Application of pharmaceutical composition in preparation of medicine for preventing relapse of cannabis sativa

Abstract

The invention relates to the technical field of medicine, in particular to application of a pharmaceutical composition in preparation of medicine for preventing relapse of cannabis sativa, the pharmaceutical composition comprises active pharmaceutical ingredients naltrexone and risperidone and can be used for treating patients suffering from cannabis sativa addiction disorder or any condition or symptom related to the cannabis sativa addiction disorder, and further, the pharmaceutical composition can be used for preventing relapse of cannabis sativa. The medicament may be used to treat patients suffering from withdrawal syndrome during rehabilitation or detoxification from treatment of abuse of cannabis and / or patients suffering from relapse of addiction after rehabilitation or detoxification from treatment of abuse of cannabis.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technologies, and particularly to the use of a pharmaceutical composition in the preparation of a drug for preventing cannabis relapse. The active pharmaceutical ingredients in the pharmaceutical composition include naltrexone and risperidone. Background Art

[0002] Cannabis was originally derived from extracts of the cannabis plant and is a mixture with a relatively complex chemical composition. It was once used as an anesthetic in clinical practice, but was later abandoned due to its potential addiction and non-negligible side effects. Currently, it is mainly traded as a drug. Short-term use of cannabis can cause adverse reactions such as sedation, congestion, increased heart rate, lung irritation cough, increased appetite, and decreased blood pressure. Long-term and high-dose use of cannabis can cause cognitive and memory disorders, leading to problems such as memory loss, anxiety, hallucinations, depression, and even psychosis. This is also one of the reasons for abandoning the use of cannabis sedatives in clinical practice. Studies have confirmed that the use of cannabis can trigger hidden mental illnesses and exacerbate personality disorders in patients with diagnosed schizophrenia. There are also studies showing that cannabis has a significant inhibitory effect on the immune system and lung function, may induce respiratory diseases such as large airway inflammation, chronic bronchitis, and pneumonia, and may also increase the probability of developing invasive testicular cancer.

[0003] Modern pharmacological studies have shown that the main component in cannabis that induces addictive behavior is cannabinoid (exogenous cannabinoid), which stimulates specific regions of the brain, thereby stimulating the corresponding reward system and causing changes in the structure and function of the brain. Although there are currently many reports on drugs for the treatment and prevention of cannabis addiction, most of these drugs are used for the detoxification treatment of addicted patients or the adjuvant treatment during the withdrawal stage. The results show that the curative effect is not obvious, and they are rarely used to prevent relapse and treat the adverse symptoms caused by cannabis addiction. Clinically, relapse is generally regarded as a different treatment stage from the aforementioned addiction and withdrawal. After drug addicts withdraw from cannabis, they are very likely to start using the addictive substances abused before withdrawal again in a short period of time. The adverse symptoms caused by addiction cause great mental trauma to patients and are important factors inducing relapse. The relapse phenomenon is not only a common problem among drug addicts but also a difficult problem that the anti-drug work has been hoping to solve.

[0004] Therefore, there is an urgent need to develop a drug that can effectively prevent cannabis relapse. Summary of the Invention

[0005] Based on this, the object of this application includes providing the use of a pharmaceutical composition in the preparation of a drug for preventing cannabis relapse. Another object of this application is to provide the use of a pharmaceutical composition in the preparation of a drug for treating the adverse symptoms caused by cannabis addiction.

[0006] To achieve the above object, the following technical solutions are provided:

[0007] Use of a pharmaceutical composition in the preparation of a drug for preventing relapse of cannabis, wherein the pharmaceutically active ingredient in the pharmaceutical composition comprises naltrexone and risperidone.

[0008] In one embodiment, the mass ratio of the naltrexone to the risperidone is (5 - 30):1.

[0009] In one embodiment, the mass ratio of the naltrexone to the risperidone is 10:1.

[0010] In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0011] In one embodiment, the pharmaceutical composition and a pharmaceutically acceptable excipient are jointly made into a clinically acceptable preparation.

[0012] In one embodiment, the preparation comprises a liquid preparation and a solid preparation.

[0013] In one embodiment, the preparation is selected from any of the following groups or a suitable combination thereof:

[0014] 1) Tablets, capsules, granules, powders, powders for external use, suspensions or solutions;

[0015] 2) Oral liquids, buccal tablets, injections, suppositories, sprays, drops or patches.

[0016] In one embodiment, the form of the preparation is an implant.

[0017] In one embodiment, the subject is a mammal.

[0018] In one embodiment, the subject is a human or a rat.

[0019] In one embodiment, the subject is a LE rat.

[0020] Use of the pharmaceutical composition according to any of the above technical solutions in the preparation of a drug for treating adverse symptoms caused by cannabis addiction.

[0021] In one embodiment, the adverse symptoms caused by cannabis addiction include psychiatric symptoms.

[0022] In one embodiment, the psychiatric symptoms include anxiety, depression and hallucinations. Description of the Drawings

[0023] To more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the accompanying drawings required for the description of the specific embodiments or the prior art. Obviously, the accompanying drawings in the following description are some embodiments of the present application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0024] Figure 1 It is a flow chart of a subject trial for the therapeutic effect of a research drug composition on the adverse symptoms caused by cannabis addiction in an embodiment of the present application. Specific embodiments

[0025] The following will further elaborate on the pharmaceutical composition of the present application and its application in the preparation of a drug for preventing cannabis relapse or treating the adverse symptoms caused by cannabis addiction in combination with the embodiments and examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. In addition, it should be understood that after reading the content taught in the present application, those skilled in the art can make various changes or modifications to the present application, and these equivalent forms also fall within the protection scope of the appended claims of the present application.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present application belongs. The terms used in the specification of the present application herein are only for the purpose of describing specific embodiments and are not intended to limit the present application.

[0027] Terms

[0028] Unless otherwise stated or there are contradictions, the terms or phrases used herein have the following meanings:

[0029] In this application, "preferred", "better", "more preferably", etc. are only used to describe embodiments or examples with better effects, and it should be understood that they do not constitute a limitation on the protection scope of the present application.

[0030] In this application, "further", "even further", "especially", etc. are used for descriptive purposes and represent differences in content, but should not be understood as a limitation on the protection scope of the present application.

[0031] In this application, among the technical features described in an open-ended manner, it includes a closed technical solution composed of the listed features, and also includes an open technical solution containing the listed features.

[0032] In this application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the selectable numerical values are considered continuous within the above-mentioned numerical intervals, and include the two numerical endpoints of this numerical range (i.e., the minimum value and the maximum value), as well as each numerical value between these two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within this numerical interval, it includes the two endpoint integers of this numerical range, as well as each integer between the two endpoints. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0033] In this application, the weight can be mass units well-known in the chemical industry such as μg, mg, g, kg, etc.

[0034] In this article, "subjects" and "patients" refer to animals, preferably mammals, more preferably humans. Subjects include, but are not limited to, patients with diseases, disorders, and / or symptoms. The term "mammal" mainly refers to warm-blooded vertebrate mammals, including but not limited to: cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats (such as rats, mice), pigs, cows, sheep, horses, humans, etc., preferably primates, more preferably humans.

[0035] In this article, "drug" includes any medicament, compound, composition or mixture that provides physiological and / or pharmacological effects in vivo or in vitro, and often provides beneficial effects. The range of physiological and / or pharmacological effects produced by the "drug" in vivo is not particularly limited, and can be a systemic effect or only a local effect. The activity of the "drug" is not particularly limited, and can be an active substance that can interact with other substances, or an inert substance that does not interact.

[0036] In this article, "pharmaceutically acceptable" refers to those ligands, materials, compositions and / or dosage forms that are suitable for administration to patients within the scope of reasonable medical judgment and commensurate with a reasonable benefit / risk ratio.

[0037] As used herein, "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are compatible with the administration of the drug. Each entity must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0038] This application relates to the use of a pharmaceutical composition in the preparation of a drug for treating cannabis relapse, and the active pharmaceutical ingredient in the pharmaceutical composition includes naltrexone and risperidone.

