WO2005032516A1 - Formulation et procede de fabrication de capsules d'aceclofenac auto-microemulsionne - Google Patents

Formulation et procede de fabrication de capsules d'aceclofenac auto-microemulsionne Download PDF

Info

Publication number
WO2005032516A1
WO2005032516A1 PCT/KR2004/001791 KR2004001791W WO2005032516A1 WO 2005032516 A1 WO2005032516 A1 WO 2005032516A1 KR 2004001791 W KR2004001791 W KR 2004001791W WO 2005032516 A1 WO2005032516 A1 WO 2005032516A1
Authority
WO
WIPO (PCT)
Prior art keywords
aceclofenac
weight
parts
composition
polyethylene glycol
Prior art date
Application number
PCT/KR2004/001791
Other languages
English (en)
Inventor
Young-Sig Gil
Chang-Hun Yu
Ki-Hoon Choung
Geon-Seok Ahn
Seok-Cheon Hong
Ki-Young Ahn
Geun-Woo Yang
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
Publication of WO2005032516A1 publication Critical patent/WO2005032516A1/fr

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
    • A61K9/127—Liposomes
    • 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
    • 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
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • Aceclofenac (2- [(2, 6- dichlorophenyl) amino] phenylacetoxyacetic acid), which is a known compound represented by the following formula, is a phenylacetic acid-based anti-inflammatory analgesic drug showing an excellent efficacy against chronic joint diseases, including rheumatoid arthritis, osteoarthrosis and ankylosing spendylitis, as well as detnalgia, post- operation pain or post-delivery pain.
  • This drug shows an excellent therapeutic effect in that it is easily penetrated into inflammatory tissues occurring in a joint and the like and thus exhibits the excellent action of inhibiting prostaglandin production, as compared to other anti-inflammatory analgesic drugs, including naproxen and dichlorofenac
  • this drug shows weak inhibition of normal prostaglandin production in gastric mucosa and thus has a reduced effect on gastrointestinal troubles, so that it is suitable for long-term application.
  • this drug is characteristic in that it inhibits the production of interleukin-1 causing the destruction of joint cartilage and promotes the production of glycosaminoglycan found in joint cartilage, thus preventing rheumatoid arthritis, osteoarthrosis and the like from being worse.
  • Aceclofenac (2-[(2,6- dichlorophenyl) amino] phenylacetoxyacetic acid) has characteristics in that it is readily soluble in an organic solvent and relatively poorly soluble in water.
  • Acelofenac is absorbed rapidly in the gastrointestinal tract upon oral administration, and distributed in kidneys, vesica, liver, thyroid gland and the like at high concentration but distributed in eye, brain, and fat tissues and the like at low concentration.
  • aceclofenac shows an onset time shorter than 30 minutes, a time to maximum blood concentration (T max ) of about 1.5-2.5 hours, and a duration time of about 12 hours.
  • aceclofenac Upon oral administration, 46-75% of the administered drug is present as aceclofenac at the time to maximum blood concentration (Tmax) and widely metabolized after T max .
  • a main metabolite is 4-hydroxyaceclofenac, which also shows activity, and it is known that 4-hydroxydichlorofenac and indole derivatives are also observed as other metabolites.
  • aceclofenac has an elimination half-life of about 4 hours.
  • Aceclofenac showed acute toxicity in a dose-dependent manner. This acute toxicity was more sensitive in females than males, and showed gastrointestinal diseases.
  • aceclofenac The LD 50 of aceclofenac was 146.2 mg/kg in females and 199.5 mg/kg in males. With respect to subacute toxicity, when administered to rats at a dose of 3 mg/kg/day, aceclofenac showed safety, and at a dose of 6 mg/kg/day, it showed a slight increase in spleen weight and a change in serum for only females and thus is believed to have drug-fastness .
  • aceclofenac showed only general toxic symptoms, which are well known in a nonsteroidal inflammatory drug. Thus, aceclofenac is believed to be relatively safe. With respect to chronic toxicity, when administered to rats at a dose of 1.5 mg/kg/day, aceclofenac showed only a slight body weight reduction and change in [Ca ++ ] and inorganic salts in blood during 2 months of the last stage of an experiment, and at a dose of
