Morphinaloxone pharmaceutical composition and application thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a morphine naloxone pharmaceutical composition and application thereof.The morphine naloxone pharmaceutical composition comprises morphine sulfate and naloxone hydrochloride as active ingredients, and the weight ratio of morphine sulfate to naloxone hydrochloride is 1: 1-6: 1; the invention also provides an application of the morphinaloxone pharmaceutical composition in preparation of a medicine for treating pain. The pharmaceutical composition is good in dissolution property and good in stability, and the technical problem of misuse of morphine sulfate can be avoided.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a morphine naloxone pharmaceutical composition and use thereof. BACKGROUND

[0002] Postoperative pain, cancer pain and other moderate to severe pain have a serious impact on the life of patients, and the adverse reactions of analgesics further reduce the quality of life. From the needs of patients, about 4.57 million new cancer cases occurred in China in 2020. Pain is one of the most common and unbearable symptoms of cancer patients, and the incidence of pain in newly diagnosed cancer patients is about 25%, and the incidence of pain in advanced cancer patients is 60-80%, of which 1 / 3 of the patients are severe pain.

[0003] Sustained-release formulations of opioid drugs have been developed to provide slow, continuous release of opioid drugs to prolong the time of pain relief and reduce the frequency of administration, as they can help maintain plasma concentration levels within the therapeutic range under steady-state conditions. This is beneficial and convenient, for example, for chronic pain patients or elderly patients. However, the sustained-release formulations that have been manipulated can be the target of abuse because they can contain higher amounts of active pharmaceutical ingredients (APIs) than immediate-release forms.

[0004] On the one hand, the treatment needs of patients are urgent; on the other hand, the abuse crisis of analgesics, especially opioid drugs, has attracted strong attention from governments around the world. How to meet the needs of pain treatment while preventing the abuse of opioid drugs has become one of the major public health problems. For example, morphine is a pure opioid receptor agonist with strong analgesic effect, but also has obvious sedative effect, is a narcotic drug specially managed by the state, and can produce drug resistance after 3-5 days of continuous use, and can be addictive after more than 1 week.

[0005] The abuse of drug dosage forms can include physical manipulation, such as crushing, hammering, cutting / slicing, grinding, milling, and grinding. The resulting powder can then be dissolved directly and swallowed, taken intranasally, or smoked. In addition, the API can be extracted from intact or crushed / milled tablets in various solvents (including ethanol) and then injected or taken orally.

[0006] In order to reduce the side effects of opioid drug abuse, the prior art obtains a compound preparation by compounding an opioid drug with some other non-opioid drugs, and the drug content in the compound preparation is important. Therefore, it is urgent to find a morphine compound preparation that can achieve analgesic effect and prevent withdrawal symptoms when taken orally. SUMMARY

[0007] The present application aims to provide a morphine naloxone pharmaceutical composition and use, the pharmaceutical composition comprising morphine sulfate and naloxone hydrochloride, the naloxone hydrochloride can antagonize the activity of morphine sulfate, so that the user cannot obtain pleasure, and causes to promote withdrawal reaction, prevent abuse, the naloxone hydrochloride can also reduce the adverse reactions of gastrointestinal tract caused by morphine sulfate, reduce the occurrence of constipation, and the pharmaceutical composition has good dissolution and good stability.

[0008] The present application provides a morphine naloxone pharmaceutical composition, comprising morphine sulfate and naloxone hydrochloride, and the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1:1-6:1.

[0009] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1.5:1-6:1.

[0010] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1:1-5:1.

[0011] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1.5:1-5:1.

[0012] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1.5:1-4.5:1.

[0013] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1.5:1-4:1.

[0014] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 2:1-4:1.

[0015] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 2:1-3:1.

[0016] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 2:5:1-4:1.

[0017] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 3:1-4:1.

[0018] In some embodiments, the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 6:1.

[0019] In some embodiments, the pharmaceutical composition comprises 5-60 mg of the morphine sulfate and 0.8-60 mg of the naloxone hydrochloride per unit preparation.

[0020] In some embodiments, each unit of the formulation comprises 5, 6, 7, 7.5, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of the morphine sulfate and 0.8, 1, 1.3, 1.7, 2, 2.2, 2.5, 3.3, 4, 5, 6, 6.7, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5, 18, 19, 20, 24, 30, 40, 45, 50, or 60 mg of the naloxone hydrochloride.

[0021] In some embodiments, each unit of the formulation contains 5-50 mg of morphine sulfate and 1-20 mg of naloxone hydrochloride.

[0022] In some embodiments, each unit of the formulation contains 10-30 mg of the morphine sulfate and 2.5-12 mg of naloxone hydrochloride.

[0023] In some embodiments, each unit of the formulation contains 10-30 mg of the morphine sulfate and 1.7-30 mg of the naloxone hydrochloride.

[0024] In some embodiments, each unit of the formulation comprises 10-30 mg of the morphine sulfate and 2-30 mg of the naloxone hydrochloride.

[0025] In some embodiments, each unit of the formulation comprises 10-30 mg of the morphine sulfate and 2-20 mg of the naloxone hydrochloride.

[0026] In some embodiments, each unit of the formulation comprises 10-30 mg of the morphine sulfate and 2.2-20 mg of the naloxone hydrochloride.

[0027] In some embodiments, each unit of the formulation comprises 10-30 mg of the morphine sulfate and 2.5-10 mg of the naloxone hydrochloride.

[0028] In some embodiments, each unit of the pharmaceutical composition comprises any of the following active ingredients: (1) 10 mg of morphine sulfate and 10 mg of naloxone hydrochloride; or, (2) 10 mg of morphine sulfate and 6.7 mg of naloxone hydrochloride; or, (3) 10 mg of morphine sulfate and 5 mg of naloxone hydrochloride; or, (4) 10 mg of morphine sulfate and 4 mg of naloxone hydrochloride; or, (5) 10 mg of morphine sulfate and 3.3 mg of naloxone hydrochloride; or, (6) 10 mg of morphine sulfate and 2.5 mg of naloxone hydrochloride; or, (7) 10 mg of morphine sulfate and 2 mg of naloxone hydrochloride; or, (8) 10 mg of morphine sulfate and 6.7 mg of naloxone hydrochloride. g and 1.7 mg of the naloxone hydrochloride; or, (9) 30 mg of the morphine sulfate and 30 mg of the naloxone hydrochloride; or, (10) 30 mg of the morphine sulfate and 20 mg of the naloxone hydrochloride; or, (11) 30 mg of the morphine sulfate and 15 mg of the naloxone hydrochloride; or, (12) 30 mg of the morphine sulfate and 12 mg of the naloxone hydrochloride; or, (13) 30 mg of the morphine sulfate and 10 mg of the naloxone hydrochloride; or, (14) 30 mg of the morphine sulfate and 7.5 mg of the naloxone hydrochloride; or, (15) 30 mg of the morphine sulfate and 6 mg of the naloxone hydrochloride; or, (16) 30 mg of the morphine sulfate and 5 mg of the naloxone hydrochloride.

[0029] This invention provides a morphine-naloxone pharmaceutical composition, wherein the active ingredients of the morphine-naloxone pharmaceutical composition comprise morphine sulfate and naloxone hydrochloride, wherein the weight ratio of morphine sulfate to naloxone hydrochloride is 2.5:1-4:1 (e.g., 2.5:1, 3:1, 3.5:1, or 4:1). This invention provides a morphine-naloxone pharmaceutical composition wherein each unit of the pharmaceutical composition contains 5-50 mg of morphine sulfate (e.g., 5, 6, 7, 7.5, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg) and 1-20 mg of naloxone hydrochloride (e.g., 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5, 18, 19, or 20 mg). In some embodiments, each unit of the pharmaceutical composition contains 10-30 mg of morphine sulfate and 2.5-12 mg of naloxone hydrochloride. In some embodiments, each unit of the pharmaceutical composition contains any of the following active ingredients: 10 mg of morphine sulfate and 2.5 mg of naloxone hydrochloride; or 10 mg of morphine sulfate and 4 mg of naloxone hydrochloride; or 30 mg of morphine sulfate and 12 mg of naloxone hydrochloride; or 30 mg of morphine sulfate and 7.5 mg of naloxone hydrochloride.

[0030] Unless otherwise stated, the content of naloxone hydrochloride in this article is calculated as anhydrous naloxone hydrochloride (in C0.05). 19 H 21 (Calculated based on NO4·HCl). Naloxone hydrochloride can be used in the form of anhydrous naloxone hydrochloride or naloxone hydrochloride dihydrate.

[0031] Unless otherwise stated, the content of morphine sulfate in this article is calculated as morphine sulfate pentahydrate (in C... 17 H 19 (Calculated as NO3)2・H2SO4・5H2O). Morphine sulfate can be used in the form of morphine sulfate pentahydrate.

[0032] Unless otherwise stated, the weight ratio of morphine sulfate to naloxone hydrochloride in this document is expressed as morphine sulfate pentahydrate (C... 17 H 19 NO3)2·H2SO4·5H2O) and anhydrous naloxone hydrochloride (C 19 H 21 The weight ratio of NO4·HCl) is measured.

[0033] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient selected from one or more fillers, flow aids, sustained-release materials, and lubricants.

[0034] In some embodiments, the excipient includes a sustained-release material. The excipient preferably includes a cellulose-based sustained-release material. In some embodiments, the excipient includes 7.50-90.00 mg of sustained-release material, preferably 19.50-39.00 mg. In some embodiments, the excipient includes 7.50-90.00 mg of sustained-release material, preferably 12.00-24.00 mg of cellulose-based sustained-release material.

[0035] In some embodiments, the excipients include a lubricant. In some embodiments, the excipients include 1.50~3.00 mg of lubricant.

[0036] In some embodiments, the excipients include: slow-release materials and lubricants.

[0037] In some embodiments, the excipients include fillers, flow aids, slow-release materials, and lubricants.

[0038] In some embodiments, the filler is selected from one or more of lactose, microcrystalline cellulose, starch, mannitol and dicalcium phosphate, preferably lactose and microcrystalline cellulose.

[0039] In some embodiments, the flow aid is colloidal silica and / or talc, preferably colloidal silica.

[0040] In some embodiments, the sustained-release material is a cellulose-based sustained-release material and / or a waxy sustained-release material; the sustained-release material is a cellulose-based sustained-release material and optionally a waxy sustained-release material; preferably, the cellulose-based sustained-release material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylcellulose and hydroxypropylcellulose, preferably hydroxypropyl methylcellulose; preferably, the waxy sustained-release material is selected from one or more of cetearyl alcohol, cetyl alcohol, octadecanol, hydrogenated vegetable oil and behenicol ester, preferably cetearyl alcohol.

[0041] In some embodiments, the lubricant is selected from one or more of magnesium stearate, calcium stearate, and sodium stearate fumarate, preferably magnesium stearate.

