WO2010054507A1 - 松属素环糊精或环糊精衍生物包合物 - Google Patents

松属素环糊精或环糊精衍生物包合物 Download PDF

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Publication number
WO2010054507A1
WO2010054507A1 PCT/CN2008/073011 CN2008073011W WO2010054507A1 WO 2010054507 A1 WO2010054507 A1 WO 2010054507A1 CN 2008073011 W CN2008073011 W CN 2008073011W WO 2010054507 A1 WO2010054507 A1 WO 2010054507A1
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Prior art keywords
cyclodextrin
derivative
pinocin
pineal
injection
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PCT/CN2008/073011
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English (en)
French (fr)
Inventor
吴松
杜冠华
戚燕
高梅
杨庆云
光红梅
李薇
王月华
童元峰
Original Assignee
石药集团中奇制药技术（石家庄）有限公司
中国医学科学院药物研究所
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Priority to ES08878067.1T priority Critical patent/ES2438294T3/es
Priority to US13/128,602 priority patent/US9949946B2/en
Priority to AU2008364165A priority patent/AU2008364165B2/en
Priority to MX2011004991A priority patent/MX2011004991A/es
Priority to EA201100730A priority patent/EA020784B1/ru
Priority to KR1020117012616A priority patent/KR101563308B1/ko
Priority to EP08878067.1A priority patent/EP2359861B1/en
Application filed by 石药集团中奇制药技术（石家庄）有限公司, 中国医学科学院药物研究所 filed Critical 石药集团中奇制药技术（石家庄）有限公司
Priority to PCT/CN2008/073011 priority patent/WO2010054507A1/zh
Priority to JP2011534985A priority patent/JP5413998B2/ja
Priority to CA2743006A priority patent/CA2743006C/en
Priority to UAA201107357A priority patent/UA99979C2/uk
Priority to AP2011005707A priority patent/AP2011005707A0/xx
Priority to BRPI0823254-7A priority patent/BRPI0823254A2/pt
Publication of WO2010054507A1 publication Critical patent/WO2010054507A1/zh
Priority to ZA2011/03244A priority patent/ZA201103244B/en
Priority to IL212819A priority patent/IL212819A/en
Priority to IL212819A priority patent/IL212819A0/en
Priority to CU2011000103A priority patent/CU24034B1/es
Priority to HK11109499.4A priority patent/HK1155094A1/xx

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to a pineal cyclodextrin or cyclodextrin derivative inclusion compound, a process for the preparation thereof, and a pharmaceutical composition comprising the pineal cyclodextrin or cyclodextrin derivative inclusion complex.
  • the invention also relates to the use of the clathrate or pharmaceutical composition. Background technique
  • Pinocembrin also known as qiaosong, pine, chemical name 5,7-dihydroxyflavanone, 2,3-dihydro-5,7-dihydroxy-2- Phenyl-4H-1-benzopyran-4-one (2,3-Dihydi-5,7-dihydroxy-2-phenyl-4H-l-benzopyran-4-one), is a water-insoluble Dihydroflavonoids, the structure is as follows:
  • Pinus prime chemical structure contains a chiral center, pinocembrin natural three-dimensional structure S configuration, than ⁇ ! [O] D 15 of -45.3 (c, 0.9, acetone as solvent).
  • (S)-Pinone is a natural product extracted from propolis.
  • this compound has been found in extracts of many plants such as Swiss pine, eucalyptus, and gum arabic (Bound Chemical Chemical 2004), but the content in these plants is very low.
  • Now pine can also be obtained by synthesis, which makes a large number of pines become a reality (Cheng Yonghao, Duan Yabo, Yan Yan, Guo Xiaozan, Tong Yuanfeng, Du Guanhua, Wu Song, Chemical Reagent, 2006, 28(7): 437) . It is reported in the literature that pinocin is sensitive to a variety of pathogenic bacteria and fungi, especially to some resistant strains (Hyun Koo, Pedro L.
  • one aspect of the invention provides a cyclodextrin or cyclodextrin derivative inclusion of pinocin.
  • the pinocin and cyclodextrin or cyclodextrin derivative may be present in any suitable ratio.
  • the molecular molar ratio between them is from 1:1 to 1:100, more preferably from 1:1 to 1:10»
  • the preparation of the pineal cyclodextrin or cyclodextrin is provided.
  • a method of derivatizing a derivative also provides a pharmaceutical composition comprising the pineal cyclodextrin or cyclodextrin derivative clathrate, and optionally a pharmaceutically acceptable carrier or excipient.
  • the invention further provides the use of the pineal cyclodextrin or cyclodextrin derivative clathrate or a pharmaceutical composition comprising the clathrate for treating or preventing a disease or condition in a subject, in one embodiment
  • the condition or disease is a cardiovascular disease or stroke or a bacterial and/or fungal infection.
  • FIG. 1 Typical histopathological histology of rabbit ears injected with saline (HE); It can be seen that the venous intima is smooth and there is no inflammatory reaction around the blood vessels; Figure 2. Rabbit ears injected with pinealin clathrate injection Typical case of histopathology
  • HE venous intima
  • DL0108 pinene hydroxypropyl- ⁇ -cyclodextrin inclusion complex
  • rCBF local cerebral blood flow
  • a cyclodextrin or cyclodextrin derivative clathrate of pinealin comprising a pinealin and a cyclodextrin or a cyclodextrin derivative
  • the molecular molar ratio of the pinealin to the cyclodextrin or the cyclodextrin derivative is from 1:1 to 1:100; in a preferred embodiment, the molecular molar ratio is from 1:1 to 1:10.
  • the term "pinein” includes levansin, dextrosin, racemic rosin, or any combination thereof. Pinusin can be of natural origin or in a chemically synthesized form.
  • the cyclodextrin or cyclodextrin derivative may be selected, for example, from ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, and derivatives of various degrees of substitution, including, but not limited to, Hydroxyethyl-hydrazine-cyclodextrin, hydroxypropyl-hydrazine-cyclodextrin, dihydroxypropyl-hydrazine-cyclodextrin, decyl-hydrazine-cyclodextrin, glucose-cyclodextrin, maltose-cyclodextrin Refined, maltotriose-cyclodextrin, carboxymethyl-cyclodextrin, sulfoal
  • the cyclodextrin or cyclodextrin derivative is hydrazine-cyclodextrin or hydroxypropyl-hydrazine-cyclodextrin.
