CN105902564A - Pharmaceutical composition for treating hypertension and preparation method thereof - Google Patents

Pharmaceutical composition for treating hypertension and preparation method thereof Download PDF

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Publication number
CN105902564A
CN105902564A CN201610275594.6A CN201610275594A CN105902564A CN 105902564 A CN105902564 A CN 105902564A CN 201610275594 A CN201610275594 A CN 201610275594A CN 105902564 A CN105902564 A CN 105902564A
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parts
vitamin
pharmaceutical composition
reserpine
hydrochlorothiazide
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CN201610275594.6A
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CN105902564B (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 CN201510732841.6A external-priority patent/CN105213425A/en
Priority claimed from CN201510733431.3A external-priority patent/CN105193841A/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
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    • 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
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    • 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
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    • 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
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    • 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

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Abstract

The invention relates to a pharmaceutical composition for treating hypertension and a preparation method thereof and aims to overcome the defects of the preparation method of a compound reserpine composition. The compound reserpine pharmaceutical composition comprises various active components such as reserpine, hydrochlorothiazide, vitamin B6, potassium chloride and rutin. The prepared compound reserpine pharmaceutical composition has the advantages that the composition is small in toxic and side effects, quick in action and lasting in medicine effect, blood pressure fluctuation is small during blood pressure lowering, long-term treatment of a patient is facilitated, medicine use safety is increased, and medicine use compliance is improved; in addition, the dissolution difference of the compound reserpine pharmaceutical composition can be lowered evidently, and sample stability and batch-to-batch evenness can be increased.

Description

A kind of pharmaceutical composition treating hypertension and preparation method
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of pharmaceutical composition treating hypertension and preparation side Method.
Background technology
Reserpine is adrenergic neuron barrier antihypertensive, by exhausting the kidney of SNE around Upper parathyrine, catecholamine and 5-hydroxy tryptamine in the heart, brain and hetero-organization thereof reach resisting hypertension, decreased heart rate and suppression maincenter god Effect through system.It is widely used in the slight and treatment of moderate hypertension;Blood pressure lowering and tranquilizer, hypotensive effect onset is slow, but Persistent, after drug withdrawal, event resolves is also slow, has particularly share good effect with thiazide diuretic, has been conventional compound hypertension medicine One of main component.Hydralazine hydrochloride is vasodilator, alignment degree essential hypertension, and hydralazine merges application diuretic Good efficacy then can be obtained with beta-blocker.Cyclopenthiazide is middle effect diuretic, also has hypotensive effect, and medication is in early days Due to diuresis, reduce blood volume and blood pressure lowering, slightly lose sodium, the low sodium of small artery parietal cell in medication later stage body, pass through Na+-Ca2+Hand over The system of changing planes makes intracellular Ca2+Amount reduces, the blood vessel reactive reduction to vaso-excitor material, and causes vasodilation, blood pressure drops；This Product also have the hypotensive effect strengthening other depressor.Hydrochlorothiazide is thiazide diuretic, antihypertensive, closes with depressor Used time, hypotensive effect is substantially strengthened.By reserpine and vasodilator, diuretic use in conjunction has synergism significantly, promotees Enter blood pressure drops, improve curative effect, reduce dosage and the untoward reaction of each medicine；Additionally hydrochlorothiazide and cyclopenthiazide all can increase Reserpine and the hypotensive effect of hydralazine hydrochloride, reduce the side effect of water-sodium retention.Promethazine hydrochloride is antihistaminic, can compete Property block H1Receptor and produce antihistamine effect, there is maincenter sedation.Rutin belongs to vitamin drug, has reduction blood capillary Permeability and the effect of fragility, keep and recover the normal elasticity of blood capillary, is used for preventing and treating hypertensive cerebral hemorrhage, can effectively press down Make hematoblastic gathering, prevent thrombotic effect.
Fumaric acid is simplest unsaturated dicarboxylic acid, also known as Fumaric acid, finds the earliest from Rhizoma Corydalis, frequently as A kind of food additive acidic flavoring agent, for refreshment drink, Fruit candy, fruit jelly, ice cream etc., also uses frequently as pharmaceutic adjuvant In pharmaceutical industry, can be as acidity regulator, antioxidation auxiliary agent etc..According to MD INDIA website, fumarate is used for always Treatment severe psoriasis.Nowadays, it was discovered by researchers that this medicine may also help in prevents multiple sclerosis (MS).This Research is published on current neurological's magazine " Brain ".Now, the neurosurgeon of Bo Hong Rule university (RUB) finds, rich Horse hydrochlorate discharges free radical in removing inflammatory process, thus protects nerve and glial cell.
Compound recipe reserpine compositions is typically by reserpine, hydrochlorothiazide, vitamin B6, potassium chloride, vitamin B1, hydrazine bend The compound preparation of the Multiple components such as piperazine, promethazine hydrochloride composition, such compound preparation has been applied For many years, effectiveness and safety have been obtained for sufficiently verifying.But owing to prescription existing vitamin B6, vitamin B1, hydrazine bend Piperazine, rutin etc., less stable, easily it is affected by the external environment (such as temperature, illumination, oxygen etc.) and changes, medicament contg Reduce.There is research worker to be studied for compound recipe reserpine composition medicine unstability situation, but the result obtained is past Past is barely satisfactory.
The Chinese patent application of application number CN201110369547 uses addition acidic materials dihydric phosphate to remain multiple The stability of effective ingredient in side's Reserpoid, but through attempting, although this inorganic acidic materials can improve vitamin B6And vitamin B1Stability, but the stability of hydralazine and rutin is improved helpless.Application number The Chinese patent application of CN201210455548 uses vitamin B1The mode being coated is to improve vitamin B1Stability, But really to unstability active component vitamin B6, hydralazine, rutin etc. do not consider, simultaneously to vitamin B1It is coated also Add processing step flow process, add substantial amounts of work.
In terms of the treatment of hypertension, the fluctuation of blood pressure in the pressure reduction of hypertension of conventional buck medicine is big, medicine Therapeutic effect is poor, and side effect is big, and onset time is long, and duration of efficacy is short.It addition, in compound recipe reserpine composite formula, bag Include reserpine and cyclopenthiazide medicament contg is extremely low, poor more than 30 times with the active component of other lower contents, higher with other Thousands of times of the active component difference of content, easily causes the medicament contg uniformity against regulation, by suitable method, improves and lives The medicament contg uniformity of property composition obtains each index the most satisfactory compound recipe reserpine composite preparation.
Summary of the invention
The present invention is directed to the defect that compound recipe reserpine composite formula traditional preparation methods exists, it is provided that one comprises profit blood Flat, hydrochlorothiazide, vitamin B6, potassium chloride, a kind of compound recipe reserpine medicine treating hypertension of the various active composition such as rutin Compositions and preparation method.Compound recipe reserpine drug combination preparation toxic and side effects prepared by the present invention is few, in pressure reduction Fluctuation of blood pressure is little, and onset time is short, and duration of efficacy is long, it is simple to patient's long-term treatment, improves drug safety, and improves The compliance of medication；Meanwhile, the present invention can significantly reduce compound recipe reserpine drug combination preparation dissolution diversity, and carries The stability of high sample and batch between uniformity.
