WO2006021160A1 - Système de relargage de médicament auto-émulsifiant à base de butylbenzènephtaléine, méthode de préparation et applications d’un tel système - Google Patents

Système de relargage de médicament auto-émulsifiant à base de butylbenzènephtaléine, méthode de préparation et applications d’un tel système Download PDF

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Publication number
WO2006021160A1
WO2006021160A1 PCT/CN2005/001332 CN2005001332W WO2006021160A1 WO 2006021160 A1 WO2006021160 A1 WO 2006021160A1 CN 2005001332 W CN2005001332 W CN 2005001332W WO 2006021160 A1 WO2006021160 A1 WO 2006021160A1
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Prior art keywords
butylphthalide
self
oil
drug delivery
emulsifying drug
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PCT/CN2005/001332
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English (en)
French (fr)
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WO2006021160A8 (en
Inventor
Zhentao Liu
Liying Yang
Hanyu Yang
Yuqing Gao
Dongmin Shen
Wenmin Guo
Xiaolong Feng
Jia Zheng
Original Assignee
Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.
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Priority to US11/574,313 priority Critical patent/US8728518B2/en
Application filed by Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. filed Critical Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.
Priority to BRPI0515070A priority patent/BRPI0515070B8/pt
Priority to JP2007528562A priority patent/JP4653810B2/ja
Priority to AT05781769T priority patent/ATE462410T1/de
Priority to MX2007002335A priority patent/MX2007002335A/es
Priority to CA2578130A priority patent/CA2578130C/en
Priority to DE602005020317T priority patent/DE602005020317D1/de
Priority to KR1020077006741A priority patent/KR100887034B1/ko
Priority to AU2005276811A priority patent/AU2005276811B8/en
Priority to EP05781769A priority patent/EP1787638B1/en
Publication of WO2006021160A1 publication Critical patent/WO2006021160A1/zh
Publication of WO2006021160A8 publication Critical patent/WO2006021160A8/zh
Priority to NO20071354A priority patent/NO336917B1/no

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    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to a novel drug delivery and release system for butylphthalide, in particular to a self-emulsifying drug delivery system of butylphthalide and a preparation process thereof and application thereof in pharmaceutical preparations.
  • Self-EmulsifyingDrugDeliverySystem is a solid or liquid dosage form containing an oil phase, a surfactant and a co-surfactant.
  • the basic feature of this system is in the gastrointestinal tract or at ambient temperature (usually referred to as The oil-in-water emulsion can be spontaneously formed under the condition of a body temperature of 37 ° C) and gentle agitation. With the increase in the amount of emulsifier, this self-emulsifying system can spontaneously form microemulsion in the gastrointestinal tract, which is called self-microemulsifying drug delivery system.
  • SEDDS Self-MicroemulsifyingDrugDeliverySystem
  • SEDDS Self-MicroemulsifyingDrugDeliverySystem
  • Rapid dispersion in the gastrointestinal tract reduces irritation caused by direct contact of the drug with the gastrointestinal wall, and the structure of the emulsion particles in the gastrointestinal tract changes or is destroyed.
  • the micron- or nano-sized particles formed after the destruction can penetrate into the mucosa of the gastrointestinal tract, and the digested oil droplets permeate into the blood circulation.
  • Self-emulsifying drug delivery systems are mainly used for fat-soluble and water-insoluble drugs, increasing drug stability and improving bioavailability.
  • Butylphthalide is the main component in celery and its seeds. It can be directly extracted from natural plant celery seed oil or obtained by synthesis.
  • Chinese patent 98126618.X levodobutyl benzoquinone is disclosed. The application of antithrombotic and antiplatelet aggregation drugs clearly shows that this product has the function of regulating NOS-NO-cGMP system function and metabolism of arachidonic acid in neurons after cerebral ischemia.
  • Chinese Patent No. 93117148.2 the use of celery and celery in the preparation of a medicament for preventing and treating diseases caused by cerebral ischemia in a mammal or human is disclosed. It is an optically active butylphthalide, which is an oily liquid with a strong celery aroma.
  • the chemical structure is as follows:
  • butylphthalide the only products of butylphthalide are soft gelatin.
  • the drug is directly encapsulated with soft rubber after the vegetable oil is dispersed.
  • the dosage form can mask the bad odor of the drug, its content is poorly dispersed in the aqueous phase, and it is dissolved in vitro. The degree cannot be directly measured, which not only affects the quality control during the production process, but also greatly affects the rate of drug absorption.
  • Chinese Patent No. 02123000.5 is a technique in which the applicant uses cyclodextrin derivative inclusion to improve the water solubility of butylphthalide.
  • the use of this technology not only improves the bad odor, but also increases the solubility in water, but the inclusion complex
  • the amount of the host molecule used in the preparation process is limited by the dosage capacity of the dosage form, and the requirements for various dosage forms of the patient cannot be fully satisfied.
  • the preparation of the hard capsule is limited by the loading amount
  • the preparation of the tablet is limited by the size of the sheet shape.
  • the amount of the main molecule of the inclusion compound should not be too large; in addition, the inclusion technology has large power consumption, and the process operation is more complicated, and the process control points are more (such as temperature, grinding method and strength, time, stirring speed and time, etc.) , making the product inclusion technology industrialization process slower.
  • the object of the present invention is to solve the shortcomings of the above-mentioned butylphthalide preparation products in clinical application, and aims to provide a new butylphthalide release system, namely a butylphthalide self-emulsifying drug release system.
  • the butylphthalide self-emulsifying drug delivery system comprises 1% - 65 % by weight Butylphthalide, 10% ⁇ 65 % emulsifier is an essential component, preferably containing 10% ⁇ 50% butylphthalide, 15% ⁇ 60% emulsifier is an essential component; Suitable excipients are required to form various formulations, wherein the appropriate amount of excipient is from 0 to 85%, preferably from 5 to 75% (the above amounts are based on the total weight of the butylphthalide self-emulsifying drug delivery system).
  • Butylphthalide is selected from the group consisting of its racemate, left-handed body and right-handed body.
  • the self-emulsifying drug delivery system of the present invention is equally applicable to oil-soluble butylphthalide derivatives.
  • the SEDDS emulsifier in the present invention is mainly a nonionic emulsifier.
  • Nonionic emulsifiers are less toxic than ionic emulsifiers and they only cause reversible changes in the permeability of the gastrointestinal wall.
