HK1185560B - Risperidone sustained release microsphere composition - Google Patents

Description

Risperidone sustained-release microsphere composition

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to a risperidone long-acting slow-release microsphere composition, a preparation method and application thereof.

Background

Schizophrenia is a serious, disabling mental disorder. With the increasing social competition, the accelerated pace of life and the change of family structure, people are under greater and greater pressure, and as a result, the mental and health problems are increasingly highlighted. Schizophrenia is the most common disease among psychiatric diseases. According to statistics, the prevalence rate of the schizophrenia in China is 6.55 per thousand, namely more than 780 ten thousand of schizophrenia patients, and the global morbidity is as high as 1.5%.

Antipsychotics, also known as nerve blockers, are effective in controlling the psychotic symptoms of schizophrenia. The main pharmacological effect of common antipsychotics, such as chlorpromazine or haloperidol, found as early as 50 in the 20 th century was the blockade of central dopamine D₂The receptor is effective to positive psychotic symptoms, but can cause extrapyramidal dyskinesia, is ineffective to negative symptoms and cognitive function impairment, is accompanied by a plurality of adverse reactions, has high toxicity to heart vessels and livers and large dosage of the drug, and has obvious side effects. To overcome the above-mentioned drawbacks, since the 80 s of the 20 th century, new antipsychotics were developed, which have a main pharmacological action of blocking 5-HT_2AAnd D₂A receptor. The advantages of the novel antipsychotic drugs are not only reflected in the treatment of acute episodes in psychotic patients, but also in the treatment of extrapyramidal symptoms and tardive dyskinesia, with few side effects and without the need to co-administer anticholinergic drugs; the tolerance and compliance of treatment are better; has strong therapeutic effect on improving positive and negative symptoms and cognitive function, and has little or no adverse reaction of extrapyramidal system (EPS) and no endocrine adverse reaction caused by prolactin level increase.

Risperidone, a representative of novel antipsychotic drugs, was developed in 1984 by the pharmaceutical company of poplar, belgium, and has a chemical name of 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) -1-piperidinyl ] ethyl ] -6,7,8, 9-tetrahydro-2-methyl-4H-pyrido [1,2- α ] pyrimidin-4-one, which has good therapeutic effects on both positive and negative symptoms of schizophrenia, and has a low incidence of extrapyramidal adverse reactions. The metabolite of risperidone, 9-hydroxy risperidone (paliperidone), has similar pharmacological actions as risperidone, and both constitute the antipsychotic active ingredient.

The clinically common dosage forms of risperidone include tablets, oral solutions, capsules, orally disintegrating tablets and the like. For the common dosage form of risperidone, it is usually necessary to take the drug every day, which is difficult for about 75% of psychiatric patients. This is also an important factor in the deterioration of the disease during the course of treatment.

To solve such problems, researchers have actively developed a risperidone long-acting sustained-release formulation. For example, CN1137756, the entire contents of which is incorporated herein by reference, has disclosed a risperidone sustained release microsphere composition made using a polymer matrix material having a molecular weight of 100,000 to 300,000. Risperidal Consta (Chinese name: Hengde), a long-acting antipsychotic drug developed based on the CN1137756 technology, was marketed in 8 months in 2002. The product is prepared by encapsulating risperidone in poly (lactide-co-glycolide) (PLGA) with a molecular weight of 150,000, suspending in solution, and administering by intramuscular injection once every 2 weeks, thereby effectively avoiding peak-to-valley concentrations of daily administration. However, the preparation only releases a small amount of drug in the first day, and then has a drug release lag phase after 3 weeks, and most of the drug is released in the 4 th to 6 th weeks along with the degradation of the microsphere skeleton [ chenqinghua, chengang and the like, the pharmacokinetic characteristics and clinical application of risperidone long-acting injection, china new medicine journal, 2006, 15 (15): 1235-1238]. Therefore, patients need to rely on oral risperidone tablets to achieve treatment effect while injecting the drug in the first 3 weeks, and as a result, clinical use is inconvenient and patient compliance is poor.

Chen nationality et al reported that a risperidone microsphere composition prepared from PLGA (50: 50, molecular weight 30,000) with a drug loading of 18% could maintain a stable blood drug level in vivo for 5-20 days [ Chen nationality, Tangjun et al, research on risperidone biodegradable microspheres, proceedings of Chinese pharmaceutical university, 2006, 37 (6): 512-515]. However, the microsphere composition has low drug loading and is accompanied by a burst release phenomenon when the drug loading is low.

CN101653422, which is incorporated herein by reference in its entirety, has disclosed a risperidone microsphere composition that can cause sustained release for more than 4 weeks, eliminating the drug release lag phase by increasing the drug loading (more than 45%), thereby fundamentally solving the burst release problem. However, the patent application CN101653422 only verifies that the laboratory level (5L scale) can achieve the intended purpose. The applicant of the present invention has found that the risperidone microspheres provided in CN101653422 have drug crystallization during the production process in a proportional scale-up manner, and the preparation stability is poor, and the in vivo release behavior of the microspheres can be changed obviously after long-term storage.

