WO2004022100A1 - Formulation nanopharmaceutique et son procede de preparation - Google Patents

Formulation nanopharmaceutique et son procede de preparation Download PDF

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Publication number
WO2004022100A1
WO2004022100A1 PCT/CN2003/000663 CN0300663W WO2004022100A1 WO 2004022100 A1 WO2004022100 A1 WO 2004022100A1 CN 0300663 W CN0300663 W CN 0300663W WO 2004022100 A1 WO2004022100 A1 WO 2004022100A1
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WIPO (PCT)
Prior art keywords
drug
preparation
complex
formulation
amphiphilic substance
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PCT/CN2003/000663
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English (en)
French (fr)
Inventor
Yunqing Liu
Xiying Liu
Wei Liu
Tong Liu
Original Assignee
Yunqing Liu
Xiying Liu
Wei Liu
Tong Liu
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority claimed from CNB021288453A external-priority patent/CN100479807C/zh
Priority claimed from CNA021491461A external-priority patent/CN1502332A/zh
Application filed by Yunqing Liu, Xiying Liu, Wei Liu, Tong Liu filed Critical Yunqing Liu
Priority to JP2004533170A priority Critical patent/JP2006500387A/ja
Priority to CA002495899A priority patent/CA2495899A1/en
Priority to AU2003257791A priority patent/AU2003257791A1/en
Priority to US10/524,808 priority patent/US20050255164A1/en
Priority to EP03793565A priority patent/EP1543841A4/en
Publication of WO2004022100A1 publication Critical patent/WO2004022100A1/zh
Priority to HK06103801.7A priority patent/HK1083749A1/xx

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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
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to a solid nanomedicine and a preparation method thereof, and more particularly, to a solid nanomedicine prepared by combining a poorly soluble organic drug with an amphiphilic matrix (carrier).
  • the invention also relates to a paclitaxel nanomedicine for injection and a preparation method thereof. Background technique
  • nanotechnology The success of nanotechnology currently depends mainly on the efficiency of the preparation technology, whether it is suitable for large-scale production and production costs, especially whether the safety of the carrier used is approved, and the formulation forms that can be processed.
  • production technology there are mainly grinding methods that have been used in production.
  • the well-known anticancer drug paclitaxel has a solubility of 0.006 mg / ml in water and is practically insoluble in water. Its intravenous infusion
  • the key technology of the formulation is to solve its solubility in water.
  • the clinically applied preparations such as Chinese product purple pigment, taxol, American product Taxol (American BMS company), Anzatax (Australian Fauliding company) and other products, all use polyoxyethylene castor oil (Cremophor EL surfactant) and anhydrous Ethanol (Wv l: l) was used as a solvent to make a solution of 30mg / 5ml, dissolved in water, and stable within 8 to 12 hours (without precipitation of crystals). After clinical application, it was diluted with a solvent for injection (such as 5% glucose, etc.) Intravenous drip.
  • these preparations have the following problems:
  • Polyoxyethylene castor oil can promote the release of histamine with strong sensitization. It is required to pre-administer antihistamines (oral and injection) and strictly monitor them before use.
  • Polyoxyethylene castor oil can dip the plasticizer dioctyl phthalate in the commonly used PVC infusion set into the liquid to increase toxicity. Therefore, polyethylene and glass infusion sets must be used.
  • Reported dosage forms that have been studied include intravenous injections, intravenous milks, submicroemulsions and microemulsions, nanoparticles (crystals), etc., and paclitaxel's polyethylene glycol derivatives, based on proteins. Significant progress has been made in preparations such as carrier complexes. However, most of them have not yet met the requirements for drug safety and industrial production, and so far no clinical and marketing reports have been reported.
  • the object of the present invention is to provide a solid nanomedicine and a preparation method thereof.
  • the present invention uses an amphiphilic
  • the solid matrix component uses the amphiphilic nature of the matrix component in the solution to prepare solid nanoparticles of the drug under conventional conditions, which meets the clinical needs.
  • the present invention is suitable for preparing a variety of insoluble or poorly soluble drugs into nanoparticles under conventional conditions.
  • the method of the present invention is particularly suitable for preparing water-soluble nanoparticles of a poorly soluble drug paclitaxel in water. Summary of invention
  • One aspect of the present invention is to provide a method for preparing a solid nanomedicine, comprising: interacting a drug with an amphiphilic system; forming a complex of an amphiphilic substance and a drug; and concentrating, solidifying and expanding to obtain a sterile solid nanomedicine.
  • Another aspect of the present invention is to provide a method for preparing a drug complex, comprising: providing a parent system; interacting a drug with a parent system; and forming a complex of a parent substance and a drug.
  • the invention also provides a solid nanoparticle of paclitaxel.
  • the paclitaxel nanoparticle can be dissolved in water to make an injection solution to form a microemulsion or submicroemulsion solution.
  • amphiphilic substance used in this specification refers to a substance having hydrophilicity and lipophilicity.
  • preferred amphiphilic substances include hydroxypropylbetacyclodextrin and phospholipids.
  • micelle used in this specification is a microstructure formed by hydroxypropylbetacyclodextrin in an aqueous solution, which is hydrophobic inside and hydrophilic on the periphery, and its size is between 1 and 10 nm.
  • vesicle used in this specification is the microstructure formed by phospholipids in water, also known as microvesicles or liposomes.
  • the inner core is water and the outer lipophilicity.
  • the inner diameter of the inner core can be 20 ⁇ 30nm depending on the situation. Ten, up to hundreds of nanometers.
  • the nanoscale of pharmaceutical preparations is usually 1 to 1000 nm.
  • complex used in the present specification refers to a complex compound formed by the aforementioned hydroxypropylbetacyclodextrin, a phospholipid, and a compound (an active substance such as a drug) by a weak bond. It can also be regarded as a complex with a specific spatial structure formed by two or more substances. As used herein, “complex” does not limit the force form or mode of action between substances, it is only used to describe the stable existence state formed by two or more substances after a certain interaction.
  • complex is especially used to refer to a complex formed by a microstructure such as a drug or a compound having a medicinal prospect with a micelle, a vesicle, and the drug or a compound having a medicinal prospect is in a micelle or a vesicle.
  • a microstructure such as a drug or a compound having a medicinal prospect with a micelle, a vesicle, and the drug or a compound having a medicinal prospect is in a micelle or a vesicle.
  • the entire complex acts as an amphoteric substance constituting micelles and vesicles with the external environment.
  • drug is simply referred to as “drug” below.
  • the method of the present invention can treat any compound that requires such treatment, especially for treating poorly soluble organic compounds, especially poorly soluble organic drugs in water.
  • concentration used in the present specification refers to reducing or removing the solvent in the solution system containing the complex using conventional techniques in the technical field to obtain the complex.
  • curing used in the present invention refers to a process in which the substances constituting micelles and vesicles in the above complexes become relatively dense. In “curing”, there may be chemical effects, such as weak bonding between molecules, or they may be just physical effects.
  • the puffing process occurs during the curing process, and the pressure is reduced under heating: the solvent evaporates quickly and foams, forming a porous loose solid and easily soluble in water, which has a similar effect to lyophilization.
  • the nanomedicine of the present invention can be explained by the principle of supramolecular chemistry.
  • hydroxypropyl beta-cyclodextrin is used to form micelles in the solution (the micelles are hydrophobic and the periphery is hydrophilic, and the size is between 5 and 10 nm).
  • Microvesicles-liposomes the inner core of the vesicles is water, the outer lipophilic, the inner diameter of the inner core can be 20 ⁇ 30nm, tens, up to several hundred nanometers depending on the situation), constitutes a kind of multiple stable parents in aqueous solution (Hydrophilic and lipophilic) systems, because micelles and vesicles can contain drug molecules to form complexes, according to the principle of molecular recognition and assembly, drugs are incorporated into the system, and drugs exist in a molecular state.
  • hydroxypropyl beta-cyclodextrin and phospholipids are used as a matrix, and a drug or a compound having medicinal potential is used, especially a water-insoluble or poorly soluble drug or a compound having medicinal potential
  • the complex is prepared as a complex bound to the complex, and the diameter of the complex particle is small, and reaches the nanometer level in pharmacology.
  • amphiphilic system of the present invention is characterized by microscopic characteristics that are both hydrophilic and lipophilic. That is, amphiphilic substances are hydrophilic and lipophilic. Therefore, the above two substances are merely exemplary, and the present invention does not limit the specific substances used in the implementation. Those skilled in the art may, according to the spirit and essence of the present invention, select other substances having such properties according to the description of the present invention, and these are included in the present invention.
  • the microscopic morphology of such substances in water, such as micelles and microcapsules, can vary with conditions, and these changes are also understood by those skilled in the art.
  • the amphiphilic system may include one solute, such as an aqueous solution of hydroxypropylbetacyclodextrin; it may also include two solutes, such as an aqueous solution containing hydroxypropylbetacyclodextrin and phospholipid; Solute is the addition of other aqueous solutions with similar properties to hydroxypropylbetacyclodextrin and / or phospholipids.
  • a parent system is a system containing a parent substance.
  • Amphiphilic substances are substances that have both hydrophilic and lipophilic properties. They can form certain microstructures in water or hydrophilic organic solvents, such as micelles and microcapsules. These structures can be viewed as miniature containers.
