Patent Application
20240016744
Naltrexone is a pure antagonist for opioid receptors, and has a block effect on δ-, and κ-opioid receptors. Naltrexone can block the effect of retaking drugs, thereby weakening the positive reinforcement and negative reinforcement, and playing a good supporting role in prevention of relapse. Naltrexone has the following chemical structure:
Risperidone has a good therapeutic effect on positive and negative symptoms and accompanying affective symptoms thereof (such as anxiety and depression). Risperidone may also reduce affective symptoms associated with schizophrenia. For patients who benefit from treatment during the acute period, this product can continue to exert its clinical efficacy during the maintenance period. Risperidone has the following chemical structure:
After intramuscular or subcutaneous injection, conventional injectable preparations, such as solution, suspension, and emulsion, will be removed from the body quickly. Therefore, frequently parenteral administration is required by treatment of chronic diseases. To solve the foregoing problem, sustained-release microparticles are proposed, which specifically refer to microcapsules prepared by encapsulating drugs into polymers or microsphere disperse systems prepared by dispersing or adsorbing drugs into polymers. Microspheres usually have a size in a unit of μm, so they can be administered to the human body or animals by intramuscular or subcutaneous injection. Microspheres may be prepared according to different drug release rates, so that the drug delivery time can be controlled. Therefore, the effective therapeutic concentration of a drug can be maintained for a long term after single administration, which reduces the total dose of the drug required by treatment to the maximum extent, and improves the patient compliance with drug therapy.
The approved VIVITROL® includes the active ingredient naltrexone, and it is proved that the preparation has a good effect of improving opioid relapse control and quitting alcohol addiction. However, the preparation cannot achieve good results in treatment of novel drug addiction, and especially cannot achieve satisfactory results in treatment of methamphetamine drug addiction.
Currently, there is no report on application of a compound composition of naltrexone and risperidone in addiction treatment.
A technical problem to be solved by the present disclosure is to provide a naltrexone sustained-release microsphere preparation capable of effectively prolonging the in vivo action time of a compound of naltrexone and risperidone to reduce the administration frequency of naltrexone and risperidone.
An objective of the present disclosure is to provide a compound sustained-release composition of naltrexone and risperidone, which includes the following components in parts by weight:
Further, the risperidone sustained-release microspheres are prepared by a W1/O/W2 double emulsion-solvent evaporation method.
Further, the naltrexone sustained-release microspheres are prepared by an 01W emulsion-solvent evaporation method.
Further, a preparation method of the risperidone sustained-release microspheres includes the following steps:
Further, the additive is selected from at least one of sodium chloride, mannitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate.
Further, the fat-soluble polymer is selected from at least one of polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polycarbonate, polyglycolic acid (PGA), polycyanoacrylate, and polyether ester.
Further, the water-soluble polymer is selected from polyvinyl alcohol.
Further, in the poly(lactic-co-glycolic acid) (PLGA), a ratio of lactic acid to glycolic acid is (1-9):1.
Further, the weight-average molecular weight (M w) of the water-soluble polymer or the fat-soluble polymer is 6,000-220,000 Da, and preferably 50,000-100,000 Da.
Further, the organic solvent is selected from at least one of dichloromethane and ethyl acetate.
Further, in S1, a dosage ratio of the additive to the purified water is 50-300 mg/mL, and preferably 75-150 mg/mL.
Further, in S2, the concentration of risperidone is 100-300 mg/mL, and preferably 100-150 mg/mL; and the concentration of the fat-soluble polymer is 100-300 mg/mL, and preferably 100-150 mg/mL.
Further, in S4, a dosage ratio of the primary emulsion to the aqueous solution of the water-soluble polymer is (1-3): 80, and preferably (2-3): 80.
Further, in S4, in the aqueous solution of the water-soluble polymer, the content of the water-soluble polymer is 0.1-2 wt %.
Further, in S4, the content of the water-soluble polymer is 0.5-0.6 wt %.
Further, the aqueous solution contains 0-5 wt % sodium chloride or 0-10 wt % sucrose.
