WO2013152641A1 - 一种盐酸乐卡地平和氯沙坦钾复方制剂及其制备方法 - Google Patents

一种盐酸乐卡地平和氯沙坦钾复方制剂及其制备方法 Download PDF

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WO2013152641A1
WO2013152641A1 PCT/CN2013/071838 CN2013071838W WO2013152641A1 WO 2013152641 A1 WO2013152641 A1 WO 2013152641A1 CN 2013071838 W CN2013071838 W CN 2013071838W WO 2013152641 A1 WO2013152641 A1 WO 2013152641A1
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losartan
compound preparation
preparation
lercanidipine
blood pressure
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PCT/CN2013/071838
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English (en)
French (fr)
Inventor
李小羿
张国辉
戴向荣
凌娟
吴艳
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ZHAOKE PHARMACEUTICAL (HEFEI) Co Ltd
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ZHAOKE PHARMACEUTICAL (HEFEI) Co Ltd
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Priority to US14/391,811 priority Critical patent/US20150079183A1/en
Priority to JP2015504845A priority patent/JP2015512919A/ja
Priority to CA2870373A priority patent/CA2870373A1/en
Priority to EP13775164.0A priority patent/EP2837380B1/en
Priority to RU2014144502A priority patent/RU2014144502A/ru
Priority to AU2013247291A priority patent/AU2013247291A1/en
Publication of WO2013152641A1 publication Critical patent/WO2013152641A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/20—Pills, tablets, discs, rods
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    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the field of medicine, in particular to a compound preparation of lercanidipine hydrochloride and losartan potassium and a preparation method thereof.
  • Hypertension is the most important risk factor for clear cardiovascular disease. Long-term development can cause serious damage to target organs such as heart, brain and kidney. Its complications such as coronary heart disease, stroke, and renal failure have high disability and death. rate. In China, high blood pressure has now become the leading cause of death. The data show that by 2006, the number of hypertensive patients in China has reached 200 million, and about 1 billion people worldwide suffer from high blood pressure. Therefore, the prevention, treatment and medication of hypertension are the top priority of pharmaceutical R&D.
  • Lercanidipine hydrochloride is a third-generation dihydropyridine calcium channel antagonist developed by the Italian company Recordati. It was first listed in the Netherlands in 1997 and subsequently listed in 18 countries including France, Australia and Germany.
  • the mechanism of action of lercanidipine hydrochloride is similar to that of similar drugs, which can block the Ca2+ influx of L-type calcium channel in vascular smooth muscle cell membrane and expand peripheral blood vessels to lower blood pressure.
  • the product has a higher lipophilicity, so the onset time is slower and the duration of action is longer.
  • lercanidipine hydrochloride In vitro and in vivo tests have shown that the negative inotropic effect of lercanidipine hydrochloride induced by selective vasodilatation is weaker than that of nifedipine, nitrendipine and felodipine; and the vascular selectivity is stronger than amlodipine, felodipine, Nitrendipine and lacidipine, in addition, lercanidipine hydrochloride also has anti-atherosclerosis and protects end-organ organs. Lercanidipine hydrochloride does not interfere with normal cardiac excitability and conductivity in hypertensive patients at therapeutic doses.
  • lercanidipine hydrochloride has protective effects on the kidney, and its mechanism may be independent of hemodynamics. Compared with similar drugs, lercanidipine hydrochloride has strong vascular selectivity, and its unique lipophilicity makes it slow and antihypertensive. Long. Lercanidipine hydrochloride is safe, has no cardiotonic effect, does not affect heart rate, and has good anti-atherosclerosis effect, especially suitable for hypertensive patients with atherosclerosis, with high clinical application. Value, market prospects are broad.
  • Losartan is an oral non-peptide angiotensin receptor antagonist ( ⁇ ) that was first introduced in 1994 and is currently approved for use in 93 countries to treat high blood pressure.
  • the in vivo renin-angiotensin system (RAS) is activated by the renin released by the kidney. Renin is able to break down a protein called angiotensinogen derived from the liver, and the product after decomposition is angiotensin I.
  • Angiotensin I itself has no biological activity, but it is an angiotensin II precursor.
  • Angiotensin II has a range of biological activities in blood vessels, heart and other tissues in the body.
  • the steroidal drug losartan blocks the angiotensin receptor (ATI), prevents angiotensin II from binding to the receptor, and ultimately prevents vasoconstriction. Clinical application shows that it has good tolerance and low side effects.
  • An object of the present invention is to provide a compound preparation of lercanidipine losartan in which lercanidipine hydrochloride is 0.5-40% and losartan potassium is 6.25-50% by mass.
  • the calcium ion antagonist lercanidipine hydrochloride dilates the blood vessel to cause reflex sympathetic excitation, and the angiotensin II receptor antagonist losartan antagonizes the neurohormonal activity to relieve the calcium channel blocker (CCB)
  • CCB calcium channel blocker
  • the mass ratio of lercanidipine hydrochloride to losartan potassium in the compound preparation provided by the present invention is 1:2-25.
  • a compound preparation of lercanidipine losartan is specifically disclosed, and the auxiliary materials used are lactose monohydrate 20-40%, microcrystalline cellulose 10-40%, and type A hydroxyethyl starch.
  • the coating is a white Opadry.
