CN116077470A - Ganaxolone preparation and preparation method thereof - Google Patents

Ganaxolone preparation and preparation method thereof Download PDF

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CN116077470A
CN116077470A CN202310068888.1A CN202310068888A CN116077470A CN 116077470 A CN116077470 A CN 116077470A CN 202310068888 A CN202310068888 A CN 202310068888A CN 116077470 A CN116077470 A CN 116077470A
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ganaxolone
preparation
mixing
solution
formulation
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王晓鹏
王永祥
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Qingdao Runxinde Biopharmaceutical Co ltd
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Qingdao Runxinde Biopharmaceutical Co ltd
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Abstract

The application relates to the field of pharmaceutical preparations, and in particular discloses a ganaxolone preparation and a preparation method thereof. A process for the preparation of ganaxolone formulation comprising the steps of: mixing ganaxolone particles, an oil phase, an emulsifier, a co-emulsifier and distilled water, and performing ultrasonic treatment for 20-30min to prepare ganaxolone microemulsion; mixing chitosan, hydroxypropyl methylcellulose and acetic acid solution to prepare a mixed solution, dissolving TPP in distilled water to prepare a TPP solution, mixing the TPP solution with the mixed solution, adding PEG400, a filler, a flavoring agent, a tackifier and a preservative, uniformly stirring, adding the ganaxolone microemulsion, uniformly stirring, standing for deaeration, film laying, drying, film uncovering and cutting. The ganaxolone preparation is in an oral cavity film-dissolving form, and has the advantages of safe and convenient application, high dissolution speed and long drug release time.

Description

Ganaxolone preparation and preparation method thereof
Technical Field
The application relates to the technical field of pharmaceutical preparations, in particular to a ganaxolone preparation and a preparation method thereof.
Background
Epilepsy is a chronic disease and syndrome of sudden, transient, recurrent central nervous system dysfunction due to abnormal overdischarge of brain neurons, status epilepticus treated with conventional anticonvulsants in emergency rooms, GABA A Positive modulators of receptors have long been used to treat central nervous system disorders, including epilepsy, anxiety, sleep disorders, and the like, typically GABA A Positive modulators of receptors include neuroactive steroids, benzodiazepines
Figure BDA0004063276530000011
Class, barbital, propofol, and the like.
Ganaxolone is a neurosteroid, also known as 3α -hydroxy-3β -methyl-5α -pregn-20-one, a 3β -methyl synthetic analogue of the endoprogestone metabolite 3α -hydroxy-5α -pregn-20-one (3α,5α -P, allopregnanolone). By combining with other than benzodiazepines
Figure BDA0004063276530000012
Interacting with unique recognition sites of barbital binding sites, ganaxolone has been shown to have potent anticonvulsant, anxiolytic and antimigraine activity in preclinical models. Clinically, ganaxolone is used in adults to treat refractory complex partial seizures, in children to treat refractory infantile spasms and other types of epilepsy, and appropriate ganaxolone compositions may also treat sleep-related disorders.
At present, the Chinese patent application document with the application number of CN2022111508553 discloses an intravenous ganaxolone preparation, the Chinese patent application document with the application number of CN2020800629958 discloses ganaxolone for treating epileptic persistance, the Chinese patent application document with the application number of CN2016800089285 discloses an intravenous ganaxolone preparation and application thereof in treating epileptic persistance and other epileptic seizure disorders, and intravenous injection methods are adopted to apply ganaxolone in the prior art.
Aiming at the related technology, the inventor finds that ganaxolone is mostly injected intravenously, but the epileptic has no sign before the seizure, the seizure is rapid and the duration is not long, so the epileptic cannot be injected and treated in time, and secretion or vomit is generated in the oral cavity of the epileptic during the seizure, and any things can not be plugged into the oral cavity of the epileptic, so that the problems of dysphagia and inconvenient and untimely administration of the epileptic can not be well solved by using ganaxolone tablets, suspensions or capsules.
Disclosure of Invention
In order to facilitate the administration of ganaxolone preparation during epileptic seizure and improve the administration efficiency and safety, the application provides a ganaxolone preparation and a preparation method thereof.
In a first aspect, the present application provides a method for preparing a ganaxolone formulation, which adopts the following technical scheme:
a method for preparing ganaxolone formulation, comprising the steps of:
preparing ganaxolone microemulsion: mixing ganaxolone particles, an oil phase, an emulsifier, a co-emulsifier and distilled water, and performing ultrasonic treatment for 20-30min to prepare ganaxolone microemulsion;
preparation of ganaxolone formulation: mixing chitosan, hydroxypropyl methylcellulose and acetic acid solution to prepare a mixed solution, dissolving TPP in distilled water to prepare a TPP solution with the concentration of 0.5-0.8wt%, mixing the TPP solution and the mixed solution according to the mass ratio of 1:3-5, adding PEG400, a filler, a flavoring agent, a tackifier and a preservative, uniformly stirring, adding the ganaxolone microemulsion, uniformly stirring, standing for deaeration, spreading a film, drying, uncovering the film, and cutting.