  • the cyclodextrin or cyclodextrin derivative is dimercapto-indole-cyclodextrin, hydroxypropyl-rhodium-cyclodextrin, sulfobutylether-indole-cyclodextrin, Hydroxyethyl-hydrazine-cyclodextrin, or any combination thereof.
  • the pineal cyclodextrin or cyclodextrin derivative inclusion complex may be in liquid or solid form, even in semi-solid form, depending on the need to formulate a pharmaceutical dosage form or therapeutic application.
  • a pharmaceutical composition comprising an effective amount of the pinealin cyclodextrin or cyclodextrin derivative inclusion complex of the invention and optionally pharmaceutically acceptable An acceptable carrier or excipient.
  • the single-dose specification of the pharmaceutical composition of the present invention is 1 - 1000 mg containing the active drug pine, preferably a single dose of 50-250 mg of the active drug-containing pine can be used by a method known to those skilled in the art.
  • the pharmaceutical composition of the present invention can be administered by various routes, for example, oral, intravenous, intramuscular, intraperitoneal or subcutaneous injection routes.
  • the pharmaceutical composition can be prepared from a liquid form of the cyclodextrin cyclodextrin or a cyclodextrin derivative inclusion compound in liquid form, for example, an injection (including an infusion solution, an aqueous solution for injection, a powder injection), an oral solution, a syrup, and the like.
  • the pharmaceutical composition may also be prepared from a cyclodextrin or a cyclodextrin derivative inclusion compound of a solid form in a solid form, for example, into tablets, capsules, granules, tablets, orally disintegrating tablets, tablets, and the like.
  • a preferred liquid dosage form comprises an injection of a hydroxypropyl- ⁇ -cyclodextrin inclusion compound of pinein, such as an aqueous injection solution.
  • the concentration of the aqueous injection solution is 0.01 ⁇ 3% (g/ml), pH 3 ⁇ 10, preferably pH 4 ⁇ 9, more preferably pH 5 ⁇ 8, especially pH 6 ⁇ 8; injectable aqueous solution may also contain sodium chloride, glucose, etc.
  • the injection solution may also be in the form of a powder needle.
  • the pH of the powder injection after dissolution is 3 to 10; It may further contain a proppant such as mannitol or lactose, and a pH adjuster such as hydrochloric acid or sodium hydroxide.
  • a method for preparing a cyclodextrin or a cyclodextrin derivative inclusion compound of pineantin is provided.
  • a cyclodextrin or a cyclodextrin derivative added to a solvent or a carrier to prepare a solution or suspension of a cyclodextrin or a cyclodextrin derivative in a concentration range of 1 to 60%, preferably 5 to 60%; Then, the pinealin is added thereto and mixed by stirring or grinding to obtain a liquid inclusion compound of a cyclodextrin or a cyclodextrin derivative of pinocin.
  • a cyclodextrin or a cyclodextrin derivative of pinocin may be a solution or suspension; stirring to a clear, transparent state, ie cyclodextrin or cyclodextrin derivative Compound solution.
  • the solvent may be removed by spray drying or distillation to obtain a solid inclusion compound of a cyclodextrin or a cyclodextrin derivative of pinocin.
  • a solid inclusion compound of a cyclodextrin or a cyclodextrin derivative of pine a dextrin or a cyclodextrin derivative having a concentration ranging from 10 to 15% by weight, and then freeze-drying
  • a solid inclusion complex of a cyclodextrin or a cyclodextrin derivative of pine may also be placed in a colloid mill or a mortar, stirred in an appropriate amount by adding a suitable solvent to form a paste, and then the pinusin is added to the paste.
  • a suitable solvent for dissolving the cyclodextrin or the cyclodextrin derivative is at least one selected from the group consisting of water, ethanol, decyl alcohol, propanol, isopropanol, ethylene glycol, glycerin, acetone, or any combination thereof, with preference being given to It is water.
  • the pinealin may be added in the form of a pineal solid or a solution of a pinocin dissolved in an appropriate amount of an organic solvent.
  • the invention further relates to the use of a cyclodextrin or cyclodextrin derivative clathrate of the present invention for the preparation of a medicament for the prevention and/or treatment of a disease or condition.
  • the disease or condition is cardiovascular and cerebrovascular disease; in a preferred embodiment, the cardiovascular and cerebrovascular disease is stroke; in another embodiment, the disease or condition is bacteria and/or Fungal infection.
  • the present invention provides a method of preventing and/or treating a disease or condition in a subject, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of the present invention.
  • the disease or condition is cardiovascular and cerebrovascular disease, particularly stroke.
  • the disease or condition is a bacterial and/or fungal infection.
  • the effective application amount of the pharmaceutical composition of the present invention it can be easily determined by a person of ordinary skill according to a conventional technique, and for example, it can be 0.001 mg to 10 mg/k of the subject weight.
  • the route of administration of the pharmaceutical composition can be It is selected according to the specific circumstances, including, for example, oral, parenteral (including intravenous, intramuscular, intradermal or subcutaneous injection, etc.).
  • the pinocin molecule is embedded in the tubular structure of the cyclodextrin or cyclodextrin derivative molecule, and becomes a cyclodextrin cyclodextrin.
  • an inclusion complex of a cyclodextrin derivative thereby greatly improving the water solubility of the pinealin.
  • a active ingredient is applied directly to the solid, liquid dosage form in the form of a clathrate.
  • a cyclodextrin or a cyclodextrin derivative is a less toxic, water-soluble pharmaceutical excipient, and a pinealin ring prepared therefrom is prepared from the present invention by a pineal cyclodextrin or a cyclodextrin.
  • the derivative inclusion compound has the characteristics of good water solubility and small vascular irritation, and is particularly suitable for preparing a liquid preparation.
  • the solid preparation prepared by the method has the characteristics of rapid disintegration, good dissolution and high bioavailability, and is more favorable for clinical application. Furthermore, clathrates made using embodiments of the present invention have good safety.
  • the results of the acute toxicity test showed that the cyclodextrin inclusion complex of the pineal of the present invention has an LD 5 o of more than 700 mg/kg for intravenous injection in mice, and is more than 100 times more effective than the effective dose.