  • aceclofenac With respect to teratogenic toxicity, when administered to females at 2.5, 5.0 and 10.0 mg/kg/day, aceclofenac had no effect on clinical symptoms, the viability of corpus luteum, and the ratio between implanted females and males of died or survived embryos. In the case of survived embryos, aceclofenac did not cause a significant change in injury of external appearance, teratogenicity, and organs. Thus, aceclofenac does not show teratogeniity in rats under the above conditions. Aceclofenac has the following clinical characteristics.
  • Aceclofenac has a reduced effect on normal prostaglandin production in a gastric mucosa such that gastrointestinal trouble is minimized.
  • Aceclofenac is penetrated into an inflammatory site, such as a joint, at high concentration, so that it has the powerful effect of inhibiting prostaglandin production in foci.
  • Aceclofenac showing this powerful effect of alleviating pain is currently developed and marketed in a tablet form.
  • a tablet among pharmaceutical formulations requires several processes in which the tablet must be first disintegrated upon oral administration, and a drug mixed with excipients is absorbed only after it was dissolved in digestive fluid or body fluid.
  • a drug is a substance poorly soluble in water, such as aceclofenac
  • the tablet generally has slow drug dissolution rate leading to low in vivo absorption rate and low bioavailability. For this reason, the onset time of the tablet will be necessarily delayed as compared to the case where pre-dissolved drugs, such as liquid formulations or soft capsules, are administered. Accordingly, the present inventors have conducted a study to develop a formulation, which can overcome shortcomings with the prior tablet and eliminate rejection against drugs.
  • Methods for formulating an internal use drug into a soft capsule are broadly divided into three categories as follows.
  • an active component drug is suspended in an oily base, such as vegetable oil (e.g., soybean oil, coconut oil, sunflower seed oil, sesame oil, perilla oil or olive oil), or middle chain fatty acid triglyceride, using a suspending agent such as bees-wax.
  • an oily base such as vegetable oil (e.g., soybean oil, coconut oil, sunflower seed oil, sesame oil, perilla oil or olive oil), or middle chain fatty acid triglyceride.
  • a suspending agent such as bees-wax.
  • an active component drug is solubilized or suspended in a water-soluble base, such as polyethylene glycol or propylene glycol.
  • a water-soluble base such as polyethylene glycol or propylene glycol.
  • a nano-emulsion concentrate using the concept of a self-microemulsifying drug delivery system, wherein a drug is dissolved by the addition of the water-soluble base, a dissolution aid, oils and a stabilizer.
  • aceclofenac is formulated into a soft capsule formulation in order to increase the dissolution rate thereof, the first method in which aceclofenac is suspended in the oily base is difficult to achieve the desired dissolution rate.
  • a method of suspending aceclofenac in a base such as polyethylene glycol 400 provides an improvement in drug dissolution rate as compared to the method of suspending aceclofenac in the oily base, but is also difficult to achieve a significant increase in dissolution rate.
  • Korean Patent Application No. 10-1999- 0027950 discloses a method of using polyethylene glycol, glycerin, and purified water to solubilize nitrendipine . However, this method is not regarded as a recommendable method since a soft capsule formulation can be softened or degraded by purified water.
  • 5,141,961 discloses an ethanol-containing liquid pharmaceutical composition obtained by solubilizing ibuprofen using ethanol, polyethylene glycol and polyvinyl pyrrolidone.
  • US Patent No. 5,071,643 discloses a method of solubilizing ibuprofen using an ionizable solvent system comprising glycerin, polyethylene glycol, polyvinyl pyrrolidone and water, but is not a recommendable method since it can affect the softening and hardening of a soft capsule formulation.
  • composition disclosed in US Patent 5,141,961 is an ethanol-containing liquid pharmaceutical composition and thus is pointed as a problem in that its safety is reduced upon long-term storage (i.e., its contents are precipitated due to a change in ethanol content) , resulting in a reduction in its bioavailability.
  • a method of solubilizing a drug with the minimum possible use of purified water or ethanol will allow the more effective preparation of a soft capsule formulation.
  • the present inventors have conducted studies to develop a formulation which has a higher drug dissolution rate and in vivo drug absorption rate than those of the existing formulations, thus showing the most rapid expression of a drug in patients.
