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WO2004073693A1 - Capsule souple contenant une cyclosporine et son procede de fabrication - Google Patents

Capsule souple contenant une cyclosporine et son procede de fabrication Download PDF

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Publication number
WO2004073693A1
WO2004073693A1 PCT/KR2003/000836 KR0300836W WO2004073693A1 WO 2004073693 A1 WO2004073693 A1 WO 2004073693A1 KR 0300836 W KR0300836 W KR 0300836W WO 2004073693 A1 WO2004073693 A1 WO 2004073693A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclosporin
soft capsule
polyethylene glycol
capsule preparation
oil
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/KR2003/000836
Other languages
English (en)
Inventor
Young-Sig Gil
Chang-Hun Yu
Seok-Cheon Hong
Dong-Hyun Cho
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.)
Korea United Pharm Inc
Original Assignee
Korea United Pharm 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 Korea United Pharm Inc filed Critical Korea United Pharm Inc
Priority to AU2003224468A priority Critical patent/AU2003224468A1/en
Publication of WO2004073693A1 publication Critical patent/WO2004073693A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/10—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
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a soft capsule preparation containing cyclosporin as an active ingredient. More particularly, the present invention relates to a liquid composition for use in soft capsule preparations, which contains various surfactants for solubilization and oils, and also to a method for producing the same.
  • Cyclosporin is a specific macromolecular cyclic oligopeptide compound (molecular weight: 1202.64) in which 11 poly-N-methylated amino acids are bonded with each other to form a cyclic peptide structure. Cyclosporin is known as showing useful pharmacological activities, particularly immuno-suppressive activity and anti-inflammatory activity. Cyclosporin, which was first discovered, is a spontaneous fungus metabolite isolated from Tolypoclad ⁇ um inflatum Gams, which is generally known as cyclosporin A and most frequently used. Currently, cyclosporin is produced in large quantities by a synthetic or semi-synthetic process.
  • Cyclosporin has been used to inhibit biological immune responses, which often occur upon the transplantation of tissues or organs, such as the heart, lungs, liver, kidney, pancreas, marrow, skin and cornea, and particularly the transplantation of exogenous tissues or organs.
  • cyclosporin is effective in inhibiting hematological disorders, such as anemia, various autoimmune diseases, such as systemic lupus erythematosus and idiopathic malabsorption, and inflammatory disorders, such as arthritis and rheumatic disorders.
  • cyclosporin is also useful for treatment of protozoal disorders, such as malaria and schistosomiasis, and particularly recently, it is used in anticancer therapy.
  • cyclosporin has been used in a very limited manner. This is because cyclosporin shows high lipophilicity and thus very low solubility in water so that it has a property in that it is well dissolved in organic solvents, such as alcohol, ether, chloroform and the like. Cyclosporin is known as showing a very low bioavailability of about 10-60% upon oral administration due to solubility in water.
  • cyclosporin may greatly vary depending on the conditions of each patient, it is difficult to maintain the effective therapeutic concentration of cyclosporin, and also cyclosporin shows side effects, such as nephrotoxicity.
  • many studies have been actively conducted in an attempt to discover a preparation suitable for the effective oral administration of cyclosporin, which can provide a suitable uniform dosage and increased bioavailability.
  • cyclosporin is formulated with a carrier comprising an ethanol as a co-surfactant, olive oil as a vegetable oil, and a trans-esterification product of natural vegetable oil triglyceride and polyalkylene glycol as a surfactant, thereby producing a liquid composition.
  • the produced liquid composition is administered as an aqueous dilution, which makes it very difficult to adapt the subject to its administration and to provide a uniform dosage for oral administration.
  • the liquid composition of an emulsion state is formulated as a soft capsule preparation before marketing.
  • the soft capsule preparation of cyclosporin contains ethanol because of the solubility requirement of cyclosporin, in which the ethanol is volatile even at room temperature and thus may permeate the gelatin shell of the capsule preparation.
  • the soft capsule preparations can be packed in a special packing material, such as an aluminum foil blister package.
