WO2006062334A1 - Oral micro-emulsion composition comprising tacrolimus - Google Patents
Oral micro-emulsion composition comprising tacrolimus Download PDFInfo
- Publication number
- WO2006062334A1 WO2006062334A1 PCT/KR2005/004152 KR2005004152W WO2006062334A1 WO 2006062334 A1 WO2006062334 A1 WO 2006062334A1 KR 2005004152 W KR2005004152 W KR 2005004152W WO 2006062334 A1 WO2006062334 A1 WO 2006062334A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- tacrolimus
- surfactant
- composition
- oil
- Prior art date
Links
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.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Dispersion Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A microemulsion composition comprising tacrolimus as an active ingredient, a co-surfactant, a surfactant, an oil and an organic acid provides improved stability as well as high bioavailability of tacrolimus when orally administered.
Description
ORAL MICRO-EMULSION COMPOSITION COMPRISING
TACROLIMUS
FIELD OF THE INVENTION
The present invention relates to a microemulsion composition for oral administration of tacrolimus, which provides improved bioavailability of the poorly water-soluble drug.
BACKGROUND OF THE INVENTION
Tacrolimus (FK506) 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.
However, the bioavailability of orally administered tacrolimus is unsatisfactorily low due to its low solubility in water (about 3.6 μg/ml at 250C water), and accordingly, there have been numerous attempts to improve its solubility.
For example, Korean Patent Publication No. 1995-7210 discloses a method for preparing a tacrolimus solid dispersion using a water-soluble polymer such as hydroxypropyl methylcellulose. However, the manufacturing process of the dispersion is very complicated. US Patent No. 5,260,301 discloses a solution preparation of tacrolimus comprising ethanol as a solvent. However, this preparation has the problems of tacrolimus precipitation and ethanol loss due to volatilization.
Accordingly, the present inventors have endeavored to develop 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.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a microemulsion composition for oral administration of tacrolimus having improved bioavailability.
In accordance with one aspect of the present invention, there is provided a microemulsion composition for oral administration of tacrolimus comprising tacrolimus, a co- surfactant, a surfactant, an oil and an organic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawings, which respectively show:
Fig. 1 : the particle-size distribution of the inventive tacrolimus preparation of Example 1 in distilled water; and
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.
DETAILED DESCRIPTION OF THE INVENTION
The 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.
The respective components employed for the preparation of the inventive microemulsion composition are described in detail as follows.
1. Active ingredient
In the present invention, tacrolimus is used as an active ingredient.
2. Co-surfactant
In the present invention, 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 LD50 for acute oral toxicity of transcutol is 7.95 ml (specific gravity,
0.989)/kg (Gattefosse product profile), and that of polyethyleneglycol is 28.9 g/kg (Handbook of pharmaceutical excipients, p570~571, 3rd Ed., American pharmaceutical association, Washington D.C.). Also, 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.
3. Surfactant The 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:
(1) 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),
(2) polyoxyethylene-sorbitan-fatty acid esters, the fatty acid being mono- or tri-lauric, palmitic, stearic or oleic acid (Tween®, ICI),
(3) polyoxyethylene fatty acid esters such as polyoxyethylene stearic acid ester (Myrj®, ICI), (4) polyoxyethylene-polyoxypropylene block copolymer (Poloxamer ,
Pluronic® and Lutrol®, BASF),
(5) mono-, di- or mono/di-glycerides such as caprylic/capric acid mono- and di-glycerides (Imwitor®, Hϋls),
(6) sorbitan fatty acid esters such as sorbitan monolauryl, sorbitan monopalmityl and sorbitan monostearyl esters (Span®, ICI), and
(7) 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.
4. Oil
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,
(3) esters of fatty acids and monovalent alkanols, preferably esters Of C8-2O fatty acids and C2-3 monovalent alkanols, such as isopropyl myristate, isopropyl palmitate, ethyl linoleate and ethyl oleate,
(4) 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
(6) tocopherols such as tocopherol, tocopherol acetate, tocopherol succinate and polyethyleneglycol-lOOO-tocopherol succinate (TPGS).
