Pharmaceutical composition of propafenone or salt thereof and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition of propafenone or a salt thereof and a preparation method of the pharmaceutical composition, and belongs to the field of medicines. The pharmaceutical composition comprises an active ingredient, a sustained-release material and a framework material, the active component comprises propafenone or a pharmaceutically acceptable salt thereof. According to the propafenone hydrochloride pharmaceutical composition disclosed by the invention, a specific sustained-release material and a framework material are preferably selected, so that the appearance property stability, the related substance stability, the moisture stability and the content stability of the obtained propafenone hydrochloride pharmaceutical composition are favorably improved, and an unexpected technical effect is achieved; the pharmaceutical composition provided by the invention is stable in in-vivo release, good in slow-release effect and small in drug concentration fluctuation, can maintain safe, effective and stable blood concentration for a long time, does not need to be injected for multiple times and does not need intravenous drip, and is beneficial to reducing the medication frequency and improving the medication compliance of a patient.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a pharmaceutical composition of propafenone or a salt thereof and a preparation method thereof. Background Art

[0002] Propafenone hydrochloride (3-phenyl-1-[2-[3-(propylamino)-2-hydroxypropoxy]phenyl]-1-propanone hydrochloride) is a drug used to prevent paroxysmal ventricular tachycardia, paroxysmal supraventricular tachycardia and preexcitation syndrome with supraventricular tachycardia, atrial flutter or atrial fibrillation, and can also be used to treat various premature beats.

[0003] (Propafenone hydrochloride) The products currently used in clinical practice mainly include propafenone hydrochloride tablets and propafenone hydrochloride injection, among which propafenone hydrochloride tablets are conventional immediate-release tablets and propafenone hydrochloride injection is a conventional true solution.

[0004] The clinical use of propafenone hydrochloride injection is as follows: intravenous injection: the common adult dose is 1-1.5 mg / kg or 70 mg diluted with 5% glucose solution, slowly injected within 10 minutes, repeated every 10-20 minutes if necessary, and the total amount shall not exceed 210 mg (5 ml: 6 vials of 35 mg; 20 ml: 3 vials of 70 mg). After the intravenous injection takes effect, it can be changed to intravenous drip, with a drip rate of 0.5-1.0 mg / minute or maintained by oral administration.

[0005] The existing propafenone hydrochloride injection has the following problems: (1) The existing products will cause patients to need multiple injections and intravenous drips during clinical use. Patients must undergo intravenous drips for a long time, which poses clinical risks. In the later stage, oral maintenance may cause unstable blood drug concentrations, and the individual differences in gastrointestinal motility among patients may lead to large fluctuations in blood drug concentrations.

[0006] (2) The raw material of propafenone hydrochloride is slightly soluble in water. The current injection concentration is 3.5 mg / ml, which is close to the solubility of propafenone hydrochloride. Ordinary solutions cannot increase the drug concentration and drug loading capacity.

[0007] (3) The existing propafenone hydrochloride injection is photo-instable and contains 5-hydroxymethylfurfural impurity, which is harmful to the human body. The impurity mainly manifests as an irritant, neurotoxic and genotoxic substance, and can be metabolized in the body into 5-sulfinylmethylfurfural, which has strong carcinogenicity and genotoxicity.

[0008] (4) Propafenone hydrochloride has poor stability. The stability of related substances, appearance, content and other properties under light or accelerated conditions is poor.

[0009] Therefore, there is still an urgent need for a propafenone hydrochloride pharmaceutical composition with good stability and sustained-release effect. Summary of the invention

[0010] In order to solve the above technical problems, the present invention provides a propafenone hydrochloride pharmaceutical composition and a preparation method thereof.

[0011] In a first aspect, the present invention provides a pharmaceutical composition.

[0012] A pharmaceutical composition comprising: a phase A and a phase B; The phase A includes active ingredients and sustained-release materials; The B phase includes a skeleton material; The active ingredient includes propafenone or a pharmaceutically acceptable salt thereof; The sustained-release material comprises at least one of a lactide-glycolide copolymer, a polyethylene glycol monomethyl ether-polylactic acid block copolymer, polylactic acid, polyglycolide, and polycaprolactone; The skeleton material in the phase B includes at least one of polylactic acid, polyglycolide, dextran, mannitol, gelatin, polycaprolactone, fatty acid monoglyceride, monostearate glyceride, chitosan, polyethylene glycol, and sodium carboxymethyl starch. The technical solution uses a sustained-release material to load the active ingredient, which is beneficial to increase the drug loading of the pharmaceutical composition and has an excellent sustained-release effect.

[0013] In some embodiments, the active ingredient is dispersed in a sustained-release material. This technical solution uses a sustained-release material as a matrix and disperses the active ingredient in the sustained-release material matrix, which is beneficial to improving the moisture stability of the obtained pharmaceutical composition under accelerated conditions, and has a good sustained-release effect in vivo and in vitro (neither too fast nor too slow), and has unexpected technical effects.

[0014] In some embodiments, at least one of the phase A or phase B further comprises an emulsifier.

[0015] In some embodiments, the B phase encapsulates the A phase.

[0016] In some embodiments, the active ingredient is propafenone hydrochloride.

[0017] In some embodiments, the sustained-release material is preferably at least one of a lactide-glycolide copolymer and a polyethylene glycol monomethyl ether-polylactic acid block copolymer. Compared with other sustained-release materials, the technical solution using at least one of a lactide-glycolide copolymer and a polyethylene glycol monomethyl ether-polylactic acid block copolymer as a sustained-release material is more conducive to improving the stability of the relevant substances and content of the pharmaceutical composition under accelerated and light conditions and the water stability under accelerated conditions, and has a good sustained-release effect in vivo and in vitro (neither too fast nor too slow), and has unexpected technical effects.

[0018] In some embodiments, the skeleton material in the phase B is preferably at least one of dextran, mannitol, gelatin, and polycaprolactone. Compared with the use of other skeleton materials, the technical solution uses at least one of dextran, mannitol, gelatin, and polycaprolactone as the skeleton material in the phase B, which is more conducive to improving the stability of the relevant substances and content of the pharmaceutical composition under accelerated and light conditions and the water stability under accelerated conditions, and has a good sustained release effect in vivo and in vitro (neither too fast nor too slow), and has unexpected technical effects. In addition, the use of skeleton materials can enable the drug to be stored in a solid state, and the drug can be quickly re-dissolved before use, and it is convenient to administer in liquid form.

[0019] In some embodiments, the emulsifier includes at least one of fatty acid monoglyceride, Tween 80, and glyceryl monostearate.

[0020] In some embodiments, the mass ratio of the active ingredient to the sustained-release material is 1:1-1:9. In some embodiments, the mass ratio of the active ingredient to the sustained-release material is 1:1, 1:2, 2.5, 1:3, 3.5, 1:3.9, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5 or 1:9. In some embodiments, the mass ratio of the active ingredient to the sustained-release material is 1:2, 1:3, 1:3.9 or 1:9.

[0021] In some embodiments, the mass ratio of the active ingredient to the framework material in the phase B is 1:1-1:15. In some embodiments, the mass ratio of the active ingredient to the framework material in the phase B is 1:1, 1:1.5, 4:7.5, 1:2, 1:2.5, 1:2.64, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14 or 1:15. In some embodiments, the mass ratio of the active ingredient to the framework material in the phase B is 1:1, 1:1.5, 4:7.5, 1:2, 1:2.64 or 1:15.

[0022] In some embodiments, the mass ratio of the active ingredient to the emulsifier is 1:0-1:0.2. In some embodiments, the mass ratio of the active ingredient to the emulsifier is 1:0, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.10, 1:0.11, 1:0.12, 1:0.125, 1:0.13, 1:0.14, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19 or 1:0.2. In some embodiments, the mass ratio of the active ingredient to the emulsifier is 1:0.08, 1:0.10 or 1:0.125.