  • Safety test local vascular irritation test, hemolytic test, allergy test, and intramuscular local irritation test).
  • the cyclodextrin inclusion complex of the pinealin of the present invention is non-irritating to blood vessels, does not cause hemolysis and allergic reaction.
  • the intramuscular injection has little local irritation, so it is safe and suitable for preparation into an injection form.
  • Pharmacological test results show that the cyclodextrin inclusion complex of the pine factor of the present invention can improve acute focal cerebral ischemia in rats Neurobehavioral damage; reducing the degree of cerebral blood flow in the cortical middle cerebral artery supply area.
  • the medicament for preventing and/or treating cardiovascular and cerebrovascular diseases can be prepared by using the pineal cyclodextrin inclusion compound of the present invention, Cardiovascular and cerebrovascular diseases are preferably stroke.
  • pinocin is sensitive to a variety of pathogenic bacteria and fungi, especially to some resistant strains.
  • the pineal cyclodextrin or cyclodextrin derivative inclusion complex of the present invention can also be used for the preparation of a medicament for preventing and/or treating bacterial and/or fungal infections.
  • the following examples are given. The examples are merely illustrative and are not to be construed as limiting the invention in any way. Various changes, modifications, or substitutions may be made by those skilled in the art to the disclosed embodiments of the present invention.
  • Example 1 Preparation of a liquid clathrate (solution) of hydroxypropyl- ⁇ -cyclodextrin of pinocin (1) Weigh 40g of hydroxypropyl- ⁇ -cyclodextrin, pour it into 400ml of distilled water, stir and dissolve ;
  • Example 2 Preparation of a solid inclusion compound of hydroxypropyl- ⁇ -cyclodextrin of pinein Steps (1), (2), (3) Same as Example 1;
  • Example 4 Preparation of sodium chloride infusion of hydroxypropyl-P-cyclodextrin inclusion compound of pinectin
  • Example 5 Glucose infusion step of preparing hydroxypropyl-P-cyclodextrin inclusion compound of pinusin (1), (2), (3) same as Example 4; (4) weighing 50 g of glucose for injection , adding water to stir and dissolve to make the volume up to 100ml, adding O.lg activated carbon, heating and boiling for 15 minutes, filtering and decarbonizing;
  • Example 6 Preparation of sterile powder needle with hydroxypropyl- ⁇ -cyclodextrin inclusion compound of pinusin
  • Example 7 Inclusion of Pinusin with P-cyclodextrin
  • Example 8 Preparation of oral capsule of P-cyclodextrin inclusion compound of pinusin 20 g of P-cyclodextrin inclusion compound of pinocin was weighed and mixed with 80 g of lactose by equal multiplication Dissolve HPMC in water as a binder, soften the material in 20 mesh sieves, dry it, dry the pellets with a 30-mesh sieve, and carry out intermediate testing. According to the active drug 50mg/granules, the capsules are sampled and dispensed. , that is.
  • Example 9 Preparation of Oral Tablets of P-Cyclodextrin Inclusion Complex of Pintoin 20 g of P-cyclodextrin inclusion compound of pinocin was weighed, and it was combined with 80 g of lactose and 5 g of sodium carboxymethyl starch. Mix by equal multiplication method, dissolve HPMC with water as binder, soften with 20 mesh sieve, dry under dry, dry granules with 30 mesh sieve, add micro-silica gel lg, mix evenly, according to active drug 50mg / tablet compression, sampling, dispensing, that is.
  • Example 10 Determination of Pintoin Solubility
  • the solubility in Table 1 indicates the solubility of pinocin.
  • the experimental results show that the use of cyclodextrin and cyclodextrin derivatives can greatly improve the solubility of pinocin, while other commonly used surfactants or solubilizers, cosolvents The non-aqueous solvent did not achieve good solubilization effect.
  • the muscle tissue injected into the test site is slightly hyperemic, and the range is below 0.5xl.0cm.
  • the muscle tissue injected into the test site is moderately hyperemic, with a range of 0.5xl.0cm or more.
  • the median neurological score of the solvent control group (hereinafter referred to as the solvent group) was 3.4 ⁇ 0.6 points; among them, most of the animals showed internal rotation or adduction of the contralateral forelimb of the operation, and the lateral extension of the contralateral muscle was weakened, and the circle or Occasionally, walking in a circle, rated 3 points; another few animals only showed a decrease in forelimb rotation and resistance, rated 2 The individual animals have severe symptoms and lack of independent activities, and are rated as 4 points.
  • Hydroxypropyl- ⁇ -cyclodextrin inclusion complex of compound pinein (1mg/kg, 3mg/kg, lOmg/kg, calculated according to the content of the active component pinocin, code DL0108, the same below) can significantly improve the animal brain
  • the symptoms of nerve injury after ischemia (P ⁇ 0.05, P ⁇ 0.01) showed a dose-effect relationship and were superior to the positive drug nimodipine (see Figure 3).
  • Exercise capacity evaluation (inclined plate experiment) The average residence time of the sham-operated rats on the inclined plate was 79.3 ⁇ 10.4 seconds. After acute cerebral ischemic injury, the residence time of the rats in the solvent group was significantly shortened on the inclined plate, with an average of 4.01 ⁇ 1.42 seconds.
  • the hydroxypropyl- ⁇ -cyclodextrin inclusion compound of the pinealin significantly prolonged the residence time of the animals on the inclined plate (P ⁇ 0.01), and showed a dose-effect relationship.
  • the hydroxypropyl- ⁇ -cyclodextrin inclusion complex of pinocin was different.
  • the dose group (3mg/kg, lOmg/kg) was superior to the positive control drug nimodipine (see Figure 4).
  • the effect of DL0108 on regional cerebral blood flow in rats with acute cerebral ischemia The blood flow in the local cortical middle blood supply area of MCAO surgery rapidly decreased to 20%-30% of the baseline value before surgery. After 24 hours of ischemia (before animal death) The site was compensated by collateral circulation. The regional cerebral blood flow (rCBF) increased compared with the operation, but it was still lower than 50% of the baseline value. The results are shown in Fig. 5A. After 30 min of ischemia in the brain tissue of rats, the rCBF value of the solvent group was 3.35 % of the soil of the fission value of fis.
