CN104173312A - Sustained-release tablet containing felodipine and metoprolol salt and preparation method of sustained-release tablet containing felodipine and metoprolol salt - Google Patents
Sustained-release tablet containing felodipine and metoprolol salt and preparation method of sustained-release tablet containing felodipine and metoprolol salt Download PDFInfo
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Abstract
The invention provides a sustained release tablet containing felodipine and metoprolol salt and a preparation method of the sustained-release tablet containing the felodipine and the metoprolol salt. The sustained-release tablet is prepared from metoprolol salt sustained-release pill, a felodipine sustained-release pill, tablet filling granules and a film coating layer, and is characterized in that the dissolution curve of the metoprolol salt sustained-release pill and the dissolution curve of the felodipine sustained-release pill do not have remarkable changes before and after tabletting. The sustained-release tablet has the advantage that the dissolution speed of active components is still kept to be constant even the tablet is broken into pieces, and can be durably slowly released in 24 hours.
Description
Technical field
The invention belongs to medical technical field, particularly relate to a kind of slow releasing tablet that contains felodipine and metoprolol salt and preparation method thereof.
Background technology
Felodipine (Felodipine) is dihydropyridine calcium channel blocker, the clinical treatment for hypertension, stable angina pectoris.Its effect is reversibility competition dihydropyridine binding site, the voltage-dependent Ca of the Cor Leporis room cell of blocking-up vascular smooth muscle and artificial culture
2+electric current, and block K
+the Mus portal vein contracture of induction.In vitro study shows, this product selects inhibitory action to be better than Myocardial Effects to vascular smooth muscle; Negative inotropic action can be detected in vitro, but in whole animal, not observe this effect.This product can make peripheral vascular resistance decline, and this pharmacological action is relevant to dosage, and follows reflexive heart rate to increase.In animal and human's body, observe the hypotensive effect of this product human peripheral blood pipe resistance and cause slight diuresis.
Pharmacokinetic shows, after 10 healthy adult human oral Felodipine tablets 10mg, peak time (tmax) is 2.01 ± 0.63 hours, and peak concentration (Cmax) is 4.78 ± 0.89ng/ml, and eliminating the phase half-life (t1/2 β) is 16.09 ± 6.07 hours.Oral felodipine sustained-release tablets, bioavailability is about 20%, after peak reaching time of blood concentration appears at and takes medicine 2.5～5 hours.Blood pressure peak concentration and area under the drug-time curve (AUC) increase with dosage is linear within the scope of 20mg.Plasma protein associative law is 99%.After youth, the oral 10mg of health volunteer, average peak valley steady plasma-drug concentration is respectively 7nmol/L and 2nmol/L.After the oral this product 20mg of hyperpietic's (64 years old mean age), average peak valley steady plasma-drug concentration is respectively 23nmol/L and 7nmol/L. because this product medium effective concentration is 4～6nmol/L, so according to different patients, oral 5～10mg this product or 20mg this product, all can expect to reach 24 hours pressure reduction effects.
Metoprolol (Metoprolol) is a kind of optionally β
1receptor blocking agent, it is to heart β
1receptor generation effect required dosage is lower than the β in its human peripheral blood pipe and bronchus
2receptor generation effect required dosage.The treatment of metoprolol can weaken the effect of the catecholamine relevant with physiology and mental workload, reduces heart rate, heart output and blood pressure.Under stress state, the epinephrine of acth secretion increases, and metoprolol can not hinder physiological vasodilation.At therapeutic dose, metoprolol is weaker than non-selective beta-blocker to the contraction of bronchial smooth muscle, this characteristic makes it to share with beta 2 receptor agonist, treatment is associated with the patient of bronchial asthma or other obvious obstructive pulmonary disease, insulin is discharged metoprolol and glycometabolic impact is less than non-selective beta-blocker, thereby can be used for diabetics.Compare metoprolol with non-selective beta-blocker as less in tachycardic impact on hypoglycemic cardiovascular response, blood glucose can rise to the speed of normal level.For hyperpietic, the blood pressure in the time of can obviously reducing orthostatism, horizontal position and motion.
The oral rear absorption of this product is complete, and drug absorption occurs in whole gastrointestinal tract, comprises colon.The bioavailability of this product is 30%-40%, and metoprolol is at liver metabolism, and approximately 5% metoprolol is with original shape by renal excretion, and all the other are all by metabolism.