By adopting the technical scheme, when taking preparations in forms such as tablets, capsules and suspension, a patient is required to have certain autonomous consciousness, and has better compliance, but when epileptic patients take seizures, the patient loses autonomous consciousness, body clonus is not in compliance, vomit or secretion can be generated in the oral cavity of the epileptic patient, if the tablets, capsules or suspension are put into the oral cavity of the epileptic patient, the airway is easy to be blocked, and the danger of suffocating is caused, so that the ganaxolone preparation in the form of an oral cavity dissolving film is adopted, when epileptic symptoms occur in the patient, the ganaxolone preparation is put into the oral cavity of the patient, the oral cavity of the patient is rapidly disintegrated, the airway of the patient is not easy to be blocked, and the oral cavity of the epileptic patient is not required to be broken off, so that the disintegration can be completed only by being plugged into the oral cavity, the administration is convenient and safe, and the rapidly disintegrated ganaxolone preparation can rapidly achieve the effect of epileptic treatment.
The ganaxolone microemulsion has the advantages that the ganaxolone particles are dispersed by using an oil phase, the microemulsion has the advantages of uniformity and stability by utilizing the emulsification effect of an emulsifier and an auxiliary emulsifier, the positive charge carried by free amino groups on the surface of chitosan and the negative charge carried by TPP free phosphate groups generate an electrostatic attraction effect, an intramolecular or intermolecular crosslinking effect is formed, a crosslinking network is further spontaneously formed, the ganaxolone microemulsion can be uniformly dispersed in the crosslinking network, PEG400 can be used as the auxiliary emulsifier and can also be used as a plasticizer during film laying, and a flat and smooth film preparation can be formed after film laying.
Optionally, the ganaxolone preparation comprises the following raw materials in parts by weight: 0.3-1 part of ganaxolone particles, 1-2 parts of oil phase, 1.5-2.5 parts of emulsifying agent, 0.3-0.6 part of auxiliary emulsifying agent, 3-5 parts of distilled water, 3-5 parts of chitosan, 1-3 parts of hydroxypropyl methyl fiber, 6-10 parts of acetic acid solution, 0.6-1 part of PEG400, 0.3-0.5 part of filling agent, 0.1-0.2 part of flavoring agent, 0.08-0.12 part of tackifier and 0.005-0.01 part of preservative.
By adopting the technical scheme, the raw materials with the above dosage can be prepared into a film preparation with smooth and non-greasy surface and sweet taste, and can be rapidly disintegrated in the oral cavity and enter intestines and stomach of epileptic patients, thereby achieving the treatment effect.
Optionally, the ganaxolone particles are made by the following method:
mixing polylactic acid-glycolic acid copolymer, carboxylated chitosan and ganaxolone powder, extruding at 100-120 ℃, granulating, and pulverizing to obtain primary particles;
mixing the disintegrating agent, deionized water and the primary particles, pressing, and drying to prepare ganaxolone spheres;
mixing the ganaxolone balls, the polyvinyl alcohol water solution and the ganaxolone powder, drying, and carrying out ultrasonic-assisted air flow superfine grinding to obtain ganaxolone particles.
