WO2022120745A1 - 用于减轻或消除阿片戒断综合症的药物及制备方法 - Google Patents

用于减轻或消除阿片戒断综合症的药物及制备方法 Download PDF

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WO2022120745A1
WO2022120745A1 PCT/CN2020/135368 CN2020135368W WO2022120745A1 WO 2022120745 A1 WO2022120745 A1 WO 2022120745A1 CN 2020135368 W CN2020135368 W CN 2020135368W WO 2022120745 A1 WO2022120745 A1 WO 2022120745A1
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hydrochloride
parts
tramadol
pharmaceutical composition
clonidine
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PCT/CN2020/135368
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English (en)
French (fr)
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梁铮林
尹述贵
颜携国
王实强
张涛
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深圳善康医疗健康产业有限公司
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Priority to EP20964683.5A priority Critical patent/EP4233862A4/en
Priority to US18/265,652 priority patent/US20240100020A1/en
Publication of WO2022120745A1 publication Critical patent/WO2022120745A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • the invention relates to the technical fields of addiction medicine and neurobiology, in particular to a medicine for alleviating or eliminating opioid withdrawal syndrome and a preparation method.
  • Drug abuse addiction has become a public hazard in the world. It not only endangers the physical and mental health of addicts, but also seriously interferes with social security and the development of productivity.
  • comprehensive medical, psychological and social measures are recommended for the treatment of opioid dependence, including stopping drug abuse, detoxification treatment for withdrawal symptoms, and rehabilitation and prevention of psychological dependence and other physical, psychological, and social functional impairments.
  • drug addiction treatment and ultimately realize the rehabilitation and social reintegration of drug addicts.
  • the severity of drug dependence should be first determined according to the type, dose, time, route, and previous drug addiction treatment, and drug addiction drugs and treatment methods should be selected based on the individual circumstances of drug addicts.
  • the existing treatment measures mainly include: 1. Substitution therapy, methadone substitution therapy and buprenorphine substitution therapy; 2. Non-replacement therapy, clonidine and lofexidine therapy; 3.
  • Traditional Chinese medicine detoxification therapy currently approved by the National Food and Drug Administration There are nearly 10 kinds of Chinese medicines for detoxification approved by the Supervision and Administration Bureau, which are suitable for drug addicts with mild to moderate opioid dependence. 4.
  • Other detoxification treatments such as acupuncture, electro-acupuncture, etc., need to be further verified.
  • Detoxification is the first stage of opioid addiction treatment. In this stage, the substitution method of opioid drugs is mostly used. Only three drugs, methadone, buprenorphine, and naltrexone, have been approved for marketing in the United States. Although these drugs are effective in suppressing withdrawal symptoms, they themselves have similar dependence-inducing potential and can be equally addictive with long-term use.
  • Clonidine is a central alpha 2 receptor agonist, excites central alpha 2 receptors, inhibits the discharge of the central locus coeruleus, reduces the release of norepinephrine, relieves symptoms, relieves nausea, vomiting, diarrhea, abdominal pain, and sweating. Compared with methadone, clonidine does not cause rebound symptoms after withdrawal, and can be used as a transition from methadone detoxification to maintenance relapse prevention with naltrexone. Clonidine is the only non-opioid treatment in the guidelines for common detoxification treatments for opioid addiction developed by the Ministry of Health. Therefore, clonidine is often used as a control drug in clinical trials of new non-opioid detoxification drugs.
  • Tramadol is an opioid receptor agonist, and its structure has opioid and non-opioid components, so in addition to acting through opioid receptors, it can also inhibit the activity of central norepinephrine or serotonin, which may be the reason for its release of opioid. The main mechanism of withdrawal-like symptoms.
  • CN103495172A discloses a medicine for treating amphetamine-type stimulant dependence and its mixed dependence with opioids.
  • antipsychotics 0.001-5% alpha 2 adrenergic agonists, 0-5% anticholinergics, 0-80% non-opioid analgesics, 0-10 % benzodiazepine composition.
  • the ⁇ 2 adrenergic receptor agonist is one or more of chlorphenoxazoline, chloracetamide, clonidine, lofexidine, and the non-opioid analgesic is fumarin.
  • the pharmaceutical composition of the invention is treated for the above-mentioned symptoms that occur in patients who abuse stimulants such as amphetamine or concomitantly abuse opioids, it achieves a more desirable effect, can rapidly and significantly control withdrawal symptoms, and has a detoxification cure rate. more than 90%.
  • the invention has long withdrawal time, poor medication compliance and medication experience of patients, and poor clinical application effect.
  • the present invention provides a medicine and application for alleviating or eliminating opioid withdrawal syndrome
  • the pharmaceutical composition is more suitable for detoxification of opioid abuse patients, the time is short, and it can be completed in 3-5 days , safe, effective, easy to operate, has obvious clinical advantages and curative effects, can improve patients' medication compliance and medication experience, and prevent abuse.
  • the present invention adopts the following technical scheme:
  • a pharmaceutical composition for reducing or eliminating opioid withdrawal syndrome comprising clonidine hydrochloride and tramadol hydrochloride.
  • the mass ratio of clonidine hydrochloride and tramadol hydrochloride is 0.01-0.8:40-60, more preferably 0.01-0.56:50.