Two kinds of medicines of felodipine and metoprolol have been widely used in the treatment of cardiovascular disease.And multinomial research shows, in hypertensive treatment, dihydropyridine type calcium antagonists and beta-blocker are considered to the most effective drug combination.Calcium antagonist can suppress the vasoconstrictor effects due to beta-blocker retardance beta receptor; Beta-blocker can prevent tachycardia and the sympathetic nerve activation that dihydropyridine type calcium antagonists causes.Astrazeneca AB researched and developed felodipine and metoprolol compound slow release preparation (trade name: Logimax), for the treatment of the cardiovascular disease such as hypertension.
Preparation method for felodipine and metoprolol compound preparation has had a plurality of patents open at present, patent No. CN101623279A discloses a kind of pharmaceutical composition that contains felodipine and metoprolol, felodipine and metoprolol are to be dispersed in respectively the double-layer tablet being prepared from pharmaceutically acceptable carrier separately in pharmaceutical composition, patent No. CN102784143A discloses a kind of single layer osmotic pump regulated-release preparations containing metoprolol and felodipine, and concrete consists of label and semi permeability film coating.Patent No. CN102727460A discloses a kind of slow releasing tablet that contains felodipine and metoprolol salt and preparation method thereof, and this slow releasing tablet is comprised of label, medicated layer, sustained release coating layer and film coating layer from inside to outside, adopts the direct coating of label to be prepared from.
Summary of the invention
The object of this invention is to provide a kind of new technology, two kinds of dissimilar ingredients are made respectively to slow-release micro-pill, two kinds of slow-release micro-pill have release characteristics separately, by two kinds of slow-release micro-pill and tablet implant mixed pressuring plate, two kinds of slow-release micro-pill are compressed in same tablet, the release characteristics of tabletting latter two composition remains unchanged, and the release profiles of micropill and two kinds of compositions of tablet does not have significant change.
Described slow releasing tablet is comprised of felodipine sustained-release micropill, metoprolol salt slow-release micro-pill, tablet filler particles, lubricant and film coating layer; Described felodipine and metoprolol salt slow-release micro-pill release profiles before and after tabletting does not have significant change; Described tablet filler particles does not have slow release characteristic, has certain fragility and compressibility.
Described felodipine sustained-release micropill is comprised of fine pellet core, medicine layer and slow release layer.Described medicine layer is comprised of felodipine, binding agent, antioxidant, solubilizing agent; Because felodipine is insoluble in water, so in order to promote the release of felodipine, in the medicine layer of felodipine sustained-release micropill, add suitable solubilizing agent on the one hand, described solubilizing agent is soluble in water and ethanol preferably, and be solid at normal temperatures, described solubilizing agent be nonionic surfactant or one or more, nonionic surfactant mainly comprises that polyhydric alcohol type is as poloxamer, Tweens, spans, polyoxyethylene-type is as polyoxyethylene hydrogenated Oleum Ricini, preferred poloxamer, described antioxidant is dibenzylatiooluene etc.Felodipine sustained-release layer adds suitable porogen on the other hand, and the plasticizer with pore effect; The preferred hypromellose of described porogen, the preferred polyethylene glycols of described plasticizer.Moreover because the film property of felodipine is poor, therefore in the medicine layer prescription of micropill, need to add appropriate binding agent, to improve coating efficiency.Described binding agent comprises one or more of polyvidone, hypromellose, hyprolose, copolyvidone.
The slow release layer of described felodipine sustained-release micropill comprises sustained release coating material, porogen, plasticizer, coating solution solvent; Described sustained release coating material is one or more of ethyl cellulose, polyacrylic resin, polymethacrylate resin, cellulose acetate, porogen is one or more of hypromellose, hyprolose, microcrystalline Cellulose, lactose class, polyethylene glycols, saccharide, salt, surfactant etc., and plasticizer is one or more of dibutyl sebacate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, polyethylene glycols.Described slow release layer sustained release coating material preferred, ethyl; The preferred hypromellose of described porogen; The preferred polyethylene glycols of described plasticizer.
The coating solution solvent of the slow release layer of described felodipine sustained-release micropill adopts one or more of ethanol, isopropyl alcohol, acetone, dichloromethane, ethyl acetate, chloroform, water.The mixed solvent that the described preferred acetone of slow release layer coating solution solvent, isopropyl alcohol, water mix according to a certain percentage for combination.