  • Preparation process After the emulsifier is fully melted and mixed in a 20 ⁇ 60 ⁇ water bath, a butyl hydrazine mixed hook is added under stirring, and an excipient is added to obtain a relying dosage form having a butylphthalide self-emulsifying drug release system.
  • the invention also provides a series of butylphthalide self-emulsifying release preparations and various butylphthalide dosage forms adopting a self-emulsifying release mechanism, and various suitable excipients, such as butylphthalide self-emulsifying release agents, are required for various dosage forms.
  • the butylphthalide self-emulsifying drug release system of the invention is especially suitable for a soft gelatin dosage form, the content of which is an oily liquid with self-emulsification characteristics, the composition of which is butylphthalide and an emulsifier, and an excipient can also be added.
  • the excipient is selected from the group consisting of an orally available vegetable oil such as sesame oil, corn oil, peanut oil, soybean oil, almond oil, peach kernel oil, cottonseed oil, sunflower oil, one of olive oil, or two or more substances.
  • An anti-oxidant and a lipophilic flavoring agent may also be added to the mixture.
  • the excipient in the self-emulsifying soft capsule of the present invention may be an excipient commonly used in the art, and the self-emulsified release system of the butylphthalide of the present invention is also suitable for the oral liquid dosage form, which is an oil having self-emulsification characteristics. Liquid, diluted with water and taken. On the basis of the above-mentioned self-emulsified release system of butylphthalide, water, a co-solvent and a suitable flavoring agent may be further included, and the oral liquid may be directly prepared.
  • the butylphthalide self-emulsifying drug release system of the invention is also suitable for oral solid powder or granules, and the oral solid preparations such as tablets (including slow and controlled release tablets) and capsules supported by the butylphthalide self-emulsifying drug release system of the invention.
  • Agent containing slow release, controlled release), granules, etc., based on the above-mentioned self-emulsified release system of butylphthalide, adding excipients, such as disintegrants, binders, flavoring agents, required for oral solid dosage forms, And a polymer skeleton material or the like, which is prepared into a solid powder or granule having a self-emulsification characteristic by a conventional process.
  • the tablet supported by the self-emulsified release system of the butylphthalide in the present invention is prepared by mixing a solid powder or granule having a self-emulsification characteristic with a suitable plasticizer, a disintegrating agent and a lubricant, and then pressing it with a suitable size die.
  • a suitable coating film such as a gastric coating, an enteric coating, or a cellulose acetate or ethyl cellulose can be used to delay or control the release of the drug.
  • the hard rubber raft supported by the styrene-butadiene self-emulsifying drug release system is prepared by solid powder or granules with self-emulsification characteristics, conventional lubricants and controlled release materials, to obtain ordinary hard plastic guanidine or controlled release. Hard plastic.
  • the content of the self-emulsifying soft plastic enamel of the invention is an oily liquid having self-emulsification ability, and the drug is rapidly dispersed into water to form an oil-in-water emulsion when disintegrating in water, and the product quality can be evaluated not only by dissolution measurement, Moreover, the contact area of butylphthalide with the gastrointestinal wall is greatly improved, thereby accelerating the absorption rate of the drug.
  • Self-emulsifying drug release system is not only simple in preparation process, but also operable Strong in nature, and has the advantages of low power consumption and high degree of industrialization during production or preparation. Butylphthalide self-emulsifying soft gelatin can remove the strong special odor and easy to swallow, easy to swallow, patient compliance, etc.
  • the invention adopts soft plastic enamel as a preferred relying form of the butylphthalide self-emulsifying drug delivery system.
  • the self-emulsifying drug soft gelatin content comprises butylphthalide and an emulsifier, and the preferred weight percentage is: butylphthalide is 10% to 50%, emulsifier is 15% to 60%, and can also be used in the liquid medicine.
  • Suitable antioxidants such as dibutylcarboxybenzazole and flavoring agents such as peppermint oil, green apple oil and the like are added to the oil.
  • the emulsifier is preferably a mixture of polyoxyethylene castor oil and polyethylene glycol-8 glyceryl octoate/caprate, and the mixing weight ratio is preferably 1: 0.5 to 1.5.
  • the weight ratio of butylphthalide to the emulsifier is preferably from 1:0.5 to 1.5.
  • the preferred preparation process the hydrogenated castor oil is fully melted in a water bath of 25 ⁇ 50 ° C, and mixed with polyethylene glycol-8 glyceryl octanoic acid / phthalate to obtain a uniform transparent oily liquid, room Add the butyl hydrazine mixed hook under warm stirring to obtain the content of the soft plastic mash.
  • the coffin of the self-emulsifying drug release soft rubber is basically composed of a rubber compound, a plasticizer and water, and the weight ratio of the three components is: 1 : 0.2 ⁇ 0.4: 0.8 ⁇ 1.3, and a suitable material can also be added to the coffin.
  • Preservatives such as ethylparaben or paraben and mixtures thereof.
  • the size may be one of gelatin, gum arabic or a mixture of the two.
  • the plasticizer can be one of glycerin, sorbitol or a mixture of both.
  • the butylphthalide soft gelatin of the present invention can be obtained by a conventional soft gum preparation process.
  • a conventional soft gum preparation process Such as manual molding, rotary molding or drop method.
  • a pressing method such as a rotary molding method is used, and an automatic rotary rolling mill is used, and the temperature is controlled between 40 and 50 ° C, so that each soft plastic bottle contains a pharmaceutically acceptable amount of butylphthalide.
  • gelatin solution gelatin 100g, glycerol 30g, water 130g and 200mg of ethylparaben.
  • the gelatin is added with an appropriate amount of water to cause it to swell.
  • glycerin, ethylparaben and the remaining water are heated in a sol pot to 70-80 ° C, mixed evenly, added to the expanded gelatin, stirred, melted, incubated for 1-2 hours, allowed to stand to float the foam, scrape off The floating foam is filtered with a clean white cloth and kept warm for use.
  • the viscosity of the formulated glue is generally 2.8 - 3.2 degrees;
  • Press soft gelatin Put the prepared gelatin glycerin and liquid chemical into the automatic rotary rolling mill, control the temperature at 40 ⁇ 50 °C, and press out each soft gelatin containing 200mg of liquid chemical.
  • the soft rubber sputum pressed by this liquid in this proportion has a moderate size and is tested to have a good uniformity.
