CN114053237A - Controlled release tablet and preparation method thereof - Google Patents

Controlled release tablet and preparation method thereof Download PDF

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CN114053237A
CN114053237A CN202110875326.9A CN202110875326A CN114053237A CN 114053237 A CN114053237 A CN 114053237A CN 202110875326 A CN202110875326 A CN 202110875326A CN 114053237 A CN114053237 A CN 114053237A
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medicine
containing layer
layer
tablet
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董良昶
陈溪山
郝佳宁
焦艳
张丹勇
郑钊铖
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Shanghai Wd Pharmaceutical Co ltd
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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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives

Abstract

The invention provides a controlled release tablet and a preparation method thereof. The controlled release tablet comprises a tablet core and a coating coated on the tablet core, wherein the tablet core comprises a drug-containing layer and a boosting layer compounded on the drug-containing layer, one side of the coating on the drug-containing layer is provided with a drug release hole, and the coating is a semi-permeable coating film; the raw materials of the medicine-containing layer comprise raw material medicines and auxiliary materials; in the medicine-containing layer, the weight of the raw material medicine is 25.0-50.0 wt% of the weight of the medicine-containing layer; in the medicine-containing layer, the raw materials of the auxiliary materials comprise one or more of poloxamer, lauryl sodium sulfate, polyoxyl stearate and vitamin E polyethylene glycol succinate, and the weight of the components is 0.0-10.0 wt% of the weight of the medicine-containing layer. The proportion of the API of the controlled release tablet in the drug-containing layer is more than or equal to 25 wt%, the weight and the size of the controlled release tablet are reduced, the controlled release tablet with small size can be prepared, the compliance of swallowing of a patient is improved, and the risk of intestinal obstruction in vivo is reduced.

Description

Controlled release tablet and preparation method thereof
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a controlled release tablet and a preparation method thereof.
Background
Nifedipine is first developed and marketed in 70 years by Bayer company in Germany, and through years of clinical application and intensive research, nifedipine becomes one of the first-choice drugs for clinically treating hypertension and angina at present. Nifedipine has strong photosensitivity and is easily degraded by light. The nifedipine ordinary preparation has adverse reactions such as reflex induction of heart rate acceleration, activation of sympathetic nervous system, adverse control on myocardial ischemia and heart failure and the like, and needs frequent administration, so that the requirement of a patient on medication is difficult to meet. Therefore, the common preparation of nifedipine is eliminated internationally, and is replaced by a long-acting sustained and controlled release preparation product of nifedipine.
At present, various sustained and controlled release dosage forms of nifedipine have been developed and researched at home and abroad, and commercially available nifedipine sustained and controlled release products are mainly divided into nifedipine sustained release tablets I and nifedipine sustained release tablets II. Compared with the ordinary nifedipine preparation, the nifedipine sustained-release tablets I and II have improved pharmacokinetic performance and half-life (t)1/2) The relative extension, the stability of the blood concentration is relatively improved, the peak valley phenomenon is reduced, and the daily administration frequency is reduced from 3 times to 2 times. However, the medicine has a certain distance away from the current advocated medicine treatment claim for hypertension in the international medical community (namely, long-acting antihypertensive medicines are adopted, namely, the medicine is taken only 1 time in 1 day, and the purposes of achieving stable antihypertensive, reducing blood pressure fluctuation and effectively controlling hypertension) are achieved.
Nifedipine controlled release tablet is a novel controlled release tablet prepared by adopting a special double-layer osmotic pump technology of ALZA company, and the drug is released at zero-order rate by a push-pull osmotic pump principle regulated and controlled by a semipermeable membrane. The nifedipine controlled release tablet on the market is originally developed into Adalat developed by Germany Bayer company
Figure BDA0003190333060000011
And procadia XL from fevery. It is one of the best known products in osmotic pump tablets, overcomes the defects of the ordinary sustained release tablets of nifedipine, releases the drug in the body in a zero-order mode within 24 hours, reduces the peak valley phenomenon of the blood concentration in the body, has the characteristic of once-a-day administration, and also improves the compliance of patients to take the drugAnd (4) sex.
At present, the water-swelling penetration-promoting polymers in the boosting layer of the nifedipine controlled-release tablet mainly comprise polyoxyethylene, carbomer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, croscarmellose sodium, crospovidone and the like. A typical representative thereof is polyoxyethylene. In marketed products, e.g. Adalat
Figure BDA0003190333060000013
(Behcet) to,
Figure BDA0003190333060000012
XL (Reyining) adopts polyoxyethylene as a main functional auxiliary material. At present, the preparation of the medicine-containing layer and boosting layer granules of the osmotic pump tablet generally adopts a wet granulation process, mainly takes polyoxyethylene as an osmotic polymer, and has some inherent defects: (1) the wet granulation is carried out by using organic solvents such as absolute ethyl alcohol, the volatile organic solvents are flammable and explosive, the operation danger is high, the production must be carried out in an explosion-proof workshop, the construction cost of the explosion-proof workshop is high, and the residual quantity of the organic solvents is high; (2) the wet granulation is carried out by using an aqueous solution, the drying temperature of polyoxyethylene in the wet granulation process is usually not higher than 40 ℃, if the drying is complete, a relatively long drying time is needed, and the quality and the release of the preparation are adversely affected. For example:
preparing a drug-containing layer and a boosting layer of the nifedipine controlled-release tablet of the Chinese patent application 201110049292.4, and performing wet granulation by adopting 10 wt% of ethanol solution of povidone K30;
preparing a drug-containing layer and a boosting layer of the nifedipine controlled-release tablet of the Chinese patent application 201110035307.1, and performing wet granulation by adopting 10 wt% of povidone K30 and 70 wt% of ethanol solution;
③ the preparation of the drug-containing layer and the boosting layer of the nifedipine controlled release tablet of the Chinese patent application 200610113984.X, the wet granulation is carried out by adopting ethanol solution with the weight percent not less than 40 percent;
fourthly, preparing the nifedipine controlled release tablet of the Chinese patent application 201210380945.1, wherein the drug-containing layer adopts the wet granulation of the water solution of polysorbate 80 in a fluidized bed, and the boosting layer adopts the wet granulation of purified water in the fluidized bed;
fifthly, preparing nifedipine controlled release tablets of Chinese patent application 201210249011.4, wherein the drug-containing layer is prepared by wet granulation of water suspension, and the boosting layer is prepared by wet granulation of purified water;
sixthly, the nifedipine controlled release tablet of the Chinese patent application No. 201010185030.6 needs an isolation coating layer between the tablet core and the controlled release film, and the drug-containing layer and the boosting layer are both granulated by adopting a 95 wt% ethanol-water solution by a wet method;
the nifedipine controlled release tablet of the Chinese patent application 200910130968.5 is prepared by dispersing nifedipine in the water solution of polyvidone K30, preparing the drug-containing compound by spray drying, mixing with other auxiliary materials, and granulating by dry method. The boosting layer is directly pressed into tablets through powder;
the nifedipine controlled release medicine-containing layer and the boosting layer of the Chinese patent application No. 201510924330.4 are granulated by mixing powder and then directly tabletting.
At present, the nifedipine controlled release tablet mainly takes polyoxyethylene as a penetration-promoting polymer which absorbs water to swell and has the following inherent defects: (1) the polyoxyethylene has a low glass transition temperature (65 ℃ to 67 ℃), has poor thermal stability and is unstable in the preparation process and storage. (2) In the high-speed tabletting process, the punching die generates heat after being repeatedly used, and the unfavorable phenomena of sticking and the like are easily caused in the tabletting process; therefore, special cooling facilities are required to control the temperature of the die or reduce the tabletting speed; (3) the water absorption speed and the hydration speed of the polyoxyethylene are both slow, and the time lag of the drug release is long; (4) under the conditions of high temperature and oxidation, polyoxyethylene is easy to degrade, the molecular weight is reduced, the viscosity of the solution is reduced, the release of the controlled release tablet is influenced to a certain extent, the variation degree of the release rate is increased, and the residual quantity of active ingredients is increased. Therefore, the storage temperature of tablets using polyoxyethylene as a carrier is not too high, and good temperature control is required during storage.
At present, the controlled release film coating process of the nifedipine controlled release tablet mainly adopts an organic solvent coating method. The coating liquid is prepared by taking an organic solvent as a medium and mostly adopting a coating pan for spray coating. The nifedipine controlled release tablet has the advantages that the film is easy to form, however, the coating weight increase of most of the existing nifedipine controlled release tablets is large, and the tablet core is difficult to be less than 10 wt%, so that a large amount of organic solvents such as acetone, ethanol, chloroform and the like are needed, volatile organic solvents are flammable and explosive, the operation risk is high, the nifedipine controlled release tablet needs to be produced in an explosion-proof workshop, and the construction cost of the explosion-proof workshop is high. A large amount of organic solvent volatilizes to the air and causes pollution, causes harm to the environment and the body of an operator, and a recovery device is required to be installed, so that the cost of the recovery device is higher. For example:
the controlled release coating of nifedipine controlled release of Chinese patent application 200610113984.X is increased by more than 20 wt%;
② the controlled release coating of nifedipine controlled release of Chinese patent application 200910130968.5 is increased by 21 wt%;
③ 13 percent of nifedipine controlled-release coating of the Chinese patent application 201210249011.4;
fourthly, the controlled release coating of nifedipine controlled release of the Chinese patent application 201110049292.4 is increased by 16 weight percent;
fifthly, the controlled release coating of the nifedipine controlled release of the Chinese patent application 201510924330.4 is increased by 10 to 20 weight percent.
At present, a drying process is needed after a controlled release film of the nifedipine controlled release tablet is coated, the controlled release film is aged, solvent residue is reduced, and meanwhile, the release rate of the product in the storage process is not greatly changed. For example, the product coated with the semipermeable membrane of the controlled release nifedipine tablet of Chinese patent application No. 201810234450.5 needs to be aged at 45 ℃ for 24 hours.
At present, the proportion of the raw material drug (API) in the nifedipine controlled release tablet in the drug-containing layer is not high, because the hydration of the drug-containing layer is difficult along with the increase of the proportion of the API, the drug release resistance is increased, the requirement on the mechanical strength of the controlled release film is high, and the controlled release film is easy to break in the release process.
In addition, the nifedipine controlled release tablet has the characteristics of not disintegrating in vivo and finally being discharged out of the body along with feces in the form of an original tablet, and for large-size nifedipine controlled release tablets (30mg, 60m and 90mg specifications), the size is larger, the swallowing compliance of a patient is poorer, and the patient with intestinal stenosis has the risk of intestinal obstruction.
As described above, the current nifedipine controlled release tablet requires a wet granulation process, is difficult to achieve a high API ratio (more than 25 wt%), is difficult to achieve a low controlled release coating weight gain (less than 10 wt%) under the condition of a high API ratio, and the high controlled release coating weight gain causes the process to require a large amount of organic solvent, is environmentally friendly and has a high economic cost.
Therefore, how to effectively increase the proportion of API in the controlled release tablet to reduce the size of the controlled release tablet is one of the technical problems to be solved in the art; on the basis of increasing the proportion of API in the controlled release tablet, how to further realize low weight gain of the controlled release coating and provide a formula and a process for reducing the use amount of an organic solvent and the economic cost is the second technical problem to be solved urgently in the field.
Disclosure of Invention
The invention aims to overcome the defects that the existing controlled release tablet (such as nifedipine controlled release tablet) has API accounting for less than 25 wt% in a drug-containing layer, has large size and has intestinal obstruction risk to patients with intestinal stenosis, and provides a controlled release tablet and a preparation method thereof. The proportion of API (raw material medicine) in the controlled release tablet in the medicine-containing layer is more than or equal to 25 wt%, the weight and the size of the controlled release tablet are reduced, the small-size nifedipine controlled release tablet can be prepared, the compliance of swallowing of a patient is increased, the risk of intestinal obstruction in vivo is reduced, and particularly the risk of intestinal obstruction of a patient with intestinal stenosis is reduced.