[0042] In some embodiments, per unit of dosage form, the pharmaceutical composition comprises, by weight, 5.0-60.0 parts of morphine sulfate, 0.8-60.0 parts of naloxone hydrochloride, and 7.50-90.00 parts of sustained-release material; preferably, it comprises: 10-30 parts of morphine sulfate, 1.7-30 parts of naloxone hydrochloride, and 7.50-90.00 parts of sustained-release material. In some embodiments, per unit of dosage form, the pharmaceutical composition comprises: 5.0-60.0 mg of morphine sulfate, 0.8-60.0 mg of naloxone hydrochloride, and 7.50-90.00 mg of sustained-release material.

[0043] In some embodiments, per unit of dosage form, the pharmaceutical composition comprises, by weight, 5.0 to 60.0 parts of morphine sulfate, 0.8 to 60.0 parts of naloxone hydrochloride, and 19.50 to 39.00 parts of sustained-release material. In some embodiments, per unit of dosage form, the pharmaceutical composition comprises 5.0 to 60.0 mg of morphine sulfate, 0.8 to 60.0 mg of naloxone hydrochloride, and 19.50 to 39.00 mg of sustained-release material.

[0044] In some embodiments, per unit of dosage form, the pharmaceutical composition comprises, by weight, 5.0 to 60.0 parts of morphine sulfate, 0.8 to 60.0 parts of naloxone hydrochloride, and 7.50 to 45.00 parts of cellulose-based sustained-release material. In some embodiments, per unit of dosage form, the pharmaceutical composition comprises 5.0 to 60.0 mg of morphine sulfate, 0.8 to 60.0 mg of naloxone hydrochloride, and 7.50 to 45.00 mg of cellulose-based sustained-release material.

[0045] In some embodiments, per unit of dosage form, the pharmaceutical composition comprises, by weight, 5.0 to 60.0 parts of morphine sulfate, 0.8 to 60.0 parts of naloxone hydrochloride, and 12.00 to 24.00 parts of cellulose-based sustained-release material. In some embodiments, per unit of dosage form, the pharmaceutical composition comprises 5.0 to 60.0 mg of morphine sulfate, 0.8 to 60.0 mg of naloxone hydrochloride, and 12.00 to 24.00 mg of cellulose-based sustained-release material.

[0046] In some embodiments, per unit of dosage form, the pharmaceutical composition comprises, by weight, 5.0-60.0 parts of morphine sulfate, 0.8-60.0 parts of naloxone hydrochloride, and 1.50-3.00 parts of lubricant; preferably, it comprises 10-30 parts of morphine sulfate, 1.7-30 parts of naloxone hydrochloride, and 1.50-3.00 parts of lubricant. In some embodiments, per unit of dosage form, the pharmaceutical composition comprises 5.0-60.0 mg of morphine sulfate, 0.8-60.0 mg of naloxone hydrochloride, and 1.50-3.00 mg of lubricant.

[0047] In some embodiments, per unit of dosage form, the pharmaceutical composition comprises, by weight, 5.0-60.0 parts of morphine sulfate, 0.8-60.0 parts of naloxone hydrochloride, 7.50-90.00 parts of sustained-release material, and 1.50-3.00 parts of lubricant; preferably, it comprises: 10-30 parts of morphine sulfate, 1.7-30 parts of naloxone hydrochloride, 7.50-90.00 parts of sustained-release material, and 1.50-3.00 parts of lubricant. In some embodiments, per unit of dosage form, the pharmaceutical composition comprises: 5.0-60.0 mg of morphine sulfate, 0.8-60.0 mg of naloxone hydrochloride, 7.50-90.00 mg of sustained-release material, and 1.50-3.00 mg of lubricant.

[0048] In some embodiments, per unit of formulation, the pharmaceutical composition comprises, by weight, 5.0-60.0 parts of morphine sulfate, 0.8-60.0 parts of naloxone hydrochloride, 90.76-218.00 parts of filler, 1.50-6.00 parts of flow aid, 7.50-45.00 parts of cellulose-based sustained-release material, 0.75-4.50 parts of lubricant, and optionally 0-45.00 parts of waxy sustained-release material. In some embodiments, per unit of formulation, the pharmaceutical composition comprises: 5.0-60.0 mg of morphine sulfate, 0.8-60.0 mg of naloxone hydrochloride, 90.76-218.00 mg of filler, 1.50-6.00 mg of flow aid, 7.50-45.00 mg of cellulose-based sustained-release material, 0.75-4.50 mg of lubricant, and optionally 0-45.00 mg of waxy sustained-release material.

[0049] In some embodiments, the pharmaceutical composition comprises, by weight, 5.0 to 60.0 parts of morphine sulfate, 0.8 to 60.0 parts of naloxone hydrochloride, 105.76 to 218.00 parts of filler, 2.25 to 4.50 parts of glidant, 12.00 to 24.00 parts of cellulose-based sustained-release material, 7.50 to 15.00 parts of waxy sustained-release material, and 1.50 to 3.00 parts of lubricant per unit of formulation. In some embodiments, each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, filler 105.76-218.00 mg, glidant 2.25-4.50 mg, cellulose-based sustained-release material 12.00-24.00 mg, waxy sustained-release material 7.50-15.00 mg, and lubricant 1.50-3.00 mg.

[0050] In some embodiments, the pharmaceutical composition comprises, by weight, 5.0 to 60.0 parts of morphine sulfate, 0.8 to 60.0 parts of naloxone hydrochloride, 45.38 to 109.00 parts of lactose, 45.38 to 109.00 parts of microcrystalline cellulose, 1.50 to 6.00 parts of colloidal silica, 7.50 to 45.00 parts of hydroxypropyl methylcellulose, 0.75 to 4.50 parts of magnesium stearate, and optionally 0 to 45.00 parts of cetearyl alcohol. In some embodiments, each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, lactose 45.38-109.00 mg, microcrystalline cellulose 45.38-109.00 mg, colloidal silica 1.50-6.00 mg, hydroxypropyl methylcellulose 7.50-45.00 mg, magnesium stearate 0.75-4.50 mg, and optionally cetearyl alcohol 0-45.00 mg; preferably, the pharmaceutical composition comprises: morphine sulfate 10.0-30.0 mg, naloxone hydrochloride 1.7-30.0 mg, lactose 45.38-109.00 mg, and microcrystalline cellulose 45.3 mg. The pharmaceutical composition comprises: 8-109.00 mg of morphine sulfate, 1.50-6.00 mg of colloidal silica, 7.50-45.00 mg of hydroxypropyl methylcellulose, 0.75-4.50 mg of magnesium stearate, and optionally 0-45.00 mg of cetearyl alcohol; more preferably, the pharmaceutical composition comprises: 10.0-30.0 mg of morphine sulfate, 2.0-20.0 mg of naloxone hydrochloride, 45.38-108.45 mg of lactose, 45.38-108.45 mg of microcrystalline cellulose, 1.50-6.00 mg of colloidal silica, 7.50-45.00 mg of hydroxypropyl methylcellulose, 0.75-4.50 mg of magnesium stearate, and optionally 0-45.00 mg of cetearyl alcohol.

[0051] In some specific embodiments, each unit of the formulation comprises: morphine sulfate 5.0 mg, naloxone hydrochloride 0.8-5.0 mg, lactose 50.63-60.42 mg, microcrystalline cellulose 50.63-60.42 mg, colloidal silica 1.50-3.00 mg, hydroxypropyl methylcellulose 7.50-22.5 mg, magnesium stearate 0.75-2.25 mg, and optionally descecaprol 0-22.5 mg.

[0052] In some specific embodiments, each unit of the formulation comprises: morphine sulfate 5.0 mg, naloxone hydrochloride 1.0-3.3 mg, lactose 51.54-60.33 mg, microcrystalline cellulose 51.54-60.33 mg, colloidal silica 1.50-3.00 mg, hydroxypropyl methylcellulose 7.50-22.5 mg, magnesium stearate 0.75-2.25 mg, and optionally descecaprol 0-22.5 mg.

[0053] In some specific embodiments, each unit of the formulation comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 1.7-10.0 mg, lactose 45.38-57.46 mg, microcrystalline cellulose 45.38-57.46 mg, colloidal silica 1.50-3.00 mg, hydroxypropyl methylcellulose 7.50-22.5 mg, magnesium stearate 0.75-2.25 mg, and optionally descecaprol 0-22.50 mg.

[0054] In some specific embodiments, each unit of the formulation comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 2.0-6.7 mg, lactose 47.21-57.28 mg, microcrystalline cellulose 47.21-57.28 mg, colloidal silica 1.50-3.00 mg, hydroxypropyl methylcellulose 7.50-22.50 mg, magnesium stearate 0.75-2.25 mg, and optionally descecaprol 0-22.50 mg.

[0055] In some specific embodiments, each unit of the formulation comprises: morphine sulfate 30.0 mg, naloxone hydrochloride 5.0-30.0 mg, lactose 80.27-109.00 mg, microcrystalline cellulose 80.27-109.00 mg, colloidal silica 3.00-6.00 mg, hydroxypropyl methylcellulose 15.00-45.00 mg, magnesium stearate 1.50-4.50 mg, and optionally descecaprol 0-45.00 mg.

[0056] In some specific embodiments, each unit of the formulation comprises: morphine sulfate 30.0 mg, anhydrous naloxone hydrochloride 6.0-20.0 mg, lactose 85.76-108.45 mg, microcrystalline cellulose 85.76-108.45 mg, colloidal silica 3.00-6.00 mg, hydroxypropyl methylcellulose 15.00-45.00 mg, magnesium stearate 1.50-4.50 mg, and optionally descecaprol 0-45.00 mg.

[0057] In some specific embodiments, each unit of the formulation comprises: morphine sulfate 60.0 mg, anhydrous naloxone hydrochloride 10.0-60.0 mg, lactose 48.78-91.26 mg, microcrystalline cellulose 48.78-91.26 mg, colloidal silica 3.00-6.00 mg, hydroxypropyl methylcellulose 15.00-45.00 mg, magnesium stearate 1.50-4.50 mg, and optionally descecaprol 0-45.00 mg.

[0058] In some specific embodiments, each unit of the formulation comprises: morphine sulfate 60.0 mg, anhydrous naloxone hydrochloride 12.0-40.0 mg, lactose 59.77-90.16 mg, microcrystalline cellulose 59.77-90.16 mg, colloidal silica 3.00-6.00 mg, hydroxypropyl methylcellulose 15.00-45.00 mg, magnesium stearate 1.50-4.50 mg, and optionally dececaprol 0-45.00 mg.

[0059] In some embodiments, each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, lactose 52.88-109.00 mg, microcrystalline cellulose 52.88-109.00 mg, colloidal silica 2.25-4.50 mg, hydroxypropyl methylcellulose 12.00-24.00 mg, cetearyl alcohol 7.50-15.00 mg, and magnesium stearate 1.50-3.00 mg.