  • the present inventors have developed a soft capsule formulation having high in vivo drug absorption rate.
  • an oily base such as vegetable oil (e.g., soybean oil, coconut oil and wheat germ oil) , mineral oil or middle chain triglyceride (MCT) , using a suspending agent such as bees-wax
  • MCT middle chain triglyceride
  • the dissolution rate of the drug can be increased as compared to the general formulation method but an increase in the effect and stability of the drug cannot be expected. Disclosure of Invention
  • the present invention has been made to solve the above-mentioned problems occurring in the prior art, and an object of the present invention is to provide a method for solubilizing aceclofenac using a self-microemulsifying drug delivery system, the method comprising dissolving 1-35 parts by weight, based on the total weight of contents, of aceclofenac, in a mixture in 10-90 parts by weight of polyethylene glycol, 1-50 parts by weight of polyoxyethylene hydrogenated castor oil (trade name: Cremophor, Nikkol HCO) or dimethyl isosorbide, 0.1-10 parts by weight of oil, 1-40 parts by weight of polysorbate (trade name: Tween) , 0.0001-0.5 parts by weight of butylated hydroxyanisole or butylated hydroxytoluene, and 0.001-5 parts by weight of tocopherol .
  • polyethylene glycol 1-50 parts by weight of polyoxyethylene hydrogenated castor oil (trade name: Cremophor, Nikkol HCO) or dimethyl
  • Another object of the present invention is provide a solubilized aceclofenac-containing liquid composition using a self-microemulsifying drug delivery system, the composition being prepared by dissolving 1-35 parts by weight, based on the total weight of contents, of aceclofenac, in a mixture of 10-90 parts by weight of polyethylene glycol, 1-50 parts by weight of polyoxyethylene hydrogenated castor oil or dimethyl isosorbide, 0.1-10 parts by weight of oils, 1-40 parts by weight of polysorbate, 0.0001-0.5 parts by weight of butylated hydroxyanisole or butylated hydroxytoluene, and 0.001-5 parts by weight of tocopherol.
  • Still another object of the present invention is to provide a soft capsule formulation including a solubilized aceclofenac-containing composition using a self- microemulsifying drug delivery system, the composition being prepared by dissolving 1-35 parts by weight, based on the total weight of contents, of aceclofenac, in a mixture of 10-90 parts by weight of polyethylene glycol, 1-50 parts by weight of polyoxyethylene hydrogenated castor oil or dimethyl isosorbide, 0.1-10 parts by weight of oils, 1-40 parts by weight of polysorbate, 0.0001-0.5 parts by weight of butylated hydroxyanisole or butylated hydroxytoluene, and 0.001-5 parts by weight of tocopherol.
  • the present invention relates to a method for preparing a solubilized aceclofenac-containing composition, the method comprising dissolving aceclofenac in a mixed solvent system of a dissolution agent, a dissolution aid, oil and a stabilizer, such that the composition is self- microemulsified by body fluid upon oral administration into the human body, as well as a soft capsule formulation containing the composition.
  • the present invention relates to a method for preparing a self- microemulsifying composition having greatly increased dissolution rate, by completely dissolving aceclofenac with heating in a mixture of polyethylene glycol, dimethyl isosorbide or polyoxyethylene 40 hydrogenated castor oil (trade name: Cremophor RH40 or HCO40) or polyoxyethylene 60 hydrogenated castor oil (trade name: Cremophor RH60 or HCO60) , middle chain fatty acid or mono- or di-glycerides, and tocopherol, as well as a soft capsule formulation containing the composition.
  • aceclofenac can be dissolved at the amount of 1-40 parts by weight, and in view of the expression of a drug effect, aceclofenac can be solubilized at the amount of 1-30 parts by weight such that its dissolution and content stabilities can be ensured.
  • Agents for solubilizing aceclofenac include polyethylene glycol and polysorbate.
  • polyethylene glycol 400 is used as a main base.
  • Polyethylene glycol 400 is preferably used at the amount of 10-90 parts by weight, and more preferably 30-60 parts by weight.
  • a polyoxyethylene hydrogenated castor oil derivative (trade name: Cremophor, HCO) is preferably used at the amount of 1-50 parts by weight and more preferably 1-30 parts by weight.
  • Oils such as middle chain fatty acid are preferably used at the amount of 0.1-10 parts by weight and more preferably 0.1-5 parts by weight.