Status epilepticus is a severe seizure disorder in which epileptics experience seizures lasting more than 5 minutes or more than 1 seizure in 5 minutes without recovery between seizures, and ganaxolone is a slightly soluble drug, is very low in water solubility, does not dissolve rapidly after oral administration, is low in dissolution, and does not provide good blood levels in a short period of time; by adopting the technical scheme, the polylactic acid-glycolic acid copolymer and carboxylated chitosan are mixed with the ganaxolone powder, the carboxylated chitosan can improve the dispersion uniformity between the ganaxolone powder and the polylactic acid-glycolic acid copolymer, then primary particles are mixed with a disintegrating agent and pressed to prepare enteric ganaxolone spheres, the ganaxolone spheres are uniformly mixed with the ganaxolone powder under the adhesion of a polyvinyl alcohol aqueous solution, the polyvinyl alcohol aqueous solution forms an adhesive film after drying, when the ganaxolone particles are mixed with an oil phase, distilled water, an emulsifying agent and the like to prepare a ganaxolone microemulsion, the adhesive film is dissolved by water, the ganaxolone spheres and the ganaxolone powder are dispersed in the ganaxolone microemulsion, and when the ganaxolone microemulsion is mixed with chitosan, TPP emulsion and the like, the carboxylated chitosan contained on the ganaxolone spheres can enhance the compatibility of the ganaxolone spheres and the chitosan, the dispersion uniformity of the ganaxolone spheres in the mixed solution is improved, and the uniformity of the film preparation is improved; when the film preparation enters the oral cavity, the rapidly disintegrating ganaxolone powder is absorbed by human body, and rapidly provides blood level, so that the patient stops the epileptic status, and the epilepsy is treated in time, and the ganaxolone ball is released in intestinal juice, so that the drug release time of the ganaxolone can be prolonged, and the epileptic continuous status of the epileptic patient can be prevented from continuously occurring in a short period of time
Optionally, the mass ratio of the polylactic acid-glycolic acid copolymer to the carboxylated chitosan to the ganaxolone powder is 1:0.2-0.4:0.4-0.5, the mass ratio of the disintegrating agent to the primary particles is 1:0.5-1, and the mass ratio of the ganaxolone spheres to the polyvinyl alcohol aqueous solution to the ganaxolone powder is 0.3-0.5:0.1-0.3:1.
By adopting the technical scheme, the ganaxolone particles prepared by using the raw materials with the dosage can not only obtain uniform and stable ganaxolone microemulsion, but also load enteric slow-release primary particles in the microemulsion, prolong the drug release time and prevent epileptic patients from secondary attacks in a short time.
Optionally, during extrusion, the feeding speed is 15-20g/h, and the screw rotating speed is 80-90r/min.
By adopting the technical scheme, under the extrusion condition, the polylactic acid-glycolic acid copolymer and carboxylated chitosan can be effectively mixed with ganaxolone powder and coated on the ganaxolone powder to form slow-release primary particles with enteric effect, and the slow-release primary particles can be decomposed after the ganaxolone preparation is dissolved in the oral cavity and enters the intestinal tract, so that the effective time of the ganaxolone is prolonged, the drug release time is prolonged, and the epileptic symptoms are prevented from happening again in a short period of time.
Optionally, the ultrasonic power is 360-400W, the temperature is 30-35 ℃, the time is 20-30min, the feeding amount of the air flow superfine grinding is 300-350g, the rotating speed of the extension machine is 40-50Hz, and the grinding time is 0.5-1h.
By adopting the technical scheme, under the action of ultrasonic waves, the ganaxolone balls and the ganaxolone powder can destroy the structures of the ganaxolone balls and the ganaxolone powder, so that the particle sizes of the ganaxolone balls and the ganaxolone powder are further reduced, the ganaxolone microemulsion is more uniform, after the polyvinyl alcohol aqueous solution is mixed with the ganaxolone balls and the ganaxolone powder and dried, the polyvinyl alcohol aqueous solution is solidified into a film, under the action of ultrasonic waves, the ganaxolone balls and the ganaxolone powder are thinned and adhered on a polyvinyl alcohol film, when the ganaxolone particles are used for preparing the microemulsion, the thinned ganaxolone balls and the ganaxolone powder are fully dispersed in an oil phase after the polyvinyl alcohol film is dissolved, so that the uniformity of the ganaxolone microemulsion is improved, and when a film preparation is prepared, the film preparation is flat and smooth and easy to disintegrate.
Optionally, the oil phase comprises castor oil and sesame oil in a mass ratio of 1:0.4-0.6.
By adopting the technical scheme, castor oil and sesame oil are used as oily vehicles, and ganaxolone has high solubility in the castor oil and the sesame oil, so that uniform, stable and uniform ganaxolone microemulsion can be formed.
Optionally, the ganaxolone formulation has a thickness of 0.17-0.19mm.
By adopting the technical scheme, the ganaxolone preparation with thinner thickness is convenient for patients with epileptic seizures to take, does not easily block the trachea, can be dissolved only by being contained in the oral cavity, and improves the application safety and convenience of the ganaxolone preparation.
Preferably, the emulsifier is at least one selected from PEG40 hydrogenated castor oil, tween-80, 15-hydroxystearic acid polyethylene glycol ester, OP-10 and tween-20;
the auxiliary emulsifier is at least one selected from polyethylene glycol 400, propylene glycol, glycerol, absolute ethyl alcohol and isopropanol;
the tackifier is at least one selected from microcrystalline cellulose, gelatin, polyvinylpyrrolidone, povidone, dextrin, sorbitol and polyethylene glycol;
the filler is at least one selected from lactose, calcium carbonate, calcium phosphate, microcrystalline cellulose, dextran and pregelatinized starch; the preservative is at least one selected from ascorbic acid, benzoic acid, benzyl alcohol, chlorobutanol and potassium sorbate;
the flavoring agent is at least one of aspartame, stevioside, aspartame and disodium glycyrrhizinate.
