US20060166931A1 - Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof - Google Patents
Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof Download PDFInfo
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- US20060166931A1 US20060166931A1 US10/524,653 US52465305A US2006166931A1 US 20060166931 A1 US20060166931 A1 US 20060166931A1 US 52465305 A US52465305 A US 52465305A US 2006166931 A1 US2006166931 A1 US 2006166931A1
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- cyclodextrin
- butylphthalide
- inclusion complex
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- HJXMNVQARNZTEE-UHFFFAOYSA-N CCCCC1OC(=O)C2=CC=CC=C21 Chemical compound CCCCC1OC(=O)C2=CC=CC=C21 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
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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
- A61K31/34—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
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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
- A61K47/50—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
- 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
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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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Definitions
- the present invention relates to pharmaceutical compositions. More particularly, it relates to the inclusion complexes of butylphthalide, which is D,L-mixed or levorotary, with cyclodextrin or its derivatives, to a process for their preparation and the use thereof.
- Butylphthalide is a water insoluble oily compound with the following formula:
- Butylphtualide can be obtained by extraction from natural celery seed oil or by chemical synthesis, as described in Chinese patent application No. 99109673.8 and the prior reference: Junshan Yang, Yalun Su, Chinese Pharmaceutical Bulletin, 1984, 31; 671, which realized the availability of butylphthalide.
- the pharmaceutical formulations are required to release active agents quickly and exert therapeutic effects rapidly when they are used to treat ischemia-induced diseases or thrombosis.
- the formulations for treating acute disease are administrated by intravenous instillation.
- the butylphthalide can only be formulated into soft capsules for oral administration because of its oily characteristics. Therefore, solubility problem of the butylphthalide must be resolved firstly in order to obtain injectable dosage forms.
- the present invention intends to provide inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof.
- it is complexed with cyclodextrin or its derivatives, wherein the butylphthalide is D,L-mixed or levorotary, and the inclusion complexes may be used to prepare various clinically applicable solid and liquid formulations.
- An inclusion complex of butylphthalide with cyclodextrin or its derivatives comprises butylphthalide and cyclodextrin or its derivatives, wherein the molar ratio of butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10.
- the butylphthalide mentioned above comprises D,L-mixed or levorotatory butylphthalide.
- the cyclodextrin mentioned above is selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
- the derivatives of cyclodextrin mentioned above are selected from the group consisting of hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, dihydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, meltotriose cyclodextrin, carboxymethyl cyclodextrin, and sulfonylalkyl cyclodextrin.
- hydroxypropyl- ⁇ -cyclodextrin is preferred.
- a solution with a concentration of 5-60% is prepared by adding cyclodextrin or its derivatives into a suitable solvent vehicle.
- a liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives is obtained by adding butylphthalide into the above solution, stirring to provide a clear and transparent solution without oil drops, wherein the molar ratio of butylphthalide to cyclodextrin or its derivatives is in the range of 1:1 to 1:10.
- the process mentioned above may further comprise drying the liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives at the temperature of 40-80° C. to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives.
- the process mentioned above may also comprise concentrating the liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives until the concentration of cyclodextrin or its derivatives is 10-15% (W/V), cooling the solution for, e.g. about 12 hours to obtain white precipitate, filtering, and drying at 40-80° C., to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives.
- a process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives comprises placing cyclodextrin or its derivatives into a colloid mill or mortar, adding an appropriate amount of suitable solvent vehicle, and stirring the mixture to provide a paste; adding butylphthalide into the paste described above, grinding for about 1-5 hours to provide a homogenous and viscous paste, then filtering the paste, and drying at 40-80° C. to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives, wherein the molar ratio butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10.
- a process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives comprises adding cyclodextrin or its derivatives into a suitable solvent vehicle to obtain a solution with a concentration of 5-60%, dissolving the butylphthalide into an appropriate amount of ethanol with purity of 99%, mixing the two solutions, stirring, and drying to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives, wherein the molar ratio butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10.
- the drying method mentioned above may be any drying method, such as direct drying, spray drying, or freeze-drying.