  • Polysorbate is preferably used at the amount of 1-40 parts by weight and more preferably 5-8 parts by weight.
  • Butylated hydroxyanisole or butylated hydroxytoluene as a stabilizer is preferably used at the amount of 0.0001-0.5 parts by weight and more preferably 0.001-0.4 parts by weight.
  • Tocopherol as another stabilizer is preferably used at the amount of 0.001-5 parts by weight and more preferably 0.2-2 parts by weight.
  • the above components are mixed to prepare a solvent system as a self- microemulsifying drug delivery system.
  • polyethylene glycol 400 and polysorbate are blended, warmed and mixed at a temperature of about 50-80 °C.
  • polyoxyethylene hydrogenated castor oil, oils, butylated hydroxyanisole or butylated hydroxytoluene, and tocopherol are added and completely dissolved.
  • a purified aceclofenac raw material is added slowly to the solvent system at a temperature of about 50 °C, and the transparent drug which had been completely dissolved is cooled to room temperature with slow stirring. Then, bubbles are removed using a vacuum pump, thus obtaining a solubilized composition.
  • a soft capsule coating film is prepared by a conventional method using a generally used soft-gel formulation containing gelatin and plasticizers .
  • the inventive soft capsule containing solubilized aceclofenac is formed using an automatic rotary filling machine according to a conventional filling method, and then subjected to drying and sorting processes, thus obtaining a test product.
  • the soft capsule formulation prepared according to the present invention has excellent drug dissolution rate and content stability.
  • this soft capsule formulation was measured for a change with time for six months under accelerated conditions and room temperature conditions, it showed little or no change in content and property with time and outstandingly excellent dissolution rate compared to the existing commercial aceclofenac tablet.
  • the present invention provides a formulation having excellent aceclofenac dissolution rate and high stability, as compared to the existing commercial formulation.
  • the present invention will hereinafter be described in further detail by examples and comparative examples. It is to be understood that the scope of the present invention is not limited to or by the examples.
  • Example 1 200 g of polyethylene glycol-400, 50 g of polyoxyethylene hydrogenated castor oil, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 362 g of a solubilized aceclofenac- containing composition.
  • Example 2 200 g of polyethylene glycol-400, 50 g of dimethyl isosorbide, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 362 g of a solubilized aceclofenac-containing composition.
  • Example 3 200 g of polyethylene glycol-400, 25 g of polyoxyethylene hydrogenated castor oil, 25 g of dimethyl isosorbide, 0.25 g of butylated hydroxytoluene, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 362 g of a solubilized aceclofenac-containing composition.
  • Example 4 125 g of polyethylene glycol-400, 125 g of polyoxyethylene hydrogenated castor oil, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 362 g of a solubilized aceclofenac- containing composition.
  • Example 5 125 g of polyethylene glycol-400, 100 g of polyoxyethylene hydrogenated castor oil, 7 g of polysorbate-20, 7 g of polysorbate-80, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are blended with each other, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 351 g of a solubilized aceclofenac-containing composition.
  • Example 6 100 g of polyethylene glycol-400 and 100 g of triacetin are mixed and solubilized. To the mixture, 50 g of polyoxyethylene hydrogenated castor oil, 8 g of polysorbate-20, 0.25 g of butylated hydroxytoluene, 2 g of tocopherol, and 10 g of middle chain fatty acid are added, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 370 g of ⁇ a solubilized aceclofenac- containing composition.
  • Example 7 100 g of polyethylene glycol-400 and 100 g of diethyleneglycol monoethylether are mixed and solubilized. To the mixture, 50 g of polyoxyethylene hydrogenated castor oil, 8 g of polysorbate-20, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are added, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred. After the mixture becomes completely transparent, it is cooled to room temperature, and bubbles are removed using a vacuum pump, thus obtaining 370 g of a solubilized aceclofenac-containing composition.