The technical scheme is that
A kind of pharmaceutical composition treating hypertension, described pharmaceutical composition is made up of the raw material of following weight portion:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 2-10 Part and pharmaceutic adjuvant.
The pharmaceutical composition of above-mentioned treatment hypertension, described pharmaceutic adjuvant comprises filler, disintegrating agent, binding agent, profit One or more in lubrication prescription, coating material and correctives；
Described filler is in mannitol, lactose, sucrose, dextrin, starch, microcrystalline Cellulose, Sargassum polysaccharides and chitosan Plant or multiple；
Described disintegrating agent is carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose With one or more in carboxymethylcellulose calcium；
Described binding agent is Opadry, hypromellose, hydroxypropyl cellulose, polyvidone, polyvinyl alcohol and carboxymethyl cellulose One or more in element sodium；
Described lubricant is Pulvis Talci, hydrogenated vegetable oil, micropowder silica gel, sodium stearyl fumarate, calcium stearate, dodecyl sulfur One or more in acid sodium, magnesium stearate and stearyl alcohol；
Described coating material is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resin IV, styrene-ethylene pyridine One or more in copolymer and polyvinylpyrrolidone；
Described correctives is the essence perfume of aspartame, acesulfame potassium, saccharin sodium, glucosan, stevioside, citric acid, various fragrance One or more of material.
The pharmaceutical composition of above-mentioned treatment hypertension, described pharmaceutical composition is made up of the raw material of following weight portion:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 3-7 Part, filler 30-80 part, disintegrating agent 2-5 part, binding agent 3-10 part and lubricant 0.5-2 part.
The pharmaceutical composition of above-mentioned treatment hypertension, described pharmaceutical composition is made up of the raw material of following weight portion:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 4-6 Part, microcrystalline Cellulose and/or lactose 60-70 part, microcrystalline Cellulose and lactose can mix with arbitrary proportion, cross-linked carboxymethyl Sodium cellulosate 3-4 part, hydroxypropyl cellulose 4-6 part and micropowder silica gel and/or magnesium stearate 1-2 part, micropowder silica gel is with hard Fatty acid magnesium can mix with arbitrary proportion.
The pharmaceutical composition of above-mentioned treatment hypertension, described pharmaceutical composition is made up of the raw material of following weight portion:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 5 parts, Lactose 61.3 parts, cross-linking sodium carboxymethyl cellulose 3.6 parts, hydroxypropyl cellulose 5 parts and magnesium stearate 1 part.
The pharmaceutical composition of above-mentioned treatment hypertension, described pharmaceutical composition makes tablet or capsule, such as oral cavity Disintegrating tablet.
The pharmaceutical composition of above-mentioned treatment hypertension, described oral cavity disintegration tablet is made up of the raw material of following weight portion:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 3-7 Part, polyacrylic resin IV 15-30 part, filler 30-150 part, disintegrating agent 2-5 part, binding agent 3-10 part, correctives 0-8 part and lubricant 0.5-2 part.
The pharmaceutical composition of above-mentioned treatment hypertension, described filler preferably microcrystalline cellulose and/or mannitol, disintegrate The preferred cross-linking sodium carboxymethyl cellulose of agent, the preferred hydroxypropyl cellulose of binding agent, the preferred aspartame of correctives, lubricant is preferred Sodium stearyl fumarate and/or magnesium stearate.
The pharmaceutical composition of above-mentioned treatment hypertension, described oral cavity disintegration tablet is made up of the raw material of following weight portion:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 4-6 Part, polyacrylic resin IV 15-25 part, microcrystalline Cellulose and/or mannitol 90-100 part, microcrystalline Cellulose and mannitol can With with arbitrary proportion mix, cross-linking sodium carboxymethyl cellulose 3-4 part, hydroxypropyl cellulose 4-6 part, aspartame 4-6 part with And sodium stearyl fumarate and/or magnesium stearate 1-2 part, sodium stearyl fumarate and magnesium stearate can mix with arbitrary proportion Close.
The pharmaceutical composition of above-mentioned treatment hypertension, described oral cavity disintegration tablet is made up of the raw material of following weight portion:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 5 parts, Polyacrylic resin IV 20 parts, 91.3 parts of mannitol, cross-linking sodium carboxymethyl cellulose 3.6 parts, hydroxypropyl cellulose 5 parts, Aspartame 5 parts and magnesium stearate 1 part.
The preparation method of the pharmaceutical composition of above-mentioned treatment hypertension, first by reserpine by weight ratio, ring penta Thiazine and hydroxypropyl cellulose are dissolved in ethanol, and remaining pharmaceutic adjuvant in addition to lubricant adds in fluidized bed granulation seed-coating machine, Spraying into after above-mentioned ethanol solution pelletizes after fluidisation mixing, dry, it is uniform to add mix lubricant after granulate, tabletting and get final product；
(1) raw material and the weight of described pharmaceutical composition are as follows:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, lactose 613g, cross-linking sodium carboxymethyl cellulose 36g, hydroxypropyl cellulose 50g and magnesium stearate 10g.
(2) process utilizing the raw material described in step (1) to be prepared comprises the following steps:
First reserpine and cyclopenthiazide are added in 95% ethanol of 1000ml, after stirring and dissolving to clarification, add hydroxypropyl Base cellulose, stirs to clarify, and obtains reserve liquid；
2. by following raw material: hydralazine hydrochloride, hydrochlorothiazide, promethazine hydrochloride, potassium chloride, rutin, Arechin (Polfa), vitamin B1, vitamin B6, fumaric acid, lactose and cross-linking sodium carboxymethyl cellulose, pulverize, sieve 80 mesh, then by above-mentioned pulverizing respectively After raw material press equal increments method mix homogeneously after, add in fluidized bed granulation seed-coating machine, be preheated to 28 DEG C, fluidized coating technique In, granule needs first to preheat, and preheating temperature is debugged according to the production capacity of coating solvent and fluid bed, regulation fluidisation Temperature to 40 DEG C, dry air flow be 100m3*h-1,
3. utilize peristaltic pump by above-mentioned reserve liquid with in the granulating coated machine of flow pump fluidized bed of top spray mode and 5ml/min Aerochamber atomization pelletize, atomizing pressure is 1.2bar, steps up and pumps into flow velocity to 40ml/min until reserve liquid is finished,
The most then raising stream temperature is to 50 DEG C, continues to take out after fluidized drying 45min in fluid bed,
5. cross 18 mesh pharmacopeia sieves, take the granule less than 18 mesh, use the content of each active component of high effective liquid chromatography for measuring, symbol After closing intermediate quality standard, add magnesium stearate, mix 5min, tabletting, pack.