[0039] Naltrexone is a non-selective antagonist of opioid receptors, and can completely block the pharmacological effects of intravenously injected opioid substances (such as heroin, etc.) through competitive binding at the opioid receptor site. Risperidone is a selective monoamine antagonist, which has a high affinity for the 5-HT2 receptor of serotonergic and the D2 receptor of dopamine, and can improve the positive symptoms of schizophrenia.

[0040] The excellent effect of naltrexone in the clinical treatment of patients addicted to opioid drugs has been confirmed, but currently, the treatment effect for drug dependence or diseases related to cannabis addiction, especially for preventing cannabis relapse, is not clear.

[0041] Through experimental research, this application discovers that the compound composition of naltrexone and risperidone has an unexpectedly excellent effect in preventing cannabis relapse. The inventor speculates that this is very likely related to the mechanism of cannabis addiction relapse.

[0042] The behavioral process of drug addiction is divided into three stages: ① formation; ② withdrawal (stopping drug use in the living environment) or extinction (stopping drug use in the training environment. Exclusive cue extinction, environmental cue extinction, exclusive + environmental cue extinction); ③ relapse (cue, priming with a small dose of drug).

[0043] ① Formation: During the formation of cannabis addiction, after cannabinoids enter the body, they increase dopamine levels by activating cannabinoid type 1 (CB1) receptors in the ventral tegmental area, thereby inducing its enhancing properties. Subsequently, some non-CB1 receptor acting systems also undergo compensatory adaptations, including the dopamine receptor acting system, 5-HT receptor acting system, opioid receptor system, GABA receptor acting system, etc.

[0044] ② Withdrawal: After stopping chronic intake of cannabis, a somatic withdrawal syndrome will occur. Some studies have shown that chronic treatment with cannabinoids and subsequent withdrawal lead to a decrease in neuronal activity in the mesolimbic dopaminergic pathway, which is involved in the long-term aversive consequences of drug withdrawal. There are also studies indicating that chronic tetrahydrocannabinol exposure alters several intracellular signal transduction processes, thereby mediating physiological and behavioral changes during withdrawal, such as CB1, AC, cAMP, and PKA. After chronic tetrahydrocannabinol exposure, synaptic inhibition induced by a decrease in the expression of CB1 receptors, as well as changes in the activities of AC, cAMP, and PKA, are observed, which may be related to the withdrawal response.

[0045] ③ Relapse: Under baseline conditions, dopamine neurons in the ventral tegmental area are inhibited by activating GABAergic neurons. After presenting drug-conditioned cues, dopamine neurons switch to a phasic firing pattern, thereby activating CB1 receptors on GABAergic neurons, inhibiting GABAergic neurons and thus disinhibiting dopaminergic neurons to increase dopamine levels. Cues conditioned on cannabis smoking can induce a drug-seeking response (i.e., craving) by triggering phasic dopamine events. Another dopamine-independent mechanism involved in the drug-seeking response involves the interaction of endocannabinoid / glutamate in the corticostriatal connection part of the reward system.

[0046] The pharmaceutical composition of the present application may play a role in preventing cannabis relapse by participating in the regulation of neural pathways related to relapse behavior.

[0047] In some of these embodiments, the pharmaceutical composition contains a therapeutically effective amount of a pharmaceutically active ingredient, and the pharmaceutically active ingredient is composed of naltrexone and risperidone in a mass ratio of (5~30):1.

[0048] In some of these embodiments, the composition of the pharmaceutical composition is as follows:

[0049] In some embodiments, the pharmaceutical composition comprises: (a) naltrexone; (b) risperidone; and (c) a pharmaceutically acceptable carrier.

[0050] In some embodiments, the carrier is poly(D,L-lactide).

[0051] In some embodiments, the pharmaceutical composition contains: (a) naltrexone at a concentration of 0.375 - 0.5 mg / mg; (b) risperidone at a concentration of 0.0375 - 0.05 mg / mg; and (c) poly(D,L-lactide).

[0052] In some embodiments, the pharmaceutical composition of the present application is formulated into a clinically acceptable preparation form jointly or separately with pharmaceutically acceptable excipients.

[0053] In some embodiments, the preparation includes liquid preparations and solid preparations.

[0054] In some embodiments, the preparation form is selected from any of the following groups or a suitable combination thereof:

[0055] 1) tablets, capsules, granules, powders, powders for external use, suspensions or solutions;

[0056] 2) oral liquids, buccal tablets, injections, suppositories, sprays, drops or patches.

[0057] In some embodiments, the preparation form is an implant.

[0058] The present application also relates to the use of a pharmaceutical composition containing a therapeutically effective amount of the above-mentioned pharmaceutically active ingredient in the preparation of a drug for preventing relapse of cannabis use.

[0059] The definitions of "pharmaceutical composition", "drug", "pharmaceutically active ingredient", etc. are the same as those above.

[0060] In some embodiments, the therapeutically effective amount is 0.4 - 0.6 mg / mg.

[0061] In some embodiments, the pharmaceutical composition contains 160 mg - 170 mg of the pharmaceutically active ingredient.

[0062] According to the above application, the present application also provides a method for preventing relapse of cannabis use, which includes administering a therapeutically effective amount of the pharmaceutical composition to a patient in need. That is, the patient is made to administer a therapeutically effective amount of the pharmaceutical composition.

[0063] Route of administration

[0064] There is no particular limitation on the dosage form and route of administration of the pharmaceutically active ingredient or its pharmaceutical composition of the present application. Representative routes of administration include but are not limited to: oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.

[0065] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier) such as sodium citrate or calcium phosphate, or with the following components: (a) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrants, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid dosage forms such as tablets, pills, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and release of the active compound or compounds in such compositions may be delayed and released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and wax-like substances. If necessary, the active compound may also be in the form of microcapsules with one or more of the above excipients.

[0066] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents conventionally used in the art such as water or other solvents, solubilizers, and emulsifying agents, specifically, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfumes. For example, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar, or mixtures of these substances.

[0067] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non - aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non - aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0068] Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. They are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required under aseptic conditions.

[0069] The drugs of the embodiments of the present invention can be added with different pharmaceutically acceptable excipients to prepare suitable clinical dosage forms, and these clinical dosage forms include but are not limited to the dosage forms described above.

[0070] These pharmaceutically acceptable excipients include, but are not limited to, diluents, wetting agents, binders, disintegrants, lubricants, color, flavor and odor regulators, solvents, solubilizers, cosolvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, local anesthetics, pH regulators, isotonic or isosmotic regulators, etc. Further: diluents such as starch, sucrose, celluloses, inorganic salts, etc.; wetting agents such as water, ethanol, etc.; binders such as starch paste, dextrin, sugar, cellulose derivatives, gelatin, povidone, polyethylene glycol, etc.; disintegrants such as starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, crospovidone, surfactants, effervescent disintegrants, etc.; lubricants such as talc, calcium stearate, magnesium stearate, magnesium lauryl sulfate, colloidal silica, polyethylene glycol, etc.; color, flavor and odor regulators such as pigments, spices, sweeteners, mucilage, odor correctors, etc., specifically such as fuchsin, xylitol; solvents such as water, oil, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil, ethyl acetate, etc.; solubilizers such as Tweens, Myrj, polyoxyethylene fatty alcohol ethers, soaps, sulfates, sulfonates, etc.; cosolvents such as organic acids (such as citric acid) and their salts, amides and amine compounds, inorganic salts, polyethylene glycol, povidone, glycerol, etc.; emulsifiers such as Spans, Tweens, Myrj, Brij, glycerol fatty acid esters, higher fatty acid salts, sulfates, sulfonates, acacia, tragacanth, gelatin, pectin, phospholipids, agar, sodium alginate, hydroxides, silica, bentonite, etc.; suspending agents such as glycerol, syrup, acacia, tragacanth, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol, thixotropic gel, etc.; antioxidants such as sulfites, metabisulfites, bisulfites, ascorbic acid, gallic acid and its esters, etc.; metal complexing agents such as disodium ethylenediaminetetraacetate, polycarboxylic compounds, etc.; inert gases such as nitrogen, carbon dioxide, etc.; preservatives such as parabens, organic acids and their salts (such as sodium benzoate), quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols and volatile oils, etc.; local anesthetics such as benzyl alcohol, chlorobutanol, lidocaine and procaine, etc.; pH regulators such as hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphates, acetates, citric acid, citrate, etc.; isotonic or isosmotic regulators such as glucose, sodium chloride, sodium citrate, sorbitol and xylitol, etc.It is understandable that the diluent described in the embodiments of the present text can also be called a filler, and it plays the same role in pharmaceutical preparations; the water described in the embodiments of the present text is water that meets the requirements of the medicament, such as water for injection, purified water, etc., and the oil is injection oil; the preservative described in the embodiments of the present text can also be called an antibacterial agent, and it plays roles such as inhibiting the growth of microorganisms and extending the shelf life in the preparation; the lubricant in the embodiments of the present text contains glidants, anti-adhesives, etc.; the sugar described in the embodiments of the present text can be powdered sugar or syrup, and the types of sugar are not limited to glucose; the fragrance described in the embodiments of the present text includes but is not limited to essence.

