WO2024083026A1 - 一种卢美哌隆药物组合物、长效微球缓释制剂及其制备方法 - Google Patents

一种卢美哌隆药物组合物、长效微球缓释制剂及其制备方法 Download PDF

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WO2024083026A1
WO2024083026A1 PCT/CN2023/124255 CN2023124255W WO2024083026A1 WO 2024083026 A1 WO2024083026 A1 WO 2024083026A1 CN 2023124255 W CN2023124255 W CN 2023124255W WO 2024083026 A1 WO2024083026 A1 WO 2024083026A1
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long
microspheres
lumepirone
release
acting
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PCT/CN2023/124255
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English (en)
French (fr)
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苏正兴
丁多浩
鲍菲
周苗苗
张晓航
赵栋
李明
张川
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四川科伦药物研究院有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention belongs to the field of pharmaceutical preparations, and relates to an antipsychotic sustained-release pharmaceutical preparation and a preparation method thereof, and in particular to a lumepirone pharmaceutical composition, a long-acting microsphere sustained-release preparation and a preparation method thereof.
  • Mental illness generally refers to psychological disorders, specifically, abnormal psychological processes, abnormal personality traits and abnormal behaviors caused by physiological, psychological or social reasons. It is a person's inability to act in a socially acceptable and appropriate manner, so that the consequences of his or her behavior are not suitable for himself or herself and society. For this reason, antipsychotic drugs are often used to treat or relieve the symptoms.
  • the representative drugs of the first-generation antipsychotics involved include chlorpromazine, perphenazine, haloperidol, penfluridol, etc., which can effectively relieve positive symptoms by blocking dopamine receptors, but are almost ineffective for negative symptoms and impaired cognitive function;
  • the representative drugs of the second-generation antipsychotics include risperidone, clozapine, olanzapine, aripiprazole, quetiapine, ziprasidone, etc., which can block dopamine receptors and 5-hydroxytryptamine receptors.
  • lumepirone can also act on the transmission of glutamine neurotransmitters, which not only improves the positive symptoms (delusions, hallucinations, abnormal behavior, etc.) of schizophrenia patients, but also negative symptoms (emotional flatness, poor speech, decreased will activity, etc.) and depressive symptoms.
  • glutamine neurotransmitters which not only improves the positive symptoms (delusions, hallucinations, abnormal behavior, etc.) of schizophrenia patients, but also negative symptoms (emotional flatness, poor speech, decreased will activity, etc.) and depressive symptoms.
  • second-generation antipsychotics compared with second-generation antipsychotics, lumepirone overcomes the shortcomings of weight gain and glucose and lipid metabolism disorders, and the chance of weight gain is reduced. Studies have shown that compared with the currently commonly used antipsychotic risperidone, lumepirone reduces the risk of weight gain by 13%.
  • the second-generation antipsychotic long-acting injection has been used as the first-line treatment for patients with schizophrenia in the acute and maintenance phases.
  • the second-generation antipsychotic long-acting injections that have been marketed in my country include: risperidone microspheres for injection once every 2 weeks, paliperidone palmitate injected once a month, and paliperidone palmitate injected once every 3 months, while the development of lumepirone long-acting sustained-release preparations is still in a blank stage.
  • Prior art CN113473988A and CN114072150A disclose that lumepirone in free form or in the form of a pharmaceutically acceptable salt can be administered by any suitable route, including oral, parenteral, transdermal or transmucosal, for example in the form of tablets, capsules, subcutaneous injections, long-acting injectables, or oral rapidly disintegrating tablets or films for sublingual or buccal administration.
  • the FDA specification states that the optimal oral dosage is 42 mg/day, and no dosage titration is required, which places stringent design requirements on the lumepirone long-acting sustained-release injection: it needs to have the characteristics of small burst release, stable and uniform release, which is also one of the biggest challenges of the lumepirone long-acting sustained-release injection at present.
  • the FDA specification states that the optimal oral dosage is 42 mg/day, and no dosage titration is required, which places stringent design requirements on the lumepirone long-acting sustained-release injection: it needs to have the characteristics of small burst release, stable and uniform release, which is also one of the biggest challenges of the lumepirone long-acting sustained-release injection at present.
  • the invention aims to overcome the deficiencies of the prior art and proposes a lumepirone pharmaceutical composition, a long-acting microsphere sustained-release preparation and a preparation method thereof.
  • a lumepirone pharmaceutical composition capable of long-acting sustained-release is obtained by specifically limiting the pharmaceutical polymer excipients; and, by further controlling the preparation process conditions, a long-acting microsphere sustained-release preparation is obtained, which can achieve a sustained-release of lumepirone for 1 week to 2 months, and can effectively improve the patient's compliance compared with general preparations (such as capsules); and, the preparation release is ensured to be stable to meet the safety and effectiveness of the drug.
  • the first aspect of the present invention provides: a lumepirone pharmaceutical composition, comprising a lumepirone active ingredient and a pharmaceutical polymer excipient, wherein the weight ratio of the lumepirone active ingredient to the pharmaceutical polymer excipient is 1: (1.5-19); wherein the pharmaceutical polymer excipient comprises a lumepirone active ingredient having a weight average molecular weight ( MW ) of 5000- 120000 daltons of glycolide-lactide copolymer (PLGA); in the glycolide-lactide copolymer, the molar ratio of lactic acid unit to glycolic acid unit is 95:5 to 50:50.
  • the present invention effectively controls the degradation rate of the glycolide-lactide copolymer and adjusts the sustained-release period, so that the lumepirone pharmaceutical composition of the present invention has the desired sustained-release effect.
  • the lumepirone active ingredient includes lumepirone free base and its available salt forms (such as lumepirone p-toluenesulfonate).
  • the weight average molecular weight (M W ) of the glycolide-lactide copolymer is 5,000 to 80,000 Daltons; more preferably, the weight average molecular weight (M W ) of the glycolide-lactide copolymer is 40,000 to 80,000 Daltons, such as 60,000 to 80,000 Daltons.
  • the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 50:50; more preferably, the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 75:25.
  • the weight ratio of lumiperone active ingredient to pharmaceutical polymer excipient is 1:(1.5-10); for example, 1:(1.5-9), 1:(2-8), 1:(2-6), 1:(3-5), more specifically 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9.
  • the second aspect of the present invention provides: a long-acting sustained-release preparation, which includes a lumepirone active ingredient and a pharmaceutical polymer excipient, wherein the lumepirone active ingredient accounts for 5 to 40% of the total weight of the long-acting sustained-release preparation, and the pharmaceutical polymer excipient accounts for 60 to 95% of the total weight of the long-acting sustained-release preparation; wherein the pharmaceutical polymer excipient includes a glycolide-lactide copolymer with a weight average molecular weight of 5,000 to 120,000 daltons; in the glycolide-lactide copolymer, the molar ratio of the lactic acid unit to the glycolic acid unit is 95:5 to 50:50.
  • the lumepirone active ingredient includes lumepirone free base and its available salt forms (such as lumepirone p-toluenesulfonate).
  • the weight average molecular weight (M W ) of the glycolide-lactide copolymer is 5,000 to 80,000 Daltons; more preferably, the weight average molecular weight (M W ) of the glycolide-lactide copolymer is 40,000 to 80,000 Daltons, such as 60,000 to 80,000 Daltons.
  • the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 50:50; more preferably, the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 75:25.
  • the weight ratio of the active ingredient of lumiperone to the pharmaceutical polymer excipient is 1:(1.5-19); more preferably, the weight ratio of the active ingredient of lumiperone to the pharmaceutical polymer excipient is 1:(1.5- 10); for example, 1:(1.5-9), 1:(2-8), 1:(2-6), 1:(3-5), more specifically 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9.
  • the long-acting sustained-release preparation is a long-acting sustained-release microgranule, which includes spherical particles and irregularly shaped particles with a particle size of 1 to 1000 ⁇ m.
  • the long-acting sustained-release microgranule prepared by microfluidics or homogenization emulsification is a spherical particle with a particle size of 20 to 200 ⁇ m, i.e., a long-acting microsphere sustained-release preparation.
  • the drug loading of the active ingredient of lumepirone can be 5-40%. More precisely, the drug loading of the active ingredient of lumepirone is 10-30%.
