WO2017133419A1 - 一种载药微球及其制备方法和应用 - Google Patents

一种载药微球及其制备方法和应用 Download PDF

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WO2017133419A1
WO2017133419A1 PCT/CN2017/070980 CN2017070980W WO2017133419A1 WO 2017133419 A1 WO2017133419 A1 WO 2017133419A1 CN 2017070980 W CN2017070980 W CN 2017070980W WO 2017133419 A1 WO2017133419 A1 WO 2017133419A1
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drug
solvent
loaded
microspheres
amount
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PCT/CN2017/070980
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English (en)
French (fr)
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张悦
梁捷
杜建英
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三捷生物科技（北京）有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers

Definitions

  • the invention relates to the field of medicine preparation, in particular to a drug-loaded microsphere and a preparation method and application thereof.
  • the drug-loaded microspheres generally refer to spherical particles having a particle size scale of 1-500 micrometers, and mainly include two components, one is a skeleton material of the microspheres, and the other is a bulk drug loaded with microspheres.
  • the drug-loaded microspheres need to be in contact with human tissues to be effective in the clinic. Therefore, the matrix materials are generally biocompatible and can be degraded in the human body, including synthetic polymers and natural polymers. Polymers, etc., both of which are described in detail in the Pharmacopoeia, are widely used as an excipient in the field of biomedicine.
  • the drug-loaded microspheres prolong the release cycle of the drug and reduce the side effects, so it can be used as an injection, an oral agent or a main component of a local tissue implant.
  • a local tissue implant Currently, it is mainly used in diseases such as pathogen infection, tumor, diabetes and depression. During treatment.
  • the current microsphere preparation process mainly includes the following:
  • the first type is the electrostatic spray method.
  • Electrostatic spray also known as electrospinning technology, in the electrospinning process, the bulk drug and the skeleton material are dissolved and dispersed in the organic solution, forming a "taylor” liquid cone under the action of electrostatic force, "taylor” liquid cone without considering gravity It is affected by electrostatic force and surface tension in the opposite direction.
  • the electrostatic force breaks through the surface tension, the "taylor” liquid cone is gradually elongated and forms micron-sized droplets under the electric field, and the microspheres are formed after the organic phase is volatilized.
  • the advantage of the electrostatic spray method is that the process is simple, but there are still great difficulties in industrialization.
  • the second is spray drying.
  • the polymer and the drug substance are dissolved in an aqueous phase or an organic phase, and the drug solution is rapidly converted into a micron-sized droplet by a nebulizer, wherein the formed droplet is brought into contact with a hot gas (air or nitrogen) to volatilize the solvent.
  • a hot gas air or nitrogen
  • the third is emulsion crosslinking.
  • the emulsion cross-linking method is generally divided into an ion cross-linking method and a glutaraldehyde cross-linking method.
  • the polymer and the raw material drug are first dissolved in an aqueous phase, and added to an oil phase containing a surfactant by stirring, ultrasonication. Etc. to form an inverse emulsion.
  • a cation such as calcium ion
  • a glutaraldehyde solution for crosslinking it is possible to selectively add a cation (such as calcium ion) or a glutaraldehyde solution for crosslinking, and the crosslinked microspheres can be obtained by centrifugation, washing and drying. This method is applicable to It can be dissolved in water skeleton material, but the removal of organic phase is difficult.
  • the fourth type is the emulsion solvent evaporation method.
  • the preparation method is divided into a one-step emulsification method and a double emulsion method.
  • the one-step emulsification method is mainly composed of an oil-in-water emulsion, and the skeleton material is generally a synthetic high molecular polymer, and the raw material drug is dissolved or dispersed in the oil phase.
  • the aqueous solution of the medicament first forms colostrum in the oil phase, and then the colostrum forms a double emulsion in the aqueous phase again.
  • the method is suitable for the bulk drug or the active biological macromolecule with high solubility in the water. .
  • the preparation of drug-loaded microspheres by the method has been widely used in the pharmaceutical industry, but there are still some problems to be solved, such as a process of slow release rate control and a process of reducing drug release.
  • the object of the present invention is to overcome the defects in the prior art that the sustained release rate of the drug is difficult to control, and to provide a drug-loaded microsphere which can effectively control the sustained release rate of the drug, a preparation method and application thereof.
  • the present invention provides a method of preparing a drug-loaded microsphere, the method comprising:
  • the first solvent is different from the second solvent, and the second solvent is miscible with the first solvent
  • the second solvent is a C 1 -C 3 alcohol, a C 1 -C 3 fatty acid And a C 1 -C 3 fatty acid ester, at least one of a C 1 -C 2 ether and acetonitrile, the first solvent being used in an amount greater than the second solvent.
  • the present invention provides a drug-loaded microsphere prepared by the above method.
  • the present invention provides the use of the above drug-loaded microspheres for the preparation of a medicament for the treatment of tumors and mucosa-related diseases.
  • the drug-loaded microspheres prepared by the method of the present invention have the appearance of spherical particles.
  • the drug-loaded microspheres prepared by the method can not only be controlled by the second solvent, but also the drug release amount within 0.5 hours is less than the currently reported value.
  • “microcapsules, microspheres and The "Liquid Formulation Guidelines” stipulates that the release amount is required to be less than 40% within the first 0.5 hours, and the microspheres prepared after the addition of the second solvent in the process of the present invention meet the requirements.
  • the microspheres prepared by the method of the invention can be used as a component of a suppository, a mucous membrane rinsing liquid (such as a vaginal douche), an effervescent tablet, an ointment, a powder, and a drug film, and are applied to related diseases requiring continuous administration, wherein
  • the drug-loaded microspheres are combined with mucosal tissues, blood or interstitial tissues of the human body by injection, oral administration, external application or implantation, and are applied to the treatment of diseases such as pathogenic infections and tumors.
  • the above related diseases may be, for example, respiratory mucosa and digestive tract Tumors associated with mucosa, urinary mucosa or reproductive system mucosa, lesions or inflammation in epithelial tissue.
  • Example 1 is a scanning electron micrograph of a drug-loaded microsphere prepared in Example 1 of the present invention.
  • Example 2 is a graph showing cumulative drug release amount of drug-loaded microspheres prepared in Example 1 of the present invention.
  • Figure 3 is a graph showing the cumulative release amount of drug-loaded microspheres prepared in Example 2-4 of the present invention.
  • Example 4 is a graph showing cumulative drug release amount of drug-loaded microspheres prepared in Example 5-7 of the present invention.
  • Figure 5 is a graph showing the cumulative release amount of drug-loaded microspheres prepared in Examples 8-10 of the present invention.
  • Figure 6 is a graph showing the cumulative release amount of drug-loaded microspheres prepared in Example 11-13 of the present invention.
  • Figure 7 is a graph showing the cumulative release amount of drug-loaded microspheres prepared in Examples 14-16 of the present invention.
  • Figure 8 is a graph showing the cumulative release amount of drug-loaded microspheres prepared in Examples 17-19 of the present invention.
  • Figure 9 is a graph showing cumulative drug release amount of drug-loaded microspheres prepared in Example 20-21 of the present invention.
  • Figure 10 is a graph showing the cumulative release amount of drug-loaded microspheres prepared in Example 22 of the present invention.
  • Fig. 11 is a graph showing the cumulative release amount of drug-loaded microspheres prepared in Comparative Example 1.
  • the invention provides a method of preparing a drug-loaded microsphere, the method comprising:
  • the first solvent is different from the second solvent, and the second solvent is miscible with the first solvent
  • the second solvent is a C 1 -C 3 alcohol, a C 1 -C 3 fatty acid And a C 1 -C 3 fatty acid ester, at least one of a C 1 -C 2 ether and acetonitrile, the first solvent being used in an amount greater than the second solvent.
