Patent Description:
Naltrexone is a pure antagonist for opioid receptors, and has a block effect on µ-, δ-, and x-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:
<CHM>.

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:
<CHM>.

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. <CIT> discloses microparticles comprising naltrexone or risperidone. Microparticles comprising naltrexone are further disclosed in <CIT>, <CIT> and <CIT>. Microparticles comprising risperidone are further disclosed in <CIT> and <CIT>.

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, a preparation method of the risperidone sustained-release microspheres
may include the following steps:.

Further, the additive may be selected from at least one of sodium chloride, mannitol,
disodium hydrogen phosphate, and sodium dihydrogen phosphate.

Further, the fat-soluble polymer may be 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 may be selected from polyvinyl alcohol.

Further, in the poly(lactic-co-glycolic acid) (PLGA), a ratio of lactic acid to glycolic acid may be (<NUM>-<NUM>): <NUM>.

Further, the weight-average molecular weight (Mw) of the water-soluble polymer
or the fat-soluble polymer may be
<NUM>,<NUM>-<NUM>,<NUM> Da, and preferably <NUM>,<NUM>-<NUM>,<NUM> Da.

Further, the organic solvent may be
selected from at least one of dichloromethane and
ethyl acetate.

Further, in S1, a dosage ratio of the additive to the purified water may be <NUM>-<NUM>/mL,
and preferably <NUM>-<NUM>/mL.

Further, in S2, the concentration of risperidone may be
<NUM>-<NUM>/mL, and preferably.

Further, in S4, a dosage ratio of the primary emulsion to the aqueous solution of the water-soluble polymer may be (<NUM>-<NUM>): <NUM>, and preferably (<NUM>-<NUM>): <NUM>.

Further, in S4, in the aqueous solution of the water-soluble polymer, the content of the water-soluble polymer may be <NUM>-<NUM> wt%.

Further, in S4, the content of the water-soluble polymer may be <NUM>-<NUM> wt%.

Further, the aqueous solution may contain <NUM>-<NUM> wt% sodium chloride or <NUM>-<NUM> wt%
sucrose.

Further, the stirring may be performed at <NUM>-<NUM>,<NUM> revolutions/minute, and preferably
<NUM>-<NUM>,<NUM> revolutions/minute, and the evaporation may be performed at <NUM>-<NUM>,<NUM>
revolutions/minute, preferably <NUM>-<NUM>,<NUM> revolutions/minute, at <NUM>-<NUM> for <NUM>.

Further, a preparation method of the naltrexone sustained-release microspheres may include the following steps:.

Further, the fat-soluble polymer may be 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 organic solvent may be selected from at least one of dichloromethane and ethyl acetate.

Further, the weight-average molecular weight (Mw) of the water-soluble polymer or the fat-soluble polymer may be <NUM>,<NUM>-<NUM>,<NUM> Da, and preferably <NUM>,<NUM>-<NUM>,<NUM> Da.

Further, in S1', the concentration of naltrexone may be <NUM>-<NUM>/mL, and preferably <NUM>-<NUM>/mL; and the concentration of the fat-soluble polymer may be <NUM>-<NUM>/mL, and preferably <NUM>-<NUM>/mL.

Further, in S2', a dosage ratio of the oil phase to the aqueous solution of the water-soluble polymer may be (<NUM>-<NUM>): <NUM>, and preferably (<NUM>-<NUM>): <NUM>.

Further, in S2', in the aqueous solution of the water-soluble polymer, the content of the water-soluble polymer may be <NUM>-<NUM> wt%, and preferably <NUM>-<NUM> wt%.

Further, the aqueous solution may contain <NUM>-<NUM> wt% sodium chloride or <NUM>-<NUM> wt% sucrose, preferably <NUM>-<NUM> wt% sucrose.

Further, the stirring may be performed at <NUM>-<NUM>,<NUM> revolutions/minute, and preferably <NUM>-<NUM>,<NUM> revolutions/minute, and the evaporation may be performed at <NUM>-<NUM>,<NUM> revolutions/minute, preferably <NUM>-<NUM>,<NUM> revolutions/minute, at <NUM>-<NUM> for <NUM>.

Another objective of the present disclosure is to provide a preparation including the composition of the invention, which is prepared by uniformly mixing the composition with a lubricant, compressing into tablets, and coating.

Further, the lubricant may be selected from at least one of sodium stearyl fumarate, magnesium stearate, and a stearic acid.

Further, a dosage of lubricant may be is <NUM>-<NUM> wt% of the composition.

Still another objective of the present disclosure is to provide a medical use of the composition of the invention 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.

The present disclosure will be further described below with reference to the drawings.

Preparation of risperidone microspheres by a W<NUM>/O/W<NUM> double emulsion-solvent evaporation method.

Preparation of naltrexone microspheres by an O/W emulsion-solvent evaporation method.