  • Example 2 Verification of styrene-butadiene self-emulsifying soft plastic enamel
  • gelatin solution 1000 g of gelatin, 300 g of glycerin, 1300 g of water and 2000 mg of ethylparaben.
  • the gelatin is added with an appropriate amount of water to cause it to swell.
  • glycerin, ethylparaben and the remaining water are heated to 70-80 ° C in a sol pot, mixed and hooked, added with expanded gelatin, stirred, melted, incubated for 1-2 hours, allowed to stand for foam floating, scraping Go to the floating foam, filter it with clean white cloth, keep warm for use.
  • the viscosity of the formulated glue is generally 2.8 ⁇ 3.2 degrees;
  • Pressing soft capsules The prepared gelatin glycerin and liquid chemical oil are placed in an automatic rotary rolling mill, and the temperature is controlled at 40 ⁇ 50 °C, and each soft capsule containing 200 mg of liquid chemical oil is pressed.
  • the soft rubber sputum pressed by this liquid in this proportion has a moderate size and is tested to have a good uniformity.
  • Dissolution test Take this product, according to the dissolution test method (Chinese Pharmacopoeia 2005 edition two appendix XC second method), with 900ml water as solvent, the rotation speed is 100 rpm, according to the law, after 45 minutes, take 10ml of solution, filtered, precise amount of 5ml of filtrate, placed in a 10ml volumetric flask, diluted with decyl alcohol to the mark, shake the hook, according to spectrophotometry (Chinese Pharmacopoeia 2000 edition two Appendix IV A), at 280nm wavelength The absorbance was measured.
  • the particle size distribution range of this product is determined:
  • the measurement was carried out using a Nano-ZS type MALVERN particle size analyzer. Operation: Take the contents of this product, dilute 100 times of artificial gastric juice as the test solution, take lml in the sample cell, set The measurement was carried out at a constant temperature of 25 ° C, and the particle size distribution range and the cumulative distribution were analyzed by a single peak statistical method. The results are shown in Table 2 and Figure 1 below. Microscopic determination: Take 0.2ml of liquid oil, gently drip into 100ml of 37 °C artificial gastric juice, and then spontaneously form a uniform oil-in-water emulsion, take 10 ⁇ on the slide, observe. The statistical droplet size ⁇ 5 ⁇ accounted for about 98.7%.
  • the total count per batch is the total count per batch.
  • gelatin liquid preparation steps are the same as in the first embodiment;
  • Soft plastic crucible pressing The procedure was the same as in Example 1, except that the final pressed soft plastic capsules each contained 220 mg of the chemical liquid oil.
  • liquid oil Weigh 100g of butylphthalide, 65g of polyethylene glycol-8 octanoic acid / phthalate, 50g of polyoxyethylene castor oil, and mix to obtain a clear transparent oily liquid;
  • Example 2 The remaining steps were the same as in Example 1, except that the final pressed soft capsules each contained 210 mg of the liquid chemical.
  • Example 2 The remaining steps are the same as in Example 1, except that the final pressed soft capsules each contain 190 mg. Herbal oil.
  • 100g of butylphthalide, 100g of polyethylene glycol-8-glyceryl octanoate, 20g of ethanol, 100mg of peppermint oil and 100mg of sweet orange flavor are mixed as a binder, added to 450g of powdered sugar and 5g of low-substituted cellulose (L-HPC) In the mixture, granulation, drying is available.
  • L-HPC low-substituted cellulose
  • 100 g of butylphthalide, 50 g of polyethylene glycol-8-glycerol octoate, 50 g of hydrogenated castor oil, 100 mg of peppermint oil and 100 mg of green apple oil are mixed as a binder, and added to 400 g of powdered sugar, 100 g of PVP and 5 g of low-substituted cellulose ( In a mixture of L-HPC, 20 mesh sieves, dried, and packed into bags, that is, obtained.
  • Core 100 g of butylphthalide, 50 g of polyethylene glycol-8-glyceryl octanoate as a binder, added to a mixture of 100 g of powdered sugar, 40 g of sodium carboxymethyl starch, 150 g of microcrystalline cellulose, 32 mesh sieve After granulation, after drying at 45 ° C, 5 g of magnesium stearyl ester was added as a lubricant, and after mixing, the tablets were pressed, that is, each tablet weighed about 0.49 g.
  • Butylphthalide 100g polyethylene glycol-8-glycerol octanoic acid 50g, hydrogenated castor oil 50g, thin
  • the oil of 100 mg is mixed as a binder and slowly added to a mixture of 100 g of hydroxypropyl decyl cellulose (HPMC K1 oo M ) 80 g of hydroxypropyl fluorenyl cellulose (HPMC K4M ) and 10 g of ethyl cellulose.
  • HPMC K1 oo M hydroxypropyl decyl cellulose
  • HPMC K4M hydroxypropyl fluorenyl cellulose
  • ethyl cellulose ethyl cellulose
  • butyl phthalate 100g, polyethylene glycol-8-glycerol octanoic acid 50g mixed and added to 120g starch, 180g microcrystalline cellulose, 100g lactose, 20g poloxamer-188 mixed powder, stir well, 32 mesh sieve granules, after drying at 45 ° C, 20 mesh granules, adding 5 g of magnesium stearyl ester as a lubricant, tableting, and coating a 0.1-0.3 mm hydroxypropyl cellulose polyvinyl acetate composite film, That is.
  • Butylphthalide 50g polyethylene glycol-8-glycerol octanoic acid 20g mixed with 100g starch as absorption, diluent, 10g polyvinylpyrrolidone (PVP) as binder, 10g low-substituted cellulose (L-HPC) as a collapse
  • PVP polyvinylpyrrolidone
  • L-HPC low-substituted cellulose
  • Butylphthalide 100g polyethylene glycol-8-glycerol octanoic acid 50g, hydrogenated castor oil 50g, peppermint oil 100mg, green apple oil 100mg mixed hook as a binder, slowly added to 100g hydroxypropyl decyl cellulose (HPMC K10 series), 80g hydroxypropyl decyl cellulose (HPMC K4M ) and 10g ethyl cellulose mixture, stir evenly, 32 mesh sieve granules, dried at 45 °C, 20 mesh Granules, 5 g of magnesium stearyl ester was added as a lubricant, and the mixture was mixed and placed in a 1 # capsule shell.