- solvent vehicles examples include water, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, glycerin, or acetone, or the mixture of any two or more above-mentioned solvent vehicles, wherein water is preferred.
- Such liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives may be directly used to produce liquid formulations, such as infusion, injection, injectable powder, liquids for oral administration, syrup, and the like;
- the solid inclusion complex of butylphthalide with cyclodextrin or its derivatives may be used to produce solid formulations, such as tablets, capsules, granules, dispersible tablets, and the like.
- cyclodextrin or its derivatives could trap the butylphthalide into their tubular structure to generate an inclusion complex of butylphthalide with cyclodextrin or its derivatives, thereby improving the water-solubility of butylphthalide.
- the active ingredient butylphthalide in the form of inclusion complexes can be directly applied in solid or liquid dosage forms. Limitations such as poor water-solubility, disability to be directly applied in solid, especially injectable dosage forms can be overcome.
- Cyclodextrin or its derivatives are water-soluble pharmaceutical excipients with little toxicity.
- the inclusion complexes of butylphthalide with cyclodextrin or its derivatives prepared thereby are suitable to be formulated into various liquid and solid dosage forms.
- the inclusion complexes have the advantages such as good water-solubility and little vascular irritation.
- the solubility of inclusion complex of butylphthalide with hydroxypropyl-o-cyclodextrin in water at 25° C. is 924 mg/100 ml.
- the inclusion complex is particularly applicable for preparing liquid dosage forms.
- the present invention overcomes the limitation that butylphthalide cannot be used to prepare liquid formulations. Due to the fact that the water-solubility is improved, the resulting solid dosage forms have the advantages such as rapid disintegration, good solubility and high bioavailability, which is more applicable for clinical use.
- vascular irritation assay using inclusion complex of butylphthalide with hydroxypropyl- ⁇ -cyclodextrin is provided as follows:
- test group Eight rabbits were divided into two groups, namely, test group and control group.
- test group 2.45 g/kg of the inclusion complex together with 40 ml of 5% glucose were instilled via the marginal ear vein of a rabbit at the rate of 1.5 ml/min. The administration was once per day and lasted for 3 days.
- control group 10% acetic acid was administrated into the ear vein on one side and 5% glucose injection was instilled into the rabbit ear on the opposite side serving as negative control. The administration lasted for 3 days. Results showed that there was no topical abnormity in the test group after 3 days, similar to the negative control of 5% glucose injection. However, topical hyperaemia, thickening, and exudation were observed after 10% acetic acid injection.
- the assay suggests that instillation of the inclusion complex has little vascular irritation, and that the inclusion complex can be used to produce injectable dosage forms.
- hydroxypropyl- ⁇ -cyclodextrin is preferably used as trapping agent.
- suitable solvent vehicle for dissolving cyclodextrin or its derivatives is water.
- the inclusion complex is prepared by
- the solid inclusion complex is prepared by
- the solid inclusion complex is prepared by
- the lyophilized injectable powder is prepared by
- the saline infusion of the inclusion complex is prepared by
- the glucose infusion of the inclusion complex is prepared by
- the sterile injectable powder is prepared by
- the complexation process is conducted by
Abstract
The present invention relates to the inclusion complexes of butylphthalide, which is D,L-mixed or levorotatory, with cyclodextrin or cyclodextrin derivatives, to a process for their preparation and the use thereof. In the invention, the butylphthalide is complexed with cyclodextrin or cyclodextrin derivatives, preferably with hydroxypropyl-β-cyclodextrin, in order to increase the water-solubility of butylphthalide, develop clinical solid or liquid formulations and improve the therapeutic effect of butylphthalide. The inclusion complex, in which the molar ratio of butylphthalide to cyclodextrin or cyclodextrin derivatives is in the range of 1:1-10, can be used to prepare infusion, injection, injectable powder, liquids for oral administration, syrup, tablets, granules, dispersible tablets and others.
Description
- The present invention relates to pharmaceutical compositions. More particularly, it relates to the inclusion complexes of butylphthalide, which is D,L-mixed or levorotary, with cyclodextrin or its derivatives, to a process for their preparation and the use thereof.
