WO2008061428A1 - Formulations pharmaceutiques, utilisation et élaboration du triacontanol - Google Patents

Formulations pharmaceutiques, utilisation et élaboration du triacontanol Download PDF

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Publication number
WO2008061428A1
WO2008061428A1 PCT/CN2007/002873 CN2007002873W WO2008061428A1 WO 2008061428 A1 WO2008061428 A1 WO 2008061428A1 CN 2007002873 W CN2007002873 W CN 2007002873W WO 2008061428 A1 WO2008061428 A1 WO 2008061428A1
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WO
WIPO (PCT)
Prior art keywords
triacontanol
weight
preparation
ethyl acetate
eluent
Prior art date
Application number
PCT/CN2007/002873
Other languages
English (en)
Chinese (zh)
Inventor
Xian'e Fan
Renwei Zhang
Huijia Cheng
Original Assignee
Fan Xian E
Renwei Zhang
Huijia Cheng
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
Priority claimed from CN2006100488523A external-priority patent/CN101190873B/zh
Priority claimed from CNA2007100661127A external-priority patent/CN101366707A/zh
Application filed by Fan Xian E, Renwei Zhang, Huijia Cheng filed Critical Fan Xian E
Publication of WO2008061428A1 publication Critical patent/WO2008061428A1/fr

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Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
    • C07C29/80—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by distillation

