CN114053241B - Solid dispersion and controlled-release tablet containing policosanol and preparation method thereof - Google Patents
Solid dispersion and controlled-release tablet containing policosanol and preparation method thereof Download PDFInfo
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- CN114053241B CN114053241B CN202010783032.9A CN202010783032A CN114053241B CN 114053241 B CN114053241 B CN 114053241B CN 202010783032 A CN202010783032 A CN 202010783032A CN 114053241 B CN114053241 B CN 114053241B
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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
- A61K9/28—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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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
- A61K9/2004—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
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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
- A61K9/2004—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Abstract
The invention relates to the technical field of policosanol preparations, and provides a solid dispersion containing policosanol, which comprises the policosanol, a surfactant and a carrier, wherein the surfactant is a nonionic surfactant for assisting dispersion; the particle size of the solid dispersion is not more than 5 μm. The invention provides a policosanol-containing controlled release tablet and a preparation method thereof, wherein the tablet comprises a double-layer tablet core and a controlled release film layer wrapping the double-layer tablet core; the double-layer tablet core consists of a medicine-containing layer and a boosting layer; the medicine-containing layer comprises policosanol, a surfactant, a filler, a carrier, an adhesive and a lubricant; the content of policosanol in each controlled release tablet is not less than 5mg. The invention can greatly reduce the particle size of the policosanol in the medicament, improve the dispersion degree and the solubility of the policosanol, control the release rate of the policosanol, prolong the release time and the administration interval, and further improve the bioavailability and the administration compliance of the policosanol in a human body.
Description
Technical Field
The invention relates to the technical field of policosanol preparations, in particular to a solid dispersion and a controlled-release tablet containing policosanol and a preparation method thereof.
Background
Policosanol is a mixture of eight higher fatty alcohols such as octacosanol extracted from Cera flava. Animal experiments show that the policosanol can reduce the serum cholesterol and low-density lipoprotein (LDL-C) levels of normal and endogenous high cholesterol animals. Various animal model researches show that the policosanol can reduce cholesterol in liver, adipose tissue and heart. The active ingredient drug has little acute toxicity when orally taken, and has no genetic toxicity, reproductive toxicity and carcinogenicity.
Policosanol tablets were first developed by cubadarma laboratories ltd and were marketed in cuba in 1991 with approval from the cub drug administration. In China, the approval of the Chinese drug administration was obtained in 2006 for the earliest time and the drug was imported into China. The traditional policosanol tablet is a common tablet, and the prescription contains the effective component of policosanol and auxiliary materials such as a diluent (also called a filler) used by the conventional oral tablet. The initial dosage of the medicine for regulating dyslipidemia is 5mg per day, and is taken at dinner. If the effect is not significant, the dose can be increased to 10 mg/day (once in the noon and evening) and for refractory patients the dose can be increased to 20 mg/day, twice daily.
At present, the existing tablets are generally taken twice a day, and the compliance of patients to take the medicine is low.
Disclosure of Invention
In view of the above, the present application provides a policosanol-containing solid dispersion, a controlled release tablet and a preparation method thereof, the solubility of the policosanol-containing solid dispersion in an oral preparation can be improved, and the controlled release tablet can slowly release the policosanol at a relatively constant speed, so that the pharmaceutical tablet can be taken once a day, the administration frequency is reduced, and the compliance is improved.
The invention provides a policosanol-containing solid dispersion, which comprises policosanol, a surfactant and a carrier, wherein the surfactant is a nonionic surfactant for assisting dispersion; the particle size of the polycosanol in the solid dispersion is not more than 5 mu m, and the preferable range is not more than 1 mu m.
Preferably, the surfactant is selected from one or more of sucrose esters, phospholipids, polysorbates, and polyoxyethylene fatty acid esters; the carrier is selected from one or more of polyethylene glycol and polyvinylpyrrolidone.
In the solid dispersion containing the policosanol, the dispersion state of the policosanol is improved through the auxiliary dispersion of the nonionic surfactant; the policosanol in the solid dispersion has smaller particle size, the particle size is not more than 5 mu m, the preferable range is not more than 1 mu m, the solubility of the policosanol can be effectively increased, the oral bioavailability is improved, and the control of the release rate of the controlled release preparation in the release process is facilitated.
The invention provides a controlled release tablet containing policosanol, which comprises the following components: the controlled release tablet comprises a double-layer tablet core and a controlled release film layer wrapping the double-layer tablet core; the double-layer tablet core consists of a medicine-containing layer and a boosting layer;
the medicine-containing layer comprises policosanol, a surfactant, a filler, a carrier, an adhesive and a lubricant; the surfactant is a nonionic surfactant for assisting dispersion; the content of policosanol in each controlled release tablet is above 5mg, preferably 5mg-80mg, more preferably 10mg-60mg.
Preferably, the surfactant is selected from one or more of sucrose esters, phospholipids, polysorbates, and polyoxyethylene fatty acid esters; the content of the surfactant is 0.5-10 times of the mass of the policosanol, the preferable range is 0.5-5 times, and the more preferable range is 0.5-3 times.
Preferably, the filler is a water-soluble filler, preferably one or more of sodium chloride, lactose, polyoxyethylene, mannitol, sorbitol and xylitol, more preferably a combination of at least two of polyoxyethylene, sodium chloride and lactose.
