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WO2005074890A1 - Formulations pharmaceutiques a matrice semi-solide - Google Patents

Formulations pharmaceutiques a matrice semi-solide Download PDF

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Publication number
WO2005074890A1
WO2005074890A1 PCT/EP2004/050057 EP2004050057W WO2005074890A1 WO 2005074890 A1 WO2005074890 A1 WO 2005074890A1 EP 2004050057 W EP2004050057 W EP 2004050057W WO 2005074890 A1 WO2005074890 A1 WO 2005074890A1
Authority
WO
WIPO (PCT)
Prior art keywords
dispersion according
stable pharmaceutical
pharmaceutical solid
semisolid dispersion
active ingredient
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/EP2004/050057
Other languages
English (en)
Inventor
Cristina Ciocca
Alessandro Martini
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.)
Pfizer Italia SRL
Original Assignee
Pharmacia Italia SpA
Pfizer Italia SRL
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 Pharmacia Italia SpA, Pfizer Italia SRL filed Critical Pharmacia Italia SpA
Priority to EP04706692A priority Critical patent/EP1713442A1/fr
Priority to PCT/EP2004/050057 priority patent/WO2005074890A1/fr
Priority to CA002552925A priority patent/CA2552925A1/fr
Priority to BRPI0418427-0A priority patent/BRPI0418427A/pt
Publication of WO2005074890A1 publication Critical patent/WO2005074890A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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 relates to pharmaceutical formulations with improved stability comprising at least one oxidation-susceptible and poorly water-soluble drug as active ingredient and a water soluble derivative of vitamin E as antioxidant agent.
  • Solid dispersions cover a wide range of systems comprising one or more active ingredients in an inert pharmaceutical carrier or matrix in the solid or semisolid state as established by Chiou and Riegelman (Journal of Pharmaceutical Sciences 1971, 60(9);
  • Solid dispersions represent a useful pharmaceutical technique for increasing and modifying the dissolution kinetics of poorly soluble drugs to improve their oral bioavailability.
  • Hydrophilic and highly soluble polymers have been widely investigated as inert carriers in solid dispersions for accelerating release profiles of poorly water-soluble drugs.
  • Polyvinyl pyrrolidone (PVP) and polyethylene glycols (PEG) of high molecular weight are the most frequently investigated polymeric carriers, although thermal decomposition of PVP makes not applicable the use of melting method and makes this polymer less attractive in formulation than PEGs.
  • Lheritier et al. (International Journal of Pharmaceutics 123, (1995) 273-279) refer the improved dissolution behavior of a new calcium family compound by means of solid dispersions containing PEG 6000.
  • This oxidative reaction happens in common oral dosage forms such as uncoated tablets, powders, fine granules, hard gelatin capsules; thus the content decreases and visual aspect alteration (for example color changes) can occur either during the manufacturing process and storage, that can be overcome through sugar coated film coated.
  • Non conventional oral dosage forms can overcome and increase the low water solubility of compounds thus impacting not only on the stability but also on the dissolution properties, the oral absorption and bioavailability of the active ingredient.
  • a hydrophilic carrier based solid dispersion is not the preferred choice for the formulation skilled in the art; especially high molecular PEGs, according to their high solubilization properties, can undergo autoxidation reactions during the storage catalyzing both its and the drug degradation.
  • Traditional formulation skills and knowledge may suggest selection of appropriate stabilizing agents for overcoming oxidation degradations and improving chemical stability. The most relevant selection criteria is miscibility of the stabilizing agent with hydrophilic carriers and good stability during the solid dispersion manufacturing process that is usually carried out by melting method at 50-70°C.
  • stabilizing agents that can at the same time adversely affect the dissolution properties of the solid dispersion formulations.
  • Conventional antioxidant agents such as ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG) and the like have been shown to be not compatible for PEGs based solid dispersions either due to physical incompatibility and chemical degradations.
  • a stability improvement has been obtained by adding a low amount of a water soluble vitamin E derivative, in particular vitamin E polyethylene glycol succinate (Vitamin E TPGS) in the solid dispersion composition.
  • Vitamin E TPGS (Eastman) is a water miscible d- ⁇ -*tocopheryl derivate obtained by esteriflcation of the acid group of crystalline d- 3tocopheryl acid succinate by polyethylene glycol (see U.S.Pharmacopeia 25 - National Formulary 20); having a dual nature of lipophilicity and hydrophilicity, similar to a surface active agent.
  • Vitamin E TPGS is already known as a pharmaceutical antioxidant active ingredient for treatment human diseases.
  • US 6,069,167 discloses the use of this water- soluble derivative of Vitamin E to treat cholestatic liver disease
  • US 5,972,993 discloses the use of tocopherol derivatives such as vitamin E TPGS for the treatment of skin disorders.
  • Vitamin E TPGS acts as a semisolid carrier in mixture with polyglycolyzed glycerides to produce a solid, semi-solid or liquid dosage form.
  • WO 01/37834 describes a stable oral pharmaceutical dosage form containing an acid benzimidazole compound mixed with pharmaceutical acceptable excipients including vegetable and/or animals oils, and/or synthetic triglycerides.