  • the second solvent is at least one of methanol, ethanol, propanol, isopropanol, propylene glycol, acetic acid, ethyl acetate, diethyl ether and acetonitrile. More preferably, it is at least one of methanol, acetic acid, ethanol, diethyl ether, acetonitrile, and isopropyl alcohol, so that effective control of drug sustained release property can be remarkably improved.
  • the first solvent may be various organic solvents in the art, and may be, for example, dichloromethane, acetone, tetrahydrofuran, chloroform, dichloroethane, n-hexane and dimethyl.
  • At least one of the formamides is preferably at least one of dichloromethane, chloroform and tetrahydrofuran, more preferably dichloromethane, so as to be able to interact with the second solvent, thereby significantly improving the effective control of sustained release of the drug. .
  • the inventors of the present invention found in the study that the second solvent can be dissolved in water or has a strong volatility.
  • the regulation of the sustained release effect of the drug exhibits two different characteristics: when the viscosity of the second solvent is greater than that of the first solvent, the ratio of the second solvent in the oil phase system increases.
  • the total amount of release also increases, but when the proportion of the second solvent in the oil phase system increases to a certain extent, the total amount of drug release decreases; when the viscosity of the second solvent is less than the first solvent, the second solvent
  • the proportion of the oil phase system increases, and the total amount of drug release decreases. In the first two cases, the total amount of drug release was greater than that of the drug without the addition of a second solvent.
  • the concentration of the surfactant may be a concentration conventional in the art, for example, the mass percentage of the surfactant to water in the aqueous phase is from 0.1% to 10%, preferably 0.5%-5%. That is, the aqueous phase prepared in the step (1) is an aqueous solution of a surfactant.
  • the aqueous solution preparation method is a conventional method in the art, and may include, for example, slowly adding a surfactant to water and then rotating at 400-500 rpm. Stir for 10-15 min, then heat the mixed solution at 90-100 ° C for 10-15 min, then cool to room temperature.
  • the kind of the surfactant may be various conventional surfactants in the art, for example, it may be an O/W type emulsifier, and preferably, the surfactant is Polyvinyl alcohol and/or polyvinylpyrrolidone, thereby improving the dispersibility of the drug in the prepared drug-loaded microspheres.
  • the weight average molecular weight of the surfactant may be a molecular weight range conventional in the art, and may be, for example, 20,000 to 30,000 g/mol.
  • the polymer material for the drug carrier may be various pharmaceutical carriers in the art, for example, polycaprolactone, polylactic acid, polyurethane, gelatin, polyacrylic acid, carboxymethyl group.
  • the polymer material for the drug carrier is polylactic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, ethyl cellulose.
  • the monomer ratio of lactic acid to glycolic acid may be 75/25 or 50/50.
  • the polymer material for a drug carrier has a weight average molecular weight of 10,000 g/mol or more, more preferably 30,000 to 300,000 g/mol, thereby being capable of improving the drug in the drug.
  • the dispersibility in the polymeric material for the carrier further enhances the effective control of drug release.
  • the first solvent is used in an amount larger than the second solvent, preferably, the first solvent is used in a volume amount and the second solvent.
  • the volume ratio is 1:0.005-0.5, preferably 1:0.01-0.1, so that effective control of drug sustained-release property can be further improved.
  • the amount of the drug is 0.01-2 g with respect to 10 ml of the first solvent, and the amount of the polymer material for the drug carrier is 0.3-3 g, more
  • the amount of the drug is from 0.03 to 3 g with respect to 10 ml of the first solvent, and the amount of the polymer material for the drug carrier is from 0.5 to 2 g, whereby the effective control of drug sustained release property can be further improved.
  • the order of mixing the drug, the drug carrier polymer material, the first solvent and the second solvent is not particularly limited as long as a uniform oil phase solution or suspension is formed after mixing.
  • the drug when the drug is compatible with the first solvent, the drug, the drug carrier may be mixed with the polymer material, the first solvent and the second solvent, and when the drug is not compatible with the first solvent, the drug may be first The solvent mixture is mixed, and the resulting mixture is mixed with the drug carrier with a polymer material, and finally a second solvent is added.
  • the drug is mixed with the first solvent at a rotational speed of 400-600 rpm for 10-15 hours, then the drug carrier is added to dissolve the polymer material, and the second solvent is added to mix uniformly.
  • the volume ratio of the aqueous phase obtained in the step (1) to the oil phase obtained in the step (2) is 1:0.01 to 0.15.
  • the mixing conditions may be conventional mixing conditions in the art, for example, the temperature may be -5 to 25 ° C, and the stirring speed is 200-2000 rpm; Preferably, the temperature is -5 to 5 ° C, and the stirring speed is 400-1000 rpm; thereby facilitating the formation of drug-loaded microspheres, thereby further improving the effective control of drug sustained-release property, wherein the stirring time can be based on actual conditions. Adjustment is required as long as the aqueous phase and the oil phase can be mixed to form microspheres, and the first solvent and the second solvent are completely evaporated.
  • step (3) the oil phase is added to the aqueous phase at a stirring speed of 100-200 rpm, and then at a stirring speed of 400-1000 r/min.
  • the mixture was stirred for 1-2 h, and finally the mixture was solid-liquid separated to obtain drug-loaded microspheres.
  • the solid-liquid separation method may be centrifugal separation or filtration separation.
  • the method may further comprise: drying the obtained drug-loaded microspheres, wherein the drying treatment may be in a conventional manner in the art, for example, a polymer material may be used according to the drug carrier.
  • the physicochemical properties of the drug are selected in the following manner for drying. One is to dry in a vacuum drying oven or a blast drying oven, and the temperature is generally set to 25 ° C to 45 ° C. The second is to freeze-dry with a freeze dryer, before lyophilization, The microspheres were placed in a refrigerator at -80 ° C for pre-cooling, the microspheres were frozen, and then lyophilized under vacuum using a pre-cooled freeze dryer.
  • the drug may be various conventional drugs in the art, for example, at least one of an antitumor drug, an anti-inflammatory drug, an analgesic drug, an antibiotic, an antiallergic drug, and an antifungal drug, and more preferably,
  • the drug is at least one of 5-fluorouracil, aspirin, ibuprofen, metronidazole, cetirizine, and miconazole nitrate, most preferably 5-fluorouracil.
  • the size of the drug may be various conventional sizes in the art, for example, the average particle diameter of the drug may be less than 50 ⁇ m, preferably 0.05-20 ⁇ m, thereby enabling polymerization of the drug in a drug carrier.
  • the dispersibility on the material further improves the effective control of drug release.
  • the present invention provides a drug-loaded microsphere prepared by the above method.
  • the drug-loaded microspheres prepared by the invention may have an average particle diameter of 60-400 ⁇ m, and the drug-encapsulating rate of the drug-loaded microspheres may be as high as 55-90%.
  • the method for qualitatively and quantitatively detecting the surface morphology of the drug-loaded microspheres is as follows: the prepared drug-loaded microspheres are adhered to the conductive adhesive, and the conductive adhesive is fixed on the electron microscope sample stage, and the micro-microscopic observation is performed at a high magnification. The size of the ball and the topographical information of the surface of the microspheres were measured using an electron microscope with software to measure the size of the microspheres.
  • the method and principle of testing the drug encapsulation rate of the drug-loaded microspheres are as follows: the drug-loaded microspheres are dissolved in a solvent capable of dissolving the polymer scaffold material, and then the drug is extracted by adding a drug solvent which is immiscible with the solvent.
  • concentration of the drug is determined by a microplate reader, an ultraviolet spectrophotometer or a liquid chromatograph.
  • the drug encapsulation ratio is equal to the ratio of the actual drug content to the theoretical content in the unit mass microsphere.