  • the invention also provides a preparation method of the compound preparation, comprising the following steps:
  • Step 1 The sieved lercanidipine hydrochloride bulk drug and losartan bulk drug with lactose-hydrate, microcrystalline cellulose, sodium hydroxyethyl starch A, povidone K30, magnesium stearate, pre The gelatinized starch and the colloidal silica are uniformly mixed, vacuum-compressed, milled and sieved, and granulated; tableting is performed to control the hardness of the core;
  • Step 2 Take Opadry, add to ethanol under stirring, stir until dispersed, and then add purified water to stir to prepare a coating solution; to isolate the coating solution to the core-coated film obtained in step 1;
  • Step 3 Take the European The batidine is added to the ethanol and stirred to prepare an enteric coating solution; the enteric coating solution is used to coat the film-coated tablets.
  • control piece core hardness described in step 1 is 2-10 kg.
  • the ethanol concentration in steps 2 and 3 is 75-100%.
  • step 2 is added with purified water and the stirring time of step 3 is 20-100 mim.
  • the Opadry described in step 2 is Y-1-7000
  • the Opadry described in step 3 is
  • the present invention provides a main drug of lercanidipine hydrochloride and losartan potassium, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone K30, magnesium stearate, pre Gelatinized starch and colloidal silica are used as excipients, and a compound preparation of tablets is prepared by coating white Opadry.
  • the calcium ion antagonist lercanidipine dilates the blood vessel to cause reflex sympathetic excitation, and after the combination with the angiotensin II receptor antagonist losartan, the latter antagonizes the neurohormone
  • the active action can relieve the calcium channel blocker (CCB).
  • the sympathetic system is over-activated during the antihypertensive process, reducing the adverse reactions caused by CCB treatment, and providing more comprehensive protection of target organs such as heart, brain and kidney.
  • the invention discloses a compound preparation of lercanidipine hydrochloride and losartan potassium and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is specifically to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the products, methods, and applications of the present invention have been described in terms of the preferred embodiments thereof, and it is obvious that the methods and applications described herein may be modified or appropriately modified and combined without departing from the spirit, scope and scope of the invention.
  • the techniques of the present invention are implemented and applied.
  • Example 1 Preparation of the lercanidipine losartan compound preparation of the present invention
  • the lencapine hydrochloride bulk drug and the losartan bulk drug were weighed and sieved; the lercanidipine hydrochloride was 0.5-40%, and the losartan potassium was 6.25-50%.
  • Vacuum compression, milling and sieving; tableting, controlling core hardness
  • a film-coated garment was obtained; the obtained core-coated film was coated with the prepared coating liquid to obtain a film-coated tablet.
  • Formulation of enteric coating solution Take the prescribed amount of Opadry and add it to the ethanol under stirring, and continue stirring to obtain an enteric coating solution.
  • Enteric coating The film-coated tablets were enteric coated with the prepared enteric coating solution, and the unit dosage prepared in the compound preparation contained lercanidipine 5 mg and losartan 20 mg.
  • Example 2 Preparation of the lercanidipine losartan compound preparation of the invention
  • the lencapine hydrochloride bulk drug and the losartan bulk drug were weighed and sieved; the lercanidipine hydrochloride was 0.5-40%, and the losartan potassium was 6.25-50%.
  • lactose-hydrate microcrystalline cellulose, sodium hydroxyethyl starch (type A), povidone K30, magnesium stearate, pregelatinized starch, colloidal silica, and mix well; lactose monohydrate in the auxiliary 20-40%, microcrystalline cellulose 10-40%, sodium hydroxyethyl starch (type A) 10-20%, povidone K30 2-8%, magnesium stearate 0.5-2.5%, pregelatinized Starch 5-15%, colloidal silica 1-10%
  • Vacuum compression, milling and sieving; tableting, controlling core hardness
  • a film-coated garment was obtained; the obtained core-coated film was coated with the prepared coating liquid to obtain a film-coated tablet.
  • Formulation of enteric coating solution Take the prescribed amount of Opadry and add it to the ethanol under stirring, and continue stirring to obtain an enteric coating solution.
  • Enteric coating The film-coated tablets were enteric coated with the prepared enteric coating solution, and the unit dosage prepared in the preparation was 7.5 mg of lercanidipine and 20 mg of losartan.
  • Example 3 Quality study of lercanidipine losartan compound preparation in which lercanidipine hydrochloride was determined.
  • the content of lercanidipine losartan compound preparation lercanidipine hydrochloride prepared in Example 1 was determined by HPLC method, and the liquid phase detection conditions are shown in Table 1.
  • Rats were anesthetized with ketamine hydrochloride 50 mg I kg and diazepam 5 mg/kg intraperitoneally.
  • the left inguinal incision was performed with a 2 cm long skin incision.
  • the femoral artery sheath was exposed and the femoral artery and femoral vein were carefully separated for femoral artery cannulation.
  • the arterial tube is wound from the root of the animal's thigh through the subcutaneous tunnel to the back, and is fixed by the head and neck. It is free to eat for 2 days after surgery.
  • SHR rats were randomly divided into lercanidipine losartan compound preparation 1 (main drug mass ratio: 50% lercanidipine hydrochloride, 12% losartan potassium), lercanidipine losartan compound 2 ( The main drug mass ratio: lercanidipine hydrochloride 30%, losartan potassium 46%), lercanidipine losartan compound preparation 3 (main drug mass ratio: lercanidipine hydrochloride 0.25%, losartan potassium 58%)
  • Each group consisted of 20 rats.