As is well known, the large-scale industrial production is always the bottleneck of the industrialization of the microsphere preparation, and therefore, the provision of a risperidone microsphere preparation with stable quality and suitable for large-scale industrial production is urgently needed.

Disclosure of Invention

The invention provides a pharmaceutical microsphere composition, which comprises an active ingredient and an uncapped lactide-glycolide copolymer, wherein the active ingredient is selected from risperidone or a salt thereof and 9-hydroxy risperidone or a salt thereof; the non-terminated lactide-glycolide copolymer consists of two copolymers; the weight content of the active ingredients in the pharmaceutical composition is 10-60%, preferably 35-55%, and more preferably 40-50%; the weight content of the non-terminated lactide-glycolide copolymer in the pharmaceutical composition is 40-90%, preferably 45-65%, and more preferably 50-60%.

The microsphere disclosed by the invention refers to small spherical or spheroidal particles formed by uniformly dissolving and/or dispersing drugs in a high polymer material, has the particle size ranging from 1 to 500 mu m, and is usually prepared into a suspension for injection.

Lactide-glycolide copolymers, also known as polyglycolide, are often abbreviated as PLGA. The term "non-end-capped lactide-glycolide copolymer" as used herein refers to a lactide-glycolide copolymer having a carboxyl end group, abbreviated herein as PLGA.

Two copolymers, two PLGAs, are a first high intrinsic viscosity non-end-capped PLGA and a second low intrinsic viscosity non-end-capped PLGA, the high intrinsic viscosity being 0.4 to 0.9dl/g, preferably 0.45 to 0.8dl/g, more preferably 0.45 to 0.55 dl/g; the low intrinsic viscosity is 0.1 to 0.35dl/g, preferably 0.1 to 0.3dl/g, and more preferably 0.2 to 0.3 dl/g. The weight ratio of the high intrinsic viscosity non-end-capped PLGA to the low intrinsic viscosity non-end-capped PLGA is (50-95): 5-50), preferably (70-90): 10-30, more preferably 80: 20. the molar ratio of lactide to glycolide in the high intrinsic viscosity uncapped PLGA is in the range of 65:35 to 90:10, preferably 75: 25; the molar ratio of lactide to glycolide in the low intrinsic viscosity uncapped PLGA is in the range of 50:50 to 75:25, preferably 50: 50.

The intrinsic viscosity of PLGA was measured as follows: PLGA was prepared as a solution of about 0.5% (w/v) in chloroform and the intrinsic viscosity of PLGA was measured at 30 ℃ using a Cannon-Fenske glass capillary viscometer.

The two PLGAs can also be a first high molecular weight non-terminated PLGA and a second low molecular weight non-terminated PLGA, the high molecular weight is 50,000-145,000, preferably 55,000-110,000, more preferably 55,000-85,000; the low molecular weight is 4,000 to 45,000, preferably 4,000 to 35,000, and more preferably 15,000 to 35,000. The weight ratio of the high molecular weight PLGA to the low molecular weight PLGA is (50-95): 5-50), preferably (70-90): 10-30), more preferably 80: 20; the molar ratio of lactide to glycolide in the high molecular weight PLGA is within the range of 65: 35-90: 10, preferably 75: 25; the molar ratio of lactide to glycolide in the low molecular weight PLGA is in the range of 50:50 to 75:25, preferably 50: 50. The term "molecular weight" as used herein refers to "weight average molecular weight", simply referred to as "molecular weight".

For convenience of description, hereinafter, the molar ratio of lactide to glycolide in PLGA and the intrinsic viscosity of PLGA are indicated in parentheses after PLGA. For example, "PLGA (75/25, 0.5A)" means a lactide-glycolide copolymer having a lactide to glycolide molar ratio of 75:25, an intrinsic viscosity of 0.5dl/g and a carboxyl group as the terminal group.

In particular, the weight ratio of the uncapped PLGA with high intrinsic viscosity (75/25, 0.5A) to uncapped PLGA with low intrinsic viscosity (50/50, 0.25A) in the present invention is preferably 80: 20.

Specifically, in the microsphere composition of the present invention, the preferred weight content of risperidone is 45% and the weight content of uncapped PLGA is 55%, and the weight ratio of the two PLGAs is 80:20, the molecular weights of the two PLGAs are respectively 55,000-85,000 and 15,000-35,000, the intrinsic viscosities of the two PLGAs are respectively 0.45-0.55 dL/g and 0.2-0.3 dL/g, and the molar ratios of lactide to glycolide in the two PLGAs are respectively 75:25 and 50: 50.

The "drug loading" used in the present invention is the actual drug loading, and is calculated according to the following equation: drug loading = [ amount of drug in microsphere/(amount of drug in microsphere + amount of polymer in microsphere) ] × 100%.

Risperidone or 9-hydroxyrisperidone in the sustained-release microspheres of the present invention may exist in the form of a salt. Acids that form salts with risperidone or 9-hydroxyrisperidone include inorganic acids such as hydrohalic acids (e.g., hydrochloric acid, or hydrobromic acid, or the like), nitric acid, sulfuric acid, or phosphoric acid; or an organic acid such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, pamoic acid, 2-oxopropanoic acid, ethanedioic acid, malonic acid, succinic acid, 2-butenedioic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid.