The above-mentioned 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.
5. Organic acid
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, sulfonic acid, sulfinic acid, formic acid, propionic acid, tannic acid, pantothenic acid, aspartic acid, aminoacetic acid and DL-α-aminopropionic acid.
The above-mentioned organic acids can be used separately or as a mixture, and erythorbic acid and citric acid are preferred.
In the preparation of the inventive microemulsion composition, 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. The resulting mixture forms emulsified microparticles having an average diameter of below 1 μm on contacting an aqueous medium. The microemulsion composition of the present invention may be formulated into a soft or hard capsule, in accordance with any of the conventional procedures.
The following Examples are intended to further illustrate the present invention without limiting its scope.
Example 1
A soft capsule was prepared using the following ingredients:
Ouantitv(mg/capsule)
Tacrolimus 1.02
Transcutol 20
Cremophor® RH40 (BASF) 27
Glyceryl monooleate 7
Labrafil® M1944CS (Gattefosse) 6
Ethyl linoleate 10
Erythorbic acid 1
Citric acid 1
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.
Comparative Example 1
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitvimg/capsule)
Tacrolimus 1.02
Transcutol 20
Cremophor® RH40 (BASF) 27
Glyceryl monooleate 7
Labrafil® Ml 944CS (Gattefosse) 6
Ethyl linoleate 10
Comparative Example 2
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitvung/capsule)
Tacrolimus 1.02
Transcutol 70
Cremophor® RH40 (BASF) 94.5
Glyceryl monooleate 24.5
Labrafil® Ml 944CS (Gattefosse) 21
Ethyl linoleate 35
BHT 1
Example 2
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitvfmg/capsule)
Tacrolimus 1.02
Transcutol 20
Labrasol® (Gattefosse) 13
Cremophor® RH40 (BASF) 27
D-α-tocopherol 10
Erythorbic acid 2
Example 3
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantityfmg/capsule)
Tacrolimus 1.02
Transcutol 20
Labrasol® (Gattefosse) 20
Cremophor® RH40 (BASF) 13
Glyceryl monooleate 7
Ethyl linoleate 10
Erythorbic acid 2
Example 4
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitvfmg/capsule)
Tacrolimus 1.02
Transcutol 20
Labrasol® (Gattefosse) 27 Cremophor® RH40 (BASF) 13
Miglyol® 812N (Abitec) 10
Erythorbic acid 2
Example 5
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantityfmg/capsule)
Tacrolimus 1.02
Transcutol 20
Cremophor® RH40 (BASF) 27
Labrafil® Ml 944CS (Gattefosse) 13
Ethyl linoleate 10
Erythorbic acid 2
Example 6
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitvfmg/capsule)
Tacrolimus 1.02
Transcutol 70
Cremophor® RH40 (BASF) 94.5
Glyceryl monooleate 24.5
Labrafil® M1944CS (Gattefosse) 21
Ethyl linoleate 35
Erythorbic acid 1
Example 7
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitvimg/capsule)
Tacrolimus 1.02
Transcutol 70
Cremophor® RH40 (BASF) 94.5
Glyceryl monooleate 24.5
Labrafil® M1944CS (Gattefosse) 21
Ethyl linoleate 35
Erythorbic acid 1
Citric acid 2
Example 8
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitvung/capsule)
Tacrolimus 1.02
Transcutol 70
Cremophor® RH40 (BASF) 94.5
Glyceryl monooleate 24.5
Labrafil® Ml 944CS (Gattefosse) 21
Ethyl linoleate 35
Citric acid 3
Example 9
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitv(mg/capsule)