  • the connection system was monitored by awake blood pressure. The line was first adapted for 4 h. The drug was administered orally during the monitoring. The administration time was 10:00 am, and the blood pressure recording started from 1 h before the administration. It ends at the 8th hour after administration.
  • the awake manometry was recorded by computer in real time for systolic blood pressure (SBP), diastolic blood pressure (DBP), cardiac interval (HP), pulse pressure (PP), and systolic blood pressure variation rate (SBPV).
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • HP cardiac interval
  • PP pulse pressure
  • SBPV systolic blood pressure variation rate
  • the data were processed by SPSS 10. 0 statistical software.
  • the test data were expressed as mean # standard deviation. Paired t-test was used before and after each group. The difference between the mean of each group was analyzed by one-way analysis of variance. Multiple comparisons were performed using the LSD-q test.
  • Test method A total of 396 patients were enrolled, 388 entered the lead-in period, and 307 entered the evaluation period. They were randomly divided into 4 groups: 1) Low-dose group of compound preparation: lercanidipine losartan compound containing lercanidipine 5 mg, losartan 20 mg; 2) high-dose single-use group 1: lercanidipine hydrochloride (Recordati Industria) Chimica e Farmaceutica SPA ), lOmg; 3 ) High-dose single-use group 2: Losartan (produced by Hangzhou Merck Pharmaceutical Co., Ltd.) lOOmg; 4) Positive control group: Amlodipine (Pfizer Pharmaceutical Co., Ltd.) 10mg, once a day, Continuous medication.
  • Blood pressure is measured according to international standards. The fixed physician visits once a week, and visits at 9:00-11:00. The heart rate and sitting blood pressure are measured 3 times each time. The average value.
  • Measurement data are calculated by the mean standard deviation. Paired t-test was used to compare the quantitative indicators before and after the four modes of administration. The chi-square test was used to compare the differences before and after treatment.
  • Diastolic blood pressure (mmHg) systolic blood pressure (mmH g )
  • the decrease of diastolic blood pressure in the lercanidipine losartan compound preparation group was larger than that in the amlodipine group, and the difference was statistically significant (PO.05).
  • the systolic blood pressure in the 4 groups also decreased significantly.
  • the lercanidipine losartan compound preparation group The decrease of systolic blood pressure was significantly higher than that of amlodipine group, and the difference was statistically significant (P ⁇ 0.05).
  • the decrease of diastolic blood pressure and systolic blood pressure in the losartan compound preparation group was significantly higher than that of the high-dose single-use group of lercanidipine hydrochloride and the high-dose single-use group of losartan. The difference was statistically significant (P ⁇ 0.05).
  • the lercanidipine losartan compound preparation group was more effective than the high-dose single-use group, and the incidence of adverse reactions was significantly reduced, and the patient was well tolerated. Therefore, the combination of lercanidipine and losartan in the treatment of mild to moderate blood pressure can improve the antihypertensive effect and is tolerable, with no significant effect on cardiac conduction and heart rate.
  • Example 6 Clinical trial study of the lercanidipine losartan compound preparation of the present invention 1. Data and method
  • Test method A total of 359 patients were enrolled, 305 entered the lead-in period, and 266 entered the evaluation period. They were randomly divided into 4 groups: 1) Low-dose group of compound preparation prepared in Example 2: lervastatin losartan compound containing 7.5 mg of lercanidipine and 20 mg of losartan; 2) high-dose single-use group 1: hydrochloric acid Recordati Industria Chimica e Farmaceutica SPA, lOmg; 3) High-dose single-use group 2: Losartan (produced by Hangzhou Merck Pharmaceutical Co., Ltd.) 100mg.
  • Measurement data are calculated by the mean standard deviation. Paired t-test was used to compare the quantitative indicators before and after the four modes of administration. The chi-square test was used to compare the differences before and after treatment.
  • Diastolic blood pressure (mmHg)
  • systolic blood pressure (mmHg)
  • 1) is a combination of lergandipine 7.5g, losartan 20g of lercanidipine losartan; 2) lercanidipine hydrochloride 10mg; 3) losartan 100mg.
  • the decrease of diastolic blood pressure in the lercanidipine losartan compound group was greater than that in the amlodipine group, and the difference was statistically significant (PO.05).
  • the systolic blood pressure was also significantly decreased in the three groups.
  • the lercanidipine losartan compound preparation group The decrease of systolic blood pressure was significantly higher than that of amlodipine group, and the difference was statistically significant (P ⁇ 0.05).
  • the decrease of diastolic blood pressure and systolic blood pressure in the losartan compound preparation group was significantly higher than that of the high-dose single-use group of lercanidipine hydrochloride and the high-dose single-use group of losartan. The difference was statistically significant (P ⁇ 0.05).
  • the lercanidipine losartan compound preparation group was more effective than the high-dose single-use group, and the incidence of adverse reactions was significantly reduced, and the patient was well tolerated. Therefore, the combination of lercanidipine and losartan in the treatment of mild to moderate blood pressure can improve the antihypertensive effect and is well tolerated, with no significant effect on cardiac conduction and heart rate.
