Classifications

• • 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
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/12—Mucolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/14—Antitussive agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • 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
• • 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
• • 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
• • 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

Definitions

• the invention relates to a complex of an organic drug with a beta-cyclodextrin derivative and a preparation method thereof. Background of the invention
• solubility of a drug in water When the solubility of a drug in water is below a certain order of magnitude, the development and bioavailability of its pharmaceutical preparations will be limited and affected, and the active drugs that are difficult to dissolve or insoluble in the active pharmaceuticals screened in the Pharmacopoeia, the Basic Drug List and the combinatorial chemistry method will be limited and affected. About one-third strong. For those drugs that are poorly soluble or insoluble in water to improve their efficacy, increasing their solubility in water is of great significance.
• beta-cyclodextrin or its derivatives in combination with drugs to increase the water solubility of drugs is a method that has been studied for many years and extensively.
• the low solubility of ⁇ -CD itself limits its application, especially when ⁇ -CD is injected intravenously, it can cause urea nitrogen in the blood to increase.
• ⁇ -CD When absorbed through renal tubules, it will crystallize due to its low water solubility, causing tissue necrosis. .
• ⁇ -CD derivatives represented by hydroxypropyl beta-cyclodextrin have large safe doses, good compatibility with blood, do not change the efficacy, and increase the water solubility of drugs. And stability, can be used to prepare various dosage forms such as intravenous injection, oral administration, etc., so it is considered to be a more promising drug carrier material.
• Beta-cyclodextrin derivatives have been used as drug carriers to prepare inclusion complexes to increase drug solubility. There have been many reports and patents. Among them, Pitha et al, Int J Pharm 1986. 29 (1): 73. It is reported that 32 drugs are treated with a concentrated solution of hydroxypropylbetacyclodextrin (2-HP- ⁇ -CD) (40-50%). The drug is solubilized. Among the listed compounds, the increase in solubility ranges from 1.3 to 13666 times. Pitha also introduced a large number of the same products in U.S. Patent No. 4,727,06, confirming that the inclusion complex of the drug and the cyclodextrin derivative has good water solubility.
• solubilizing drugs using ⁇ -cyclodextrin derivatives as carriers are mostly used for parenteral administration, intravenous drip, and have not been widely used in oral preparations. The possible reason is that a simple method for industrial production has not been found.
• the characteristics of the literature preparation method over the years are as follows: 1. Use a higher concentration of HP- ⁇ -CD aqueous solution (such as> 40%), and use the solubilization effect based on the critical micelle concentration of cmc to dissolve the poorly soluble drugs; 2. Use mechanical agitation, ultrasonic crushing and other methods to highly disperse the solid drug to accelerate its dissolution; 3. Use suitable acid, alkali surfactant, and subsolvent to help dissolve and increase stability; 4. Through crystallization and co-precipitation method Precipitate from the saturated solution, and then spray-dry or freeze-dry; 5. The process cycle is long, and the drug must be processed at a clean or low temperature for tens of hours or days.
• Itraconazole injection which was clinically tested in 2000, was the first itraconazole-hydroxypropylbeta-cyclodextrin inclusion complex to be injected intravenously into the clinical trial, but it was used in its formulation. A considerable amount of acid, latent solvent, etc. are used to increase the stability of the preparation, and the mass ratio of the drug to hydroxypropylbetacyclodextrin is 1:40. Journal of Spectroscopy, Vol. 17, No. 3. June 2000. A report on the preparation and properties of norfloxacin-hydroxypropylbeta-cyclodextrin solid inclusion compounds was reported using higher concentrations of HP- ⁇ .
• the inclusion compound prepared by the above method improves the solubility of the drug to a certain extent, but the solid powdery inclusion compound often does not always dissolve when dissolved in water, or insoluble matter precipitates when the solution is diluted with water. Dilution and redissolution are unstable and irreversible. The reason is the instability of the composition.
• the solid powder is an inclusion complex without forming a stable compound in the sense of supramolecular chemistry.
• An object of the present invention is to provide a method for preparing a complex of an organic drug and a beta-cyclodextrin derivative, and a complex prepared by the preparation method.
• the complex prepared by this method has stable composition and is a complex compound in the sense of supramolecular chemistry.
• the product is extremely easy or soluble N03 / 00337
• the present invention provides a method for preparing a complex of an organic drug and a beta-cyclodextrin derivative, including:
• step b a step of removing the organic solvent in the solution obtained in step a to obtain the organic drug and the beta cyclodextrin derivative aqueous solution;
• the organic solvent is a hydrophilic organic solvent.
• the above-mentioned hydrophilic organic solvent is selected from the group consisting of lower fatty acid ester solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, furan solvents, amide solvents, lower fatty alcohols, and clear solvents, Ketone solvents and their mixtures.