  • the values are 40.76 soil 6.58 %, 50.09 soil 7.09 %, 53.28 soil 8.03%, 55.58 soil 6.09%, respectively. It can be seen that all groups can quickly restore cerebral blood flow, which is significantly improved compared with the solvent group.
  • the above results prove that: pineal hydroxypropyl-P-cyclodextrin inclusion complex can improve the neurobehavioral damage caused by acute focal cerebral ischemia in rats; reduce the degree of cerebral blood flow in the cortical middle cerebral artery supply area .

Description

松属素环糊精或环糊精衍生物包合物 技术领域
本发明涉及松属素环糊精或环糊精衍生物包合物、其制备方法和 含有所述松属素环糊精或环糊精衍生物包合物的药物组合物。本发明 还涉及所述包合物或药物组合物的用途。 背景技术
松属素（ pinocembrin )， 又名乔松素、 生松素， 化学名 5,7-二羟 基黄烷酮 （ 5，7-Dihydroxyflavanone )、 2,3-二氢 -5,7-二羟基 -2-苯基 -4H-1-苯并吡喃 -4- 酮 （ 2，3-Dihydi -5，7-dihydroxy-2-phenyl- 4H-l-benzopyran-4-one ), 是一种不溶于水的二氢黄酮类化合物， 结 构如下：
Figure imgf000002_0001
松属素化学结构中含有一个手性中心，天然松属素立体结构为 S 构型， 比^! [ o ]D 15为 -45.3 ( c， 0.9，丙酮为溶剂）。
(S)-松属素是从蜂胶（ propolis )中提取出的一种天然产物。 另外 在瑞士五针松、桉树叶、阿拉伯树胶等很多植物的提取物中也发现了 这种化合物（ Combined Chemical Dictionary 2004 )， 但在这些植物 中的含量均很低。现在松属素也可通过合成获得，这使得松属素的大 量得到变成现实 （程永浩，段亚波，戚燕，郭晓赞，童元峰，杜冠华，吴松， 化学试剂， 2006， 28(7):437 )。 文献报道松属素对多种致病细菌和真菌敏感，尤其是对一些耐药 菌株表现出较高的抗菌效果（ Hyun Koo, Pedro L. Rosalen, Jaime A. Cury, Yong K. Park, and William H. Bowen, Antimicrob. Agents & Chemother. 2002, 46(5), 1302-1309 )。 中国专利 200410037860.9公开 了左旋松属素对脑卒中具有很好的疗效。 由于松属素不溶于水， 口服吸收较差， 因此口服的生物利用度很 低。 另外， 由于其不溶于水也难以制成注射剂。特别是用于脑卒中等 急性病症而言， 需要所使用的药物制剂能达到快速释放、 快速起效， 采用静脉注射是临床上治疗急性病症的最常用方法，要将松属素制成 注射剂， 就必须首先解决其不溶于水的问题。 因此， 现有技术中迫切需要水溶性较好的松属素制剂。 发明内容
本发明人出乎意料地发现，通过环糊精或环糊精衍生物将松属素 制成包合物， 可以大大提高其水溶性。 因此，本发明一方面提供了松属素的环糊精或环糊精衍生物包合 物。在该包合物中，松属素和环糊精或环糊精衍生物可以任何合适的 比例存在。 优选地， 它们之间的分子摩尔比为 1:1~1:100， 更优选为 1:1-1:10» 本发明另一方面提供了制备所述松属素环糊精或环糊精衍生物 包合物的方法。 本发明还提供了含有所述松属素环糊精或环糊精衍生物包合物 以及任选地药学上可接受的载体或赋形剂的药物组合物。 本发明进一步提供了所述松属素环糊精或环糊精衍生物包合物 或包含该包合物的药物组合物用于治疗或预防对象中疾病或病症的 用途，在一个实施方案中，所述病症或疾病是心血管疾病或脑卒中或 细菌和 /或真菌感染。 附图说明
图 1. 注射生理盐水的兔耳病理组织学典型图例 （HE ); 由图可 见， 静脉内膜光滑， 血管周围未见炎性反应； 图 2. 注射松属素包合物注射液的兔耳病理组织学典型图例
( HE ); 由图可见， 静脉内膜光滑， 血管周围未见炎性反应； 图 3. DL0108 (松属素羟丙基 -β-环糊精包合物）对 MCAO手术 损伤大鼠 Bederson评分的影响； 4. DL0108对 MCAO手术损伤动物神经症状学评分的影响; 图 5. MCAO手术损伤后脑皮层中动脉供血区的不同时间段的 rCBF (局部脑血流量）值（ A ) 以及化合物 DL0108对 MCAO手术 损伤大鼠 rCBF值的影响 (B)。 图 3-图 5的数据均用平均值土 S.E.M表示。通过单因素 ANOVA 分析， 并通过 Dunett，s 检验。 n=10， ##P<0.01 vs. 空白对照组， *P<0.05, **P<0.01 vs.溶剂对照组。 具体实施方式 在本发明的第一个方面，提供了松属素的环糊精或环糊精衍生物 包合物，所述包合物含有松属素和环糊精或环糊精衍生物，其中松属 素与环糊精或环糊精衍生物的分子摩尔比为 1:1~1:100； 在一个优选 的实施方案中， 其分子摩尔比为 1:1~1:10。 