CN1079233C - Medicinal compositions for curing cardio-vascular diseases and benign prostatomegaly - Google Patents

Abstract

The present invention discloses a medical composition for treating cardiovascular diseases and/or benign prostatic hyperplasia by using phenoprolamine hydrochloride. The composition comprises various pharmaceutical dosage forms, and is particularly suitable for cardiovascular disease patients who also suffer from benign prostatic hyperplasia.

Description

The pharmaceutical composition of treatment cardiovascular diseases and benign prostatic hyperplasia

The present invention relates to treat containing of cardiovascular system diseases and benign prostatic hyperplasia (hereinafter to be referred as BPH) with antagonism α ₁-AR is for leading and have concurrently more weak calcium antagonism pharmaceutical composition, the hydrochloric Fei Luopu that relates generally to treatment hypertension and BPH is 1-(2, the 6-dimethyl phenoxy)-pharmaceutical composition of 2-(3,4-dimethoxy-phenylethylamine base) propane hydrochloride salt (hereinafter to be referred as DDPH).

Be used for antihypertensive drug now and have tens kinds, roughly has similar hypotensive effect, but the biological action that its mechanism of action, toxicity, blood medicine kinetics, lipid and carbohydrate metabolism reach blood vessel all has bigger difference, patient's situation varies, and it is also more and more thinner that the doctor selects medicine to treat.It is so single that but patient's practical situation and symptom can not resemble pharmacological model, clinical need be to the cardiovascular system diseases especially wider medicine of hypertension adaptability.Present α as one of line antihypertensive drug ₁-AR antagonist such as prazosin, terazosin etc. are all to α ₁-AR has strong affinity, and promptly antihypertensive effect is very good.But often because of the blood pressure rapid drawdown often produces many untoward reaction, common giddy arranged, feel sick, reflexive palpitating speed, cardiopalmus etc. after the hyperpietic takes medicine, small number of patients often is mixed with first-dose response and postural hypotension takes place.

And many male's senile hypertension patients are with BPH.Benign prostatic hyperplasia is at present still based on operative treatment, and purpose is to remove to block.Yet prostate can produce the panimmunity globulin; can synthesize have an antibacterial action contain the zinc polypeptide; and protect reproductive system to exempt from the local immunity function of antibacterial and the invasion and attack of other pathogenic microorganism in addition, therefore ten minutes needs the medicine of good curing benign prostatic hyperplasia.Experimental results show that α ₁-AR receptor antagonist can be used for treating BPH, but its strong effect to cardiovascular system often produces many side effect, has influence on clinical practice.Terazosin for example, the first clinical being tested in 1988 with its treatment BPH carried out, and dosage is 10mg/day, and the result urinates the flow velocity degree and obviously improves.Main side effect is slight headache, faintness, unable, cardiopalmus and hypotension etc.(LEPOR H, AUERBACHS, PURAS-BAEZ A, NARAYAN P, SOLOWAY M, et al.A randomized, placebo-controlled multicenter study of the efficacy and safety of terazosin in thetreatment of benign prostatic hyperplasia.J.Urol.1992; 148:1467～74; Chen Quanlin compiles: cardiovascular drugs ten is said, Chongqing publishing house 1990.

The objective of the invention is to invent existing stable, gentle hypotensive effect, the dysuria of alleviating old prostate patient is arranged again, thereby be applicable to the hyperpietic's who suffers from prostatosis medicine.The bad drug interaction of avoiding it to take multiple medicine and take multiple medicine generation.

The present invention also aims to invent a kind of strong α that has concurrently simultaneously ₁The antihypertensive of effect of-receptor blocking and more weak calcium antagonism double action mechanism, thereby clinical wide adaptability, and blood pressure lowering mitigation, steady can not cause cardiovascular side effects such as reflexive heart beating.