The risperidone sustained-release microspheres can be prepared by a conventional method, such as an emulsification-solvent evaporation method, a spray drying method or a spray extraction method.

Emulsion-solvent evaporation method: dissolving risperidone or salt thereof or 9-hydroxy risperidone or salt thereof and PLGA in a proper organic solvent, injecting the organic solvent into an aqueous phase solution prepared by water-soluble polymers for dispersion and emulsification, volatilizing the organic solvent, washing residues and filtering to obtain the microspheres. The organic solvent may be selected from halogenated hydrocarbons (e.g., dichloromethane, chloroform, ethyl chloride, or trichloroethane, etc.), ethyl acetate, ethyl formate, diethyl ether, cyclohexane, benzyl alcohol, or combinations thereof. The water-soluble polymer can be selected from at least one of polyvinyl alcohol (PVA), sodium carboxymethylcellulose (CMC-Na), polyvinylpyrrolidone (PVP), sodium polymethacrylate, and sodium polyacrylate, or their combination. The dispersion emulsification can be carried out with mechanical stirring or by means of a static mixer.

Spray drying method: risperidone or a salt thereof or 9-hydroxy risperidone or a salt thereof and PLGA are dissolved in a proper organic solvent, filtered, and prepared into microspheres by a conventional spray drying method. The organic solvent may be selected from dichloromethane, chloroform, ethyl acetate, diethyl ether, acetone, benzyl alcohol, glacial acetic acid, or combinations thereof.

Spray extraction method: risperidone or a salt thereof or 9-hydroxy risperidone or a salt thereof and PLGA are dissolved in a suitable organic solvent to form a solution, and then the solution is sprayed on an organic non-solvent (i.e., the organic solvent in which risperidone or a salt thereof or 9-hydroxy risperidone or a salt thereof and PLGA are insoluble) or water, and the solvent is extracted to form microspheres. The organic solvent may be selected from dichloromethane, chloroform, ethyl acetate, diethyl ether, acetone, benzyl alcohol, glacial acetic acid, or combinations thereof. The organic non-solvent may be selected from methanol, ethanol, propanol, isopropanol, petroleum ether, alkane, paraffin, etc. or their combination.

The invention also provides the use of risperidone microspheres in the preparation of antipsychotics, wherein psychosis includes acute schizophrenia and chronic schizophrenia, other psychotic states with marked positive symptoms (such as hallucinations, delusions, thought disorder, hostility, suspicion) and marked negative symptoms (such as dyslexia, mood disorder, social apathy, or whisper) and schizophrenia-related affective symptoms (such as depression, guilt, or anxiety), preferably schizophrenia, anxiety, depression, periodic headaches, etc.

In another embodiment, the present invention provides a method of treating psychosis by administering a risperidone microsphere formulation described herein. Psychosis includes acute and chronic schizophrenia, other significant positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, or suspicions) and significant negative symptoms (such as blunted reaction, mood swings, social apathy, or whispering), as well as affective symptoms associated with schizophrenia (such as depression, guilt, or anxiety), preferably schizophrenia, anxiety, depression, periodic headaches, and the like.

Microspheres according to embodiments of the present invention may be present in the form of a sterile powder. Sterile powders may contain the risperidone microsphere composition and mannitol and may be prepared by the following method: washing the sustained release microsphere composition with water for injection, transferring the sustained release composition to a freeze-drying tray, adding mannitol and an appropriate amount of water for injection, freeze-drying the freeze-drying tray in a freeze-drying machine, sieving and mixing the freeze-dried products, aseptically packaging, and capping to obtain sterile powder. The sterile powder is suspended in an acceptable dispersion vehicle prior to administration to a patient. The dispersion solvent is at least one selected from suspending agent, pH regulator, isotonic regulator, surfactant and water for injection. The suspending agent may be selected from at least one of sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, and glycerin. The isotonic adjusting agent may be at least one selected from the group consisting of sodium chloride, glucose, mannitol, and sorbitol. The surfactant is nonionic surfactant, such as polysorbate series (such as polysorbate 80 or polysorbate 60), or poloxamer series (such as poloxamer 188).

The risperidone sustained release microsphere composition according to the embodiment of the present invention is generally administered parenterally, for example, intramuscular injection, subcutaneous injection, intradermal injection, intraperitoneal injection, etc. For a patient with the weight of 60kg, the dosage of the drug is 12.5-150 mg in terms of risperidone. Namely, the effective treatment amount of the risperidone sustained-release microsphere composition is 0.2-2.5 mg risperidone/kg body weight, preferably 0.4-1.7 mg risperidone/kg body weight.

The sustained release microsphere composition has the following advantages: 1) under the condition of high drug loading or low drug loading, the drug can be released immediately after entering the body, and the drug release lag period does not exist; 2) is beneficial to the production of proportional amplification (the scale is more than 75L), and no medicine is crystallized and separated out in the production process; 3) is extremely stable, so that the release behavior in vivo does not change after long-term storage.

