CN112933055A - Paliperidone gastric retention tablet and preparation method thereof - Google Patents
Paliperidone gastric retention tablet and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Abstract
The application belongs to the technical field of medicines, and particularly relates to paliperidone gastric retention tablets and a preparation method thereof. The paliperidone gastric retention tablet comprises the following raw materials in parts by weight: 2-3 parts of paliperidone, 10-15 parts of glyceryl monostearate, 20-30 parts of lecithin, 1-2 parts of surfactant, 10-15 parts of hydroxypropyl methylcellulose, 10-15 parts of polyoxyethylene, 24-30 parts of filler, 8-12 parts of foaming agent, 0.5-1 part of bleaching aid and 0.1-0.5 part of glidant. The paliperidone gastric retention tablet enables drugs to float and be retained in gastric juice through the synergistic effect of all components, the retention time of the paliperidone drug in the gastric juice is prolonged, the drugs are slowly released, the release time of the drugs in the digestive tract is prolonged, absorption is enhanced, blood concentration fluctuation is reduced, and therefore bioavailability is improved.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to paliperidone gastric retention tablets and a preparation method thereof.
Background
Schizophrenia is a psychiatric disease, is a serious mental disease which is persistent and usually chronic, is the most serious mental disease in psychosis, is the most common mental disease which is mainly characterized by basic personality, division of thinking, emotion and behavior and incoordination between mental activities and environments, and is caused by the disease in many young years, so that the behavior and the emotion are influenced.
Paliperidone is an atypical antipsychotic, is a main active metabolite of plasma of risperidone, exerts drug effect mainly by antagonizing 5-hydroxytryptamine and dopamine receptors, plays an auxiliary treatment role in affinity action of other 5-hydroxytryptamine receptor subtypes, and is widely used for treating schizophrenia.
At present, the paliperidone sustained release tablet on the market adopts a three-layer transdermal pump tablet formulation, is prepared by wrapping a tablet core by a semipermeable membrane, and the tablet core consists of a first drug layer, a second drug layer and a boosting layer, and has complex preparation process and high cost. The injection preparation is almost imported and is expensive.
Disclosure of Invention
The application aims to provide a paliperidone gastric retention tablet and a preparation method thereof, and aims to solve the problems that the existing paliperidone sustained-release tablets, injections and other preparations are complex in process, high in difficulty and low in sustained-release effect to a certain extent.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the application provides a paliperidone gastric retention tablet, which comprises the following raw materials in parts by weight:
in a second aspect, the present application provides a method for preparing paliperidone gastric retention tablet, comprising the following steps:
mixing and dissolving the formula amount of glyceryl monostearate, lecithin and paliperidone with anhydrous ethanol to obtain an organic phase;
mixing an aqueous solution of a surfactant with the organic phase, and heating and concentrating to obtain paliperidone-solid lipid nanoparticles;
mixing the paliperidone-solid lipid nanoparticles with hydroxypropyl methylcellulose, polyoxyethylene, pregelatinized starch, a foaming agent, a bleaching aid and a flow aid according to the formula ratio, and performing dry tabletting to obtain the paliperidone gastric retention tablet.