Purpose of the present invention still is to invent a kind of, safety wide to cardiovascular system diseases adaptability medicine preferably, not only can treat hypertension, prevention and treatment prostate hyperplasia but also have the pharmacologically active of cardiovascular aspect widely, as arrhythmia, inhibition vascular smooth muscle propagation, thereby the left ventricular hypertrophy that inhibition hypertension causes prevents sudden death, suppresses effects such as pulmonary hypertension and anticoagulant.

For achieving the above object, technical scheme of the present invention is a kind of angiocardiopathy/or the pharmaceutical composition of benign prostatic hyperplasia, it is characterized in that: contain phenoprolamine hydrochloride, claim 1-(2 again, the 6-dimethyl phenoxy)-2-(3,4-dimethoxy-phenylethylamine base) propane hydrochloride salt is active component, also contains pharmaceutically useful carrier simultaneously.

Described pharmaceutical composition is characterized in that the method for knowing in the available pharmacy industry is prepared into various pharmaceutical dosage forms, comprises tablet, pill, injection, capsule, infusion solution, controlled release agent, slow releasing agent and percutaneous controlled-release membrane.

Pharmaceutical composition of the present invention contains nontoxic inert pharmaceutical carrier commonly used in the active ingredient DDPH of 5%～95% (W/W) and the preparation.Pharmaceutical carrier commonly used has (a) filler, absorbent and diluent, as starch, lactose, sucrose, glucose, mannitol, three silicon oxides, Kaolin and bentonite; (b) binding agent and blocker are as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone (PVP), polyacrylic resin, hypromellose, methylcellulose, ethyl cellulose, dextrin, paraffin, hexadecanol, octadecanol, glyceryl monostearate; (c) wetting agent is as glycerol, carbamide, ketopyrrolidine, vaseline; (d) disintegrating agent: starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linked pvp, cross-linked carboxymethyl cellulose, calcium carbonate, magnesium carbonate and sodium bicarbonate; (e) absorption enhancer is as tween, sodium lauryl sulphate, quaternary ammonium compound, Salicylate, phospholipid, PVP; (f) lubricant is as Pulvis Talci, magnesium stearate, liquid Paraffin, solid polyethylene glycol; Or cited (a) in front is to the mixture of (f) component.

The active ingredient content of slow/controlled release preparation is at 40%～90% (W/W) among the present invention, used blocker is ethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, kappa nurse (carbopol), polyacrylic acid resin II, III, stearic acid, Cera Flava, paraffin, liquid Paraffin, sodium alginate, gelatin, arabic gum etc., the particle diameter of may command principal agent is below 5um in case of necessity, to quicken the stripping of principal agent, the surfactant that can add 0.1～2% (W/W), as Tween 80, sodium lauryl sulphate.Available 40%～50% ethanol is as wetting agent, or with 5% starch slurry as binding agent.

The DDPH slow releasing tablet can divide matrix tablet (erosion type and insoluble) and film control sheet (release-controlled film and osmotic pump type).The main adjuvant of selecting for use has: hypromellose, hyprolose, low-substituted hydroxypropyl cellulose, ethyl cellulose and aqueous dispersion thereof, methylcellulose, sodium carboxymethylcellulose pyce, carboxymethylstach sodium, carbomer, polyacrylic resin II, III, IV, Eudragit RL.RS. xanthan gum, chitin and chitosan, sodium alginate, gelatin, polyvinylpyrrolidone, ion exchange resin, stearic acid, octadecanol, Cera Flava, glyceryl monostearate, castor oil hydrogenated, polylactic acid, polyvinyl alcohol, polrvinyl chloride, polyethylene, silicone rubber, the O-phthalic cellulose acetate, cellulose acetate, arabic gum etc.The preparation technology of matrix tablet adopts dry method or wet granule compression tablet technology; First tabletting core is adopted in the preparation of film chamber sheet, the technology of back bag film-coat; Osmotic pump type adopts tabletting, coating, laser boring technology.

