WO1996022103A1 - Formulations solides pour l'administration de cyclosporine a par voie orale - Google Patents

Formulations solides pour l'administration de cyclosporine a par voie orale Download PDF

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Publication number
WO1996022103A1
WO1996022103A1 PCT/KR1996/000008 KR9600008W WO9622103A1 WO 1996022103 A1 WO1996022103 A1 WO 1996022103A1 KR 9600008 W KR9600008 W KR 9600008W WO 9622103 A1 WO9622103 A1 WO 9622103A1
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WO
WIPO (PCT)
Prior art keywords
solid
cyclosporine
micell
solution
dispersion
Prior art date
Application number
PCT/KR1996/000008
Other languages
English (en)
Inventor
Sung-Joo Hwang
Sun Hee Park
Eun Ju Jeong
Original Assignee
Cheil Foods & Chemicals, Inc.
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 Cheil Foods & Chemicals, Inc. filed Critical Cheil Foods & Chemicals, Inc.
Priority to AU44009/96A priority Critical patent/AU4400996A/en
Publication of WO1996022103A1 publication Critical patent/WO1996022103A1/fr

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Classifications

    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to a novel solid micell dispersion imparting the remarkably improved bioavailability of cyclosporine A, and oral solid dosage forms containing the same.
  • Cyclosporine A is a hydrophobic cyclic oligopeptidc obtained from Cylindrocarpon lucidum, Tolypocladium inflatum and other fungi imperfecti I A. Ruegger et al., Hel ⁇ . Chim. Acta 59, 1075 (1976); M . Drey fuss et al, J. ⁇ ppl. Microbiol. 3, 125 (1976) ] . It has been well known to be a powerful immunosuppresant that appears to act mainly on T cells. It would be evaluated as an effective immunosuppresive drug in the following treatments : skin grafts, marrow transfer, cornea transfer or organ transfer such as heart, liver, kidney , pancreas, and the like. It has also been gradually applied for healing autoimmune diseases or inflammatory conditions (in particular, arthritis and rheumatoid diseases).
  • cyclosporine A (C62II111N11O12) has a relatively large molecular weight of 1,202.63 and is very hydrophobic. Due to such properties, cyclosporine A is slightly soluble in water (7.3 ⁇ g/ml at 37T ) [G. Ismailos et al., J. Pharm. Pharmcol., 43. 287-289, 1991 1 and the bioavailability of cyclosporine A for oral administration is no more than 30% [K. Takada et al., Drug Delivery System 1 , 1 -7, 19861.
  • U.S Pat. No. 4,388,307 describes a solution in which the poor solubility of cyclosporine A is to be compensated by the use of Labrafil and olive oil as surfactant and solvent, respectively, along with the use of a large amount of ethanol.
  • Labrafil and olive oil as surfactant and solvent, respectively
  • the content of ethanol in the solution is reduced by its evaporation and, thus, precipitates form.
  • the solution has an unpleasant palatability.
  • the solution cannot be formulated into a solid dosage form.
  • Korean Patent Publication No. 90-4348 relates to cyclosporine microemulsion which consists of hydrophilic phase, hydrophobic phase and surface-active substances.
  • the microemulsion is formulated into a soft capsule.
  • the formulation of the microemulsion into a hard capsule is only possible using the Quali-Seal technique, and the formulation of the microemulsion into a tablet is impossible.
  • Korean Patent Publication No. 90-12625 teaches a method of preparing a solid dosage unit for oral administration of cyclosporine by dissolving cyclosporine and fatty acid saccharidc monoester (e.g ., saccharose monolaurate L-1695) in ethanol and then by evaporating the ethanol.
  • fatty acid saccharidc monoester e.g ., saccharose monolaurate L-1695
  • this method is commercially disadvantageous because the fatty acid saccharide monoester is expensive, and, in a case where a solid dosage unit (one capsule or tablet) containing 100 mg of cyclosporine is prepared according to the procedures of this method, very large amounts of fatty acid sacchride monoester (ranging from approximately 924 mg to 1960 mg) are required. As such, it is impossible for patients to swallow a single dosage unit, and thereby it must be divided into multiple dosages.
  • fatty acid saccharidc monoester e.g ., saccharose monol
  • cyclosporine in oil phase must be dissolved in gastric juice of aqueous phase in order to be absorbed into the gastrointestinal tract.
  • degree of dissolution of cyclosporine in gastric juice varies greatly in individual patients because it depends on the amount of bile juice secreted by the individual patient and the kinds and amount of food eaten by the patient, among other factors.
  • the solid dispersion method is to disperse slightly soluble drugs on hydrophilic macromolecular matrices, for example polyvinylpyrolidonc, macromolecular polyethyleneglycol and Eudragit, so that the particle size of the drugs is reduced down to the molecular size of the drug.
  • This method may be useful for the development of the solid formulations.
  • the hydrophilic matrices are dissolved, and, immediately , the rapid dissolution of the drugs with molecular size proceeds until the phase gets temporarily supersaturated. Soon, equilibrium of the phase is no longer maintained, and the phase reaches saturation with the formation of the crystals of the drugs.
  • the mixture of slightly soluble drugs with surfactants has a disadvantage, in that, when it is administered in the form of solid formulations, the release of the drugs in the gastrointestinal tract is very slow.