Further, the stirring is performed at 500-5,000 revolutions/minute, and preferably 700-1,000 revolutions/minute, and the evaporation is performed at 200-3,000 revolutions/minute, preferably 500-1,000 revolutions/minute, at 30-40° C. for 24 h.
Further, a preparation method of the naltrexone sustained-release microspheres includes the following steps:
Further, the fat-soluble polymer is selected from at least one of polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polycarbonate, polyglycolic acid (PGA), polycyanoacrylate, and polyether ester.
Further, the water-soluble polymer is selected from polyvinyl alcohol.
Further, the organic solvent is selected from at least one of dichloromethane and ethyl acetate.
Further, in the poly(lactic-co-glycolic acid) (PLGA), a ratio of lactic acid to glycolic acid is (1-9): 1.
Further, the weight-average molecular weight (M w) of the water-soluble polymer or the fat-soluble polymer is 6,000-220,000 Da, and preferably 50,000-100,000 Da.
Further, in S1′, the concentration of naltrexone is 50-300 mg/mL, and preferably 100-150 mg/mL; and the concentration of the fat-soluble polymer is 100-300 mg/mL, and preferably 100-150 mg/mL.
Further, in S2′, a dosage ratio of the oil phase to the aqueous solution of the water-soluble polymer is (1-3): 80, and preferably (2-3): 80.
Further, in S2′, in the aqueous solution of the water-soluble polymer, the content of the water-soluble polymer is 0.1-2 wt %, and preferably 0.5-1 wt %.
Further, the aqueous solution contains 0-10 wt % sodium chloride or 0-20 wt % sucrose, preferably 8-10 wt % sucrose.
Further, the stirring is performed at 500-5,000 revolutions/minute, and preferably 700-1,000 revolutions/minute, and the evaporation is performed at 200-3,000 revolutions/minute, preferably 500-1,000 revolutions/minute, at 30-40° C. for 24 h.
Another objective of the present disclosure is to provide a preparation including the composition, which is prepared by uniformly mixing the composition with a lubricant, compressing into tablets, and coating.
Further, the lubricant is selected from at least one of sodium stearyl fumarate, magnesium stearate, and a stearic acid.
Further, a dosage of lubricant is 0.05-0.1 wt % of the composition.
Still another objective of the present disclosure is to provide application of the composition and the preparation, which is application in preparation of a product for treating or relieving amphetamine, ketamine, cocaine or cannabis addiction.
The present disclosure has the following advantages.
Patients with opioid or drug addiction usually develop psychiatric symptoms in addition to addiction symptoms. Therefore, during treatment of patients with opioid or drug addiction, ancillary interventions for mental stability of the patients are also important. In the present disclosure, naltrexone and risperidone are combined into a compound for use, which further improve the therapeutic effect on patients with opioid or drug addiction.
1. The sustained-release preparation of the present disclosure is composed of naltrexone, risperidone, a biodegradable pharmaceutical polymer material, and an additive.
2. The preparation method of the present disclosure improves the stability of naltrexone and risperidone in the preparation process and release process, is simple and easy to operate, and has good repeatability.
3. The sustained-release microspheres of the present disclosure may be sustainably released in vitro for more than 12 weeks, the release conforms to a zeroth-order approximation mode, and the release rate is stable.
4. The suitable preparation method and parameter control are adopted in the present disclosure, so that naltrexone sustained-release microspheres and risperidone sustained-release microspheres are released synchronously, and an administration period is easier to control to avoid an uncertain administration period due to non-synchronous release of the two drugs.
5. In view of the fact that there is no anti-amphetamine relapse product on the market, the preparation of the present disclosure can better help patients avoid relapse during the window period due to frequent medications by virtue of its sustained-release characteristics.
The present disclosure will be further described below with reference to the drawings.
1. Preparation of Risperidone Microspheres
Preparation of Risperidone Microspheres by a W1/O/W2 Double Emulsion-Solvent Evaporation Method
(1) 0.6 g of sodium chloride was dissolved in 3 mL of purified water to form an inner water phase.
