WO2004084883A1 - Complexes d'isotretinoine avec beta ou gamma-cyclodextrine naturelle - Google Patents

Complexes d'isotretinoine avec beta ou gamma-cyclodextrine naturelle Download PDF

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Publication number
WO2004084883A1
WO2004084883A1 PCT/FI2004/000161 FI2004000161W WO2004084883A1 WO 2004084883 A1 WO2004084883 A1 WO 2004084883A1 FI 2004000161 W FI2004000161 W FI 2004000161W WO 2004084883 A1 WO2004084883 A1 WO 2004084883A1
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WIPO (PCT)
Prior art keywords
isotretinoin
cyclodextrin
complex
complexes
solubility
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PCT/FI2004/000161
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English (en)
Inventor
Pekka Jarho
Faeis Khaliefi
Saara Honkala
Tomi Järvinen
Original Assignee
Pekka Jarho
Faeis Khaliefi
Saara Honkala
Jaervinen Tomi
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.)
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Application filed by Pekka Jarho, Faeis Khaliefi, Saara Honkala, Jaervinen Tomi filed Critical Pekka Jarho
Publication of WO2004084883A1 publication Critical patent/WO2004084883A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents

Definitions

  • the present invention describes the use of low-solubility complexes of natural cyclodextrins (CDs) in order to improve the bioavailability of isotretinoin after oral administration.
  • CDs natural cyclodextrins
  • the complexation of isotretinoin with natural CDs increases the aqueous solubility and dissolution rate of isotretinoin, which results in improved absorption of isotretinoin.
  • the present innovation can be used in various oral dosage forms (tablet, capsule, etc.) and it includes a novel method to prepare solid formulations (e.g. tablet) from isotretinoin.
  • Retinoids are a group of compounds related to vitamin A, also called retinol, a vitamin
  • Isotretinoin 13-cis retinoic acid
  • tretinoin all-trans retinoic acid
  • isotretinoin has been used orally or topically in the treatment of acne.
  • the major pharmaceutical problem of isotretinoin is its low stability and aqueous solubility. Isotretinoin has been shown to degrade under the influence of light and because of that the commercially available formulations are stored in light resistant containers. Because isotretinoin is practically insoluble in water and sparingly soluble in alcohol it is usually formulated in soft gelatin capsules containing a suspension of the drug in soybean oil.
  • the oral bioavailability of isotretinoin, after administration of these formulations, is only 25 % mainly due to poor solubility/dissolution characteristics of the compound (Orfanos et al 1998).
  • the metabolism in the gut wall and first-pass metabolism in the liver has been also reported to account for the low bioavailability of isotretinoin (Cotler et al. 1983).
  • Cyclodextrins are cyclic oligosaccharides consisting of ( ⁇ -l,4)-linked ⁇ -D- glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface (Fr ⁇ mming and Szejtli, 1994). CDs are able to form inclusion complexes with many drugs by taking up the whole drug, or more commonly, the lipophilic moiety of the molecule, into the cavity. The most abundant natural CDs are ⁇ -cyclodextrin ( ⁇ -CD), ⁇ -cyclodextrin ( ⁇ -CD) and ⁇ -cyclodextrin ( ⁇ -CD), containing six, seven, and eight glucopyranose units, respectively.
  • ⁇ -CD appears to be the most useful pharmaceutical complexing agent because of its cavity size, availability, low cost and other properties.
  • CD derivatives available, such as hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) and methylated CDs.
  • CDs have been used mainly to increase the aqueous solubility, stability and bioavailability of various drugs (Fr ⁇ mming and Szejtli, 1994).
  • CDs can also be used to convert liquid compounds into microcrystalline powders, prevent drug- drug or drug-additive interactions, reduce gastro-intestinal or ocular irritation, and reduce or eliminate unpleasant taste and smell.