[0060] Preferably, the pharmaceutical composition comprises: morphine sulfate 10.0~30.0 mg, naloxone hydrochloride 1.7~30.0 mg, lactose 52.88~109.00 mg, microcrystalline cellulose 52.88~109.00 mg, colloidal silica 2.25~4.50 mg, hydroxypropyl methylcellulose 12.00~24.00 mg, cetearyl alcohol 7.50~15.00 mg, and magnesium stearate 1.50~3.00 mg;

[0061] More preferably, the pharmaceutical composition comprises: morphine sulfate 10.0~30.0 mg, naloxone hydrochloride 2.0~20.0 mg, lactose 54.71~108.45 mg, microcrystalline cellulose 54.71~108.45 mg, colloidal silica 2.25~4.50 mg, hydroxypropyl methylcellulose 12.00~24.00 mg, cetearyl alcohol 7.50~15.00 mg, and magnesium stearate 1.50~3.00 mg.

[0062] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 10.0 mg, lactose 52.88 mg, microcrystalline cellulose 52.88 mg, colloidal silica 2.25 mg, hydroxypropyl methylcellulose 12.00 mg, cetearyl alcohol 7.50 mg, and magnesium stearate 1.50 mg.

[0063] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 6.7 mg, lactose 54.71 mg, microcrystalline cellulose 54.71 mg, colloidal silica 2.25 mg, hydroxypropyl methylcellulose 12.00 mg, cetearyl alcohol 7.50 mg, and magnesium stearate 1.50 mg.

[0064] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 5.0 mg, lactose 55.63 mg, microcrystalline cellulose 55.63 mg, colloidal silica 2.25 mg, hydroxypropyl methylcellulose 12.00 mg, cetearyl alcohol 7.50 mg, and magnesium stearate 1.50 mg.

[0065] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 4.0 mg, lactose 56.18 mg, microcrystalline cellulose 56.18 mg, colloidal silica 2.25 mg, hydroxypropyl methylcellulose 12.00 mg, cetearyl alcohol 7.50 mg, and magnesium stearate 1.50 mg.

[0066] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 3.3 mg, lactose 56.54 mg, microcrystalline cellulose 56.54 mg, colloidal silica 2.25 mg, hydroxypropyl methylcellulose 12.00 mg, cetearyl alcohol 7.50 mg, and magnesium stearate 1.50 mg.

[0067] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 2.5 mg, lactose 57.00 mg, microcrystalline cellulose 57.00 mg, colloidal silica 2.25 mg, hydroxypropyl methylcellulose 12.00 mg, cetearyl alcohol 7.50 mg, and magnesium stearate 1.50 mg.

[0068] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 2.0 mg, lactose 57.28 mg, microcrystalline cellulose 57.28 mg, colloidal silica 2.25 mg, hydroxypropyl methylcellulose 12.00 mg, cetearyl alcohol 7.50 mg, and magnesium stearate 1.50 mg.

[0069] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 10.0 mg, naloxone hydrochloride 1.7 mg, lactose 57.46 mg, microcrystalline cellulose 57.46 mg, colloidal silica 2.25 mg, hydroxypropyl methylcellulose 12.00 mg, cetearyl alcohol 7.50 mg, and magnesium stearate 1.50 mg.

[0070] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 30.0 mg, naloxone hydrochloride 30.0 mg, lactose 95.27 mg, microcrystalline cellulose 95.27 mg, colloidal silica 4.50 mg, hydroxypropyl methylcellulose 24.00 mg, cetearyl alcohol 15.00 mg, and magnesium stearate 3.00 mg.

[0071] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 30.0 mg, naloxone hydrochloride 20.0 mg, lactose 100.76 mg, microcrystalline cellulose 100.76 mg, colloidal silica 4.50 mg, hydroxypropyl methylcellulose 24.00 mg, cetearyl alcohol 15.00 mg, and magnesium stearate 3.00 mg.

[0072] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 30.0 mg, naloxone hydrochloride 15.0 mg, lactose 103.51 mg, microcrystalline cellulose 103.51 mg, colloidal silica 4.50 mg, hydroxypropyl methylcellulose 24.00 mg, cetearyl alcohol 15.00 mg, and magnesium stearate 3.00 mg.

[0073] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 30.0 mg, naloxone hydrochloride 12.0 mg, lactose 105.16 mg, microcrystalline cellulose 105.16 mg, colloidal silica 4.50 mg, hydroxypropyl methylcellulose 24.00 mg, cetearyl alcohol 15.00 mg, and magnesium stearate 3.00 mg.

[0074] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 30.0 mg, naloxone hydrochloride 10 mg, lactose 106.26 mg, microcrystalline cellulose 106.26 mg, colloidal silica 4.50 mg, hydroxypropyl methylcellulose 24.00 mg, cetearyl alcohol 15.00 mg, and magnesium stearate 3.00 mg.

[0075] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 30.0 mg, naloxone hydrochloride 7.5 mg, lactose 107.63 mg, microcrystalline cellulose 107.63 mg, colloidal silica 4.50 mg, hydroxypropyl methylcellulose 24.00 mg, cetearyl alcohol 15.00 mg, and magnesium stearate 3.00 mg.

[0076] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 30.0 mg, naloxone hydrochloride 6.0 mg, lactose 108.45 mg, microcrystalline cellulose 108.45 mg, colloidal silica 4.50 mg, hydroxypropyl methylcellulose 24.00 mg, cetearyl alcohol 15.00 mg, and magnesium stearate 3.00 mg.

[0077] In some specific embodiments, the pharmaceutical composition comprises: morphine sulfate 30.0 mg, naloxone hydrochloride 5.0 mg, lactose 109.00 mg, microcrystalline cellulose 109.00 mg, colloidal silica 4.50 mg, hydroxypropyl methylcellulose 24.00 mg, cetearyl alcohol 15.00 mg, and magnesium stearate 3.00 mg.

[0078] In some embodiments, the pharmaceutical composition is an oral solid dosage form; preferably, the oral solid dosage form is a tablet, granule, or capsule, and more preferably a tablet; more preferably, the pharmaceutical composition is a morphine-naloxone extended-release tablet.

[0079] In some embodiments, the filler in each unit dosage form of the pharmaceutical composition comprises 50-150 mg, preferably 99 mg; preferably, the filler is lactose and microcrystalline cellulose, with 25-75 mg of lactose and 25-75 mg of microcrystalline cellulose; more preferably, 49.5 mg of lactose and 49.5 mg of microcrystalline cellulose. In some embodiments, the gliding agent in each unit dosage form of the pharmaceutical composition comprises 1-5 mg, preferably 2.25 mg. In some embodiments, the sustained-release material in each unit dosage form of the pharmaceutical composition comprises 16-68 mg, preferably 34.5 mg; preferably, the sustained-release material is a cellulose-based sustained-release material and a waxy sustained-release material; the cellulose-based sustained-release material comprises 6-18 mg, preferably 12 mg, and the waxy sustained-release material comprises 10-50 mg, preferably 22.5 mg. In some embodiments, the lubricant in each unit dosage form of the pharmaceutical composition comprises 1-3 mg, preferably 1.5 mg.

[0080] In some embodiments, each unit of the pharmaceutical composition comprises: morphine sulfate 5-50 mg, preferably 10-30 mg; naloxone hydrochloride 1-20 mg, preferably 2.5-12 mg; filler 50-150 mg, preferably 99 mg; gliding agent 1-5 mg, preferably 2.25 mg; sustained-release material 16-68 mg, preferably 34.5 mg; and lubricant 1-3 mg, preferably 1.5 mg.

[0081] In some embodiments, the pharmaceutical composition comprises a core material and a coating, wherein each unit of formulation comprises: morphine sulfate 5-50 mg, preferably 10-30 mg; naloxone hydrochloride 1-20 mg, preferably 2.5-12 mg; filler 50-150 mg, preferably 99 mg; gliding agent 1-5 mg, preferably 2.25 mg; sustained-release material 16-68 mg, preferably 34.5 mg; and lubricant 1-3 mg, preferably 1.5 mg.

[0082] In some embodiments, each unit of the pharmaceutical composition comprises: morphine sulfate 5-50 mg, preferably 10-30 mg; naloxone hydrochloride 1-20 mg, preferably 2.5-12 mg; lactose 25-75 mg, preferably 49.5 mg; microcrystalline cellulose 25-75 mg, preferably 49.5 mg; colloidal silica 1-5 mg, preferably 2.25 mg; hydroxypropyl methylcellulose 6-18 mg, preferably 12 mg; cetearyl alcohol 10-50 mg, preferably 22.5 mg; and magnesium stearate 1-3 mg, preferably 1.5 mg.

[0083] In some embodiments, each unit of the pharmaceutical composition comprises: 10 mg of morphine sulfate, 2.5 mg of naloxone hydrochloride, 49.5 mg of lactose, 49.5 mg of microcrystalline cellulose, 2.25 mg of colloidal silica, 12 mg of hydroxypropyl methylcellulose, 22.5 mg of cetearyl alcohol, and 1.5 mg of magnesium stearate. In some specific embodiments, the pharmaceutical composition is a tablet consisting of a core and a coating; the core comprises 10 mg of morphine sulfate, 2.5 mg of naloxone hydrochloride, 49.5 mg of lactose, 49.5 mg of microcrystalline cellulose, 2.25 mg of colloidal silica, 12 mg of hydroxypropyl methylcellulose, 22.5 mg of cetearyl alcohol, and 1.5 mg of magnesium stearate; the coating comprises 4.50 mg of a film-coating premix.

[0084] This invention provides the use of the above-described morphine-naloxone pharmaceutical composition in the preparation of a medicament for treating pain.

[0085] In some embodiments, the pain includes: moderate pain and severe pain; more preferably, the pain is treatment for moderate to severe pain requiring the use of opioid analgesics.

[0086] The beneficial effects achieved by this invention are as follows:

[0087] 1. The active ingredients of the morphine-naloxone pharmaceutical composition of the present invention comprise morphine sulfate and naloxone hydrochloride. Naloxone hydrochloride is a pure opioid receptor antagonist with no intrinsic activity; however, it competitively antagonizes various opioid receptors and has a strong affinity for μ receptors. Naloxone hydrochloride has a rapid onset of action and a strong antagonistic effect. It can rapidly reverse respiratory depression caused by opioid analgesics, induce hyperexcitability, and promote cardiovascular hyperactivity. Therefore, when the pharmaceutical composition of the present invention is crushed and administered nasally or intravenously, the resulting naloxone is rapidly released and absorbed. Naloxone antagonizes the activity of morphine, preventing the user from experiencing euphoria and causing a rapid withdrawal reaction, greatly reducing its appeal to abusers and thus further preventing abuse.

