CN114869845A - Oseltamivir phosphate sustained-release suspension and preparation method thereof - Google Patents
Oseltamivir phosphate sustained-release suspension and preparation method thereof Download PDFInfo
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- CN114869845A CN114869845A CN202210490058.3A CN202210490058A CN114869845A CN 114869845 A CN114869845 A CN 114869845A CN 202210490058 A CN202210490058 A CN 202210490058A CN 114869845 A CN114869845 A CN 114869845A
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- resin
- oseltamivir phosphate
- oseltamivir
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- drug
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- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 title claims abstract description 127
- 229960002194 oseltamivir phosphate Drugs 0.000 title claims abstract description 93
- 239000000725 suspension Substances 0.000 title claims abstract description 84
- 238000013268 sustained release Methods 0.000 title claims abstract description 54
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
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- 238000003756 stirring Methods 0.000 claims description 51
- 239000000463 material Substances 0.000 claims description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 39
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 34
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 13
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 11
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 3
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 3
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- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 3
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- 229940083037 simethicone Drugs 0.000 description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 3
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- 241000416162 Astragalus gummifer Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 2
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- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
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Classifications
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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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Pulmonology (AREA)
- Emergency Medicine (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of preparation of pharmaceutical preparations, and particularly relates to an oseltamivir phosphate sustained-release suspension and a preparation method thereof. The invention utilizes the emulsion solvent coating technology and adopts a solvent volatilization method to prepare the oseltamivir resin microcapsule; and uniformly dispersing the oseltamivir resin microcapsules in the suspension matrix to obtain the oseltamivir phosphate sustained-release suspension. The preparation method has simple process and lower cost, and is easy for industrial production; the emulsion coating can slowly release the medicine, reduce the irritation to stomach, prolong the action time of the medicine and reduce the administration times of patients. Compared with the common quick-release preparation, the sustained-release preparation of the invention is convenient to carry and can reduce the taking times. Is more suitable for children and dysphagia patients, and can improve the medication compliance of patients. Meanwhile, the medicine hardly undergoes ion exchange in the oral cavity, and the bitter taste of the medicine can be effectively masked.
Description
Technical Field
The invention belongs to the technical field of preparation of pharmaceutical preparations, and particularly relates to an oseltamivir phosphate sustained-release suspension and a preparation method thereof.
Background
Oseltamivir Phosphate (OP) is a potent and highly selective influenza NA inhibitor (NAIs). OP having the formula C 16 H 28 N 2 O 4 . H 3 PO 4 (ii) a Is white or off-white crystalline powder, is easily soluble in water or methanol, slightly soluble in N, N-dimethylformamide, and hardly soluble in diethyl ether. OP is mainly absorbed in stomach and small intestine after oral administration, more than 75% of OP is converted into an active metabolite-Oseltamivir Carboxylate (OC) through esterase of liver and intestinal wall, and the OC is a powerful neuraminidase inhibitor, has extremely high selectivity and is especially effective on influenza A and B viruses. Neither OP nor OC are substrates or inhibitors of cytochrome P450 isozymes and therefore do not trigger drug-drug interactions.
The oral liquid sustained and controlled release technology is more and more concerned by the market due to strong compliance, large drug-loading rate and small gastrointestinal tract stimulation, and becomes an important development direction in the pharmaceutical field. Because the domestic oral liquid sustained and controlled release preparation starts late, and is impacted by the solid sustained and controlled release preparation with relatively simple process and lower threshold, the oral liquid sustained and controlled release preparation is not paid enough attention to and developed, and is still at a lower level at present. Compared with the conventional preparations, such as tablets, capsules and the like, the oral liquid suspension has good absorption after oral administration; is convenient for patients to take in divided doses, and the dose can be adjusted according to the age, weight difference and course of disease of children patients. Compared with other oral solid preparations, the oral liquid sustained-release preparation can reduce the administration times, and has the characteristics of less stimulation to stomach and reduction of toxic and side effects. The oseltamivir phosphate is available in the market at present in the dosage forms of granules, capsules, dry suspensions and the like. No oseltamivir phosphate sustained-release dosage form is on the market at present, and research on an oseltamivir phosphate sustained-release suspension is lacked in the prior art. Therefore, the development of the oseltamivir phosphate sustained-release suspension which has good drug stability, high drug loading rate, good taste, excellent drug sustained-release effect and small irritation to the gastrointestinal tract is very significant.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an oseltamivir phosphate sustained-release suspension and a preparation method thereof. The oseltamivir phosphate sustained-release suspension prepared by creatively utilizing the drug resin and combining the coating technology to control the drug release has the characteristics of good drug stability, high drug loading, excellent drug sustained-release effect, good compliance and the like.
In order to achieve the above object, the present invention provides the following technical solutions:
in a first aspect, the invention provides an oseltamivir phosphate sustained-release suspension, which is prepared from the following raw materials: oseltamivir phosphate, cation exchange resin, impregnant, coating material and other pharmaceutically acceptable auxiliary materials; according to weight percentage, each dosage unit contains 1.2 percent of oseltamivir phosphate, 0.6 to 3.6 percent of cation exchange resin, 0 to 0.048 percent of impregnant, 0.12 to 0.48 percent of coating material and the balance of auxiliary materials.