在本发明中， 术语 "松属素" 包括左旋松属素、 右旋松属素、 外 消旋松属素， 或者其任意组合。松属素可以是天然来源的， 或者是化 学合成的形式。 在本发明中， 环糊精或环糊精衍生物可选自例如 α-环糊精、 Ρ- 环糊精、 γ-环糊精， 以及各种取代度的衍生物， 例如包括但不限于羟 乙基 -Ρ-环糊精、 羟丙基 -Ρ-环糊精、 二羟丙基 -Ρ-环糊精、 曱基 -Ρ-环糊 精、 葡萄糖-环糊精、 麦芽糖-环糊精、 麦芽三糖-环糊精、 羧曱基-环 糊精、 磺烷基-环糊精、 磺丁基醚 -β-环糊精， 及其任意组合。 在一个 实施方案中， 所述环糊精或环糊精衍生物是 Ρ-环糊精或羟丙基 -Ρ-环 糊精。在又一个实施方案中，所述环糊精或环糊精衍生物是二曱基 -Ρ- 环糊精、 羟丙基 -Ρ-环糊精、 磺丁基醚 -Ρ-环糊精、 羟乙基 -Ρ-环糊精， 或者其任意组合。 在本发明中，松属素环糊精或环糊精衍生物包合物可以是液体或 固体形式的，甚至可以是半固体形式的，这取决与配制药物剂型或治 疗应用的需要。 在本发明的另一个方面，提供了一种药物组合物，其包含有效量 的本发明所述松属素环糊精或环糊精衍生物包合物以及任选地药学 上可接受的载体或赋形剂。优选地，本发明药物组合物的单剂量规格 为含活性药物松属素 1 - lOOOmg，优选单剂量规格为含活性药物松属 素 50 - 250mg„可采用本领域技术人员所公知的方法，将本发明的松 用的药、物组 物、的适当形式。 P ' 、 可采用各种途径施用本发明中的药物组合物，例如口服、静脉内、 肌肉内、 腹膜内或皮下注射途径。 所述药物组合物可以由液体形式的所述松属素的环糊精或环糊 精衍生物包合物制备成例如注射液（包括输液、 注射水溶液、粉针）、 口服液、糖浆剂等液体剂型； 所述药物组合物也可以由固体形式的所 属素的环糊精或环糊精衍生物包合物制备成例如片剂、胶嚢、颗 粒剂、 片、 口崩片、 含片等多种固体剂型。 优选的液体剂型包括松属素的羟丙基- β -环糊精包合物的注射 液， 例如注射水溶液。在一个实施方案中， 所述注射水溶液的浓度为 0.01~3%(g/ml), pH值为 3~10， 优选为 pH 4~9， 更优选为 pH 5~8， 尤其是 pH 6~8; 注射水溶液中还可含有氯化钠、 葡萄糖等渗透压调 节剂及盐酸、 氢氧化钠等 pH调节剂。 所述注射液还可以是粉针的形式。在一个实施方案中，所述粉针 剂溶解后的 pH值为 3 ~ 10; 所述粉针中还可含有甘露醇、 乳糖等支 撑剂及盐酸、 氢氧化钠等 pH调剂。 在本发明的另一方面，提供了制备松属素的环糊精或环糊精衍生 物包合物的方法： 将环糊精或环糊精衍生物加入溶剂或载体中，制成重量浓度范围 为 1~60%、 优选 5~60%的环糊精或环糊精衍生物的溶液或混悬液， 然后向其中加入松属素，通过搅拌或研磨进行混合， 即得松属素的环 糊精或环糊精衍生物的液体包合物。松属素的环糊精或环糊精衍生物 的液体包合物可以是溶液或混悬液；搅拌至澄清透明状态的， 即是松 属素的环糊精或环糊精衍生物包合物的溶液。 或喷雾干燥或蒸馏浓缩等方式除去溶剂，即得松属素的环糊精或环糊 精衍生物的固体包合物。 在制备松属素的环糊精或环糊精衍生物的固体包合物的过程中， 糊精或环糊精衍生物重量浓度范围在 10~15%的溶液，再进行冷冻干 燥， 即得松属素的环糊精或环糊精衍生物的固体包合物。 在本发明的一个实施方案中，还可以将环糊精或环糊精衍生物置 于胶体磨或研钵中， 加入适量的适宜溶剂搅拌， 使成糊状物， 然后将 松属素加入上述糊状物中，研磨 1~5小时， 得均一的粘稠糊状物， 随 后过滤、浓缩或冷冻干燥， 即得松属素的环糊精或环糊精衍生物的固 体包合物。 可溶解环糊精或环糊精衍生物的适宜溶剂选自水、 乙醇、 曱醇、 丙醇、 异丙醇、 乙二醇、 丙三醇、 丙酮中至少一种或其任意组合， 其 中优选的是水。 在上述制备方法中，所述松属素可以是以松属素固体或用适量有 机溶剂溶解的松属素溶液的形式加入。 在本发明的另一方面，还涉及本发明的松属素的环糊精或环糊精 衍生物包合物在制备预防和 /或治疗疾病或病症的药物中的用途。 在一个实施方案中，所述疾病或病症是心脑血管疾病；在一个优 选方案中， 所述心脑血管疾病是脑卒中； 在另一个实施方案中， 所述 疾病或病症是细菌和 /或真菌感染。 此外， 本发明还提供了一种预防和 /或治疗对象中疾病或病症的 方法，所述方法包括给有此需要的对象施用有效量的本发明药物组合 物。 所述对象包括哺乳动物例如猫、 狗、 马、 羊、 牛、 猴、 猩猩等， 尤其是人。在此方面的一个实施方案中，所述疾病或病症是心脑血管 疾病， 尤其是脑卒中。在另一个实施方案中， 所述疾病或病症是细菌 和 /或真菌感染。 至于本发明药物组合物的有效施用量， 则是普通技 术人员根据常规技术可以容易地确定的， 例如可以是 0.001mg~10mg/k 对象体重。另外，所述药物组合物的施用途径可以 根据具体的情况加以选择， 包括例如口服、 胃肠外（包括静脉内、肌 肉内、 内或皮下注射等）。 通过本发明的实施方案， 可以实现以下的有益效果。 通过利用环糊精或环糊精衍生物对松属素进行包合，使松属素分 子包埋于环糊精或环糊精衍生物分子的管状结构中，成为松属素的环 糊精或环糊精衍生物的包合物，从而大大提高了松属素的水溶性。经 测定在 25°C时， 松属素羟丙基 -P-环糊精包合物在水中的溶解度可达 到 2000mg/100ml， 这显著高于未包合的松属素的溶解度。 具体结果 见实施例 10。