  • surfactants can be used.
  • a surfactant Tween 80 may be further added in order to promote the fusion of the micelles and microcapsules formed respectively in the aqueous solution.
  • the solvent of the amphiphilic system of the present invention is preferably water. It can also be other hydrophilic organic solvents, such as ethanol.
  • the hydrophilic organic solvent of the present invention may be selected from solvents such as lower fatty acids, hydrocarbon solvents, halogenated hydrocarbon solvents, furan solvents, amide solvents, lower fatty alcohols, nitrile solvents, ketone solvents and their mixture. But the presence of water is necessary.
  • the organic solvent is selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, petroleum ether, cyclohexane, chloroform, chloroform, tetrahydrofuran, dimethylacetamide, dimethyl Formamide, methanol, ethanol, propanol, butanol, acetonitrile, acetone and mixtures thereof.
  • the selection criterion of the solvent is whether the solute can form a certain microstructure in an appropriate solvent, such as the aforementioned micelles and vesicles.
  • the solutes used are hydroxypropylbetacyclodextrin and phospholipids; the solvent is water.
  • the solute in the amphiphilic system of the present invention may function as a carrier of the drug during the preparation of the drug of the present invention, and is also called a "matrix" or a “carrier". Therefore, the "matrix formula" in the present invention has the same meaning, and is used to represent the solute formula in the parent system of the present invention.
  • surfactants and stabilizers can be used, so the “matrix formulation” can further include surfactants and stabilizers.
  • a specific case of the matrix formulation is 100% hydroxypropylbetacyclodextrin.
  • another specific case of the matrix formulation is hydroxypropylbetacyclodextrin and phospholipid, and their ratio is 1: 0.05 to 0.3.
  • amphiphilic solutes suitable one or more surfactants, and one or more stabilizers may be added to the matrix formulation as appropriate.
  • One of the effects of these surfactants is to promote the interaction between the microstructures formed by the solute in the amphiphilic system of the present invention. Therefore, it is within the scope of the present invention to use similar substances instead of the surfactants described herein. Of course, these added ingredients may not be added to the matrix formulation, but used in other steps.
  • the preparation process of the parent system of the present invention is essentially a dissolution process.
  • the corresponding solvents and solutes are selected according to the specific properties of the target drug or a compound with medicinal prospects, and the amphiphilic system used for the target substance is dissolved and prepared.
  • the dissolution process is performed at a temperature of 30 to 100 ° C, preferably at a temperature of 60 to 75 ° C.
  • a temperature of 30 to 100 ° C preferably at a temperature of 60 to 75 ° C.
  • solvent there can be various changes in the solute type and dissolution order in the matrix formulation, and there are many choices for the solvent, but it only needs to meet the requirements to form the required microstructure in the solution, such as microcapsules or micelles.
  • operations such as stirring and adjusting the pH during the dissolution process can also be performed as needed.
  • Microstructures such as micelles and vesicles in the parent system can contain drug molecules and form complexes with drug molecules.
  • the present invention is based on the principle of molecular recognition and assembly, which integrates drugs into the system, and the drugs exist in the molecular state.
  • the matrices in which hydroxypropylbetacyclodextrin is complexed with phospholipids are water-soluble and they dissolve in water to become a transparent solution or a transparent microemulsion. Adding a drug to it, the drug will be contained in the micelles formed by hydroxypropylbetacyclodextrin and the microcapsules formed by phospholipids.
  • the amphiphilic system provided by the present invention is a special liquid system containing microstructures such as microcapsules and micelles.
  • microstructures such as microcapsules and micelles.
  • the differences in the lipophilic and hydrophilic properties of the microstructures, inside and outside, and the volume of these microstructures themselves, are the basis for their ability to disperse insoluble substances in water, including drugs and compounds with clinical application prospects, with practical value.
  • An object of the present invention is to prepare a new form of an existing drug, that is, a solid nanomedicine.
  • Another object of the present invention is to prevent the selection and misselection of a compound having a clinical application prospect. Therefore, in the present invention, the drug should In a broad sense, it refers to a substance that needs to increase its solubility. Therefore, the use of the method of the present invention may not be limited to the fields of pharmaceutical and pharmaceutical research.
  • drugs are added. Drugs are encapsulated in the microstructure of the parent system through intermolecular interactions. This suspension can be supplied to the market through conventional processing procedures such as dispensing. The microstructure of the parent system effectively achieves drug dispersion.
  • a parent system containing a drug or a target substance can obtain solid particulate matter through a certain processing means.
  • the matrices of hydroxypropylbetacyclodextrin and phospholipids are water-soluble, and they dissolve in water to become transparent solutions or transparent microemulsions.
  • the drug is contained in microcapsules formed by hydroxypropylbetacyclodextrin and phospholipids. It is a transparent solution when it is in liquid state. When it is concentrated under reduced pressure under heating, it undergoes a transparent or translucent glassy process, solidifies, and is bulky and porous after being expanded and dried.
  • hydrophilic Soluble organic solvents dissolve hydroxypropylbetacyclodextrin and phospholipids, and their changes are not significantly different.
  • hydrophilic Soluble organic solvents dissolve hydroxypropylbetacyclodextrin and phospholipids, and their changes are not significantly different.
  • Drug compounds are ordered.
  • the loose porous material after puffing and drying can be made into loose porous solid sterile particles or powder. Such particles or powders are immediately dissolved in water to form microemulsions or submicroemulsions. Because both hydroxypropylbetacyclodextrin and phospholipids have the property of preventing the aggregation of drug molecules, the drug is in a solution with a particle size of 1 nm to about 300 nm, preferably 30 nm to about 300 nm, more preferably 50 nm to about 200 nm, and an average 100 to 200 nm Diameter, relatively stable suspension in solution. The effect is better if stabilizers are added.
  • the indicators for screening and evaluating the matrix formula are drug loading; particle size and particle size distribution; suspension stability, etc.
  • the method of the present invention can be applied to a variety of drugs, such as, but not limited to:
  • phospholipids include various phospholipids, such as soy phospholipid and the like.
  • the surface active agent can be Tween 80, 0 / W type, and the amount of it can be determined through experiments according to different drugs.
  • the stabilizer can be povidone (PVP K 30; K 15 ) or dextran 40, 70, etc., and the amount can be determined by tests. .
  • the nano-medicine of the invention has quick-release property, and the prepared tablet is an oral fusion tablet, which is fast-release and highly effective; With long circulation and targeting.
  • the process of the present invention can use conventional pharmaceutical equipment. It is capable of large-scale, high-efficiency production, stable product properties, and can be directly or secondary processed to prepare multiple preparations for injection or oral administration. It is a unique and universally applicable, low-cost method for preparing nanomedicines.
  • loose porous solid sterile granules or powders that can be directly or secondary processed into formulations are as follows:
  • the object of the present invention is to provide a method for preparing a novel solid nanomedicine from an organic drug that is hardly soluble in water according to the above-mentioned principle of supramolecular chemistry.
  • the method enables the poorly soluble drugs to significantly increase the solubility and the dissolution rate in water, and has a targeted and a certain degree of sustained release and delay effect to stabilize and improve the drug effect. It can be directly divided into preparations for injection. It can also be used for secondary processing to prepare tablets, capsules, granules and other dosage forms for oral administration.
  • the invention adopts commonly used safe auxiliary materials and conventional equipment, and is a widely applicable and efficient and low-cost preparation method.
  • a matrix and a surfactant are used; in another specific technical solution, a matrix, a surfactant, and a stabilizer are used.
  • Surfactants and stabilizers are added on a case-by-case basis.
  • the matrix and related reagents used are physiologically compatible and proven safe and reliable after many years of clinical application. Adjusting the matrix formulation can control the particle size of the drug particles in a certain range in order to meet the requirements of different drug target tissues. Because the matrix contains polyhydroxy groups, according to the literature and experiments, intravenous infusion has the characteristics of long circulation, that is, invisibility.
  • the general implementation process of the method of the present invention is as follows: Under heating conditions of 30 to 100 ° C and a clean environment (class 10,000), the matrix is dissolved in water or a hydrophilic organic solvent, and a drug is added. If necessary, a surfactant and a Stabilizer; adjust acidity if necessary, stir to dissolve completely. Decolorization, depyrogenation, filtration and sterilization, the clarified solution is concentrated under reduced pressure under heating, solidified, expanded, and dried. It is discharged and pulverized into granules or powders for preparation.
  • the first is to dissolve the matrix in a hydrophilic organic solvent or water.
  • the matrix can be hydroxypropyl beta cyclodextrin, or a composition containing hydroxypropyl beta cyclodextrin, such as hydroxypropyl beta cyclodextrin and Composition of phospholipids.
  • the dissolution process will vary depending on the composition of the matrix.
  • Each component of the matrix can be added to the solvent one after the other or simultaneously.
  • the solvent may be water, or other suitable organic solvents.
  • the temperature during dissolution is generally 30 to 100 ° C, preferably 60 to 75 ° C, and more preferably 60 to 70 ° C. To promote dissolution, stirring may be performed.
  • the requirements for environmental conditions, such as in a clean environment (class 10,000), should be determined according to the situation. Whether it is heated or not depends on the type of solute.
  • a drug is added to the solution in which the matrix is dissolved, and a complex of the drug and the matrix microstructure is formed in the solution.