Definitions

  • Triacontanol pharmaceutical preparation application and preparation method
  • the present invention relates to a process for the preparation of existing compounds, specific pharmaceutical formulations and novel uses thereof. Background technique
  • Triacontanol the molecular formula is C 3 . 3 ⁇ 4 2 0, the structural formula is C3 ⁇ 4-(CH 2 ) 28 -CH 2 -OH, which has been reported in the prior art, and its reports are focused on tridecyl alcohol for vegetables, fruits, plants and food crops. Growth regulators and nutrients have also been reported as pesticides.
  • Chinese Patent Application No. 93109943.9 discloses a "total sterol for lowering blood fat", which is a mixture containing octadecyl alcohol to tridecyl sterol, the main components of which are triacontanol, octacosanol and Tridodecanol, used to lower blood fat, anti-atherosclerosis, can also be used for weight loss.
  • This application does not explain the proportional relationship between the respective alkanols in the mixture, nor does it describe the contents and ratios of tridecyl alcohol, octadecyl alcohol and tridodecyl alcohol as main components, throughout the specification.
  • the total sterols described in this product are mixtures containing octacosanol to tridecyl sterol. They are all long-chain fatty compounds, have great chemical stability, are odorless, tasteless waxy solids, insoluble in water, and have a decrease in primary hyperlipidemia and subsequent hyperlipidemia. Lipid action has no side effects on heart, liver, kidney, lung, nerve and gonad, and also has the effect of reducing body weight.
  • the application discloses a total alkanol, that is, a mixture, without limiting and indicating the content of each component in the mixture.
  • there is no experimental data in the application and it is not confirmed whether it is effective or not.
  • Chinese Patent Application No. 03113007.0 discloses "a preparation method of rice bran active material octadecyl alcohol and tridecyl alcohol", using crude rice bran wax as a raw material, and extracting crude rice wax by using isopropyl alcohol as a solvent extraction method. Deoiling and purifying refined wax; using ultrasonic hydrolysis of rice bran wax to obtain fatty alcohol and fatty acid salt mixture; using acetone extraction method for alcohol and acid separation, extracting and refining mixed fatty alcohol; finally using molecular distillation technology to separate twenty Octadecanol, triacontanol.
  • 85103562 discloses "a new method for purifying triterpene alcohol", which is a simple purification method for preparing high-purity triterpene alcohol from natural resources such as beeswax, which can produce octadecyl alcohol content.
  • the object of the present invention is to overcome the deficiencies of the prior art and to provide a sustained release pharmaceutical preparation containing tridecyl alcohol as the sole active ingredient.
  • Another object of the present invention is to provide a novel application of triacontanol as a medicament for the preparation of a hyperlipidemic disease.
  • a further object of the present invention is to provide a process for preparing triacontanol from Euphorbiaceae.
  • the triacontanol preparation of the invention consists of a pharmaceutically active ingredient, a sustained release part and an immediate release part, and the weight of each ingredient is as follows: tridecyl alcohol 90-110, ethyl cellulose 50-70, Acryl resin No. II No. 10-30, starch 50-70.
  • tridecyl alcohol is the main active ingredient and is the only medicinal ingredient in the pharmaceutical preparation, so the weight fraction of the whole pharmaceutical preparation does not necessarily have strict requirements;
  • starch is a medicinal auxiliary It is also an immediate release agent in the pharmaceutical preparation;
  • ethyl cellulose and acrylic resin II are pharmaceutical excipients, and are also sustained release agents in the pharmaceutical preparations.
  • the preparation method of the pharmaceutical preparation for treating hyperlipemia diseases comprises the following steps: 1. taking the above parts by weight of ethyl cellulose and acrylic acid resin No. II and adding ethanol to dissolve, adding half of the above-mentioned parts by weight Triacontanol, made of soft material, sifted, made into wet granules, dried, sieved, whole, ready for use;
  • the above-mentioned ethanol and talc powder are all required according to the conventional process, and the addition amount and concentration thereof are conventional, and there is no special requirement in the present application.
  • the principle of the controlled release preparation is mainly designed to reduce the dissolution rate of the drug in the preparation and the diffusion rate of the drug molecule.
  • the amount of drug absorbed is proportional to the amount of drug eluted and diffused from the dosage form. Therefore, this study intends to slow down the dissolution and diffusion rate of the drug from the formulation to design a water-insoluble skeleton controlled release tablet.
  • the hydrophobic polymer adjuvant ethyl cellulose is selected as a retarder, which can delay the dissolution rate of the drug.
  • the starch is used as the immediate release agent, so the tablet is divided into two parts, namely, the sustained release part and the speed. Release part.
  • the present invention relates to the use of tridecyl alcohol as a medicament for the preparation of a medicament for treating hyperlipemia.
  • the preparation method of the triacontanol of the present invention comprises the following steps:
  • the solid matter is mixed with more than one-fold column chromatography silica gel, and subjected to silica gel column chromatography, first eluting with n-hexane as an eluent, and the washing liquid is discarded, and then using n-hexane: ethyl acetate
  • the eluent of 100:3-10 was eluted with a gradient.
  • the eluent containing 5-10% ethyl acetate was collected, and the solvent was recovered to give a solid material which crystallised from ethyl acetate to give flaky crystals.
  • the Euphorbia genus is Euonymus sinensis, Big Stellera chamaejasme, Little Stellera chamaejasme or Chicken colegulosa; the amount of petroleum ether and the amount of chloroform described in the second step are generally not more than 10 times; The amount of column chromatography silica gel of the mixed solids described herein is 1-3 times.
  • the present invention explores new medical uses for the known compound triacontanol and opens up a number of new applications.
  • the triacontanol of the invention is safe, non-toxic, and has strong pharmacological effects, indicating a good medicinal prospect.
  • the present invention provides a process for obtaining triacontanol from plants, which increases the route of obtaining the known compound tridecyl alcohol.
  • 60 healthy SD rats were randomly divided into 6 groups, 10 in each group, respectively, in the A-F group:
  • the high dose group of the present invention is 150 mg kg (the present invention is the same as the first embodiment of the present invention)
  • the dosage group 100 mg/kg
  • the above groups of animals were observed for blood lipid levels after 10 days of observation under ether anesthesia.
  • the other groups of animals began to feed high-fat diet (1% cholesterol, 10 ° / lard, 10% egg yolk powder and 79% basic feed), blood collection review after 5 weeks Blood lipid level, to determine whether the model is successful.
  • the animals in the CF group were administered with the same dosage of the drug of the first embodiment (the dosage volume was 2 ml/100 g body weight), and the animals in groups A and B were intragastrically administered with an equal volume of normal saline. 3 weeks. During the administration period, except for the blank control group, the other groups of animals continued to be fed with high-fat materials.
  • the blood lipid levels were observed as: total cholesterol (TC;), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and density lipoprotein cholesterol (HDL-C).
  • TC total cholesterol
  • TG triglyceride
  • LDL-C low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • the present invention 150 0.47 ⁇ 0.27 5.79 ⁇ 0.86** 3.12 + 0.64** 1.47 ⁇ 0.29 1.31 ⁇ 0.14 * 1.70 ⁇ 0.24 *
  • the sustained-release portion triglyceride 50 g, ethyl cellulose 60 g, acryl resin No. II 20 g, and ethanol (75%).
  • Immediate release 30 g of sterol, 60 g of starch, and appropriate amount of talcum powder.
  • Ethyl cellulose and acrylic resin were weighed and dissolved in 75% by volume of ethanol, and 50 g of tridecyl alcohol was added to make a soft material. After passing through a 20 mesh sieve, wet granules were formed and dried at 60 ° C. Sift, whole, spare.
  • Tableting The prepared two kinds of granules are thoroughly mixed, and an appropriate amount of talc powder is mixed, and each tablet contains 30 mg of 30 sterol tablets, thereby obtaining a triacontanol sustained-release tablet.
  • In vitro experiments are an important means of screening prescriptions for determining the process, and they play an important role in the quality control of the preparations.
  • the screening prescriptions are usually based on the dissolution rate, the selection of excipients, the process conditions and whether the prescriptions are in line with mass production. It is mainly examined by the dissolution rate. Appropriate formulation and process conditions must have appropriate dissolution rate data to show that the amount of drug dissolved from the formulation should not be too fast or too slow in a unit of time.
  • the eluate containing 5-10% ethyl acetate was collected, and the solvent was recovered to give a solid material which crystallised from ethyl acetate to give flaky crystals.
  • Crystalline melting point 84-85 ° C, by ultraviolet, infrared, nuclear magnetic resonance mass spectrometry, the obtained flaky crystals have a molecular formula of 0: 3 () 2 0, molecular weight 438, the structural formula is CH r (CH 2 ) 28 -CH 2 - OH. That is, triacontanol.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