The oseltamivir phosphate slow-release suspension takes cation exchange resin as a carrier of the oseltamivir phosphate medicament, the oseltamivir phosphate is loaded on the cation exchange resin material, and the medicament is coated by an emulsion solvent volatilization method, so that the medicament is released directionally, the action time of the medicament is prolonged, and the administration times of patients are reduced.
In some embodiments of the invention, the cation exchange resin comprises a strong acid cation exchange resin and a weak acid cation exchange resin; the weak acid cation exchange resin is Amberlite ® IRP64 and/or Amberlite ® IRP 88; the strong-acid cation exchange resin is Amberlite ® IRP69。
The impregnant is one or more of methyl cellulose, polyethylene glycol 2000 and polyethylene glycol 4000.
The coating material comprises a coating capsule material and a plasticizer; the coating capsule wall material is Eudragit RS100 and/or Eudragit RL 100; the plasticizer is any one or the combination of at least two of propylene glycol, polyethylene glycol 200 or polyethylene glycol 400.
The pharmaceutical adjuvant comprises any one or combination of at least two of suspending agent, wetting agent, correctant, flavoring agent, thickening agent, antiseptic, defoaming agent or colorant.
The combination of at least two of the above components, such as the combination of a dispersing agent and a humectant, the combination of a sweetener, a flavoring agent and a coloring agent, the combination of a thickener and a preservative, and the like, can be selected in any combination manner, and thus, the details are not repeated.
The suspending agent comprises xanthan gum, microcrystalline cellulose-sodium carboxymethylcellulose (Avicel CL-611), hydroxypropyl methylcellulose, microcrystalline cellulose, and/or sodium carboxymethylcellulose.
The correctant comprises one or more of mannitol, sorbitol, sucrose, saccharin sodium, fructus Citri sinensis essence, herba Menthae essence, and fructus Citri Tangerinae essence. The combination of at least two of the above-mentioned compounds, such as the combination of mannitol and sorbitol, the combination of sorbitol and sucrose, the combination of mannitol and sucrose and sweet orange essence, etc., can be selected in any other combination manner, and is not repeated herein.
The humectant comprises one or more of ethanol, propylene glycol and glycerol.
The preservative comprises one or more of methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate or sodium benzoate. The combination of at least two of the above-mentioned compounds, such as methyl hydroxybenzoate and ethyl hydroxybenzoate, ethyl hydroxybenzoate and propyl hydroxybenzoate, propyl hydroxybenzoate and sodium benzoate, can be selected in any combination manner, and will not be described herein again.
The defoaming agent comprises dimethyl silicone oil. The colorant includes FD & C yellow No. 6.
In a second aspect, the present invention also provides a preparation method of the oseltamivir phosphate sustained-release suspension according to the first aspect, wherein the preparation method comprises the following steps:
(1) mixing oseltamivir phosphate and cation exchange resin in deionized water to prepare a drug-loaded resin compound;
(2) impregnating the drug-loaded resin compound obtained in the step (1) with an impregnant, stirring, drying and sieving to obtain impregnating resin;
(3) coating the impregnating resin obtained in the step (2) and a coating material by a solvent volatilization method to obtain an oseltamivir resin microcapsule;
(4) and (4) mixing the oseltamivir resin microcapsules obtained in the step (3) with auxiliary materials and water to obtain the oseltamivir phosphate sustained-release suspension.
The mass ratio of the cation exchange resin to oseltamivir phosphate in the step (1) is 0.5-3: 1, preferably 1-2: 1.
the preparation method of the drug-loaded resin compound in the step (1) comprises the following steps: mixing oseltamivir phosphate with water, adding ion exchange resin, and performing suction filtration and drying when the concentration of the drug in the solution does not change along with time; or mixing cation exchange resin with water, placing into a chromatographic column, adding oseltamivir phosphate solution into the chromatographic column for chromatography, and washing with water and drying when the concentration of the effluent is equal to that of the added solution; the concentration of the oseltamivir phosphate is 1-7 mg/mL; the temperature in the preparation process is 25-45 ℃.
The dipping temperature in the step (2) is 50-60 ℃.
The coating material in the step (3) contains a coating capsule material and a plasticizer; the coating capsule wall material is acrylic resin (Eudragit RS 100) and/or acrylic resin (Eudragit RL 100).
In the step (3), the ratio of the coating capsule material to the impregnating resin is 1: 5-20%; the concentration of the coating capsule wall material is 1-5%.
Further, the plasticizer is any one of propylene glycol, polyethylene glycol 200 or polyethylene glycol 400 or a combination of at least two of the two. The plasticizer accounts for 0-10% of the coating capsule material.
The solvent volatilization method in the step (3) is to mix and dissolve the span 80 in the liquid paraffin under stirring to form a continuous phase; dissolving a coating material and a plasticizer in an organic solvent to form a dispersion phase, adding impregnating resin into the dispersion phase to form a suspension state, dropwise adding the suspension-state dispersion phase into a continuous phase, stirring for 2-6 h at 25-60 ℃, drying and sieving at 50-60 ℃ to obtain the oseltamivir resin microcapsule.