In the paliperidone gastric retention tablet provided by the first aspect of the application, 2-3 parts of paliperidone, 10-15 parts of glyceryl monostearate and 20-30 parts of lecithin jointly form the pharmaceutical activity of the paliperidone gastric retention tablet. 10-15 parts of hydroxypropyl methyl cellulose and 10-15 parts of polyoxyethylene have hydrophilicity, and are used as a hydrophilic gel skeleton in the paliperidone gastric retention tablet, so that the paliperidone gastric retention tablet can form a gel layer after encountering gastric juice, the floatability of the paliperidone gastric retention tablet is maintained, the retention time of the tablet is prolonged, and the release of the drug is controlled. 8-12 parts of foaming agent can react with gastric acid to generate CO2Gas, increasing the floating force of paliperidone gastric retention tablet, and CO2When the gas is released, a large number of pore channels are generated in the tablet, which is beneficial to water penetration and drug release. 0.5-1 part of bleaching assistant can further increase the floating performance of the paliperidone gastric retention tablet. 0.1-0.5 part of glidant is beneficial to the preparation of retention tablets, so that sticking and washing can be prevented and the inter-particle friction force can be reduced during tabletting. The paliperidone gastric retention tablet provided by the embodiment of the application enables the medicine to float and be retained in gastric juice through the synergistic effect of the components, so that the paliperidone is increasedThe detention time of the medicament in gastric juice enables the medicament to be slowly released, the release time of the medicament in the digestive tract is prolonged, the absorption is enhanced, and the blood concentration fluctuation is reduced, so that the bioavailability is improved.
In the preparation method of paliperidone gastric retention tablet provided by the second aspect of the application, firstly, the formula amount of the glyceryl monostearate, the lecithin, the paliperidone and the absolute ethyl alcohol are mixed and dissolved to obtain an organic phase; mixing with surfactant, heating to remove solvent and water, and concentrating to obtain paliperidone-solid lipid nanoparticles. Then, the paliperidone-solid lipid nanoparticles are mixed with the hydroxypropyl methyl cellulose, the polyoxyethylene, the pregelatinized starch, the foaming agent, the bleaching aid, the flow aid and other components, so that other components form a coating layer on the surface of the paliperidone-solid lipid nanoparticles, and the paliperidone gastric retention tablet can be obtained by dry tabletting. The preparation method of the paliperidone gastric retention tablet in the embodiment of the application has the advantages of simple process and simple and convenient operation, and is suitable for industrial large-scale production and application. The prepared paliperidone gastric retention tablet floats and is retained in gastric juice through the synergistic effect of the components, so that the retention time of the paliperidone medicament in the gastric juice is prolonged, the medicament is slowly released, the release time of the medicament in the digestive tract is prolonged, the absorption is enhanced, the blood concentration fluctuation is reduced, and the bioavailability is improved.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
In the present invention, the term "and/or" describes the association relationship of the associated objects, and means that there may be three relationships, for example, a and/or B, which may mean: a is present alone, A and B are present simultaneously, and B is present alone. Wherein A and B can be singular or plural. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
In the present invention, "at least one" means one or more, "a plurality" means two or more. "at least one of the following" or similar expressions refer to any combination of these items, including any combination of the singular or plural items. For example, "at least one (one) of a, b, or c," or "at least one (one) of a, b, and c," may each represent: a, b, c, a-b (i.e., a and b), a-c, b-c, or a-b-c, wherein a, b, and c may be single or plural, respectively.
It should be understood that, in various embodiments of the present invention, the sequence numbers of the above-mentioned processes do not mean the execution sequence, some or all of the steps may be executed in parallel or executed sequentially, and the execution sequence of each process should be determined by its function and inherent logic, and should not constitute any limitation to the implementation process of the embodiments of the present invention.
The terminology used in the embodiments of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the examples of the invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The weight of the related components mentioned in the description of the embodiments of the present invention may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, the content of the related components is scaled up or down within the scope disclosed in the description of the embodiments of the present invention as long as it is in accordance with the description of the embodiments of the present invention. Specifically, the mass in the description of the embodiments of the present invention may be a mass unit known in the chemical industry field such as μ g, mg, g, kg, etc.