  • the total mass fraction of the clonidine hydrochloride and tramadol hydrochloride in the pharmaceutical composition is 15-20%, more preferably 17-19%.
  • the present invention also provides the application of the above-mentioned pharmaceutical composition in the preparation of medicines for alleviating or eliminating opioid withdrawal syndrome.
  • the present invention also provides a medicament, which is composed of the above-mentioned pharmaceutical composition for alleviating or eliminating opioid withdrawal syndrome and a pharmaceutically acceptable auxiliary material.
  • the medicaments include but are not limited to compound tablets, pills, granules, injections, powders, sprays, sublingual tablets, capsules and liquid preparations.
  • the present invention also provides a compound tablet for alleviating or eliminating opioid withdrawal syndrome, comprising clonidine hydrochloride, tramadol hydrochloride, lactose hydrochloride, microcrystalline cellulose, silicon dioxide and magnesium stearate.
  • the compound tablet is calculated in parts by mass, and the dosage of clonidine hydrochloride is 0.01-0.8 part.
  • the compound tablet is calculated in parts by mass, and the dosage of tramadol hydrochloride is 40-60 parts.
  • the compound tablet is calculated in parts by mass, and the consumption of lactose water is 110-120 parts.
  • the compound tablet is calculated in parts by mass, and the dosage of microcrystalline cellulose is 100-120 parts.
  • the compound tablet is measured in parts by mass, and the amount of silicon dioxide used is 0.5-1 part.
  • the compound tablet is calculated in parts by mass, and the consumption of magnesium stearate is 2.0-3.6 parts.
  • the compound tablet includes the following components by mass: 0.01-0.8 parts of clonidine hydrochloride, 40-60 parts of tramadol hydrochloride, 110-120 parts of lactose hydrate, 100-120 parts of microcrystalline cellulose, two Silica 0.5-1 parts and magnesium stearate 2.0-3.6 parts.
  • the mass ratio of clonidine hydrochloride and tramadol hydrochloride is 0.01-0.56:50, one of which is preferably a compound tablet, and its specific components in parts by mass include: 0.01-0.56 part of clonidine hydrochloride, 50 parts of tramadol hydrochloride, 114.5 parts of lactose water, 112 parts of microcrystalline cellulose, 0.7 parts of silicon dioxide and 2.8 parts of magnesium stearate.
  • a preparation method for a compound tablet for alleviating or eliminating opioid withdrawal syndrome comprising the following steps:
  • step (2) the granule obtained in step (1) is mixed with the tramadol hydrochloride and the lactose water of the recipe quantity, then the silicon dioxide and the magnesium stearate of the recipe quantity are added and mixed, and the coating is compressed into a tablet to obtain the described Compound tablets.
  • the present invention also provides the application of the above-mentioned medicament in the preparation of medicine for alleviating or eliminating opioid withdrawal syndrome.
  • the present invention has the following advantages and effects:
  • the present invention is more suitable for detoxification of opioid abuse patients, the time is short, 3-5 days are completed, safe and effective, easy to operate, has obvious clinical advantages and curative effects, and can improve the medication compliance and medication experience of patients, prevent abuse.
  • the pharmaceutical composition of the present invention has a better effect of alleviating or eliminating the withdrawal symptoms of morphine-dependent mice through the synergistic compounding of clonidine hydrochloride and tramadol hydrochloride, and has low addiction and good safety. .
  • the preparation method of the present invention is simple and convenient, the cost is low, and the prepared compound tablet has good stability.
  • the raw materials used in the present invention are all common commercially available products.
  • Embodiment 1-3 A kind of compound tablet for alleviating or eliminating opioid withdrawal syndrome
  • Table 1 shows the prescription of a compound tablet for alleviating or eliminating the opioid withdrawal syndrome of Examples 1-3.
  • Table 1 A prescription for a combination tablet for alleviating or eliminating opioid withdrawal syndrome (each tablet contains/mg)
  • Example 1 Example 2
  • Example 3 clonidine hydrochloride 0.6 0.7 0.8 tramadol hydrochloride 40 50 60 Lactose monohydrate 110 115 120 microcrystalline cellulose 110 112 120 silica 0.5 0.7 1 Magnesium stearate 2 3 3.6 total 263.1 281.4 305.4
  • Embodiment 4-10 A kind of compound tablet for alleviating or eliminating opioid withdrawal syndrome
  • Table 2 shows the prescription of a compound tablet for alleviating or eliminating the opioid withdrawal syndrome of Examples 4-10.
  • the preparation method of the compound tablet comprises the following steps:
  • step (2) the granule obtained in step (1) is mixed with the tramadol hydrochloride and lactose monohydrate of recipe quantity, then silicon dioxide and the magnesium stearate of recipe quantity are added and mixed, and the coating is compressed into a tablet, and the resulting The compound tablet.
  • Example 10 The difference between the present invention and Example 10 is that clonidine hydrochloride is not included.
  • Example 10 The difference between the present invention and Example 10 is that tramadol hydrochloride is not included.
  • the content is determined according to high performance liquid chromatography ("Chinese Pharmacopoeia” 2020 edition general rule 0512), specifically:
  • Test solution 1 Take 15-20 tablets of this product, accurately weigh, grind finely, take an appropriate amount (equivalent to tramadol hydrochloride 50mg), accurately weigh, put it in a 100ml measuring bottle, add an appropriate amount of mobile phase ultrasonic to dissolve , let it cool, add the mobile phase to dilute to the mark, shake well, filter, and take the continuous filtrate.