Preferably, the carrier is selected from one or more of polyethylene glycol and polyvinylpyrrolidone; the content of the carrier is 1-20 times, preferably 2-10 times of the mass of the policosanol.
Preferably, the lubricant is selected from one or more of stearic acid, magnesium stearate and sodium stearyl fumarate, preferably sodium stearyl fumarate; the adhesive is selected from one or more of polyvinylpyrrolidone, hypromellose and hydroxypropyl cellulose.
Preferably, the controlled release film layer is mainly formed by a film coating material and a pore-forming agent and is provided with a plurality of drug release holes.
The invention also provides a preparation method of the controlled release tablet containing the policosanol, which comprises the following steps:
mixing policosanol, a surfactant, a carrier material and a solvent to obtain a drug-containing solution; the drug-containing solution, the filler and the lubricant are granulated by a wet method to obtain drug-containing layer granules; optionally adding a binder to the drug-containing solution or during wet granulation;
respectively providing boosting layer particles and coating material solution;
tabletting the medicine-containing layer particles and the boosting layer particles to obtain a double-layer tablet core;
and coating the double-layer tablet core by adopting the coating material solution, and then punching to obtain the controlled-release tablet containing policosanol.
Preferably, heating the medicine-containing solution containing the policosanol, the surfactant and the carrier material to volatilize the solvent, so as to obtain a solid dispersion with the particle size of the policosanol not more than 5 mu m; the solid dispersion, the adhesive, the filler and the lubricant are subjected to wet granulation to obtain the drug-containing layer granules.
Preferably, the solvent is selected from one or more of small molecule alcohols and ketones, preferably one or more of ethanol, propylene glycol, isopropanol and acetone; the mixing temperature is from 40 ℃ to 100 ℃, preferably in the range of from 50 ℃ to 90 ℃.
Compared with the common policosanol tablet, the invention provides the policosanol controlled-release tablet which has a double-layer tablet core structure and is coated with a controlled-release film coat; the main body of the preparation consists of a tablet core medicine-containing layer and a tablet core boosting layer, wherein the medicine-containing layer consists of a certain amount of policosanol, a surfactant, a filling agent, a carrier, an adhesive and a lubricant. In the invention, the content of the policosanol in each controlled-release tablet is more than 5mg, preferably 5-80 mg; the surfactant is a nonionic surfactant for assisting dispersion. The invention can greatly reduce the particle size of the policosanol in the medicament, improve the dispersion degree and the solubility of the policosanol, control the release rate of the policosanol, prolong the release time and the medicament taking interval, can take the medicinal tablet once a day, reduce the administration frequency and further improve the bioavailability of the policosanol in a human body and the compliance of medicament administration.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a policosanol-containing solid dispersion, which comprises policosanol, a surfactant and a carrier, wherein the surfactant is a nonionic surfactant for assisting dispersion; the particle size of policosanol in the solid dispersion is not more than 5 mu m.
The solid dispersion containing the policosanol provided by the invention has smaller particle size, can improve the dispersion degree and the solubility in an oral preparation, and further improves the bioavailability.
Solid dispersions, which are intermediates for pharmaceutical preparations, are dispersions of a drug highly dispersed in a solid carrier, usually composed of a drug and a carrier.
The preparation method provided by the embodiment of the invention adopts a formula containing policosanol, a surfactant and a carrier, so that the solid dispersion with a small particle size of the policosanol can be prepared. Wherein policosanol is effective component of medicine for regulating blood lipid abnormality, and is mixture containing eight kinds of higher fatty alcohols such as octacosanol extracted from Cera flava.
In the invention, the surfactant is a pharmaceutically acceptable nonionic (type) surfactant, and mainly plays a role in assisting dispersion. The nonionic surfactant is preferably one or more selected from sucrose esters, phospholipids, polysorbates and polyoxyethylene fatty acid esters, and more preferably sucrose esters, phospholipids or polyoxyethylene fatty acid esters. The sucrose ester is called sucrose fatty acid ester (SE) completely, and the HLB value distribution is wide; the current commercial products are mainly monoesters, diesters, triesters and mixed esters of sucrose esterified with stearic acid, palmitic acid or oleic acid. Phospholipids are a class of lipids containing phosphate groups, such as phosphoglycerides. The polyoxyethylene fatty acid ester, also called fatty acid polyoxyethylene (ether) ester, has hydrophilicity proportional to the degree of polymerization of ethoxy groups. The dosage of the surfactant is 0.5-10 times of the mass of the policosanol, the preferable range is 0.5-5 times, and the more preferable range is 0.5-3 times, so that the performance of the solid dispersion is facilitated.
In the embodiment of the present invention, a water-soluble carrier material is mainly used, and the carrier can be selected from one or more of polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP, povidone). Wherein, the relative molecular mass of the polyethylene glycol can be 1000 to 30000, preferably 1000 to 20000, such as polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, etc.; the relative molecular mass of the polyvinylpyrrolidone may be from 2500 to 50000. The dosage of the carrier is 1-20 times, preferably 2-10 times of the mass of the policosanol.
The surfactant and the carrier with the prescription amount are weighed in the embodiment of the invention, can be respectively added into the solvent with a certain proportion in a stirring state, are uniformly dispersed, and preferably are slowly heated to the set temperature to obtain the carrier solution. Wherein, the solvent can be selected from one or more of small molecular alcohol and ketone, preferably one or more of ethanol, propylene glycol, isopropanol and acetone, and more preferably ethanol and/or acetone.