  • the solvent for dissolving the polymer scaffold material may be dichloromethane
  • the drug solvent which is immiscible with methylene chloride may be water.
  • the drug release efficiency test method for the drug-loaded microspheres can be as follows: the drug-loaded microspheres are dispersed in a phosphate buffer solution of pH 7.4, and the drug is released under a shaking condition at 37 ° C, and a certain volume of the release liquid is taken at intervals. Then, the same volume of phosphate buffer pH 7.4 was added and continuously measured for a while. Calculate the cumulative release of the drug and plot the release profile of the drug.
  • the present invention provides the use of the above-described drug-loaded microspheres for the preparation of a medicament for the treatment of tumors and mucosa-related diseases.
  • the above-mentioned drug-loaded microspheres can be used as a component of a suppository, a mucous membrane rinsing liquid (such as a vaginal douche), an effervescent tablet, an ointment, a powder, and a drug film by various conventional methods, and applied.
  • a mucous membrane rinsing liquid such as a vaginal douche
  • an effervescent tablet such as a vaginal douche
  • an ointment such as a vaginal douche
  • a powder such as a powder
  • a drug film such as a suppository
  • the drug-loaded microspheres are combined with mucosal tissues, blood or interstitial tissues of the human body by injection, oral administration, external application or implantation, thereby applying to the pathogen infection and tumor.
  • the above related diseases may be, for example, a respiratory mucosa, a digestive tract mucosa, a urinary mucosa or a mucosa associated with the mucous membrane of the reproductive system, a lesion or inflammation in the epithelial tissue.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • aqueous phase 2 g of polyvinyl alcohol PVA (weight average molecular weight: 20000 g/mol, purchased from Acros Organics) was weighed, slowly added to 100 ml of water, and then stirred at 500 r/min for 10 minutes, and then polyvinyl alcohol. The mixture with water was taken out in a water bath at 90 ° C, heated in a water bath for 10 minutes, and taken out for 1 h to bring the temperature down to room temperature for use.
  • PVA weight average molecular weight: 20000 g/mol, purchased from Acros Organics
  • the mixed solution was collected, subjected to solid-liquid separation by centrifugation, and the microsphere particles were collected, and the microsphere particles were dried in a blast drying oven at 30 ° C to prepare a 5-FU-loaded L-polylactic acid microsphere.
  • L-polylactic acid microspheres carrying 5-FU are used for the preparation of a medicament for treating tumors and mucosa-related diseases.
  • Drug-loaded microspheres were prepared as in Example 1 except that the second solvent, anhydrous ethanol, was not added.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • aqueous phase 2 g of polyvinyl alcohol (weight average molecular weight: 30,000 g/mol, purchased from Acros Organics) was weighed, slowly added to 100 ml of water, and then stirred at 500 r/min for 10 minutes, and then polyvinyl alcohol and The mixture of water was taken out in a water bath at 90 ° C, heated in a water bath for 10 minutes, and taken out for 1 h to bring the temperature down to room temperature for use.
  • polyvinyl alcohol weight average molecular weight: 30,000 g/mol, purchased from Acros Organics
  • the mixed solution was collected, subjected to solid-liquid separation by centrifugation, microsphere particles were collected, and the microsphere particles were dried in a blast drying oven at 30 ° C to prepare a polylactic acid-glycolic acid copolymer loaded with 5-FU. Microspheres.
  • Polylactic acid-glycolic acid copolymer microspheres carrying 5-FU are used for the preparation of a medicament for treating tumors and mucosa-related diseases.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • Drug-loaded microspheres were prepared in the same manner as in Example 2 except that the amount of isopropanol was 150 ⁇ l and 300 ⁇ l, respectively, to obtain 5-FU-loaded polylactic acid-glycolic acid copolymer microspheres.
  • Drug-loaded microspheres were prepared as in Example 2 except that the second solvent, isopropanol, was not added.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • the drug-loaded microspheres were prepared according to the method of Example 1, except that the amount of 5-FU used was 60 mg, and ethanol was replaced with acetic acid, and the amounts of acetic acid were 30 ⁇ l, 150 ⁇ l, and 300 ⁇ l, respectively, to obtain 5-FU.
  • L-polylactic acid microspheres L-polylactic acid microspheres.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • Drug-loaded microspheres were prepared according to the method of Example 1, except that ethanol was replaced with methanol, and the amounts of methanol were 30 ⁇ l, 150 ⁇ l, and 300 ⁇ l, respectively, to obtain 5-FU-loaded L-polylactic acid microspheres.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • the drug-loaded microspheres were prepared according to the method of Example 1, except that the amount of 5-FU used was 60 mg, and ethanol was replaced with acetonitrile. The amounts of acetonitrile were 30 ⁇ l, 150 ⁇ l, and 300 ⁇ l, respectively, and 5-FU was obtained. L-polylactic acid microspheres.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • the drug-loaded microspheres were prepared according to the method of Example 1, except that the amount of 5-FU used was 60 mg, and ethanol was replaced with diethyl ether, and the amounts of diethyl ether were 30 ⁇ l, 150 ⁇ l, and 300 ⁇ l, respectively, to obtain 5-FU.
  • L-polylactic acid microspheres L-polylactic acid microspheres.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • the drug-loaded microspheres were prepared according to the method of Example 1, except that the amount of 5-fluorouracil (5-FU) was 45 mg, and the amounts of absolute ethanol were 150 ⁇ l, 240 ⁇ l, and 300 ⁇ l, respectively, to obtain 5-FU.
  • L-polylactic acid microspheres L-polylactic acid microspheres.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • the drug-loaded microspheres were prepared according to the method of Example 1, except that the amount of 5-fluorouracil (5-FU) was 16 mg, the amount of dichloromethane was 2 ml, and the amount of L-polylactic acid PLLA was 160 mg, and the amount of polyvinyl alcohol PVA was used. For 1 g, the amount of absolute ethanol was 20 ⁇ l and 60 ⁇ l, respectively, to obtain 5-FU-loaded L-polylactic acid microspheres.
  • 5-FU 5-fluorouracil
  • dichloromethane was 2 ml
  • L-polylactic acid PLLA 160 mg
  • polyvinyl alcohol PVA polyvinyl alcohol
  • Drug-loaded microspheres were prepared as in Example 20 except that the second solvent, anhydrous ethanol, was not added.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • the drug-loaded microspheres were prepared according to the method of Example 1, except that the volume of dichloromethane was 8 ml, the amount of 5-fluorouracil (5-FU) was 128 mg, the amount of L-polylactic acid PLLA was 1600 mg, and the amount of polyvinyl alcohol PVA was 4 g of anhydrous ethanol was used in an amount of 80 ⁇ l and 400 ⁇ l, respectively, to obtain 5-FU-loaded L-polylactic acid microspheres.
  • Drug-loaded microspheres were prepared as in Example 22 except that no second solvent, absolute ethanol, was added.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • the drug-loaded microspheres were prepared according to the method of Example 1, except that the second stirring speed was 400 r/min. Continue to stir for 2h.
  • This embodiment is for explaining the drug-loaded microsphere of the present invention and a preparation method and application thereof.
  • Drug-loaded microspheres were prepared according to the method of Example 2 except that the PLGA molecular weight was 300,000 g/mol, and 5-FU-loaded polylactic acid-glycolic acid copolymer microspheres were prepared.
  • the prepared drug-loaded microspheres are adhered to the conductive adhesive, and the conductive adhesive is fixed on the electron microscope sample stage, and the size of the microspheres and the surface morphology information of the microspheres are observed at high magnification (see FIG. 1), using electrons.
  • the microscope comes with software to measure the size of the microspheres. The results are shown in Table 1 below.