  • Test solution 2 Take 15-20 tablets of this product, accurately weigh, grind finely, accurately weigh an appropriate amount (equivalent to 0.4mg of clonidine hydrochloride), put it in a 100ml measuring bottle, add an appropriate amount of mobile phase to dissolve by ultrasonic, put it in Cool, dissolve and dilute to volume with mobile phase, shake well, filter, and take the subsequent filtrate.
  • Clonidine reference substance stock solution take 20mg of clonidine hydrochloride reference substance, accurately weigh it, put it in a 100ml measuring bottle, add blank solution to dissolve and dilute to the mark, shake well, and then get it.
  • Reference solution take 25mg of tramadol hydrochloride, accurately weigh it, put it in a 50ml measuring bottle, add an appropriate amount of blank solution to dissolve, accurately add 1.0ml of clonidine hydrochloride reference substance stock solution, add blank solution to dissolve and dilute to the mark, shake well , that is.
  • Chromatographic conditions see related substances.
  • the applicability of the system requires that the number of theoretical plates is not less than 1500 calculated on the basis of the tramadol peak.
  • Determination method Precisely measure the test solution and the reference solution and inject them into the liquid chromatograph respectively. Calculate the peak area by the external standard method.
  • m is the weighing sample size of the test sample, and the unit is mg;
  • V is the dilution volume of the reference solution, in ml
  • A is the peak area of the test solution
  • M is the average tablet weight, in mg
  • Mr is the labeled amount, the unit is mg.
  • Test solution take an appropriate amount of fine powder, accurately weigh it, add mobile phase to dissolve and quantitatively dilute to make a solution containing 2 mg of tramadol hydrochloride per 1 ml, shake well, filter, and take the subsequent filtrate.
  • Tramadol impurity I reference substance solution take an appropriate amount of tramadol impurity I reference substance, accurately weigh it, add mobile phase to dissolve and quantitatively dilute to make a solution containing 0.6 mg per 1 ml.
  • Clonidine hydrochloride reference substance stock solution solution take an appropriate amount of clonidine hydrochloride reference substance, accurately weigh, add blank solution to dissolve and dilute to make a solution containing 0.2mg per 1ml.
  • System suitability solution Precisely pipette 1ml of the test solution, 2ml of the stock solution of clonidine hydrochloride reference solution, and 1ml of the reference solution of tramadol impurity I, put them in a 100ml volumetric flask, add mobile phase to dissolve and dilute to the mark, shake. Evenly, that is.
  • Control solution Precisely measure 1ml of the test solution, in the same 100ml volumetric flask, dissolve and dilute to the mark with mobile phase, and shake well.
  • Chromatographic conditions use octadecylsilane bonded silica gel as filler (recommended column: Welch C18 4.6*250nm, 5 ⁇ m); use acetic acid-sodium acetate buffer (pH 4.5) (18g sodium acetate trihydrate, add ice) Acetic acid 9.8ml, add water to dilute to 1000ml)-methanol (65:35) as the mobile phase; the detection wavelength is 271nm; the injection volume is 20ul;
  • the applicability of the system requires that the number of theoretical plates is not less than 1500 according to the tramadol peak, and the order of peaks is clonidine, tramadol impurity I and tramadol, and the separation degree of impurity I peak and tramadol peak should be greater than 2.0.
  • Determination method Precisely measure the test solution and the control solution, and inject them into a liquid chromatograph until three times the retention time of the main component peak.
  • the area of the impurity I peak shall not be greater than 0.3 times (0.3%) of the main peak area of the control, and the sum of the areas of other impurity peaks shall not be greater than the area of the main peak of the control (1.0%).
  • the compound tablet prepared by the present invention has good stability.
  • mice were randomly divided into blank control group and drug group 1-12 by body weight, wherein, drug group 1-12 (respectively administered compound tablets prepared in Example 1-10 and single tablets prepared in Comparative Example 1-2), Divided into low-dose group, middle-dose group and high-dose group, 10 in each group.
  • drug group 1-12 (respectively administered compound tablets prepared in Example 1-10 and single tablets prepared in Comparative Example 1-2), Divided into low-dose group, middle-dose group and high-dose group, 10 in each group.
  • All groups were intraperitoneally injected with morphine, 6 times a day, with a dose of 10 mg/kg/time on the first day, 10 mg/kg/time on the 2nd-3rd day, 50 minutes after the last injection of morphine, the low-dose group of the drug , middle-dose group and high-dose group were administered by intragastric administration of 36 mg/kg, 72 mg/kg and 143 mg/kg respectively, and the blank control group was administered an equal volume of normal saline. After 30 minutes of intragastric administration, each group was intraperitoneally injected with naloxone 15 mg/kg, the number of jumps within 15 minutes and the change of body weight in 1 hour were observed. The results are shown in Table 4.
  • mice fed with the compound tablets prepared in Examples 4-10 had extremely significant differences (P ⁇ 0.01) in the number of jumps and weight loss after being urged by naloxone (P ⁇ 0.01), indicating that , when the weight ratio of clonidine hydrochloride and tramadol hydrochloride is 0.01-0.56:50, the compound tablet of the present invention has a better effect on reducing withdrawal symptoms in morphine-dependent mice.