Then, the policosanol in the prescribed amount is weighed in the embodiment of the invention, added into the carrier solution under stirring, and continuously stirred until the policosanol is dissolved, so as to obtain a drug-containing solution. The policosanol can be dissolved in hot organic solvents, such as ethanol, propylene glycol, isopropanol and acetone, and preferably ethanol and acetone; the temperature of mixing or dissolving is 40 ℃ to 100 ℃, preferably in the range of 50 ℃ to 90 ℃.
In the embodiment of the invention, the medicine-containing solution containing policosanol, the surfactant and the carrier material is continuously heated to raise the temperature, wherein the temperature rise range is 40-100 ℃, and the preferred range is 50-90 ℃; dissolving policosanol in hot organic solvent, uniformly dispersing in mixture of other surfactant and carrier, volatilizing organic solvent to obtain solid dispersion containing policosanol with small particle size, pulverizing at low temperature, and sieving with 100 mesh sieve. The solid dispersion is typically a light yellow solid; wherein the particle size of the policosanol is not more than 5 μm, the preferable range is not more than 1 μm, such as 0.01-1 μm, the solubility of the policosanol can be effectively increased, and the control of the release rate of the controlled release tablet in the release process is facilitated.
In addition, the present invention provides a controlled-release tablet containing policosanol, comprising: a double-layer tablet core and a controlled release film layer wrapping the double-layer tablet core; the double-layer tablet core consists of a medicine-containing layer and a boosting layer;
the medicine-containing layer comprises policosanol, a surfactant, a filler, a carrier, an adhesive and a lubricant; the surfactant is a nonionic surfactant for assisting dispersion; the content of policosanol in each controlled release tablet is above 5mg.
The policosanol-containing controlled-release tablet provided by the invention can slowly release policosanol at a relatively constant speed, so that the pharmaceutical tablet can be taken once a day, the taking frequency is reduced, and the compliance of taking medicine is improved.
The controlled release tablet provided by the embodiment of the invention is a double-layer controlled release tablet, wherein a double-layer tablet core consists of a tablet core drug-containing layer and a tablet core boosting layer and is coated with a controlled release film coat. In the double-layer tablet core, the medicine-containing layer consists of a certain amount of policosanol, a surfactant, a filling agent, a carrier, an adhesive and a lubricant. In the present invention, the policosanol content in each controlled-release tablet is 5mg or more, preferably 5mg to 80mg, more preferably 10mg to 60mg, for example, 10mg, 20mg, 30mg, 40mg, etc.
In the tablet core medicament-containing layer, the surfactant is a pharmaceutically acceptable nonionic (type) surfactant and is mainly used for assisting in dispersion. The nonionic surfactant is preferably one or more selected from sucrose esters, phospholipids, polysorbates and polyoxyethylene fatty acid esters, and more preferably sucrose esters, phospholipids or polyoxyethylene fatty acid esters. The sucrose ester is called sucrose fatty acid ester (SE) completely, and the HLB value distribution is wide; the current commercial products are mainly monoesters, diesters, triesters and mixed esters of sucrose and stearic acid, palmitic acid or oleic acid. Phospholipids are a class of lipids containing phosphate groups, such as phosphoglycerides. The polyoxyethylene fatty acid ester, also called fatty acid polyoxyethylene (ether) ester, has hydrophilicity proportional to the degree of polymerization of ethoxy groups. The content of the surfactant is 0.5-10 times of the mass of the policosanol, the preferable range is 0.5-5 times, and the more preferable range is 0.5-3 times.
In the embodiment of the present invention, the filler is preferably a water-soluble filler, more preferably one or more of sodium chloride, lactose, polyoxyethylene, mannitol, sorbitol, and xylitol, and more preferably a combination of at least two of polyoxyethylene, sodium chloride, and lactose. The filler is matched with a surfactant and the like, and can control the release of the polycosanol at a relatively constant rate after contacting with water in a machine body. In some embodiments, the filler is a combination of polyoxyethylene and sodium chloride; in other embodiments, the filler is a combination of polyoxyethylene and lactose, and has good compatibility with drugs. The content of the filler is preferably 2 to 6 times, for example, 2, 3, 4, 5, 6 times, etc., the mass of the policosanol.
In the embodiment of the invention, a water-soluble carrier material is mainly adopted, and the carrier can be selected from one or more of polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP and povidone). Wherein, the relative molecular mass of the polyethylene glycol can be 1000 to 30000, preferably 1000 to 20000, such as polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, etc.; the relative molecular mass of the polyvinylpyrrolidone may be from 2500 to 50000. The content of the carrier is 1-20 times, preferably 2-10 times of the mass of the policosanol.
The prescription of the medicine-containing layer of the tablet core also comprises a binding agent and a lubricant which are pharmaceutic adjuvants, wherein the lubricant can be one or more of stearic acid, magnesium stearate and sodium stearate fumarate, and is preferably magnesium stearate or sodium stearate fumarate, so that the surface characteristics of the prepared granules can be improved, and tabletting is convenient. In addition, the content of the lubricant can be 0.1-0.5 time of the mass of the policosanol, and the performance of the tablet is easily influenced by the excessive use amount. The binder may be polyvinylpyrrolidone, cellulose derivatives, etc., preferably one or more of polyvinylpyrrolidone, hypromellose (HPMC) and hydroxypropyl cellulose (HPC), more preferably polyvinylpyrrolidone.