  • Example 16 Preparation of Butylphthalide Self-Emulsifying Oral Liquid (Oil)
  • An oil-in-water emulsion is formed in an aqueous solution of % ethyl p-hydroxybenzoate, and is added to 5 mL of a 10 ml, 20 ml or 50 ml oral liquid bottle according to the needs of the patient.
  • the formulation is basically the same as in the case of Example 12, except that a bacteriostatic agent such as ethylparaben and aspartame are added in the preparation of the liquid oil (the aspartame can be first dispersed in a trace amount of alcohol), and then mixed.
  • Colorless clarified oily liquid directly into the graduated oral liquid bottle, that is. When taken, it can be taken by adding water to form an oil-in-water emulsion; it can also be taken directly, and an oil-in-water emulsion is automatically formed after the body fluid is encountered.
  • Example 18 Pharmacokinetics experiment of butylphthalide self-emulsifying soft capsule in rats After oral administration of the butylphthalide self-emulsifying soft capsule prepared in Example 1, the pharmacokinetic test was carried out in rats, and the obtained result was obtained from the market.
  • Soft gum the content is a mixture of butylphthalide lOOmg and vegetable oil 300mg, produced by Shijiazhuang Group NBP). The results are shown in Table 3.
  • SEDDS self-emulsifies into milk droplets after entering the gastrointestinal tract, and then rapidly disperses in the gastrointestinal tract, which reduces the difference in individual absorption due to poor oil droplet dispersion, and reduces the drug and gastrointestinal wall.
  • Stimulation caused by direct contact, emulsion The structure of the granules in the gastrointestinal tract will change or be destroyed.
  • the self-emulsifying drug delivery system is applied to the fat-soluble and water-insoluble oily drug butylphthalide, which will have greater clinical value.

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Description

丁苯酞自乳化释药体系及其制备方法和应用 技术领域
本发明涉及丁苯酞新型药物传递与释放系统， 具体而言， 涉及丁苯 酞自乳化释药体系及其制备工艺以及在药物制剂中的应用。 背景技术
自乳化药物传递系统（Self-EmulsifyingDrugDeliverySystem， 简称 SEDDS)是包含油相、 表面活性剂和助表面活性剂的固体或液体剂型， 这 一系统的基本特征是在胃肠道内或在环境温度 (通常指体温 37°C)及温和 搅拌的情况下能自发形成水包油乳剂。 随着乳化剂用量的增多， 这种自 乳化系统可在胃肠道内自发形成微乳， 被称之为自微乳化药物传递系统
(Self-MicroemulsifyingDrugDeliverySystem，SMEDDS)。 SEDDS进入胃肠 道后， 先自乳化成乳滴。 快速分散于胃肠道中， 减少了由于药物与胃肠 壁的直接接触引起的刺激， 乳剂微粒在胃肠道内结构会改变或被破坏。 破坏后形成的微米级或纳米级微粒能渗透进入胃肠道的粘膜层， 经消化 的油滴渗透进入血液循环。 极大的提高了药物的生物利用度。 自乳化释 药体系主要用于脂溶性及水难溶性药物， 增加药物的稳定性， 提高生物 利用度。
丁苯酞是芹菜及其籽中的主要成分， 它既可以从天然植物芹菜籽油 中直接提取得到， 也可以通过合成获得， 在中国专利 98125618.X中， 公 开了左旋丁苯酞在制备抗血栓形成及抗血小板凝聚药物中的应用， 清楚 地表明本品具有调节 NOS-NO-cGMP系统功能及脑缺血后神经细胞花生 四烯酸代谢的作用。 在中国专利 93117148.2中， 公开了芹菜曱素在制备 预防和治疗哺乳动物或人类脑缺血引起的疾病的药物中的应用， 芹菜曱 素即无旋光活性的丁苯酞， 为油状液体， 具有浓烈的芹菜香味， 化学结 构式如下：