  • the rats were randomly divided into blank control group and drug group 1-12 by body weight, wherein, drug group 1-12 (respectively administered compound tablets prepared in Example 1-10 and single tablets prepared in Comparative Example 1-2) , divided into low-dose group, middle-dose group and high-dose group, with 15 rats in each group. All groups were intraperitoneally injected with morphine, 3 times a day, at a dose of 10 mg/kg/time on the first day, 20 mg/kg/time on the 2nd-3rd day, and 30 mg/kg/time on the 4th-10th day.
  • the blank control group and the drug group were treated by oral gavage from the eighth day of the experiment, once a day (4.5 hours after the third intraperitoneal injection of morphine), for 3 consecutive days, wherein the dosage of the low-dose group was The dose of 25 mg/kg, 50 mg/kg in the middle-dose group and 100 mg/kg in the high-dose group, the blank control group was given an equal volume of normal saline, and 5 hours after the last intraperitoneal injection of morphine, intraperitoneal injection of sodium 10 mg/kg of oxone, withdrawal symptoms and body weight changes were observed within 1 hour, and the results are shown in Table 5.
  • the rats were stimulated with naloxone, and there was no significant difference in the scores of withdrawal symptoms and weight loss between the low-dose group and the middle-dose group.
  • the scores of withdrawal symptoms and weight loss of the dose group were significantly different P ⁇ 0.5
  • the scores of withdrawal symptoms and weight loss of the low-dose group of Example 4-10 were significantly different P ⁇ 0.5
  • the middle-dose group and the high-dose group were significantly different P ⁇ 0.5
  • the scores of withdrawal symptoms and weight loss were significantly different P ⁇ 0.01.
  • the results showed that the compound tablets prepared by the invention had the effect of alleviating the withdrawal symptoms of morphine-dependent rats. It was also found that when clonidine hydrochloride and trama hydrochloride When the weight ratio is 0.01-0.56:50, the compound tablet of the present invention has a better effect on reducing withdrawal symptoms in morphine-dependent mice.
  • the compound tablet prepared, compound tablet group 2 is the compound tablet prepared in Example 2
  • compound tablet group 3 is the compound tablet prepared in Example 3
  • compound tablet group 4 is the compound tablet prepared in Example 6
  • compound tablet group 5 is the compound tablet prepared in Example 6.
  • the compound tablet prepared in Example 7 and the compound tablet group 6 are the compound tablet prepared in Example 10).
