WO2017097197A1 - 美西替康的药物组合物 - Google Patents

美西替康的药物组合物 Download PDF

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WO2017097197A1
WO2017097197A1 PCT/CN2016/108841 CN2016108841W WO2017097197A1 WO 2017097197 A1 WO2017097197 A1 WO 2017097197A1 CN 2016108841 W CN2016108841 W CN 2016108841W WO 2017097197 A1 WO2017097197 A1 WO 2017097197A1
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Prior art keywords
phosphatidylcholine
phospholipid
group
sucrose
lyoprotectant
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PCT/CN2016/108841
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English (en)
French (fr)
Inventor
张喜全
董平
张焕青
程艳菊
周浩
蒋波
刘飞
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正大天晴药业集团股份有限公司
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Priority to CN201680071229.1A priority Critical patent/CN108289877A/zh
Publication of WO2017097197A1 publication Critical patent/WO2017097197A1/zh

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present application relates to a pharmaceutical composition of mexican and a process for the preparation thereof.
  • emulsions and micelles In order to improve the solubility of poorly water-soluble or water-insoluble drugs, formulation techniques such as emulsions and micelles are used in the formulation development of such drugs.
  • emulsions and micelle formulations have some disadvantages.
  • emulsions are thermodynamically unstable systems, which tend to accumulate, fuse, flocculate, oxidize, degrade, hydrolyze, etc. during storage, thereby affecting the quality of the emulsion and the efficacy of the drug.
  • micellar formulations typically utilize a surfactant to form micelles to solubilize the drug.
  • surfactants can cause toxic side effects during clinical use, trigger hypersensitivity reactions, and affect drug safety.
  • Mexiticol is insoluble or almost insoluble in water and aqueous media and is a poorly water-soluble drug.
  • the stability is poor and the micelle formulation is too toxic. Therefore, there is an urgent need to develop new formulations suitable for methiocarb and methods for their preparation.
  • the application provides a pharmaceutical composition of mexicocon, which comprises mexicotine, a phospholipid or a mixture of phospholipids and cholesterol, and a lyoprotectant, wherein mexicot, a phospholipid or a mixture of phospholipids and cholesterol is frozen
  • the weight ratio between the dry protectants is 1-5:10-400:10-100.
  • the present application provides a method of preparing a pharmaceutical composition of mexicol, which comprises:
  • the present application provides another method of preparing a pharmaceutical composition of mexican, which comprises:
  • the lyoprotectant is added to the aqueous phase of step (1) or prior to the sterile filtration in step (3).
  • references to “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are meant to be included in the at least one embodiment.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • the application provides a pharmaceutical composition of mexicocon, which comprises mexicotine, a phospholipid or a mixture of phospholipids and cholesterol, and a lyoprotectant, wherein mexicot, a phospholipid or a mixture of phospholipids and cholesterol is frozen
  • the weight ratio between the dry protectants is 1-5:10-400:10-100, preferably 2:30-200:20-60, more preferably 2:40:60.
  • the pharmaceutical composition is a liposome, which may be, for example, a normal liposome, a long-circulating liposome, a thermosensitive liposome, an immunoliposome, or other special effects. Liposomes.
  • the phospholipid is selected from the group consisting of egg yolk phosphatidylcholine, hydrogenated egg phosphatidylcholine, soybean phosphatidylcholine, hydrogenated soybean phosphatidylcholine, bisphosphonic acid phosphatidylcholine, Decanoylphosphatidylcholine, dipalmitoylphosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, dicetyl phosphate, Dimyristoyl phosphatidylcholine, distearoylphosphatidylcholine, dilauroyl Phosphatidylcholine, dioleoylphosphatidylcholine, di-erucylphosphatidylcholine, 1-myristoyl-2-palmit
  • the phospholipid is selected from one or more of egg yolk phosphatidylcholine, hydrogenated egg phosphatidylcholine, soybean phosphatidylcholine or hydrogenated soybean phosphatidylcholine. More preferably, the phospholipid is selected from the group consisting of egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine. Still more preferably, the phospholipid is selected from the group consisting of a combination of egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine in a weight ratio of 3:1.
  • the phospholipid to cholesterol weight ratio is 3:1 or 2:1 in a mixture of phospholipids and cholesterol
  • the phospholipids include, but are not limited to, egg yolk phosphatidylcholine, hydrogenated egg yolk Phosphatidylcholine, soybean phosphatidylcholine, hydrogenated soybean phosphatidylcholine, bis-lipoic acid phosphatidylcholine, didecanoylphosphatidylcholine, dipalmitoylphosphatidylcholine, phosphatidylserine, phosphatidyl Inositol, phosphatidylethanolamine, cultured phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, dicetyl phosphate, dimyristoyl phosphatidylcholine, distearoylphosphatidylcholine, dilauroyl phospholipid Acylcholine, dio
  • the lyoprotectant is selected from one or more of the group consisting of mannitol, glucose, galactose, sucrose, lactose, maltose, or trehalose.
  • the lyoprotectant is selected from one or more of sucrose, trehalose or mannitol. More preferably, the lyoprotectant is selected from the group consisting of sucrose or a combination of sucrose and mannitol. Still more preferably, the lyoprotectant is a combination of sucrose or a weight ratio of sucrose to mannitol of 2:1.
  • the pharmaceutical composition of the present application comprises: mexeticol, a phospholipid, and a lyoprotectant, wherein the weight ratio between mexican, phospholipid, and lyoprotectant is 2: 30-200: 20-60, wherein the phospholipid is selected from the group consisting of egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine, wherein the weight ratio of egg yolk phosphatidylcholine to hydrogenated soybean phosphatidylcholine is 3:1.
  • the lyoprotectant is selected from sucrose.
  • the pharmaceutical composition of the present application comprises: mexeticol, a phospholipid, and a lyoprotectant, wherein the weight ratio between mexican, phospholipid, and lyoprotectant is 2: 30-200: 20-60, wherein the phospholipid is selected from the group consisting of egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine, wherein the weight ratio of egg yolk phosphatidylcholine to hydrogenated soybean phosphatidylcholine is 3:1.
  • the lyoprotectant is selected from the group consisting of sucrose and mannitol, wherein the weight ratio of sucrose to mannitol is 2:1.
  • the pharmaceutical composition of the present application comprises: mexeticol, a phospholipid, and a lyoprotectant, wherein the weight ratio between mexican, phospholipid, and lyoprotectant is 2:40:60, the phospholipid is selected from the group consisting of egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine, wherein the weight ratio of egg yolk phosphatidylcholine to hydrogenated soybean phosphatidylcholine is 3:1, said frozen
  • the dry protective agent is selected from sucrose.
  • the pharmaceutical composition of the present application comprises: mexeticol, a phospholipid, and a lyoprotectant, wherein the weight ratio between mexican, phospholipid, and lyoprotectant is 2:40:60, the phospholipid is selected from the group consisting of egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine, wherein the weight ratio of egg yolk phosphatidylcholine to hydrogenated soybean phosphatidylcholine is 3:1, said frozen
  • the dry protectant is selected from the group consisting of sucrose and mannitol in which the weight ratio of sucrose to mannitol is 2:1.
  • the pharmaceutical composition of the present application comprises: mexeticol, a mixture of phospholipids and cholesterol, a lyoprotectant, wherein mexitic, a mixture of phospholipids and cholesterol, and a lyoprotectant
  • the weight ratio between them is 2:30-200:20-60
  • the phospholipid is selected from the group consisting of egg yolk phosphatidylcholine, wherein the weight ratio of egg yolk phosphatidylcholine to cholesterol is 3:1 or 2:1.
  • the dry protective agent is selected from sucrose.
  • the pharmaceutical compositions described herein may further comprise an antioxidant, a metal ion chelating agent, and/or a pH adjusting agent.
  • the antioxidant is selected from the group consisting of sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium thiosulfate, vitamin C, ascorbyl palmitate, t-butyl p-hydroxyanisole (BHA), di-tert-butyl-p-cresol (BHT).
  • BHA t-butyl p-hydroxyanisole
  • BHT di-tert-butyl-p-cresol
  • the antioxidant is selected from the group consisting of sodium metabisulfite, tert-butyl p-hydroxyanisole, di-tert-butyl-p-cresol, and vitamin E acetate. More preferably, the antioxidant is selected from the group consisting of di-tert-butyl-p-cresol or sodium metabisulfite.