  • the present invention provide a novel solid micell dispersion suitable for oral administration of cyclosporine A, which comprises, based on 100 mg of cyclosporine A, 70 to 200 mg of hydrophilic macromolecular matrix, 100 to 200 mg of surfactant and 10 to 50 mg of cosolvent.
  • the present invention provides the oral solid formulations containing the solid micell dispersion.
  • the solid formulations of the present invention exhibit the remarkably superior bioavailability of cyclosporine A over currently commercial solid medicament preparations.
  • Figure 1 shows analyses of the differential scanning calorimetry on cyclosporine A (I), a physically mixed composition of the ingredients of Example 9 (II), and a solid micell dispersion of Example 9 (III).
  • Figure 2 shows analyses of the differential scanning calorimetry on cyclosporine A (I), a physically mixed composition of the ingredients of Example 10 (II), and a solid micell dispersion of Example 10 (III).
  • Figure 3 shows analyses of the differential scanning calorimetry on a solid micell dispersion of Example 9 (I), as prepared by a solvent evaporation method, and a solid micell dispersion (II), as prepared by a fusion and solvent evaporation method using the same ingredients as Example 9.
  • Figure 4 shows a time-to-concentration profile of cyclosporine A in whole blood after SD white male rats were orally adminstered with Sandimmun (• ), formulations CyA-A(O ) and CyA-B(A ) of Examples 13 and 14, respectively.
  • solid micell dispersion herein is defined as the solid composition containing surfactants, which can dissolve slightly water-soluable drugs repidly and prevent the precipitation of drugs by forming micells in aqueous medium.
  • the solid micell dispersion are prepared by conducting the following steps: (a) 5 to 10 ml of ethanol is mixed with 10 to 50 mg of cosolvcnt,
  • hydrophilic macromolecular matrix 70 to 200 mg of hydrophilic macromolecular matrix and 100 to 200 mg of surfactant are subsequently added to the solution, (d) once the dissolution of the added ingredients in the solution is completed, the solvent is evaporated to yield the solids, and (e) the solids are dried to obtain the said solid micell dispersion.
  • the hydrophilic macromolecular matrix PVP (polyvinylpyrolidone) K-30; PEG (polyethyleneglycol) 4000; PEG 6000; or a mixture of the two or more.
  • the ratio of the composition may vary greatly, provided that PEG 6000 must be used in amounts of no more than 30 mg in order to avoid the precipitation of cyclosporine A.
  • the preferred surfactant is Poloxamer 407 (Lutrol ® F 127, block copolymer of polyoxyethylene and polyoxypropylene) or Poloxamer 188.
  • the preferred amounts range from 100 mg to 200 mg based on 100 mg of cyclosporine A, and the more preferred amount is 150 mg.
  • cosolvent glycerine, IICO-60, IICO-10, a mixture of HCO-60 and glycerine and a mixture of HCO-10 and glycerine.
  • Preferred is a mixture of HCO-60 and glycerine.
  • the most preferred cosolvent is a mixture of 20 mg of IICO-60 with 10 mg of glycerine.
  • glycerine is used in single, the amount must be between 20 mg and 50 mg because the deviation from the amount results in the poor dispersiblity or solidity of the solid micells.
  • HCO-10 is used in single, the amounts ranging from 30 mg to 50 mg result in the good dispersibility , solidity and solubility.
  • the finished solid micell dispersion (following the final drying step) contains no ethanol.
  • the inventors discovered a suitable method to produce the solid micell dispersion in bulk, in place of the solvent evaporation method.
  • the inventors founded that, in the solvent evaporation method, when heating is conducted in order to accelerate the dissolution of the ingredients, the amount of ethanol can be decreased to approximately 1/80 of the amount currently used in the solvent evaporation method.
  • the heated solution is cooled to a room temperature, since the cool solution contains an appropriate amount of ethanol to sieve the solution, it is not necessary to evaporate the ethanol. After the cool solution is sieved through mesh 7 to mesh 10, the micells thus obtained arc well dried at temperatures of 35 to 40t without the occurrence of the "case hardening" effects.
  • the present invention provides a process for producing , in bulk, the solid micell dispersion (hereinafter "fusion and solvent evaporation method” ), which comprises the following steps: (a) a solvent ethanol is mixed at 60TC with cosolvent, cyclosporine A, hydrophilic macromolecular matrix and surfactant to form the solution,
  • solid formulations tablets, pills, dragees, granules, powders, capsules and sachets.
  • Such solid formulations are prepared by mixing the solid dispersing micells of the present invention with pharmaceutically acceptable carriers.
  • diluent a lubricant (glidant) and disintegrant
  • diluent corn starch, lactose, spray-dried lactose and microcrystalline cellulose.
  • lubricant(glidant) talc, colloidal silicon dioxide (e.g., Aerosil 200).
  • disintegrant carboxymethylcellulose, sodium starch glycolate (e.g., Primojel ® ), cross-linked polyvinylpyrolidone (e.g., Kollidon CL ® ), cross-linked carboxymethylcellulose sodium (e.g., Ac-Di-Sol ).
  • the most preferred disintegrant is Kollidon CL or the mixture of
  • Example 1 illustrate solid micell dispersions of the present invention and a process for their production according to the solvent evaporation method or the fusion and solvent evaporation method.