  • the drug solubility may even start to decrease in B-type phase- solubility behaviour because at high CD concentrations the drug molecule forms lower solubility (higher order) complexes with CDs.
  • the B-type phase-solubility behaviour is typical for natural CDs and has been described earlier e.g. with steroids (Uekama et al 1982).
  • CDs are major problems in the use of CDs in pharmaceutical formulations. This is the reason why the use of CDs in oral formulations is usually limited to drugs containing a low therapeutic dose.
  • the benefit of natural CDs, compared to CD derivatives, is their ability sometimes to form low solubility complexes, which can be considered as "pure" complexed materials because they do not contain free drug or free CD molecules.
  • isotretinoin has been complexed with ⁇ -CD or ⁇ -CD that significantly improves the dissolution rate of isotretinoin which also improves the bioavailability of the isotretinoin.
  • the present invention is based on two novel findings. The first finding shows that isotretinoin forms low solubility complexes with ⁇ -CD and ⁇ -CD which allows the preparation of pure isotretionin/CD complexes with these natural CDs. The second finding shows that low solubility complexes of isotretinoin with ⁇ - CD and ⁇ -CD can be used to significantly improve the dissolution rate of isotretinoin, to improve the bioavailability of the compound.
  • these two novel findings provide a useful method to prepare solid isotretinoin/CD formulations with good dissolution properties for oral drug delivery, especially for the treatment of acne.
  • the invention is in a first aspect directed to the use of a complex of isotretinoin with a cyclodextrin selected from ⁇ -CD and ⁇ -CD for the preparation of a pharmaceutical composition for oral administration.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one orally acceptable carrier, adjuvant or additive, and a therapeutically effective amount of a complex of isotretinoin with a cyclodextrin selected from ⁇ -CD and ⁇ -CD.
  • the invention is directed to a process for the preparation of a complex of isotretinoin with a cyclodextrin selected from ⁇ -CD and ⁇ -CD.
  • the present invention describes the use of ⁇ -CD and ⁇ -CD to improve the dissolution rate and bioavailability of isotretinoin in oral drug formulations.
  • the solid complexes of isotretinoin with ⁇ -CD and/or ⁇ -CD can be prepared by stirring isotretinoin in a CD containing aqueous solution which leads to the precipitation of the solid complexes of isotretinoin (i.e. , isotretinoin is inside of the cyclodextrin cavity).
  • the present invention shows that these low-solubility complexes can be used to improve the dissolution rate of isotretinoin, in order to improve the bioavailability of isotretinoin.
  • One of the major benefits of the present invention is the finding that precipitation of low solubility complexes of isotretinoin with natural ⁇ -CD and natural ⁇ -CD produces "pure" complexes of isotretinoin which improves the pharmaceutical usefulness of
  • CDs in isotretinoin formulations and enables the preparation of novel solid formulations from isotretinoin.
  • HP- ⁇ -CD improves the bioavailability of tretinoin, the all-trans form of retinoic acid.
  • HP- ⁇ -CD is a water-soluble CD derivative. From phase-solubility studies it can be calculated that in order to complex 10 mg or 20 mg of isotretinoin, 940 mg or 1880 mg of HP- ⁇ -CD is needed. This is absolutely far too much for oral solid formulations.
  • ⁇ -CD is a water-soluble CD derivative
  • CD the same result can be achieved with 180 mg and 360 mg, respectively, of natural ⁇ -CD because the complexed material contains only "pure” complexes and no free CD molecules.
  • the inclusion complexes of the present invention can be prepared in the conventional manner, known to a person skilled in art, in solution, in a heterogenous state or in the solid state, including using methods such as precipitation, freeze-drying, spray-drying, kneading, grinding, slurry-method, co-precipitation, and neutralization, and separating said complex.