In the development process, the inventor finds that, with the increase of the proportion of the API, the hydration of the drug-containing layer becomes difficult, the drug release resistance is increased, the requirement on the mechanical strength of the controlled release membrane is high, the controlled release membrane is easy to break in the release process, the mechanical strength of the membrane needs to be increased or the weight of the membrane needs to be increased, and the two change the release behavior of the controlled release tablet, namely, the release is further slowed. However, on the basis of increasing the proportion of API in the drug-containing layer in the controlled-release tablet, the controlled-release tablet can realize that the API is not easy to break in the release process, can further realize low controlled-release coating weight gain, preferably can obtain the controlled-release tablet with the controlled-release coating weight gain accounting for less than 12 wt% of the tablet core, reduces the cost, reduces the use amount of organic solvent, and is more economic and environment-friendly.
The invention provides a controlled release tablet, which comprises a tablet core and a coating coated on the tablet core, wherein the tablet core comprises a medicine-containing layer and a boosting layer compounded on the medicine-containing layer, one side of the coating on the medicine-containing layer is provided with a medicine release hole, and the coating is a semi-permeable coating film; the raw materials of the medicine-containing layer comprise raw material medicines and auxiliary materials;
in the drug-containing layer, the raw material drugs are nifedipine, tofacitinib or pharmaceutically acceptable salts thereof;
in the medicine-containing layer, the weight of the raw material medicine is 25.0-50.0 wt% of the weight of the medicine-containing layer;
in the medicine-containing layer, the raw materials of the auxiliary materials comprise an auxiliary material A, wherein the auxiliary material A is one or more of poloxamer, sodium dodecyl sulfate, polyoxyl (40) stearate and vitamin E polyethylene glycol succinate, such as poloxamer; the weight of the auxiliary material A is 0.0-10.0 wt% of the weight of the medicine-containing layer.
In the invention, in the medicine-containing layer, the pharmaceutically acceptable salt of tofacitinib can be tofacitinib citrate.
In the present invention, in the drug-containing layer, the weight of the raw material drug is preferably 30.0 to 50.0 wt%, for example 30.0 wt%, 35.0 wt%, 40.0 wt% or 45.0 wt% of the weight of the drug-containing layer.
In the present invention, in the drug-containing layer, the weight of the auxiliary material a is preferably 3.0 to 10.0 wt%, more preferably 3.0 to 9.0 wt%, for example, 3.0 wt%, 5.0 wt%, 7.0 wt%, or 9.0 wt% of the weight of the drug-containing layer.
When the auxiliary material A is poloxamer, the weight of the poloxamer is preferably 3.0-9.0 wt%, such as 3.0 wt%, 4.0 wt%, 5.0 wt%, 7.0 wt% or 9.0 wt% of the weight of the medicine-containing layer.
In the invention, preferably, in the medicine-containing layer, the weight of the raw material medicine is 25.0-30.0 wt% of the weight of the medicine-containing layer, and the weight of the auxiliary material A is 0.0-5.0 wt% of the weight of the medicine-containing layer.
In the invention, preferably, in the medicine-containing layer, the weight of the raw material medicine is 30.0-50.0 wt% of the weight of the medicine-containing layer, and the weight of the auxiliary material A is 3.0-10.0 wt% of the weight of the medicine-containing layer. The weight of the auxiliary material A is more preferably 3.0-9.0 wt%, such as 3.0 wt%, 5.0 wt%, 7.0 wt% or 9.0 wt% of the weight of the medicine-containing layer.
In the present invention, in the drug-containing layer, the weight of the auxiliary material is preferably 50.0 to 75.0 wt%, such as 60.0 wt%, 65.0 wt% or 70.0 wt% of the weight of the drug-containing layer.
In the invention, in the medicine-containing layer, the raw materials of the auxiliary materials can also comprise one or more of a filling agent, a medicine carrier, an anti-sticking agent, a lubricating agent and a coloring agent.
Wherein the filler is selected from one or more of lactose, starch, pregelatinized starch, dextrin, mannitol, sorbitol and microcrystalline cellulose, such as mannitol.
Wherein the filler is present in an amount of 0 to 52.0 wt%, such as 2.0 to 34.0 wt%, and further such as 2.0 wt%, 4.0 wt%, 6.0 wt%, 9 wt%, 14.0 wt%, 16 wt%, 19 wt%, 29.0 wt%, or 34.0 wt%, based on the weight of the drug-containing layer.
The drug carrier is generally a natural or synthetic polymer material, and may be selected from one or more of povidone, copovidone, carbomer, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, and sodium alginate, such as hydroxypropyl cellulose.
Wherein the content of the drug carrier can be 20.0-72.0 wt%, such as 30.0-50.0 wt%, and further such as 30.0 wt%, 40.0 wt% or 50.0 wt% of the weight of the drug-containing layer.
When the drug carrier is hydroxypropylcellulose, the content of hydroxypropylcellulose may be 20.0 to 72.0 wt%, such as 30.0 to 50.0 wt%, and further such as 30.0 wt%, 40.0 wt% or 50.0 wt% of the weight of the drug-containing layer.
Wherein, the antisticking agent can be colloidal silicon dioxide and/or talcum powder.
Wherein the content of the anti-sticking agent can be 0-7.0 wt% of the weight of the auxiliary materials in the medicine-containing layer.
Wherein, the lubricant can be one or more of stearic acid, magnesium stearate, calcium stearate, polyethylene glycol and sodium stearyl fumarate, such as magnesium stearate.
Wherein the lubricant is present in an amount of 0 to 2.0 wt%, for example 1.0 wt%, based on the weight of the drug-containing layer.
Wherein the colorant can be one or more of red iron oxide, yellow iron oxide, purple iron oxide and black iron oxide, such as red iron oxide.
Wherein the content of the colorant can be 0-2.0 wt% of the weight of the medicine-containing layer.
When the auxiliary materials of the medicine-containing layer contain hydroxypropyl cellulose, preferably, the medicine-containing layer contains: the weight of the raw material medicine is 30.0-50.0 wt% of the weight of the medicine-containing layer, the weight of the auxiliary material A (such as poloxamer) is 3.0-9.0 wt% of the weight of the medicine-containing layer, and the content of the hydroxypropyl cellulose is 30.0-50.0 wt% of the weight of the medicine-containing layer.
When the auxiliary materials of the medicine-containing layer contain hydroxypropyl cellulose and mannitol, preferably, the medicine-containing layer contains: the weight of the raw material medicine is 30.0-50.0 wt% of the weight of the medicine-containing layer, the weight of the auxiliary material A (such as poloxamer) is 3.0-9.0 wt% of the weight of the medicine-containing layer, the content of hydroxypropyl cellulose is 30.0-50.0 wt% of the weight of the medicine-containing layer, and the content of mannitol is 2.0-34.0 wt% of the weight of the medicine-containing layer.
When the auxiliary materials of the medicine-containing layer contain hydroxypropyl cellulose, mannitol and magnesium stearate, preferably, the medicine-containing layer contains: the weight of the raw material medicine is 30.0-50.0 wt% of the weight of the medicine-containing layer, the weight of the auxiliary material A (such as poloxamer) is 3.0-9.0 wt% of the weight of the medicine-containing layer, the content of the hydroxypropyl cellulose is 30.0-50.0 wt% of the weight of the medicine-containing layer, the content of the mannitol is 2.0-34.0 wt% of the weight of the medicine-containing layer, and the content of the magnesium stearate is 1-2.0 wt% of the weight of the medicine-containing layer.
In the present invention, preferably, the composition of the drug-containing layer is: 25.0-30.0 wt% of raw material medicine, 0.0-5.0 wt% of auxiliary material A, 20.0-72.0 wt% of medicine carrier, 0-52.0 wt% of filling agent, 0-7.0 wt% of anti-sticking agent, 0-2.0 wt% of colorant and 0-2.0 wt% of lubricant, wherein the percentage refers to the weight of each component accounting for the weight of the medicine-containing layer.
In the present invention, preferably, the composition of the drug-containing layer is: 30.0-50.0 wt% of raw material medicine, 3.0-10.0 wt% of auxiliary material A, 30.0-50.0 wt% of medicine carrier, 4-34.0 wt% of filling agent, 0-7.0 wt% of anti-sticking agent, 0-2.0 wt% of colorant and 0-2.0 wt% of lubricant, wherein the percentage refers to the weight of each component accounting for the weight of the medicine-containing layer.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 40.0 wt% of hydroxypropyl cellulose (HPC), 3.00 wt% of poloxamer (407), 16.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 40.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 14.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 30.0 wt% of nifedipine, 30.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 34.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 35.0 wt% of nifedipine, 30.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 29.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 35.0 wt% of nifedipine, 40.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 19.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 35.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 9.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 3.00 wt% of poloxamer (407), 6.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 4.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of tofacitinib citrate, 40.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 14.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 7.00 wt% of poloxamer (407), 2.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 9.00 wt% of poloxamer (407), 0.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 30.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 19.0 wt% of mannitol and 1.00 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 45.0 wt% of nifedipine, 45.0 wt% of hydroxypropyl cellulose (HPC), 9.0 wt% of poloxamer (407) and 1.00 wt% of magnesium stearate.
In the present invention, the ratio of the weight of the drug-containing layer to the weight of the boosting layer may be 1:0.3 to 1:2, for example, 1:0.38, 1:0.44, 1:0.46, 1:0.5, 1:0.58, or 1: 0.93.
In the present invention, the raw material in the boosting layer may be a conventional raw material in the controlled release tablet, and generally includes one or more of an expanding agent, an osmotic pressure promoter, a lubricant and a coloring agent, such as an expanding agent, an osmotic pressure promoter, a lubricant and a coloring agent.
The swelling agent is generally a material which can cause volume expansion through a physicochemical reaction, and can be selected from one or more of sodium carboxymethyl starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, carbomer, xanthan gum, sodium alginate and kappa carrageenan, such as one or more of hydroxypropyl cellulose, sodium carboxymethyl cellulose, xanthan gum, sodium alginate and kappa carrageenan, and further such as "hydroxypropyl cellulose and sodium carboxymethyl cellulose", "hydroxypropyl cellulose and xanthan gum", "hydroxypropyl cellulose and sodium alginate" or "hydroxypropyl cellulose and kappa carrageenan".
Wherein the amount of said swelling agent may be 20.0 to 95.0 wt%, such as 20.0 wt%, 49.0 wt%, 59.0 wt%, 65 wt%, 69.0 wt% or 79.0 wt%, for example 30 to 95 wt%, based on the weight of said boosting layer.
When the swelling agent comprises hydroxypropylcellulose, the content of hydroxypropylcellulose may be 10.0 to 30.0 wt%, for example 20.0 wt%, of the weight of the boosting layer.
When the bulking agent comprises sodium carboxymethylcellulose, the amount of sodium carboxymethylcellulose can be 49.0 to 79.0 wt%, such as 49.0 wt%, 55 wt%, 59.0 wt%, 69.0 wt%, or 79.0 wt%, based on the weight of the boosting layer.
When the swelling agent comprises xanthan gum, the xanthan gum can be present in an amount of 49.0 wt% based on the weight of the boosting layer.
When the swelling agent comprises sodium alginate, the sodium alginate may be present in an amount of 49.0 wt% of the weight of the boosting layer.
When the swelling agent comprises carrageenan, the content of the carrageenan can be 49.0 wt% of the weight of the boosting layer.