• the above-mentioned hydrophilic organic solvent is selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, petroleum ether, cyclohexane, dichloromethane, chloroform, water, tetrahydrofuran, and dimethylethane. Amides; dimethylformamide, methanol, ethanol, propanol, butanol, acetone, acetone and mixtures thereof.
• the dissolving in step a is performed at a temperature of 30 to 10 ° C.
• the dissolution of step a is performed at a temperature of 60 to 75 ° C.
• the molar ratio or mass ratio of the organic drug to the beta-cyclodextrin derivative is a critical molar ratio or a critical mass ratio, or is smaller than a critical molar ratio or a critical mass ratio, or is larger than a critical molar ratio. Or critical mass ratio.
• the critical value of the organic drug and the beta-cyclodextrin derivative is determined by a unit test or a method of preparing a saturated solution.
• the above-mentioned beta-cyclodextrin derivative is selected from the group consisting of hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, sulfo-beta-cyclodextrin, and ether-based beta. Cyclodextrin, methyl beta cyclodextrin and ethyl beta cyclodextrin.
• the above-mentioned beta-cyclodextrin derivative is hydroxypropylbeta-cyclodextrin.
• the above method further includes a solution obtained in step a. Perform the steps of sterile filtration.
• the organic drug is a water-insoluble or water-insoluble organic drug.
• the organic drug is selected from at least one of the drugs shown in Table 1 and any mixture thereof.
• the above method comprises subjecting the above complex to heating and vacuum expansion and drying to form porous sterile granules or powders.
• the above method comprises directly dispensing the above complex into a powder injection for injection or for preparing a lyophilized powder, cake or solution.
• the above method comprises preparing the above-mentioned complex together with a pharmaceutically acceptable excipient into tablets, granules, capsules, pills, chewing agents, suppositories, and patches.
• the above method comprises making the above complex into a powder atomized inhalation medicament.
• the method includes preparing the above-mentioned complex as a medicinal solution for eye drops, nose drops, gargles, aerosols, rectums, rinses, and washes.
• the above method comprises preparing the above-mentioned complex to be used for controlling diseases and insect pests, hormones, and nutritional supplements for livestock, poultry, crops, and plants other than humans.
• the above method includes using the above complex for chemical engineering to prepare an enzyme preparation and a catalyst.
• the present invention also provides a complex of an organic drug and a beta-cyclodextrin derivative prepared by any one of the methods described above.
• the present invention further provides a complex containing a beta-cyclodextrin derivative and a water-insoluble or poorly-soluble organic drug.
• the organic medicine is selected from at least one of the organic medicines shown in Table 1.
• the above-mentioned beta cyclodextrin derivative and the above-mentioned organic drug are present in the complex in a critical molar ratio or a critical mass ratio.
• the above-mentioned beta-cyclodextrin derivative and the above-mentioned organic drug are present in the complex in a greater than a critical molar ratio or a critical mass ratio.
• the above-mentioned beta-cyclodextrin derivative and the above-mentioned organic drug are present in the complex at a critical molar ratio or a critical mass ratio.
• the above complex further comprises a pharmaceutically acceptable excipient, carrier or diluent.
• the method of the present invention is based on the principle of intermolecular interaction, using beta cyclodextrin derivatives as the main body, organic drug molecules or other organic molecules as the guest, and the necessary conditions in the presence of water to generate stable weak bonds ( Non-bond) binding complexes (or complexes, supramolecular compounds), organic drugs and beta-cyclodextrin derivatives form stable, water-soluble complexes.
• the process cycle of the present invention is short, generally only 3 to 4 hours, and mainly includes the following steps: a. Under a clean environment, the organic drug is dissolved in a hydrophilic organic solvent in a closed reactor, and if necessary, 30 ⁇ : L00 ° C Heat to dissolve. Mixing a solution of an organic drug with an aqueous solution of a beta-cyclodextrin derivative of a critical molar ratio or a critical mass ratio;
• step b removing the solvent under heating from the mixed solution obtained in step a above to obtain an aqueous system of a drug and beta-cyclodextrin;
• step b The solution obtained in step b is concentrated under reduced pressure so that the water content reaches a predetermined amount, thereby obtaining a complex of the drug and betacyclodextrin as a bulked body.
• the morphology of the expanded bulk body prepared by the method of the present invention can be used to prepare the following preparations:
• the drug and beta-cyclodextrin may be simultaneously dissolved in a predetermined solvent at a critical molar ratio to obtain a mixed solution.
• the solution can be subjected to ultrafiltration to sterilize and decolorize and depyrogenize.
• heat treatment can be performed as needed to promote dissolution.
• the heating temperature is generally 30 ⁇ : L00 V.