  • the matrix is dissolved in organic solvents or water to form microstructures such as micelles and vesicles. Drugs form complexes by entering these microstructures. The formation of such a complex changes the physical properties of the drug and achieves the purpose of the present invention. Therefore, one aspect of the present invention is the preparation of a pharmaceutical complex.
  • Microstructures such as micelles and vesicles can be regarded as special carriers for drug preparation proposed by the present invention. However, these microstructures are universal, and those skilled in the art can naturally think of other drugs that are not mentioned in the present invention and can also use this carrier.
  • one aspect of the present invention is to propose a special carrier for the preparation of a medicament.
  • the substances and methods capable of forming such a microstructure are not limited to those explicitly described in the present invention.
  • the use of a supramolecular structure to change the properties of a drug is the gist of the present invention, and any application of this idea can be regarded as utilizing the present invention.
  • surfactants and stabilizers can also be used.
  • the surfactant can be added after the matrix is dissolved, or added when the drug is added. Its role is to promote the interaction between microstructures such as micelles and vesicles.
  • a stabilizer may also be added, preferably after the drug is added to the matrix solution, for stabilizing the supramolecular complex. If necessary, acids or bases can be added.
  • the formed drug complex is a supramolecular ordering body. Since drugs are encapsulated in the microstructure formed by hydroxypropylbetacyclodextrin, phospholipids, etc., many drugs can be modified in this way. Modifications are used in a broader sense in the present invention. The water solubility, biocompatibility, etc. of the modified drug complex will depend on the nature of the substance coated on the outside of the drug. Drugs exist in the interior in a relatively independent form and are protected from the direct effects of the external environment.
  • the molecules in the above microstructures can be cross-linked or undergo other physical and chemical changes through the action of other chemical reagents; even antibodies can be coupled to the surface of the microstructures. And other molecules to deliver a specific drug to a specific site.
  • a nano-scale solid medicine can be prepared from the solution containing the supramolecular ordering body.
  • the temperature of the reduced pressure concentration is controlled to 30 to 100 ° C, preferably 60 to 75 ° C, and more preferably 60 to 70 ° C.
  • Concentration under reduced pressure promotes intermolecular interactions such as hydroxypropylbetacyclodextrin, phospholipids, and the like, so that the periphery of the supramolecular ordered body becomes a relatively dense structure.
  • the drugs are relatively in a closed internal environment and may exist in various forms, such as liquid, semi-liquid, solid, semi-solid, crystalline, or mixed forms. It may also be in the form of a solution.
  • the drug provided by the present invention is in a special physical state: that is, a film or a coating formed by one or more amphiphilic substances on the periphery, and a drug or a substance containing the drug on the inside.
  • a feature of the drug complex prepared according to the method of the present invention is that its size is between 1 nm and about 300 nm in particle diameter, preferably 30 nm to about 300 nm, more preferably 50 nm to about 200 nm, and an average diameter of 100 200
  • the surface substance of the complex becomes relatively dense. From the appearance, the complex can be regarded as solid particles. As mentioned above, the drug inside the complex can be in other forms, such as liquid. Therefore, the nano-scale solid drugs described in the present invention are named according to their appearance and particle size.
  • the substances on the surface of the complex such as hydroxypropylbetacyclodextrin, phospholipids, etc., are not necessarily solid. In fact, they are just a relatively dense, well-ordered structure, a microstructure such as a liquid crystal state that contains drugs. Therefore, the present invention more emphasizes the difference between the drug and its surrounding coating substance, and this difference changes the solubility characteristics of the internal drug.
  • One aspect of the invention is the discovery of microstructures for containing drugs.
  • concentration under reduced pressure may be performed by other methods such as spray drying. Any method can be used as long as the complex formed therein can be stabilized. For example, sonication and vigorous stirring. Various methods and combinations of these methods can be used to convert the complex into solid particles. If a condensing system is configured, the evaporated solvent can be recycled.
  • the complex After the complex is cured, it mainly refers to the solidification of the outer layer of the complex, such as hydroxypropylbetacyclodextrin, phospholipids, etc., in which the contained drug is coated and is in a relatively independent state.
  • This material can also be processed by bulking, drying, etc., and a bulky solid can be obtained. It is powder or granular.
  • compositions or droplets coated with amphiphilic substances are suitable for formulation into a variety of dosage forms for medical use. Such as making oral or injectable preparations.
  • the term "nano" is applicable to indicate a pharmacological order of magnitude, and means that the diameter of the particles is below 1000 nanometers. Therefore, in pharmacology, the size of the drug complex prepared by the present invention is on the nanometer level.
  • paclitaxel for injection is prepared.
  • This paclitaxel (nanoparticles) for injection does not contain polyoxyethylene castor oil and is a preparation that eliminates sensitization.
  • hydroxypropylbetacyclodextrin is formed into micelles in an aqueous solution, and phospholipids are formed into vesicles in water.
  • a suitable surfactant is used to fuse the two characteristics to form a multivariate stable Parent system.
  • the drug is then incorporated in the molecular state to form a homogeneous system. Concentrated and dried to make sterile loose particles or powder. Refer to Figure 3 for purple for injection.
  • paclitaxel paclitaxel nanoparticles
  • H22 liver cancer
  • S-180 sarcoma
  • lung cancer Lewis Lung Cancer, LLC
  • the tumor inhibition test was administered by intravenous injection, intraperitoneal injection, or intragastric administration at clinical doses and concentrations. The test results show that the tumor inhibition rate is better than Commercial preparation.
  • Acute Toxicity Test LD 5 both formulations. There were no differences between 84.73 mg / kg and 84.55 mg / kg, respectively.
  • Figure 1 is a process flow diagram of the method of the present invention.
  • Figure 2 is a process flow chart of paclitaxel for injection.
  • Figure 3 is a transmission electron microscopy (50,000 times) of the particle size of paclitaxel particles (in water) for injection. It can be seen that the particles with a size of ⁇ 50nm are the overwhelming majority. Examples
  • Paclitaxel for injection Specification 30mg / 2.5g
  • Dihydroartemisinin for injection Specification 40mg / 1.5g
  • Matrix formulation Hydroxypropylbetacyclodextrin 31.5 Phospholipid 3 Tween 80 3
  • Main parameters Drug loading% 2.7
  • Nimodipine for injection Specification 12mg / 0.9g
  • Matrix formula Hydroxypropylbetacyclodextrin 64
  • Nimodipine is intended for oral use 10.
  • Cinnarizine for injection Specification 20mg / 0.22g
  • Matrix formulation Hydroxypropylbetacyclodextrin 8 Phospholipid 1 Tween 80 0.5
  • Nifedipine Specification 5,10,20mg / tablet Matrix formulation: Hydroxypropylbetacyclodextrin 8 Phospholipid 1.0 Povidone 2 Tween 80 2 Main parameters: Drug loading% 7.7
  • Matrix formulation hydroxypropyl beta-cyclodextrin 36.5 phospholipid 1.0 Tween 80 1.5 Main parameters: drug loading% 2.5 12. Simvastatin
  • the materials used are: Hydroxypropybeta-cyclodextrin (for injection) Hydroxypropy- / 3-Cyclodextrin for Injection; Soya Phospholide for Injection; Adjuvant Polysorbate 80 Polysorbate- 80 (Tween 80); Povidone K 30 , Polydone K 3 . Or ⁇ 15 (PVP K 3Q or ⁇ 15 ); and small molecule dextran, etc.
  • the formulation for preparing paclitaxel (nanoparticles) for injection 30mg / 2.5g (branch) is:
  • the drug loading% of the present invention was determined according to the routine: '1.19.
  • Adjusting the formula to change the ratio of matrix and adjuvant can affect the solubility of the drug and control the particle size of the particle within a certain range to meet the requirements of the drug.
  • the matrix (carrier) and adjuvant in the formula are physiologically compatible, safe and easy to purchase.
  • povidone is a suspension stabilizer
  • polysorbate 80 is a surfactant 0 / W type.
  • the preparation method is as follows: in a clean environment, dissolve the matrix in an appropriate amount of a hydrophilic organic solvent according to the formula, add an auxiliary agent and stir to completely dissolve it, heat it to 30-100 ° C, add activated carbon to decolorize, depyrogenize, filter, and clarify The liquid was added with paclitaxel, and after being dissolved, it was filtered and sterilized. The filtrate was placed in a rotary reaction tank equipped with a condenser and a solvent recovery system at 30 to 100 ° C (optimal temperature 60 to 70 ° C), 100 to 120 (rev.
  • the finished product has the following properties:
  • This product is white or almost white amorphous particles or powder, which is hygroscopic. No odor or slight odor of soybeans (soybean phosphate smell).
  • This product is prepared as a homogeneous system.
  • particles When dissolved in water (or solvent for injection), particles are precipitated due to reduced solubility in water, and due to hydroxypropylbetacyclodextrin, phospholipids, povidone K 3 o, and polysorbate.
  • the presence of 80 makes the precipitated particles fine and difficult to aggregate, relatively stable. Observe and count the particle size and distribution of the particles in the pictures through transmission electron microscope pictures. The following are the results observed immediately after dissolution, 1 hour and 2 hours
  • the particle size distribution is as follows:
  • the acute toxicity test was performed using commercially available cyanogen as a control, and the two were the same.