一活性成分以包合物的形式直接应用于固体、液体剂型。环糊精或环 糊精衍生物是一种毒性较小的水溶性药用辅料，用其制备的松属素环 用本 明、的实施方案制成的松属素环糊精或环糊精衍生物包合物具 有水溶性好、血管刺激性小的特点， 特别适用于制备液体制剂。 利用 本发明的实施方案，解决了松属素水溶性低， 不能直接用于液体剂型 尤其是注射剂型的技术问题。另外由于提高了水溶性，用其制备的固 体制剂具有崩解快、溶出好、生物利用度高的特点，更利于临床应用。 此外， 利用本发明的实施方案制成的包合物具有良好的安全性。 急性毒性试验结果表明：本发明的松属素的环糊精包合物，对于小鼠 静脉注射的 LD5o大于 700毫克 /千克， 较有效剂量高 100倍以上。 安 全性试验（局部血管刺激性试验、溶血性试验、过敏试验以及肌肉注 射局部刺激反应试验 兌明本发明的松属素的环糊精包合物对血管无 刺激性、 不发生溶血和过敏反应、肌肉注射局部刺激性很小， 因此安 全性良好， 适合制备成注射剂型。 药理试验结果表明：本发明的松属素的环糊精包合物能够改善大 鼠急性局灶性脑缺血造成的神经行为学损伤；减轻皮层大脑中动脉供 应区脑血流的下降程度。可以利用本发明的松属素环糊精包合物制备 预防和 \或治疗心脑血管疾病的药物， 所述的心脑血管疾病优选脑卒 中。 现有技术中松属素对多种致病细菌和真菌敏感，尤其是对一些耐 药菌株表现出较高的抗菌效果。 因此，预计本发明的松属素环糊精或 环糊精衍生物包合物也可以用于制备用于预防和 /或治疗细菌和 \或真 菌感染的药物。 为更好地理解本发明的技术方案，给出以下实施例。所述实施例 仅是示例性的， 而不能理解为对本发明的任何限制。本领域技术人员 可以对本发明的公开的技术方案做出的各种改变、变换或替代也属于 本发明的范围。 实施例 1: 制备松属素的羟丙基 -β-环糊精的液体包合物（溶液） ( 1 )称取 40g羟丙基 -β-环糊精， 倒入 400ml蒸馏水中， 搅拌溶 解；
( 2 )另称取松属素 lg， 加入 20ml无水乙醇溶解， 将该溶液倒 入上述羟丙基 -β-环糊精溶液中；
( 3 )将混合液以磁力搅拌方法在 40~50°C下搅拌 20分钟， 观察 溶液至澄清透明， 即得松属素的羟丙基 -P-环糊精衍生物的包合物溶 液。 实施例 2: 制备松属素的羟丙基- β -环糊精的固体包合物 步骤（1 )、 （2 )、 ( 3 ) 同实施例 1;
( 4 ): 将所得的松属素羟丙基 环糊精衍生物包合物溶液进行 冷冻干燥， 即得松属素的羟丙基 环糊精的固体包合物。 实施例 3: 制备松属素的羟丙基 环糊精的固体包合物
( 1 )称取 20g羟丙基- β -环糊精， 研钵中加入 100ml蒸馏 水中， 研磨使成糊状；
( 2 )另称取松属素 3g， 加入 20ml无水乙醇溶解， 将该溶液倒 入上述羟丙基- β -环糊精溶液中；
( 3 )将混合液研磨 2小时， 得到均一糊状物， 过滤， 减压蒸干， 即得松属素的环糊精衍生物的固体包合物。 实施例 4: 制备松属素的羟丙基 -P-环糊精包合物的氯化钠输液
(1)称取 20g羟丙基 -β-环糊精， 倒入 200ml蒸馏水中， 搅拌溶 解， 加入 0.5g输液用活性炭， 搅拌加热至 80°C， 保温 15分钟， 过滤 脱炭； (2) 另称取松属素 2g， 加入 20ml无水乙醇溶解， 将该溶液倒 入上述羟丙基 -β-环糊精溶液中；
( 3 )将混合液以磁力搅拌方法在 40~50°C下搅拌 20分钟， 观察 溶液至澄清透明， 得到松属素的羟丙基 -P-环糊精衍生物包合物溶液；
(4)将包合物溶液补水至 800ml， 加入注射用氯化钠 7~8g， 调 节 pH至 8~9， 并用 0.05M的盐酸或 0.05M的氢氧化钠调节 PH至
3.5-7, 补水至 1000ml, 加入 O.lg注射用活性炭， 搅拌 20分钟；
(5)将溶液脱炭， 灌装， 于 115 30分钟热压灭菌即得。 实施例 5: 制备松属素的羟丙基 -P-环糊精包合物的葡萄糖输液 步骤（1)、 （2)、 (3) 同实施例 4; (4)称取注射用葡萄糖 50g, 加水搅拌溶解使体积达 100ml, 加入 O.lg活性炭， 加热微沸 15分钟， 过滤脱炭；
(5)将葡萄糖液倒入包合物溶液中， 补水至 800ml， 用 0.05M 的盐酸或 0.05M的氢氧化钠调节 pH至 6~7， 补水至 1000ml， 加入 O.lg注射用活性炭， 搅拌 20分钟； (6)将溶液分别用过滤器和砂滤棒（孔径 1.0μιη、 0.45μιη、
0.22μιη )进行粗滤和精滤， 然后灌装， 于 115 30分钟热压灭菌即 得。 实施例 6: 用松属素的羟丙基- β -环糊精包合物制备无菌粉针
(1)在无菌操作室内， 称取 40g羟丙基 -Ρ-环糊精， 加水溶解成 80ml, 加入 O.lg活性炭， 加热微沸 15分钟， 过滤脱炭；
(2) 另称取松属素 lg， 加入 20ml无水乙醇溶解， 将该溶液倒 入上述羟丙基 -β-环糊精溶液中;
( 3 )将混合液以磁力搅拌方法在 下搅拌 20分钟，搅拌， 观察溶液至澄清透明， 得到松属素的羟丙基 -Ρ-环糊精衍生物的包合 物溶液； ( 4 )将包合物溶液补水至 100ml,过 0.22μιη滤膜，分装于 10ml 的西林瓶中 （2~3ml/瓶）， 置入冻干机中冷冻干燥， 压盖， 即得无菌 粉针。 实施例 7: 用 P-环糊精包合松属素 称取 40g P-环糊精， 加入 100ml蒸馏水， 加热至 40 50C 使 β -环糊精溶解，加入用 20ml无水乙醇溶解的 lg松属素，磁力搅拌 2~3 小时后， 过滤， 冷冻干燥， 即得 P-环糊精松属素包合物。
实施例 8: 松属素的 P-环糊精包合物的口服胶嚢的制备 称取松属素的 P-环糊精包合物 20g，将其与 80g乳糖按等量倍增 法混匀， 用水溶解 HPMC作为粘合剂制软材， 20目筛制粒， 下 干燥，干颗粒用 30目筛整粒，进行中间体检验，按含活性药物 50mg/ 粒装胶嚢， 抽检， 分装， 即得。 实施例 9: 松属素的 P-环糊精包合物的口服片剂的制备 称取松属素的 P-环糊精包合物 20g， 将其与 80g乳糖和 5g羧曱 基淀粉钠按等量倍增法混匀， 用水溶解 HPMC作为粘合剂制软材， 20目筛制粒， 下干燥，干颗粒用 30目筛整粒，加入微粉硅胶 lg, 混和均匀， 按含活性药物 50mg/片压片， 抽检， 分装， 即得。 实施例 10: 松属素溶解度测定