  • Example 8 100 g of polyethylene glycol-400, 50 g of triacetin, 50 g of propylene glycol are mixed and solubilized. To the mixture, 50 g of polyoxyethylene hydrogenated castor oil, 8 g of polysorbate-20, 0.25 g of butylated hydroxyanisole, 2 g of tocopherol, and 10 g of middle chain fatty acid are added, warmed to about 60 °C, and completely mixed at this temperature. Then, 100 g of aceclofenac is added slowly to the mixture at the same temperature and stirred.
  • a soft ' capsule coating film used in the present invention is prepared by a conventional method using a generally known soft gel formulation which contains 324 mg gelatin, 145 mg glycerin, 30 mg polyethylene glycol-400, 1.0 mg methyl paraoxybenzoate, 1.0 mg propyl paraoxybenzoate per capsule.
  • a soft capsule formulation including the inventive composition containing solubilized aceclofenac is prepared by forming the composition into an Oval 6 type by a conventional filling method using a general automatic rotary filling machine, and then drying and sorting the resulting capsule. The obtained soft capsule is used as a test product .
  • Comparative Example 1 100 g of aceclofenac is mixed with 250 g of middle chain fatty acid, and the mixture is sufficiently crushed using a colloid mill, to which 10 g of Span-80 is then added and mixed well. This gives 360 g of an aceclofenac- containing composition. This composition is used as a comparative soft capsule composition.
  • Test Example 1 Dissolution rate test and comparative evaluation The comparative evaluation of dissolution rates was carried out with the inventive soft capsule formulations (Examples 1-8) each including the self-microemulsifying composition containing the solubilized aceclofenac drug, the comparative soft capsule formulation (Comparative Example 1) having the aceclofenac suspended in the oil- soluble base, and a commercial tablet (trade name: Airtal) . The results are given in Table 1 below.
  • a dissolution test for aceclofenac was carried out according to a dissolution test method for Clanza tablet, an aceclofenac-containing tablet marketed in the name of this applicant.
  • the dissolution test was carried out at a paddle rotating speed of 100 rpm in 900 mL of phosphate buffer (pH 7.8) according to a dissolution test method of this applicant, and it was carried out according to the second dissolution method of general test methods described in Korea Pharmacopeia.
  • As a sample solution a solution, which had been filtered through a 0.45 ⁇ m membrane filter, was used. Meanwhile, for use as a standard solution, lOOmg of an aceclofenac standard was precisely weighed and dissolved in 900ml of the dissolution solution. The contents of aceclofenac in these solutions were analyzed by liquid chromatography.
  • Table 1 Results of dissolution rate test of self- microemulsifying aceclofenac formulation
  • the solubilized aceclofenac formulation using a micro-emulsifying system as in the present invention is a soft capsule formulation having a higher dissolution rate than that of the prior formulation.
  • the inventive soft capsule formulation -. has a characteristic in that it shows increased aceclofenac dissolution rate leading to a great increase in the in vivo absorption rate of aceclofenac, thus greatly increasing the pharmacological effect of aceclofenac.
  • Test Example 2 Test for stability with time
  • the soft capsule formulations according to Examples 1-5 and Comparative Example 1 were tested for a change with time under a room temperature condition and an accelerated condition of 40 °C for six months. The results are given in Table 2.
  • the soft capsule formulations prepared according to the present invention did not show browning, layer separation or precipitation, which occurred in the formulation of Comparative Example 1.
  • the present invention provides the solubilized aceclofenac-containing composition which has high in vivo drug absorption rate and thus shows a more rapid therapeutic effect than that of the existing formulation, as well as the soft capsule containing the composition.
  • a hydrophilic solubilizing base e.g., polyethylene glycol 400
  • a surfactant oil and a stabilizer
  • a soft capsule formulation which shows a great increase in the dissolution rate of aceclofenac can be provided.
  • the present invention allows the development of new formulation products which show an increase in the dissolution of poorly soluble drugs and an improvement in the in vivo absorption rate of the drugs, which were not achieved by the existing similar formulations.