[0023] In some embodiments, the pharmaceutical composition comprises phase A and phase B; phase A comprises an active ingredient and a sustained-release material; phase B comprises a skeleton material; the active ingredient is propafenone hydrochloride; the weight proportions of propafenone hydrochloride, the sustained-release material and the skeleton material in phase B are: Propafenone hydrochloride: 1-4 parts by weight (e.g., 1, 2, 3, 3.5, 3.6, 3.7, 3.75 or 4 parts by weight); Sustained-release material: 3.9-12 parts by weight (e.g., 3.9, 4, 5, 6, 7, 7.5, 8, 9, 10, 11 or 12 parts by weight); and Framework material in phase B: 7.5-15 parts by weight (e.g., 7.5, 8, 9, 10, 11, 12, 3, 14 or 15 parts by weight).

[0024] In some embodiments, the pharmaceutical composition comprises phase A and phase B; phase A comprises an active ingredient and a sustained-release material; phase B comprises a skeleton material; at least one of phase A or phase B further comprises an emulsifier; the active ingredient is propafenone hydrochloride; the weight proportions of propafenone hydrochloride, sustained-release material, emulsifier and skeleton material in phase B are: Propafenone hydrochloride: 1-4 parts by weight (e.g., 1, 2, 3, 3.5, 3.6, 3.7, 3.75 or 4 parts by weight); Sustained-release material: 3.9-12 parts by weight (e.g., 3.9, 4, 5, 6, 7, 7.5, 8, 9, 10, 11 or 12 parts by weight); Framework material in phase B: 7.5-15 parts by weight (e.g., 7.5, 8, 9, 10, 11, 12, 3, 14 or 15 parts by weight); and Emulsifier: 0.1-0.5 parts by weight (e.g., 0.1, 0.2, 0.3, 0.4 or 0.5 parts by weight).

[0025] In some embodiments, the pharmaceutical composition comprises phase A and phase B; the phase A comprises an active ingredient and a sustained-release material; the phase B comprises a skeleton material; at least one of the phase A or phase B further comprises an emulsifier; the active ingredient is propafenone hydrochloride; the sustained-release material is at least one of a lactide-glycolide copolymer and a polyethylene glycol monomethyl ether-polylactic acid block copolymer, the skeleton material in the phase B comprises at least one of dextran, gelatin and polycaprolactone, and the emulsifier comprises at least one of fatty acid monoglyceride, Tween 80 and monostearate glyceryl; the weight proportions of propafenone hydrochloride, the sustained-release material, the emulsifier and the skeleton material in the phase B are: Propafenone hydrochloride: 1-4 parts by weight (e.g., 1, 2, 3, 3.5, 3.6, 3.7, 3.75 or 4 parts by weight); Sustained-release material: 3.9-12 parts by weight (e.g., 3.9, 4, 5, 6, 7, 7.5, 8, 9, 10, 11 or 12 parts by weight); Framework material in phase B: 7.5-15 parts by weight (e.g., 7.5, 8, 9, 10, 11, 12, 3, 14 or 15 parts by weight); and Emulsifier: 0.1-0.5 parts by weight (e.g., 0.1, 0.2, 0.3, 0.4 or 0.5 parts by weight).

[0026] In some embodiments, the pharmaceutical composition comprises phase A and phase B; phase A comprises an active ingredient and a sustained-release material; phase B comprises a skeleton material and an emulsifier; the active ingredient is propafenone hydrochloride, the sustained-release material comprises a lactide-co-glycolide copolymer, the skeleton material in phase B comprises gelatin, and the emulsifier comprises Tween 80; the weight portion of propafenone hydrochloride in the pharmaceutical composition is 4, the weight portion of the lactide-co-glycolide copolymer is 12, the weight portion of the gelatin is 7.5, and the weight portion of the Tween 80 is 0.5.

[0027] In some embodiments, the pharmaceutical composition comprises phase A and phase B; the phase A comprises propafenone hydrochloride, a sustained-release material and an emulsifier; the phase B comprises a skeleton material; the active ingredient is propafenone hydrochloride, the sustained-release material comprises polyethylene glycol monomethyl ether-polylactic acid block copolymer, the skeleton material in the phase B comprises polycaprolactone, the emulsifier comprises glyceryl monostearate, the weight portion of propafenone hydrochloride in the pharmaceutical composition is 1, the weight portion of the polyethylene glycol monomethyl ether-polylactic acid block copolymer is 3.9, the weight portion of the polycaprolactone is 15, and the weight portion of the glyceryl monostearate is 0.1.

[0028] In some embodiments, the pharmaceutical composition further comprises a C phase comprising a matrix material.

[0029] In some embodiments, the skeleton material in the C phase includes at least one of poly(lactide-glycolide) copolymer, polyethylene glycol monomethyl ether-polylactic acid block copolymer, polylactic acid, polyglycolide, dextran, mannitol, gelatin, polycaprolactone, fatty acid monoglyceride, monostearate glyceride, chitosan, polyethylene glycol, and sodium starch glycolate.

[0030] In some embodiments, the skeleton material in the C phase is preferably at least one of dextran, mannitol, gelatin, and polycaprolactone.

[0031] In some embodiments, the mass ratio of the active ingredient to the framework material in the C phase is 1:0-1:5. In some embodiments, the mass ratio of the active ingredient to the framework material in the C phase is 1:0, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.53, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4 or 1:5. In some embodiments, the mass ratio of the active ingredient to the framework material in the C phase is 1:0.53.

[0032] In some embodiments, the pharmaceutical composition comprises phase A, phase B and phase C, and the preparation method of the pharmaceutical composition comprises: wrapping phase A with phase B to obtain phase A wrapped in B, and then mixing phase A wrapped in B with phase C.

[0033] In some embodiments, the pharmaceutical composition comprises phase A, phase B and phase C; the phase A comprises an active ingredient and a sustained-release material; the phase B comprises a skeleton material; the phase C comprises a skeleton material; at least one of the phase A or phase B further comprises an emulsifier; the active ingredient is propafenone hydrochloride; the sustained-release material is at least one of a lactide-glycolide copolymer and a polyethylene glycol monomethyl ether-polylactic acid block copolymer, and the skeleton material in the phase B is at least one of dextran, gelatin and polycaprolactone; the skeleton material in the phase C comprises mannitol; the emulsifier comprises at least one of fatty acid monoglyceride, Tween 80 and monostearate glyceryl; the weight proportions of propafenone hydrochloride, sustained-release material, emulsifier, skeleton material in phase B and skeleton material in phase C are: Propafenone hydrochloride: 1-4 parts by weight (e.g., 1, 2, 3, 3.5, 3.6, 3.7, 3.75 or 4 parts by weight); Sustained-release material: 3.9-12 parts by weight (e.g., 3.9, 4, 5, 6, 7, 7.5, 8, 9, 10, 11 or 12 parts by weight); Framework material in phase B: 7.5-15 parts by weight (e.g., 7.5, 8, 9, 10, 11, 12, 3, 14 or 15 parts by weight); Emulsifier: 0.1-0.5 parts by weight (e.g., 0.1, 0.2, 0.3, 0.4 or 0.5 parts by weight); and Framework material in phase C: 1-5 parts by weight (eg, 1, 2, 3, 4 or 5 parts by weight).

[0034] In some embodiments, the pharmaceutical composition comprises phase A, phase B and phase C; phase A comprises an active ingredient and a sustained-release material; phase B comprises a skeleton material and an emulsifier; phase C comprises a skeleton material; the active ingredient is propafenone hydrochloride; the sustained-release material comprises a lactide-glycolide copolymer, and the skeleton material in phase B comprises dextran; the skeleton material in phase C comprises mannitol; the emulsifier comprises fatty acid monoglyceride; the weight portion of propafenone hydrochloride in the pharmaceutical composition is 3.75, the weight portion of the lactide-glycolide copolymer is 7.5, the weight portion of the fatty acid monoglyceride is 0.3, the weight portion of the dextran is 9.9, and the weight portion of the mannitol is 2.