  • liver cancer H22
  • sarcoma S-180
  • lung cancer Lewis Lung Cancer, LLC
  • this product is dissolved in glucose injection or sodium chloride injection at a concentration of 300mg / 1000ml / three-hour infusion, three weeks (or four weeks) once therapy. Or the concentration is 100mg / 300 ⁇ 500ml / time, once a week, and it is also suitable for 400mg / 1000ml / time high-dose therapy.
  • the present invention uses hydroxypropylbetacyclodextrin and phospholipids as the matrix, and according to the characteristics of molecular aggregates such as supramolecular chemical micelles, vesicles, etc., under conditions of hydrophilic organic solvents and water
  • the nano-medicines prepared under warming and decompression are loose, porous sterile granules or powders, which are directly provided for intravenous infusion preparations, and have targeted, certain sustained release and long circulation.
  • As an oral solid preparation it is delicious and fast-release, fast-acting and improves bioavailability.
  • the nanomedicine can adopt safe excipients and conventional equipment and methods, and is universally applicable and easy to be produced on a large scale.
  • the anticancer drug paclitaxel intravenous injection provided by the invention does not contain polyoxyethylene castor oil and has no sensitization, and its safety and efficacy are better than those of commercially available paclitaxel injections.

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Description

固体纳米药物及其制备方法 技术领域 本发明涉及一种固体纳米药物及其制备方法，具体而言涉及将难溶性有机药物 与一种两亲性基质（载体）配合， 制备成固体纳米药物。本发明还涉及注射用紫杉 醇纳米药物及其制备方法。 背景技术
对于水中难溶性药物而言，采用常规方法制备的配方制剂，其生物利用度差而 且高度可变， 从而影响了药效。对于新的活性化合物， 采用常规方法制备的配方制 剂， 则会影响临床前筛选和临床试验的结果， 甚至造成筛选的失误。据报道， 估计 约有 40 %通过组合化学筛选的活性物质难溶于水，这与临床应用的难溶药物所占比 例基本相同。 由此可见， "增溶 "无疑是药物研究的重大课题。
近年来研究的热点除制备为水溶性配合物等方法外， 一项新发展是纳米技术。 这种技术是利用物理或物理化学的方法，将药物高度分散为稳定的亚微米颗粒（纳 米晶）， 使药物具有诸多新特性， 如增加溶解度， 显著提高生物利用度， 稳定和提 高药效， 赋予靶向性， 缓释和延效等。经这样处理的药物可用于加工胃肠道和胃肠 道外用药， 特别是静脉输注用药等剂型， 发展前景广阔。
纳米技术的成功与否目前主要决定于制备技术的效率、是否适合大规模生产及 生产成本、特别是所采用载体的安全性是否被认可以及所能加工的制剂剂型。就生 产技术而言， 已用于生产的主要有研磨法。 如 Elan公司的 NanoCrystal技术 （在稳 定剂存在下制备纳米晶）， 另一类是超临界流体技术， 以及一些派生的类似技术。 Elan公司用 NanoCrystal技术生产的片剂西罗莫司 （Sirolimus免疫抑制剂） 于 2001 年上市， 为纳米技术药物首例上市， 尚有其他品种在开发中。 以上方法都需要专有 设备和专门的技术， 一般制药企业难以掌握。
常规的制药方法以种种赋形剂作载体的纳米药物制剂， 由于载体（赋形剂）和 制备方法尚不能适合临床需要和适应工业生产的要求， 多数处于研究阶段。
著名抗癌药紫杉醇的水中溶解度为 0.006mg/ml， 在水中实际不溶， 其静脉输注 制剂的关键技术是解决它在水中的溶解性。 目前临床应用的制剂如中国产品紫素， 泰素， 美国产品 Taxol (美国 BMS公司）， Anzatax (澳大利亚 Fauliding公司)等产品， 都是采用聚氧乙烯蓖麻油 （Cremophor EL表面活性剂）和无水乙醇（Wv l:l )作溶 剂， 制成 30mg/5ml的溶液， 加水溶解， 并在 8〜12h内稳定 （不析出结晶）， 临床应 用时用注射用溶剂（如 5%葡萄糖等）稀释后静脉滴注。但这些制剂存在以下问题：
1.聚氧乙烯蓖麻油可促进组胺的释放， 具强致敏性， 要求用药前即预服抗组胺 药 （口服和注射）， 并严格监控。
2.聚氧乙烯蓖麻油可以将常用的聚氯乙烯输液器中的增塑剂邻苯二甲酸二辛 酯浸提到药液中增加毒性。 因此， 必须采用聚乙烯和玻璃输液器。
这些问题给患者和医生都造成诸多不便，增加患者的痛苦和医疗成本。成为一 个亟需解决的问题。因此制备不含聚氧乙烯蓖麻油的紫杉醇静脉注射制剂，便成为 研究的热点。近年来国内外的药学家作了大量研究 ， 例如， "不含聚氧乙烯蓖麻油 的紫杉醇静脉注射剂研究进展， 魏晓慧等， 中国医药工业杂志 Chinese Journal
Pharmaceuticals 2001.32(4) 188页"。 报道已经研究的剂型包括静脉注射液， 静脉注 射普通乳， 亚微乳及微乳， 毫微粒（晶）等以及紫杉醇的聚乙二醇衍生物， 以蛋白 质作载体的复合物等制剂取得了明显的进展。但大都尚不符合用药的安全性和工业 生产的要求， 至今未见上临床和上市的报道。
最近以聚谷氨酸为载体的水溶性静脉注射剂，在美国和英国分别进行 II期和 I 期临床试验。 见" Scrip 2001(2690)14" 0 Acusphere公司一种独特的紫杉醇配方进入 了临床试验， 这种制剂属于疏水药物输送系统 （HDDS), 见"因特网信息 （May 30,2002) "， 韩国三洋公司的紫杉醇新配方 Genexol-PM (l)经美国 FDA的许可将进 行 I期临床试验， 见" Scrip 2002(2734/35)31"。 以上报道说明研究工作取得了突破 性进展， 并且是多方面的。 这些制剂大都属于纳米制剂。
国内的研究仍处于实验室阶段，无论是载体的采用和制备工艺与生产和临床均 有相当的距离， 见"紫杉醇长循环固态脂质纳米粒的制备和体内外研究， 陈大兵等， 药学学报 Acta Pharmaceutical Sinica 2002,37(1) 54〜58"。 纳米制剂作为水中难溶药 物非肠道和肠道用药的新技术是目前药物制剂研究的热点。但其进入临床和生产的 成功与否取决于载体的安全性， 易选择性， 工艺设备及方法的常规化等。
本发明的目的在于提供一种固体纳米药物及其制备方法。本发明使用一种两亲 性基质成分，利用基质成分在溶液中的两亲特性，在常规条件下制备出了药物的固 体纳米颗粒， 满足了临床需要。并且， 本发明适合于在常规条件下将多种水中不溶 或者难溶的药物制备为纳米颗粒。本发明的方法尤其是适用于制备水中难溶性药物 紫杉醇的水溶性纳米颗粒。 发明概述
本发明的一个方面， 在于提供一种制备固体纳米药物的方法， 包括： 将药物与 双亲体系作用； 形成双亲物质与药物的配合物； 和浓缩、 固化膨化得到无菌的固体 纳米药物。 '
本发明的另一个方面， 在于提供一种制备药物配合物的方法， 包括： 提供一种 双亲体系； 将药物与双亲体系作用； 和形成双亲物质与药物的配合物。
本发明还提供一种紫杉醇的固体纳米颗粒，该紫杉醇纳米颗粒可以溶解于水中 制成注射液， 形成微乳或者亚微乳状溶液。 发明的详细说明
