WO2012026896A1 - Particules cristallines de tacrolimus micronisé à surface modifiée et compositions pharmaceutiques associées - Google Patents

Particules cristallines de tacrolimus micronisé à surface modifiée et compositions pharmaceutiques associées Download PDF

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Publication number
WO2012026896A1
WO2012026896A1 PCT/TN2011/000003 TN2011000003W WO2012026896A1 WO 2012026896 A1 WO2012026896 A1 WO 2012026896A1 TN 2011000003 W TN2011000003 W TN 2011000003W WO 2012026896 A1 WO2012026896 A1 WO 2012026896A1
Authority
WO
WIPO (PCT)
Prior art keywords
tacrolimus
pharmaceutical composition
surface modified
particles
crystalline
Prior art date
Application number
PCT/TN2011/000003
Other languages
English (en)
Inventor
Lassaâd BOUJBEL
Mohamed Amine Boujbel
Stephen Lukas
Karel Ren
Original Assignee
Les Laboratoires Medis Sa
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 Les Laboratoires Medis Sa filed Critical Les Laboratoires Medis Sa
Priority to MA35763A priority Critical patent/MA34586B1/fr
Publication of WO2012026896A1 publication Critical patent/WO2012026896A1/fr

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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
    • A61K9/141—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
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K9/145—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 compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention is directed to pharmaceutical composition comprising surface modified micronized tacrolimus crystalline particles having d90 value of from2 urn to 10 urn.
  • the present invention relates to solid dosage units comprising micronized tacrolimus crystalline particles suspended in suitable vehicle together with one or more surface modifier. It further relates to a pharmaceutical composition comprising said particles
  • Tacrolimus also known as KF 506 is a macrocyclic lactone produced by fermentation of soil microorganisms Streptomyces tsukubaensis, a monotypic species of Streptomyces. Tacrolimus has the empirical formula C44H69NO12.H20 a molecular weight of 822.05, and the following chemical formula:
  • Tacrolimus is available in various dosage forms such as capsules, injections and an ointment.
  • the conventional capsule dosage form is sold commercially as Prograf® and is approved for prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants.
  • Absorption of orally administered tacrolimus from the gastrointestinal tract is incomplete and variable.
  • the absolute bioavailability of tacrolimus is typically 17 ⁇ 10%.
  • In adult liver transplant patients (N 17), typically 23 ⁇ 9%.
  • tacrolimus together with cyclosporine A, rapamycin and the morpholinoester or sodium salt of mycophenolic acid, represents the standard approach in management of organ rejection or treatment of autoimmune diseases.
  • a solid dispersion is a pharmaceutical formulation comprising a multicomponent System having an amorphous drug dispersed in and around a hydrophilic solid carrier.
  • the drug and solid carrier are dissolved in organic solvent, fused and then dried or cooled.
  • the formulations were prepared by solubilization of tacrolimus in organic solvent together with a water soluble polymer, especially, or exclusively represented by hydroxy propyl methyl cellulose, providing a solid dispersion with tacrolimus present in the amorphous state.
  • the amorphous state is supposed to give a drug, higher thermodynamic activity than in crystalline form.
  • Higher energy level of the active ingredient is believed to result in rapid dissolution, however, in fact with tacrolimus it results in quite unstable product, with high tendency to revert back to the crystalline form which is characterised by variable and decreased solubility/dissolution/bioavailability.
  • United States Patent Application Publication No. 2008/0152720 discloses a nanoparticulate tacrolimus formulation comprising particles of tacrolimus and at least one surfactant stabilizer which can be added to the dispersion media before, during or after particle size reduction. Effective average particle size of tacrolimus is below 2000 nm. Where the formulations are to be injected the particle size should be less than 600 nm.