[0071] In some embodiments, the dose of the pharmaceutical composition is at least 2 units, and each unit of the pharmaceutical composition is 300 mg to 400 mg.

[0072] In some embodiments, the dosing frequency is once every 3 months.

[0073] In some embodiments, the administration method of the pharmaceutical composition is implantation. Further, in some embodiments, the implantation sites are the abdominal cavity and the arm.

[0074] In some embodiments, the administered dose is at least 2 units of the pharmaceutical composition, and each unit of the pharmaceutical composition is 300 mg to 400 mg.

[0075] In some embodiments, the subject is a mammal.

[0076] In some embodiments, the subject is a rat or a human.

[0077] In some embodiments, the subject is a LE rat. Further, the administered dose is at least 2 units, each unit of the pharmaceutical composition is 300 mg to 400 mg, the pharmaceutical composition for administration contains at least 300 mg of naltrexone, and at least 30 mg of risperidone.

[0078] To improve the sustained-release effect, the pharmaceutical composition can be prepared into a sustained-release implant.

[0079] In some of these embodiments, the sustained-release implant is prepared by steps including the following preparation method:

[0080] Prepare naltrexone into naltrexone sustained-release microspheres;

[0081] Prepare risperidone into risperidone sustained-release microspheres;

[0082] Weigh the required amount of risperidone sustained-release microspheres and naltrexone sustained-release microspheres according to the weight ratio, and add pharmaceutically acceptable excipients to prepare an implant;

[0083] Among them, the mass ratio of naltrexone to risperidone in the implant is (5 - 30):1.

[0084] In some of these embodiments, the pharmaceutical composition comprises, by mass percentage: 37.5% - 50% of naltrexone, 3.75% - 5% of risperidone, and 0.4% - 0.6% of magnesium stearate.

[0085] In some of these embodiments, the preparation method of the sustained-release implant refers to the technical solution in WO2022095203A, and the prepared sustained-release implant has the same technical effects as those described in this patent, including: 1) It can achieve sustained release in vitro for more than 12 weeks; 2) The release conforms to an approximate zero-order pattern, and the release rate is stable; 3) The release rates of the naltrexone sustained-release microspheres and the risperidone sustained-release microspheres in vivo are synchronized.

[0086] In some of these embodiments, when the sustained-release implant is implanted for 3 months, it can still prevent relapse in cannabis addicts.

[0087] The following are some specific embodiments.

[0088] For the experimental parameters not specified in the following specific embodiments, preference is given to referring to the guidance given in this application document. It is also possible to refer to the experimental manuals in this field or other experimental methods known in this field, or to the experimental conditions recommended by the manufacturers.

[0089] The raw materials and reagents involved in the following specific embodiments can be obtained commercially, or those skilled in the art can prepare them according to known means.

[0090] I. Studying the prevention of relapse in cannabis addicts by the pharmaceutical composition

[0091] Example 1

[0092] This example provides a preparation method of an implant containing a pharmaceutically active ingredient and the product prepared by this method, including a naltrexone implant, a risperidone implant, and a naltrexone-risperidone compound implant.

[0093] (1) Preparation of the naltrexone implant

[0094] ① Preparation of naltrexone microspheres

[0095] Dissolve naltrexone and poly(D,L-)lactide in dichloromethane to form an oil phase; prepare a continuous phase solution from water, the surfactant polyvinyl alcohol, and the osmotic pressure regulator sucrose; drop the oil phase into the continuous phase solution, stir well to homogenize and volatilize the organic solvent, and obtain dry microspheres after filtration and vacuum drying.

[0096] ② Material mixing and tabletting

[0097] Add the above-mentioned naltrexone microspheres and magnesium stearate to the hopper mixer according to the prescription amount, mix evenly, and tablet to obtain a plain tablet with a specification of 150 mg / tablet.

[0098] ③ Coating and Drying

[0099] The bare tablets are soaked and coated with an ethyl acetate solution of poly(D,L-lactide), and then dried to obtain the product.

[0100] ④ Packaging

[0101] The tablets are filled into vials according to the specified filling volume and then sealed by plugging and capping.

[0102] (2) Preparation of Risperidone Implant

[0103] ① Preparation of Risperidone Microspheres

[0104] Sodium chloride is dissolved in purified water to form the internal aqueous phase; risperidone and poly(D,L-lactide) are dissolved in dichloromethane to form the oil phase; water, the surfactant polyvinyl alcohol, and the osmotic pressure regulator sodium chloride are prepared into a continuous phase solution; then the internal aqueous phase is added to the oil phase, and ultrasonic emulsification is carried out to form the primary emulsion. Finally, the primary emulsion is dropped into the continuous phase solution, stirred and homogenized thoroughly to volatilize the organic solvent, and the dried microspheres are obtained after filtration and vacuum drying.

[0105] ② Material Mixing and Tableting

[0106] The above-mentioned risperidone microspheres and magnesium stearate are added to the hopper mixer according to the prescription amount and mixed evenly, and then tabletted to obtain the bare tablets with a specification of 15 mg / tablet.

[0107] ③ Coating and Drying

[0108] The bare tablets are soaked and coated with an ethyl acetate solution of poly(D,L-lactide), and then dried to obtain the product.

[0109] ④ Packaging

[0110] The tablets are filled into vials according to the specified filling volume and then sealed by plugging and capping.

[0111] (3) Preparation of Naltrexone-Risperidone Compound Implant

[0112] ① Preparation of Naltrexone Microspheres

[0113] Naltrexone and poly(D,L-lactide) are dissolved in dichloromethane to form the oil phase; water, the surfactant polyvinyl alcohol, and the osmotic pressure regulator sucrose are prepared into a continuous phase solution; the oil phase is dropped into the continuous phase solution, stirred and homogenized thoroughly to volatilize the organic solvent, and the dried microspheres are obtained after filtration and vacuum drying.

[0114] ② Dissolve sodium chloride in purified water to form the internal aqueous phase; dissolve risperidone and poly(D,L-lactide) in dichloromethane respectively to form the oil phase; prepare a continuous phase solution with water, the surfactant polyvinyl alcohol and the osmotic pressure regulator sodium chloride; then add the internal aqueous phase to the oil phase, and form a primary emulsion by ultrasonic emulsification. Finally, add the primary emulsion dropwise to the continuous phase solution, stir well to homogenize and volatilize the organic solvent, filter, and then dry in vacuum to obtain dry microspheres.

[0115] ③ Material mixing and tabletting

[0116] Add the above compound microspheres and magnesium stearate in the prescribed amounts to a hopper mixer and mix evenly, then tablet to obtain the naked tablets, with the specification of naltrexone: risperidone being 150 mg: 15 mg / tablet.

[0117] ④ Coating and drying

[0118] Immerse the naked tablets in an ethyl acetate solution of poly(D,L-lactide) for coating, and then dry to obtain the tablets. The weight of each naltrexone-risperidone implant tablet is 300 mg to 400 mg.

[0119] ⑤ Packaging

[0120] According to the specified filling volume, load the tablets into vials and press the stoppers and crimp the caps for sealing.

[0121] The following Examples 2 to 4 study the effects of the pharmaceutical composition of the present application in treating cannabis addiction and preventing relapse.

