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
  • A61K9/113—Multiple emulsions, e.g. oil-in-water-in-oil
• • 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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

• the present invention relates to a microemulsion composition for oral administration of tacrolimus, which provides improved bioavailability of the poorly water-soluble drug.
• Tacrolimus found in a fermentation broth of Streptomyces tsukubaensis is one of the macrolide antibiotics having immuno-suppressive activity, and it has been known to inhibit T cell activation by binding with FKBP 12 (FK506 binding protein 12) to form FK506-FKBP complex, to block the serine/threonine phosphatase activity. Accordingly, tacrolimus has been used for alleviating chronic or acute tissue rejection that follows kidney or liver transplantation, and the effect of tacrolimus was reported to be higher than that of cyclosporin A when employed in first-line therapy for preventing acute tissue rejection or for reducing the use of corticosteroid.
• Korean Patent Publication No. 1995-7210 discloses a method for preparing a tacrolimus solid dispersion using a water-soluble polymer such as hydroxypropyl methylcellulose.
• a water-soluble polymer such as hydroxypropyl methylcellulose.
• US Patent No. 5,260,301 discloses a solution preparation of tacrolimus comprising ethanol as a solvent.
• this preparation has the problems of tacrolimus precipitation and ethanol loss due to volatilization.
• a microemulsion composition for oral administration of tacrolimus that is free from the above problems, and have found that a microemulsion composition for oral administration of tacrolimus comprising tacrolimus, a co-surfactant, a surfactant, an oil and an organic acid exhibits improved thermodynamic stability as well as high bioavailability of tacrolimus.
• a microemulsion composition for oral administration of tacrolimus comprising tacrolimus, a co- surfactant, a surfactant, an oil and an organic acid.
• Fig. 1 the particle-size distribution of the inventive tacrolimus preparation of Example 1 in distilled water
• Fig. 2 the dissolution rates (time-dependent drug concentrations in blood) of the inventive tacrolimus preparation of Example 1 and a commercially available tacrolimus preparation (Prograf ® , Fujisawa Ireland), respectively, when orally administered.
• composition of the present invention is a microemulsion in which tacrolimus is completely dissolved. It is stable without forming any precipitate for a long period of time, and is spontaneously and easily emulsified in biological fluids to exhibit a high tacrolimus dissolution rate, and therefore it can be advantageously used for in vivo absorption of tacrolimus through oral administration.
• tacrolimus is used as an active ingredient.
• the co-surfactant serves to dissolve tacrolimus and to aid the emulsification of the preparation.
• Representative examples thereof include a non-toxic transcutol (diethyleneglycol monoethylether), polyethyleneglycol (preferably having a molecular weight of 200 to 600), triacetin or a mixture thereof.
• the LD 50 for acute oral toxicity of transcutol is 7.95 ml (specific gravity,
• the inventive composition comprising polyethyleneglycol can be formulated into a stable soft capsule because it does not degrade a gelatin film unlike other hydrophilic co- surfactants such as propylene glycol, ethanol or propylene glycol monoacetate.
• Triacetin may be used as a coating polymer for capsules, tablets or granules.
• surfactant used in the present invention may be any one of the known pharmaceutically acceptable surfactants, which can be used for forming a stable emulsion of oils and hydrophilic ingredients such as the co-surfactant in water.
• Representative examples of the surfactant include:
• reaction products of a natural or hydrogenated vegetable oil with polyethylene glycol i.e., polyoxyethylene glycolated natural or hydrogenated vegetable oils such as polyoxyethylene glycolated natural or hydrogenated castor oil (Cremophor ® , BASF; and HCO ® , Nikkol),
• polyoxyethylene-sorbitan-fatty acid esters the fatty acid being mono- or tri-lauric, palmitic, stearic or oleic acid (Tween ® , ICI),
• polyoxyethylene fatty acid esters such as polyoxyethylene stearic acid ester (Myrj ® , ICI), (4) polyoxyethylene-polyoxypropylene block copolymer (Poloxamer ,
• mono-, di- or mono/di-glycerides such as caprylic/capric acid mono- and di-glycerides (Imwitor ® , H ⁇ ls),
• sorbitan fatty acid esters such as sorbitan monolauryl, sorbitan monopalmityl and sorbitan monostearyl esters (Span ® , ICI), and
• trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols (Labrafil ® and Labrasol ® , Gattefosse) etc.
• the above-mentioned surfactants can be used separately or as a mixture, and polypolyoxyethylene glycolated hydrogenated vegetable oils such as Cremophor ® ; polyoxyethylene-sorbitan-fatty acid esters such as Tween ® ; and trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols such as Labrafil ® are preferred.
• polypolyoxyethylene glycolated hydrogenated vegetable oils such as Cremophor ®
• polyoxyethylene-sorbitan-fatty acid esters such as Tween ®
• trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols such as Labrafil ® are preferred.
• the oil may be any one of the known pharmaceutically acceptable oils which are compatible with the surfactant used and it becomes emulsified together with other ingredients in water to form a stable microemulsion.
• Representative examples of the oil include: (1) fatty acid triglycerides, preferably medium chain fatty acid triglycerides, such as fractionated coconut oil (Miglyol ® , HuIs; and Captex ® , Abitec), (2) mono-, di- or mono/di-glycerides, preferably mono- or di-glycerides of oleic acid,
• esters of fatty acids and monovalent alkanols preferably esters Of C 8-2O fatty acids and C 2-3 monovalent alkanols, such as isopropyl myristate, isopropyl palmitate, ethyl linoleate and ethyl oleate,