The DDPH slow releasing capsule can divide the capsule of slow-releasing granules and two kinds of contents of slow-release micro-pill

The main adjuvant of selecting for use has: sucrose, starch, dextrin, microcrystalline Cellulose, hypromellose, polyvinylpyrrolidone, hyprolose, low-substituted hydroxypropyl cellulose, ethyl cellulose and aqueous dispersion thereof, sodium alginate, carboxymethylstach sodium, diethyl phthalate, castor oil hydrogenated, polyacrylic resin II, III, IV, Eudragit RL, RS, chitin and chitosan, xanthan gum, gelatin, arabic gum, stearic acid, octadecanol, glyceryl monostearate, carbomer, polyvinyl alcohol etc.

The preparation of slow-releasing granules can be adopted dry method and wet granulation technology; The technology of coating after the preparation of slow-release micro-pill can be adopted fluid bed or centrifugal pelletize pill and coating or adopt extruding, cutting, stranding garden pill.Micropill can be matrix type or film controlling type, and quantitatively the embedding capsule gets final product.

DDPH percutaneous controlled-release membrane has matrix type and Drug Storage film controlling type, and the main adjuvant of selecting for use has: ethyl cellulose, polyvinyl alcohol, ethylene-vinyl acetate copolymer, the acrylic compounds pressure sensitive adhesive, the silicone rubber pressure sensitive adhesive, polyisobutylene class pressure sensitive adhesive, gelatin, alginic acid, Carboxymethyl cellulose sodium, azone, oleic acid, sodium laurylsulfate, propylene glycol, α-pyrrolidone, isopropyl alcohol lima bean ester, Polyethylene Glycol, Oleum menthae, eucalyptus oil, a-amino acid, cyclodextrin, phospholipid, cholate, polyethylene, polypropylene, polystyrene, Merlon, paraffin, methyl-silicone oil, hypromellose, carbomer, polrvinyl chloride etc.The preparation of membrane mainly comprises the processing (corrosion method, pulling method, radioprotective legal system are equipped with release-controlled film) of film material and the composite molding of film material (coating, dry, compound suppressing).

DDPH is the α of a moderate strength ₁-AR antagonist has more weak calcium antagonism simultaneously concurrently, has two kinds of different mechanism of action in the same molecule, uses the pharmaceutical composition of its preparation to have following good pharmacological action.

1. the pharmaceutical composition that contains DDPH is the α that the moderate strength effect is arranged ₁-AR receptor antagonism has the depressor of the tool double action mechanism of more weak calcium antagonism simultaneously concurrently, clinical adaptability is wider, blood pressure lowering mitigation, steady, can not cause side effect such as first-dose response, reflexive heart beating cardiopalmus, do not occur toleration and depot action behind the successive administration yet, can take for a long time.

Phenoprolamine hydrochloride (DDPH) is irritated stomach or quiet notes all have tangible hypotensive effect to experimental hypertension rat and dog.Clear-headed spontaneous hypertensive rat (SHR), DDPH 12.5,25,50, and 100mg/kg irritates stomach (ig), dose dependent ground reduces systolic pressure (SAP) and diastolic pressure (DAP), makes SAP and DAP reduce by 5.6,10.3,20.7 respectively, 31.7% and 6,10,21,32.5%.12.5～50mg/kg does not have obvious influence to heart rate.100mg/kg ig makes decreased heart rate simultaneously in blood pressure lowering.DDPH 25,50,100mg/kgig are to the SHR treatment that experimentizes, and continuous 7 days, toleration did not appear in its hypotensive effect.Renal hypertension dog, DDPH 2.5,5, and 10mg/kg and 4mg/kg oral (P.o.) all have good hypotensive effect, and are dose dependent, single oral DDPH 4mg/kg, blood pressure lowering is held and is imitated 6h.Heart rate does not have significant change, and electrocardiogram does not occur obviously unusual yet.DDPH 5mg/kg P.o. is to the renal hypertension dog treatment that experimentizes, and continuous 21 days, the tolerance phenomenon also appearred in its hypotensive effect.