Compared with the prior art, the invention has the beneficial effects that:
the invention adopts the technology of impregnating the drug resin compound, and the drug resin compound is obtained after the oseltamivir phosphate, the drug carrier and the solvent are mixed, dissolved and separated; then the drug resin compound reacts with an impregnant to obtain an impregnated drug resin compound; then preparing coated oseltamivir phosphate-resin compound microcapsules by an emulsion solvent coating technology and a solvent volatilization method; and then preparing a suspension matrix, and uniformly dispersing the coated oseltamivir phosphate-resin compound microcapsules in the suspension matrix to obtain the oseltamivir phosphate sustained-release suspension. The resin material can cover the bitter taste of the medicine and is easier for patients to swallow; meanwhile, the oseltamivir phosphate has high drug loading capacity and excellent stability and redispersibility; the emulsion coating can slowly release the medicine, reduce the irritation to stomach, prolong the action time of the medicine and reduce the administration times of patients. The invention takes oseltamivir phosphate as a model drug for the first time, prepares an oseltamivir resin compound by applying an ion exchange resin technology, investigates the release characteristics of the oseltamivir resin compound, and prepares a drug resin sustained-release microcapsule with good sustained-release effect by combining an impregnation technology and a coating technology. The medicine hardly generates ion exchange in the oral cavity, can effectively cover the bitter taste of the medicine, is easy to be taken by special patients such as children and old people, and enriches the medicine for children to a certain extent.
Detailed Description
The invention discloses an oseltamivir phosphate sustained-release suspension and a preparation method thereof. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention. The starting materials and reagents used in the embodiments of the invention are commercially available. Wherein, cation exchange resin Amberlite ® IRP64、Amberlite ® IRP88、Amberlite ® IRP69 is available from the dow chemical company.
Example 1
100mg of cation exchange resin Amberlite was weighed ® IRP69 was put into 200mL of OP solution with a concentration of 1mg/mL, magnetically stirred at 37.0 ℃. + -. 0.5 ℃ for 4 hours, sampled at predetermined time points, filtered, and absorbance was measured at a wavelength of UV 238 nm to calculate the OP concentration at each time point. Determining the original concentration of oseltamivir phosphate and the drug concentration in the solution after drug loading balance to obtain the formula Q t =（C 0 -C t ）V/W R And E = (C) 0 -C t ）/C 0 Calculation of C 0 (mg/mL) is the initial concentration of drug; c t (mg/mL) is the drug concentration in the solution at time t; v (mL) is the volume of the solution; w R (mg) is the mass of the resin; q t (mg/mg) is the drug loading of the resin at time t, and E (%) is the drug utilization rate. Table 1 is a table comparing the drug loading and drug utilization of the resin as a result of sampling at predetermined time points.
TABLE 1 comparison table of drug loading and drug utilization of resin at predetermined time points
| Time (min) | Q t （mg/mg） | E（%） |
| 15 | 0.357 | 17.9 |
| 30 | 0.533 | 26.7 |
| 60 | 0.676 | 33.8 |
| 120 | 0.704 | 35.2 |
| 180 | 0.720 | 36.0 |
| 240 | 0.718 | 35.9 |
As can be seen from Table 1, the drug loading balance can be achieved after 3 hours of reaction, the balance drug loading amount is 0.72mg/mg, the drug concentration after balance is 0.64 mg/mL, and the drug utilization rate is 36%.
Example 2
Weighing 300mg of blank resin, filling the blank resin into a glass chromatographic column with the diameter of 2cm, adding deionized water pretreatment resin for 30min, and after the deionized water completely flows out from the lower end, adding the deionized water along the wall to enable the resin layer to be flat and uniform. At the beginning of drug loading, 1mg/mL OP solution was slowly poured from the top of the column, the flow rate was controlled at 0.6mL/min by rotating the lower piston, and samples were taken at regular times to determine the OP concentration. When the effluent begins to detect the drug, the dynamic loading reaches the point of penetration; the concentration of the effluent liquid is increased continuously along with the continuous combination of the medicine and the resin, and the reaction reaches the equilibrium when the concentration of the effluent liquid is close to the initial concentration of the liquid medicine.
The penetration rate of the drug-loaded resin is calculated by the specific operation method: determining the original concentration of oseltamivir phosphate and the drug concentration in the solution after drug loading balance according to the formula P r =C t /C 0 And (4) calculating. Wherein, C t OP concentration, C in the effluent at time point t 0 Is the initial concentration of OP solution. Table 2 is the penetration rate of the nodes at different times.
TABLE 2 penetration rate of different time nodes
| Time (min) | P r (penetration Rate) |
| 5 | 0.012 |
| 15 | 0.010 |
| 30 | 0.015 |
| 60 | 0.015 |
| 120 | 0.031 |
| 150 | 0.099 |
| 180 | 0.255 |
| 240 | 0.503 |
| 285 | 0.688 |
| 330 | 0.928 |
| 360 | 0.942 |
| 390 | 0.942 |
| 420 | 0.937 |
As can be seen from table 2, when the dynamic drug loading was performed by controlling the outflow rate to be 0.6mL/min, the penetration point appeared at 2 hours, and 6 hours were required to achieve drug loading balance.