The controlled release tablet also comprises a tablet core boosting layer, and the prescription mainly comprises a filling agent, an adhesive and a lubricant, so that the tablet has the function of assisting in drug release. The formulation of the boosting layer can be selected from the same types as the medicament-containing layer of the tablet core, and for example, the filling agent is preferably one or more of sodium chloride, lactose, polyoxyethylene, mannitol, sorbitol and xylitol. In the formula of the tablet core boosting layer, the adhesive can be polyvinylpyrrolidone, hydroxypropyl methylcellulose and the like; the lubricant is selected from one or more of stearic acid, magnesium stearate and sodium stearate fumarate, preferably magnesium stearate or sodium stearate fumarate. In the boosting layer, the using amount of the adhesive is 3% -10% of the total amount of auxiliary materials of the boosting layer, and the optimal selecting amount is 4-6%; the dosage of the lubricant is 2 to 3 percent of the total amount of the auxiliary materials; the rest is filling agent.
In the invention, the controlled-release film layer is wrapped on the double-layer tablet core, and is a film coating which mainly controls the release speed of the medicine. The controlled release film layer is mainly formed by a film coating material and a pore-forming agent and is provided with a plurality of drug release holes. Wherein, the film coating material is preferably cellulose acetate. The control agent is also called release rate regulator, and can adopt one or more of hydroxypropyl cellulose and polyethylene glycol.
The weight of each tablet of the controlled-release tablet containing the polycosanol in the embodiment of the invention is changed along with the change of the content of the polycosanol, and is about 10-40 times of the content of the polycosanol, wherein the medicine-containing layer accounts for 25-50% of the weight of the whole tablet, the boosting layer accounts for 40-60% of the weight of the whole tablet, and the coating layer accounts for 5-15% of the weight of the whole tablet.
Some embodiments of the present invention provide a method for preparing a controlled release tablet containing policosanol as described hereinbefore, comprising the steps of:
mixing policosanol, a surfactant, a carrier material, an adhesive and a solvent to obtain a medicine-containing solution; the drug-containing solution, the filler and the lubricant are granulated by a wet method to obtain drug-containing layer granules;
respectively providing boosting layer particles and coating material solution;
tabletting the medicine-containing layer particles and the boosting layer particles to obtain a double-layer tablet core;
and coating the double-layer tablet core by adopting the coating material solution, and then punching to obtain the controlled-release tablet containing policosanol.
The specific types and the dosage of the effective components of the medicine and each auxiliary material are as described in the prescription above. In the embodiment of the present invention, the prescribed amounts of the surfactant, the carrier and the binder can be taken, added into a certain amount of the solvent respectively under stirring, dispersed uniformly, and slowly heated to a set temperature to obtain a carrier solution. According to the embodiment of the invention, the policosanol with the formula amount is weighed, preferably added into the carrier solution in a stirring state, and continuously stirred until the policosanol is dissolved, so as to obtain a medicine-containing solution. The policosanol raw material meeting the national quality standard is adopted in the embodiment of the invention, and the auxiliary material is a corresponding commercial product.
In the embodiment of the invention, the filling agent with the prescription amount is weighed and placed in a granulation container for mixing, and then the medicine-containing solution is added into the granulation container for granulation; drying the granulated granules to obtain dry granules, and adding a prescription amount of lubricant for mixing to obtain the medicine-containing layer granules.
And tabletting the medicine-containing layer particles and the boosting layer particles to form a double-layer tablet core, and finally coating and punching medicine releasing holes to prepare the policosanol double-layer controlled release tablet.
In other embodiments of the present invention, the preparation method of the controlled release tablet containing policosanol comprises the following steps:
mixing policosanol, a surfactant, a carrier material and a solvent to obtain a drug-containing solution; heating the medicine-containing solution to raise the temperature, and volatilizing the solvent to obtain a solid dispersion; the solid dispersion, the adhesive, the filler and the lubricant are subjected to wet granulation to obtain medicine-containing layer granules;
the rest steps are consistent with the preparation process.
The preparation of the drug-containing layer particles according to the preferred embodiment of the present invention is carried out in the second way, and the preparation process will be described in detail below. The method comprises the steps of weighing a surfactant and a carrier according to the prescription amount, respectively adding the surfactant and the carrier into a certain amount of solvent under the stirring state, uniformly dispersing, and slowly heating to a set temperature to obtain a carrier solution. Wherein, the solvent can be selected from one or more of small molecular alcohol and ketone, preferably one or more of ethanol, propylene glycol, isopropanol and acetone, and more preferably ethanol and/or acetone. And the dosage of the solvent is 3-15 times, preferably 3-10 times of the dosage of the policosanol.
In addition, the policosanol in the formula amount is weighed in the embodiment of the invention, is preferably added into the carrier solution in a stirring state, and is continuously stirred until the policosanol is dissolved, so that a medicine-containing solution is obtained. The policosanol can be dissolved in hot organic solvents, such as ethanol, propylene glycol, isopropanol and acetone, and preferably ethanol and acetone; the temperature of mixing or dissolving is 40 ℃ to 100 ℃, preferably in the range of 50 ℃ to 90 ℃, such as 50 ℃, 60 ℃, 70 ℃ and the like.
