WO2009130394A1 - Formulation de cyclosporine gastro-résistante - Google Patents

Formulation de cyclosporine gastro-résistante Download PDF

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Publication number
WO2009130394A1
WO2009130394A1 PCT/FI2009/050326 FI2009050326W WO2009130394A1 WO 2009130394 A1 WO2009130394 A1 WO 2009130394A1 FI 2009050326 W FI2009050326 W FI 2009050326W WO 2009130394 A1 WO2009130394 A1 WO 2009130394A1
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WO
WIPO (PCT)
Prior art keywords
cyclodextrin
cya
cyclosporin
pharmaceutical formulation
drug delivery
Prior art date
Application number
PCT/FI2009/050326
Other languages
English (en)
Inventor
Pekka Jarho
Kristiina JÄRVINEN
Janne Mannila
Tomi Järvinen
Original Assignee
Pedipharm Oy
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 Pedipharm Oy filed Critical Pedipharm Oy
Publication of WO2009130394A1 publication Critical patent/WO2009130394A1/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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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

Definitions

  • the present invention describes the use of cyclodextrins (CDs) in the oral formulations of cyclosporin A (CyA).
  • CDs cyclodextrins
  • the invention can be utilized especially with solid, CD containing CyA formulations to improve the oral bioavailability of CyA.
  • the method can, however, be utilized in all orally administered solid, semi-solid and liquid CyA formulations containing CDs.
  • CyA is an immunosuppressive drug which is mainly used in the treatment of autoimmune diseases and to prevent the rejection of transplanted organs (Martindale 2005). From pharmaceutical point of view the major problems of CyA are its poor aqueous solubility and dissolution rate which lead to the low and variable oral bioavailability of CyA. To improve the dissolution characteristics of CyA the drug has nowadays been formulated as microemulsion capsules which contain surfactant, lipophilic solvent, hydrophilic solvent and ethanol (Mueller et al. 1994). This mi- croemulsion formulation has been shown to improve the oral absorption of CyA and nowadays various generic formulations based on this technique have come to the market (Cattaneo et al. 2005). Microemulsion formulation is nowadays also in the market as an oral solution (Martindale 2005).
  • CyA capsules The quality standards for CyA capsules have been presented in the United States Pharmacopeia (USP27/NF24 2004).
  • the monograph for CyA capsules contains a dissolution test which prescribes that CyA capsules containing liquid formulation (mi- croemulsion) should rupture in 15 minutes.
  • CDs 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.
  • CDs In drug formulations, CDs have been used mainly to increase the aqueous solubility, stability and bioavailability of various lipophilic compounds. In oral drug delivery the increased bioavailability has been usually correlated with the improved aqueous solubility and dissolution rate of the lipophilic drug.
  • CDs have also known to interact with cell membranes which may also improve the drug absorption.
  • CDs can be used to improve aqueous solubility and biopharmaceutical properties of CyA (Kanai et. al 1989, Miyake 1999a, Miyake 1999b, Okada et al 1999, Ran et al 2001, Fukaya et al. 2003).
  • Kanai et al. (1989) showed that natural ⁇ -CD can be used to improve the aqueous solubility and absorption of CyA into the eye.
  • Fukaya et al. 2003 have shown that maltosyl- ⁇ -CD can be used to improve the inhalation properties of CyA. Dealing with the oral drug delivery Miyake et al.
  • the present inventors have found that after oral administration of CD containing CyA solution and powder very small amount of CyA is absorbed into the body. However, duodenal administration of CD containing CyA solution results in high plasma levels of CyA.
  • the invention shows that oral formulations containing Cy A/CD inclusion complex have to be delivered by using gastroresistant materials.
  • the invention can be utilized especially with solid, CD containing CyA formulations to improve the oral bioavailability of CyA.
  • the method can, however, be util- ized in all orally administered solid, semi-solid and liquid CyA formulations containing CDs.
  • CyA As discussed before, one of the main problems of CyA is poor aqueous solubility and dissolution rate which lead to the low and variable oral bioavailability of CyA.
  • the present invention is based on the finding that after oral administration of CyA/ ⁇ -CD solution very low amounts of CyA are absorbed into the body. However, after intraduodenal administration of CyA/ ⁇ -CD solution very high concentrations of CyA can be achieved (Example 1). In addition, very low concentrations of CyA were also achieved after oral administration of solid CyA/ ⁇ -CD powder (Example 2).
  • the present data suggest very strongly that the major problem in the use of CDs in oral CyA formulations is the degradation of CyA because of acidic pH of gastric fluids. Oliyai et al (1994) have shown in vitro that CyA degrades rapidly due to acid catalyzed degradation which supports the hypothesis above.
  • CyA is degrading in stomach when it is administered as CD containing solu- tion but it is not degraded when administered as commercially available microsus- pension (Example 3).
  • CD containing solution all the CyA molecules are in soluble form and molecules are degraded due to acidic gastric fluids.
  • CyA molecules are mainly in micelle type structures where most of the CyA molecules are not exposed to degradation.
  • the low absorption of CyA after oral administration solid CyA/ ⁇ -CD powder can also be explained with low stability of CyA due to very fast dissolution of CyA/ ⁇ -CD powder.
  • the present invention shows that oral formulations containing CyA/CD inclusion complex have to be delivered by using gastroresistant drug delivery systems.
  • a substantially improved bioavailability of CyA is achieved if the CyAJCD inclusion complex is allowed to pass the stomach region into the lower digestive tract before it is released.
  • this objective is reached if the oral formulation comprising CyA/CD inclusion complex is a gas- troresistant drug delivery system.
  • Said oral formulation according to the invention seems to improve bioavailability of CyA not only compared to the enteric coated CyA which has not been complexed with CD, but also compared to the commercially available CyA microsuspension.