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 ethanol, and rest activity composition and fumaric acid add in fluidized bed granulation seed-coating machine, after fluidisation mixing Spray into above-mentioned ethanol solution to pelletize, after completing, spray into the ethanol solution of polyacrylic resin IV, terminate post-drying, add after granulate Filler, disintegrating agent, correctives and mix lubricant are uniform, tabletting and get final product；
(1) raw material and the weight of described oral cavity disintegration tablet are as follows:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, polyacrylic acid Resin IV 200g, mannitol 913g, cross-linking sodium carboxymethyl cellulose 36g, hydroxypropyl cellulose 50g, aspartame 50g Part and magnesium stearate 10g；
(2) process utilizing the raw material described in step (1) to be prepared comprises the following steps:
1. reserpine and cyclopenthiazide are added in 95% ethanol of 1000ml, after stirring and dissolving to clarification, add hydroxypropyl fine Dimension element, stirs to clarify, obtains reserve liquid 1；
2. polyacrylic resin IV is added in 95% ethanol of 2000ml, after stirring and dissolving to clarification, obtain reserve liquid 2；
3. by following raw material: hydralazine hydrochloride, hydrochlorothiazide, promethazine hydrochloride, potassium chloride, rutin, Arechin (Polfa), vitamin B1, vitamin B6 and fumaric acid, pulverize, sieve 80 mesh respectively, and then the raw material after above-mentioned pulverizing is pressed the mixing of equal increments method After Jun Yun, adding in fluidized bed granulation seed-coating machine, be preheated to 28 DEG C, in fluidized coating technique, granule needs first to preheat, in advance Hot temperature is debugged according to the production capacity of coating solvent and fluid bed, and regulation stream temperature is to 40 DEG C, dry air flow For 100m3*h-1；
4. utilize peristaltic pump by reserve liquid 1 with in the granulating coated machine of flow pump fluidized bed of top spray mode and 5ml/min Aerochamber atomization is pelletized, and atomizing pressure is 1.4bar, steps up and pumps into flow velocity to 40ml/min until reserve liquid 1 is finished,
5. the aerochamber atomization system that reserve liquid 2 is pumped in fluidized bed granulation seed-coating machine in top spray mode by peristaltic pump is continued with Grain, with step 4., when fluidized coating and granulation, flow velocity to adjust at any time the control mode of flow velocity according to fluidized state, in order to avoid going out Existing electrostatic the phenomenon such as granule adhesive aggregation, improve stream temperature after terminating to 50 DEG C, continue in fluid bed after fluidized drying 45min Take out,
6. cross 18 mesh pharmacopeia sieves, take the granule less than 18 mesh, use the content of each active component of high effective liquid chromatography for measuring, symbol After closing intermediate quality standard, add mannitol, cross-linking sodium carboxymethyl cellulose, aspartame, after mixing 30min, add hard Fatty acid magnesium, mixes 5min, tabletting, packs.
Beneficial effects of the present invention:
(1) drug combination preparation utilizing technical scheme to prepare solve hydralazine hydrochloride in composite formula, The problem of the chemically unstables such as rutin, vitamin B1 and vitamin B6, improves the stability of composite preparation, reduces poison secondary Effect, ensure that quality and curative effect simultaneously；Improve the standard of original pharmaceutical preparation, comply with the compliance of hyperpietic, And preparation technology is suitable for the requirement of industrialized production.The present invention verifies through lot of experiments, increases appropriate in the composition Fumaric acid, make to create between fumaric acid and active substance synergism, significantly improve curative effect and this pharmaceutical composition Stability.
(2) the drug combination preparation toxic and side effects utilizing technical scheme to prepare is few, blood pressure in pressure reduction Fluctuating little, onset time is short, and duration of efficacy is long, it is simple to patient's long-term treatment, improves drug safety.The present invention is simultaneously Have employed new recipe and new technology prepares this 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 impact of gastric emptying change, absorption in vivo in vivo There is good repeatability, can avoid may causing the risk of medicine pulse due to uniformity of dosage units and dissolution difference, reduce Weakness, weakness, confusion, hypotension, dizziness, heart block may be caused due to medicine pulse, even draw Play death, improve drug safety.
(3) drug combination preparation utilizing technical scheme to prepare solve reserpine, cyclopenthiazide etc. because of Content is seldom not easy the problem of mix homogeneously, and production technology uses totally-enclosed fluidized bed granulation technique, decreases pollution, simultaneously Decrease and water, light, the contacting of thermal source, it is to avoid the influencing each other of chemical drugs in formula, ensure that the matter of product Amount and curative effect.Selected raw material is all easy to get feasible with preparation method, suitably expands industrialized production, and the method used has Good repeatability.The most currently preferred formula and preparation method, be the preferred plan obtained through screening, select excellent The prescription changed, uses fluidized bed granulation method to prepare drug combination preparation, can realize the release performance that this dosage form is the best.
(4) utilize drug combination preparation prepared by technical solution of the present invention, show, in hypertension through preliminary test research Pressure reduction in fluctuation of blood pressure less, improve the therapeutic effect of medicine, extend duration of efficacy, reduce gastrointestinal tract Stimulation and blood plasma drug concentration peak value, reduce the possibility that has side effects, improve the compliance of patient medication.The present invention Product drug combination preparation, preparation process is simple for process, use fluidized bed granulation technique, solve uniformity of dosage units and The problems such as poor stability and corresponding patient's compliance, fluidized bed granulation technique and tablet forming technique combine, and meet big production Requirement, production efficiency is high.Utilize oral cavity disintegration tablet prepared by technical solution of the present invention, use fluidized bed powder coating method and pressure Blade technolgy, productivity reaches more than 95%, and can prepare the oral cavity disintegration tablet of multiple different size；Meanwhile, the present invention prepares gained Oral cavity disintegration tablet disintegration time within 30 seconds, hardness reaches more than 40N, is conducive to packaging, transport and the carrying of patient.
(5) the dissolution feature relatively prior art utilizing drug combination preparation prepared by technical scheme has significantly Ground improves, and bioavailability is high, and individual variation is little；The solid composition preparation prepared has preferably uniformity of dosage units with preferable Stability, prepared drug combination preparation uniformity of dosage units and dissolution all meet the requirement of 2015 editions Chinese Pharmacopoeias.Logical Spend oral cavity disintegration tablet dissolution and disintegration etc. to evaluate, find that the drug port cavity disintegrating tablet dissolution that the present invention provides is rapid, collapse The solution time is short, has greatly complied with the pathological characteristic of aged patients with hypertension.
(6) utilize drug port cavity disintegrating tablet taking convenience prepared by technical solution of the present invention, have no side effect, in good taste, Without grittiness, it is simple to patient's long-term treatment, greatly comply with the pathological characteristic of hyperpietic, it is adaptable to hyperpietic is outstanding It is the treatment of aged patients with hypertension of dysphagia.The orally disintegrating tablet preparation utilizing technical solution of the present invention to prepare solves In Orally disintegrating slice prescription there is the problem of chemically unstable in hydralazine hydrochloride, rutin, vitamin B1 and vitamin B6 etc., carries The high stability of orally disintegrating tablet preparation, reduces toxic and side effects, ensure that quality and curative effect simultaneously；Improve original medicine The standard of preparation, has complied with the compliance of hyperpietic, and preparation technology has been suitable for industrialized requirement.