1. 定义
在本说明书所用术语"双亲物质"，是指具有亲水性和亲脂性的物质。本发明中， 优选的双亲物质包括羟丙基倍他环糊精和磷脂。
在本说明书所用术语 "胶束"， 是羟丙基倍他环糊精在水溶液中形成的微观结 构， 内呈疏水性， 外围亲水， 其大小在 l〜10nm之间。
在本说明书所用术语 "囊泡"， 是磷脂在水中形成的微观结构， 也叫作微泡体或 者脂质体， 内核为水， 外围亲脂， 内核直径视不同情况可有 20〜30nm， 数十、 直 至数百纳米。 药物制剂的纳米尺度通常为 l〜1000 nm。
在本说明书所用术语 "配合物"， 是指前文所述羟丙基倍他环糊精， 磷脂与化合 物（药物等活性物质） 以弱键结合形成的配位化合物。也可以将其看作两种或者两 种以上的物质形成的具有特定空间结构的复合物。在此所用， "配合物"并不限定物 质之间的作用力形式或者作用方式，仅仅是用于描述两种或者两种以上的物质经过 一定的相互作用后形成的稳定存在状态。在本发明中， "配合物"尤其用于指称药物 或者具有药用前景的化合物以胶束、囊泡等微观结构形成的复合物，其中药物或者 具有药用前景的化合物处于胶束、囊泡等的内部，存在于一种相对封闭的微观环境 中； 而整个复合物是以构成胶束、囊泡的两性物质与外界环境作用。为了描述的方 便， 下文将 "药物或者具有药用前景的化合物 "简称为"药物"。 本技术领域的技术人 员应该理解到本发明的方法可以处理任何一种需要这种处理的化合物，尤其用于处 理难溶性有机化合物， 特别是水中难溶性有机药物。
在本说明书所用术语"浓缩"是指用本技术领域的常规技术，减少或者除去含有 配合物的溶液体系中的溶剂， 得到配合物。
在本发明书所用术语 "固化"， 是指上述配合物中构成胶束、囊泡的物质变得相 对致密的过程。 "固化 "中， 有可能发生了化学作用， 比如分子间的弱键结合， 也有 可能仅仅是物理作用。膨化过程发生在固化过程中， 于加热下减压： 溶剂快速蒸发 而发泡， 形成多孔的疏松固体而易溶于水， 与冻干有类似的效果。
本发明纳米药物可以用超分子化学原理来解释。在具体步骤中，包括将羟丙基 倍他环糊精在溶液中形成胶束（胶束内呈疏水性， 外围亲水， 其大小在 5〜10nm之 间）， 磷脂在水中形成囊泡 （微泡体- -脂质体， 囊泡内核为水， 外围亲脂， 内核直 径视不同情况可有 20〜30nm， 数十、 直至数百纳米）， 在水溶液中构成一种多元的 稳定的双亲（亲水、亲脂）体系， 由于胶束、囊泡都可以包容药物分子形成配合物， 依分子识别和组装的原理， 将药物结合进该系统， 药物以分子态存在其中。
在本发明的一个实施方案中，是将羟丙基倍他环糊精和磷脂作为基质，把药物 或者具有药用前景的化合物，特别是水不溶性或者难溶性的药物或者具有药用前景 的化合物制备为与其结合的配合物，该配合物颗粒直径较小，达到了药物学上的纳 米水平。
本发明的双亲体系的特征在于既亲水又亲脂的微观特性。也就是说，双亲物质 具有亲水性和亲脂性。所以上述两种物质仅仅是例举性的，本发明并不限制实施当 中使用的具体物质。本技术领域的技术人员在得到本发明的说明的情况下，可以依 据本发明的精神和实质选择其他具有这类性质的物质，这些包括在本发明之内。这 类物质在水中形成的微观形态， 例如胶束和微囊等形态， 可以随条件有所变化， 这 些变化也是在本技术领域的技术人员的理解之中。
双亲体系可以是包括一种溶质的，例如为羟丙基倍他环糊精的水溶液；也可以 包括两种溶质，比如含有羟丙基倍他环糊精和磷脂的水溶液;还可以包括多种溶质， 就是加入其他具有与羟丙基倍他环糊精和 /或磷脂具有类似性质的物质的水溶液。 在此所用，双亲体系是含有双亲物质的体系。双亲物质就是既有亲水特性又有亲脂 特性的物质， 它们在水中或者亲水性有机溶剂中可以形成一定的微观结构， 比如胶 束和微囊等。 这些结构可以看作微型容器。
进一步而言，为了促进不同的具有双亲性质的溶质在水溶液中的微观结构间的 融合，可以使用适宜的表面活性剂。例如在羟丙基倍他环糊精和磷脂的水溶液中可 以进一步加入表面活性剂吐温 80，以便促进在水溶液中的它们分别形成的胶束和微 囊的融合。
本发明的双亲体系的溶剂优选水。 也可以是其他亲水性有机溶剂， 例如乙醇。 本发明的亲水性有机溶剂可以选自低级脂肪酸之类溶剂，烃类溶剂，卤代烃类溶剂， 呋喃类溶剂， 酰胺类溶剂， 低级脂肪醇类， 腈类溶剂， 酮类溶剂和它们的混合物。 但水的存在是必要的。
在本发明的具体实施方案中， 上述有机溶剂选自乙酸甲酯， 乙酸乙酯， 乙酸丁 酯， 石油醚， 环己垸， 二氯甲垸， 氯仿， 四氢呋喃， 二甲基乙酰胺， 二甲基甲酰胺， 甲醇， 乙醇， 丙醇， 丁醇， 乙腈， 丙酮和它们的混合物。
在制备本发明的双亲体系时，溶剂的选择标准为是否该溶质可以在适当的溶剂 中形成一定的微观结构，比如前述的胶束和囊泡。在本发明的一个优选实施方案中， 所用溶质为羟丙基倍他环糊精和磷脂； 溶剂为水。 ，
本发明的双亲体系中的溶质在本发明的药物制备过程中，可能作为药物的载体 发挥作用，也称为 "基质 "或者 "载体"。所以在本发明中"基质配方"具有同样的涵义， 用以表示本发明的双亲体系中的溶质配方。在本发明的制备过程中，可以使用表面 活性剂和稳定剂等， 所以"基质配方"也可以进一步包括表面活性剂和稳定剂等。
在本发明中， 基质配方的一个具体情况是 100%的羟丙基倍他环糊精。 在本发 明中， 基质配方的另一个具体情况是羟丙基倍他环糊精和磷脂， 它们的比例为 1:0.05〜0.3。
基质配方中可以视情况加入其他具有双亲性质的溶质，适宜的一种或者多种表 面活性剂，一种或者多种稳定剂。这些表面活性剂的一种作用是促进本发明的双亲 体系中溶质形成的微观结构间的融合等相互作用，因此采用类似物质替代此处所述 表面活性剂也在本发明范围之内。当然这些添加成分也可以不加入基质配方中，而 是在其他步骤中使用。 本发明的双亲体系的制备过程本质上是一个溶解过程。
根据目标药物或者具有药用前景的化合物的具体性质选择相应的上述溶剂和 溶质， 溶解制备用于该目标物质的双亲体系。
溶解过程在 30〜100°C的条件下进行， 优选在 60〜75°C的条件下进行。 基质配 方中的溶质种类和溶解顺序可以有多种变化，溶剂也可以有多种选择，但是只要满 足溶解后在溶液中形成需要的微观结构即可，例如微囊或者胶束等。当然在溶解过 程中进行搅拌、 调节酸碱度等操作也可以视需要进行。
双亲体系中的胶束、囊泡等微观结构都可以包容药物分子，形成与药物分子的 配合物。本发明是依据分子识别和组装的原理， 将药物结合进该系统， 药物以分子 态存在其中。
在本发明的一个优选实施方案中，羟丙基倍他环糊精与磷脂配合的基质是水溶 性的， 它们溶于水成为透明溶液或透明的微乳。在其中加入药物， 药物就会被包容 进羟丙基倍他环糊精形成的胶束与磷脂形成的微囊中。
药物与双亲体系的作用凭借了分子间的相互作用。如上所述，本发明提供的双 亲体系是包含有微囊、胶束等微观结构的特殊液体体系。微观结构的内外亲脂和亲 水性能的不同，以及这些微观结构本身的体积大小，是它们能够将水中难溶性物质， 包括药物和具有临床应用前景的化合物，进行有实用价值的分散的基础。本发明的 一个目的在于制备现有药物的新形态， 即固体纳米药物；本发明的另外一个目的在 于防止对具有临床应用前景的化合物发生漏选和误选，所以在本发明中，药物应该 作广义理解， 泛指需要增加其溶解度的物质。 因此， 本发明的方法的用途可以不限 于制药和药物研究领域。
在双亲体系中，加入药物。药物通过分子间的相互作用被包入双亲体系的微观 结构中，这种混悬液经过分装等常规的处理过程可以供应市场。双亲体系的微观结 构有效实现了药物的分散。
进一步地， 含有药物， 或者目标物质的双亲体系可以通过一定的处理手段， 获 得固态的颗粒物质。例如， 羟丙基倍他环糊精与磷脂配合的基质是水溶性的， 它们 溶于水成为透明溶液或透明的微乳。在其中加入药物，药物就会被包容进羟丙基倍 他环糊精形成的胶束与磷脂形成的微囊中。液态时为透明的溶液，加热下减压浓缩 时经透明或半透明玻璃状过程， 固化， 膨化干燥后呈疏松、 多孔状。 如果使用亲水 性有机溶剂溶解羟丙基倍他环糊精与磷脂， 其变化没有明显不同。在本发明中， 其 中含有包含药物的微观结构的溶液在浓缩过程中，羟丙基倍他环糊精、磷脂等分子 间有可能形成分子间以弱键结合的配合物， 从而形成一个包被药物的化合物有序 体。
膨化干燥后的疏松多孔状物质可以制成疏松多孔的固体无菌颗粒或粉末。这种 颗粒或粉末在水中立即溶解，形成微乳或者亚微乳状液。由于羟丙基倍他环糊精和 磷脂都具有阻止药物分子聚集的性能， 药物在溶液中以 lnm至约 300nm， 优选 30nm 至约 300nm， 更优选 50 nm至约 200nm， 平均 100〜200nm的粒径， 相对稳定地混悬 在溶液中。 如果加入了稳定剂， 则效果更好。
透视电镜测定表明粒径分布在 l〜300nm之间， 并在数小时， 数日或更长的时 间内相对稳定。筛选和评定基质配方的指标是载药量； 粒径及粒径分布； 混悬稳定 性等。
本发明的方法可以用于多种药物， 例如， 但不限于：
A 紫杉醇 （Paclitexel，Taxol) 制剂； .