  • the third aspect of the present invention provides: a method for preparing a long-acting microsphere sustained-release preparation, which adopts a homogenizing emulsification technology and specifically comprises the following steps:
  • Preparation of aqueous phase Dissolve the surfactant in water to obtain an aqueous phase for later use;
  • Emulsification Take a certain volume of the aqueous phase obtained in step B1 as the external aqueous phase I; start high-speed shearing, add the oil phase obtained in step A1 to the external aqueous phase I, and continue shearing to obtain an incompletely solidified emulsion or suspension;
  • Solvent evaporation Take a certain volume of the aqueous phase obtained in step B1 as the external aqueous phase II; start stirring, place the incompletely solidified emulsion or suspension obtained in step C1 in the external aqueous phase II, and continue stirring until the solvent evaporates to obtain crude microspheres;
  • step D1 The crude microspheres obtained in step D1 are washed with pure water, the microspheres are collected by sieving, and dried to obtain a long-acting microsphere sustained-release preparation.
  • the method comprises the following steps:
  • A1 Preparation of the oil phase: dissolving the active ingredient (active drug) of lumepirone and the pharmaceutical polymer excipient (molecular skeleton) in an organic solvent, and completely dissolving them by stirring, vortexing or ultrasound to form a transparent solution, i.e., the oil phase, which is temporarily stored at 4 to 10° C. for later use;
  • Preparation of aqueous phase Dissolve the surfactant in water to obtain an aqueous phase, and store it at 4 to 10 ° C for later use;
  • Emulsification Take a certain volume of the water phase obtained in step B1, named as external water phase I (W1); start the high-speed shearing of the homogenizer (e.g., the rate is 1000-3000 rpm), slowly and evenly add the oil phase obtained in step A1 to the external water phase I, continue shearing, and finally, obtain an incompletely solidified Emulsion or suspension;
  • W1 external water phase I
  • start the high-speed shearing of the homogenizer e.g., the rate is 1000-3000 rpm
  • Solvent evaporation Take a certain volume of the aqueous phase obtained in step B1, named as external aqueous phase II (W2); start stirring (e.g., at a speed of 50 to 1000 rpm), place the incompletely solidified emulsion or suspension obtained in step C1 in the external aqueous phase II, and continue stirring at temperature T1 until the solvent evaporates to obtain crude microspheres;
  • W2 external aqueous phase II
  • step D1 The crude microspheres obtained in step D1 are washed with pure water, the microspheres are collected by sieving, and dried to obtain a long-acting microsphere sustained-release preparation.
  • the mass fraction of the active ingredient of lumepirone in the oil phase can be 2-15%
  • the concentration of the pharmaceutical polymer excipient in the oil phase can be 5-25%
  • the mass fraction of the surfactant in the water phase can be 0.5-5%, preferably, the mass fraction of the surfactant in the water phase can be 0.5-2%.
  • the organic solvent comprises one or a mixture of any two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, chloroform, ethyl ether, benzyl alcohol, N,N-dimethylformamide and N,N-dimethylacetamide.
  • the surfactant includes one or a mixture of any two or more of Pluronic F-127, sodium dodecyl sulfonate, sodium dodecyl sulfate and polyvinyl alcohol (PVA).
  • Pluronic F-127 sodium dodecyl sulfonate
  • sodium dodecyl sulfate sodium dodecyl sulfate
  • PVA polyvinyl alcohol
  • the volume ratio between the oil phase and the external aqueous phase I is 1:5 to 1:50. More preferably, the volume ratio between the oil phase and the external aqueous phase I is 1:10 to 1:20.
  • the volume ratio between the oil phase and the external aqueous phase II is 1:10 to 1:200. More preferably, the volume ratio between the oil phase and the external aqueous phase II is 1:10 to 1:100.
  • step D1 is performed at a temperature T1 of 0 to 40°C, wherein the temperature T1 may be a constant temperature or a temperature gradient within the range. More preferably, the temperature T1 is 3 to 30°C.
  • the fourth aspect of the present invention provides: a method for preparing a long-acting microsphere sustained-release preparation, which adopts microfluidic technology and specifically comprises the following steps:
  • step A2 and part of the water phase obtained in step B2 are respectively injected into the microfluidic device by using a syringe pump, and the flow rate of the oil phase and the flow rate of the water phase are controlled to finally obtain an oil-in-water emulsion, and the mixture is collected.
  • D2 solvent evaporation The semi-cured microspheres obtained in step C2 in the receiver are placed in a evaporator and stirred continuously until the solvent evaporates to obtain fully cured microspheres;
  • step D2 The fully solidified microspheres obtained in step D2 are washed with pure water, the microspheres are collected by sieving, and dried to obtain a long-acting microsphere sustained-release preparation.
  • the method comprises the following steps:
  • Preparation of the oil phase dissolving the active ingredient (active drug) of lumepirone and the pharmaceutical polymer excipient (molecular skeleton) in an organic solvent, and completely dissolving them by stirring, vortexing or ultrasound to form a transparent solution, i.e., the oil phase, which is temporarily stored at 4 to 10° C. for later use;
  • Preparation of aqueous phase dissolve the surfactant in water to obtain an aqueous phase, and store it at 4-10°C for later use;
  • the oil phase (i.e., dispersed phase) obtained in step A2 and part of the aqueous phase (i.e., continuous phase) obtained in step B2 are respectively injected into the microfluidic device by using a syringe pump, and the flow rate of the oil phase and the flow rate of the aqueous phase are controlled. Finally, an oil-in-water emulsion is obtained, which is collected and temporarily stored in a receiver containing part of the aqueous phase obtained in step B2 to obtain semi-solidified microspheres;
  • D2 solvent evaporation The semi-cured microspheres obtained in step C2 of the receiver are placed in a evaporator and stirred continuously at a temperature T2 until the solvent evaporates to obtain fully cured microspheres;
  • step D2 The fully solidified microspheres obtained in step D2 are washed with pure water, the microspheres are collected by sieving, and dried to obtain a long-acting microsphere sustained-release preparation.
  • the mass fraction of the active ingredient of lumepirone in the oil phase can be 2-15%
  • the concentration (mass fraction) of the pharmaceutical polymer excipient in the oil phase can be 5-25%
  • the mass fraction of the surfactant in the water phase can be 0.5-5%; preferably, the mass fraction of the surfactant in the water phase can be 0.5-2%.
  • the organic solvent comprises one or a mixture of any two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, chloroform, ether, benzyl alcohol, N,N-dimethylformamide and N,N-dimethylacetamide.
  • the surfactant includes one or a mixture of any two or more of Pluronic F-127, sodium dodecyl sulfonate, sodium dodecyl sulfate and polyvinyl alcohol (PVA).
  • Pluronic F-127 sodium dodecyl sulfonate
  • sodium dodecyl sulfate sodium dodecyl sulfate
  • PVA polyvinyl alcohol
  • the temperature in the microfluidic device is controlled to be 4-10°C to ensure The oil-in-water emulsion is effectively formed, and semi-solidified microspheres are formed in the receiver.
  • the flow rate ratio between the oil phase and the water phase is controlled to be 1:2 to 1:200. More preferably, the flow rate ratio between the oil phase and the water phase is 1:10 to 1:100.
  • step D2 is performed at a temperature T2 of 3 to 40°C, and the temperature T2 may be a constant temperature or a temperature gradient within the range. More preferably, the temperature T2 is 3 to 35°C.
  • Lumidoperone active ingredient refers to lumepirone free base or its available salt form.
  • Available salt forms refers to pharmaceutically acceptable salts of lumepirone free base, such as, but not limited to, hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, citrate, acetate, oxalate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
  • hydrochloride sulfate, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, cit
  • Drug loading refers to the amount of drug loaded per unit weight or per unit volume of microspheres, of which the amount of drug that can be released is the effective drug loading. Except for the irreversible binding of the drug to the matrix, the drug loading can be regarded as the drug content of the microspheres.
  • Encapsulation rate refers to the percentage of the encapsulated substance (such as a drug) in the total drug input, reflecting the degree to which the drug is encapsulated by the carrier.
  • the present invention obtains a lumepirone pharmaceutical composition by specifically limiting the pharmaceutical polymer excipients; and further controls the preparation process conditions to obtain a long-acting sustained-release preparation, especially a long-acting sustained-release microsphere, which can achieve a sustained release of lumepirone for 1 week to 2 months, and can effectively improve the patient's compliance compared with general preparations (such as capsules); and ensure that the preparation releases smoothly to meet the safety and effectiveness of the drug;
  • the present invention provides a method for preparing a long-acting microsphere sustained-release preparation based on homogenization emulsification technology.