Drawings

FIG. 1-1 is an electron microscope scanning photograph of risperidone microspheres in CN101653422, in which the drug was crystallized out.

Fig. 1-2 are scanning electron micrographs of risperidone microspheres in example 6, in which no drug was crystallized out, indicating that risperidone microspheres according to embodiments of the present invention are suitable for large-scale industrial production.

Fig. 2 shows plasma concentration-time curves of in vivo release of risperidone microsphere compositions (prepared according to CN 101653422) before and after 6 months of storage, which shows that in vivo release behavior of the risperidone microspheres disclosed in CN101653422 after 6 months of storage is significantly changed and the quality of the risperidone microspheres disclosed in CN101653422 is unstable.

Fig. 3 shows plasma concentration-time curves of in vivo release of the risperidone microspheres of example 1 before and after 6 months of storage, which indicates that there is no significant change in the in vivo release behavior of the risperidone microspheres of example 1 after 6 months of storage, and the quality of the risperidone microspheres according to the embodiments of the present invention is more stable.

Fig. 4 shows the plasma concentration-time curves of the risperidone microspheres of example 3 released in vivo before and after 6 months of storage, which shows that the in vivo drug release behavior of the risperidone microspheres of example 3 after 6 months of storage has no significant change, and the quality of the risperidone microspheres according to the embodiment of the present invention is more stable.

Fig. 5 shows plasma concentration-time curves of in vivo release of the risperidone microspheres of example 4 before and after 6 months of storage, which indicates that there is no significant change in the in vivo release behavior of the risperidone microspheres of example 4 after 6 months of storage, and the quality of the risperidone microspheres according to the embodiments of the present invention is more stable.

Fig. 6 shows plasma concentration-time curves of in vivo release of the risperidone microspheres of example 6 before and after 6 months of storage, which indicates that there is no significant change in the in vivo release behavior of the risperidone microspheres of example 6 after 6 months of storage, and the quality of the risperidone microspheres according to the embodiments of the present invention is more stable.

Fig. 7 shows plasma concentration-time curves of in vivo release of the risperidone microspheres of example 7 before and after 6 months of storage, which indicates that there is no significant change in the in vivo release behavior of the risperidone microspheres of example 7 after 6 months of storage, and the quality of the risperidone microspheres according to the embodiments of the present invention is more stable.

Fig. 8 shows plasma concentration-time curves of in vivo release of the risperidone microspheres of example 9 before and after 6 months of storage, which indicates that there is no significant change in the in vivo release behavior of the risperidone microspheres of example 9 after 6 months of storage, and the quality of the risperidone microspheres according to the embodiments of the present invention is more stable.

Fig. 9 shows the plasma concentration-time curve of in vivo release of risperidone microspheres of comparative experiment 2, which shows that even when the drug loading of risperidone microspheres according to an embodiment of the present invention is as low as about 20%, the drug is released immediately after entering the body without a release lag period.

Detailed Description

As described herein, various embodiments relate to pharmaceutical compositions comprising: an active ingredient selected from risperidone, a salt of risperidone, 9-hydroxyrisperidone, and a salt of 9-hydroxyrisperidone; a polymer blend comprising a first uncapped lactide-glycolide copolymer and a second uncapped lactide-glycolide copolymer, wherein the weight content of the active ingredient in the pharmaceutical composition is in the range of 10-60%, preferably 35-55%, more preferably 40-50%; the weight content of the polymer blend in the pharmaceutical composition is within the range of 40-90%, preferably 45-65%, and more preferably 50-60%; the pharmaceutical composition is in the form of microspheres.

In a pharmaceutical composition according to an embodiment of the invention, the polymer blend consists of a first uncapped lactide-glycolide copolymer and a second uncapped lactide-glycolide copolymer.

In the pharmaceutical composition of one embodiment of the present invention, the first non-terminated lactide-glycolide copolymer has a high intrinsic viscosity of 0.4 to 0.9dl/g, preferably 0.45 to 0.8dl/g, more preferably 0.45 to 0.55 dl/g; the second non-terminated lactide-glycolide copolymer has a low intrinsic viscosity of 0.1 to 0.35dl/g, preferably 0.1 to 0.3dl/g, more preferably 0.2 to 0.3 dl/g; the weight ratio of the first non-terminated lactide-glycolide copolymer to the second non-terminated lactide-glycolide copolymer is (50-95): 5-50, preferably (70-90): 10-30, more preferably 80: 20; the molar ratio of lactide to glycolide in the first uncapped lactide-glycolide copolymer is in the range of 65:35 to 90:10, preferably 75: 25; the molar ratio of lactide to glycolide in the second uncapped lactide-glycolide copolymer is in the range of 50:50 to 75:25, preferably 50: 50.