By adopting the technical scheme, the emulsifying agent and the auxiliary emulsifying agent can fully disperse the ganaxolone in the oil phase, so that the solubility of ganaxolone particles in the oil phase is improved; the filler can reduce the viscosity of the mixed solution, so that the film laying is easier to carry out, the disintegration time is shortened, the adhesion force between the preparation and the liquid in the oral cavity is increased by the tackifier, and the film preparation is prevented from flowing out of the oral cavity along with the oral water of an epileptic patient; the preservative can be used for inhibiting bacterial growth, preventing degradation of the active agent, and inhibiting microbial growth; the flavoring agent can improve the taste of ganaxolone preparation, and has sweet taste, and has low calorie of aspartame, stevioside, etc., which is not easy to cause obesity, and can give the preparation sweet taste.
In a second aspect, the present application provides a ganaxolone formulation, which adopts the following technical scheme:
a ganaxolone preparation is prepared from ganaxolone preparation.
By adopting the technical scheme, the ganaxolone preparation is in an oral cavity membranous form, can rapidly dissolve and release internal ganaxolone particles in the oral cavity, can play a timely treatment effect on epileptic patients losing consciousness, is safer in oral cavity membranous form ganaxolone administration, does not produce dysphagia or cause suffocation danger of the patients, is convenient to carry, and improves the convenience and safety of administration.
In summary, the present application has the following beneficial effects:
1. the ganaxolone particles, the oil phase, the emulsifying agent and the like are firstly prepared into the microemulsion, and then the microemulsion is embedded by utilizing the crosslinking action of chitosan and TPP solution to form the membrane preparation containing the ganaxolone particles, so that the membrane preparation can be rapidly disintegrated in an oral cavity, is convenient to take, can be conveniently applied under the condition of no better independent consciousness and compliance even when epileptic patients take the drugs, has better convenience in taking the drugs, can be timely applied, has no experience requirement on a drug applicator, does not need higher injection experience like intravenous injection, can be taken when epileptic patients take the drugs, does not need to be sent to emergency treatment, and can prevent the best treatment time from being delayed.
2. In the application, polylactic acid-glycolic acid copolymer, carboxylated chitosan and ganaxolone powder are preferably adopted to be mixed and extruded firstly, primary particles are prepared and then are pressed with a disintegrating agent to prepare ganaxolone balls with enteric slow release property, then polyvinyl alcohol is utilized to bond the ganaxolone balls and the ganaxolone powder, and then ultra-air flow micro-crushing is carried out under the assistance of ultrasound, so that ganaxolone particles are refined, the surface of a formed film preparation is smooth, and the enteric slow release ganaxolone balls are released in intestinal juice, so that the drug release time is prolonged, and the second seizure of epilepsy in a short period of time is prevented.
3. In the application, castor oil and sesame oil are preferably used as oil phases, and ganaxolone powder can be well dissolved under the action of an emulsifier and a co-emulsifier to form uniform and stable ganaxolone microemulsion.
Detailed Description
Preparation examples 1 to 6 of ganaxolone particles
Preparation example 1: (1) Mixing 1kg of polylactic acid-glycolic acid copolymer, 0.4kg of carboxylated chitosan and 0.5kg of ganaxolone powder with the particle size of 300nm, extruding at the feeding rate of 15g/h, the screw rotating speed of 80r/min and the extrusion temperature of 120 ℃, granulating, and crushing to 1 mu m to obtain primary particles;
(2) Mixing 1kg of disintegrating agent, 0.5kg of deionized water and 1kg of primary particles, pressing, drying, and preparing into ganaxolone balls, wherein the disintegrating agent is povidone K30;
(3) Mixing 0.5kg of ganaxolone balls, 0.3kg of polyvinyl alcohol aqueous solution with concentration of 3wt% and 1kg of ganaxolone powder with particle size of 300nm, drying, carrying out ultrasonic-assisted air flow superfine grinding to obtain ganaxolone particles, wherein the ultrasonic power is 360W, the ultrasonic temperature is 35 ℃, the ultrasonic time is 20min, the feeding amount of air flow superfine grinding is 300g, the extension rotating speed is 50Hz, and the grinding time is 0.5h.
