WO2011034396A2 - Dispersion solide comprenant un médicament de type fibrate, et procédé de préparation de la dispersion solide - Google Patents

Dispersion solide comprenant un médicament de type fibrate, et procédé de préparation de la dispersion solide Download PDF

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Publication number
WO2011034396A2
WO2011034396A2 PCT/KR2010/006464 KR2010006464W WO2011034396A2 WO 2011034396 A2 WO2011034396 A2 WO 2011034396A2 KR 2010006464 W KR2010006464 W KR 2010006464W WO 2011034396 A2 WO2011034396 A2 WO 2011034396A2
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WO
WIPO (PCT)
Prior art keywords
solid dispersion
drug
fibrate
polymer
surfactant
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PCT/KR2010/006464
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English (en)
Korean (ko)
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WO2011034396A3 (fr
Inventor
김경희
이현기
배철민
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주식회사 삼양사
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Publication of WO2011034396A2 publication Critical patent/WO2011034396A2/fr
Publication of WO2011034396A3 publication Critical patent/WO2011034396A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to a solid dispersion of a fibrate-based drug prepared using a heat melting process and a method for preparing the same. More specifically, the present invention, in order to improve the bioavailability of the fibrate-based drugs used in the treatment of hyperlipidemia, to form a molten complex by thermal melting the fibrate-based drugs, polymer melt base, surfactant and polymer solubilizer, The present invention relates to a solid dispersion of a fibrate-based drug obtained by solidifying and grinding the powder, and a method for producing the same.
  • solid dispersion has been widely studied as a method for dispersing a drug in an inert carrier.
  • solvent method After dissolving a water-soluble polymer as a carrier in a solvent such as an organic solvent, the solvent is distilled off or a drug is dissolved in a solvent to disperse in a carrier and then the solvent is distilled off to prepare a solid dispersion.
  • Japanese Patent Publication No. 3-1288 and Japanese Patent No. 3028404 which are prior art documents on the solvent method, are granules in which lactose and the like are granulated with a water-soluble polymer such as hydroxypropylcellulose.
  • a solid dispersion obtained by spraying and drying a liquid obtained by dissolving a polymer base of polyvinylpyrrolidone, hydroxymethyl cellulose, and methyl cellulose in an organic solvent.
  • WO 01/80828 discloses a process for preparing a mixture of a drug and one or more surfactants, heating the mixture to the melting point or higher of the poorly soluble drug, and then homogenizing the heated suspension. have.
  • the process of obtaining the final formulation is complicated and there is a fear that the drug may be recrystallized by homogenization in water.
  • 'fenofibrate 2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-propanoic acid, 1-methelethyl ester
  • 'fenofibrate' 2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-propanoic acid, 1-methelethyl ester
  • Micronization of fenofibrate the combination of micronized fenofibrate and surfactant, to some extent increases the bioavailability of fenofibrate, which has the advantage that the bioavailability in the fed state is the same, but the amount administered can be reduced.
  • the actual bioavailability of fenofibrate is still low, and there is room for improvement since the use of surfactants harmful to the human body can cause toxicity.
  • the present inventors have endeavored to find the optimum process conditions for preparing solid dispersions in consideration of the specificity that the fibrate-based drugs have a relatively low melting point.
  • the fibrate-based drugs, polymer melt groups, surfactants and polymers When the solubilizer is melted by heat (hot melt) to prepare a solid dispersion of the amorphous fibrate-based drug, the dissolution rate and bioavailability are remarkably improved compared to the conventional spray drying method, so that even when a small amount of drug is administered, an equivalent drug can be obtained. And the present invention was completed.
  • the solid dispersion according to the heat melting method of the present invention has the following advantages over the spray drying method.
  • the spray drying method must use high pressure and must use organic solvents, so it can be harmful to human body such as workers, environmental pollution, and organic solvents may remain in the final product.
  • the spray-dried ' manufactured by the spray drying method is too large to be difficult to formulate a large volume and the process of smashing for the reduction of the volume is essential.
