CN116650444B - Tacrolimus slow-release drug and preparation method thereof - Google Patents
Tacrolimus slow-release drug and preparation method thereof Download PDFInfo
- Publication number
- CN116650444B CN116650444B CN202310946896.1A CN202310946896A CN116650444B CN 116650444 B CN116650444 B CN 116650444B CN 202310946896 A CN202310946896 A CN 202310946896A CN 116650444 B CN116650444 B CN 116650444B
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- release
- tacrolimus
- sustained
- coating liquid
- prepared
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the technical field of medical preparations, in particular to a tacrolimus sustained-release drug and a preparation method thereof. Comprises a tacrolimus slow release pellet and a capsule body wrapping the tacrolimus slow release pellet; the tacrolimus sustained-release pellet comprises a drug carrier, a separator and a sustained-release body which are sequentially coated, wherein the sustained-release body is prepared by spraying a sustained-release body coating liquid on the surface of the separator and air-drying, the separator is prepared by spraying a separator coating liquid on the surface of the drug carrier and air-drying, and the drug carrier comprises an ethanol aqueous solution and a suspending agent prepared from tacrolimus as a cosolvent and is prepared by air-drying. The invention reduces the technical defect of relying on organic solvent in the prior art on the basis of meeting the enteric requirement, and reduces the technical problem of reducing the dissolution rate of the drug carrier due to the reaction between the tacrolimus slow release pellets and the capsule body due to the existence of the slow release body and the isolator.
Description
Technical Field
The invention relates to the technical field of medical preparations, in particular to a tacrolimus sustained-release drug and a preparation method thereof.
Background
Tacrolimus is a white crystal or crystalline powder, is easily soluble in ethanol, is very easily soluble in methanol and chloroform, and is almost insoluble in water. Is a macrolide potent immunosuppressant isolated from fermentation medium of Streptomyces tsukubaensis (a fungus-like bacterium found in soil samples by Tsukuba) by Japanese rattan corporation (Fujisawa) in 1984. The immunosuppressive effect of tacrolimus is 10-100 times stronger than that of cyclosporine A (CsA), so that the clinical dosage is greatly reduced, and adverse reaction is obviously reduced. Tacrolimus is a powerful immunosuppressant, is mainly used for preventing and treating rejection reaction after organ transplantation of patients, has a similar and wider immunosuppression effect as cyclosporin A, but has higher efficacy than that of cyclosporin A and lower toxic and side effects. Its mechanism of action may be related to its inhibition of T lymphocyte activation: tacrolimus forms a complex with the FKBP-12, calcium ion, calmodulin, calcineurin, a T cytoplasmic FK-506 binding protein, thereby inhibiting calcineurin activity. This process inhibits gene transcription of cytokines such as interleukin-1 and gamma-interferon by inhibiting dephosphorylation and nuclear translocation of T-cell nuclear factors, and eventually inhibits cytokine production and T-lymphocyte activation, resulting in immunosuppression.
Tacrolimus is available in various dosage forms, including capsules, injections and ointments, and can be used for preventing organ rejection in patients transplanted in the liver, kidneys or heart. The pharmacokinetic profile of tacrolimus varies greatly in individuals, which is a substrate for cytochrome P450 (CYP 3A), resulting in large individual metabolic differences, obvious hepatic first pass effects, poor bioavailability, and variable bioavailability in individuals. This variability, along with its narrow therapeutic index, is necessary to monitor tacrolimus blood levels for optimal efficacy while minimizing the risk of toxicity.
Tacrolimus has the characteristics of strong drug effect, low dosage, high organ survival rate, low incidence rate of acute rejection and the like. Tacrolimus is a biological pharmacy classification system II (BCSII) drug, the treatment window is narrow, the dosage of the drug is adjusted according to the blood concentration, and an individual drug scheme is adopted. In order to maintain the effective blood concentration to prevent rejection, an Si Talai company provides a tacrolimus slow release capsule (new plectane) based on the original common capsule, and the tacrolimus slow release capsule is marketed in China in 2011. The solid dispersion technology is applied to the new plerosis, namely, the medicine is dispersed in a carrier material consisting of a water-soluble polymer, a water-insoluble polymer and other excipients by a solvent volatilization method, so that the problem of poor dissolution of the tacrolimus which is a water-insoluble medicine is solved, and the medicine slow-release effect is obtained.
