Pharmaceutical composition of morphin-6-glucuronid for transdermal administration and preparation method and application of pharmaceutical composition

Abstract

The invention discloses a pharmaceutical composition for transdermal administration. The pharmaceutical composition comprises morphin-6-glucuronid or a pharmaceutically acceptable salt thereof, a polymer disperse carrier material, a hot melt protecting agent and an optional fluxing agent, wherein the pharmaceutical composition for transdermal administration is prepared by mixing the morphin-6-glucuronid or the pharmaceutically acceptable salt thereof, the polymer disperse carrier material, the hot melt protecting agent and the optional fluxing agent, and then carrying out hot melt extrusion and micronization to obtain particles of the morphin-6-glucuronid or the pharmaceutically acceptable salt thereof. In addition, the invention further provides a preparation method and application of thepharmaceutical composition. According to the pharmaceutical composition for transdermal administration, the morphin-6-glucuronid or the pharmaceutically acceptable salt thereof can be quickly absorbed to achieve the target of postoperative analgesia without affecting breathing, so that an adverse psychological effect to a patient caused by acupuncture of intramuscular injection or intravenous acupuncture is avoided; and meanwhile, the pharmaceutical composition can also be used for preventing and / or treating lumbar and cervical diseases of the patient.

Description

technical field

[0001] The invention relates to pharmaceutical preparation technology, more specifically to a pharmaceutical composition for transdermal administration of morphine-6-glucuronide and its preparation method and application. Background technique

[0002] Morphine-6-glucuronide [Morphine-6-glucuronide, referred to as M6G, as shown in formula (I), is the active metabolite of morphine in vivo. Morphine as an opioid is currently the most widely used narcotic analgesic for the treatment of moderate to severe pain, but studies have shown that it is not morphine itself that acts as an analgesic. Morphine is mainly combined with glucuronide in the liver and produces two metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M6G can bind to opioid receptors, and animal experiments show that its analgesic effect is stronger than that of morphine, and its adverse reactions are milder. M3G has a low affinity with opioid receptors and has no analgesic ...

Examples

Embodiment 1

[0066] Embodiment 1 Transdermal patch preparation of morphine-6-glucuronide hydrobromide

[0067] (1) Micronize 5 g of morphine-6-glucuronide hydrobromide, 2 g of povidone (PVP-S630) and 0.1 g of magnesium stearate, mix well to obtain a physical mixture, and add polyethylene glycol (Molecular weight 2000) 2.9g;

[0068] (2) Set the extrusion temperature of the twin-screw extruder to 120°C, start the screw after rising to the set temperature, add the physical mixture in step (1) to the extruder, heat-melt and extrude, It is extruded in the form of spherical particles to obtain amorphous particles, which are then micronized, and the particle size is controlled at about 100-150nm.

[0069] (3) Weigh 5 g of micronized amorphous particles prepared in step (2), 0.2 g of soybean lecithin, 0.03 g of cholesterol, 3 g of absolute ethanol, and 1.77 g of water;

[0070] (4) Dissolving soybean lecithin, cholesterol, and morphine-6-glucuronide hydrobromide microparticles in absolute ethan...

Embodiment 2

[0074] Embodiment 2 Transdermal patch preparation of morphine-6-glucuronide hydrochloride

[0075] (1) Micronize morphine-6-glucuronide hydrochloride 6g, povidone (PVP-S630) 1g, and talcum powder 0.2g, mix well to obtain a physical mixture, add polyethylene glycol (molecular weight 3000 )2.8g;

[0076] (2) Set the extrusion temperature of the twin-screw extruder to 100°C, start the screw after rising to the set temperature, add the physical mixture in step (1) to the extruder, heat-melt and extrude, It is extruded in the form of spherical particles to obtain amorphous particles, which are then micronized, and the particle size is controlled at about 150-200nm.

[0077] (3) Weigh 5 g of micronized amorphous particles prepared in step (2), 0.2 g of phosphatidylcholine, 0.08 g of cholesterol, 3 g of propylene glycol, and 1.72 g of water;

[0078] (4) Dissolving phosphatidylcholine, cholesterol, and morphine-6-glucuronide hydrochloride microparticles in propylene glycol, and hea...

Embodiment 3

[0082] Embodiment 3 Transdermal patch preparation of morphine-6-glucuronide sulfate

[0083] (1) morphine-6-glucuronide sulfate 7g and povidone (PVP-VA64) 1.5g magnesium stearate 0.1g are micronized, mix homogeneously, make physical mixture, add polyethylene glycol (molecular weight 4000) 1.4g;

[0084] (2) Set the extrusion temperature of the twin-screw extruder to 140°C, start the screw after rising to the set temperature, add the physical mixture in step (1) to the extruder, heat-melt and extrude, It is extruded in the form of spherical particles to obtain amorphous particles, which are then micronized, and the particle size is controlled at about 250-300nm.