(2) 3.5 g of risperidone and 3.5 g of PLA (Mw 80,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of risperidone was 150 mg/mL and the concentration of PLA was 150 mg/mL.
(3) The inner water phase was added to the oil phase, and the mixture was ultrasonically emulsified to form a primary emulsion.
(4) The primary emulsion was added dropwise to an aqueous solution (containing 0.5% polyvinyl alcohol and 5% sodium chloride) according to a ratio of 1:40, the mixture was thoroughly stirred at 1,000 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 800 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were washed, collected, and dried.
2. Preparation of Naltrexone Microspheres
Preparation of Naltrexone Microspheres by an O/W Emulsion-Solvent Evaporation Method
(1) 3.5 g of naltrexone and 3.5 g of PLA (M w 80,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of naltrexone was 150 mg/mL and the concentration of PLA was 150 mg/mL.
(2) The oil phase was added dropwise to an aqueous solution (containing 0.5% polyvinyl alcohol and 10% sucrose) according to a ratio of 1:40, the mixture was thoroughly stirred at 1,000 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 800 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were collected and dried.
3. Mixing and Compression
10 parts of prepared naltrexone microspheres, 1 part of prepared risperidone microspheres, and 0.05% magnesium stearate were mixed and compressed into tablets.
4. The tablets were coated by spraying to obtain a compound sustained-release preparation of naltrexone and risperidone.
An in vitro cumulative release curve of the compound sustained-release preparation of naltrexone and risperidone prepared in this example is shown in
1. Preparation of Risperidone Microspheres
Preparation of Risperidone Microspheres by a W1/O/W2 Double Emulsion-Solvent Evaporation Method
(1) 0.3 g of sodium dihydrogen phosphate was dissolved in 2 mL of water to form an inner water phase.
(2) 4.0 g of risperidone and 6.0 g of PLGA (lactic acid: glycolic acid=90:10, Mw 50,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of risperidone was 100 mg/mL and the concentration of PLGA was 150 mg/mL.
(3) The inner water phase was added to the oil phase, and the mixture was ultrasonically emulsified to form a primary emulsion.
(4) The primary emulsion was added dropwise to an aqueous solution (containing polyvinyl alcohol and 5% sodium chloride) according to a ratio of 3:80, the mixture was thoroughly stirred at 700 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 1,000 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were washed, collected, and dried.
2. Preparation of Naltrexone Microspheres
Preparation of Naltrexone Microspheres by an O/W Emulsion-Solvent Evaporation Method
(1) 4.5 g of naltrexone and 6 g of PLGA (lactic acid: glycolic acid=90:10, M w Da) were dissolved in dichloromethane to form an oil phase in which the concentration of naltrexone was 150 mg/mL and the concentration of PLGA was 200 mg/mL.
(2) The oil phase was added dropwise to an aqueous solution (containing 1.0% polyvinyl alcohol and 8% sucrose) according to a ratio of 3:80, the mixture was thoroughly stirred at 700 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 1,000 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were collected and dried.
3. Mixing and Compression
5 parts of prepared naltrexone microspheres, 1 part of prepared risperidone microspheres, and 0.1% sodium stearyl fumarate were mixed and compressed into tablets.
4. The tablets were coated by spraying to obtain a compound sustained-release preparation of naltrexone and risperidone.
An in vitro cumulative release curve of the compound sustained-release preparation of naltrexone and risperidone prepared in this example is shown in
1. Preparation of Risperidone Microspheres
Preparation of Risperidone Microspheres by a W1/O/W2 Double Emulsion-Solvent Evaporation Method
(1) 0.5 g of disodium hydrogen phosphate was dissolved in 5 mL of water to form an inner water phase.
(2) 5.0 g of risperidone and 6.0 g of PLGA (lactic acid: glycolic acid=50:50, Mw 100,000 Da) were dissolved in ethyl acetate to form an oil phase in which the concentration of risperidone was 100 mg/mL and the concentration of PLGA was 120 mg/mL.
(3) The inner water phase was added to the oil phase, and the mixture was ultrasonically emulsified to form a primary emulsion.