Chinese patent CN112351773a discloses a sustained release agent of tacrolimus, the preparation method of the sustained release agent comprises: adding hydroxypropyl methylcellulose, ethylcellulose, lactose and croscarmellose sodium to an organic solvent to prepare a solid dispersion, and mixing the prepared solid dispersion, lactose and magnesium stearate.
Chinese patent CN101103981a discloses a pharmaceutical composition comprising tacrolimus, which comprises tacrolimus and a pharmaceutically acceptable solid matrix selected from polyethylene glycol, poloxamer or mixtures thereof. The tacrolimus is prepared into solid dispersion by adopting a solid melting method, and then proper excipients are added to prepare solid preparations for oral administration, such as tablets, capsules, granules and the like.
Chinese patent cn107595784B discloses a sustained release pharmaceutical composition of tacrolimus. The preparation method comprises the following steps: (1) preparing a solid dispersion with slow release performance by using tacrolimus, ethylcellulose, hydrophilic polymer material, calcium silicate, citric acid and a part of water-soluble diluent with ethanol, (2) uniformly mixing the solid dispersion obtained in the step (1) with the rest of water-soluble diluent and lubricant, and (3) preparing the mixed material obtained in the step (2) into a pharmaceutical preparation form.
Chinese patent CN2022113692518A discloses a sustained release pharmaceutical composition of tacrolimus. The preparation method comprises the following steps: comprises a solid dispersion prepared from a raw material by fluidized bed granulation; wherein the raw materials comprise the following components: tacrolimus, a water-insoluble polymer material, a hydrophilic polymer material, an organic solvent, a water-soluble diluent and a granulating substrate.
Although the release rate of tacrolimus can be improved to a certain extent in the prior art, compared with the prior art, the sustained-release capsule in the prior art has a certain difference in release efficiency and release time.
Disclosure of Invention
In order to solve the problems, the invention provides the tacrolimus sustained-release drug, and the sustained-release effect of the sustained-release capsule is improved under the condition of meeting the drug dissolution rate by arranging the sustained-release coating structures with different structures.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect, the invention provides a tacrolimus sustained-release drug, which comprises tacrolimus sustained-release pellets and a capsule body wrapping the tacrolimus sustained-release pellets; the tacrolimus sustained-release pellet comprises a drug carrier, a separator and a sustained-release body which are sequentially coated, wherein the sustained-release body is prepared by spraying a sustained-release body coating liquid on the surface of the separator and air-drying, the separator is prepared by spraying a separator coating liquid on the surface of the drug carrier and air-drying, and the drug carrier comprises an ethanol aqueous solution and a suspending agent prepared by a cosolvent tacrolimus and is prepared by air-drying; the spacer coating liquid is prepared by stirring hydroxypropyl methylcellulose, polyethylene glycol 6000 and talcum powder with ethanol, and the slow-release coating liquid is a methacrylic acid-ethyl acrylate aqueous dispersion obtained by a water emulsion polymerization treatment method.
Further, the preparation method of the methacrylic acid-ethyl acrylate water dispersion comprises the following steps: and heating the initiator, the molecular regulator and the emulsifier to 75-80 ℃ based on nitrogen atmosphere to obtain a mixed solution, dropwise adding a mixed solution of methacrylic acid and ethyl acrylate monomers into the mixed solution, heating to 85-90 ℃ to react, and cooling to 40 ℃ after the reaction is completed.
Further, the molar ratio of the methacrylic acid to the ethyl acrylate monomer is 1:1.
Further, the emulsifier is sodium dodecyl sulfate and polysorbate in a molar ratio of 1:3.
Further, the initiator is ammonium persulfate accounting for 0.3% -0.6% of the mixed solution.
Further, the molecular regulator is dodecyl mercaptan accounting for 0.5% -0.7% of the mixed solution.
Further, the mass ratio of the hypromellose to the polyethylene glycol 6000 to the talcum powder is 10:1:1.
Furthermore, the spacer coating liquid is prepared by adding the hypromellose into the ethanol for dissolution to obtain a first dissolved substance, adding the polyethylene glycol 6000 into the first dissolved substance for dissolution to obtain a second dissolved substance, and adding the talcum powder into the second dissolved substance for stirring.