The first aspect of the embodiment of the application provides paliperidone gastric retention tablet, which comprises the following raw materials in parts by weight:
in the paliperidone gastric retention tablet provided by the first aspect of the application, 2-3 parts of paliperidone, 10-15 parts of glyceryl monostearate and 20-30 parts of lecithin are used togetherThe pharmaceutical activity of the paliperidone gastric retention tablet is formed. 10-15 parts of hydroxypropyl methyl cellulose and 10-15 parts of polyoxyethylene have hydrophilicity, and are used as a hydrophilic gel skeleton in the paliperidone gastric retention tablet, so that the paliperidone gastric retention tablet can form a gel layer after encountering gastric juice, the floatability of the paliperidone gastric retention tablet is maintained, the retention time of the tablet is prolonged, and the release of the drug is controlled. 8-12 parts of foaming agent can react with gastric acid to generate CO2Gas, increasing the floating force of paliperidone gastric retention tablet, and CO2When the gas is released, a large number of pore channels are generated in the tablet, which is beneficial to water penetration and drug release. 0.5-1 part of bleaching assistant can further increase the floating performance of the paliperidone gastric retention tablet. 0.1 to 0.5 portion of glidant is beneficial to the preparation of paliperidone gastric retention tablets, so that the adhesion and the impact can be prevented and the inter-particle friction can be reduced during tabletting. The paliperidone gastric retention tablet provided by the embodiment of the application enables the drug to float and be retained in gastric juice through the synergistic effect of the components, so that the retention time of the paliperidone drug in the gastric juice is prolonged, the drug is slowly released, the release time of the drug in the digestive tract is prolonged, the absorption is enhanced, the blood concentration fluctuation is reduced, and the bioavailability is improved. The paliperidone gastric retention tablet has a good slow release effect, and can be slowly released within 24 hours, so that the drug can achieve the long-acting purpose.
In some embodiments, the paliperidone gastric retention tablet has a tablet diameter of not greater than 0.2 mm. According to the principle of a hydrodynamics balance controlled release system, the paliperidone gastric retention tablet disclosed by the embodiment of the application has the advantages that the tablet diameter is not more than 0.2 mm, the granule is small, the density is less than that of gastric juice, and the paliperidone gastric retention tablet can float in the gastric juice for a long time without influencing gastric emptying. The paliperidone gastric retention tablet preparation floats on the gastric contents, the drug is slowly released from the preparation at an expected speed, and after the drug is completely released, the residual part is emptied from the stomach, so that the retention time of the drug in the stomach is prolonged, and the fluctuation of the blood concentration is reduced. Not only can obviously improve the bioavailability of the medicine, but also has small stimulation to intestines and stomach, and improves the compliance of patients to the medicine.
In some embodiments, the surfactant is selected from: at least one of Tween 80, span 80, poloxamer aqueous solution and sodium cholate, wherein the surfactants are composed of hydrophilic groups with affinity with water and lipophilic groups with affinity with oil, can be dissolved in a polar solvent and a nonpolar solvent, have amphipathy, can increase the mutual fusion of the raw material components in the paliperidone gastric retention tablet, and can improve the distribution coefficient of the medicine. In some embodiments, the surfactant is selected from a poloxamer aqueous solution with a mass percentage concentration of 0.4%, and can play a role in emulsification, stabilization, solubilization, slow release and the like simultaneously in the gastric retention tablet. The entrapment rate and the drug loading rate of the paliperidone gastric-retention tablet are increased along with the increase of the concentration of the surfactant, but when the concentration of the surfactant is higher than a certain concentration, the entrapment rate and the drug loading rate are reduced along with the increase of the concentration of the surfactant, so that the paliperidone gastric-retention tablet has the most proper entrapment rate and drug loading rate when the concentration of the poloxamer aqueous solution is selected to be 0.4%.
In some embodiments, the blowing agent is selected from: at least one of sodium bicarbonate and ammonium bicarbonate, wherein the foaming agent is capable of reacting with gastric acid to form CO2Gas, increasing the floating force of paliperidone gastric retention tablet, and CO2When the gas is released, a large number of pore channels are generated in the tablet, which is beneficial to water penetration and drug release. With the increase of the content of foaming agents such as sodium bicarbonate and ammonium bicarbonate, the rising and floating time of the gastric retention tablet is shortened, and the embodiment researches show that when the content of the foaming agents in the paliperidone gastric retention tablet is selected to be 8-12 parts, the gastric retention tablet has proper rising and floating time. In some embodiments, the foaming agent is selected from sodium bicarbonate.