  • the metal ion chelating agent is selected from the group consisting of disodium edetate, sodium edetate, 1,2-diaminocyclohexanetetraacetic acid, diethylenetriaminepentaacetic acid, and N-(2-hydroxyethyl)-B. Trisodium diamine triacetate or N-bis(2-hydroxyethyl)glycine.
  • the metal ion chelating agent is selected from the group consisting of disodium edetate or sodium calcium edetate.
  • the pH adjusting agent is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, citric acid, tartaric acid, maleic acid, sodium hydroxide, sodium hydrogencarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate or sodium citrate.
  • the pH adjusting agent is selected from the group consisting of hydrochloric acid or sodium hydroxide.
  • the pH is adjusted in the range of 2-10, preferably 4-7.
  • the pharmaceutical composition is a solid, such as a solid obtained by freeze-drying, characterized by rapid reconstitution after addition of water or an aqueous solvent, and the particle size after reconstitution is 50-400 nm. It is preferably from 100 to 250 nm.
  • the particle size dispersion coefficient is ⁇ 0.5, preferably, the particle size dispersion coefficient is ⁇ 0.23.
  • the pharmaceutical composition is in liquid form prior to lyophilization, which further comprises Organic solvents and water.
  • the organic solvent is selected from the group consisting of anhydrous ethanol, 95% ethanol, methanol, propanol, chloroform, dichloromethane, tert-butanol, n-butanol, acetone, methylpyrrolidone, ethyl acetate, isopropyl ether or One or more of the ethers.
  • the organic solvent is selected from the group consisting of absolute ethanol, 95% ethanol or tert-butanol. More preferably, the organic solvent is selected from the group consisting of anhydrous ethanol.
  • the present application provides a method of preparing a pharmaceutical composition of mexicol, which comprises:
  • the lyoprotectant may be added in the aqueous phase of step (1) or prior to the freeze drying in step (3).
  • water for injection is added and dispensed prior to performing the freeze-drying in step (3).
  • step (3) prior to lyophilization in step (3), water for injection is added and sterilized for filtration and then dispensed.
  • the present application provides another method of preparing a pharmaceutical composition of mexican, which comprises:
  • the lyoprotectant is added to the aqueous phase of step (1) or prior to the sterile filtration in step (3).
  • an antioxidant may also be added to the organic phase in step (1).
  • the components of the organic phase may be added simultaneously, or a portion of the components may be added first, followed by the remaining components. Further, the order of addition of the components is not particularly limited, and for example, mexicokon may be added first, or mexicocan may be added last.
  • the aqueous phase comprises or consists essentially of water, for example, deionized water, distilled water, purified water, water for injection, and the like, preferably water for injection.
  • the aqueous phase in step (1) may further comprise a metal ion chelating agent.
  • the components of the aqueous phase may be added simultaneously, or a portion of the components may be added first, followed by the remaining components. Further, the order of addition of the components is not particularly limited, and for example, the lyoprotectant may be added first, or the lyoprotectant may be added last.
  • the mixing of the organic phase with the aqueous phase can be carried out while stirring or shearing the aqueous phase, or under nitrogen.
  • the polycarbonate membrane has a pore size selected from the group consisting of 0.015, 0.03, 0.05, 0.08, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 2.0, 3.0, 5.0, 8.0, 10.0 or 12.0 microns, preferably 0.1 microns or 0.2 microns.
  • a layer of polyester film can be added under the polycarbonate film.
  • the extrusion may be performed in any manner as long as a large particle size liposome can be passed through the membrane or a pore of a certain pore size to become a small particle size.
  • the liposome is sufficient.
  • This step requires controlling the temperature of the feed liquid to be 25-80 ° C, preferably 55-65 ° C.
  • a pH adjusting agent may also be added prior to performing freeze drying in step (3).
  • the components in step (3), the components may be added simultaneously, or a portion of the components may be added first, followed by the remaining components. Further, the order of addition of the components is not particularly limited, and for example, the lyoprotectant may be added first, or the lyoprotectant may be added last.
  • the sterile filtration and freeze drying described in step (3) are techniques well known to those skilled in the art and widely used in the art.
  • the pharmaceutical composition of mexicotine of the present application can be administered to a patient or a subject by any appropriate route, such as intravenous administration, intraarterial administration, intramuscular administration, intraperitoneal administration, subcutaneous administration, Intra-articular administration, intrathecal administration, intracerebroventricular administration, nasal spray, pulmonary inhalation, oral administration, and other suitable routes of administration known to those skilled in the art.
  • Tissue lesions that can be treated with the pharmaceutical compositions of mexiciline of the present application include, but are not limited to, lesions of tissues such as the bladder, liver, lungs, kidneys, bones, soft tissues, muscles, breasts, and the like.
  • the pharmaceutical composition of mexicanol of the present application has a markedly improved stability, is easy to store and transport, and has a markedly reduced toxicity. Moreover, it has been more surprisingly found that the pharmaceutical composition is concentrated in specific organs and tissues in the body, has a targeting property, and enhances the pharmacological effect of the pharmaceutical preparation.
  • the pharmaceutical composition of the present application has a high encapsulation efficiency (>99%), the drug does not leak during storage and the encapsulation efficiency does not decrease; it has better reproducibility, is easily reconstituted and complex The particle size distribution after dissolution is uniform, and the dispersion coefficient can be 0.18 or less.
  • the preparation method of the meclizine pharmaceutical composition of the present application is simple and easy to operate, stable and controllable, and is particularly suitable for industrial production.
  • Figure 1 Tissue distribution of mexitic in vivo after intravenous injection of 30 mg/kg of mexicokonium liposomes into rats.
  • Figure 2 Tissue distribution map of the active metabolite SN38 in vivo after intravenous injection of 30 mg/kg of mexitidine liposomes into rats.
  • Figure 3 Distribution of fluorescent marker IR623 and IR623-labeled mexiticone liposomes in mice.
  • Figure 4 Distribution of fluorescent marker IR623 and IR623-labeled methiocan liposome in tumor sites and organs of mice
  • Preparation process formulating amount of mexiticol, egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine in a formula amount of absolute ethanol, heating and dissolving at 60 ° C, as an organic phase; taking a formula of 70 % of water for injection, heated to 60 ° C, as an aqueous phase; while shearing the aqueous phase, the organic phase was added to the aqueous phase to obtain a liposome feed; the resulting liposome solution was passed through a 0.1 ⁇ m polycarbonate The film was extruded 3 times; the amount of sucrose was added, and diluted with water for injection to 1000 g; it was dispensed into a neutral borosilicate glass controlled injection bottle (west bottle) and then freeze-dried. The encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process formulating amount of mexiticol, egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine in a formula amount of absolute ethanol, heating and dissolving at 60 ° C, as an organic phase; taking a formula of 70 % of water for injection, heated to 60 ° C, as an aqueous phase; while shearing the aqueous phase, the organic phase was added to the aqueous phase to obtain a liposome feed; the resulting liposome solution was passed through a 0.2 ⁇ m polycarbonate The film was extruded 3 times; the amount of sucrose was added, and diluted with water for injection to 15 kg; sub-packaged to neutral boron The silica glass controlled injection bottle (the vial) is obtained by freeze-drying in the middle. The encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process formulating amount of mexiticol, egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine in a formula amount of absolute ethanol, heating and dissolving at 60 ° C, as an organic phase; taking a formula amount of sucrose And the formulated amount of 70% of water for injection is heated and dissolved at 60 ° C as an aqueous phase; while the aqueous phase is sheared or stirred, the organic phase is added to the aqueous phase to obtain a liposome feed liquid;
  • the plastid material solution was extruded 3 times through a 0.4 ⁇ m polycarbonate membrane; diluted with water for injection to 1000 g; and dispensed into a neutral borosilicate glass controlled injection bottle (west bottle) and then freeze-dried.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process formulating amount of mexiticol, egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine in a formula amount of absolute ethanol, heating and dissolving at 60 ° C, as an organic phase; taking a formula of 70 % of water for injection, heated to 60 ° C, as an aqueous phase; while shearing or stirring the aqueous phase, the organic phase is added to the aqueous phase to obtain a liposome feed; the resulting liposome solution is passed through 0.2 ⁇ m.