  • the prepared long-acting microsphere sustained-release preparation can achieve a stable sustained release of 1 week to 2 months compared with general oral preparations, effectively improving patient compliance and improving clinical treatment effects;
  • the present invention is based on microfluidic technology to prepare microspheres with uniform size and good morphology.
  • microfluidic Lumepiride Long microspheres are closer to zero-order release and have a smooth release, meeting the requirements of drug safety and efficacy and solving the problem of unstable release of homogeneous emulsified microspheres.
  • FIG1 is a schematic diagram of the structure of the lumepirone long-acting sustained-release microspheres of the present invention (left: lumepirone long-acting sustained-release microspheres prepared by microfluidics; right: lumepirone long-acting sustained-release microspheres prepared by homogenization emulsification);
  • FIG2 is the result of in vitro release test of the lumepirone long-acting sustained-release microspheres obtained in Example 2-4;
  • FIG3 is the result of in vitro release test of the lumepirone long-acting sustained-release microspheres obtained in Example 5-7;
  • FIG. 4 shows the results of in vitro release testing of the lumepirone long-acting sustained-release microspheres obtained in Examples 8-10.
  • FIG5 is a SEM image of the lumepirone long-acting sustained-release microspheres obtained in Example 17.
  • FIG6 is a cross-sectional SEM image of the lumepirone long-acting sustained-release microspheres obtained in Example 17.
  • FIG. 7 shows the in vivo release results of the lumepirone long-acting sustained-release microspheres obtained in Examples 14, 15, 17 and 18 in mice.
  • FIG8 shows the in vivo release results of the lumepirone long-acting sustained-release microspheres obtained in Examples 16 and 19-21 in mice.
  • This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing lumepirone drugs, and the preparation method comprises the following steps:
  • step 4 taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and volatilizing at 4° C. for 2 h, then raising the temperature to 25° C., stirring and volatilizing for 2 h, and obtaining microspheres;
  • step 5) filtering the microspheres obtained in step 4) through a sieve, washing, collecting, and drying to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release test, and the actual drug loading of the microspheres was found to be 16.34%, and the encapsulation rate was 81.7%.
  • This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing lumepirone drugs, and the preparation method comprises the following steps:
  • step 4 taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and volatilizing at 4° C. for 2 h, then raising the temperature to 25° C., stirring and volatilizing for 2 h, and obtaining microspheres;
  • step 5) filtering the microspheres obtained in step 4) through a sieve, washing, collecting, and drying to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release test, and the actual drug loading of the microspheres was found to be 16.02%, and the encapsulation rate was 80.1%.
  • This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing lumepirone drugs, and the preparation method comprises the following steps:
  • step 4 taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and volatilizing at 10° C. for 2 h, then raising the temperature to 25° C., stirring and volatilizing for 2 h, and obtaining microspheres;
  • step 5) filtering the microspheres obtained in step 4) through a sieve, washing, collecting, and drying to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG2 .
  • This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing lumepirone drugs, and the preparation method comprises the following steps:
  • step 4 taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and volatilizing at 10° C. for 2 h, then raising the temperature to 25° C., stirring and volatilizing for 2 h, and obtaining microspheres;
  • step 5) filtering the microspheres obtained in step 4) through a sieve, washing, collecting, and drying to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG2 .
  • This embodiment adopts microfluidic technology to prepare a long-acting sustained-release microsphere containing lumepirone drugs, and the preparation method comprises the following steps:
  • step 4) After the receiver is full, the semi-cured microspheres obtained in step 3) are transferred to the volatilizer and stirred; the temperature control program is started (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours), and the organic solvent is evaporated to obtain fully cured microspheres;
  • step 5) washing the fully solidified microspheres obtained in step 4) with pure water, filtering, collecting the finished wet microspheres, and drying to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG3 .
  • This embodiment uses microfluidics technology to prepare a long-acting sustained-release microsphere containing lumepirone drugs.
  • the preparation method comprises the following steps:
  • step 4) After the receiver is full, the semi-cured microspheres obtained in step 3) are transferred to the volatilizer and stirred; the temperature control program is started (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours), and the organic solvent is evaporated to obtain fully cured microspheres;
  • step 5) Washing the fully solidified microspheres obtained in step 4) with pure water, filtering, collecting the finished wet microspheres, and freeze-drying to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG3 .
  • This embodiment adopts microfluidic technology to prepare a long-acting sustained-release microsphere containing lumepirone drugs, and the preparation method comprises the following steps:
  • step 4) After the receiver is full, transfer the semi-cured microspheres obtained in step 3) into the evaporator and start stirring; start the temperature control program (4°C for 1 hour, 15°C for 1 hour, 25°C for 2 hours) to evaporate the organic Solvent to obtain fully cured microspheres;
  • step 5) Washing the fully solidified microspheres obtained in step 4) with pure water, filtering, collecting the finished wet microspheres, and drying to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG3 .
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG4 .
  • PLGA with a molecular weight of 49,000 was selected, and then homogenization emulsification technology was used, and the rest was the same as in Example 3 to prepare lumepirone long-acting sustained-release microspheres.
  • the discussion on low molecular weight screening of PLGA was achieved, and this technical solution was further explained.
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG4 .
  • PLGA with a molecular weight of 116,000 was selected, and then homogenization emulsification technology was used, and the rest was the same as in Example 3 to prepare lumepirone long-acting sustained-release microspheres.
  • the discussion on high molecular weight screening of PLGA was achieved, and this technical solution was further explained.
  • the obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG4 .
  • the amount of lumepirone added is 0.11 g, and then the homogenization emulsification technology is used, and the rest is the same as in Example 3 to prepare lumepirone long-acting sustained-release microspheres.
  • the discussion of low feed amount screening is further illustrated by this technical solution.
  • the feeding amount of lumepirone is 1.39 g, and then the homogenization emulsification technology is used, and the rest is the same as in Example 3 to prepare lumepirone long-acting sustained-release microspheres.
  • the discussion on the high feeding amount screening of PLGA is realized, and this technical solution is further explained.
  • This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing lumepirone active ingredient.
  • the preparation method comprises the following steps:
  • step 4 taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the crude emulsion obtained in step 3) into the external aqueous phase II, stirring and volatilizing at 4° C. for 2 h, then raising the temperature to 25° C., stirring and volatilizing for 2 h, and obtaining microspheres;
  • step 4) The microspheres obtained in step 4) are filtered through a sieve, washed, collected, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release tablet containing the active ingredient of lumepirone.
  • the preparation method comprises the following steps:
  • step 4 taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and volatilizing at 4° C. for 2 h, then raising the temperature to 25° C., stirring and volatilizing for 2 h, and obtaining microspheres;
  • step 4) The microspheres obtained in step 4) are washed and collected through a sieve, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing lumepirone active ingredient.
  • the preparation method comprises the following steps:
  • step 4) taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring continuously at 10° C., raising the temperature to 25° C., and stirring continuously to obtain microspheres;
  • step 5) washing and collecting the microspheres obtained in step 4) through a sieve, and drying them to obtain finished microspheres, That is, lumepirone long-acting sustained-release microspheres.
  • This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing lumepirone active ingredient.
  • the preparation method comprises the following steps:
  • step 4 taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and volatilizing at 10° C. for 2 h, then raising the temperature to 25° C., stirring and volatilizing for 2 h, and obtaining microspheres;
  • step 4) The microspheres obtained in step 4) are washed and collected through a sieve, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing lumepirone active ingredient.
  • the preparation method comprises the following steps:
  • step 4) transferring the crude emulsion obtained in step 3) into a evaporator and starting stirring; starting a temperature control program (4° C. for 1 h, 15° C. for 1 h, and 25° C. for 2 h), evaporating the organic solvent to obtain fully cured microspheres;
  • step 5) Washing the fully solidified microspheres obtained in step 4) with pure water, filtering, collecting the finished wet microspheres, and drying to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • This embodiment adopts homogenization emulsification technology to propose a method for preparing long-acting sustained-release microspheres containing lumepirone active ingredient, comprising the following steps:
  • step 4) transferring the crude emulsion obtained in step 3) into a evaporator and starting stirring; starting a temperature control program (4° C. for 1 h, 15° C. for 1 h, and 25° C. for 2 h), evaporating the organic solvent to obtain fully cured microspheres;
  • step 5) Washing the fully solidified microspheres obtained in step 4) with pure water, filtering, collecting the finished wet microspheres, and drying to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.
