CN112294772A - Shuxinding sulfate double-release orally disintegrating tablet and preparation method thereof - Google Patents
Shuxinding sulfate double-release orally disintegrating tablet and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Abstract
The invention discloses a sulcardine sulfate double-release orally disintegrating tablet, which is prepared by mixing taste-masking quick-release particles, slow-release particles, a filling agent, a flow aid, a disintegrating agent and a flavoring agent and then pressing into tablets; wherein, the taste-masking quick-release particles are particles obtained by coating the first sulcardine sulfate particle core with coating liquid containing taste-masking coating materials; the first sulcardine sulfate granular core is a granular core with the grain size of 100-200 meshes, and is obtained by granulating the first sulcardine sulfate and a first adhesive; wherein the sustained-release particles are particles obtained by coating the second sulcardine sulfate particle cores with coating liquid containing sustained-release coating materials; the second sulcardine sulfate granular core is a granular core with the grain size of 80-160 meshes, and is obtained by granulating second sulcardine sulfate and a second adhesive. The invention solves the problem that the low dose of sulcardine sulfate is metabolized quickly in vivo and can only take effect when reaching a certain threshold value through the sustained-release particles, prolongs the administration time interval of patients and improves the compliance of the patients.
Description
Technical Field
The invention relates to the field of pharmacy, and in particular relates to a sulcardine sulfate double-release orally disintegrating tablet and a preparation method thereof.
Background
Sulcardine sulfate (Sulcardine sulfate) with the chemical name of 4-methoxy-N- (3, 5-bis- (1-pyrrolidinemethyl) -4-hydroxybenzyl) benzenesulfonamide sulfate is an innovative drug designed and synthesized in Shanghai drug research of Chinese academy of sciences (Chinese patent number ZL99124236.X), and at present, no dosage form is available in the clinical stage. Pharmacological experiments show that the sulcardine sulfate has good treatment effect on various experimental arrhythmia models, has obvious effect of resisting arrhythmia, and has the effect of preventing atrial fibrillation. In preclinical toxicology and pharmacology studies, a high dose group of 1000mg/kg was observed to be a toxic dose with low toxicity. Meanwhile, sulcardine sulfate is a compound sodium, calcium and potassium channel blocker and has a novel arrhythmia resistance mechanism. The new action mechanism can ensure that the sulcardine sulfate has the characteristics of safety and high efficiency, can not obviously inhibit L-type calcium current, is expected to be safely used in patients with coronary heart disease and heart failure, and has good application prospect and great social significance for treating arrhythmia.
However, sulcardine sulfate also has the problem that the metabolism of low dose in vivo is fast, and the sulcardine sulfate can take effect only when reaching a certain threshold value, which limits the clinical application of the sulcardine sulfate, so that an oral dosage form which can carry large dose of medicine, does not influence swallowing, takes effect quickly and can maintain blood concentration for a period of time is needed for administration, thereby exerting the curative effect more safely and effectively and improving the compliance of patients.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problem in the prior art and provides a sulcardine sulfate double-release orally disintegrating tablet so as to improve the clinical use effect of sulcardine sulfate.
The technical problem to be solved by the invention is to provide a preparation method of the sulcardine sulfate double-release orally disintegrating tablet.
In order to solve the first technical problem, the invention discloses a sulcardine sulfate double-release orally disintegrating tablet, which is prepared by mixing taste-masking quick-release particles, slow-release particles, a filling agent, a glidant, a disintegrant and a flavoring agent and then pressing the mixture into tablets.
Wherein, the taste-masking quick-release particles are particles obtained by coating the first sulcardine sulfate particle core with coating liquid containing taste-masking coating materials; the first sulcardine sulfate granular core is a granular core with the grain size of 100-200 meshes, and the granular core is obtained by granulating first sulcardine sulfate powder and a first binding agent.