  • the carbonate film was extruded 3 times; the formulated amount of sucrose and mannitol were added, and diluted with water for injection to 1000 g; and dispensed into a neutral borosilicate glass controlled injection bottle (west bottle), and then freeze-dried.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process the formula amount of BHT and mestatin is dissolved in the formula of absolute ethanol, dissolved at 60 ° C, dissolved, and then added to the formula amount of egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine, Dissolved by heating at 60 ° C, dissolved as an organic phase; take 70% of the preparation water for injection, heated to 60 ° C, as an aqueous phase; while shearing or stirring the aqueous phase, adding the organic phase to the aqueous phase, Liposomal material solution; the obtained liposome liquid is extruded through a 0.2 ⁇ m polycarbonate film to obtain a liposome liquid having a certain particle size and a certain particle size distribution; adding a formula amount of sucrose, plus The water for injection is diluted to 1000 g; it is dispensed into a neutral borosilicate glass controlled injection bottle (west bottle) and then freeze-dried. The encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process the formula amount of mestatin is dissolved in the formula amount of absolute ethanol, dissolved at 60 ° C, dissolved, and then added to the formula amount of egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine, at 60 Dissolve and dissolve at °C, dissolve and use as organic phase; take the formula amount of disodium edetate and 70% of the water for injection, and dissolve at 60 ° C as water phase; shear or stir the water phase, The organic phase is added to the aqueous phase to obtain a liposome liquid; the obtained liposome solution is extruded through a 0.1 ⁇ m polycarbonate film to obtain a liposome having a certain particle size and a certain particle size distribution. Liquid; add the formula amount of sucrose, add water for injection to 1000g; dispense into neutral borosilicate glass control injection bottle (west bottle) and freeze-dry. The encapsulation efficiency was >99% as measured by ultrafiltration.
  • the formula amount of mestatin is dissolved in the formula amount of absolute ethanol, dissolved at 60 ° C, dissolved, and then added to the formula amount of egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine, at 60 Dissolve and dissolve at °C, dissolve it as organic phase; take 70% of the water for injection in the preparation, and keep it as the water phase after 60 °C; while adding or stirring the aqueous phase, add the organic phase to the aqueous phase to obtain the lipid.
  • the obtained liposome solution is extruded through a 0.2 ⁇ m polycarbonate film to obtain a liposome solution having a certain particle size and a certain particle size distribution; adding a formula amount of sucrose, and adding hydrochloric acid or Sodium hydroxide was adjusted to pH 5, and diluted with water for injection to 1000 g; it was dispensed into a neutral borosilicate glass controlled injection bottle (west bottle) and then freeze-dried.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process The specific implementation steps are the same as those in Embodiment 2.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process The specific implementation steps are the same as those in Embodiment 2.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process The specific implementation steps are the same as those in Embodiment 2.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process The specific implementation steps are the same as those in Embodiment 2.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process formulating amount of mexiticol, egg yolk phosphatidylcholine and cholesterol in a formula amount of absolute ethanol, heating and dissolving at 60 ° C, as an organic phase; taking a preparation amount of 70% of water for injection, Heated to 60 ° C, as an aqueous phase; while shearing the aqueous phase, the organic phase was added to the aqueous phase to obtain a liposome feed; the resulting liposome solution was extruded 3 times through a 0.2 ⁇ m polycarbonate membrane.
  • Add the formula amount of sucrose add water for injection to 1000g; dispense to neutral borosilicate glass control
  • the injection bottle (the vial) is obtained by freeze-drying in the middle.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process The specific implementation steps are the same as those in Embodiment 2.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process The specific implementation steps are the same as those in Embodiment 2.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process The specific implementation steps are the same as those in Embodiment 2.
  • the encapsulation efficiency was >99% as measured by ultrafiltration.
  • Preparation process taking the formula amount of mexiticol, polyoxyethylene castor oil, glycerin and absolute ethanol, heating and dissolving in a 45 ° C water bath, dissolving and sterilizing, filtering, and dispensing.
  • Preparation process 1 Take the formula amount of mexitic, vitamin E and anhydrous ethanol to heat and dissolve; 2 take the formula amount of F68 and the formula amount of water to dissolve; 3 take 2 half of the solution, cut 1 The obtained solution is added thereto, and after sufficiently shearing, the other half of the obtained solution is added thereto, and the mixture is sheared and mixed; 4 The solution obtained by 3 is subjected to high-pressure homogenization treatment 10 times, and is obtained by dispensing.
  • Preparation process taking the formula amount of mexicot and tert-butanol, heating and dissolving, sterilizing and filtering, and lyophilizing after dispensing to obtain mexiticol powder.
  • Preparation process Take the formula amount of ELP, glycerin and absolute ethanol, mix and sterilize and filter, and dispense to obtain special solvent.
  • Example 2 According to the formulation and preparation process of Example 2, one batch of the pharmaceutical composition containing mestatin was prepared; and according to the formulation and preparation process of Comparative Example 3, one batch of micelle preparation containing mexicoc was prepared.
  • the obtained two batches of the pharmaceutical preparations were subjected to an acute toxicity test of mice, an acute toxicity test of rats, and a toxicity test of rat administration for 4 weeks in mice and rats at the same dose.
  • the toxicity test results of the two pharmaceutical preparations were compared and the results were as follows:
  • Example 2 According to the formulation and preparation process of Example 2, one batch of the pharmaceutical composition containing mestatin was prepared; and according to the formulation and preparation process of Comparative Example 3, one batch of micelle preparation containing mexicoc was prepared.
  • the obtained two batches of drugs were tested in NCI-H292 lung cancer nude mice for the inhibition of xenograft tumor growth.
  • the results of the efficacy test of the two pharmaceutical preparations are as follows:
  • Example 2 According to the formulation and preparation process of Example 2, one batch of the pharmaceutical composition containing mestatin was prepared; and according to the formulation and preparation process of Comparative Example 3, one batch of micelle preparation containing mexicoc was prepared. The resulting two batches of the drug were tested for long-term toxicity in rats. Rats were administered at doses of 60, 30 and 10 mg/kg, respectively. The test results of the two pharmaceutical preparations were compared and the results were as follows:
  • One batch of the pharmaceutical composition containing mexicilin was prepared in accordance with the formulation and preparation process of Example 2. Eighteen SD rats were divided into 3 groups, 6 in each group, 3 females and 3 males. After administration of 30 mg/kg of methacetal to the rats in each group, blood samples and tissues were anesthetized at 15 min, 2 h and 6 h after administration, and blood samples and tissues were treated to obtain plasma and Tissue homogenate samples were established by LC-MS/MS to determine mesitylene and its active metabolite SN-38 in plasma and tissue homogenates (chemical name: 20(s)-7-ethyl-10-hydroxyl Camptothecin), the results are shown in Figures 1 and 2.
  • Figure 1 shows that mexicokon is mainly distributed in the rectum, liver, lung, plasma, colon, kidney, ovary and heart.
  • Figure 2 shows that SN-38 is mainly distributed in the colon, rectum, liver, lung, plasma, ovary, In the jejunum, ileum, duodenum and kidneys.
  • the concentrations of ciscocon and SN-38 in the rectum were very high, while in the colon, although the concentration of mexeticol was lower than that of plasma, the concentration of the active metabolite SN-38 of mexican was the highest, indicating the application of the present application.
  • the pharmaceutical composition is concentrated in a particular organ or tissue in the body. Both mexican and SN-38 have the lowest concentrations in the brain and testis.
  • Example 1 According to the formulation of Example 1 (additional addition of about 0.8% (w/w, based on the total amount of phospholipids in the formulation) of DSPE with fluorescent probe IR623 (added and dissolved in the organic phase) And a preparation process to prepare a batch of methiocan pharmaceutical composition (particle size about 100 nm) containing a fluorescent probe (IR623).
  • Example 3 According to the formulation of Example 3 (additional addition of about 0.8% (w/w, based on the total amount of phospholipids in the formulation) of DSPE with fluorescent probe IR623 (added and dissolved in the organic phase) And a preparation process to prepare a batch of methiocan pharmaceutical composition (particle size about 400 nm) containing a fluorescent probe (IR623). Two batches of the drug composition were used in the in vivo targeting study of HT29 intestinal cancer-bearing nude mice by near-infrared in vivo imaging technique, and compared with the in vivo targeting of the fluorescent probe IR623. The results are shown in Fig. 3 and 4.
  • the mice injected with mexicokonium liposome with fluorescent probe with a particle diameter of 100 nm were all distributed with fluorescence signals at 0.5 h. The fluorescence signal began to concentrate at the tumor site from 4 h, and the fluorescence signal intensity of the tumor site at 8 h. The strongest, the fluorescent signal of the tumor site began to weaken after 8h, and there was still a fluorescent signal at the tumor site at 48h (see Figure 3 for the results).