-
- There are two optical isomers, levorotary and dextrorotary butylphthalide, due to the presence of a chiral carbon therein. Chinese patent application No. 98125618.X disclosed the use of levorotary butylphthalide in the preparation of pharmaceutical compositions for preventing thrombosis and platelet agglomeration. It was found that butylphthalide could regulate the function of NOS-NO-cGMP system and the metabolism of arachidonic acid in the neurocytes after ischemia. Chinese patent application No. 93117148.2 disclosed the use of racemic butylphthalide mixture in the preparation of pharmaceuticals for preventing and treating ischemia-induced diseases in mammals or human.
- Butylphtualide can be obtained by extraction from natural celery seed oil or by chemical synthesis, as described in Chinese patent application No. 99109673.8 and the prior reference: Junshan Yang, Yalun Su, Chinese Pharmaceutical Bulletin, 1984, 31; 671, which realized the availability of butylphthalide.
- The pharmaceutical formulations are required to release active agents quickly and exert therapeutic effects rapidly when they are used to treat ischemia-induced diseases or thrombosis. Usually, the formulations for treating acute disease are administrated by intravenous instillation. However, the butylphthalide can only be formulated into soft capsules for oral administration because of its oily characteristics. Therefore, solubility problem of the butylphthalide must be resolved firstly in order to obtain injectable dosage forms.
- For the purpose of investigation of the clinical value of butylphthalide, the present applicant has filed a Chinese patent application titled “A inclusion complex of butylphthalide with cyclodextrin derivatives, a process for its preparation and the use thereof” on Jun. 18, 2001, in which solubility problem of butylphthalide was resolved. However, the levorotatory butylphthalide was not mentioned in that application.
- The present invention intends to provide inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof. In order to improve water-solubility of butylphthalide, it is complexed with cyclodextrin or its derivatives, wherein the butylphthalide is D,L-mixed or levorotary, and the inclusion complexes may be used to prepare various clinically applicable solid and liquid formulations.
- The embodiments according to the present invention are as follows:
- An inclusion complex of butylphthalide with cyclodextrin or its derivatives comprises butylphthalide and cyclodextrin or its derivatives, wherein the molar ratio of butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10.
- The butylphthalide mentioned above comprises D,L-mixed or levorotatory butylphthalide.
- The cyclodextrin mentioned above is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.
- The derivatives of cyclodextrin mentioned above are selected from the group consisting of hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, meltotriose cyclodextrin, carboxymethyl cyclodextrin, and sulfonylalkyl cyclodextrin.
- Among the derivatives of cyclodextrin mentioned above, hydroxypropyl-β-cyclodextrin is preferred.
- A process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives is provided as follows:
- A solution with a concentration of 5-60% is prepared by adding cyclodextrin or its derivatives into a suitable solvent vehicle. A liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives is obtained by adding butylphthalide into the above solution, stirring to provide a clear and transparent solution without oil drops, wherein the molar ratio of butylphthalide to cyclodextrin or its derivatives is in the range of 1:1 to 1:10.
- The process mentioned above may further comprise drying the liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives at the temperature of 40-80° C. to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives.
- The process mentioned above may also comprise concentrating the liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives until the concentration of cyclodextrin or its derivatives is 10-15% (W/V), cooling the solution for, e.g. about 12 hours to obtain white precipitate, filtering, and drying at 40-80° C., to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives.
- A process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives according to another aspect of the present invention comprises placing cyclodextrin or its derivatives into a colloid mill or mortar, adding an appropriate amount of suitable solvent vehicle, and stirring the mixture to provide a paste; adding butylphthalide into the paste described above, grinding for about 1-5 hours to provide a homogenous and viscous paste, then filtering the paste, and drying at 40-80° C. to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives, wherein the molar ratio butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10.
- A process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives according to yet another aspect of the present invention comprises adding cyclodextrin or its derivatives into a suitable solvent vehicle to obtain a solution with a concentration of 5-60%, dissolving the butylphthalide into an appropriate amount of ethanol with purity of 99%, mixing the two solutions, stirring, and drying to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives, wherein the molar ratio butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10.