Abstract

L'invention concerne un procédé de préparation d'une composition auto-microémulsionnée par dissolution de l'acéclofénac, peu soluble dans l'eau, dans un solvant mélangé de polyéthylène glycol, de dérivé d'huile de ricin de polyoxyéthylène (nom commercial: Cremophor, HCO), de diméthyléther d'isosorbide, d'acide gras à chaîne moyenne, d'hydroxyanisole butylé, d'hydroxytoluène butylé et de tocophérol, et analogue, ainsi qu'un procédé de préparation d'une formulation contenant de l'acéclofénac présentant une stabilité accrue et une meilleure solubilité de médicament, par remplissage de la composition dans une capsule molle. L'invention concerne en outre la préparation d'une composition contenant de l'acéclofénac solubilisé dont la caractéristique et l'intérêt résident dans le fait qu'elle a un taux élevé d'absorption de médicament in vivo, présentant ainsi un effet thérapeutique plus rapide en comparaison avec la formulation actuelle, ainsi que la préparation d'une formulation de capsule molle contenant ladite composition.
PCT/KR2004/001791 2003-10-09 2004-07-19 Formulation et procede de fabrication de capsules d'aceclofenac auto-microemulsionne WO2005032516A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020030070177A KR20050034299A (ko) 2003-10-09 2003-10-09 아세클로페낙 자가유화에멀젼 및 이를 이용한 연질캅셀제조성물 및 그의 제조방법
KR10-2003-0070177 2003-10-09

Publications (1)

Publication Number Publication Date
WO2005032516A1 true WO2005032516A1 (fr) 2005-04-14

Family

ID=34420561

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2004/001791 WO2005032516A1 (fr) 2003-10-09 2004-07-19 Formulation et procede de fabrication de capsules d'aceclofenac auto-microemulsionne

Country Status (2)

Country Link
KR (1) KR20050034299A (fr)
WO (1) WO2005032516A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080171687A1 (en) * 2004-09-16 2008-07-17 Abraxis Bioscience, Inc. Compositions And Methods For The Preparation And Administration Of Poorly Water Soluble Drugs

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100986531B1 (ko) * 2008-07-18 2010-10-07 한국콜마 주식회사 액상의 아세클로페낙을 함유하는 캡슐제