In a second aspect, a preparation method of a tacrolimus sustained-release capsule is provided, and the preparation method comprises the following steps: and (3) air-drying the suspending agent prepared from the ethanol aqueous solution, the cosolvent and the tacrolimus to prepare a drug carrier, spraying a spacer coating liquid on the surface of the drug carrier, air-drying to prepare a spacer, spraying a slow-release coating liquid on the surface of the spacer, air-drying to prepare tacrolimus slow-release pellets, and filling the tacrolimus slow-release pellets into a hollow capsule to obtain the tacrolimus slow-release capsule.
Further, the slow-release coating liquid is prepared by carrying out polymerization reaction on methacrylic acid and ethyl acrylate, sequentially dripping sodium dodecyl sulfate and polysorbate in the polymerization reaction process for emulsification treatment, adding ammonium persulfate, and adding dodecyl mercaptan based on bottom spray.
The invention has the beneficial effects that:
according to the technical scheme provided by the invention, the separator structure and the slow-release body structure are arranged on the outer surface of the tacrolimus drug-loaded body, wherein the slow-release body structure in the technical scheme is based on a methacrylic acid-ethyl acrylate aqueous dispersion, the technical defect that an organic solvent is relied on in the prior art is reduced on the basis of meeting the enteric requirement, and the technical problem that the dissolution rate of the drug-loaded body is reduced due to the reaction between the tacrolimus slow-release pellets and the capsule body is reduced due to the existence of the slow-release body and the separator.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for the description of the embodiments will be briefly described below, and it is apparent that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
Fig. 1 is a flowchart of a preparation method of a tacrolimus sustained-release drug provided by an embodiment of the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. The embodiments described below are some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art without the benefit of the teachings of this invention, are intended to be within the scope of the invention.
In one specific embodiment of the invention, the invention provides a tacrolimus sustained-release drug, which comprises tacrolimus sustained-release pellets and a capsule body wrapping the tacrolimus sustained-release pellets.
In a preferred embodiment of the invention, the tacrolimus sustained-release pellets comprise a coated drug carrier, a separator and a sustained-release body in sequence.
Specifically, the sustained-release preparation is prepared by spraying a sustained-release coating liquid on the surface of the separator through air drying, the separator is prepared by spraying a separator coating liquid on the surface of the medicine carrying body through air drying, and the medicine carrying body comprises an ethanol water solution, a cosolvent and a suspending agent prepared from tacrolimus through air drying; the slow-release body coating liquid is a methacrylic acid-ethyl acrylate water dispersion obtained by a water emulsion polymerization treatment method, and is prepared by stirring hydroxypropyl methylcellulose, polyethylene glycol 6000 and talcum powder through ethanol.
In an embodiment of the present invention, the method for preparing the aqueous methacrylic acid-ethyl acrylate dispersion comprises: and heating the initiator, the molecular regulator and the emulsifier to 75-80 ℃ based on nitrogen atmosphere to obtain a mixed solution, dropwise adding a mixed solution of methacrylic acid and ethyl acrylate monomers into the mixed solution, heating to 85-90 ℃ to react, and cooling to 40 ℃ after the reaction is completed.
Further, the emulsifier in the examples of the present invention is sodium dodecyl sulfate and polysorbate in a molar ratio of 1:3.
Further, the initiator in the embodiment of the invention is ammonium persulfate with the content accounting for 0.3% -0.6% of the mixed solution.
Further, the molecular regulator in the embodiment of the invention is dodecyl mercaptan accounting for 0.5% -0.7% of the mixed solution.
The mass ratio of the hypromellose, the polyethylene glycol 6000 and the talcum powder in the embodiment of the invention is 10:1:1.
The preparation method comprises the steps of adding hydroxypropyl methylcellulose into ethanol for dissolution to obtain a first dissolved substance, adding polyethylene glycol 6000 into the first dissolved substance for dissolution to obtain a second dissolved substance, and adding talcum powder into the second dissolved substance for stirring.
The tacrolimus sustained-release drug provided by the embodiment of the invention is mainly prepared from tacrolimus sustained-release pellets, wherein the tacrolimus sustained-release pellets comprise tacrolimus drug-carrying bodies, the tacrolimus sustained-release pellets are mainly used for wrapping tacrolimus main components, the isolating bodies are used for wrapping the tacrolimus sustained-release bodies outside the sustained-release bodies through coating liquid, the sustained-release bodies are arranged on the outermost layers of the pellets and are in direct contact with capsules, the sustained-release bodies are obtained through methacrylic acid-ethyl acrylate water dispersion obtained through a water emulsion polymerization treatment method, the dissolution rate of the tacrolimus caused by contact with the capsules is low, and the dependence on organic solvents is reduced through the water dispersion.