When the swelling agent is hydroxypropyl cellulose and sodium carboxymethylcellulose, the content of the hydroxypropyl cellulose can be 20.0 wt% of the boosting layer; the amount of sodium carboxymethylcellulose may be 49-79 wt%, for example 49.0 wt%, 55 wt%, 59.0 wt%, 69.0 wt% or 79.0 wt% of the weight of the boosting layer.
When the swelling agent is hydroxypropyl cellulose and xanthan gum, the content of the hydroxypropyl cellulose can be 20.0 wt% of the boosting layer; the xanthan gum may be present in an amount of 49.0 wt% based on the weight of the boosting layer.
When the swelling agent is hydroxypropyl cellulose and sodium alginate, the content of the hydroxypropyl cellulose can be 20.0 wt% of the boosting layer; the sodium alginate can be contained in an amount of 49.0 wt% of the weight of the boosting layer.
When the expanding agent is hydroxypropyl cellulose and carrageenan, the content of the hydroxypropyl cellulose can be 20.0 wt% of the boosting layer; the content of the carrageenan can be 49.0 wt% of the weight of the boosting layer.
Wherein the osmotic pressure promoting agent is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, magnesium sulfate, ascorbic acid, tartaric acid, mannitol, sorbitol, xylitol, glucose and sucrose, such as one or more of sodium chloride, mannitol, sorbitol and sucrose, and further such as mannitol and/or sorbitol.
Wherein the content of the osmotic pressure promoter may be 5.0 to 70.0 wt%, such as 10.0 to 30.0 wt%, and further such as 10.0 wt%, 20.0 wt%, 30.0 wt% or 34 wt% of the weight of the boosting layer.
Wherein, the lubricant in the boosting layer can be one or more of stearic acid, magnesium stearate, calcium stearate, polyethylene glycol and sodium stearyl fumarate, such as magnesium stearate.
Wherein the lubricant in the boosting layer can be 0-3 wt%, for example 0.5 wt%, of the weight of the boosting layer.
Wherein, the colorant in the boosting layer can be one or more of iron oxide red, iron oxide yellow, iron oxide purple and iron oxide black, such as iron oxide red.
Wherein the content of the colorant in the boosting layer can be 0-2 wt%, for example 0.5 wt%, of the weight of the boosting layer.
When sodium carboxymethylcellulose and sorbitol are included in the boosting layer, preferably, in the boosting layer: the weight of the sodium carboxymethyl cellulose is 49-89 wt%, preferably 49-79 wt% (e.g. 49.0 wt%, 59.0 wt%, 69.0 wt%, 79.0 wt% or 89 wt%) of the weight of the boosting layer, and the weight of the sorbitol is 10.0-34.0 wt%, preferably 10.0-30.0 wt% (e.g. 10 wt%, 20 wt%, 30 wt% or 34 wt%) of the weight of the boosting layer.
When sodium carboxymethylcellulose and mannitol are included in the boosting layer, preferably, in the boosting layer: the weight of the sodium carboxymethyl cellulose is 49-79 wt% (such as 49.0 wt%) of the weight of the boosting layer, and the weight of the mannitol is 10.0-30.0 wt% (such as 30 wt%) of the weight of the boosting layer.
When the boosting layer contains xanthan gum, sodium alginate or carrageenan and sorbitol, preferably, the boosting layer contains: the weight of the xanthan gum, the sodium alginate or the carrageenan is 49-79 wt% (for example, 49.0 wt%) of the boosting layer, and the weight of the sorbitol is 10.0-30.0 wt% (for example, 30 wt%) of the boosting layer.
In the present invention, preferably, the composition of the boosting layer is: 30.0-95.0 wt% of expanding agent, 5.0-70.0 wt% of osmotic pressure promoter, 0-3.0 wt% of lubricant and 0-2 wt% of colorant, wherein the percentages refer to the weight of the components accounting for the weight of the drug-containing layer.
In a preferred embodiment of the present invention, the boosting layer has a composition of: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the boosting layer has a composition of: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of mannitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the boosting layer has a composition of: 49.0 wt% of xanthan gum, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the boosting layer has a composition of: 49.0 wt% of sodium alginate, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the boosting layer has a composition of: 49.0 wt% of carrageenan, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the boosting layer has a composition of: 59.0 wt% of sodium carboxymethylcellulose, 20.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the boosting layer has a composition of: 69.0 wt% of sodium carboxymethylcellulose, 10.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the boosting layer has a composition of: 79.0 wt% of sodium carboxymethylcellulose, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the boosting layer has a composition of: 55.0 wt% of sodium carboxymethylcellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate. In the present invention, preferably, in the controlled release tablet, the composition of the drug-containing layer is: 25.0-30.0 wt% of raw material medicine, 30.0-50.0 wt% of medicine carrier, 0-5.00 wt% of auxiliary material A, 19.0-34.0 wt% of filling agent and 0.00-2.00 wt% of lubricant; the boosting layer comprises the following components: 65.0-69.0 wt% of expanding agent, 30.0-34.0 wt% of osmotic pressure promoter, 0.00-2.00 wt% of colorant and 0.00-3.00 wt% of lubricant.
More preferably, in the controlled release tablet, the composition of the drug-containing layer is: 25.0-30.0 wt% of nifedipine, 30.0-50.0 wt% of hydroxypropyl cellulose (HPC), 0-5.00 wt% of poloxamer (407), 19.0-34.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0-55.0 wt% of sodium carboxymethylcellulose, 30.0-34.0 wt% of sorbitol, 10.0-20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In the present invention, preferably, in the controlled release tablet, the composition of the drug-containing layer is: 30.0-50.0 wt% of raw material medicine, 30.0-50.0 wt% of medicine carrier, 3-5.00 wt% of auxiliary material A, 4.0-34.0 wt% of filling agent and 0.00-2.00 wt% of lubricant; the boosting layer comprises the following components: 69.0-79.0 wt% of expanding agent, 20.0-30.0 wt% of osmotic pressure promoter, 0.00-2.00 wt% of colorant and 0.00-3.00 wt% of lubricant.
More preferably, in the controlled release tablet, the composition of the drug-containing layer is: 30.0-50.0 wt% of nifedipine, 30.0-50.0 wt% of hydroxypropyl cellulose (HPC), 3-5.00 wt% of auxiliary material A, 4.0-34.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0-59.0 wt% of sodium carboxymethylcellulose, 20.0-30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 40.0 wt% of hydroxypropyl cellulose (HPC), 3.00 wt% of poloxamer (407), 16.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 40.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 14.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 30.0 wt% of nifedipine, 30.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 34.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 35.0 wt% of nifedipine, 30.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 29.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 35.0 wt% of nifedipine, 40.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 19.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 35.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 9.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 3.00 wt% of poloxamer (407), 6.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 4.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 4.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of mannitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 4.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of xanthan gum, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 4.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of carrageenan, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 4.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 59.0 wt% of sodium carboxymethylcellulose, 20.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 4.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 69.0 wt% of sodium carboxymethylcellulose, 10.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 4.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 79.0 wt% of sodium carboxymethylcellulose, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of tofacitinib citrate, 40.0 wt% of hydroxypropyl cellulose (HPC), 5.00 wt% of poloxamer (407), 14.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 7.00 wt% of poloxamer (407), 2.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 59.0 wt% of sodium carboxymethylcellulose, 20.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 40.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 9.00 wt% of poloxamer (407), 0.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 59.0 wt% of sodium carboxymethylcellulose, 20.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 30.0 wt% of nifedipine, 50.0 wt% of hydroxypropyl cellulose (HPC), 19.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 55.0 wt% of sodium carboxymethylcellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In a preferred embodiment of the present invention, the composition of the drug-containing layer is: 45.0 wt% of nifedipine, 45.0 wt% of hydroxypropyl cellulose (HPC), 9.0 wt% of poloxamer (407) and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 59.0 wt% of sodium carboxymethylcellulose, 20.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
In the invention, the semipermeable membrane can be prepared by adopting a conventional method in the field, for example, coating the coating solution of the film-forming material containing the semipermeable membrane.
The film-forming material of the semipermeable membrane can be one or more of film-forming materials conventional in the art, such as cellulose acetate, cellulose acetate butyrate, ethyl cellulose and acrylic resin, and is preferably cellulose acetate, cellulose acetate butyrate or "cellulose acetate and ethyl cellulose".
Wherein, the film forming material of the semi-permeable film is one or more of cellulose acetate, ethyl cellulose and acrylic resin.
When the film forming material of the semipermeable membrane is cellulose acetate and ethyl cellulose, the weight ratio of the cellulose acetate to the ethyl cellulose is preferably (1-10): 1, such as 4:1 or 9: 1.
Wherein, the coating solution of the film-forming material containing the semipermeable membrane generally contains a solvent, and the solvent can be acetone and/or ethanol, such as acetone or a mixed solution of acetone and ethanol.
When the solvent comprises acetone and ethanol, the ratio of acetone to ethanol may be (2-20): 1, preferably (4-20): 1, for example 2.33:1, 4:1, 5.67:1, 6.14:1 or 19: 1.
When the solvent comprises acetone and ethanol, the ratio of acetone to ethanol can be (4-20): 1.
In the coating solution containing the film-forming material of the semipermeable membrane, the solid content of the film-forming material of the semipermeable membrane can be 2.0-8.0%, for example, 4.0% or 6.0%.
Wherein, the film forming material of the semi-permeable membrane can also comprise a pore-foaming agent and/or a plasticizer.
The pore-forming agent can be one or more selected from polyethylene glycol, glycerol, povidone, copovidone and hydroxypropyl methylcellulose.
The plasticizer may be selected from one or more of polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, triacetin and castor oil.
In the present invention, the semipermeable coating film may be one or more of a cellulose acetate film, a cellulose acetate butyrate film, an ethyl cellulose film and an acrylic resin film, such as a cellulose acetate film, a cellulose acetate butyrate film or a mixed film of "cellulose acetate and ethyl cellulose".
In the present invention, the semipermeable membrane may be one or more of a cellulose acetate membrane, an ethyl cellulose membrane, and an acrylic resin membrane.
In the present invention, the weight ratio of the semipermeable membrane to the core tablet may be a ratio conventionally used in the art, and is preferably 1.0 to 18.5 wt% or 5.0 to 18.5 wt%, such as 3.7 wt%, 5.0 wt%, 6.0 wt%, 6.1 wt%, 6.3 wt%, 6.4 wt%, 6.6 wt%, 7.0 wt%, 7.1 wt%, 7.5 wt%, 8.0 wt%, 8.1 wt%, 8.3 wt%, 8.4 wt%, 9.2 wt%, 9.4 wt%, 9.8 wt%, 10.0 wt%, 12.2 wt%, 12.6 wt%, 12.7 wt%, 15.0 wt%, 15.2 wt%, 15.3 wt%, 17.9 wt%, 18.0 wt%, 18.1 wt% or 18.2 wt%, preferably 1.0 to 12.2 wt% or 5 to 12.2 wt%, and further preferably 2.0 to 10.0 wt% or 5 to 10.5 wt%.
In the invention, the weight ratio of the semipermeable membrane to the tablet core is the weight gain of the coating.
In the invention, the drug releasing holes on the coating can be obtained by punching by a laser punching method or a mechanical punching method.
In the present invention, the size of the drug release hole may be 0.3mm to 1.2mm, for example, 0.5mm or 1.0 mm.
In the invention, the tablet core and the coating can also comprise an isolation coating layer.
Wherein, the content of the isolation coating layer can be 1-12 wt% of the weight of the whole controlled release tablet.
In the present invention, the coating outer layer may further comprise a moisture-proof film coating layer.