Utilisation du triacontanol dans la production de médicaments pour le traitement de l'hyperlipidémie, formulations pharmaceutiques renfermant ce produit et procédé d'élaboration du produit. Les formulations comprennent des agents pharmaceutiquement actifs, un composant de libération contrôlée et un composant de libération immédiate, selon les rapports de poids suivants: triacontanol 90-110, éthyl cellulose 50-70, Eudragit II 10-30 et amidon 50-70. Le procédé d'élaboration est le suivant: (1) utilisation de poudre brute de plante entière d'Euphorbiaceae Euphorbia comme matière première, après extraction en reflux thermique avec de l'éthanol, puis concentration de l'extrait; (2) dégraissage du produit issu de l'étape (1) pour donner des solides; (3) chromatographie de ces solides sur gel de silice, collecte d'éluants, récupération de solvants et cristallisation de solide résultant avec de l'éthyl acétate pour donner un produit cristallin en paillettes.
PCT/CN2007/002873 2006-11-24 2007-09-30 Formulations pharmaceutiques, utilisation et élaboration du triacontanol WO2008061428A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN2006100488523A CN101190873B (zh) 2006-11-24 2006-11-24 三十烷醇的制备方法
CN200610048852.3 2006-11-24
CNA2007100661127A CN101366707A (zh) 2007-08-14 2007-08-14 三十烷醇在制备治疗高血脂疾病的药物中的应用和药物制剂及制备方法
CN200710066112.7 2007-08-14

Publications (1)

Publication Number Publication Date
WO2008061428A1 true WO2008061428A1 (fr) 2008-05-29

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PCT/CN2007/002873 WO2008061428A1 (fr) 2006-11-24 2007-09-30 Formulations pharmaceutiques, utilisation et élaboration du triacontanol

Country Status (1)

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WO (1) WO2008061428A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1098906A (zh) * 1993-08-20 1995-02-22 广东省广州白云山企业集团公司 用于降血脂的总烷醇
US6225354B1 (en) * 1999-06-21 2001-05-01 Cholesterol Control Laboratories, Inc. High molecular weight primary aliphatic alcohols obtained from beeswax and pharmaceutical use thereof
WO2005067903A1 (fr) * 2004-01-20 2005-07-28 Panacea Biotec Ltd. Compositions pharmaceutiques comprenant des alcools primaires superieurs et un ezetimibe, et procede de preparation de celles-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1098906A (zh) * 1993-08-20 1995-02-22 广东省广州白云山企业集团公司 用于降血脂的总烷醇
US6225354B1 (en) * 1999-06-21 2001-05-01 Cholesterol Control Laboratories, Inc. High molecular weight primary aliphatic alcohols obtained from beeswax and pharmaceutical use thereof
WO2005067903A1 (fr) * 2004-01-20 2005-07-28 Panacea Biotec Ltd. Compositions pharmaceutiques comprenant des alcools primaires superieurs et un ezetimibe, et procede de preparation de celles-ci

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