The invention also provides a preparation method of the tacrolimus sustained-release drug, which comprises the following steps:
s1, preparing a drug carrier by air-drying a suspending agent prepared from an ethanol water solution, a cosolvent and tacrolimus;
s2, spraying a spacer coating liquid on the surface of the drug-carrying body, and drying by air to obtain a spacer;
s3, spraying a slow-release coating liquid on the surface of the separator, and air-drying and drying to obtain tacrolimus slow-release pellets;
and S4, filling the tacrolimus sustained-release pellets into hollow capsules to obtain the tacrolimus sustained-release capsules.
The tacrolimus sustained-release capsule and the preparation method thereof according to the present invention are further described below by means of specific examples.
Example 1: 740ml of ethanol water solution with the concentration of 95% is weighed, 50g of povidone K30 is added into the ethanol water solution and stirred until the povidone K30 is dissolved, 50g of tacrolimus active ingredient is added into the solution and stirred, the suspension is prepared, and the suspension is filtered through a 60-mesh sieve and the filtrate is taken. And placing 500 blank sugar pellets at the bottom of the fluidized bed, and coating and applying medicine in a bottom spraying mode, wherein the air inlet temperature for the fluidized bed is 45 ℃, the material temperature is 35 ℃, the air inlet frequency is 10Hz, and the liquid spraying frequency is 5Hz. And after the medicine feeding is finished, the pellets are placed in a blast drying oven to be dried for 2 hours at 35 ℃ to obtain the medicine carrying body.
13g of hypromellose, 1.3g of polyethylene glycol 6000 and 7.5g of talcum powder are weighed and sequentially added into 320ml of absolute ethyl alcohol, stirring is carried out until the mixture is dissolved, an isolating layer coating liquid is prepared, and the isolating layer coating liquid is subjected to bottom spraying on a medicine carrying body in a fluidized bed. Wherein the bottom spraying air inlet temperature of the fluidized bed is 40 ℃, the material temperature is 30 ℃, the fan frequency is 15Hz, the spraying frequency is 5Hz, and the pellets after spraying the liquid are dried for 2 hours at 40 ℃ in a blast drying box, so that the isolator containing pellets are prepared, wherein the isolator accounts for 4% of the total mass of the pellets.
44g of methacrylic acid and 52g of ethyl acrylate are weighed and polymerized at 75 ℃, 0.3g of sodium dodecyl sulfate and 0.9g of polysorbate are sequentially added dropwise in the reaction process for emulsification treatment, 0.24g of ammonium persulfate is added, 0.5g of dodecyl mercaptan is added for high-speed stirring and homogenization for 15min, and a 40-mesh sieve is used for filtering, so that the filtrate is taken as 80g of slow-release coating liquid. And spraying the coating liquid of the slow release body on the separator pellets in a fluidized bed, wherein the air inlet temperature is 23 ℃ in the fluidized bed bottom spraying process, the material temperature is 23 ℃, the fan frequency is 18Hz, the liquid spraying frequency is 5Hz, and the pellets after liquid spraying are placed in a blast drying oven to be solidified for 24 hours at 40 ℃ to prepare the slow release body pellets, namely the tacrolimus slow release pellets.
And filling the tacrolimus sustained-release pellets into hollow capsules to obtain the tacrolimus sustained-release capsules.
Example 2: 740ml of ethanol water solution with the concentration of 95% is weighed, 50g of povidone K30 is added into the ethanol water solution and stirred until the povidone K30 is dissolved, 50g of tacrolimus active ingredient is added into the solution and stirred, the suspension is prepared, and the suspension is filtered through a 60-mesh sieve and the filtrate is taken. And placing 500 blank sugar pellets at the bottom of the fluidized bed, and coating and applying medicine in a bottom spraying mode, wherein the air inlet temperature for the fluidized bed is 45 ℃, the material temperature is 35 ℃, the air inlet frequency is 10Hz, and the liquid spraying frequency is 5Hz. And after the medicine feeding is finished, the pellets are placed in a blast drying oven to be dried for 2 hours at 35 ℃ to obtain the medicine carrying body.