  • the heat-dissolving solid dispersion according to the present invention does not use the organic solvent, there is no problem caused by the use of the organic solvent as described above, the volume of the powder is convenient to handle and layer the molten composition in the accelerator The advantage of being able to make a product have.
  • the present invention is to improve the dissolution rate and bioavailability of fibrate, a poorly soluble drug, by providing a solid dispersion of the fibrate-based drug obtained by thermal melting of the fibrate-based drug, a polymer melting base, a surfactant and a polymer solubilizer. .
  • the present invention is to provide a method for producing a solid dispersion of the fibrate-based drug by a heat melting method.
  • the present invention provides a solid dispersion of a fibrate drug obtained by thermal melting a fibrate drug, a polymer melting base, a surfactant, and a polymer solubilizer.
  • Another aspect of the present invention comprises the steps of melting the fibrate-based drug, the polymer melt base, the surfactant and the polymer solubilizer at 50 to 150 ° C to form a polymer melt complex; Cooling the polymer melt mixture to 15 to 30 ° C. to solidify it; And to provide a method for producing a solid dispersion of the fibrate-based drug comprising the step of preparing the fine particles by grinding the solidified polymer complex.
  • the present invention also provides a pharmaceutical composition for treating hyperlipidemia, which comprises a solid dispersion of a fibrate drug obtained by thermal melting a fibrate drug, a polymer melting machine, a surfactant, and a polymer solubilizer as an active ingredient.
  • the present invention provides a solid dispersion of the fibrate-based drug comprising a fibrate-based drug, a polymer melt base, a surfactant, and a polymer solubilizer.
  • the present invention provides a solid dispersion of a fibrate drug obtained by thermal melting a fibrate drug, a polymer melt base, a surfactant, and a polymer solubilizer.
  • the fibrate-based drug is used to treat hyperlipidemia.
  • Fenofibric acid esters including fenofibrate, known to be shown, fenofibric acid, benzafibrate, binifibrate, clinofibrate, ciprofibrate, clofibrate ), Clofibride, etofibrate, etofiline clofibrate, gemfibrozil, pirifibrate, ronifibrate, ronfibrate, simfibrate ( simfirate), or a pharmaceutically acceptable salt thereof.
  • the present invention prepares a solid dispersion by melting the fibrate-based drug and the polymer melt base with heat so that the fibrate-based drug is eluted in the intestinal tract, which is an absorption site.
  • polymer melt base examples include polyethylene glycol, polypropylene glycol, polyvinylpyrrolidone binil acetate copolymer, polyvinyl alcohol, polyacrylic acid polymer, and the like, and preferably polystyrene glycol.
  • the average molecular weight of the polymer melter agent is 2,000 to 10,000 Daltons, preferably 4,000 to 8,000 Daltons.
  • the melter agent helps to melt the drug to be uniformly mixed in the oil phase and serves as an absorption improvement mechanism.
  • the weight ratio of the fibrate-based drug and the polymer melter may be in the range of 1: 0.1 to 1: 3, preferably, 1 : 5 to 1: 2. If the ratio of the polymer melt base to the drug is greater than 3, it is unsuitable for formulation due to the sticky surface properties, and if it is less than 0.1, there is no effect of improving the bioavailability of the drug.
  • the surfactant of the present invention is a polymer surfactant, preferably poloxamer, alpha tocopheryl polyethylene glycol succinate, polyoxyl 40 stearate, polysorbate, Sodium lauryl sulfate, docusate sodium (docusate) one or two or more combinations selected from the group consisting of sodium). More preferably poloxamer. Since the surfactant of the present invention mediates the bond between the amorphous fibrate-based drug produced after melting and cooling and the polymer melt base, the surfactant and the polymer melt base serve to increase the dissolution of the fibrate-based drug.
  • the poloxamer may have a HLB value of 20 to 30, and preferably poloxamer 188,407 and the like.
  • the weight ratio of the fibrate-based drug and the surfactant may range from 1: 0.1 to 1: 5, preferably 1: 1 to 1: 3. If the ratio of the surfactant to the drug is less than 0.1, there is no effect of improving the bioavailability of the drug, and if it exceeds 5, the dosage of the agent increases, which causes problems in formulation.
  • the weight ratio of polymer melt base to surfactant is 10: 1 to 1:10, more preferably 2: 1 to 1: 2.
  • the polymer solubilizer according to the present invention preferably has a melting temperature of 40 to 60 ° C, a glass transition temperature of 100 to 200 ° C. Specifically, it is hydroxypropyl methyl cellulose (HPMC), polyvinylpyridone (PVP), etc., Preferably it is HPMC.
  • HPMC hydroxypropyl methyl cellulose
  • PVP polyvinylpyridone
  • HPMC HPMC