Preparation example 2: (1) Mixing 1kg of polylactic acid-glycolic acid copolymer, 0.2kg of carboxylated chitosan and 0.4kg of ganaxolone powder with the particle size of 300nm, extruding at the feeding rate of 20g/h, the screw rotating speed of 90r/min and the extrusion temperature of 100 ℃, granulating, and crushing to 1 mu m to obtain primary particles;
(2) Mixing 1kg of disintegrating agent, 0.5kg of deionized water and 0.5kg of primary particles, pressing, drying, and preparing into ganaxolone balls, wherein the disintegrating agent is povidone K30;
(3) Mixing 0.3kg ganaxolone ball, 0.1kg polyvinyl alcohol water solution with concentration of 3wt% and 1kg ganaxolone powder with particle size of 300nm, drying, ultrasonic assisted air flow superfine grinding to obtain ganaxolone particles, wherein the ultrasonic power is 400W, the ultrasonic temperature is 30 ℃, the ultrasonic time is 30min, the feeding amount of air flow superfine grinding is 350g, the extension rotational speed is 40Hz, and the grinding time is 1h.
Preparation example 3: the difference from preparation example 1 is that in the step (3), grinding is carried out for 1h at the rotating speed of 800r/min, and ultrasonic auxiliary air flow superfine grinding is replaced.
Preparation example 4: the difference from the preparation example 1 is that the steps (1) and (2) are not performed, specifically: mixing 0.3kg of polyvinyl alcohol water solution with concentration of 3wt% and 1kg of ganaxolone powder with particle size of 300nm, drying, and carrying out ultrasonic-assisted air flow superfine grinding to obtain ganaxolone particles, wherein the ultrasonic power is 360W, the ultrasonic temperature is 35 ℃, the ultrasonic time is 20min, the feeding amount of air flow superfine grinding is 300g, the rotating speed of an extension machine is 50Hz, and the grinding time is 0.5h.
Preparation example 5: the difference from preparation example 1 is that step (1) is specifically: 1kg of polylactic acid-glycolic acid copolymer, 0.4kg of carboxylated chitosan and 10kg of acetone are mixed, 0.5kg of ganaxolone powder is added, and after uniform mixing, the mixture is granulated and dried to prepare primary granules with the particle size of 10 mu m.
Preparation example 6: the difference from preparation example 1 is that carboxylated chitosan was not added in step (1).
Examples
Example 1: a method for preparing ganaxolone formulation, comprising the steps of:
s1, preparing ganaxolone microemulsion: mixing 1kg of ganaxolone particles, 2kg of oil phase, 2.5kg of emulsifying agent, 0.6kg of auxiliary emulsifying agent and 5kg of distilled water, and performing ultrasonic treatment at 200W for 30min to prepare a ganaxolone microemulsion, wherein the oil phase comprises castor oil and sesame oil in a mass ratio of 1:0.6, the ganaxolone particles are prepared by the preparation method 1, the emulsifying agent is PEG40 hydrogenated castor oil, and the auxiliary emulsifying agent is polyethylene glycol 400;
s2, preparing a ganaxolone preparation: mixing 5kg of chitosan, 3kg of hydroxypropyl methylcellulose and 10kg of acetic acid solution to prepare a mixed solution; dissolving TPP in distilled water to prepare a TPP solution with the concentration of 0.5wt%, mixing the TPP solution and the mixed solution according to the mass ratio of 1:3, adding 1kg of PEG400, 0.5kg of filler, 0.2kg of flavoring agent, 0.12kg of tackifier and 0.01kg of preservative, uniformly stirring, adding the prepared ganaxolone microemulsion, uniformly stirring, standing for deaeration, pouring into a mould for film laying, drying at 50 ℃ for 65min, uncovering the film, cutting, and preparing the ganaxolone preparation with the thickness of 0.19mm, wherein the filler is levo-dextran, the flavoring agent is aspartame, the preservative is potassium sorbate, and the tackifier is microcrystalline cellulose.