  • the mass of the microspheres was weighed to 30 mg, and an appropriate amount of dichloromethane was added. After stirring and dissolved, 30 ml of pure water was added, and the mixture was stirred at 800 r/min, and the dichloromethane was evaporated until no liquid phase stratification was observed in the beaker. A part of the liquid was taken, filtered through a 0.45 um filter, and the absorbance at 266 nm was measured using an ultraviolet spectrophotometer. The concentration N of 5-FU in the solution was calculated from the 5-FU absorbance curve. The encapsulation efficiency and the drug loading of the microspheres were calculated. The results are shown in Table 2 below.
  • Example Average particle size of drug-loaded microspheres ( ⁇ m)
  • Example 1 182 ⁇ m Comparative example 1 185 ⁇ m
  • Example 2-4 83.3 ⁇ m Comparative example 2 78 ⁇ m
  • Example 5-7 170.9 ⁇ m
  • Example 8-10 225.75 ⁇ m
  • Example 11-13 168.9 ⁇ m
  • Example 14-16 183 ⁇ m
  • Example 17-19 145.7 ⁇ m
  • Example 20-21 130.3 ⁇ m Comparative example 3 125 ⁇ m
  • Example 23 381 ⁇ m
  • Example 24 240 ⁇ m
  • Example 25 173 ⁇ m Comparative example 4 190 ⁇ m
  • Example Encapsulation rate (%) Microsphere drug loading (%) Example 1 68.6 11.44 Comparative example 1 39.6 6.6
  • Example 2 78 9.17
  • Example 4 69 8.12 Comparative example 2 39.1 4.6
  • Example 5 90.3 10.6
  • Example 6 81.5 9.6
  • Example 7 72.6 8.5
  • Example 8 82.3 13.7
  • Example 9 76 12.7
  • Example 10 75.6 12.6
  • Example 12 69.05 Example 13 68.09 8
  • Example 15 71.11 8.37
  • Example 16 62.83 7.39
  • Example 17 65.01 5.91
  • Example 19 57.3 5.21
  • Example 20 68.42 6.22
  • Example 21 74.91 6.81 Comparative example 3 36.3 3.3
  • Example 22 74.25 5.5
  • Example 23 66.15 4.9 Comparative example 4 62.1 4.6
  • the drug-loaded microspheres prepared in Example 1 had a drug release rate of 3.9% in half an hour, while the drug-loaded microspheres prepared in Comparative Example 1 were released in half an hour.
  • the amount is 3.75%, and it can be seen that when the second solvent is added, the control of the sustained release effect of the drug can be remarkably improved.
  • the drug-loaded microspheres prepared in Example 2-4 had a drug release amount of 2.74%, 6.53%, 3.83% in half an hour, and the drug-loading prepared in Example 2-4.
  • the total amount of drug release of the microspheres within 24 hours showed a corresponding change with the increase of the volume ratio of the second solvent acetic acid, and both were superior to the comparative example 2.
  • the drug-loaded microspheres prepared in Examples 5-7 had drug release amounts of 1.33%, 7.69%, 10.02% in half an hour, and the drug-loaded preparations obtained in Examples 5-7.
  • the total amount of drug release of the microspheres within 24 hours showed a corresponding change as the volume ratio of the second solvent acetic acid increased, and both were superior to Comparative Example 1.
  • the drug-loaded microspheres prepared in Examples 8-10 had drug release amounts of 3.78%, 12.54%, 8.83% in half an hour, and the drug-loaded preparations obtained in Examples 8-10.
  • the total amount of drug release in the microspheres within 24 hours showed a corresponding change as the volume ratio of the second solvent methanol increased, and both were superior to Comparative Example 1.
  • the drug-loaded microspheres prepared in Examples 11-13 have a drug release amount of 4.25%, 5.06%, and 5.62% in half an hour, and the drug-loaded microparticles prepared in Examples 11-13.
  • the total amount of drug release within 24 hours of the ball increased correspondingly with the increase of the volume ratio of the second solvent acetonitrile, and both were superior to Comparative Example 1.
  • the drug-loaded microspheres prepared in Examples 22 and 23 had a drug release amount of 5.89% and 8.24%, respectively, within half an hour, and the total amount of drug release in 24 hours was accompanied by the second solvent. Corresponding changes occurred in the increase in the volume ratio of ethanol, and both were superior to Comparative Example 4.
  • the drug-loaded microspheres prepared by the method of the present invention have the appearance of spherical particles.
  • the drug-loaded microspheres prepared by the method can not only be controlled by the second solvent, but also the drug release amount within 0.5 hours is less than the currently reported value.
  • “microcapsules, microspheres and The "Liquid Formulation Guidelines” stipulates that the release amount is required to be less than 40% within the first 0.5 hours, and the microspheres prepared after the addition of the second solvent in the process of the present invention meet the requirements.
  • the microspheres prepared by the method of the invention can be used as a component of a suppository, a mucous membrane rinsing liquid (such as a vaginal douche), an effervescent tablet, an ointment, a powder, and a drug film, and are applied to related diseases requiring continuous administration, wherein
  • the drug-loaded microspheres are combined with mucosal tissues, blood or interstitial tissues of the human body by injection, oral administration, external application or implantation, and are applied to the treatment of diseases such as pathogenic infections and tumors.
  • the above related diseases may be, for example, a respiratory mucosa, a digestive tract mucosa, a mucosa of the urinary system or a mucosa associated with the mucous membrane of the reproductive system, a lesion or inflammation in the epithelial tissue.