  • the above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

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Description

一种盐酸乐卡地平和氯沙坦钾复方制剂及其制备方法
本申请要求于 2012 年 4 月 11 日提交中国专利局、 申请号为 201210104974.5、 发明名称为 "一种盐酸乐卡地平和氯沙坦钾复方制剂及 其制备方法" 的中国专利申请的优先权， 其全部内容通过引用结合在本 申请中。 技术领域
本发明涉及医药领域， 具体涉及一种盐酸乐卡地平和氯沙坦钾复方 制剂及其制备方法。 背景技术
高血压是明确的心血管疾病最重要的危险因素， 长期发展可致心、 脑、 肾等靶器官的严重损害， 其并发症冠心病、 脑卒中、 肾功能衰竭等 具有高度致残率和致死率。 在我国， 高血压现在已经成为主要死因的第 一位。 数据表明， 至 2006年我国高血压患者已达 2亿， 而全球约 10亿 人遭受高血压的困扰。 因此， 高血压的预防和治疗、 用药是医药研发任 务的重中之重。
盐酸乐卡地平是由意大利 Recordati公司研制开发的第三代二氢吡啶 类钙通道拮抗剂， 于 1997年首先在荷兰上市， 随后分别在法国、 澳大利 亚、 德国等十八个国家上市。 盐酸乐卡地平作用机制与同类药物相似， 即可逆地阻滞血管平滑肌细胞膜 L型钙通道的 Ca2+内流， 扩张外周血管 而降低血压。 该品亲脂性较高， 因此起效时间较慢， 而作用持续时间较 长。 体内外试验表明， 盐酸乐卡地平选择性血管扩张作用所致的负性肌 力作用较硝苯地平、 尼群地平和非洛地平弱； 而血管选择性强于氨氯地 平、 非洛地平、 尼群地平及拉西地平， 此外， 盐酸乐卡地平还具有抗动 脉粥样硬化和保护终末器官作用。 盐酸乐卡地平在治疗剂量时不干扰高 血压患者的正常心脏兴奋性和传导性， 动物实验表明， 盐酸乐卡地平对 肾脏有保护作用， 其机制可能与血流动力学无关。 盐酸乐卡地平与同类 药相比具有较强的血管选择性， 其独特的亲脂性使之降压作用緩慢而持 久。 盐酸乐卡地平安全性高， 无强心作用， 不影响心率， 同时还有艮好 的抗动脉粥样硬化作用， 尤其适合于伴有动脉粥样硬化的高血压病人， 具有较高的临床应用价值， 市场前景广阔。
氯沙坦是口服非肽类血管紧张素 Π受体拮抗剂 （ΑΠΑ ), 于 1994年 首次上市， 目前已在 93个国家被批准使用， 用以治疗高血压。 体内肾素 -血管紧张素系统（ RAS )被肾脏译放的肾素激活。 肾素能够分解来源于 肝脏的一种叫做血管紧张素原的蛋白， 分解后的产物就是血管紧张素 I。 血管紧张素 I本身没有什么生物活性， 但其为血管紧张素 II前体， 血管 紧张素 II对于血管、 心脏和体内其他组织具有一系列生物活性。 ΑΠΑ类 药物氯沙坦能够阻断血管紧张素受体（ATI ), 避免血管紧张素 II结合到 受体上， 最终达到防止血管收缩的目的。 临床应用显示其具有较好的耐 受性， 副作用较低。
目前市场上均为单方制剂， 关于两者联合用于治疗高血压仍未见报 道。 发明内容
本发明的目的是提供一种乐卡地平氯沙坦复方制剂， 以质量百分比 计， 盐酸乐卡地平为 0.5-40%, 氯沙坦钾为 6.25-50%。
本发明提供的复方制剂中， 钙离子拮抗剂盐酸乐卡地平扩张血管引 起反射性交感神经兴奋， 血管紧张素 II受体拮抗剂氯沙坦拮抗神经激素 活性作用可解除钙通道阻滞药 （CCB ) 降压过程中交感系统过度激活， 减少 CCB治疗过程中所引起的不良反应， 提供更全面的心、 脑、 肾等靶 器官保护， 抗动脉粥样硬化作用及治疗高血压疗效更好。
更优选地， 本发明提供的复方制剂中盐酸乐卡地平和氯沙坦钾的质 量比为 1:2-25。
在本发明的具体实施方式中， 具体公开了一种乐卡地平氯沙坦复方 制剂， 所用辅料为乳糖一水合物 20-40%, 微晶纤维素 10-40%, A型羟基 乙基淀粉钠 10-20%, 聚维酮 K30 2-8%, 硬脂酸镁 0.5-2.5%, 预胶化淀粉 5-15%, 胶体二氧化硅 1-10%。 优选地， 选用包衣为白色欧巴代。
本发明还提供所述复方制剂的制备方法， 包括以下步骤：
步骤 1 : 将过筛后的盐酸乐卡地平原料药和氯沙坦原料药与乳糖-水 合物、 微晶纤维素、 A型羟基乙基淀粉钠、 聚维酮 K30、 硬脂酸镁、 预胶 化淀粉、 胶体二氧化硅搅拌混合均匀后真空压缩、 碾磨过筛制粒； 压片， 控制片芯硬度；