(4) The primary emulsion was added dropwise to an aqueous solution (containing polyvinyl alcohol and 15% sucrose) according to a ratio of 1:40, the mixture was thoroughly stirred at 800 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 700 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were washed, collected, and dried.
2. Preparation of Naltrexone Microspheres
Preparation of Naltrexone Microspheres by an O/W Emulsion-Solvent Evaporation Method
(1) 5 g of naltrexone and 5 g of PLGA (50:50, Mw 100,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of naltrexone was 100 mg/mL and the concentration of PLGA was 100 mg/mL.
(2) The oil phase was added dropwise to an aqueous solution (containing 0.7% polyvinyl alcohol and 10% sucrose) according to a ratio of 1:40, the mixture was thoroughly stirred at 900 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 700 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were collected and dried.
3. Mixing and Compression
5 parts of prepared naltrexone microspheres, 2 parts of prepared risperidone microspheres, 0.025% sodium stearyl fumarate, and 0.025% magnesium stearate were mixed and compressed into tablets.
4. The tablets were coated by spraying to obtain a compound sustained-release preparation of naltrexone and risperidone.
An in vitro cumulative release curve of the compound sustained-release preparation of naltrexone and risperidone prepared in this example is shown in
1. Preparation of Risperidone Microspheres
Preparation of Risperidone Microspheres by an O/W Emulsion-Solvent Evaporation Method
(1) 3 g of risperidone and 3 g of PLA (M w 80,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of risperidone was 150 mg/mL and the concentration of PLA was 150 mg/mL.
(2) The oil phase was added dropwise to an aqueous solution (containing 0.5% polyvinyl alcohol and 10% sucrose) according to a ratio of 1:40, the mixture was thoroughly stirred at 1,000 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 800 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were washed, collected, and dried.
2. Preparation of Naltrexone Microspheres
Preparation of Naltrexone Microspheres by an O/W Emulsion-Solvent Evaporation Method
(1) 3 g of naltrexone and 3 g of PLA (M w 80,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of naltrexone was 150 mg/mL and the concentration of PLA was 150 mg/mL.
(2) The oil phase was added dropwise to an aqueous solution (containing 0.5% polyvinyl alcohol and 10% sucrose) according to a ratio of 1:40, the mixture was thoroughly stirred at 1,000 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 800 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were collected and dried.
3. Mixing and Compression
10 parts of prepared naltrexone microspheres, 1 part of prepared risperidone microspheres, and 0.05% magnesium stearate were mixed and compressed into tablets.
4. The tablets were coated by spraying to obtain a compound sustained-release preparation of naltrexone and risperidone.
An in vitro cumulative release curve of the compound sustained-release preparation of naltrexone and risperidone prepared in this Comparative Example is shown in
1. Preparation of Risperidone Microspheres
Preparation of Risperidone Microspheres by a W1/O/W2 Double Emulsion-Solvent Evaporation Method
(1) 0.6 g of sodium chloride was dissolved in 3 mL of purified water to form an inner water phase.
(2) 3.5 g of risperidone and 3.5 g of PLA (M w 80,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of risperidone was 150 mg/mL and the concentration of PLA was 150 mg/mL.
(3) The inner water phase was added to the oil phase, and the mixture was ultrasonically emulsified to form a primary emulsion.
(4) The primary emulsion was added dropwise to an aqueous solution (containing polyvinyl alcohol and 5% sodium chloride) according to a ratio of 1:40, the mixture was thoroughly stirred at 1,000 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 800 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were collected and dried.
2. Preparation of Naltrexone Microspheres
Preparation of Naltrexone Microspheres by a W1/O/W2 Double Emulsion-Solvent Evaporation Method
(1) 0.6 g of sodium chloride was dissolved in 4 mL of purified water to form an inner water phase.
(2) 3.5 g of naltrexone and 3.5 g of PLA (Mw 80,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of naltrexone was 150 mg/mL and the concentration of PLA was 150 mg/mL.