  • the administration method is as follows: (1) blank control PO: 0 mg/kg/time; (2) morphine group ip: 5 mg/kg/time in the first week; 10 mg/kg/time in the second week; 20 mg/kg/time in the third week times; 30 mg/kg/time on days 22-30; (3) tramadol group PO: 25 mg/kg/time in the first week; 50 mg/kg/time in the second week; 100 mg/kg/time in the third week; 200 mg/kg/time for 22-30 days; (4) Clonidine group PO: 0.075 mg/kg/time in the first week; 0.15 mg/kg/time in the second week; 0.3 mg/kg/time in the third week; -30 days 0.6 mg/kg/time; (5) PO in the composite tablet group: 25 mg/kg/time in the first week; 50 mg/kg/time in the second week; 100 mg/kg/time in the third week; Days 22-30 200 mg/kg/time; the withdrawal symptoms and body weight changes in

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Abstract

本发明提供了用于减轻或消除阿片戒断综合症的药物组合物及制备方法，所述药物组合物包括盐酸可乐定和盐酸曲马多，该药物组合物的复方片由盐酸可乐定、盐酸曲马多、水乳糖、微晶纤维素、二氧化硅和硬脂酸镁制成；制备方法包括以下步骤：(1)将处方量的盐酸可乐定溶于水中，与处方量微晶纤维素制粒后过筛，烘干，得到颗粒；(2)将步骤(1)得到的颗粒与处方量的盐酸曲马多和水乳糖混合，再加入处方量的二氧化硅和硬脂酸镁混合，压制成片后包衣，即得所述复方片。

Description

用于减轻或消除阿片戒断综合症的药物及制备方法 技术领域
本发明涉及成瘾医学和神经生物学技术领域，具体涉及用于减轻或消除阿片戒断综合症的药物及制备方法。
背景技术
药物滥用成瘾已成为世界公害，它不仅危害成瘾者的身心健康，还严重干扰社会治安和生产力发展。目前对阿片类药物依赖的治疗推荐采用医学、心理、社会等综合措施，包括停止滥用药物、针对戒断症状给予脱毒治疗、针对心理依赖及其它躯体、心理、社会功能损害进行康复和防复吸治疗，最终实现吸毒人员的康复和回归社会。治疗时应根据滥用药物的种类、剂量、时间、途径、既往戒毒治疗情况等首先确定药物依赖的严重程度，结合吸毒人员的个体情况选择戒毒药物和治疗方法。
现有治疗措施主要包括：1、替代治疗，美沙酮替代治疗和丁丙诺啡替代治疗；2、非替代治疗，可乐定和洛非西定治疗；3、中药脱毒治疗，目前经国家食品药品监督管理局批准的戒毒中药近10种，适用于轻、中度阿片类药物依赖的吸毒人员，对重度依赖的吸毒人员单纯使用中药疗效尚不够理想，需要与其他药物联合使用。4、其他脱毒治疗，如针灸、电针等，疗效需进一步验证。
脱毒是阿片成瘾治疗的第一阶段，该阶段多采用阿片类药物的替代递减方法，美国仅批准了美沙酮、丁丙诺啡、纳曲酮三种治疗阿片依赖性药物上市。尽管这些药物可有效抑制戒断症状，但它们自身有相似的致依赖性潜能，长期使用可同样成瘾。
可乐定是中枢α 2受体激动剂，兴奋中枢α 2受体，抑制中枢蓝斑核的放电，减少去甲肾上腺素的释放，缓解症状，减轻恶心、呕吐、腹泻腹痛和出汗。与美沙酮相比，可乐定不引起撤药后症状反跳，可作为从美沙酮脱毒治疗过渡到用纳曲酮维持防复吸用药。在卫生部制定的阿片类药物成瘾常用戒毒疗法的指导原则中，可乐定是唯一的非阿片类治疗药。因此，可乐定常被作为非阿片类戒毒新药临床试验的对照药。
近几年常采用可乐定、纳曲酮快速脱毒。曲马多系阿片受体激动剂，其结构具有阿片样及非阿片样成份，因此除通过阿片受体发生作用外，还可抑制中枢去甲肾上腺素或五羟色胺的活性，这可能是其解除阿片类戒断症状的主要机理。
CN103495172A公开了一种治疗苯丙胺类兴奋剂依赖症及其与阿片类物质混合依赖症的药物。由重量百分比为2-95％的抗精神病药物、0.001-5％的α 2肾上腺素能受体激动剂、0-5％的抗胆碱药、0-80％的非阿片类镇痛药、0-10％的苯二氮卓类药物组成。其中所述的α 2肾上腺素能受体激动剂是氯苯氧唑啉、氯醋胺咪、可乐定、洛非西定中的一种或几种，非阿片类镇痛药是延胡索乙素、曲马多、平痛新、痛可宁、颅痛定、四氮卓、四氢巴马汀中的一种或几种。该发明的药物组合物对于滥用苯丙胺等兴奋剂、或合并滥用阿片类物质的患者出现的上述症状进行治疗时，达到了较理想的效果，能迅速、明显地控制戒断症状，脱毒治愈率达90％以上。但是该发明戒断时间长，患者的用药依从性和用药体验差，临床应用效果差。
发明内容
为了解决上述技术问题，本发明提供了一种用于减轻或消除阿片戒断综合症的药物及应用，该药物组合物更适合阿片类药物滥用患者的脱毒，时间短，3-5天完成，安全有效，操作方便，具有明显的临床优势和疗效，能够提高患者的用药依从性和用药体验，防止滥用。
为了实现上述目的，本发明采用以下的技术方案：
一种用于减轻或消除阿片戒断综合症的药物组合物，包括盐酸可乐定和盐酸曲马多。
优选地，所述盐酸可乐定和盐酸曲马多的质量比为0.01-0.8:40-60，进一步优选为0.01-0.56：50。
优选地，所述盐酸可乐定和盐酸曲马多在所述药物组合物中的总质量分数为15-20％，进一步优选为17-19％。
本发明还提供了上述药物组合物在制备减轻或消除阿片戒断综合症药物中的应用。
本发明还提供了一种药剂，有上述减轻或消除阿片戒断综合症的药物组合物和药学上可接受的辅料组成。
所述药剂包括但不限于复方片、丸剂、颗粒剂、注射剂、粉剂、喷雾剂、舌下片剂、胶囊剂和液体制剂。
本发明还提供了一种用于减轻或消除阿片戒断综合症的复方片，包括盐酸可乐定、盐酸曲马多、水乳糖、微晶纤维素、二氧化硅和硬脂酸镁。
所述复方片按质量份计，盐酸可乐定的用量为0.01-0.8份。
所述复方片按质量份计，盐酸曲马多的用量为40-60份。
所述复方片按质量份计，水乳糖的用量为110-120份。
所述复方片按质量份计，微晶纤维素的用量为100-120份。
所述复方片按质量份计，二氧化硅的用量为0.5-1份。
所述复方片按质量份计，硬脂酸镁的用量为2.0-3.6份。