  • Nanonization of poorly soluble drug is a complex process and requires additional step during manufacturing. It is true that nanization increases the surface area available for dissolution, however, it also increases change in free energy of the system when exposed to aqueous solution. This results in particle aggregation and decreases the dissolution rate. Also, very fine particles are difficult to handle due to static charge that develops on particle surface during processing.
  • Working with surface modified micronized crystals we identified formulations which have been found to be much more stable and less variable than formulations based on the amorphous tacrolimus. We have found that by using this approach we were able to formulate a product using the crystalline form, which has a similar dissolution profile as a product base on the use of tacrolimus in the amorphous state.
  • the present invention therefore provides a new approach to prepare more stable products by suspending of surface modified crystalline micronized tacrolimus.
  • the present invention therefore provides a product containing crystalline micronized tacrolimus with d90 value of from 2pm to 10 pm, and one or more surface modifiers which provides the desired in vitro and in vivo profile.
  • the invention provides tacrolimus particles having d90 values from 2 pm to 10 ⁇ .
  • the invention provides a pharmaceutical composition comprising micronized particles of crystalline tacrolimus having d90 value of from 2pm to 10 pm.
  • the invention provides a pharmaceutical composition of tacrolimus comprising dispersion of tacrolimus particles and at least one pharmaceutically acceptable excipients wherein said tacrolimus particles have d90 value from 2 pm to 10 pm.
  • the invention provides a process of preparing a pharmaceutical composition comprising the steps of:
  • step b dispersing tacrolimus particles in the dispersion/solution of step a; wherein said tacrolimus particles have d90 value of from about 2 pm to about 10 pm.
  • the invention provides a process of preparing a pharmaceutical composition of tacrolimus particles, comprising the steps of: a) dissolving or dispersing one or more pharmaceutically acceptable excipients in a vehicle; b) dispersing sirolimus particles in the dispersion/solution of step a); and
  • step b) processing the dispersion of step b) into suitable pharmaceutical composition
  • said tacrolimus particles have d90 value of from about 2 m to about 10 ⁇ .
  • the invention provides a method of treatment of organ or tissue transplant rejection, or autoimmune disease, the method comprising: orally administering to a subject a pharmaceutical composition comprising tacrolimus particles having d90 value of from about 2 ⁇ to about 10 ⁇ .
  • Tacrolimus as used herein means crystalline form of both tacrolimus base, tacrolimus monohydrate, or any other crystalline form of tacrolimus API.
  • d90 value means at least 90% of tacrolimus particles have volume diameter in the specified range when measured by a light scattering method Malvern Mastersizer.
  • Micronization may be carried out using dry milling technique. Various conventional mills available for dry milling can be applied. The milling may be carried out using the tacrolimus alone or with other pharmaceutically acceptable excipients. The desired particle size may be also obtained by modifying the reaction conditions during the manufacturing of tacrolimus API.
  • “Pharmaceutical composition” as used herein includes both liquid and solid dosage forms such as solution, suspension, tablet, capsule, granules, and pills.
  • the term 'pharmaceutically acceptable excipients" as used herein include surface modifiers, binders, diluents, lubricants/glidant, disintegrating agent, antioxidants, and coloring agents.
  • surface modifiers means agents which are used to disperse the drug in a particular vehicle and also enhance wetting properties of the drug.
  • excipients include various polymers, low molecular weight oligomers, natural products and surfactants.
  • Representative examples include gelatin, casein, lecithin (phosphatides), gum Arabica, cholesterol, tagacanth, stearic acid, benzalconium chloride, calcium stearate, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone.
  • Surfactants include both non-ionic and ionic surfactants suitable for use in pharmaceutical dosage forms.
  • the vehicle used to prepare the dispersion may be selected from water or its mixture with other organic solvent such as ethanol, methanol, isopropyl alcohol, and ether.
  • tacrolimus particles are prepared by micronising tacrolimlus coarser particles by dry milling technique to obtain a desired particle size range.