Wherein the sustained-release particles are particles obtained by coating the second sulcardine sulfate particle cores with coating liquid containing sustained-release coating materials; the second sulcardine sulfate granular core is a granular core with the grain size of 80-160 meshes, and the granular core is obtained by granulating second sulcardine sulfate powder and a second adhesive.
The mass ratio of the first sulcardine sulfate in the taste-masking quick-release particles to the second sulcardine sulfate in the slow-release particles is 5: 1-1: 4.
Wherein the total mass of the first sulcardine sulfate and the second sulcardine sulfate is 20-60% of the total mass of the orally disintegrating tablet.
In the first sulcardine sulfate granular core, the first adhesive accounts for 0.1-8% of the total mass of the first adhesive and the first sulcardine sulfate, and preferably 0.3-6%; the first sulcardine sulfate accounts for 92-99.9 percent of the total mass of the first adhesive and the first sulcardine sulfate, and preferably 94-99.7 percent.
In the second sulcardine sulfate granule core, the second binder accounts for 0.5-12% of the total mass of the second binder and the second sulcardine sulfate, and the second sulcardine sulfate accounts for 88-99.5% of the total mass of the second binder and the second sulcardine sulfate, and is preferably 0.5-11%: 89 to 99.5 percent.
Wherein, compared with the mass of the first sulcardine sulfate grain core, the coating liquid containing the taste masking coating material improves the mass of the particles coated by the first sulcardine sulfate grain core by 10 to 50 percent, preferably 20 to 45 percent.
Wherein, compared with the mass of the second sulcardine sulfate granule core, the coating liquid containing the slow-release coating material improves the mass of the coated particles of the second sulcardine sulfate granule core by 15 to 100 percent, preferably by 35 to 78 percent.
Wherein the slow-release coating material comprises the following components in percentage by mass:
30 to 70 percent of slow-release high polymer material
0 to 10 percent of plasticizer
20 to 70 percent of anti-sticking agent.
Preferably, the mass percentages of the components in the slow-release coating layer are as follows:
40 to 60 percent of slow-release high polymer material
0 to 7 percent of plasticizer
33 to 60 percent of anti-sticking agent.
Wherein, the orally disintegrating tablet comprises the following components in percentage by mass:
preferably, the orally disintegrating tablet comprises the following components in percentage by mass:
wherein the filler is any one or combination of more of microcrystalline cellulose, lactose, starch, mannitol and calcium hydrogen phosphate, preferably any one or combination of more of microcrystalline cellulose, lactose and mannitol.
The glidant is any one or combination of magnesium stearate, calcium stearate, aerosil and talcum powder, and preferably any one or combination of magnesium stearate, aerosil and talcum powder.
The disintegrating agent is any one or combination of more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low-substituted hydroxypropyl cellulose, preferably any one or combination of more of crospovidone, sodium carboxymethyl starch and croscarmellose sodium.
The flavoring agent is one or more of sucrose, aspartame, peppermint essence and citric acid, preferably one or more of sucrose, aspartame and peppermint essence.
The adhesive is any one or combination of several of polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose, preferably any one or combination of two of polyvinylpyrrolidone and hydroxypropyl methylcellulose.
The plasticizer is any one or combination of triethyl citrate, polyvinyl alcohol, dibutyl sebacate, oleic acid and triacetyl glycerine, and preferably any one or combination of triethyl citrate, dibutyl sebacate and triacetyl glycerine.
Wherein, the taste-masking coating material is a taste-masking high molecular material, including but not limited to acrylic resin and ethyl cellulose, and is preferably acrylic resin.
Wherein, the slow release polymer material is any one or a combination of a plurality of acrylic resin and ethyl cellulose.
