CN105902564B - A kind of pharmaceutical composition and preparation method for treating hypertension - Google Patents

A kind of pharmaceutical composition and preparation method for treating hypertension Download PDF

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Publication number
CN105902564B
CN105902564B CN201610275594.6A CN201610275594A CN105902564B CN 105902564 B CN105902564 B CN 105902564B CN 201610275594 A CN201610275594 A CN 201610275594A CN 105902564 B CN105902564 B CN 105902564B
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parts
vitamin
reserpine
pharmaceutical composition
hydrochioro
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CN105902564A (en
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任逢晓
杨艳丽
王延敏
高敬轩
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Zhengzhou Taifeng Pharmaceutical Co Ltd
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Zhengzhou Taifeng Pharmaceutical Co Ltd
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Priority claimed from CN201510733431.3A external-priority patent/CN105193841A/en
Priority claimed from CN201510732841.6A external-priority patent/CN105213425A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50

Abstract

The present invention relates to a kind of pharmaceutical compositions and preparation method for treating hypertension.The present invention provides a kind of comprising reserpine, Hydrochioro, vitamin B for defect existing for compound reserpine composite formula traditional preparation methods6, potassium chloride, a variety of active ingredients such as rutin a kind of compound reserpine pharmaceutical composition and preparation method for treating hypertension.Compound reserpine drug combination preparation toxic side effect prepared by the present invention is few, and fluctuation of blood pressure is small in pressure reduction, and onset time is short, and duration of efficacy is long, is convenient for patient's long-term treatment, improves drug safety, and improve the compliance of medication；Meanwhile the present invention can significantly reduce compound reserpine drug combination preparation dissolution otherness, and improve sample stability and batch between uniformity.

Description

A kind of pharmaceutical composition and preparation method for treating hypertension
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of pharmaceutical composition that treating hypertension and preparation side Method.
Background technology
Reserpine is adrenergic neuron blocking property antihypertensive, by the kidney for exhausting surrounding sympathetic nerve endings Upper parathyrine, catecholamine and serotonin in the heart, brain and its hetero-organization reach anti-hypertension, reducing heart rate and inhibit maincenter god Effect through system.It is widely used in slight and moderate hypertension treatment;Blood pressure lowering and tranquilizer, antihypertensive effect work slowly, but Persistent, event resolves are also slow after drug withdrawal, and good effect has especially been shared with thiazide diuretic, are common compound hypertension medicines One of main component.Hydralazine hydrochloride is vasodilator agent, and to Moderate Essential Hypertension, hydrolazine, which merges, applies diuretics Good efficacy can be then obtained with beta-blocker.Cyclopenthiazide is middle effect diuretics, also has antihypertensive effect, medication early stage Due to diuresis, reduces blood volume and be depressured, sodium is slightly lost in medication later stage body, the low sodium of parteriole parietal cell passes through Na+-Ca2+It hands over The system of changing planes makes intracellular Ca2+Amount is reduced, and blood vessel reduces the reactivity of vaso-excitor material, and causes vasodilation, and blood pressure declines；This Product also have the antihypertensive effect for enhancing other depressor.Hydrochioro is thiazide diuretic, antihypertensive, is closed with depressor Used time, antihypertensive effect are obviously reinforced.By reserpine and vasodilator agent, diuretics use in conjunction, which has, significantly to act synergistically, and promotees Decline into blood pressure, improves curative effect, reduce dosage and the adverse reaction of each medicine；In addition Hydrochioro and Cyclopenthiazide can increase The antihypertensive effect of reserpine and hydralazine hydrochloride reduces the side effect of water-sodium retention.Promethazine hydrochloride is antihistamine, can be competed Property block H1Receptor and generate antihistamine effect, have maincenter sedation.Rutin category vitamin drug, there is reduction capillary Permeability and brittle effect, the normal elasticity for keeping and restoring capillary can effectively press down for preventing hypertensive cerebral hemorrhage The aggregation of blood platelet processed, prevents thrombosis.
Fumaric acid is simplest unsaturated dicarboxylic acid, also known as fumaric acid, is found from corydalis tuber earliest, frequently as A kind of food additives --- acid is also used frequently as pharmaceutic adjuvant for cold drink, fruit drops, jelly, ice cream etc. In pharmaceutical industry, acidity regulator, anti-oxidant auxiliary agent etc. can be used as.According to the websites MD INDIA, fumarate is used for always Treat severe psoriasis.Nowadays, it was discovered by researchers that this drug, which may also help in, prevents multiple sclerosis（MS）.This Research is published in current neurology magazine《Brain》On.Now, Bo Hong Rule university（RUB）Neurosurgeon find, it is rich Horse hydrochlorate discharges free radical in removing inflammatory process, to protect nerve and spongiocyte.
Compound reserpine composition is typically by reserpine, Hydrochioro, vitamin B6, potassium chloride, vitamin B1, hydrazine bend The compound preparation of the Multiple components such as piperazine, promethazine hydrochloride composition, such compound preparation have clinically been applied For many years, validity and safety have been obtained for adequately verifying.But since there are vitamin Bs in prescription6, vitamin B1, hydrazine bend Piperazine, rutin etc., stability is poor, is easily affected by the external environment（Such as temperature, illumination, oxygen etc.）And change, medicament contg It reduces.There is researcher to be studied for compound reserpine composition medicine unstability situation, but the result obtained is past Past is barely satisfactory.
The Chinese patent application of application number CN201110369547 remains multiple using acidic materials dihydric phosphate is added The stability of active ingredient in square Reserpoid, by attempting, although the inorganic acidic materials can improve vitamin B6And vitamin B1Stability, but to the stability of hydrolazine and rutin improve it is helpless.Application number The Chinese patent application of CN201210455548 is used to vitamin B1The mode that is coated improves vitamin B1Stability, But really to unstability active constituent vitamin B6, hydrolazine, rutin etc. do not consider, while to vitamin B1It is coated Processing step flow is increased, a large amount of work is increased.
In terms of the treatment of hypertension, the fluctuation of blood pressure in the pressure reduction of high blood pressure of conventional buck drug is big, drug Therapeutic effect is poor, and side effect is big, and onset time is long, and duration of efficacy is short.In addition, in compound reserpine composite formula, packet It includes reserpine and Cyclopenthiazide medicament contg is extremely low, it is higher with other with poor 30 times of the active constituent of other lower contents or more Thousands of times of the active constituent difference of content, easily causes the medicament contg uniformity against regulation, by suitable method, improves and lives The medicament contg uniformity of property ingredient obtains the satisfactory compound reserpine composite preparation of each index.
Invention content
The present invention provides a kind of comprising sharp blood for defect existing for compound reserpine composite formula traditional preparation methods Flat, Hydrochioro, vitamin B6, potassium chloride, a variety of active ingredients such as rutin a kind of compound reserpine medicine for treating hypertension Compositions and preparation method.Compound reserpine drug combination preparation toxic side effect prepared by the present invention is few, in pressure reduction Fluctuation of blood pressure is small, and onset time is short, and duration of efficacy is long, is convenient for patient's long-term treatment, improves drug safety, and improve The compliance of medication；Meanwhile the present invention can significantly reduce compound reserpine drug combination preparation dissolution otherness, and carry The stability of high sample and batch between uniformity.