Tacrolimus 1.02
Transcutol 70
Cremophor® RH40 (BASF) 94.5
Glyceryl monooleate 24.5
Labrafil® Ml 944CS (Gattefosse) 21
Ethyl linoleate 35
Erythorbic acid 0.5
Citric acid 5
Example 10
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantityfmg/capsule)
Tacrolimus 1.02
Transcutol 20
Tween® 20 (ICI) 40 Glyceryl monooleate 7
Labrafil® Ml 944CS (Gattefosse) 6
Miglyol® 812N (Abitec) 10
Citric acid 5
Example 11
A soft capsule was prepared by the procedure of Example 1 using the
following ingredients:
Ouantitvfmg/capsule)
Tacrolimus 1.02
Transcutol 20
Polyethylene glycol 400 50
Cremophor® RH40 (BASF) 27
Glyceryl monooleate 7
Labrafil® M1944CS (Gattefosse) 6
Ethyl linoleate 10
Citric acid 5
Example 12
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
OuantitvCmg/capsule)
Tacrolimus 1.02
Transcutol 20
Polyethylene glycol 200 50
Cremophor® RH40 (BASF) 27
Glyceryl monooleate 7
Labrafil® Ml 944CS (Gattefosse) 6
Ethyl linoleate 10
Erythorbic acid 1
Citric acid 1
Example 13
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitvύng/capsule)
Tacrolimus 1.02
Polyethylene glycol 200 200
Cremophor® RH40 (BASF) 270
Glyceryl monooleate 40
Labrafil® Ml 944CS (Gattefosse) 30
Ethyl linoleate 50
Erythorbic acid 1
Citric acid 1
Example 14
A soft capsule was prepared by the procedure of Example 1 using the following ingredients :
Ouantitvfmg/capsule)
Tacrolimus 1.02
Transcutol 50
Polyethylene glycol 400 50
Cremophor® RH40 (BASF) 135
Labrafil® M1944CS (Gattefosse) 65
D-α-tocopherol 50
Erythorbic acid 1
Citric acid 1
Example 15
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Quantityfmg/capsule)
Tacrolimus 1.02
Polyethylene glycol 400 200
Tween® 20 (ICI) 200
Glyceryl monooleate 70 Miglyol® 812N (Abitec) 50
Erythorbic acid 1
Citric acid 1
Example 16
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantitvung/capsule)
Tacrolimus 1.02
Transcutol 50
Polyethylene glycol 400 50
Cremophor® RH40 (BASF) 135
Labrafil® Ml 944CS (Gattefosse) 65
Ethyl linoleate 35
Erythorbic acid 0.5
Citric acid 5
Example 17
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantity(mg/capsule) Tacrolimus 1.02
Transcutol 70
Tween® 20 (ICI) 150
Labrafil® M1944CS (Gattefosse) 21
Ethyl linoleate 35
D-α-tocopherol 20
Erythorbic acid 0.5 Citric acid 1
Example 18
A soft capsule was prepared by the procedure of Example 1 using the following ingredients :
Ouantitvfmg/capsule)
Tacrolimus 1.02
Transcutol 70
Labrasol® (Gattefosse) 100
Tween® 20 (ICI) 50
Labrafil® Ml 944CS (Gattefosse) 20
Miglyol® 812N (Abitec) 30
D-α-tocopherol 20
Citric acid 2
Example 19
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
Ouantityfmg/capsule)
Tacrolimus 1.02
Transcutol 20
Polyethylene glycol 400 70
Cremophor® RH40 (BASF) 50
Tween® 20 (ICI) 50
Glyceryl monooleate 30
Ethyl linoleate 40
Erythorbic acid 2
Example 20
A soft capsule was prepared by the procedure of Example 1 using the following ingredients:
OuantitvCmg/capsule)
Tacrolimus 1.02
Triacetin 50
Cremophor® RH40 (BASF) 75
Miglyol® 812N (Abitec) 25
Citric acid 2
Test Example 1: Analysis of the emulsified drug microparticles
In order to examine whether the inventive preparation would spontaneously emulsify to form microparticles upon contact with an aqueous solution, particle size distribution analysis was carried out, as follows.