In the present invention, the shape of the controlled-release tablet may be circular or irregular. The profile can be olive-shaped, oval-shaped, capsule-shaped or polygonal. The polygon may be a quadrangle or a triangle.
In the present invention, the controlled-release tablet may have a size of 11 mg/tablet, 22 mg/tablet, 30 mg/tablet, 60 mg/tablet or 90 mg/tablet.
When the specification of the controlled release tablet is 30 mg/tablet and the controlled release tablet is in a special shape, at least one side length of the controlled release tablet can be less than or equal to 8mm, preferably 4-8 mm, and more preferably 6-7 mm.
When the controlled release tablet has the specification of 60 mg/tablet and is specially shaped, at least one side of the controlled release tablet has a size of less than or equal to 10mm, preferably 6-9 mm, more preferably 7-8 mm, for example 8 mm.
When the controlled release tablet is 90 mg/tablet and is shaped in a special shape, at least one side of the controlled release tablet can be smaller than or equal to 12mm, preferably 7-11 mm, more preferably 9-10 mm, for example 10 mm.
Wherein, when the profile has sides, the sides in the controlled release tablet generally refer to the sides of the profile, such as the sides of a quadrangle or a triangle. When the profile does not have an edge, the edge length in the controlled-release tablet generally refers to the length of a connecting line between two points which are farthest away in the profile, such as the long axis in an ellipse.
When the controlled release tablet has a size of 11 mg/tablet and a circular shape, the diameter thereof may be 8mm or less, preferably 4 to 8mm, more preferably 5 to 7mm, for example 5 mm.
When the controlled release tablet has a size of 22 mg/tablet and a circular shape, the diameter thereof may be 8mm or less, preferably 4 to 8mm, more preferably 6 to 7mm, for example 6 mm.
When the controlled release tablet has a size of 30 mg/tablet and a circular shape, the diameter thereof may be 8mm or less, preferably 4 to 8mm, more preferably 6 to 7mm, for example 6 mm.
When the controlled release tablet has a specification of 60 mg/tablet and a circular shape, the diameter of the controlled release tablet can be less than or equal to 10mm, preferably 6-9 mm, and more preferably 7-8 mm.
When the controlled release tablet can be 90 mg/tablet and is circular in shape, the diameter of the controlled release tablet can be less than or equal to 12mm, preferably 7-11 mm, and more preferably 9-10 mm.
The invention also provides a preparation method of the controlled release tablet, which comprises the following steps:
(1) compounding and pressing the raw material particles of the medicine-containing layer and the raw material particles of the boosting layer, wherein the boosting layer is compounded on the medicine-containing layer to form the tablet core;
(2) coating the coating on the tablet core, and punching a hole on the coating on one side of the drug-containing layer to form a drug release hole;
when the controlled release tablet further comprises an isolation coating layer, coating the isolation coating layer on the tablet core, and coating the coating on the isolation coating layer;
when the controlled-release tablet further comprises a moisture-proof film coating layer, the moisture-proof film coating layer is coated on the coating layer.
In step (1), the raw material granules of the drug-containing layer can be prepared by a conventional method in the art, for example, the raw material medicines and the auxiliary materials in the drug-containing layer are mixed and granulated to obtain granules.
Wherein, the granulating mode can be dry granulating, wet granulating, hot melting granulating or fluidized bed granulating.
Preferably, the wet granulation is carried out using a fluidized bed or after a certain period of time under certain humidity conditions.
Preferably, when the auxiliary materials of the drug-containing layer include a lubricant, the raw material drugs in the drug-containing layer and the auxiliary materials except the lubricant are uniformly mixed, a belt-shaped material is obtained through dry granulation, and the belt-shaped material is mixed with the lubricant after being granulated. The whole granules can be sieved by a stainless steel sieve with 16 meshes.
In step (1), the raw material particles of the boosting layer can be prepared according to conventional methods in the art, for example, by mixing the raw materials in the boosting layer and granulating to obtain particles.
Wherein, the granulating mode can be dry granulating, wet granulating, hot melting granulating or fluidized bed granulating.
When the raw materials of the boosting layer comprise the lubricant, preferably, the raw materials except the lubricant in the boosting layer are uniformly mixed, a belt-shaped object is obtained through dry granulation, and the belt-shaped object is crushed by a crusher and then mixed with the lubricant.
In the step (1), the composite compression may be compressed using a double-layer tablet press.
In step (1), the composite compression may be performed by a conventional compression method in the art, for example, in a bi-layer tablet press, the raw material granules of the drug-containing layer are filled first, pre-compressed, the raw material granules of the boosting layer are filled again, and compacted.
In step (2), the coating may be obtained by a method conventional in the art, for example, by dissolving the film-forming material of the coating in a coating pan to form a coating solution and spray-coating.
Wherein the dissolved solvent may be selected from one or more of acetone, water, ethanol, isopropanol, dichloromethane, methanol and ethyl acetate, such as acetone and/or ethanol.
After the spray coating, the coating is generally dried sufficiently to remove solvent residues.
In the step (2), the drug release holes can be obtained by punching by a laser punching method or a mechanical punching method.
In the step (2), the number of the drug release holes can be one or more.
In the present invention, wt% means weight percentage.
In the present invention, the hydroxypropylcellulose can be hydroxypropylcellulose conventional in the art, such as hydroxypropylcellulose with weight average molecular weight of 80K, and further such as hydroxypropylcellulose available from tianjin Jian trades ltd.
In the present invention, the poloxamer may be a poloxamer as is conventional in the art, such as a poloxamer having a weight average molecular weight of 12K, and further such as poloxamers available from Shanghai shipping Macro chemical formulation excipients technology, Inc.
In the present invention, the sodium carboxymethyl cellulose may be sodium carboxymethyl cellulose conventional in the art, such as sodium carboxymethyl cellulose with a weight average molecular weight of 725K, and further such as sodium carboxymethyl cellulose available from tianjin three-health trade company, ltd.
In the present invention, the cellulose acetate may be cellulose acetate conventional in the art, for example, cellulose acetate available from Shanghai Jissi International trade company, Inc.
In the present invention, the ethylcellulose can be ethylcellulose conventional in the art, such as ethylcellulose having a weight average molecular weight of 75K, and further such as ethylcellulose available from tianjin three-health commercial ltd.
In the present invention, the xanthan gum may be a xanthan gum conventional in the art, such as xanthan gum available from alzelesse international trade (shanghai) ltd.
In the present invention, the sodium alginate may be sodium alginate which is conventional in the art, for example, sodium alginate available from Qingdao Mingyue seaweed group, Inc.
In the present invention, the carrageenan may be a carrageenan conventional in the art, such as carrageenan available from Dow chemical (Dow) or qinhuang island pharmaceutical capsules, inc.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
(1) compared with the existing nifedipine controlled release tablet, the controlled release tablet of the invention which has small size and high proportion of raw material medicines (the proportion of API in the medicine-containing layer is more than or equal to 25wt percent) improves the compliance of swallowing of patients, reduces the risk of intestinal obstruction of patients with intestinal stenosis, and has the same overall release rate and cumulative release amount as the existing nifedipine controlled release tablet.
(2) On the basis of the controlled-release tablet of the bulk drug with small size and high proportion, the invention further realizes the low controlled-release coating weight gain (can realize the coating weight gain of less than 20 percent, preferably less than 18.5 percent by weight, and further preferably can obtain the coating weight gain of less than 12 percent by weight), reduces the cost and reduces the use amount of organic solvent.
Drawings
Fig. 1 is a release profile of the nifedipine controlled release tablet of example 1.
Fig. 2 is a release profile of the nifedipine controlled release tablet of example 2.
Fig. 3 is a graph showing the rupture of the controlled release membrane during the release of the nifedipine controlled release tablet in comparative example 1.
Fig. 4 is a release profile of the nifedipine controlled-release tablet in comparative example 2.
Fig. 5 is a release curve of the nifedipine controlled release tablet in example 3 and comparative example 3.
FIG. 6 is a release profile of nifedipine controlled release tablets in examples 4-1, 4-2, 4-3.
Fig. 7 is a release profile of the nifedipine controlled release tablet of example 5.
Fig. 8 is a release profile of the nifedipine controlled release tablet of example 6.
Fig. 9 is a release profile of nifedipine controlled release tablets in example 7.
Fig. 10 is a release profile of the nifedipine controlled release tablet of example 8.
Fig. 11 is a release profile of nifedipine controlled release tablets in example 9.
Fig. 12 is a release profile of nifedipine controlled release tablets of example 11.
Fig. 13 is a release profile of nifedipine controlled release tablets in example 12.
Fig. 14 is a release curve of the nifedipine controlled release tablet in example 13 and a commercially available nifedipine controlled release tablet.
Fig. 15 is a release curve of the nifedipine controlled release tablet in example 14 and a commercially available nifedipine controlled release tablet.
Fig. 16 is a release curve of the nifedipine controlled release tablet in example 15 and a commercially available nifedipine controlled release tablet.
Fig. 17 is a release profile of the nifedipine controlled release tablets in example 16 and comparative example 4 versus a commercially available nifedipine controlled release tablet.
FIG. 18A is a comparison of the properties of the controlled release tablets in the soaking test in comparative examples 5 to 8.
Fig. 18B is a release profile of the nifedipine controlled release tablets in example 14 and comparative example 8 versus a commercially available nifedipine controlled release tablet.
Fig. 19 is a release profile of the nifedipine controlled release tablets of example 17 versus a commercially available nifedipine controlled release tablet.
Fig. 20 is a release profile of the nifedipine controlled release tablets of example 18 versus a commercially available nifedipine controlled release tablet.
Fig. 21 is a release profile of the nifedipine controlled release tablets of example 19 versus a commercially available nifedipine controlled release tablet.
Fig. 22 is a release curve of the nifedipine controlled release tablet of example 20 and a commercially available nifedipine controlled release tablet.
Fig. 23 is a release curve of the nifedipine controlled release tablet in example 21 and a commercially available nifedipine controlled release tablet.
FIG. 24 is a view showing the controlled release film rupture phenomenon during the release process of the nifedipine controlled release tablets of comparative examples 2 to 3 and examples 3 to 4.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples and comparative examples:
hydroxypropylcellulose (HPC EXF): the weight average molecular weight is 80K, and the product is sourced from Tianjin three-health commercial and trade company Limited;
polyoxyethylene (N80): weight average molecular weight 20K, available from Shanghai Kalekang coating technology, Inc.;
polyoxyethylene (coaglunt): the weight-average molecular weight is 500K, and the source is Shanghai Kalekang coating technology, Inc.;
poloxamer (407): the weight average molecular weight is 12K, and the source is Shanghai shipping macro chemical preparation auxiliary material technology company;
polyoxyl (40) stearate: sourced from south beijing wil pharmaceuticals, inc;
vitamin E polyethylene glycol succinate: from Zhejiang pharmaceutical products, Inc.;
sodium lauryl sulfate: source Sichuan Yuela technologies, Inc.;
sodium carboxymethylcellulose: the weight average molecular weight is 725K, sourced from Tianjin three-health commercial and trade company, Inc.;
cellulose acetate: source Istmann Inc;
ethyl cellulose: the weight average molecular weight is 75K, and the product is sourced from Tianjin three-health commercial and trade company Limited;
xanthan gum: source alzelesi international trade (shanghai) ltd;
sodium alginate: sourced Qingdao Mingyue algae group, Inc.;
kappa carrageenan: sourced Dow chemical (Dow) or qinhuang island capsules limited.