- The drying method mentioned above may be any drying method, such as direct drying, spray drying, or freeze-drying.
- Examples of the above-mentioned solvent vehicles are water, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, glycerin, or acetone, or the mixture of any two or more above-mentioned solvent vehicles, wherein water is preferred.
- Such liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives may be directly used to produce liquid formulations, such as infusion, injection, injectable powder, liquids for oral administration, syrup, and the like; The solid inclusion complex of butylphthalide with cyclodextrin or its derivatives may be used to produce solid formulations, such as tablets, capsules, granules, dispersible tablets, and the like.
- Not wish to be bound by any theory, the inventors believe that cyclodextrin or its derivatives could trap the butylphthalide into their tubular structure to generate an inclusion complex of butylphthalide with cyclodextrin or its derivatives, thereby improving the water-solubility of butylphthalide. Accordingly, the active ingredient butylphthalide in the form of inclusion complexes can be directly applied in solid or liquid dosage forms. Limitations such as poor water-solubility, disability to be directly applied in solid, especially injectable dosage forms can be overcome.
- Cyclodextrin or its derivatives are water-soluble pharmaceutical excipients with little toxicity. The inclusion complexes of butylphthalide with cyclodextrin or its derivatives prepared thereby are suitable to be formulated into various liquid and solid dosage forms. The inclusion complexes have the advantages such as good water-solubility and little vascular irritation. The solubility of inclusion complex of butylphthalide with hydroxypropyl-o-cyclodextrin in water at 25° C. is 924 mg/100 ml. The inclusion complex is particularly applicable for preparing liquid dosage forms. The present invention overcomes the limitation that butylphthalide cannot be used to prepare liquid formulations. Due to the fact that the water-solubility is improved, the resulting solid dosage forms have the advantages such as rapid disintegration, good solubility and high bioavailability, which is more applicable for clinical use.
- The vascular irritation assay using inclusion complex of butylphthalide with hydroxypropyl-β-cyclodextrin is provided as follows:
- Eight rabbits were divided into two groups, namely, test group and control group. For the test group, 2.45 g/kg of the inclusion complex together with 40 ml of 5% glucose were instilled via the marginal ear vein of a rabbit at the rate of 1.5 ml/min. The administration was once per day and lasted for 3 days. For the control group, 10% acetic acid was administrated into the ear vein on one side and 5% glucose injection was instilled into the rabbit ear on the opposite side serving as negative control. The administration lasted for 3 days. Results showed that there was no topical abnormity in the test group after 3 days, similar to the negative control of 5% glucose injection. However, topical hyperaemia, thickening, and exudation were observed after 10% acetic acid injection.
- The assay suggests that instillation of the inclusion complex has little vascular irritation, and that the inclusion complex can be used to produce injectable dosage forms.
- In the examples according to the present invention, hydroxypropyl-β-cyclodextrin is preferably used as trapping agent.
- In the examples according to the present invention, suitable solvent vehicle for dissolving cyclodextrin or its derivatives is water.
- To illustrate the present invention, the following examples are particularly described, but the present invention is not intended to be limited thereto.
- The inclusion complex is prepared by
- (1) weighing 32.38 g (0.0210 mol) hydroxypropyl-β-cyclodextrin, adding it into 400 ml distilled water, and dissolving it with stirring;
- (2) weighing 1 g (0.0052 mol) butylphthalide separately, and adding it into the hydroxypropyl-β-cyclodextrin solution mentioned above;
- (3) stirring the mixed solution for 20 minutes by magnetic stirring method at a speed that the solution cannot be spattered, until the solution is clear and transparent, to obtain the liquid inclusion complex of butylphthalide with hydroxypropyl-β-cyclodextrin;
- (4) filtering the liquid inclusion complex of butylphthalide with hydroxypropyl-β-cyclodextrin through a film, dividing it into vials, and freeze-drying it.