In the embodiment of the invention, the medicated solution containing policosanol, the surfactant and the carrier material is heated continuously, the temperature rise range is 40 ℃ to 100 ℃, and the preferred range is 50 ℃ to 90 ℃; the policosanol can be uniformly dispersed in a mixture of other surfactants and carriers after being dissolved in a hot organic solvent, can form a solid dispersion after the organic solvent is volatilized, and is obtained by low-temperature crushing and 100-mesh sieving. The solid dispersion is typically a light yellow solid; wherein the particle size of the policosanol is not more than 5 μm, the preferable range is not more than 1 μm, the solubility of the policosanol can be effectively increased, and the control of the release rate of the controlled release tablet in the release process is facilitated.
After the solid dispersion is obtained, the solid dispersion and the prescribed amount of filler are mixed in a wet granulator, then a binder solution (which can be dissolved in a solvent in advance) is added into the granulation equipment for granulation, the granules after granulation are dried to obtain dry granules, and finally the prescribed amount of lubricant is added for mixing to obtain medicine-containing layer granules for later use. The wet granulation process of the present invention is not particularly limited, and may be carried out in a conventional manner.
According to the tablet core boosting layer formula, the preparation of boosting layer particles is carried out in the embodiment of the invention; the method specifically comprises the following steps:
(1) Weighing the adhesive in the prescription amount, respectively adding the adhesive into a certain amount of solvent under the stirring state, and uniformly stirring and dispersing to obtain an adhesive solution;
(2) The prescribed amount of filler is weighed and placed in a granulation vessel for mixing. Adding the binder solution in the step (1) into the granulation container for granulation;
(3) Drying the granulated particles to obtain dry particles, adding a lubricant in a prescription amount, and mixing to obtain the boosting layer particles for later use. Wherein, the solvent used for preparing the boosting layer particles is selected from one or more of ethanol, propylene glycol, isopropanol and acetone, and ethanol or acetone is preferred.
In addition, the embodiment of the invention prepares a coating material solution (coating solution for short): adding a certain amount of film coating material and pore-forming agent into solvent, stirring and dispersing uniformly to obtain coating material solution for later use. The optional types of the film coating material and the pore-forming agent are as described above; the solvent involved may be one or more of water, ethanol, propylene glycol, isopropanol and acetone.
Finally, the obtained granules containing the medicine layer are filled into a double-layer tablet press for first tabletting, and after the first tabletting is finished, the granules containing the boosting layer are filled into the double-layer tablet press for second tabletting to obtain a double-layer tablet core; coating the double-layer tablet core by adopting the coating material solution to obtain a coated tablet; and (3) perforating the coated tablet by adopting a laser perforation technology or a mechanical perforation technology to obtain the policosanol controlled release tablet. The invention has no special limitation on the setting of the process parameters such as tabletting, coating, punching and the like, and is a process operation commonly used by people in the field.
After obtaining the controlled release tablet containing the policosanol, the dissolution rate of the controlled release tablet is determined by the embodiment of the invention. The controlled-release tablet is a medicine with a slow-release curative effect and capable of regulating dyslipidemia, and can slowly release policosanol at a relatively constant speed, so that the controlled-release tablet can be taken once a day, the taking frequency is reduced, and the compliance is improved. In addition, the preparation process is simple and feasible, and is suitable for large-scale industrial application.
For further understanding of the present application, the solid dispersion containing policosanol, the controlled release tablet and the preparation method thereof provided by the present application are specifically described below with reference to examples. It should be understood, however, that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention, which is defined by the following examples.
Example 1
The prescription of the medicine-containing layer of the tablet core:
the preparation process of the medicine-containing layer particles comprises the following steps:
(1) Weighing the soybean phospholipid and the polyethylene glycol 6000 with the prescription amount, respectively adding the soybean phospholipid and the polyethylene glycol 6000 into the acetone with the prescription amount under the stirring state, uniformly dispersing, and slowly heating to 50 ℃.
(2) Weighing policosanol according to the prescription amount, adding the policosanol into the solution in the step (1) under the stirring state, and continuously stirring until the policosanol is dissolved to obtain a medicine-containing solution.
(3) Heating the solution containing medicine in (2) to obtain light yellow solid after acetone volatilization, pulverizing the solid at low temperature, and sieving with 100 mesh sieve.
(4) Weighing polyvinylpyrrolidone in a prescription amount, adding the polyvinylpyrrolidone in ethanol in the prescription amount, and stirring and dissolving to obtain an adhesive solution.
(5) Weighing lactose and polyoxyethylene in the prescription amount, and putting the lactose and polyoxyethylene and the solid sieved by the 100-mesh sieve in the step (3) into a wet granulator together, and mixing.
(6) Adding the binder solution in the step (4) into a wet granulator for granulation.
(7) Drying the granulated granules to obtain dry granules, adding magnesium stearate in a prescription amount, and mixing to obtain medicine-containing layer granules for later use.