  • An object of the invention is therefore a pharmaceutical formulation for oral use containing as an active agent cyclosporin A complexed with a cyclodextrin, wherein said formulation is a gastroresistant drug delivery system.
  • the oral drug delivery system according to the invention is enteric coated with a film which dissolves at a pH of the lower digestive tract to make it gastrore- sistant. More preferably said system is coated with a film which dissolves at a pH of from 5.5 to 6.5, even more preferably with a film which dissolves at a pH of from 6.0 to 6.5.
  • film forming agents suitable for the purpose of the invention and a person skilled in the art can easily choose a suitable agent among the commercially available substances.
  • film forming agents may be mentioned i.a. shellac, cellulose acetate phthalate, hydroxypropyl methylcellu- lose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, as well as various methacrylic acid deriva- tives.
  • a preferred film forming agent to be used in the invention is cellulose acetate phthalate.
  • the cyclodextrin to be used in the oral drug delivery system according to the invention can be a natural cyclodextrin such as ⁇ -cyclodextrin ( ⁇ -CD), ⁇ -cyclodextrin ( ⁇ - CD) or ⁇ -cyclodextrin ( ⁇ -CD), or it can be a modified cyclodextrin, such as hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD), sulfobutylether- ⁇ -cyclodextrin (SBE- ⁇ - CD), a methylated CD, including dimethyl- ⁇ -cyclodextrin (DM- ⁇ -CD), trimethyl- ⁇ - cyclodextrin (TM- ⁇ -CD) and randomly methylated ⁇ -cyclodextrin (RM- ⁇ -CD).
  • the cyclodextrin is ⁇ -cyclodextrin.
  • cyclodextrin with cyclosporin A can be carried out in a conventional manner known to a person skilled in the art, for example following the procedure described in WO 2007/101915 which is incorporated herein by reference.
  • the gastroresistant drug delivery system described in present invention can be pre- pared in conventional manner.
  • the oral drug delivery system according to the invention can be of any shape and form suitable to be provided with an enteric coating or with other means to make the system gastoresistant.
  • Alternative means to make the drug delivery system gastroresistant include for example various slow release formulations where the complex comprising CyA and cyclodextrin is em- bedded in a suitable organic or inorganic polymer.
  • Representative examples of the gastroresistant drug delivery system according to the invention include tablets, capsules, microparticles, granules, pills and nanoparticles.
  • the formulation according to the invention may, in addition to the CyA/CD inclusion complex, contain conventional additives, such as carriers, diluents, fillers, lubricants, disintegrating agents etc. These are known in the art.
  • the amount of the CyA/CD inclusion complex in the formulation can vary within wide limits, e.g. from 10 to 95% by weight.
  • the invention also concerns a process for the preparation of the oral formulation of the invention, which process comprises complexing cyclosporin A with the selected cyclodextrin, combining the obtained CyA/CD inclusion complex with a pharmaceutically acceptable carrier or other adjuvants, and formulating the obtained mixture into a gastroresistant drug delivery system.
  • a further object of the invention is a method for increasing bioavailability of cyclosporin A from an oral pharmaceutical formulation, the method comprising the steps of complexing cyclosporin A with a cyclodextrin; optionally combining the obtained CyA/CD inclusion complex with a pharmaceutically acceptable carrier or other adjuvants; and formulating the complex into a gastroresistant drug delivery system.
  • a still further object of the invention is a method for treating an individual for a condition responsive to treatment with cyclosporin A, said method comprising the steps of administering an effective amount of a complex of cyclosporin A and a cyclodextrin in the form of a gastroresistant drug delivery system to the individual in need of such treatment.
  • conditions responsive to treatment with CyA may be mentioned autoimmune diseases and rejection of transplanted organs.
  • Figure 1 shows the plasma levels of CyA after oral and duodenal administration of ⁇ -CD/CyA- solution (dose normalized to 3 mg/kg) to rabbits. The results show that after oral administration very low concentrations of CyA in rabbits' plasma have been achieved. However, after duodenal administration of ⁇ -CD/CyA solution high plasma concentrations of CyA have been achieved.
  • EXAMPLE 2 shows the plasma levels of CyA after oral and duodenal administration of ⁇ -CD/CyA- solution (dose normalized to 3 mg/kg) to rabbits. The results show that after oral administration very low concentrations of CyA in rabbits' plasma have been achieved. However, after duodenal administration of ⁇ -CD/CyA solution high plasma concentrations of CyA have been achieved.
  • FIG. 2 shows the plasma levels of CyA after oral administration of CyA/ ⁇ -CD powder (dose normalized to 3 mg/kg) in gelatine capsule to rabbits. The results show that after oral administration of CyA/ ⁇ -CD powder very low concentrations of CyA in rabbits' plasma have been achieved.
  • FIG 3 shows the plasma concentrations of CyA after two individual oral administrations of Sandimmun Neoral (25 mg) to rabbits. The results show that after oral administration of Sandimmun Neoral reasonably high concentrations of CyA in the rabbit plasma have been achieved.
  • Jarho P Jarvinen T
  • Jarvinen K Matilainen L
  • Mannila J Method for enhancing cyclodextrin complexation WO 2007/101915.
  • Kanai A, Alba T, Kobayashi TC, Nakajima A, Kurihara K, Yokoyama T, Fukami M The effect on the cornea of alphacyclodextrin vehicle for cyclosporin eyedrops. Transplantation Proceedings 21: 3150 - 3152, 1989.
  • Miyake K, Me T, Hirayama F, Uekama K Improved solubility and oral bioavailability of cyclosporin a by hydrophilc cyclodextrin complexation. Proceedings of the ninth international symposium of cyclodextrins. Santiago de Compostela, Spain, May 31 - June 3, 1998.
  • Miyake K, Arima H, Me T, Hirayama F, Uekama K Enhanced absorption of cyclosporin by complexation with dimethyl- ⁇ -cyclodextrin in bile duct-canylated and noncanylated rats. Biol. Pharm. Bull 22: 66-72, 1999a.
  • Miyake K, Hirayama F, Uekama K Solubility and mass and nuclear magnetic reso- nance spectroscopic studies on interaction of cyclosporin A with dimethyl- ⁇ - and - ⁇ -cyclodextrins in aqueous solutions. J. Pharm. Sci. 88: 39- 45, 1999b.
  • CiA ciclosporin A