In another embodiment of the pharmaceutical composition of the present invention, the first uncapped lactide-glycolide copolymer has a weight-average molecular weight of 50,000 to 145,000, preferably 55,000 to 110,000, more preferably 55,000 to 85,000; the second uncapped lactide-glycolide copolymer has a weight average molecular weight of 4,000 to 45,000, preferably 4,000 to 35,000, more preferably 15,000 to 35,000; the weight ratio of the first non-terminated lactide-glycolide copolymer to the second non-terminated lactide-glycolide copolymer is (50-95): 5-50), preferably (70-90): 10-30, more preferably 80: 20; the molar ratio of lactide to glycolide in the first uncapped lactide-glycolide copolymer is in the range of 65:35 to 90:10, preferably 75: 25; the molar ratio of lactide to glycolide in the second uncapped lactide-glycolide copolymer is in the range of 50:50 to 75:25, preferably 50: 50.

In a preferred embodiment of the pharmaceutical composition of the present invention, the risperidone is present in an amount of 45% by weight, the polymer blend is present in an amount of 55% by weight, and the weight ratio of the first uncapped PLGA to the second uncapped PLGA is 80:20, the molecular weight of the first non-end-capped PLGA is 55,000-85,000, the molecular weight of the second non-end-capped PLGA is 15,000-35,000, the intrinsic viscosity of the first non-end-capped PLGA is 0.45-0.55 dL/g, the intrinsic viscosity of the second non-end-capped PLGA is 0.2-0.3 dL/g, the molar ratio of lactide to glycolide in the first non-end-capped PLGA is 75:25, and the molar ratio of lactide to glycolide in the second non-end-capped PLGA is 50: 50.

In the pharmaceutical composition of one embodiment of the present invention, the salt of risperidone or the salt of 9-hydroxy risperidone is selected from inorganic acid salts and organic acid salts; the inorganic acid salt is selected from hydrochloride, hydrobromide, nitrate, sulfate and phosphate; the organic acid salt is selected from the group consisting of acetate, propionate, glycolate, 2-hydroxypropionate, pamoate, 2-oxopropionate, ethanedioate, malonate, succinate, 2-butenedioate, methanesulfonate, ethanesulfonate, benzenesulfonate and toluenesulfonic acid.

The present invention also provides the use of any of the pharmaceutical compositions described above in the preparation of an antipsychotic agent, wherein the psychotic disorder comprises acute schizophrenia and chronic schizophrenia, other positive symptoms and negative symptoms apparent in various psychotic states, and affective symptoms associated with schizophrenia.

Another embodiment of the present invention provides a sustained release microsphere formulation for injection, comprising any one of the above pharmaceutical compositions; and the microspheres are suspended in a pharmaceutically acceptable dispersion solvent; the dispersing solvent is selected from suspending agent, pH regulator, isotonic regulator, surfactant, water, and physiological saline; wherein the suspending agent is selected from sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, and glycerol; wherein the isotonic adjusting agent is selected from the group consisting of sodium chloride, glucose, mannitol, and sorbitol; wherein the surfactant is a nonionic surfactant and is selected from polysorbate series or poloxamer series.

The invention will be further illustrated by the following examples and test examples, which are not intended to limit the scope of the invention in any way.

Example 1

Clear solutions were prepared by weighing 72g of 74,000M PLGA (75/25, 0.52A), 18g of 25,000M PLGA (50/50, 0.25A) and 110g of risperidone and dissolving them in 1000ml of dichloromethane with stirring. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 100L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered with a screen, washed with deionized water, and lyophilized to give powdered microspheres. No crystal is precipitated. The drug loading of the microspheres is 45.9%, and the encapsulation efficiency is 83.5%.

Example 2

67.5g of PLGA (75/25, 0.42A) having a molecular weight of 55,000, 7.5g of PLGA (50/50, 0.25A) having a molecular weight of 25,000, and 75g of risperidone were weighed and dissolved in 750ml of dichloromethane with stirring to prepare a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdery microspheres. No crystal is precipitated. The drug loading of the microspheres is 40.2%, and the encapsulation efficiency is 80.4%.

Example 3

A clear solution was prepared by weighing 56g of PLGA (75/25, 0.90A) having a molecular weight of 125,000, 24g of PLGA (50/50, 0.25A) having a molecular weight of 25,000, and 120g of risperidone and dissolving them in 1000ml of dichloromethane with stirring. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 100L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. Then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr; the residue was filtered through a screen, washed with deionized water, and lyophilized to give powdery microspheres. No crystal is precipitated. The drug loading of the microspheres is 51.5%, and the encapsulation efficiency is 85.8%.

Example 4

64.125g of 74,000M PLGA (75/25, 0.52A), 3.375g PLGA (50/50, 0.10A) with a molecular weight of 4,200, and 82.5g risperidone were weighed out and dissolved in 750ml dichloromethane with stirring to obtain a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdery microspheres. No crystal is precipitated. The drug loading of the microspheres is 45.5%, and the encapsulation efficiency is 82.7%.

Example 5

63g of PLGA (75/25, 0.52A) with a molecular weight of 74,000, 27g of PLGA (50/50, 0.35A) with a molecular weight of 40,000, and 60g of risperidone were weighed and dissolved in 750ml of dichloromethane with stirring to prepare a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdery microspheres. No crystal is precipitated. The drug loading of the microspheres is 33.1%, and the encapsulation efficiency is 82.8%.