[0122] Subcutaneous implantation method of naltrexone sustained-release preparation One day before implanting the test article, shave the hair on both sides of the animal's back spine to expose the skin for convenient implantation of the naltrexone implant. After the animal is anesthetized with isoflurane, disinfect the local skin with an alcohol cotton ball. After making an incision about 0.5 cm in size with a scalpel, push the puncture needle forward about 3 cm to 4 cm, move it left and right to ensure correct entry into the cortex, and then inject the corresponding dose of tablets. The injection site should be as far away from the spine as possible to avoid causing pain and injury to the animal due to movement and friction of the tablets. After suturing, sprinkle anti-inflammatory powder on the wound to ensure wound healing. Thereafter, disinfect the wound surface with iodophor every day until the wound completely heals. The surgical instruments are sterilized in advance.

[0123] Example 2

[0124] This example studies the anti-relapse effect of the pharmaceutical composition of the present application in the self-administration model of LE rats.

[0125] 2.1. Drugs and reagents

[0126] WIN 55,212-2, off-white powder (131543-23-2, Shanghai Yuansi Standard Substance Technology Co., Ltd.);

[0127] Rimonabant, white solid (HY-14137, Shanghai Haoyuan Biopharmaceutical Technology Co., Ltd.);

[0128] The naltrexone-risperidone compound implant prepared in Example 1;

[0129] The naltrexone implant prepared in Example 1;

[0130] The risperidone implant prepared in Example 1;

[0131] The drugs used in the following examples are solutions, and their preparation solvents and dosages are shown in Table 1.

[0132] Table 1

[0133]

[0134] 2.2. Experimental animals

[0135] SPF LE rats (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.), weighing 220g-250g, were randomly divided into groups with 10 rats in each group.

[0136] 2.3. Establishment of the self-administration model

[0137] Experimental apparatus: Rat self-administration system / 16 channels, rat self-administration operation cage: 30.5cm×24.1cm×21cm in size, placed in a ventilated and soundproof box, each experimental cage is equipped with two lever operation devices with a hole diameter of 2.5cm on the operation surface, respectively, "valid" lever and "invalid" lever. The distance between the levers is 15cm, the height is 5cm, and an LED signal light is installed above each lever; a 1cm diameter white LED cage light is installed on the top of the operation surface, and the infusion connection system consists of an infusion pipeline, an infusion shaft and an infusion pump; the infusion pipeline is covered with an infusion spring connecting rod to protect the infusion pipeline from being bitten by animals; the experimental cage is controlled by a computer.

[0138] Experimental methods

[0139] 2.4.1. Food training

[0140] On the third day of postoperative recovery, the animals were restricted to 12 g of food. On the 4th to 6th days, they were trained to self-feed food pellets at a fixed ratio of 1 (FR1) for 1 hour per day to help them learn the lever-pressing behavior. Pressing the effective lever resulted in: (i) the cue light above the effective lever turned on and remained on for 10 seconds; (ii) a grain appeared in the trough; (iii) the indoor light turned off for 20 seconds, entering the refractory period (time-out). After the 20-second timed isolation, the indoor light turned on and a new round of trials began.

[0141] Another strut is an invalid strut, which is not coupled with any continuous event but is always recorded.

[0142] 2.4.2. Self-administration training

[0143] Seven days after postoperative recovery, self-administration training was started (WIN55, 212-2, WIN55, 212-2 is a cannabis injection solution, concentration: 12.5 μg / kg / infusion, rat body weight is about 200 g): The rats were placed in a self-administration training box and connected to a self-administration injection system. Reinforcement training was carried out using a fixed ratio of 1 (FR1, gradually increased to FR3), training for 2 h every day and continuing training. During each self-administration process, when the effective lever was touched, the injection system automatically administered the drug (intraperitoneal injection), about 0.1 mL each time, with a duration of 4 s to 6 s. At the same time, each injection would be accompanied by the effective lever light being on for 10 s and the chamber light being off for 20 s. When the chamber light was turned off, a 20-s refractory period entered. During this period, when the rats touched the effective lever, no drug injection was carried out, but the number of effective strut responses could be recorded. The data of touching the invalid lever was recorded, but no drug injection was given. During the training process, the computer automatically recorded the effective and invalid struts and the number of injection needles. The food was restricted to 12 g during the training process. The standard for successful training was that the number of cannabis injection needles in rats gradually increased and stabilized with the accumulation of training days, and the difference in the number of effective struts in the last 3 days was stable at about 20%.

[0144] 2.4.3. Self-administration extinction training

[0145] After the self-administration model was established, each round of extinction training for rats received 2 h of environmental extinction. During the extinction process, only the spatial environment and levers during training were presented, without other cues such as lights and pump sounds and drug injection. The computer automatically recorded the behavioral response numbers of the rats, and the rats reached the extinction standard (that is, the total number of effective struts decreased to 20% of the total number of effective struts on the first day of extinction training or less than 10 times).

[0146] 2.4.4. Grouping and drug administration

[0147] After the self-administration training and extinction were completed, the rats were randomly divided into a compound naltrexone risperidone implant group, a naltrexone implant group, and a risperidone implant group according to the number of injection needles and the number of effective struts. The compound naltrexone risperidone implant, naltrexone implant, and risperidone implant were implanted subcutaneously; the control group and the rimonabant group underwent sham surgery. After postoperative care for three days, corresponding relapse tests were started on the fourth day.

[0148] 2.4.5. Effect of the compound on cue-induced relapse behavior

[0149] The rimonabant group of rats will be given a rimonabant injection 15 minutes before the test, at a dose of 2 mg / kg. The control group will be given normal saline 15 minutes before the test. The compound groups of the compound naltrexone risperidone implant, naltrexone implant, and risperidone implant groups will not be administered drugs. Then, the animals will undergo a 2-hour environmental cue-induced relapse test. The cues will be consistent with the self-administration training, including lever pressing, cage lighting, and the sound of the infusion pump, but there will be no drug in the infusion pump. The number of injections and valid lever press data will be recorded by a computer.

[0150] 2.4.6. Extinction training

[0151] The rats will undergo another 2-hour environmental extinction. During the extinction process, only the spatial environment during self-administration training will be presented, without other cues such as lighting, pump sounds, or drug injections. The computer will automatically record the number of behavioral responses of the rats, and the extinction will continue until the standard is reached.

[0152] 2.4.7. Effect of the compound on drug (WIN55, 212-2)-combined environmental cue-induced relapse behavior

[0153] The rats in the rimonabant group will be given a rimonabant injection (2 mg / kg, ip) 15 minutes before the test, at a dose of 2 mg per kilogram of body weight by intraperitoneal injection. The control group will be given normal saline 15 minutes before the test. The implant administration groups will not be administered drugs. All rats will receive cannabis (WIN55, 212-2 injection 0.3 mg / kg, ip), at a dose of 0.5 mg per kilogram of body weight by intraperitoneal injection, and then immediately undergo a 2-hour drug-combined environmental cue relapse test. The cues will be consistent with the self-administration training, including lever pressing and the sound of the infusion pump, but there will be no drug in the infusion pump. The number of injections and valid lever press data will be recorded by a computer.

[0154] 2.5. Experimental results

[0155] 2.5.1. Results of the effect of the compound on environmental cue-induced relapse behavior

[0156] In the environmental cue-induced relapse test, the control group showed significant relapse behavior, manifested as a significant increase in the number of valid lever presses compared with the last extinction. The naltrexone implant and compound naltrexone risperidone implant groups could significantly reduce the cue-induced relapse behavior, manifested as a significant decrease in the number of valid lever presses compared with the control group (Table 2). The reference compound rimonabant did not show a significant inhibitory effect in the relapse test. There was no significant difference in the number of invalid lever presses among the groups.

[0157] Table 2 Effect of the compound on environmental cue-induced relapse behavior (mean±SD, n = 10).