• the reduced pressure concentration temperature in the above step c is generally 30 to 10 ° C., preferably 60 to 75 ° C.
• the dried loose body can be pulverized in the reactor into porous particles of a desired particle size or Powder.
• the moisture content after drying may be determined appropriately depending on the drug and the preparation. In order to facilitate the processing of the expanded bulk into granules or powder, the moisture content is preferably 1 wt% or less.
• the critical molar ratio or critical mass ratio in the present invention means that the complex of the organic drug and the beta-cyclodextrin derivative prepared by the method of the present invention is exactly dissolved in a prescribed amount of water and is shaped. T N03 / 00337
• the molar ratio or the mass ratio is used.
• the ratio of the organic drug to the beta-cyclodextrin derivative is preferably a critical molar ratio or a critical mass ratio.
• the ratio of the drug to the beta-cyclodextrin derivative may be less than the critical molar ratio or the critical mass ratio.
• the ratio of the drug to the beta-cyclodextrin derivative may be greater than the critical molar ratio or the critical mass ratio.
• the critical molar ratio and critical mass ratio of the organic drug of the present invention and the beta-cyclodextrin derivative can be determined by the following unit test method.
• the organic drugs and beta-cyclodextrin derivatives of various molar ratios or mass ratios are prepared according to the above-mentioned method of the present invention into puffed loose-type complexes, and the complexes with different proportions are respectively added to prescribed water. Observe the properties of the solution, and take the ratio of exactly dissolved in water and stable solution as the critical molar ratio or critical mass ratio of the present invention.
• the critical molar ratio and critical mass ratio of the present invention can also be determined by the following saturated solution method.
• critical mole ratio of drug average moles of betacyclodextrin / average moles of drug
• critical mole ratio of other cyclodextrin is by the following method Measured: The accurately weighed artemisinin was ground into a fine powder with a tissue grinder, put into a beaker, and then gradually added an accurately metered 40% hydroxypropylbetacyclodextrin aqueous solution under stirring until the artemisinin Just completely dissolved in the solution. Calculate the mass numbers of both at this time and convert them into moles. This experiment was repeated three times, and the critical mole ratio of artemisinin was calculated from the average number of moles according to the above formula to be about 5.
• Simvastatin 29 N Other and volatile famotidine 9 sex substance sibutramine 2
• Borneol 6 camphor 8 ligustrazine 12 trichlorobutanol 6 vanillin 9 In the present invention, whether the molar ratio or the mass ratio is used depends on the nature of the organic drug and the convenience of calculation. There is no difference between the two in essence.
• the beta-cyclodextrin derivative of the present invention may generally be hydroxypropyl beta-cyclodextrin, hydroxyethyl beta-cyclodextrin, sulfobeta-cyclodextrin, ether beta-cyclodextrin, or Gitabeta cyclodextrin and ethyl beta cyclodextrin.
• Preferred is hydroxypropylbetacyclodextrin.
• the molecular formula of hydroxypropylbetacyclodextrin is (Gft) V (C 3 H 6 0) n, MS 5, with a molecular weight range between 1367 and 1716 and an average molecular weight of 1600. Based on the dry product, it contains hydroxypropoxyl 0% ⁇ Base (one C 3 0) is 22. 0 ⁇ 41. 0%.
• the solvent used in the present invention may be any hydrophilic organic solvent. From the perspective of pharmaceutical preparations, suitable solvents should generally meet the following requirements: have appropriate solubility for drugs and carriers; residual trace solvents are easy to remove or do not affect drug safety; can be compatible with water and easily removed under reduced pressure .
• the solvents generally used in the present invention are: esters: lower fatty acid esters, such as methyl acetate, ethyl acetate, butyl acetate, etc .; hydrocarbons: petroleum ether, cyclohexane, etc .; halogenated hydrocarbons: Dichloromethane, chloroform, etc .; water, furans; amides: dimethylacetamide; dimethylformamide, etc .; alcohols: lower fatty alcohols; sunny types: acetonitrile; ketones: acetone, etc.
• esters lower fatty acid esters, such as methyl acetate, ethyl acetate, butyl acetate, etc .
• hydrocarbons petroleum ether, cyclohexane, etc .
• halogenated hydrocarbons Dichloromethane, chloroform, etc .
• water, furans amides: dimethylacetamide; dimethylformamide, etc .
• alcohols lower fatty
• the amount of water is not particularly limited.
• the proper amount of water may be added water, or it may be water present in organic drugs or beta-cyclodextrin derivatives. When water is present in the organic drug or the beta-cyclodextrin derivative, no additional water may be added to the solvent.
• the method of the present invention is applicable to any water-insoluble or poorly-soluble organic medicine.