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Nanotechnology (AREA)
  • Biophysics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
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Abstract

La présente invention porte sur l'utilisation de cyclodextrines (CD) dans les formulations orales de la cyclosporine A (Cy A). L'invention peut être utilisée en particulier avec des formulations de Cy A contenant CD, solides, pour améliorer la biodisponibilité orale de Cy A. Cependant, le procédé peut être utilisé dans la totalité des formulations Cy A solides, semi-solides et liquides administrées par voie orale, contenant des CD.
PCT/FI2009/050326 2008-04-25 2009-04-24 Formulation de cyclosporine gastro-résistante WO2009130394A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI20085369A FI20085369A0 (fi) 2008-04-25 2008-04-25 Gastroresistentti siklosporiiniformulaatio
FI20085369 2008-04-25

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WO2009130394A1 true WO2009130394A1 (fr) 2009-10-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20121264A1 (it) * 2012-07-19 2014-01-20 Recordati Ind Chimica E Farma Ceutica S P A Forma farmaceutica gastro-resistente a rilascio ritardato

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002101A1 (fr) * 2001-06-26 2003-01-09 Farmatron Ltd. Compositions pharmaceutiques orales a biodisponibilite amelioree de l'ingredient pharmaceutique actif
WO2007101915A1 (fr) * 2006-03-08 2007-09-13 Pedipharm Oy Méthode d'amplification de la complexation de la cyclodextrine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002101A1 (fr) * 2001-06-26 2003-01-09 Farmatron Ltd. Compositions pharmaceutiques orales a biodisponibilite amelioree de l'ingredient pharmaceutique actif
WO2007101915A1 (fr) * 2006-03-08 2007-09-13 Pedipharm Oy Méthode d'amplification de la complexation de la cyclodextrine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MALAEKEH-NIKOUEI ET AL.: "Preparation and Characterization of PLGA Microspheres Loaded by Cyclosporine-Cyclodextrin Complex.", IRANIAN JOURNAL OF PHARMACEUTICAL SCIENCES., vol. 1, no. 4, 2005, pages 195 - 201 *
OLIYAI ET AL.: "Kinetics of acid- catalyzed degradation of cyclosporine A and its analogs in aqueous solutions.", INT. J. PEPTIDE PROTEIN RES., vol. 43, 1994, pages 239 - 247 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20121264A1 (it) * 2012-07-19 2014-01-20 Recordati Ind Chimica E Farma Ceutica S P A Forma farmaceutica gastro-resistente a rilascio ritardato
WO2014013008A1 (fr) * 2012-07-19 2014-01-23 Recordati Industria Chimica E Farmaceutica Spa Formulation pharmaceutique gastro-résistante à libération retardée

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