[0158]

[0159] In Table 2, the data are expressed as Mean ± SEM, and two-way repeated measures ANOVA was used (compared with the last-ext-Vehicle group: ****p < 0.0001; compared with the Cue-Vehicle group: # p < 0.05, ## p < 0.01)

[0160] 2.5.2. Effect of the compound on drug combined with environmental cue-induced relapse behavior

[0161] In the relapse test induced by drug combined with environmental cue, the control group showed significant relapse behavior, manifested as a significant increase in the number of effective lever presses compared with the last extinction. While the naltrexone implant and compound naltrexone risperidone implant groups could significantly reduce the relapse behavior induced by cue combined with drug, manifested as a significant decrease in the number of effective lever presses compared with the control group (Table 3). The reference compound rimonabant did not show a significant inhibitory effect in the relapse test.

[0162] Table 3 Effect of the compound on drug combined with environmental cue-induced relapse behavior (mean±SD, n = 10)

[0163]

[0164] The data are expressed as Mean ± SEM, and two-way repeated measures ANOVA was used (compared with the re-ext-Vehicle group: *p < 0.05; compared with the Cue+Drug-Vehicle group: #p < 0.05, ##p < 0.01)

[0165] In this example, female LE rats could form stable WIN 55,212-2 self-administration, indicating successful establishment of the model; after self-administration training and extinction were completed, when randomly grouped, there were no significant differences among the control group, rimonabant group, naltrexone implant group, risperidone implant group and compound naltrexone risperidone implant group during the training and extinction phases; in the environmental-induced relapse test, the control group showed significant relapse behavior, and the naltrexone implant and compound naltrexone risperidone implant groups could significantly reduce the relapse behavior induced by cues; in the relapse test induced by drug combined with environmental cue, the control group showed significant relapse behavior, and the naltrexone implant and compound naltrexone risperidone implant groups could significantly reduce the relapse behavior induced by cue combined with drug; the positive drug rimonabant did not show a significant inhibitory effect in the two relapse tests. It can be seen that the compound naltrexone risperidone implant has good efficacy in preventing cannabis relapse, and the compound naltrexone risperidone implant has better efficacy than the single drug.

[0166] Example 3

[0167] This example studies the effect of the pharmaceutical composition of the present application on the formation of self - administration addiction in LE rats.

[0168] 3.1 Grouping and administration

[0169] Animals were randomly divided into a model control group, a rimonabant group, a compound naltrexone risperidone implant group, a naltrexone implant group, and a risperidone implant group. On the day of intravenous intubation surgery, the compound naltrexone risperidone implant, naltrexone implant, and risperidone implant were implanted subcutaneously synchronously; the control group and the rimonabant group underwent sham surgery. After postoperative care for three days, addiction formation training began on the fourth day.

[0170] 3.2 Effect of the drug on the establishment of the intravenous self - administration model

[0171] Rats in the control group and the rimonabant group were given the corresponding compounds 15 minutes before each daily training. Rimonabant, 2 mg / kg, i.p., the control group was given normal saline, and the implant administration groups were not given drugs. The training operation was the same as the self - administration training in Example 1. During the training process, the computer automatically recorded the effective and ineffective lever presses and the number of injection needles. Food was restricted to 12 g during the training process. The standard for successful training was that the number of cannabis injection needles in rats gradually increased and stabilized with the accumulation of training days, and the difference in the number of effective lever presses in the last 3 days was stable at about 20%.

[0172] 3.3 Effect of the drug on the extinction of drug - seeking behavior

[0173] After the self - administration model was established, rats received 2 - hour environmental extinction in each round of extinction training. During the extinction process, only the spatial environment and lever during training were presented, without other cues such as lights, pump sounds, etc. and drug injection. The computer automatically recorded the behavioral response numbers of rats. Rats reached the extinction standard (that is, the total number of effective lever presses dropped to 20% of the total number of effective lever presses on the first day of extinction training or less than 10 times).

[0174] 3.4 Experimental results

[0175] The number of effective lever presses of rats during extinction and the number of days to reach extinction stability were recorded. The results are shown in Table 4. According to Table 4, after administration of rimonabant, compound naltrexone risperidone implant, and naltrexone implant, the increase in the number of effective lever presses caused by win55,212 - 2 (cannabis) addiction formation could be significantly inhibited. Except for the risperidone administration group, the differences between other administration groups and the control group were significant, and the compound naltrexone risperidone implant group had the strongest inhibitory effect. It shows that compared with the administration of naltrexone or risperidone alone, the combined administration of naltrexone and risperidone has a synergistic effect.

[0176] In the extinction procedure, the groups that reached the extinction criteria in ascending order of speed were the compound naltrexone-risperidone implant group, naltrexone and rimonabant were comparable, the risperidone group, and the normal saline control group. The results showed that each administration group had a certain inhibitory effect on the extinction process of cannabis addiction. The compound had the most significant inhibitory effect on addiction extinction, and the effect was better than that of the combined administration group and the single-drug group.

[0177] Table 4 Self-administration training and extinction of WIN55,212-2 in female LE rats (mean±SD, n = 10)

[0178]

[0179] Data are expressed as Mean ± SEM. Two-way repeated measures ANOVA was used (compared with the Vehicle group: *p < 0.05, **p < 0.01; ***p < 0.001)

[0180] 3.5 Conclusion

[0181] 3.5.1 Effects of rimonabant at different stages of cannabis addiction

[0182] From the experimental data, it can be seen that rimonabant has a significant inhibitory effect on the formation stage of cannabis addiction. It can accelerate the extinction procedure and reduce the number of extinction days during the extinction period. It has an inhibitory effect on cue-induced reinstatement and cue + drug-induced reinstatement, but not significantly. It is suggested that rimonabant can prevent cannabis addiction.

[0183] The behavioral process of drug addiction is divided into three stages: ① formation; ② withdrawal (stopping drug use in the living environment) or extinction (stopping drug use in the training environment. Specific cue extinction, environmental cue extinction, specific + environmental cue extinction); ③ relapse (cue, low-dose drug-induced reinstatement). During the formation process of cannabis addiction, after cannabinoids enter the body, they increase dopamine levels by activating the type 1 cannabinoid (CB1) receptor in the ventral tegmental area, thereby inducing its potentiating property. Subsequently, some non-CB1 receptor-acting systems also undergo compensatory adaptation, including the dopamine receptor-acting system, 5-HT receptor-acting system, opioid receptor system, GABA receptor system, etc. Rimonabant is an inhibitor of the type 1 cannabinoid receptor (CB1), so it was selected as the positive drug for the cannabis addiction model. Its blocking effect on the CB1 receptor is more effective in the initial stage of cannabis addiction formation. In the relapse stage of cannabis addiction (including cue-induced reinstatement or cue + drug-induced reinstatement), the non-CB1 receptor-acting system plays a very important role, and the blocking effect of the CB1 receptor is limited, so the effect of rimonabant is relatively limited.

[0184] 3.5.2 Effects of naltrexone-risperidone at different stages of cannabis addiction

[0185] It can be seen from the experimental data that when the combined implantation amount of naltrexone risperidone implant is more than 2 tablets, that is, 300 mg of naltrexone: 30 mg of risperidone, compared with the model group, the combined implant can significantly inhibit the formation and relapse of cannabis addiction during cannabis formation, extinction, cue-induced reinstatement, and cue-plus-drug-induced reinstatement, and can significantly accelerate the stable formation of extinction. Therefore, the naltrexone risperidone implant can not only prevent the formation of cannabis addiction, accelerate the withdrawal of cannabis, but also effectively prevent the relapse of cannabis.

[0186] Example 4

[0187] This example studies the effects of different doses of drug compositions on the reinstatement behavior of self-administration and the results of blood drug concentration.

[0188] 4.1. Grouping and drug administration

[0189] The training operation is the same as that in Example 1. After the self-administration training and extinction are completed, according to the number of injection needles and the number of effective lever presses, the animals are randomly divided into a control group, a low-dose group, a medium-dose group, and a high-dose group of compound naltrexone risperidone implant. The low-dose group, medium-dose group, and high-dose group of compound naltrexone risperidone implant are implanted subcutaneously; the control group undergoes a sham operation. After postoperative care for three days, corresponding reinstatement tests are started on the fourth day. Immediately after the reinstatement test ends on the same day, the animals are bled from the heart, the plasma is taken by centrifugation, and the drug contents of naltrexone, 6-β-naltrexol, risperidone, and 9-OH-risperidone in the plasma are measured.