Described metoprolol salt slow-release micro-pill is comprised of fine pellet core, medicine layer and slow release layer; Described medicine layer is comprised of metoprolol salt, binding agent; Because metoprolol salt film property is poor, therefore in the medicine layer prescription of micropill, need to add appropriate binding agent, to improve coating efficiency, described binding agent comprises one or more of polyvidone, hypromellose, hyprolose, copolyvidone.Moreover because metoprolol salt is water-soluble, so in order to suppress the release of metoprolol salt, increase on the one hand slow release layer weightening finish, metoprolol sustained-release layer weightening finish of the present invention preferably 15～25%.Select on the other hand to have the plasticizer that delays release, the slow release layer of described metoprolol salt slow-release micro-pill comprises sustained release coating material, porogen, plasticizer, coating solution solvent; Described sustained release coating material is one or more of ethyl cellulose, polyacrylic resin, polymethacrylate resin, cellulose acetate, porogen is one or more of hypromellose, hyprolose, microcrystalline Cellulose, lactose class, polyethylene glycols, saccharide, salt, surfactant, and plasticizer is one or more of dibutyl sebacate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, polyethylene glycols.Described sustained release coating material preferred, ethyl; The preferred hypromellose of described porogen; One or more of the preferred dibutyl sebacate of described plasticizer, triethyl citrate, acetyl tributyl citrate.
Described metoprolol salt slow-release micro-pill slow release layer coating solution solvent adopts one or more of ethanol, isopropyl alcohol, acetone, dichloromethane, ethyl acetate, chloroform, water.The mixed solvent that the described preferred acetone of slow release layer coating solution solvent, isopropyl alcohol, water mix according to a certain percentage for combination.
The present invention prevents the measure of breaking and taking in slow-release micro-pill tabletting process, first improves intensity and the toughness of slow release layer, and secondly tabletting filler particles keeps certain porosity and fragility, and slow-release micro-pill and filler particles keep suitable ratio again.
Improve intensity and the pliability of slow release layer, in slow release layer material, add appropriate plasticizer on the one hand, one or more of the described preferred dibutyl sebacate of plasticizer metoprolol sustained-release layer, triethyl citrate, acetyl tributyl citrate, the preferred polyethylene glycols of felodipine sustained-release layer.Slow release layer coating solution solvent has very large impact to the intensity of slow release layer and toughness on the other hand, the mixed solvent that the preferred acetone-isopropanol-water of slow release layer coating solution solvent of the present invention mixes according to a certain percentage.
Tabletting filler particles, in order to keep certain porosity and fragility, need to be selected suitable diluent and wetting agent.Described tablet filler particles comprises diluent and binding agent, does not have slow release characteristic, and has certain fragility and compressibility; Described diluent comprises one or more of microcrystalline Cellulose, lactose, Lactis Anhydrous, mannitol, pregelatinized Starch, silicon dioxide, starch, sucrose, dextrin, fructose, sorbitol, Polyethylene Glycol etc.; Described binding agent comprises one or more of polyvidone, hypromellose, hyprolose, copolyvidone.Described diluent preferably be take microcrystalline Cellulose as main, and other diluent is selected one or more of lactose, Lactis Anhydrous, mannitol, pregelatinized Starch, silicon dioxide, starch, sucrose, dextrin, fructose, sorbitol, Polyethylene Glycol etc.Wetting agent of the present invention is 50%～90% ethanol preferably.Tabletting filler particles can add the adjuvants such as appropriate sodium stearyl fumarate, magnesium stearate, Pulvis Talci as lubricant, is conducive to tabletting.
Slow-release micro-pill and filler particles need to keep certain ratio, and the ratio of the preferred filler particles of the present invention and slow-release micro-pill is 1:1 to 2:1.
In described slow releasing tablet, the consumption of felodipine is 5mg～10mg, and described metoprolol salt includes but not limited to succinate, tartrate, fumarate, benzene sulfonate, hydrochlorate of metoprolol etc., and consumption is 40mg～120mg.
Described slow releasing tablet preparation method is as follows:
A. metoprolol salt and binding agent are dissolved in suitable solvent, prepare medicine layer coating solution, then slow release layer sustained release coating material, plasticizer, porogen are dissolved in coating solution solvent, prepare slow release layer coating solution.Fine pellet core is joined in fluid bed, first pass into medicine layer coating solution and carry out coating in end spray mode, obtain metoprolol salt bag medicine micropill.Bag medicine micropill passes into slow release layer coating solution again and carries out coating in end spray mode, obtains metoprolol salt slow-release micro-pill.