DDPH12.5,25,50mg/kg ig can reduce clear-headed renal hypertensive rat blood pressure; 4,8mg/kg ⅳ can reduce anesthesia renal hypertensive rat blood pressure, and make LVP, ± dP/dt _MaxReduce, but T value and LVEDP are not had obvious change, cardiac systolic function and diastolic function are not had obvious influence.DDPH 2,4,8mg/kgiv or 5,10, the 20mg/kg duodenal administration also has remarkable and persistent hypotensive effect to anesthetized open-chest dog, and the effect of the effect of DAP being compared SAP is strong, blood pressure lowering accompanies heart rate (HR) slightly to slow down simultaneously, and cardiac output descends in short-term or do not have obviously and changes.

The blood pressure lowering mechanism analysis, the hypotensive effect of DDPH and its selective exclusion α ₁It is relevant that adrenoceptor reaches more weak calcium antagonism.Radioligand is in conjunction with experiment showed, that DDPH is to α ₁Receptor has stronger affinity, and Ki is 0.15 μ molL ^-1, IC ₅₀(α ₂/ α ₁) be 112.Prove that with ruining spinal rat experiment, rabbit aorta, portal vein and electric Physiological Experiment such as rat anus musculus caudalis, rat spermatic duct experiment DDPH is at rabbit aorta, portal vein and rat anus musculus caudalis antagonism α ₁The pA of receptor stimulating agent methoxamedrine ₂Be 7.2,6.9 and 7.3, the selection percentage (α of blocking-up α receptor ₁/ α ₂) be 162.At extrasomatic rabbit heart papillary muscle, isolated rat working heart, rat heart-lung apparatus, confirm that also DDPH is to α ₁Receptor has blocking effect.Autoradiography studies confirm that DDPH dose dependent blocking-up rat heart muscle α ₁And α ₂Receptor, and with blocking-up α ₁Receptor is main.

DDPH has retardation to tame rabbit aorta strip voltage dependent channel (PDC), but than a little less than the verapamil, its action intensity is about the latter's 1/174; Confirm that with patch-clamp and radioligand experimental technique DDPH has inhibitory action to the calcium current of the single ventricular muscle cell film of rat, and the rat heart muscle calcium channel is had retardation.

Phenoprolamine hydrochloride (DDPH) is except that having hypotensive effect, and experimental results show that also has antagonism to anesthetized cat and rat myocardial ischemia and reperfusion institute proarrhythmia.DDPH shortens APD to dog ventricular muscles and Pu Shi fiber action potential ₂₀, APD ₅₀, suppress V _Max, prolong APD ₉₀, and be concentration and frequency dependence; Guinea-pig ventricular's papillary muscle action potential experimental result shows that DDPH is to myocardium Ca ²⁺Transmembrane transport is inhibited.

Several animal models proves that its antihypertensive effect is definite, and rapid-action, and long (6h) holds time.Significantly dose-dependence is arranged simultaneously, and blood pressure lowering diastolic pressure (DAP) can omit strong by force rate systolic pressure (SAP).It has good hypotensive effect.

(1) hypotensive effect is rapid, and effect in 45 minutes reaches the peak behind a drug, and action intensity is tangible dose dependent, shows that DDPH may be applicable to the treatment of various hypertension.

(2) during medication, the blood pressure of every day all can be more controlled, and recover in 1 day after drug withdrawal, but surpass the preceding level of treatment.The hypotensive effect of this explanation DDPH does not have toleration and cumulative action, so may be applicable to hypertensive patient's long-term treatment.

(3) it is strong that the effect that reduces diastolic pressure reduces the effect of systolic pressure, and heart rate is not had influence, helps improving the blood-pumping function of heart and the hemoperfusion of important organ.