  • the preferred stabilizing agent is Vitamin E TPGS added for improving chemical stability of labile acids active ingredient but in this case the stabilization effect is not linked to oxidation but to liability to acid of said molecules.
  • Vitamin E TPGS added for improving chemical stability of labile acids active ingredient but in this case the stabilization effect is not linked to oxidation but to liability to acid of said molecules.
  • Object of the present invention is a stable pharmaceutical solid or semisolid dispersion comprising at least one oxidation-susceptible and poorly water-soluble drug as active ingredient, a hydrophilic carrier, a water-soluble vitamin E derivative as antioxidant agent and optionally other excipients.
  • Another object of the invention is a method of inliibiting oxidative degradation of pharmaceutical formulations containing at least one oxidation-susceptible and poorly water-soluble drug as active ingredient which method comprises adding to the formulation a low amount of a water soluble vitamin E derivative as antioxidant.
  • a further object of the invention is a simple, quick and cheap manufacturing process for preparing a stable solid or semisolid dispersion for oral administration of an oxidation - susceptible and poorly water-soluble drug which process comprises mixing the oxidation-susceptible and poorly water-soluble drug, the hydrophilic carrier and the water soluble vitamin E derivative, and melting the resultant mixture.
  • active ingredients incorporating at least one amine, aldheyde or hydroxy functional group or having at least a double or triple bond in their chemical structure and having an intrinsic solubility in water of less than about 500 g/mL, especially less of about 200 gg/mL are preferred.
  • active ingredients which can be used in the present invention are posaconazole, tocoretinate, nitrendipine, tiagabine, hydrocortisone/cortisol, tacrolimus, testosterone, metaclazepam, morphine, metamethasone valerate, captopril, nicotine, dronabinol, fonnestane, atamestane and exemestane.
  • Exemestane is the most preferred oxidation-susceptible and poorly water-soluble drug according to the present invention.
  • exemestane is an irreversible aromatase inactivator that works on the aromatase enzyme inhibiting the conversion of androgens to estrogens.
  • This compound has low water solubility, about 70 gg/mL, that could affect the oral administration and absorption of this active drug.
  • exemestane exhibits poor chemical stability properties due to oxidative reaction under stressed conditions.
  • the drug can be dispersed in the pharmaceutical solid dispersion in the range of from about 25% to 1% and more preferably from 15% to 2%.
  • the pharmaceutical composition of this invention further comprises a hydrophilic carrier, a water soluble vitamin E derivative as antioxidant and optionaly further excipients.
  • Hydrophilic polymers are added as inert carrier of the solid dispersion to improve the dissolution release profile and the solubilization of the active drug from the pharmaceutical dosage form.
  • hydrophilic carriers are high molecular weight polyethylene glycols such as
  • Hydrophilic carriers can be in an amount from 20% to 95% w/w and preferably from
  • the antioxidant agent is water soluble vitamin E derivative, preferably d-alpha- tocopherol polyethylene glycol ester, and more preferably d-alpha-tocopherol polyethylene glycol 1000 succinate, also known as vitamin E TPGS.
  • the water-soluble vitamin E derivative is used in the range from 1% to 0.01% w/w of the pharmaceutical composition, and preferably from 0.5% to 0.02% w/w.
  • Suitable excipients which can be optionally added to the pharmaceutical composition of the invention are surface active agents for improving the dissolution of the active drug from the solid dispersion filled in capsules. They may comprise polysorbates (for example Tween 80) and/or pluronics in the range from 20% to 0.5 % w/w and preferably from 5 % to 1 % w/w of the pharmaceutical composition.
  • the preferred manufacturing process is mixing the oxidation-susceptible and poorly water-soluble drug, the hydrophilic carrier and the water soluble vitamin E derivative, then optionally adding one or more other pharmaceutical components and melting the final mixture at temperatures between 50°C and 70°C.
  • Example 1 Solid dispersion of exemestane in PEG 4000. 5 mL of PEG 4000 were melted at 70°C and 750 mg of exemestane were dispersed under magnetic stirrer. After 4, 24 and 48 hours at 60°C, "4" size hard gelatin capsules were manually filled with 0.16O mL of molted dispersion and correlates assay is perforated by means HPLC method.
  • the accepted limit content of the known degradation exemestane compounds is the following:
  • PEG 4000 88.5 % (w/w) exemestane 11% (w/w) propyl gallate 0.5 % (w/w) was prepared by the melting method described in Example 1.
  • Example 3 Solid dispersions having the following composition: PEG 4000 87.3 % (w/w) exemestane 12.7% (w/w) were prepared by the melting method described in Example 1, adding respectively 0.2% w/w, 0.02% w/w of butylated hydroxyanisole (BHT) or butylated hydroxytoluene
  • Vitamin E TPGS 0.2 % (w/w) was prepared by the melting method described in Example 1.
  • Vitamin E TPGS 0. 02 % (w/w) was prepared by the melting method described in Example 1.
  • Tween 80 3 % (w/w) was prepared by the melting method described in Example 1. After 48 hours at 60°C, "2" size hard gelatin capsules were manually filled with 0.247 mL of molted dispersion.