In some embodiments, the sheeting aid is selected from: at least one of glyceryl monostearate, cetyl alcohol, stearyl alcohol glyceryl monostearate, stearyl alcohol, stearic acid, carnauba wax, white wax and hydrogenated vegetable oil, wherein the floating assisting agents can increase the floating performance of the gastric retention tablet, the continuous floating time of the gastric retention tablet is increased along with the increase of the content of the floating assisting agents in the gastric retention tablet, and the floating assisting agent has proper floating time when the content is 0.5-1 part. In some embodiments, the bleaching aid is selected from glyceryl monostearate, has an oleophilic long chain alkyl group and two hydrophilic hydroxyl groups, has good surface activity, and can perform the functions of emulsifying, foaming, dispersing, defoaming, resisting starch aging and the like.
In some embodiments, the glidant is selected from: at least one of magnesium stearate, stearic acid and magnesium lauryl sulfate, and the glidants can prevent viscosity impact, reduce the inter-particle friction and facilitate granulation when the gastric retention tablets are tableted; but also can make the prepared stomach retention tablet have smoother tablet surface and better patient compliance. In some embodiments, the glidant is selected from magnesium stearate, which is mainly used as a lubricant, an anti-sticking agent and a glidant, and is particularly suitable for granulating oil and extract medicines, so that the prepared gastric retention tablet has good flowability and compressibility.
In some embodiments, the filler is selected from: at least one of pregelatinized starch, dextrin, sucrose, mannitol, and microcrystalline cellulose, which are used for facilitating the formation and dosage of the gastric retention tablet. In some embodiments, the filler is selected from pregelatinized starch, which can increase the flowability and compressibility of the raw material components of the gastric retentive tablet, and can also act as a binder in a dry tableting process, and can also act as a self-lubricant.
In some embodiments, the weight part ratio of paliperidone to the glyceryl monostearate is 1 (5-10). Experiments in the embodiment of the application show that the encapsulation efficiency is increased along with the increase of the medicine-fat ratio, the medicine loading rate is reduced, and the medicine has the best comprehensive performance when the weight part ratio of the paliperidone to the glyceryl monostearate is 1 (5-10). In some embodiments, the parts by weight ratio of paliperidone to monostearate glyceride may be 1:5, 1:6, 1:7, 1:8, 1:9, or 1: 10.
In some embodiments, the weight ratio of the monostearyl glyceride to the lecithin is 1:2, the encapsulation efficiency and the drug loading capacity increase with increasing lecithin ratio, and the gastric retention tablet has the best overall performance when the weight ratio of the monostearyl glyceride to the lecithin is 1: 2.
In some embodiments, the total weight of the hydroxypropyl methylcellulose and the polyoxyethylene is 22-26 parts. Hydroxypropyl methylcellulose and polyoxyethylene are used as hydrophilic gel framework materials to form a gel layer after encountering gastric juice, so that the floatability of the tablet is maintained, the residence time of the tablet is prolonged, the drug release is controlled, and the hydroxypropyl methylcellulose and the polyoxyethylene are important carriers of the gastric retention tablet. Experiments show that when the total weight of the hydroxypropyl methyl cellulose and the polyoxyethylene accounts for 20-24 parts, the extruded retention tablet has uniform color, no obvious granular feeling on the surface and no sticking, but the floating time is less than 12 hours; when the total weight of the hydroxypropyl methylcellulose and the polyoxyethylene is 26-28 parts, the extruded paliperidone gastric retention tablet has high sticking impact rate, the appearance of the prepared tablet is poor, and the floating time is longer than 12 hours. Therefore, when the total weight of the hydroxypropyl methylcellulose and the polyoxyethylene is 22-26 parts, the stomach retention tablet has the best comprehensive performance.