  • the formation of the inclusion complex can be facilitated by using proper pH adjustment and solvents, such as organic solvents, for example methanol or ethanol.
  • solvents such as organic solvents, for example methanol or ethanol.
  • the temperature can vary to some degree, but it is typically for convenience the ambient temperature.
  • the weight ratio (dry weight to dry weight) between isotretinoin and cyclodextrin is between 1: 1 and 1: 1000.
  • the said weight ratio is 1: 1 to 1:20.
  • the pharmaceutical preparation according to the invention contains the said complex in a pharmaceutically acceptable amount together with at least one pharmaceutically acceptable carrier, adjuvant or vehicle known in the art.
  • the manufacture of such pharmaceutical formulations is well known in the art.
  • the pharmaceutical composition may be in a dosage form suitable for oral use, such as tablets, capsules, lozenges, pills, pastilles etc. All such formulations are made using per se known formulation techniques and carriers, adjuvants and/or additives.
  • the therapeutic dose to be given to a patient in need of treatment will vary depending on the body weight and age of the patient, the particular condition being treated as well as the manner of administration and are easily determined by a person skilled in the art. Generally an amount of 0.1 mg to 50 mg isotretinoin, typically 0.1 mg to 50 mg per unit dose, to be given for example 1 to 4 times a day, would be suitable for most purposes.
  • Figure 4 shows the effect of HP- ⁇ -CD on the aqueous solubility of isotretinoin at pH
  • phase-solubility diagram of isotretinoin with HP- ⁇ -CD can be classified as A L -type, which shows that isotretinoin forms a soluble complex with HP- ⁇ -CD.
  • the therapeutLc dose of isotretinoin is 10 - 20 mg (Roaccuran, Roche Ltd) and from phase-solubility studies it can be calculated that in order to complex 10 mg or 20 mg of isotretinoin, 9-40 mg or
  • HP- ⁇ -CD 1880 mg of HP- ⁇ -CD is needed.
  • the major problem in the use of HP- ⁇ -C D in oral isotretinoin formulations is the fact that after freeze- or spray-drying the solution, the material contains high amounts of free HP- ⁇ -CD molecules which increases the formulation bulk.
  • the method above produced a white precipitate which contained 5 mg of isotretinoin in 90 mg of the precipitate. Based on the isotretinoin content in the powder (assuming that the remaining part of the powder was ⁇ -CD), the stoichiometry of the isotretinoin/ ⁇ -CD complex was calculated to be 1 :4.
  • the dissolution rate of isotretinoin and isotretinoin/ ⁇ -CD was studied at pH 7.4 by using an USP 23 apparatus 2 (rotating paddle method) at 37 °C. Powdered samples containing 5 mg of isotretinoin or 90 mg isotretinoin/ ⁇ -CD complex were gently spread on the surface of the dissolution medium, which was stirred at 100 rpm. The solution was sampled (3.0 ml) at appropriate time intervals and the samples were filtered rapidly through a membrane filter (0.22 ⁇ m) and analyzed by HPLC. In all of the studies the dissolution medium contained 2 % HP- ⁇ -CD to ensure the full solubility of isotretinoin.
  • Figures 5 and 6 show that the complexation of isotretinoin with natural ⁇ -CD significantly increases the dissolution rate of isotretinoin.
  • ⁇ - CD/isotretinoin formulation isotretinoin is fully dissolved in 2 minutes. Without ⁇ - CD the dissolution rate is much slower and isotretinoin is not fully dissolved even in 5 hours.
  • Brzokewicz A Caron D, Shroot B: Topical gels containing retinoic acid and beta- cyclodextrin with gelling agent, hydroxylated amine and water.
  • WO9014082 (1990).
  • Orfanos C E, Zouboulis C C Oral retinoids in the treatment of seborrhoea and acne. Dermatology 196: 140 - 147, 1998.
  • Rolland A, Shroot B Aqueous gel based on retinoic acid and hydroxypropyl-beta- cyclodextrin. EP486395 (1992).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nanotechnology (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
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  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
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Abstract