[0035] In some embodiments, the molar percentage of lactide and glycolide in the lactide-glycolide copolymer is 50:50. In some embodiments, the molar percentage of lactide and glycolide in the lactide-glycolide copolymer is 50:50; the intrinsic viscosity of the lactide-glycolide copolymer is in the range of 0.01 dl / g-0.6dl / g (e.g., 0.01 dl / g, 0.1 dl / g, 0.2 dl / g, 0.3 dl / g, 0.4 dl / g, 0.5 dl / g or 0.6dl / g), the molecular weight distribution coefficient D (Mw / Mn) shall not exceed 2.5, and the weight average molecular weight is about 15,000 to 40,000 (e.g., 15,000, 20,000, 25,000, 30,000, 35,000 or 40,000). In some embodiments, the molar percentage of lactide and glycolide in the lactide-glycolide copolymer is 50:50; the intrinsic viscosity of the lactide-glycolide copolymer is in the range of 0.01 dl / g, 0.1 dl / g, 0.2 dl / g, 0.3 dl / g, 0.4 dl / g, 0.5 dl / g or 0.6 dl / g. In some embodiments, the molar percentage of lactide and glycolide in the lactide-glycolide copolymer is 50:50; the weight average molecular weight of the lactide-glycolide copolymer is about 15,000 to 40,000. In some embodiments, the molar percentage of lactide and glycolide in the lactide-glycolide copolymer is 50:50; the weight average molecular weight of the lactide-glycolide copolymer is about 15,000, 20,000, 25,000, 30,000, 35,000 or 40,000.

[0036] In some embodiments, the polyethylene glycol monomethyl ether-polylactic acid block copolymer is a block copolymer formed by ring-opening polymerization of D,L-lactide and polyethylene glycol monomethyl ether, wherein the mass ratio of polyethylene glycol monomethyl ether to D,L-lactide is 50:50-80:20 (for example, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25 or 80:20); the weight average molecular weight of the polyethylene glycol monomethyl ether-polylactic acid block copolymer is 5000-20000 (for example: 5000, 6000, 7000, 8000, 9000, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000 or 20000).

[0037] In some embodiments, the intrinsic viscosity of the polycaprolactone is in the range of 0.01 to 0.5 dl / g. In some embodiments, the intrinsic viscosity of the polycaprolactone is in the range of 0.01 dl / g, 0.1 dl / g, 0.2 dl / g, 0.3 dl / g, 0.4 dl / g or 0.5 dl / g.

[0038] In some embodiments, the pharmaceutical composition is in the form of an injection.

[0039] In some embodiments, the pharmaceutical composition is in the form of an injectable powder.

[0040] In some embodiments, the dosage form of the pharmaceutical composition is a sustained-release injection.

[0041] In some embodiments, the dosage form of the pharmaceutical composition is a sustained-release injectable powder.

[0042] In a second aspect, the present invention provides an injection.

[0043] The injection comprises the pharmaceutical composition described in the first aspect.

[0044] In some embodiments, the injection is an injectable powder.

[0045] In some embodiments, the injection is a sustained release injection.

[0046] In some embodiments, the injection is a sustained-release injection powder.

[0047] In a third aspect, the present invention provides a pharmaceutical preparation.

[0048] A pharmaceutical preparation comprises the pharmaceutical composition of the first aspect and a reconstitution solvent; the pharmaceutical composition and the reconstitution solvent are packaged separately.

[0049] In some embodiments, the reconstitution solvent includes at least one of a 0.9% sodium chloride aqueous solution with a pH value of 4.5-7.5 (e.g., 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5), a 5% glucose aqueous solution with a pH value of 3.0-7.0 (e.g., 3.0, 3.5, 4.0, 4.5, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 6.0, 6.5, or 7.0), and water for injection.

[0050] In a fourth aspect, the present invention provides a method for preparing the pharmaceutical composition of the first aspect.

[0051] In some embodiments, a method for preparing the pharmaceutical composition of the first aspect, wherein the pharmaceutical composition comprises phase A and phase B, the method for preparing the pharmaceutical composition comprises: (1) mixing the other components in phase A except the active ingredient with the first solvent, and then mixing with the active ingredient to obtain a mixed solution 1a; (2) concentrating the mixed solution 1a to obtain a mixed solution 1a-1; (3) mixing the components in phase B with the second solvent to obtain a mixed solution 2a; (4) Adding the mixed solution 1a-1 to the mixed solution 2a, mixing and homogenizing to obtain a microemulsion, stirring to solidify the microemulsion, and drying to obtain the pharmaceutical composition.

[0052] In some embodiments, the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, ethyl acetate, water, ethanol, propylene glycol, and glycerol.

[0053] In some embodiments, the sustained-release material in phase A includes at least one of poly(lactide-co-glycolide), polylactic acid, polyglycolide, and polycaprolactone, and the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate.

[0054] In some embodiments, the sustained-release material in phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, and the first solvent includes at least one of water, ethanol, propylene glycol, and glycerol.

[0055] In some embodiments, the second solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, ethyl acetate, water, ethanol, propylene glycol, and glycerol.

[0056] In some embodiments, the backbone material in the phase B includes at least one of polylactic acid, polyglycolide, and polycaprolactone, and the second solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate.

[0057] In some embodiments, the skeleton material in phase B includes at least one of dextran, mannitol, gelatin, fatty acid monoglycerides, monostearate glyceride, chitosan, polyethylene glycol, and sodium starch glycolate, and the second solvent includes at least one of water, ethanol, propylene glycol, and glycerol.

[0058] In some embodiments, the content of the active ingredient in the mixed solution 1a is 0.2wt%-12.5wt%. In some embodiments, the content of the active ingredient in the mixed solution 1a is 0.2wt%, 1.0wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.9wt%, 8.0wt%, 9.0wt%, 10.0wt%, 11.0wt%, 12.0wt% or 12.5wt%.

[0059] In some embodiments, the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1a is 0.2wt%-12.5wt%. In some embodiments, the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1a is 0.2wt%, 1.0wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.9wt%, 8.0wt%, 9.0wt%, 10.0wt%, 11.0wt%, 12.0wt% or 12.5wt%.

[0060] In some embodiments, the sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone; the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; and the content of the active ingredient in the mixed solution 1a is 0.2wt%-12.5wt%. In some embodiments, the sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone, and the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1a is 0.2wt%, 1.0wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.9wt%, 8.0wt%, 9.0wt%, 10.0wt%, 11.0wt%, 12.0wt% or 12.5wt%.

[0061] In some embodiments, the first solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1a is 0.2 wt%-0.9wt%. In some embodiments, the first solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1a is 0.2 wt%, 0.3 wt%, 0.4wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt% or 0.9wt%.

[0062] In some embodiments, the sustained-release material in the phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, the first solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1a is 0.2 wt%-0.9wt%. In some embodiments, the sustained-release material in the phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, the first solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1a is 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt% or 0.9wt%.

[0063] In some embodiments, the content of the active ingredient in the mixed solution 1a-1 is 1.0wt%-25.0wt%. In some embodiments, the content of the active ingredient in the mixed solution 1a-1 is 1.0wt%, 1.1wt%, 1.2.0wt%, 1.3wt%, 1.4wt%, 1.5wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 8.0wt%, 9.0wt%, 10.0wt%, 15.0wt%, 16.0wt%, 17.0wt%, 18.0wt%, 19.0wt%, 20.0wt%, 21.0wt%, 22.0wt%, 23.0wt%, 24.0wt% or 25.0wt%.

[0064] In some embodiments, the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; and the content of the active ingredient in the mixed solution 1a-1 is 1.0 wt%-25.0 wt%. In some embodiments, the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1a-1 is 1.0wt%, 1.1 wt%, 1.2.0 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 8.0wt%, 9.0wt%, 10.0wt%, 15.0wt%, 16.0wt%, 17.0wt%, 18.0wt%, 19.0wt%, 20.0wt%, 21.0wt%, 22.0wt%, 23.0wt%, 24.0wt% or 25.0wt%.