In some embodiments, the paliperidone gastric retention tablet comprises the following raw material components in parts by weight:
wherein the weight part ratio of paliperidone to glyceryl monostearate is 1 (5-10); the weight part ratio of the glyceryl monostearate to the lecithin is 1: 2; the total weight of the hydroxypropyl methyl cellulose and the polyoxyethylene is 22-26 parts.
The paliperidone gastric retention tablet of the examples of this application can be prepared by the following example method.
In a second aspect, the embodiments of the present application provide a method for preparing paliperidone gastric retention tablet, which includes the following steps:
s10, mixing and dissolving the formula amount of glyceryl monostearate, lecithin, paliperidone and absolute ethyl alcohol to obtain an organic phase;
s20, mixing the surfactant with the organic phase, and heating and concentrating to obtain paliperidone-solid lipid nanoparticles;
s30, mixing the paliperidone-solid lipid nanoparticles with hydroxypropyl methyl cellulose, polyoxyethylene, pregelatinized starch, a foaming agent, a bleaching aid and a flow aid in a formula amount, and performing dry tabletting to obtain the paliperidone gastric retention tablet.
In the preparation method of paliperidone gastric retention tablet provided by the second aspect of the application, firstly, the formula amount of the glyceryl monostearate, the lecithin, the paliperidone and the absolute ethyl alcohol are mixed and dissolved to obtain an organic phase; mixing with surfactant, heating to remove solvent and water, and concentrating to obtain paliperidone-solid lipid nanoparticles. Then, the paliperidone-solid lipid nanoparticles are mixed with the hydroxypropyl methyl cellulose, the polyoxyethylene, the pregelatinized starch, the foaming agent, the bleaching aid, the flow aid and other components, so that other components form a coating layer on the surface of the paliperidone-solid lipid nanoparticles, and the paliperidone gastric retention tablet can be obtained by dry tabletting. The preparation method of the paliperidone gastric retention tablet in the embodiment of the application has the advantages of simple process and simple and convenient operation, and is suitable for industrial large-scale production and application. The prepared paliperidone gastric retention tablet floats and is retained in gastric juice through the synergistic effect of the components, so that the retention time of the paliperidone medicament in the gastric juice is prolonged, the medicament is slowly released, the release time of the medicament in the digestive tract is prolonged, the absorption is enhanced, the blood concentration fluctuation is reduced, and the bioavailability is improved.
In some embodiments, in step S10, the formula amounts of glyceryl monostearate, lecithin, and paliperidone are mixed with anhydrous ethanol at a temperature of 40-50 ℃ to dissolve; through proper heating conditions, the dissolution and mixing of the raw material components can be promoted more efficiently.
Mixing a surfactant and an organic phase for 0.5-2 hours at the rotation speed of 900-1100r/min, volatilizing the solvent at the temperature of 50-80 ℃, and concentrating to obtain the paliperidone-solid lipid nanoparticles. Mixing of the surfactant and the organic phase is promoted by stirring at 900-1100r/min, and the ethanol solvent is volatilized and removed by heating at 50-80 ℃, so that the stability of the paliperidone-solid lipid nanoparticles is improved.
In some embodiments, in step S20, the paliperidone-solid lipid nanoparticle, the hydroxypropyl methylcellulose, the polyoxyethylene, the pregelatinized starch, the foaming agent, the bleaching aid and the glidant in the formula amount are sieved by a sieve of 80-100 meshes, mixed and tabletted by a dry method, so as to obtain the paliperidone gastric retention tablet with the hardness of 3-4 kg. In the embodiment of the application, the hardness of the gastric retention tablet is measured by adopting a tablet four-purpose instrument, the influence of the hardness of the tablet on the floatability is considered, the hardness of the gastric retention tablet is found to be within the range of 3-4 kg, and the tablet within the range has good floatability.