  • the weight ratio of the fibrate-based drug and the polymer solubilizer may range from 1: 0.1 to 1: 2, preferably from 1 :(). 5 to 1: 2. If the weight ratio of the polymer solubilizer is greater than 2, the amount of the polymer solubilizer is too high to prepare a melt mixture, and if it is less than 0.1, there is no solubility improvement effect.
  • the polymer solubilizing agent of the present invention is included to increase the solubility of the solid dispersion, and may be included in the solid dispersion by melting and cooling with the fibrate-based drug.
  • the dissolution rate of the drug may be increased. I can regulate it. As the content of the surfactant and the polymer solubilizing agent increases, the dissolution rate of the drug increases, but it is preferable not to exceed 10 times the weight of the fibrate-based drug in consideration of one dose.
  • the size and shape of the solid dispersion according to the present invention is not particularly limited, but is in the form of fine particles of 10 to l, 000 um, more preferably 500 to 800 um, more preferably 300 to 800 um.
  • the most preferred weight ratio of fibrate-based drug: polymer melt base: surfactant: polymer solubilizer is 1: 1: 2: 1.
  • a fibrate-based drug, a polymer melting base, a surfactant, and a polymer solubilizing agent are melted under 50 to 150 ° C., preferably 80 to 120 ° C., more preferably 80 to 100 ° C. Forming a homogeneous melt mixture; Cooling the polymer melt mixture to 15 to 30 ° C. to solidify it; And to provide a method for producing a solid dispersion of the fibrate-based drug comprising the step of preparing the fine particles by grinding the solidified polymer complex.
  • the drug, the polymer melt base, the surfactant and the polymer solubilizer may be melted at the same time after mixing or individually melted in any order.
  • a surfactant such as poloxamer and 10 to 40 parts by weight of polyethylene glycol are mixed and melted under stirring at 80 to 100 ° C., followed by 10 to 40 parts by weight of hydroxypropylmethylsalose.
  • the mixture is homogenized with stirring, 20 parts by weight of the fibrate-based drug is added thereto, melted with stirring, and finely pulverized into fine particles to prepare a solid dispersion.
  • the present invention also provides a pharmaceutical composition for treating hyperlipidemia comprising a solid dispersion of a fibrate drug obtained by thermal melting of a fibrate drug, a polymer melting base, a surfactant, and a polymer solubilizer.
  • the solid dispersion of the fibrate-based drug according to the present invention has a markedly improved dissolution rate and bioavailability, so that even when a small amount of drug is administered, an equivalent drug can be obtained.
  • the solid dispersion obtained by thermal melting of the fibrate-based drug, the polymer melt base, the surface active agent, the polymer solubilizing agent is the dissolution test according to the second method (Rotational speed lOOrpm) to 80 by weight of the drug 0/0 or higher is eluted within 30 minutes.
  • the solid dispersion according to the invention for Pharmacopoeia ninth revised second method for measuring the dissolution rate by, within 5 minutes fibrate 30 parts by weight of a drug 0/0 or more has a dissolution pattern that is dissolved within 60 parts by weight of a drug 0/0 or more, at least 80 wt% of the drug within 30 minutes and 15 minutes.
  • the present invention provides a method for Pharmacopoeia ninth revised second method (paddle method, rotation number lOOrpm) for measuring the dissolution rate by, within 5 minutes fibrate 50 parts by weight of a drug 0/0 or more, within 15 minutes of drug of 80 wt% or more, within 30 minutes 95 parts by weight of a drug 0/0 provides a solid dispersion having an elution pattern is dissolved.
  • addle method rotation number lOOrpm
  • Solid dispersions or pharmaceutical compositions according to the invention may be prepared from pharmaceutically acceptable surfactants, preservatives, complexes, electrolytes, diluents, disintegrants, binders, lubricants, glidants, sweeteners, flavoring agents, and coloring agents as necessary. It may further include one or more selected, and may further include an antihypertensive agent, an antihyperlipidemic agent and the like as other active ingredients. Any of the above components can be added during formulation of the solid dispersion of the present invention or after preparation.
  • Solid dispersions or pharmaceutical compositions of the fibrate-based drugs prepared according to the present invention may be formulated into pharmaceutical preparations containing a therapeutically effective amount of the drug.
  • it may be prepared as an oral dosage form such as tablets, tablets, granules and dry syrups, eye drops, nasal sprays or inhaled pharmaceutical compositions.
  • tablet formulations more preferably tablets by direct method, are most preferred, in which case they can be prepared by excipients and manufacturing techniques for conventional tablet formulations.