The formula of the tablet core boosting layer is as follows:
the preparation process of the boosting layer particles comprises the following steps:
(1) Weighing polyvinylpyrrolidone in a prescription amount, adding the polyvinylpyrrolidone into ethanol in the prescription amount under a stirring state, and uniformly stirring and dispersing to obtain a binder solution.
(2) Lactose and polyoxyethylene in the prescribed amount are weighed and placed in a wet granulator for mixing. Adding the binder solution in the step (1) into a granulator for granulation.
(3) And drying the granulated granules to obtain dry granules, adding magnesium stearate in a prescription amount, and mixing to obtain the boosting layer granules for later use.
Coating formula:
the preparation process of the coating liquid comprises the following steps:
weighing the cellulose acetate, the hydroxypropyl cellulose and the polyethylene glycol according to the prescription amount, respectively adding the mixture into the mixed solution of water and acetone under the stirring state, and uniformly stirring and dispersing to obtain a coating material solution for later use.
The preparation process of the policosanol controlled release tablet comprises the following steps:
(1) And filling the medicine-containing layer granules into a double-layer tablet press for first tabletting, and filling the boosting layer granules into the double-layer tablet press for second tabletting after the first tabletting is finished to obtain the double-layer tablet core.
(2) And (3) coating the double-layer tablet core in the step (1) by adopting a coating material solution to obtain a coated tablet. Perforating the coated tablet by adopting a laser perforating technology to obtain policosanol controlled release tablets, about 10000 tablets; the content of policosanol in each controlled release tablet is 60mg.
Example 2
The prescription of the medicine-containing layer of the tablet core:
the preparation process of the medicine-containing layer particles comprises the following steps:
(1) Weighing sucrose ester, polyethylene glycol and polyvinylpyrrolidone according to the prescription amount, respectively adding into ethanol according to the prescription amount under the stirring state, uniformly dispersing, and slowly heating to 70 ℃.
(2) Weighing policosanol according to the prescription amount, adding the policosanol into the solution in the step (1) under the stirring state, and continuously stirring until the policosanol is dissolved to obtain a medicine-containing solution.
(3) Weighing sodium chloride and polyoxyethylene according to the prescription amount, and placing the sodium chloride and the polyoxyethylene in a fluidized bed granulator for mixing. Adding the solution in the step (2) into a fluidized bed granulator for granulation.
(4) Drying the granulated granules to obtain dry granules, adding a lubricant in a prescription amount, and mixing to obtain medicine-containing layer granules for later use.
The formula of the tablet core boosting layer is as follows:
the preparation process of the boosting layer particles comprises the following steps:
(1) Weighing hydroxypropyl cellulose with the formula amount, adding the hydroxypropyl cellulose into ethanol with the formula amount under the stirring state, and uniformly stirring and dispersing to obtain the adhesive solution.
(2) Weighing sodium chloride and polyoxyethylene according to the prescription amount, and placing the sodium chloride and the polyoxyethylene in a wet granulator for mixing. Adding the binder solution in the step (1) into a granulator for granulation.
(3) And drying the granulated particles to obtain dry particles, adding a lubricant in a prescription amount, and mixing to obtain the boosting layer particles for later use.
Coating formula:
the preparation process of the coating liquid comprises the following steps:
weighing the cellulose acetate, the hydroxypropyl cellulose and the polyethylene glycol according to the prescription amount, respectively adding the mixture into the mixed solution of water and acetone under the stirring state, and uniformly stirring and dispersing to obtain a coating material solution for later use.
The preparation process of the policosanol tablet comprises the following steps:
(1) And filling the medicine-containing layer granules into a double-layer tablet press for first tabletting, and filling the boosting layer granules into the double-layer tablet press for second tabletting after the first tabletting is finished to obtain the double-layer tablet core.
(2) And (3) coating the double-layer tablet core in the step (1) by adopting a coating material solution to obtain a coated tablet. And (3) perforating the coated tablet by adopting a laser perforating technology to obtain the policosanol controlled release tablet which is about 10000 tablets.
Example 3
The prescription of the medicine-containing layer of the tablet core is as follows:
the preparation process of the medicine-containing layer particles comprises the following steps:
(1) Weighing polyoxyethylene oleate, polyethylene glycol and polyvinylpyrrolidone in the prescription amount, respectively adding the polyoxyethylene oleate, polyethylene glycol and polyvinylpyrrolidone in 70% ethanol in the prescription amount under the stirring state, uniformly dispersing, and slowly heating to 70 ℃.
(2) Weighing policosanol according to the prescription amount, adding the policosanol into the solution in the step (1) under the stirring state, and continuously stirring until the policosanol is dissolved to obtain a medicine-containing solution.
(3) Heating the solution containing medicine in (2) to obtain light yellow solid after ethanol volatilization, pulverizing at low temperature, and sieving with 100 mesh sieve.
(4) And (4) mixing the medicine-containing powder sieved by the 100-mesh sieve in the step (3) with the sodium chloride and the polyoxyethylene in the prescribed amount in a wet granulating machine.
(5) Weighing 30% of ethanol according to the prescription amount, and adding the ethanol into the wet granulator in the step (4) for granulation.
(6) Drying the granulated granules to obtain dry granules, adding sodium stearyl fumarate of the prescribed amount, and mixing to obtain medicinal layer granules for later use.