Cellulose acetate butyrate: source Istmann Inc;
copovidone VA 64: sourced from Shanghai shipping Macro chemical preparation auxiliary materials technology Co., Ltd;
polyethylene glycol 3350: sourced Guangzhou city Tianyun pharmaceutical Co., Ltd;
example 1
The prescription is as follows:
Figure BDA0003190333060000131
Figure BDA0003190333060000141
the preparation method comprises the following steps:
1. preparing a medicine-containing layer: and (4) avoiding light. Mixing nifedipine with other adjuvants (except magnesium stearate) in the medicinal layer, adding into dry granulating machine, pressing into strip, sieving with 16-mesh stainless steel sieve, and adding magnesium stearate.
2. Preparation of a boosting layer: premixing auxiliary materials (except magnesium stearate) of the boosting layer, adding into a dry granulating machine, pressing into strips, granulating through a 16-mesh stainless steel screen, and adding magnesium stearate for mixing.
3. Tabletting: and (4) avoiding light. And (3) pressing the double-layer tablet by using a double-layer tablet press, wherein the size of a punching die is 6mm round tablet, firstly filling 82.5mg of the medicine-containing layer material, prepressing, filling 41.3mg of the boosting layer material again, and compacting to obtain the double-layer tablet with the tablet core weight of 123.8 mg/tablet.
4. And (3) coating of a semipermeable membrane: the bilayer tablet cores were coated with the controlled release coating solution described above using a coating pan to a weight gain of 15.0 wt% and 17.9 wt% (percentages are weight percentages relative to the tablet core) (sample lots BN122124-A, BN122127-a, respectively). The method for specifically controlling the weight gain of different coatings comprises the following steps: in the coating process, 2 target coating increases are set, when the first coating increase point is reached, a part of controlled release coating tablets are taken out, the rest part of controlled release coating tablets are coated continuously, and when the 2 nd coating increase point is reached, the controlled release coating tablets are taken out. The hole is punched by adopting a mechanical punching or laser punching mode, and the aperture of the medicine releasing hole is 0.5 mm. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm.
5. Method for measuring release: and (4) avoiding light. Taking the product, placing the tablet into a settling basket according to a dissolution and release determination method (second method of 0931 in the fourth part of Chinese pharmacopoeia 2015 edition), using 900ml of phosphate-citric acid solution (pH6.8) of 1 wt% sodium dodecyl sulfate as a solvent, and rotating at 100 rpm, and operating according to the method. Weighing about 16.5mg of nifedipine as a reference substance, precisely weighing, placing into a 50mL brown measuring flask, adding 25mL of mixed solution I (acetonitrile: methanol: 50), dissolving by ultrasonic, adding a proper amount of water to the near scale, fully mixing, standing for 15 minutes, diluting with water to the scale, shaking up, precisely weighing into a 5mL to 50mL brown measuring flask, diluting with mixed solution II (acetonitrile: methanol: water: 25:50) to the scale, shaking up to obtain a reference substance solution. According to chromatographic conditions under the content measurement item of the second method of 0931 in the general rule of the four parts of the 'Chinese pharmacopoeia 2015 edition', precisely measuring 10 mu L of each of the test solution and the reference solution, respectively injecting the solution and the reference solution into a liquid chromatograph, recording the chromatogram, and calculating the release amount of each tablet in 1 wt% of sodium dodecyl sulfate phosphate-citric acid solution (pH6.8) by peak area according to an external standard method. Fig. 1 is a release profile of the nifedipine controlled release tablet of example 1. The slices are not broken.
Example 2
The prescription is as follows:
Figure BDA0003190333060000142
Figure BDA0003190333060000151
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 123.8 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 15.3 wt% and 18.1 wt% and the aperture of a drug release is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 2 is a release profile of the nifedipine controlled release tablet of example 2. The slices are not broken.
Comparative example 1
The prescription is as follows:
Figure BDA0003190333060000152
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 123.8 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 10.0 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. The controlled-release tablet of nifedipine of comparative example 1 broke the controlled-release membrane during the release process, as shown in fig. 3.
Comparative example 2
The prescription is as follows:
Figure BDA0003190333060000153
Figure BDA0003190333060000161
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 123.8 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 7.3 wt% and 10.2 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 4 is a release curve (incomplete release, large SD value) of the nifedipine controlled release tablet in comparative example 2.
In the present comparative example, the release rate of the controlled-release tablet coated with 7.3% was slower than that of the controlled-release tablet coated with 10.2%, probably because the controlled-release film coated with 10.2% was broken during the release process. See fig. 24 for an observation of whether the controlled release membrane is ruptured during the release process.
Example 3
The prescription is as follows:
Figure BDA0003190333060000162
the preparation method comprises the following steps: the preparation method of the double-layer tablet core is the same as that of example 1, the weight of each double-layer tablet core is 165mg, and the weight of the boosting layer is 55.0 mg/tablet. The double-layer tablet core is coated by the controlled-release coating liquid in a coating pan, the weight of the coating is increased by 15.0 percent, and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 7 mm. See fig. 24 for an observation of whether the controlled release membrane is ruptured during the release process.
Comparative example 3
The prescription is as follows:
Figure BDA0003190333060000163
Figure BDA0003190333060000171
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 165 mg. The double-layer tablet core is coated by the controlled-release coating liquid in a coating pan, the weight of the coating is increased by 15.0 percent, and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 7 mm.
Fig. 5 is a release curve of nifedipine controlled release tablets in example 3 and comparative example 3, and it can be seen from fig. 5 that the semipermeable membrane of the 30% API prescription without P407 is broken, and the difference between incomplete tablets of drug release is large; and 5% 407 is added, so that the tablet is not broken and the release is quick, and the poloxamer 407 added in the prescription can effectively reduce the drug release resistance and also reduce the mechanical pressure on the controlled release film. See fig. 24 for an observation of whether the controlled release membrane is ruptured during the release process.
Example 4
The prescription is as follows:
Figure BDA0003190333060000172
Figure BDA0003190333060000173
Figure BDA0003190333060000181
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 141.5 mg. The double-layer tablet core is coated by the controlled-release coating liquid in a coating pan, the weight of the coating is increased as shown in the table above, and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. FIG. 6 is a release profile of nifedipine controlled release tablets in examples 4-1, 4-2 and 4-3, and it can be seen from FIG. 6 that none of the nifedipine controlled release tablets were broken after dissolution; under the premise that the 35% API prescription contains 5% P407, the prescription of 30% HPC releases more residues and incomplete release within 24 hours; in contrast, both the 40% and 50% HPC formulation release profiles gave superior release profiles and lower residual levels. See fig. 24 for an observation of whether the controlled release membrane is ruptured during the release process.
Example 5
The prescription is as follows:
Figure BDA0003190333060000182
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 123.8 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 15.2 wt% and 18.2 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 7 is a release profile of the nifedipine controlled release tablet of example 5. The slices are not broken.
Example 6
The prescription is as follows:
Figure BDA0003190333060000183
Figure BDA0003190333060000191
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 123.8 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 15.0 wt% and 18.0 wt% and the aperture of the drug release is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 8 is a release profile of the nifedipine controlled release tablet of example 6. The slices are not broken.
Example 7
The prescription is as follows:
Figure BDA0003190333060000192
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 123.8 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 9.2 wt% and 12.2 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 9 is a release profile of nifedipine controlled release tablets in example 7. Sorbitol is preferably used as the penetration enhancer in the boosting layer formula. The slices are not broken.
Example 8
The prescription is as follows:
Figure BDA0003190333060000193
Figure BDA0003190333060000201
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 123.8 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 6.0 wt% and 9.2 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 10 is a release profile of the nifedipine controlled release tablet of example 8. The slices are not broken.
Example 9
The prescription is as follows:
Figure BDA0003190333060000202
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 123.8 mg/tablet. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 7.5 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 11 is a release profile of nifedipine controlled release tablets in example 9. The slices are not broken.
Example 10-1 (tofacitinib 22 mg/tablet)
The prescription is as follows:
Figure BDA0003190333060000211
note:1corresponding to 22mg of tofacitinib.
The preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 125.0 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 5.0 wt%, 8.0 wt% and 10.0 wt%, and the aperture of a drug release hole is 1.0 mm. The controlled release tablet in this example was 22 mg/tablet in size, and the tablet had a diameter of 6mm in a circular shape.
Example 10-2 (tofacitinib 11 mg/tablet)
The prescription is as follows:
Figure BDA0003190333060000212
note:1corresponding to 11mg of tofacitinib.
The preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with the weight of each bilayer tablet core being 66.6 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 5.0 wt%, 8.0 wt% and 10.0 wt% and the aperture of a drug release is 0.5 mm. The controlled release tablet in this example was in the form of 11 mg/tablet, circular tablet having a diameter of 5 mm.
Example 11
The prescription is as follows:
Figure BDA0003190333060000221
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 123.8 mg. The double-layer tablet core is coated by the controlled-release coating liquid in a coating pan, the weight gains of the coating of the four formulas are respectively 6.0 wt%, 6.1 wt%, 6.3 wt% and 6.6 wt%, and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 12 is a release profile of nifedipine controlled release tablets of example 11. The slices are not broken.
Example 12
The prescription is as follows:
Figure BDA0003190333060000222
Figure BDA0003190333060000231
the preparation method comprises the following steps: the preparation method of the double-layer tablet core is the same as that of example 1, the weight of each double-layer tablet core is 123.8 mg/tablet (the formula of the boosting layer is (2) -1, the weight of the boosting layer is 41.3 mg/tablet) and 130.5 mg/tablet (the formula of the boosting layer is (2) -2, and the weight of the boosting layer is 48.0 mg/tablet). The double-layer tablet core is coated by the controlled-release coating liquid in a coating pan, the coating weight gains of the two formulas are respectively 7.0 wt% and 7.1 wt%, and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 13 is a release profile of nifedipine controlled release tablets in example 12. The slices are not broken.
Example 13
The prescription is as follows:
Figure BDA0003190333060000232
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with each bilayer tablet core weighing 130.5 mg/tablet. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 9.4 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. FIG. 14 is a graph showing the release curves of the nifedipine controlled release tablets of example 13 and a commercial nifedipine controlled release tablet (manufacturer German Bayer, size 30mg, size 9mm, coating weight gain about 15%). The similar factor F2 of the release curve of the preparation of the embodiment and the release curve of the commercially available nifedipine controlled release tablet is 75.8. The slices are not broken.
Example 14
The prescription is as follows:
Figure BDA0003190333060000241
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with the weight of each bilayer tablet core being 130.5 mg. The bilayer tablet cores were coated with the controlled release coating solution described above using a pan coater until the weight gain was 8.1 wt%, 8.3 wt% or 8.4 wt% (see fig. 15, where BJ44066 is a commercially available formulation, as in example 13), with a drug release pore size of 0.5 mm. The method for measuring the release rate was the same as in example 1. The result shows that the controlled release tablet releases well when the proportion of poloxamer 407 is within the range of 5% -9%. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 15 and the following table show the release curve and the release data of the nifedipine controlled release tablet in example 14. The slices are not broken.
Figure BDA0003190333060000242
Figure BDA0003190333060000251
Note: the reason why the cumulative release amount of nifedipine in the above table exceeds 100% is that: the release percentage of the controlled release tablet is calculated according to the marked amount, and the actual content of the nifedipine in the controlled release tablet is higher than the marked amount, for example, when the specification of the controlled release tablet is 30 mg/tablet, the actual content of the controlled release tablet is 33 mg/tablet.
Example 15
This example is a study of the preparation and release profiles of formulations containing different surfactants in the drug-containing layer at 40% API content.
The prescription is as follows:
Figure BDA0003190333060000252
Figure BDA0003190333060000261
the preparation method comprises the following steps: the bilayer tablet cores were prepared as in example 1 except for the weight of the boost layer, with each bilayer tablet core weighing 130.5 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 8.0 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. Fig. 16 is a release profile of nifedipine controlled release tablets of example 15.