  • freeze drying or vacuum drying may be used, wherein the freeze drying procedures involved are shown in Table 1.
  • FIG4 it can be seen that: in the preparation process of lumepirone long-acting sustained-release microspheres, there is little difference between the ester-terminated PLGA and the carboxyl-terminated PLGA, and the PLGA molecular weight has a greater influence on the release.
  • the sustained-release period and release curve of the lumepirone long-acting sustained-release microspheres can be adjusted, and finally, a microsphere preparation that meets clinical needs can be prepared;
  • the lumepirone microspheres of Examples 14-21 were selected for animal experiments. A number of male rats weighing about 250 g were selected and randomly divided into groups of 5 rats each. The samples were mixed with a solvent (0.5% CMC-Na, 0.1% Tween-20, 0.9% NaCl) and mixed evenly. The drugs of Examples 14-18 and 21 were intramuscularly injected at 10.5 mg/kg, and the drugs of Examples 19 and 20 were intramuscularly injected at 21 mg/kg. Venous blood was collected before and after administration to determine the concentration of lumepirone in plasma after administration.
  • the present invention has achieved a long-acting sustained-release effect ranging from 12 days to 63 days, and the burst release is good, with almost no hysteresis period, and the blood drug concentration curve is normally distributed.
  • microspheres of the present invention are round in shape, evenly distributed, and compact inside.

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Abstract

本发明公开了含卢美哌隆活性成分的组合物、长效缓释制剂及其制备方法，属于药物制剂领域。通过对药用高分子辅料的特别限定，得到一种能长效缓释的含卢美哌隆活性成分的组合物；以及，再对制备工艺条件做进一步控制，得到一种含卢美哌隆活性成分的长效缓释制剂，实现卢美哌隆为1周～2月缓释，相比于一般制剂(如：胶囊剂)，能有效改善患者的顺应性；以及，在保证药物安全和有效性的前提下，同时满足药物平稳释放的临床需求。

Description

一种卢美哌隆药物组合物、长效微球缓释制剂及其制备方法 技术领域
本发明属于药物制剂领域，涉及抗精神病类缓释药物制剂及其制备方法，尤其涉及一种卢美哌隆药物组合物、长效微球缓释制剂及其制备方法。
背景技术
精神病一般指心理障碍，具体是指一个人由于生理、心理或社会原因而导致的各种异常心理过程、异常人格特征的异常行为方式，是一个人表现为没有能力按照社会认可的适宜方式行动，以致其行为的后果对本人和社会都是不适应的。为此，常采用抗精神病药来治疗或者缓解该症状。
其中，涉及的第一代抗精神病药的代表药物有氯丙嗪、奋乃静、氟哌啶醇、五氟利多等，通过阻断多巴胺受体，有效缓解阳性症状，但对阴性症状及认知功能受损几乎无效；第二代抗精神病药的代表药物有利培酮、氯氮平、奥氮平、阿立哌唑、喹硫平、齐拉西酮等，可阻断多巴胺受体和5‐羟色胺受体，与大多数第一代药物相比，锥体外系不良反应发生率较低，但大部分的第二代药物会导致体重增加和糖脂代谢紊乱(发胖)；近两年，公开一种多靶点作用的新型抗精神病药——卢美哌隆，CAS号：313368‐91‐1，英文名称：ITI‐722或Lumateperone，于2019年12月被批准在美国上市，用于成人精神分裂症的治疗。不同于第一代和第二代抗精神病药，其一般只针对5‐羟色胺和多巴胺两种神经递质，卢美哌隆还能作用于谷氨酰胺神经递质的传递，这使其不仅能改善精神分裂症患者的阳性症状(妄想、幻觉、行为异常等)，对阴性症状(情感平淡、言语贫乏、意志活动减退等)及抑郁症状也有效。此外，相较于第二代抗精神病药物，卢美哌隆克服了体重增加和糖脂代谢紊乱的缺点，发生体重增加的几率减少。研究显示，卢美哌隆和目前常用的抗精神病药利培酮相比，体重增加的风险降低了13％。
目前，对于已有的抗精神病药的用药情况，患者不能坚持规律地用药是导致疾病复发的主要原因之一。临床试验证实，已有的抗精神病药长效针剂相比于口服抗精神病药可显著降低患者的住院率、治疗中断率，是预防复发的重要治疗方法。每隔一段时间打一次针，患者平常不用担心忘记服药，减 轻每天的负担，而且生活工作中不用担心服药被别人发现，有效保护自己隐私，另外也可以防止药物滥用。当下，第二代抗精神病药长效针剂已作为急性期和维持期精神分裂症患者的一线治疗用药，我国已上市的第二代抗精神病药长效针剂有：每2周注射1次注射用利培酮微球、每月注射1次的棕榈酸帕利哌酮和每3个月注射1次的棕榈帕利哌酮酯，而卢美哌隆长效缓释制剂的开发尚处于空白阶段。
现有技术CN113473988A、CN114072150A中公开：游离形式或可药用盐形式的卢美哌隆可以通过任意适宜的途径施用，包括口服、胃肠外、经皮或经粘膜，例如以片剂、胶囊剂、皮下注射、长效可注射或用于舌下或颊施用的口服快速崩解片或膜的形式。就剂量和效果而言，FDA说明书指出口服的最佳剂量为42mg/天，不需要剂量滴定，这对卢美哌隆长效缓释注射剂提出了苛刻的设计要求：需要具有突释小、释放稳定且均匀的特点，这也是卢美哌隆长效缓释注射剂目前最大的挑战之一。目前尚无专利或论文文献公开有效的卢美哌隆长效缓释注射剂的制备方法。
因此，开发突释小、释放平稳的卢美哌隆长效制剂，以充分发挥卢美哌隆在抗精神病领域的临床优势(如：克服体重增加和糖脂代谢紊乱的缺点，提高安全性；能同时改善精神分裂症患者的阳性、阴性症状(情感平淡、言语贫乏、意志活动减退等)及抑郁症状)，成为急需解决的技术问题。
发明概述
旨在克服现有技术的不足，提出一种卢美哌隆药物组合物、长效微球缓释制剂及其制备方法。在本技术方案中，通过对药用高分子辅料的特别限定，得到一种能长效缓释的卢美哌隆药物组合物；以及，再对制备工艺条件做进一步控制，得到一种长效微球缓释制剂，实现卢美哌隆为1周～2月缓释，相比于一般制剂(如：胶囊剂)，能有效改善患者的顺应性；以及，保证制剂释放平稳，满足药物的安全性和有效性。
为了实现上述技术目的，提出如下的技术方案：
本发明第一方面提供：一种卢美哌隆药物组合物，其包括卢美哌隆活性成分和药用高分子辅料，卢美哌隆活性成分与药用高分子辅料的重量配比为1：(1.5～19)；其中，药用高分子辅料包括重均分子量(MW)为5000～ 120000道尔顿的乙交酯丙交酯共聚物(PLGA)；在乙交酯丙交酯共聚物中，乳酸单元和羟基乙酸单元的摩尔比为95:5～50:50。本发明通过有效控制乙交酯丙交酯共聚物的降解速率，调节缓释周期，从而使本发明的卢美哌隆药物组合物具有期望的缓释效果。
进一步地，所述卢美哌隆活性成分包括卢美哌隆游离碱及其可用盐型(如：对甲苯磺酸卢美哌隆)。
作为优选，所述乙交酯丙交酯共聚物的重均分子量(MW)为5000～80000道尔顿；更优选地，所述乙交酯丙交酯共聚物的重均分子量(MW)为40000～80000道尔顿，例如60000～80000道尔顿。