优选地，所述复方片，包括以下质量份的组分：盐酸可乐定0.01-0.8份、盐酸曲马多40-60份、水乳糖110-120份、微晶纤维素100-120份、二氧化硅0.5-1份和硬脂酸镁2.0-3.6份。
以上技术方案均能够实现本发明所述的技术效果，但在一些优选的实施方案中，所达到的技术效果优于其他方案。
盐酸可乐定和盐酸曲马多的质量比为0.01-0.56：50，其中一个优选地复方片，其具体组分按质量份计包括：盐酸可乐定0.01-0.56份、盐酸曲马多50份、水乳糖114.5份、微晶纤维素112份、二氧化硅0.7份和硬脂酸镁2.8份。
一种用于减轻或消除阿片戒断综合症的复方片的制备方法，包括以下步骤：
(1)将处方量的盐酸可乐定溶于水中，与处方量微晶纤维素制粒后过筛，烘干，得到颗粒；
(2)将步骤(1)得到的颗粒与处方量的盐酸曲马多和水乳糖混合，再加入处方量的二氧化硅和硬脂酸镁混合，压制成片后包衣，即得所述复方片。
本发明还提供了上述药剂在制备减轻或消除阿片戒断综合症药物中的应用。
本发明与现有技术相比，具有以下优点和效果：
(1)本发明更适合阿片类药物滥用患者的脱毒，时间短，3-5天完成，安全有效，操作方便，具有明显的临床优势和疗效，能够提高患者的用药依从性和用药体验，防止滥用。
(2)本发明的药物组合物通过盐酸可乐定和盐酸曲马多的协同复配，具有较好的减轻或消除吗啡依赖小鼠的戒断症状的效果，且成瘾性低，安全性好。
(3)本发明制备方法简便，成本低，且制备的复方片的稳定性好。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面对本发明的技术方案做进一步详述。
当实施例给出数值范围时，应理解，除非本发明另有说明，每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义，本文中使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同意义。
如无特殊说明，本发明所采用的原料均为普通市售产品。
实施例1-3一种用于减轻或消除阿片戒断综合症的复方片
实施例1-3的一种用于减轻或消除阿片戒断综合症的复方片的处方如表1所示。
表1.一种用于减轻或消除阿片戒断综合症的复方片的处方(每片含/mg)
原料 实施例1 实施例2 实施例3
盐酸可乐定 0.6 0.7 0.8
盐酸曲马多 40 50 60
一水乳糖 110 115 120
微晶纤维素 110 112 120
二氧化硅 0.5 0.7 1
硬脂酸镁 2 3 3.6
总计 263.1 281.4 305.4
实施例4-10一种用于减轻或消除阿片戒断综合症的复方片
实施例4-10的一种用于减轻或消除阿片戒断综合症的复方片的处方如表2所示。
表2.一种用于减轻或消除阿片戒断综合症的复方片的处方(每片含/mg)
Figure PCTCN2020135368-appb-000001
Figure PCTCN2020135368-appb-000002
所述复方片的制备方法，包括以下步骤：
(1)将处方量的盐酸可乐定溶于水中，与处方量微晶纤维素制粒后过筛，烘干，得到颗粒；
(2)将步骤(1)得到的颗粒与处方量的盐酸曲马多和一水乳糖混合，再加入处方量的二氧化硅和硬脂酸镁混合，压制成片后包衣，即得所述复方片。
对比例1
本发明与实施例10的区别在于，不包括盐酸可乐定。
对比例2
本发明与实施例10的区别在于，不包括盐酸曲马多。
一、稳定性实验
分别取50片实施例1-10制备的复合片，在温度为40±2℃、相对湿度为75±5％的条件下放置6个月，在第1个月，2个月，3个月和6个月后取出测定其含量和有关物质。
其中，
(1)含量照高效液相色谱法(《中国药典》2020年版通则0512)测定，具体为：
供试品溶液1：取本品15-20片，精密称定，研细，取适量(相当于盐酸曲马多50mg)，精密称定，置100ml量瓶中，加流动相适量超声使溶解，放冷，加流动相稀释至刻度，摇匀，滤过，取续滤液，即得。
供试品溶液2：取本品15-20片，精密称定，研细，精密称取适量(约相当于盐酸可乐定0.4mg)，置100ml量瓶中，加适量流动相超声溶解，放冷，用流动相溶解稀释至刻度，摇匀，滤过，取续滤液。
可乐定对照品储备液：取盐酸可乐定对照品20mg，精密称定，置100ml量瓶中，加空白溶液溶解并稀释至刻度，摇匀，即得。
对照品溶液：取盐酸曲马多25mg，精密称定，置50ml量瓶中，加适量空白溶液使溶解，精密加入盐酸可乐定对照品贮备液1.0ml，加空白溶液溶解稀释至刻度，摇匀，即得。
色谱条件：见有关物质项下。
系统适用性要求理论塔板数按曲马多峰计算不低于1500。
测定法：精密量取供试品溶液和对照品溶液，分别注入液相色谱仪。按外标法以峰面积计算。
计算公式为：
Figure PCTCN2020135368-appb-000003
其中，m为供试品称样量，单位为mg；
V为对照品溶液稀释体积，单位为ml；
A为供试品溶液峰面积；
F为计算因子；
M为平均片重，单位为mg；
Mr为标示量，单位为mg。
(2)有关物质照高效液相色谱法(《中国药典》2020年版通则0512)测定，具体为：
供试品溶液：取细粉适量，精密称定，加流动相溶解并定量稀释制成每1ml含盐酸曲马多2mg的溶液，摇匀，滤过，取续滤液。
曲马多杂质I对照品溶液：取曲马多杂质I对照品适量，精密称定，加流动相溶解并定量稀释制成每1ml含0.6mg的溶液。
盐酸可乐定对照品储备液溶液：取盐酸可乐定对照品适量，精密称定，加空白溶液溶解并稀释制成每1ml中含0.2mg的溶液。
系统适用性溶液：分别精密移取供试品溶液1ml、盐酸可乐定对照品溶液储备液2ml，曲 马多杂质I对照品溶液1ml，置100ml量瓶中，加流动相溶解稀释至刻度，摇匀，即得。
对照溶液：精密量取供试品溶液1ml，同一100ml量瓶中，用流动相溶解稀释至刻度，摇匀，即得。
色谱条件：用十八烷基硅烷键合硅胶为填充剂(推荐色谱柱：Welch C18 4.6*250nm，5μm)；以醋酸-醋酸钠缓冲液(pH4.5)(三水合醋酸钠18g，加冰醋酸9.8ml，再加水稀释至1000ml)-甲醇(65:35)为流动相；检测波长为271nm；进样体积20ul；
系统适用性要求理论塔板数按曲马多峰计算不低于1500，出峰顺序依次为可乐定、曲马多杂质I与曲马多，杂质I峰与曲马多峰的分离度应大于2.0。
测定法：精密量取供试品溶液与对照溶液，分别注入液相色谱仪至主成分峰保留时间的3倍。
限度：供试品溶液如有杂质峰，杂质I峰面积不得大于对照主峰面积的0.3倍(0.3％)，其他各杂质峰面积的和不得大于对照主峰面积(1.0％)。
试验结果如表3所示。
表3.