Landscapes

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

Abstract

Cette invention concerne une composition pharmaceutique comprenant des particules cristallines de tacrolimus micronisé à surface modifiée ayant une valeur d90 comprise entre 2 μm et 10 μm.
PCT/TN2011/000003 2010-08-25 2011-08-24 Particules cristallines de tacrolimus micronisé à surface modifiée et compositions pharmaceutiques associées WO2012026896A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
MA35763A MA34586B1 (fr) 2010-08-25 2011-08-24 Particules cristallines de tacrolimus micronise a surface modifiee et compositions pharmaceutiques associees

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TN10391 2010-08-25
TNTN2010/0391 2010-08-25

Publications (1)

Publication Number Publication Date
WO2012026896A1 true WO2012026896A1 (fr) 2012-03-01

Family

ID=44910279

Family Applications (1)

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PCT/TN2011/000003 WO2012026896A1 (fr) 2010-08-25 2011-08-24 Particules cristallines de tacrolimus micronisé à surface modifiée et compositions pharmaceutiques associées

Country Status (2)

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MA (1) MA34586B1 (fr)
WO (1) WO2012026896A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014201236A1 (fr) * 2013-06-12 2014-12-18 Surmodics, Inc. Procédés en solvant pour l'élaboration de particules de macrolides cristallins, compositions, et articles contenant les particules
US9439892B2 (en) 2013-05-16 2016-09-13 Surmodics, Inc. Macrolide particulates, methods for preparation, and medical devices associated therewith
CN107595772A (zh) * 2017-09-26 2018-01-19 山东省药学科学院 一种他克莫司纳米混悬滴眼液的制备方法
US10098846B2 (en) 2016-03-31 2018-10-16 Surmodics, Inc. Drug-containing particulate composition with cationic agent, associated medical devices, and methods for treatment
CN113242732A (zh) * 2018-12-04 2021-08-10 莱昂纳米药物有限公司 包含他克莫司的纳米粒
US11123459B2 (en) 2016-12-16 2021-09-21 Surmodics, Inc. Hydrophobic active agent particle coatings and methods for treatment

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184162A2 (fr) 1984-12-03 1986-06-11 Fujisawa Pharmaceutical Co., Ltd. Composés tricycliques, procédé pour leur préparation et composition pharmaceutique les contenant
EP0240773A1 (fr) 1986-04-02 1987-10-14 Fujisawa Pharmaceutical Co., Ltd. Dispersion solide de la substance FR-900506
EP1064942A1 (fr) * 1998-03-26 2001-01-03 Fujisawa Pharmaceutical Co., Ltd. Preparations a liberation prolongee
US20060159766A1 (en) * 2004-12-15 2006-07-20 Elan Pharma International Limited Nanoparticulate tacrolimus formulations
WO2008013416A1 (fr) * 2006-07-27 2008-01-31 Amorepacific Corporation Procédé pour la préparation d'une poudre comprenant des nanoparticules de médicament peu soluble

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184162A2 (fr) 1984-12-03 1986-06-11 Fujisawa Pharmaceutical Co., Ltd. Composés tricycliques, procédé pour leur préparation et composition pharmaceutique les contenant
EP0240773A1 (fr) 1986-04-02 1987-10-14 Fujisawa Pharmaceutical Co., Ltd. Dispersion solide de la substance FR-900506
US4916138A (en) 1986-04-02 1990-04-10 Fujisawa Pharmaceutical Co., Ltd. Solid dispersion composition of FR-900506 substance
EP1064942A1 (fr) * 1998-03-26 2001-01-03 Fujisawa Pharmaceutical Co., Ltd. Preparations a liberation prolongee
US20060159766A1 (en) * 2004-12-15 2006-07-20 Elan Pharma International Limited Nanoparticulate tacrolimus formulations
US20080152720A1 (en) 2004-12-15 2008-06-26 Elan Pharma International Limited Nanoparticulate tacrolimus formulations
WO2008013416A1 (fr) * 2006-07-27 2008-01-31 Amorepacific Corporation Procédé pour la préparation d'une poudre comprenant des nanoparticules de médicament peu soluble

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9439892B2 (en) 2013-05-16 2016-09-13 Surmodics, Inc. Macrolide particulates, methods for preparation, and medical devices associated therewith
US9949957B2 (en) 2013-05-16 2018-04-24 Surmodics, Inc. Macrolide particulates, methods for preparation, and medical devices associated therewith
US10449180B2 (en) 2013-05-16 2019-10-22 Surmodics, Inc. Macrolide particulates, methods for preparation, and medical devices associated therewith
WO2014201236A1 (fr) * 2013-06-12 2014-12-18 Surmodics, Inc. Procédés en solvant pour l'élaboration de particules de macrolides cristallins, compositions, et articles contenant les particules
US9770537B2 (en) 2013-06-12 2017-09-26 Surmodics, Inc. Solvent methods for preparing crystalline macrolide particulates, compositions, and articles containing particulates
US10098846B2 (en) 2016-03-31 2018-10-16 Surmodics, Inc. Drug-containing particulate composition with cationic agent, associated medical devices, and methods for treatment
US11123459B2 (en) 2016-12-16 2021-09-21 Surmodics, Inc. Hydrophobic active agent particle coatings and methods for treatment
CN107595772A (zh) * 2017-09-26 2018-01-19 山东省药学科学院 一种他克莫司纳米混悬滴眼液的制备方法
CN107595772B (zh) * 2017-09-26 2020-09-18 山东省药学科学院 一种他克莫司纳米混悬滴眼液的制备方法
CN113242732A (zh) * 2018-12-04 2021-08-10 莱昂纳米药物有限公司 包含他克莫司的纳米粒

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MA34586B1 (fr) 2013-10-02

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