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

Abstract

L'invention concerne une dispersion pharmaceutique solide ou semi-solide comprenant au moins un médicament faiblement hydrosoluble et sensible à l'oxydation en tant que principe actif, un excipient hydrophile, un dérivé de vitamine E hydrosoluble utilisé en tant qu'agent antioxydant et éventuellement d'autres excipients.
PCT/EP2004/050057 2004-01-30 2004-01-30 Formulations pharmaceutiques a matrice semi-solide Ceased WO2005074890A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP04706692A EP1713442A1 (fr) 2004-01-30 2004-01-30 Formulations pharmaceutiques a matrice semi-solide
PCT/EP2004/050057 WO2005074890A1 (fr) 2004-01-30 2004-01-30 Formulations pharmaceutiques a matrice semi-solide
CA002552925A CA2552925A1 (fr) 2004-01-30 2004-01-30 Formulations pharmaceutiques a matrice semi-solide
BRPI0418427-0A BRPI0418427A (pt) 2004-01-30 2004-01-30 formulações farmacêuticas de matriz semi-sólida

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2004/050057 WO2005074890A1 (fr) 2004-01-30 2004-01-30 Formulations pharmaceutiques a matrice semi-solide

Publications (1)

Publication Number Publication Date
WO2005074890A1 true WO2005074890A1 (fr) 2005-08-18

Family

ID=34833876

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2004/050057 Ceased WO2005074890A1 (fr) 2004-01-30 2004-01-30 Formulations pharmaceutiques a matrice semi-solide

Country Status (4)