Example 6

42g of PLGA (65/35, 0.55A) having a molecular weight of 85,000, 10.5g of PLGA (50/50, 0.25A) having a molecular weight of 25,000, and 97.5g of risperidone were weighed and dissolved in 750ml of dichloromethane with stirring to prepare a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdery microspheres. No crystal is precipitated. The drug loading of the microspheres is 55.0%, and the encapsulation efficiency is 84.6%.

Example 7

57.75g PLGA with a molecular weight of 67,000 (90/10, 0.45A), 24.75g PLGA with a molecular weight of 25,000 (50/50, 0.25A), and 67.5g risperidone were weighed and dissolved in 750ml dichloromethane with stirring to make a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdery microspheres. No crystal is precipitated. The drug loading of the microspheres was 35.8% and the encapsulation efficiency was 79.6%.

Example 8

68.25g of PLGA (85/15, 0.71A) having a molecular weight of 110,000, 36.75g of PLGA (50/50, 0.25A) having a molecular weight of 25,000, and 45g of risperidone were weighed and dissolved in 750ml of dichloromethane with stirring to prepare a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdery microspheres. No crystal is precipitated. The drug loading of the microspheres was 23.9%, and the encapsulation efficiency was 79.7%.

Example 9

54g of 74,000M PLGA (75/25, 0.52A), 13.5g of 25,000M PLGA (75/25, 0.20A) and 82.5g of risperidone were weighed and dissolved in 750ml of dichloromethane with stirring to obtain a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdery microspheres. No crystal is precipitated. The drug loading of the microspheres is 45.3%, and the encapsulation efficiency is 82.4%.

Example 10

60g of PLGA (85/15, 0.71A) having a molecular weight of 110,000, 60g of PLGA (50/50, 0.25A) having a molecular weight of 25,000, and 30g of risperidone were weighed and dissolved in 750ml of dichloromethane with stirring to prepare a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdered microspheres. No crystal is precipitated. The drug loading of the microspheres was 13.9% and the encapsulation efficiency was 69.5%.

Example 11

48g of 92,000 molecular weight PLGA (75/25, 0.61A), 12g of 5,000 molecular weight PLGA (65/35, 0.12A), and 140g of risperidone were weighed and dissolved in 1000ml of dichloromethane with stirring to prepare a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 100L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdered microspheres. No crystal is precipitated. The drug loading of the microspheres is 60.6%, and the encapsulation efficiency is 84.3%.

Example 12

54g of 74,000M PLGA (75/25, 0.52A), 13.5g PLGA (50/50, 0.25A) with a molecular weight of 25,000 and 85.65g 9-hydroxy risperidone were weighed and dissolved in 750ml dichloromethane to prepare a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer was turned on and homogenized, and the clear solution was homogenized at 380rpm for 1 min. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdery microspheres. No crystal is precipitated. The drug loading of the microspheres is 45.9%, and the encapsulation efficiency is 83.5%.

Example 13

64.8g of PLGA (75/25, 0.52A) having a molecular weight of 74,000, 16.2g of PLGA (50/50, 0.25A) having a molecular weight of 25,000, and 192.6g of risperidone pamoate were weighed and dissolved in 750ml of dichloromethane with stirring to prepare a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdered microspheres. No crystal is precipitated. The drug loading of the microspheres is 45.9%, and the encapsulation efficiency is 83.5%.

Example 14

The microspheres obtained in example 1 were washed with water for injection and transferred to a freeze-dried dish. Adding 4g mannitol and appropriate amount of injection, and freeze drying in freeze drying machine. Sieving the freeze-dried product, mixing uniformly, performing aseptic subpackaging, and capping to obtain the risperidone sustained-release microspheres for injection.

Comparative experiment 1Scale-up production of risperidone microspheres disclosed in CN101653422 (75L)

1) Test materials

Risperidone, PLGA with molecular weight of 74,000 (75/25, 0.52A)

2) The method and the result are as follows:

60g of PLGA (75/25, 0.52A) with molecular weight of 74,000 and 90g of risperidone were weighed and dissolved in 750ml of dichloromethane with stirring to obtain a clear solution. This clear solution was added by peristaltic pump to a microsphere preparation kettle containing 75L of PVA solution (0.5%) cooled to 6 ℃. The stirrer and homogenizer were turned on and the clear solution was homogenized and emulsified for 1min at 380 rpm. And then, reducing the rotation speed of the homogenizer, volatilizing to remove the organic solvent, and continuing for 3-5 hr. The residue was filtered through a screen, washed with deionized water, and lyophilized to give powdered microspheres. Upon microscopic observation, drug crystals were found, as shown in FIG. 1-1.

In contrast, in the microspheres obtained in examples 1 to 10 of the present invention, it was shown by microscopic observation that there was no precipitated drug crystal. FIGS. 1-2 are scanning electron micrographs of risperidone microspheres from example 6.

The results show that the risperidone microspheres according to the embodiments of the present invention are more suitable for large-scale industrial production.

Comparative experiment 2Stability comparison test of embodiment of the invention and CN101653422

1) Test materials

Test drugs:

the invention comprises the following steps: the risperidone microspheres prepared in examples 1, 3, 4, 6,7, and 9 were stored for 0 month and 6 months, respectively.