- IR (KBr): 3393.46, 2931.26, 1158.24, 1081.60, 1032.07, 946.55, 580.68.13C-NMR: δ 131.47, 105.07, 84.03, 76.29, 75.04, 74.93, 62.89 ppm.
- The solid inclusion complex is prepared by
- (1) weighing 32.38 g (0.0210 mol) hydroxypropyl-β-cyclodextrin, adding it into a mixed solvent of 400 ml distilled water and 20 ml absolute ethanol, and dissolving it with stirring;
- (2) weighing 1 g (0.0052 mol) levorotatory butylphthalide separately, and adding it into the hydroxypropyl-β-cyclodextrin solution mentioned above;
- (3) stirring the mixed solution for 20 minutes by magnetic stirring method at a speed that the solution cannot be spattered, until the solution is clear and transparent, to obtain the liquid inclusion complex of levorotatory butylphthalide with hydroxypropyl-β-cyclodextrin;
- (4) concentrating the liquid inclusion complex of levorotatory butylphthalide with hydroxypropyl-β-cyclodextrin, and drying it under reduced pressure, to obtain the solid inclusion complex of levorotatory butylphthalide with hydroxypropyl-β-cyclodextrin.
- The solid inclusion complex is prepared by
- (1) weighing 8.2 g (0.0053 mol) hydroxypropyl-β-cyclodextrin, placing it into a mortar, adding about 4 ml water and grinding the mixture into a paste; then weighing 1 g (0.0052 mol) butylphthalide and adding it into the mortar;
- (2) grinding the mixture for 2 hours to obtain a homogenous and viscous paste, filtering the paste, then drying at 60° C. for 4 hours and grinding, to obtain the target inclusion complex.
- The lyophilized injectable powder is prepared by
- (1) weighing 1 g (0.0052 mol) levorotatory butylphthalide;
- (2) weighing 82 g (0.053 mol) hydroxypropyl-β-cyclodextrin separately and dissolving it into 150 ml distilled water;
- (3) adding the levorotatory butylphthalide into the hydroxypropyl-β-cyclodextrin solution mentioned above and stirring the mixture;
- (4) placing the mixture into a freeze drier, freeze-drying and capping to obtain the lyophilized injectable powder.
- The saline infusion of the inclusion complex is prepared by
- (1) weighing 32.38 g (0.0210 mol) hydroxypropyl-β-cyclodextrin, adding it into 400 ml distilled water and dissolving with stirring, adding 0.5 g active carbon, then stirring and heating to 80° C. for 14 minutes, and filtering to remove active carbon;
- (2) weighing I g (0.0052 mol) butylphthalide separately and dissolving it into 10 ml ethanol, adding the solution into the hydroxypropyl-β-cyclodextrin solution mentioned above, and magnetically stirring for 20 minutes (the speed is controlled so that the liquid cannot be spattered) to obtain a clear and transparent solution of the inclusion complex of butylphthalide with hydroxypropyl-β-cyclodextrin without oil drops of butylphthalide;
- (3) supplementing water to reach a volume of 800 ml, adding 7-8 g injectable sodium chloride, measuring pH and adjusting the pH to 3.5-7 with 0.05 N of HCl and 0.05 N of NaOH, supplementing water to reach a volume of 1000 ml, adding 0.1 g active carbon, and stirring for 20 minutes;
- (4) separating carbon from the solution, filling the solution into bottles (100 ml/bottle), and autoclaving at 115° C. for 30 minutes.
- The glucose infusion of the inclusion complex is prepared by
- (1) preparing the solution of the inclusion complex of butylphthalide with hydroxypropyl-β-cyclodextrin as described in step (1) and (2) of EXAMPLE 5;
- (2) weighing 50 g injectable glucose, adding water to reach a volume of 100 ml and dissolving with stirring, then adding 0.1 g active carbon and heating the mixture until the mixture begin to boil and maintaining that status for 15 minutes, then removing carbon;
- (3) adding the glucose solution into the solution of inclusion complex, supplementing water to reach a volume of 800 ml, and adjusting its pH to 4 with 0.05 N of HCl and 0.05 N of NaOH, supplementing water to reach a volume of 1000 ml, then adding 0.1 g active carbon into the solution, and stirring the solution for 20 minutes;
- (4) filtering the solution coarsely and finely with filters or filter stick (pore size of 1.0 μm, 0.45 μm, or 0.22 μm), filling it into bottles and autoclaving at 115° C. for 30 minutes.