(3) The inner water phase was added to the oil phase, and the mixture was ultrasonically emulsified to form a primary emulsion.
(4) The primary emulsion was added dropwise to an aqueous solution (containing polyvinyl alcohol and 10% sucrose) according to a ratio of 1:40, the mixture was thoroughly stirred at 1,000 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 800 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were collected and dried.
3. Mixing and Compression
10 parts of prepared naltrexone microspheres, 1 part of prepared risperidone microspheres, and 0.05% magnesium stearate were mixed and compressed into tablets.
4. The tablets were coated by spraying to obtain a compound sustained-release preparation of naltrexone and risperidone.
An in vitro cumulative release curve of the compound sustained-release preparation of naltrexone and risperidone prepared in this Comparative Example is shown in
It can be seen from Example 1 and Comparative Example 1 that in a case that the preparation methods of risperidone microspheres are different and the preparation methods of naltrexone microspheres are the same, the release behaviors of risperidone are similar, and the release behaviors of naltrexone are greatly different. Moreover, it can be seen from Example 1 and Comparative Example 2 that in a case that the preparation methods of risperidone microspheres are the same and the preparation methods of naltrexone microspheres are different, the release behaviors of naltrexone are similar, and the release behaviors of risperidone are greatly different. It shows the complexity of the release behaviors of the two sustained-release microspheres of the present disclosure when mixed, and to achieve the synchronous release of the two sustained-release microspheres, the parameters need to be limited within the ranges required by the present disclosure.
1. Preparation of Risperidone Microspheres
Preparation of Risperidone Microspheres by a W1/O/W2 Double Emulsion-Solvent Evaporation Method
(1) 0.6 g of sodium chloride was dissolved in 3 mL of purified water to form an inner water phase.
(2) 3.5 g of risperidone and 3.5 g of PLA (Mw 5,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of risperidone was 150 mg/mL and the concentration of PLA was 150 mg/mL.
(3) The inner water phase was added to the oil phase, and the mixture was ultrasonically emulsified to form a primary emulsion.
(4) The primary emulsion was added dropwise to an aqueous solution (containing 0.5% polyvinyl alcohol and 5% sodium chloride) according to a ratio of 1:40, the mixture was thoroughly stirred at 1,000 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 800 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were collected and dried.
2. Preparation of Naltrexone Microspheres
Preparation of Naltrexone Microspheres by an O/W Emulsion-Solvent Evaporation Method
(1) 3.5 g of naltrexone and 3.5 g of PLA (Mw 5,000 Da) were dissolved in dichloromethane to form an oil phase in which the concentration of naltrexone was 150 mg/mL and the concentration of PLA was 150 mg/mL.
(2) The oil phase was added dropwise to an aqueous solution (containing 0.5% polyvinyl alcohol and 10% sucrose) according to a ratio of 1:40, the mixture was thoroughly stirred at 1,000 revolutions/minute until uniform, the organic solvent was evaporated by stirring at 800 revolutions/minute at 35° C. for 24 h to obtain sustained-release microspheres, and the microspheres were collected and dried.
3. Mixing and Compression
10 parts of prepared naltrexone microspheres, 1 part of prepared risperidone microspheres, and 0.05% magnesium stearate were mixed and compressed into tablets.
4. The tablets were coated by spraying to obtain a compound sustained-release preparation of naltrexone and risperidone.
In this case, naltrexone and risperidone cannot be released synchronously.
Example In Vitro Release
An appropriate amount of naltrexone reference was taken and accurately weighed, a release medium was added to dissolve the naltrexone reference and quantitatively dilute to obtain a solution containing about 50 μg/mL naltrexone reference, and the solution was taken as a naltrexone reference solution.
An appropriate amount of risperidone reference was taken and accurately weighed, a release medium was added to dissolve the risperidone reference and quantitatively dilute to obtain a solution containing about 50 μg/mL risperidone control, and the solution was taken as a risperidone reference solution.