Example 2: a method for preparing ganaxolone formulation, comprising the steps of:
s1, preparing ganaxolone microemulsion: mixing 0.3kg of ganaxolone particles, 1kg of oil phase, 1.5kg of emulsifying agent, 0.3kg of auxiliary emulsifying agent and 3kg of distilled water, carrying out ultrasonic treatment at 200W for 30min to prepare ganaxolone microemulsion, wherein the oil phase comprises castor oil and sesame oil in a mass ratio of 1:0.4, the ganaxolone particles are prepared by a preparation example 2, the emulsifying agent is Tween-80, and the auxiliary emulsifying agent is absolute ethyl alcohol;
s2, preparing a ganaxolone preparation: mixing 3kg of chitosan, 1kg of hydroxypropyl methylcellulose and acetic acid solution to prepare a mixed solution, dissolving TPP in distilled water to prepare a TPP solution with the concentration of 0.8wt%, mixing the TPP solution and the mixed solution according to the mass ratio of 1:5, adding 0.6kg of PEG400, 0.3kg of filler, 0.1kg of flavoring agent, 0.08kg of tackifier and 0.005kg of preservative, uniformly stirring, adding the prepared ganaxolone microemulsion, uniformly stirring, standing for deaeration, pouring into a mould for film laying, drying at 55 ℃ for 60min, uncovering the film, cutting to prepare the ganaxolone preparation with the thickness of 0.17mm, wherein the filler is microcrystalline cellulose, the flavoring agent is stevioside, the tackifier is gelatin, and the preservative is benzoic acid.
Example 3: a process for the preparation of ganaxolone formulation, which differs from example 1 in that ganaxolone particles are prepared from preparation example 2.
Example 4: a process for the preparation of ganaxolone formulation, which differs from example 1 in that ganaxolone particles are prepared from preparation example 3.
Example 5: a process for the preparation of ganaxolone formulation, which differs from example 1 in that ganaxolone particles are prepared from preparation example 4.
Example 6: a process for the preparation of ganaxolone formulation, which differs from example 1 in that ganaxolone particles are prepared from preparation example 5.
Example 7: a process for the preparation of ganaxolone formulation, which differs from example 1 in that ganaxolone particles are prepared from preparation example 6.
Example 8: a process for the preparation of ganaxolone formulation differs from example 1 in that the oil phase is castor oil.
Example 9: a process for the preparation of ganaxolone formulation, which differs from example 1 in that the oil phase is glyceryl triacetate.
Comparative example
Comparative example 1: the preparation method of the ganaxolone preparation comprises the following steps: 1kg of ganaxolone particles, 0.5kg of filler, 0.2kg of flavoring agent, 0.12kg of tackifier and 0.01kg of preservative are uniformly stirred and tabletted to prepare the ganaxolone tablet, wherein the filler is levo-dextran, the flavoring agent is aspartame, the preservative is potassium sorbate, and the tackifier is microcrystalline cellulose.
Comparative example 2: a process for the preparation of ganaxolone formulation, which differs from example 1 in that an equivalent amount of polyvinyl alcohol is used instead of chitosan.
Comparative example 3: a ganaxolone suspension made from the ingredients in table 1.
Table 1 raw material amount of ganaxolone suspension in comparative example 3
Composition of the components Grade ％W/W mg/mL
Ganaxolone (ganaxolone) GMP 4.91 50
Hydroxypropyl methylcellulose USP/EP 5 50.91
Polyvinyl alcohol USP/EP 1 10.18
Sodium dodecyl sulfate USP/EP 0.1 1.02
P-hydroxybenzoic acid methyl ester NF/EP 0.1 1.02
Propyl p-hydroxybenzoate NF/EP 0.02 0.2
Sodium benzoate NF/EP 0.09 0.92
Citric acid USP/EP 0.12 1.22
Sodium citrate dihydrate USP/EP 0.0093 0.095
Cherry artificial flavoring agent Pharmaceutical agents 0.0025 0.025
Sucralose NF 0.02 0.2
30% simethicone emulsion USP 0.0333 0.34
Pure water USP q.s100 q.s100
Performance test ganaxolone formulations were prepared according to the methods in examples and comparative examples, and the performance of the ganaxolone formulations was tested with reference to the following methods, and the test results are recorded in table 2.
1. Disintegration time: 20ml of distilled water with the temperature of 37 ℃ is measured in a surface dish, a ganaxolone preparation is clamped up and down by a 30-mesh metal net and is horizontally placed in the distilled water, the upper surface and the lower surface of the preparation are soaked, the timing is started, the disintegration time of the preparation is recorded, the test is repeated for three times, and the average value is calculated.
2. The weight of the preparation is as follows: the total weight of the 20 formulations prepared in examples and comparative examples was weighed.
3. Dissolution rate: according to the third method of CHP dissolution rate measurement, the test temperature is 36-38 ℃, 250 milliliters of phosphate buffer solution containing 10% SDS and pH of 6.8 is used as dissolution medium, the rotation speed is 100r/min, the method is operated, 10 milliliters of solution is taken at 5min, 15min and 30min, rapid filtration is carried out, the subsequent filtrate is taken as sample solution, about 20mg of the sample reference substance is taken, the sample reference substance is placed in a 100mL measuring flask, methanol solution is added and diluted to scale, shaking is carried out, 1mL of the sample reference substance is precisely measured, the sample reference substance is placed in a 10mL measuring flask, the sample reference substance is diluted to scale and shaking is carried out, absorbance is measured at the wavelength of 250nm by an ultraviolet-visible photometer, and the dissolution rate of each tablet is calculated.