Example 3
The embodiment provides an oseltamivir phosphate sustained-release suspension which comprises the following auxiliary materials: 200mg of xanthan gum, 250mg of mannitol, 250mg of cane sugar, 40mg of propylene glycol, 8mg of methyl p-hydroxybenzoate, 2.6mg of propyl p-hydroxybenzoate, 25mg of simethicone, 15mg of orange essence, 5mg of FD & C yellow No. 6 and 50mL of distilled water; the preparation process comprises the following steps:
(1) preparation of pharmaceutical resins
An Oseltamivir Phosphate (OP) aqueous solution with the concentration of 3mg/mL and an ion exchange resin Amberlite ® IRP69 is mixed by mass ratio of 1: 1, mixing, magnetically stirring for 3 hours at 37 ℃, washing off unadsorbed drugs on the surface of the resin by using deionized water, drying at 50 ℃, and sieving to obtain drug-loaded resin;
(2) impregnation of pharmaceutical resins
Weighing 2g of polyethylene glycol 4000, dissolving in 8mL of deionized water, heating to 50 ℃, adding 1g of the drug-loaded resin prepared in the step (1), stirring for 30 minutes, and drying and sieving at 50 ℃ to obtain impregnating resin;
(3) preparation of drug resin microcapsules
Dissolving a coating capsule wall material (Eudragit RS100 and Eudragit RL100 are mixed according to the mass ratio of 1: 1) and a plasticizer polyethylene glycol 400 in an organic solvent ethanol, and stirring to dissolve to obtain a dispersion phase; slowly adding the impregnating resin obtained in the step (2) into the dispersion phase, and stirring to enable the dispersion phase to be in a suspension state (the mass ratio of the coating capsule material to the impregnating resin is 1: 10%, the proportion of the plasticizer in the coating capsule material is 5%, and the concentration of the coating capsule material is 1%). And adding liquid paraffin, ethanol and span 80 according to a volume ratio of 20: 3:1, mixing uniformly to obtain a continuous phase. Dropwise adding the suspended dispersion phase into the continuous phase, stirring for 4 hours at 40 ℃, performing suction filtration, washing filter residues with petroleum ether, drying and sieving at 50-60 ℃ to obtain the oseltamivir resin microcapsule.
(4) Preparation of pharmaceutical resin microcapsule suspension
Respectively adding mannitol and sucrose into distilled water, stirring for dissolving, adding xanthan gum, and stirring for 1 h; dissolving methyl p-hydroxybenzoate and propyl p-hydroxybenzoate in propylene glycol; mixing the two parts, adding dimethyl silicone oil, orange essence and FD & C yellow 6, stirring for 30min, and mixing to obtain suspension matrix; and (3) adding 5mL of suspension matrix into the oseltamivir resin microcapsule prepared in the step (3) of 150 mg, and uniformly mixing to obtain an oseltamivir phosphate sustained-release suspension (containing 60 mg of oseltamivir).
Example 4:
the embodiment provides an oseltamivir phosphate sustained-release suspension which comprises the following auxiliary materials: 200mg of xanthan gum, 250mg of cane sugar, 40mg of propylene glycol, 8mg of methyl p-hydroxybenzoate, 25mg of simethicone, 15mg of sweet orange essence, 5mg of FD & C yellow No. 6 and 50mL of distilled water; the preparation process comprises the following steps:
(1) the OP aqueous solution with the concentration of 1mg/mL and the ion exchange resin Amberlite ® IRP69 is mixed by mass ratio of 1: 1, magnetically stirring for 3 hours at normal temperature, washing off the surface adsorbed drugs by using deionized water, drying at 50 ℃, and sieving to obtain drug-loaded resin;
(2) weighing 2g of polyethylene glycol 4000, dissolving in 8mL of deionized water, heating to 60 ℃, adding 1g of the drug-loaded resin prepared in the step (1), stirring for 30 minutes, drying at 50 ℃, and sieving to obtain impregnating resin;
(3) dissolving the coating capsule wall material (Eudragit RS 100) and a plasticizer propylene glycol in an organic solvent acetone, stirring and dissolving to obtain a dispersion phase, slowly adding the impregnating resin prepared in the step (2) into the dispersion phase, and stirring to obtain a suspension state (the mass ratio of the coating capsule wall material to the impregnating resin is 1: 20%, the mass ratio of the plasticizer to the coating capsule wall material is 1: 5, and the concentration of the coating capsule wall material is 3%). Liquid paraffin and span 80 (liquid paraffin: acetone: span 80 = 8: 3: 1) were mixed uniformly as a continuous phase. Dropwise adding the dispersed phase in a suspension state into the continuous phase, and stirring for 4 hours at 40 ℃; and (4) carrying out suction filtration, washing filter residues by using petroleum ether, drying and sieving at 50 ℃ to obtain the oseltamivir resin microcapsule.