In order to solve the second technical problem, the present invention discloses a method for preparing the orally disintegrating tablet, comprising the following steps:
(1) preparing taste-masking quick-release particles: preparing a first adhesive aqueous solution and first sulcardine sulfate powder into sulcardine sulfate particles by adopting a fluidized bed according to a formula ratio, drying until the moisture is 0.5% -4%, and sieving by a sieve of 100-200 meshes to obtain a first sulcardine sulfate particle core; coating the first sulcardine sulfate granular core in a fluidized bed by using a coating solution containing a taste-masking coating material until the target weight is increased, drying for 10-15min in the fluidized bed, weighing again to calculate the weight increase, estimating the remaining time of the granular core coating until the target weight is increased, continuing coating, drying for 10-15min, repeating the steps until the dried granules reach the target weight increase, and obtaining the taste-masking quick-release particles;
(2) preparing sustained-release particles: preparing a second adhesive aqueous solution and second sulcardine sulfate powder into sulcardine sulfate particles by adopting a fluidized bed according to a formula ratio, drying until the moisture content is 0.5% -4%, and sieving by 80-160 meshes to obtain a second sulcardine sulfate particle core; coating liquid prepared from a slow-release high polymer material, a plasticizer and an anti-sticking agent is the coating liquid containing the slow-release coating material; coating the second sulcardine sulfate particle cores with a coating solution containing a slow-release coating layer in a fluidized bed until the target weight is increased, drying for 10-15min in the fluidized bed, weighing again to calculate the weight increase, estimating the remaining time of the particle cores coated until the target weight is increased, continuing coating, drying for 10-15min, and repeating the steps until the dried particles reach the target weight increase to obtain the slow-release particles;
(3) and (3) according to the formula ratio, uniformly mixing the filler, the glidant, the disintegrant and the flavoring agent with the taste-masking quick-release particles prepared in the step (1) and the slow-release particles prepared in the step (2), and tabletting to obtain the tablet.
In the step (1), the concentration of the adhesive in the first adhesive aqueous solution is 0.1-15% (w/w).
In the step (2), the concentration of the adhesive in the second adhesive aqueous solution is 0.1-10% (w/w).
In the step (1), the solvent of the coating liquid containing the taste-masking coating material is any one or a mixture of ethanol and water, and the solid content of the coating liquid is 1-35% (w/w).
In the step (2), the solvent of the coating solution containing the slow-release coating material is any one or a mixture of ethanol and water, and the solid content of the coating solution is 3-32% (w/w).
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) the sulcardine sulfate double-release orally disintegrating tablet disclosed by the invention has the advantages that the taste is masked and the granules are quickly released, the tablet does not have bitter taste after being taken, the effect is quickly achieved, the blood concentration in a body reaches the effective concentration, the medicine is continuously released within 8h through the sustained release granules, the blood concentration in the body is maintained at a certain level, the problem that the low dose of the sulcardine sulfate is quickly metabolized in the body and can only reach a certain threshold value to achieve the effect is solved, the administration time interval of a patient is prolonged, and the compliance of the patient is improved.
(2) The sulcardine sulfate needs a larger dose to have better drug effect, while the problem that the tablet is too large and difficult to swallow exists when the large dose is generally made into a solid oral tablet, and the tablet is an orally disintegrating tablet which can disintegrate in a short time after being taken, thereby being beneficial to the administration of old patients or patients with dysphagia.
Drawings
The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
FIG. 1 shows the results of the first sulcardine sulfate particle size distribution test in example 1 of the present invention.
FIG. 2 shows the second sulcardine sulfate particle size distribution test result of example 1.
FIG. 3 shows the results of the first sulcardine sulfate particle size distribution test of comparative example 2 in accordance with the present invention.
FIG. 4 shows the results of the second sulcardine sulfate particle core size distribution test of comparative example 2 in the present invention.
FIG. 5 shows the results of the first sulcardine sulfate particle size distribution test of comparative example 3 in the present invention.
FIG. 6 shows the results of the second sulcardine sulfate particle size distribution test of comparative example 3 in the present invention.