  • mice injected with mexicokonium liposome with fluorescent probe with a diameter of 400 nm showed obvious fluorescence signal in the abdomen at 0.5 h, and the abdominal fluorescent signal increased at 4 h, and the fluorescent signal was concentrated in the abdomen. (The results are shown in Figure 3).
  • the tumor-bearing mice were dissected, and the organs in each body (tumor, liver, spleen, kidney and intestine) were observed in the living imager for the fluorescence distribution of each organ. From Figure 4, we can see that the fluorescence of the organs of mice injected with free fluorescent probes is very weak and almost completely metabolized. In the organs of mice injected with mexicokonium liposome having a fluorescent probe having a particle diameter of 100 nm, the tumor has strong fluorescence compared to other organs. In the organs of mice injected with mexicokonium liposomes with a fluorescent probe having a particle diameter of 400 nm, the fluorescence of the liver was the strongest.
  • the mexicokonium liposome with a fluorescent probe with a particle diameter of 100 nm has passive tumor targeting, while the mexican liposome with a fluorescent probe with a particle diameter of 400 nm is mainly Liver accumulation. Fluorescent probes are mainly excreted through the intestinal and renal metabolism.

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Abstract

美西替康的药物组合物，其包含美西替康、磷脂或磷脂与胆固醇的混合物和冻干保护剂，其中美西替康、磷脂或磷脂与胆固醇的混合物和冻干保护剂之间的重量比为1-5:10-400:10-100。

Description

美西替康的药物组合物
相关申请的引用
本申请要求于2015年12月08日向中华人民共和国国家知识产权局提交的申请号为201510896290.7的中国发明专利申请的权益。
技术领域
本申请涉及美西替康的药物组合物及其制备方法。
背景技术
为了提高水溶性差或水不溶性药物的溶解度，乳剂和胶束等制剂技术被用于此类药物的制剂开发中。但乳剂和胶束制剂存在一些缺点。例如，乳剂属于热力学不稳定系统，在储存过程中易出现聚集、融合、絮凝、氧化、降解、水解等现象，从而影响乳剂的质量和药物的疗效。再如，胶束制剂通常会利用表面活性剂来形成胶束以增溶药物。然而，表面活性剂在临床使用时会产生毒副作用，引发超敏反应，影响用药安全。
中国专利(专利号：ZL201110355747.5)公开了如式I所示的化合物(又称美西替康)，
Figure PCTCN2016108841-appb-000001
美西替康在水及水性介质中不溶或几乎不溶，属于水难溶性药物。该专利提及可以将该药物配制成乳液、微乳液或胶束制剂。然而，我们发现将该药物配制成乳液、微乳液或胶束制剂后，稳定性很差且胶束制剂的毒性太大。因此，亟需开发新的适用于美西替康的制剂及其制备方法。
发明概述
一方面，本申请提供美西替康的药物组合物，其包含美西替康、磷脂或磷脂与胆固醇的混合物和冻干保护剂，其中美西替康、磷脂或磷脂与胆固醇的混合物和冻干保护剂之间的重量比为1-5:10-400:10-100。
再一方面，本申请提供美西替康的药物组合物的制备方法，其包括：
(1)将美西替康和磷脂或磷脂与胆固醇的混合物溶解于有机溶剂中，得到有机相，然后与水相混合得脂质体料液；
(2)将步骤(1)所得的脂质体料液经聚碳酸脂膜挤出；
(3)冷冻干燥。
另一方面，本申请还提供了美西替康的药物组合物的另一制备方法，其包括：
(1)将美西替康和磷脂或磷脂与胆固醇的混合物溶解于有机溶剂中，得到有机相，然后与水相混合得脂质体料液；
(2)将步骤(1)所得脂质体料液经聚碳酸脂膜挤出；
(3)加入注射用水并除菌过滤，分装和冷冻干燥；
其中在步骤(1)的水相中或者在实施步骤(3)中的除菌过滤之前加入冻干保护剂。
发明详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求，在整个说明书和其后的权利要求书中，词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包括“催化剂”的反应包括一种催化剂，或两种或多种催化剂。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。
一方面，本申请提供美西替康的药物组合物，其包含美西替康、磷脂或磷脂与胆固醇的混合物和冻干保护剂，其中美西替康、磷脂或磷脂与胆固醇的混合物和冻干保护剂之间的重量比为1-5:10-400:10-100，优选为2:30-200:20-60，更优选为2:40:60。
在本申请的一个优选实施方案中，所述药物组合物为脂质体，例如可为普通脂质体、长循环脂质体、热敏脂质体、免疫脂质体，或其他具有特殊功效的脂质体。
在本申请的一些实施方案中，所述磷脂选自蛋黄磷脂酰胆碱、氢化蛋黄磷脂酰胆碱、大豆磷脂酰胆碱、氢化大豆磷脂酰胆碱、双软脂酸磷脂酰胆碱、二癸酰基磷脂酰胆碱、二棕榈酰磷脂酰胆碱、磷酯酰丝氨酸、磷脂酰肌醇、磷脂酰乙醇胺、培化磷脂酰乙醇胺、磷脂酰甘油、磷脂酰胆碱、二鲸蜡磷酸酯、二肉豆蔻酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二月桂酰 磷脂酰胆碱、二油酰磷脂酰胆碱、二芥酰基磷脂酰胆碱、1-肉豆蔻酰基-2-棕榈酰基磷脂酰胆碱、1-棕榈酰基-2-硬脂酰基磷脂酰胆碱、1-棕榈酰基-2-肉豆蔻酰基磷脂酰胆碱、1-硬脂酰基-2-肉豆蔻酰基磷脂酰胆碱、1-硬脂酰基-2-棕榈酰基磷脂酰胆碱、1-肉豆蔻酰基-2-油酰基磷脂酰胆碱、1-棕榈酰基-2-油酰基磷脂酰胆碱、1-硬脂酰基-2-油酰基磷脂酰胆碱、二肉豆蔻酰基磷脂酰乙醇胺、二棕榈酰基磷脂酰乙醇胺、二硬脂酰基磷脂酰乙醇胺、二油酰基磷脂酰乙醇胺、二芥酰基磷脂酰乙醇胺或1-棕榈酰基-2-油酰基磷脂酰乙醇胺中的一种或多种。优选的，所述磷脂选自蛋黄磷脂酰胆碱、氢化蛋黄磷脂酰胆碱、大豆磷脂酰胆碱或氢化大豆磷脂酰胆碱中的一种或多种。更优选的，所述磷脂选自蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱的组合。还更优选的，所述磷脂选自其中蛋黄磷脂酰胆碱与氢化大豆磷脂酰胆碱的重量比为3:1的组合。