[0065] In some embodiments, the sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone; the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; and the content of the active ingredient in the mixed solution 1a-1 is 1.0wt%-25.0wt%. In some embodiments, the sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone, and the first solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1a-1 is 1.0wt%, 1.1 wt%, 1.2.0 wt%, 1.3 wt%, 1.4wt%, 1.5 wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 8.0wt%, 9.0wt%, 10.0wt%, 15.0wt%, 16.0wt%, 17.0wt%, 18.0wt%, 19.0wt%, 20.0wt%, 21.0wt%, 22.0wt%, 23.0wt%, 24.0wt% or 25.0wt%.

[0066] In some embodiments, the first solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1a-1 is 1.0wt%-2.0wt%. In some embodiments, the first solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1a-1 is 1.0wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt%, 1.5wt%, 1.6wt%, 1.7wt%, 1.8wt%, 1.9wt% or 2.0wt%.

[0067] In some embodiments, the sustained-release material in the phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, the first solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1a-1 is 1.0wt%-2.0wt%. In some embodiments, the sustained-release material in the phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, the first solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1a-1 is 1.0wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7wt%, 1.8 wt%, 1.9 wt% or 2.0wt%.

[0068] In some embodiments, the content of the skeleton material in the mixed solution 2a is 5.0wt%-15.0wt%. In some embodiments, the content of the skeleton material in the mixed solution 2a is 7.5wt%-11.6wt%. In some embodiments, the content of the skeleton material in the mixed solution 2a is 5.0wt%, 5.5wt%, 6.0wt%, 6.5wt%, 7.0wt%, 7.5wt%, 8.0wt%, 8.5wt%, 9.0wt%, 9.4wt%, 9.5wt%, 10.0wt%, 10.5wt%, 11.0wt%, 11.5wt%, 11.6wt%, 12.0wt%, 12.5wt%, 13.0wt%, 13.5wt%, 14.0wt%, 14.5wt% or 15.0wt%.

[0069] In some embodiments, a method for preparing the pharmaceutical composition of the first aspect, wherein the pharmaceutical composition comprises phase A, phase B and phase C, and the method for preparing the pharmaceutical composition comprises: (i) mixing the other components in phase A except the active ingredient with a third solvent, and then mixing with the active ingredient to obtain a mixed solution 1b; (ii) concentrating the mixed solution 1b to obtain a mixed solution 1b-1; (iii) mixing the components in phase B and the fourth solvent to obtain a mixed solution 2b; (iv) adding the mixed solution 1b-1 to the mixed solution 2b, mixing and homogenizing to obtain a microemulsion, stirring to solidify the microemulsion; then adding phase C, mixing, and drying to obtain the pharmaceutical composition.

[0070] In some embodiments, the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, ethyl acetate, water, ethanol, propylene glycol, and glycerol.

[0071] In some embodiments, the sustained-release material in phase A includes at least one of poly(lactide-co-glycolide), polylactic acid, polyglycolide, and polycaprolactone, and the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate.

[0072] In some embodiments, the sustained-release material in phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, and the third solvent includes at least one of water, ethanol, propylene glycol, and glycerol.

[0073] In some embodiments, the fourth solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, ethyl acetate, water, ethanol, propylene glycol, and glycerol.

[0074] In some embodiments, the backbone material in the phase B includes at least one of polylactic acid, polyglycolide, and polycaprolactone, and the fourth solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate.

[0075] In some embodiments, the skeleton material in phase B includes at least one of dextran, mannitol, gelatin, fatty acid monoglycerides, monostearate glyceride, chitosan, polyethylene glycol, and sodium starch glycolate, and the fourth solvent includes at least one of water, ethanol, propylene glycol, and glycerol.

[0076] In some embodiments, the content of the active ingredient in the mixed solution 1b is 0.2wt%-12.5wt%. In some embodiments, the content of the active ingredient in the mixed solution 1b is 0.2wt%, 1.0wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.9wt%, 8.0wt%, 9.0wt%, 10.0wt%, 11.0wt%, 12.0wt% or 12.5wt%.

[0077] In some embodiments, the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1b is 0.2wt%-12.5wt%. In some embodiments, the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1b is 0.2wt%, 1.0wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.9wt%, 8.0wt%, 9.0wt%, 10.0wt%, 11.0wt%, 12.0wt% or 12.5wt%.

[0078] In some embodiments, the sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone; the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; and the content of the active ingredient in the mixed solution 1b is 0.2wt%-12.5wt%. In some embodiments, the sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone, and the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1b is 0.2wt%, 1.0wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.9wt%, 8.0wt%, 9.0wt%, 10.0wt%, 11.0wt%, 12.0wt% or 12.5wt%.

[0079] In some embodiments, the third solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1b is 0.2 wt%-0.9wt%. In some embodiments, the third solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1b is 0.2 wt%, 0.3 wt%, 0.4wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt% or 0.9wt%.

[0080] In some embodiments, the sustained-release material in the phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, the third solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1b is 0.2 wt%-0.9wt%. In some embodiments, the sustained-release material in the phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, the third solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1b is 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt% or 0.9wt%.

[0081] In some embodiments, the content of the active ingredient in the mixed solution 1b-1 is 1.0wt%-25.0wt%. In some embodiments, the content of the active ingredient in the mixed solution 1b-1 is 1.0wt%, 1.1wt%, 1.2.0wt%, 1.3wt%, 1.4wt%, 1.5wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 8.0wt%, 9.0wt%, 10.0wt%, 15.0wt%, 16.0wt%, 17.0wt%, 18.0wt%, 19.0wt%, 20.0wt%, 21.0wt%, 22.0wt%, 23.0wt%, 24.0wt% or 25.0wt%.

[0082] In some embodiments, the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; and the content of the active ingredient in the mixed solution 1b-1 is 1.0 wt%-25.0 wt%. In some embodiments, the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1b-1 is 1.0wt%, 1.1 wt%, 1.2.0 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 8.0wt%, 9.0wt%, 10.0wt%, 15.0wt%, 16.0wt%, 17.0wt%, 18.0wt%, 19.0wt%, 20.0wt%, 21.0wt%, 22.0wt%, 23.0wt%, 24.0wt% or 25.0wt%.

[0083] In some embodiments, the sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone; the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; and the content of the active ingredient in the mixed solution 1b-1 is 1.0wt%-25.0wt%. In some embodiments, the sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone, and the third solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; the content of the active ingredient in the mixed solution 1b-1 is 1.0wt%, 1.1 wt%, 1.2.0 wt%, 1.3 wt%, 1.4wt%, 1.5 wt%, 2.0wt%, 3.0wt%, 4.0wt%, 5.0wt%, 6.0wt%, 7.0wt%, 8.0wt%, 9.0wt%, 10.0wt%, 15.0wt%, 16.0wt%, 17.0wt%, 18.0wt%, 19.0wt%, 20.0wt%, 21.0wt%, 22.0wt%, 23.0wt%, 24.0wt% or 25.0wt%.

[0084] In some embodiments, the third solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1b-1 is 1.0wt%-2.0wt%. In some embodiments, the third solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1b-1 is 1.0wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt%, 1.5wt%, 1.6wt%, 1.7wt%, 1.8wt%, 1.9wt% or 2.0wt%.

[0085] In some embodiments, the sustained-release material in the phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, the third solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1b-1 is 1.0wt%-2.0wt%. In some embodiments, the sustained-release material in the phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, the third solvent is at least one of water, ethanol, propylene glycol, and glycerol, and the content of the active ingredient in the mixed solution 1b-1 is 1.0wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7wt%, 1.8 wt%, 1.9 wt% or 2.0wt%.