13g of hypromellose, 1.3g of polyethylene glycol 6000 and 7.5g of talcum powder are weighed and sequentially added into 320ml of absolute ethyl alcohol, stirring is carried out until the mixture is dissolved, an isolating layer coating liquid is prepared, and the isolating layer coating liquid is subjected to bottom spraying on a medicine carrying body in a fluidized bed. Wherein the bottom spraying air inlet temperature of the fluidized bed is 40 ℃, the material temperature is 30 ℃, the fan frequency is 15Hz, the spraying frequency is 5Hz, and the pellets after spraying the liquid are dried for 2 hours at 40 ℃ in a blast drying box, so that the isolator containing pellets are prepared, wherein the isolator accounts for 4% of the total mass of the pellets.
44g of methacrylic acid and 52g of ethyl acrylate are weighed and polymerized at 75 ℃, 0.6g of sodium dodecyl sulfate and 0.6g of polysorbate are sequentially added dropwise in the reaction process for emulsification treatment, 0.24g of ammonium persulfate and 0.5g of dodecyl mercaptan are added for high-speed stirring and homogenization for 15min, and a 40-mesh sieve is used for filtering, so that the filtrate is taken as 80g of slow-release coating liquid. And spraying the coating liquid of the slow release body on the separator pellets in a fluidized bed, wherein the air inlet temperature is 23 ℃ in the fluidized bed bottom spraying process, the material temperature is 23 ℃, the fan frequency is 18Hz, the liquid spraying frequency is 5Hz, and the pellets after liquid spraying are placed in a blast drying oven to be solidified for 24 hours at 40 ℃ to prepare the slow release body pellets, namely the tacrolimus slow release pellets.
And filling the tacrolimus sustained-release pellets into hollow capsules to obtain the tacrolimus sustained-release capsules.
Example 3: 740ml of ethanol water solution with the concentration of 95% is weighed, 50g of povidone K30 is added into the ethanol water solution and stirred until the povidone K30 is dissolved, 50g of tacrolimus active ingredient is added into the solution and stirred, the suspension is prepared, and the suspension is filtered through a 60-mesh sieve and the filtrate is taken. And placing 500 blank sugar pellets at the bottom of the fluidized bed, and coating and applying medicine in a bottom spraying mode, wherein the air inlet temperature for the fluidized bed is 45 ℃, the material temperature is 35 ℃, the air inlet frequency is 10Hz, and the liquid spraying frequency is 5Hz. And after the medicine feeding is finished, the pellets are placed in a blast drying oven to be dried for 2 hours at 35 ℃ to obtain the medicine carrying body.
13g of hypromellose, 1.3g of polyethylene glycol 6000 and 7.5g of talcum powder are weighed and sequentially added into 320ml of absolute ethyl alcohol, stirring is carried out until the mixture is dissolved, an isolating layer coating liquid is prepared, and the isolating layer coating liquid is subjected to bottom spraying on a medicine carrying body in a fluidized bed. Wherein the bottom spraying air inlet temperature of the fluidized bed is 40 ℃, the material temperature is 30 ℃, the fan frequency is 15Hz, the spraying frequency is 5Hz, and the pellets after spraying the liquid are dried for 2 hours at 40 ℃ in a blast drying box, so that the isolator containing pellets are prepared, wherein the isolator accounts for 4% of the total mass of the pellets.
44g of methacrylic acid and 52g of ethyl acrylate are weighed and polymerized at 75 ℃, 0.9g of sodium dodecyl sulfate and 0.3g of polysorbate are sequentially added dropwise in the reaction process for emulsification treatment, 0.24g of ammonium persulfate and 0.5g of dodecyl mercaptan are added for high-speed stirring and homogenization for 15min, and a 40-mesh sieve is used for filtering, so that the filtrate is taken as 80g of slow-release coating liquid. And spraying the coating liquid of the slow release body on the separator pellets in a fluidized bed, wherein the air inlet temperature is 23 ℃ in the fluidized bed bottom spraying process, the material temperature is 23 ℃, the fan frequency is 18Hz, the liquid spraying frequency is 5Hz, and the pellets after liquid spraying are placed in a blast drying oven to be solidified for 24 hours at 40 ℃ to prepare the slow release body pellets, namely the tacrolimus slow release pellets.
And filling the tacrolimus sustained-release pellets into hollow capsules to obtain the tacrolimus sustained-release capsules.