In order to make the above implementation details and operations clearly understood by those skilled in the art and to make the improvement of the paliperidone gastric retention tablet and the preparation method thereof obviously appear in the examples of the present application, the above technical solution is exemplified by a plurality of examples by selecting the prescribed amounts of the raw material components such as glyceryl monostearate, lecithin, surfactant, etc. as the factors for investigation.
Example 1
Paliperidone-lipid nanoparticles, which are prepared by the steps of: mixing the formula amount of glyceryl monostearate, lecithin, paliperidone and anhydrous ethanol, heating to 40-50 deg.C, and dissolving to obtain organic phase; mixing and stirring the surfactant and the organic phase for 1h at the stirring speed of 900-; pulverizing, and sieving with 80 mesh sieve.
A single-factor investigation test is adopted, the encapsulation rate and the drug-loading rate are used as evaluation indexes, different factors such as paliperidone, glyceryl monostearate, surfactant type and surfactant concentration are investigated, the influence on the preparation of the paliperidone-lipid nanoparticles is detected, an orthogonal test is further utilized, and formula combination is optimized. The initial formula combination is paliperidone 3g, glyceryl monostearate 30g, lecithin 30g, and tween 804 g. The content of the main drug is unchanged, and other components are implemented according to the content of the prescription under the condition of controlling a single variable. The experimental results are shown in the following tables 1 to 4:
TABLE 1
TABLE 2
TABLE 3
TABLE 4
As can be seen from the test results in the table 1, the encapsulation efficiency is increased and the drug loading rate is reduced with the increase of the drug-to-lipid ratio, and the drug-to-lipid ratio of 1:5 to 1:10 is more suitable for the application in consideration of environmental protection.
As can be seen from the test results in Table 2, the encapsulation efficiency and the drug loading capacity are increased with the increase of the lecithin ratio, and the ratio of the monostearin to the lecithin is more suitable to be 1:2 in consideration of the factors such as the cost, the content of the active pharmaceutical ingredients, the matching relationship among the components and the like.
As can be seen from the results of the above tests in tables 3 and 4, the aqueous poloxamer solution as a surfactant has better encapsulation efficiency and drug loading. The encapsulation efficiency and drug loading rate increase with increasing surfactant concentration, but above a certain concentration, the encapsulation efficiency and drug loading rate decrease with increasing surfactant concentration, so that the optimal overall performance is achieved when the concentration of poloxamer in water is selected to be 0.4%.
According to the results of orthogonal experiments, the optimal formula combination of the paliperidone-solid lipid nanoparticles is preferably that the drug-lipid ratio is 1:7, the stearin ester: lecithin is 1: 2; the concentration of the poloxamer aqueous solution was 0.4%.
Example 2
Paliperidone gastric retention tablet, which is prepared by the steps of:
firstly, mixing 21g of monostearin, 41g of lecithin and 3g of paliperidone with 2g of absolute ethyl alcohol according to the formula amount, and heating to maintain the temperature at 40-50 ℃ for dissolution to obtain an organic phase; mixing 2g of 0.4% poloxamer aqueous solution F68(m/V) with an organic phase at a stirring speed of 900-; pulverizing, and sieving with 80 mesh sieve.
Weighing HPMC-K15M, polyoxyethylene, pregelatinized starch, sodium bicarbonate, glyceryl monostearate and magnesium stearate in the prescribed amount, sieving with a 80-mesh sieve, uniformly mixing with the paliperidone-solid lipid nanoparticles obtained in the step I, directly tabletting by a dry method, and controlling the hardness to be 3-4 kg to obtain the paliperidone gastric retention tablet with smooth appearance.
