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 PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyclodextrin
- derivative
- pinocin
- pineal
- injection
- Prior art date
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- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- 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
- A61K47/30—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
- 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
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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
- A61K9/0012—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
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- 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
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- 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
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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 .
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Description
Claims
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES08878067.1T ES2438294T3 (es) | 2008-11-11 | 2008-11-11 | Complejos de inclusión de pinocembrina con ciclodextrina o sus derivados |
KR1020117012616A KR101563308B1 (ko) | 2008-11-11 | 2008-11-11 | 피노셈브린과 사이클로덱스트린 또는 그의 유도체와의 포접 화합물 |
CA2743006A CA2743006C (en) | 2008-11-11 | 2008-11-11 | Inclusion complexes of pinocembrin with cyclodextrin or its derivatives |
MX2011004991A MX2011004991A (es) | 2008-11-11 | 2008-11-11 | Complejos de inclusion de pinocembrina con ciclodextrina o sus derivados. |
US13/128,602 US9949946B2 (en) | 2008-11-11 | 2008-11-11 | Inclusion complexes of pinocembrin with cyclodextrin or its derivatives |
EP08878067.1A EP2359861B1 (en) | 2008-11-11 | 2008-11-11 | Inclusion complexes of pinocembrin with cyclodextrin or its derivatives |
AP2011005707A AP2011005707A0 (en) | 2008-11-11 | 2008-11-11 | Inclusion complexes of pinocembrin with cyclodextrin or its derivatives. |
BRPI0823254-7A BRPI0823254A2 (pt) | 2008-11-11 | 2008-11-11 | Complexos de inclusão de pinocembrina com ciclodextrina ou seus derivados |
JP2011534985A JP5413998B2 (ja) | 2008-11-11 | 2008-11-11 | シクロデキストリンまたはその誘導体によるピノセンブリンの封入複合体 |
PCT/CN2008/073011 WO2010054507A1 (zh) | 2008-11-11 | 2008-11-11 | 松属素环糊精或环糊精衍生物包合物 |
EA201100730A EA020784B1 (ru) | 2008-11-11 | 2008-11-11 | Комплекс включения пиноцембрина с циклодекстрином, способ его получения и применения |
AU2008364165A AU2008364165B2 (en) | 2008-11-11 | 2008-11-11 | Inclusion complexes of pinocembrin with cyclodextrin or its derivatives |
UAA201107357A UA99979C2 (uk) | 2008-11-11 | 2008-11-11 | Комплекси включення піноцембрину з циклодекстрином або його похідними |
ZA2011/03244A ZA201103244B (en) | 2008-11-11 | 2011-05-05 | Inclusion complexes of pinocembrin with cyclodextrin or its derivatives |
CU2011000103A CU24034B1 (es) | 2008-11-11 | 2011-05-11 | Complejos de inclusión de pinocembrina con ciclodextrina o sus derivados |
IL212819A IL212819A (en) | 2008-11-11 | 2011-05-11 | Compositions of pinosambrin and cyclodextrin and their uses |
IL212819A IL212819A0 (en) | 2008-11-11 | 2011-05-11 | Inclusion complexes of pinocembrin with cyclodextrin or its derivatives |
HK11109499.4A HK1155094A1 (en) | 2008-11-11 | 2011-09-08 | Inclusion complexes of pinocembrin with cyclodextrin or its derivatives |
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PCT/CN2008/073011 WO2010054507A1 (zh) | 2008-11-11 | 2008-11-11 | 松属素环糊精或环糊精衍生物包合物 |
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US (1) | US9949946B2 (zh) |
EP (1) | EP2359861B1 (zh) |
JP (1) | JP5413998B2 (zh) |
KR (1) | KR101563308B1 (zh) |
AP (1) | AP2011005707A0 (zh) |
AU (1) | AU2008364165B2 (zh) |
BR (1) | BRPI0823254A2 (zh) |
CA (1) | CA2743006C (zh) |
CU (1) | CU24034B1 (zh) |
EA (1) | EA020784B1 (zh) |
ES (1) | ES2438294T3 (zh) |
HK (1) | HK1155094A1 (zh) |
IL (2) | IL212819A (zh) |
MX (1) | MX2011004991A (zh) |
UA (1) | UA99979C2 (zh) |
WO (1) | WO2010054507A1 (zh) |
ZA (1) | ZA201103244B (zh) |
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AU2008364165A1 (en) | 2010-05-20 |
CU24034B1 (es) | 2014-10-02 |
IL212819A0 (en) | 2011-07-31 |
CA2743006A1 (en) | 2010-05-20 |
ZA201103244B (en) | 2011-12-28 |
KR20110098906A (ko) | 2011-09-02 |
EP2359861A1 (en) | 2011-08-24 |
EA020784B1 (ru) | 2015-01-30 |
CA2743006C (en) | 2016-02-09 |
JP5413998B2 (ja) | 2014-02-12 |
KR101563308B1 (ko) | 2015-10-26 |
CU20110103A7 (es) | 2012-01-31 |
HK1155094A1 (en) | 2012-08-03 |
US9949946B2 (en) | 2018-04-24 |
MX2011004991A (es) | 2011-07-29 |
JP2012508191A (ja) | 2012-04-05 |
EP2359861B1 (en) | 2013-09-11 |
US20110218173A1 (en) | 2011-09-08 |
EA201100730A1 (ru) | 2011-10-31 |
ES2438294T3 (es) | 2014-01-16 |
AU2008364165B2 (en) | 2015-01-29 |
BRPI0823254A2 (pt) | 2015-06-23 |
IL212819A (en) | 2015-07-30 |
AP2011005707A0 (en) | 2011-06-30 |
UA99979C2 (uk) | 2012-10-25 |
EP2359861A4 (en) | 2012-05-02 |
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