(4) Preparation of pharmaceutical resin microcapsule suspension
Adding sucrose into distilled water, adding xanthan gum after dissolving, and stirring for 1 h; dissolving methyl p-hydroxybenzoate in propylene glycol; and (3) mixing the two parts, adding dimethyl silicone oil, sweet orange essence and FD & C yellow 6, stirring for 30min to obtain a suspension matrix, adding 5mL of the suspension matrix into 150 mg of the oseltamivir resin microcapsules prepared in the step (3), and uniformly mixing to obtain the oseltamivir phosphate sustained-release suspension (containing 60 mg of oseltamivir).
Example 5
The embodiment provides an oseltamivir phosphate sustained-release suspension which comprises the following auxiliary materials: 200mg of tragacanth, 500mg of mannitol, 1g of propylene glycol, 0.5g of glycerol, 8mg of methylparaben, 5mg of FD & C yellow No. 6 and 50mL of distilled water; the preparation process comprises the following steps: (1) preparation of pharmaceutical resins
The OP aqueous solution with the concentration of 1mg/mL and the ion exchange resin Amberlite ® IRP69 is mixed by mass ratio of 1: 1, magnetically stirring for 3 hours at normal temperature, washing away unadsorbed drugs on the surface by using deionized water, drying at 60 ℃, and sieving to obtain drug-loaded resin;
(2) impregnation of pharmaceutical resins
Weighing 1.6g of polyethylene glycol 2000, dissolving in 8mL of deionized water, heating to 60 ℃, adding 1g of the drug-loaded resin prepared in the step (1), stirring for 30 minutes, and drying and sieving at 60 ℃ to obtain impregnating resin;
(3) preparation of drug resin microcapsules
Dissolving the coating capsule material (Eudragit RL 100) in acetone as a disperse phase, slowly adding the impregnating resin prepared in the step (2) into the disperse phase, and stirring to keep the coating capsule material in a suspension state (the mass ratio of the coating capsule material to the impregnating resin is 5%, the mass ratio of PEG to the coating capsule material is 0%, and the concentration of the coating capsule material is 5%). Liquid paraffin and span 80 (liquid paraffin: acetone: span 80 = 8: 3: 1) were mixed uniformly to obtain a continuous phase. The dispersed phase in suspension was added dropwise to the continuous phase and stirred at 40 ℃ for 6 h. And (4) carrying out suction filtration, washing filter residues by using petroleum ether, drying and sieving at 60 ℃ to obtain the oseltamivir resin microcapsule.
(4) Preparation of pharmaceutical resin microcapsule suspension
Adding mannitol into deionized water, stirring, dissolving, adding tragacanth, and stirring for 1 hr; dissolving methyl p-hydroxybenzoate in propylene glycol and glycerol; mixing the two parts, adding FD & C yellow 6, stirring for 30min, and mixing to obtain suspension matrix; and (3) adding 5mL of suspension matrix into the oseltamivir resin microcapsule prepared in the step (3) of 150 mg, and uniformly mixing to obtain an oseltamivir phosphate sustained-release suspension (containing 60 mg of oseltamivir).
Example 6
The embodiment provides an oseltamivir phosphate sustained-release suspension, which is prepared by the following process:
(1) preparation of pharmaceutical resins
Weighing 300mg of oseltamivir phosphate, dissolving the oseltamivir phosphate in 100mL of deionized water, adding 300mg of ion exchange resin after complete dissolution, magnetically stirring the mixture for 3 hours at 37 ℃, washing off the surface adsorbed drug by using the deionized water, and drying and sieving the washed drug at 50-60 ℃ to obtain the drug-loaded resin.
(2) Impregnation of pharmaceutical resins
Weighing 1.6g of polyethylene glycol 4000, dissolving in 8mL of deionized water, heating to 60 ℃, adding 1g of drug-loaded resin, stirring for 30 minutes, drying and sieving at 50-60 ℃ to obtain the impregnated drug resin.
(3) Preparation of drug resin microcapsules
Weighing 90mg of RS100, dissolving in 9mL of acetone, adding 18mg of PEG400, stirring and dissolving to obtain a dispersion phase; 1.8g of the impregnated oseltamivir resin was slowly added to the dispersed phase and stirred to be in a suspended state. 24mL of liquid paraffin and 3mL of span 80 were weighed out and mixed uniformly to serve as a continuous phase. The dispersed phase was added dropwise to the continuous phase and stirred at 50 ℃ for 4 h. And (3) carrying out suction filtration, washing residual liquid paraffin on the surface of the coating by using petroleum ether, drying and sieving at 50-60 ℃ to obtain the oseltamivir resin microcapsule.
(4) Preparation of pharmaceutical resin microcapsule suspension
Weighing 0.4% of xanthan gum, 0.5% of mannitol and 0.5% of sucrose, placing the xanthan gum in a 25mL beaker, adding 0.08% of propylene glycol, and stirring uniformly; dissolving mannitol and sucrose in appropriate amount of distilled water, slowly adding xanthan gum dropwise into mannitol and sucrose solution under stirring, stirring for half an hour, and adding 0.05% dimethyl silicone oil, 0.016% methyl p-hydroxybenzoate, 0.005% methyl p-hydroxybenzoate, 0.03% orange essence, and 0.01% FD & C yellow 6 to obtain suspension matrix. And (4) adding the oseltamivir resin microcapsules prepared in the step (3) into the suspension matrix, and uniformly mixing to obtain the oseltamivir phosphate sustained-release suspension (the percentages are percentages of distilled water).