• propyleneglycol mono- or di-fatty acid esters such as propyleneglycol dicaprylate, propyleneglycol monocaprylate, propyleneglycol dilaurate, propyleneglycol isostearate, propyleneglycol monolaurate and propyleneglycol ricinolate, (5) carbohydrates such as squalene and squalane, and
• tocopherols such as tocopherol, tocopherol acetate, tocopherol succinate and polyethyleneglycol-lOOO-tocopherol succinate (TPGS).
• oils can be used separately or as a mixture, and esters of fatty acids and monovalent alkanols such as ethyl linoleate; fatty acid triglycerides such as Miglyol ® and Captex ® ; mono-, di- or mono/di-glycerides; and tocopherols are preferred.
• the organic acid may be any one of the known pharmaceutically acceptable organic acids, which is used to stabilize tacrolimus.
• Representative examples of the organic acid include erythorbic acid, citric acid, tartaric acid, ascorbic acid, lactic acid, malic acid, succinic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, dimethyl triaminepenta-acetic acid, pyruvic acid, malonic acid, myristic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p- aminobenzoic acid, benzenesulfonic acid, benzoic acid, edetic acid, sorbic acid, adipic acid, gluconic acid, aminocaproic acid, glycyrrhizinic acid, isostearic acid, dodecylbenzenesulfonic acid, fumaric acid, maleic acid, oxalic acid, butyric acid, palmitic acid,
• the above-mentioned organic acids can be used separately or as a mixture, and erythorbic acid and citric acid are preferred.
• the active ingredient (tacrolimus), the co-surfactant, the surfactant, the oil and the organic acid are used in amounts corresponding to a weight ratio in the range of 1 : 5-200 : 5-400 : 1-100 : 0.01-50, preferably, 1 : 10-150 : 10-300 : 2-80 : 0.1-20.
• the inventive microemulsion composition for oral administration may be prepared by uniformly dissolving tacrolimus in the co-surfactant, and adding the surfactant, oil and organic acid thereto.
• microemulsion composition of the present invention may be formulated into a soft or hard capsule, in accordance with any of the conventional procedures.
• a soft capsule was prepared using the following ingredients:
• Tacrolimus was uniformly dissolved in transcutol, and other ingredients were successively added and dissolved therein to obtain a microemulsion pre- concentrate. Then, the resulting pre-concentrate was filled into a soft capsule in accordance with the conventional method described in the General Preparation Rule of the Korean Pharmacopoeia.
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• Cremophor ® RH40 (BASF) 94.5
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• Cremophor ® RH40 (BASF) 13
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients: Ouantitvfmg/capsule)
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• Cremophor ® RH40 (BASF) 94.5
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• Cremophor ® RH40 (BASF) 94.5
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• Cremophor ® RH40 (BASF) 94.5
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• Cremophor ® RH40 (BASF) 94.5
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients: Ouantitv ⁇ ng/capsule)
• Cremophor ® RH40 (BASF) 270
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients :
• Cremophor ® RH40 (BASF) 135
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• Cremophor ® RH40 (BASF) 135
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients :
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• a soft capsule was prepared by the procedure of Example 1 using the following ingredients:
• Test Example 1 Analysis of the emulsified drug microparticles
• particle size distribution analysis was carried out, as follows.
• Example 1 0.1 g of the preparation of Example 1 was diluted with 10 ml of distilled water, and then, the particle size distribution of the emulsified preparation was determined with a particle analyzer (Shimadzu, SALD-2002 model, Japan). The result is shown in Fig. 1.
• the inventive microemulsion composition forms emulsified microparticles having an average particle size of below 1 ⁇ m upon contact with an aqueous solution, to form a microemulsion.
• Example 1 In order to examine whether the inventive preparation forms precipitations upon contact with an aqueous solution, 0.1 g of the preparation of Example 1 was diluted to 10 ml of distilled water, artificial gastric juice or artificial intestinal juice, and then, the formation of precipitate was observed.
• the inventive microemulsion preparation does not form precipitates upon contact with an aqueous solution.
• the microemulsion composition of Example 1 has an improved stability as compared to the composition of Comparative Examples 1 and 2 which do not contain an organic acid, under the accelerate test condition. Further, the microemulsion composition of Example 1 was more stable than the comparative preparation, Prograf ® which is a solid preparation (a hard capsule), owing to the use of an organic acid as a stabilizer.
• Example 1 Experimental preparation
• Prograf ® Fujisawa Ireland
• the rats were divided into two groups each consisting of three rats, and were orally administered with the experimental and comparative preparations, respectively, in an amount corresponding to 10 mg/kg weight of tacrolimus.
• Blood samples were taken from the rats before the administration, and 0.5, 1, 1.5, 2, 3, 4, 5, 7 and 24 hours after the administration.
• Example 1 As shown in Table 3 and Fig. 2, the bioavailability of the inventive preparation of Example 1 was improved over that of Prograf ® by a factor of more than 2 times.

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• 2004
  • 2004-12-06 KR KR1020040101673A patent/KR100678829B1/ko active IP Right Grant
• 2005
  • 2005-12-06 WO PCT/KR2005/004152 patent/WO2006062334A1/en active Application Filing

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