Figure imgf000004_0001
目前丁苯酞上市产品仅有软胶嚢剂， 即将药物以植物油分散后直接 灌封软胶嚢， 该剂型虽可掩盖药物的不良气味， 但其内容物在水相中分 散较差， 体外溶出程度无法直接测得， 不仅影响到产品生产过程中的质 量控制， 且很大程度上影响到药物吸收的速率。
另外， 中国专利 02123000.5是本申请人采用环糊精衍生物包合改善 丁苯酞水溶性的一项技术， 此技术的使用不仅改善了不良气味， 更增加 了在水中的溶解度， 但包合物制备过程中所使用主分子的用量受剂型容 量所限制， 不能完全满足患者对各种剂型的需求， 如硬胶囊剂的制备受 装量限制， 片剂制备受片形大小适宜度限制， 包合物主分子用量不宜太 大； 另外， 包合技术动力消耗较大， 且工艺操作多、 较为复杂， 工艺控 制点较多 （如温度、 研磨方式与力度、 时间、 搅拌速度与时间等）， 使得 该产品包合技术产业化进程较慢。
发明内容
本发明的目的是解决上述丁苯酞制剂产品在临床应用方面的缺欠， 旨在提供一种新的丁苯酞释药体系， 即丁苯酞自乳化释药体系。
本发明所提供的丁苯酞自乳化释药体系包含重量百分比 1 % - 65 % 的丁苯酞、 10 % ~ 65 %的乳化剂为必要组成部分， 优选包含 10% ~ 50% 的丁苯酞、 15% ~ 60%的乳化剂为必要组成部分； 再加以各种依托剂型所 需的适宜赋形剂形成各种制剂， 其中赋形剂的适当用量为 0 ~ 85%, 优选 5 - 75% (上述含量均以丁苯酞自乳化释药体系的总重量为基准）。
丁苯酞选自其消旋体、 左旋体和右旋体。
本发明的自乳化释药体系同样适用于油溶性丁苯酞衍生物。
本发明中 SEDDS乳化剂主要为非离子乳化剂。非离子乳化剂比离子 乳化剂毒性低， 它们只引起胃肠道壁渗透性的可逆性转变。 本发明中 SEDDS乳化剂选自下列乳化剂中的一种物质、 或两种或两种以上物质的 混合物：液体或固体乙氧基聚氧乙烯甘油酯、 聚氧乙烯油酸酯、 液态卵磷 脂（如 Ophase31， HLB=4.0 )、聚氧乙烯蓖麻油（ CremophorEL, HLB=13.5 )、 椰子油、 聚乙二醇甘油酯 （LabrafacCMlO, HLB=10 )、 杏仁油油酸聚乙 二醇甘油酯 （ LabrafilM1944CSD， HLB=3 ~ 4 ; LabrafilM2125CS , HLB=3 ~ 4)、 聚氧乙烯 (25)甘油三油酸酯（TagatTO, HLB=11.3 )、 聚氧乙 烯 (20)山梨醇油酸酯（Tween80, HLB=11.0 )、 聚乙二醇 -8甘油辛酸 /癸酸 酯 ( Labrasol, HLB=14 )等。
制备过程： 20 ~ 60Ό水浴中使乳化剂充分溶融并混勾后， 搅拌下加 入丁苯酞混勾， 加入赋形剂， 制得具有丁苯酞自乳化释药体系的依托剂 型。
本发明还提供了系列丁苯酞自乳化释药制剂及采用自乳化释药机理 的各种丁苯酞剂型， 加以各种依托剂型所需的适宜赋形剂， 如丁苯酞自 乳化释药片剂、 软胶嚢、 颗粒剂、 硬胶嚢、 口服液等制剂。
本发明丁苯酞自乳化释药体系尤其适用于软胶嚢剂型， 其内容物为 具备自乳化特征的油状液， 其组成为丁苯酜和乳化剂， 还可加入赋形剂， 赋形剂选自可口服的植物油， 如麻油、 玉米油、 花生油、 豆油、 杏仁油、 桃仁油、 棉籽油、 葵花籽油、 橄榄油中的一种物质、 或两种或两种以上 物质的混合物， 也可加入抗氧剂和亲脂性的矫味剂。
本发明所涉及的自乳化软胶嚢中赋形剂可为本领域中常用的赋形 剂， 本发明丁苯酞自乳化释药体系同样适用于口服液剂型， 它是具备自 乳化特征的油状液， 用水稀释后服用。 在前述丁苯酞自乳化释药体系基 础上， 还可包括水、 助溶剂及适宜的矫味剂， 直接制成口服液。
本发明丁苯酞自乳化释药体系同样适用于口服固体粉末或颗粒， 本 发明中丁苯酞自乳化释药体系所依托的口服固体制剂如片剂 （包括緩、 控释片）、 胶嚢剂 （含緩、 控释）、 颗粒剂等， 在前述丁苯酞自乳化释药 体系基础上， 加入口服固体剂型所需的赋形剂， 如崩解剂、 粘合剂、 矫 味剂、 及高分子骨架材料等， 经常规工艺制备成具有自乳化特征的固体 粉末或颗粒。
本发明中丁苯酞自乳化释药体系所依托的片剂 , 由具备自乳化特征 的固体粉末或颗粒加适宜增塑剂、 崩解剂及润滑剂混匀后采用适宜大小 的冲模压制而成， 必要时可包以适宜的衣膜如胃溶衣、 肠溶衣、 或醋酸 纤维素及乙基纤维素等可延緩或控制药物释放的衣膜。
本发明中丁苯酞自乳化释药体系所依托的硬胶嚢， 由具备自乳化特征 的固体粉末或颗粒加常规的润滑剂、 緩控释材料， 制得普通硬胶嚢或控、 緩释硬胶嚢。
本发明所述自乳化软胶嚢中内容物为具有自乳化能力的油状液， 其 在水中崩解时药物迅速向水中分散形成水包油乳剂， 不仅可通过溶出度 测定对产品质量进行评价， 而且大大提高了丁苯酞与胃肠壁的接触面积， 从而加快药物的吸收速率。 自乳化释药体系不仅制备工艺简单， 可操作 性强， 且具有生产或制备过程中动力消耗小， 工业化程度高等优点。 丁苯酞自乳化软胶嚢除具普通软胶嚢可掩盖其强烈的特殊气味且服 用方便、 易于吞咽、 病人依从性好等特点外， 更可使油状活性成分在与 胃液接触时迅速分散并形成水包油乳剂而提高吸收的程度和速度。 本品 经加速试验和长期实验结果表明： 尽管在加热条件下软胶嚢壳老化现象 明显， 崩解时间有所延长， 但仍小于 60分钟， 符合中国药典有关规定， 外观、 含量、 降解物、 自乳化时间及体外释放度等各项指标均无明显变 化。
附图说明 由图 1可知， 粒径小于 5 μ ηι的乳滴超过 98 %， 属于自^：乳化释药体 系范畴，且由图中体积不足百分率曲线可知本体系中粒子分布范围比 较集中、 均匀。 具体实施方式