CN 101653422: the risperidone microspheres prepared in example 3 of CN101653422 were stored for 0 month and 6 months. A clear solution was prepared by weighing 4.0g of PLGA (75/25, 0.52A) having a molecular weight of 74,000 and 6.0g of risperidone and dissolving in 50ml of dichloromethane with stirring. This clear solution was added by a peristaltic pump to a high speed stirred microsphere preparation kettle containing 5000ml of PVA solution (0.5%) cooled to 6 ℃ and dispersed and emulsified at 1000rpm for 1 min. Thereafter, the rotation speed was adjusted to 300rpm, the rotation speed of the paddle was 150rpm, and any organic solvent was evaporated off for 6 hr. The residue was filtered through a screen, washed 5 times with deionized water, and lyophilized to give powdery microspheres. The drug loading of the microspheres is 50.7%, and the encapsulation efficiency is 84.5%.

Test animals: the weight of the healthy Beagle dog (Beagle) is 9.5-10.5 kg, and each group comprises 4 healthy Beagle dogs (Beagle) and 28 females and 28 males.

The test instrument: an API model 4000 triple quadrupole tandem mass spectrometer equipped with an ion spray ionization source and analysis 1.4 data processing software, Applied biosystems, usa; agilent1100 hplc.

2) Method and results

The test animals were randomly divided into 2 groups (month 0 and month 6 groups), 4 animals per group, and each beagle dog was administered a dose of 1.5mg/kg (in risperidone) by intramuscular injection, and 3ml of blood was taken from the forelimb vein of each dog before (0 h) and 1h, 3h, 6h, 1d, 2d, 3d, 5d, 7d, 9d, 11d, 14d, 16d, 18d, 21d, 23d, 25d, and 28d before (0 h) and after administration, immediately placed in a heparin-treated centrifuge tube, and centrifuged for 10min (3600 rpm). Plasma was separated and stored at-37 ℃ in a refrigerator for testing. The blood concentrations of risperidone and its metabolite, 9-hydroxyrisperidone, in plasma were measured, and the results are shown in table 1 and fig. 2-8.

From the results, the risperidone microspheres disclosed in CN101653422 have obvious change of drug release behavior in vivo after 6 months of storage; after the risperidone microspheres are stored for 6 months, the drug release behavior in vivo has no obvious change, and the quality is more stable.

TABLE 1 plasma concentration (ng/mL) at different times after intramuscular administration to individual dogs of microspheres according to an embodiment of the invention and CN101653422 after 6 months of storage

Comparative experiment 3Compared with the release result of the risperidone microspheres with different drug-loading rates in the dog body, the release result of the risperidone microspheres with different drug-loading rates in the dog body is shown in the specification

1) Test materials

Test drugs:

the invention comprises the following steps: risperidone microspheres with drug-loading rates of 13.9%, 23.9%, 33.1% and 40.2% were prepared in examples 2, 5, 8 and 10, respectively.

CN 101653422: risperidone microspheres with drug loading of 45.5%, 40.3% and 35.6% respectively prepared in CN101653422 and examples 7-9.

Test animals: 24 healthy beagle dogs with 4 dogs, 12 females and 12 males in each group, and the weight of the beagle dogs is 9.5-10.5 kg.

The test instrument: as in comparative experiment 2.

2) Method and results

The test method is the same as that of comparative test 2.

The test results are shown in table 2 and fig. 9.

The results show that, for the risperidone microspheres in CN101653422, when the drug loading is below 45%, the drug is not released immediately after entering the body, i.e. there is a release lag phase. In contrast, with the risperidone microspheres according to the embodiments of the present invention, when the drug loading is as low as about 10%, the drug is released immediately after entering the body, i.e., there is no release lag phase.

TABLE 2 plasma concentration (ng/mL) at different times after intramuscular administration of microspheres according to an embodiment of the invention and CN101653422 to individual dogs

Claims (18)

1. A pharmaceutical composition comprising: an active ingredient selected from risperidone or a salt thereof, 9-hydroxyrisperidone or a salt thereof; and a polymer blend comprising a first uncapped lactide-glycolide copolymer and a second uncapped lactide-glycolide copolymer, wherein the weight ratio of the first uncapped lactide-glycolide copolymer to the second uncapped lactide-glycolide copolymer is 50-95: 5-50; the intrinsic viscosity of the first non-terminated lactide-glycolide copolymer is 0.4-0.9 dl/g, the weight average molecular weight is 50,000-145,000, and the molar ratio of lactide to glycolide is 65: 35-90: 10; the intrinsic viscosity of the second non-terminated lactide-glycolide copolymer is 0.1-0.35 dl/g, the weight-average molecular weight is 4,000-45,000, and the molar ratio of lactide to glycolide is 50: 50-75: 25; the weight content of the active ingredients in the pharmaceutical composition is 10-60%; the weight content of the polymer blend in the pharmaceutical composition is 40-90%; the pharmaceutical composition is in the form of microspheres.