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.
As shown in Fig. 1, the inventive microemulsion composition forms emulsified microparticles having an average particle size of below 1 μm upon contact with an aqueous solution, to form a microemulsion.
Test Example 2: Precipitation Formation Test
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 result of the precipitation test is shown in Table 1 (precipitation: +, no precipitation: -).
<Table 1>
As shown in Table 1, the inventive microemulsion preparation does not form precipitates upon contact with an aqueous solution.
Test Example 3: Stability Test
1 mg each of the preparations prepared in Example 1, and Comparative Examples 1 and 2; and 1 mg of the commercially available hard capsule, Prograf® (Fujisawa Ireland) as a comparative preparation were kept at 600C, and the time- dependent change of the tacrolimus content ((measured content / initial content) x 100) of each capsule was analyzed by HPLC under the following conditions. The results are shown in Table 2: - Column: Inertsil ODS2 (250 mm x 4.6 mm)
- Mobile phase: a mixture of acetonitrile, distilled water and phosphoric acid (60:40:1)
- Injection volume: 10 μl
- Oven temperature: 500C - Detector: UV 210 nm
<Table 2>
As shown in Table 2, 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.
Test Example 4: Absorption Test
In order to investigate the bioavailability of the drug contained in the inventive preparation, an in vivo absorption test was carried out as follows employing the preparation of Example 1 (Experimental preparation) and the commercially available preparation (Prograf®; Fujisawa Ireland) as a comparative preparation.
Six 14 to 15-week old male Sprague-Dawley rats (weight: 250 g) were acclimated for more than 4 days while allowing free access to the feed and water. The rats were then put on a 48-hour fast, while they were allowed free access to water.
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.
400 μl of a mixture of methanol and 0.2 M zinc sulfate (MeOH : 0.2 M
ZnSO4 = 2 : 8) was added to 200 μl of each blood sample, and the mixture was shaken. Each mixture was centrifuged at 3,000 rpm for 10 minutes to obtain a supernatant, which was then filtered through a 0.22 μm filter and the filtrate was analyzed by LC-MS, under the following condition:
- Column: Waters MS C 18 (2.1 x 150 mm with guard column)
- Mobile phase: 65% methanol, 95% methanol
- Injection volume: 30 μl
- Flow rate: 0.3 ml /min.
- Detector: SIR mode m/z : 826.7 (Na adduct)
The results are shown in Table 3 and Fig. 2.
<Table 3>
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.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes
may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.
Claims
1. A microemulsion composition for oral administration of tacrolimus comprising tacrolimus, a co-surfactant, a surfactant, an oil and an organic acid.
2. The composition of claim 1, wherein the tacrolimus : co-surfactant : surfactant : oil : organic acid weight ratio is in the range of 1 : 5-200 : 5-400 : 1-100 : 0.01-50.
3. The composition of claim 1, wherein the co-surfactant is selected from the group consisting of transcutol, polyethyleneglycol, triacetin and a mixture thereof.
4. The composition of claim 1 , wherein the surfactant is selected from the group consisting of polyoxyethylene glycolated hydrogenated vegetable oils; polyoxyethylene-sorbitan-fatty acid esters; trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols; and a mixture thereof.
5. The composition of claim 1, wherein the oil is selected from the group consisting of esters of fatty acids and monovalent alkanols; fatty acid tri-, mono-, di- or mono/di-glycerides; tocopherols; and a mixture thereof.