本发明选用软胶嚢作为丁苯酞自乳化释药体系的优选依托剂型。 本发明中自乳化释药软胶嚢内容物包含丁苯酞与乳化剂，优选的重 量百分比是： 丁苯酞为 10% ~ 50%， 乳化剂为 15% ~ 60%， 亦可在药液 油中加入适宜的抗氧剂如二丁基羧基曱苯及矫味剂如薄荷油、青苹果油 等。
乳化剂优选聚氧乙浠蓖麻油与聚乙二醇 - 8甘油辛酸 /癸酸酯的混 合物， 混合重量比优选为 1 : 0.5 ~ 1.5。 丁苯酞与乳化剂的重量比优选 为 1 : 0.5 ~ 1.5。
优选的制备工艺： 25 ~ 50°C水浴中使氢化蓖麻油充分溶融， 搅拌下 加入聚乙二醇 - 8甘油辛酸 /癸酸酯混合， 得到均匀的透明油状液， 室 温搅拌下加入丁苯酞混勾， 即得软胶嚢内容物。
本发明中自乳化释药软胶嚢的嚢材基本由胶料、 增塑剂、 水组成， 三者重量比例为： 1 : 0.2 ~ 0.4: 0.8 ~ 1.3 , 还可以在嚢材中加入适宜的 防腐剂如尼泊金乙酯或尼泊金曱酯及其混合物。
胶料可以是明胶、 阿拉伯胶中的一种或二者的混合物。
增塑剂可以是甘油、 山梨醇中的一种或两者的混合物。
本发明丁苯酞软胶嚢可以采用常规的软胶嚢制备工艺制得。如手工 模压法、 旋转模压法或滴制法。 一般选用压制法如旋转模压法， 使用自 动旋转轧嚢机， 温度控制在 40 ~ 50°C之间， 使每个软胶嚢中含有可药 用量的丁苯酞。
为更好地说明本发明的技术方案， 特给出以下实施例， 但本发明并 不仅限于此。
实施例 1 丁苯酞自乳化软胶囊的制备
明胶液的制备： 明胶 100g， 甘油 30g, 水 130g和 200mg尼泊金乙 酯。 取明胶加入适量的水使其吸水膨胀。 另将甘油、 尼泊金乙酯及余下 的水置溶胶锅中加热至 70 - 80°C , 混合均匀， 加入膨胀的明胶搅拌， 熔融， 保温 1 - 2小时， 静置使泡沫上浮， 刮去上浮的泡沫， 以洁净白 布过滤， 保温待用。 配成胶液的粘度一般为 2.8 - 3.2度；
药液油的制备： 称取丁苯酞 100g， 聚乙二醇- 8甘油辛酸 /癸酸酯 与聚氧乙烯蓖麻油各 50g, 充分搅勾即得；
压制软胶嚢： 将已制好的明胶甘油和药液油装入自动旋转轧嚢机 中， 温度控制在 40 ~ 50°C , 压制出每粒含 200mg药液油的软胶嚢。
药液油按此比例压制的软胶嚢， 外形大小适中， 经检验含量均匀度 好。
实施例 2: 丁苯酞自乳化软胶嚢工艺验证 明胶液的制备： 明胶 1000g, 甘油 300g， 水 1300g和 2000mg尼泊 金乙酯。 取明胶加入适量的水使其吸水膨胀。 另将甘油、 尼泊金乙酯及 余下的水置溶胶锅中加热至 70 - 80°C , 混合均勾， 加入膨胀的明胶搅 拌， 熔融， 保温 1 - 2小时， 静置使泡沫上浮， 刮去上浮的泡沫， 以洁 净白布过滤， 保温待用。 配成胶液粘度一般为 2.8 ~ 3.2度；
药液油的制备： 称取丁苯酞 1000g, 聚乙二醇 - 8甘油辛酸 /癸酸 酯与聚氧乙烯蓖麻油各 500g, 充分搅匀即得；
压制软胶囊： 将已制好的明胶甘油和药液油装入自动旋转轧嚢机 中， 温度控制在 40 ~ 50 °C， 压制出每粒含 200mg药液油的软胶囊。
药液油按此比例压制的软胶嚢， 外形大小适中， 经检验含量均匀度 好。
依实施例 2操作制备三批样品， 考察三批样品的溶出度及粒度重现 性， 溶出度及粒度测定方法如下：
溶出度测定法： 取本品， 照溶出度测定法（中国药典 2005年版二部 附录 X C第二法）， 以 900ml水为溶剂， 转速为每分钟 100转， 依法操 作， 经 45分钟时， 取溶液 10ml, 滤过， 精密量取续滤液 5ml, 置 10ml 量瓶中， 加曱醇稀释至刻度， 摇勾， 照分光光度法 (中国药典 2000年版 二部附录 IV A)， 在 280nm的波长处测定吸收度。 另精密称取丁苯酞对 照品 25.0mg, 置 50ml量瓶中， 加曱醇溶解并稀释至刻度， 摇匀； 精密 量取 5ml， 置 50ml量瓶中， 加曱醇 20ml, 用水稀释至刻度， 摇匀， 作 为对照溶液， 同法测定， 计算出每粒的溶出量。 测定结果见表 1。
本品粒径分布范围测定：
采用 Nano-ZS型 MALVERN粒径测定仪进行测定。 操作： 取本品内 容物， 以人工胃液稀释 100倍作为供试品溶液， 取 lml置样品池中， 设 定温度 25°C进行测定， 采用单峰统计法对粒径分布范围及累计分布情况 进行分析， 结果见表 2及后附图 1。 显微镜测定法： 取药液油 0.2ml, 轻微搅拌下滴至 100ml37°C人工胃 液中， 旋即自发形成均一水包油乳剂， 取 10 μΐ置载玻片上， 进行观察。 统计乳滴粒径 <5μιη者约占 98.7%。 与马尔文粒径分布检测结果基本一 致属微乳化范畴， 故才 Μ居本剂型特点， 称为丁苯酞自乳化（自微乳化） 释药体系。 表 1 三批样品的溶出度检测结果
Figure imgf000010_0001
表 2三批样品的粒度测定结果
粒径分布％
粒径
031201 031202 031203 备注
>5 μχη 2.78 3.05 2.54
每批次计数总量为
\ ~ 5 μχη 4.64 5.64 5.01
300个
<1 /m 92.68 91.31 92.45
结论 1 三批样品均为自微乳化释药体系 本品稳定性实验数据如表 3 :
表 3 丁苯酞自乳化软胶嚢初步稳定性考察
考察条件 自乳化
兮入里 降解物 体外释放度
夕卜 观 时间 崩解时限 时间（月） ( wt % ) ( wt % ) ( wt % )
(秒）
初 黄色透明软胶
0 100.3 0.61 2.33 99.3 5 '50" 始 囊
黄色透明软胶
1 101.1 0.66 2.67 100.2 6 '45" 嚢
加 黄色透明软胶
2 99.3 0.63 3.33 99.6 14Ί0" 速 嚢
试 黄色透明软胶
3 98.4 0.62 3.5 100.2 2830" 验 嚢
黄色透明软胶
6 99.0 0.58 3.33 98.5 49 '52" 囊
黄色透明软胶
1 100.1 0.63 2.50 100.5 6Ί5" 嚢
室 黄色透明软胶
3 101.0 0.67 2.50 98.9 835" 囊