2.DDPH influence to the prostatic hyperplasia rat

Experiment one: spice: DDPH (WM:379.92) is provided by China Medicine University, and chemical purity is more than 99%, with distilled water temperature dissolving a little.Estradiol, androlin is produced by Shanghai the 9th pharmaceutical factory.Olive oil is produced by chemical reagent station, Shanghai packing factory.♂ Wistar rat, 100～200g is provided by Hubei Prov. Health ﹠ Epidemic Prevention Station.

Method two: the foundation of rat prostatic hyperplasia model and experiment grouping, press the propanoic acid testis, after the week, subcutaneous injection is dissolved in the propionyl Testosterone 0.5mg/0.1ml/rat of olive oil.Begin drug treating simultaneously.Experiment divides 5 groups: 1. positive controls, operation back the 2nd week beginning 50ug/kg sc.Estradiol, continuous 4 weeks; 2. negative control group begins to irritate stomach 0.25% tragakanta suspension (with administration group isometric(al)) the 2nd week after the operation, continuously 4wk; 3. DDPH ₁Group, the 2nd week of postoperative is irritated stomach DDPH (12.5mgkg ^-1D ^-1), continue 4wk; 4. DDPH ₂Group, the 2nd week of postoperative is irritated stomach DDPH (25mgkg ^-1D ^-1), continue 4wk; 5. DDPH ₃Group, the 2nd week of postoperative is irritated stomach DDPH (50mgkg ^-1D ^-1), continue 4wk.

The result: (1) DDPH is to the influence of prostatic hyperplasia rat prostate volume; (2) each leaf is prostatic

Negative control group positive controls DDPH ₁Group DDPH ₂DDPH ₃Several 10 10 10 10 10 prostate volumes of example (ml) 0.948 ± 0.088 0.718 ± 0.041 ^*0.909 ± 0.031 ^*0.859 ± 0.033 ^*0.721 ± 0.036 ^*Head lobe weight in wet base (g) 0.168 ± 0.011 0.123 ± 0.010 ^*0.160 ± 0.007 0.156 ± 0.007 ^*0.131 ± 0.012 ^*Head lobe dry weight (g) 0.0488 ± 4.25 * 10 ^-30.0346 ± 2.84 * 10 ^-30.0464 ± 2.82 * 10 ^-30.0452 ± 2.82 * 10 ^-3*0.0373 ± 3.66 * 10 ^-3**Back lateral lobe weight in wet base (g) 0.377 ± 0.0256 0.282 ± 0.0318 ^*0.357 ± 0.0279 0.3325 ± 0.0304 ^*0.299 ± 0.0376 ^*Rear side leaf dry weight (g) 0.0566 ± 4.57 * 10 ^-30.0424 ± 4.78 * 10 ^-3**0.0532 ± 4.69 * 10 ^-30.0499 ± 4.564 * 10 ^-3**0.0449 ± 5.6410 ^-3**Frontal lobe weight in wet base (g) 0.401 ± 0.0336 0.279 ± 0.0227 ^*0.3775 ± 0.0325 0.362 ± 0.319 ^*0.311 ± 0.0219 ^*Preceding leaf dry weight (g) 0.0801 ± 7.14 * 10 ^-30.0558 ± 4.53 * 10 ^-3**0.0752 ± 6.38 * 10 ^-30.0723 ± 6.37 * 10 ^-3*0.0621 ± 4.49 * 10 ^-3**Epithelial cell height (um) 28.07 ± 1.93 21.33 ± 2.22 ^*25.99 ± 1.92 ^*25.22 ± 2.15 ^*22.24 ± 2.01 ^*

Compare .*P＜0.05 with negative control group, ^*P＜0.01; Weight in wet base and dry weight; (3) lumen of gland diameter and glandular epithelium cell height.