Example 4: 740ml of ethanol water solution with the concentration of 95% is weighed, 50g of povidone K30 is added into the ethanol water solution and stirred until the povidone K30 is dissolved, 50g of tacrolimus active ingredient is added into the solution and stirred, the suspension is prepared, and the suspension is filtered through a 60-mesh sieve and the filtrate is taken. And placing 500 blank sugar pellets at the bottom of the fluidized bed, and coating and applying medicine in a bottom spraying mode, wherein the air inlet temperature for the fluidized bed is 45 ℃, the material temperature is 35 ℃, the air inlet frequency is 10Hz, and the liquid spraying frequency is 5Hz. And after the medicine feeding is finished, the pellets are placed in a blast drying oven to be dried for 2 hours at 35 ℃ to obtain the medicine carrying body.
13g of hypromellose, 1.3g of polyethylene glycol 6000 and 7.5g of talcum powder are weighed and sequentially added into 320ml of absolute ethyl alcohol, stirring is carried out until the mixture is dissolved, an isolating layer coating liquid is prepared, and the isolating layer coating liquid is subjected to bottom spraying on a medicine carrying body in a fluidized bed. Wherein the bottom spraying air inlet temperature of the fluidized bed is 40 ℃, the material temperature is 30 ℃, the fan frequency is 15Hz, the spraying frequency is 5Hz, and the pellets after spraying the liquid are dried for 2 hours at 40 ℃ in a blast drying box, so that the isolator containing pellets are prepared, wherein the isolator accounts for 4% of the total mass of the pellets.
44g of methacrylic acid and 52g of ethyl acrylate are weighed and polymerized at 75 ℃, 0.3g of sodium dodecyl sulfate and 0.9g of polysorbate are sequentially added dropwise in the reaction process for emulsification treatment, 0.32g of ammonium persulfate and 0.5g of dodecyl mercaptan are added for high-speed stirring and homogenization for 15min, and a 40-mesh sieve is used for filtering, so that the filtrate is taken as 80g of slow-release coating liquid. And spraying the coating liquid of the slow release body on the separator pellets in a fluidized bed, wherein the air inlet temperature is 23 ℃ in the fluidized bed bottom spraying process, the material temperature is 23 ℃, the fan frequency is 18Hz, the liquid spraying frequency is 5Hz, and the pellets after liquid spraying are placed in a blast drying oven to be solidified for 24 hours at 40 ℃ to prepare the slow release body pellets, namely the tacrolimus slow release pellets.
And filling the tacrolimus sustained-release pellets into hollow capsules to obtain the tacrolimus sustained-release capsules.
Weighing lauric acid and polyethylene glycol with the molar ratio of 1:1 and p-toluenesulfonic acid accounting for 0.75% of the total mass ratio, and carrying out esterification reaction for 2 hours at the temperature of 100 ℃ to obtain lauric acid polyethylene glycol glyceride, wherein the HLB value of the lauric acid polyethylene glycol glyceride is 14, and the melting point of the lauric acid polyethylene glycol glyceride is 47 ℃. And 3g of tacrolimus, 48.5g of lauric acid polyethylene glycol glyceride, 43.65g of stearic acid and 4.85g of hydroxypropyl cellulose are weighed and mixed to obtain a mixture, the mixture is put into a hot-melt extruder to be hot-melt extruded at 50 ℃, the hot-melt extrudate is crushed to obtain a crushed material, and the crushed material is mixed with a suspending agent and a flavoring agent to obtain the tacrolimus sustained-release pharmaceutical composition. Wherein, the suspending agent and the flavoring agent are auxiliary materials, and are not described in detail in the embodiment of the invention.
Example 5: 740ml of ethanol water solution with the concentration of 95% is weighed, 50g of povidone K30 is added into the ethanol water solution and stirred until the povidone K30 is dissolved, 50g of tacrolimus active ingredient is added into the solution and stirred, the suspension is prepared, and the suspension is filtered through a 60-mesh sieve and the filtrate is taken. And placing 500 blank sugar pellets at the bottom of the fluidized bed, and coating and applying medicine in a bottom spraying mode, wherein the air inlet temperature for the fluidized bed is 45 ℃, the material temperature is 35 ℃, the air inlet frequency is 10Hz, and the liquid spraying frequency is 5Hz. And after the medicine feeding is finished, the pellets are placed in a blast drying oven to be dried for 2 hours at 35 ℃ to obtain the medicine carrying body.