  • a cyclosporin galen preparation comprising cyclosporin, fatty acid monoester, a diluent and a carrier, but this preparation is disadvantageous in that it shows reduced stability since the surfactant used in this preparation has very strong hygroscopicity.
  • Japanese patent No. 193129/1987 discloses a technique of producing a solid dispersion using sucrose, sorbitol, urea, cellulose acetate phthalate as an enteric soluble base, and hydroxypropylmethylcellulose, etc., but this is also insufficient to solve the problems.
  • Korean patent publication No. 93-6430 discloses a method of solubilizing cycrosporin by liposome. However, in this method, it may be impossible to formulate cyclosporin due to an increased dosage of cyclosporin, and also in mass production, various problems can occur.
  • the present inventors have conducted many studies in an attempt to provide a composition where cyclosporin is pharmaceutically highly stable. As a result, we have found that when cyclosporin is formulated with a suitable mixture of various surfactants and oils and particularly co-surfactants, the above-mentioned stability requirement can be satisfied. On the basis of this point, the present invention was perfected.
  • the present invention provides a soft capsule preparation containing a self-emulsifying liquid composition having a HLB value of 6-10, in which the composition comprises cyclosporin as an active ingredient, polyethylene glycol and propylene glycol as hydrophilic components, a mixture of an esterified compound of fatty acid and monovalent alkanol, middle-chain fatty acid triglyceride and fatty acid monoglyceride, as an oil component, and a surfactant having a hydrophilic lipophilic balance (HLB) value of 10-17.
  • HLB hydrophilic lipophilic balance
  • the present invention provides a method of producing the soft capsule preparation.
  • the present invention provides a soft capsule preparation comprising cyclosporin as an active ingredient, hydrophilic component polyethylene glycol and propylene glycol serving as main solvent components, an oil component, and Cremophor as a hydrophobic surfactant, and also provides a method of producing the same.
  • the present invention is to produce a self-emulsified liquid cyclosporin preparation, which shows a reduced change in composition according to the passage of time and also excellent storage stability, and contains cyclosporin as an active ingredient, polyethylene glycol and propylene glycol as hydrophilic components, an oil component and a surfactant .
  • a specially designed gelatin shell needs to be used.
  • composition is formulated using a gelatin shell containing glycerin as a plasticizer, glycerin present in the shell of the capsule will be introduced into the liquid composition, so that an emulsified state of the composition will be changed to remarkably reduce the solubility of cyclosporin, thereby causing the problem of the precipitation of cyclosporin.
  • the self-emulsifying composition produced in the present invention utilizes a gelatin capsule shell containing no glycerin while ethanol as a volatile solvent is not used in the present invention, so that there is produced a soft capsule preparation which shows high stability and thus little or no aging during its storage period.
  • the present invention relates to a cyclosporin-containing soft capsule preparation, which contains a composition containing cyclosporin as an active ingredient, hydrophilic polyethylene glycol and propylene glycol as main solvent components, a mixture of an esterified compound of fatty acid and monovalent alkanol, fatty acid monoglyceride and medium-chain fatty acid, as an oil ingredient, and a surfactant with a HLB value of 10-17.
  • cyclosporin used as pharmaceutically active ingredient is a cyclic oligo- peptide compound having immunosuppressive and anti- inflammatory activities.
  • examples of cyclosporin that can be used in the present invention include cyclosporin A, B, C, D and G. Among these substances, it is most preferred to use the cyclosporin A whose clinical utility and pharmacological properties were most well established in the prior art .
  • hydrophilic component polyethylene glycol and propylene glycol which show reduced permeability to a gelatin capsule shell and also high solubility in cyclosporin, which is difficultly soluble in water.
  • hydrophilic component polyethylene glycol although there may be used any polyethylene glycol which can be liquefied, it is preferred to use polyethylene glycol with a molecular weight of 200- 600, and most preferably, polyethylene glycol 400 with a molecular weight of 400.
  • the weight ratio between cyclosporin, polyethylene glycol and propylene glycol is advantageously 1:1-10:1-10 in view of the solubility of the active ingredient .
  • the third essential component of the liquid composition according to the present invention is an oil component.