Figure PCTCN2020135368-appb-000004
Figure PCTCN2020135368-appb-000005
由上表可知，本发明制备的复方片的稳定性好。
实验例二、药物抑制吗啡戒断症状主要药效学研究
(1)小鼠跳跃试验
将小鼠按体重随机分为空白对照组和药物组1-12，其中，药物组1-12(分别给药实施例1-10制备的复方片和对比例1-2制备的单方片)，分为低剂量组、中剂量组和高剂量组，每 组10只。各组均腹腔注射吗啡，每天6次，给药剂量为第1天10mg/kg/次，第2-3天为10mg/kg/次，最后一次注射吗啡后的50分钟，药物的低剂量组、中剂量组和高剂量组分别按36mg/kg，72mg/kg，143mg/kg的剂量灌胃，空白对照组给药等体积生理盐水，灌胃30分钟后，各组均腹腔注射纳洛酮15mg/kg，观察15分钟内小鼠跳跃次数及1小时体重变化，结果如表4所示。
表4.药物对吗啡依赖小鼠跳跃试验的影响
Figure PCTCN2020135368-appb-000006
Figure PCTCN2020135368-appb-000007
注：与空白对照组相比，*P<0.5，呈显著性差异，*P<0.01，呈极显著性差异。
从上表可知，本发明制备的复方片小鼠经纳洛酮催促后，与空白对照组相比，跳跃次数及体重减轻程度均有显著性差异(P<0.5)，表明本发明的复方片对吗啡依赖小鼠具有减轻其戒断症状作用。
同时发现，灌胃实施例4-10制备的复方片的小鼠经纳洛酮催促后，与空白对照组相比，跳跃次数及体重减轻程度均有极显著性差异(P<0.01)，表明，当盐酸可乐定和盐酸曲马多的重量比为0.01-0.56：50时，本发明的复方片对吗啡依赖小鼠具有较佳的减轻戒断症状作用。
(2)大鼠催促试验：
将大鼠按体重随机分为空白对照组和药物组1-12，其中，药物组1-12(分别给药实施例1-10的制备的复方片和对比例1-2制备的单方片)，分为低剂量组、中剂量组和高剂量组，每组15只。各组均腹腔注射吗啡，每天3次，给药剂量为第一天10mg/kg/次、第2-3天20mg/kg/次、第4-10天30mg/kg/次。空白对照组和药物组于试验第八天起口服灌胃治疗，每天一次(在 第三次腹腔注射吗啡后的4.5小时开始灌胃)，连续3天，其中，低剂量组的给药量为25mg/kg、中剂量组的给药量为50mg/kg和高剂量组的给药量为100mg/kg，空白对照组给予等体积生理盐水，在最后一次腹腔注射吗啡后5小时，腹腔注射纳洛酮10mg/kg，观察1小时内戒断症状及体重改变，结果如表5所示。
表5.药物对吗啡依赖大鼠催促试验的影响
Figure PCTCN2020135368-appb-000008
Figure PCTCN2020135368-appb-000009
注：与空白对照组相比，*P<0.5，呈显著性差异，*P<0.01，呈极显著性差异。
由上表可知，各组吗啡致大鼠依赖后，用纳洛酮催促，结果发现空白组大鼠表现为高度激惹、腹泻、流涎、咬牙、异常姿势及体重明显减轻，其戒断症状明显。而本发明实施例1-10制备的复方片各组在停用吗啡后，见轻微流泪、腹泻、流涎及体重减轻。
与空白对照组相比，实施例1-3的吗啡致大鼠依赖后，用纳洛酮催促，其灌胃低剂量组和中剂量组的戒断症状分数和体重减轻无显著性差异，高剂量组的戒断症状分数和体重减轻呈显著性差异P<0.5，实施例4-10的低剂量组的戒断症状分数和体重减轻呈显著性差异P<0.5，中剂量组和高剂量组的戒断症状分数和体重减轻呈极显著性差异P<0.01，结果表明，本发明制备的复方片对吗啡依赖大鼠有减轻其戒断症状作用，同时发现，当盐酸可乐定和盐酸曲马多的重量比为0.01-0.56：50时，本发明的复方片对吗啡依赖小鼠具有较佳的减轻戒断症状作用。
实验例三 曲马多、可乐定单方及复方片的成瘾性评估
取体重为150g左右的大鼠，雌雄各半，随机分为10组，即空白对照组、吗啡组、曲马多组、可乐定组和复方片组1-6(复方片组1为实施例1制备的复方片、复方片组2为实施例2制备的复方片、复方片组3为实施例3制备的复方片、复方片组4为实施例6制备的复方片、复方片组5为实施例7制备的复方片、复方片组6为实施例10制备的复方片)。
每天给药三次，共30天。给药方法如下：(1)空白对照PO：0mg/kg/次；(2)吗啡组ip：第一周5mg/kg/次；第二周10mg/kg/次；第三周20mg/kg/次；第22-30天30mg/kg/次；(3)曲马多组PO：第一周25mg/kg/次；第二周50mg/kg/次；第三周100mg/kg/次；第22-30天200mg/kg/次；(4)可乐定组PO：第一周0.075mg/kg/次；第二周0.15mg/kg/次；第三周0.3mg/kg/次；第22-30天0.6mg/kg/次；(5)复合片组PO：第一周25mg/kg/次；第二周50mg/kg/次；第三周100mg/kg/次；第22-30天200mg/kg/次；观察以上各组戒断后一周内戒断症状及体重改变，结果如表6所示。
表6.