The technical scheme is that：
A kind of pharmaceutical composition for treating hypertension, described pharmaceutical composition are made of the raw material of following parts by weight：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, hydrochloric acid isopropyl 2 parts of piperazine, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 2-10 parts and pharmaceutic adjuvant.
The pharmaceutical composition of above-mentioned treatment hypertension, the pharmaceutic adjuvant include filler, disintegrant, adhesive, profit It is one or more in lubrication prescription, coating material and corrigent；
The filler is in mannitol, lactose, sucrose, dextrin, starch, microcrystalline cellulose, algal polysaccharides and chitosan It is one or more；
The disintegrant is sodium carboxymethyl starch, crospovidone, croscarmellose sodium, low substituted hydroxy-propyl fibre It is one or more in dimension element and calcium carboxymethylcellulose；
Described adhesive is Opadry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol and carboxymethyl It is one or more in sodium cellulosate；
The lubricant is talcum powder, hydrogenated vegetable oil, superfine silica gel powder, sodium stearyl fumarate, calcium stearate, dodecane It is one or more in base sodium sulphate, magnesium stearate and stearyl alcohol；
The coating material is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resin IV, styrene-ethylene It is one or more in pyridine copolymer and polyvinylpyrrolidone；
The corrigent is the perfume (or spice) of Aspartame, 3,4-Dihydro-6-methyl-1,2,3-oxathiazin-4-one 2,2-dioxide potassium salt, saccharin sodium, glucan, Stevioside, citric acid, various fragrance Smart fragrance it is one or more.
The pharmaceutical composition of above-mentioned treatment hypertension, described pharmaceutical composition are made of the raw material of following parts by weight：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, hydrochloric acid isopropyl 2 parts of piperazine, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 3-7 parts, 30-80 parts of filler, 2-5 parts of disintegrant, 0.5-2 parts of 3-10 parts of adhesive and lubricant.
The pharmaceutical composition of above-mentioned treatment hypertension, described pharmaceutical composition are made of the raw material of following parts by weight：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, hydrochloric acid isopropyl 2 parts of piperazine, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 4-6 parts, microcrystalline cellulose and/or 60-70 parts of lactose, microcrystalline cellulose and lactose can be mixed with arbitrary proportion, be crosslinked carboxylic first 3-4 parts of base sodium cellulosate, 4-6 parts of hydroxypropyl cellulose and superfine silica gel powder and/or 1-2 parts of magnesium stearate, superfine silica gel powder and Magnesium stearate can be mixed with arbitrary proportion.
The pharmaceutical composition of above-mentioned treatment hypertension, described pharmaceutical composition are made of the raw material of following parts by weight：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, hydrochloric acid isopropyl 2 parts of piperazine, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 5 1 part of part, 61.3 parts of lactose, 3.6 parts of croscarmellose sodium, 5 parts of hydroxypropyl cellulose and magnesium stearate.
Tablet or capsule, such as oral cavity is made in the pharmaceutical composition of above-mentioned treatment hypertension, described pharmaceutical composition Disintegrated tablet.
The pharmaceutical composition of above-mentioned treatment hypertension, the oral disnitegration tablet are made of the raw material of following parts by weight：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, hydrochloric acid isopropyl 2 parts of piperazine, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 3-7 parts, 15-30 parts of polyacrylic resin IV, 30-150 parts of filler, 2-5 parts of disintegrant, 3-10 parts of adhesive, flavoring 0.5-2 parts of 0-8 parts of agent and lubricant.
The pharmaceutical composition of above-mentioned treatment hypertension, the filler preferably microcrystalline cellulose and/or mannitol, disintegration The preferred croscarmellose sodium of agent, the preferred hydroxypropyl cellulose of adhesive, the preferred Aspartame of corrigent, lubricant are preferred Sodium stearyl fumarate and/or magnesium stearate.
The pharmaceutical composition of above-mentioned treatment hypertension, the oral disnitegration tablet are made of the raw material of following parts by weight：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, hydrochloric acid isopropyl 2 parts of piperazine, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 4-6 parts, 15-25 parts of polyacrylic resin IV, microcrystalline cellulose and/or 90-100 parts of mannitol, microcrystalline cellulose and sweet dew Alcohol can be mixed with arbitrary proportion, 3-4 parts of croscarmellose sodium, 4-6 parts of hydroxypropyl cellulose, Aspartame 4-6 Part and sodium stearyl fumarate and/or 1-2 parts of magnesium stearate, sodium stearyl fumarate and magnesium stearate can be arbitrarily to compare Example mixing.
The pharmaceutical composition of above-mentioned treatment hypertension, the oral disnitegration tablet are made of the raw material of following parts by weight：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, hydrochloric acid isopropyl 2 parts of piperazine, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 5 Part, 20 parts of polyacrylic resin IV, 91.3 parts of mannitol, 3.6 parts of croscarmellose sodium, hydroxypropyl cellulose 5 Part, 1 part of 5 parts of Aspartame and magnesium stearate.
The preparation method of the pharmaceutical composition of above-mentioned treatment hypertension, first by reserpine, ring penta by weight ratio Thiazine and hydroxypropyl cellulose are dissolved in ethyl alcohol, remaining pharmaceutic adjuvant in addition to lubricant is added in fluidized bed granulation seed-coating machine, It after spraying into above-mentioned ethanol solution granulation after fluidisation mixing, dries, addition mix lubricant is uniform after whole grain, and tabletting to obtain the final product；
（1）The raw material and weight of described pharmaceutical composition are as follows：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, breast Sugared 613g, croscarmellose sodium 36g, hydroxypropyl cellulose 50g and magnesium stearate 10g.
(2) step is utilized（1）Process prepared by the raw material includes the following steps：
1. reserpine and Cyclopenthiazide are added in 95% ethyl alcohol of 1000ml first, stirring and dissolving is added to after clarifying Hydroxypropyl cellulose stirs to clarify, and obtains reserve liquid；
2. by following raw material：Hydralazine hydrochloride, Hydrochioro, promethazine hydrochloride, potassium chloride, rutin, chloroquine diphosphate, dimension life Plain B1, vitamin B6, fumaric acid, lactose and croscarmellose sodium crush, 80 mesh of sieving, respectively then by above-mentioned powder Raw material after broken after mixing, is added in fluidized bed granulation seed-coating machine by equal increments method, is preheated to 28 DEG C, fluidized coating work In skill, particle needs first to be preheated, and preheating temperature is debugged according to the production capacity of coating solvent and fluid bed, adjusts stream It is 100m to change temperature to 40 DEG C, dry air flow3*h-1,
3. by peristaltic pump by above-mentioned reserve liquid in the way of top spray and the flow pump fluidized bed of 5ml/min is granulating coated Spray chamber atomization granulation in machine, atomizing pressure 1.2bar are stepped up and are pumped into flow velocity to 40ml/min until reserve liquid is used It is complete,
4. then improving stream temperature to 50 DEG C, taken out after continuing fluidized drying 45min in a fluidized bed,
5. crossing 18 mesh pharmacopeia sieve, the particle less than 18 mesh is taken, using containing for each active constituent of high effective liquid chromatography for measuring Amount after meeting intermediate quality standard, is added magnesium stearate, mixes 5min, tabletting, packaging.