作为优选，在乙交酯丙交酯共聚物中，乳酸单元和羟基乙酸单元的摩尔比为85:15～50:50；更优选地，乳酸单元和羟基乙酸单元的摩尔比为85:15～75:25。
作为优选，卢美哌隆活性成分与药用高分子辅料的重量配比为1：(1.5-10)；例如1：(1.5-9)、1：(2-8)、1：(2-6)、1：(3-5)，更具体地为1:1.5、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9。
本发明第二方面提供：一种长效缓释制剂，其包括卢美哌隆活性成分和药用高分子辅料，卢美哌隆活性成分占长效缓释制剂总重量的5～40％，药用高分子辅料占长效缓释制剂总重量的60～95％；其中，药用高分子辅料包括重均分子量为5000～120000道尔顿的乙交酯丙交酯共聚物；在乙交酯丙交酯共聚物中，乳酸单元和羟基乙酸单元的摩尔比为95:5～50:50。
进一步地，所述卢美哌隆活性成分包括卢美哌隆游离碱及其可用盐型(如：对甲苯磺酸卢美哌隆)。
作为优选，所述乙交酯丙交酯共聚物的重均分子量(MW)为5000～80000道尔顿；更优选地，所述乙交酯丙交酯共聚物的重均分子量(MW)为40000～80000道尔顿，例如60000～80000道尔顿。
作为优选，在乙交酯丙交酯共聚物中，乳酸单元和羟基乙酸单元的摩尔比为85:15～50:50；更优选地，乳酸单元和羟基乙酸单元的摩尔比为85:15～75:25。
作为优选，卢美哌隆活性成分与药用高分子辅料的重量配比为1：(1.5～19)；更优选地，卢美哌隆活性成分与药用高分子辅料的重量配比为1：(1.5- 10)；例如1：(1.5-9)、1：(2-8)、1：(2-6)、1：(3-5)，更具体地为1:1.5、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9。
进一步地，所述长效缓释制剂为长效缓释微颗粒剂，长效缓释微颗粒剂包括粒径为1～1000μm的球形颗粒和不规则形状颗粒。作为优选，采用微流控法或均质乳化法，制备的长效缓释微颗粒剂为粒径20～200μm的球形颗粒，即长效微球缓释制剂。
对于长效微球缓释制剂，可实现卢美哌隆活性成分载药量为5～40％。更为精准的，卢美哌隆活性成分载药量为10～30％。
本发明第三方面提供：一种长效微球缓释制剂的制备方法，其采用均质乳化技术，具体包括如下步骤：
A1.油相的制备：将卢美哌隆活性成分和药用高分子辅料溶于有机溶剂中，得油相，备用；
B1.水相的制备：将表面活性剂溶于水中，得水相，备用；
C1.乳化：取一定体积的步骤B1所得的水相，作为外水相I；开启高速剪切，将步骤A1所得的油相加入至外水相I中，持续剪切，得未完全固化的乳液或悬浮液；
D1.溶剂挥发：取一定体积的步骤B1所得的水相，作为外水相II；开启搅拌，将步骤C1所得的未完全固化的乳液或悬浮液置于外水相II中，持续搅拌，至溶剂挥发结束，得到粗制微球；
E1.后处理：将步骤D1所得的粗制微球用纯水洗涤，过筛收集微球，干燥，即得长效微球缓释制剂。
优选地，所述方法包括如下步骤：
A1.油相的制备：将卢美哌隆活性成分(活性药物)和药用高分子辅料(分子骨架)溶于有机溶剂中，通过搅拌、涡旋或超声等方法使其完全溶解，形成透明溶液，即油相，暂存于4～10℃条件下，备用；
B1.水相的制备：将表面活性剂溶于水中，得水相，暂存于4～10℃条件下，备用；
C1.乳化：取一定体积的步骤B1所得的水相，命名为外水相Ⅰ(W1)；开启均质乳化机的高速(如：速率为1000～3000rpm)剪切，将步骤A1所得的油相缓慢而匀速加入至外水相Ⅰ中，持续剪切，最终，得到未完全固化的 乳液或悬浮液；
D1.溶剂挥发：取一定体积的步骤B1所得的水相，命名为外水相Ⅱ(W2)；开启搅拌(如：转速在50～1000rpm)，将步骤C1所得的未完全固化的乳液或悬浮液置于外水相Ⅱ中，在温度T1下持续搅拌，至溶剂挥发结束，得到粗制微球；
E1.后处理：将步骤D1所得的粗制微球用纯水洗涤，过筛收集微球，干燥，即得长效微球缓释制剂。
其中，根据设计目标，所述卢美哌隆活性成分在油相中的质量分数可为2～15％；药用高分子辅料在油相中的浓度可为5～25％。表面活性剂在水相中的质量分数为0.5～5％；优选地，表面活性剂在水相中的质量分数可为0.5～2％。
作为优选，在步骤A1中，所述有机溶剂包括二氯甲烷、二甲亚砜、甲醇、乙酸乙酯、三氯甲烷、乙醚、苯甲醇、N,N‐二甲基甲酰胺及N,N‐二甲基乙酰胺中的一种或任意两种以上的混合物。
作为优选，在步骤B1中，所述表面活性剂包括Pluronic F‐127、十二烷基磺酸钠、十二烷基硫酸钠及聚乙烯醇(PVA)中的一种或任意两种以上的混合物。
作为优选，在步骤C1中，油相与外水相Ⅰ之间的体积比为1:5～1:50。更优选地，油相与外水相Ⅰ之间的体积比为1:10～1:20。
作为优选，在步骤D1中，油相与外水相Ⅱ之间的体积比为1:10～1:200。更优选，油相与外水相Ⅱ之间的体积比为1:10～1:100。
作为优选，步骤D1是在0～40℃的温度T1下进行，其中温度T1可以为恒温，也可以为在该范围内的温度梯度。更优选，温度T1为3～30℃。
本发明第四方面提供：一种长效微球缓释制剂的制备方法，其采用微流控技术，具体包括如下步骤：
A2.油相的制备：将卢美哌隆活性成分和药用高分子辅料溶于有机溶剂中，得油相，备用；
B2.水相的制备：将表面活性剂溶于水中，得水相，备用；
C2.将步骤A2所得的油相和步骤B2所得的部分水相分别用注射泵注入至微流控装置中，控制油相流速与水相流速，最终得到水包油乳液，收集， 暂存于盛有步骤B2所得的部分水相的接收器中，得半固化微球；
D2.溶剂挥发：将接收器中步骤C2所得的半固化微球置于挥发器中，持续搅拌，至溶剂挥发结束，得到全固化微球；
E2.后处理：将步骤D2所得的全固化微球用纯水洗涤，过筛收集微球，干燥，即得长效微球缓释制剂。
优选地，所述方法包括如下步骤：
A2.油相的制备：将卢美哌隆活性成分(活性药物)和药用高分子辅料(分子骨架)溶于有机溶剂中，通过搅拌、涡旋或超声等方法使其完全溶解，形成透明溶液，即油相，暂存于4～10℃条件下，备用；
B2：水相的制备：将表面活性剂溶于水中，得水相，暂存于4～10℃条件下，备用；
C2.将步骤A2所得的油相(即分散相)和步骤B2所得的部分水相(即连续相)分别用注射泵注入至微流控装置中，控制油相流速和水相流速，最终，得到水包油乳液，收集后，暂存于盛有步骤B2所得的部分水相的接收器中，得半固化微球；
D2.溶剂挥发：将接收器中步骤C2所得的半固化微球置于挥发器中，在温度T2下持续搅拌，至溶剂挥发结束，得到全固化微球；
E2.后处理：将步骤D2所得的全固化微球用纯水洗涤，过筛收集微球，干燥，即得长效微球缓释制剂。
其中，根据设计目标，所述卢美哌隆活性成分在油相中的质量分数可为2～15％，药用高分子辅料在油相中的浓度(质量分数)可为5～25％。表面活性剂在水相中的质量分数为0.5～5％；优选地，表面活性剂在水相中的质量分数可为0.5～2％。
作为优选，在步骤A2中，所述有机溶剂包括二氯甲烷、二甲亚砜、甲醇、乙酸乙酯、三氯甲烷、乙醚、苯甲醇、N,N‐二甲基甲酰胺及N,N‐二甲基乙酰胺中的一种或任意两种以上的混合物。
作为优选，在步骤B2中，所述表面活性剂包括Pluronic F‐127、十二烷基磺酸钠、十二烷基硫酸钠及聚乙烯醇(PVA)中的一种或任意两种以上的混合物。
作为优选，在步骤C2中，控制微流控装置内温度为4～10℃，以保证有 效地形成水包油乳液，以及，再在接收器中形成半固化微球。
作为优选，在步骤C2中，控制油相与水相之间的流速比为1:2～1:200。更优选，所述油相与水相之间的流速比为1:10～1:100。
作为优选，步骤D2在3～40℃的温度T2下进行，温度T2可以为恒温，也可以为在该范围内的温度梯度。更优选，温度T2为3～35℃。
在本文中，涉及的术语包括：
卢美哌隆活性成分：指卢美哌隆游离碱或其可用盐型。
可用盐型：指卢美哌隆游离碱的药学上可接受的盐，例如但不限于盐酸盐、硫酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、柠檬酸盐、乙酸盐、草酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和扑酸盐。
载药量：指单位重量或单位体积微球所负载的药量，其中能释放的药量为有效载药量。除药物与基质发生不可逆结合外，载药量可看成是微球的含药量。
包封率：是指被包裹物质(如某药物)占药物总投料量的百分比，反映了药物被载体包封的程度。
采用本发明，带来的有益技术效果为：
一、本发明通过对药用高分子辅料的特别限定，得到一种卢美哌隆药物组合物；以及，再对制备工艺条件做进一步控制，得到一种长效缓释制剂，特别是长效缓释微球，可实现卢美哌隆为1周～2月缓释，相比于一般制剂(如：胶囊剂)，能有效改善患者的顺应性；以及，保证制剂释放平稳，满足药物的安全性和有效性；