B 蒿甲醚 （Artemether) 制剂；
C、 双氢青蒿素 （Dihydroartemisinine) 制剂；
D、 白消安 （Busulfan) 制剂；
E、 尼莫地平 （Nimodipine)制剂；
F、 尼群地平 （Nitrendipine) 制剂；
G、 硝苯地平 （Nifedipine) 制剂；
" H、 地西泮 （Diazipam) 制剂；
I、 桂利嗪 （Cinnarizine)制剂；
J、 洛伐他汀 （Lovastatine) 制剂；
K、 辛伐他汀 （Simvastatins) 制齐 !j。
在本发明中， 磷脂包括各种磷脂， 例如豆磷脂等。
表面活性剂可以为吐温 80， 0/W型， 其用量视不同药物经试验确定； 稳定剂可以为聚维酮 （PVP K30; K15) 或右旋糖酐 40、 70等， 其用量经试验 确定。
本发明的纳米药物具速释性， 制成的片剂为口融片， 速释高效； 作静脉输注还 具有长循环性及靶向性等。
本发明的工艺方法可以釆用常规的制药设备。 能够进行大规模、 高效率生产， 产品的性状稳定，可直接或二次加工制备供注射或口服的多种制剂， 是制备纳米药 物的独特和普遍适用的， 低成本的方法。
疏松多孔的固体无菌颗粒或粉末可直接或二次加工为制剂的具体实例如下：
1.直接分装制备注射用粉针剂；
2.加入辅料制备各种口服制剂；
3.制成各种液体药剂等等。
特定而言之，本发明的目的是提供一种按上述超分子化学原理，将难溶于水的 有机药物制备成新型固体纳米药物的方法。 该方法使难溶药物显著增加水中溶解 度， 溶解速度， 并具靶向性及一定程度的缓释和延效作用， 以稳定和提高药效。可 直接分装制备注射用针剂， 也可用于二次加工制备供口服的片剂、胶囊、颗粒剂以 及其他多种剂型。本发明采用常用的安全的辅料及常规设备，是一种广泛适用和高 效、 低成本的制备方法。
在一个具体技术方案中，使用了基质和表面活性剂；在另外一个具体技术方案 中， 使用了基质、表面活性剂和稳定剂。表面活性剂和稳定剂是依据具体情况选择 性加入的。 采用的基质及相关试剂均为生理相容性的， 并经临床多年应用证实其 安全可靠。调整基质配方可在一定范围控制药物粒子的粒径， 以便适应不同药物靶 组织的要求。 由于该基质含多羟基， 按文献和试验证明， 作静脉输注具有长循环的 特性， 即隐形性。
本发明的方法的大致实施过程如下：在 30〜100°C加热条件和洁净环境（万级) 下， 将基质溶于水或亲水性有机溶剂， 加入药物， 如果必要可以加入表面活性剂和 稳定剂； 必要时调节酸度， 搅拌使完全溶解。 脱色， 脱热原， 过滤除菌， 澄清液在 加热下减压浓缩， 固化， 膨化， 干燥。 出料， 粉碎为颗粒或粉末， 供制剂用。
现在参考图 1， 详细说明本发明的方法。 首先是将基质溶解在亲水性有机溶剂 或者水中， 基质可以是羟丙基倍他环糊精， 或者含有羟丙基倍他环糊精的组合物， 例如羟丙基倍他环糊精和磷脂的组合物。基质的组成不同，其溶解过程会有所不同。 基质中的各个成分可以先后或者同时加入溶剂中。溶剂可以是水，或者其他适当的 有机溶剂。溶解时的温度一般为 30〜100°C， 优选为 60〜75°C， 更优选为 60〜70°C。 为了促进溶解， 可以进行搅拌。 其中对于环境条件的要求， 例如洁净环境 （万级） 下， 应该视情况而定。 是否加热也可以视溶质种类而定。
然后向溶解有基质的溶液中，加入药物，在溶液中形成药物与基质微结构的配 合物。从微观而言， 基质溶解于有机溶剂或者水形成了胶束、囊泡等微观结构， 药 物通过进入这些微观结构形成了配合物。 这种配合物的形成改变了药物的物理性 质， 达到了本发明的目的。 因此， 本发明的一个方面就是制备药物配合物。 胶束、 囊泡等微观结构可以看作本发明提出的用于药物制备的特殊载体。但是这些微观结 构具有通用性，本领域的技术人员可以自然联想到本发明没有提及的其他药物也可 以应用这种载体。 因此， 本发明的一个方面是提出制备药物用的特殊载体。 能够形 成这种微观结构的物质和方法并不限于本发明所明确叙述的这些。将超分子结构用 于改变药物的性质是本发明的主旨，任何应用这种思想的做法均可以看作利用了本 发明。
在本发明中， 也可以使用表面活性剂和稳定剂。其中表面活性剂可以在基质溶 解后加入， 或者在加入药物时加入， 其作用在于促进胶束、囊泡等微观结构之间的 相互作用。也可以加入稳定剂， 优选在加入药物到基质溶液中以后加入， 用于稳定 超分子配合物。 必要时， 可以加入酸或碱。
在本发明中，形成的药物配合物是一种超分子有序体。由于药物是包裹进羟丙 基倍他环糊精、磷脂等形成的微观结构中的，所以多种药物可以通过这种方式加以 修饰。在本发明中修饰是以一种更广泛的涵义而使用的。修饰后的药物配合体的水 溶性、生物相容性等将取决于包被在药物外面的物质的性质。药物则以一种相对独 立的形式存在于内部， 可以免受外界环境的直接作用。更进一步而言， 在药物被包 容进这些微观结构之后，还可以通过其他化学试剂作用，使上述微观结构中的分子 发生交联或者其他物理化学变化；甚至于在微观结构的表面偶联上抗体等分子， 以 便将特定的药物输送到特定部位。
通过减压浓縮， 可以从上述含有超分子有序体的溶液中制备出纳米级固体药 物。 减压浓缩的温度控制在 30〜100°C， 优选为 60〜75°C， 更优选为 60〜70°C。 减 压浓缩促进了羟丙基倍他环糊精、磷脂等分子间的相互作用，使得上述超分子有序 体的外围变成相对致密的结构。而其中的药物则相对处于封闭的内部环境中，有可 能以多种形态存在， 比如液态、 半液态、 固态、 半固态、 晶体或者混合形式存在。 也有可能是溶液形式。 因此， 本发明所提供的药物处于一种特殊的物理状态下： 也 就是外围为一种或者多种双亲性物质形成的薄膜或者包衣，内部为药物或者含有药 物的物质。根据本发明的方法制备的药物配合物的一个特征就是其大小在为颗粒直 径在 lnm至约 300nm， 优选 30 nm至约 300nm， 更优选 50nm至约 200nm， 平均直径为 100 200
减压浓缩以后，配合物表面物质变得相对致密，从外观而言这种配合物可以看 作固体颗粒。如上所述， 配合物内部的药物可以为其他形态， 比如液态。所以本发 明所述纳米级固体药物， 是从其外观形态和颗粒大小上命名的。其实， 配合物表面 的物质， 比如羟丙基倍他环糊精、磷脂等， 也不一定是一般的固态。 实际上， 它们 只是一种相对致密、排列有序的结构， 是一种容纳药物的微型结构如液晶态。所以 本发明更加强调的是药物和其外围包被物质的不同，以及这种不同改变了内部药物 的溶解特性等。
本发明的一个方面就是发现了用于容纳药物的微型结构。
在本发明中，减压浓縮也可以使用其他方法进行例如喷雾干燥。只要可以稳定 其中形成的配合物， 任何方法均可以使用。 比如超声处理、 剧烈搅拌等方法。将配 合物转化为固体颗粒可以使用多种方法以及这些方法的组合使用。其中如果配置冷 凝系统， 蒸发出的溶剂可以循环使用。
配合物固化后， 主要是指配合物外层物质， 例如羟丙基倍他环糊精、磷脂等的 固化， 其中包容的药物就被包被起来， 处于相对独立的状态下。对于这种物质还可 以经过膨化、 干燥等处理， 就能得到膨松多孔的固体。 为粉末或者颗粒状。
用双亲物质包被的药物颗粒或者液滴适用于配制为多种剂型，用于医疗。 比如 制成口服或注射制剂等。
在本发明中， 术语"纳米"适用于表示药物学上的量级， 是指颗粒的直径在 1000 纳米以下。 因此， 在药物学上， 本发明制备的药物配合物的大小在纳米水平。
在本发明的一个实施方案中， 制备了注射用紫杉醇。这种注射用紫杉醇（纳米 粒） 不含聚氧乙烯蓖麻油， 是一种消除致敏性的制剂。 参考图 2， 先将羟丙基倍他 环糊精在水溶液中形成胶束，磷脂在水中形成囊泡，用适宜的表面活性剂将两种特 性融合，在水溶液中构成一种多元的稳定的双亲体系。再将药物以分子态结合于其 中， 形成均相系统。 浓缩干燥制成无菌的疏松颗粒或粉末， 参考图 3， 为注射用紫 杉醇粒子（在水中） 的粒径透射电镜图 （5万倍）， 其中粒子直径 <50nm的为绝大多 数。这种颗粒或粉末在水中能迅速溶解， 由于在水中的溶解度较制备时低， 析出药 物， 所以形成微乳， 亚微乳状液。 按本法制备的注射用紫杉醇（紫杉醇纳米粒） 的 药效实验， 是试验其抗肿瘤作用。 选用三种瘤株， 肝癌 （H22) ，肉瘤 （S— 180)， 肺癌（Lewis Lung Cancer,LLC)， 在 ICR种及 C57BL/6种小鼠接种， 于次日给药作药 效试验- -抑瘤试验， 与临床应用的紫杉醇注射液（北京协和药厂， 批号 020202) 比 较， 按临床剂量和浓度以静脉注射， 腹腔注射， 灌胃三种途径给药， 试验结果说明 抑瘤率优于市售制剂。
两种制剂的小鼠急性毒性试验 LD5。分别为 84 .73mg/kg和 84.55mg/kg两者无差 别。 附图说明
图 1为本发明的方法的工艺流程图。
图 2为注射用紫杉醇的工艺流程图。
图 3为注射用紫杉醇粒子 （在水中） 的粒径透射电镜图 （5万倍）。 可见制剂以 <50nm的粒子为绝大多数。 实施例
下面是用实施例对本发明进行更详细的说明，结合附图可以对本发明有更完整 的认识。但是应该理解的是， 本发明可以有各种各样的变化， 这些变化只要遵循了 本发明的精神和实质也应该包括在本发明之中。 本发明仅受所附权利要求书的限 制。 实施例仅仅是为了说明的目的， 而不可看作是对本发明的限制。 实施例 1. 例举性原料配方
1.注射用紫杉醇 规格： 30mg/2.5g
基质配方： 羟丙基倍他环糊精 60
磷脂 8
吐温 80 9
主要参数： 载药量％ 1.2 2.注射用蒿甲醚 规格： 60mg/2.2g 基质配方： 羟丙基倍他环糊精 31.5 磷脂 3 吐温 80 1.5 主要参数： 载药量％ 2.7
3.注射用双氢青蒿素 规格： 40mg/1.5g 基质配方： 羟丙基倍他环糊精 31.5 磷脂 3 吐温 80 3 主要参数： 载药量％ 2.7
4 . 白消安 规格： 2mg 基质配方： 羟丙基倍他环糊精 17
磷脂 1.7 吐温 80 0.75 主要参数： 载药量％ 5.1
5 . 注射用尼莫地平 规格： 12mg/0.9g 基质配方： 羟丙基倍他环糊精 64
磷脂 3.5 吐温 80 5 主要参数： 载药量％ 1.3
6 . 尼莫地平供口服 10. 制剂 规格： 20mg/片 基质配方： 羟丙基倍他环糊精 7.5 磷脂 1.0 柠檬酸 0.5 吐温 80 1.0 主要参数： 载药量％ 10 7.尼群地平供口服制剂 规格： 10mg/片 基质配方： 羟丙基倍他环糊精 13.5 磷脂 1.0 柠檬酸 0.5 吐温 80 1.0 主要参数： 载药量％ 6.3