药物(mg/kg，po) 动物数 跳跃次数 体重减轻(g)
空白对照组 6 4.1±1.5 2.1±0.8
吗啡组 6 20.1±2.1** 10.1±2.1**
曲马多组 6 17.3±1.9** 9.6±2.3**
可乐定组 6 4.2±1.3 1.9±0.5
复合片组1 6 5.6±1.6 3.0±0.7
复合片组2 6 5.4±1.4 2.9±0.8
复合片组3 6 5.9±1.5 3.2±0.9
复方片组4 6 4.2±1.5 2.2±0.9
复合片组5 6 4.0±1.4 2.0±0.7
复合片组6 6 3.9±1.2 1.6±0.6
注：与空白对照组相比，*P<0.5，呈显著性差异，**P<0.01，呈极显著性差异。
由上表可知，当连续给大鼠口服本品30天后，与空白对照组相比，本发明复合片组大鼠的跳跃次数和体重减轻无显著性差异，吗啡组和曲马多组呈极显著性差异P<0.01。表明，本发明制备的复方片组未见有戒断症状产生，成瘾性低，安全性好。
需要强调的是，本发明所述的实施例是说明性的，而不是限定性的，因此本发明包括并不限于具体实施方式中所述的实施例，凡是由本领域技术人员根据本发明的技术方案得出的其他实施方式，同样属于本发明保护的范围。

Claims (10)

  1. 一种用于减轻或消除阿片戒断综合症的药物组合物，其特征在于，包括盐酸可乐定和盐酸曲马多；
    所述盐酸可乐定和盐酸曲马多的质量比为0.01-0.8：40-60。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述盐酸可乐定和盐酸曲马多在所述药物组合物中的总质量分数为15-20％。
  3. 根据权利要求2所述的药物组合物，其特征在于，所述盐酸可乐定和盐酸曲马多的质量比为0.01-0.56：50，所述盐酸可乐定和盐酸曲马多在所述药物组合物中的总质量分数为17-19％。
  4. 根据权利要求1-3任一项所述的药物组合物在制备减轻或消除阿片戒断综合症药物中的应用。
  5. 根据权利要求1-3任一项所述的药物组合物制备的药剂，其特征在于，由权利要求1-3任一项所述的药物组合物和药学上可接受的辅料组成。
  6. 根据权利要求5所述的药剂，其特征在于，所述药型包括复方片、丸剂、颗粒剂、注射剂、粉剂、喷雾剂、舌下片剂、胶囊剂和液体制剂。
  7. 根据权利要求6所述的药剂，其特征在于，所述药剂为复方片，所述复方片，按质量份计，包括盐酸可乐定为0.01-0.8份，盐酸曲马多40-60份，水乳糖110-120份，微晶纤维素100-120份，二氧化硅0.5-1份，硬脂酸镁2.0-3.6份。
  8. 根据权利要求7所述的药剂，其特征在于，所述复方片，按质量份计，包括盐酸可乐定0.01-0.56份，盐酸曲马多50份，水乳糖114.5份，微晶纤维素112份，二氧化硅0.7份，硬脂酸镁2.8份。
  9. 根据权利要求7或8所述的药剂，其特征在于，所述复方片的制备方法，包括以下步骤：
    (1)将处方量的盐酸可乐定溶于水中，与处方量微晶纤维素制粒后过筛，烘干，得到颗 粒；
    (2)将步骤(1)得到的颗粒与处方量的盐酸曲马多和水乳糖混合，再加入处方量的二氧化硅和硬脂酸镁混合，压制成片后包衣，即得所述复方片。
  10. 一种权利要求5-9任一项所述的药剂在制备减轻或消除阿片戒断综合症药物中的应用。
PCT/CN2020/135368 2020-12-07 2020-12-10 用于减轻或消除阿片戒断综合症的药物及制备方法 WO2022120745A1 (zh)

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