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000179A1 (fr) * 1998-06-27 2000-01-06 Won Jin Biopharma Co., Ltd. Preparation a dispersion solide d'un medicament faiblement hydrosoluble contenant de l'huile, un acide gras ou leurs melanges
WO2001066088A1 (fr) * 2000-03-08 2001-09-13 Astrazeneca Ab Nouveau systeme de delivrance d'un medicament auto-emulsifiant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000179A1 (fr) * 1998-06-27 2000-01-06 Won Jin Biopharma Co., Ltd. Preparation a dispersion solide d'un medicament faiblement hydrosoluble contenant de l'huile, un acide gras ou leurs melanges
WO2001066088A1 (fr) * 2000-03-08 2001-09-13 Astrazeneca Ab Nouveau systeme de delivrance d'un medicament auto-emulsifiant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG ET AL.: "Preparation and evaluation of aceclofenac microemulsion for transdermal delivery system", ARCH. PHAR. RES., vol. 25, no. 4, 2002, pages 534 - 540 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080171687A1 (en) * 2004-09-16 2008-07-17 Abraxis Bioscience, Inc. Compositions And Methods For The Preparation And Administration Of Poorly Water Soluble Drugs

Also Published As

Publication number Publication date
KR20050034299A (ko) 2005-04-14

Similar Documents

Publication Publication Date Title
TWI490216B (zh) 用作ｃ型肝炎病毒蛋白酶抑制劑之醫藥組合物
CA2567075C (fr) Suspension pharmaceutique
EP1109532B1 (fr) Composition orale de silybine sous forme de microemulsion
CN1196477C (zh) 用于口服给药的药物组合物
JPH09503495A (ja) 高濃度アセトアミノフェン溶液含有ゼラチンカプセル
US20030232097A1 (en) Oily wax matrix suspension formulation comprising ibuprofen free acid and potassium salt of ibuprofen
KR101025641B1 (ko) 매스틱 자가유화에멀젼 조성물 및 이를 함유하는 캡슐
WO2008070950A1 (fr) Formulations de solutions pharmaceutiques pour une encapsulation dans des capsules de gélatine ou autres formes posologiques
JP2006508104A (ja) 難溶性風邪薬の経口投与用マイクロエマルション濃縮液及びその製造方法
RU2708254C2 (ru) Пероральная композиция целекоксиба для лечения боли
WO2009069139A1 (fr) Forme posologique fournissant un remplissage liquide contenant de l'ibuprofène
BRPI0008228B1 (pt) composição farmacêutica contendo n-benzoil estaurosporina e agentes solubilizantes
KR20070113289A (ko) 멘톨 또는 ｐｅｇ/폴록사머를 함유하는 개선된페노피브레이트 제제
EP0152292A2 (fr) Gélules contenant de l'acétaminophène
EP1485081B1 (fr) Solution d'ibuprofene pour gelules dures a coque
CN101143142A (zh) 水飞蓟宾过饱和自微乳组合物及其制备方法
WO2014005363A1 (fr) Capsule molle de 2,2',6,6'-tétra-isopropyl-4,4'-2-bisphénol et son procédé de préparation
WO2016084099A1 (fr) Composition de capsule en gélatine souple d'agents antitussifs
WO2005032516A1 (fr) Formulation et procede de fabrication de capsules d'aceclofenac auto-microemulsionne
KR101096429B1 (ko) 안정성이 향상된 아세클로페낙의 경구용 연질캅셀제
WO2005120459A2 (fr) Composition pharmaceutique renfermant une solution stable et claire de medicament anti-inflammatoire contenue dans une capsule gelatineuse molle, et procede de production correspondant
WO2004047834A1 (fr) Formulation et procede de production de capsules molles d'aceclofenac solubilise
KR100558070B1 (ko) 가용성 덱시부프로펜의 연질캅셀제 조성물 및 그의 제조방법
KR100494096B1 (ko) 감기약 성분을 함유하는 경구투여용 조성물
KR100740015B1 (ko) 가용화된 탈니플루메이트의 연질캡슐제 조성물 및 그의제조방법

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 KP KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL 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): 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 IT LU 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
122 Ep: pct application non-entry in european phase