By adopting a single-factor investigation test, the appearance, the rising time and the remaining time of the paliperidone gastric retention tablet are taken as evaluation indexes to investigate the HPMC-K15M, the polyoxyethylene content and the NaHCO content3The influence of different factors such as content, glyceryl monostearate content and the like on the preparation of the paliperidone gastric retention tablet is utilized, and an optimal preparation method is selected by utilizing orthogonal tests and optimizing formula combination. The initial formula composition was HPMC-K15M 18g, polyoxyethylene 18g, pregelatinized starch 35g, sodium bicarbonate 18g, glyceryl monostearate 3g, and magnesium stearate 3 g. When the single variable is changed, the contents of other components are controlled to be implemented according to the formula combination. The experimental results are shown in the following tables 5 to 7:
TABLE 5
TABLE 6
TABLE 7
From the above test results, HPMC-K15M and polyoxyethylene as hydrophilic gel matrix material can form gel layer after encountering gastric juice, thereby maintaining floatability of tablet, prolonging retention time of tablet, and controlling drug release, and is an important carrier for gastric floating tablet. Table 4 the test results show that when the total amount of HPMC-K15M and polyoxyethylene is 20 parts, 22 parts, the pressed tablets are uniform in colour, indicating no distinct granular sensation, no sticking, and a floating time < 12 h; when the total amount of HPMC-K15M and polyoxyethylene is 24 parts, 26 parts and 28 parts, the sticking punching rate of the extruded tablet is high, and the prepared tablet has poor appearance and has floating time of more than 12 h. The best combination of properties is obtained when the amounts of HPMC-K15M and polyoxyethylene in the formulation are chosen to be around 24 parts.
The results are similar from Table 5 above, using NaHCO3As a foaming agent, it reacts with gastric acid to form CO2Gas, increasing the floating force; with CO2The release of the active ingredient can generate a plurality of pore passages on the tablet, thereby being beneficial to the water penetration and the drug release. With NaHCO3The content is increased, and the floating time of the stomach retention tablet is shortened, so NaHCO3The content is selected to be about 10 parts, and the stomach retention tablet has good floating and lasting floating performance.
Similar to the results from the above table 6, glyceryl monostearate, as a sheeting aid, increased the floating properties of the tablet; tests show that the floating time of the stomach retention tablet is increased along with the increase of the content of the glyceryl monostearate, and when the content of the glyceryl monostearate is 0.8 part, the stomach retention tablet has good floating and floating maintaining performances.
Example 3
A paliperidone gastric retention tablet is prepared by the following steps:
weighing 21g of glyceryl monostearate, 41g of lecithin and 3g of paliperidone according to the prescription amount. Adding into anhydrous ethanol, heating at 40-50 deg.C to dissolve the sample to obtain organic phase;
② taking another 2g of 0.4 percent poloxamer aqueous solution F68(m/V) and heating to the same temperature as the organic phase to form a water phase.
Thirdly, injecting the organic phase into the water phase at the stirring speed of 900 plus materials at 1100r/min, stirring for 1h, volatilizing the organic solvent, and concentrating by volume to obtain a semitransparent nano emulsion, namely the paliperidone-solid lipid nanoparticle colloidal solution, and storing at the low temperature of 0-4 ℃ to obtain the paliperidone-solid lipid nanoparticle. Pulverizing, and sieving with 80 mesh sieve.
Weighing HPMC-K15M 21g, polyoxyethylene 21g, pregelatinized starch 44.5g and NaHCO according to the prescription amount315.5g, 1.5g of glyceryl monostearate and 2.5g of magnesium stearate, sieving with a 80-mesh sieve, uniformly mixing with the paliperidone-solid lipid nanoparticles obtained in the step III, directly tabletting by a dry method, and controlling the hardness to be 3-4 kg to obtain the paliperidone gastric retention tablet with smooth appearance.