- The sterile injectable powder is prepared by
- (1) weighing 32.38 g (0.0210 mol) hydroxypropyl-β-cyclodextrin in a sterile operation room, dissolving it into water to reach a volume of 90 ml, adding 0.1 g active carbon into the solution, then heating the mixture until the mixture begin to boil and maintaining that status for 15 minutes, and filtering to remove the carbon;
- (2) weighing 1 g (0.0052 mol) levorotatory butylphthalide and adding it into the solution of hydroxypropyl-β-cyclodextrin;
- (3) magnetically stirring the mixed solution for 20 minutes (the speed is controlled so that the liquid cannot be spattered) to obtain a clear and transparent solution of the inclusion complex of levorotatory butylphthalide with hydroxypropyl-β-cyclodextrin without oil drop of butylphthalide;
- (4) supplementing water to reach a volume of 100 ml, filtering through 0.22 μm membrane, filling into 10 ml vials (2-3 ml per vial), freeze drying and capping.
- The complexation process is conducted by
- Weighing 3.5 g β-cyclodextrin, adding it into 100 ml distilled water and heating the mixture at 40-60° C. to dissolve β-cyclodextrin, then adding 1 g levorotatory butylphthalide and mechanically stirring for 2-3 hours, cooling in the refrigerator for 4 hours, filtering, washing with ethanol and then drying to obtain the inclusion complex of levorotatory butylphthalide with β-cyclodextrin. The inclusion complex is formulated into various solid dosage forms such as tablets and capsules, etc.
Claims (16)
1. An inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives, comprising butylphthalide and cyclodextrin or cyclodextrin derivative, wherein the molar ratio of butylphthalide to cyclodextrin or cyclodextrin derivatives is 1:1-10.
2. The inclusion complex according to claim 1 , wherein said butylphthalide is D,L-mixed or levorotatory butylphthalide.
3. The inclusion complex according to claim 1 , wherein said cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.
4. The inclusion complex according to claim 1 , wherein said cyclodextrin derivatives are selected from the group consisting of hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, meltotriose cyclodextrin, carboxymethyl cyclodextrin and sulfonylalkyl cyclodextrin.
5. The inclusion complex according to claim 1 or 4 , wherein the cyclodextrin derivative is hydroxypropyl-β-cyclodextrin.
6. A process for preparing the inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives, comprising the steps of adding cyclodextrin or cyclodextrin derivatives into a suitable solvent vehicle to obtain a solution with a concentration of 5-60%, adding butylphthalide into the solution, stirring to obtain a liquid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives.
7. The process according to claim 6 , further comprising the step of drying the liquid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives to obtain a solid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives.
8. The process according to claim 6 , further comprising the steps of concentrating the liquid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives into a solution with a concentration of 10-15% (W/V), cooling to obtain white precipitate, filtering, and drying to obtain a solid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives.
9. A process for preparing the inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives, comprising the steps of placing the cyclodextrin or cyclodextrin derivatives into a colloid mill or mortar, adding a suitable solvent vehicle to obtain a paste, adding butylphthalide into the paste, filtering, and drying to obtain a solid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives.
10. A process for preparing the inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives, comprising the steps of adding cyclodextrin or cyclodextrin derivatives into a suitable solvent vehicle to obtain a solution with a concentration of 5-60%, dissolving butylphthalide into a selected amount of ethanol with purity of 99%, mixing the two solutions, stirring, and drying to obtain a solid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives.
11. The process according to claim 6 , 9 or 10, wherein said suitable solvent vehicle is selected from the group consisting of water, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, glycering, acetone, and a mixed solvent vehicle of any two or more of the solvent vehicles.
12. A pharmaceutical composition comprising a therapeutically effective amount of the inclusion complex according to claim 1 and a suitable carrier.