[0086] In some embodiments, the content of the skeleton material in the mixed solution 2b is 5.0wt%-15.0wt%. In some embodiments, the content of the skeleton material in the mixed solution 2b is 7.5wt%-11.6wt%. In some embodiments, the content of the skeleton material in the mixed solution 2b is 5.0wt%, 5.5wt%, 6.0wt%, 6.5wt%, 7.0wt%, 7.5wt%, 8.0wt%, 8.5wt%, 9.0wt%, 9.4wt%, 9.5wt%, 10.0wt%, 10.5wt%, 11.0wt%, 11.5wt%, 11.6wt%, 12.0wt%, 12.5wt%, 13.0wt%, 13.5wt%, 14.0wt%, 14.5wt% or 15.0wt%.

[0087] In some embodiments, the drying in any of the above preparation methods includes spray drying, freeze drying or vacuum drying. Beneficial effects:

[0088] Compared with the prior art, a certain technical solution of the present invention has at least one of the following beneficial technical effects: (1) The preparation process and auxiliary materials used are all stable, harmless to the human body, and biodegradable materials. After the preparation, the product has good stability and no adverse reactions or compatibility issues.

[0089] (2) Compared with propafenone hydrochloride injections of other prescriptions, the propafenone hydrochloride pharmaceutical composition provided by the present invention has better appearance stability, related substance stability, moisture stability and content stability, and the propafenone hydrochloride pharmaceutical composition provided by the present invention can avoid the production of 5-hydroxymethylfurfural (5-hydroxymethylfurfural has certain harm to the human body. This impurity mainly manifests as irritation, neurotoxicity, genotoxicity, and can be metabolized in the body to 5-sulfinylmethylfurfural, which has strong carcinogenicity and genotoxicity), and has unexpected technical effects.

[0090] (3) Compared with other sustained-release materials, the sustained-release material provided by the present invention (such as: lactide-glycolide copolymer and / or polyethylene glycol monomethyl ether-polylactic acid block copolymer) is beneficial to improving the stability of appearance properties, stability of related substances, moisture stability and content stability of the obtained propafenone hydrochloride pharmaceutical composition, and has unexpected technical effects.

[0091] (4) Compared with other skeleton materials, the skeleton material provided by the present invention (such as at least one of dextran, mannitol, gelatin, and polycaprolactone) is beneficial to improving the stability of appearance properties, stability of related substances, water stability, and content stability of the obtained propafenone hydrochloride pharmaceutical composition, and has unexpected technical effects.

[0092] (5) The pharmaceutical composition provided by the present invention has stable release in vivo, good sustained-release effect, small fluctuation of drug concentration, and can maintain safe, effective and stable blood drug concentration for a long time. It does not require multiple injections or intravenous drips, which is beneficial to reduce the number of medications and improve patients' medication compliance.

[0093] (6) In the later stage of clinical use, the drug will be taken orally for maintenance, which may cause unstable blood drug concentration, different gastrointestinal motility among individual patients, and large fluctuations in blood drug concentration. The present invention achieves sustained release of the drug in the body, which can be administered once for continuous release, maintain blood drug concentration in the body, and avoid adverse reactions caused by fluctuations in blood drug concentration.

[0094] (7) The raw material of propafenone hydrochloride is slightly soluble in water. The current injection concentration is 3.5 mg / ml, which is close to the solubility of propafenone hydrochloride. Ordinary solutions cannot increase the drug concentration and drug loading. However, the drug composition provided by the present invention has a high drug loading and has unexpected technical effects.

[0095] Terminology Before describing the present invention in more detail, it should be understood that the present invention is not limited to the specific embodiments described herein, because such embodiments may vary. It should also be understood that the terms used herein are only used for the purpose of describing specific embodiments, and the terms are not used for limitation. Unless otherwise specified, all technical and scientific terms used herein have the same meanings generally understood by those skilled in the art. All publications and patents referenced herein are incorporated herein by reference in their entirety.

[0096] Where a numerical range is provided, it is understood that, unless the context clearly indicates otherwise, to one tenth of the unit of the lower limit, intervening values ​​between the upper and lower limits of the range and any other stated or intervening values ​​in the range are encompassed within the present invention. These smaller range limits may be independently included within the smaller range and are also encompassed within the present invention, subject to any specific exclusion of limitation within the range. Where the range includes one or both of the limits, the range excluding either or both of those including the limits is also encompassed within the present invention.

[0097] The term "wt%" means percent by weight.

[0098] The term "optionally", "optional" or "optionally" means that the subsequently described event or situation may but need not occur, and the description includes situations where the event or situation occurs, and situations where the event or situation does not occur. For example, the composition of the present invention includes an optional binder, which means that the composition may include the binder or may not include the binder.

[0099] The term “comprise” or “include” is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0100] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and toxicologically compatible with the other ingredients comprising the formulation and the mammal to be treated with it. Preferably, the "pharmaceutically acceptable" of the present invention refers to those approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in animals, especially humans.

[0101] The term "pharmaceutically acceptable salt" refers to organic salts and inorganic salts of the compound propafenone of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: Berge et al., describepharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. In some embodiments, the pharmaceutically acceptable salts of the present invention include but are not limited to hydrochloride, benzenesulfonate, p-toluenesulfonate, sulfate, hydrobromide, etc. Preferably, the pharmaceutically acceptable salt of the present invention is hydrochloride.

[0102] For these and other pharmaceutically acceptable excipients or processes mentioned herein, reference is made to the extensive literature on this subject, in particular to Handbook of Pharmaceutical Excipients, 3rd edition, Arthur H. Kibbe, ed., American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, ed. HP Fiedler, 4th edition, ed. Cantor, Aulendorf and earlier editions.

[0103] The term "parts by weight" indicates the relative weight ratio of each component; it is not a specific mass value, but a ratio relationship. For example, a pharmaceutical composition contains 2 parts by weight of component A and 3 parts by weight of component B, which means that the weight ratio of component A to component B is 2:3. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] Figure 1 This is the blood drug concentration-time curve of the pharmaceutical composition of Example 1 in Test Example 3.

[0105] Figure 2 This is the blood drug concentration-time curve of the pharmaceutical composition of Example 2 in Test Example 3.

[0106] Figure 3 This is the blood drug concentration-time curve of the drug composition of Comparative Example 7 in Test Example 3.

[0107] Figure 4 This is a blood drug concentration-time curve of the commercially available product propafenone hydrochloride injection (hereinafter referred to as the commercially available preparation) in Experimental Example 3. DETAILED DESCRIPTION

[0108] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0109] 1. Detection methods for related substances:

[0110] 2. 5-Hydroxymethylfurfural detection method: This impurity is produced by the degradation of glucose. This test is only conducted on products containing glucose. Products that do not contain glucose will not be tested for this item.

[0111]

[0112] 3. In vitro dissolution method The in vitro dissolution methods of the following embodiments and comparative examples of the present invention are as follows: Dissolution method: basket method; Dissolution medium: phosphate buffer solution + 0.05% sodium dodecyl sulfate; pH of dissolution medium: 7.4; Dissolution temperature: 37℃±0.5℃; Dissolution medium volume: 200 ml; Sampling time: 0h, 0.5h, 1h, 2h, 6h, 12h, 24h, 36h, 48h. 4. High molecular polymers used in the examples:

[0113] Unless otherwise specified, the specifications, models and sources of the polymers in the following examples and comparative examples are as follows: Lactide-glycolide copolymer: Lactide-glycolide copolymer (5050) is used, which is a ring-opening polymer of cyclic dimer of lactide and glycolide under the catalysis of nucleophilic initiator; the molar percentage of lactide and glycolide is 50:50, the intrinsic viscosity range is 0.01-0.6 dl / g, the molecular weight distribution coefficient D (Mw / Mn) shall not exceed 2.5, and the weight average molecular weight is about 30,000. Manufacturer: Shandong Luye Pharmaceutical Co., Ltd.; Batch number: 20230101L.

[0114] Polyethylene glycol monomethyl ether-polylactic acid block copolymer: the mass ratio of polyethylene glycol monomethyl ether to D,L-lactide is 75:25, the weight average molecular weight distribution is about 15,000, manufacturer: Suzhou Hi-Bio Biotechnology Co., Ltd.; batch number: MP-23031001.