步骤 2: 取欧巴代， 搅拌条件下加入乙醇中， 搅拌至分散， 然后加入 纯化水搅拌， 配制隔离衣液； 以隔离衣液对步骤 1得到的片芯包薄膜衣； 步骤 3: 取欧巴代加入到乙醇搅拌均勾配制成肠溶衣液； 以肠溶衣液 对薄膜衣片包肠溶衣。
优选地， 步骤 1所述的控制片芯硬度为 2-10kg。
优选地， 步骤 2及步骤 3所述乙醇浓度为 75-100%。
优选地， 步骤 2 加入纯化水搅拌及步骤 3 所述搅拌的时间为 20-100mim。
优选地， 步骤 2所述的欧巴代为 Y-1-7000, 步骤 3所述的欧巴代为
OY-P, 91S型。
本发明提供一种以盐酸乐卡地平和氯沙坦钾为主药， 以乳糖一水合 物、 微晶纤维素、 淀粉羟乙酸钠（A型）、 聚维酮 K30, 硬脂酸镁、 预胶 化淀粉、 胶体二氧化硅为辅料， 以白色欧巴代为包衣制成片剂的复方制 剂。
本发明提供的乐卡地平氯沙坦复方制剂中， 钙离子拮抗剂乐卡地平 扩张血管引起反射性交感神经兴奋， 和血管紧张素 II受体拮抗剂氯沙坦 合用后， 后者拮抗神经激素活性作用可解除钙通道阻滞药 （CCB ) 降压 过程中交感系统过度激活， 减少 CCB治疗过程中所引起的不良反应， 提 供更全面的心、 脑、 肾等靶器官保护。
临床试验显示， 乐卡地平氯沙坦复方制剂组与单方组比较， 治疗轻、 中度血压有效率显著提高， 且不良反应的发生率显著降低， 患者耐受性 良好， 提高了降压疗效， 具有良好的临床应用前景。 具体实施方式
本发明公开了盐酸乐卡地平和氯沙坦钾复方制剂及其制备方法， 本 领域技术人员可以借鉴本文内容， 适当改进工艺参数实现。 特别需要指 出的是， 所有类似的替换和改动对本领域技术人员来说是显而易见的， 它们都被视为包括在本发明。 本发明的产品、 方法及应用已经通过较佳 实施例进行了描述， 相关人员明显能在不脱离本发明内容、 精神和范围 内对本文所述的方法和应用进行改动或适当变更与组合， 来实现和应用 本发明技术。
为了使本领域的技术人员更好地理解本发明的技术方案， 下面结合 具体实施例对本发明作进一步的详细说明。 实施例 1: 本发明所述乐卡地平氯沙坦复方制剂的制备
称取盐酸乐卡地平原料药和氯沙坦原料药过筛备用； 盐酸乐卡地平 为 0.5-40%, 氯沙坦钾为 6.25-50%。
称取乳糖-水合物、 微晶纤维素、 羟基乙基淀粉钠 （A 型）、 聚维酮
K30 、 硬脂酸镁、 预胶化淀粉、 胶体二氧化硅搅拌混合均匀； 辅料中乳 糖一水合物 20-40%,微晶纤维素 10-40%,羟基乙基淀粉钠（ A型）10-20%, 聚维酮 K30 2-8%, 硬脂酸镁 0.5-2.5%, 预胶化淀粉 5-15%, 胶体二氧化 硅 1-10%
真空压缩、 碾磨过筛制粒； 压片， 控制片芯硬度。
配制隔离衣液： 取欧巴代， 搅拌条件下加入乙醇中， 搅拌至分散， 然后加入纯化水搅拌， 配成隔离衣液。
包薄膜衣； 以所制备的隔离衣液对得到的片芯包薄膜衣， 得到薄膜 衣片。
配制肠溶衣液： 取处方量欧巴代在搅拌下加入到乙醇中， 继续搅拌， 得到肠溶衣液。
包肠溶衣： 以所制备的肠溶衣液对薄膜衣片包肠溶衣， 制得的复方 制剂中单位剂量含乐卡地平 5mg , 氯沙坦 20mg。 实施例 2: 本发明所述乐卡地平氯沙坦复方制剂的制备
称取盐酸乐卡地平原料药和氯沙坦原料药过筛备用； 盐酸乐卡地平 为 0.5-40%, 氯沙坦钾为 6.25-50%。
称取乳糖-水合物、 微晶纤维素、 羟基乙基淀粉钠 （A 型）、 聚维酮 K30 、 硬脂酸镁、 预胶化淀粉、 胶体二氧化硅搅拌混合均匀； 辅料中乳 糖一水合物 20-40%,微晶纤维素 10-40%,羟基乙基淀粉钠（ A型）10-20%, 聚维酮 K30 2-8%, 硬脂酸镁 0.5-2.5%, 预胶化淀粉 5-15%, 胶体二氧化 硅 1-10%
真空压缩、 碾磨过筛制粒； 压片， 控制片芯硬度。
配制隔离衣液： 取欧巴代， 搅拌条件下加入乙醇中， 搅拌至分散， 然后加入纯化水搅拌， 配成隔离衣液。
包薄膜衣； 以所制备的隔离衣液对得到的片芯包薄膜衣， 得到薄膜 衣片。
配制肠溶衣液： 取处方量欧巴代在搅拌下加入到乙醇中， 继续搅拌， 得到肠溶衣液。
包肠溶衣： 以所制备的肠溶衣液对薄膜衣片包肠溶衣， 制得的复方 制剂中单位剂量含乐卡地平 7.5mg, 氯沙坦 20mg。 实施例 3:对乐卡地平氯沙坦复方制剂进行质量研究其中盐酸乐卡地 平的含量测定
HPLC方法测定实施例 1制备的乐卡地平氯沙坦复方制剂盐酸乐卡地 平的含量， 液相检测条件如表 1。
表 1 复方制剂中盐酸乐卡地平的 HPLC含量测定条件
流动相 A: 緩冲液： B: 乙腈 =50:50 柱子 C18, Waters 250 mm 4.6 mm; 5μηι 流速 1.0 ml/min 检测波长 210 nm