二、本发明基于均质乳化技术，提供一种适应于长效微球缓释制剂制备的方法，制备的长效微球缓释制剂，较一般口服制剂而言，实现1周～2月的平稳缓释，有效改善患者顺应性，提高临床治疗效果；
三、本发明基于微流控技术，制备尺寸均一、形貌良好的微球，通过控制油相与水相之间的流速比、控制微流控装置内条件等，保证微流控卢美哌 隆微球更接近于零级释放，且释放平稳，满足了药物安全性和有效性的要求，解决了均质乳化微球释放不稳定的问题。
附图说明
图1为本发明的卢美哌隆长效缓释微球的结构示意图(左：为采用微流控法制备的卢美哌隆长效缓释微球；右：为采用均质乳化法制备的卢美哌隆长效缓释微球)；
图2为对实施例2‐4所得的卢美哌隆长效缓释微球进行体外释放检测的结果；
图3为对实施例5‐7所得的卢美哌隆长效缓释微球进行体外释放检测的结果；
图4为对实施例8‐10所得的卢美哌隆长效缓释微球进行体外释放检测的结果。
图5为实施例17所得的卢美哌隆长效缓释微球的SEM图。
图6为实施例17所得的卢美哌隆长效缓释微球的剖面SEM图。
图7为实施例14、15、17和18所得的卢美哌隆长效缓释微球的小鼠体内释放结果。
图8为实施例16、19-21所得的卢美哌隆长效缓释微球的小鼠体内释放结果。
实施例
以下通过实施例对本发明做进一步阐述。本发明的实施例仅用于说明本发明的技术方案，并非用于限定本发明的范围，本领域技术人员可在不违背本发明的精神的情况下进行一些非本质的改进和调整，仍属于本发明的保护范围。
实施例1
本实施例采用均质乳化技术，制得一种含卢美哌隆类药的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝95:5，分子量78000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下 备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)取90mL水相作为外水相Ⅰ，开启均质乳化机的高速剪切，控制转速为2000rpm；将油相转移到20mL注射器中，使用注射泵匀速(0.3mL/s)地将油相打入外水相Ⅰ中，整个过程约30s；持续剪切至180s，乳化结束，得悬浮液；
4)取540mL水相作为外水相Ⅱ，开启搅拌；将步骤3)所得的悬浮液倒入外水相Ⅱ，在4℃下持续搅拌挥发2h，随后，将温度升至25℃，持续搅拌挥发2h，得微球；
5)将步骤4)所得的所得的微球经筛网过滤、洗涤、收集，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，将所得的该卢美哌隆长效缓释微球进行体外释放检测，得出微球实际载药量为16.34％，包封率81.7％。
实施例2
本实施例采用均质乳化技术，制得一种含卢美哌隆类药的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝50:50，分子量61000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)取90mL水相作为外水相Ⅰ，开启均质乳化机的高速剪切，控制转速为2000rpm；将油相转移到20mL注射器中，使用注射泵匀速(0.3mL/s)地将油相打入外水相Ⅰ中，整个过程约30s；持续剪切至180s，乳化结束，得悬浮液；
4)取540mL水相作为外水相Ⅱ，开启搅拌；将步骤3)所得的悬浮液倒入外水相Ⅱ，在4℃下持续搅拌挥发2h，随后，将温度升至25℃，持续搅拌挥发2h，得微球；
5)将步骤4)所得的所得的微球经筛网过滤、洗涤、收集，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，将所得的该卢美哌隆长效缓释微球进行体外释放检测，得出微球实际载药量为16.02％，包封率80.1％。
实施例3
本实施例采用均质乳化技术，制得一种含卢美哌隆类药的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝75:25，分子量74000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)取90mL水相作为外水相Ⅰ，开启均质乳化机，控制转速为2000rpm；将油相转移到20mL注射器中，使用注射泵匀速(0.3mL/s)地将油相打入外水相Ⅰ中，整个过程约30s；持续剪切至180s，乳化结束，得悬浮液；
4)取540mL水相作为外水相Ⅱ，开启搅拌；将步骤3)所得的悬浮液倒入外水相Ⅱ，在10℃下持续搅拌挥发2h，随后，将温度升至25℃，持续搅拌挥发2h，得微球；
5)将步骤4)所得的所得的微球经筛网过滤、洗涤、收集，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为16.46％，包封率82.3％。将所得的该卢美哌隆长效缓释微球进行体外释放检测，所得结果如图2所示。
实施例4
本实施例采用均质乳化技术，制得一种含卢美哌隆类药的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝85:15，分子量72000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)取90mL水相作为外水相Ⅰ，开启均质乳化机，控制转速为2000rpm；将油相转移到20mL注射器中，使用注射泵匀速(0.3mL/s)地将油相打入外 水相Ⅰ中，整个过程约30s；持续剪切至180s，乳化结束，得悬浮液；
4)取540mL水相作为外水相Ⅱ，开启搅拌；将步骤3)所得的悬浮液倒入外水相Ⅱ，在10℃下持续搅拌挥发2h，随后，将温度升至25℃，持续搅拌挥发2h，得微球；
5)将步骤4)所得的所得的微球经筛网过滤、洗涤、收集，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为16.69％，包封率83.4％。将所得的该卢美哌隆长效缓释微球进行体外释放检测，所得结果如图2所示。
实施例5
本实施例采用微流控技术，制得一种含卢美哌隆类药的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝50:50，分子量61000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)将油相(分散相)流体和水相(连续相)流体分别用注射泵注入微流控装置中，调节油相流速为100μL/h，水相流速为2000μL/h，通过在微流控装置中连续相将分散相剪切，得到水包油乳液，收集，得半固化微球；置于盛有水相的接收器中，全程温度控制在10℃；
4)待接收器收满后，将步骤3)所得的半固化微球转入挥发器中，开启搅拌；启动控温程序(4℃持续1h，15℃持续1h，25℃持续2h)，挥干有机溶剂，得到全固化微球；
5)将步骤4)所得的全固化微球用纯水洗涤，过滤，收集成品湿微球，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为18.75％，包封率93.7％。将所得的该卢美哌隆长效缓释微球进行体外释放检测，所得结果如图3所示。
实施例6
本实施例采用微流控技术，制得一种含卢美哌隆类药的长效缓释微球， 该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝75:25，分子量74000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)将油相(分散相)流体和水相(连续相)流体分别用注射泵注入微流控装置中，调节油相流速为100μL/h，水相流速为2000μL/h，通过在微流控装置中连续相将分散相剪切，得到水包油乳液，收集，得半固化微球；置于盛有水相的接收器中，全程温度控制10℃；
4)待接收器收满后，将步骤3)所得的半固化微球转入挥发器中，开启搅拌；启动控温程序(4℃持续1h，15℃持续1h，25℃持续2h)，挥干有机溶剂，得到全固化微球；
5)将步骤4)所得的全固化微球用纯水洗涤，过滤，收集成品湿微球，冻干后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为19.30％，包封96.5％。将所得的该卢美哌隆长效缓释微球进行体外释放检测，所得结果如图3所示。
实施例7
本实施例采用微流控技术，制得一种含卢美哌隆类药的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝85:15，分子量72000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)将油相(分散相)流体和水相(连续相)流体分别用注射泵注入微流控装置中，调节油相流速为100μL/h，水相流速为2000μL/h，通过在微流控装置中连续相将分散相剪切，得到水包油乳液，收集，得半固化微球；置于盛有水相的接收器中，全程温度控制10℃；