In the preparation of the embodiment, under the condition that other prescription components are identical, the release curves of the formula samples of the four surfactants are acceptable, the release is complete within 24 hours, and the controlled release membrane is not cracked.
Example 16
This example is a study of the preparation and release profile of the formulated product at an API content of 30%.
The prescription is as follows:
Figure BDA0003190333060000262
the preparation method comprises the following steps: the preparation method of the double-layer tablet core is the same as that of the example 1 except for the weight and the size of the punch die, the circular tablet with the size of 7mm is pressed into a tablet, 110mg of the medicine-containing layer material is filled firstly, prepressing is carried out, 55mg of the boosting layer material is filled again, and the double-layer tablet core with the weight of 165 mg/tablet is obtained by compacting. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 7.0 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 7 mm.
Comparative example 4
Comparative example 4, as opposed to example 16, is a preparation and release profile of a formulation using polyethylene oxide (PEO) in the original research product as a drug-containing layer drug carrier and a booster layer expander.
The prescription is as follows:
Figure BDA0003190333060000271
the preparation method comprises the following steps:
1. preparing a medicine-containing layer: and (4) avoiding light. Mixing nifedipine with other adjuvants (except magnesium stearate) in the medicinal layer, sieving with 20 mesh stainless steel sieve, and adding magnesium stearate.
2. Preparation of a boosting layer: and (4) avoiding light. The auxiliary materials of the boosting layer (except the magnesium stearate) are premixed, pass through a stainless steel screen with 20 meshes, and are added with the magnesium stearate to be mixed.
3. Tabletting: and (4) avoiding light. And (3) pressing the double-layer tablet by using a double-layer tablet press, filling 110mg of medicine-containing layer material into a round tablet with the die size of 7mm, prepressing, filling 55mg of boosting layer material, and compacting to obtain the double-layer tablet core with the weight of 165 mg/tablet.
4. And (3) coating of a semipermeable membrane: the bilayer tablet cores were coated with the controlled release coating solution described above using a pan coater until the weight gain was 8.0 wt% (weight percent relative to tablet core). The hole is punched by adopting a mechanical punching or laser punching mode, and the aperture of the medicine releasing hole is 0.5 mm. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 7 mm.
5. Method for measuring release: the same as the method of the previous embodiment.
Fig. 17 is a release profile of nifedipine controlled release tablets in example 16 and comparative example 4. As can be seen, when the API content is 30% of the prescription proportion of the drug-containing layer, the release rate of the formula of the embodiment is close to that of the original research, and the F2 factor reaches 62.8. And when the API accounts for 30 percent of the prescription of the drug-containing layer in the simulated original formula, the release residue is up to 50 percent in 24 hours, and the phenomenon of the rupture of the controlled release film occurs in the dissolution test process.
Comparative example 5
This comparative example is a formulation using polyoxyethylene as the boosting layer expander in the original ground product, as opposed to BN-145038-C in example 14.
The prescription is as follows:
Figure BDA0003190333060000281
comparative example 6
This comparative example is a formulation using polyoxyethylene as the drug-containing layer carrier and the booster layer expander in the original product, as opposed to BN-145038-C in example 14.
The prescription is as follows:
Figure BDA0003190333060000282
Figure BDA0003190333060000291
comparative example 7
This comparative example is a formulation using polyoxyethylene in the original ground product as the drug-containing layer carrier and the booster layer expander, and 5% of poloxamer 407 was added to the drug-containing layer to improve the hydratability of the drug-containing layer, as opposed to BN-145038-C in example 14.
The prescription is as follows:
Figure BDA0003190333060000292
Figure BDA0003190333060000301
comparative example 8
This comparative example is a formulation using polyoxyethylene in the original product as a drug carrier for a drug-containing layer, as opposed to BN-145038-C in example 14, in which 5% of poloxamer 407 is added to the drug-containing layer in order to improve the hydratability of the drug-containing layer.
The prescription is as follows:
Figure BDA0003190333060000302
the above comparative examples 5 to 8 were prepared as follows:
1. preparing a medicine-containing layer: the drug-containing layer was prepared as in example 8 using hydroxypropylcellulose as the drug carrier. The drug-containing layer using polyoxyethylene as the drug carrier was prepared as in comparative example 4.
2. Preparation of a boosting layer: the same procedure as in example 8 was followed using hydroxypropylcellulose as the drug carrier. The same procedure as in comparative example 4 was followed to prepare a boosting layer using polyoxyethylene as the drug carrier.
3. Tabletting: and (4) avoiding light. And (3) pressing the double-layer tablet by using a double-layer tablet press, wherein the size of a punching die is 6mm round tablet, firstly filling 82.5mg of the medicine-containing layer material, prepressing, filling 48mg of the boosting layer material, and compacting to obtain the double-layer tablet core with the weight of 130.5 mg/tablet.
4. And (3) coating of a semipermeable membrane: the bilayer tablet cores were coated with the controlled release coating solution described above using a pan coater until the weight gain was 8.0 wt% (weight percent relative to tablet core). The hole is punched by adopting a mechanical punching or laser punching mode, and the aperture of the medicine releasing hole is 0.5 mm. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm.
FIG. 18A is a graph showing a comparison of the properties of controlled release tablets in a soaking test in comparative example 5 (product batch BN-145089-G), comparative example 6 (product batch BN-145089-E), comparative example 7(BN-145089-F), and comparative example 8 (product batch BN-145089-H). The soaking test method comprises the following steps: the tablets were placed in a 2L beaker, 1.8L purified water was added, and the tablet was placed in a 40 ℃ oven and the 24H tablet core was observed for immersion. The controlled-release films of the controlled-release tablets of comparative examples 5, 6 and 7 were all ruptured except for the controlled-release tablet of comparative example 8. The release rate was measured for comparative example 8 in which the controlled release membrane was not broken, in the same manner as in example 1.
FIG. 18B is a graph showing the release curves of the controlled release tablets of BN-145038-C of example 14 and the controlled release tablets of nifedipine of comparative example 8 compared with those of the original ground product. When the API content is 40% of the prescription proportion of the drug-containing layer, the release rate of the prescription BN-145038-C in the example 14 is close to that of the original research, and the F2 factor reaches 76.3. And when the API content of the simulated original formula accounts for 40% of the prescription of the drug-containing layer, namely the controlled release tablet of the comparative example 8, the release residue is up to 50%.
Example 17
This example is the preparation and release rate measurement of a controlled release tablet using cellulose acetate and ethylcellulose N100 as controlled release membrane materials.
The prescription is as follows:
Figure BDA0003190333060000311
Figure BDA0003190333060000321
the preparation method comprises the following steps:
1. preparing a medicine-containing layer: same as BN-145038-C in example 14.
2. Preparation of a boosting layer: BN-145038-C from example 14.
3. Tabletting: BN-145038-C from example 14.
4. And (3) coating of a semipermeable membrane: the bilayer tablet cores were coated with the controlled release coating solution described above using a pan coater until the weight gain was 6.0 wt% (weight percent relative to tablet core). The hole is punched by adopting a mechanical punching or laser punching mode, and the aperture of the medicine releasing hole is 0.5 mm. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm.
5. Method for measuring release: the same as in example 1.
Fig. 19 is a comparison of the nifedipine controlled release tablets of example 17 with the original release profile. The release curve was close to that of the original study, and the factor F2 reached 92.3.
Example 18
This example is the preparation and release rate measurement of a controlled release tablet using cellulose acetate butyrate as the controlled release membrane material and copovidone VA64 as the pore-forming agent.
The prescription is as follows:
Figure BDA0003190333060000322
Figure BDA0003190333060000331
the preparation method comprises the following steps:
1. preparing a medicine-containing layer: same as BN-145038-C in example 14.
2. Preparation of a boosting layer: BN-145038-C from example 14.
3. Tabletting: BN-145038-C from example 14.
4. And (3) coating of a semipermeable membrane: the bilayer tablet cores were coated with the controlled release coating solution described above using a pan coater until the weight gain was 3.7 wt% (weight percent relative to tablet core). The hole is punched by adopting a mechanical punching or laser punching mode, and the aperture of the medicine releasing hole is 0.5 mm. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm.
5. Method for measuring release: the same as in example 1.
Fig. 20 is a comparison of the nifedipine controlled release tablets of example 18 with the original release profile. The release curve was close to that of the original study and the factor F2 reached 62.3.
Example 19
This example is the preparation and release rate measurement of a controlled release tablet using cellulose acetate butyrate as the controlled release membrane material and polyethylene glycol 3350 as the plasticizer.
The prescription is as follows:
Figure BDA0003190333060000332
Figure BDA0003190333060000341
the preparation method comprises the following steps:
1. preparing a medicine-containing layer: same as BN-145038-C in example 14.
2. Preparation of a boosting layer: BN-145038-C from example 14.
3. Tabletting: BN-145038-C from example 14.
4. And (3) coating of a semipermeable membrane: the bilayer tablet cores were coated with the controlled release coating solution described above using a pan coater until the weight gain was 6.4 wt% (weight percent relative to tablet core). The hole is punched by adopting a mechanical punching or laser punching mode, and the aperture of the medicine releasing hole is 0.5 mm. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm.
5. Method for measuring release: the same as in example 1.
Fig. 21 is a comparison of the nifedipine controlled release tablets of example 19 with the original release profile. The release profile was close to that of the original study and the factor F2 reached 63.3.
Example 20
This example is the preparation and release rate measurement of controlled release tablets using controlled release membrane materials of cellulose acetate and cellulose acetate butyrate.
The prescription is as follows:
Figure BDA0003190333060000342
the preparation method comprises the following steps:
1. preparing a medicine-containing layer: same as BN-145038-C in example 14.
2. Preparation of a boosting layer: BN-145038-C from example 14.
3. Tabletting: BN-145038-C from example 14.
4. And (3) coating of a semipermeable membrane: the bilayer tablet cores were coated with the controlled release coating solution described above using a pan coater until the weight gain was 9.8 wt% (weight percent relative to tablet core). The hole is punched by adopting a mechanical punching or laser punching mode, and the aperture of the medicine releasing hole is 0.5 mm. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm.
5. Method for measuring release: the same as in example 1.
Fig. 22 is a comparison of the nifedipine controlled release tablets of example 20 with the original release profile. The release curve was close to that of the original study and the factor F2 reached 59.6.
Example 21
The prescription is as follows:
Figure BDA0003190333060000351
the preparation method comprises the following steps: the bilayer tablet core was prepared as in example 1, with the weight of each bilayer tablet core being 115.9 mg. Coating the double-layer tablet core by using the controlled-release coating solution in a coating pan until the weight is increased by 6.1 wt% and the drug release aperture is 0.5 mm. The method for measuring the release rate was the same as in example 1. The controlled release tablet in this example was in the form of a 30 mg/tablet, circular tablet having a diameter of 6 mm. FIG. 23 is the release curve of nifedipine controlled release tablet in example 21, which is 51.6 compared with factor F2 in the previous study.
Effect example 1
The release profiles of the nifedipine controlled-release tablets of examples 1 to 21 and comparative examples 2 to 8 and the release profiles of the commercially available nifedipine controlled-release tablets were measured by the method for measuring the release rate described in example 1, and specific data thereof are shown in the following table.
Figure BDA0003190333060000361
Figure BDA0003190333060000371
Figure BDA0003190333060000381
Note: the reason why the cumulative release amount of nifedipine in the above table exceeds 100% is that: the release percentage of the controlled release tablet is calculated according to the marked amount, and the actual content of the nifedipine in the controlled release tablet is higher than the marked amount, for example, when the specification of the controlled release tablet is 30 mg/tablet, the actual content of the controlled release tablet is 33 mg/tablet.