8.注射用地西泮 规格： 10mg/0.1g 基质配方： 羟丙基倍他环糊精 8 磷脂 1 主要参数： 载药量％ 11
9.注射用桂利嗪 规格： 20mg/0.22g 基质配方： 羟丙基倍他环糊精 8 磷脂 1 吐温 80 0.5 主要参数： 载药量％ 10.5
10.硝苯地平 规格： 5,10,20mg/片 基质配方： 羟丙基倍他环糊精 8 磷脂 1.0 聚维酮 2 吐温 80 2 主要参数： 载药量％ 7.7
11. 洛伐他汀
基质配方： 羟丙基倍他环糊精 36.5 磷脂 1.0 吐温 80 1.5 主要参数： 载药量％ 2.5 12、 辛伐他汀
Figure imgf000015_0001
实施例 2.
注射用紫杉醇的制备
在制备中 ， 所用材料为 ： 羟丙基倍他环糊精 （注射用 ） Hydroxypropy-/3-Cyclodextrin for Injection; 大豆磷月旨 (注射用 ) Soya Phospholide for Injection;辅助剂聚山梨酯 80 Polysorbate-80 ( Tween 80 )；聚维酮 K30， Polydone K3。 或 κ15 (PVP K3Q或 κ15)； 和小分子右旋糖酐等。
制备注射用紫杉醇 （纳米粒） 30mg/2.5g (支） 的配方为：
紫杉醇 lg
羟丙基倍他环糊精 （注射用） 60g
磷脂 （注射用） 8g
聚维酮 K3Q 5g
聚山梨酯 80 9g
30mg/2.5g (支）
根据常规测定本发明载药量％: ' 1.19。
调整配方改变基质，辅助剂的比例，可在一定范围内影响药物的溶解度和控制 粒子的粒径， 以适应用药的要求。
配方中的基质 （载体）及辅助剂均为生理相容性的， 安全和易于购买。 其中， 聚维酮为混悬稳定剂， 聚山梨酯 80为表面活性剂 0/W型。
制备方法为： 在洁净环境下， 按配方将基质溶于适量亲水有机溶剂中， 加入辅 助剂搅拌使完全溶解， 加热至 30〜100°C， 加活性碳脱色， 脱热原， 过滤， 澄清液 加入紫杉醇， 溶解后， 过滤除菌， 滤液置于配有冷凝器和溶剂回收系统的旋转反应 罐中， 于 30〜100°C (最佳温度 60〜70°C )， 100〜120 (转）减压浓縮， 固化， 膨化 固结后， 减压干燥 2〜3小时， 出料， 按需要粉碎为颗粒或粉末， 直接分装为注射用 粉针剂。 收率 >98%。 成品具有如下性状：
1. 性状
本品为白色或近白色无定形颗粒或粉末， 具引湿性。无臭或微有豆腥气（豆磷 脂气味）。
2. 溶解性
在稀醇中溶解为澄明溶液，水中溶解同时析出微粒、自行乳化均匀分散为微乳、 亚微乳状溶液， 均匀混悬， 相对稳定。
3. 粒径及粒径分布
本品制备时为均相系统， 加水（或注射用溶剂）溶解时因在水中的溶解度降低 析出微粒， 同时由于羟丙基倍他环糊精， 磷脂， 聚维酮 K3o以及聚山梨酯 80的存在 使析出的微粒细小和不易聚集，相对稳定。通过透射电镜图片观察并统计图片中粒 子的粒径及其分布。 以下是溶解后立即， 1小时及 2小时观察的结
当浓度为临床应用浓度 300mg/1000ml时， 粒径分布 o如下表：
时间 /粒径 <50nm 50〜扇腿 200nm
立即 1474 20 0 0
1360 19 0 0
l h 1754 29 1 0
2 h 1272 41 3 1
制剂经室温贮存和加速试验后， 加水溶解观察， 粒径无增大倾向， 贮存对粒子 粒径的稳定性无影响。
4. 安全性
急性毒性试验以市售紫素作对照， 两者相同。
5. 药效比较
以市售紫素作对照的三株小鼠肿瘤瘤株： 肝癌 （H22) ，肉瘤 （S— 180), 肺癌 (Lewis Lung Cancer,LLC),以临床用药浓度和剂量试验时，抑瘤率较市售品高 27〜 49.7%, 显示药效增强。
临床应用
本品临用前以葡萄糖注射液或氯化钠注射液溶解， 浓度为 300mg/1000ml/次 3 小时输注、 三周 （或四周） 一次疗法。 或浓度为 100mg/300〜500ml/次、 一周一次 疗法， 也适用于 400mg/1000ml/次大剂量疗法。 工业上利用的可能性 本发明以羟丙基倍他环糊精与磷脂为基质，根据超分子化学胶束、囊泡等分子 聚集体的特性， 以亲水性有机溶剂和水为条件，在加温和减压下制备的纳米药物为 疏松、 多孔的无菌颗粒或粉末， 直接供静脉输注制剂， 具靶向性、一定的缓释性和 长循环性。 作口服固体制剂， 可口融， 具速释性， 速效和提高生物利用度。 该纳米 药物可采用安全的辅料和常规的设备和方法，普遍适用和易于大规模生产。本发明 提供的抗癌药紫杉醇静脉注射剂，其中不含聚氧乙烯蓖麻油无致敏性，其安全性和 药效优于市售紫杉醇注射液。

Claims

权利要求书
1、 一种固体纳米药物的制备方法， 包括：
A.提供含有双亲物质的溶液；
B.将药物加入所述双亲物质的溶液中；
C.形成药物与双亲物质的配合物； 和
D.减压浓縮使配合物转变为固体颗粒。
2、根据权利要求 1所述的制备方法，其中所述双亲物质选自羟丙基倍他环糊精、 磷脂或它们的组合。
3、根据权利要求 1所述的制备方法，其中溶解所述双亲物质的溶剂选自亲水性 有机溶剂、 水或它们的组合。
4、根据权利要求 2所述的制备方法，其中所述双亲物质为羟丙基倍他环糊精和 磷脂， 其质量比为 1:0.05〜0.3。
5、 根据权利要求 1所述的制备方法， 其中溶解所述双亲物质是在 30〜100°C下 进行。
6、根据权利要求 5所述的制备方法，其中溶解所述双亲物质是在 60〜75°C下进 行。
7、 根据权利要求 1所述的制备方法， 其中所述药物选自： 紫杉醇； 蒿甲醚； 双 氢青蒿素； 白消安； 尼莫地平； 尼群地平； 硝苯地平； 地西泮； 桂利嗪； 洛伐他汀； 以及辛伐他汀的至少一种。
8、根据权利要求 1所述的制备方法，其中所述药物与所述双亲物质形成的配合 物的颗粒直径在 300nm以下， 外围是双亲物质， 内部是药物。
9、 根据权利要求 1和 7中任一项所述的制备方法， 其中可以进一步使用稳定剂 和表面活性剂。
10、 根据权利要求 9所述的制备方法， 其中所述表面活性剂为聚山梨酯 80。
11、 根据权利要求 10所述的制备方法， 其中所述稳定剂选自聚维酮 K3o或 K1: (PVP) 和右旋糖酐 40、 70。
12、 根据权利要求 1至 11任一项所述的制备方法制备的固体纳米药物。
13、 根据权利要求 12所述的固体纳米药物， 其中所述药物为紫杉醇。
14、 根据权利要求 12或 13所述的固体纳米药物， 其特征在于可用于静脉输注， 腹腔注射， 雾化吸入或口服治疗。
15、 一种用权利要求 12所述的固体纳米药物配制的注射液。
16、 根据权利要求 15所述的注射液， 其中所述药物为紫杉醇。
17、 一种药物配合物的制备方法， 该方法包括：
Α.提供含有双亲物质的溶液；
Β.将药物加入所述双亲物质的溶液中； 和
C.形成药物与双亲物质的配合物。
18、 根据权利要求 17所述的药物配合物的制备方法， 其特征在于：
还包括将所述配合物减压浓缩制备为无菌固体颗粒的工序。
19、根据权利要求 17或 18所述的制备方法，其中所述双亲物质选自羟丙基倍他 环糊精、 磷脂或它们的组合。
20、根据权利要求 17所述的制备方法，其中溶解所述双亲物质的溶剂选自亲水 性有机溶剂、 水或它们的组合。
21、 根据权利要求 1所述的制备方法， 其中所述药物选自： 紫杉醇； 蒿甲醚； 双氢青蒿素； 白消安； 尼莫地平； 尼群地平； 硝苯地平； 地西泮； 桂利嗪； 洛伐他 汀； 以及辛伐他汀的至少一种。
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4884975B2 (ja) * 2004-10-01 2012-02-29 エーザイ・アール・アンド・ディー・マネジメント株式会社 微粒子含有組成物およびその製造方法
WO2012110469A1 (en) 2011-02-17 2012-08-23 F. Hoffmann-La Roche Ag A process for controlled crystallization of an active pharmaceutical ingredient from supercooled liquid state by hot melt extrusion
WO2013149981A1 (en) 2012-04-03 2013-10-10 F. Hoffmann-La Roche Ag Pharmaceutical composition with improved bioavailability, safety and tolerability
WO2014114575A1 (en) 2013-01-22 2014-07-31 F. Hoffmann-La Roche Ag Pharmaceutical composition with improved bioavailability
CN104013601A (zh) * 2014-06-06 2014-09-03 重庆医科大学 姜黄色素羟丙环糊精磷脂纳米粒及其制备方法

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076295A2 (en) * 2005-12-16 2007-07-05 University Of Kansas Nanoclusters for delivery of therapeutics
KR100917809B1 (ko) * 2006-05-22 2009-09-18 에스케이케미칼주식회사 우수한 저장안정성을 갖는 도세탁셀 함유 주사제 조성물
WO2007142440A1 (en) * 2006-06-02 2007-12-13 Sk Chemicals Co., Ltd. Stable pharmaceutical composition containing paclitaxel and a method of manufacturing the same
CN101511348B (zh) * 2006-08-30 2012-04-18 国立大学法人九州大学 含有包封他汀类之纳米颗粒的药物组合物
GB0623838D0 (en) * 2006-11-29 2007-01-10 Malvern Cosmeceutics Ltd Novel compositions