留 黄色透明软胶
6 99.4 0.66 2.67 100.1 9 '45 " 样 嚢
黄色透明软胶
12 99.1 0.62 2.83 99.7 17 '50" 嚢 实施例 3 丁苯酞软胶嚢的制备
称取丁苯酞 100g，聚乙二醇 - 8甘油辛酸 /癸酸酯与聚氧乙烯蓖麻 油各 50g; 其余步骤与实施例 1相同， 只是在药液油的制备步骤中另加 入助溶剂如丙二醇 20g，充分搅匀即得，最后压制的软胶嚢每个含 220mg 的药液油。
实施例 4 丁苯酞软胶囊的制备
明胶液的制备：明胶 100g，甘油 40g、水 120g和尼泊金乙酯 200mg, 明胶液制备步骤与实施例 1相同；
药液油的制备： 称取丁苯酞 500g与聚乙二醇 _ 8 -甘油辛酸 600g 及调味剂鲜橙浊 500mg, 充分搅勾即得；
软胶嚢压制： 步骤与实施例 1相同， 只是最后压制的软胶嚢每个包 含 220mg的药液油。
实施例 5 丁苯酞软胶嚢的制备
药液油的制备： 称取丁苯酞 100g、 聚乙二醇- 8甘油辛酸 /癸酸酯 65g、 聚氧乙烯蓖麻油 50g， 混匀得澄清透明油状液；
明胶液的制备： 明胶 100g, 甘油 30g、 水 120g和 20gPEG400， 明 胶液制备步骤与实施例 1相同；
其余步骤与实施例 1 相同， 只是最后压制的软胶嚢每个含 210mg 的药液油。
实施例 6 丁苯酞软胶嚢的制备
称取丁苯酞 100g、 聚乙二醇 - 8甘油辛酸 /癸酸酯 40g、 聚氧乙烯 蓖麻油 50g， 混勾得澄清透明油状液；
明胶液的制备： 明胶 100g， 甘油 40g、 水 120g和 10gPEG400, 明 胶液制备步骤与实施例 1相同；
其余步骤与实施例 1 相同， 只是最后压制的软胶嚢每个含 190mg 的药液油。
实施例 7 丁苯酞自乳化颗粒的制备
丁苯酞 100g、 聚乙二醇 - 8 -甘油辛酸 100g、 乙醇 20g、 薄荷油 lOOmg及甜橙香精 lOOmg混匀作为粘合剂， 加至 450g糖粉与 5g低取 代纤维素 （L - HPC ) 的混合物中， 制粒， 烘干即得。
实施例 8 丁苯酞自乳化颗粒的制备
丁苯酞 100g、 聚乙二醇- 8 -甘油辛酸 50g、 氢化蓖麻油 50g、 薄 荷油 lOOmg及青苹果油 lOOmg 混匀作为粘合剂， 加至 400g糖粉、 lOOgPVP与 5g低取代纤维素 （L - HPC ) 的混合物中， 20 目筛制粒， 烘干， 分装入袋， 即得。
实施例 9 丁苯酞自乳化片剂的制备
丁苯酞 lOOg, 聚乙二醇 - 8 -甘油辛酸 50g、 氢化蓖麻油 40g, 混匀 作为粘合剂， 加至 100g糖粉、 40g羧曱基淀粉钠、 150g微晶纤维素的 混合物中， 32目筛制粒， 45X供干后， 外加入 5g硬脂酯镁作为润滑剂， 以青苹果固体粉末香精为矫味剂，混匀后压片，即得，每片片重约 0.49g。
实施例 10 丁苯酞自乳化片剂的制备
片芯： 丁苯酞 100g、聚乙二醇 - 8 -甘油辛酸 50g混匀作为粘合剂， 加至 100g糖粉、 40g羧曱基淀粉钠、 150g微晶纤维素的混合物中， 32 目筛制粒， 45°C烘干后， 外加入 5g硬脂酯镁作为润滑剂， 混匀后压片， 即得， 每片片重约 0.49g。
衣膜： 羟丙基曱基纤维素 60g溶于 80%乙醇溶液 1000ml中， 加入 0.5g食用绿色素， 混匀， 采用滚转包衣法， 片床温度 35-45°C , 进行包 衣， 得淡绿色薄膜衣片。
实施例 11 丁苯酞自乳化緩释片的制备
丁苯酞 100g、 聚乙二醇 - 8 -甘油辛酸 50g、 氢化蓖麻油 50g、 薄 荷油 lOOmg 混匀作为粘合剂， 緩緩加至 100g 羟丙基曱基纤维素 ( HPMCK1ooM ) 80g羟丙基曱基纤维素 （HPMCK4M ) 及 10g 乙基纤维 素的混合物中， 搅拌均匀， 32 目筛制粒， 45 °C烘干后， 20 目筛整粒， 加入 5g硬脂酯镁作为润滑剂， 压片， 即得。
实施例 12 丁苯酞自乳化控释片的制备
片芯： 丁苯酞 100g， 聚乙二醇- 8 -甘油辛酸 50g 混勾后加入至 120g淀粉、 180g微晶纤维素、 100g乳糖, 20g泊洛沙姆 -188的混合粉 中， 搅拌均匀， 32目筛制粒， 45°C烘干后， 20目整粒， 加入 5g硬脂酯 镁作为润滑剂， 压片， 包以 0.1-0.3mm的羟丙基纤维素聚醋酸乙烯酯复 合膜， 即得。
实施例 13 丁苯酞自乳化硬胶嚢的制备
丁苯酞 50g, 聚乙二醇- 8 -甘油辛酸 20g混勾用 100g淀粉作为吸 收、 稀释剂， 10g聚乙烯吡咯烷酮 （PVP )作为粘合剂, 10g低取代纤维 素（L - HPC )作为崩解剂， 32目筛制粒， 烘干， 20目筛整粒， 加入硬 脂酸镁作为润滑剂， 分装入 1#胶嚢壳， 即得。
实施例 14 丁苯酞自乳化硬胶嚢的制备
丁苯酞 50g, 聚乙二醇 - 8 -甘油辛酸 20g， 以泊洛沙姆 40g、 麦芽 糖糊精 60g、 微晶纤维素 60g及羧曱基淀粉钠 8g等吸附后， 以 32目筛 制粒， 45 ~ 50°C烘干， 20 目筛整粒后， 加入滑石粉作为润滑剂， 混匀 分装入 2#胶嚢壳
实施例 15 丁苯酞自乳化緩释胶嚢的制备
丁苯酞 100g, 聚乙二醇- 8 -甘油辛酸 50g, 氢化蓖麻油 50g， 薄荷 油 lOOmg,青苹果油 lOOmg混勾作为粘合剂，缓緩加至 100g羟丙基曱基 纤维素 （HPMCK10編 ）、 80g羟丙基曱基纤维素 （HPMCK4M ) 及 10g 乙 基纤维素的混合物中， 搅拌均匀， 32 目筛制粒， 45 °C烘干后， 20 目整 粒， 加入 5g硬脂酯镁作为润滑剂， 混匀后分装入 1#胶囊壳中即得。 实施例 16 丁苯酞自乳化口服液（油） 的制备
丁苯酞 100g，聚乙二醇 - 8 -甘油辛酸 50g， 氢化蓖麻油 50g, 鲜橙 浊 O.lg及薄荷油 O.lg混匀后， 加入至 5L含 1 %天冬甜精、 及 0.01 %对 羟基苯甲酸乙酯钠的水溶液中形成水包油乳剂，依患者不同需求分装入 5mL 10ml、 20ml或 50ml口服液瓶中。