在本申请的一些实施方案中，在磷脂与胆固醇的混合物中，磷脂与胆固醇的重量比为3:1或2:1，其中所述磷脂的实例包括但不限于蛋黄磷脂酰胆碱、氢化蛋黄磷脂酰胆碱、大豆磷脂酰胆碱、氢化大豆磷脂酰胆碱、双软脂酸磷脂酰胆碱、二癸酰基磷脂酰胆碱、二棕榈酰磷脂酰胆碱、磷酯酰丝氨酸、磷脂酰肌醇、磷脂酰乙醇胺、培化磷脂酰乙醇胺、磷脂酰甘油、磷脂酰胆碱、二鲸蜡磷酸酯、二肉豆蔻酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二油酰磷脂酰胆碱、二芥酰基磷脂酰胆碱、1-肉豆蔻酰基-2-棕榈酰基磷脂酰胆碱、1-棕榈酰基-2-硬脂酰基磷脂酰胆碱、1-棕榈酰基-2-肉豆蔻酰基磷脂酰胆碱、1-硬脂酰基-2-肉豆蔻酰基磷脂酰胆碱、1-硬脂酰基-2-棕榈酰基磷脂酰胆碱、1-肉豆蔻酰基-2-油酰基磷脂酰胆碱、1-棕榈酰基-2-油酰基磷脂酰胆碱、1-硬脂酰基-2-油酰基磷脂酰胆碱、二肉豆蔻酰基磷脂酰乙醇胺、二棕榈酰基磷脂酰乙醇胺、二硬脂酰基磷脂酰乙醇胺、二油酰基磷脂酰乙醇胺、二芥酰基磷脂酰乙醇胺或1-棕榈酰基-2-油酰基磷脂酰乙醇胺中的一种或多种。优选的，所述磷脂选自蛋黄磷脂酰胆碱、氢化蛋黄磷脂酰胆碱、大豆磷脂酰胆碱或氢化大豆磷脂酰胆碱中的一种或多种。
在本申请的一些实施方案中，所述冻干保护剂选自甘露醇、葡萄糖、半乳糖，蔗糖、乳糖、麦芽糖或海藻糖中的一种或多种。优选的，所述冻干保护剂选自蔗糖、海藻糖或甘露醇中的一种或多种。更优选的，所述冻干保护剂选自蔗糖或蔗糖与甘露醇的组合。还更优选的，所述冻干保护剂为蔗糖或蔗糖与甘露醇的重量比为2:1的组合。
在本申请的一个优选实施方案中，本申请的药物组合物包含：美西替康、磷脂和冻干保护剂，其中美西替康、磷脂和冻干保护剂之间的重量比为2:30-200:20-60，所述磷脂选自蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱的组合，其中蛋黄磷脂酰胆碱与氢化大豆磷脂酰胆碱的重量比为3:1，所述冻干保护剂选自蔗糖。
在本申请的一个优选实施方案中，本申请的药物组合物包含：美西替康、磷脂和冻干保护剂，其中美西替康、磷脂和冻干保护剂之间的重量比为2:30-200:20-60，所述磷脂选自蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱的组合，其中蛋黄磷脂酰胆碱与氢化大豆磷脂酰胆碱的重量比为3:1，所述冻干保护剂选自蔗糖与甘露醇的组合，其中蔗糖与甘露醇的重量比为2:1。
在本申请的一个更优选的实施方案中，本申请的药物组合物包含：美西替康、磷脂和冻干保护剂，其中美西替康、磷脂和冻干保护剂之间的重量比为2:40:60，所述磷脂选自蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱的组合，其中蛋黄磷脂酰胆碱与氢化大豆磷脂酰胆碱的重量比为3:1，所述冻干保护剂选自蔗糖。
在本申请的一个更优选的实施方案中，本申请的药物组合物包含：美西替康、磷脂和冻干保护剂，其中美西替康、磷脂和冻干保护剂之间的重量比为2:40:60，所述磷脂选自蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱的组合，其中蛋黄磷脂酰胆碱与氢化大豆磷脂酰胆碱的重量比为3:1，所述冻干保护剂选自蔗糖与甘露醇的组合，其中蔗糖与甘露醇的重量比为2:1。
在本申请的一个优选实施方案中，本申请的药物组合物包含：美西替康、磷脂与胆固醇的混合物、冻干保护剂，其中美西替康、磷脂与胆固醇的混合物和冻干保护剂之间的重量比为2:30-200:20-60，所述磷脂选自蛋黄磷脂酰胆碱，其中蛋黄磷脂酰胆碱与胆固醇的重量比为3:1或2:1，所述冻干保护剂选自蔗糖。
在本申请的一些实施方案中，除上述组分外，本申请所述的药物组合物还可以进一步包含抗氧化剂、金属离子螯合剂和/或pH调节剂。所述抗氧化剂选自亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、维生素C、抗坏血酸棕榈酸酯，叔丁基对羟基茴香醚(BHA)、二叔丁基对甲酚(BHT)、维生素E醋酸酯、半胱氨酸和蛋氨酸中的一种或多种。优选的，所述抗氧化剂选自焦亚硫酸钠、叔丁基对羟基茴香醚、二叔丁基对甲酚、维生素E醋酸酯。更优选的，所述抗氧化剂选自二叔丁基对甲酚或焦亚硫酸钠。所述金属离子螯合剂选自依地酸二钠、依地酸钙钠、1,2-二氨基环己烷四乙酸、二乙三胺五乙酸、N-(2-羟乙基)-乙二胺三乙酸三钠或N-二(2-羟乙基)甘氨酸。优选的，所述金属离子螯合剂选自依地酸二钠或依地酸钙钠。所述pH调节剂选自盐酸、硫酸、乙酸、磷酸、枸橼酸、酒石酸、马来酸、氢氧化钠、碳酸氢钠、磷酸氢二钠、磷酸二氢钠或枸橼酸钠。优选的，所述pH调节剂选自盐酸或氢氧化钠。在本申请的一些实施方案中，pH的调节范围为2-10，优选为4-7。
在本申请的一些实施方案中，所述药物组合物为固体，如经冷冻干燥法制得的固体，其特征在于加水或水性溶剂后快速复溶，复溶后的颗粒粒径为50-400nm，优选为100-250nm。在本申请的一些实施方案中，粒径分散系数≤0.5，优选地，粒径分散系数≤0.23。
在本申请的一些实施方案中，所述药物组合物在冷冻干燥前为液体形式，其进一步包含 有机溶剂和水。所述有机溶剂选自无水乙醇，95％的乙醇，甲醇、丙醇、三氯甲烷、二氯甲烷、叔丁醇，正丁醇、丙酮、甲基吡咯烷酮、乙酸乙酯、异丙醚或乙醚中的一种或多种。优选的，所述有机溶剂选自无水乙醇、95％的乙醇或叔丁醇。更优选的，所述有机溶剂选自无水乙醇。
再一方面，本申请提供美西替康的药物组合物的制备方法，其包括：
(1)将美西替康和磷脂或磷脂与胆固醇的混合物溶解于有机溶剂中，得到有机相，然后与水相混合得脂质体料液；
(2)将步骤(1)所得的脂质体料液经聚碳酸脂膜挤出；
(3)冷冻干燥。
在本申请的一些实施方案中，可以在步骤(1)的水相中或者在实施步骤(3)中的冷冻干燥之前加入冻干保护剂。
在本申请的一些实施方案中，在实施步骤(3)中的冷冻干燥之前，加入注射用水并分装。
在本申请的一些实施方案中，在实施步骤(3)中的冷冻干燥之前，加入注射用水并除菌过滤，然后分装。
另一方面，本申请还提供了美西替康的药物组合物的另一制备方法，其包括：
(1)将美西替康和磷脂或磷脂与胆固醇的混合物溶解于有机溶剂中，得到有机相，然后与水相混合得脂质体料液；
(2)将步骤(1)所得脂质体料液经聚碳酸脂膜挤出；
(3)加入注射用水并除菌过滤，分装和冷冻干燥；
其中在步骤(1)的水相中或者在实施步骤(3)中的除菌过滤之前加入冻干保护剂。
在本申请的一些实施方案中，还可以向步骤(1)中的所述有机相中加入抗氧化剂。在本申请的一些实施方案中，在步骤(1)中，有机相的各组分可同时加入，也可以先加入一部分组分，然后再加入剩余组分。此外，各组分的加入顺序不特别限制，例如可以最先加入美西替康，也可以最后加入美西替康。
在本申请的一些实施方案中，所述水相包含水作为主要组分或基本上由水组成，例如，去离子水、蒸馏水、纯化水、注射用水等，优选注射用水。
在本申请的一些实施方案中，步骤(1)中的所述水相中还可以包含金属离子螯合剂。在本申请的一些实施方案中，在步骤(1)中，水相的各组分可同时加入，也可以先加入一部分组分，然后再加入剩余组分。此外，各组分的加入顺序不特别限制，例如可以最先加入冻干保护剂，也可以最后加入冻干保护剂。
在本申请的一些实施方案中，所述有机相与水相的混合可以边搅拌或剪切水相边进行，也可以在氮气保护下进行。
在本申请的一些实施方案中，所述聚碳酸酯膜(Polycarbonate)的孔径选自0.015、0.03、0.05、0.08、0.1、0.2、0.4、0.6、0.8、1.0、2.0、3.0、5.0、8.0、10.0或12.0微米，优选0.1微米或0.2微米。任选地，可在聚碳酸酯膜的下面再加一层聚酯膜(Polyester)。
在本申请的一些实施方案中，所述挤出可以是以任何方式实施的挤出，只要能使大粒径的脂质体通过所述膜或一定孔径的小孔后变成小粒径的脂质体即可，该步骤需要控制料液的温度为25-80℃，优选为55-65℃。
在本申请的一些实施方案中，还可以在步骤(3)中实施冷冻干燥之前加入pH调节剂。在本申请的一些实施方案中，在步骤(3)中，各组分可同时加入，也可以先加入一部分组分，然后再加入剩余组分。此外，各组分的加入顺序不特别限制，例如可以最先加入冻干保护剂，也可以最后加入冻干保护剂。
在本申请的一些实施方案中，步骤(3)中所述的除菌过滤和冷冻干燥是本领域技术人员熟知且在该领域广泛应用的技术。
本申请的美西替康的药物组合物可以通过任何适当的途径向患者或受试者给药，例如静脉内给药、动脉内给药、肌肉给药、腹膜内给药、皮下给药、关节内给药、鞘内给药、侧脑室内给药、鼻腔喷雾、肺部吸入、口服给药以及本领域技术人员已知的其他合适的给药途径。可以利用本申请的美西替康的药物组合物治疗的组织病变包括但不限于膀胱、肝脏、肺部、肾脏、骨骼、软组织、肌肉、乳房等组织的病变。