EP1952803A1 (en) 2007-01-23 2008-08-06 KTB-Tumorforschungs GmbH Solid pharmaceutical dosage form containing hydrogenated phospholipids
CA2686756A1 (en) * 2007-05-11 2008-11-20 F. Hoffmann-La Roche Ag Pharmaceutical compositions for poorly soluble drugs
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GB201609222D0 (en) 2016-05-25 2016-07-06 F2G Ltd Pharmaceutical formulation
CN106092861B (zh) * 2016-05-26 2019-02-26 国家纳米科学中心 用于纳米颗粒的光谱椭偏拟合方法
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KR20190141244A (ko) 2017-05-03 2019-12-23 사이덱스 파마슈티칼스, 인크. 사이클로덱스트린 및 부설판을 함유하는 조성물
US11819503B2 (en) 2019-04-23 2023-11-21 F2G Ltd Method of treating coccidioides infection

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0132027A1 (en) * 1983-05-20 1985-01-23 Taisho Pharmaceutical Co. Ltd Fat emulsion containing prostaglandin
WO1992016196A1 (en) * 1991-03-20 1992-10-01 Novo Nordisk A/S A composition comprising a peptide for nasal administration
EP0602700A2 (en) * 1992-12-17 1994-06-22 NanoSystems L.L.C. Novel formulations for nanoparticulate X-ray blood pool contrast agents using high molecular weight surfactants
WO2000066635A1 (fr) * 1999-04-29 2000-11-09 Commissariat A L'energie Atomique Cyclodextrines amphiphiles, leur preparation et leur utilisation pour solubiliser des systemes organises et incorporer des molecules hydrophobes
CN1424035A (zh) * 2002-12-13 2003-06-18 北京东方天翔医药技术开发有限公司 尼莫地平冻干组合物

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4950432A (en) * 1987-10-16 1990-08-21 Board Of Regents, The University Of Texas System Polyene microlide pre-liposomal powders
DE4140185C2 (de) * 1991-12-05 1996-02-01 Alfatec Pharma Gmbh Ein 2-Arylpropionsäurederivat in Nanosolform enthaltendes Arzneimittel und seine Herstellung
DK0695169T3 (da) * 1993-04-22 2003-03-17 Skyepharma Inc Multivesikulære liposomer med indkapslet cyclodextrin og farmakologisk aktive forbindelser samt fremgangsmåder til anvendelse af disse
WO1995015746A1 (en) * 1993-12-10 1995-06-15 The School Of Pharmacy Liposome delivery systems
JPH10500982A (ja) * 1994-05-27 1998-01-27 ファーマーク、ネダーランド、ベスローテン、フェンノートシャップ 医薬組成物
US5902604A (en) * 1995-06-06 1999-05-11 Board Of Regents, The University Of Texas System Submicron liposome suspensions obtained from preliposome lyophilizates
US5993856A (en) * 1997-01-24 1999-11-30 Femmepharma Pharmaceutical preparations and methods for their administration
GB9711643D0 (en) * 1997-06-05 1997-07-30 Janssen Pharmaceutica Nv Glass thermoplastic systems
HUP9701945A3 (en) * 1997-11-10 2000-04-28 Hexal Ag Pharmaceutical composition for injection containing cyclodextrin and taxoids
FR2775435B1 (fr) * 1998-02-27 2000-05-26 Bioalliance Pharma Nanoparticules comprenant au moins un polymere et au moins un compose apte a complexer un ou plusieurs principes actifs
IL140218A0 (en) * 1998-06-16 2002-02-10 Microwave Solutions Ltd Oscillator circuit
ES2272496T3 (es) * 2000-02-04 2007-05-01 Lipoxen Technologies Limited Procedimiento de deshidratacion/rehidritacion para la preparacion de lipososmas.

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0132027A1 (en) * 1983-05-20 1985-01-23 Taisho Pharmaceutical Co. Ltd Fat emulsion containing prostaglandin
WO1992016196A1 (en) * 1991-03-20 1992-10-01 Novo Nordisk A/S A composition comprising a peptide for nasal administration
EP0602700A2 (en) * 1992-12-17 1994-06-22 NanoSystems L.L.C. Novel formulations for nanoparticulate X-ray blood pool contrast agents using high molecular weight surfactants
WO2000066635A1 (fr) * 1999-04-29 2000-11-09 Commissariat A L'energie Atomique Cyclodextrines amphiphiles, leur preparation et leur utilisation pour solubiliser des systemes organises et incorporer des molecules hydrophobes
CN1424035A (zh) * 2002-12-13 2003-06-18 北京东方天翔医药技术开发有限公司 尼莫地平冻干组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1543841A4 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4884975B2 (ja) * 2004-10-01 2012-02-29 エーザイ・アール・アンド・ディー・マネジメント株式会社 微粒子含有組成物およびその製造方法
WO2012110469A1 (en) 2011-02-17 2012-08-23 F. Hoffmann-La Roche Ag A process for controlled crystallization of an active pharmaceutical ingredient from supercooled liquid state by hot melt extrusion
WO2013149981A1 (en) 2012-04-03 2013-10-10 F. Hoffmann-La Roche Ag Pharmaceutical composition with improved bioavailability, safety and tolerability
WO2014114575A1 (en) 2013-01-22 2014-07-31 F. Hoffmann-La Roche Ag Pharmaceutical composition with improved bioavailability
CN104013601A (zh) * 2014-06-06 2014-09-03 重庆医科大学 姜黄色素羟丙环糊精磷脂纳米粒及其制备方法

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