The preparation method of the pharmaceutical composition of above-mentioned treatment hypertension, first by the reserpine of recipe quantity, Cyclopenthiazide and Hydroxypropyl cellulose is dissolved in ethyl alcohol, and rest activity ingredient and fumaric acid are added in fluidized bed granulation seed-coating machine, after fluidizing mixing Spray into the granulation of above-mentioned ethanol solution, spray into the ethanol solution of polyacrylic resin IV after the completion, after dry, be added after whole grain Filler, disintegrant, corrigent and mix lubricant are uniform, and tabletting to obtain the final product；
(1) raw material of the oral disnitegration tablet and weight are as follows：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g gather Acrylic resin IV 200g, mannitol 913g, croscarmellose sodium 36g, hydroxypropyl cellulose 50g, A Siba 50g parts of sweet tea and magnesium stearate 10g；
(2) step is utilized（1）Process prepared by the raw material includes the following steps：
1. reserpine and Cyclopenthiazide are added in 95% ethyl alcohol of 1000ml, hydroxypropyl is added to after clarifying in stirring and dissolving Base cellulose, stirs to clarify, and obtains reserve liquid 1；
2. polyacrylic resin IV is added in 95% ethyl alcohol of 2000ml, stirring and dissolving obtains reserve liquid 2 to after clarifying；
3. by following raw material：Hydralazine hydrochloride, Hydrochioro, promethazine hydrochloride, potassium chloride, rutin, chloroquine diphosphate, dimension life Plain B1, vitamin B6 and fumaric acid crush, 80 mesh of sieving, then mix the raw material after above-mentioned crushing by equal increments method respectively After closing uniformly, it is added in fluidized bed granulation seed-coating machine, is preheated to 28 DEG C, in fluidized coating technique, particle needs first to be preheated, Preheating temperature is debugged according to the production capacity of coating solvent and fluid bed, adjusts stream temperature to 40 DEG C, dry air stream Amount is 100m3*h-1；
4. by peristaltic pump by reserve liquid 1 in the way of top spray and the flow pump fluidized bed granulator coater of 5ml/min In spray chamber atomization granulation, atomizing pressure 1.4bar, step up be pumped into flow velocity to 40ml/min until reserve liquid 1 use It is complete,
5. continuing with the spray chamber that reserve liquid 2 is pumped into fluidized bed granulation seed-coating machine by peristaltic pump in a manner of top spray to be atomized Granulation, the control mode of flow velocity with step 4., fluidized coating and granulation when, flow velocity will at any time be adjusted according to fluidized state, in order to avoid Occur electrostatic particle adhesive aggregation phenomena such as, after improve stream temperature to 50 DEG C, continue fluidized drying 45min in a fluidized bed After take out,
6. crossing 18 mesh pharmacopeia sieve, the particle less than 18 mesh is taken, using containing for each active constituent of high effective liquid chromatography for measuring Amount after meeting intermediate quality standard, is added mannitol, croscarmellose sodium, Aspartame, after mixing 30min, adds Enter magnesium stearate, mixes 5min, tabletting, packaging.
Beneficial effects of the present invention：
（1）The drug combination preparation prepared using technical scheme of the present invention is solved hydrazine hydrochloride in composite formula and bent The problem of chemically unstables such as piperazine, rutin, vitamin B1 and vitamin B6, improves the stability of composite preparation, reduces Toxic side effect, while ensure that quality and curative effect；The standard for improving original pharmaceutical preparation has complied with the compliance of hypertensive patient Property, and preparation process is suitble to the requirement of industrialized production.The present invention is verified by a large number of experiments, is increased in the composition suitable The fumaric acid of amount makes to produce synergistic effect between fumaric acid and active material, significantly improves curative effect and the pharmaceutical composition Stability.
（2）The drug combination preparation toxic side effect prepared using technical scheme of the present invention is few, blood pressure in pressure reduction Fluctuate small, onset time is short, and duration of efficacy is long, is convenient for patient's long-term treatment, improves drug safety.The present invention is simultaneously It uses new recipe and new process prepares the drug combination preparation, significantly reduce preparation differences between batches, improve sample Stability.The drug combination preparation of the present invention is little affected by the influence of gastric emptying variation, absorption in vivo in vivo With good reproducibility, the avoidable risk that may be caused drug pulse due to uniformity of dosage units and dissolution rate difference is reduced Weak, weak and feeble, confusion may be caused due to drug pulse, low blood pressure, dizziness, heart block, even drawn Death is played, drug safety is improved.
（3）Using technical scheme of the present invention prepare drug combination preparation solve reserpine, Cyclopenthiazide etc. because Content is seldom not easy uniformly mixed problem, and production technology uses totally-enclosed fluidized bed granulation technique, reduces pollution, simultaneously Decrease with the contact of water, light, heat source, avoid chemicals in formula and influence each other, ensure that the matter of product Amount and curative effect.Selected raw material is easy to get feasible with preparation method, and suitable for expanding industrialized production, used method has Good reproducibility.Especially currently preferred formula and preparation method are the preferred plan obtained by screening, select excellent The prescription of change prepares drug combination preparation, it can be achieved that the dosage form good release performance in vivo using fluidized bed granulation method.
（4）The drug combination preparation prepared using technical solution of the present invention, through preliminary test studies have shown that in hypertension Pressure reduction in fluctuation of blood pressure it is smaller, improve the therapeutic effect of drug, extend duration of efficacy, reduce gastrointestinal tract Stimulation and blood plasma drug concentration peak value, reduce generate side effect possibility, improve the compliance of patient medication.The present invention Product drug combination preparation, preparation process is simple for process, using fluidized bed granulation technique, solve uniformity of dosage units and The problems such as stability difference and corresponding patient's compliance, fluidized bed granulation technique and tablet forming technique are combined, and meet big production Requirement, production efficiency is high.The oral disnitegration tablet prepared using technical solution of the present invention, using fluidized bed powder coating method and pressure Blade technolgy, yield reaches 95% or more, and can prepare the oral disnitegration tablet of multiple and different specifications；Meanwhile the present invention prepares gained Oral disnitegration tablet disintegration time within 30 seconds, hardness reaches 40N or more, be conducive to packaging, transport and patient carrying.
（5）The dissolution feature of the drug combination preparation prepared using technical scheme of the present invention is had significantly compared with the prior art Ground improves, and bioavilability is high, and individual difference is small；Solid composition preparation obtained is with preferable uniformity of dosage units and preferably Stability, drug combination preparation uniformity of dosage units and dissolution rate obtained meet the requirement of 2015 editions Chinese Pharmacopoeias.It is logical The evaluations such as oral disnitegration tablet dissolution rate and disintegration time limited are crossed, it is found that drug oral disnitegration tablet dissolution provided by the invention is rapid, collapse The solution time is short, has greatly complied with the pathological characteristic of aged patients with hypertension.