  • Example 4 5 ml of ethanol was mixed with 20 mg of HCO-60 and 10 mg of glycerine. 100 mg of cyclosporine A was dissolved in the mixed solvents. 150 mg of PVP K-30 and 100 mg of Poloxamer 407 were subsequently added to the solution. After the complete dissolution, the solvents were evaporated at a temperature of 35 TJ under reduced pressure using an evaporator to obtain the solid products. The obtained solid products were dried on a desiccator for 24 hours to produce the desired solid micell dispersion.
  • Example 4 5 ml of ethanol was mixed with 20 mg of HCO-60 and 10 mg of glycerine. 100 mg of cyclosporine A was dissolved in the mixed solvents. 150 mg of PVP K-30 and 100 mg of Poloxamer 407 were subsequently added to the solution. After the complete dissolution, the solvents were evaporated at a temperature of 35 TJ under reduced pressure using an evaporator to obtain the solid products. The obtained solid products were dried on a desiccator
  • Example 6 10 ml of ethanol was mixed with 30 mg of HCO-60. 100 mg of cyclosporine A was dissolved in the mixed solvents. 20 mg of PEG 4000, 50 mg of PVP K-30 and 150 mg of Poloxamer 407 were subsequently added to the solution. After the complete dissolution, the solvents were evaporated at a temperature of 35 TJ under reduced pressure using an evaporator to obtain the solid products. The obtained solid products were dried on a desiccator for 24 hours to produce the desired solid micell dispersion.
  • Example 7 10 ml of ethanol was mixed with 30 mg of HCO-60. 100 mg of cyclosporine A was dissolved in the mixed solvents. 50 mg of PEG 4000, 20 mg of PEG 6000 and 150 mg of Poloxamer 407 were subsequently added to the solution. After the complete dissolution, the solvents were evaporated at a temperature of 35 TJ under reduced pressure using an evaporator to obtain the solid products. The obtained solid products were dried on a desiccator for 24 hours to produce the desired solid micell dispersion.
  • Example 8 10ml of ethanol was mixed with 20 mg of HCO-60 and 10 mg of glycerine. 100 mg of cyclosporine A was dissolved in the mixed solvents. 150 mg of PVP K-30 and 100 mg of Poloxamer 407 were subsequently added to the solution. After the complete dissolution, the solvents were evaporated at a temperature of 35 TJ under reduced pressure using an evaporator to obtain the solid products. The obtained solid products were dried on a desiccator for 24 hours to produce the desired solid micell dispersion.
  • Example 9 5ml of ethanol was mixed with 20 mg of HCO-60 and 10 mg of glycerine. 100 mg of cyclosporine A was dissolved in the mixed solvents. 50 mg of PEG 4000, 50 mg of PVP K-30 and 150 mg of Poloxamer 407 were subsequently added to the solution. After the complete dissolution, the solvents were evaporated at a temperature of 35 J under reduced pressure using an evaporator to obtain the solid products. The obtained solid products were dried on a desiccator for 24 hours to produce the desired solid micell dispersion.
  • thermodynamic property of the solid micell dispersion of the present invention using the differential scanning calorimetry
  • Example 9 All of the solid micell dispersion prepared by Examples 1 to 12 have sufficiently good solubility, dispersibility and solidity to produce solid formulations.
  • the solid micell dispersion of Example 9 are superior over the others, in that 24 hours after the solid micells were dispersed in a distilled water, precipitates did not form.
  • the solid micell dispersion of Example 10 are not as dispersible as those of Example 9, but they are comparable to the solid micell dispersion of Example 9 in terms of solubility and solidity.
  • thermodynamic properties of the solid micell dispersions of Examples 9 and 10 were analyzed by the differential scanning calorimetry .
  • Figure 1 shows the endothermal peaks of cyclosporine A (I) in the vicinity of 150TJ , physical mixture of Example 9 (II) in the vicinity of 60TJ and 130TJ , and solid micell dispersion of Example 9 (III) in the vicinity of 135TJ .
  • Figure 2 shows the endothermal peaks of cyclosporine A (I) in the vicinity of 150TJ , physical mixture of Example 10 (II) in the vicinity of 60TJ and 143TJ , and solid micell dispersion of Example 10 (III) in the vicinity of 145 TJ .
  • Example 12 was also analyzed in the same manner as the aforementioned and was compared with the solid micell dispersion of Example 9. The results are shown in Figure 3. This shows that both micell dispersions are homogeneous and a decreased crystallinity .
  • Example 13 The following were mixed and pressed to give a tablet which weighs 200 mg and which contains 25 mg of cyclosporine:
  • the tablet in Example 13 was film-coated using the following formula:
  • Example 14 The tablet in Example 14 was film-coated using the following formula:
  • Example 13 and 14 The solid formulations of Examples 13 and 14 were used as test samples and were designated as CyA-A and CyA-B, respectively .
  • Sandimmun ® (Lot No. 096 MFD 0393 EXP 0996) was used as a control.
  • Blood samples were analyzed by a monoclonal fluorescence polarization immunoassay using TD X Cyclosporine Monoclonal Whole Blood reagent (Abbott Labs).
  • 150 ⁇ l of whole blood, 50ul of buffer containing 4% Triton-XlOO surfactant, and 300 ⁇ l of zinc sulfate solution (dissolved in a mixture of methanol and ethylene glycol) were blended in the test tube and then centrifuged at 9,500g for 5 minutes.
  • the maximum concentration (C raax ) and the area under the curve (AUC ) increased significantly for formulations of the present invention, and the time of peak blood level decreased. Mean residence times were not significantly different among them.
  • the relative bioavailabilities of cyclosporine A from formulations of the present invention were almost twice as high as Sandimmun .