Fig. 7 shows the results of the release rate of orally disintegrating tablets obtained in examples 1 and 2 and comparative examples 1 and 2 and 3 at pH 4.0.
Detailed Description
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
EXAMPLE 1 preparation of sulcardine sulfate dual release orally disintegrating tablets
Wherein the Eudragit NE30D is emulsion polymerization product, water dispersion, and the mass content of the polymer is 30%.
The preparation method comprises the following steps:
(1) preparing taste-masking quick-release particles: preparing 5% (w/w) of aqueous solution by using a formula amount of adhesive, preparing sulcardine sulfate powder into sulcardine sulfate particles by adopting a fluidized bed (top spraying) granulation mode, wherein the air volume is 0.2m3The method comprises the following steps of (1) drying the mixture at air inlet temperature of 40-48 ℃, spraying pressure of 1.2bar, sector pressure of 0.4bar, material temperature of 35 ℃, liquid inlet speed of 1.0mL/min until the water content is 0.5-4%, and screening sulcardine sulfate particles of 100-200 meshes as a first sulcardine sulfate particle core for later use; the sieved first sulcardine sulfate grain core is coated by a coating liquid prepared by a taste masking high polymer material in a fluidized bed (top spraying mode), and the air volume is 0.3m3The method comprises the following steps of (1)/min, air inlet temperature of 35-45 ℃, spray pressure of 0.6bar, material temperature of 30 ℃, liquid inlet speed of 1.2mL/min, drying in a fluidized bed for 10-15min after coating to a target weight gain (40%), weighing again to calculate the weight gain, estimating the remaining time of the coating of the particle core to the target weight gain, continuing coating, drying for 10-15min, repeating the steps until the dried particles reach the target weight gain, obtaining taste-masking quick-release particles, and detecting the content of sulcardine sulfate in the taste-masking quick-release particles;
(2) preparing sustained-release particles: preparing 4% (w/w) of aqueous solution by using a formula amount of adhesive, preparing sulcardine sulfate powder into sulcardine sulfate particles by adopting a fluidized bed (top spraying) granulation mode, wherein the air volume is 0.4m3The air inlet temperature is 40-48 ℃, the spraying pressure is 1.0bar, the material temperature is 37 ℃, the liquid inlet speed is 1.0mL/min, the mixture is dried until the water content is 0.5-4%, and the sulcardine sulfate particles of 80-160 meshes are screened as a second sulcardine sulfate particle core for later use; the sieved second sulcardine sulfate granule core is coated by a fluidized bed by coating liquid prepared by slow-release high molecular materials, plasticizers and anti-sticking agents according to the formula proportion, and the air volume is 0.5m3Coating to mesh at air inlet temperature of 30-38 deg.C, spray pressure of 0.5bar, material temperature of 25 deg.C, and liquid inlet speed of 1.2mL/minAfter the weight is increased by a standard amount (40%), drying the granules in a fluidized bed for 10-15min, weighing again to calculate the weight increase, estimating the remaining time from the coating of the granule cores to the target weight increase, continuing coating, drying for 10-15min, repeating the steps until the dried granules reach the target weight increase, obtaining the sustained-release particles, and detecting the content of the sulcardine sulfate in the sustained-release particles;
(3) and (2) referring to the content of the sulcardine sulfate in the taste-masking quick-release particles and the sustained-release particles, discarding redundant part of the taste-masking quick-release particles or sustained-release particles according to the prescription proportion, weighing the filler, the glidant, the disintegrant and the flavoring agent according to the prescription amount, uniformly mixing the filler, the glidant, the disintegrant and the flavoring agent with the taste-masking quick-release particles and the sustained-release particles, and tabletting to obtain the tablet.