（6）The drug oral disnitegration tablet prepared using technical solution of the present invention is convenient to take, has no toxic side effect, in good taste, Without grittiness, it is convenient for patient's long-term treatment, has greatly complied with the pathological characteristic of hypertensive patient, it is outstanding is suitable for hypertensive patient It is the treatment of the aged patients with hypertension of dysphagia.It is solved using orally disintegrating tablet preparation prepared by technical solution of the present invention In Orally disintegrating slice prescription there is chemically unstable in hydralazine hydrochloride, rutin, vitamin B1 and vitamin B6 etc., carry The high stability of orally disintegrating tablet preparation, reduces toxic side effect, while ensure that quality and curative effect；Improve original drug The standard of preparation has complied with the compliance of hypertensive patient, and preparation process is suitble to industrialized requirement.
（7）Drug oral disnitegration tablet prepared by technical solution of the present invention has different for the bitter taste of active constituents of medicine etc. Taste is obviously improved performance, improves the powder coating taste masking used when mouthfeel principle is mainly of the invention prepare and flavoring technology, Selected auxiliary material be easy to get with preparation method it is feasible, suitable for expand industrialized production, have good reproducibility.Especially originally The preferred formula of invention and preparation method, are the preferred plan obtained by screening, the prescription of optimization are selected, using fluid bed powder Last coating method and pressed disc method prepare oral disnitegration tablet, it can be achieved that the apparent mouthfeel improvement of oral disnitegration tablet.
Specific implementation mode
It is the specific implementation mode of the present invention below, embodiment is to further describe the present invention rather than limits this hair It is bright.All technical solutions equivalent with the present invention all belong to the scope of protection of the present invention.
1 medicinal composition tablets of embodiment and preparation method
First reserpine, Cyclopenthiazide and hydroxypropyl cellulose are dissolved in ethyl alcohol, remaining auxiliary material in addition to lubricant is added In fluidized bed granulation seed-coating machine, after above-mentioned ethanol solution granulation is sprayed into after fluidisation mixing, dries, mix lubricant is added after whole grain Uniformly, tabletting to obtain the final product.
(1) composite formula
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, breast Sugared 613g, croscarmellose sodium 36g, hydroxypropyl cellulose 50g and magnesium stearate 10g.
(2) according to step（1）Above-mentioned raw materials are weighed, preparation process is as follows
1. reserpine and Cyclopenthiazide are added in 95% ethyl alcohol of 1000ml first, stirring and dissolving is added to after clarifying Hydroxypropyl cellulose stirs to clarify, and obtains reserve liquid；
2. by following raw material：Hydralazine hydrochloride, Hydrochioro, promethazine hydrochloride, potassium chloride, rutin, chloroquine diphosphate, dimension life Plain B1, vitamin B6, fumaric acid, lactose and croscarmellose sodium crush, 80 mesh of sieving, respectively then by above-mentioned powder Raw material after broken after mixing, is added in fluidized bed granulation seed-coating machine by equal increments method, preheating, adjusts stream temperature to 40 DEG C, dry air flow be 100m3*h-1；
3. by peristaltic pump by above-mentioned reserve liquid in the way of top spray and the flow pump fluidized bed of 5ml/min is granulating coated Spray chamber atomization granulation in machine, atomizing pressure 1.2bar are stepped up and are pumped into flow velocity to 40ml/min until reserve liquid is used It is complete；
4. then improving stream temperature to 50 DEG C, taken out after continuing fluidized drying 45min in a fluidized bed；
5. choosing the particle less than 18 mesh, after passed examination, magnesium stearate is added, mixes 5min, tabletting, packaging.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
2 medicinal composition tablets of embodiment and preparation method
It is substantially the same manner as Example 1, the difference is that：
The composite formula of embodiment 2 is：
Reserpine 0.6g, hydralazine hydrochloride 20g, Cyclopenthiazide 0.5g, Hydrochioro 30g, promethazine hydrochloride 40g, Potassium chloride 600g, rutin 100g, chloroquine diphosphate 50g, vitamin B1 20g, vitamin B6 20g, fumaric acid 120g, lactose 1300g, croscarmellose sodium 70g, hydroxypropyl cellulose 100g, magnesium stearate 30g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of the composition of embodiment 2 is the same as embodiment 1.
3 medicinal composition tablets of embodiment and preparation method
It is substantially the same manner as Example 1, the difference is that：
The composite formula of embodiment 3 is：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, breast Sugared 315g, microcrystalline cellulose 315g, croscarmellose sodium 35g, hydroxypropyl cellulose 50g, superfine silica gel powder 5g and Magnesium stearate 10g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of the composition of embodiment 3 is the same as embodiment 1.
4 medicinal composition tablets of embodiment and preparation method
It is substantially the same manner as Example 1, the difference is that：
The composite formula of embodiment 4 is：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 70g, breast Sugared 450g, microcrystalline cellulose 225g, crospovidone 45g, hydroxypropyl cellulose 75g and sodium stearyl fumarate 15g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of the composition of embodiment 4 is the same as embodiment 1.
5 medicinal composition tablets of embodiment and preparation method
It is substantially the same manner as Example 1, the difference is that：
The composite formula of embodiment 5 is：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g form sediment Powder 240g, dextrin 40 0 g and magnesium stearate 10g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of the composition of embodiment 5 is the same as embodiment 1.
6 medicament composition capsule agent of embodiment and preparation method
First reserpine, Cyclopenthiazide and hydroxypropyl cellulose are dissolved in ethyl alcohol, remaining auxiliary material in addition to lubricant is added In fluidized bed granulation seed-coating machine, after above-mentioned ethanol solution granulation is sprayed into after fluidisation mixing, dries, mix lubricant is added after whole grain Uniformly, it is packed into capsule to obtain the final product.
(1) composite formula
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, breast Sugared 613g, croscarmellose sodium 36g, hydroxypropyl cellulose 50g and magnesium stearate 10g.
(2) according to step（1）Above-mentioned raw materials are weighed, preparation process is as follows
1. reserpine and Cyclopenthiazide are added in 95% ethyl alcohol of 1000ml first, stirring and dissolving is added to after clarifying Hydroxypropyl cellulose stirs to clarify, and obtains reserve liquid；
2. by following raw material：Hydralazine hydrochloride, Hydrochioro, promethazine hydrochloride, potassium chloride, rutin, chloroquine diphosphate, dimension life Plain B1, vitamin B6, fumaric acid, lactose and croscarmellose sodium crush, 80 mesh of sieving, respectively then by above-mentioned powder Raw material after broken after mixing, is added in fluidized bed granulation seed-coating machine by equal increments method, preheating, adjusts stream temperature to 40 DEG C, dry air flow be 100m3*h-1；
3. by peristaltic pump by above-mentioned reserve liquid in the way of top spray and the flow pump fluidized bed of 5ml/min is granulating coated Spray chamber atomization granulation in machine, atomizing pressure 1.2bar are stepped up and are pumped into flow velocity to 40ml/min until reserve liquid is used It is complete；
4. then improving stream temperature to 50 DEG C, taken out after continuing fluidized drying 45min in a fluidized bed；
5. choosing the particle less than 18 mesh, after passed examination, magnesium stearate is added, mixes 5min, is packed into capsule, packaging is It can.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate.