4)待接收器收满后，将步骤3)所得的半固化微球转入挥发器中，开启搅拌；启动控温程序(4℃持续1h，15℃持续1h，25℃持续2h)，挥干有机 溶剂，得到全固化微球；
5)将步骤4)所得的全固化微球用纯水洗涤，过滤，收集成品湿微球，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为18.98％，包封94.9％。将所得的该卢美哌隆长效缓释微球进行体外释放检测，所得结果如图3所示。
实施例8
本实施例选用以酯基封端、分子量为74000的PLGA，然后采用均质乳化技术，其余同实施例3，用于制备卢美哌隆长效缓释微球。以此，实现对PLGA端基筛选的讨论，以本技术方案做进一步的说明。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为18.92％，包封94.6％。将所得的该卢美哌隆长效缓释微球进行体外释放检测，所得结果如图4所示。
实施例9
本实施例选用分子量为49000的PLGA，然后采用均质乳化技术，其余同实施例3，用于制备卢美哌隆长效缓释微球。以此，实现对PLGA的低分子量筛选的讨论，以本技术方案做进一步的说明。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为19.42％，包封97.1％。将所得的该卢美哌隆长效缓释微球进行体外释放检测，所得结果如图4所示。
实施例10
本实施例选用分子量为116000的PLGA，然后采用均质乳化技术，其余同实施例3，用于制备卢美哌隆长效缓释微球。以此，实现对PLGA的高分子量筛选的讨论，以本技术方案做进一步的说明。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为18.04％，包封率90.2％。将所得的该卢美哌隆长效缓释微球进行体外释放检测，所得结果如图4所示。
实施例11
在本实施例中，卢美哌隆的投料量为0.11g，然后采用均质乳化技术，其余同实施例3，用于制备卢美哌隆长效缓释微球。以此，实现对卢美哌隆 的低投料量筛选的讨论，以本技术方案做进一步的说明。
其中，卢美哌隆长效缓释微球的理论载药量约为0.11/(0.11+2.08)＝5％，得出微球实际载药量为4.76％，包封率95.2％。
实施例12
在本实施例中，卢美哌隆的投料量为1.39g，然后采用均质乳化技术，其余同实施例3，用于制备卢美哌隆长效缓释微球。以此，实现对PLGA的高投料量筛选的讨论，以本技术方案做进一步的说明。
其中，卢美哌隆长效缓释微球的理论载药量约为1.39/(1.39+2.08)＝40％，得出微球实际载药量为30.48％，包封率76.2％。
实施例13
本实施例采用均质乳化技术，制得一种含卢美哌隆活性成分的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝95:5，分子量42000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)取90mL水相作为外水相Ⅰ，开启均质乳化机的高速剪切，控制转速为1500rpm；将油相转移到10mL注射器中，使用注射泵匀速(0.3mL/s)地将油相打入外水相Ⅰ中，整个过程约30s；持续剪切至180s，乳化结束，得到粗乳液；
4)取540mL水相作为外水相Ⅱ，开启搅拌；将步骤3)所得的粗乳液倒入外水相Ⅱ，在4℃下持续搅拌挥发2h，随后，将温度升至25℃，持续搅拌挥发2h，得微球；
5)将步骤4)所得的微球经筛网过滤、洗涤、收集，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为16.61％，包封率83.05％，粒径：65.590μm，Span：0.766。
实施例14
本实施例采用均质乳化技术，制得一种含卢美哌隆活性成分的长效缓 释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝50:50，分子量28000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)取90mL水相作为外水相Ⅰ，开启均质乳化机的高速剪切，控制转速为2000rpm；将油相转移到10mL注射器中，使用注射泵匀速(0.3mL/s)地将油相打入外水相Ⅰ中，整个过程约30s；持续剪切至180s，乳化结束，得悬浮液；
4)取540mL水相作为外水相Ⅱ，开启搅拌；将步骤3)所得的悬浮液倒入外水相Ⅱ，在4℃下持续搅拌挥发2h，随后，将温度升至25℃，持续搅拌挥发2h，得微球；
5)将步骤4)所得的微球经筛网洗涤、收集，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为17.89％，包封率89.45％。
实施例15
本实施例采用均质乳化技术，制得一种含卢美哌隆活性成分的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝75:25，分子量74000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)取90mL水相作为外水相Ⅰ，开启均质乳化机，控制转速为2000rpm；将油相转移到10mL注射器中，使用注射泵匀速(0.3mL/s)地将油相打入外水相Ⅰ中；持续剪切，乳化结束得悬浮液；
4)取540mL水相作为外水相Ⅱ，开启搅拌；将步骤3)所得的悬浮液倒入外水相Ⅱ，在10℃下持续搅拌后，将温度升至25℃，持续搅拌，得微球；
5)将步骤4)所得的微球经筛网洗涤、收集，干燥后，得到微球成品， 即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为17.09％，包封率85.47％。
实施例16
本实施例采用均质乳化技术，制得一种含卢美哌隆活性成分的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝85:15，分子量42000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)取90mL水相作为外水相Ⅰ，开启均质乳化机，控制转速为2000rpm；将油相转移到10mL注射器中，使用注射泵匀速(0.3mL/s)地将油相打入外水相Ⅰ中，整个过程约30s；持续剪切至180s，乳化结束，得悬浮液；
4)取540mL水相作为外水相Ⅱ，开启搅拌；将步骤3)所得的悬浮液倒入外水相Ⅱ，在10℃下持续搅拌挥发2h，随后，将温度升至25℃，持续搅拌挥发2h，得微球；
5)将步骤4)所得的微球经筛网洗涤、收集，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为17.65％，包封率88.26％。
实施例17
本实施例采用均质乳化技术，制得一种含卢美哌隆活性成分的长效缓释微球，该制备方法包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝75:25，分子量51000，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)将油相(分散相)流体和水相(连续相)流体分别用注射泵注入乳化装置中，调节油相流速为18mL/min，水相流速为540mL/min，通过在作为乳化装置的在线剪切机中油相被剪切，得到粗乳液；
4)将步骤3)所得的粗乳液转入挥发器中，开启搅拌；启动控温程序(4℃持续1h，15℃持续1h，25℃持续2h)，挥干有机溶剂，得到全固化微球；
5)将步骤4)所得的全固化微球用纯水洗涤，过滤，收集成品湿微球，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为17.51％，包封率87.53％。
实施例18
本实施例采用均质乳化技术，提出一种含卢美哌隆活性成分的长效缓释微球的制备方法，包括以下步骤：
1)称取0.52g卢美哌隆和2.08g PLGA(LA:GA＝75:25，分子量27500，羧基封端)，加入11.8g二氯甲烷溶解，得到澄澈的油相溶液，在10℃条件下备用；
2)配制0.5wt％的PVA水溶液，为水相，在10℃条件下备用；
3)将油相(分散相)流体和水相(连续相)流体分别用注射泵注入乳化装置中，调节油相流速为18mL/min，水相流速为540mL/min，通过在作为乳化装置的在线剪切机中油相被剪切，得到粗乳液；
4)将步骤3)所得的粗乳液转入挥发器中，开启搅拌；启动控温程序(4℃持续1h，15℃持续1h，25℃持续2h)，挥干有机溶剂，得到全固化微球；
5)将步骤4)所得的全固化微球用纯水洗涤，过滤，收集成品湿微球，干燥后，得到微球成品，即卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.52/(0.52+2.08)＝20％，得出微球实际载药量为18.18％，包封率90.89％。