• the present invention will be described below by means of implementation methods and examples. It is worth noting that these implementation methods and examples are only for better understanding and implementation of the present invention, and do not constitute any limitation to the present invention. method of execution
• Solvent According to the physical and chemical properties of the drug and the above requirements for the solvent, select a suitable solvent.
• Dissolution and solution treatment If necessary, heat the solution. After dissolution, the solution can be decolorized, depyrogenized, and filtered to obtain a clear solution (preparation of preparations for oral administration can be simplified).
• the filtrate is input into a rotating tank at a rotation speed of 120 rpm. Under heating, it is concentrated under reduced pressure, the solvent is removed, and it is converted into a water system until the material is glassy. During the process of concentration and transformation, it must be maintained as a homogeneous system without insoluble matter precipitation.
• Puffing and drying Puffing is performed at 120 rpm, and drying is performed at slow speed.
• the materials in the above 4 continue to be heated, decompressed, the materials are dehydrated and puffed, become milky or opaque, and foaming and bulging until dry, to obtain a loose porous solid.
• Equipment Rotating tank (volume can be 1, 5, 10, 20, 50 liters or more). Controllable temperature (0 ⁇ : L00 ° C), speed: 0 ⁇ 150 rpm, adjustable, with solvent condensation recovery device. Vacuum pump: 30 ⁇ 80 liters / water pump (or other pump), vacuum degree 0 ⁇ IMpao
• the property index of the complex of the drug double-cyclodextrin derivative It is easily soluble in water, and the dilution stability is not less than 8 hours, which meets the requirements of intravenous infusion. There is no such requirement for oral administration.
• Prednisone 2g and hydroxypropylbetacyclodextrin 36g (the critical molar ratio of both is 4), dissolved with tetrahydrofuran, heated, decolorized with activated carbon, depyrogenized, filtered, and the filtrate is input into a 1 liter rotary tank 5 ⁇ 4h ⁇ , holding 65 ⁇ 75 ° C, concentrating under reduced pressure, recovering the solvent, and converting to a water system, continuing to keep warm, reducing the pressure to expand the material, drying, time course 2. 5 ⁇ 3h, the whole process 3. 5 ⁇ 4h. Receive PT / C Listen Touch 37
• Metronidazole 4g and hydroxypropylbetacyclodextrin 36g (the critical mass ratio of the two is 9), add ethanol to dissolve, filter if necessary, filter the filtrate into a 1 liter rotary tank, keep 60 ⁇ 70 ° C, reduce 5 ⁇ 4h ⁇ Concentrated under pressure, the solvent was recovered, and converted into a water system, continued to keep warm, the material was expanded under reduced pressure, dried, time course 2. 5 ⁇ 3h, the whole process 3. 5 ⁇ 4h. Yield: 98%. Solvent recovery: 85%.
• Example 26 Example 26
• a complex of artemisinin and hydroxypropylbetacyclodextrin kills malaria Pharmacological efficacy test of Plasmodium falciparum, and the results of killing Plasmodium falciparum in infected mice
• sibutramine hydrochloride-HP- ⁇ -CD complex (easy to dissolve in water) to make oral fast-dissolving tablets. For animal tests (dogs). Compared with oral capsules, the bioavailability of oral fast-dissolving tablets is higher than that of capsules. 1 time or more. Zolpidem tartrate orally dissolving tablets are faster than ordinary tablets, and their bioavailability is doubled. Industrial applicability
• the method of the present invention has the following advantages: 1. The process is simpler than the prior art, and the cycle is short, generally requiring only 3 to hours; 2. It is not necessary to add an acid, an alkali surfactant, or a latent solvent, which enhances the drug effect and reduces side effects; 3 5. Dissolve the organic drug with water or organic solvent, and then convert it into an aqueous solution. Through molecular assembly, generate a complex and make it into a loose porous solid, so that it is easily or easily soluble in water, has a fast dissolution rate, and has infinite dilution stability; 4. Determine the critical value of the organic drug and the beta-cyclodextrin derivative by unit test or the method of preparing a saturated solution, and prepare it according to the critical value ratio to stabilize the complex composition; and other effects.
• all water-insoluble or poorly-soluble organic drugs or other organic compounds can be made into complexes that are completely soluble in water and are sterile.
• extremely convenient conditions for the industrial use of such organic drug formulations and other organic compounds are provided.

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• 2002
  • 2002-05-10 CN CNB021167664A patent/CN1232539C/zh not_active Expired - Fee Related
• 2003
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  • 2003-05-09 JP JP2004503512A patent/JP2005530866A/ja active Pending
  • 2003-05-09 KR KR10-2004-7018140A patent/KR20050013548A/ko not_active Ceased
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  • 2003-05-09 AU AU2003242083A patent/AU2003242083A1/en not_active Abandoned

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