TABLE 2
Figure BDA0004063276530000081
Figure BDA0004063276530000091
As can be seen from the data in Table 2, the ganaxolone film preparations prepared in examples 1 and 2 have a single weight of 14-15mg, the film preparation has a light weight and is easy to take, and can be completely disintegrated within 30 seconds, the disintegration rate is fast, the dissolution rate in water reaches more than 75% within 5 minutes, the dissolution rate reaches more than 80% at 30 minutes, and ganaxolone spheres are dissolved in a phosphate buffer solution with pH of 6.8, so that the dissolution rate of ganaxolone is further increased, and the dissolution rate of ganaxolone preparation is further increased, which means that the dissolution rate can be further increased in intestinal solution.
The ganaxolone particles prepared in preparation example 2 were used in example 3, and the ganaxolone film preparation thus prepared had similar disintegration rate, weight and dissolution properties to those in example 1.
In example 4, the ganaxolone particles prepared in preparation example 3 were used, and instead of the ultra-fine pulverization by ultrasonic-assisted air flow, the disintegration time of the ganaxolone film preparation prepared in example 4 was increased, the weight change was not large, and the dissolution rate at 5min was reduced, which indicates that the ultra-fine pulverization by ultrasonic-assisted air flow could improve the particle size of ganaxolone particles and further improve the dissolution rate, as shown in table 2.
The ganaxolone particles prepared in example 4 were used in example 5, in which ganaxolone pellets prepared by extrusion and compression of polylactic acid-glycolic acid polymer, carboxylated chitosan and ganaxolone powder were not added, and ganaxolone particles were prepared by using only ganaxolone powder and aqueous polyvinyl alcohol solution, and it is shown in table 2 that the disintegration rate of the ganaxolone film preparation prepared in example 5 was accelerated, and the weight was reduced, but the dissolution rate in phosphate buffer emulsion was not greatly changed from that in water, indicating that ganaxolone pellets could be dissolved in phosphate buffer solution (i.e., intestinal solution) having pH of 6.8, further increasing blood content of ganaxolone in blood, prolonging release time period, and improving epileptic treatment.
In example 6, the polylactic acid-glycolic acid copolymer, carboxylated chitosan and the like were not extruded, but dissolved by using acetone, and the dissolution rate of the ganaxolone preparation prepared in example 6 in water was not changed much, and the disintegration time and weight were similar to those of example 1, but the dissolution rate in phosphate buffer was increased, and the controlled release effect was reduced, compared with example 1.
In example 7, the ganaxolone particles prepared in preparation example 6 were used, and in preparation example 6, carboxylated chitosan was not added, so that the ganaxolone preparation prepared in example 7 had a slower disintegration rate, a less significant change in dissolution rate in water, a poorer dissolution rate in phosphate buffer, and a higher blood level of ganaxolone could not be provided in a short period of time, and the effect of suppressing the sudden epileptic symptoms was reduced.
Example 8 as compared to example 1, ganaxolone microemulsion was prepared using only castor oil as the oil phase, and the ganaxolone formulation prepared in example 8 had a slower disintegration rate in water, an increased disintegration time, and a slower dissolution rate in water.
In example 9, glyceryl triacetate was used as the oil phase, and the ganaxolone preparation had a slower disintegration rate, an increased disintegration time, and a smaller dissolution rate in water than in example 8.
In comparative example 1, ganaxolone particles, a filler and the like were tableted to obtain tablets, the disintegration time of the tablets in water was more than 60s, the mass of each tablet was 200mg or more, the dissolution rate in water was slow, and the dissolution rate in phosphate buffer was reduced.
Comparative example 2, in which polyvinyl alcohol was used instead of chitosan, the dissolution rate of ganaxolone formulation prepared in comparative example 2 in water and phosphate buffer was reduced as compared with example 1.
Comparative example 3 is a ganaxolone suspension prepared in the prior art, and when epileptic seizure occurs, the suspension is poured into the oral cavity of a patient, and the patient is choked into the trachea to cause the risk of choking, so that the ganaxolone suspension is generally used as a therapeutic medicament and cannot be used as an emergency medicament.
The present embodiment is merely illustrative of the present application and is not intended to be limiting, and those skilled in the art, after having read the present specification, may make modifications to the present embodiment without creative contribution as required, but is protected by patent laws within the scope of the claims of the present application.