相比于美西替康的乳液、微乳液或胶束制剂，本申请的美西替康的药物组合物的稳定性显著提高，易于储存和运输、且毒性明显降低。而且，更加意外地发现该药物组合物在体内特定的器官和组织集中分布，具有靶向性，增强了药物制剂的药效。另外，本申请的药物组合物还具有包封率高(＞99％)，在贮存过程中药物无渗漏且包封率不会降低；具有更好的重现性，易被复溶且复溶后粒径分布均匀、分散系数可以在0.18以下等优点。此外，本申请的美西替康的药物组合物的制备方法简便易操作，稳定可控，特别适合工业化生产。
本申请不限于本文所述的特定方法、方案和试剂，因为它们可变化。另外，本文使用的术语仅用于描述特定实施方案的目的而不旨在限制本申请的范围。除非文中明确指示，否则措辞“包含”和“包括”将解读为开放式的而不是封闭式的。
附图说明
图1：向大鼠静脉注射30mg/kg美西替康脂质体后，美西替康在体内的组织分布图。
图2：向大鼠静脉注射30mg/kg美西替康脂质体后，活性代谢产物SN38在体内的组织分布图。
图3：荧光标记物IR623和经IR623标记的美西替康脂质体在小鼠体内的分布图。
图4：荧光标记物IR623和经IR623标记的美西替康脂质体在小鼠肿瘤部位和各脏器的分布图
实施例
通过以下实施例示例性说明本申请的具体制备方法，但本申请的保护范围不局限于此，任何熟悉本技术领域的技术人员在本申请披露的技术范围内，根据本申请的技术方案及其发明构思进行的等同替换或改变都应涵盖在本申请的保护范围之内。
实施例1
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
无水乙醇 60g
蔗糖 60g
注射用水 加至1000g
制备工艺：将配方量的美西替康、蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱溶解于配方量的无水乙醇中，在60℃下加热溶解，作为有机相；取配制量的70％的注射用水，加热至60℃，作为水相；边剪切水相，边将有机相加入水相中，得到脂质体料液；将所得的脂质体料液经0.1μm聚碳酸酯膜挤出3次；加入配方量的蔗糖，再加注射用水稀释至1000g；分装至中性硼硅玻璃管制注射剂瓶(西林瓶)中后冷冻干燥即得。用超滤法测得包封率＞99％。
实施例2
配方：
15kg配制量 配方量
美西替康 30g
蛋黄磷脂酰胆碱 450g
氢化大豆磷脂酰胆碱 150g
无水乙醇 900g
蔗糖 900g
注射用水 加至15kg
制备工艺：将配方量的美西替康、蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱溶解于配方量的无水乙醇中，在60℃下加热溶解，作为有机相；取配制量的70％的注射用水，加热至60℃，作为水相；边剪切水相，边将有机相加入水相中，得到脂质体料液；将所得的脂质体料液经0.2μm聚碳酸酯膜挤出3次；加入配方量的蔗糖，再加注射用水稀释至15kg；分装至中性硼 硅玻璃管制注射剂瓶(西林瓶)中后冷冻干燥即得。用超滤法测得包封率＞99％。
实施例3
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
无水乙醇 60g
蔗糖 60g
注射用水 加至1000g
制备工艺：将配方量的美西替康、蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱溶解于配方量的无水乙醇中，在60℃下加热溶解，作为有机相；取配方量的蔗糖和配制量的70％的注射用水，在60℃下加热溶清后作为水相；边剪切或搅拌水相，边将有机相加入水相中，得到脂质体料液；将所得的脂质体料液经0.4μm聚碳酸酯膜挤出3次；再加注射用水稀释至1000g；分装至中性硼硅玻璃管制注射剂瓶(西林瓶)中后冷冻干燥即得。用超滤法测得包封率＞99％。
实施例4
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
无水乙醇 60g
蔗糖 40g
甘露醇 20g
注射用水 加至1000g
制备工艺：将配方量的美西替康、蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱溶解于配方量的无水乙醇中，在60℃下加热溶解，作为有机相；取配制量的70％的注射用水，加热至60℃，作为水相；边剪切或搅拌水相，边将有机相加入水相中，得到脂质体料液；将所得的脂质体料液经0.2μm聚碳酸酯膜挤出3次；加入配方量的蔗糖和甘露醇，再加注射用水稀释至1000g；分装至中性硼硅玻璃管制注射剂瓶(西林瓶)中后冷冻干燥即得。用超滤法测得包封率＞99％。
实施例5
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
BHT 0.1g
无水乙醇 60g
蔗糖 60g
注射用水 加至1000g
制备工艺：将配方量的BHT和美西替康溶解于配方量的无水乙醇中，在60℃下加热溶解，溶清后加入配方量的蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱，在60℃下加热溶解，溶清后作为有机相；取配制量的70％的注射用水，加热至60℃，作为水相；边剪切或搅拌水相，边将有机相加入水相中，得到脂质体料液；将所得的脂质体料液经0.2μm聚碳酸酯膜挤出可得具有一定粒径大小和一定粒径分布的脂质体料液；加入配方量的蔗糖，再加注射用水稀释至1000g；分装至中性硼硅玻璃管制注射剂瓶(西林瓶)中后冷冻干燥即得。用超滤法测得包封率＞99％。
实施例6
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
依地酸二钠 0.1g
无水乙醇 60g
蔗糖 60g
注射用水 加至1000g
制备工艺：将配方量的美西替康溶解于配方量的无水乙醇中，在60℃下加热溶解，溶清后加入配方量的蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱，在60℃下加热溶解，溶清后作为有机相；取配方量的依地酸二钠和配制量的70％的注射用水，在60℃下加热溶解，作为水相；边剪切或搅拌水相，边将有机相加入水相中，得到脂质体料液；将所得的脂质体料液经0.1μm聚碳酸酯膜挤出可得具有一定粒径大小和一定粒径分布的脂质体料液；加入配方量的蔗糖，再加注射用水稀释至1000g；分装至中性硼硅玻璃管制注射剂瓶(西林瓶)中后冷冻干燥即得。用超滤法测得包封率＞99％。
实施例7
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
盐酸或氢氧化钠 适量
无水乙醇 60g
蔗糖 60g
注射用水 加至1000g
制备工艺：将配方量的美西替康溶解于配方量的无水乙醇中，在60℃下加热溶解，溶清后加入配方量的蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱，在60℃下加热溶解，溶清后作为有机相；取配制量的70％的注射用水，60℃保温后作为水相；边剪切或搅拌水相，边将有机相加入水相中，得到脂质体料液；将所得的脂质体料液经0.2μm聚碳酸酯膜挤出可得具有一定粒径大小和一定粒径分布的脂质体料液；加入配方量的蔗糖，并加盐酸或氢氧化钠调节pH至5，再加注射用水稀释至1000g；分装至中性硼硅玻璃管制注射剂瓶(西林瓶)中后冷冻干燥即得。用超滤法测得包封率＞99％。
实施例8
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 22.5g
氢化大豆磷脂酰胆碱 7.5g
无水乙醇 60g
蔗糖 60g
注射用水 加至1000g
制备工艺：具体实施步骤同实施例2。用超滤法测得包封率＞99％。
实施例9
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 150g
氢化大豆磷脂酰胆碱 50g
无水乙醇 60g
蔗糖 60g
注射用水 加至1000g
制备工艺：具体实施步骤同实施例2。用超滤法测得包封率＞99％。
实施例10
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
无水乙醇 18g
蔗糖 60g