EXAMPLE 2 preparation of sulcardine sulfate double-release orally disintegrating tablets
The preparation method comprises the following steps:
(1) preparing taste-masking quick-release particles: preparing 5% (w/w) of aqueous solution by using a formula amount of adhesive, preparing sulcardine sulfate powder into sulcardine sulfate particles by adopting a fluidized bed (top spraying) granulation mode, wherein the air volume is 0.2m3The method comprises the following steps of (1) drying the mixture at a temperature of 40-48 ℃ for each min, under the conditions of air inlet temperature, spray pressure of 1.2bar, sector pressure of 0.4bar, material temperature of 35 ℃ and liquid inlet speed of 1.0mL/min until the water content is 0.5-4%, and screening sulcardine sulfate particles of 100-200 meshes as first sulcardine sulfate particle cores for later use; the sieved first sulcardine sulfate grain core is coated by a coating liquid prepared by a taste masking high polymer material in a fluidized bed (top spraying mode), and the air volume is 0.3m3The air inlet temperature is 35-45 ℃, the spraying pressure is 0.6bar, the material temperature is 30 ℃, the liquid inlet speed is 1.5mL/min, after the coating is coated to the target weight gain (31%), the coating is dried in a fluidized bed for 10-15min, the weight gain is calculated by weighing again, the residual time of the coating of the particle cores to the target weight gain is estimated, the coating is continued, the drying is carried out for 10-15min, and the steps are repeated until the dried particles are particlesThe target weight increment is achieved, the taste-masking quick-release granules are obtained, and the content of the sulcardine sulfate in the taste-masking quick-release particles is detected;
(2) preparing sustained-release particles: preparing 5% (w/w) of aqueous solution by using a formula amount of adhesive, preparing sulcardine sulfate powder into sulcardine sulfate particles by adopting a fluidized bed (top spraying) granulation mode, wherein the air volume is 0.3m3The air inlet temperature is 40-48 ℃, the spraying pressure is 1.2bar, the material temperature is 37 ℃, the liquid inlet speed is 1.0mL/min, the mixture is dried until the water content is 0.5-4%, and the sulcardine sulfate particles of 80-160 meshes are screened as a second sulcardine sulfate particle core for later use; the sieved second sulcardine sulfate granule core is coated by a fluidized bed by coating liquid prepared by slow-release high molecular materials, plasticizers and anti-sticking agents according to the formula proportion, and the air volume is 0.5m3The air inlet temperature is 38-45 ℃, the spraying pressure is 0.8bar, the material temperature is 30 ℃, the liquid inlet speed is 1.2mL/min, after the coating is coated until the target weight gain (64.6%), the coating is dried in a fluidized bed for 10-15min, the weight gain is calculated by weighing again, the remaining time of the coating of the grain core until the target weight gain is estimated, the coating is continued, the drying is carried out for 10-15min, the steps are repeated until the dried grains reach the target weight gain, the slow release particles are obtained, and the content of the sulcardine sulfate in the slow release particles is detected;
(3) and (2) referring to the content of the sulcardine sulfate in the taste-masking quick-release particles and the sustained-release particles, discarding redundant part of the taste-masking quick-release particles or sustained-release particles according to the prescription proportion, weighing the filler, the glidant, the disintegrant and the flavoring agent according to the prescription amount, uniformly mixing the filler, the glidant, the disintegrant and the flavoring agent with the taste-masking quick-release particles and the sustained-release particles, and tabletting to obtain the tablet.