[0190] 4.2. Effects of drugs on cue-induced reinstatement behavior

[0191] The control group is given normal saline 15 minutes before the test, and the implant group is not given drugs. Then, the animals undergo a 2-hour cue-induced reinstatement test. The cues are the same as those in the self-administration training, including lever pressing, cage lighting, and the sound of the injection pump, but there is no drug in the injection pump. The number of injections and the data of effective lever presses are recorded by a computer.

[0192] 4.3. Extinction training

[0193] The rats are again subjected to 2 hours of environmental extinction. During the extinction process, only the spatial environment during the self-administration training is presented, without other cues such as lighting, pump sound, and drug injection. The computer automatically records the behavioral response numbers of the rats, and continuous extinction is carried out until the standard is reached.

[0194] 4.4. Effects of drugs on drug-plus-cue-induced reinstatement behavior

[0195] The control group was given normal saline 15 minutes before the test, and the implant group was not given any drugs. All rats received WIN55,212-2 (0.3 mg / kg, i.p.) by intraperitoneal injection, and then immediately underwent a 2-hour relapse test with drug-associated environmental cues. The cues were consistent with the self-administration training, including lever pressing and the sound of the injection pump, but there was no drug in the injection pump. The number of injections and valid lever press data were recorded by a computer.

[0196] 4.5. Experimental results

[0197] The results of the different-dose groups of naltrexone risperidone combination on cue-induced reinstatement and cue + drug-induced reinstatement are shown in the following table (Table 4). The experimental results showed that as the implantation dose (number of tablets) increased, the blood drug concentration in the rats also increased accordingly. The specific results are shown in the following table. In the addiction model induced by win55,212-2, when 4 tablets and 2 tablets of the compound implant were implanted, there was a significant inhibitory effect on cue-induced reinstatement and cue + drug-induced reinstatement. When 1 tablet was implanted, there was a slight inhibitory effect, but there was no significant difference; the inhibitory effect of the implant on relapse was dose-dependent.

[0198] That is to say, the compound naltrexone risperidone implant starts to take effect from 2 tablets, each tablet is 150 mg / 15 mg, and the sustained-release time is 3 months.

[0199] Table 5 Effects of different-dose drugs on self-administration relapse behavior and blood drug concentration results (mean±SD, n = 10)

[0200]

[0201] In Table 5, the data are expressed as Mean ± SEM, and two-way repeated measures ANOVA was used (compared with the Last-ext-Vehicle group: **p < 0.01, ****p < 0.0001; compared with the Cue-Vehicle group and Cue+Drug-Vehicle group: #p <0.05, ##p < 0.01)

[0202] II. Therapeutic effect of the research drug combination on the adverse symptoms caused by cannabis addiction

[0203] This example is a study on the effectiveness and safety of naltrexone risperidone implant for the prevention of relapse after detoxification in patients with cannabis drug dependence, and it involves the improvement effect of naltrexone risperidone implant on mental symptoms for the prevention of relapse after detoxification in patients with cannabis drug dependence.

[0204] 1. Experimental design

[0205] This study is a single-center, randomized, open-label, blank-controlled clinical trial initiated by the researcher. 100 patients with cannabis drug dependence were selected.

[0206] Subjects participating in the trial must meet all of the following criteria to be included in this study:

[0207] (1) Voluntarily participate in the clinical study; fully understand and be informed of this study and sign the informed consent; be willing to follow and be able to complete all trial procedures;

[0208] (2) ≥18 years old at the time of signing the informed consent;

[0209] (3) Meet the DSM-5 diagnostic criteria for cannabis use disorder and complete detoxification treatment;

[0210] (4) Negative urine qualitative cannabis test (TLC);

[0211] (5) Female subjects have evidence of postmenopausal status, or premenopausal female subjects have a negative serum pregnancy test before drug administration. Eligible subjects of childbearing age (male and female) must agree to take effective contraceptive measures (hormonal or barrier methods or abstinence) with their partners during the trial.

[0212] Subjects participating in the trial cannot be included if they meet any of the following criteria:

[0213] (1) The investigator determines that participation in this study is not in the best interests of the subject, or any other situation that does not allow the subject to safely participate in the study;

[0214] (2) Pregnant, pregnant test positive in childbearing women, or lactating women, including women of childbearing age planning to become pregnant during the study. Note: Women of childbearing age here refer to women with reproductive capacity. They must meet the following criteria regardless of their sexual orientation or whether they have had a tubal ligation: 1) Have not had a hysterectomy or bilateral oophorectomy; or 2) Have not had natural menopause for more than 12 consecutive months (i.e., have had a menstrual period at any time in the previous 12 consecutive months);

[0215] (3) Significantly abnormal liver function (such as AST or ALT higher than 2 times the upper limit of the normal value) or liver failure [including but not limited to: ascites, prolonged prothrombin time, international normalized ratio (INR) ≥1.7, esophageal varices disease] or the results of liver and gallbladder B-ultrasound show a great impact on the judgment of the efficacy and safety of the study drug;

[0216] (4) Suffering from clinically uncontrolled active infectious diseases, such as active hepatitis B [positive hepatitis B surface antigen (HBsAg) test and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) copy number > 1000 IU / ml], active hepatitis C [positive hepatitis C virus antibody and hepatitis C virus (HCV)-ribonucleic acid (RNA) positive], etc.;

[0217] (5) History of congenital hemorrhagic diseases (such as hemophilia) or any active clinically significant bleeding, or platelet function abnormalities, or the prothrombin time (PT) in the coagulation function test exceeding the upper limit of the normal value by more than 3 seconds (sec), or platelet count < 50 × 109 / L;

[0218] (6) In the judgment of the researcher, the subject has any severe / uncontrolled systemic diseases (such as diseases of the respiratory system, circulatory system, digestive system, nervous system, hematological system, urogenital system, endocrine system) or mental diseases (such as major depressive disorder, schizophrenia, bipolar disorder, etc.) or other major diseases, etc., which the researcher believes will prevent the provision of informed consent, make participation in the study unsafe, complicate the interpretation of the study outcome data, or otherwise affect the achievement of the study purpose;

[0219] (7) May require hospitalization or surgery during the study period, including planned elective surgery or hospitalization that cannot be postponed;

[0220] (8) Currently (within one year before randomization / drug administration) diagnosed with a substance use disorder other than cannabinoids, such as: benzodiazepines, opioids, or cocaine, etc.;

[0221] (9) Used relapse prevention drugs (such as naltrexone, risperidone, etc.) within 30 days before randomization / drug administration;

[0222] (10) Currently receiving treatment for substance use disorders such as opioids, alcohol, etc., or received opioids within 7 days before randomization / drug administration, may require opioid treatment during the study period, or the urine opioid, cannabis, and other drug tests are positive or the naloxone challenge test is positive on the day of randomization / drug administration;

[0223] (11) Allergic to the study drug or its excipients (polylactic acid, magnesium stearate), local anesthetics;

[0224] (12) Currently participating in any study of drugs or devices, or having used any study drugs or devices within 30 days before randomization / drug administration;

[0225] (13) There is skin infection at the implant operation site or systemic skin diseases, which are judged to affect the effectiveness evaluation and safety evaluation of the study drug;

[0226] (14) Clinical or laboratory evidence shows human immunodeficiency virus (HIV) or syphilis carriage / infection.

[0227] When a subject who has been enrolled shows a situation where it is not appropriate to continue the study during the research process, the researcher decides to withdraw this case from the study, including:

[0228] (1) During the clinical trial, certain comorbidities, complications, or deterioration of the condition occurred in the subject, and the researcher determined that it was not appropriate for the subject to continue participating in the trial;

[0229] (2) Major protocol deviations. After randomization / drug administration, it was found that the subject did not meet the inclusion criteria of the research protocol, or the subject had poor compliance, did not follow the requirements of the research protocol or doctor's advice, and used other treatments without permission, thus affecting the determination of efficacy and safety. Or the researcher determined that continued participation in the study might pose an unacceptable risk to the subject's health;

[0230] (3) The researcher believed that continued treatment was not beneficial to the patient (e.g., pregnancy);

[0231] (4) An adverse event or serious adverse event occurred in the subject, and the researcher determined that it was not appropriate for the subject to continue participating in the trial;

[0232] (5) Lack of efficacy. The researcher determined that the subject could not benefit from the research treatment, and continued participation in the study might pose an unacceptable risk to the subject;

[0233] (6) Other factors not covered above need to be noted.