Example 7
(1) Preparation of pharmaceutical resins
Weighing 300mg of oseltamivir phosphate, dissolving the oseltamivir phosphate in 100mL of deionized water, adding 300mg of ion exchange resin after complete dissolution, magnetically stirring the mixture for 3 hours at 37 ℃, washing off the surface adsorbed drug by using the deionized water, and drying and sieving the washed drug at 50-60 ℃ to obtain the drug-loaded resin.
(2) Impregnation of pharmaceutical resins
Taking a proper amount of drug-loaded resin, adding the drug-loaded resin into a 25% aqueous solution of polyethylene glycol 4000, stirring the mixture for 30 minutes at 50 ℃, drying and sieving the mixture at 50-60 ℃ to obtain the impregnated drug resin.
(3) Preparation of drug resin microcapsules
Weighing 100mg RL100, dissolving in 30mL ethanol, adding 5mg PEG400, stirring and dissolving to obtain a dispersion phase; 1g of the impregnated oseltamivir resin was slowly added to the dispersion phase and stirred to be in a suspended state. 200mL of liquid paraffin and 10mL of span 80 are weighed and uniformly mixed according to a certain proportion to be used as a continuous phase. The dispersed phase was added dropwise to the continuous phase and stirred at 30 ℃ for 6 h. And (4) carrying out suction filtration, washing residual liquid paraffin on the surface of the coating by using petroleum ether, drying and sieving at 55 ℃ to obtain the oseltamivir resin microcapsule.
(4) Preparation of pharmaceutical resin microcapsule suspension
Weighing 0.5% of xanthan gum and 1% of mannitol, placing the xanthan gum in a 25mL beaker, adding 2% of glycerol and 2% of propylene glycol, stirring uniformly, dissolving the mannitol in a proper amount of distilled water in another 200mL beaker, slowly dripping the xanthan gum into the mannitol solution under the stirring state, stirring for half an hour, and adding 0.05% of simethicone, 0.03% of methyl p-hydroxybenzoate, 0.03% of orange essence and 0.01% of FD & C yellow 6 to obtain the suspension matrix. And (4) adding the oseltamivir resin microcapsules prepared in the step (3) into the suspension matrix, and uniformly mixing to obtain the oseltamivir phosphate sustained-release suspension (the percentages are percentages of distilled water).
Example 8
(1) Preparation of pharmaceutical resins
Weighing 300mg of oseltamivir phosphate, dissolving the oseltamivir phosphate in 100mL of deionized water, adding 300mg of ion exchange resin after complete dissolution, magnetically stirring the mixture for 3 hours at 37 ℃, washing off the surface adsorbed drug by using the deionized water, and drying and sieving the washed drug at 50 ℃ to obtain the drug-loaded resin.
(2) Impregnation of pharmaceutical resins
Taking a proper amount of drug-loaded resin, adding the drug-loaded resin into a 25% aqueous solution of polyethylene glycol 4000, stirring the mixture for 30 minutes at 50 ℃, and drying and sieving the mixture at 50 ℃ to obtain the impregnated drug resin.
(3) Preparation of drug resin microcapsules
Weighing 50mg RL100 and 50mg RS100, dissolving in 30mL acetone, adding 5mg PEG200, stirring and dissolving to obtain a dispersion phase; 1g of the impregnated oseltamivir resin was slowly added to the dispersion phase and stirred to be in a suspended state. 80mL of liquid paraffin and 10mL of span 80 are weighed and uniformly mixed to be used as a continuous phase. The dispersed phase was added dropwise to the continuous phase and stirred at 40 ℃ for 4 h. And (4) carrying out suction filtration, washing residual liquid paraffin on the surface of the coating by using petroleum ether, drying and sieving at 50 ℃ to obtain the oseltamivir resin microcapsule.
(4) Preparation of pharmaceutical resin microcapsule suspension
Weighing 0.8% of xanthan gum and 1% of mannitol, placing the xanthan gum in a 25L beaker, adding 4% of glycerol, stirring uniformly, dissolving the mannitol in distilled water, slowly dripping the xanthan gum into the mannitol solution under the stirring state, stirring for half an hour, and adding 0.06% of methyl p-hydroxybenzoate, 0.03% of orange essence and 0.01% of FD & C yellow 6 to obtain the suspension matrix. And (4) adding the oseltamivir resin microcapsules prepared in the step (3) into the suspension matrix, and uniformly mixing to obtain the oseltamivir phosphate sustained-release suspension (the percentages are percentages of distilled water).
Example 9
(1) Preparation of pharmaceutical resins
Weighing 300mg of oseltamivir phosphate, dissolving the oseltamivir phosphate in 100mL of deionized water, adding 300mg of ion exchange resin after complete dissolution, magnetically stirring the mixture for 3 hours at 37 ℃, washing off the surface adsorbed drug by using the deionized water, and drying and sieving the washed drug at 60 ℃ to obtain the drug-loaded resin.