注射用水 加至1000g
制备工艺：具体实施步骤同实施例2。用超滤法测得包封率＞99％。
实施例11
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
无水乙醇 100g
蔗糖 60g
注射用水 加至1000g
制备工艺：具体实施步骤同实施例2。用超滤法测得包封率＞99％。
实施例12
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
胆固醇 10g
无水乙醇 18g
蔗糖 60g
注射用水 加至1000g
制备工艺：将配方量的美西替康、蛋黄磷脂酰胆碱和胆固醇溶解于配方量的无水乙醇中，在60℃下加热溶解，作为有机相；取配制量的70％的注射用水，加热至60℃，作为水相；边剪切水相，边将有机相加入水相中，得到脂质体料液；将所得的脂质体料液经0.2μm聚碳酸酯膜挤出3次；加入配方量的蔗糖，再加注射用水稀释至1000g；分装至中性硼硅玻璃管制 注射剂瓶(西林瓶)中后冷冻干燥即得。用超滤法测得包封率＞99％。
实施例13
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
胆固醇 15g
无水乙醇 18g
蔗糖 60g
注射用水 加至1000g
制备工艺：具体实施步骤同实施例12。用超滤法测得包封率＞99％。
实施例14
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
培化磷脂酰乙醇胺 0.5g
无水乙醇 18g
蔗糖 60g
注射用水 加至1000g
制备工艺：具体实施步骤同实施例2。用超滤法测得包封率＞99％。
实施例15
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
氢化大豆磷脂酰胆碱 10g
二硬脂酰基磷脂酰乙醇胺 1g
无水乙醇 18g
蔗糖 60g
注射用水 加至1000g
制备工艺：具体实施步骤同实施例2。用超滤法测得包封率＞99％。
实施例16
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 30g
胆固醇 10g
无水乙醇 18g
蔗糖 60g
注射用水 加至1000g
制备工艺：具体实施步骤同实施例12。用超滤法测得包封率＞99％。
实施例17
配方：
1kg配制量 配方量
美西替康 2g
蛋黄磷脂酰胆碱 20g
二棕榈酰磷脂酰胆碱 20g
无水乙醇 18g
蔗糖 60g
注射用水 加至1000g
制备工艺：具体实施步骤同实施例2。用超滤法测得包封率＞99％。
对比实施例1：胶束制剂1
1kg配制量 配方量
美西替康 2g
聚氧乙烯蓖麻油 30g
甘油 10g
无水乙醇 58g
制备工艺：取配方量的美西替康、聚氧乙烯蓖麻油、甘油和无水乙醇，于45℃水浴中加热溶清，溶清后除菌过滤，分装即得。
对比实施例2：乳剂
1kg配制量 配方量
美西替康 1g
维生素E 50g
F68(泊洛沙姆188) 20g
水 1000
无水乙醇 10g
制备工艺：①取配方量的美西替康、维生素E和无水乙醇加热溶清；②取配方量的F68和配方量的水溶清；③取②所得溶液的一半，边剪切边将①所得溶液加入其中，充分剪切后，将②所得溶液的另一半加入其中，剪切混匀；④将③所得溶液经高压均质处理10次，分装即得。
对比实施例3:胶束制剂2
1kg配制量 配方量
美西替康 5g
叔丁醇加至 1000g
制备工艺：取配方量的美西替康和叔丁醇，加热溶清后除菌过滤，分装冻干后可得美西替康粉末。
1kg配制量 配方量
ELP(蓖麻油聚烃氧酯(35)) 315g
甘油 105g
无水乙醇(药用级) 610g
制备工艺：取配方量的ELP、甘油和无水乙醇，混匀后除菌过滤，分装即得专用溶媒。
用法：用100倍量的专用溶媒溶解美西替康粉末后得到注射液，即可进行稀释用药。
实施例18：稳定性试验
按照实施例1-7和对比实施例1-3中的配方和制备工艺，制备含有美西替康的药物组合物10批。将每批样品置于40℃下保存15天，检测各样品中的性状和有关物质并与第0天检测结果进行比较，结果如下。
Figure PCTCN2016108841-appb-000002
实施例19：长期稳定性试验
按照实施例1-7的配方和制备工艺，制备含有美西替康的药物组合物7批，将每批药物组合物分别置于6℃和25℃条件下保存。在6℃下保存样品时分别于第3、6、9、12月取样检测有关物质，在25℃下保存样品时分别于第1、2、3、6月取样检测有关物质，并与第0天检测结果进行比较，结果如下：
Figure PCTCN2016108841-appb-000003
Figure PCTCN2016108841-appb-000004
实施例20：毒性试验
按照实施例2的配方和制备工艺，制备含有美西替康的药物组合物1批；按照对比实施例3的配方和制备工艺，制备含有美西替康的胶束制剂1批。将所得的2批药物制剂分别以相同的剂量在小鼠和大鼠身上进行了小鼠的急性毒性试验、大鼠的急性毒性试验和大鼠给药4周的毒性试验。并将两种药物制剂的毒性试验结果进行了对比，结果如下：
Figure PCTCN2016108841-appb-000005
Figure PCTCN2016108841-appb-000006
实施例21：药效试验
按照实施例2的配方和制备工艺，制备含有美西替康的药物组合物1批；按照对比实施例3的配方和制备工艺，制备含有美西替康的胶束制剂1批。将所得的2批药物在NCI-H292肺癌裸小鼠身上进行了药效试验，即对异种移植肿瘤生长的抑制作用。两种药物制剂的药效试验结果如下：
Figure PCTCN2016108841-appb-000007
实施例22：长毒试验
按照实施例2的配方和制备工艺，制备含有美西替康的药物组合物1批；按照对比实施例3的配方和制备工艺，制备含有美西替康的胶束制剂1批。将所得的2批药物在大鼠身上进行了长期毒性试验。大鼠的给药剂量分别为60、30和10mg/kg。将两种药物制剂的试验结果进行了对比，结果如下：
Figure PCTCN2016108841-appb-000008
实施例23：组织分布
按照实施例2的配方和制备工艺，制备含有美西替康的药物组合物1批。取SD大鼠18只，分为3组，每组6只，3雌3雄。向各组大鼠经尾静脉注射给予30mg/kg美西替康的药物组合物后，分别于给药后15min、2h和6h麻醉并采集血样和组织，血样和组织分别经处理后得到血浆和组织匀浆液样品，建立LC-MS/MS法以测定血浆和组织匀浆液中的美西替康及其活性代谢物SN-38(化学名：20(s)-7-乙基-10-羟基喜树碱)，结果见图1和图2。图1显示美西替康主要分布在直肠、肝、肺、血浆、结肠、肾、卵巢和心等器官中，图2显示SN-38主要分布在结肠、直肠、肝、肺、血浆、卵巢、空肠、回肠、十二指肠和肾等器官中。直肠中美西替康和SN-38浓度均非常高，而结肠中虽然美西替康浓度低于血浆，但是美西替康的活性代谢产物SN-38的浓度却最高，这表明本申请的药物组合物在体内特定的器官或组织中集中分布。美西替康和SN-38均在脑和睾丸中浓度最低。
实施例24：体内靶向性研究
按照实施例1的配方(需再加入约0.8％(w/w，以配方中的磷脂总量为100％计)的接有荧光探针IR623的DSPE(将其加入并溶解在有机相里))和制备工艺制备一批含有荧光探针(IR623)的美西替康药物组合物(粒径约100nm)。按照实施例3的配方(需再加入约0.8％(w/w，以配方中的磷脂总量为100％计)的接有荧光探针IR623的DSPE(将其加入并溶解在有机相里))和制备工艺制备一批含有荧光探针(IR623)的美西替康药物组合物(粒径约400nm)。两批药物组合物分别在HT29肠癌荷瘤裸小鼠身上采用近红外在体显影技术进行体内靶向性研究，并和荧光探针IR623的体内靶向性进行对比，结果见图3和图4。
结果显示：游离的荧光探针经尾静脉注射至体内后，0.5h时在腹部有明显的荧光信号。随着时间的推移，荧光信号逐渐减弱，并被代谢到体外(结果见图3)。注射了粒径为100nm的具有荧光探针的美西替康脂质体的小鼠，0.5h时全身遍布荧光信号，从4h开始荧光信号开始向肿瘤部位集中，8h时肿瘤部位的荧光信号强度最强，8h后肿瘤部位的荧光信号开始减弱，48h时肿瘤部位仍有荧光信号(结果见图3)。而注射了粒径为400nm的具有荧光探针的美西替康脂质体的小鼠，0.5h时在腹部有明显的荧光信号，4h的时候腹部荧光信号增强，而后荧光信号一直集中在腹部(结果见图3)。