L'invention concerne l'utilisation d'un complexe d'isorétinoïne comprenant une cyclodextrine choisie entre une CD-β et une CD-η, pour la préparation d'une composition pharmaceutique à administration orale, destinée en particulier au traitement de l'acné.
PCT/FI2004/000161 2003-03-24 2004-03-22 Complexes d'isotretinoine avec beta ou gamma-cyclodextrine naturelle WO2004084883A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI20030426A FI20030426A (fi) 2003-03-24 2003-03-24 Syklodekstriinikompleksit
FI20030426 2003-03-24

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2421433B (en) * 2004-12-08 2008-01-02 Sytera Inc Use of compositions for treating age related macular degeneration or dystrophy
US7432307B2 (en) 2004-11-04 2008-10-07 Sirion Therapeutics, Inc. Modulators of retinol-retinol binding protein (RBP)-transthyretin (TTR) complex formation
WO2010116097A1 (fr) * 2009-04-09 2010-10-14 Pierre Fabre Medicament Procede de preparation de complexes moleculaires entre un agent retinoïde et des cyclodextrines
US8314152B2 (en) 2004-06-23 2012-11-20 Acucela, Inc. Methods and compositions for treating ophthalmic conditions with retinyl derivatives
US10716774B1 (en) 2018-01-05 2020-07-21 Yale Pharmaceuticals LLC Pharmaceutical compositions containing isotretinoin with improved dissolution profile and enhanced stability

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982000251A1 (fr) * 1980-07-21 1982-02-04 Commerce Us Forme soluble dans l'eau de retinoides
WO1990014082A1 (fr) * 1989-05-17 1990-11-29 Centre International De Recherches Dermatologiques (Cird) Gel aqueux a base d'acide retinoique
US5472954A (en) * 1992-07-14 1995-12-05 Cyclops H.F. Cyclodextrin complexation
US5985296A (en) * 1997-03-27 1999-11-16 Wacker-Chemie Gmbh Complexes of gamma-cyclodextrin and retinol or retinol derivatives, processes for their preparation and their use
WO2002024172A1 (fr) * 2000-09-22 2002-03-28 Galephar M/F Composition pharmaceutique semi-solide d'isotretinoine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982000251A1 (fr) * 1980-07-21 1982-02-04 Commerce Us Forme soluble dans l'eau de retinoides
WO1990014082A1 (fr) * 1989-05-17 1990-11-29 Centre International De Recherches Dermatologiques (Cird) Gel aqueux a base d'acide retinoique
US5472954A (en) * 1992-07-14 1995-12-05 Cyclops H.F. Cyclodextrin complexation
US5985296A (en) * 1997-03-27 1999-11-16 Wacker-Chemie Gmbh Complexes of gamma-cyclodextrin and retinol or retinol derivatives, processes for their preparation and their use
WO2002024172A1 (fr) * 2000-09-22 2002-03-28 Galephar M/F Composition pharmaceutique semi-solide d'isotretinoine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AMDIDOUCHE D., ET AL.: "Inclusion of retinoic acid in Beta-cyclodextrin", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 54, 1989, pages 175 - 179, XP002979233 *
MONTASSIER P., ET AL.: "Inclusion complexes of tretinoin with cyclodextrins", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 153, 1997, pages 199 - 209, XP002979232 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8314152B2 (en) 2004-06-23 2012-11-20 Acucela, Inc. Methods and compositions for treating ophthalmic conditions with retinyl derivatives
US8410168B2 (en) 2004-06-23 2013-04-02 Acucela, Inc. Methods and compositions for treating ophthalmic conditions with retinyl derivatives
US7432307B2 (en) 2004-11-04 2008-10-07 Sirion Therapeutics, Inc. Modulators of retinol-retinol binding protein (RBP)-transthyretin (TTR) complex formation
GB2421433B (en) * 2004-12-08 2008-01-02 Sytera Inc Use of compositions for treating age related macular degeneration or dystrophy
WO2010116097A1 (fr) * 2009-04-09 2010-10-14 Pierre Fabre Medicament Procede de preparation de complexes moleculaires entre un agent retinoïde et des cyclodextrines
FR2944278A1 (fr) * 2009-04-09 2010-10-15 Pf Medicament Procede de preparation de complexes moleculaires entre un agent retinoide et des cyclodextrines
US10716774B1 (en) 2018-01-05 2020-07-21 Yale Pharmaceuticals LLC Pharmaceutical compositions containing isotretinoin with improved dissolution profile and enhanced stability

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FI20030426A (fi) 2004-09-25

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