[0115] Polycaprolactone: weight average molecular weight is about 20,000. Manufacturer: Tianjin Xiensi Biochemical Technology Co., Ltd.

[0116] Fatty acid monoglyceride, also known as monoglyceride; manufacturer: Kerry Ingredients & Flavours Ltd; batch number is B266711.

[0117] Dextran: The following examples and comparative examples use dextran 70, manufacturer: Xi'an Wanlong Pharmaceutical Co., Ltd., batch number: CC-20230418.

[0118] Gelatin: Gelatin is derived from pig skin, model B, is alkaline hide glue, mainly processed from animal skin, characterized by high freezing force and high viscosity. Manufacturer: Baotou Dongbao Biotechnology Co., Ltd., batch number Y24147.

[0119] Example 1: Propafenone hydrochloride pharmaceutical composition Prescription: See Table 1.

[0120] Table 1: Prescription of propafenone hydrochloride pharmaceutical composition

[0121] Note: The contents in the embodiments and comparative examples of the present invention have been rounded off. Due to the rounding off, the sum of the contents of each component may not be 100%.

[0122] Preparation method: (1) Mixing the other components of the mixed solution 1b except the active ingredient, and then mixing with the active ingredient to obtain a mixed solution 1b; (2) concentrating the mixed solution 1b to obtain a mixed solution 1b-1, wherein the active ingredient content of the mixed solution 1b-1 is 25 wt %; (3) mixing the components in the mixed solution 2b to obtain a mixed solution 2b; (4) Adding the mixed solution 1b-1 to the mixed solution 2b, mixing and homogenizing to obtain a microemulsion, stirring to solidify the microemulsion; then adding phase C to mix, dispensing into colorless transparent vials, freeze-drying, and sealing the vials to obtain the pharmaceutical composition.

[0123] Example 2: Propafenone hydrochloride pharmaceutical composition Prescription: See Table 2.

[0124] Table 2: Prescription of propafenone hydrochloride pharmaceutical composition

[0125] Preparation method: (1) Mixing the other components of the mixed solution 1a except the active ingredient, and then mixing with the active ingredient to obtain a mixed solution 1a; (2) concentrating the mixed solution 1a to obtain a mixed solution 1a-1, wherein the active ingredient content of the mixed solution 1a-1 is 20 wt %; (3) mixing the components in the mixed solution 2a to obtain a mixed solution 2a; (4) Adding the mixed solution 1a-1 to the mixed solution 2a, mixing and homogenizing to obtain a microemulsion, stirring to solidify the microemulsion; spray drying to obtain a dry solid powder, packaging the powder into colorless and transparent vials, and sealing the vials to obtain the pharmaceutical composition.

[0126] Example 3: Propafenone hydrochloride pharmaceutical composition Prescription: See Table 3.

[0127] Table 3: Prescription of propafenone hydrochloride pharmaceutical composition

[0128] Preparation method: (1) Mixing the other components of the mixed solution 1a except the active ingredient, and then mixing with the active ingredient to obtain a mixed solution 1a; (2) concentrating the mixed solution 1a to obtain a mixed solution 1a-1, wherein the active ingredient content of the mixed solution 1a-1 is 1.4 wt %; (3) mixing the components in the mixed solution 2a to obtain a mixed solution 2a; (4) Adding the mixed solution 1a-1 to the mixed solution 2a, mixing and homogenizing to obtain a microemulsion, stirring to solidify the microemulsion; spray drying to obtain a dry solid powder, packaging the powder into colorless and transparent vials, and sealing the vials to obtain the pharmaceutical composition.

[0129] Comparative Example 1: Investigation of the order of adding active ingredients Prescription: The order of adding active ingredients was investigated based on the prescription of Example 3. The prescription of Comparative Example 1 is shown in Table 4.

[0130] Table 4: Prescription of propafenone hydrochloride pharmaceutical composition

[0131] Preparation method: (1) mixing the components in the mixed solution 1 to obtain a mixed solution 1; (1) concentrating the mixed solution 1 to one seventh of its original weight to obtain a mixed solution 1-1; (2) mixing the components in the mixed solution 2 to obtain a mixed solution 2; (3) Mixing the mixed solution 1-1 and the mixed solution 2, homogenizing to obtain a microemulsion, stirring to solidify the microemulsion; then adding the active ingredient and mixing; spray drying to obtain a dry solid powder, packaging the powder into colorless and transparent vials, and sealing the vials to obtain the pharmaceutical composition.

[0132] Comparative Example 2-Comparative Example 4: Investigation of sustained-release materials Refer to the prescription and preparation method of Example 1, and replace the sustained-release material with the sustained-release material in Table 5 with the same content, and the rest of the operations are the same as Example 1.

[0133] Table 5: Investigation of sustained-release materials

[0134] Comparative Examples 5-7: Investigation of Skeleton Materials Refer to the prescription and preparation method of Example 1, and replace the framework material with the framework material in Table 6 with the same content, and the rest of the operations are the same as Example 1.

[0135] Table 6: Framework material investigation

[0136] Comparative Example 8: Propafenone hydrochloride injection (commercially available propafenone hydrochloride injection prescription) Prescription: See Table 7.

[0137] Table 7: Prescription composition:

[0138] Preparation method: The propafenone hydrochloride is dissolved in water for injection, anhydrous glucose is added, the pH value is adjusted to 5.3, and the mixture is sealed in a colorless transparent ampoule to obtain the propafenone hydrochloride injection.

[0139] Comparative Example 9: Propafenone hydrochloride lyophilized powder injection Prescription: See Table 8.

[0140] Table 8: Prescription composition

[0141] Preparation method: Dissolve β-cyclodextrin in water for injection, add propafenone hydrochloride, mix, homogenize, and spray-dry to obtain a dry powder solid. Pack the obtained dry powder solid into vials, cover, and roll the cap to obtain propafenone hydrochloride lyophilized powder injection.

[0142] Comparative Example 10: Propafenone hydrochloride lyophilized powder injection Prescription: See Table 9.

[0143] Table 9: Propafenone hydrochloride lyophilized powder injection

[0144] Preparation method: Sodium polyacrylate is dissolved in water for injection, propafenone hydrochloride is added and mixed, and the resulting solution is too viscous to be spray-dried; freeze-drying of the resulting solution cannot completely remove water, and the product after freeze-drying is still a semi-solid containing water, which is difficult to reconstitute for clinical use.

[0145] Test Example 1: Stability Study The above embodiments and comparative examples were placed under accelerated conditions (40°C ± 2°C, humidity 75% ± 5%) for 6 months and illumination conditions (4500 Lux ± 500 Lux) for 6 months, and the appearance, related substances, moisture and active ingredient content were tested. The results are shown in Tables 10 to 15.

[0146] Table 10: Appearance properties under accelerated conditions

[0147] Table 11: Appearance characteristics under lighting conditions

[0148] Table 12: Related substances (total impurities) test results

[0149] Table 13: Related substances (5-hydroxymethylfurfural) test results

[0150] Note: This impurity is produced by the degradation of glucose. Therefore, the 5-hydroxymethylfurfural content is only tested for the products containing glucose. Since the other examples and comparative examples except comparative example 8 do not contain glucose, the 5-hydroxymethylfurfural content is not tested for the products of the examples and comparative examples not containing glucose.

[0151] Table 14: Moisture test results

[0152] Table 15: Active ingredient content

[0153] in conclusion: (1) Compared with propafenone hydrochloride injections of other prescriptions, the propafenone hydrochloride pharmaceutical composition provided by the present invention has better appearance stability, related substance stability, moisture stability and content stability, and has unexpected technical effects.

[0154] (2) The propafenone hydrochloride pharmaceutical composition provided by the present invention can avoid the production of 5-hydroxymethylfurfural (5-hydroxymethylfurfural is harmful to the human body. This impurity mainly manifests itself as an irritant, has neurotoxicity and genotoxicity, and can be metabolized in the body to 5-sulfinylmethylfurfural, which has strong carcinogenicity and genotoxicity), and has unexpected technical effects.

