route, the selection of the above ingredients is done by keeping in mind their compatibilities and stability during the rigorous process for lyophilization and also in terms of safety for use in patients as an intravenous injectable which is isotonic with blood tonicity.
  • the active ingredient of the composition needs to be dissolved sufficiently in the composition i.e. be free from visible particles.
  • freeze dried/lyophilized powder is used to obtain clear colourless solution, free from visible particles.
  • Freeze drying process involves cooling of product at suitable temperature not less than - 50°C, raising temperature to 0°Cat suitable pressure of 200 mtorr to 100 mtorr in 38 hours, then at 75 mtorr, further raising temperature to +30°C in 25 hrs.
  • the freeze dried Rifabutin when reconstituted with 10 ml of suitable vehicle contain final drug concentrate of 6.0 mg/ml.
  • the pharmaceutical formulation of the invention described herein is freeze dried formulation, which may also be prepared by dissolving Rifabutin first in aqueous vehicle containing solubilizing agent and then adjusting pH to desired range using acidifying agent.
  • freeze drying process for such a low soluble active ingredient needs special care and it is an art in its own way because of low concentration of solute (about 0.5%) and maximum amount of aqueous vehicle e.g. water for injection.
  • the freeze dried drug may be diluted with suitable diluents before administration as IV injection.
  • the final concentration of solution may be reduced to further desired level using 5% Dextrose infusion prior to administration to a patient.
  • the invention provides a method of treating or preventing an infection caused by a fungus or a parasite in an animal in need thereof which comprises administering to said animal an effective amount of the pharmaceutical formulation of the instant invention.
  • the present invention relates to the use of Rifabutin parenteral formulation for treating or preventing an infectious disease caused by a fungus or a parasite in an animal in need thereof.
  • the pharmaceutical formulation of the present invention is administered to a patient according to a dosing regimen.
  • a dosing regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, specific disease being treated, and the severity of the condition among other factors and the judgment of the treating physician.
  • the pharmaceutical formulation comprising Rifabutin as active is in parenteral form.
  • the pharmaceutical formulation is stable for the entire period of the shelf life.
  • Rifabutin (active) or pharmaceutically acceptable salt was added to an aqueous solution containing pre-decided quantity of Kollidon PF 12 and stirred for some time. Solution was further sonicated. The solution was divided in to 4 equal parts.
  • citric acid solution was added but the resulting clear solution changed color and assay of active went down and out of specifications when measured by spectrophotometer.
  • Suitable trial was done using micelle forming surfactant like Polysorbate 80 to dissolve active product Rifabutin in aqueous base along with suitable acidifying agent like citric acid, buffering agent like Tri-sodium citrate and bulking agent like Mannitol, to check and compare solubility and stability of liquid preparation. Accordingly following process was followed:
  • Suitable trial was done using micelle forming surfactant like Polysorbate 80 to dissolve active product Rifabutin in aqueous base along with suitable acidifying agent like Ortho- phosphoric acid, buffering agent like disodium hydrogen orthophosphate and bulking agent like Mannitol, to check and compare solubility and stability of liquid preparation. Accordingly following process was followed:
  • Suitable trial was done using micelle forming surfactant like Polysorbate 80 to dissolve active product Rifabutin in aqueous base along with suitable acidifying agent like Succinic acid,buffering agent like Sodium hydroxide and bulking agent like Mannitol, to ; check and compare solubility and stability of liquid preparation. Accordingly following process was followed:
  • Suitable trial was done using micelle forming surfactant like Polysorbate 80 to dissolve active product Rifabutin in aqueous base along with suitable Bulking agent like Mannitol, to check and compare solubility and stability of liquid preparation. Accordingly following process was followed:
  • Example 12 is without addition of acidifying agent and buffering agent, which show fewer amounts of Total impurities at initial analysis as compared to Example 9 to 11.
  • freeze-dried pharmaceutical formulation so obtained dissolved easily in 10 ml water for injection, to form clear red coloured solution.
  • the present invention provides water soluble Rifabutin as freeze dried stable formulation, stable for 6 months, when stored at 25°C.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
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  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique lyophilisée de rifabutine conjointement à un agent solubilisant et un agent gonflant appropriés, destinée à être administrée par voie parentérale, et qui permet d'obtenir une solubilisation et une stabilisation suffisantes de la rifabutine, améliorant ainsi la durée de conservation et réduisant la probabilité de précipitation pendant le stockage. L'invention concerne également un procédé de préparation de ladite formulation pharmaceutique.
PCT/IN2015/000348 2015-05-04 2015-09-07 Formulation pharmaceutique lyophilisée de rifabutine et procédé de préparation associé Ceased WO2016178240A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EA201792417A EA201792417A1 (ru) 2015-05-04 2015-09-07 Лиофилизированный фармацевтический состав рифабутина и способ его получения
EP15891266.7A EP3291798A4 (fr) 2015-05-04 2015-09-07 Formulation pharmaceutique lyophilisée de rifabutine et procédé de préparation associé