(7) it is different that the drug port cavity disintegrating tablet that prepared by technical solution of the present invention has bitterness for active constituents of medicine etc. Taste is obviously improved performance, and it improves the powder coating taste masking and taste masking technology used time prepared by the mouthfeel principle predominantly present invention, Selected adjuvant is all easy to get feasible with preparation method, suitably expands industrialized production, has good repeatability.Particularly originally Invent preferred formula and preparation method, be the preferred plan obtained through screening, select the prescription optimized, use fluid bed powder End coating method, and pressed disc method prepares oral cavity disintegration tablet, can realize the obvious mouthfeel of oral cavity disintegration tablet and improve effect.
Detailed description of the invention
Being below the detailed description of the invention of the present invention, embodiment is for further describing the present invention rather than limiting this Bright.All and present invention equivalence technical scheme belongs to protection scope of the present invention.
Embodiment 1 medicinal composition tablets and preparation method
First reserpine, cyclopenthiazide and hydroxypropyl cellulose being dissolved in ethanol, remaining adjuvant in addition to lubricant adds fluidisation In the granulating coated machine of bed, after spraying into the granulation of above-mentioned ethanol solution after fluidisation mixing, dry, add mix lubricant after granulate equal Even, tabletting and get final product.
(1) composite formula
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, lactose 613g, cross-linking sodium carboxymethyl cellulose 36g, hydroxypropyl cellulose 50g and magnesium stearate 10g.
(2) weighing above-mentioned raw materials according to step (1), preparation process is as follows
First reserpine and cyclopenthiazide are added in 95% ethanol of 1000ml, after stirring and dissolving to clarification, add hydroxypropyl Base cellulose, stirs to clarify, and obtains reserve liquid；
2. by following raw material: hydralazine hydrochloride, hydrochlorothiazide, promethazine hydrochloride, potassium chloride, rutin, Arechin (Polfa), vitamin B1, vitamin B6, fumaric acid, lactose and cross-linking sodium carboxymethyl cellulose, pulverize, sieve 80 mesh, then by above-mentioned pulverizing respectively After raw material press equal increments method mix homogeneously after, add in fluidized bed granulation seed-coating machine, preheating, regulation stream temperature is to 40 DEG C, dry air flow be 100m3*h-1；
3. utilize peristaltic pump by above-mentioned reserve liquid with in the granulating coated machine of flow pump fluidized bed of top spray mode and 5ml/min Aerochamber atomization pelletize, atomizing pressure is 1.2bar, steps up and pumps into flow velocity to 40ml/min until reserve liquid is finished；
The most then raising stream temperature is to 50 DEG C, continues to take out after fluidized drying 45min in fluid bed；
5. choose the granule less than 18 mesh, after passed examination, add magnesium stearate, mix 5min, tabletting, pack.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
Embodiment 2 medicinal composition tablets and preparation method
Substantially the same manner as Example 1, difference is:
The composite formula of embodiment 2 is:
Reserpine 0.6g, hydralazine hydrochloride 20g, cyclopenthiazide 0.5g, hydrochlorothiazide 30g, promethazine hydrochloride 40g, chlorination Potassium 600g, rutin 100g, Arechin (Polfa) 50g, vitamin B1 20g, vitamin B6 20g, fumaric acid 120g, lactose 1300g, cross-linking sodium carboxymethyl cellulose 70g, hydroxypropyl cellulose 100g, magnesium stearate 30g.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of the compositions of embodiment 2 is with embodiment 1.
Embodiment 3 medicinal composition tablets and preparation method
Substantially the same manner as Example 1, difference is:
The composite formula of embodiment 3 is:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, lactose 315g, microcrystalline Cellulose 315g, cross-linking sodium carboxymethyl cellulose 35g, hydroxypropyl cellulose 50g, micropowder silica gel 5g are with hard Fatty acid magnesium 10g.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of the compositions of embodiment 3 is with embodiment 1.
Embodiment 4 medicinal composition tablets and preparation method
Substantially the same manner as Example 1, difference is:
The composite formula of embodiment 4 is:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 70g, lactose 450g, microcrystalline Cellulose 225g, polyvinylpolypyrrolidone 45g, hydroxypropyl cellulose 75g and sodium stearyl fumarate 15g.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of the compositions of embodiment 4 is with embodiment 1.
Embodiment 5 medicinal composition tablets and preparation method
Substantially the same manner as Example 1, difference is:
The composite formula of embodiment 5 is:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, starch 240g, DEXTRIN 0 g and magnesium stearate 10g.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of the compositions of embodiment 5 is with embodiment 1.
Embodiment 6 medicament composition capsule agent and preparation method
First reserpine, cyclopenthiazide and hydroxypropyl cellulose being dissolved in ethanol, remaining adjuvant in addition to lubricant adds fluidisation In the granulating coated machine of bed, after spraying into the granulation of above-mentioned ethanol solution after fluidisation mixing, dry, add mix lubricant after granulate equal Even, load capsule and get final product.
(1) composite formula
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, lactose 613g, cross-linking sodium carboxymethyl cellulose 36g, hydroxypropyl cellulose 50g and magnesium stearate 10g.
(2) weighing above-mentioned raw materials according to step (1), preparation process is as follows
First reserpine and cyclopenthiazide are added in 95% ethanol of 1000ml, after stirring and dissolving to clarification, add hydroxypropyl Base cellulose, stirs to clarify, and obtains reserve liquid；
2. by following raw material: hydralazine hydrochloride, hydrochlorothiazide, promethazine hydrochloride, potassium chloride, rutin, Arechin (Polfa), vitamin B1, vitamin B6, fumaric acid, lactose and cross-linking sodium carboxymethyl cellulose, pulverize, sieve 80 mesh, then by above-mentioned pulverizing respectively After raw material press equal increments method mix homogeneously after, add in fluidized bed granulation seed-coating machine, preheating, regulation stream temperature is to 40 DEG C, dry air flow be 100m3*h-1；
3. utilize peristaltic pump by above-mentioned reserve liquid with in the granulating coated machine of flow pump fluidized bed of top spray mode and 5ml/min Aerochamber atomization pelletize, atomizing pressure is 1.2bar, steps up and pumps into flow velocity to 40ml/min until reserve liquid is finished；
The most then raising stream temperature is to 50 DEG C, continues to take out after fluidized drying 45min in fluid bed；
5. choose the granule less than 18 mesh, after passed examination, add magnesium stearate, mix 5min, load capsule, pack.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate.
Embodiment 7 medicament composition capsule agent and preparation method
Substantially the same manner as Example 1, difference is:
The composite formula of embodiment 7 is:
Reserpine 0.6g, hydralazine hydrochloride 20g, cyclopenthiazide 0.5g, hydrochlorothiazide 30g, promethazine hydrochloride 40g, chlorination Potassium 600g, rutin 100g, Arechin (Polfa) 50g, vitamin B1 20g, vitamin B6 20g, fumaric acid 120g, lactose 1300g, cross-linking sodium carboxymethyl cellulose 70g, hydroxypropyl cellulose 100g, magnesium stearate 30g.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of embodiment 7 composition capsule is with embodiment 6.
Embodiment 8 medicament composition capsule agent and preparation method
Substantially the same manner as Example 1, difference is:
The composite formula of embodiment 8 is:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, starch 240g, DEXTRIN 0 g and magnesium stearate 10g.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of embodiment 8 composition capsule is with embodiment 6.