  • the oil component that can be used in the present invention there is an oil mixture of an esterified compound of fatty acid and monovalent alkanol, medium-chain fatty acid triglyceride (if any) and fatty acid monoglyceride.
  • esterified compound of fatty acid and monovalent alkanol include an esterified compound of fatty acid with 8-20 carbon atoms and monovalent alkanol with 2-3 carbon atoms, for example, isopropyl myristate, isopropyl palmitate, ethyl linolate, ethyl oleate, with an esterified compound of linoleic acid and ethanol being particularly preferable.
  • the medium-chain fatty acid triglyceride includes saturated fatty acid triglyceride having 8-10 carbon atoms, and preferably, caprylic/caprylic acid triglyceride as vegetable oil triglyceride of saturated fatty acid.
  • fatty acid monoglyceride that can be used as the oil component of the composition according to the present invention includes fatty acid monoceride having 18-20 carbon atoms, and more preferably, oleic acid monoglyceride.
  • the third essential component includes vegetable oil, such as soybean oil, olive oil, corn oil, coconut oil or a mixture of two or more thereof .
  • the oil component is used at the ratio of 0.1-2 parts by weight, and preferably 0.1-1 part by weight, relative to one part by weight of cyclosporin.
  • the mixing ratio between monovalent alkanol and medium-chain triglyceride is generally 1:0.1-1, and preferably 1:0.1-0.5, on the basis of weight.
  • the weight ratio between cyclosporin, medium-chain fatty acid and monovalent alkanol is preferably 1:0.1-1:0.1-1, in view of the formation of an emulsion.
  • the fourth essential component contained in the composition according to the present invention is a surfactant .
  • a surfactant Among pharmaceutically acceptable surfactants allowing formation of a stable micro-emulsion by emulsifying of the lipophilic component cyclosporin- containing hydrophilic component consisting of the oil component and the co-surfactant, in water, any surfactant having a HLB value of 10-17 may be used in the present invention.
  • Preferred surfactants include a polyoxyethylene product of hydrogenated vegetable oil, namely, polyoxyl hydrogenated castor oil, polyoxyethylene-sorbitan-fatty acid ester and the like, for example, NIKKOL HCO-50, NIKKOL HCO-40, NIKKOL HCO-60, TWEEN 20, T EEN 21, TWEEN 40, T EEN 60, TWEEN 80, and TWEEN 81, etc.
  • the surfactants that is particularly preferable for use in the composition of the present invention include the trademark Cremophor RH40 having an acid value of less than 1, a saponification value of about 50-60, a hydroxyl value of about 60-80, and a pH (5%) of 6.0-7.0, the trademark Cremophor- EL having an acid value of less than 2, a saponification value of about 65-70, a hydroxyl value of about 65-78, and a pH (5%) of 6.0-8.0, polyoxyethylene 20 sorbitan monolaurate commercially available under the trademark Tween 20, and polyoxyethylene 80 sorbitan monooleate commercially available under the trademark Tween 80.
  • these surfactants may be used alone, they are preferably used in the form of a mixture of two or more thereof.
  • the surfactant is present at the weight ratio of 1-10 parts by weight, and preferably 2-8 parts by weight, relative to one part by weight of cyclosporin.
  • the mixing ratio of polyoxyethylene 40 hydrogenated castor oil to polyoxyethylene 20 sorbitan monolaurate is preferably 1:0.1-5, and more preferably 1:0.5-2.
  • cyclosporin, polyoxyl hydrogenated caster oil 40, polyoxyl hydrogenated caster oil EL, polyoxyethylene 20 and polyoxyethylene 80 are present at the weight ratio of 1:1-10:1-10:0.1-1:0.1-1 in the composition of the present invention.
  • the cyclosporin, the solvent component, the oil component, and the surfactant are present at the weight ratio of 1:1- 10:0.1-10:1-10, and preferably at the weight ratio of 1:1- 5:0.1-0.6:2-8.
  • the cyclosporin, polyethylene glycol, propylene glycol, the oil component and the surfactant are present at the weight ratio 1:1-10:1-10:0.1-1:0.1-10, and preferably 1:1-2:1-5:0.1-0.6:0.1-7, in view of the stability of the preparation.
  • compositions according to the present invention which are illustrated in Examples below, can be regarded as preferred additional compositions .
  • the soft capsule preparation according to the present invention contains no ethanol as a volatile solvent of low boiling point, it is pharmaceutically stable and also allows achievement of the desired end, such as the improvement of the bioavailability of cyclosporin. However, it cannot be produced with productivity by a shell formulation and producing method of conventional soft capsule preparations.
  • a capsule shell composition containing a mixture of polyethylene glycol and propylene glycol as a plasticizer was used in preparing the self-emulsified content without using glycerin and sorbitol, so that there could be obtained a more stable soft capsule preparation showing no precipitation.