[0088] 2. The morphine-naloxone pharmaceutical composition of the present invention exhibits good solubility and excellent absorption in vivo, and remains stable even after long-term storage. Furthermore, the present invention selects suitable sustained-release materials to ensure good solubility, resulting in a sustained-release effect in the pharmaceutical composition. Further, under the specified ratio, specifications, and related excipients of morphine sulfate and naloxone hydrochloride described in the present invention, it exhibits good solubility, stable release, excellent sustained-release effect, and excellent absorption and stability in vivo.

[0089] 3. Opioids react with receptors outside the central nervous system, producing side effects. For example, morphine sulfate acts in the gastrointestinal (GI) tract, inhibiting gastric emptying and intestinal peristalsis, thereby reducing intestinal transit rate and causing constipation. The pharmaceutical composition of this invention can be an oral solid dosage form, preferably morphine-naloxone sustained-release tablets. When taken orally, naloxone binds to opioid receptors on neurons in the myenteric nerve bundle of the gastrointestinal tract, competitively antagonizing the binding of morphine to these receptors. The morphine-naloxone pharmaceutical composition of this invention can improve the inhibitory effect of morphine on small intestinal motility, reduce morphine-induced gastrointestinal adverse reactions, and decrease the occurrence of constipation. The pharmaceutical composition of this invention shows an effective improvement in morphine-induced constipation in terms of first defecation time, total number of defecations within 6 hours, small intestinal push rate, and small intestinal inhibition rate. Attached Figure Description

[0090] Figure 1 The graph shows the time to first bowel movement (Second).

[0091] Figure 2 This is a graph showing the number of stool particles excreted over 6 hours. Detailed Implementation

[0092] The present invention will be further described in detail below with reference to the embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art based on the disclosure of the present invention shall fall within the protection scope of the present invention.

[0093] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0094] Unless otherwise stated, the term "optional" as used herein means that the object or event it modifies exists or does not exist, or occurs or does not occur.

[0095] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms associated with the disease, including inhibiting the progression of the disease or condition and alleviating the disease or condition.

[0096] In this invention, the pharmaceutical excipients or reagents involved can all be obtained from commercial sources.

[0097] In this invention, unless otherwise specified, "%" in the embodiments of this application refers to the mass percentage.

[0098] Unless otherwise specified, the reaction temperature in this invention is 20~30℃.

[0099] Unless otherwise stated, the dosage of morphine sulfate in this document is calculated as morphine sulfate pentahydrate (in C... 17 H 19The amount of naloxone hydrochloride used is calculated as anhydrous naloxone hydrochloride (based on C2·H2·5H2O). 19 H 21 (NO4·HCl)

[0100] In the embodiments and experimental examples of this invention, the amount of morphine sulfate in the weight of the coated tablets is calculated as morphine sulfate pentahydrate (as per C). 17 H 19 The amount of naloxone hydrochloride used is calculated as naloxone dihydrate (based on C2·H2·5H2O). 19 H 21 The weight ratio of morphine sulfate to naloxone hydrochloride is calculated as morphine sulfate pentahydrate (C4·HCl·2H2O). 17 H 19 NO3)2·H2SO4·5H2O) and anhydrous naloxone hydrochloride (C 19 H 21 The dosage is calculated based on the weight ratio of NO4·HCl. In Test Examples 3 and 4 of this invention, morphine refers to morphine sulfate, used in the form of morphine sulfate pentahydrate, and the dosage is calculated based on morphine sulfate pentahydrate (in C... 17 H 19 (Calculated as NO3)2·H2SO4·5H2O); Naloxone refers to naloxone hydrochloride, used in the form of naloxone hydrochloride dihydrate, and the dosage is calculated as anhydrous naloxone hydrochloride (in C). 19 H 21 (Calculated based on NO4·HCl).

[0101] In this invention, embodiment 1 is provided: a morphine-naloxone pharmaceutical composition comprising morphine sulfate and naloxone hydrochloride, wherein the weight ratio of morphine sulfate to naloxone hydrochloride is 1:1 to 6:1.

[0102] Implementation Scheme 2: The composition as described in Implementation Scheme 1, wherein the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1:1 to 5:1.

[0103] Implementation Scheme 3: The composition as described in Implementation Scheme 1, wherein the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1.5:1 to 5:1;

[0104] Implementation Scheme 4: The composition as described in Implementation Scheme 1, wherein the weight ratio of the morphine sulfate to the naloxone hydrochloride is 1.5:1 to 4.5:1;

[0105] Implementation Scheme 5: The composition as described in Implementation Scheme 1, wherein the weight ratio of the morphine sulfate to the naloxone hydrochloride is 2:1 to 4:1;

[0106] Implementation Scheme 6: The composition as described in Implementation Scheme 1, wherein the weight ratio of the morphine sulfate to the naloxone hydrochloride is 2:1 to 3:1;

[0107] Implementation Scheme 7: The composition as described in Implementation Scheme 1, wherein the weight ratio of the morphine sulfate to the naloxone hydrochloride is 3:1 to 4:1.

[0108] Implementation Scheme 8: The composition as described in any one of Implementation Schemes 1-7, wherein each unit of the formulation comprises 5-60 mg of the morphine sulfate and 0.8-60 mg of the naloxone hydrochloride.

[0109] Implementation Scheme 9: The composition as described in Implementation Scheme 8, wherein each unit of the formulation comprises 10-30 mg of the morphine sulfate and 1.7-30 mg of the naloxone hydrochloride.

[0110] Implementation Scheme 10: The composition as described in Implementation Scheme 8, wherein each unit of the formulation comprises 10-30 mg of the morphine sulfate and 2-30 mg of the naloxone hydrochloride.

[0111] Implementation Scheme 11: The composition as described in Implementation Scheme 8, wherein each unit of the formulation comprises 10-30 mg of the morphine sulfate and 2-20 mg of the naloxone hydrochloride.

[0112] Implementation Scheme 12: The composition as described in Implementation Scheme 8, wherein each unit of the formulation comprises 10-30 mg of the morphine sulfate and 2.2-20 mg of the naloxone hydrochloride.

[0113] Implementation Scheme 13: The composition as described in Implementation Scheme 8, wherein each unit of the formulation comprises 10-30 mg of the morphine sulfate and 2.5-10 mg of the naloxone hydrochloride.

[0114] Implementation Scheme 14: The composition of any one of Implementation Schemes 1-13, wherein the composition additionally comprises: a sustained-release material.

[0115] Embodiment 15: The composition as described in any one of Embodiment 14, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 7.50-90.00 parts of the sustained-release material. Alternative Embodiment 15: The composition as described in any one of Embodiment 14, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 19.50-39.00 parts of the sustained-release material.

[0116] Embodiment 16: The composition as described in any one of Embodiments 1-15, wherein each unit of formulation contains 7.50 to 90.00 mg of the sustained-release material. Alternative Embodiment 16: The composition as described in any one of Embodiments 1-15, wherein each unit of formulation contains 19.50 to 39.00 mg.

[0117] Implementation Scheme 17: The composition of any one of Implementation Schemes 1-16, wherein the composition additionally comprises: a cellulose-based sustained-release material.

[0118] Embodiment 18: The composition as described in Embodiment 17, wherein the cellulose-based sustained-release material is hydroxypropyl methylcellulose. Alternative Embodiment 18, the composition as described in Embodiment 17, wherein the cellulose-based sustained-release material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylcellulose, and hydroxypropylcellulose.

[0119] Embodiment 19: The composition as described in any one of Embodiments 1-18, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 7.50-45.00 parts of the cellulose-based sustained-release material. Alternative Embodiment 19: The composition as described in any one of Embodiments 1-18, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 12.00-24.00 parts of the cellulose-based sustained-release material.

[0120] Embodiment 20: The composition as described in any one of Embodiments 1-19, wherein each unit of formulation comprises 7.50-45.00 mg of the cellulose-based sustained-release material. Alternative Embodiment 20: The composition as described in any one of Embodiments 1-19, wherein each unit of formulation comprises 12.00-24.00 mg of the cellulose-based sustained-release material.

[0121] Implementation Scheme 21: The composition as described in Implementation Schemes 1-20, wherein the composition additionally comprises: a waxy sustained-release material.

[0122] Implementation Scheme 22: The composition as described in Implementation Scheme 21, wherein the waxy sustained-release material is cetearyl alcohol. Alternative Implementation Scheme 22, the composition as described in Implementation Scheme 21, wherein the waxy sustained-release material is selected from one or more of cetearyl alcohol, cetyl alcohol, octadecyl alcohol, hydrogenated vegetable oil, and glyceryl behenate.

[0123] Embodiment 23: The composition as described in any one of Embodiments 1-22, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 0-45.00 parts of the waxy sustained-release material. Alternative Embodiment 23: The composition as described in any one of Embodiments 1-22, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 7.50-15.00 parts of the waxy sustained-release material.

[0124] Embodiment 24: The composition as described in any one of Embodiments 1-23, wherein each unit of formulation comprises 0-45.00 mg of the waxy sustained-release material. Alternative Embodiment 24: The composition as described in any one of Embodiments 1-23, wherein each unit of formulation comprises 7.50-15.00 mg of the waxy sustained-release material.

[0125] Embodiment 25: The composition of any one of Embodiments 1-24, wherein the composition additionally comprises: a lubricant.

[0126] Embodiment 26: The composition as described in Embodiment 25, wherein the lubricant is magnesium stearate. Alternative Embodiment 26, the composition as described in Embodiment 25, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, and sodium stearate fumarate.

[0127] Embodiment 27: The composition of any one of Embodiments 1-26, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 0.75-4.50 parts of the lubricant. Alternative Embodiment 27: The composition of any one of Embodiments 1-26, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 1.50-3.00 parts of the lubricant.

[0128] Embodiment 28: The composition as described in any one of Embodiments 1-27, wherein each unit of formulation contains 0.75 to 4.50 mg of the lubricant. Alternative Embodiment 28: The composition as described in any one of Embodiments 1-27, wherein each unit of formulation contains 1.50 to 3.00 mg of the lubricant.

[0129] Embodiment 29: The composition of any one of Embodiments 1-28, wherein the composition additionally comprises: a filler.

[0130] Embodiment 30: The composition as described in Embodiment 29, wherein the filler is lactose and microcrystalline cellulose. Alternative Embodiment 30, the composition as described in Embodiment 29, wherein the filler is selected from one or more of lactose, microcrystalline cellulose, starch, mannitol, and dicalcium phosphate.

[0131] Embodiment 31: The composition as described in any one of Embodiments 1-30, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 90.76-218.00 parts of the filler. Alternative Embodiment 31: The composition as described in any one of Embodiments 1-30, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 105.76-218.00 parts of the filler. Alternative Embodiment 31: The composition as described in any one of Embodiments 1-30, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 50-150 parts of the filler. Alternative embodiment 31, the composition of any one of embodiments 1-30, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, 25-75 parts of lactose, and 25-75 parts of microcrystalline cellulose.