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Abstract

一种制备载药微球的方法，该方法制备的微球及应用，包括：将表面活性剂与水混合，制得水相；将药物、药物载体用聚合物材料、第一溶剂和第二溶剂混合，制得油相；将油相加入到水相中进行混合；其中，第一溶剂与第二溶剂不同，且第二溶剂与第一溶剂互溶，所述第二溶剂为C1-C3的醇、C1-C3的脂肪酸、C1-C3的脂肪酸酯、C1-C2的醚和乙腈中的至少一种，第一溶剂的用量大于第二溶剂的用量。

Description

一种载药微球及其制备方法和应用 技术领域
本发明涉及药物制备领域，具体地，涉及一种载药微球及其制备方法和应用。
背景技术
载药微球一般指粒径尺度为1-500微米的球形颗粒，其主要包括两种组成成分，一是微球的骨架材料，另一是微球包载的原料药。载药微球需要与人体组织接触才能够在临床中发挥药效，因此骨架材料一般是生物相容性良好且可在人体中被降解的材料，包括人工合成的高分子聚合物以及天然高分子聚合物等，上述两类材料在药典中均有详细的描述，作为辅料被广泛的应用在生物医药领域中。载药微球延长了药物的释放周期，并降低了毒副作用，因此可以作为注射剂、口服剂或局部组织植入剂的主要成分，目前主要应用在病菌感染、肿瘤、糖尿病以及抑郁症等疾病的治疗中。
由于原料药以及骨架材料的物理化学性质不同，其相应载药微球的制备工艺也有所差异，现行的微球制备工艺主要包括以下几种：
第一种为静电喷雾法。静电喷雾又称电纺技术，电纺过程中，原料药与骨架材料溶解分散在有机溶液中，在静电力的作用下形成“taylor”液锥，在不考虑重力的情况下“taylor”液锥受到静电力作用与反方向的表面张力作用。当静电力突破表面张力束缚时，“taylor”液锥逐渐被拉长并在电场下形成微米级的液滴，有机相挥发之后即形成微球。静电喷雾法优点是工序简单，但是走向产业化还有很大的困难。
第二种为喷雾干燥法。制备过程中，将聚合物与原料药溶解于水相或者有机相，通过喷雾器使药物溶液迅速变成微米级的液滴，其中形成的液滴与热气体(空气或者氮气)接触使溶剂挥发，从而得到聚集于干燥塔底部的干燥颗粒。喷雾干燥法在食品工业中应用广泛，但应用于载药微球的制备过程中，其产率与药物缓释效果的优化还需要探索。
第三种是乳液交联法。乳液交联法一般分为离子交联法与戊二醛交联法，制备过程中，首先将聚合物与原料药溶解于水相，并加入到含有表面活性剂的油相中通过搅拌、超声等形成反相乳液。根据骨架材料的性质不同，可以选择加入阳离子(如钙离子)或者戊二醛溶液进行交联，交联后的微球通过离心、洗涤、干燥即可获取。本方法适用于 可以溶于水的骨架材料，但有机相的去除比较困难。
第四种为乳液溶剂挥发法。该制备方法分为一步乳化法以及复乳法。一步乳化法以水包油类乳液为主，骨架材料一般是合成的高分子聚合物，原料药溶解或者分散在油相中。复乳法制备过程中，药物水溶液首先在油相中形成初乳，然后初乳再次在水相中形成复乳，本方法适合于包载水中溶解度较高的原料药或者有活性的生物大分子。本方法制备载药微球已经在医药工业中广泛应用，但仍有一些问题需要解决，例如缓释速度控制的工艺以及降低药物突释的工艺等。
发明内容
本发明的目的是为了克服现有技术中药物缓释速度难以控制的缺陷，提供一种可以有效控制药物缓释速度的载药微球及其制备方法和应用。
为了实现上述目的，一方面，本发明提供了一种制备载药微球的方法，该方法包括：
(1)将表面活性剂与水混合，制得水相；
(2)将药物、药物载体用聚合物材料、第一溶剂和第二溶剂混合，制得油相；
(3)将油相加入到水相中进行混合；
其中，所述第一溶剂与所述第二溶剂不同，且所述第二溶剂与所述第一溶剂互溶，所述第二溶剂为C1-C3的醇、C1-C3的脂肪酸、C1-C3的脂肪酸酯、C1-C2的醚和乙腈中的至少一种，所述第一溶剂的用量大于所述第二溶剂的用量。
第二方面，本发明提供了上述方法制备的载药微球。
第三方面，本发明提供了上述载药微球在制备用于治疗肿瘤以及粘膜相关的疾病的药物中的应用。
本发明方法制备的载药微球的外观为球形颗粒。采用本方法制备的载药微球，其药物缓释效果不仅可以通过第二溶剂进行控制，0.5小时内的药物突释量也比目前报道的数值要少，药典中“微囊、微球与脂质体制剂指导原则”中规定在开始的0.5小时内释放量要求低于40％，本发明工艺中加入第二溶剂后所制备的微球均达到了要求。本发明的方法制成的微球可以作为栓剂、粘膜冲洗液(如阴道冲洗液)、泡腾片、软膏、粉剂以及药膜的组成成分，并应用于需要持续给药的相关疾病，其中，利用注射、口服、外用或植入等给药方式，将载药微球与人体的粘膜组织、血液或者间质组织结合，从而应用到病菌感染、肿瘤等疾病的治疗中去。上述相关疾病例如可以为呼吸道粘膜、消化道 粘膜、泌尿系统粘膜或生殖系统粘膜相关的肿瘤、上皮组织内病变或炎症。
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。
附图说明
图1是本发明实施例1制得的载药微球扫描电镜图；
图2是本发明实施例1制得的载药微球药物累计释放量曲线图；
图3是本发明实施例2-4制得的载药微球药物累计释放量曲线图；
图4是本发明实施例5-7制得的载药微球药物累计释放量曲线图；
图5是本发明实施例8-10制得的载药微球药物累计释放量曲线图；
图6是本发明实施例11-13制得的载药微球药物累计释放量曲线图；
图7是本发明实施例14-16制得的载药微球药物累计释放量曲线图；
图8是本发明实施例17-19制得的载药微球药物累计释放量曲线图；
图9是本发明实施例20-21制得的载药微球药物累计释放量曲线图；
图10是本发明实施例22制得的载药微球药物累计释放量曲线图；
图11是对比例1制得的载药微球药物累计释放量曲线图。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。
一方面，本发明提供了一种制备载药微球的方法，该方法包括：
(1)将表面活性剂与水混合，制得水相；
(2)将药物、药物载体用聚合物材料、第一溶剂和第二溶剂混合，制得油相；
(3)将油相加入到水相中进行混合；
其中，所述第一溶剂与所述第二溶剂不同，且所述第二溶剂与所述第一溶剂互溶，所述第二溶剂为C1-C3的醇、C1-C3的脂肪酸、C1-C3的脂肪酸酯、C1-C2的醚和乙腈中的至少一种，所述第一溶剂的用量大于所述第二溶剂的用量。
根据本发明所述的方法，步骤(2)中，优选地，所述第二溶剂为甲醇、乙醇、丙醇、异丙醇、丙二醇、乙酸、乙酸乙酯、乙醚和乙腈中的至少一种，更优选为甲醇、乙酸、乙醇、乙醚、乙腈和异丙醇中的至少一种，从而能够显著提高对药物缓释性的有效控制。
根据本发明所述的方法，步骤(2)中，第一溶剂可以为本领域各种有机溶剂，例如可以为二氯甲烷、丙酮、四氢呋喃、氯仿、二氯乙烷、正己烷和二甲基甲酰胺中的至少一种，优选为二氯甲烷、氯仿和四氢呋喃中的至少一种，更优选为二氯甲烷，从而能够与第二溶剂相互配合，进而显著提高对药物缓释性的有效控制。
本发明的发明人在研究中发现，第二溶剂可以溶解于水中或挥发性较强。根据第二溶剂粘度的不同，其对药物缓释效果的调控呈现出两个不同的特点：当第二溶剂粘度大于第一溶剂时，随着第二溶剂在油相体系中比例的增加，药物释放的总量也增加，但当第二溶剂在油相体系中比例增加到一定程度时，药物释放的总量反而减小；当第二溶剂粘度小于第一溶剂时，随着第二溶剂在油相体系中比例的增加，药物释放的总量随之降低。前两种情况之下，药物释放的总量整体上均比没有加第二溶剂时的药物释放量要大。
根据本发明所述的方法，步骤(1)中，表面活性剂的浓度可以为本领域常规的浓度，例如，水相中表面活性剂与水的质量体积百分数为0.1％-10％，优选为0.5％-5％。即步骤(1)制得的水相是表面活性剂的水溶液，该水溶液配制方法为本领域的常规方法，例如可以包括：将表面活性剂缓慢加入到水中，然后在400-500r/min转速下搅拌10-15min，再将该混合溶液在90-100℃下加热10-15min，然后降温至室温。