7 medicament composition capsule agent of embodiment and preparation method
It is substantially the same manner as Example 1, the difference is that：
The composite formula of embodiment 7 is：
Reserpine 0.6g, hydralazine hydrochloride 20g, Cyclopenthiazide 0.5g, Hydrochioro 30g, promethazine hydrochloride 40g, Potassium chloride 600g, rutin 100g, chloroquine diphosphate 50g, vitamin B1 20g, vitamin B6 20g, fumaric acid 120g, lactose 1300g, croscarmellose sodium 70g, hydroxypropyl cellulose 100g, magnesium stearate 30g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of 7 composition capsule of embodiment is the same as embodiment 6.
8 medicament composition capsule agent of embodiment and preparation method
It is substantially the same manner as Example 1, the difference is that：
The composite formula of embodiment 8 is：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g form sediment Powder 240g, dextrin 40 0 g and magnesium stearate 10g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of 8 composition capsule of embodiment is the same as embodiment 6.
1 compatibility test of test example
By following active constituent：0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, Hydrochioro 1.5 parts, 2 parts of promethazine hydrochloride, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1, vitamin 1 part of B6, according to the above ratio prepare seven parts of samples, will wherein five parts of samples respectively with potassium dihydrogen phosphate, sodium dihydrogen phosphate, lemon Acid, tartaric acid, fumaric acid is according to 1:The ratio of 5 (w/w) is pelletized after mixing, and a sample is with fumaric acid according to 1:10(w/ W) ratio is pelletized after mixing, and remaining portion is pelletized after evenly mixing, and particle obtained is respectively charged into open bottle, In more exacting terms（60 DEG C of high temperature, 90%RH high humiditys and the strong light of 4500lx）It is lower to place 10 days, respectively at the 5th day and the 10th Its sampling, investigates sample property, the leading indicators such as content have unchanged, and by result compared with 0 day, test result is shown in Table 1.
【Assay】It is protected from light operation.
Reserpine, Hydrochioro and promethazine hydrochloride shine high performance liquid chromatography（General rule CP2015 0512) it measures.
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；With 0.06mol/L phosphorus Acid dihydride potassium solution-methanol（90 :10) (pH 3.0) is mobile phase A, and acetonitrile is Mobile phase B, and according to the form below carries out gradient elution； Detection wavelength is 268nm.Number of theoretical plate is calculated by reserpine peak is not less than 3000, the separation between each main peak and other chromatographic peaks Degree should meet the requirements.
Measuring method takes this product 10, sets respectively in 25mL measuring bottles, adds diluent [sodium acetate solution（9.0 g of sodium acetate is taken, Add water 1000mL to make dissolving, add triethylamine 3.0mL, pH values are adjusted to 5.0)-acetonitrile with glacial acetic acid（55:45)] ultrasound makes dissolving And it is diluted to scale, it shakes up, filters, take subsequent filtrate as test solution, precision measures 20 μ L and notes people's liquid chromatograph, record Chromatogram；It is another to take reserpine reference substance, Hydrochioro reference substance and promethazine hydrochloride reference substance each appropriate, it is accurately weighed, add dilute Agent is released to dissolve and quantify dilution that 1.2 μ g of Esidri in every lmL, 60 μ g of Hydrochioro is made is molten with 80 μ g's of promethazine hydrochloride Liquid is measured in the same method.Go out the content of every middle each component with calculated by peak area by external standard method, and finds out being averaged for 10 middle each components Content to get.
Hydralazine hydrochloride, vitamin B1With vitamin B6According to high performance liquid chromatography（0512 ＞ of CP2015 general rules is measured
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；With buffer solution （0.11% sodium hexanesulfonate, 0. 02% sodium heptanesulfonate mixed solution adjust pH values to 3.5)-acetonitrile-methanol with glacial acetic acid （80: 10:10) it is mobile phase;Detection wavelength is 210nm.Number of theoretical plate is calculated by hydralazine hydrochloride peak is not less than 3000；Respectively Separating degree between chromatographic peak should meet the requirements.
Measuring method takes this product 10, and respectively plus 0.1% phosphoric acid solution is appropriate, and grinding is transferred in 100mL measuring bottles, is shaken 30 minutes, it is diluted to scale with 0.1% phosphoric acid solution, is shaken up, centrifuged, take supernatant as test solution, precision measures 20 μ L injects liquid chromatograph, records chromatogram；Another precision weighs hydralazine hydrochloride reference substance, vitamin B1Reference substance and vitamin B6 Reference substance is each appropriate, adds 0.1% phosphoric acid solution to dissolve and quantifies dilution 10 μ g of hydrochloric hydrolazine, vitamin B in every lmL is made1 10 μ g and vitamin B6 The solution of 10 μ g, is measured in the same method.Go out the content of every middle each component with calculated by peak area by external standard method, and Find out the average content of 10 middle each components to get.
Rutin shines high performance liquid chromatography（0512 ＞ of CP2015 general rules
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；With methanol- 0.2mol/L acetic acid（40:60）For mobile phase；Flow velocity 1.0mL/min；Detection wavelength is 355nm.Number of theoretical plate is calculated by rutin Not less than 3000；Separating degree between each chromatographic peak should meet the requirements.
Measuring method takes this product 10 respectively, finely ground, sets in 100mL measuring bottles, mobile phase is added to make dissolving, and filtration takes continuous filter Liquid, precision measure 10ml and are diluted to 100mL with mobile phase.It shakes up, filters, take subsequent filtrate as test solution, precision measures 20 μ L note people's liquid chromatograph, record chromatogram；It is appropriate that another precision weighs control substance of Rutin, adds flowing phased soln and quantifies dilution The solution of the 5 μ g containing rutin in every lmL is made, is measured in the same method.Go out the content of every middle rutin with calculated by peak area by external standard method, and Find out the average content of 10 middle rutins to get.
1 compatibility test result of table
It can be seen that from the compatibility test result of table 1 and fumaric acid be added in mixture of active principles（1：5, w/w）Respectively The different degrees of raising of the stability of active constituent, when addition fumaric acid（1：10, w/w）When, vitamin B1, vitamin B6 and The stability of rutin is further increased, but the stability of hydralazine hydrochloride does not rise anti-drop；Relative to remaining document report The acidic materials in road such as potassium dihydrogen phosphate etc., fumaric acid has a clear superiority to the raising of composition stability.
2 uniformity of dosage units of test example and dissolution determination
【Uniformity of dosage units】
Reserpine, Hydrochioro, promethazine hydrochloride, hydralazine hydrochloride, rutin, vitamin B1With vitamin B6
It is protected from light operation.By the every content calculation measured under assay item, regulation should be met（Chinese Pharmacopoeia 2015 editions is logical Then 0941).Measurement result is shown in Table 2 uniformity of dosage units and dissolution determination result.
【Dissolution rate】
Hydrochioro and promethazine hydrochloride
It is protected from light operation.This product is taken, according to dissolution rate and drug release determination method（2015 editions general rules of Chinese Pharmacopoeia, 0,931 second method）, Using 0.lmol/L hydrochloric acid solutions 900mL as dissolution medium, rotating speed is 50 turns per minute, operates in accordance with the law, when through 30 minutes, takes solution About 10mL is filtered with the miillpore filter in 0. 45 μm of apertures, takes subsequent filtrate as test solution；Another precision weighs Hydrochioro Reference substance and promethazine hydrochloride reference substance are each appropriate, add under assay item diluent to dissolve and quantify dilution and are made in every lmL Solution containing 1.7 μ g of Hydrochioro, 2.2 μ g of promethazine hydrochloride, as a contrast product solution.Precision measures test solution and control Each 20 μ L of product solution, except mobile phase is [0.06mol/L potassium dihydrogen phosphates-methanol（90 :10) (pH 3.0)]-acetonitrile (65 ：35) it outside, is measured according to method under " reserpine, Hydrochioro and promethazine hydrochloride " assay item, by external standard method with peak face Product calculates the stripping quantity of every middle Hydrochioro and promethazine hydrochloride.