实施例19
本实施例选用以酯基封端、分子量为41000的PLGA(LA:GA＝85：15)，按照0.26g卢美哌隆和2.34g PLGA称量原辅料，其余同实施例15，用于制备卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.26g/(0.26g+2.34)＝10％，得出微球实际载药量为9.06％，包封率90.6％。
实施例20
本实施例选用以酯基封端、分子量为103000的PLGA(LA:GA＝85：15)，按照0.13g卢美哌隆和2.47g PLGA称量原辅料，然后采用均质乳化技术，其余同实施例15，用于制备卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为0.13/(0.13+2.47)＝5％，得出微球实际载药量为4.585％，包封率91.7％。
实施例21
本实施例选用以酯基封端、分子量为43000的PLGA(LA:GA＝85：15)，按照1.04g卢美哌隆和1.56g PLGA称量原辅料，然后采用均质乳化技术，其余同实施例15，用于制备卢美哌隆长效缓释微球。
其中，卢美哌隆长效缓释微球的理论载药量为1.04/(1.04+1.56)＝40％，得出微球实际载药量为31.28％，包封率78.2％。
实施例22
在实施例1‐21的干燥工序中，具体可采用冷冻干燥或真空干燥，其中，涉及的冷冻干燥程序如表1所示。
表1
试验例1
本试验例将经实施例1‐12所制备的卢美哌隆长效缓释微球进行体外释放检测【根据中华人民共和国药典(P.473)的规定】，以对本发明做进一 步的说明。具体包括：
一、配制0.01mol/L生理等渗磷酸盐缓冲溶液，pH 7.4，其中，含有0.05％泊洛沙姆和0.05％叠氮化钠)；
二、精密称取经实施例1‐12所制备的卢美哌隆长效缓释微球，置于试管中，加至30mL的生理等渗磷酸盐缓冲溶液中，置于37℃的恒温摇床培养；
三、分别取样，将样品过滤后，采用HPLC‐UV法，分别测样品液介质中活性药物含量。
结论：
1)从本发明的实施例可知：由于微流控技术本身的特点(药物和辅料均在微通道内形成微球)，除了溶出和少量损失，活性药物几乎没有损耗，所以，微流控法较均质乳化法制备卢美哌隆长效缓释微球的包封率要高；
2)根据图2‐4，可知：采用本方案提供的均质乳化法和微流控法，可制备得缓释1～6周的卢美哌隆长效缓释微球，其中，通过微流控法制备的产品具有尺寸均一、形貌良好(如图1)、突释低、释放稳定的特点。通过对工艺条件参数的控制，可以制备得到符合突释小、释放平稳的卢美哌隆缓释微球制剂；
3)根据图4，可知：在卢美哌隆长效缓释微球制备过程中，选用酯基封端的PLGA与羧基封端的PLGA的差别不大，PLGA分子量对释放有较大影响。通过特别限定PLGA分子量，可以调整卢美哌隆长效缓释微球的缓释周期和释放曲线，最终，以制备符合临床需求的微球制剂；
4)在对活性成分卢美哌隆高(40％的理论载药量)和低(5％的理论载药量)投料量的筛选实验中，发现：低投料量，虽然能保证较高的包封率，但是制剂中PLGA含量过高，这意味着临床实践时固体总量增加，将引起疼痛感；而高投料量，会对制剂产生不良的影响，包封率降低，且一定程度影响释放行为。
试验例2
选择实施例14-21的卢美哌隆微球进行动物实验。筛选体重在250g左右雄性大鼠若干，随机分组，每组5只，将样品与溶媒(0.5％CMC-Na，0.1％吐温-20，0.9％NaCl)混合均匀。实施例14-18和实施例21肌内注射给予10.5mg/kg药物，实施例19和20肌内注射给予21mg/kg药物，均给药 一次。分别于给药前和给药后静脉采血，测定给药后血浆中卢美哌隆浓度。
从图7和图8可以看出，本发明已实现从12天到63天不等的长效缓释效果，且突释情况良好，几乎无迟滞期，血药浓度曲线呈正态分布。
从图5和图6可以看出本发明所述微球形态圆整，分布均匀，内部紧实。

Claims (12)

  1. 一种卢美哌隆药物组合物，其特征在于，其包括卢美哌隆活性成分和药用高分子辅料，所述卢美哌隆活性成分与所述药用高分子辅料的重量配比为1：(1.5～19)；其中，所述药用高分子辅料包括重均分子量为5000～120000道尔顿的乙交酯丙交酯共聚物；在所述乙交酯丙交酯共聚物中，乳酸单元和羟基乙酸单元的摩尔比为95:5～50:50。
  2. 根据权利要求1所述的卢美哌隆药物组合物，其特征在于，所述卢美哌隆活性成分包括卢美哌隆游离碱及其可用盐型。
  3. 根据权利要求1所述的卢美哌隆药物组合物，其特征在于，所述乙交酯丙交酯共聚物的重均分子量为5000～80000道尔顿；在所述乙交酯丙交酯共聚物中，所述乳酸单元和所述羟基乙酸单元的摩尔比为85:15～50:50。
  4. 一种长效微球缓释制剂，其特征在于，所述长效微球缓释制剂包括卢美哌隆活性成分和药用高分子辅料，所述卢美哌隆活性成分占所述长效微球缓释制剂总重量的5～40％，所述药用高分子辅料占所述长效微球缓释制剂总重量的60～95％；其中，所述药用高分子辅料包括重均分子量为5000～120000道尔顿的乙交酯丙交酯共聚物；在所述乙交酯丙交酯共聚物中，乳酸单元和羟基乙酸单元的摩尔比为95:5～50:50；
    所述长效微球缓释制剂采用微流控法或均质乳化法制备而成，所述长效微球缓释制剂为粒径20～200μm的球形颗粒。
  5. 根据权利要求4所述的长效微球缓释制剂，其特征在于，所述卢美哌隆活性成分包括卢美哌隆游离碱及其可用盐型。
  6. 根据权利要求4所述的长效微球缓释制剂，其特征在于，所述乙交酯丙交酯共聚物的重均分子量为5000～80000道尔顿；在所述乙交酯丙交酯共聚物中，所述乳酸单元和所述羟基乙酸单元的摩尔比为85:15～50:50。
  7. 一种根据权利要求4‐6中任意一项所述的长效微球缓释制剂的制备方法，其特征在于，所述方法采用均质乳化法，包括如下步骤：
    A1.油相的制备：将所述卢美哌隆活性成分和所述药用高分子辅料溶于有机溶剂中，得油相，备用；
    B1.水相的制备：将表面活性剂溶于水中，得水相，备用；
    C1.乳化：取一定体积的步骤B1所得的所述水相，为外水相I；开启高速剪切，将步骤A1所得的所述油相加入至所述外水相I中，持续剪切，得未完全固化的乳液或悬浮液；
    其中，所述油相与所述外水相I之间的体积比为1:5～1:50；
    D1.溶剂挥发：取一定体积的步骤B1所得的所述水相，为外水相II；开启搅拌，将步骤C1所得的所述未完全固化的乳液或悬浮液置于所述外水相II中，持续搅拌，至溶剂挥发结束，得到粗制微球；
    其中，所述油相与所述外水相II之间的体积比为1:10～1:200；
    E1.后处理：将步骤D1所得的所述粗制微球用纯水洗涤，过筛收集微球，干燥，即得所述长效微球缓释制剂。
  8. 根据权利要求7所述的长效微球缓释制剂的制备方法，其特征在于，在步骤A1中，所述有机溶剂包括二氯甲烷、二甲亚砜、甲醇、乙酸乙酯、三氯甲烷、乙醚、苯甲醇、N,N‐二甲基甲酰胺及N,N‐二甲基乙酰胺中的一种或任意两种以上的混合物。
  9. 根据权利要求7所述的长效微球缓释制剂的制备方法，其特征在于，在步骤B1中，所述表面活性剂包括Pluronic F‐127、十二烷基磺酸钠、十二烷基硫酸钠及聚乙烯醇中的一种或任意两种以上的混合物。
  10. 一种根据权利要求4‐6中任意一项所述的长效微球缓释制剂的制备方法，其特征在于，所述方法采用微流控法，包括如下步骤：
    A2.油相的制备：将所述卢美哌隆活性成分和所述药用高分子辅料溶于有机溶剂中，得油相，备用；
    B2.水相的制备：将表面活性剂溶于水中，得水相，备用；
    C2.将步骤A2所得的所述油相和步骤B2所得的部分水相分别用注射泵注入至微流控装置中，控制所述油相与所述水相之间的流速比为1:2～1:200，控制所述微流控装置内温度为4～10℃，得到水包油乳液，收集，暂存于盛有步骤B2所得的部分水相的接收器中，得半固化微球；
    D2.溶剂挥发：将所述接收器中步骤C2所得的所述半固化微球置于挥发器中，持续搅拌，至溶剂挥发结束，得到全固化微球；
    E2.后处理：将步骤D2所得所得的所述全固化微球用纯水洗涤，过筛收集微球，干燥，即得所述长效微球缓释制剂。
  11. 根据权利要求10所述的长效微球缓释制剂的制备方法，其特征在于，在步骤A2中，所述有机溶剂包括二氯甲烷、二甲亚砜、甲醇、乙酸乙酯、三氯甲烷、乙醚、苯甲醇、N,N‐二甲基甲酰胺及N,N‐二甲基乙酰胺中的一种或任意两种以上的混合物。
  12. 根据权利要求10所述的长效微球缓释制剂的制备方法，其特征在于，在步骤B2中，所述表面活性剂包括Pluronic F‐127、十二烷基磺酸钠、十二烷基硫酸钠及聚乙烯醇(PVA)中的一种或任意两种以上的混合物。
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