[0132] Embodiment 32: The composition as described in any one of Embodiments 1-31, wherein each unit of formulation contains 90.76-218.00 mg of the filler. Alternative Embodiment 32: The composition as described in any one of Embodiments 1-31, wherein each unit of formulation contains 105.76-218.00 mg of the filler. Alternative Embodiment 32: The composition as described in any one of Embodiments 1-31, wherein each unit of formulation contains 50-150 mg of the filler. Alternative Embodiment 32: The composition as described in any one of Embodiments 1-31, wherein each unit of formulation contains 25-75 mg of lactose and 25-75 mg of microcrystalline cellulose.

[0133] Implementation Scheme 33: The composition of any one of Implementation Schemes 1-32, wherein the composition additionally comprises: a flow aid.

[0134] Embodiment 34: The composition as described in Embodiment 33, wherein the flow aid is colloidal silica. An alternative embodiment 34, the composition as described in Embodiment 33, wherein the flow aid is colloidal silica and / or talc.

[0135] Embodiment 35: The composition as described in any one of Embodiments 1-34, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 1.50-6.00 parts of the flow aid. Alternative Embodiment 35: The composition as described in any one of Embodiments 1-34, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 1.00-5.00 parts of the flow aid. Alternative Embodiment 35: The composition as described in any one of Embodiments 1-34, wherein the composition comprises 5-60 parts of the morphine sulfate, 0.8-60 parts of the naloxone hydrochloride, and 2.25-4.50 parts of the flow aid.

[0136] Embodiment 36: The composition as described in any one of Embodiments 1-35, wherein each unit of formulation contains 1.50-6.00 mg of the gliding agent. Alternative Embodiment 36: The composition as described in any one of Embodiments 1-35, wherein each unit of formulation contains 1.00-5.00 mg of the gliding agent. Alternative Embodiment 36: The composition as described in any one of Embodiments 1-35, wherein each unit of formulation contains 2.25-4.50 mg of the gliding agent.

[0137] Implementation Scheme 37: The composition as described in any one of Implementation Schemes 1-36, wherein the composition is an oral solid dosage form.

[0138] Embodiment 38: The composition as described in Embodiment 37, wherein the oral solid dosage form is a tablet. Alternative Embodiment 38: The composition as described in Embodiment 37, wherein the oral solid dosage form is a granule or capsule.

[0139] Implementation Scheme 39: The composition as described in Implementation Scheme 38, wherein the composition is a morphine naloxone sustained-release tablet.

[0140] Implementation Scheme 40: The composition as described in any one of Implementation Schemes 1-39, wherein the dissolution of the composition is determined according to the second method (paddle method) of the General Chapter 0931 Dissolution and Release Determination Method in Part IV of the Chinese Pharmacopoeia 2020, and the dissolution of the morphine sulfate and the naloxone hydrochloride is ≤60% after 1 hour.

[0141] Implementation Scheme 41: The composition as described in any one of Implementation Schemes 1-40, wherein the dissolution of the composition is determined according to the second method (paddle method) of the Dissolution and Release Determination Method 0931, Part IV, Chinese Pharmacopoeia 2020, and the dissolution of the morphine sulfate and the naloxone hydrochloride is 40% to 80% after 2 hours.

[0142] Implementation Scheme 42: The composition as described in any one of Implementation Schemes 1-41, wherein the dissolution of the composition is determined according to the second method (paddle method) of the General Chapter 0931 Dissolution and Release Determination Method in Part IV of the Chinese Pharmacopoeia 2020, and the dissolution of the morphine sulfate and the naloxone hydrochloride is ≥80% after 6 hours.

[0143] Implementation Scheme 43: The composition as described in any one of Implementation Schemes 1-42, wherein the dissolution rate of the composition is determined according to the second method (paddle method) of Dissolution and Release Determination Method 0931, General Chapter 4, Chinese Pharmacopoeia 2020 Edition, and the dissolution rate of the morphine sulfate and the naloxone hydrochloride is ≥90% after 12 hours. Alternative Implementation Scheme 43: The composition as described in any one of Implementation Schemes 1-42, wherein the dissolution rate of the composition is determined according to the second method (paddle method) of Dissolution and Release Determination Method 0931, General Chapter 4, Chinese Pharmacopoeia 2020 Edition, and the dissolution rate of the morphine sulfate and the naloxone hydrochloride is ≥95% after 12 hours.

[0144] Implementation Scheme 44: The composition as described in any one of Implementation Schemes 40-43, wherein the dissolution rate of the composition is determined according to the second method (paddle method) of Dissolution and Release Determination Method 0931, Part IV, Chinese Pharmacopoeia 2020, with a rotation speed of 50 rpm, a pH 1.0 hydrochloric acid solution as the dissolution medium, a medium volume of 900 ml, and a medium temperature of 37℃ ± 0.5℃.

[0145] Implementation Scheme 45: The composition of any one of Implementation Schemes 1-44, wherein the active ingredients of the composition are the morphine sulfate and the naloxone hydrochloride.

[0146] Implementation Scheme 46: The composition of any one of Implementation Schemes 1-44, wherein the composition further comprises a coating agent.

[0147] Implementation Scheme 47: The composition as described in Implementation Scheme 46, wherein the coating agent is a film coating premix.

[0148] Embodiment 48: The composition as described in Embodiments 46 or 47, wherein the weight gain of the coating agent after coating is 2% to 4% (w / w) relative to the uncoated weight. Alternative Embodiment 48: The composition as described in Embodiments 46 or 47, wherein the weight gain of the coating agent after coating is 3% (w / w) relative to the uncoated weight.

[0149] Implementation Scheme 49: The composition of any one of Implementation Schemes 1-48, wherein the composition is an oral solid dosage form comprising a core and a coating.

[0150] Implementation Scheme 50: The composition as described in Implementation Scheme 49, wherein the core material comprises: a filler, a flow aid, a slow-release material, and a lubricant; the coating comprises a coating agent, and the coating is a film coating.

[0151] Implementation Scheme 51: The composition as described in Implementation Scheme 49 or 50, wherein the coating is prepared from a coating solution having a solid content of 10-20% (w / w).

[0152] Embodiment 52: The composition as described in Embodiment 51, wherein the coating solution comprises a film coating premix and water. Alternative Embodiment 52, the composition as described in Embodiment 51, wherein the coating solution comprises a film coating premix and water.

[0153] Examples 1-32: Formulations and Preparation

[0154] Preparation Examples 1-32: 1000 tablets of each morphine-naloxone sustained-release tablet were prepared. The only difference between the examples was the amount of raw materials and excipients used. The weights of the raw materials and excipients are shown in the table below (unit: g):

[0155] Table 1 (for 1000 tablets)

[0156]

[0157] Table 2 (for 1000 tablets)

[0158]

[0159] Table 3 (for 1000 tablets)

[0160]

[0161] Table 4 (for 1000 tablets)

[0162]

[0163] Tablet preparation method: Morphine sulfate, naloxone hydrochloride, microcrystalline cellulose, lactose, colloidal silica, hydroxypropyl methylcellulose and cetearyl alcohol are mixed in a hopper mixer, granulated, and sieved to obtain a mixture. The mixture is then mixed with magnesium stearate and compressed into tablets.

[0164] Example 33 Formulation and Preparation

[0165] The following table shows the weights of raw materials and excipients used to prepare 1000 morphine-naloxone sustained-release tablets: (unit: g)

[0166] Table 5

[0167]

[0168] Tablet preparation method:

[0169] Preparation of uncoated tablets: Morphine sulfate, naloxone hydrochloride, microcrystalline cellulose, lactose monohydrate, colloidal silica, hydroxypropyl methylcellulose and cetearyl alcohol are mixed in a hopper mixer and then granulated. The granulated and sieved mixture is mixed with magnesium stearate and then pressed into uncoated tablets.

[0170] Coating: Weigh water and film coating premix (gastric-soluble type) (Opadry) and stir evenly to prepare a film coating solution with a solid content of 15% (w / w). Coat the tablets with the film coating solution to obtain the final tablets.

[0171] Example 34: Formulation and Preparation

[0172] The following table shows the weights of raw materials and excipients used to prepare 1000 morphine-naloxone sustained-release tablets: (unit: g)

[0173] Table 6

[0174]

[0175] Tablet preparation method:

[0176] Preparation of uncoated tablets: Morphine sulfate, naloxone hydrochloride, lactose monohydrate, microcrystalline cellulose and polyoxyethylene are mixed in a hopper mixer and then granulated. The granulated and sieved mixture is mixed with magnesium stearate and then pressed into uncoated tablets.

[0177] Coating: Weigh water and film coating premix (gastric-soluble type) (Opadry) and stir evenly to prepare a film coating solution with a solid content of 15% (w / w). Coat the tablets with the film coating solution to obtain the final tablets.

[0178] Example 35: Formulation and Preparation

[0179] The following table shows the weights of raw materials and excipients used to prepare 1000 morphine-naloxone sustained-release tablets: (unit: g)

[0180] Table 7

[0181]

[0182] Tablet preparation method:

[0183] Preparation of uncoated tablets: Morphine sulfate, naloxone hydrochloride, lactose monohydrate, microcrystalline cellulose, cetearyl alcohol and ethyl cellulose are mixed in a hopper mixer and then granulated. The granulated and sieved mixture is mixed with magnesium stearate, then compressed into uncoated tablets and coated with a film to obtain the final tablets.

[0184] Coating: Weigh water and film coating premix (gastric-soluble type) (Opadry) and stir evenly to prepare a film coating solution with a solid content of 15% (w / w). Coat the tablets with the film coating solution to obtain the final tablets.

[0185] Examples 36-41

[0186] Examples 36-41 were prepared with reference to Example 33 (the only difference from Example 1 is the type and amount of excipients).

[0187] Table 8

[0188]

[0189] Example 1: Evaluation of in vitro dissolution profile

[0190] 1. Test materials

[0191] Samples prepared according to the examples;

[0192] Example 42: The difference from Example 9 is that hydroxyethyl cellulose is used instead of hydroxypropyl methylcellulose;

[0193] Example 43: The difference from Example 9 is that hydroxypropyl cellulose is used instead of hydroxypropyl methylcellulose;

[0194] Example 44: The difference from Example 9 is that ethyl cellulose is used instead of hydroxypropyl methylcellulose;

[0195] Example 45: The difference from Example 9 is that polyoxyethylene is used instead of hydroxypropyl methylcellulose;

[0196] Example 46: The difference from Example 9 is that hexadecyl alcohol is used instead of hexadecyloctadecyl alcohol;

[0197] Example 47: The difference from Example 9 is that octadecyl alcohol is used instead of hexadecyl alcohol;

[0198] Example 48: The difference from Example 9 is that hydrogenated vegetable oil is used instead of cetearyl alcohol;

[0199] Example 49: The difference from Example 9 is that glyceryl behenate is used instead of hexadecyl alcohol;

[0200] Example 50: Under the condition that the total amount of sustained-release material remains unchanged, the difference from Example 9 is that hexadecanoic acid is omitted;

[0201] Example 51: The difference from Example 9 is that sodium stearate fumarate is used instead of magnesium stearate;

[0202] Example 52: The difference from Example 9 is that magnesium stearate is omitted.