The results are combined to show that: as can be seen from example 3 and comparative example 3, the mechanical pressure on the controlled release membrane can be reduced and the tablet breakage can be avoided by adding poloxamer into the drug-containing layer; from comparative examples 4-7, it can be seen that in the case of high drug loading, the drug-containing layer using PEO as the drug carrier and the booster layer using PEO as the swelling agent are more easily broken during release than when HPC is used; from comparative example 8, it is understood that PEO for a booster layer expander, although not broken, has a large residue in the 24-hour release amount.
From examples 15 to 21, it is clear that the present application can achieve the effect equivalent to the release rate and release amount of the commercially available pharmaceutical preparation under the conditions of high API and small weight gain of the coating, and the similar factor f2 can reach 51.6 to 92.3.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.

Claims (10)

1. A controlled release tablet is characterized by comprising a tablet core and a coating coated on the tablet core, wherein the tablet core comprises a medicine-containing layer and a boosting layer compounded on the medicine-containing layer, one side of the coating on the medicine-containing layer is provided with a medicine release hole, and the coating is a semipermeable coating film; the raw materials of the medicine-containing layer comprise raw material medicines and auxiliary materials;
in the drug-containing layer, the raw material drugs are nifedipine, tofacitinib or pharmaceutically acceptable salts thereof;
in the medicine-containing layer, the weight of the raw material medicine is 25.0-50.0 wt% of the weight of the medicine-containing layer;
in the medicine-containing layer, the raw materials of the auxiliary materials comprise an auxiliary material A, wherein the auxiliary material A is one or more of poloxamer, sodium dodecyl sulfate, polyoxyl stearate and vitamin E polyethylene glycol succinate, such as poloxamer; the weight of the auxiliary material A is 0.0-10.0 wt% of the weight of the medicine-containing layer.
2. The controlled release tablet of claim 1, wherein in the drug-containing layer, the pharmaceutically acceptable salt of tofacitinib is tofacitinib citrate;
and/or in the drug-containing layer, the weight of the raw material drug is 30.0-50.0 wt%, such as 30.0 wt%, 35.0 wt%, 40.0 wt% or 45.0 wt% of the weight of the drug-containing layer;
and/or in the medicine-containing layer, the weight of the auxiliary material A is 3.0-10.0 wt%, preferably 3.0-9.0 wt%, such as 3.0 wt%, 4.0 wt%, 5.0 wt%, 7.0 wt% or 9.0 wt% of the weight of the medicine-containing layer; when the auxiliary material A is poloxamer, the weight of the poloxamer is preferably 3.0-9.0 wt%, such as 3.0 wt%, 5.0 wt%, 7.0 wt% or 9.0 wt% of the weight of the medicine-containing layer;
and/or in the medicine-containing layer, the weight of the raw material medicine is 25.0-30.0 wt% of the weight of the medicine-containing layer, and the weight of the auxiliary material A is 0.0-5.0 wt% of the weight of the medicine-containing layer;
and/or in the medicine-containing layer, the weight of the raw material medicine is 30.0-50.0 wt% of the weight of the medicine-containing layer, and the weight of the auxiliary material A is 3.0-10.0 wt% of the weight of the medicine-containing layer; wherein, the weight of the auxiliary material A is preferably 3.0-9.0 wt%, such as 3.0 wt%, 5.0 wt%, 7.0 wt% or 9.0 wt% of the weight of the medicine-containing layer;
and/or, in the drug-containing layer, the weight of the auxiliary material is 50.0-75.0 wt%, such as 60.0 wt%, 65.0 wt% or 70.0 wt% of the weight of the drug-containing layer;
and/or in the medicine-containing layer, the raw materials of the auxiliary materials also comprise one or more of a filling agent, a medicine carrier, an anti-sticking agent, a lubricating agent and a coloring agent.
3. The controlled-release tablet according to claim 2, wherein when the raw material of the auxiliary material in the drug-containing layer further comprises a filler, the filler is selected from one or more of lactose, starch, pregelatinized starch, dextrin, mannitol, sorbitol, and microcrystalline cellulose, such as mannitol;
and/or, when the raw material of the auxiliary material in the drug-containing layer further comprises a filler, the content of the filler is 0-52.0 wt%, such as 2.0-34.0 wt%, and further such as 2.0 wt%, 4.0 wt%, 6.0 wt%, 9 wt%, 14.0 wt%, 16 wt%, 19 wt%, 29.0 wt% or 34.0 wt% of the weight of the drug-containing layer;
and/or, when the raw materials of the auxiliary materials in the medicine-containing layer further comprise a medicine carrier, the medicine carrier is selected from one or more of povidone, copovidone, carbomer, hypromellose, hyprolose, hydroxyethyl cellulose, ethyl cellulose and sodium alginate, such as hydroxypropyl cellulose;
and/or, when the raw material of the auxiliary material in the drug-containing layer further comprises a drug carrier, the content of the drug carrier is 20.0-72.0 wt%, such as 30.0-50.0 wt%, and further such as 30.0 wt%, 40.0 wt% or 50.0 wt% of the weight of the drug-containing layer;
and/or, when the raw material of the auxiliary material in the medicine-containing layer also comprises an anti-sticking agent, the anti-sticking agent is colloidal silicon dioxide and/or talcum powder;
and/or when the raw materials of the auxiliary materials in the medicine-containing layer also comprise an anti-sticking agent, the content of the anti-sticking agent is 0-7.0 wt% of the weight of the medicine-containing layer;
and/or, when the raw materials of the auxiliary materials in the medicine-containing layer further comprise a lubricant, the lubricant is one or more of stearic acid, magnesium stearate, calcium stearate, polyethylene glycol and sodium stearyl fumarate, such as magnesium stearate;
and/or when the raw materials of the auxiliary materials in the medicine-containing layer further comprise a lubricant, the content of the lubricant is 0-2.0 wt% of the weight of the medicine-containing layer, such as 1.0 wt%;
and/or when the raw materials of the auxiliary materials in the medicine-containing layer also comprise a colorant, the colorant is one or more of iron oxide red, iron oxide yellow, iron oxide purple and iron oxide black, such as iron oxide red;
and/or when the raw materials of the auxiliary materials in the medicine-containing layer also comprise a colorant, the content of the colorant is 0-2.0 wt% of the weight of the medicine-containing layer;
and/or the medicine-containing layer comprises the following components: 25.0-30.0 wt% of raw material medicine, 0.0-5.0 wt% of auxiliary material A, 20.0-72.0 wt% of medicine carrier, 0-52.0 wt% of filling agent, 0-7.0 wt% of anti-sticking agent, 0-2.0 wt% of colorant and 0-2.0 wt% of lubricant, wherein the percentage refers to the weight of each component accounting for the weight of the medicine-containing layer;
or the medicine-containing layer comprises the following components: 30.0-50.0 wt% of raw material medicine, 3.0-10.0 wt% of auxiliary material A, 30.0-50.0 wt% of medicine carrier, 4-34.0 wt% of filling agent, 0-7.0 wt% of anti-sticking agent, 0-2.0 wt% of colorant and 0-2.0 wt% of lubricant, wherein the percentage refers to the weight of each component accounting for the weight of the medicine-containing layer.
4. The controlled release tablet of claim 3, wherein when the excipients of the drug-containing layer comprise hydroxypropylcellulose, the drug-containing layer comprises: the weight of the raw material medicine is 30.0-50.0 wt% of the weight of the medicine-containing layer, the weight of the auxiliary material A is 3.0-9.0 wt% of the weight of the medicine-containing layer, and the content of hydroxypropyl cellulose is 30.0-50.0 wt% of the weight of the medicine-containing layer;
or when the auxiliary materials of the medicine-containing layer contain hydroxypropyl cellulose and mannitol, the medicine-containing layer contains: the weight of the raw material medicine is 30.0-50.0 wt% of the weight of the medicine-containing layer, the weight of the auxiliary material A is 3.0-9.0 wt% of the weight of the medicine-containing layer, the content of hydroxypropyl cellulose is 30.0-50.0 wt% of the weight of the medicine-containing layer, and the content of mannitol is 2.0-34.0 wt% of the weight of the medicine-containing layer;
or when the auxiliary materials of the medicine-containing layer contain hydroxypropyl cellulose, mannitol and magnesium stearate, the medicine-containing layer contains: the weight of the raw material medicine is 30.0-50.0 wt% of the weight of the medicine-containing layer, the weight of the auxiliary material A is 3.0-9.0 wt% of the weight of the medicine-containing layer, the content of the hydroxypropyl cellulose is 30.0-50.0 wt% of the weight of the medicine-containing layer, the content of the mannitol is 2.0-34.0 wt% of the weight of the medicine-containing layer, and the content of the magnesium stearate is 1-2.0 wt% of the weight of the medicine-containing layer.
5. The controlled-release tablet according to claim 1, wherein the ratio of the weight of the drug-containing layer to the weight of the boosting layer is 1:0.3 to 1:2, such as 1:0.38, 1:0.44, 1:0.46, 1:0.5, 1:0.58 or 1: 0.93;
and/or the material of the boosting layer comprises one or more of swelling agent, osmotic pressure promoter, lubricant and colorant, such as swelling agent, osmotic pressure promoter, lubricant and colorant.
6. The controlled release tablet of claim 5, wherein when the material of the boosting layer further comprises a swelling agent, the swelling agent is selected from one or more of sodium carboxymethyl starch, hypromellose, hyprolose, sodium carboxymethylcellulose, hydroxyethyl cellulose, carbomer, xanthan gum, sodium alginate and kappa carrageenan, such as one or more of hydroxypropyl cellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate and kappa carrageenan, such as "hyprolose and sodium carboxymethylcellulose", "hyprolose and xanthan gum", "hyprolose and sodium alginate" or "hyprolose and kappa carrageenan";
and/or, when the raw material of the boosting layer further comprises a swelling agent, the content of the swelling agent is 20.0-95.0 wt%, such as 20.0 wt%, 49.0 wt%, 59.0 wt%, 65 wt%, 69.0 wt% or 79.0 wt%, and further such as 30-95 wt% of the weight of the boosting layer;
and/or, when the raw material of the boosting layer further comprises an osmotic pressure promoter, the osmotic pressure promoter is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, magnesium sulfate, ascorbic acid, tartaric acid, mannitol, sorbitol, xylitol, glucose and sucrose, such as one or more of sodium chloride, mannitol, sorbitol and sucrose, and further such as mannitol and/or sorbitol;
and/or, when the raw material of the boosting layer further comprises an osmotic pressure promoter, the content of the osmotic pressure promoter is 5.0-70.0 wt%, such as 10.0-30.0 wt%, and further such as 10.0 wt%, 20.0 wt%, 30.0 wt% or 34 wt% of the weight of the boosting layer;
and/or, when the raw materials of the boosting layer further comprise a lubricant, the lubricant in the boosting layer is one or more of stearic acid, magnesium stearate, calcium stearate, polyethylene glycol and sodium stearyl fumarate, such as magnesium stearate;
and/or, when the raw material of the boosting layer further comprises a lubricant, the content of the lubricant in the boosting layer is 0-3 wt%, for example 0.5 wt% of the weight of the boosting layer;
and/or when the raw material of the boosting layer also comprises a colorant, the colorant in the boosting layer is one or more of iron oxide red, iron oxide yellow, iron oxide purple and iron oxide black, such as iron oxide red;
and/or, when the raw material of the boosting layer further comprises a colorant, the content of the colorant in the boosting layer is 0-2 wt%, for example 0.5 wt%, of the weight of the boosting layer;
and/or the boosting layer comprises the following components: 30.0-95.0 wt% of an expanding agent, 5.0-70.0 wt% of an osmotic pressure promoter, 0-3.0 wt% of a lubricant and 0-2 wt% of a colorant, wherein the percentages refer to the weight of the components accounting for the weight of the boosting layer;
or, in the controlled release tablet, the composition of the drug-containing layer is as follows: 25.0-30.0 wt% of raw material medicine, 30.0-50.0 wt% of medicine carrier, 0-5.00 wt% of auxiliary material A, 19.0-34.0 wt% of filling agent and 0.00-2.00 wt% of lubricant; the boosting layer comprises the following components: 65.0-69.0 wt% of an expanding agent, 30.0-34.0 wt% of an osmotic pressure promoter, 0.00-2.00 wt% of a coloring agent and 0.00-3.00 wt% of a lubricating agent;
preferably, in the controlled release tablet, the composition of the drug-containing layer is: 25.0-30.0 wt% of nifedipine, 30.0-50.0 wt% of hydroxypropyl cellulose, 0-5.00 wt% of poloxamer, 19.0-34.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0-55.0 wt% of sodium carboxymethylcellulose, 30.0-34.0 wt% of sorbitol, 10.0-20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate;
or, in the controlled release tablet, the composition of the drug-containing layer is as follows: 30.0-50.0 wt% of raw material medicine, 30.0-50.0 wt% of medicine carrier, 3-5.00 wt% of auxiliary material A, 4.0-34.0 wt% of filling agent and 0.00-2.00 wt% of lubricant; the boosting layer comprises the following components: 69.0-79.0 wt% of an expanding agent, 20.0-30.0 wt% of an osmotic pressure promoter, 0.00-2.00 wt% of a coloring agent and 0.00-3.00 wt% of a lubricating agent;
preferably, in the controlled release tablet, the composition of the drug-containing layer is: 30.0-50.0 wt% of nifedipine, 30.0-50.0 wt% of hydroxypropyl cellulose, 3-5.00 wt% of auxiliary material A, 4.0-34.0 wt% of mannitol and 1.00 wt% of magnesium stearate; the boosting layer comprises the following components: 49.0-59.0 wt% of sodium carboxymethylcellulose, 20.0-30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate.