柱温 50 °C 上样量 20 μΐ 运行时间 120 min
A緩冲液的配制方法： 1.36 g磷酸二氢钾溶于 1 L水， 待溶解后向加 入 1 g疏酸基正辛坑盐（ octane sulphonic acid sodium salt ), 超声处理， 使 用 10%磷酸（ v/v)调节 pH至 2.5士 0.05。 实施例 4: 复方制剂药效学研究
材料与方法
1.1、 材料
雌性清洁级自发性高血压大鼠模型（SHR )大鼠 60 只， 200 g左右， 清 醒尾动脉收缩压（ SBP) 160 mmH g ( 1 mmH g= 0. 133 kPa)。
1. 2、 实验方法
1. 2. 1、 实验模型制备及分组
大鼠以盐酸氯胺酮 50mg I kg和地西泮 5 mg/ kg腹腔注射麻醉， 左侧 腹股沟行约 2 cm长皮肤切口， 暴露股动脉鞘， 仔细分离股动脉和股静脉 行股动脉插管。 动脉管由动物大腿根部经皮下隧道绕至背部， 由头颈部 引出固定， 术后自由进食 2 d。
将 SHR大鼠各自随机分为乐卡地平氯沙坦复方制剂 1 (主药质量比： 盐酸乐卡地平为 50%,氯沙坦钾为 12% ),乐卡地平氯沙坦复方制剂 2 (主 药质量比： 盐酸乐卡地平为 30%, 氯沙坦钾为 46% ), 乐卡地平氯沙坦复 方制剂 3 (主药质量比： 盐酸乐卡地平为 0.25% , 氯沙坦钾为 58% )每组 均为 20 只大鼠， 连接系统行清醒血压监测， 先联机适应 4 h,监测过程中 口服给药，给药时间在上午 10: 00,血压记录从给药前 1 h开始到给药后 第 8 h结束。
1. 2. 2、 检测指标
清醒测压由计算机实时记录每搏收缩压（SBP) 、 舒张压（DBP) 、 心 动间期（H P) 、 脉压（PP) 、 收缩压变异率（SBPV) 。 经 4 h 的适应性稳 定后， 开始记录每搏血压信号,记录时间为 9 h(观察雅静胶嚢急性一次给 药的降压作用时，从给药前 l h记录到给药后第 8 h 结束， 即给药当天 9: 00 至当天 22: 00) , 而后脱机分析总的血流动力学指标。 1. 2. 3、 统计学处理
采用 SPSS 10. 0 统计软件处理，检测数据以均数#标准差表示， 各 组给药前后比较用配对 t检验， 各组均数间差别比较采用单向方差分析, 各组均数间差别的多重比较采用 LSD-q检验。
1. 3、 结果
SHR 大鼠在三组给药后血压变化情况。 口服给药后乐卡地平氯沙坦 复方制剂 1和乐卡地平氯沙坦复方制剂 3均较给药前血压有一定的变化， 乐卡地平氯沙坦复方制剂 2用药前后血压变化显著， 具有统计学意义。 实施例 5: 本发明所述乐卡地平氯沙坦复方制剂的临床试验研究
1、 资料与方法
1.1 病例的选择： 年龄 18-75岁的轻中度舒张型高血压（仰卧位舒张 压 95-115mmHg ) 的病人， 排除严重高血压 (舒张压>1151111111¾)、 继发性 高血压、 心脏病、 心肌梗死、 休克、 近克、 近 3 个月内短暂的缺血性中 风、 窦緩或窦速、 低血容量、 肝肾功能不全、 糖尿病。 经过 14-20天的清 洗期， 进入 14-30天的导入期，此期间均服用单盲的安慰剂，每 7-10天回 访测量血压。 合适的病人按随机原则分配治疗组。
1.2 试验方法： 总共 396个病人入选， 388个进入导入期， 307个进 入评估期。 随机分为 4组： 1 )复方制剂低剂量组： 含乐卡地平 5mg, 氯 沙坦 20mg的乐卡地平氯沙坦复方制剂； 2 ) 高剂量单用组 1 : 盐酸乐卡 地平 ( Recordati Industria Chimica e Farmaceutica S.P.A. ), lOmg; 3 ) 高剂 量单用组 2: 氯沙坦（杭州默沙东制药有限公司生产） lOOmg; 4 ) 阳性 对照组： 氨氯地平 （辉瑞制药有限公司 ) 10mg, 每天一次， 连续用药。
1.3 观察指标与方法： 按国际标准要求测血压， 由固定医师每周随访 1次， 于 9:00-11 :00就诊， 每次测心率和坐位血压 3次， 取 2次数值较高 者计算其平均值。
1.4 实验室检查 全面患者试验前后进行心电图、 血尿常规、 肝肾功 能、 血糖、 血脂、 血电解质检查。
1.5 疗效评价： 按照 1979年全国心血管流行病学及人群防治汇报讨 论会议纪要的规定： （1) 显效： 舒张压下降^ lOmmHg , 并降至正常 ( <90mmHg )或下降 20mmHg以上； （ 有效： 舒张压下降 10- 19mmHg , 或下降 <10mmHg, 但已达正常； （3)无效： 未达上述标准。