The formula of the tablet core boosting layer is as follows:
the preparation process of the boosting layer particles comprises the following steps:
(1) Weighing polyvinylpyrrolidone in a prescription amount, adding the polyvinylpyrrolidone into ethanol in the prescription amount under a stirring state, and uniformly stirring and dispersing to obtain the adhesive solution.
(2) Weighing sodium chloride and polyoxyethylene according to the prescription amount, and placing the sodium chloride and the polyoxyethylene in a wet granulator for mixing. Adding the binder solution in the step (1) into a granulator for granulation.
(3) And drying the granulated particles to obtain dry particles, adding a lubricant in a prescription amount, and mixing to obtain the boosting layer particles for later use.
Coating formula:
the preparation process of the coating liquid comprises the following steps:
weighing the formula amount of cellulose acetate, hydroxypropyl cellulose and polyethylene glycol, respectively adding the mixture into a mixed solution of water and acetone under the stirring state, and uniformly stirring and dispersing to obtain a coating material solution for later use.
The preparation process of the policosanol tablets comprises the following steps:
(1) And filling the medicine-containing layer granules into a double-layer tablet press for first tabletting, and filling the boosting layer granules into the double-layer tablet press for second tabletting after the first tabletting is finished to obtain the double-layer tablet core.
(2) And (3) coating the double-layer tablet core in the step (1) by adopting a coating material solution to obtain a coated tablet. And (3) perforating the coated tablet by adopting a laser perforating technology to obtain the policosanol controlled release tablet which is about 10000 tablets.
Comparative example 1
The prescription of the medicine-containing layer of the tablet core is as follows:
the preparation process of the medicine-containing layer particles comprises the following steps:
(1) Weighing policosanol according to the prescription amount, adding the policosanol into ethanol according to the prescription amount under the stirring state, continuously stirring, and slowly heating to 50 ℃ to obtain a drug-containing suspension.
(2) Weighing hydroxypropyl cellulose, starch and polyoxyethylene according to the prescription amount, placing the hydroxypropyl cellulose, the starch and the polyoxyethylene into a wet granulator, and mixing.
(3) And (2) adding the suspension containing the medicine in the step (1) into a wet granulating machine for granulation.
(4) Drying the granulated granules to obtain dry granules, adding magnesium stearate in a prescription amount, and mixing to obtain medicine-containing layer granules for later use.
The formula of the tablet core boosting layer is as follows:
the preparation process of the boosting layer particles comprises the following steps:
(1) Weighing polyvinylpyrrolidone in a prescription amount, adding the polyvinylpyrrolidone into ethanol in the prescription amount under a stirring state, and uniformly stirring and dispersing to obtain a binder solution.
(2) Weighing polyoxyethylene with a prescription amount, and placing the polyoxyethylene in a wet granulator. Adding the binder solution in the step (1) into a granulator for granulation.
(3) And drying the granulated granules to obtain dry granules, adding magnesium stearate in a prescription amount, and mixing to obtain the boosting layer granules for later use.
Coating formula:
the preparation process of the coating liquid comprises the following steps:
weighing the formula amount of cellulose acetate, hydroxypropyl cellulose and polyethylene glycol, respectively adding the mixture into a mixed solution of water and acetone under the stirring state, and uniformly stirring and dispersing to obtain a coating material solution for later use.
The preparation process of the policosanol tablets comprises the following steps:
(1) And filling the medicine-containing layer particles into a double-layer tablet press for first tabletting, and after the first tabletting is finished, filling the boosting layer particles into the double-layer tablet press for second tabletting to obtain the double-layer tablet core.
(2) And (2) coating the double-layer tablet core in the step (1) by adopting a coating material solution to obtain a coated tablet.
(3) And (3) perforating the coated tablets by adopting a laser perforating technology to obtain about 10000 policosanol controlled release tablets.
Dissolution determination
Putting 6 policosanol controlled release tablets prepared above into a dissolution cup, wherein the dissolution medium is phosphate buffer solution with pH6.8, the temperature is 37 ℃, and the stirring speed is 50r/min. Sampling at 1h, 2h, 4h, 8h, 12h, 18h and 24h, determining the content of octacosanol by gas chromatography, calculating the release amount of the polycosanol controlled release tablet at different time points according to the content, and taking an average value.
Specific release data are shown in table 1:
TABLE 1 Release Rate data of policosanol controlled Release tablets in phosphate buffer at pH6.8
As can be seen from the table, in the formulation of comparative example 1, there were no surfactants, water-soluble fillers, etc., resulting in that the cumulative amount of policosanols released in the release medium at each time point was much smaller than that of 3 examples of the present invention, and the release was not complete at 24 hours, failing to achieve the desired effect of controlled release of the drug.
Compared with the traditional policosanol tablet, the invention can greatly reduce the particle size of the policosanol in the medicament, improve the dispersion degree and the solubility of the policosanol, control the release rate of the policosanol, prolong the release time and the administration interval, and further improve the bioavailability of the policosanol in a human body and the administration compliance of the policosanol.
The above description is only a preferred embodiment of the present invention, and it should be noted that various modifications to these embodiments can be implemented by those skilled in the art without departing from the technical principle of the present invention, and these modifications should be construed as the scope of the present invention.