根据本发明所述的方法，步骤(1)中，表面活性剂的种类可以为本领域各种常规的表面活性剂，例如可以为O/W型乳化剂，优选地，所述表面活性剂为聚乙烯醇和/或聚乙烯吡咯烷酮，从而能够提高药物在制得的载药微球中的分散性。其中，表面活性剂的重均分子量可以为本领域常规的分子量范围，例如可以为20000-30000g/mol。
根据本发明所述的方法，步骤(2)中，药物载体用聚合物材料可以为本领域各种药物载体，例如可以为聚己内酯、聚乳酸、聚氨酯、明胶、聚丙烯酸、羧甲基纤维素钠、聚卡波非、壳聚糖、乙基纤维素、纤维醋法酯、低取代羟丙纤维素、羟丙甲纤维素邻苯二甲酸酯、聚丙烯酸树脂、醋酸纤维素、聚乙烯吡咯烷酮、聚乳酸-羟基乙酸共聚物和聚乙烯醇中的至少一种。为了进一步提高对药物缓释性的有效控制，优选地，所述药物载体用聚合物材料为聚乳酸、聚乳酸-羟基乙酸共聚物、聚己内酯、乙基纤维素。其中，所述药物载体用聚合物材料为聚乳酸-羟基乙酸共聚物时，其乳酸与羟基乙酸的单体配比可以为75/25或者50/50。
根据本发明所述的方法，步骤(2)中，优选地，所述药物载体用聚合物材料的重均分子量为10000g/mol以上，更优选为30000-300000g/mol，从而能够提高药物在药物 载体用聚合物材料中的分散性，进一步提高对药物缓释性的有效控制。
根据本发明所述的方法，步骤(2)中，所述第一溶剂的用量只要大于所述第二溶剂的用量即可，优选地，所述第一溶剂的体积用量与所述第二溶剂的体积用量比例为1：0.005-0.5，优选为1：0.01-0.1，从而能够进一步提高对药物缓释性的有效控制。
根据本发明所述的方法，步骤(2)中，优选地，相对于10ml第一溶剂，所述药物的用量为0.01-2g，所述药物载体用聚合物材料的用量为0.3-3g，更优选地，相对于10ml第一溶剂，所述药物的用量为0.03-1g，所述药物载体用聚合物材料的用量为0.5-2g，从而能够进一步提高对药物缓释性的有效控制。
根据本发明所述的方法，步骤(2)中，药物、药物载体用聚合物材料、第一溶剂和第二溶剂混合顺序没有特别地限定，只要混合后形成均匀的油相溶液或者悬浮液即可。例如，当药物与第一溶剂互容时，可以将药物、药物载体用聚合物材料、第一溶剂和第二溶剂一起混合，当药物与第一溶剂不互容时，可以先将药物与第一溶剂混合，再将得到的混合液与药物载体用聚合物材料混合，最后再加入第二溶剂。
在一种具体的实施方式中，将药物与第一溶剂在400-600r/min转速下混合10-15h，然后加入药物载体用聚合物材料溶解，再加入第二溶剂混合均匀。
根据本发明所述的方法，步骤(3)中，更优选地，步骤(1)得到的水相和步骤(2)得到的油相的体积比为1：0.01-0.15。
根据本发明所述的方法，步骤(3)中，所述混合的条件可以为本领域常规的混合条件，例如可以包括：温度为-5～25℃，搅拌速度为200-2000转/分钟；优选地，温度为-5～5℃，搅拌速度为400-1000转/分钟；从而更有利于形成载药微球，进而进一步提高对药物缓释性的有效控制，其中搅拌的时间可以根据实际需要调整，只要能够使得水相和油相混合形成微球，且第一溶剂和第二溶剂挥发完全即可。
根据本发明所述的方法，在一种优选实施方式中，步骤(3)中，在100-200r/min搅拌速度下，将油相加入到水相中，然后在400-1000r/min搅拌速度下搅拌1-2h，最后将混合液固液分离，得到载药微球。其中，固液分离的方式可以为离心分离或者过滤分离。
根据本发明所述的方法，该方法还可以包括：将得到的载药微球进行干燥处理，其中，所述干燥处理的方式可以为本领域的常规方式，例如可以根据药物载体用聚合物材料与药物的物理化学性质选择以下方式进行干燥。一是在真空干燥箱或者鼓风干燥箱中烘干，温度一般设置为25℃到45℃。二是利用冷冻干燥机进行冻干，冻干之前，将 微球放置于-80℃的冰箱中进行预冷，使微球冻住，然后利用已经预冷的冷冻干燥机在真空条件下进行冻干。
本发明中，所述药物可以为本领域各种常规的药物，例如可以为抗肿瘤药、消炎药、止痛药、抗生素、抗过敏药以及抗真菌药中的至少一种，更优选地，所述药物为5-氟尿嘧啶、阿司匹林、布洛芬、甲硝唑、西替利嗪和硝酸咪康唑中的至少一种，最优选为5-氟尿嘧啶。
根据本发明所述的方法，其中，所述药物的大小可以为本领域各种常规的尺寸，例如药物的平均粒径可以小于50μm，优选为0.05-20μm，从而能够提高药物在药物载体用聚合物材料上的分散性，进而进一步提高对药物缓释性的有效控制。
第二方面，本发明提供了上述方法制备的载药微球。
本发明制得的载药微球的平均粒径可以为60-400μm，载药微球的药物包封率可以高达55-90％。
本发明中，载药微球表面形貌定性以及定量检测的方法如下：将制备的载药微球粘附于导电胶上，并将导电胶固定于电子显微镜样品台上，在高倍下观察微球的尺寸以及微球表面的形貌信息，利用电子显微镜自带软件测量微球的尺寸。
载药微球的药物包封率测试方法和原理如下：将载药微球溶解于可溶解高分子支架材料的溶剂中，然后加入与所述溶剂不互溶的药物溶剂中进行药物的萃取，取萃取液利用酶标仪、紫外分光光度计或液相色谱仪测定药物浓度，药物包封率等于单位质量微球中实际的药物含量与理论含量之比。例如溶解高分子支架材料的溶剂可以为二氯甲烷，与二氯甲烷不互溶的药物溶剂可以为水。
载药微球的药物释放效率测试方法可以如下：将载药微球分散于pH 7.4的磷酸盐缓冲液中，在37℃摇床条件下进行药物释放，每隔一段时间取一定体积的释放液，然后补加相同体积的pH7.4的磷酸盐缓冲液，连续测定一段时间。计算药物的累计释放量并绘制药物的释放曲线。
第三方面，本发明提供了上述的载药微球在制备用于治疗肿瘤以及粘膜相关的疾病的药物中的应用。
根据本发明所述的应用，可以采用各种常规的方法将上述载药微球作为栓剂、粘膜冲洗液(如阴道冲洗液)、泡腾片、软膏、粉剂以及药膜的组成成分，并应用于需要持续给药的相关疾病，其中，利用注射、口服、外用或植入等给药方式，将载药微球与人体的粘膜组织、血液或者间质组织结合，从而应用到病菌感染、肿瘤等疾病的治疗中 去，上述相关疾病例如可以为呼吸道粘膜、消化道粘膜、泌尿系统粘膜或生殖系统粘膜相关的肿瘤、上皮组织内病变或炎症。
实施例1
本实施例用于说明本发明的载药微球及其制备方法和应用。
(1)水相制备：称取2g聚乙烯醇PVA(重均分子量为20000g/mol，购自Acros Organics)，缓慢加入100ml水中，然后在500r/min转速下搅拌10分钟，再将聚乙烯醇与水的混合液在90℃水浴锅中，水浴加热10分钟后取出，放置1h将温度降至室温备用。
(2)油相制备：将90mg 5-氟尿嘧啶(5-FU)与3ml二氯甲烷在500r/min转速下搅拌混合12h，然后再加入450mg左旋聚乳酸PLLA(重均分子量为80000g/mol，购自济南岱罡生物工程有限公司)涡旋溶解1分钟，再加入150μl无水乙醇，涡旋混匀1min。
(3)微球制备：将3ml上述制得的油相倒入烧杯100ml水相中，利用冰浴将液体温度控制在0℃，使用磁力搅拌器以200r/min的转速进行低速搅拌，边低速搅拌边将制得的油相加入水相中。随后将搅拌速度提高至800r/min，持续搅拌1h。然后收集混合液，利用离心的方法进行固液分离，收集微球颗粒，将该微球颗粒在30℃鼓风干燥箱中烘干，制备成载有5-FU的左旋聚乳酸微球。
(4)载有5-FU的左旋聚乳酸微球用于制备治疗肿瘤以及粘膜相关的疾病的药物。
对比例1
按照实施例1的方法制备载药微球，不同的是，不加入第二溶剂无水乙醇。
实施例2
本实施例用于说明本发明的载药微球及其制备方法和应用。