13. The pharmaceutical composition according to claim 12 in a liquid dosage form.
14. The pharmaceutical composition according to claim 12 in a solid dosage form.
15. A method of treating ischemia-induced disease comprising administering a therapeutically effective amount of the inclusion complex according to claim 1 to a patient.
16. A method of treating thrombosis comprising administering a therapeutically effective amount of the inclusion complex according to claim 1 to a patient.
Priority Applications (1)
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US12/200,130 US7678776B2 (en) | 2002-08-21 | 2008-08-28 | Inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2002/000579 WO2004018444A1 (en) | 2002-08-21 | 2002-08-21 | Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparations and the use there of |
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US12/200,130 Continuation US7678776B2 (en) | 2002-08-21 | 2008-08-28 | Inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof |
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US20060166931A1 true US20060166931A1 (en) | 2006-07-27 |
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US12/200,130 Expired - Lifetime US7678776B2 (en) | 2002-08-21 | 2008-08-28 | Inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof |
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US12/200,130 Expired - Lifetime US7678776B2 (en) | 2002-08-21 | 2008-08-28 | Inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof |
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US (2) | US20060166931A1 (en) |
EP (1) | EP1535916B1 (en) |
JP (1) | JP4378755B2 (en) |
AT (1) | ATE489972T1 (en) |
AU (1) | AU2002327307B8 (en) |
BR (1) | BR0215848A (en) |
CA (1) | CA2494157C (en) |
DE (1) | DE60238510D1 (en) |
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HK (1) | HK1074200A1 (en) |
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Cited By (7)
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US20070112065A1 (en) * | 2003-10-10 | 2007-05-17 | Shijiazhuang Pharma. Group Zhongqi Pharmaceutical | Use of l-butylphthalide in the manufacture of medicaments for prevention and treatment of cerebral infarct |
US20070134316A1 (en) * | 2003-12-05 | 2007-06-14 | Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Soft capsule of butylphthalide and a process for preparing the same |
US10463614B2 (en) | 2005-12-16 | 2019-11-05 | Shijiazhuang Pharma Group Nbp Pharmaceutical Co. | Butylphthalide intravenous emulsion and application thereof |
CN110548004A (en) * | 2018-05-30 | 2019-12-10 | 成都施贝康生物医药科技有限公司 | Stable large-capacity butylphthalide injection and preparation method thereof |
CN112386571A (en) * | 2020-12-04 | 2021-02-23 | 成都施贝康生物医药科技有限公司 | Stable butylphthalide sodium chloride injection, preparation method and application thereof |
CN114685410A (en) * | 2020-12-26 | 2022-07-01 | 四川汇宇制药股份有限公司 | Preparation method of butylphthalide |
WO2023165094A1 (en) * | 2022-03-04 | 2023-09-07 | 中国医学科学院药用植物研究所 | Hydroxypentyl benzoic acid diester compound, and preparation method therefor and use thereof |
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EP1757286B1 (en) | 2004-06-18 | 2017-09-06 | CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | The application of l-n-butylphthalide in preventing and treating alzheimer's disease |
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CN112999175B (en) * | 2021-04-26 | 2021-08-03 | 奥信阳光(北京)药业科技有限公司 | Butylphthalide oral freeze-dried powder and preparation method and application thereof |
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CN1048158C (en) | 1993-09-09 | 2000-01-12 | 中国医学科学院药物研究所 | Apiolin-A use in preparation of medicine for prevention and treatment of diseases caused by cerebral ischemia |