实施例 17 丁苯酞自乳化口服液油的制备
配制处方基本同实施例 12, 只是在药液油配制时就加入抑菌剂如 尼泊金乙酯及阿斯巴甜（阿斯巴甜可先以微量酒精分散后混入）， 混匀 后得无色澄清油状液， 直接分装入具刻度口服液瓶， 即得。 用时定量取 出可加入水形成水包油乳剂服用； 亦可直接服用， 遇体液后自动形成水 包油乳剂。
实施例 18 丁苯酞自乳化软胶嚢的大鼠口服后药物动力学实验 以实施例 1 所制备的丁苯酞自乳化软胶嚢进行大鼠口服后药物动 力学试验， 所得结果与市售软胶嚢（内容物为丁苯酞 lOOmg与植物油 300mg的混合物,由石药集团 NBP公司生产） 比较， 结果见表 3
大鼠灌胃给药后不同时间内血浆中的药物浓度
血药浓度 ( g/ml )
取样点 （hr )
普通软胶囊 自乳化软胶嚢
0.08 5.32 13.62
0.17 6.79 16.17
0.5 8.06 12.25
0.8 7.02 9.3
1 10.15 9.32
2 4.22 6.61
3 4.31 7.43
5 4.04 4.36
7 9.5 2.54
9 5.16 1.92
12 2.5 1.36 由表 3可见，自乳化释药体系给药后达峰明显快于普通油状内容物, 其 tmax分别为 0.1和 1.0h， 且达峰浓度亦高于普通软胶嚢内容物， 且个 体差异较小。
发明人认为这说明 SEDDS进入胃肠道后， 先自乳化成乳滴， 随后 快速分散于胃肠道中， 减少了因油滴分散较差造成的个体吸收差异， 同 时减少了由于药物与胃肠壁的直接接触引起的刺激，乳剂 ：粒在胃肠道 内结构会改变或被破坏。 综上所述， 自乳化释药体系应用于脂溶性及水 难溶性油状药物一丁苯酞， 将有较大的临床使用价值。

Claims

权 利 要 求
1、 一种丁苯酞自乳化释药体系， 其特征是含有重量百分比 1 % ~ 65 %的丁苯酞、 10 % ~ 65 %的乳化剂和 0% ~ 85%的赋形剂， 以所述丁苯酞 自乳化释药体系的重量为基准。
2、 按照权利要求 1所述的丁苯酞自乳化释药体系， 其中含有重量百 分比 10% ~ 50%的丁苯酞、 15% ~ 60%的乳化剂和 5% - 75%的赋形剂， 以 所述丁苯酞自乳化释药体系的重量为基准。
3、 按照权利要求 1或 2所述的丁苯酞自乳化释药体系， 其中所述丁 苯酞选自其消旋体、 左旋体和右旋体。
4、 按照权利要求 1或 2所述的丁苯酞自乳化释药体系， 其中所述乳 化剂选自下列一种物质、 或两种或两种以上物质的混合物： 液体或固体乙 氧基聚氧乙婦甘油酯、 聚氧乙烯油酸酯、 液态卵磷脂、 聚氧乙烯蓖麻油、 椰子油、 聚乙二醇甘油酯、 杏仁油油酸聚乙二醇甘油酯、 聚氧乙烯甘油三 油酸酯、 聚氧乙烯山梨醇油酸酯、 聚乙二醇 -8甘油辛酸 /癸酸酯。
5、 按照权利要求 1或 2所述的丁苯酞自乳化释药体系， 其中还包括 水、 助溶剂及矫味剂。
6、 按照权利要求 1或 2所述的丁苯酞自乳化释药体系， 其中所述赋 形剂选自可口服的植物油。
7、 按照权利要求 6所述的丁苯酞自乳化释药体系， 其中所述植物油 选自下列一种物质、 或两种或两种以上物质的混合物： 麻油、 玉米油、 花 生油、 豆油、 杏仁油、 4兆仁油、 棉籽油、 葵花籽油、 橄榄油。
8、 按照权利要求 4所述的丁苯酞自乳化释药体系， 其中所述乳化剂 为聚氧乙烯蓖麻油与聚乙二醇 - 8甘油辛酸 /癸酸酯的混合物， 混合重量 比为 1 : 0.5 ~ 1.5。
9、 按照权利要求 1所述的丁苯酞自乳化释药体系， 其中所述丁苯酞 自乳化释药体系为口服液、 软胶嚢、 硬胶嚢、 緩释胶嚢、 口服固体粉末或 颗粒、 片剂或緩释片剂形式。
10、 按照权利要求 1 的丁苯酞自乳化释药体系的制备方法， 包括在 20 ~ 60 °C水浴中使乳化剂充分溶融并混勾后， 搅拌下加入丁苯酞混勾， 添 加赋形剂， 制得具有丁苯酞自乳化释药体系的依托剂型。
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JP2008510737A (ja) 2008-04-10
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DE602005020317D1 (de) 2010-05-12
AU2005276811A1 (en) 2006-03-02
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US8728518B2 (en) 2014-05-20
EP1787638A4 (en) 2008-12-03
KR100887034B1 (ko) 2009-03-04
ES2341265T3 (es) 2010-06-17
KR20070046948A (ko) 2007-05-03
CA2578130A1 (en) 2006-03-02
JP4653810B2 (ja) 2011-03-16
BRPI0515070B8 (pt) 2021-05-25
BRPI0515070A2 (pt) 2009-08-04
RU2371176C2 (ru) 2009-10-27
AU2005276811B2 (en) 2008-11-13
ATE462410T1 (de) 2010-04-15
ES2341265T4 (es) 2011-04-27
EP1787638B1 (en) 2010-03-31
EP1787638A1 (en) 2007-05-23
RU2007111120A (ru) 2008-10-20
NO336917B1 (no) 2015-11-23
CN1726909A (zh) 2006-02-01
BRPI0515070B1 (pt) 2020-09-08
CN100361656C (zh) 2008-01-16
CA2578130C (en) 2010-08-31
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