13g of hypromellose, 1.3g of polyethylene glycol 6000 and 7.5g of talcum powder are weighed and sequentially added into 320ml of absolute ethyl alcohol, stirring is carried out until the mixture is dissolved, an isolating layer coating liquid is prepared, and the isolating layer coating liquid is subjected to bottom spraying on a medicine carrying body in a fluidized bed. Wherein the bottom spraying air inlet temperature of the fluidized bed is 40 ℃, the material temperature is 30 ℃, the fan frequency is 15Hz, the spraying frequency is 5Hz, and the pellets after spraying the liquid are dried for 2 hours at 40 ℃ in a blast drying box, so that the isolator containing pellets are prepared, wherein the isolator accounts for 4% of the total mass of the pellets.
44g of methacrylic acid and 52g of ethyl acrylate are weighed and polymerized at 75 ℃, 0.6g of sodium dodecyl sulfate and 0.6g of polysorbate are sequentially added dropwise in the reaction process for emulsification treatment, 0.48g of ammonium persulfate and 0.5g of dodecyl mercaptan are added for high-speed stirring and homogenization for 15min, and a 40-mesh sieve is used for filtering, so that the filtrate is taken as 80g of slow-release coating liquid. And spraying the coating liquid of the slow release body on the separator pellets in a fluidized bed, wherein the air inlet temperature is 23 ℃ in the fluidized bed bottom spraying process, the material temperature is 23 ℃, the fan frequency is 18Hz, the liquid spraying frequency is 5Hz, and the pellets after liquid spraying are placed in a blast drying oven to be solidified for 24 hours at 40 ℃ to prepare the slow release body pellets, namely the tacrolimus slow release pellets.
And filling the tacrolimus sustained-release pellets into hollow capsules to obtain the tacrolimus sustained-release capsules.
Example 6: the difference between this embodiment and embodiments 1 to 5 is that the air inlet temperature in the slow release body bottom spraying process in this embodiment is 30 ℃ and the material temperature is 30 ℃.
Example 7: the difference between this example and examples 1-6 is that the air inlet temperature in the slow release body bottom spraying process in this example is 35 ℃ and the material temperature is 35 ℃.
Experimental example 1: release degree experiments are carried out on the tacrolimus sustained-release capsules in the embodiments 1-7 of the invention, and release degree results of the tacrolimus sustained-release capsules in the embodiments 1-7 under the conditions of 0 month, 3 months, 6 months, 9 months, 12 months and 18 months respectively are obtained, wherein dissolution media are 0.1 mol.L respectively -1 Hydrochloric acid solution and pH=6 phosphate buffer for 0.1 mol.L each -1 Hydrochloric acid solution for 1h and 2h, and phosphate buffer for 2h, wherein the experimental results are shown in tables 1-7.
Table 1 sustained release tacrolimus capsules of example 1 release
Table 2 degree of release of tacrolimus sustained-release capsules of example 2
TABLE 3 Tacrolimus sustained Release degree of Tacrolimus sustained Release Capsule of EXAMPLE 3
TABLE 4 Tacrolimus sustained Release degree of Tacrolimus sustained Release Capsule of example 4
TABLE 5 Tacrolimus sustained Release degree of Tacrolimus sustained Release Capsule of example 5
TABLE 6 Tacrolimus sustained Release degree of Tacrolimus sustained Release Capsule of EXAMPLE 6
TABLE 7 Tacrolimus sustained Release degree of Tacrolimus sustained Release Capsule of EXAMPLE 7
Referring to the release degree data in each experimental example in tables 1 to 7, it can be explained that the release result is optimal in the experimental example corresponding to the embodiment 1, so the embodiment 1 is selected as the optimal embodiment.
Experimental example 2: the tacrolimus sustained-release capsule of example 1 was selected, and the tacrolimus sustained-release capsule advargaf was selected from the group consisting of ® And comparing animal experiments to determine the absorption efficiency.