Comparative example 1 preparation of sulcardine sulfate dual release orally disintegrating tablet
The preparation method comprises the following steps:
(1) preparing taste-masking quick-release particles: the adhesive is prepared into 5 percent according to the formula amount(w/w) preparing the sulcardine sulfate powder into sulcardine sulfate particles by adopting a fluidized bed (top spraying) granulation mode, wherein the air volume is 0.2m3The method comprises the following steps of (1) drying the mixture at a temperature of 40-48 ℃ for each min, under the conditions of air inlet temperature, spray pressure of 1.2bar, sector pressure of 0.4bar, material temperature of 35 ℃ and liquid inlet speed of 1.0mL/min until the water content is 0.5-4%, and screening sulcardine sulfate particles of 100-200 meshes as first sulcardine sulfate particle cores for later use; the sieved first sulcardine sulfate grain core is coated by a coating liquid prepared by a taste masking high polymer material in a fluidized bed (top spraying mode), and the air volume is 0.3m3The method comprises the following steps of (1)/min, air inlet temperature of 35-45 ℃, spray pressure of 0.6bar, material temperature of 30 ℃, liquid inlet speed of 1.2mL/min, drying in a fluidized bed for 10-15min after coating to a target weight gain (28%), weighing again to calculate the weight gain, estimating the remaining time of the coating of the grain core to the target weight gain, continuing coating, drying for 10-15min, repeating the steps until the dried grains reach the target weight gain, obtaining taste-masking quick-release grains, and detecting the content of the sulcardine sulfate in the taste-masking quick-release grains;
(2) preparing sustained-release particles: preparing 4% (w/w) of aqueous solution by using a formula amount of adhesive, preparing sulcardine sulfate powder into sulcardine sulfate particles by adopting a fluidized bed (top spraying) granulation mode, wherein the air volume is 0.4m3The air inlet temperature is 40-48 ℃, the spraying pressure is 1.0bar, the material temperature is 37 ℃, the liquid inlet speed is 1.0mL/min, the mixture is dried until the water content is 0.5-4%, and the sulcardine sulfate particles of 80-160 meshes are screened as a second sulcardine sulfate particle core for later use; the sieved second sulcardine sulfate granule core is coated by a fluidized bed by coating liquid prepared by slow-release high molecular materials, plasticizers and anti-sticking agents according to the formula proportion, and the air volume is 0.5m3The air inlet temperature is 30-38 ℃, the spraying pressure is 0.5bar, the material temperature is 25 ℃, the liquid inlet speed is 1.2mL/min, after the coating is coated to the target weight gain (40%), the coating is dried in a fluidized bed for 10-15min, the weight gain is calculated by weighing again, the remaining time of the coating of the particle core to the target weight gain is estimated, the coating is continued, the drying is carried out for 10-15min, the steps are repeated until the dried particles reach the target weight gain, the slow release particles are obtained, and the content of the sulcardine sulfate in the slow release particles is detected;
(3) and (2) referring to the content of the sulcardine sulfate in the taste-masking quick-release particles and the sustained-release particles, discarding redundant part of the taste-masking quick-release particles or sustained-release particles according to the prescription proportion, weighing the filler, the glidant, the disintegrant and the flavoring agent according to the prescription amount, uniformly mixing the filler, the glidant, the disintegrant and the flavoring agent with the taste-masking quick-release particles and the sustained-release particles, and tabletting to obtain the tablet.
Comparative example 2 preparation of sulcardine sulfate dual release orally disintegrating tablet
In the same way as in example 1, the particle sizes of the first sulcardine sulfate granule core and the second sulcardine sulfate granule core are respectively modified to be 60-90 meshes and 40-60 meshes.
Comparative example 3 preparation of sulcardine sulfate dual release orally disintegrating tablet
In the same way as in example 1, the particle sizes of the first sulcardine sulfate granule core and the second sulcardine sulfate granule core are respectively modified to be 60-90 meshes and 170-200 meshes.
Example 3 sizing method determination of particle size distribution of first sulcardine sulfate particle core and second sulcardine sulfate particle core
Taking the first sulcardine sulfate granule core or the second sulcardine sulfate granule core which are respectively screened and obtained in the target particle size ranges of example 1, comparative example 2 and comparative example 3, uniformly mixing, weighing about 50g of materials, stacking standard sieves in the order of the pore size from large to small, installing the sieve bottoms, pouring the weighed samples into the uppermost layer of sieve, adding the sieve covers, installing the sieve covers on a vibrating sieve machine, starting the vibrating sieve machine, vibrating for 3 minutes, taking down the sieves, respectively weighing the sample mass on each sieve and in the chassis, recording, and carrying out parallel test for 2 times.