Abstract

Cette invention se rapporte à une nouvelle dispersion micellaire solide conférant à la cyclosporine A une assimilabilité remarquablement améliorée, ainsi qu'à des formulations solides à administration orale contenant cette dispersion. Cette dispersion micellaire solide est préparée selon un procédé comprenant les étapes suivantes: (a) 5 à 10 ml d'éthanol sont mélangés avec 10 à 50 mg d'un cosolvant; (b) 100 mg de cyclosporine A sont complètement dissous dans les solvants mélangés; (c) 70 à 200 mg d'une matrice macromoléculaire hydrophile et 100 à 200 mg d'un tensioactif sont ensuite ajoutés à la solution; (d) une fois que la dissolution des ingrédients ajoutés dans la solution est terminée, le solvant est amené à s'évaporer dans des conditions de pression réduite pour produire les particules solides, et (e) on fait sécher ces particules solides pour obtenir la dispersion micellaire solide objet de cette invention.
PCT/KR1996/000008 1995-01-21 1996-01-20 Formulations solides pour l'administration de cyclosporine a par voie orale WO1996022103A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44009/96A AU4400996A (en) 1995-01-21 1996-01-20 Solid formulations for oral administration of cyclosporine a

Applications Claiming Priority (2)

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KR1995-1118 1995-01-21
KR1019950001118A KR100239799B1 (ko) 1995-01-21 1995-01-21 경구투여용 사이클로스포린 에이 고체미셀분산체, 이의 제조 방법 및 고형제제