B. felodipine and binding agent, antioxidant, solubilizing agent are dissolved in suitable solvent, prepare medicine layer coating solution, then slow release layer sustained release coating material, plasticizer, porogen are dissolved in coating solution solvent, prepare slow release layer coating solution.Fine pellet core is joined in fluid bed, first pass into medicine layer coating solution and carry out coating in end spray mode, obtain felodipine bag medicine micropill.Bag medicine micropill passes into slow release layer coating solution again and carries out coating in end spray mode, obtains felodipine sustained-release micropill.
C. a, b and suitable tabletting implant are mixed, tabletting, coating.The slow releasing tablet that the present invention is made, with reference to two appendix X D drug release determination first methods of Chinese Pharmacopoeia version in 2010, adopts high performance liquid chromatography to measure respectively the burst size of 2,4,8,12,16,20,24 hours.
The advantage of maximum of the present invention is that the release characteristics of two kinds of compositions controlled by slow-release micro-pill, even if tablet is broken into two with one's hands or the fracture that is squeezed can not affect release profiles yet, not having prominent releasing or danger that active component is revealed.
Accompanying drawing explanation:
Fig. 1 is metoprolol salt release profiles of the present invention;
Fig. 2 is felodipine release profiles of the present invention.
the specific embodiment
Below by embodiment, the present invention is described in further detail, and those skilled in the art can understand, and the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention.And those skilled in the art should also be understood that the replacement that is equal to that content of the present invention is done, or improve accordingly, within still belonging to protection scope of the present invention.
Embodiment 1
Prescription:
Felodipine sustained-release micropill prescription
According to the embodiment of the present invention 1 prescription, make every containing the tablet of 5mg felodipine and 47.5mg metroprolol succinate, this piece preparation method is as follows:
A. take metroprolol succinate, PVP K30, add in recipe quantity purified water, stir and make to dissolve completely, as medicine layer coating solution.Ethyl cellulose-N20, hypromellose-E6, dibutyl sebacate are joined in acetone, the solvent of isopropyl alcohol and water with certain proportion mixing, be stirred to dissolve, as slow release layer coating solution.Fine pellet core is joined in fluid bed, first pass into medicine layer coating solution and carry out coating in end spray mode, obtain metroprolol succinate bag medicine micropill.Bag medicine micropill passes into slow release layer coating solution again and carries out coating in end spray mode, obtains metroprolol succinate sustained-release micropill.
B. take felodipine, PVP K30, PLURONICS F87, dibenzylatiooluene, add in recipe quantity 70% ethanol, stir and make to dissolve completely, as medicine layer coating solution.Ethyl cellulose-N20, hypromellose-E6, PEG400 are joined in acetone, the solvent of isopropyl alcohol and water with certain proportion mixing, be stirred to dissolve, as slow release layer coating solution.Fine pellet core is joined in fluid bed, first pass into medicine layer coating solution and carry out coating in end spray mode, obtain felodipine bag medicine micropill.Bag medicine micropill passes into slow release layer coating solution again and carries out coating in end spray mode, obtains felodipine sustained-release micropill.
C. microcrystalline Cellulose 102, Lactis Anhydrous, PVP K30 are pressed recipe quantity weighing, put into wet granulator, and 50% ethanol of take is granulated as wetting agent, and dry, granulate, obtains tabletting filler particles.
D. a, b, c product and sodium stearyl fumarate are mixed, tabletting, coating, obtains.
Embodiment 2
Prescription:
Felodipine sustained-release micropill prescription
According to the embodiment of the present invention 2 prescriptions, make every containing the tablet of 10mg felodipine and 100mg spectinomycin hydrochloride, this piece preparation method is with reference to the embodiment of the present invention 1.
The compound recipe felodipine metoprolol sustained-release sheet of the commodity LOGIMAX by name that the metoprolol sustained-release micropill of above-described embodiment 1 and embodiment 2, felodipine sustained-release micropill, slow releasing tablet and AstraZeneca are produced carries out release profiles comparison, and method is as follows:
With reference to two appendix X D drug release determination first methods of Chinese Pharmacopoeia version in 2010, adopt the device of dissolution method (appendix X C) first method, Revolution Per Minute 100 turns, and the phosphate buffered solution 500ml of the pH6.5 that contains 1% sodium lauryl sulphate of take is solvent, operation in accordance with the law.Respectively at 2,4,8,12,16,20,24 hours, sampling detected, and assay method adopts high performance liquid chromatography, calculated the cumulative release amount of different time by external standard method.Discharge data in Table 1, table 2, release profiles is shown in Fig. 1, Fig. 2.