Measurement result see the table below：
2 uniformity of dosage units of table and dissolution determination result
Pass through the comprehensive analysis to the uniformity of dosage units of compound reserpine composite preparation, dissolution rate made from each embodiment Show that composite preparation uniformity of dosage units and dissolution rate produced by the present invention meet the requirement of 2015 editions Chinese Pharmacopoeias, improves The standard of original preparation, has complied with the compliance of hypertensive patient, and preparation process is suitble to industrialized requirement.
Oral disnitegration tablet refers to that one kind is placed on lingual surface and can be disintegrated into countless particles and sweet mouthfeel in 30 seconds automatically New medicinal preparation.Since its disintegration rate is fast, it is rapid to absorb, and water delivery service, saliva need not be used it can be made to collapse when medication Solution or dissolving, can not only be swallowed by conventional tablet, but also be can be placed in water and taken after disintegration, can also be not required to be taken medicine with water swallow, especially Suitable for old man, children, some especial patients（Mental disease, senile dementia, epileptic patient etc.）And water intaking inconvenience person's medication carries Convenience is supplied.Certain method can be used in the preparation simultaneously improves the mouthfeel of preparation, is greatly improved the medication of child patient Compliance solves the problems, such as taking baby ' hardly possible.Oral cavity is applied to technical scheme of the present invention with reference to specific embodiment Disintegrated tablet, which is made, to be illustrated.
9 pharmaceutical composition oral disnitegration tablet of embodiment and preparation method
First reserpine, Cyclopenthiazide and hydroxypropyl cellulose are dissolved in ethyl alcohol, remaining auxiliary material in addition to lubricant is added In fluidized bed granulation seed-coating machine, after above-mentioned ethanol solution granulation is sprayed into after fluidisation mixing, dries, mix lubricant is added after whole grain Uniformly, tabletting to obtain the final product.
(1) composite formula
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g gather Acrylic resin IV 200g, mannitol 913g, croscarmellose sodium 36g, hydroxypropyl cellulose 50g, A Siba 50g parts of sweet tea and magnesium stearate 10g.
(2) according to step（1）Above-mentioned raw materials are weighed, preparation process is as follows
1. reserpine and Cyclopenthiazide are added in 95% ethyl alcohol of 1000ml, hydroxypropyl is added to after clarifying in stirring and dissolving Base cellulose, stirs to clarify, and obtains reserve liquid 1；
2. polyacrylic resin IV is added in 95% ethyl alcohol of 2000ml, stirring and dissolving obtains reserve liquid 2 to after clarifying；
3. by following raw material：Hydralazine hydrochloride, Hydrochioro, promethazine hydrochloride, potassium chloride, rutin, chloroquine diphosphate, dimension life Plain B1, vitamin B6 and fumaric acid crush, 80 mesh of sieving, then mix the raw material after above-mentioned crushing by equal increments method respectively It after closing uniformly, is added in fluidized bed granulation seed-coating machine, is preheated to 28 DEG C, adjusting stream temperature to 40 DEG C, dry air flow is 100m3*h-1；
4. by peristaltic pump by reserve liquid 1 in the way of top spray and the flow pump fluidized bed granulator coater of 5ml/min In spray chamber atomization granulation, atomizing pressure 1.4bar, step up be pumped into flow velocity to 40ml/min until reserve liquid 1 use It is complete,
5. continuing with the spray chamber that reserve liquid 2 is pumped into fluidized bed granulation seed-coating machine by peristaltic pump in a manner of top spray to be atomized Granulation（5 ~ 40ml/min of flow velocity）, after improve stream temperature to 50 DEG C, continue to take after fluidized drying 45min in a fluidized bed Go out,
6. particle crosses 18 mesh pharmacopeia sieve, the particle less than 18 mesh is taken, using each active constituent of high effective liquid chromatography for measuring Content, after meeting intermediate quality standard, be added filler, disintegrant, corrigent, mix 30min after, be added lubricant, Mix 5min, tabletting, packaging.The oral disnitegration tablet pressure of gained in 40N or more, the intraoral disintegration time 30 seconds with It is interior, and without bitter.
Explanation：The purified water and ethyl alcohol that the present embodiment is added all are volatilized through drying process.
10 pharmaceutical composition oral disnitegration tablet of embodiment and preparation method
It is substantially the same manner as Example 9, the difference is that：
The formula of the oral disnitegration tablet of embodiment 10 is：
Reserpine 0.6g, hydralazine hydrochloride 20g, Cyclopenthiazide 0.5g, Hydrochioro 30g, promethazine hydrochloride 40g, Potassium chloride 600g, rutin 100g, chloroquine diphosphate 50g, vitamin B1 20g, vitamin B6 20g, fumaric acid 120g, poly- third Olefin(e) acid resin IV 500g, mannitol 913g, microcrystalline cellulose 913g, croscarmellose sodium 70g, hydroxy propyl cellulose Plain 100g, 80g parts of Aspartame and sodium stearyl fumarate 30g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of the oral disnitegration tablet of embodiment 10 is the same as embodiment 9.
11 pharmaceutical composition oral disnitegration tablet of embodiment and preparation method
It is substantially the same manner as Example 9, the difference is that：
The formula of the oral disnitegration tablet of embodiment 11 is：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 70g gather Acrylic resin IV 300g, mannitol 1000g, croscarmellose sodium 35g, hydroxypropyl cellulose 40g, A Siba Sweet tea 50g, citric acid 50g and magnesium stearate 10g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of the oral disnitegration tablet of embodiment 11 is the same as embodiment 9.
12 pharmaceutical composition oral disnitegration tablet of embodiment and preparation method
It is substantially the same manner as Example 9, the difference is that：
The formula of the oral disnitegration tablet of embodiment 12 is：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g gather Acrylic resin IV 250g, algal polysaccharides 1000g, low-substituted hydroxypropyl cellulose 50g, hydroxypropyl cellulose 70g and hard Fatty acid magnesium 8g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of the oral disnitegration tablet of embodiment 12 is the same as embodiment 9.
13 pharmaceutical composition oral disnitegration tablet of embodiment and preparation method
It is substantially the same manner as Example 9, the difference is that：
The formula of the oral disnitegration tablet of embodiment 13 is：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, potassium chloride 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 70g gather Acrylic resin IV 150g, mannitol 800g, crospovidone 50g, povidone 40g, 3,4-Dihydro-6-methyl-1,2,3-oxathiazin-4-one 2,2-dioxide potassium salt 30g, citric acid 30g and Calcium stearate 10g.
Explanation：The purified water and ethyl alcohol that the present embodiment is added pass through preparation method, finally through being dried to obtain product, are added Purified water and ethyl alcohol all evaporate；
The preparation process of the oral disnitegration tablet of embodiment 13 is the same as embodiment 9.