[0203] 2. Experimental Methods

[0204] The dissolution and release rate determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II (Paddle Method)) was adopted. The rotation speed was 50 rpm, and hydrochloric acid solution with pH 1.0 was selected as the dissolution medium. The medium volume was 900 ml, and the medium temperature was 37℃±0.5℃. The dissolution curves of each sample were measured at 1h, 2h, 3h, 4h, 6h, 8h, 10h, and 12h. The cumulative dissolution of the formulation at each time point was detected by high performance liquid chromatography.

[0205] 3. Test Results

[0206] The morphine-naloxone pharmaceutical composition of the present invention exhibits a sustained-release effect of morphine sulfate and naloxone hydrochloride.

[0207] Table 9. Dissolution profiles of exemplary morphine sulfate pharmaceutical compositions in pH 1.0 medium (cumulative dissolution percentage (%))

[0208]

[0209] Table 10 Dissolution curves of naloxone hydrochloride in pH 1.0 medium (cumulative dissolution percentage (%))

[0210]

[0211] (1) Buffer material

[0212] It was observed that the morphine-naloxone pharmaceutical composition of the present invention exhibited similar dissolution effects after 12 hours using hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and hydroxypropyl methyl cellulose.

[0213] It was observed that the morphine-naloxone pharmaceutical composition of the present invention had a dissolution rate of more than 20% lower than that of hydroxypropyl methylcellulose after 1, 2, 3 and 4 hours using polyoxyethylene, and a dissolution effect similar to that of hydroxypropyl methylcellulose after 12 hours.

[0214] It was observed that the morphine-naloxone pharmaceutical composition of the present invention, omitting the waxy sustained-release material (such as cetearyl alcohol), and using cetearyl alcohol, octadecanol, hydrogenated vegetable oil, behenicol glyceryl ester and waxy sustained-release materials with similar dissolution effects after 12 hours;

[0215] (2) Lubricant

[0216] It was observed that the morphine naloxone pharmaceutical composition of the present invention has similar sustained-release effects when using magnesium stearate, sodium stearate fumarate and magnesium stearate.

[0217] It was observed that the morphine naloxone pharmaceutical composition of the present invention exhibited burst release and uneven release when the lubricant (e.g., magnesium stearate) was omitted.

[0218] Conclusion: The results show that the morphine-naloxone pharmaceutical composition of the present invention exhibits a sustained-release effect, with a dissolution rate of ≤60% at 1 hour, 40%–80% at 2 hours, ≥80% at 6 hours, and ≥90% at 12 hours; preferably, the dissolution rate at 12 hours is ≥95%. Complete dissolution within 12 hours aligns with the dosing cycle of once every 12 hours, indicating that under the ratio (morphine sulfate to naloxone hydrochloride weight ratio of 1:1 to 6:1), specifications, and related excipients described in this invention, relatively complete dissolution within 12 hours can be ensured, resulting in a sustained-release effect. Preferably, a ratio of morphine sulfate to naloxone hydrochloride of 3:1 to 5:1, specifically 3:1, 3.5:1, 4:1, and 4.5:1, exhibits a sustained-release effect, a superior dissolution plateau, and more complete dissolution of the active pharmaceutical ingredient.

[0219] Furthermore, the morphine-naloxone pharmaceutical composition of the present invention includes excipients comprising sustained-release materials (such as cellulose-based sustained-release materials, cellulose-based sustained-release materials, and / or waxy sustained-release materials), and the sample release is stable;

[0220] Furthermore, the morphine-naloxone pharmaceutical composition of the present invention includes a lubricant as an excipient, and the sample release is stable.

[0221] Experiment Example 2: Influencing Factors Experiment

[0222] 1. Experimental Materials

[0223] Samples prepared according to the examples;

[0224] Example 42: The difference from Example 9 is that hydroxyethyl cellulose is used instead of hydroxypropyl methylcellulose;

[0225] Example 43: The difference from Example 9 is that hydroxypropyl cellulose is used instead of hydroxypropyl methylcellulose;

[0226] Example 44: The difference from Example 9 is that ethyl cellulose is used instead of hydroxypropyl methylcellulose;

[0227] Example 45: The difference from Example 9 is that polyoxyethylene is used instead of hydroxypropyl methylcellulose;

[0228] Example 46: The difference from Example 9 is that hexadecyl alcohol is used instead of hexadecyloctadecyl alcohol;

[0229] Example 47: The difference from Example 9 is that octadecyl alcohol is used instead of hexadecyl alcohol;

[0230] Example 48: The difference from Example 9 is that hydrogenated vegetable oil is used instead of cetearyl alcohol;

[0231] Example 49: The difference from Example 9 is that glyceryl behenate is used instead of hexadecyl alcohol;

[0232] Example 50: Under the condition that the total amount of sustained-release material remains unchanged, the difference from Example 9 is that hexadecyl alcohol is omitted.

[0233] 2. Test Methods

[0234] (1) High temperature conditions: 60℃±2℃, with inner packaging.

[0235] (2) High humidity conditions: RH 92.5%±5%, with inner packaging.

[0236] (3) Illumination conditions: 4500 lx ± 500 lx, near-ultraviolet energy 1 W / m 2 Includes inner packaging.

[0237] (4) Test procedure: The sample was placed under high temperature, high humidity and light conditions for 1 month. The sample was then sampled for content and related substances (refer to (General Chapter 0931, Part IV, Chinese Pharmacopoeia 2020 Edition)) and the stability of the sample under the above conditions was investigated.

[0238] 3. Experimental Results

[0239] The morphine-naloxone pharmaceutical composition sample of the present invention showed no significant changes in content, impurity B, and related substances after being placed under high temperature, high humidity, and light conditions for one month, indicating stable quality. The morphine-naloxone pharmaceutical composition of the present invention exhibits stable quality and is industrially viable.

[0240] See Tables 12 and 13.

[0241] Table 11

[0242]

[0243] Table 12 Test Results of Factors Affecting Exemplary Morphine Sulfate Pharmaceutical Compositions

[0244]

[0245] Table 13. Test Results of Factors Affecting Exemplary Morphine Sulfate Compositions

[0246]

[0247] It was observed that the morphine-naloxone pharmaceutical composition of the present invention has similar stability when using hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

[0248] It was observed that the morphine naloxone pharmaceutical composition of the present invention, using hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose under high temperature conditions for 1 month, high humidity conditions for 1 month, and light conditions for 1 month, had a morphine impurity B content of <0.1%.

[0249] The morphine-naloxone pharmaceutical composition of the present invention, using ethyl cellulose under high temperature conditions for one month, showed a total impurity content of ≥1.4%.

[0250] It was observed that the morphine-naloxone pharmaceutical composition of the present invention, using polyoxyethylene instead of hydroxypropyl methylcellulose, under high temperature conditions for 1 month, had a morphine impurity B content ≥1.0% and a total impurity content ≥2.0%.

[0251] It was observed that the morphine-naloxone pharmaceutical composition of the present invention, omitting the waxy sustained-release material (such as cetearyl alcohol), has similar stability to the cetearyl alcohol, octadecanol, hydrogenated vegetable oil, behenicol glyceryl ester used in the waxy sustained-release material and the cetearyl alcohol used in the waxy sustained-release material.

[0252] Conclusion: The results show that the morphine-naloxone pharmaceutical composition samples of the present invention, after being placed under high temperature, high humidity, and light conditions for one month, exhibited no significant changes in sample content and related substances, demonstrating stable quality. This indicates that the stability of the composition can be ensured under the morphine sulfate to naloxone hydrochloride ratio (weight ratio 1:1~6:1), specifications, and related excipients described in this invention. Furthermore, the sample stability is even better under high temperature conditions when the morphine sulfate to naloxone hydrochloride weight ratio of the present invention is 3:1~4:1.

[0253] Furthermore, the morphine-naloxone pharmaceutical composition of the present invention, with excipients including sustained-release materials (such as cellulose-based sustained-release materials, cellulose-based sustained-release materials and / or waxy sustained-release materials), exhibits good sample stability.

[0254] Furthermore, samples using cellulose-based hydrophilic sustained-release materials (such as hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose) exhibit superior stability.

[0255] Example 3: Dissolution Stability Evaluation

[0256] The morphine naloxone sustained-release tablets prepared in the examples were packaged in commercially available packaging, i.e., aluminum-plastic blister packs with cardboard boxes as the outer packaging. The tablets were subjected to high-temperature conditions (60°C), accelerated conditions (temperature 40±2°C, relative humidity 75±5%), and long-term conditions (30±2°C, relative humidity 65±5%), and the stability of the tablet dissolution was examined according to the dissolution test method under the commercially available quality standards.

[0257] Experimental Example 4: Effect of Naloxone on the Analgesic Effect of Morphine

[0258] 1. Test materials

[0259] A. Solvent: Purified water.

[0260] B. Compound preparation.

[0261] Morphine preparation method: Accurately weigh the morphine sulfate sample, calculate the purity correction, add purified water, and prepare a morphine solution of 1 mg / mL.

[0262] Morphine and naloxone in different ratios: Weigh morphine sulfate samples and naloxone hydrochloride samples, add purified water, and obtain mixed solutions with a unit volume mass ratio of morphine sulfate and naloxone hydrochloride of 1:1, 3:1, 4:1, and 6:1.

[0263] 2. Experimental animals

[0264] SPF grade SD rats

[0265] 3. Experimental Methods

[0266] 3.2 Animal Experiments

[0267] 3.2.1 Experimental Grouping

[0268] Animals were grouped according to their baseline pain threshold as follows: Group 1: Normal group (n=10) (G-1); Group 2: Model group (n=10) (G-2); Group 3: Morphine group (n=10) (G-3); Group 4: Morphine-Naloxone 1:1 (n=10) (G-4); Group 5: Morphine-Naloxone 3:1 (n=10) (G-5); Group 6: Morphine-Naloxone 4:1 (n=10) (G-6); and Group 7: Morphine-Naloxone 6:1 (n=10) (G-7).

[0269] 3.2.2 Information on laboratory animals

[0270] Table 14

[0271]

[0272] 3.3 Experimental grouping and dosing regimen

[0273] Two hours after surgical modeling, a single oral dose of 10 mL / kg was administered. The specific dosing regimen is shown in Table 15.

[0274] Table 15 Experimental Groups and Dosing Regimens

[0275]

[0276] 3.6 Experimental Endpoint

[0277] The experiment ended after the final pain test, and the experimental animals were euthanized.