1.6数据处理与统计方法： 计量资料以均数士标准差计算。 4种给药 方式前后定量指标比较采用配对 t检验。 用药前后差值比较采用卡方检 验。
2、 结果
疗效分析： (1) 治疗 12周末血压变化： 治疗 12周末， 4组患者的血 压都明显下降， 差异有显著统计学意义（PO.05 ) (如表 2 )。
表 2中， 1 )为实施例 1制备的含乐卡地平 5g, 氯沙坦 20g的乐卡地 平氯沙坦复方制剂； 2 )为盐酸乐卡地平 lOmg; 3 ) 为氯沙坦 lOOmg; 4 ) 为氨氯地平 lOmg, 四组患者治疗前及治疗 12周末平均舒张压、 收缩压 变化。
表 2四组患者治疗前及治疗 12周末平均舒张压、 收缩压变化
舒张压 （mmHg ) 收缩压 ( mmH g )
分组 有效率 用药前 用药后 变化值 用药前 用药后 变化值
1 ) ( 80例） 106±6 85±6 21±6 156±5 130±7 25±7 85.2%
2 ) ( 75例 ) 104±9 88±7 13±8 152±9 139±8 19±3 70.8%
3 ) ( 73例 ) 100±5 81±9 11±5 152±9 138±6 15±9 75.1%
4 ) ( 79例） 104±10 89±9 15±6 153±8 135±8 11±8 74.9% 注： 与用药前比较， P<0.05; 与氨氯地平组比较， P<0.05。
乐卡地平氯沙坦复方制剂组舒张压下降幅度较氨氯地平组更大， 差 异有统计学显著意义（PO.05 ); 4组收缩压也有显著下降， 乐卡地平氯 沙坦复方制剂组收缩压下降幅度明显高于氨氯地平组， 差异有统计学显 著意义（P<0.05 )。 卡地平氯沙坦复方制剂组舒张压和收缩压下降幅度显 著高于盐酸乐卡地平高剂量单用组和氯沙坦高剂量单用组， 差异有统计 学显著意义（P<0.05 )。
(2) 降压有效率比较： 乐卡地平氯沙坦复方制剂组在治疗 12 周末降 压的总有效率为 85.2%, 显著高于单用盐酸乐卡地平组（70.8% )和单用 氯沙坦组（ 75.1% ) ( P<0.05 )。
单用盐酸乐卡地平组 2例出现胃肠道症状， 1例头晕。 单用氯沙坦组 4例出现胃肠道症状， 1例口干。 均较轻微， 不影响继续用药。 两组不良 反应发生率无显著差别。 联合用药组均未出现明显不良反应， 治疗 12周 3组患者实验室检查结果与心电图变化无显著性差异。
3、 结论
乐卡地平氯沙坦复方制剂组， 与高剂量单用组比较， 有效率显著， 且不良反应的发生率显著降低， 患者耐受性良好。 因此， 乐卡地平氯沙 坦复方制剂治疗轻、 中度血压可提高降压疗效， 且可耐受性， 对心脏传 导和心率没有明显影响。 实施例 6: 本发明所述乐卡地平氯沙坦复方制剂的临床试验研究 1、 资料与方法
1.1 病例的选择： 年龄 18-75岁的轻中度舒张型高血压（仰卧位舒张 压 95-115mmHg ) 的病人， 排除严重高血压 (舒张压>1151111111¾)、 继发性 高血压、 心脏病、 心肌梗死、 休克、 近克、 近 3 个月内短暂的缺血性中 风、 窦緩或窦速、 低血容量、 肝肾功能不全、 糖尿病。 经过 14-20天的清 洗期， 进入 14-30天的导入期，此期间均服用单盲的安慰剂，每 7-10天回 访测量血压。 合适的病人按随机原则分配治疗组。
1.2 试验方法： 总共 359个病人入选， 305个进入导入期， 266个进 入评估期。 随机分为 4组： 1 ) 实施例 2制备的复方制剂低剂量组： 含乐 卡地平 7.5mg, 氯沙坦 20mg的乐卡地平氯沙坦复方制剂； 2 ) 高剂量单 用组 1：盐酸乐卡地平 ( Recordati Industria Chimica e Farmaceutica S.P.A. ), lOmg; 3 )高剂量单用组 2:氯沙坦（杭州默沙东制药有限公司生产）100mg。
1.3 观察指标与方法： 按国际标准要求测血压， 由固定医师每周随访
1次， 于 9:00-11 :00就诊， 每次测心率和坐位血压 3次， 取 2次数值较高 者计算其平均值。
1.4 实验室检查 全面患者试验前后进行心电图、 血尿常规、 肝肾功 能、 血糖、 血脂、 血电解质检查。 1.5 疗效评价： 按照 1979年全国心血管流行病学及人群防治汇报讨 论会议纪要的规定： （1) 显效： 舒张压下降^ lOmmHg , 并降至正常 ( <90mmHg )或下降 20mmHg以上； （ 有效： 舒张压下降 10- 19mmHg , 或下降 <10mmHg, 但已达正常； （3)无效： 未达上述标准。
1.6数据处理与统计方法： 计量资料以均数士标准差计算。 4种给药 方式前后定量指标比较采用配对 t检验。 用药前后差值比较采用卡方检 验。