Test example 1 compatibility test
By following active component: reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 Part, promethazine hydrochloride 2 parts, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 Part, seven parts of samples of preparation according to the above ratio, will wherein five parts of samples respectively with potassium dihydrogen phosphate, sodium dihydrogen phosphate, citric acid, wine Stone acid, fumaric acid pelletizes according to after the ratio mix homogeneously of 1:5 (w/w), and a sample and fumaric acid are according to the ratio of 1:10 (w/w) Pelletize after example mix homogeneously, pelletize after remaining a uniformly mixing, prepared granule is respectively charged in uncovered bottle, more Place 10 days under exacting terms (60 DEG C of high temperature, 90%RH high humidity and 4500lx high light), took respectively at the 5th day and the 10th day Sample, investigating the leading indicator such as sample property, content has unchanged, and result is compared with 0 day, and result of the test is shown in Table 1.
[assay] lucifuge operates.
Reserpine, hydrochlorothiazide measure according to high performance liquid chromatography (general rule CP2015 0512) with promethazine hydrochloride.
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler；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 and is not less than 3000, separates between each main peak with other chromatographic peaks Degree should meet the requirements.
Algoscopy takes this product 10, puts respectively in 25mL measuring bottle, add diluent [sodium acetate solution (take sodium acetate 9.0 g, The 1000mL that adds water makes dissolving, adds triethylamine 3.0mL, by glacial acetic acid regulation pH value to 5.0)-acetonitrile (55:45)] ultrasonic make dissolving And it is diluted to scale, and shaking up, filter, take subsequent filtrate as need testing solution, precision measures 20 μ L and notes people's chromatograph of liquid, record Chromatogram；Separately take reserpine reference substance, hydrochlorothiazide reference substance and promethazine hydrochloride reference substance each in right amount, accurately weighed, add dilute Release agent dissolve and quantitatively dilution to make Esidri 1.2 μ g in every lmL, hydrochlorothiazide 60 μ g molten with promethazine hydrochloride 80 μ g's Liquid, is measured in the same method.The content of each component in going out every by external standard method with calculated by peak area, and obtain the average of each component in 10 Content, to obtain final product.
Hydralazine hydrochloride, vitamin B1With vitamin B6According to high performance liquid chromatography, (CP2015 general rule 0512 ＞ measures
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler；With buffer, (0.11% is own Alkyl sulfonic acid sodium, 0. 02% sodium heptanesulfonate mixed solution, by glacial acetic acid regulation pH value to 3.5)-acetonitrile-methanol (80:10: 10) for flowing phase;Detection wavelength is 210nm.Number of theoretical plate is calculated by hydralazine hydrochloride peak and is not less than 3000；Between each chromatographic peak Separating degree should meet the requirements.
Algoscopy takes this product 10, adds 0.1% phosphoric acid solution respectively appropriate, grinds, is transferred in 100mL measuring bottle, shaking 30 minutes, it is diluted to scale with 0.1% phosphoric acid solution, shakes up, centrifugal, take supernatant as need testing solution, precision measures 20 μ L injects chromatograph of liquid, records chromatogram；Another precision weighs hydralazine hydrochloride reference substance, vitamin B1Reference substance and vitamin B6 Reference substance is each in right amount, add 0.1% phosphoric acid solution dissolve and quantitatively dilution make hydrochloric hydralazine 10 μ g, vitamin B in every lmL1 10 μ g and vitamin Bs6 The solution of 10 μ g, is measured in the same method.The content of each component in going out every by external standard method with calculated by peak area, and Obtain the average content of each component in 10, to obtain final product.
Rutin is according to high performance liquid chromatography (CP2015 general rule 0512 ＞
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler；With methanol-0.2mol/L vinegar Acid (40:60) is flowing phase；Flow velocity 1.0mL/min；Detection wavelength is 355nm.Number of theoretical plate is calculated by rutin and is not less than 3000； Separating degree between each chromatographic peak should meet the requirements.
Algoscopy takes this product 10 respectively, finely ground, puts in 100mL measuring bottle, adds flowing and makes dissolving mutually, filters, and takes continuous filter Liquid, precision measures 10ml flowing phase dilution to 100mL.Shake up, filter, take subsequent filtrate and measure as need testing solution, precision 20 μ L note people's chromatograph of liquid, record chromatogram；It is appropriate that another precision weighs control substance of Rutin, adds flowing phased soln and quantitatively dilutes Make the solution containing rutin 5 μ g in every lmL, be measured in the same method.Go out the content of every middle rutin with calculated by peak area by external standard method, and Obtain the average content of 10 middle rutins, to obtain final product.
Table 1 compatibility test result
From the compatibility test result of table 1 it can be seen that add fumaric acid (1:5, w/w) each activity mixture of active principles The raising the most in various degree of the stability of composition, when adding fumaric acid (1:10, w/w), vitamin B1, vitamin B6 and rutin Stability obtained further raising, but the stability of hydralazine hydrochloride does not rise anti-fall；Report relative to remaining document Acidic materials such as potassium dihydrogen phosphates etc., fumaric acid has clear superiority to the raising of compositions stability.
Test example 2 uniformity of dosage units and dissolution determination
[uniformity of dosage units]
Reserpine, hydrochlorothiazide, promethazine hydrochloride, hydralazine hydrochloride, rutin, vitamin B1With vitamin B6
Lucifuge operates.By the every cubage recorded under assay item, regulation (2015 editions general rules of Chinese Pharmacopoeia should be met 0941) .Measurement result is shown in Table 2 uniformity of dosage units and dissolution determination result.
[dissolution]
Hydrochlorothiazide and promethazine hydrochloride
Lucifuge operates.Take this product, according to dissolution and drug release determination method (Chinese Pharmacopoeia 2015 editions general rules 0,931 second method), with 0.lmol/L hydrochloric acid solution 900mL is dissolution medium, and rotating speed is 50 turns per minute, operates in accordance with the law, through 30 minutes time, takes solution about 10mL, filters with the microporous filter membrane in 0. 45 μm apertures, takes subsequent filtrate as need testing solution；Another precision weighs hydrochlorothiazide pair Each in right amount according to product and promethazine hydrochloride reference substance, add under assay item diluent and dissolve and quantitatively dilution is made in every lmL and contained Hydrochlorothiazide 1.7 μ g, the solution of promethazine hydrochloride 2.2 μ g, as reference substance solution.Precision measures need testing solution and reference substance The each 20 μ L of solution, except flowing is [0.06mol/L potassium dihydrogen phosphate-methanol (90: 10) (pH 3.0)]-acetonitrile (65 mutually : 35) outward, measure according to method under " reserpine, hydrochlorothiazide and promethazine hydrochloride " assay item, by external standard method in terms of peak area Calculate every middle hydrochlorothiazide and the stripping quantity of promethazine hydrochloride.
Measurement result see table:
Table 2 uniformity of dosage units and dissolution determination result
By the uniformity of dosage units of compound recipe reserpine composite preparation that each embodiment is prepared, the summary analysis of dissolution Bright, composite preparation uniformity of dosage units that the present invention prepares and dissolution all meet the requirement of 2015 editions Chinese Pharmacopoeias, improve The standard of original preparation, has complied with the compliance of hyperpietic, and preparation technology has been suitable for industrialized requirement.