  • polyethylene glycol serving as a plasticizer there is preferably used polyethylene glycol having a molecular weight of 200-600, and more preferably, polyethylene glycol 300 or 400.
  • the mixture of polyethylene glycol and propylene glycol, which is used as a plasticizer in the shell formulation of the soft capsule preparation according to the present invention is preferably used at the ratio of 0.1-0.6 parts by weight, and more preferably 0.3-0.5 parts by weight, and most preferably, 0.3-0.4 parts by weight, relative to one part by weight of gelatin used in the shell.
  • propylene glycol is preferably present at the ratio of 1-10 parts by weight, and more preferably 2-7 parts by weight, and most preferably 3-6 parts by weight, relative to one part by weight of polyethylene glycol .
  • a main solvent (co-surfactant) , an oil component and a surfactant are first uniformly mixed and then gently warmed to about 60 °C such that they are sufficiently mixed and dissolved. After lowering the temperature to 50 °C, cyclosporin is added to the resulting solution, and the mixture is stirred such that cyclosporin is dissolved.
  • the resulting concentrate is introduced into a soft capsule encapsulation machine intact or after subjecting to a required treatment process.
  • the soft capsule preparations produced according to the present invention were stored at room temperature. During this storage period, whether the precipitation of its content occurs or not was observed. The results are given in Table 2 below. As can be seen in Table 2, the content of the soft capsule preparation produced according to the present invention did not show its precipitation and a poorly emulsified state. On the other hand, when the emulsified state is poor as in Comparative Example, crystals started to be formed after about 3 days, and the content was mostly crystallized after about one month.
  • Table 2 Stability of content of capsule preparations according to shell formulation Note: 0: stable state of content; +: poorly emulsified state of content; formation of fine precipitates; and +++: formation of precipitates
  • Example 1 was encapsulated with a shell formulation given in Table 3. A change in properties of the content of the soft capsule preparation caused by the inflow of glycerin used as a placticizer in the encapsulation was observed. The results are given in Table 4 below.
  • the present invention allows production of the self-emulsifying liquid composition having a HLB value of 6-10 without using ethanol, the self- emulsifying liquid composition comprising cyclosporin as an active ingredient, polyethylene glycol and propylene glycol as hydrophilic components, an esterified compound of fatty acid and monovalent alkanol as an oil component, and a surfactant having a HLB value of 10-17.
  • the cyclosporin- containing gelatin capsule preparation can be obtained by forming the gelatin capsule shell on the liquid composition without using glycerin.
  • the soft capsule preparation of the present invention is a very stable preparation showing no formation of pharmaceutical precipitation therein and advantageous in that it is administered in a simple and easy way.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention se rapporte à une composition liquide auto-émulsifiante contenant une cyclosporine et un tensioactif pour solubilisation et également une préparation d'une capsule souple obtenue à l'aide de la composition et du tensioactif. Dans cette invention, le tensioactif et un composant d'huile sont mélangés ensemble mélange auquel on ajoute ensuite une cyclosporine que l'on dissout pour obtenir un mélange uniforme des composants respectifs. Cremophor ayant une valeur HLB de 10-17, Tween ayant une valeur semblable HLB ou leur mélange, tenant lieu de tensioactif, sont utilisés pour obtenir une préparation de capsule plus stable. Afin d'obtenir un système d'administration d'un mélange auto-émulsifiant, on utilise un mélange d'un composé estérifié d'acide gras et d'alcanol monovalent, de triglycérides à chaîne moyenne et de monoglycéride comme composant d'huile. La composition ainsi obtenue que l'on utilise dans la préparation de capsule souple a une valeur HLB de 6-10. Ainsi, la préparation de capsule souple obtenue à l'aide de la composition auto-émusifiante d'après cette invention est plus stable que les préparations connues à ce jour contenant un éthanol, et elle est en outre plus facilement administrée.
PCT/KR2003/000836 2003-02-19 2003-04-25 Capsule souple contenant une cyclosporine et son procede de fabrication Ceased WO2004073693A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003224468A AU2003224468A1 (en) 2003-02-19 2003-04-25 Soft capsule containing cyclosporine and it's manufacturing process