[0234] The subject is unwilling to continue participating in the clinical study (according to the provisions of the informed consent form, the subject has the right to withdraw from the study at any stage of the research), including:

[0235] (1) Although the subject did not explicitly withdraw from the study, the subject was lost to follow-up (or "dropped out") because the subject no longer accepted the tests;

[0236] (2) Unable to continue participating in the clinical study for other reasons;

[0237] (3) Lost to follow-up without explanation, etc. Lost to follow-up is defined as the subject losing contact. The researcher should try to understand the reason for their withdrawal or dropout and record it. For example, the subject felt that they could not tolerate certain adverse reactions.

[0238] For patients who terminate or withdraw from the study, the naltrexone implant or placebo shall be removed. The investigator must fill in the reason for withdrawal in the case report form, and contact the patient as much as possible to complete the assessable items, fill in the end-of-treatment follow-up record form, and record the last follow-up time as accurately as possible. For those who withdraw due to adverse events and are finally judged to be related to the investigational drug after follow-up, it must be recorded in the case report form and notified to the sponsor. Regardless of the reason, for withdrawn cases, the case report form shall be retained, and the final visit shall be completed. The last test result shall be transferred as the final result, and a comprehensive data analysis of efficacy and adverse reactions shall be conducted. All study-related toxicities and SAEs existing at the time of withdrawal from the study must be followed up until remission, unless, in the opinion of the investigator, remission is not possible due to the patient's underlying disease. For patients who withdraw from the study prematurely, no replacement will be provided. For patients who withdraw from the study prematurely and still have a need for alcohol abstinence treatment (referral or hospitalization), necessary medical support shall be provided, and their safety shall continue to be followed up. For subjects who withdraw from the study prematurely but refuse to have the naltrexone implant or placebo removed, they shall receive safety follow-up (telephone follow-up for adverse events and concomitant medication information) at each subsequent scheduled visit, unless the subject clearly indicates that they no longer wish to receive any follow-up.

[0239] After signing the informed consent form and being screened according to the inclusion / exclusion criteria, the subjects participating in the trial will be randomly assigned to receive drug treatment (naltrexone-risperidone implant) or enter the blank group at a ratio of 2:1.

[0240] Subjects will be randomly screened at a drug rehabilitation center from -28 days to -1 day before drug administration. On day 0, the naltrexone-risperidone implant (naltrexone: risperidone = 150 mg: 15 mg) will be implanted in the subjects, and the blank group will not be given any investigational drug. Follow-up will be conducted once a week after drug administration until week 14.

[0241] 1. Efficacy indicators

[0242] 1.1 Primary efficacy indicator

[0243] The primary efficacy indicator includes the percentage of weeks without using cannabis drugs. Specifically, record whether cannabis drugs are used each week to determine the number of weeks without drug use. The "number of weeks without drug use" is divided by the "number of weeks at risk of drug use". The above days are calculated until the end of efficacy observation. The "number of weeks at risk of drug use" is defined as the number of weeks during which the subject is under efficacy observation in the study. The "number of weeks without drug use" is defined as a negative urine test at each weekly follow-up.

[0244] 1.2 Secondary efficacy indicators

[0245] The secondary efficacy indicators include: (1) the patient dropout time (calculated from the first administration); (2) the Marijuana Craving Questionnaire (MCQ): the craving scale scores from baseline to the pre-specified weekly visits; (3) the incidence rate of subjects with recurrent physical drug dependence during the 14-week treatment period; (4) the Brief Psychiatric Rating Scale: the Brief Psychiatric Rating Scale from baseline to the pre-specified weekly visits.

[0246] The patient dropout time (calculated from the first administration) refers to the time from randomization / administration to loss to follow-up / end of the trial.

[0247] The Marijuana Craving Questionnaire (MCQ) refers to the weekly marijuana craving scores after randomization / administration; the items are scored on a Likert-type scale from 1 (strongly disagree) to 7 (strongly agree). The factor score for each participant is obtained by adding up the 3 items in each factor scale, with the resulting scores ranging from 3 to 21. The 4 factor scales are: 1) compulsion, inability to control marijuana use; 2) emotional, using marijuana to relieve withdrawal or negative emotions; 3) expectancy, anticipation of positive outcomes from using marijuana; 4) purpose, intention, and plan to use marijuana to achieve positive outcomes. The highest score is 84 and the lowest score is 12. The higher the value, the more severe the marijuana craving symptoms recognized by the subject.

[0248] The incidence rate of subjects with recurrent physical drug dependence during the 14-week treatment period refers to the proportion of subjects who relapse from randomization / administration to loss to follow-up / end of the trial.

[0249] The Brief Psychiatric Rating Scale refers to the weekly psychiatric scores (Brief Psychiatric Rating Scale) after randomization / administration. The BPRS is a psychiatric rating scale used by clinicians or researchers to measure the mental symptoms of patients, such as depression, anxiety, hallucinations, and other abnormal behaviors, mainly assessing the mental symptoms and on-site conversation situation in the most recent week. It is a 7-level rating, and the rating is based on the intensity, frequency, duration of symptoms, and the degree of impact on relevant functions. (1) No symptoms; (2) Suspected or very mild, there seem to be some signs, but the clinical significance is uncertain; (3) Mild, although the symptoms are mild, the clinical significance is already certain; (4) Moderate; (5) More severe; (6) Severe; (7) Extremely severe. The total score (168 points) reflects the severity of the disease. The higher the total score, the more severe the condition. The change in the total score before and after treatment reflects the efficacy. The greater the difference, the better the efficacy. Generally, the inclusion criteria for the study can be set at >35 points.

[0250] 2. Safety assessment indicators

[0251] Adverse events (AE) and serious adverse events (SAE) (including local AE and SAE at the implantation site), the occurrence of abnormalities in vital signs, physical examinations, electrocardiograms of 12 or more leads, laboratory safety data (blood routine, urine routine, clinical biochemistry, coagulation routine) and other indicators before and after treatment.

[0252] 3. Investigational Medicinal Product

[0253] The investigational medicinal product is the naltrexone risperidone implant prepared in Example 1, with a specification of 150 mg: 15 mg / tablet;

[0254] The administration method and dose are subcutaneous implantation in the abdomen, with a single administration.

[0255] During the 4-week screening period (Day - 28 to Day - 1), the subjects participating in the trial will undergo a screening visit (Visit 1). The eligible subjects will be randomized at Visit 2 (D0). The subjects enrolled in the trial group will receive treatment with the naltrexone risperidone implant. The subjects will receive a single subcutaneous implantation in the abdomen on the day of randomization (D0, Visit 2). The control group will not be given the drug. After randomization / drug administration, the subjects will be followed up for a total of 14 weeks, and the patients need to return to the research center for a visit once a week. There will be a total of 15 follow-up visits.

[0256] Calculation method of sample size: Assume that after using the drug, the relapse rate is reduced by 20%. That is, calculated according to 14 weeks, the natural abstinence rate is 40%, and the abstinence rate in the trial group is 70%. Then, according to statistical calculation, a sample size of 100 cases can meet the statistical requirements.

[0257] Calculation method of analysis set:

[0258] Randomized analysis set: According to the intention-to-treat (ITT) principle, it includes all subjects randomized and enrolled;

[0259] Per-protocol analysis set (PPS): It includes the subjects who have completed 14-week follow-up after randomization / drug administration in all randomized analysis sets and have not seriously violated the trial protocol. As a subset of the randomized analysis set, it will be marked in the randomized analysis set;

[0260] Safety analysis set (SS): It includes all subjects who are randomly enrolled, have received the investigational medicinal product treatment, and have undergone at least one safety assessment;

[0261] Among them, the analysis of demographic and baseline characteristics uses the randomized analysis set, the efficacy analysis uses the randomized analysis set, the PPS-based analysis can provide supplementary evidence, and the safety analysis is based on the safety analysis set.