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0939640A1 (fr) * 1996-08-16 1999-09-08 Supratek Pharma, Inc. Ameliorations apportees a des compositions polymeres pour chimiotherapie et methodes therapeutiques utilisant ces compositions
WO1999059541A2 (fr) * 1998-05-15 1999-11-25 Basf Aktiengesellschaft Preparations de cyclosporine
WO2000071163A1 (fr) * 1999-05-24 2000-11-30 Sonus Pharmaceuticals, Inc. Excipient en emulsion pour medicaments faiblement solubles
WO2001000175A1 (fr) * 1999-06-25 2001-01-04 Basf Aktiengesellschaft Formes d'administration pharmaceutiques mecaniquement stables, contenant des agents tensioactifs liquides ou semi-solides
DE10000792A1 (de) * 2000-01-11 2001-07-19 Bernhard C Lippold Formulierungen von Wirkstoffen in Form einer festen Dispersion
WO2002026208A2 (fr) * 2000-09-27 2002-04-04 Sonus Pharmaceuticals, Inc. Excipient emulsionne pour medicaments a faible solubilite
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
WO2002089773A2 (fr) * 2001-05-09 2002-11-14 Novartis Ag Compositions pharmaceutiques solides contenant de la cyclosporine
US6727280B2 (en) 1997-01-07 2004-04-27 Sonus Pharmaceuticals, Inc. Method for treating colorectal carcinoma using a taxane/tocopherol formulation
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US7423004B2 (en) 2003-01-31 2008-09-09 Smithkline Beecham Corporation Solid dispersion compositions

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100425226B1 (ko) * 2001-07-03 2004-03-30 주식회사 팜트리 아세클로페낙을 함유하는 경제적인 경구용 제제의 조성 및제법
KR101819310B1 (ko) * 2015-12-29 2018-01-18 단국대학교 천안캠퍼스 산학협력단 사이클로스포린을 포함하는 약학 조성물
KR20170078972A (ko) * 2015-12-29 2017-07-10 단국대학교 천안캠퍼스 산학협력단 사이클로스포린을 포함하는 약학 조성물

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4388307A (en) * 1978-03-07 1983-06-14 Sandoz Ltd. Galenical compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4388307A (en) * 1978-03-07 1983-06-14 Sandoz Ltd. Galenical compositions

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0939640A4 (fr) * 1996-08-16 2001-09-12 Supratek Pharma Inc Ameliorations apportees a des compositions polymeres pour chimiotherapie et methodes therapeutiques utilisant ces compositions
EP0939640A1 (fr) * 1996-08-16 1999-09-08 Supratek Pharma, Inc. Ameliorations apportees a des compositions polymeres pour chimiotherapie et methodes therapeutiques utilisant ces compositions
US6660286B1 (en) 1997-01-07 2003-12-09 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6727280B2 (en) 1997-01-07 2004-04-27 Sonus Pharmaceuticals, Inc. Method for treating colorectal carcinoma using a taxane/tocopherol formulation
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6982282B2 (en) 1997-01-07 2006-01-03 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6667048B1 (en) 1997-01-07 2003-12-23 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
WO1999059541A3 (fr) * 1998-05-15 2000-01-20 Basf Ag Preparations de cyclosporine
WO1999059541A2 (fr) * 1998-05-15 1999-11-25 Basf Aktiengesellschaft Preparations de cyclosporine
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
WO2000071163A1 (fr) * 1999-05-24 2000-11-30 Sonus Pharmaceuticals, Inc. Excipient en emulsion pour medicaments faiblement solubles
WO2001000175A1 (fr) * 1999-06-25 2001-01-04 Basf Aktiengesellschaft Formes d'administration pharmaceutiques mecaniquement stables, contenant des agents tensioactifs liquides ou semi-solides
DE10000792A1 (de) * 2000-01-11 2001-07-19 Bernhard C Lippold Formulierungen von Wirkstoffen in Form einer festen Dispersion
US8021688B2 (en) 2000-01-11 2011-09-20 Knoll Gmbh Formulations of active components in the form of a solid dispersion
WO2002026208A2 (fr) * 2000-09-27 2002-04-04 Sonus Pharmaceuticals, Inc. Excipient emulsionne pour medicaments a faible solubilite
WO2002026208A3 (fr) * 2000-09-27 2003-01-23 Sonus Pharma Inc Excipient emulsionne pour medicaments a faible solubilite
WO2002089773A3 (fr) * 2001-05-09 2003-02-06 Novartis Ag Compositions pharmaceutiques solides contenant de la cyclosporine
WO2002089773A2 (fr) * 2001-05-09 2002-11-14 Novartis Ag Compositions pharmaceutiques solides contenant de la cyclosporine
US7423004B2 (en) 2003-01-31 2008-09-09 Smithkline Beecham Corporation Solid dispersion compositions

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KR100239799B1 (ko) 2000-02-01
AU4400996A (en) 1996-08-07
KR960028917A (ko) 1996-08-17

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