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2003-0010405 2003-02-19
KR10-2003-0010405A KR100525234B1 (ko) 2003-02-19 2003-02-19 사이클로스포린 함유 연질캅셀제 및 그 제조방법

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017334A3 (fr) * 2006-08-08 2008-03-27 Jordanian Pharmaceutical Mfg §formulation microémulsionnée de médicament
US7635675B2 (en) 2003-08-13 2009-12-22 Biocon Limited Micro-particle fatty acid salt solid dosage formulations for therapeutic agents

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101458466B1 (ko) * 2013-06-24 2014-11-07 한국화학연구원 면역억제제가 봉입된 마이셀을 함유하는 경구제

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589455A (en) * 1994-12-28 1996-12-31 Hanmi Pharm. Ind. Co., Ltd. Cyclosporin-containing soft capsule compositions
KR980000466A (ko) * 1996-06-19 1998-03-30 정지석 사이클로스포린-함유 연질캅셀제
KR0131064B1 (ko) * 1991-06-27 1998-04-17 예안 크레이머, 한스 루돌프 하우스 사이클로스포린 함유 약학 조성물
KR0148748B1 (ko) * 1988-09-16 1998-08-17 장 크라메르, 한스 루돌프 하우스 사이클로스포린을 함유하는 약학조성물
KR100200174B1 (ko) * 1993-09-28 1999-06-15 군터블랑켄혼 연질 젤라틴 캡슐 제조 방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR0148748B1 (ko) * 1988-09-16 1998-08-17 장 크라메르, 한스 루돌프 하우스 사이클로스포린을 함유하는 약학조성물
KR0131064B1 (ko) * 1991-06-27 1998-04-17 예안 크레이머, 한스 루돌프 하우스 사이클로스포린 함유 약학 조성물
KR100200174B1 (ko) * 1993-09-28 1999-06-15 군터블랑켄혼 연질 젤라틴 캡슐 제조 방법
US5589455A (en) * 1994-12-28 1996-12-31 Hanmi Pharm. Ind. Co., Ltd. Cyclosporin-containing soft capsule compositions
KR980000466A (ko) * 1996-06-19 1998-03-30 정지석 사이클로스포린-함유 연질캅셀제

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7635675B2 (en) 2003-08-13 2009-12-22 Biocon Limited Micro-particle fatty acid salt solid dosage formulations for therapeutic agents
WO2008017334A3 (fr) * 2006-08-08 2008-03-27 Jordanian Pharmaceutical Mfg §formulation microémulsionnée de médicament

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Publication number Publication date
AU2003224468A1 (en) 2004-09-09
KR20040074504A (ko) 2004-08-25
KR100525234B1 (ko) 2005-10-28

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