[0262] Efficacy analysis method: The efficacy analysis is based on the randomized analysis set, and the efficacy analysis results based on PPS can provide supplementary evidence.

[0263] Safety analysis method: Analyze safety based on SS. Use the terms of the International Medical Dictionary (MedDRA) (the latest version at the time of analysis) to code adverse events, and conduct descriptive statistical analysis according to the System Organ Class (SOC) / Preferred Term (PT). Calculate the overall incidence rates of adverse events, adverse reactions (i.e., adverse events with a correlation judgment other than "definitely unrelated"), adverse events occurring during the treatment period, serious adverse events, and calculate the incidence rates differentiated by SOC / PT. Statistically count the number of occurrences and the number of person-times of adverse events and adverse reactions occurring during the treatment period according to SOC / PT and severity. Make a detailed list of adverse events, adverse reactions, adverse events occurring during the treatment period, serious adverse events, etc.

[0264] For laboratory tests, use the conversion cross-tabulation of normal / abnormal before and after medication to illustrate the changes in results before and after medication. Make a detailed list of the laboratory test results.

[0265] For electrocardiogram (ECG) examinations, use the conversion cross-tabulation of normal / abnormal before and after medication to illustrate the changes in results before and after medication. And conduct statistical descriptions of the measured values of QTc intervals according to >450 ms, >480 ms, >500 ms, and an increase of >30 ms and >60 ms compared to the baseline.

[0266] Make a detailed list of the electrocardiogram examination results and the results of hepatobiliary B-ultrasound examinations.

[0267] Analyze and make a detailed list of the results of vital signs and physical examination indicators for each visit. See the general principles for the analysis method.

[0268] The trial flow chart is shown in Figure 1 , Figure 1 , in which, before starting any research-related procedures, patients need to sign an informed consent form. Demographic information includes: gender, age, ethnicity, height, weight, body mass index, history of allergies, history of drug abuse, smoking history, alcoholism history, blood donation history; vital signs include: body temperature (forehead temperature), sitting blood pressure, heart rate, and respiratory rate. Sitting blood pressure and heart rate should be measured after resting for 5 minutes; conduct an assessment by organ and system, and a comprehensive physical examination includes: general condition, head and neck, lymph nodes, skin, chest, abdomen, musculoskeletal system (including limbs and spine), and nervous system. Fasting blood samples and urine samples for laboratory tests should be collected on the morning of the visit day before randomization / drug administration, including urine samples and / or blood samples for serum pregnancy tests for women of childbearing potential.

[0269] Laboratory examinations include: 1) Blood routine: including hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), red blood cell count (RBC), white blood cell count (WBC), differential white blood cell count (including neutrophils, lymphocytes, monocytes, basophils, eosinophils), and platelet (PLT);

[0270] 2) Urine routine: including pH, urinary protein (U-PRO), urinary white blood cell (U-WBC), urinary red blood cell (U-RBC), urinary glucose (U-GLU), urinary occult blood, and urinary ketone body (U-KET);

[0271] 3) Serum biochemistry: including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyltransferase (GGT), total bilirubin (TBIL), direct bilirubin (DBIL), albumin (ALB), total protein (TP), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C); serum creatinine (sCr), urea, or blood urea nitrogen (BUN), uric acid (UA), potassium (K), sodium (Na), chloride (Cl), calcium (Ca), phosphorus (P), magnesium (Mg), and blood glucose (GLU);

[0272] 4) Pregnancy test (only for women of childbearing age): Serum pregnancy test is only conducted during the screening period and visit 9. The serum pregnancy test for women of childbearing age must be negative. Urine pregnancy test can be conducted as needed during the study treatment. If the urine pregnancy result is positive, a serum pregnancy test is required for confirmation. If it is confirmed to be positive, the subject needs to withdraw from this trial, and the investigator will continue to follow up the subject until the end of pregnancy;

[0273] 5) Serum virology examination: including human immunodeficiency virus (HIV) antibody, hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B virus (HBV) deoxyribonucleic acid (DNA), HCV ribonucleic acid (RNA), and syphilis specific antibody (Anti-TP). Serum virology examination is only conducted during the screening period;

[0274] 6) Coagulation function: including prothrombin time (PT), international normalized ratio of prothrombin time (INR, only conducted during the screening period), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB);

[0275] 7) 12-lead or more electrocardiogram: including heart rate, ventricular rate, PR interval, QT / QTc interval, and QRS complex morphology after lying supine for at least 5 minutes.

[0276] 8) Hepatobiliary B-ultrasound: It is detected before randomization / administration, on the morning of the visit day when the subject is fasting, and only carried out at Visit 1 and Visit 14;

[0277] 9) The naltrexone risperidone implant is implanted subcutaneously in the abdomen. The subject is observed in the hospital for 2 hours after administration. The dressing is changed by the patient himself on the 3rd day after the operation;

[0278] 10) For the subjects who withdraw from the study in advance, they need to have a withdrawal visit within 2 weeks after confirming the withdrawal from the study. The content of the visit is the same as that of the end-of-study visit;

[0279] The research results of this example show that the naltrexone risperidone implant can effectively reduce the relapse rate of patients. At the 4th week and subsequent visits, the positive rate of the urine test results of the patients is lower than that of the placebo group, indicating that the naltrexone risperidone implant can effectively prevent the relapse of cannabis-addicted patients. Through the scoring results of the cannabis craving questionnaire, it can be found that the naltrexone risperidone implant can significantly reduce the craving of patients for cannabis. Through the scoring results of the Brief Psychiatric Rating Scale (BPRS), it can be found that the naltrexone risperidone implant can significantly improve the mental symptoms of cannabis-addicted patients, especially improve mental symptoms such as anxiety, depression, and hallucinations caused by cannabis addiction.

[0280] All the documents mentioned in this application are cited in this application as references, just as if each document is cited separately as a reference. Unless it conflicts with the application purpose and / or technical solution of this application, the cited documents involved in this application are cited for all contents and all purposes. When this application involves cited documents, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When this application involves cited documents, the examples and preferred methods of the relevant technical features cited can also be incorporated into this application as references, but only to the extent that this application can be implemented. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or be modified adaptively according to the description of this application.

[0281] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity of description, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered to be within the scope described in this specification.

[0282] The above-described embodiments merely represent several implementation manners of the present application, but should not be construed as limiting the scope of the patent application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all fall within the protection scope of the present application. In addition, it should be understood that after reading the above teachings of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning, or limited experiments based on the technical solutions provided by the present application are all within the protection scope of the appended claims of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims, and the specification can be used to explain the content of the claims.

Claims

1. Use of a pharmaceutical composition in the preparation of a drug for preventing relapse of cannabis, characterized in that, the drug active ingredients in the pharmaceutical composition include naltrexone and risperidone.

2. The use according to claim 1, characterized in that, the mass ratio of the naltrexone to the risperidone is (5~30):

1.

3. The use according to claim 1 or 2, characterized in that, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

4. The use according to claim 3, characterized in that, the pharmaceutical composition and a pharmaceutically acceptable excipient are jointly made into a clinically acceptable preparation.

5. The use according to claim 4, characterized in that, the preparation is selected from any of the following groups or a suitable combination thereof: 1) tablets, capsules, granules, powders, powders for external use, suspensions or solutions; 2) oral liquids, buccal tablets, injections, suppositories, sprays, drops or patches.

6. The use according to claim 4, characterized in that, the form of the preparation is an implant.

7. The use according to claim 1, characterized in that, the subject is a mammal.

8. The use according to claim 7, characterized in that, the subject is a human or a rat.

9. Use of the pharmaceutical composition in the use according to any one of claims 1~8 in the preparation of a drug for treating adverse symptoms caused by cannabis addiction.

10. The use according to claim 9, characterized in that, the adverse symptoms caused by cannabis addiction include psychiatric symptoms.

11. The use according to claim 10, characterized in that, the psychiatric symptoms include anxiety, depression and hallucinations.

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