在注射药物48h后，解剖荷瘤小鼠，取其体内各脏器(肿瘤、肝、脾、肾和肠)在活体成像仪中观察各脏器的荧光分布情况。从图4中，我们可以看到注射游离的荧光探针的小鼠的器官的荧光很弱，几乎代谢完全。在注射粒径为100nm的具有荧光探针的美西替康脂质体的小鼠的器官中，相比于其他器官，肿瘤有较强的荧光。而在注射粒径为400nm的具有荧光探针的美西替康脂质体的小鼠的器官中，肝脏的荧光是最强的。
从而可以推断，粒径为100nm的具有荧光探针的美西替康脂质体有被动的肿瘤靶向性，而粒径为400nm的具有荧光探针的美西替康脂质体主要是在肝脏蓄积。荧光探针主要是通过肠道及肾脏代谢排出体外。

Claims (9)

  1. 美西替康的药物组合物，其包含美西替康、磷脂或磷脂与胆固醇的混合物和冻干保护剂，其中所述美西替康、所述磷脂或所述磷脂与胆固醇的混合物和所述冻干保护剂之间的重量比为1-5:10-400:10-100；优选为2:30-200:20-60；更优选为2:40:60。
  2. 如权利要求1所述的药物组合物，其中所述磷脂选自蛋黄磷脂酰胆碱、氢化蛋黄磷脂酰胆碱、大豆磷脂酰胆碱、氢化大豆磷脂酰胆碱、双软脂酸磷脂酰胆碱、二癸酰基磷脂酰胆碱、二棕榈酰磷脂酰胆碱、磷酯酰丝氨酸、磷脂酰肌醇、磷脂酰乙醇胺、培化磷脂酰乙醇胺、磷脂酰甘油、磷脂酰胆碱、二鲸蜡磷酸酯、二肉豆蔻酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二油酰磷脂酰胆碱、二芥酰基磷脂酰胆碱、1-肉豆蔻酰基-2-棕榈酰基磷脂酰胆碱、1-棕榈酰基-2-硬脂酰基磷脂酰胆碱、1-棕榈酰基-2-肉豆蔻酰基磷脂酰胆碱、1-硬脂酰基-2-肉豆蔻酰基磷脂酰胆碱、1-硬脂酰基-2-棕榈酰基磷脂酰胆碱、1-肉豆蔻酰基-2-油酰基磷脂酰胆碱、1-棕榈酰基-2-油酰基磷脂酰胆碱、1-硬脂酰基-2-油酰基磷脂酰胆碱、二肉豆蔻酰基磷脂酰乙醇胺、二棕榈酰基磷脂酰乙醇胺、二硬脂酰基磷脂酰乙醇胺、二油酰基磷脂酰乙醇胺、二芥酰基磷脂酰乙醇胺或1-棕榈酰基-2-油酰基磷脂酰乙醇胺中的一种或多种；优选地，所述磷脂选自蛋黄磷脂酰胆碱、氢化蛋黄磷脂酰胆碱、大豆磷脂酰胆碱或氢化大豆磷脂酰胆碱中的一种或多种；更优选地，所述磷脂选自蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱的组合；还更优选地，所述磷脂选自蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱的组合，其中蛋黄磷脂酰胆碱与氢化大豆磷脂酰胆碱的重量比为3:1。
  3. 如权利要求1或2所述的药物组合物，其中所述冻干保护剂选自甘露醇、葡萄糖、半乳糖，蔗糖、乳糖、麦芽糖或海藻糖中的一种或多种；优选地，所述冻干保护剂选自蔗糖、海藻糖或甘露醇中的一种或多种；更优选地，所述冻干保护剂选自蔗糖或蔗糖与甘露醇的组合；还更优选地，所述冻干保护剂选自蔗糖或蔗糖与甘露醇的组合，其中蔗糖与甘露醇的重量比为2:1。
  4. 如权利要求1-3中任一项所述的药物组合物，其包含美西替康、磷脂和冻干保护剂，其中所述美西替康、所述磷脂和所述冻干保护剂之间的重量比为2:30-200:20-60，优选为2:40:60，所述磷脂选自蛋黄磷脂酰胆碱和氢化大豆磷脂酰胆碱的组合，其中蛋黄磷脂酰胆碱与氢化大豆磷脂酰胆碱的重量比为3:1，所述冻干保护剂选自蔗糖或蔗糖与甘露醇的组合，其中蔗糖与甘露醇的重量比为2:1。
  5. 如权利要求1-3中任一项所述的药物组合物，其中在所述磷脂与胆固醇的混合物中，所述磷脂与所述胆固醇的重量比为3:1或2:1。
  6. 如权利要求1-3中任一项所述的药物组合物，其包含美西替康、磷脂与胆固醇的混合 物和冻干保护剂，其中美西替康、磷脂与胆固醇的混合物和冻干保护剂之间的重量比为2:30-200:20-60，所述磷脂选自蛋黄磷脂酰胆碱，其中蛋黄磷脂酰胆碱与胆固醇的重量比为3:1或2:1，所述冻干保护剂选自蔗糖。
  7. 如权利要求1-6中任一项所述的药物组合物，其还包含抗氧化剂、金属离子螯合剂和/或pH调节剂，所述抗氧化剂选自亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、维生素C、抗坏血酸棕榈酸酯，叔丁基对羟基茴香醚、二叔丁基对甲酚、维生素E醋酸酯、半胱氨酸和蛋氨酸中的一种或多种，所述金属离子螯合剂选自依地酸二钠、依地酸钙钠、1,2-二氨基环己烷四乙酸、二乙三胺五乙酸、N-(2-羟乙基)-乙二胺三乙酸三钠或N-二(2-羟乙基)甘氨酸，以及所述pH调节剂选自盐酸、硫酸、乙酸、磷酸、枸橼酸、酒石酸、马来酸、氢氧化钠、碳酸氢钠、磷酸氢二钠、磷酸二氢钠或枸橼酸钠。
  8. 如权利要求1-7中任一项所述的药物组合物，其为固体形式，优选为经冷冻干燥法制得的固体，所述固体在用水或水性溶剂后复溶后，颗粒的粒径为50-400nm，优选为100-250nm。
  9. 权利要求1-8中任一项所述的药物组合物，其在冷冻干燥前为液体形式，其还包含有机溶剂和水，所述有机溶剂选自无水乙醇，95％的乙醇，甲醇、丙醇、叔丁醇，正丁醇、丙酮、甲基吡咯烷酮、乙酸乙酯、异丙醚或乙醚；优选地，所述有机溶剂选自无水乙醇、95％的乙醇或叔丁醇。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116803393A (zh) * 2023-08-24 2023-09-26 成都金瑞基业生物科技有限公司 一种pan-HER抑制剂的药物组合物及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071466A2 (en) * 2003-02-11 2004-08-26 Neopharm, Inc. Manufacturing process for liposomal preparations
CN101244039A (zh) * 2008-03-20 2008-08-20 江苏先声药物研究有限公司 一种制备难溶性药物脂质体制剂的新方法
CN101283983A (zh) * 2007-10-26 2008-10-15 南京长澳医药科技有限公司 一种稳定的喜树碱类药物脂质体组合物
CN101874788A (zh) * 2010-05-31 2010-11-03 沈阳药科大学 一种7-乙基-10-羟基喜树碱脂质体冻干粉针及其制备方法
CN102516258A (zh) * 2011-11-11 2012-06-27 南京美西宁医药科技有限责任公司 水溶性维生素e衍生物修饰的脂溶性抗癌药物化合物和制剂、该化合物的制备方法及应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071466A2 (en) * 2003-02-11 2004-08-26 Neopharm, Inc. Manufacturing process for liposomal preparations
CN101283983A (zh) * 2007-10-26 2008-10-15 南京长澳医药科技有限公司 一种稳定的喜树碱类药物脂质体组合物
CN101244039A (zh) * 2008-03-20 2008-08-20 江苏先声药物研究有限公司 一种制备难溶性药物脂质体制剂的新方法
CN101874788A (zh) * 2010-05-31 2010-11-03 沈阳药科大学 一种7-乙基-10-羟基喜树碱脂质体冻干粉针及其制备方法
CN102516258A (zh) * 2011-11-11 2012-06-27 南京美西宁医药科技有限责任公司 水溶性维生素e衍生物修饰的脂溶性抗癌药物化合物和制剂、该化合物的制备方法及应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116803393A (zh) * 2023-08-24 2023-09-26 成都金瑞基业生物科技有限公司 一种pan-HER抑制剂的药物组合物及其制备方法
CN116803393B (zh) * 2023-08-24 2023-11-21 成都金瑞基业生物科技有限公司 一种pan-HER抑制剂的药物组合物及其制备方法

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