Test example 3
The uniformity of dosage units, dissolution rate, disintegration time limited of the oral disnitegration tablet prepared by embodiment 9 to 13 are surveyed below It is fixed.
【Uniformity of dosage units】
Reserpine, Hydrochioro, promethazine hydrochloride, hydralazine hydrochloride, rutin, vitamin B1 and vitamin B6
It is protected from light operation.By the every content calculation measured under assay item, regulation should be met（CP2015 general rules 0941) 。
【Dissolution rate】
Hydrochioro and promethazine hydrochloride
It is protected from light operation.This product is taken, according to dissolution rate and drug release determination method（0,931 second method of CP2015 general rules）, with 0.lmol/L hydrochloric acid solutions 900ml is dissolution medium, and rotating speed is 50 turns per minute, operates in accordance with the law, when through 30 minutes, takes solution about 10ml is filtered with the miillpore filter in 0. 45 μm of apertures, takes subsequent filtrate as test solution；Another precision weighs Hydrochioro pair It is each appropriate according to product and promethazine hydrochloride reference substance, add under assay item diluent to dissolve and quantify dilution and be made in every lml and contains The solution of 1.7 μ g of Hydrochioro, 2.2 μ g of promethazine hydrochloride, as a contrast product solution.Precision measures test solution and reference substance Each 20 μ l of solution, except mobile phase is [0.06mol/L potassium dihydrogen phosphates-methanol（90 :10) (pH 3.0)]-acetonitrile (65 ：35) it outside, is measured according to method under " reserpine, Hydrochioro and promethazine hydrochloride " assay item, by external standard method in terms of peak area Calculate the stripping quantity of every middle Hydrochioro and promethazine hydrochloride.
【Disintegration time limited】
This product is taken, with reference to disintegration time limited inspection method（Chinese Pharmacopoeia four annex general rules 0921 of version in 2015）, by hanging basket It is hung on metallic support by the stainless steel shaft of upper end, when invading in 1000ml beakers, and adjusting hanging basket position and make its decline Sieve fills the water that temperature is 37 DEG C ± 1 DEG C away from beaker bottom 25mm in beaker, adjust sieve when height of water level makes hanging basket rise At the 15mm of underwater.It takes test sample 6, in the glass tube for setting above-mentioned hanging basket respectively, starts disintegration tester and checked, from tablet Start to start timing when contacting water, record particle passes through the time of sieve completely.Measurement result see the table below：
3 uniformity of dosage units of table, dissolution rate, disintegration time mensuration result
By to the uniformity of dosage units of compound reserpine orally disintegrating tablet preparation, dissolution rate, disintegration made from each embodiment The comprehensive analysis in time limit etc. shows that orally disintegrating tablet preparation disintegration produced by the present invention is rapid, and release is fast, is disintegrated in 30 seconds Completely, it can work in time, uniformity of dosage units and dissolution rate meet the requirement of 2015 editions Chinese Pharmacopoeias, improve original preparation Standard, complied with the compliance of hypertensive patient, and preparation process is suitble to industrialized requirement.
Test example 4 investigates influence of the present composition to pigeon nausea model
1, experimental animal：Healthy pigeon, male and female dual-purpose, 350 ± 50g of weight, regular grade are purchased from cultivation base.
2, experimental drug and dosage：
Healthy pigeon 70, is randomly divided into 7 groups.Adaptability is raised 1 week before experiment, and room temperature is kept for 22~24 DEG C, is kept Cleaning, well-ventilated, normal diet is drunk water during raising, fasting 4h before testing.Following each reagent group administration, dosage are pressed respectively Homogeneously it is same as 0.03mg reserpines（Rest activity components in certain proportion）The starch of/kg the weight of animals or same amount （Blank control）.The each index of close observation, normally feed water inlet after 8h.
(1) test group 1-3,3 groups, the respectively compound reserpine oral disnitegration tablet of embodiment 9,10 and 11, dosage be 0.03mg reserpines（Rest activity components in certain proportion）/ kg the weight of animals.
(2) control group A, in the mixture of active principles that the ratio of each active constituent in embodiment 9 is mixed to get, is given by 1 group Dose is 0.03mg reserpines（Rest activity components in certain proportion）/ kg the weight of animals.
(3) control group B, 1 group, starch, dosage is 44mg starch/kg the weight of animals.
(4) control group C, forms the physical mixture being mixed to get, dosage is by each raw material in embodiment 9 by 1 group 0.03mg reserpines（Rest activity components in certain proportion）/ kg the weight of animals.
(5) control group D, 1 group, commercially available reserpine similar tablet, manufacturer's Roche, dosage is 0.03mg reserpines （Rest activity components in certain proportion）/ kg the weight of animals.
3, experimental method：
Observation index：Vomiting incubation period occurs for pigeon（The time vomitted for the first time extremely occurs after showing medicine）, vomiting number （It shows and occurs per the number vomitted for a moment after medicine, stretch neck wherein a burst of vomiting refers to from pigeon, dehisce, shrug, abdomen contraction It restores calm to pigeon and is calculated as 1 vomiting）And vomiting frequency（Refer to pigeon in every gust of vomiting to stretch neck, dehisce, shrug, abdomen The number of contraction）.
By the above grouping every animal pharmaceuticals 0.03mg reserpine is given through gavage（Rest activity components in certain proportion）/ kg is dynamic Object weight records vomiting incubation period (min) after every animal gavage, while 5 hours recording every animal since the gavage Interior vomiting number and vomiting frequency.
In every group, there is the number of animals (n) vomitted in statistics, and (includes vomiting and the nothing of vomitus for there is vomiting The summation of the retch of vomitus) animal calculate their incubation period (min, ± s), average vomiting number and average vomiting frequency Rate.As a result it see the table below：
4 pigeon zoopery of table vomiting situation compares（± s, n=10）
By table 4 as it can be seen that the vomiting animals caused by the oral disnitegration tablet of the present invention are few, incubation period is long and vomiting number and Vomiting frequency is few.
It should be noted last that：Technical scheme of the present invention that the above embodiments are only illustrative and not limiting is any right The equivalent replacement and do not depart from the modification of spirit and scope of the invention or local replacement that the present invention carries out, should all cover in this hair Within bright protective scope of the claims.

Claims (9)

1. a kind of pharmaceutical composition for treating hypertension, which is characterized in that described pharmaceutical composition is by the original of following parts by weight Material is made：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 2-10 Part and other pharmaceutic adjuvants；Other described pharmaceutic adjuvants include filler, disintegrant, adhesive, lubricant, coating material and It is one or more in corrigent；
The filler is one in mannitol, lactose, sucrose, dextrin, starch, microcrystalline cellulose, algal polysaccharides and chitosan Kind is a variety of；
The disintegrant is sodium carboxymethyl starch, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose With it is one or more in calcium carboxymethylcellulose；
Described adhesive is Opadry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol and carboxymethyl cellulose It is one or more in plain sodium；
The lubricant is talcum powder, hydrogenated vegetable oil, superfine silica gel powder, sodium stearyl fumarate, calcium stearate, dodecyl sulphur It is one or more in sour sodium, magnesium stearate and stearyl alcohol；
The coating material is hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyacrylic resinⅣ, styrene-ethylene pyridine are total It is one or more in polymers and povidone；
The corrigent is one or more in Aspartame, 3,4-Dihydro-6-methyl-1,2,3-oxathiazin-4-one 2,2-dioxide potassium salt, saccharin sodium, glucan, Stevioside and citric acid.