CN1086942C (en) * | 1998-12-18 | 2002-07-03 | 中国医学科学院药物研究所 | Application of butyl phthalide in preparing medicines curing thrombosis and thrombocyte coagulation |
CN1136209C (en) * | 1999-07-05 | 2004-01-28 | 中国医学科学院药物研究所 | Process for preparing optically active 3-n-butyl phenylphthaleine |
-
2002
- 2002-08-21 US US10/524,653 patent/US20060166931A1/en not_active Abandoned
- 2002-08-21 DK DK02760059.2T patent/DK1535916T3/en active
- 2002-08-21 AT AT02760059T patent/ATE489972T1/en active
- 2002-08-21 ES ES02760059T patent/ES2355133T3/en not_active Expired - Lifetime
- 2002-08-21 AU AU2002327307A patent/AU2002327307B8/en not_active Expired
- 2002-08-21 CA CA2494157A patent/CA2494157C/en not_active Expired - Lifetime
- 2002-08-21 DE DE60238510T patent/DE60238510D1/en not_active Expired - Lifetime
- 2002-08-21 JP JP2004529646A patent/JP4378755B2/en not_active Expired - Lifetime
- 2002-08-21 WO PCT/CN2002/000579 patent/WO2004018444A1/en active Application Filing
- 2002-08-21 BR BR0215848-5A patent/BR0215848A/en not_active Application Discontinuation
- 2002-08-21 EP EP02760059A patent/EP1535916B1/en not_active Expired - Lifetime
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2005
- 2005-02-04 NO NO20050629A patent/NO20050629L/en not_active Application Discontinuation
- 2005-08-03 HK HK05106659.4A patent/HK1074200A1/en not_active IP Right Cessation
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2008
- 2008-08-28 US US12/200,130 patent/US7678776B2/en not_active Expired - Lifetime
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US4727064A (en) * | 1984-04-25 | 1988-02-23 | The United States Of America As Represented By The Department Of Health And Human Services | Pharmaceutical preparations containing cyclodextrin derivatives |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070112065A1 (en) * | 2003-10-10 | 2007-05-17 | Shijiazhuang Pharma. Group Zhongqi Pharmaceutical | Use of l-butylphthalide in the manufacture of medicaments for prevention and treatment of cerebral infarct |
US8598225B2 (en) | 2003-10-10 | 2013-12-03 | Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Use of L-butylphthalide in the manufacture of medicaments for treatment of cerebral infarct |
US20070134316A1 (en) * | 2003-12-05 | 2007-06-14 | Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Soft capsule of butylphthalide and a process for preparing the same |
US10463614B2 (en) | 2005-12-16 | 2019-11-05 | Shijiazhuang Pharma Group Nbp Pharmaceutical Co. | Butylphthalide intravenous emulsion and application thereof |
CN110548004A (en) * | 2018-05-30 | 2019-12-10 | 成都施贝康生物医药科技有限公司 | Stable large-capacity butylphthalide injection and preparation method thereof |
CN112386571A (en) * | 2020-12-04 | 2021-02-23 | 成都施贝康生物医药科技有限公司 | Stable butylphthalide sodium chloride injection, preparation method and application thereof |
CN114685410A (en) * | 2020-12-26 | 2022-07-01 | 四川汇宇制药股份有限公司 | Preparation method of butylphthalide |
WO2023165094A1 (en) * | 2022-03-04 | 2023-09-07 | 中国医学科学院药用植物研究所 | Hydroxypentyl benzoic acid diester compound, and preparation method therefor and use thereof |
Also Published As
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DK1535916T3 (en) | 2011-03-14 |
AU2002327307B2 (en) | 2009-02-12 |
NO20050629L (en) | 2005-03-17 |
US20080318898A1 (en) | 2008-12-25 |
HK1074200A1 (en) | 2005-11-04 |
CA2494157C (en) | 2010-10-12 |
EP1535916A1 (en) | 2005-06-01 |
EP1535916A4 (en) | 2006-09-20 |
BR0215848A (en) | 2005-06-21 |
DE60238510D1 (en) | 2011-01-13 |
JP2006500367A (en) | 2006-01-05 |
WO2004018444A1 (en) | 2004-03-04 |
EP1535916B1 (en) | 2010-12-01 |
ATE489972T1 (en) | 2010-12-15 |
JP4378755B2 (en) | 2009-12-09 |
ES2355133T3 (en) | 2011-03-23 |
AU2002327307B8 (en) | 2009-02-26 |
CA2494157A1 (en) | 2004-03-04 |
US7678776B2 (en) | 2010-03-16 |
AU2002327307A1 (en) | 2004-03-11 |
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