Oral cavity disintegration tablet refers to that one disintegrate can become countless microgranule and sweet mouthfeel in being placed on lingual surface upper 30 second automatically New medicinal preparation.Owing to its disintegration rate is fast, it is rapid to absorb, and need not use water delivery service when taking medicine, saliva can make it collapse Solve or dissolve, both can swallow by conventional tablet, and can be placed in water again and take after disintegrate, and also can be not required to take medicine, especially with water swallow It is applicable to old man, children's, some especial patients (psychosis, senile dementia, epileptic patient etc.) and water intaking inconvenience person take medicine and carry Supply convenience.Certain method can be used in the preparation to improve the mouthfeel of preparation simultaneously, be greatly improved taking medicine of child patient Compliance, solves the problem that taking baby ' is difficult.Below in conjunction with specific embodiment, technical scheme is applied to oral cavity Disintegrating tablet is made and being illustrated.
Embodiment 9 pharmaceutical composition oral cavity disintegration tablet and preparation method
First reserpine, cyclopenthiazide and hydroxypropyl cellulose being dissolved in ethanol, remaining adjuvant in addition to lubricant adds fluidisation In the granulating coated machine of bed, after spraying into the granulation of above-mentioned ethanol solution after fluidisation mixing, dry, add mix lubricant after granulate equal Even, tabletting and get final product.
(1) composite formula
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, polyacrylic acid Resin IV 200g, mannitol 913g, cross-linking sodium carboxymethyl cellulose 36g, hydroxypropyl cellulose 50g, aspartame 50g part With magnesium stearate 10g.
(2) weighing above-mentioned raw materials according to step (1), preparation process is as follows
1. reserpine and cyclopenthiazide are added in 95% ethanol of 1000ml, after stirring and dissolving to clarification, add hydroxypropyl fine Dimension element, stirs to clarify, obtains reserve liquid 1；
2. polyacrylic resin IV is added in 95% ethanol of 2000ml, after stirring and dissolving to clarification, obtain reserve liquid 2；
3. by following raw material: hydralazine hydrochloride, hydrochlorothiazide, promethazine hydrochloride, potassium chloride, rutin, Arechin (Polfa), vitamin B1, vitamin B6 and fumaric acid, pulverize, sieve 80 mesh respectively, and then the raw material after above-mentioned pulverizing is pressed the mixing of equal increments method After Jun Yun, add in fluidized bed granulation seed-coating machine, be preheated to 28 DEG C, regulation stream temperature to 40 DEG C, dry air flow be 100m3*h-1；
4. utilize peristaltic pump by reserve liquid 1 with in the granulating coated machine of flow pump fluidized bed of top spray mode and 5ml/min Aerochamber atomization is pelletized, and atomizing pressure is 1.4bar, steps up and pumps into flow velocity to 40ml/min until reserve liquid 1 is finished,
5. the aerochamber atomization granulation that reserve liquid 2 is pumped in fluidized bed granulation seed-coating machine in top spray mode by peristaltic pump is continued with (flow velocity 5 ~ 40ml/min), after terminating, raising stream temperature is to 50 DEG C, continues to take out after fluidized drying 45min in fluid bed,
6. granule crosses 18 mesh pharmacopeia sieves, takes the granule less than 18 mesh, uses containing of each active component of high effective liquid chromatography for measuring Amount, after meeting intermediate quality standard, adds filler, disintegrating agent, correctives, after mixing 30min, adds lubricant, mixing 5min, tabletting, pack.The oral cavity disintegration tablet pressure of gained is at more than 40N, in the intraoral disintegration time within 30 seconds, And without bitter.
Illustrate: the purified water of the present embodiment addition and ethanol drying operation, all volatilize.
Embodiment 10 pharmaceutical composition oral cavity disintegration tablet and preparation method
Substantially the same manner as Example 9, difference is:
The formula of the oral cavity disintegration tablet of embodiment 10 is:
Reserpine 0.6g, hydralazine hydrochloride 20g, cyclopenthiazide 0.5g, hydrochlorothiazide 30g, promethazine hydrochloride 40g, chlorination Potassium 600g, rutin 100g, Arechin (Polfa) 50g, vitamin B1 20g, vitamin B6 20g, fumaric acid 120g, polyacrylic acid Resin IV 500g, mannitol 913g, microcrystalline Cellulose 913g, cross-linking sodium carboxymethyl cellulose 70g, hydroxypropyl cellulose 100g, aspartame 80g part and sodium stearyl fumarate 30g.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of the oral cavity disintegration tablet of embodiment 10 is with embodiment 9.
Embodiment 11 pharmaceutical composition oral cavity disintegration tablet and preparation method
Substantially the same manner as Example 9, difference is:
The formula of the oral cavity disintegration tablet of embodiment 11 is:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 70g, polyacrylic acid Resin IV 300g, mannitol 1000g, cross-linking sodium carboxymethyl cellulose 35g, hydroxypropyl cellulose 40g, aspartame 50g, citric acid 50g and magnesium stearate 10g.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of the oral cavity disintegration tablet of embodiment 11 is with embodiment 9.
Embodiment 12 pharmaceutical composition oral cavity disintegration tablet and preparation method
Substantially the same manner as Example 9, difference is:
The formula of the oral cavity disintegration tablet of embodiment 12 is:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, polyacrylic acid Resin IV 250g, Sargassum polysaccharides 1000g, low-substituted hydroxypropyl cellulose 50g, hydroxypropyl cellulose 70g and magnesium stearate 8g。
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of the oral cavity disintegration tablet of embodiment 12 is with embodiment 9.
Embodiment 13 pharmaceutical composition oral cavity disintegration tablet and preparation method
Substantially the same manner as Example 9, difference is:
The formula of the oral cavity disintegration tablet of embodiment 13 is:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 70g, polyacrylic acid Resin IV 150g, mannitol 800g, polyvinylpolypyrrolidone 50g, polyvidone 40g, acesulfame potassium 30g, citric acid 30g and stearic acid Calcium 10g.
Illustrate: the purified water of the present embodiment addition and ethanol are through preparation method, and final drying obtains product, and it adds Purified water and ethanol all evaporate；
The preparation process of the oral cavity disintegration tablet of embodiment 13 is with embodiment 9.
Test example 3
Below the uniformity of dosage units of the oral cavity disintegration tablet prepared by embodiment 9 to 13, dissolution, disintegration are measured.
[uniformity of dosage units]
Reserpine, hydrochlorothiazide, promethazine hydrochloride, hydralazine hydrochloride, rutin, vitamin B1 and vitamin B6
Lucifuge operates.By the every cubage recorded under assay item, regulation (CP2015 general rule 0941) should be met.