The results of the particle size distribution test are shown in fig. 1, fig. 2, fig. 3, fig. 4, fig. 5, and fig. 6.
Example 4 disintegration time test
The disintegration time was measured by taking samples of example 1, example 2 and comparative example 1, respectively, according to the method for measuring orally disintegrating tablets in 0921, the four general guidelines of the pharmacopoeia of China (2020 edition). The results are shown in Table 1.
TABLE 1 disintegration time limit test results
| Sample (I) | Disintegration time (n ═ 6) |
| Example 1 | ＜60s |
| Example 2 | ＜60s |
| Comparative example 1 | ＞5min |
As can be seen from the results in Table 1, both the examples 1 and 2 meet the disintegration requirements of orally disintegrating tablets in Chinese pharmacopoeia, and can disintegrate rapidly after entering the mouth, while the comparative example 1 has a slow disintegration rate and does not meet the requirements.
Example 5 in vitro Release test
Taking samples of example 1, example 2, comparative example 1, comparative example 2 and comparative example 3 respectively, according to the second method of 0931 of the general rules of the four ministry of China pharmacopoeia (2020 edition), adding water to dissolve and dilute a pH 4.0 acetate buffer solution (taking 1.22g of sodium acetate and 20.5mL of 2mol/L of acetic acid solution) to 1000mL to obtain 900mL of release medium, controlling the temperature to be 37 +/-0.5 ℃ and the rotating speed to be 100 revolutions per minute, operating according to the method, taking 10mL of solution when the solution is respectively 0.25h, 0.5h, 1h, 2h, 4h, 6h and 8h, filtering, taking 2.5mL of subsequent filtrate, placing in a 25mL volumetric flask, using water, shaking up to serve as a sample solution, taking a proper amount of a sudoxin sulfate control, dissolving with ultrasonic waves of pH 4.0 acetate buffer solution, preparing 22 mu g/mL of acetate buffer solution with pH 4.0 acetate buffer solution again to serve as a control solution, taking the two solutions, respectively measuring the absorption degrees at 240nm, the amount released was calculated for each tablet.
The in vitro release degree test of the sulcardine sulfate dual-release orally disintegrating tablet in example 5 is shown in fig. 7, and it can be seen from the figure that the sulcardine sulfate dual-release orally disintegrating tablet within the design parameter range of the invention can release the drug rapidly and release the drug continuously within 8h, and the drug effect is maintained.
EXAMPLE 6 pharmacodynamic study of Shuxinding sulfate dual-release orally disintegrating tablets
An arrhythmia model is induced by adopting a dog coronary artery left anterior descending two-phase ligation method, and the treatment effect of the Shuxinding sulfate double-release orally disintegrating tablet on dog arrhythmia is observed. 24 hours after the operation, each group of dogs was administered 30mg/kg and 60mg/kg of quinidine to the samples of example 1 and example 2, respectively, and electrocardiograms of conscious dogs were continuously recorded, and changes in heart rate and arrhythmia within 8 hours after the administration were observed. The results are shown in Table 2.
TABLE 2 pharmacodynamic study of sulcardine sulfate dual release orally disintegrating tablets
The results show that the sulcardine sulfate double-release orally disintegrating tablet has obvious anti-arrhythmia effect within 8 hours.
The invention provides a sulcardine sulfate double-release orally disintegrating tablet and a preparation method thereof, and a method and a way for realizing the technical scheme are many, the above description is only a preferred embodiment of the invention, and it should be noted that for a person skilled in the art, a plurality of improvements and decorations can be made without departing from the principle of the invention, and the improvements and decorations should also be regarded as the protection scope of the invention. All the components not specified in the present embodiment can be realized by the prior art.