筛选可用于注射剂的增溶剂、助溶剂及非水溶剂，分别采用其在 注射剂中常规用量进行试验，考察其对松属素的增溶效果，具体结果 见表 1: 表 1 松属素溶解情况
Figure imgf000011_0001
表 1中的溶解度表示的是松属素的溶解度， 实验结果表明，采用 环糊精和环糊精衍生物能够很大程度提高松属素溶解度，而其他常用 表面活性剂或增溶剂、 助溶剂、 非水溶剂均未取得良好的增溶效果。
安全性试验 松属素包合物注射液动物安全性试验 松属素包合物注射液的制备：按照实施例 4的方法制备松属素羟 丙基 -β-环糊精包合物的氯化钠输液， 然后再以 0.9 %的氯化钠溶液稀 释至 10倍体积即得。
1、 局部血管刺激性试验 经家兔耳缘静脉注射松属素包合物注射液 10 mL (含松属素 2 mg ), 每天一次， 连续 3天， 注射部位及四周血管均完整清晰， 未见 明显红肿充血等炎性及刺激性反应，与注射生理盐水的部位比较无明 显差异。 病理组织学观察未见明显病理改变。 结果见图 1、 2。
2 溶血性试验 取试管 7只， 按表 2配比量依次加入红细胞混悬液、 生理盐水、 不同量的松属素包合物注射液（浓度为 0.20 mg/mL )或蒸馏水。 将 上述试管轻轻摇匀后 水浴中保温，观察混合后 0.5、 1、 2、 3h 的 溶血现象。临床浓度的松属素包合物注射液各加药管与生理盐水空白 对照管无明显差异。 结果见表 3。 溶血试验加样分配表 试管编号 1 2 3 4 5 6 7
2%红细胞混悬液 (mL) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 生理盐水（mL) 2.4 2.3 2.2 2.1 2.0 2.5 - 蒸馏水 (mL) 2.5 松属素包合物注射液 0.1 0.2 0.3 0.4 0.5 - - ( 0.20 mg/mL ) (mL)
表 3 松属素包合物注射液对溶血的影响
0.5 h — — ― — — ― + l h — — ― — — ― +
2 h — — ― — — ― +
3 h — — ― — — ― + 注： "+" 表示完全溶血， "-" 表示无溶血。
3 过敏试验 依据表 4判别 14天和 21天静脉给予豚鼠受试药（松属素包合物 注射液）、 阳性对照药 （卵蛋白）后过敏反应的严重程度。 结果见表 表 4 过敏反应等级判断标准
反应级数 反应症状
0 无明显反应
1 只有轻微抓鼻， 颤抖或竖毛
2 有几次咳嗽， 有抓鼻， 颤抖或竖毛
3 多次或连续咳嗽， 伴有呼吸困难或痉挛， 抽摇
4 痉挛， 抽摇， 大小便失禁， 休克死亡
松属素包合物注射液对豚鼠全身自动过敏反应的影响 过敏反应级数 药 品
14 天 21 天 受试药（松属素包合物注射液） 0 0
阳性对照药 （卵蛋白） 4 4
4 肌肉注射局部刺^^应试验 依据表 6判别肌肉反应的严重程度。家兔注射松属素包合物注射 液 48h后，给药部位仅有轻度充血（直径 < 0.5cm )，无明显刺激反应， 其刺^ ^应平均分在 2.0以下，表明松属素包合物注射液肌肉注射局 部刺激性^ ί艮小。 结果见表 7。 表 6肌肉组织反应分^ 反应级数 反应症状
0 注射供试品部位的肌肉组织与对照部位肌肉组织无明显差异
1 注射供试品部位的肌肉组织轻度充血， 范围在 0.5xl.0cm以下
2 注射供试品部位的肌肉组织中度充血， 范围在 0.5xl.0cm以上
3 注射供试品部位的肌肉组织重度充血， 伴有肌肉变性
4 注射供试品部位的肌肉组织出现坏死， 有褐色病变
5 注射供试品部位的肌肉组织出现广泛性坏死
表 7松属素注射液对肌肉注射局部刺激性 组别 动物数 评分 平均分 生理盐水 4 0 1 1 0 0.50 松属素包合物注射液 4 1 0 1 1 0.75
药理实验 松属素的羟丙基 -P-环糊精包合物对大鼠急性局灶性脑缺血损伤 的保护作用 试验方法： 按文献报道的 MCAO模型方法进行试验（张均田主 编，现代药理实验方法，北京医科大学中国协和医科大学联合出版社， 1998年 10月第一版）。 神经症状学评分 ( Bederson's Value ) 假手术组动物行为学评分为 0分。溶剂对照组（以下简称溶剂组） 动物神经学评分平均值为 3.4 ± 0.6分； 其中， 多数动物表现为手术对 侧前肢内旋或内收，侧向挤压对侧肌伸力量减弱，转圈或偶尔转圈行 走， 评为 3 分； 另外少数动物仅出现前肢内旋和抗力下降， 评为 2 分； 个别动物症状较重， 缺乏自主活动， 评为 4分。 化合物松属素的羟丙基 -β-环糊精包合物 （lmg/kg、 3mg/kg、 lOmg/kg, 按活性成分松属素含量计算， 代号 DL0108, 下同） 能显 著改善动物脑缺血后的神经损伤症状（ P<0.05， P<0.01 )， 并呈现剂量 -效应关系， 且均优于阳性药物尼莫地平 （见图 3 )。 运动能力评价（倾斜板实验） 假手术组大鼠在倾斜板上停留时间平均值为 79.3土 10.4秒。急性 脑缺血损伤后，溶剂组大鼠在倾斜板上停留时间明显缩短，平均值为 4.01 ± 1.42 秒， 与溶剂组相比， 松属素的羟丙基 -β-环糊精包合物 ( 3mg/kg, lOmg/kg ) 能显著延长动物在倾斜板上的停留时间 ( P<0.01 ), 并呈现剂量-效应关系， 松属素的羟丙基 -β-环糊精包合 物不同剂量组（3mg/kg、 lOmg/kg )的作用效果优于阳性对照药物尼 莫地平 （见图 4 )。