[dissolution]
Hydrochlorothiazide and promethazine hydrochloride
Lucifuge operates.Take this product, according to dissolution and drug release determination method (CP2015 general rule 0,931 second method), with 0.lmol/L Hydrochloric acid solution 900ml is dissolution medium, and rotating speed is 50 turns per minute, operates in accordance with the law, through 30 minutes time, takes solution about 10ml, uses The microporous filter membrane in 0. 45 μm apertures filters, and takes subsequent filtrate as need testing solution；Another precision weighs hydrochlorothiazide reference substance and salt Acid promethazine reference substance is each in right amount, adds under assay item diluent and dissolves and quantitatively dilution is made in every lml containing hydrochlorothiazide 1.7 μ g, the solution of promethazine hydrochloride 2.2 μ g, as reference substance solution.Precision measures need testing solution and reference substance solution each 20 μ l, except flowing is in addition to [0.06mol/L potassium dihydrogen phosphate-methanol (90: 10) (pH 3.0)]-acetonitrile (65: 35) mutually, Measure according to method under " reserpine, hydrochlorothiazide and promethazine hydrochloride " assay item, by external standard method with calculated by peak area every Middle hydrochlorothiazide and the stripping quantity of promethazine hydrochloride.
[disintegration]
Take this product, with reference to inspection method disintegration (Chinese Pharmacopoeia four annex general rules 0921 of version in 2015), hanging basket is passed through The stainless steel shaft of upper end hangs on metal rack, invades in 1000ml beaker, and regulates screen cloth when hanging basket position makes it decline Filling the water that temperature is 37 DEG C ± 1 DEG C in beaker bottom 25mm, beaker, when regulation height of water level makes hanging basket rise, screen cloth is at water Under face at 15mm.Take test sample 6, put in the glass tubing of above-mentioned hanging basket respectively, start disintegration tester and check, from the beginning of tablet Starting timing during contact water, record granule is completely by the time of screen cloth.Measurement result see table:
Table 3 uniformity of dosage units, dissolution, disintegration time mensuration result
By the uniformity of dosage units of compound recipe reserpine orally disintegrating tablet preparation that each embodiment is prepared, dissolution, disintegration Etc. the summary analysis of aspect bright, the orally disintegrating tablet preparation disintegrate that the present invention prepares is rapid, and release is fast, and in 30 seconds, disintegrate is complete Entirely, it is possible to onset in time, uniformity of dosage units and dissolution all meet the requirement of 2015 editions Chinese Pharmacopoeias, improve original preparation Standard, has complied with the compliance of hyperpietic, and preparation technology has been suitable for industrialized requirement.
Test example 4 investigates the present composition impact on pigeon nausea model
1, laboratory animal: healthy pigeon, male and female dual-purpose, body weight 350 ± 50g, regular grade, is purchased from cultivation base.
2, Experimental agents and dosage:
Healthy pigeon 70, is randomly divided into 7 groups.Experiment prospective adaptation is raised 1 week, and room temperature keeps 22～24 DEG C, keeps clear Clean, well-ventilated, normal diet drinking-water during raising, fasting 4h before experiment.Being administered by following each reagent group respectively, dosage is equal It is same as 0.03mg reserpine (rest activity components in certain proportion)/kg the weight of animals, or the starch of same amount is (empty White comparison).Each index of close observation, water inlet of normally taking food after 8h.
(1) test group 1-3,3 groups, the respectively compound recipe reserpine oral cavity disintegration tablet of embodiment 9,10 and 11, dosage is 0.03mg reserpine (rest activity components in certain proportion)/kg the weight of animals.
(2) control group A, 1 group, the mixture of active principles being mixed to get in the ratio of active component each in embodiment 9, give Dose is 0.03mg reserpine (rest activity components in certain proportion)/kg the weight of animals.
(3) matched group B, 1 group, starch, dosage is 44mg starch/kg the weight of animals.
(4) matched group C, is formed the physical mixture being mixed to get by each raw material in embodiment 9 by 1 group, and dosage is 0.03mg reserpine (rest activity components in certain proportion)/kg the weight of animals.
(5) matched group D, 1 group, commercially available reserpine similar tablet, manufacturer's Roche, dosage is 0.03mg reserpine (rest activity components in certain proportion)/kg the weight of animals.
3, experimental technique:
Observation index: pigeon occurs vomiting incubation period (time of vomiting for the first time extremely occurs after showing medicine), and vomiting number of times (is showed There is the number of times of every a burst of vomiting after medicine, wherein a burst of vomiting refer to from pigeon stretch neck, dehisce, shrug, abdominal part contraction is got home Columba livia restores calm and is calculated as 1 vomiting) and vomiting frequency (refer in every gust of vomiting pigeon stretch neck, dehisce, shrug, abdominal part contraction Number of times).
Give every animal pharmaceuticals 0.03mg reserpine (rest activity components in certain proportion)/kg by above packet through gavage to move Object weight, records and vomits incubation period (min) after every animal gavage, record simultaneously every animal from gavage start 5 hours Interior vomiting number of times and vomiting frequency.
In often organizing, there is the number of animals (n) of vomiting in statistics, for occurring that vomiting (includes vomiting and the nothing of vomitus The summation of the retch of vomitus) animal calculate their incubation period (min, ± s), average vomiting number of times and averagely vomit frequency Rate.Result see table:
Table 4 pigeon zoopery vomiting situation compares (± s, n=10)
From table 4, the vomiting animals that the oral cavity disintegration tablet of the present invention is caused is few, incubation period length and vomit number of times and vomiting Frequency is few.
It should be noted last that: above-described embodiment is merely to illustrate and unrestricted technical scheme, any right The equivalent that the present invention is carried out and amendment or local without departing from spirit and scope of the invention are replaced, and it all should be contained at this Within bright protective scope of the claims.

Claims (10)

1. the pharmaceutical composition treating hypertension, it is characterised in that described pharmaceutical composition is former by following weight portion Material is made:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B 11 parts, vitamin B6 1 part, fumaric acid 2-10 Part and pharmaceutic adjuvant.
The pharmaceutical composition for the treatment of hypertension the most according to claim 1, it is characterised in that: described pharmaceutic adjuvant comprises to be filled out Fill one or more in agent, disintegrating agent, binding agent, lubricant, coating material and correctives；
Described filler is in mannitol, lactose, sucrose, dextrin, starch, microcrystalline Cellulose, Sargassum polysaccharides and chitosan Plant or multiple；
Described disintegrating agent is carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose With one or more in carboxymethylcellulose calcium；
Described binding agent is Opadry, hypromellose, hydroxypropyl cellulose, polyvidone, polyvinyl alcohol and carboxymethyl cellulose One or more in element sodium；
Described lubricant is Pulvis Talci, hydrogenated vegetable oil, micropowder silica gel, sodium stearyl fumarate, calcium stearate, dodecyl sulfur One or more in acid sodium, magnesium stearate and stearyl alcohol；
Described coating material be hypromellose, hydroxypropyl cellulose, polyacrylic resin Ⅳ, styrene-ethylene pyridine altogether One or more in polymers and polyvidone；
Described correctives is the essence perfume of aspartame, acesulfame potassium, saccharin sodium, glucosan, stevioside, citric acid, various fragrance One or more of material.
The pharmaceutical composition for the treatment of hypertension the most according to claim 2, it is characterised in that described pharmaceutical composition be by The raw material of following weight portion is made:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 3-7 Part, filler 30-80 part, disintegrating agent 2-5 part, binding agent 3-10 part and lubricant 0.5-2 part.