7. A controlled release tablet according to claim 6, wherein when the swelling agent comprises hydroxypropylcellulose, the hydroxypropylcellulose is present in an amount of 10.0 to 30.0 wt%, for example 20.0 wt%, based on the weight of the boosting layer;
and/or, when the bulking agent comprises sodium carboxymethylcellulose, the amount of sodium carboxymethylcellulose is 49.0 to 79.0 wt%, such as 49.0 wt%, 55 wt%, 59.0 wt%, 69.0 wt%, or 79.0 wt%, of the weight of the boosting layer;
and/or, when said swelling agent comprises xanthan gum, said xanthan gum is present in an amount of 49.0 wt% based on the weight of said boosting layer;
and/or, when the swelling agent comprises sodium alginate, the content of the sodium alginate is 49.0 wt% of the weight of the boosting layer;
and/or when the swelling agent comprises carrageenan, the content of the carrageenan is 49.0 wt% of the boosting layer;
or when the swelling agent is hydroxypropyl cellulose and sodium carboxymethyl cellulose, the content of the hydroxypropyl cellulose is 20.0 wt% of the boosting layer; the content of the sodium carboxymethyl cellulose is 49-79 wt% of the weight of the boosting layer, such as 49.0 wt%, 55 wt%, 59.0 wt%, 69.0 wt% or 79.0 wt%;
or when the swelling agent is hydroxypropyl cellulose and xanthan gum, the content of the hydroxypropyl cellulose is 20.0 wt% of the boosting layer; the content of the xanthan gum is 49.0 wt% of the weight of the boosting layer;
or when the swelling agent is hydroxypropyl cellulose and sodium alginate, the content of the hydroxypropyl cellulose is 20.0 wt% of the boosting layer; the content of the sodium alginate is 49.0 wt% of the weight of the boosting layer;
or when the swelling agent is hydroxypropyl cellulose and carrageenan, the content of the hydroxypropyl cellulose is 20.0 wt% of the boosting layer; the content of the carrageenan is 49.0 wt% of the boosting layer;
or when the boosting layer comprises sodium carboxymethyl cellulose and sorbitol, the boosting layer comprises: the weight of the sodium carboxymethyl cellulose is 49-89 wt%, preferably 49-79 wt% of the weight of the boosting layer, and the weight of the sorbitol is 10.0-34.0 wt%, preferably 10.0-30.0 wt% of the weight of the boosting layer;
or, when sodium carboxymethyl cellulose and mannitol are included in the boosting layer, the ratio of the sodium carboxymethyl cellulose to the mannitol in the boosting layer is as follows: the weight of the sodium carboxymethylcellulose is 49-79 wt% of the weight of the boosting layer, and the weight of the mannitol is 10.0-30.0 wt% of the weight of the boosting layer;
or when the boosting layer contains xanthan gum, sodium alginate or carrageenan and sorbitol, the boosting layer comprises: the weight of the xanthan gum, the sodium alginate or the kappa carrageenan accounts for 49-79 wt% of the boosting layer, and the weight of the sorbitol accounts for 10.0-30.0 wt% of the boosting layer.
8. The controlled-release tablet according to claim 1, wherein the semipermeable membrane is prepared by the following method: coating the tablet core by coating liquid containing a film forming material of the semipermeable coating film to obtain the semipermeable coating film; the film forming material of the semipermeable membrane can be selected from one or more of cellulose acetate, cellulose acetate butyrate, ethyl cellulose and acrylic resin, and is preferably cellulose acetate, cellulose acetate butyrate or 'cellulose acetate and ethyl cellulose'; when the film forming material of the semipermeable membrane is cellulose acetate and ethyl cellulose, the weight ratio of the cellulose acetate to the ethyl cellulose is preferably (1-10): 1, such as 4:1 or 9: 1; in the coating solution of the film forming material containing the semipermeable membrane, a solvent can be acetone and/or ethanol, such as acetone or a mixed solution of acetone and ethanol, and when the solvent contains acetone and ethanol, the ratio of the acetone to the ethanol can be (2-20): 1, preferably (4-20): 1, such as 2.33:1, 4:1, 5.67:1, 6.14:1 or 19: 1; in the coating solution containing the film-forming material of the semipermeable membrane, the solid content of the film-forming material of the semipermeable membrane can be 2.0-8.0%, for example, 4.0% or 6.0%; the film forming material of the semi-permeable membrane also comprises a pore-foaming agent and/or a plasticizer; the pore-forming agent can be selected from one or more of polyethylene glycol, glycerol, povidone, copovidone and hydroxypropyl methylcellulose, and the plasticizer can be selected from one or more of polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, triacetin and castor oil;
alternatively, the semipermeable coating membrane is one or more of cellulose acetate membrane, cellulose acetate butyrate membrane, ethyl cellulose membrane and acrylic resin membrane, such as cellulose acetate membrane, cellulose acetate butyrate membrane or mixed membrane of "cellulose acetate and ethyl cellulose";
and/or the weight ratio of the semipermeable membrane to the core is 1.0-18.5 wt% or 5.0-18.5 wt%, such as 3.7 wt%, 5.0 wt%, 6.0 wt%, 6.1 wt%, 6.3 wt%, 6.4 wt%, 6.6 wt%, 7.0 wt%, 7.1 wt%, 7.5 wt%, 8.0 wt%, 8.1 wt%, 8.3 wt%, 8.4 wt%, 9.2 wt%, 9.4 wt%, 9.8 wt%, 10.0 wt%, 12.2 wt%, 12.6 wt%, 12.7 wt%, 15.0 wt%, 15.2 wt%, 15.3 wt%, 17.9 wt%, 18.0 wt%, 18.1 wt% or 18.2 wt%, more preferably 1.0-12.2 wt% or 5.0-12.2 wt%, and still more preferably 2.0-10.0 wt% or 5.0-10.0 wt%;
and/or, the medicine releasing holes on the coating are obtained by punching by adopting a laser punching method or a mechanical punching method;
and/or the pore size of the drug release pore is 0.3 mm-1.2 mm, such as 0.5mm or 1.0 mm;
and/or the tablet core and the coating also comprise an isolation coating layer, and the content of the isolation coating layer can be 1-12 wt% of the weight of the whole controlled release tablet;
and/or, the coating outer layer also comprises a moisture-proof film coating layer.
9. The controlled-release tablet according to any one of claims 1 to 8, wherein the controlled-release tablet has a shape of a circle or a profile, the profile may be an olive shape, an oval shape, a capsule shape or a polygon shape, and the polygon may be a quadrangle or a triangle; and/or the specification of the controlled release tablet is 11 mg/tablet, 22 mg/tablet, 30 mg/tablet, 60 mg/tablet or 90 mg/tablet;
when the specification of the controlled release tablet is 30 mg/tablet and the controlled release tablet is in a special shape, the size of at least one side of the controlled release tablet can be less than or equal to 8mm, preferably 4-8 mm, and more preferably 6-7 mm;
when the specification of the controlled release tablet is 60 mg/tablet and the controlled release tablet is shaped in a special shape, the size of at least one side of the controlled release tablet can be less than or equal to 10mm, preferably 6-9 mm, further preferably 7-8 mm, such as 8 mm;
when the specification of the controlled release tablet is 90 mg/tablet and the controlled release tablet is shaped in a special shape, the size of at least one side of the controlled release tablet can be less than or equal to 12mm, preferably 7-11 mm, further preferably 9-10 mm, for example 10 mm;
when the controlled release tablet is 11 mg/tablet and is circular in shape, the diameter of the controlled release tablet can be less than or equal to 8mm, preferably 4-8 mm, more preferably 5-7 mm, for example 5 mm;
when the controlled release tablet is 22 mg/tablet and is circular in shape, the diameter of the controlled release tablet can be less than or equal to 8mm, preferably 4-8 mm, more preferably 6-7 mm, such as 6 mm;
when the controlled release tablet is 30 mg/tablet and is circular in shape, the diameter of the controlled release tablet can be less than or equal to 8mm, preferably 4-8 mm, more preferably 6-7 mm, such as 6 mm;
when the specification of the controlled release tablet is 60 mg/tablet and the controlled release tablet is circular, the diameter of the controlled release tablet can be less than or equal to 10mm, preferably 6-9 mm, and further preferably 7-8 mm;
when the controlled release tablet can be 90 mg/tablet and is circular in shape, the diameter of the controlled release tablet can be less than or equal to 12mm, preferably 7-11 mm, and more preferably 9-10 mm.
10. A method for preparing a controlled release tablet according to any one of claims 1 to 9, comprising the steps of:
(1) compounding and pressing the raw material particles of the medicine-containing layer and the raw material particles of the boosting layer, wherein the boosting layer is compounded on the medicine-containing layer to form the tablet core;
(2) coating the coating on the tablet core, and punching a hole on the coating on one side of the drug-containing layer to form a drug release hole;
when the controlled release tablet further comprises an isolation coating layer, coating the isolation coating layer on the tablet core, and coating the coating on the isolation coating layer;
when the controlled release tablet further comprises a moisture-proof film coating layer, coating the moisture-proof film coating layer on the coating layer;
in the step (1), the raw material granules of the drug-containing layer can be obtained by granulation, and the granulation mode can be dry granulation, wet granulation, hot melt granulation or fluidized bed granulation;
in the step (1), the raw material particles of the boosting layer can be obtained by granulation, and the granulation mode can be dry granulation, wet granulation, hot melt granulation or fluidized bed granulation.
CN202110875326.9A 2020-07-30 2021-07-30 Controlled release tablet and preparation method thereof Pending CN114053237A (en)

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