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1770/MUM/2015 2015-05-04
IN1770MU2015 2015-05-04

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WO2016178240A1 true WO2016178240A1 (fr) 2016-11-10

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EP (1) EP3291798A4 (fr)
EA (1) EA201792417A1 (fr)
WO (1) WO2016178240A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021048612A1 (fr) * 2019-09-12 2021-03-18 BioVersys AG Procédés de traitement à base de rifabutine, utilisations et compositions
CN114980889A (zh) * 2019-09-12 2022-08-30 生物验证系统股份公司 利福布汀治疗方法、用途和组合物
US11903934B2 (en) 2019-09-18 2024-02-20 BioVersys AG Rifabutin treatment methods, uses, and compositions
WO2026022215A1 (fr) 2024-07-23 2026-01-29 BioVersys AG Formulations lyophilisées de rifabutine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009002227A1 (fr) * 2007-06-26 2008-12-31 Avtonomnaya Nekommercheskaya Organizatsiya 'institut Molekulyarnoy Diagnostiki' Médicament à base de rifabutine, préparation antimicrobienne comprenant des nanoparticules et procédé de fabrication
CA2550811C (fr) * 2003-12-24 2012-05-01 Jane Hirsh Formulations thermostables et methodes de mise au point desdites formulations
AU2009212097B2 (en) * 2008-02-08 2013-06-13 Red Hill Biopharma Ltd Methods and compositions for treating inflammatory bowel disease

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA013569B1 (ru) * 2009-02-24 2010-06-30 Ооо "Научно-Производственный Комплекс "Наносистема"" Фармацевтическая композиция рифабутина для лечения туберкулеза и заболеваний, опосредованных helicobacter pylori, способ ее получения и способ лечения

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2550811C (fr) * 2003-12-24 2012-05-01 Jane Hirsh Formulations thermostables et methodes de mise au point desdites formulations
WO2009002227A1 (fr) * 2007-06-26 2008-12-31 Avtonomnaya Nekommercheskaya Organizatsiya 'institut Molekulyarnoy Diagnostiki' Médicament à base de rifabutine, préparation antimicrobienne comprenant des nanoparticules et procédé de fabrication
AU2009212097B2 (en) * 2008-02-08 2013-06-13 Red Hill Biopharma Ltd Methods and compositions for treating inflammatory bowel disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3291798A4 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021048612A1 (fr) * 2019-09-12 2021-03-18 BioVersys AG Procédés de traitement à base de rifabutine, utilisations et compositions
CN113015519A (zh) * 2019-09-12 2021-06-22 生物验证系统股份公司 利福布汀治疗方法、用途和组合物
CN114980889A (zh) * 2019-09-12 2022-08-30 生物验证系统股份公司 利福布汀治疗方法、用途和组合物
JP2022548858A (ja) * 2019-09-12 2022-11-22 バイオバーシズ アーゲー リファブチンの処置方法、使用および組成物
US12257241B2 (en) 2019-09-12 2025-03-25 BioVersys AG Rifabutin treatment methods, uses, and compositions
CN113015519B (zh) * 2019-09-12 2025-03-28 生物验证系统股份公司 利福布汀治疗方法、用途和组合物
US12370184B2 (en) 2019-09-12 2025-07-29 BioVersys AG Antibiotic combination therapies
AU2020346414B2 (en) * 2019-09-12 2025-10-02 BioVersys AG Rifabutin treatment methods, uses, and compositions
JP7777518B2 (ja) 2019-09-12 2025-11-28 バイオバーシズ アーゲー リファブチンの処置方法、使用および組成物
US11903934B2 (en) 2019-09-18 2024-02-20 BioVersys AG Rifabutin treatment methods, uses, and compositions
US12403133B2 (en) 2019-09-18 2025-09-02 BioVersys AG Rifabutin treatment methods, uses, and compositions
WO2026022215A1 (fr) 2024-07-23 2026-01-29 BioVersys AG Formulations lyophilisées de rifabutine

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EA201792417A1 (ru) 2018-04-30
EP3291798A1 (fr) 2018-03-14
EP3291798A4 (fr) 2019-01-16

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