6. The composition of claim 1, wherein the organic acid is selected from the group consisting of 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, sulfonic acid, sulfinic acid, formic acid, propionic acid, tannic acid, pantothenic acid, aspartic acid, aminoacetic acid, DL-α-aminopropionic acid and a mixture thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2004-0101673 | 2004-12-06 | ||
| KR1020040101673A KR100678829B1 (en) | 2004-12-06 | 2004-12-06 | Oral micro-emulsion composition comprising tacrolimus |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006062334A1 true WO2006062334A1 (en) | 2006-06-15 |
Family
ID=36578122
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2005/004152 WO2006062334A1 (en) | 2004-12-06 | 2005-12-06 | Oral micro-emulsion composition comprising tacrolimus |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR100678829B1 (en) |
| WO (1) | WO2006062334A1 (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008122425A2 (en) * | 2007-04-06 | 2008-10-16 | Monteresearch S.R.L. | Oral compositions containing tacrolimus in amorphous form |
| WO2009098649A1 (en) | 2008-02-05 | 2009-08-13 | Igloo Zone Chile S.A. | Immunosuppressive macrolide powder for oral suspension |
| JP2010132607A (en) * | 2008-12-05 | 2010-06-17 | Taisho Pharm Ind Ltd | Ointment for use in cure for atopic dermatitis |
| JP2010202546A (en) * | 2009-03-02 | 2010-09-16 | Taisho Pharm Ind Ltd | Ointment preparation for treating atopic dermatitis |
| EP2308468A1 (en) * | 2009-10-08 | 2011-04-13 | Novaliq GmbH | Novel pharmaceutical composition comprising a macrolide immunosuppressant drug |
| EP2345414A1 (en) * | 2008-10-08 | 2011-07-20 | Takata Seiyaku Co., Ltd. | Tacrolimus preparation for external applications |
| US20140038998A9 (en) * | 2008-05-30 | 2014-02-06 | Lifecycle Pharma A/S | Stabilized tacrolimus composition |
| JP2014098039A (en) * | 2007-11-21 | 2014-05-29 | Innopharmax Inc | Pharmaceutical composition with enhanced bioavailability |
| WO2017031105A1 (en) * | 2015-08-19 | 2017-02-23 | Selten Pharma, Inc. | Pharmaceutical formulations |
| US11065195B2 (en) | 2007-03-15 | 2021-07-20 | MC2 Therapeutics Limited | Topical composition |
| US11458125B2 (en) | 2016-04-04 | 2022-10-04 | MC2 Therapeutics Limited | Topical composition comprising tacrolimus |
| US11696919B2 (en) | 2018-03-19 | 2023-07-11 | MC2 Therapeutics Limited | Topical composition |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101701577B1 (en) | 2014-12-30 | 2017-02-03 | 중앙대학교 산학협력단 | Hydrophilic external gel formulations for enhanced topical delivery of tacrolimus |
| KR20160117070A (en) * | 2015-03-31 | 2016-10-10 | 한미약품 주식회사 | An oral solid formulation containing oseltamivir and a process for the preparation thereof |
| KR101953294B1 (en) * | 2018-04-12 | 2019-03-04 | 한미약품 주식회사 | An oral solid formulation containing oseltamivir and a process for the preparation thereof |
| CN115813857B (en) * | 2022-10-12 | 2024-01-09 | 浙江大学 | Tacrolimus self-microemulsion drug delivery system and preparation and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000053212A1 (en) * | 1999-03-09 | 2000-09-14 | Hangzhou Zhongmeihuadong Pharmaceutical Co. Ltd. | Pharmaceutical composition containing cyclosporin |
| WO2004012771A1 (en) * | 2002-08-02 | 2004-02-12 | Smyth, Gyles, Darren | Pharmaceutical compositions comprising cyclosporin for oral administration |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100342942B1 (en) * | 1999-07-05 | 2002-07-02 | 민경윤 | Oral micro-emulsion composition comprising Carduus marianus extract or silybin isolated therefrom |