2. The pharmaceutical composition of claim 1, wherein the first uncapped lactide-glycolide copolymer has an intrinsic viscosity of 0.45 to 0.8 dl/g; the intrinsic viscosity of the second non-terminated lactide-glycolide copolymer is 0.1-0.3 dl/g.

3. The pharmaceutical composition of claim 2, wherein the first uncapped lactide-glycolide copolymer has an intrinsic viscosity of 0.45 to 0.55 dl/g; the intrinsic viscosity of the second non-terminated lactide-glycolide copolymer is 0.2-0.3 dl/g.

4. The pharmaceutical composition of claim 1, wherein the first uncapped lactide-glycolide copolymer has a weight average molecular weight of 55,000 to 110,000; the second non-terminated lactide-glycolide copolymer has a weight-average molecular weight of 4,000 to 35,000.

5. The pharmaceutical composition of claim 4, wherein the first uncapped lactide-glycolide copolymer has a weight average molecular weight of 55,000 to 85,000; the second non-terminated lactide-glycolide copolymer has a weight average molecular weight of 15,000 to 35,000.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the active ingredient is present in the pharmaceutical composition in an amount of 35 to 55% by weight; the weight content of the polymer blend in the pharmaceutical composition is 45-65%.

7. The pharmaceutical composition according to claim 1, wherein the weight content of the active ingredient in the pharmaceutical composition is 40-50%; the weight content of the polymer blend in the pharmaceutical composition is 50-60%.

8. The pharmaceutical composition of any of claims 1-5, wherein the polymer blend consists of a first uncapped lactide-glycolide copolymer and a second uncapped lactide-glycolide copolymer.

9. The pharmaceutical composition of any of claims 1-5, wherein the weight ratio of the first uncapped lactide-glycolide copolymer to the second uncapped lactide-glycolide copolymer is 70-90: 10-30.

10. The pharmaceutical composition of claim 9, wherein the weight ratio of the first uncapped lactide-glycolide copolymer to the second uncapped lactide-glycolide copolymer is 80: 20.

11. The pharmaceutical composition of any of claims 1-5, wherein the first uncapped lactide-glycolide copolymer has a lactide to glycolide molar ratio of 75: 25; the molar ratio of lactide to glycolide in the second uncapped lactide-glycolide copolymer was 50: 50.

12. The pharmaceutical composition of any one of claims 1-5, wherein the risperidone is present at 45 wt%, the polymer blend is present at 55 wt%, and the weight ratio of the first uncapped lactide-glycolide copolymer to the second uncapped lactide-glycolide copolymer is 80:20, the intrinsic viscosity of the first uncapped lactide-glycolide copolymer is 0.45-0.55 dL/g, the intrinsic viscosity of the second uncapped lactide-glycolide copolymer is 0.2-0.3 dL/g, the molar ratio of lactide to glycolide in the first uncapped lactide-glycolide copolymer is 75:25, and the molar ratio of lactide to glycolide in the second uncapped lactide-glycolide copolymer is 50: 50.

13. The pharmaceutical composition of any one of claims 1-5, wherein the risperidone is present at 45 wt%, the polymer blend is present at 55 wt%, and the weight ratio of the first uncapped lactide-glycolide copolymer to the second uncapped lactide-glycolide copolymer is 80: and 20, the molecular weight of the first uncapped lactide-glycolide copolymer is 55,000-85,000, the molecular weight of the second uncapped lactide-glycolide copolymer is 15,000-35,000, the molar ratio of lactide to glycolide in the first uncapped lactide-glycolide copolymer is 75:25, and the molar ratio of lactide to glycolide in the second uncapped lactide-glycolide copolymer is 50: 50.

14. The pharmaceutical composition according to any one of claims 1 to 5, wherein the salt of risperidone or the salt of 9-hydroxyrisperidone is selected from inorganic acid salts and organic acid salts; the inorganic acid salt is selected from hydrochloride, hydrobromide, nitrate, sulfate and phosphate; the organic acid salt is selected from acetate, propionate, glycollate, 2-hydroxypropionate, pamoate, 2-oxopropionate, oxalate, malonate, succinate, 2-butenedioate, methanesulfonate, ethanesulfonate, benzenesulfonate or toluenesulfonic acid.

15. Use of a pharmaceutical composition according to any one of claims 1-5 for the preparation of an antipsychotic, wherein psychosis comprises acute and chronic schizophrenia, significant positive and significant negative symptoms of other psychotic states, and affective symptoms associated with schizophrenia.

16. An injectable sustained release microsphere comprising the pharmaceutical composition of any one of claims 1 to 5.

17. The sustained-release microspheres for injection according to claim 16, comprising the pharmaceutical composition according to any one of claims 1 to 5 and mannitol.

18. The sustained-release microspheres for injection according to claim 16 or 17, wherein the microspheres are suspended in a pharmaceutically acceptable dispersion vehicle; the dispersing solvent is selected from suspending agent, pH regulator, isoosmotic regulator, surfactant, water and physiological saline; the suspending agent is selected from sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate or glycerol; the isotonic regulator is selected from sodium chloride, glucose, mannitol or sorbitol; the surfactant is a nonionic surfactant selected from polysorbate series and poloxamer series.