(2) Impregnation of pharmaceutical resins
Taking a proper amount of drug-loaded resin, adding the drug-loaded resin into a 25% methyl cellulose aqueous solution, stirring the mixture for 30 minutes at the temperature of 60 ℃, and drying and sieving the mixture at the temperature of 60 ℃ to obtain the impregnated drug resin.
(3) Preparation of drug resin microcapsules
The oseltamivir resin microcapsule is prepared by an emulsion solvent volatilization method. Weighing 75mg of RS100, dissolving in 1.80mL of ethanol, adding 7.5mg of PEG400, and stirring to dissolve to obtain a dispersion phase; 0.5g of the impregnated oseltamivir resin was slowly added to the dispersed phase and stirred to be in a suspended state. 4.8mL of liquid paraffin and 0.6mL of span 80 are weighed and uniformly mixed according to a certain proportion to be used as a continuous phase. The dispersed phase was added dropwise to the continuous phase and stirred at 40 ℃ for 4 h. And (4) carrying out suction filtration, washing residual liquid paraffin on the surface of the coating by using petroleum ether, drying and sieving at 60 ℃ to obtain the oseltamivir resin microcapsule.
(4) Preparation of pharmaceutical resin microcapsule suspension
Weighing 1% of microcrystalline cellulose, 0.5% of mannitol and 0.5% of sucrose, placing the microcrystalline cellulose in a 25L beaker, adding 2% of glycerol, and stirring uniformly; dissolving mannitol in distilled water, slowly adding microcrystalline cellulose dropwise into mannitol solution under stirring, stirring for half an hour, and adding 0.16% sodium benzoate, 0.03% orange essence, and 0.01% FD & C yellow 6 to obtain suspension matrix. And (4) adding the oseltamivir resin microcapsules prepared in the step (3) into the suspension matrix, and uniformly mixing to obtain the oseltamivir phosphate sustained-release suspension (the percentages are percentages of distilled water).
Example 10: sedimentation volume ratio and redispersibility evaluation of oseltamivir phosphate sustained-release suspension
In this example, the sedimentation volume ratio and redispersibility of the oseltamivir phosphate sustained-release suspension prepared in each example were evaluated. The specific operation method of the sedimentation volume ratio comprises the following steps: the oseltamivir phosphate sustained-release suspensions were placed in 50mL measuring cylinders, and the height (H) of the suspension at that time was recorded 0 ) After 3H at 25 ℃, the final height (H) of the sediment was recorded and the sedimentation volume ratio was calculated (F = H/H) 0 ). The specific operation method for the redispersibility evaluation is as follows: and (3) placing the suspension after standing for 3 hours in the sedimentation volume ratio experiment into a centrifuge tube, centrifuging for 10 minutes at normal temperature in a high-speed refrigerated centrifuge under the condition of the rotating speed of 500 r/min, taking out the suspension, performing turnover shaking at the same speed, and recording the turnover frequency when the suspension reaches a uniform dispersion system again. The results were evaluated as good, fair and poor (good when uniformly dispersed not more than 12 times, good when uniformly dispersed requiring 12 to 60 times, general when uniformly dispersed over 60 times, and poor when not uniformly dispersed).
Through the sedimentation volume ratio and the redispersibility evaluation, the prepared oseltamivir phosphate sustained-release suspension has the sedimentation volume ratio of more than 0.98 and the redispersibility evaluation result is good.
Example 11: in vitro release degree experiment of oseltamivir phosphate sustained-release suspension
In vitro experiments are important means for screening prescription determination processes, play an important role in quality control of preparations and are mainly investigated through dissolution rates. In this example, the oseltamivir phosphate sustained-release suspension prepared in example 3 was used as a test solution, and three parallel experiments were performed to examine the in vitro release rate. Adopting 900mL of 0.15mol/L NaCl subjected to degassing treatment as a release medium; the rotating speed is 50r/min, and the temperature is 37 +/-0.5 ℃. Operating according to a paddle method in an annex XC dissolution determination method of 2000 edition of Chinese pharmacopoeia, sucking 5mL of solution from a dissolution instrument at 0.5, 1, 2, 4, 6, 8 and 12h respectively, filtering the solution through a 0.45 mu m microporous membrane, taking a subsequent filtrate for later use, supplementing corresponding media with the same temperature and the same volume in time, sucking the subsequent filtrate, injecting the subsequent filtrate into HPLC, recording peak area, and calculating the concentration of each time point according to a standard curve so as to investigate the relation between the accumulated release amount and the time. Table 3 is the cumulative drug release amount of the oseltamivir phosphate sustained release suspension at different time nodes.
TABLE 3 cumulative drug release amount of oseltamivir phosphate sustained-release suspension at different time nodes
| Time (h) | Average cumulative drug release (%) |
| 0.5 | 15.42 |
| 1 | 25.08 |
| 2 | 37.08 |
| 4 | 56.58 |
| 6 | 69.25 |
| 8 | 77.56 |
| 12 | 82.40 |
As can be seen from Table 3, the average cumulative drug release rate of the prepared oseltamivir phosphate sustained-release suspension with the in-vitro release degree of 12 hours reaches 82.40%. Therefore, the prepared oseltamivir phosphate sustained-release suspension meets the requirement of the sustained-release preparation on the release degree, and can slowly release the medicament into the body.