2. it is according to claim 1 treatment hypertension pharmaceutical composition, which is characterized in that described pharmaceutical composition be by The raw material of following parts by weight is made：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 3-7 0.5-2 parts of part, 30-80 parts of filler, 2-5 parts of disintegrant, 3-10 parts of adhesive and lubricant.
3. the pharmaceutical composition for the treatment of hypertension according to claim 2, it is characterised in that：Described pharmaceutical composition be by The raw material of following parts by weight is made：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 4-6 Part, 60-70 parts of microcrystalline cellulose and/or lactose, 3-4 parts of croscarmellose sodium, 4-6 parts of hydroxypropyl cellulose with And 1-2 parts of superfine silica gel powder and/or magnesium stearate.
4. the pharmaceutical composition for the treatment of hypertension according to claim 3, it is characterised in that：Described pharmaceutical composition be by The raw material of following parts by weight is made：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6,5 parts of fumaric acid, 1 part of 61.3 parts of lactose, 3.6 parts of croscarmellose sodium, 5 parts of hydroxypropyl cellulose and magnesium stearate.
5. the pharmaceutical composition for the treatment of hypertension according to claim 1, it is characterised in that：Described pharmaceutical composition is made Oral disnitegration tablet or capsule, the oral disnitegration tablet are made of the raw material of following parts by weight：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 3-7 Part, 15-30 parts of polyacrylic resin IV, 30-150 parts of filler, 2-5 parts of disintegrant, 3-10 parts of adhesive, corrigent 0-8 parts and 0.5-2 parts of lubricant.
6. it is according to claim 5 treatment hypertension pharmaceutical composition, which is characterized in that the oral disnitegration tablet be by The raw material of following parts by weight is made：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6, fumaric acid 4-6 90-100 parts of part, 15-25 parts of polyacrylic resin IV, microcrystalline cellulose and/or mannitol, croscarmellose sodium 3-4 parts, 4-6 parts of hydroxypropyl cellulose, 4-6 parts of Aspartame and sodium stearyl fumarate and/or 1-2 parts of magnesium stearate.
7. the pharmaceutical composition for the treatment of hypertension according to claim 6, it is characterised in that：The oral disnitegration tablet be by The raw material of following parts by weight is made：
0.03 part of reserpine, 1 part of hydralazine hydrochloride, 0.025 part of Cyclopenthiazide, 1.5 parts of Hydrochioro, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, 5 parts of rutin, 2.5 parts of chloroquine diphosphate, 1 part of vitamin B1,1 part of vitamin B6,5 parts of fumaric acid, 20 parts of polyacrylic resin IV, 91.3 parts of mannitol, 3.6 parts of croscarmellose sodium, 5 parts of hydroxypropyl cellulose, 1 part of 5 parts of Aspartame and magnesium stearate.
8. the preparation method of the pharmaceutical composition for the treatment of hypertension according to claim 4, which is characterized in that including following Step：
（1）The raw material and weight of described pharmaceutical composition are as follows：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, lactose 613g, croscarmellose sodium 36g, hydroxypropyl cellulose 50g and magnesium stearate 10g；
（2）Utilize step（1）Process prepared by the raw material includes the following steps：
1. reserpine and Cyclopenthiazide are added in 95% ethyl alcohol of 1000ml first, hydroxypropyl is added to after clarifying in stirring and dissolving Base cellulose, stirs to clarify, and obtains reserve liquid；
2. by following raw material：Hydralazine hydrochloride, Hydrochioro, promethazine hydrochloride, potassium chloride, rutin, chloroquine diphosphate, vitamin B1, vitamin B6, fumaric acid, lactose and croscarmellose sodium crush, 80 mesh of sieving, respectively then by above-mentioned crushing Raw material afterwards after mixing, is added in fluidized bed granulation seed-coating machine by equal increments method, is preheated to 28 DEG C, adjusts stream temperature It is 100m to 40 DEG C, dry air flow3*h-1,
3. by peristaltic pump by above-mentioned reserve liquid in the way of top spray and in the flow pump fluidized bed granulator coater of 5ml/min Fluidized bed granulation seed-coating machine in spray chamber atomization granulation, atomizing pressure 1.2bar steps up and is pumped into flow velocity to 40ml/ Min is finished up to reserve liquid,
4. then improving stream temperature to 50 DEG C, taken out after continuing fluidized drying 45min in a fluidized bed,
5. choosing the particle less than 18 mesh, after passed examination, magnesium stearate is added, mixes 5min, tabletting, packaging.
9. the preparation method of the pharmaceutical composition for the treatment of hypertension according to claim 7, which is characterized in that including following Step：
(1) raw material of the oral disnitegration tablet and weight are as follows：
Reserpine 0.3g, hydralazine hydrochloride 10g, Cyclopenthiazide 0.25g, Hydrochioro 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, chloroquine diphosphate 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, polyacrylic acid Resin IV 200g, mannitol 913g, croscarmellose sodium 36g, hydroxypropyl cellulose 50g, Aspartame 50g Part and magnesium stearate 10g；
(2) step is utilized（1）Process prepared by the raw material includes the following steps：
1. reserpine and Cyclopenthiazide are added in 95% ethyl alcohol of 1000ml, it is fine that hydroxypropyl is added to after clarifying in stirring and dissolving Dimension element, stirs to clarify, obtains reserve liquid 1；
2. polyacrylic resin IV is added in 95% ethyl alcohol of 2000ml, stirring and dissolving obtains reserve liquid 2 to after clarifying；
3. by following raw material：Hydralazine hydrochloride, Hydrochioro, promethazine hydrochloride, potassium chloride, rutin, chloroquine diphosphate, vitamin B1, vitamin B6 and fumaric acid crush, 80 mesh of sieving, then mix the raw material after above-mentioned crushing by equal increments method respectively It after uniformly, is added in fluidized bed granulation seed-coating machine, is preheated to 28 DEG C, adjusting stream temperature to 40 DEG C, dry air flow is 100m3*h-1；
4. by peristaltic pump by reserve liquid 1 in the way of top spray and in the flow pump fluidized bed granulator coater of 5ml/min Spray chamber atomization granulation in fluidized bed granulation seed-coating machine, atomizing pressure 1.4bar are stepped up and are pumped into flow velocity to 40ml/ Min is finished up to reserve liquid 1,
5. continuing with the fluidized bed granulation that reserve liquid 2 is pumped into fluidized bed granulation seed-coating machine by peristaltic pump in a manner of top spray to be coated Spray chamber atomization granulation in machine, after improve stream temperature to 50 DEG C, continue to take after fluidized drying 45min in a fluidized bed Go out,
6. choosing the particle less than 18 mesh, after passed examination, mannitol, croscarmellose sodium, Aspartame is added, mixes After closing 30min, magnesium stearate is added, mixes 5min, tabletting, packaging.
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