DL0108对大鼠急性脑缺血组织局部脑血流量的影响 MCAO手术造成局部皮层中动脉供血区血流量迅速下降到手术 前基础值的 20%-30%， 缺血 24h后 （动物处死前） 同部位受到侧枝 循环代偿， 局部脑血流量（regional cerebral blood flow, rCBF )较手 术时有所上升， 但仍低于基础值的 50%， 结果如图 5A所示。 大鼠脑组织缺血 30min后， 溶剂组 rCBF值为^ fi¾值的 31.09土 5.35 % , 包合物 DL0108 ( lmg/kg、 3mg/kg、 10mg/kg )给药组、 尼 莫地平组的 rCBF值分别为基础值的 40.76土 6.58 %、 50.09土 7.09 %、 53.28土 8.03 %、 55.58土 6.09%， 可见给药各组均可快速恢复脑血流， 较溶剂组均有明显提高， 其中松属素 （3、 lOmg/kg )给药组、 尼莫 地平 （3mg/kg )组与溶剂组相比具有显著性差异（P<0.05 )， 结果如 图 5B所示。 以上结果证明： 松属素羟丙基 -P-环糊精包合物能够改善大鼠急 性局灶性脑缺血造成的神经行为学损伤；减轻皮层大脑中动脉供应区 脑血流的下降程度。

Claims

权 利 要 求
1.一种松属素环糊精或环糊精衍生物包合物， 其含有松属素和 环糊精或环糊精衍生物，优选所述松属素与所述环糊精或环糊精衍生 物的分子摩尔比为 1:1~1:100， 更优选为 1:1~1:10。
2.根据权利要求 1的松属素环糊精或环糊精衍生物包合物， 其 中所述松属素选自左旋松属素、右旋松属素、外消旋松属素或其任意 组合。
3.根据权利要求 1或 2的松属素环糊精或环糊精衍生物包合物， 其中所述环糊精或环糊精衍生物选自 α-环糊精、 Ρ-环糊精、 γ-环糊精， 羟乙基 -Ρ-环糊精、 羟丙基 -Ρ-环糊精、 二羟丙基 -Ρ-环糊精、 曱基 -Ρ- 环糊精、 葡萄糖-环糊精、 麦芽糖-环糊精、 麦芽三糖-环糊精、羧曱基 -环糊精、 磺烷基-环糊精、 磺丁基醚 环糊精， 或者其任意组合。
4. 一种药物组合物， 其包含有效量的权利要求 1~3 中任一项所 述松属素环糊精或环糊精衍生物包合物以及任选地药学上可接受的 载体或赋形剂。
5.权利要求 4的药物组合物， 其通过口服、 静脉内、 肌肉内、 腹膜内或皮下注射途径施用。
6.权利要求 4的药物组合物， 其为以下形式： 输液、 注射液、 粉针、 口服液、 糖浆剂、 片剂、 胶嚢、 颗粒剂、 片、 口崩片、 含 片或其它剂型。
7.权利要求 4或 5或 6的药物组合物， 其为松属素的羟丙基 -β- 环糊精包合物的注射液， 其浓度为 0.01~3%(g/ml)。
8.权利要求 4或 5或 6的药物组合物， 其为松属素的羟丙基 -β- 环糊精包合物的粉针剂， 其溶解后的 ρΗ值为 3~10。
9. 制备权利要求 1~3中任一项的松属素环糊精或环糊精衍生物 包合物的方法， 包括以下步骤： （ 1 )将环糊精或环糊精衍生物溶于或 混悬于溶剂中制成重量浓度范围在 1~60%的溶液或混悬液； （2 )将 上述溶液或混悬液与适量的松属素通过搅拌或研磨进行混合包合，和
( 3 )任选地从步骤（2 ) 中获得的包合混合物中除去溶剂。
10.根据权利要求 9的方法， 其中所述的溶剂选自水、 乙醇、 曱 醇、 丙醇、 异丙醇、 乙二醇、 丙三醇、 丙酮或其任意组合。
11.权利要求 1~3中任一项所述的松属素环糊精或环糊精衍生物 包合物在制备预防和 /或治疗疾病或病症尤其是心脑血管疾病或脑卒 中或细菌和 /或真菌感染的药物中的应用。
12. 一种治疗或预防疾病或病症尤其是心脑血管疾病或脑卒中 或细菌和 /或真菌感染的方法， 包括给有此需要的对象施用根据权利 要求 4~8中任一项的药物组合物。
PCT/CN2008/073011 2008-11-11 2008-11-11 松属素环糊精或环糊精衍生物包合物 WO2010054507A1 (zh)

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EA020784B1 (ru) 2015-01-30
AP2011005707A0 (en) 2011-06-30
ZA201103244B (en) 2011-12-28
CU24034B1 (es) 2014-10-02
IL212819A (en) 2015-07-30
US9949946B2 (en) 2018-04-24
EP2359861A1 (en) 2011-08-24
ES2438294T3 (es) 2014-01-16
KR20110098906A (ko) 2011-09-02
JP5413998B2 (ja) 2014-02-12
JP2012508191A (ja) 2012-04-05
MX2011004991A (es) 2011-07-29
CA2743006C (en) 2016-02-09
AU2008364165A1 (en) 2010-05-20
BRPI0823254A2 (pt) 2015-06-23
CA2743006A1 (en) 2010-05-20
KR101563308B1 (ko) 2015-10-26
UA99979C2 (uk) 2012-10-25
AU2008364165B2 (en) 2015-01-29
HK1155094A1 (en) 2012-08-03
EP2359861B1 (en) 2013-09-11
IL212819A0 (en) 2011-07-31

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