| KR20020013174A (en) * | 2000-08-11 | 2002-02-20 | 민경윤 | Oral composition for enhancing absorbability of a drug of which absorption rate in oral administration is low |
| US6656460B2 (en) | 2001-11-01 | 2003-12-02 | Yissum Research Development | Method and composition for dry eye treatment |
| KR20040047056A (en) * | 2002-11-29 | 2004-06-05 | 한미약품 주식회사 | Oral micro-emulsion composition comprising biphenyldimethyldicarboxylate |
-
2004
- 2004-12-06 KR KR1020040101673A patent/KR100678829B1/en active IP Right Grant
-
2005
- 2005-12-06 WO PCT/KR2005/004152 patent/WO2006062334A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000053212A1 (en) * | 1999-03-09 | 2000-09-14 | Hangzhou Zhongmeihuadong Pharmaceutical Co. Ltd. | Pharmaceutical composition containing cyclosporin |
| WO2004012771A1 (en) * | 2002-08-02 | 2004-02-12 | Smyth, Gyles, Darren | Pharmaceutical compositions comprising cyclosporin for oral administration |
Non-Patent Citations (2)
| Title |
|---|
| UNO ET AL: "Pharmacokinetic advantages of a newly developed tacrolimus oil-in-water-type emulsion via the enteral route.", LIPIDS., vol. 34, no. 3, 1999, pages 249 - 254 * |
| UNO ET AL: "Pharmacokinetics of water-in-oil-in-water-type multiple emulsion of a new tacrolimus formulation.", LIPIDS., vol. 32, no. 5, 1997, pages 543 - 548 * |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11065195B2 (en) | 2007-03-15 | 2021-07-20 | MC2 Therapeutics Limited | Topical composition |
| WO2008122425A3 (en) * | 2007-04-06 | 2009-01-08 | Monteres S R L | Oral compositions containing tacrolimus in amorphous form |
| WO2008122425A2 (en) * | 2007-04-06 | 2008-10-16 | Monteresearch S.R.L. | Oral compositions containing tacrolimus in amorphous form |
| JP2014098039A (en) * | 2007-11-21 | 2014-05-29 | Innopharmax Inc | Pharmaceutical composition with enhanced bioavailability |
| JP2016106152A (en) * | 2007-11-21 | 2016-06-16 | イノファーマックス インコーポレイテッド | Pharmaceutical composition with enhanced bioavailability |
| WO2009098649A1 (en) | 2008-02-05 | 2009-08-13 | Igloo Zone Chile S.A. | Immunosuppressive macrolide powder for oral suspension |
| US10166190B2 (en) | 2008-05-30 | 2019-01-01 | Veloxis Pharmaceuticals A/S | Stabilized tacrolimus composition |
| US20140038998A9 (en) * | 2008-05-30 | 2014-02-06 | Lifecycle Pharma A/S | Stabilized tacrolimus composition |
| US11419823B2 (en) | 2008-05-30 | 2022-08-23 | Veloxis Pharmaceuticals, Inc. | Stabilized tacrolimus composition |
| US9549918B2 (en) * | 2008-05-30 | 2017-01-24 | Veloxis Pharmaceuticals A/S | Stabilized tacrolimus composition |
| EP2345414A4 (en) * | 2008-10-08 | 2012-02-22 | Takata Seiyaku Co Ltd | Tacrolimus preparation for external applications |
| JP5135441B2 (en) * | 2008-10-08 | 2013-02-06 | 高田製薬株式会社 | Tacrolimus external preparation |
| JP2012149097A (en) * | 2008-10-08 | 2012-08-09 | Takada Seiyaku Kk | Tacrolimus preparation for external application |
| EP2345414A1 (en) * | 2008-10-08 | 2011-07-20 | Takata Seiyaku Co., Ltd. | Tacrolimus preparation for external applications |
| US8575189B2 (en) | 2008-10-08 | 2013-11-05 | Takata Seiyaku Co., Ltd. | Tacrolimus preparation for external applications |
| JP2010132607A (en) * | 2008-12-05 | 2010-06-17 | Taisho Pharm Ind Ltd | Ointment for use in cure for atopic dermatitis |