With similarity f
2factorization method is evaluated compound recipe felodipine metoprolol sustained-release sheet and embodiment 1 and 2 of the commodity LOGIMAX by name of AstraZeneca production.FDA and EMEA regulation: if the f between the stripping curve of tested and reference preparation
2value is not less than 50, thinks that both are similar.The results are shown in Table 1 and table 2.
F
2computing formula and the release profiles similarity criterion of value:
Wherein, Rt is with reference to the stripping percentage rate of product when t; Tt is the stripping percentage rate of trial target when t; N counts for testing.F
2span is between 0～100, along with the increase of stripping percentage difference, f
2value significantly reduces; f
2value is large represents that between two curves, difference is little, and similarity is large.When two release curves are when identical, f
2=100; When two curves on average differ 10%, f
2=50.Work as f
2value in 50～100 scopes time, shows two release Similar Broken Lines; Work as f
2be less than at 50 o'clock, show that two release curves have significant difference.
Table 1 metoprolol discharges data
Table 2 felodipine discharges data
Claims (10)
1. a slow releasing tablet that contains felodipine and metoprolol salt, is characterized in that: this slow releasing tablet is comprised of felodipine sustained-release micropill, metoprolol salt slow-release micro-pill, tablet filler particles, lubricant and film coating layer; Tablet filler particles does not have slow release characteristic, has certain fragility and compressibility.
2. slow releasing tablet according to claim 1, is characterized in that: in described slow releasing tablet, the consumption of felodipine is 5mg～10mg; Described metoprolol salt comprises succinate, tartrate, fumarate, benzene sulfonate, hydrochlorate, and consumption is 40mg～120mg.
3. slow releasing tablet according to claim 1, is characterized in that: described felodipine sustained-release micropill is comprised of fine pellet core, medicine layer and slow release layer, medicine layer is comprised of felodipine, binding agent, antioxidant, solubilizing agent, and binding agent comprises one or more of polyvidone, hypromellose, hyprolose, copolyvidone, one or more that solubilizing agent is nonionic surfactant, slow release layer comprises sustained release coating material, porogen, plasticizer, coating solution solvent, sustained release coating material is ethyl cellulose, polyacrylic resin, polymethacrylate resin, one or more of cellulose acetate, porogen is hypromellose, hyprolose, microcrystalline Cellulose, lactose class, polyethylene glycols, saccharide, salt, one or more of surfactant, plasticizer is dibutyl sebacate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, one or more of polyethylene glycols, coating solution solvent is ethanol, isopropyl alcohol, acetone, dichloromethane, ethyl acetate, chloroform, one or more of water.
4. slow releasing tablet according to claim 1, is characterized in that: described metoprolol salt slow-release micro-pill is comprised of fine pellet core, medicine layer and slow release layer, medicine layer is comprised of metoprolol salt, binding agent, and binding agent comprises one or more of polyvidone, hypromellose, hyprolose, copolyvidone, slow release layer comprises sustained release coating material, porogen, plasticizer, coating solution solvent, sustained release coating material is ethyl cellulose, polyacrylic resin, polymethacrylate resin, one or more of cellulose acetate, porogen is hypromellose, hyprolose, microcrystalline Cellulose, lactose class, polyethylene glycols, saccharide, salt, one or more of surfactant, plasticizer is dibutyl sebacate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, one or more of polyethylene glycols, coating solution solvent is ethanol, isopropyl alcohol, acetone, dichloromethane, ethyl acetate, chloroform, one or more of water.
5. slow releasing tablet according to claim 3, is characterized in that: described nonionic surfactant comprises poloxamer, Tweens, the spans of polyhydric alcohol type, the polyoxyethylene hydrogenated Oleum Ricini of polyoxyethylene-type.
6. according to the slow releasing tablet described in claim 3 or 5, it is characterized in that: described nonionic surfactant is poloxamer.
7. slow releasing tablet according to claim 3, it is characterized in that: the sustained release coating material of described felodipine sustained-release micropill slow release layer is ethyl cellulose, porogen is hypromellose, plasticizer is polyethylene glycols, and coating solution solvent is by acetone, isopropyl alcohol, the mixed solvent of water for mixing according to a certain percentage.
8. slow releasing tablet according to claim 4, it is characterized in that: the sustained release coating material of described metoprolol salt slow-release micro-pill slow release layer is ethyl cellulose, porogen is hypromellose, plasticizer is one or more of dibutyl sebacate, triethyl citrate, acetyl tributyl citrate, and coating solution solvent is by acetone, isopropyl alcohol, the mixed solvent of water for mixing according to a certain percentage.