Country Link
EP (1) EP1713442A1 (fr)
BR (1) BRPI0418427A (fr)
CA (1) CA2552925A1 (fr)
WO (1) WO2005074890A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129297A1 (fr) * 2008-04-15 2009-10-22 Schering Corporation Compositions pharmaceutiques orales semi-solides
WO2010010367A1 (fr) * 2008-07-25 2010-01-28 Arrow International Limited Composition pharmaceutique solide contenant de l'exémestane
WO2012063498A3 (fr) * 2010-11-12 2012-07-19 富士化学工業株式会社 Nouvelle dispersion solide d'exémestane
US8628796B2 (en) 2004-12-09 2014-01-14 Insys Therapeutics, Inc. Room-temperature stable dronabinol formulations
EP2197429B1 (fr) * 2007-09-03 2016-04-20 Nanotherapeutics, Inc. Compositions particulaires pour l'administration de médicaments faiblement solubles
CN114948901A (zh) * 2022-05-06 2022-08-30 郑州大学第一附属医院 一种协同治疗乳腺癌的依西美坦纳米粒、制剂及其制备方法
US11813246B2 (en) 2008-03-28 2023-11-14 Astrazeneca Ab Pharmaceutical composition

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110638767B (zh) * 2019-10-12 2021-09-10 山东省食品发酵工业研究设计院 一种维生素e固体片剂及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045918A1 (fr) * 1998-03-10 1999-09-16 Napro Biotherapeutics, Inc. Methodes et compositions d'administration de taxanes
WO2000003753A2 (fr) * 1998-07-14 2000-01-27 Em Industries, Inc. Systemes d'apport de medicaments par microdispersion
WO2003057208A1 (fr) * 2001-12-28 2003-07-17 Ivax Research, Inc. Compositions a base de taxane et procedes d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045918A1 (fr) * 1998-03-10 1999-09-16 Napro Biotherapeutics, Inc. Methodes et compositions d'administration de taxanes
WO2000003753A2 (fr) * 1998-07-14 2000-01-27 Em Industries, Inc. Systemes d'apport de medicaments par microdispersion
WO2003057208A1 (fr) * 2001-12-28 2003-07-17 Ivax Research, Inc. Compositions a base de taxane et procedes d'utilisation

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8628796B2 (en) 2004-12-09 2014-01-14 Insys Therapeutics, Inc. Room-temperature stable dronabinol formulations
EP2197429B1 (fr) * 2007-09-03 2016-04-20 Nanotherapeutics, Inc. Compositions particulaires pour l'administration de médicaments faiblement solubles
EP3064198A1 (fr) * 2007-09-03 2016-09-07 Nanotherapeutics, Inc. Compositions particulaires pour l'administration de médicaments faiblement solubles
US11813246B2 (en) 2008-03-28 2023-11-14 Astrazeneca Ab Pharmaceutical composition
US12220403B2 (en) 2008-03-28 2025-02-11 Astrazeneca Ab Pharmaceutical composition
US12318367B2 (en) 2008-03-28 2025-06-03 Astrazeneca Ab Pharmaceutical composition
US12364684B2 (en) 2008-03-28 2025-07-22 Astrazeneca Ab Pharmaceutical composition
US12465593B2 (en) 2008-03-28 2025-11-11 Astrazeneca Ab Pharmaceutical composition
WO2009129297A1 (fr) * 2008-04-15 2009-10-22 Schering Corporation Compositions pharmaceutiques orales semi-solides
WO2010010367A1 (fr) * 2008-07-25 2010-01-28 Arrow International Limited Composition pharmaceutique solide contenant de l'exémestane
WO2012063498A3 (fr) * 2010-11-12 2012-07-19 富士化学工業株式会社 Nouvelle dispersion solide d'exémestane
CN114948901A (zh) * 2022-05-06 2022-08-30 郑州大学第一附属医院 一种协同治疗乳腺癌的依西美坦纳米粒、制剂及其制备方法

Also Published As

Publication number Publication date
BRPI0418427A (pt) 2007-06-12
EP1713442A1 (fr) 2006-10-25
CA2552925A1 (fr) 2005-08-18

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