Claims (10)

1. A method for preparing ganaxolone formulation, comprising the steps of:
preparing ganaxolone microemulsion: mixing ganaxolone particles, an oil phase, an emulsifier, a co-emulsifier and distilled water, and performing ultrasonic treatment for 20-30min to prepare ganaxolone microemulsion;
preparation of ganaxolone formulation: mixing chitosan, hydroxypropyl methylcellulose and acetic acid solution to prepare a mixed solution, dissolving TPP in distilled water to prepare a TPP solution with the concentration of 0.5-0.8wt%, mixing the TPP solution and the mixed solution according to the mass ratio of 1:3-5, adding PEG400, a filler, a flavoring agent, a tackifier and a preservative, uniformly stirring, adding the ganaxolone microemulsion, uniformly stirring, standing for deaeration, spreading a film, drying, uncovering the film, and cutting.
2. A process for the preparation of ganaxolone formulation according to claim 1, wherein: the ganaxolone preparation comprises the following raw materials in parts by weight: 0.3-1 part of ganaxolone particles, 1-2 parts of oil phase, 1.5-2.5 parts of emulsifying agent, 0.3-0.6 part of auxiliary emulsifying agent, 3-5 parts of distilled water, 3-5 parts of chitosan, 1-3 parts of hydroxypropyl methyl fiber, 6-10 parts of acetic acid solution, 0.6-1 part of PEG400, 0.3-0.5 part of filling agent, 0.1-0.2 part of flavoring agent, 0.08-0.12 part of tackifier and 0.005-0.01 part of preservative.
3. A process for the preparation of ganaxolone formulation according to claim 1, wherein: the ganaxolone particles are prepared by the following method:
mixing polylactic acid-glycolic acid copolymer, carboxylated chitosan and ganaxolone powder, extruding at 100-120 ℃, granulating, and pulverizing to obtain primary particles;
mixing the disintegrating agent, deionized water and the primary particles, pressing, and drying to prepare ganaxolone spheres;
mixing the ganaxolone balls, the polyvinyl alcohol water solution and the ganaxolone powder, drying, and carrying out ultrasonic-assisted air flow superfine grinding to obtain ganaxolone particles.
4. A process for the preparation of ganaxolone formulation as claimed in claim 3, wherein: the mass ratio of the polylactic acid-glycolic acid copolymer to the carboxylated chitosan to the ganaxolone powder is 1:0.2-0.4:0.4-0.5, the mass ratio of the disintegrating agent to the primary particles is 1:0.5-1, and the mass ratio of the ganaxolone balls to the polyvinyl alcohol aqueous solution to the ganaxolone powder is 0.3-0.5:0.1-0.3:1.
5. A process for the preparation of ganaxolone formulation as claimed in claim 3, wherein: during extrusion, the feeding speed is 15-20g/h, and the screw rotating speed is 80-90r/min.
6. A process for the preparation of ganaxolone formulation as claimed in claim 3, wherein: the ultrasonic power is 360-400W, the temperature is 30-35 ℃, the time is 20-30min, the feeding amount of the air flow superfine grinding is 300-350g, the rotating speed of the extension machine is 40-50Hz, and the grinding time is 0.5-1h.
7. A process for the preparation of ganaxolone formulation according to claim 1, wherein: the oil phase comprises castor oil and sesame oil with a mass ratio of 1:0.4-0.6.
8. The process for the preparation of ganaxolone formulation of claim 1, wherein the ganaxolone formulation has a thickness of 0.17-0.19mm.
9. The method for preparing ganaxolone formulation of claim 1, wherein the emulsifier is at least one selected from the group consisting of PEG40 hydrogenated castor oil, tween-80, 15-hydroxystearic acid polyethylene glycol ester, OP-10, tween-20;
the auxiliary emulsifier is at least one selected from polyethylene glycol 400, propylene glycol, glycerol, absolute ethyl alcohol and isopropanol;
the tackifier is at least one selected from microcrystalline cellulose, gelatin, polyvinylpyrrolidone, povidone, dextrin, sorbitol and polyethylene glycol;
the filler is at least one selected from lactose, calcium carbonate, calcium phosphate, microcrystalline cellulose, dextran and pregelatinized starch;
the preservative is at least one selected from ascorbic acid, benzoic acid, benzyl alcohol, chlorobutanol and potassium sorbate;
the flavoring agent is at least one of aspartame, stevioside, aspartame and disodium glycyrrhizinate.
10. A ganaxolone formulation prepared by the process of any one of claims 1-9.
CN202310068888.1A 2023-02-06 2023-02-06 Ganaxolone preparation and preparation method thereof Pending CN116077470A (en)

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