9. slow releasing tablet according to claim 1, is characterized in that: described tablet filler particles comprises diluent and binding agent, does not have slow release characteristic, has certain fragility and compressibility; Diluent comprises one or more of microcrystalline Cellulose, lactose, Lactis Anhydrous, mannitol, pregelatinized Starch, silicon dioxide, starch, sucrose, dextrin, fructose, sorbitol, Polyethylene Glycol etc.; Binding agent comprises one or more of polyvidone, hypromellose, hyprolose, copolyvidone.
10. slow releasing tablet according to claim 9, it is characterized in that: described tablet filler particles diluent be take microcrystalline Cellulose as main, other diluent is one or more of lactose, Lactis Anhydrous, mannitol, pregelatinized Starch, silicon dioxide, starch, sucrose, dextrin, fructose, sorbitol, Polyethylene Glycol.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105030718A (en) * | 2015-08-18 | 2015-11-11 | 石家庄格瑞药业有限公司 | Arotinolol hydrochloride preparation and preparation method thereof |
| CN106309399A (en) * | 2015-06-29 | 2017-01-11 | 深圳翰宇药业股份有限公司 | Pellet type sustained-release tablet and preparation method thereof |
| CN107149597A (en) * | 2017-03-27 | 2017-09-12 | 广西厚德大健康产业股份有限公司 | A kind of preparation method of metroprolol succinate sustained-release compaction of pellet |
| CN107153100A (en) * | 2017-03-27 | 2017-09-12 | 广西厚德大健康产业股份有限公司 | The method of quality control of impurity in felodipine Metoprolol succinate sustained-release tablets |
| CN107149598A (en) * | 2017-03-27 | 2017-09-12 | 广西厚德大健康产业股份有限公司 | A kind of preparation method of felodipine sustained-release compaction of pellet |
| CN110787647A (en) * | 2019-11-11 | 2020-02-14 | 上海输血技术有限公司 | Platelet leukocyte-removing filter membrane and preparation method thereof |
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| WO2013030725A1 (en) * | 2011-08-26 | 2013-03-07 | Wockhardt Limited | Methods for treating cardiovascular disorders |
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Patent Citations (1)
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| WO2013030725A1 (en) * | 2011-08-26 | 2013-03-07 | Wockhardt Limited | Methods for treating cardiovascular disorders |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106309399A (en) * | 2015-06-29 | 2017-01-11 | 深圳翰宇药业股份有限公司 | Pellet type sustained-release tablet and preparation method thereof |
| CN106309399B (en) * | 2015-06-29 | 2019-07-26 | 深圳翰宇药业股份有限公司 | A kind of micro-pill type sustained release tablets and preparation method thereof |
| CN105030718A (en) * | 2015-08-18 | 2015-11-11 | 石家庄格瑞药业有限公司 | Arotinolol hydrochloride preparation and preparation method thereof |
| CN107149597A (en) * | 2017-03-27 | 2017-09-12 | 广西厚德大健康产业股份有限公司 | A kind of preparation method of metroprolol succinate sustained-release compaction of pellet |
| CN107153100A (en) * | 2017-03-27 | 2017-09-12 | 广西厚德大健康产业股份有限公司 | The method of quality control of impurity in felodipine Metoprolol succinate sustained-release tablets |
| CN107149598A (en) * | 2017-03-27 | 2017-09-12 | 广西厚德大健康产业股份有限公司 | A kind of preparation method of felodipine sustained-release compaction of pellet |
| CN107153100B (en) * | 2017-03-27 | 2019-08-06 | 广西厚德大健康产业股份有限公司 | The method of quality control of impurity in felodipine Metoprolol succinate sustained-release tablets |
| CN110787647A (en) * | 2019-11-11 | 2020-02-14 | 上海输血技术有限公司 | Platelet leukocyte-removing filter membrane and preparation method thereof |
| CN110787647B (en) * | 2019-11-11 | 2024-01-19 | 上海输血技术有限公司 | Platelet leukocyte-removing filter membrane and preparation method thereof |
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Address after: 530007, 56 Garden Avenue, Nanning, the Guangxi Zhuang Autonomous Region Applicant after: GUANGXI BOKE PHARMACEUTICAL CO., LTD., GUANGXI Address before: 530007, 56 Garden Avenue, Nanning, the Guangxi Zhuang Autonomous Region Applicant before: Boke Pharmaceutical Co., Ltd., Guangxi |
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