[0085] (3) Weighing 7 g of micronized amorphous particles prepared in step (2), 2 g of dipalmitoylphosphatidylcholine, 0.3 g of cholesterol, 30 g of absolute ethanol, and 60.7 g of water;

[0086] (4) Dissolving dipalmitoylphosphatidylcholine, cholesterol, and morphine-6-glucuronide sulfate particles in absolute eth...

technical field

[0001] The invention relates to pharmaceutical preparation technology, more specifically to a pharmaceutical composition for transdermal administration of morphine-6-glucuronide and its preparation method and application. Background technique

[0002] Morphine-6-glucuronide [Morphine-6-glucuronide, referred to as M6G, as shown in formula (I), is the active metabolite of morphine in vivo. Morphine as an opioid is currently the most widely used narcotic analgesic for the treatment of moderate to severe pain, but studies have shown that it is not morphine itself that acts as an analgesic. Morphine is mainly combined with glucuronide in the liver and produces two metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M6G can bind to opioid receptors, and animal experiments show that its analgesic effect is stronger than that of morphine, and its adverse reactions are milder. M3G has a low affinity with opioid receptors and has no analgesic ...

Examples

Embodiment 1

[0066] Embodiment 1 Transdermal patch preparation of morphine-6-glucuronide hydrobromide

[0067] (1) Micronize 5 g of morphine-6-glucuronide hydrobromide, 2 g of povidone (PVP-S630) and 0.1 g of magnesium stearate, mix well to obtain a physical mixture, and add polyethylene glycol (Molecular weight 2000) 2.9g;

[0068] (2) Set the extrusion temperature of the twin-screw extruder to 120°C, start the screw after rising to the set temperature, add the physical mixture in step (1) to the extruder, heat-melt and extrude, It is extruded in the form of spherical particles to obtain amorphous particles, which are then micronized, and the particle size is controlled at about 100-150nm.

[0069] (3) Weigh 5 g of micronized amorphous particles prepared in step (2), 0.2 g of soybean lecithin, 0.03 g of cholesterol, 3 g of absolute ethanol, and 1.77 g of water;

[0070] (4) Dissolving soybean lecithin, cholesterol, and morphine-6-glucuronide hydrobromide microparticles in absolute ethan...

Embodiment 2

[0074] Embodiment 2 Transdermal patch preparation of morphine-6-glucuronide hydrochloride

[0075] (1) Micronize morphine-6-glucuronide hydrochloride 6g, povidone (PVP-S630) 1g, and talcum powder 0.2g, mix well to obtain a physical mixture, add polyethylene glycol (molecular weight 3000 )2.8g;

[0076] (2) Set the extrusion temperature of the twin-screw extruder to 100°C, start the screw after rising to the set temperature, add the physical mixture in step (1) to the extruder, heat-melt and extrude, It is extruded in the form of spherical particles to obtain amorphous particles, which are then micronized, and the particle size is controlled at about 150-200nm.

[0077] (3) Weigh 5 g of micronized amorphous particles prepared in step (2), 0.2 g of phosphatidylcholine, 0.08 g of cholesterol, 3 g of propylene glycol, and 1.72 g of water;

[0078] (4) Dissolving phosphatidylcholine, cholesterol, and morphine-6-glucuronide hydrochloride microparticles in propylene glycol, and hea...

Embodiment 3

[0082] Embodiment 3 Transdermal patch preparation of morphine-6-glucuronide sulfate

[0083] (1) morphine-6-glucuronide sulfate 7g and povidone (PVP-VA64) 1.5g magnesium stearate 0.1g are micronized, mix homogeneously, make physical mixture, add polyethylene glycol (molecular weight 4000) 1.4g;

[0084] (2) Set the extrusion temperature of the twin-screw extruder to 140°C, start the screw after rising to the set temperature, add the physical mixture in step (1) to the extruder, heat-melt and extrude, It is extruded in the form of spherical particles to obtain amorphous particles, which are then micronized, and the particle size is controlled at about 250-300nm.

[0085] (3) Weighing 7 g of micronized amorphous particles prepared in step (2), 2 g of dipalmitoylphosphatidylcholine, 0.3 g of cholesterol, 30 g of absolute ethanol, and 60.7 g of water;

[0086] (4) Dissolving dipalmitoylphosphatidylcholine, cholesterol, and morphine-6-glucuronide sulfate particles in absolute eth...

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