Claims (10)
1. The sulcardine sulfate double-release orally disintegrating tablet is characterized in that taste-masking quick-release particles, slow-release particles, a filling agent, a glidant, a disintegrant and a flavoring agent are mixed and then pressed into tablets;
wherein, the taste-masking quick-release particles are particles obtained by coating the first sulcardine sulfate particle core with coating liquid containing taste-masking coating materials; the first sulcardine sulfate granular core is a granular core with the grain size of 100-200 meshes, and is obtained by granulating the first sulcardine sulfate and a first adhesive;
wherein the sustained-release particles are particles obtained by coating the second sulcardine sulfate particle cores with coating liquid containing sustained-release coating materials; the second sulcardine sulfate granular core is a granular core with the grain size of 80-160 meshes, and is obtained by granulating second sulcardine sulfate and a second adhesive.
2. The orally disintegrating tablet according to claim 1, wherein the mass ratio of the first sulcardine sulfate in the taste-masked quick-release particles to the second sulcardine sulfate in the sustained-release particles is 5: 1-1: 4.
3. The orally disintegrating tablet according to claim 1, wherein the total mass of the first sulcardine sulfate and the second sulcardine sulfate is 20-60% of the total mass of the orally disintegrating tablet.
4. The orally disintegrating tablet according to claim 1, wherein the first sulcardine sulfate granules have a first binder accounting for 0.1-8% of the total mass of the first binder and the sulcardine sulfate, and the first sulcardine sulfate accounting for 92-99.9% of the total mass of the first binder and the sulcardine sulfate.
5. The orally disintegrating tablet according to claim 1, wherein the second sulcardine sulfate granules have a second binder accounting for 0.5-12% of the total mass of the second binder and the second sulcardine sulfate, and the second sulcardine sulfate accounting for 88-99.5% of the total mass of the second binder and the second sulcardine sulfate.
6. The orally disintegrating tablet of claim 1, wherein the coating solution comprising the taste masking coating material provides a 10% to 50% improvement in the mass of the coated particles of the first sulcardine sulfate granulate core compared to the mass of the first sulcardine sulfate granulate core.
7. The orally disintegrating tablet according to claim 1, wherein the coating solution containing the sustained release coating material improves the mass of the coated particles of the second sulcardine disulfate cores by 15% to 100% compared to the mass of the second sulcardine disulfate cores.
8. The orally disintegrating tablet of claim 1, wherein the sustained release coating material comprises the following components in percentage by mass:
30 to 70 percent of slow-release high polymer material
0 to 10 percent of plasticizer
20 to 70 percent of anti-sticking agent.
9. The orally disintegrating tablet according to claim 1, wherein the orally disintegrating tablet comprises the following components in percentage by mass:
10. the method for producing an orally disintegrating tablet according to any one of claims 1 to 9, characterized by comprising the steps of:
(1) preparing taste-masking quick-release particles: preparing the first adhesive aqueous solution and the first sulcardine sulfate into sulcardine sulfate particles according to the formula ratio, and screening to obtain a first sulcardine sulfate particle core; coating the first sulcardine sulfate granule core with a coating solution containing a taste-masking coating material, and drying to obtain taste-masking quick-release granules;
(2) preparing sustained-release particles: preparing the second adhesive aqueous solution and the second sulcardine sulfate into sulcardine sulfate particles according to the formula ratio, and screening to obtain a second sulcardine sulfate particle core; coating the second sulcardine sulfate granules with a coating solution containing a slow-release coating material, and drying to obtain the taste-masking quick-release granules;
(3) and (3) according to the formula ratio, uniformly mixing the filler, the glidant, the disintegrant and the flavoring agent with the taste-masking quick-release particles prepared in the step (1) and the slow-release particles prepared in the step (2), and tabletting to obtain the tablet.
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| CN1613442A (en) * | 2003-11-06 | 2005-05-11 | 常州市第四制药厂有限公司 | Disintegrants for deodoring effectively and their preparation |
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