(1)水相制备：称取2g聚乙烯醇(重均分子量为30000g/mol，购自Acros Organics)，缓慢加入100ml水中，然后在500r/min转速下搅拌10分钟，再将聚乙烯醇与水的混合液在90℃水浴锅中，水浴加热10分钟后取出，放置1h将温度降至室温备用。
(2)油相制备：将60mg 5-氟尿嘧啶(5-FU)与3ml二氯甲烷在500r/min转速下搅拌混合12h，然后再加入450mg聚乳酸-羟基乙酸共聚物PLGA(重均分子量为40000g/mol，单体比例为75/25，购自济南岱罡生物工程有限公司)涡旋溶解1分钟，再加入30μl异丙醇，涡旋混匀1min。
(3)微球制备：将3ml上述制得的油相倒入烧杯100ml水相中，利用冰浴将液体温度控制在3℃，使用磁力搅拌器以200r/min的转速进行低速搅拌，边低速搅拌边将制得的油相加入水相中。随后将搅拌速度提高至600r/min，持续搅拌2h。然后收集混合液，利用离心的方法进行固液分离，收集微球颗粒，将该微球颗粒在30℃鼓风干燥箱中烘干，制备成载有5-FU的聚乳酸-羟基乙酸共聚物微球。
(4)载有5-FU的聚乳酸-羟基乙酸共聚物微球用于制备治疗肿瘤以及粘膜相关的疾病的药物。
实施例3-4
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例2的方法制备载药微球，不同的是，异丙醇的用量分别为150μl、300μl，制得载有5-FU的聚乳酸-羟基乙酸共聚物微球。
对比例2
按照实施例2的方法制备载药微球，不同的是，不加入第二溶剂异丙醇。
实施例5-7
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例1的方法制备载药微球，不同的是，5-FU的使用量是60mg，将乙醇替换为乙酸，乙酸的用量分别为30μl、150μl、300μl，制得载有5-FU的左旋聚乳酸微球。
实施例8-10
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例1的方法制备载药微球，不同的是，将乙醇替换为甲醇，甲醇的用量分别为30μl、150μl、300μl，制得载有5-FU的左旋聚乳酸微球。
实施例11-13
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例1的方法制备载药微球，不同的是，5-FU的使用量是60mg，将乙醇替换为乙腈，乙腈的用量分别为30μl、150μl、300μl，制得载有5-FU的左旋聚乳酸微球。
实施例14-16
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例1的方法制备载药微球，不同的是，5-FU的使用量是60mg，将乙醇替换为乙醚，乙醚的用量分别为30μl、150μl、300μl，制得载有5-FU的左旋聚乳酸微球。
实施例17-19
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例1的方法制备载药微球，不同的是，5-氟尿嘧啶(5-FU)的用量为45mg，无水乙醇的用量分别为150μl、240μl、300μl，制得载有5-FU的左旋聚乳酸微球。
实施例20-21
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例1的方法制备载药微球，不同的是，5-氟尿嘧啶(5-FU)的用量为16mg，二氯甲烷的量为2ml，左旋聚乳酸PLLA用量为160mg，聚乙烯醇PVA用量为1g，无水乙醇的用量分别为20μl、60μl，制得载有5-FU的左旋聚乳酸微球。
对比例3
按照实施例20的方法制备载药微球，不同的是，不加入第二溶剂无水乙醇。
实施例22-23
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例1的方法制备载药微球，不同的是，二氯甲烷体积为8ml，5-氟尿嘧啶(5-FU)的用量为128mg，左旋聚乳酸PLLA用量为1600mg，聚乙烯醇PVA用量为4g，无水乙醇的用量分别为80μl、400μl，制得载有5-FU的左旋聚乳酸微球。
对比例4
按照实施例22的方法制备载药微球，不同的是，不加入第二溶剂无水乙醇。
实施例24
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例1的方法制备载药微球，不同的是，第二次的搅拌速度为400r/min，持 续搅拌2h。
实施例25
本实施例用于说明本发明的载药微球及其制备方法和应用。
按照实施例2的方法制备载药微球，不同的是，PLGA分子量为300000g/mol，制备载有5-FU的聚乳酸-羟基乙酸共聚物微球。
测试例
1.1微球粒径统计
将制备的载药微球粘附于导电胶上，并将导电胶固定于电子显微镜样品台上，在高倍下观察微球的尺寸以及微球表面的形貌信息(参见图1)，利用电子显微镜自带软件测量微球的尺寸，结果见下表1。
1.2微球的包封率测试
称取微球质量30mg，加入二氯甲烷适量，搅拌溶解后，加入30ml纯水，以800r/min转速搅拌，蒸发二氯甲烷，直至烧杯中不见液相分层。取部分液体，经0.45um滤膜过滤，使用紫外分光光度计测量266nm处吸光度。根据5-FU吸光度曲线计算溶液中5-FU的浓度N。计算得包封率和微球载药量，结果见下表2。
1.3微球的缓释性能测试
量取微球11mg置于15ml离心管，加入PBS 10ml，旋紧管盖，在37℃水浴摇床中，于放置后不同时间点取出离心管离心，取样，补液。样品在266nm处测得吸光度，根据5-FU吸光度曲线计算药物释放量结果见下表3-11和图1-11。
表1
实施例 载药微球平均粒径(μm)
实施例1 182μm
对比例1 185μm
实施例2-4 83.3μm
对比例2 78μm
实施例5-7 170.9μm
实施例8-10 225.75μm
实施例11-13 168.9μm
实施例14-16 183μm
实施例17-19 145.7μm
实施例20-21 130.3μm
对比例3 125μm
实施例22 233.7μm
实施例23 381μm
实施例24 240μm
实施例25 173μm
对比例4 190μm
表2
实施例 包封率(％) 微球载药量(％)
实施例1 68.6 11.44
对比例1 39.6 6.6
实施例2 78 9.17
实施例3 59.4 6.98
实施例4 69 8.12
对比例2 39.1 4.6
实施例5 90.3 10.6
实施例6 81.5 9.6
实施例7 72.6 8.5
实施例8 82.3 13.7
实施例9 76 12.7
实施例10 75.6 12.6
实施例11 78.51 9.2
实施例12 69.05 8.1
实施例13 68.09 8
实施例14 88.67 10.43
实施例15 71.11 8.37
实施例16 62.83 7.39
实施例17 65.01 5.91
实施例18 61.58 5.6
实施例19 57.3 5.21
实施例20 68.42 6.22
实施例21 74.91 6.81
对比例3 36.3 3.3
实施例22 74.25 5.5
实施例23 66.15 4.9
对比例4 62.1 4.6
实施例24 76.8 12.8
实施例25 59.4 10.8
表3
Figure PCTCN2017070980-appb-000001
Figure PCTCN2017070980-appb-000002
表4
Figure PCTCN2017070980-appb-000003
表5
Figure PCTCN2017070980-appb-000004
表6
Figure PCTCN2017070980-appb-000005
表7
Figure PCTCN2017070980-appb-000006