The pharmaceutical composition for the treatment of hypertension the most according to claim 3, it is characterised in that: described pharmaceutical composition be by The raw material of following weight portion is made:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 4-6 Part, microcrystalline Cellulose and/or lactose 60-70 part, cross-linking sodium carboxymethyl cellulose 3-4 part, hydroxypropyl cellulose 4-6 part with And micropowder silica gel and/or magnesium stearate 1-2 part.
The pharmaceutical composition for the treatment of hypertension the most according to claim 4, it is characterised in that: described pharmaceutical composition be by The raw material of following weight portion is made:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 5 parts, Lactose 61.3 parts, cross-linking sodium carboxymethyl cellulose 3.6 parts, hydroxypropyl cellulose 5 parts and magnesium stearate 1 part.
The pharmaceutical composition for the treatment of hypertension the most according to claim 2, it is characterised in that: described pharmaceutical composition is made Oral cavity disintegration tablet or capsule, described oral cavity disintegration tablet is made up of the raw material of following weight portion:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 3-7 Part, polyacrylic resin IV 15-30 part, filler 30-150 part, disintegrating agent 2-5 part, binding agent 3-10 part, correctives 0-8 part and lubricant 0.5-2 part.
The pharmaceutical composition for the treatment of hypertension the most according to claim 6, it is characterised in that described oral cavity disintegration tablet be by The raw material of following weight portion is made:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 4-6 Part, polyacrylic resin IV 15-25 part, microcrystalline Cellulose and/or mannitol 90-100 part, cross-linking sodium carboxymethyl cellulose 3-4 part, hydroxypropyl cellulose 4-6 part, aspartame 4-6 part and sodium stearyl fumarate and/or magnesium stearate 1-2 part.
The pharmaceutical composition for the treatment of hypertension the most according to claim 7, it is characterised in that: described oral cavity disintegration tablet be by The raw material of following weight portion is made:
Reserpine 0.03 part, hydralazine hydrochloride 1 part, cyclopenthiazide 0.025 part, hydrochlorothiazide 1.5 parts, promethazine hydrochloride 2 Part, 30 parts of potassium chloride, rutin 5 parts, Arechin (Polfa) 2.5 parts, vitamin B1 1 part, vitamin B6 1 part, fumaric acid 5 parts, Polyacrylic resin IV 20 parts, 91.3 parts of mannitol, cross-linking sodium carboxymethyl cellulose 3.6 parts, hydroxypropyl cellulose 5 parts, Aspartame 5 parts and magnesium stearate 1 part.
The preparation method of the pharmaceutical composition for the treatment of hypertension the most according to claim 5, it is characterised in that include following Step:
(1) raw material and the weight of described pharmaceutical composition are as follows:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, lactose 613g, cross-linking sodium carboxymethyl cellulose 36g, hydroxypropyl cellulose 50g and magnesium stearate 10g；
(2) process utilizing the raw material described in step (1) to be prepared comprises the following steps:
First reserpine and cyclopenthiazide are added in 95% ethanol of 1000ml, after stirring and dissolving to clarification, add hydroxypropyl Base cellulose, stirs to clarify, and obtains reserve liquid；
2. by following raw material: hydralazine hydrochloride, hydrochlorothiazide, promethazine hydrochloride, potassium chloride, rutin, Arechin (Polfa), vitamin B1, vitamin B6, fumaric acid, lactose and cross-linking sodium carboxymethyl cellulose, pulverize, sieve 80 mesh, then by above-mentioned pulverizing respectively After raw material press equal increments method mix homogeneously after, add in fluidized bed granulation seed-coating machine, be preheated to 28 DEG C, regulate stream temperature To 40 DEG C, dry air flow be 100m3*h-1,
3. utilize peristaltic pump by above-mentioned reserve liquid with in the granulating coated machine of flow pump fluidized bed of top spray mode and 5ml/min Fluidized bed granulation seed-coating machine in aerochamber atomization pelletize, atomizing pressure is 1.2bar, steps up and pumps into flow velocity to 40ml/ Min until reserve liquid is finished,
The most then raising stream temperature is to 50 DEG C, continues to take out after fluidized drying 45min in fluid bed,
5. choose the granule less than 18 mesh, after passed examination, add magnesium stearate, mix 5min, tabletting, pack.
The preparation method of the pharmaceutical composition for the treatment of hypertension the most according to claim 8, it is characterised in that include with Lower step:
(1) raw material and the weight of described oral cavity disintegration tablet are as follows:
Reserpine 0.3g, hydralazine hydrochloride 10g, cyclopenthiazide 0.25g, hydrochlorothiazide 15g, promethazine hydrochloride 20g, chlorine Change potassium 300g, rutin 50g, Arechin (Polfa) 25g, vitamin B1 10g, vitamin B6 10g, fumaric acid 50g, polyacrylic acid Resin IV 200g, mannitol 913g, cross-linking sodium carboxymethyl cellulose 36g, hydroxypropyl cellulose 50g, aspartame 50g Part and magnesium stearate 10g；
(2) process utilizing the raw material described in step (1) to be prepared comprises the following steps:
1. reserpine and cyclopenthiazide are added in 95% ethanol of 1000ml, after stirring and dissolving to clarification, add hydroxypropyl fine Dimension element, stirs to clarify, obtains reserve liquid 1；
2. polyacrylic resin IV is added in 95% ethanol of 2000ml, after stirring and dissolving to clarification, obtain reserve liquid 2；
3. by following raw material: hydralazine hydrochloride, hydrochlorothiazide, promethazine hydrochloride, potassium chloride, rutin, Arechin (Polfa), vitamin B1, vitamin B6 and fumaric acid, pulverize, sieve 80 mesh respectively, and then the raw material after above-mentioned pulverizing is pressed the mixing of equal increments method After Jun Yun, add in fluidized bed granulation seed-coating machine, be preheated to 28 DEG C, regulation stream temperature to 40 DEG C, dry air flow be 100m3*h-1；
4. utilize peristaltic pump by reserve liquid 1 with in the granulating coated machine of flow pump fluidized bed of top spray mode and 5ml/min Aerochamber atomization in fluidized bed granulation seed-coating machine is pelletized, and atomizing pressure is 1.4bar, steps up and pumps into flow velocity to 40ml/ Min until reserve liquid 1 is finished,
5. the fluidized bed granulation coating that reserve liquid 2 is pumped in fluidized bed granulation seed-coating machine in top spray mode by peristaltic pump is continued with Aerochamber atomization in machine is pelletized, and after terminating, raising stream temperature is to 50 DEG C, continues to take after fluidized drying 45min in fluid bed Go out,
6. choose the granule less than 18 mesh, after passed examination, add mannitol, cross-linking sodium carboxymethyl cellulose, aspartame, mixed After closing 30min, add magnesium stearate, mix 5min, tabletting, pack.
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CN201510732841.6A CN105213425A (en) 2015-11-03 2015-11-03 One treats hypertensive compound recipe reserpine oral cavity disintegration tablet and preparation method thereof
CN2015107328416 2015-11-03
CN2015107334313 2015-11-03
CN201510733431.3A CN105193841A (en) 2015-11-03 2015-11-03 Compound reserpine medicine composition for treating hypertension and preparation method of compound reserpine medicine composition

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