| JP2010202546A (en) * | 2009-03-02 | 2010-09-16 | Taisho Pharm Ind Ltd | Ointment preparation for treating atopic dermatitis |
| WO2011042485A1 (en) | 2009-10-08 | 2011-04-14 | Novaliq Gmbh | Novel pharmaceutical composition comprising a macrolide immunosuppressant drug |
| AU2010305404B2 (en) * | 2009-10-08 | 2015-04-02 | Bay Pharma Gmbh | Novel pharmaceutical composition comprising a macrolide immunosuppressant drug |
| US8574562B2 (en) | 2009-10-08 | 2013-11-05 | Novaliq Gmbh | Microemulsion pharmaceutical composition comprising a macrolide immunosuppressant drug |
| KR101790257B1 (en) * | 2009-10-08 | 2017-10-26 | 노바리크 게엠베하 | Novel pharmaceutical composition comprising a macrolide immunosuppressant drug |
| JP2013507337A (en) * | 2009-10-08 | 2013-03-04 | ノバリック ゲーエムベーハー | Novel pharmaceutical composition comprising a macrolide immunosuppressant |
| CN102510752A (en) * | 2009-10-08 | 2012-06-20 | 诺瓦利克有限责任公司 | Novel pharmaceutical composition comprising a macrolide immunosuppressant drug |
| EP2308468A1 (en) * | 2009-10-08 | 2011-04-13 | Novaliq GmbH | Novel pharmaceutical composition comprising a macrolide immunosuppressant drug |
| WO2017031105A1 (en) * | 2015-08-19 | 2017-02-23 | Selten Pharma, Inc. | Pharmaceutical formulations |
| US11458125B2 (en) | 2016-04-04 | 2022-10-04 | MC2 Therapeutics Limited | Topical composition comprising tacrolimus |
| US11696919B2 (en) | 2018-03-19 | 2023-07-11 | MC2 Therapeutics Limited | Topical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20060062734A (en) | 2006-06-12 |
| KR100678829B1 (en) | 2007-02-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1059913B1 (en) | Emulsion preconcentrates containing cyclosporin or a macrolide | |
| JPH10509699A (en) | Pharmaceutical composition | |
| US20110152201A1 (en) | Emulsion preconcentrates containing cyclosporin or a macrolide | |
| JPH11315022A (en) | Galenus preparation | |
| WO2006062334A1 (en) | Oral micro-emulsion composition comprising tacrolimus | |
| US20020049158A1 (en) | Oral drug composition containing a verapamil derivative as a drug-absorption promotor | |
| AU719251B2 (en) | Cyclosporin-containing soft capsule preparations | |
| CN112168781B (en) | Tacrolimus self-microemulsion composition and preparation method thereof | |
| US20060233842A1 (en) | Microemulsion composition for oral administration of biphenyldimethyldicarboxylate | |
| RU2292887C2 (en) | Pharmaceutical composition, using carboxylic acid for stabilizing macrolide in this composition and method for stabilizing macrolide | |
| WO2000009085A2 (en) | Oral formulation containing cyclosporin | |
| KR101848124B1 (en) | Pharmaceutical compositions of tacrolimus for improved oral absorption | |
| AU741923B2 (en) | Pharmaceutical compositions | |
| RU2181054C2 (en) | Microemulsion preconcentrate | |
| GB2380674A (en) | Emulsion preconcentrates containing a cyclosporin or a macrolide | |
| WO2004073693A1 (en) | Soft capsule containing cyclosporine and it's manufacturing process | |
| AU753018B2 (en) | Cyclosporin-containing soft capsule preparations | |
| AU1944200A (en) | Cyclosporin-containing soft capsule preparations | |
| MXPA99008438A (en) | Pharmaceutical compositions | |
| MXPA00008735A (en) | Emulsion preconcentrates containing cyclosporin or a macrolide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| DPE1 | Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101) | ||
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 05819119 Country of ref document: EP Kind code of ref document: A1 |