2、 结果
疗效分析： (1) 治疗 12周末血压变化： 治疗 12周末， 4组患者的血 压都明显下降， 差异有显著统计学意义（PO.05 ) (如表 3 )。
表 3 三组患者治疗前及治疗 12周末平均舒张压、 收缩压变化
舒张压 （mmHg ) 收缩压 （mmHg )
分组 有效率 用药前 用药后 变化值 用药前 用药后 变化值
1 ) ( 89例） 105±9 86±8 23±8 158±8 133±9 28±9 87.4%
2 ) ( 90例 ) 106±8 89±7 16±6 156±8 136±7 19±7 71.6%
3 ) ( 87例） 102±6 83±8 14±5 152±7 139±5 17±5 77.3% 注： 与用药前比较， P<0.05„
其中， 1 ) 为含乐卡地平 7.5g, 氯沙坦 20g的乐卡地平氯沙坦复方制 剂； 2 ) 为盐酸乐卡地平 10mg; 3 ) 为氯沙坦 100mg。
乐卡地平氯沙坦复方制剂组舒张压下降幅度较氨氯地平组更大， 差 异有统计学显著意义（PO.05 ); 3 组收缩压也有显著下降， 乐卡地平氯 沙坦复方制剂组收缩压下降幅度明显高于氨氯地平组， 差异有统计学显 著意义（P<0.05 )。 卡地平氯沙坦复方制剂组舒张压和收缩压下降幅度显 著高于盐酸乐卡地平高剂量单用组和氯沙坦高剂量单用组， 差异有统计 学显著意义（P<0.05 )。
(2) 降压有效率比较： 乐卡地平氯沙坦复方制剂组在治疗 12 周末降 压的总有效率为 87.4%, 显著高于单用盐酸乐卡地平组（71.6% )和单用 氯沙坦组 ( 77.3% ) ( P<0.05 )。
单用盐酸乐卡地平组 1例出现胃肠道症状， 1例头晕。 单用氯沙坦组 2例出现胃肠道症状， 1例口干。 均较轻微， 不影响继续用药。 两组不良 反应发生率无显著差别。 联合用药组均未出现明显不良反应， 治疗 12周 3组患者实验室检查结果与心电图变化无显著性差异。
3、 结论
乐卡地平氯沙坦复方制剂组， 与高剂量单用组比较， 有效率显著， 且不良反应的发生率显著降低， 患者耐受性良好。 因此， 乐卡地平氯沙 坦复方制剂治疗轻、 中度血压可提高降压疗效， 且可耐受性好， 对心脏 传导和心率没有明显影响。 以上所述仅是本发明的优选实施方式， 应当指出， 对于本技术领域 的普通技术人员来说， 在不脱离本发明原理的前提下， 还可以做出若干 改进和润饰， 这些改进和润饰也应视为本发明的保护范围。

Claims

权 利 要 求
1、 一种乐卡地平氯沙坦复方制剂， 其特征在于， 以占复方制剂的质 量百分比计， 盐酸乐卡地平为 0.5-40%, 氯沙坦钾为 6.25-50%。
2、 根据权利要求 1所述的复方制剂， 其特征在于， 此复方制剂处方 中主药盐酸乐卡地平和氯沙坦钾的质量比最优为 1 :2-25。
3、 根据权利要求 1所述的复方制剂， 其特征在于， 所用辅料为乳 糖一水合物 20-40%, 微晶纤维素 10-40%, A型羟基乙基淀粉钠 10-20%, 聚维酮 K30 2-8%, 硬脂酸镁 0.5-2.5%, 预胶化淀粉 5-15%, 胶体二氧化 硅 1-10%。
4、 根据权利要求 3所述的复方制剂， 其特征在于， 选用包衣为白 色欧巴代。
5、 根据权利要求 4所述复方制剂的制备方法， 其特征在于， 包括 以下步骤：
步骤 1 : 将过筛后的盐酸乐卡地平原料药和氯沙坦原料药与乳糖-水 合物、 微晶纤维素、 Α型羟基乙基淀粉钠、 聚维酮 K30、 硬脂酸镁、 预胶 化淀粉、 胶体二氧化硅搅拌混合均匀后真空压缩、 碾磨过筛制粒； 压片， 控制片芯硬度；
步骤 2: 取欧巴代， 搅拌条件下加入乙醇中， 搅拌至分散， 然后加入 纯化水搅拌， 配制隔离衣液； 以隔离衣液对步骤 1得到的片芯包薄膜衣； 步骤 3: 取欧巴代加入到乙醇搅拌均勾配制成肠溶衣液； 以肠溶衣液 对薄膜衣片包肠溶衣。
6、 根据权利要求 5所述的制备方法， 其特征在于， 步骤 1所述的 控制片芯硬度为 2-10kg。
7、 根据权利要求 5所述的制备方法， 其特征在于， 步骤 2及步骤 3 所述乙醇浓度为 75-100%。
8、 根据权利要求 5所述的制备方法， 其特征在于， 步骤 2加入纯 化水搅拌及步骤 3所述搅拌的时间为 20-100mim。
9、 根据权利要求 5所述的制备方法， 其特征在于， 步骤 2所述的 欧巴代为 Y- 1-7000, 步骤 3所述的欧巴代为 ΟΥ-Ρ, 91S型。
+
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