Example 12: stability test of oseltamivir phosphate sustained-release suspension
Stability experiments of the oseltamivir phosphate sustained-release suspension prepared in each example of the invention were performed at high temperature (60 ℃), high humidity (75%) and light intensity of 4500Lx ± 500Lx for 3 months. The results show that the content of the drug in the oseltamivir phosphate sustained-release suspension is still more than 96.9 percent after high temperature, high humidity, illumination and exposure to air for 3 months, the related substances are not obviously changed, and the drug dissolution rate isf 2 >50 (with first day release profile, respectively)f 2 The evaluation of the factors is carried out,f 2 >50 indicates that the two release profiles are similar); therefore, the prepared oseltamivir phosphate sustained-release suspension has better stability.
As described above, the oseltamivir phosphate sustained-release suspension prepared by the invention has a good sustained-release effect, the dissolution rate and the stability meet the standards of the sustained-release suspension, and the effective blood concentration can be provided by only once administration every day. Compared with the traditional and improved medicinal preparation, the medicament has remarkable treatment effect, brings great medication convenience to patients, and improves the medicament compliance of the patients.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. The oseltamivir phosphate sustained-release suspension is characterized by comprising the following raw materials in parts by weight: oseltamivir phosphate, cation exchange resin, impregnant, coating material and other pharmaceutically acceptable auxiliary materials; according to weight percentage, each dosage unit contains 1.2 percent of oseltamivir phosphate, 0.6 to 3.6 percent of cation exchange resin, 0 to 0.048 percent of impregnant, 0.12 to 0.48 percent of coating material and the balance of auxiliary materials.
2. The oseltamivir phosphate sustained-release suspension according to claim 1, wherein the cation exchange resin comprises a strong acid cation exchange resin and a weak acid cation exchange resin; the weak acid cation exchange resin is Amberlite ® IRP64 and/or Amberlite ® IRP 88; the strong-acid cation exchange resin is Amberlite ® IRP69。
3. The oseltamivir phosphate sustained-release suspension according to claim 1, wherein the impregnant is one or more of methylcellulose, polyethylene glycol 2000 and polyethylene glycol 4000.
4. The oseltamivir phosphate sustained-release suspension according to claim 1, wherein the coating material comprises a coating capsule material and a plasticizer; the coating capsule material is Eudragit RS100 and/or Eudragit RL 100.
5. A preparation method of oseltamivir phosphate sustained-release suspension is characterized by comprising the following steps:
(1) mixing oseltamivir phosphate and cation exchange resin in deionized water to prepare a drug-loaded resin compound;
(2) impregnating the drug-loaded resin compound obtained in the step (1) with an impregnant, stirring, drying and sieving to obtain impregnating resin;
(3) coating the impregnating resin obtained in the step (2) and a coating material by a solvent volatilization method to obtain an oseltamivir resin microcapsule;
(4) and (4) mixing the oseltamivir resin microcapsules obtained in the step (3) with auxiliary materials and water to obtain the oseltamivir phosphate sustained-release suspension.
6. The preparation method according to claim 5, wherein the mass ratio of the cation exchange resin to oseltamivir phosphate in the step (1) is 0.5-3: 1.
7. The preparation method according to claim 5, wherein the preparation method of the drug-loaded resin complex in the step (1) comprises the following steps: mixing oseltamivir phosphate with water, adding ion exchange resin, and performing suction filtration and drying when the concentration of the drug in the solution does not change along with time; or mixing the cation exchange resin with water, placing the mixture into a chromatographic column, adding the oseltamivir phosphate solution into the chromatographic column for chromatography, and washing and drying the mixture until the concentration of the effluent is equal to that of the added solution.
8. The method according to claim 5, wherein the coating material in the step (3) comprises a coating capsule material and a plasticizer; the proportion of the coating capsule material to the impregnating resin is 1: 5-20%; the concentration of the coating capsule wall material is 1-5%.
9. The preparation method according to claim 8, wherein the plasticizer is any one of propylene glycol, polyethylene glycol 200 or polyethylene glycol 400 or a combination of at least two of the foregoing; the plasticizer accounts for 0-10% of the coating capsule material.
10. The preparation method according to claim 5, wherein the solvent volatilization method in the step (3) is to mix span 80 into liquid paraffin with stirring to form a continuous phase; dissolving a coating material and a plasticizer in an organic solvent to form a dispersion phase, adding impregnating resin into the dispersion phase to form a suspension state, dropwise adding the suspension-state dispersion phase into a continuous phase, stirring for 2-6 h at 25-60 ℃, drying and sieving at 50-60 ℃ to obtain the oseltamivir resin microcapsule.
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| WO2010143207A1 (en) * | 2009-06-11 | 2010-12-16 | Rubicon Research Private Limited | Taste-masked oral formulations of influenza antivirals |
| WO2015003479A2 (en) * | 2013-07-11 | 2015-01-15 | Sun Weidong | Orally administered solid pellet for infants and children and preparation method therefor |
| CN113710280A (en) * | 2019-10-10 | 2021-11-26 | 美国倍利年制药有限公司 | Pharmaceutical composition based on micronized pharmaceutical resinate and preparation method thereof |
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