3 batches of paliperidone gastric retention tablets were prepared as described above, and each batch was randomly sampled, observed for appearance, time to rise and time to stay, and cumulative release (%) for 2, 4, 6, 8, 10, 14, 18, 24 hours, and subjected to a validation test with the following test results in tables 8 and 9:
TABLE 8
TABLE 9
As can be seen from the test results in tables 8 and 9, the paliperidone-gastric retention tablet in the embodiment of the application slowly releases in 24 to achieve the purpose of long acting, and the in vitro accumulative release rate of 3 batches has no significant difference, the process reproducibility is good, and the formulation is successfully optimized.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (10)
1. The paliperidone gastric retention tablet is characterized by comprising the following raw materials in parts by weight:
2. the paliperidone gastric retention tablet of claim 1, wherein the tablet diameter of the paliperidone gastric retention tablet is not greater than 0.2 mm.
3. The paliperidone gastric retention tablet of claim 2, wherein the surfactant is selected from the group consisting of: at least one of tween 80, span 80, poloxamer water solution and sodium cholate;
and/or, the blowing agent is selected from: at least one of sodium bicarbonate and ammonium bicarbonate.
4. The paliperidone gastric retention tablet of claim 3, wherein the bleaching aid is selected from the group consisting of: at least one of glyceryl monostearate, cetyl alcohol, stearyl glyceryl monostearate, stearyl alcohol, stearic acid, carnauba wax, white wax, and hydrogenated vegetable oil.
5. The paliperidone gastric retention tablet of claim 4, wherein the glidant is selected from the group consisting of: at least one of magnesium stearate, stearic acid and magnesium lauryl sulfate;
and/or, the filler is selected from: at least one of pregelatinized starch, dextrin, sucrose, mannitol, and microcrystalline cellulose.
6. The paliperidone gastric retention tablet of claim 5, wherein the surfactant is selected from an aqueous solution of poloxamer at 0.4% by mass;
and/or, the foaming agent is selected from sodium bicarbonate;
and/or the bleaching aid is selected from glyceryl monostearate;
and/or, the glidant is selected from magnesium stearate;
and/or the filler is selected from pregelatinized starch.
7. The paliperidone gastric retention tablet of any one of claims 1 to 6, wherein the ratio of the paliperidone to the glyceryl monostearate in parts by weight is 1 (5-10);
and/or the weight part ratio of the monostearin to the lecithin is 1: 2;
and/or the total weight of the hydroxypropyl methyl cellulose and the polyoxyethylene is 22-26 parts.
8. A method for preparing paliperidone gastric retention tablet as claimed in any one of claims 1 to 7, characterized by comprising the following steps:
mixing and dissolving the formula amount of glyceryl monostearate, lecithin and paliperidone with anhydrous ethanol to obtain an organic phase;
mixing a surfactant with the organic phase, and heating and concentrating to obtain paliperidone-solid lipid nanoparticles;
mixing the paliperidone-solid lipid nanoparticles with hydroxypropyl methylcellulose, polyoxyethylene, pregelatinized starch, a foaming agent, a bleaching aid and a flow aid according to the formula ratio, and performing dry tabletting to obtain the paliperidone gastric retention tablet.
9. The process for preparing paliperidone gastric retention tablet as claimed in claim 8, wherein the formula amount of the glyceryl monostearate, the lecithin, the paliperidone and the absolute ethanol are mixed and dissolved at a temperature of 40 ℃ to 50 ℃;
mixing the surfactant and the organic phase for 0.5-2 hours at the rotation speed of 900-1100r/min, volatilizing the solvent at the temperature of 50-80 ℃, and cooling at the temperature of 0-4 ℃ to obtain the paliperidone-solid lipid nanoparticles.
10. The preparation method of the paliperidone gastric retention tablet as claimed in claim 8 or 9, characterized in that the paliperidone-solid lipid nanoparticles, the hydroxypropyl methylcellulose, the polyoxyethylene, the pregelatinized starch, the foaming agent, the bleaching aid and the glidant in the formula amount are sieved by a sieve of 80-100 meshes, mixed and processed, and subjected to dry tabletting to obtain the paliperidone gastric retention tablet with the hardness of 3-4 kg.
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