[0155] (3) Compared with other sustained-release materials, the sustained-release material provided by the present invention (such as: lactide-glycolide copolymer. Polyethylene glycol monomethyl ether-polylactic acid block copolymer (see Example 1-Example 3)) is beneficial to improving the stability of appearance properties, stability of related substances, moisture stability and content stability of the obtained propafenone hydrochloride pharmaceutical composition, and has unexpected technical effects.

[0156] (4) Compared with other skeleton materials, the skeleton material provided by the present invention (such as at least one of dextran, mannitol, gelatin, and polycaprolactone (see Examples 1 to 3)) is beneficial to improving the stability of the appearance, related substances, water content, and content of the obtained propafenone hydrochloride pharmaceutical composition, and has unexpected technical effects.

[0157] Test Example 2: In vitro dissolution test The pharmaceutical compositions obtained in the above examples or comparative examples were respectively subjected to in vitro dissolution tests. The results are shown in Table 16.

[0158] Table 16: In vitro dissolution test results (unit %)

[0159] Note: During the dissolution process of Comparative Example 10, the sample swelled and became larger in volume, and the drug was no longer released in the later stage, and could not be released slowly and continuously, so it was not suitable for in vivo injection.

[0160] Conclusion: Comparative Example 10 swells and cannot be released after partial release. Comparative Examples 1, 5, 6, 7, and 8 release faster, while Comparative Examples 2, 3, and 4 release too slowly and can hardly be released. The pharmaceutical composition provided by the present invention has a good release effect, can meet the requirements of slow administration, and has a good external sustained-release effect.

[0161] Test Example 3: In vivo release test Example 1 and Example 2 were respectively injected intramuscularly into rabbits at a dosage of 0.05 mg / kg (the dosage concentration was 0.05 mg / ml, and the pharmaceutical compositions of Example 1 and Example 2 were first diluted to 0.05 mg / ml with 5% glucose solution), and the blood drug concentration was monitored and the blood drug concentration-time curve was drawn. The results are shown in Figure 1-Figure 2 .

[0162] Comparative Example 7 and the commercially available product propafenone hydrochloride injection (hereinafter referred to as the commercial preparation; manufacturer: Famar HealthCare Services Madrid SAU-Madrid (Spagna); specification: 20ml:70mg, batch number: 245381A) were injected intramuscularly into rabbits at a dosage of 2ug / kg (the dosage concentration was 2ug / ml, and the pharmaceutical composition of Example 7 and the commercially available product was first diluted to 2ug / ml with 5% glucose solution), and the blood drug concentration was monitored, and the blood drug concentration-time curve was drawn. The results are shown in Figure 3-Figure 4 .

[0163] in conclusion: (1) The pharmaceutical composition provided by the present invention has stable release in vivo, good sustained-release effect, small fluctuation of drug concentration, and can maintain safe, effective and stable blood drug concentration for a long time. It does not require multiple injections or intravenous drips, which is beneficial to reduce the number of medications and improve patients' medication compliance.

[0164] (2) In the later stage of clinical use, the drug will be taken orally for maintenance, which may cause unstable blood drug concentration, different gastrointestinal motility among individual patients, and large fluctuations in blood drug concentration. The present invention achieves sustained release of the drug in the body, which can be administered once for continuous release, maintain blood drug concentration in the body, and avoid adverse reactions caused by concentration fluctuations.

[0165] (3) The propafenone hydrochloride raw material is slightly soluble in water. The current injection concentration is 3.5 mg / ml, which is close to the solubility of propafenone hydrochloride. Ordinary solutions cannot increase the drug concentration and drug loading. The pharmaceutical composition provided by the present invention has a high drug loading and has unexpected technical effects.

[0166] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A pharmaceutical composition, characterized in that include: Phase A and Phase B; The phase A includes active ingredients and sustained-release materials; The B phase includes a skeleton material; At least one of the phase A or phase B further comprises an emulsifier; The active ingredient is dispersed in the sustained-release material; the phase B encapsulates the phase A; The active ingredient includes propafenone or a pharmaceutically acceptable salt thereof; The sustained-release material comprises at least one of a lactide-glycolide copolymer, a polyethylene glycol monomethyl ether-polylactic acid block copolymer, polylactic acid, polyglycolide, and polycaprolactone; The skeleton material in the phase B includes at least one of polylactic acid, polyglycolide, dextran, mannitol, gelatin, polycaprolactone, fatty acid monoglyceride, monostearate glyceride, chitosan, polyethylene glycol, and sodium carboxymethyl starch; The mass ratio of the active ingredient to the sustained-release material is 1:1-1:9; The mass ratio of the active ingredient to the framework material in the phase B is 1:1-1:15; The mass ratio of the active ingredient to the emulsifier is 1:0-1:0.

2.

2. The pharmaceutical composition according to claim 1, characterized in that The active ingredient is propafenone hydrochloride.

3. The pharmaceutical composition according to claim 1, characterized in that The sustained-release material is at least one of a lactide-glycolide copolymer and a polyethylene glycol monomethyl ether-polylactic acid block copolymer; The skeleton material in the phase B is at least one of dextran, mannitol, gelatin, and polycaprolactone; The emulsifier includes at least one of fatty acid monoglyceride, Tween 80, and glyceryl monostearate.

4. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the active ingredient to the sustained-release material is 1:2, 1:3, 1:3.9 or 1:9; The mass ratio of the active ingredient to the framework material in the phase B is 1:1, 1:1.5, 4:7.5, 1:2, 1:2.64 or 1:15; The mass ratio of the active ingredient to the emulsifier is 1:0.08, 1:0.10 or 1:0.

125.

5. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition comprises phase A and phase B; the phase A comprises an active ingredient and a sustained-release material; the phase B comprises a skeleton material; at least one of the phase A or phase B further comprises an emulsifier; the active ingredient is propafenone hydrochloride; the weight proportions of the propafenone hydrochloride, the sustained-release material, the emulsifier and the skeleton material in phase B are: Propafenone hydrochloride: 1-4 parts by weight; Sustained release material: 3.9-12 parts by weight; Framework material in phase B: 7.5-15 parts by weight; and Emulsifier: 0.1-0.5 parts by weight.

6. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition comprises phase A and phase B; the phase A comprises an active ingredient and a sustained-release material; the phase B comprises a skeleton material; at least one of the phase A or phase B further comprises an emulsifier; the active ingredient is propafenone hydrochloride; the sustained-release material is at least one of a lactide-glycolide copolymer and a polyethylene glycol monomethyl ether-polylactic acid block copolymer; the skeleton material in the phase B comprises at least one of dextran, gelatin and polycaprolactone; the emulsifier comprises at least one of fatty acid monoglyceride, Tween 80 and glyceryl monostearate; the weight proportions of the propafenone hydrochloride, the sustained-release material, the emulsifier and the skeleton material in the phase B are: Propafenone hydrochloride: 1-4 parts by weight; Sustained release material: 3.9-12 parts by weight; Framework material in phase B: 7.5-15 parts by weight; and Emulsifier: 0.1-0.5 parts by weight.

7. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition comprises phase A, phase B and phase C; the phase A comprises an active ingredient and a sustained-release material; the phase B comprises a skeleton material; the phase C comprises a skeleton material; at least one of the phase A or phase B further comprises an emulsifier; the active ingredient is propafenone hydrochloride; the sustained-release material is at least one of a lactide-glycolide copolymer and a polyethylene glycol monomethyl ether-polylactic acid block copolymer, the skeleton material in the phase B is at least one of dextran, gelatin and polycaprolactone; the skeleton material in the phase C comprises mannitol; the emulsifier comprises at least one of fatty acid monoglyceride, Tween 80 and monostearate glyceryl; the weight proportions of propafenone hydrochloride, the sustained-release material, the emulsifier, the skeleton material in the phase B and the skeleton material in the phase C are: Propafenone hydrochloride: 1-4 parts by weight; Sustained release material: 3.9-12 parts by weight; Framework material in phase B: 7.5-15 parts by weight; Emulsifier: 0.1-0.5 parts by weight; and Framework material in phase C: 1-5 parts by weight.

8. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition comprises phase A and phase B; the phase A comprises an active ingredient and a sustained-release material; the phase B comprises a skeleton material and an emulsifier; the active ingredient is propafenone hydrochloride, the sustained-release material comprises a lactide-co-glycolide copolymer, the skeleton material in the phase B comprises gelatin, and the emulsifier comprises Tween 80; the weight portion of propafenone hydrochloride in the pharmaceutical composition is 4, the weight portion of the lactide-co-glycolide copolymer is 12, the weight portion of the gelatin is 7.5, and the weight portion of the Tween 80 is 0.5; or The pharmaceutical composition comprises a phase A and a phase B; the phase A comprises propafenone hydrochloride, a sustained-release material and an emulsifier; the phase B comprises a skeleton material; the active ingredient is propafenone hydrochloride, the sustained-release material comprises a polyethylene glycol monomethyl ether-polylactic acid block copolymer, the skeleton material in the phase B comprises polycaprolactone, the emulsifier comprises glyceryl monostearate, the weight portion of propafenone hydrochloride in the pharmaceutical composition is 1, the weight portion of the polyethylene glycol monomethyl ether-polylactic acid block copolymer is 3.9, the weight portion of the polycaprolactone is 15, and the weight portion of the glyceryl monostearate is 0.

1.

9. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The pharmaceutical composition further comprises a C phase, wherein the C phase comprises a matrix material.

10. The pharmaceutical composition according to claim 9, characterized in that The skeleton material in the C phase includes at least one of a lactide-glycolide copolymer, a polyethylene glycol monomethyl ether-polylactic acid block copolymer, polylactic acid, polyglycolide, dextran, mannitol, gelatin, polycaprolactone, fatty acid monoglyceride, monostearate glyceride, chitosan, polyethylene glycol, and sodium carboxymethyl starch.

11. The pharmaceutical composition according to claim 10, characterized in that The skeleton material in the C phase is at least one of dextran, mannitol, gelatin and polycaprolactone.

12. The pharmaceutical composition according to claim 9, characterized in that The mass ratio of the active ingredient to the framework material in the C phase is 1:0-1:

5.

13. The pharmaceutical composition according to claim 9, characterized in that The mass ratio of the active ingredient to the framework material in the C phase is 1:0.

53.

14. The pharmaceutical composition according to claim 9, characterized in that The preparation method of the pharmaceutical composition comprises: wrapping the phase A with the phase B to obtain the phase A wrapped with the phase B, and then mixing the phase A wrapped with the phase B with the phase C.

15. The pharmaceutical composition according to claim 10, characterized in that The pharmaceutical composition comprises phase A, phase B and phase C; phase A comprises an active ingredient and a sustained-release material; phase B comprises a skeleton material and an emulsifier; phase C comprises a skeleton material; the active ingredient is propafenone hydrochloride; the sustained-release material comprises a lactide-glycolide copolymer, and the skeleton material in phase B comprises dextran; the skeleton material in phase C comprises mannitol; the emulsifier comprises fatty acid monoglyceride; the weight portion of propafenone hydrochloride in the pharmaceutical composition is 3.75, the weight portion of the lactide-glycolide copolymer is 7.5, the weight portion of the fatty acid monoglyceride is 0.3, the weight portion of the dextran is 9.9, and the weight portion of the mannitol is 2.

16. An injection, characterized in that: The injection comprises the pharmaceutical composition according to any one of claims 1 to 15.

17. The injection according to claim 16, characterized in that: The injection is a sustained-release injection.

18. A pharmaceutical preparation, characterized in that It comprises the pharmaceutical composition according to any one of claims 1 to 15 and a reconstitution solvent; the pharmaceutical composition and the reconstitution solvent are packaged separately.

19. The pharmaceutical preparation according to claim 18, characterized in that: The reconstitution solvent includes at least one of a 0.9% sodium chloride aqueous solution with a pH value of 4.5-7.5, a 5% glucose aqueous solution with a pH value of 3.0-7.0, and water for injection.

20. The method for preparing the pharmaceutical composition according to any one of claims 1 to 8, characterized in that: The pharmaceutical composition comprises phase A and phase B, and the preparation method of the pharmaceutical composition comprises: (1) mixing the other components in phase A except the active ingredient with the first solvent, and then mixing with the active ingredient to obtain a mixed solution 1a; (2) concentrating the mixed solution 1a to obtain a mixed solution 1a-1; (3) mixing the components in phase B with the second solvent to obtain a mixed solution 2a; (4) Adding the mixed solution 1a-1 to the mixed solution 2a, mixing and homogenizing to obtain a microemulsion, stirring to solidify the microemulsion, and drying to obtain the pharmaceutical composition.

21. The preparation method according to claim 20, characterized in that: The sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone, and the first solvent includes at least one of dichloromethane, chloroform, dichloroethylene, trichloroethylene, and ethyl acetate; or the sustained-release material in phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, and the first solvent includes at least one of water, ethanol, propylene glycol, and glycerol; The skeleton material in the phase B includes at least one of polylactic acid, polyglycolide, and polycaprolactone, and the second solvent includes at least one of dichloromethane, chloroform, dichloroethylene, trichloroethylene, and ethyl acetate; or the skeleton material in the phase B includes at least one of dextran, mannitol, gelatin, fatty acid monoglyceride, monostearate glyceride, chitosan, polyethylene glycol, and sodium carboxymethyl starch, and the second solvent includes at least one of water, ethanol, propylene glycol, and glycerol; The content of active ingredients in the mixed solution 1a is 0.2wt%-12.5wt%; The content of active ingredients in the mixed solution 1a-1 is 1.0wt%-25.0wt%; The content of the skeleton material in the mixed solution 2a is 5.0wt%-15.0wt%.

22. The method for preparing the pharmaceutical composition according to any one of claims 9 to 15, characterized in that: The pharmaceutical composition comprises phase A, phase B and phase C, and the preparation method of the pharmaceutical composition comprises: (i) mixing the other components in phase A except the active ingredient with a third solvent, and then mixing with the active ingredient to obtain a mixed solution 1b; (ii) concentrating the mixed solution 1b to obtain a mixed solution 1b-1; (iii) mixing the components in phase B and the fourth solvent to obtain a mixed solution 2b; (iv) adding the mixed solution 1b-1 to the mixed solution 2b, mixing and homogenizing to obtain a microemulsion, stirring to solidify the microemulsion; then adding phase C, mixing, and drying to obtain the pharmaceutical composition.

23. The preparation method according to claim 22, characterized in that: The sustained-release material in phase A includes at least one of lactide-glycolide copolymer, polylactic acid, polyglycolide, and polycaprolactone, and the third solvent includes at least one of dichloromethane, chloroform, dichloroethylene, trichloroethylene, and ethyl acetate; or the sustained-release material in phase A includes polyethylene glycol monomethyl ether-polylactic acid block copolymer, and the third solvent includes at least one of water, ethanol, propylene glycol, and glycerol; The framework material in the phase B includes at least one of polylactic acid, polyglycolide, and polycaprolactone, and the fourth solvent includes at least one of dichloromethane, chloroform, dichloroethane, trichloroethane, and ethyl acetate; or the framework material in the phase B includes at least one of dextran, mannitol, gelatin, fatty acid monoglyceride, monostearate glyceride, chitosan, polyethylene glycol, and sodium carboxymethyl starch, and the fourth solvent includes at least one of water, ethanol, propylene glycol, and glycerol; The content of active ingredients in the mixed solution 1b is 0.2wt%-12.5wt%; The content of active ingredients in the mixed solution 1b-1 is 1.0wt%-25.0wt%; The content of the skeleton material in the mixed solution 2b is 5.0wt%-15.0wt%.

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