<NUM> parts of prepared naltrexone microspheres, <NUM> part of prepared risperidone microspheres, and <NUM>% magnesium stearate were mixed and compressed into tablets.

An in vitro cumulative release curve of the compound sustained-release preparation of naltrexone and risperidone prepared in this example is shown in <FIG>, and it can be seen that the in vitro cumulative release period exceeds <NUM> days, and naltrexone and risperidone are released synchronously.

<NUM> parts of prepared naltrexone microspheres, <NUM> part of prepared risperidone microspheres, and <NUM>% sodium stearyl fumarate were mixed and compressed into tablets.

<NUM> parts of prepared naltrexone microspheres, <NUM> parts of prepared risperidone microspheres, <NUM>% sodium stearyl fumarate, and <NUM>% magnesium stearate were mixed and compressed into tablets.

The tablets were coated by spraying to obtain a compound sustained-release preparation of naltrexone and risperidone.

Preparation of risperidone microspheres by an O/W emulsion-solvent evaporation method.

An in vitro cumulative release curve of the compound sustained-release preparation of naltrexone and risperidone prepared in this Comparative Example is shown in <FIG>, and it can be seen that the in vitro cumulative release period is only <NUM> days, and naltrexone and risperidone cannot be released synchronously.

An in vitro cumulative release curve of the compound sustained-release preparation of naltrexone and risperidone prepared in this Comparative Example is shown in <FIG>, and it can be seen that the release periods of naltrexone and risperidone are less than <NUM> days, and naltrexone and risperidone cannot be released synchronously.

It can be seen from Example <NUM> and Comparative Example <NUM> 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 <NUM> and Comparative Example <NUM> 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.

Comparative Example <NUM> Preparation by using a fat-soluble polymer with a molecular weight different from Example <NUM>.

In this case, naltrexone and risperidone cannot be released synchronously.

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 <NUM>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 <NUM>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 <NUM> conical flasks with stoppers, <NUM> of <NUM> anhydrous dipotassium hydrogen phosphate solution (a solution prepared by accurately sucking and placing <NUM> of <NUM> sodium hydroxide solution into a <NUM>,<NUM> volumetric flask, adding a <NUM> anhydrous dipotassium hydrogen phosphate solution for dilution, and regulating the pH value of the diluted solution to <NUM>±<NUM>) was used as a solvent, and the conical flasks were tightly covered with the stoppers and shaken in a water bath oscillator at <NUM> times/minute at <NUM>+<NUM>. The medium was replaced on day <NUM>, day <NUM>, day <NUM>, day <NUM>, day <NUM>, day <NUM>,. , and day <NUM>, 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 <NPL>) at a wavelength of <NUM>.

In vitro cumulative release results are shown in <FIG>, and it can be seen that the release period of the product of the present disclosure is more than <NUM> weeks, and the naltrexone and risperidone drugs are released synchronously. However, the two drugs cannot be released synchronously in Comparative Examples, and a difference between release end points is more than <NUM> weeks.

SD rats, half male and half female, were taken as experimental animals. The naltrexone compound preparation sample of Example <NUM> 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 <NUM> 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 <NUM>,<NUM> rpm at <NUM> for about <NUM>) within <NUM>, and the centrifuged plasma sample was stored below -<NUM>. Naltrexone and its metabolite 6β-naltrexol, and risperidone and its metabolite <NUM>-hydroxyrisperidone in the blood sample were detected by LC-MS/MS. Blood was collected for analysis once a week at time points <NUM>, <NUM>, D1, D3, D7, D10, D16, D39, D45, D60, D75, and D90.

Drug-time analysis results are shown in <FIG>, and it can be seen that the product of the present disclosure can effectively release risperidone and naltrexone into the blood in the body of the experimental animal, and the plasma concentration is kept stable within <NUM> days.

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.

<NUM> SD mice weighing <NUM>-<NUM>, half male and half female, were taken. The mice were randomly divided into <NUM> groups: a positive control group, a negative control group, and a model group. The compound sustained-release preparation (prepared in Example <NUM>) 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 (<NUM>/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 <NUM> consecutive days. During the conversion period, the drug was withdrawn for <NUM> days without any treatment. The expression period lasted for <NUM> weeks, during the expression period, methylamphetamine (<NUM>/kg) was intraperitoneally injected into each mouse every <NUM> days for stimulation, and spontaneous activities of the mice were observed <NUM> minutes after injection.

Claim 1:
A compound sustained-release composition of naltrexone and risperidone, comprising the following components in parts by weight:
<NUM>-<NUM> parts of naltrexone sustained-release microspheres; and
<NUM>-<NUM> parts of risperidone sustained-release microspheres,
the risperidone sustained-release microspheres being prepared by a W<NUM>/O/W<NUM> double emulsion-solvent evaporation method, and the naltrexone sustained-release microspheres being prepared by an O/W emulsification-solvent evaporation method.