The product of the present disclosure was taken and placed into six 100 mL conical flasks with stoppers, 80 mL of 0.1 M anhydrous dipotassium hydrogen phosphate solution (a solution prepared by accurately sucking and placing 25 mL of 1 M sodium hydroxide solution into a 1,000 mL volumetric flask, adding a 0.1 M anhydrous dipotassium hydrogen phosphate solution for dilution, and regulating the pH value of the diluted solution to 11.2±0.05) was used as a solvent, and the conical flasks were tightly covered with the stoppers and shaken in a water bath oscillator at 100 times/minute at 37±0.5° C. The medium was replaced on day 1, day 3, day 6, day 9, day 12, day 15, . . . , and day 120, the solution was filtered, a subsequent filtrate was taken as a test solution, and the release medium was replenished in the operating container in time. The test solution was detected by high-performance liquid chromatography (a high-performance liquid chromatography method described in General Rule 0512 of Chinese Pharmacopoeia 2020) at a wavelength of 280 nm.
In vitro cumulative release results are shown in
Example Pharmacokinetics in Animals
SD rats, half male and half female, were taken as experimental animals. The naltrexone compound preparation sample of Example 1 was used. The compound sustained-release preparation was implanted into the back of each rat, and blood of each rat was collected at set time points for analysis of drug-time data.
Blood collection method: the rat was anesthetized with isoflurane, about 1 mL of blood was collected from the retroorbital venous plexus, the collected whole blood was placed into an EP tube containing heparin immediately, the EP tube was shaken by reversing top and bottom three times, and placed in crushed ice, and centrifugation was performed (at 4,000 rpm at 4° C. for about 5 min) within 1 h, and the centrifuged plasma sample was stored below −20° C. Naltrexone and its metabolite 6β-naltrexol, and risperidone and its metabolite 9-hydroxyrisperidone in the blood sample were detected by LC-MS/MS. Blood was collected for analysis once a week at time points 0 h, 4 h, D1, D3, D7, D10, D16, D39, D45, D60, D75, and D90.
Drug-time analysis results are shown in
Example Animal Pharmacodynamic Evaluation
All mice were bred under the same conditions. The product of the present disclosure was surgically implanted into each mouse in a model group before an experiment. Except implantation of the product of the present disclosure, other experimental conditions of a positive control group were the same as those of the model group. Mice in a negative control group were normally bred without undergoing experimental treatment. Behavioral differences among the model group, the positive control group, and the negative control group were observed during the experiment.
36 SD mice weighing 120-150 g, half male and half female, were taken. The mice were randomly divided into 3 groups: a positive control group, a negative control group, and a model group. The compound sustained-release preparation (prepared in Example 1) was implanted into the back of each mouse in the model group before administration, and a challenge experiment was carried out on the second day after surgery.
During the formative period, methylamphetamine (2 mg/kg) was daily intraperitoneally injected into each mouse in the positive control group and the model group, an equal amount of normal saline was intraperitoneally injected into each mouse in the negative control group for 7 consecutive days. During the conversion period, the drug was withdrawn for 7 days without any treatment. The expression period lasted for 12 weeks, during the expression period, methylamphetamine (2 mg/kg) was intraperitoneally injected into each mouse every 7 days for stimulation, and spontaneous activities of the mice were observed 30 minutes after injection.
Results are shown in
Finally, it should be noted that the above content is only used to describe the technical solutions of the present disclosure, rather than to limit the scope of protection of the present disclosure. Simple modifications or equivalent replacements made by those of ordinary skill in the art to the technical solutions of the present disclosure will not depart from the essence and scope of the technical solutions of the present disclosure.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202011243436.5 | Nov 2020 | CN | national |
This application is a U.S. National Stage Application under 35 U.S.C. 371 of International Application PCT/CN2020/135369, filed Dec. 10, 2020, which claims priority to Chinese Application No. 202011243436.5, filed Nov. 9, 2020, the contents of each of which is hereby incorporated by reference in its entirety. Invention Field The present disclosure relates to a method for producing a preparation, and specifically, to a compound sustained-release composition of naltrexone and risperidone, and preparation method and application thereof.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2020/135369 | 12/10/2020 | WO |