Claims (15)
1. A controlled release tablet containing policosanol, characterized in that it comprises: a double-layer tablet core and a controlled release film layer wrapping the double-layer tablet core; the double-layer tablet core consists of a medicine-containing layer and a boosting layer;
the medicine-containing layer comprises policosanol, a surfactant, a filler, a carrier, an adhesive and a lubricant; the surfactant is a nonionic surfactant for assisting dispersion; the content of policosanol in each controlled release tablet is more than 5 mg; the nonionic surfactant is selected from one or more of sucrose ester, phospholipid, polysorbate and polyoxyethylene fatty acid ester; the carrier is selected from one or more of polyethylene glycol and polyvinylpyrrolidone; the filler is one or more of sodium chloride, lactose, polyoxyethylene, mannitol, sorbitol and xylitol; the lubricant is selected from one or more of stearic acid, magnesium stearate and sodium stearyl fumarate; the adhesive is selected from one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose;
the preparation method of the controlled release tablet comprises the following steps:
mixing policosanol, a surfactant, a carrier material and a solvent to obtain a medicine-containing solution; heating the medicine-containing solution containing policosanol, a surfactant and a carrier material to raise the temperature, and volatilizing the solvent to obtain a solid dispersion with the particle size of the policosanol not larger than 5 microns; the solid dispersion, the adhesive, the filler and the lubricant are granulated by a wet method to obtain the medicine-containing layer particles; adding a binder into the drug-containing solution or wet granulation; the solvent is selected from one or more of small molecular alcohol and ketone;
respectively providing boosting layer particles and coating material solution;
tabletting the medicine-containing layer particles and the boosting layer particles to obtain a double-layer tablet core;
and coating the double-layer tablet core by adopting the coating material solution, and then punching to obtain the controlled-release tablet containing policosanol.
2. The controlled-release tablet according to claim 1, characterized in that the particle size of the polycosanols in the solid dispersion is not more than 1 μm.
3. The controlled-release tablet of claim 1, wherein the policosanol content of each controlled-release tablet is 5mg to 80mg.
4. The controlled-release tablet of claim 3, wherein the policosanol content of each controlled-release tablet is 10mg to 60mg.
5. The controlled-release tablet according to claim 1, wherein the content of the surfactant is 0.5 to 10 times the mass of the policosanol.
6. The controlled-release tablet according to claim 5, wherein the surfactant content is 0.5 to 5 times by mass of policosanol.
7. The controlled-release tablet according to claim 6, wherein the surfactant content is 0.5 to 3 times by mass of policosanol.
8. The controlled-release tablet according to claim 1, wherein the filler is a combination of at least two of polyoxyethylene, sodium chloride and lactose.
9. The controlled-release tablet according to any one of claims 1 to 8, wherein the content of the carrier is 1 to 20 times the mass of the polycosanol.
10. The controlled-release tablet according to claim 9, wherein the content of the carrier is 2-10 times of the mass of the policosanol.
11. The controlled release tablet of any one of claims 1 to 8, wherein the lubricant is sodium fumarate stearate.
12. The controlled-release tablet according to any one of claims 1 to 8, wherein the controlled-release film layer is mainly formed of a film coating material and a pore-forming agent, and has a plurality of release pores.
13. The process for the preparation of the policosanol-containing controlled release tablet according to any one of claims 1 to 12, comprising the steps of:
mixing policosanol, a surfactant, a carrier material and a solvent to obtain a medicine-containing solution; heating the medicine-containing solution containing policosanol, a surfactant and a carrier material to raise the temperature, and volatilizing the solvent to obtain a solid dispersion with the particle size of the policosanol not larger than 5 microns; the solid dispersion, the adhesive, the filler and the lubricant are granulated by a wet method to obtain the medicine-containing layer particles; adding a binder into the drug-containing solution or wet granulation; the solvent is selected from one or more of small molecular alcohol and ketone;
respectively providing boosting layer particles and coating material solution;
tabletting the medicine-containing layer particles and the boosting layer particles to obtain a double-layer tablet core;
and coating the double-layer tablet core by adopting the coating material solution, and then punching to obtain the controlled-release tablet containing the policosanol.
14. The method of claim 13, wherein the mixing temperature is 40 ℃ to 100 ℃.
15. The method according to claim 14, wherein the solvent is one or more of ethanol, propylene glycol, isopropyl alcohol, and acetone; the mixing temperature is 50 ℃ to 90 ℃.
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| CN101390839A (en) * | 2008-10-28 | 2009-03-25 | 广西万寿堂药业有限公司 | Policosanol drop pill and preparation method thereof |
| CN104857515A (en) * | 2014-02-25 | 2015-08-26 | 中国科学院上海药物研究所 | Controlled release dosing medicine core composition and osmotic pump preparation comprising medicine core composition |
| CN111000811A (en) * | 2019-12-31 | 2020-04-14 | 济南大学 | Orally rapidly disintegrating tablet containing policosanol |
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| CN101390839A (en) * | 2008-10-28 | 2009-03-25 | 广西万寿堂药业有限公司 | Policosanol drop pill and preparation method thereof |
| CN104857515A (en) * | 2014-02-25 | 2015-08-26 | 中国科学院上海药物研究所 | Controlled release dosing medicine core composition and osmotic pump preparation comprising medicine core composition |
| CN111000811A (en) * | 2019-12-31 | 2020-04-14 | 济南大学 | Orally rapidly disintegrating tablet containing policosanol |
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