Figure PCTCN2017070980-appb-000007
表8
Figure PCTCN2017070980-appb-000008
表9
Figure PCTCN2017070980-appb-000009
表10
Figure PCTCN2017070980-appb-000010
Figure PCTCN2017070980-appb-000011
表11
Figure PCTCN2017070980-appb-000012
通过表3和图2、11可以看出，实施例1制得的载药微球在半小时内药物释放量为3.9％，而对比例1制得的载药微球在半小时内药物释放量为3.75％，比较可以看出，当加入第二溶剂时，能够显著提高对药物缓释效果的控制。
通过表4和图3可以看出，实施例2-4制得的载药微球在半小时内药物释放量为2.74％，6.53％，3.83％，并且实施例2-4制得的载药微球在24小时内药物释放的总量随着第二溶剂乙酸体积比的增加而出现相应的变化，且均优于对比例2。
通过表5和图4可以看出，实施例5-7制得的载药微球在半小时内药物释放量为1.33％，7.69％，10.02％，并且实施例5-7制得的载药微球在24小时内药物释放的总量随着第二溶剂乙酸体积比的增加而出现相应的变化，且均优于对比例1。
通过表6和图5可以看出，实施例8-10制得的载药微球在半小时内药物释放量为3.78％，12.54％，8.83％，并且实施例8-10制得的载药微球24小时内药物释放的总量随着第二溶剂甲醇体积比的增加而出现相应的变化，且均优于对比例1。
通过表7和图6可以看出，实施例11-13制得的载药微球在半小时内药物释放量为4.25％，5.06％，5.62％，实施例11-13制得的载药微球24小时内药物释放的总量随着第二溶剂乙腈体积比的增加而出现相应的变化，且均优于对比例1。
通过表8和图7可以看出，实施例14-16制得的载药微球在半小时内药物释放量为1.26％，3.80％，8.92％，实施例14-16制得的载药微球24小时内药物释放的总量随着第二溶剂乙腈体积比的增加而出现相应的变化，且均优于对比例1。
通过表9和图8可以看出，实施例17-19制得的载药微球在半小时内药物释放量为14.83％，10.40％，15.81％，实施例17-19制得的载药微球24小时内药物释放的总量随着第二溶剂乙醇体积比的增加而出现相应的变化，且均优于对比例1。
通过表10和图9可以看出，实施例20-21制得的载药微球在半小时内药物释放量为7.15％，3.28％，24小时内药物释放的总量随着第二溶剂乙醇体积比的增加而出现相应的变化，且均优于对比例3。
通过表11和图10可以看出，实施例22和23制得的载药微球在半小时内药物释放量分别为5.89％，8.24％，24小时内药物释放的总量随着第二溶剂乙醇体积比的增加而出现相应的变化，且均优于对比例4。
通过表11的数据还可以看出，实施例24制得的载药微球在半小时内药物释放量为4.99％，实施例25制得的载药微球在半小时内药物释放量为0.44％。
由图1可以看出，本发明方法制备的载药微球的外观为球形颗粒。采用本方法制备的载药微球，其药物缓释效果不仅可以通过第二溶剂进行控制，0.5小时内的药物突释量也比目前报道的数值要少，药典中“微囊、微球与脂质体制剂指导原则”中规定在开始的0.5小时内释放量要求低于40％，本发明工艺中加入第二溶剂后所制备的微球均达到了要求。
本发明的方法制成的微球可以作为栓剂、粘膜冲洗液(如阴道冲洗液)、泡腾片、软膏、粉剂以及药膜的组成成分，并应用于需要持续给药的相关疾病，其中，利用注射、口服、外用或植入等给药方式，将载药微球与人体的粘膜组织、血液或者间质组织结合，从而应用到病菌感染、肿瘤等疾病的治疗中去。上述相关疾病例如可以为呼吸道粘膜、消化道粘膜、泌尿系统粘膜或生殖系统粘膜相关的肿瘤、上皮组织内病变或炎症。
以上结合附图详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。

Claims (15)

  1. 一种制备载药微球的方法，其特征在于，该方法包括：
    (1)将表面活性剂与水混合，制得水相；
    (2)将药物、药物载体用聚合物材料、第一溶剂和第二溶剂混合，制得油相；
    (3)将油相加入到水相中进行混合；
    其中，所述第一溶剂与所述第二溶剂不同，且所述第二溶剂与所述第一溶剂互溶，所述第二溶剂为C1-C3的醇、C1-C3的脂肪酸、C1-C3的脂肪酸酯、C1-C2的醚和乙腈中的至少一种，所述第一溶剂的用量大于所述第二溶剂的用量。
  2. 根据权利要求1所述的方法，其中，所述第二溶剂为甲醇、乙醇、丙醇、异丙醇、丙二醇、乙酸、乙酸乙酯、乙醚和乙腈中的至少一种，优选为甲醇、乙酸、乙醇、乙醚、乙腈和异丙醇中的至少一种。
  3. 根据权利要求1或2所述的方法，其中，所述第一溶剂为二氯甲烷、丙酮、四氢呋喃、氯仿、二氯乙烷、正己烷和二甲基甲酰胺中的至少一种，优选为二氯甲烷、氯仿和四氢呋喃中的至少一种，更优选为二氯甲烷。
  4. 根据权利要求1-3中任意一项所述的方法，其中，所述药物载体用聚合物材料为聚己内酯、聚乳酸、聚氨酯、明胶、聚丙烯酸、羧甲基纤维素钠、聚卡波非、壳聚糖、乙基纤维素、纤维醋法酯、低取代羟丙纤维素、羟丙甲纤维素邻苯二甲酸酯、聚丙烯酸树脂、醋酸纤维素、聚乙烯吡咯烷酮、聚乳酸-羟基乙酸共聚物和聚乙烯醇中的至少一种。
  5. 根据权利要求4所述的方法，其中，所述药物载体用聚合物材料为聚乳酸和/或聚乳酸-羟基乙酸共聚物；
    优选地，所述药物载体用聚合物材料的重均分子量为10000g/mol以上，优选为30000-300000g/mol。
  6. 根据权利要求1-3中任意一项所述的方法，其中，步骤(2)中，所述第一溶剂的体积用量与所述第二溶剂的体积用量比例为1：0.005-0.5，优选为1：0.01-0.1。
  7. 根据权利要求6所述的方法，其中，步骤(2)中，相对于10ml第一溶剂，所述药物的用量为0.01-2g，所述药物载体用聚合物材料的用量为0.3-3g；
    优选地，相对于10ml第一溶剂，所述药物的用量为0.03-1g，所述药物载体用聚合物材料的用量为0.5-2g。
  8. 根据权利要求1-3中任意一项所述的方法，其中，步骤(1)中，水相中表面活性剂与水的质量体积百分数为0.1％-10％，优选为0.5％-5％。
  9. 根据权利要求7或8所述的方法，其中，步骤(1)得到的水相和步骤(2)得到的油相的体积比为1：0.01-0.15。
  10. 根据权利要求1-3中任意一项所述的方法，其中，步骤(3)中，所述混合的条件包括：温度为-5～25℃，搅拌速度为200-2000转/分钟；优选地，温度为-5～5℃，搅拌速度为400-1000转/分钟。
  11. 根据权利要求1-3中任意一项所述的方法，其中，所述药物为抗肿瘤药、消炎药、止痛药、抗生素、抗过敏药以及抗真菌药中的至少一种；
    更优选地，所述药物为5-氟尿嘧啶、阿司匹林、布洛芬、甲硝唑、西替利嗪和硝酸咪康唑中的至少一种；
    优选地，所述药物的平均粒径小于50μm，优选为0.05-20μm。
  12. 根据权利要求1-3或8中任意一项所述的方法，其中，所述表面活性剂为O/W型乳化剂，优选为聚乙烯醇和/或聚乙烯吡咯烷酮。
  13. 权利要求1-12中任意一项所述的方法制备的载药微球。
  14. 权利要求13所述的载药微球在制备用于治疗肿瘤以及粘膜相关的疾病的药物中的应用。
  15. 根据权利要求14所述的应用，其中，所述粘膜相关的疾病为与呼吸道粘膜、消化道粘膜、泌尿系统粘膜或生殖系统粘膜相关的肿瘤、上皮组织内病变或炎症。
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