In experimental setting, the tacrolimus slow-release capsule in the example 1 is precisely weighed, and an intestinal perfusion solution 500 mL with the tacrolimus mass concentration of 40 mug.mL-1 is prepared by using a Krebs-Ringer buffer solution (pH 7.4), dissolved by ultrasonic and filtered for later use as a test sample. Simultaneously, the commercial tacrolimus slow-release capsule ADVAGRAF is precisely weighed ® 20mg of a reference solution was prepared in the same manner. And (3) performing small intestine section intubation on the rat, cleaning intestinal tracts with normal saline, performing a unidirectional intestinal perfusion experiment by using the prepared K-R test solution, and collecting perfusion solution, namely blank intestinal circulation solution. Rats fasted overnight (free-drinking) prior to the experiment were selected, anesthetized with 10% aqueous chloroaldehyde solution (4.5 mL kg-1), fixed on a surgical table, maintained at 37 ℃ body temperature, and were cut about 3cm along the ventral midline to ligate the intestinal segments of the rats: a duodenum; jejunum segment; an ileum segment; a colon segment. And connecting the cannula with the constant flow pump to form a loop. The intestinal tract is firstly washed by normal saline at 37 ℃, then the K-R solution at 37 ℃ is balanced for 15min at the flow rate of 0.3 mL min < -1 >, and then the K-R solution is discharged by air. The sample solution and the reference solution (40. Mu.g.mL-1) were refluxed at a flow rate of 0.28 mL.min-1, the sample solution was poured into a vial having a known weight at the inlet, the sample solution was collected 1 time from another vial having a known weight at the outlet every 15min, the weights of the sample solution vial and the sample solution vial were weighed at this time, the sample solution was centrifuged at 12000 rpm for 6min, and the supernatant was collected and the tacrolimus concentration was measured in a high performance liquid phase for 120 min. After the experiment, the rat spinal dislocation was sacrificed, the section of the irrigated intestine was cut off, and the length and the inner diameter thereof were measured with a thin wire. The drug absorption rate constant and the drug apparent absorption coefficient were calculated.
The behavior in example 1 with respect to the drug absorption rate constant is shown in the absorption rate table:
absorption rate constant meter
From the above table, the absorption rate constants at the individual intestinal segments for example 1 were not different from the commercially available drugs.
The behavior in example 1 with respect to the apparent absorption coefficient of the drug is shown in the absorption coefficient table:
absorption coefficient meter
From the above absorption coefficient table, the absorption coefficient of tacrolimus in each intestinal section was significantly improved for the tacrolimus sustained-release capsule in example 1. For and commercial ADVAGRAF ® In contrast, the effect of example 1 is comparable.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the invention, but any modifications, equivalents, improvements, etc. within the principles of the present invention should be included in the scope of the present invention.
Claims (3)
1. The tacrolimus sustained-release drug is characterized by comprising tacrolimus sustained-release pellets and a capsule body wrapping the tacrolimus sustained-release pellets;
the tacrolimus sustained-release pellets comprise a drug carrier, a separator and a sustained-release body which are sequentially wrapped; the slow release body is prepared by spraying slow release body coating liquid on the surface of the separator and air-drying; the separator is prepared by spraying a separator coating liquid on the surface of the medicine carrying body and air-drying;
the drug carrier comprises an ethanol aqueous solution, a suspending agent prepared from a cosolvent povidone K30 and tacrolimus, and is prepared by air drying;
the spacer coating liquid is prepared by adding hydroxypropyl methylcellulose, polyethylene glycol 6000 and talcum powder into ethanol and stirring; the mass ratio of the hypromellose to the polyethylene glycol 6000 to the talcum powder is 10:1:1;
the slow-release body coating liquid is methacrylic acid-ethyl acrylate water dispersion obtained by a water emulsion polymerization treatment method;
the slow-release coating liquid is polymerized by methacrylic acid and ethyl acrylate, sodium dodecyl sulfate and polysorbate are sequentially dripped into the slow-release coating liquid in the polymerization process to carry out emulsification treatment, ammonium persulfate is added, and dodecyl mercaptan is added to carry out high-speed stirring homogenization; the molar ratio of the methacrylic acid to the ethyl acrylate monomer is 1:1, and the molar ratio of the sodium dodecyl sulfate to the polysorbate is 1:3.
2. The tacrolimus sustained-release drug according to claim 1, wherein: the spacer coating liquid is prepared by adding the hypromellose into the ethanol for dissolution to obtain a first dissolved substance, adding the polyethylene glycol 6000 into the first dissolved substance for dissolution to obtain a second dissolved substance, and adding the talcum powder into the second dissolved substance for stirring.
3. The method for preparing the tacrolimus sustained-release drug according to claim 1 or 2, characterized in that the preparation method comprises the following steps: the suspending agent prepared from ethanol water solution, cosolvent povidone K30 and tacrolimus is dried to prepare a medicine carrier; spraying a spacer coating liquid on the surface of the medicine carrying body, and air-drying to obtain a spacer; spraying a slow-release coating liquid on the surface of the separator, and air-drying to obtain tacrolimus slow-release pellets; and filling the tacrolimus sustained-release pellets into hollow capsules to obtain tacrolimus sustained-release capsules.
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