  • Oral dosage forms formed into tablets can be prepared by conventional tablet preparation techniques, including conventional ingredients or excipients, including surfactants, preservatives, complexes, electrolytes, diluents, disintegrants, binders, lubricants, glidants, Sweetening, flavoring or coloring agents may be further included.
  • the tablets have stability, flavor, convenience of taking, appearance, etc. Film-coating can be done for the purpose of improvement.
  • Dosage and frequency of administration of the pharmaceutical composition according to the present invention may be adjusted in consideration of factors such as the age, condition, weight of the patient, the severity of the disease to be treated.
  • the dosage of the pharmaceutical composition according to the present invention may be about 40 to 200 mg / day, which may be administered once or in several doses.
  • the solid dispersion of the fibrate-based drug according to the present invention has a remarkably improved dissolution rate and bioavailability compared to the fenofibrate preparation prepared by the conventional spray drying method, so that even when a small amount of drug is administered, an equivalent drug can be obtained.
  • the method for producing a solid dispersion according to the present invention is not only economical process because the process is simple and does not require additional equipment, and there is no fear that the organic solvent will remain in the final product because the organic solvent is not used in the chemical manufacturing step. It is an environmentally friendly and bio-friendly manufacturing process with no possibility of environmental pollution by organic solvents.
  • Example 1 is a SEM photograph of the solid dispersion of Example 1.
  • FIG. 2 is a DSC analysis result of the solid dispersion and the control sample 1 (lipidyl supra ® tablet) of Example 1 based on the control sample 2 (crystalline fenofibrate).
  • the solidified mass was crushed to a suitable size and pulverized into fine particles using ERWEKA AR402 (ERWEKA GmbH, Germany) equipped with 800um stainless steel sieve to obtain a solid dispersion.
  • Example 3 Fine particles were obtained by the same ingredients and processes as in Example 1, except that 10 g of hydroxypropylmethylcell was used.
  • Fine particles were obtained by the same ingredients and processes as in Example 1, except that 4 g of hydroxypropylmethylsalose was used.
  • Example 4 20 g polyethylene glycol 4000 (Macrogol 6000, Sanyo chemical industries, Japan), 20 g poloxamer 188 (Lutrol F68, BASF, Germany), 10 g hydroxypropylmethylcelose 2910 (Pharmacoat 606, ShinEtsu, Japan).
  • 20 g of fenofibrate was placed in a beaker and mixed while heating to about 90 ° C. After complete melting and mixing, it was spread out in a separate container for 4 hours, and allowed to stand at room temperature.
  • Example 2 the solid dispersion obtained in Example 1 was used, and Lipidyl Supra 8 tablet (Green Cross, South Korea) and crystalline fenofibrate (East FTL, South Korea), which are commercially available fenofibrate formulations, were used as Control Samples 1 and 2.
  • Control Sample 1 (lipidyl supra ® tablets) showed the same crystallinity as Control Sample 2 (crystalline fenofibrate), it can be seen that the solid dispersion of Example 1 is present in an amorphous form.
  • Dissolution test conditions are as follows.
  • the test method was the 9th amendment of the Korean Pharmacopoeia and the 2nd method (paddle method) and LABFINE Dissolution tester (LABFINE, Republic of Korea) was used as the dissolution apparatus.
  • LABFINE Dissolution tester (LABFINE, Republic of Korea) was used as the dissolution apparatus.
  • Sodium lauryl sulfate (Sigma, USA) 0.025M solution in 100 mL of temperature was maintained at 37 ⁇ 0.5 ° C, each group was tested for dissolution behavior by rotating the paddle at 100 rpm.
  • Control sample 2 (crystalline fenofibrate) showed a very low dissolution rate at a given dissolution condition, whereas commercial control sample 1 (lipidyl supra ® tablets) showed a relatively high dissolution rate, and the solid dispersion according to the invention Excellent dissolution rate and dissolution rate were shown.
  • Test Example 2
  • Example 2 showed an excellent aspect in both dissolution rate and dissolution rate compared to the sample of Comparative Example 1 or 2.
  • Test Example 3
  • Example 1 the solid dispersion obtained in Example 1 was used, and as a control sample, Lipidyl Supra 8 tablet (Green Cross, South Korea), a commercially available fenofibrate formulation, was administered to white rats under the following conditions.
  • Lipidyl Supra 8 tablet Green Cross, South Korea
  • AUC 24hr and Cmax increased by approximately 14 and 172%, respectively, compared to the control sample, which is a commercial product, indicating that the bioavailability was improved.