[0278] 3.7 Data Analysis

[0279] The analgesic rate was calculated by measuring the pain threshold of animals at different time points using different drug dosages. Relevant data were processed using Office Excel 2013 and GraphPad Prism 8.0, and are expressed as Mean ± SEM (standard error). Two-way ANOVA was used for analysis, and Tukey's test for statistical significance was employed for comparisons between groups. A two-tailed t-test was used for comparisons between two groups; a p-value < 0.05 was considered statistically significant.

[0280] 4. Experimental Results:

[0281] Changes in mechanical pain threshold

[0282] Before modeling, the average PWT (paw withdrawal threshold) of female animals in all groups ranged from 44.95 to 53.06 g. After modeling, the PWT in the model group was significantly lower than that in the normal group before drug administration, indicating that the incision pain model was successfully established. The PWT at 1 h, 2 h, and 4 h after morphine administration was significantly higher than that in the model group (p<0.01, p<0.001, p<0.01), indicating a significant analgesic effect. The analgesic effect was strongest at 2 hours, and then gradually weakened. The PWT of the morphine-naloxone 1:1 (G-4), 3:1 (G-5), 4:1 (G-6), and 6:1 (G-7) groups at 30 min, 1 h, 2 h, and 4 h after administration were not statistically different from those of the morphine group. This indicates that naloxone did not significantly affect the analgesic effect of morphine under different ratios of naloxone-morphine combination, and its analgesic effect was similar to that of morphine alone.

[0283] Before modeling, the average PWT (post-operative weight loss) of male animals in all groups ranged from 44.35 to 46.37 g. After modeling, the PWT in the model group was significantly lower than that in the normal group before drug administration (p<0.001), indicating that the incision pain model was successfully established. At 30 min, 1 h, 2 h, and 4 h after morphine administration, the PWT was significantly higher than that in the model group (p<0.01, p<0.001, p<0.001, p<0.01), indicating significant analgesic effects at these time points; the analgesic effect was strongest at 2 hours, and then gradually weakened.

[0284] Formula for calculating analgesia rate:

[0285] Changes in maximum analgesic effect between females and males:

[0286] Model group (G-2): -2% to 2% at time points 30 min, 1 h, 2 h, and 4 h after drug administration.

[0287] The MPE in the morphine group (G-3) at 30 min, 1 h, 2 h, and 4 h after administration ranged from 7% to 33%.

[0288] The MPE at 30 min, 1 h, 2 h, and 4 h after administration of morphine-naloxone 1:1 (G-4) was 13%–25%.

[0289] The MPE at 30 min, 1 h, 2 h, and 4 h after administration of morphine-naloxone 3:1 (G-5) was 16%–24%.

[0290] The MPE at 30 min, 1 h, 2 h, and 4 h after administration of morphine-naloxone 4:1 (G-6) was 15%–24%.

[0291] The MPE (metabolism-free potential) of morphine-naloxone 6:1 (G-7) at time points of 30 min, 1 h, 2 h, and 4 h after administration was 11%–26%.

[0292] In this experiment, the PWT of the model group animals was significantly lower than that of the normal group before drug administration, 30 min after drug administration, 1 h after drug administration, 2 h after drug administration, and 4 h after drug administration, indicating that the modeling was successful. Using this model to evaluate the effect of naloxone on the efficacy of morphine, the following conclusions were drawn:

[0293] The PWT of the morphine-naloxone 1:1 (G-4), 3:1 (G-5), 4:1 (G-6), and 6:1 (G-7) groups at 30 min, 1 h, 2 h, and 4 h after administration were not statistically different from those of the morphine group. This indicates that naloxone did not significantly affect the analgesic effect of morphine under different ratios of naloxone-morphine combination, and its analgesic effect was similar to that of morphine alone.

[0294] Therefore, in both male and female animals, naloxone did not significantly affect the analgesic effect of morphine at different combination ratios; its analgesic effect was similar to that of morphine alone. The morphine-naloxone pharmaceutical composition of this invention has an analgesic effect similar to that of morphine alone.

[0295] Experimental Example 5: Study on the effect of naloxone on morphine-induced constipation

[0296] 1. Test materials

[0297] Solvent: Purified water.

[0298] The test sample was prepared using the sample prepared according to the example and morphine sulfate sustained-release tablets.

[0299] The following are examples of sample preparation:

[0300] Table 16

[0301]

[0302] 2. Experimental animals

[0303] SPF grade C57 mice.

[0304] Weight at the start of the experiment: 18-22g.

[0305] 3. Experimental Methods

[0306] 3.1. Animal grouping and dosage.

[0307] Table 17

[0308]

[0309] 3.1.1. Drug administration related information

[0310] Administration route: oral gavage; the drug should be prepared fresh for use and mixed using a vortex mixer.

[0311] Dosage frequency and cycle: Administer once daily for 8 consecutive days;

[0312] The day of first administration is defined as day 1 of the dosing period (D1).

[0313] 3.2. Sample Collection and Processing

[0314] 3.2.1. First bowel movement

[0315] Observation time: Observation was carried out immediately after administration on day 7;

[0316] 3.2.2. Total number of stool particles in 6 hours

[0317] Collection time: 6 hours after administration on day 7;

[0318] 3.3.3. Small intestine sample

[0319] Data collection time: Data was collected 35 minutes after administration on day 8.

[0320] 3.4. Weight

[0321] Measurement time: 1 measurement during the adaptation period, and 1 measurement per day during the drug administration period;

[0322] Animals tested: All experimental animals.

[0323] 4. Data Collection and Analysis

[0324] All raw data for this experiment were manually collected according to the experimental protocol requirements, and the collected data were transcribed into an Excel spreadsheet for analysis and reporting.

[0325] 5. Data processing and statistical analysis

[0326] The measurement indicators are expressed as Mean±SEM.

[0327] All quantitative indicators were statistically analyzed using Excel 2013 and GraphPad Prism 8.0.1.244 software. Raw data were entered into the Excel spreadsheet, and the Mean was calculated using raw data. One-way ANOVA was performed in GraphPad Prism.

[0328] 6. Test Results

[0329] 6.1. First bowel movement time and total number of bowel movements in 6 hours:

[0330] Compared with administration of morphine alone, administration of the morphine-naloxone pharmaceutical composition of the present invention improved the time to first defecation and the number of defecations within 6 hours in mice.

[0331] Examples of results are shown in Table 18. Figure 1 (First bowel movement time (Second)) Figure 2 (6-hour stool volume (particles)).

[0332] Table 18 First defecation time and total number of defecations in 6 hours

[0333]

[0334] Figure 1 Medium, one-way ANOVA: * p<0.05 vs. G2, ** p<0.01 vs. G2, *** p<0.001 vs. G2; & p<0.05 vs. G1-G2, && p<0.01 vs. G1-G2 &&& p<0.001 vs. G1-G2

[0335] Figure 2 Medium, one-way ANOVA: * p<0.05 vs. G2, ** p<0.01 vs. G2, *** p<0.001 vs. G2; & p<0.05 vs. G1-G2, && p<0.01 vs. G1-G2 &&& p<0.001 vs. G1-G2

[0336] (1) Time of first defecation

[0337] After 7 consecutive days of administration, the time to first defecation (Mean ± SEM) for groups G1, G2, G3, G4, G5, G6, G7, and G8 were 10.70 ± 2.94 min, 295.14 ± 6.99 min, 140.29 ± 12.91 min, 145.71 ± 22.55 min, 140.38 ± 21.49 min, 173.63 ± 10.16 min, 174.50 ± 5.60 min, and 203.90 ± 7.21 min, respectively (see Table 17). Compared with the solvent group (G1), the total number of defecation particles in morphine-treated mice was significantly reduced at 6 hours (P < 0.001). Compared with morphine administration, the first bowel movement time of morphine-naloxone 1.5:1~5:1 prescriptions was significantly shorter, with the first bowel movement time of morphine-naloxone 1.5:1, 2:1, and 2.5:1 prescriptions being shorter than that of morphine-naloxone 3:1 and 4:1 prescriptions, which were shorter than that of morphine-naloxone 5:1 prescriptions.

[0338] (2) Total number of stool particles excreted within 6 hours

[0339] After 7 consecutive days of administration, the total number of fecal particles excreted in 6 hours for groups G1, G2, G3, G4, G5, G6, G7, and G8 were 33.40±2.70, 5.10±0.71, 20.70±3.45, 15.00±1.95, 21.70±1.78, 19.70±1.55, 20.20±1.99, and 18.00±0.80, respectively (Table 17). Compared with the solvent group (G1), the number of fecal particles excreted within 6 hours after morphine administration was significantly reduced (P<0.001). Compared with morphine administration, the number of fecal particles excreted within 6 hours after morphine-naloxone administration (1.5:1–5:1) was significantly increased.

[0340] 6.3 Small intestinal pushing rate and small intestinal inhibition rate

[0341] Compared with administration of morphine alone, administration of the morphine-naloxone pharmaceutical composition of the present invention resulted in an increased small intestinal push-out rate and a decreased small intestinal inhibition rate.

[0342] Examples of results are shown in Table 19.

[0343] Table 19 Small intestinal pushing rate and small intestinal inhibition rate

[0344]

[0345] (1) Small intestine push rate

[0346] When the morphine sulfate and naloxone hydrochloride drug composition of the present invention, with the specified ratio, specifications, and related excipients, is administered, the small intestinal push-out rate is improved compared to the morphine monotherapy group.

[0347] (2) Small intestinal inhibition rate

[0348] The morphine-naloxone drug composition of the present invention, with the specified ratio, specifications, and related excipients of morphine sulfate and naloxone hydrochloride, showed a decreased small intestinal inhibition rate compared to the morphine monotherapy group.

[0349] 7. Conclusion

[0350] Under the conditions of this experiment, none of the animals were observed to be near death or die during the experiment.

[0351] In mice, administration of morphine alone prolonged the time to defecation after the first dose, reduced defecation, decreased small intestinal push rate, and increased small intestinal inhibition rate. The morphine-naloxone drug composition of this invention showed effective improvement in morphine-induced constipation in four indicators: time to defecation after the first dose, total number of defecation doses over 6 hours, small intestinal push rate, and small intestinal inhibition rate.

[0352] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A morphine-naloxone pharmaceutical composition, characterized in that, It contains morphine sulfate and naloxone hydrochloride, wherein the weight ratio of morphine sulfate to naloxone hydrochloride is 1:1 to 6:

1.

2. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of morphine sulfate to naloxone hydrochloride is 1:1 to 5:1; Preferably, the weight ratio of morphine sulfate to naloxone hydrochloride is 1.5:1 to 5:1; Preferably, the weight ratio of morphine sulfate to naloxone hydrochloride is 1.5:1 to 4.5:1; Preferably, the weight ratio of morphine sulfate to naloxone hydrochloride is 2.5:1 to 4:1; Preferably, the weight ratio of morphine sulfate to naloxone hydrochloride is 2:1 to 4:1; Preferably, the weight ratio of morphine sulfate to naloxone hydrochloride is 2:1 to 3:1; Preferably, the weight ratio of morphine sulfate to naloxone hydrochloride is 3:1 to 4:

1.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, Each unit of the formulation comprises 5-60 mg of the morphine sulfate and 0.8-60 mg of the naloxone hydrochloride; Preferably, in each unit of formulation, the pharmaceutical composition comprises 10-30 mg of morphine sulfate and 1.7-30 mg of naloxone hydrochloride; Preferably, in each unit of formulation, the pharmaceutical composition comprises 10-30 mg of morphine sulfate and 2-30 mg of naloxone hydrochloride; Preferably, in each unit of formulation, the pharmaceutical composition comprises 10-30 mg of morphine sulfate and 2-20 mg of naloxone hydrochloride; Preferably, in each unit of formulation, the pharmaceutical composition comprises 10-30 mg of morphine sulfate and 2.2-20 mg of naloxone hydrochloride; Preferably, in each unit of formulation, the pharmaceutical composition comprises 10-30 mg of morphine sulfate and 2.5-10 mg of naloxone hydrochloride; Preferably, each unit of the pharmaceutical composition comprises, in the following amounts: (1) 10 mg of morphine sulfate and 10 mg of naloxone hydrochloride; or, (2) The morphine sulfate 10 mg and the naloxone hydrochloride 6.7 mg; or, (3) The morphine sulfate 10 mg and the naloxone hydrochloride 5 mg; or, (4) The morphine sulfate 10 mg and the naloxone hydrochloride 4 mg; or, (5) The morphine sulfate 10 mg and the naloxone hydrochloride 3.3 mg; or, (6) The morphine sulfate 10 mg and the naloxone hydrochloride 2.5 mg; or, (7) The morphine sulfate 10 mg and the naloxone hydrochloride 2 mg; or, (8) The morphine sulfate 10 mg and the naloxone hydrochloride 1.7 mg; or, (9) the morphine sulfate 30 mg and the naloxone hydrochloride 30 mg; or, (10) 30 mg of morphine sulfate and 20 mg of naloxone hydrochloride; or, (11) The morphine sulfate 30 mg and the naloxone hydrochloride 15 mg; or, (12) The morphine sulfate 30 mg and the naloxone hydrochloride 12 mg; or, (13) The morphine sulfate 30 mg and the naloxone hydrochloride 10 mg; or, (14) the morphine sulfate 30 mg and the naloxone hydrochloride 7.5 mg; or, (15) The morphine sulfate 30 mg and the naloxone hydrochloride 6 mg; or, (16) 30 mg of morphine sulfate and 5 mg of naloxone hydrochloride.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The pharmaceutical composition further comprises a pharmaceutically acceptable excipient; the excipient is selected from one or more of fillers, flow aids, sustained-release materials, and lubricants. Preferably, the excipients include: sustained-release materials; more preferably, the excipients include: cellulose-based sustained-release materials. Preferably, the auxiliary materials include: lubricant; More preferably, the excipients include: a slow-release material and a lubricant; More preferably, the excipients include: fillers, flow aids, slow-release materials, and lubricants.

5. The pharmaceutical composition according to claim 4, characterized in that, The filler is selected from one or more of lactose, microcrystalline cellulose, starch, mannitol and dicalcium phosphate, preferably lactose and microcrystalline cellulose; And / or, the flow aid is colloidal silica and / or talc, preferably colloidal silica; And / or, the sustained-release material is a cellulose-based sustained-release material and / or a waxy sustained-release material; preferably, the sustained-release material is a cellulose-based sustained-release material and optionally a waxy sustained-release material; preferably, the cellulose-based sustained-release material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylcellulose, and hydroxypropylcellulose, preferably hydroxypropyl methylcellulose; preferably, the waxy sustained-release material is selected from one or more of cetearyl alcohol, cetyl alcohol, octadecanol, hydrogenated vegetable oil, and behenicol, preferably cetearyl alcohol; And / or, the lubricant is selected from one or more of magnesium stearate, calcium stearate and sodium stearate fumarate, preferably magnesium stearate.

6. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, Based on parts by weight, each unit of the formulation comprises: 5.0-60.0 parts of morphine sulfate, 0.8-60.0 parts of naloxone hydrochloride, and 7.50-90.00 parts of sustained-release material; or Based on parts by weight, each unit of the formulation comprises: 5.0 to 60.0 parts of morphine sulfate, 0.8 to 60.0 parts of naloxone hydrochloride, and 1.50 to 3.00 parts of lubricant; Preferably, per unit of formulation, the pharmaceutical composition comprises, by weight, 5.0-60.0 parts of morphine sulfate, 0.8-60.0 parts of naloxone hydrochloride, 7.50-90.00 parts of sustained-release material, and 1.50-3.00 parts of lubricant; Preferably, each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, and sustained-release material 7.50-90.00 mg; or Each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, and sustained-release material 19.50-39.00 mg; or Each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, and cellulose-based sustained-release material 7.50-45.00 mg; or Each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, and cellulose-based sustained-release material 12.00-24.00 mg; or Each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, and lubricant 1.50-3.00 mg; More preferably, in each unit of formulation, the pharmaceutical composition comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, filler 90.76-218.00 mg, glidant 1.50-6.00 mg, cellulose-based sustained-release material 7.50-45.00 mg, lubricant 0.75-4.50 mg, and optionally waxy sustained-release material 0-45.00 mg; or Each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, filler 105.76-218.00 mg, glidant 2.25-4.50 mg, cellulose-based sustained-release material 12.00-24.00 mg, waxy sustained-release material 7.50-15.00 mg, and lubricant 1.50-3.00 mg.

7. The pharmaceutical composition according to claim 6, characterized in that, By weight, each unit of the formulation contains 5.0–60.0 parts morphine sulfate, 0.8–60.0 parts naloxone hydrochloride, 45.38–109.00 parts lactose, 45.38–109.00 parts microcrystalline cellulose, 1.50–6.00 parts colloidal silica, 7.50–45.00 parts hydroxypropyl methylcellulose, 0.75–4.50 parts magnesium stearate, and optionally 0–45.00 parts cetearyl alcohol; or By weight, each unit of the formulation contains 5.0-60.0 parts morphine sulfate, 0.8-60.0 parts naloxone hydrochloride, 52.88-109.00 parts lactose, 52.88-109.00 parts microcrystalline cellulose, 2.25-4.50 parts colloidal silica, 12.00-24.00 parts hydroxypropyl methylcellulose, 7.50-15.00 parts cetearyl alcohol, and 1.50-3.00 parts magnesium stearate; Preferably, each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, lactose 45.38-109.00 mg, microcrystalline cellulose 45.38-109.00 mg, colloidal silica 1.50-6.00 mg, hydroxypropyl methylcellulose 7.50-45.00 mg, magnesium stearate 0.75-4.50 mg, and optionally cetearyl alcohol 0-45.00 mg; More preferably, the pharmaceutical composition comprises: morphine sulfate 10.0-30.0 mg, naloxone hydrochloride 1.7-30.0 mg, lactose 45.38-109.00 mg, microcrystalline cellulose 45.38-109.00 mg, colloidal silica 1.50-6.00 mg, hydroxypropyl methylcellulose 7.50-45.00 mg, magnesium stearate 0.75-4.50 mg, and optionally cetearyl alcohol 0-45.00 mg; More preferably, the pharmaceutical composition comprises: morphine sulfate 10.0-30.0 mg, naloxone hydrochloride 2.0-20.0 mg, lactose 45.38-108.45 mg, microcrystalline cellulose 47.21-108.45 mg, colloidal silica 1.50-6.00 mg, hydroxypropyl methylcellulose 7.50-45.00 mg, magnesium stearate 0.75-4.50 mg, and optionally cetearyl alcohol 0-45.00 mg; Preferably, each unit of the formulation comprises: morphine sulfate 5.0-60.0 mg, naloxone hydrochloride 0.8-60.0 mg, lactose 52.88-109.00 mg, microcrystalline cellulose 52.88-109.00 mg, colloidal silica 2.25-4.50 mg, hydroxypropyl methylcellulose 12.00-24.00 mg, cetearyl alcohol 7.50-15.00 mg, and magnesium stearate 1.50-3.00 mg; More preferably, the pharmaceutical composition comprises: morphine sulfate 10.0~30.0 mg, naloxone hydrochloride 1.7~30.0 mg, lactose 52.88~109.00 mg, microcrystalline cellulose 52.88~109.00 mg, colloidal silica 2.25~4.50 mg, hydroxypropyl methylcellulose 12.00~24.00 mg, cetearyl alcohol 7.50~15.00 mg, and magnesium stearate 1.50~3.00 mg; More preferably, the pharmaceutical composition comprises: morphine sulfate 10.0~30.0 mg, naloxone hydrochloride 2.0~20.0 mg, lactose 54.71~108.45 mg, microcrystalline cellulose 54.71~108.45 mg, colloidal silica 2.25~4.50 mg, hydroxypropyl methylcellulose 12.00~24.00 mg, cetearyl alcohol 7.50~15.00 mg, and magnesium stearate 1.50~3.00 mg.

8. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, include: The pharmaceutical composition is an oral solid dosage form; Preferably, the oral solid dosage form is a tablet, granule, or capsule, and more preferably a tablet; More preferably, the pharmaceutical composition is morphine-naloxone extended-release tablets.

9. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The dissolution rate of the pharmaceutical composition was determined according to the second method (paddle method) of Dissolution and Release Determination Method 0931, General Chapter IV, Chinese Pharmacopoeia 2020 Edition, Part IV. The dissolution rate of the morphine sulfate and the naloxone hydrochloride was ≤60% after 1 hour; and / or The dissolution rate of the pharmaceutical composition was determined according to Method II (paddle method) of Dissolution and Release Determination in General Chapter 0931, Part IV, Chinese Pharmacopoeia 2020. The dissolution rates of the morphine sulfate and naloxone hydrochloride were within the range of 40% to 80% after 2 hours; and / or The dissolution rate of the pharmaceutical composition was determined according to the second method (paddle method) of Dissolution and Release Determination in General Chapter 0931, Part IV, Chinese Pharmacopoeia 2020. The morphine sulfate and naloxone hydrochloride showed a dissolution rate of ≥80% after 6 hours; and / or The dissolution rate of the pharmaceutical composition was determined according to the second method (paddle method) of the General Chapter 0931 Dissolution and Release Determination Method in Part IV of the Chinese Pharmacopoeia 2020. The dissolution rate of the morphine sulfate and the naloxone hydrochloride was ≥90% after 12 hours.

10. Use of the morphine-naloxone pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a medicament for treating pain; Preferably, the pain includes: Moderate and / or severe pain.

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