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Abstract

La présente invention concerne une dispersion solide et un procédé pour la préparer. La dispersion solide est préparée par fusion à chaud d'un médicament de type fibrate, d'un matériau de base pour polymère fondu, d'un tensioactif, et d'un agent de solubilisation de polymère. La dispersion solide comprend le médicament de type fibrate qui s'utilise dans le traitement de l'hyperlipidémie et qui bénéficie d'une biodisponibilité accrue.
PCT/KR2010/006464 2009-09-21 2010-09-20 Dispersion solide comprenant un médicament de type fibrate, et procédé de préparation de la dispersion solide WO2011034396A2 (fr)

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KR20090089048 2009-09-21
KR10-2009-0089048 2009-09-21

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WO2011034396A2 true WO2011034396A2 (fr) 2011-03-24
WO2011034396A3 WO2011034396A3 (fr) 2011-09-01

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KR101420919B1 (ko) * 2012-05-30 2014-07-16 성균관대학교산학협력단 궤양 치료를 위한 약제학적 고체 분산체 제제 및 이의 제조방법
KR102489384B1 (ko) * 2020-09-29 2023-01-18 애드파마 주식회사 생체이용율이 개선된 페노피브레이트 입자를 포함하는 약제학적 조성물

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10505574A (ja) * 1994-07-26 1998-06-02 ラボラトワール エフィク 乾燥製剤の製造方法と、この方法で得られる医薬組成物
US20070134324A1 (en) * 2004-07-22 2007-06-14 Jallal Messadek Therapeutic combinations
WO2008013416A1 (fr) * 2006-07-27 2008-01-31 Amorepacific Corporation Procédé pour la préparation d'une poudre comprenant des nanoparticules de médicament peu soluble
US20080031825A1 (en) * 2004-08-20 2008-02-07 Yisheng Chen Pharmaceutical Compositions Comprising Effervescent Agents And Fenofibrate

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KR100767349B1 (ko) * 2006-08-01 2007-10-17 삼천당제약주식회사 페노피브레이트를 함유하는 경구용 약제 조성물 및 그의제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10505574A (ja) * 1994-07-26 1998-06-02 ラボラトワール エフィク 乾燥製剤の製造方法と、この方法で得られる医薬組成物
US20070134324A1 (en) * 2004-07-22 2007-06-14 Jallal Messadek Therapeutic combinations
US20080031825A1 (en) * 2004-08-20 2008-02-07 Yisheng Chen Pharmaceutical Compositions Comprising Effervescent Agents And Fenofibrate
WO2008013416A1 (fr) * 2006-07-27 2008-01-31 Amorepacific Corporation Procédé pour la préparation d'une poudre comprenant des nanoparticules de médicament peu soluble

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WO2011034396A3 (fr) 2011-09-01
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