Compare with negative control group, three administration groups of DDPH make the hypertrophy prostate volume, each leaf weight of prostate, and the glandular epithelium height reduces in various degree, reduces by 5%, 10%, 20% respectively approximately; But positive controls is promptly used the estrin treatment group, can make prostate volume, and each leaf is wet, and dry weight reduces more than 25%.Illustrate that DDPH has therapeutical effect to prostatic hyperplasia, but more lower slightly than matched group.

Experiment two:

(1) (proved and only contained α at the rat spleen _1BHypotype) (contains α with brain cortex _1A, α _1BWith α _1DThree kinds of hypotypes), by the DDPH antagonism ¹²⁵I-BE α α 5U and α ₁-AR is in conjunction with suppressing experimental result: (Mean ± SEM, difference)

N pKi Aill coefficient gland 4 7.11 ± 0.10 0.91 ± 0.15 cortex 4 6.87 ± 0.06 0.79 ± 0.10

(2) at difference transfection α _1A, α _1BOr α _1DThe clone HEK293 cell of DNA and stably express, DDPH competes inhibition ¹²⁵I-BE α α 54 and α ₁The bonded pK of-AR ₁Value

α _1A(n＝5)：6.90±0.12

α _1B(n＝4)：6.58±0.04

α _1D(n＝4)：6.96±0.06

(3) (only be α at stripped R Mus aorta _1DHypotype) (only be α with renal artery _1AHypotype) glue, the pAI of the DDPH antagonism epinephrine contraction that records in the functional experiment:

N pA _αSlope aorta 4 7.40 ± 0.23 1.24 ± 0.11 renal artery 4 7.41 ± 0.04 0.91 ± 0.10

3. the pharmaceutical composition that contains DDPH is wider to the cardiovascular system diseases adaptability, has the activity of cardiovascular aspect widely.

Endothelin-1 (ET-1 0.1 μ molL is adopted in the influence of short vascular smooth muscle cell proliferation of 1-(2, the 6-dimethyl phenoxy)-2-(3,4-dimethoxy benzene ethylamino) propane hydrochloride salt post Endothelin and oncogene expression ^-1) set up the vascular smooth muscle cell proliferation model of cultivating, use [ ³H] thymidine ([ ³H] TdR) participate in method, flow cytometry, immunocytochemistry and Northern blot method, flow cytometry, immunocytochemistry and Northern blot method have been observed 1-(2, the 6-dimethyl phenoxy)-2-(3,4-dimethoxy benzene ethylamino) propane hydrochloride salt (DDPH 0.1 μ molL ^-1) to the effect of vascular smooth muscle cell proliferation and to proto-oncogene and suppress the influence of oncogene.Found that: DDPH can reverse due to the ET-1 [ ³H] the TdR amount of participating in increases, and stops vascular smooth muscle cell by (G resting stage ₀/ G ₁Phase) enters DNA synthesis stage (S phase) and mitotic phase (G ₂/ M the phase), and can reverse the c-fos that ET-1 causes, c-myc, c-sis proto-oncogene related antigen and mRNA express and strengthen, P53 antioncogene related antigen and mRNA express and strengthen, P53 antioncogene related antigen and mRNA express and weaken, and prompting DDPH can suppress vascular smooth muscle cell proliferation, and be relevant with the molecular biology mechanism of oncogene regulation and control.

1-(2, the 6-dimethyl phenoxy)-2-(3,4-dimethoxy-phenylethylamine base) propane hydrochloride salt pair spontaneous hypertensive rat vascular smooth muscle cell proliferation reaches PDGF-B, bFGF, c-sis, the influence of c-myc.With tritiated thymidine ( ³H-TdR) mix method, Electronic Speculum, SABC, in-situ hybridization method, (SHR) observed 1-(2 at spontaneous hypertensive rat, the 6-dimethyl phenoxy)-2-(3,4-dimethoxy-phenylethylamine base) propane hydrochloride salt (DDPH) is to the effect of vascular smooth muscle cell (VSMC) propagation and to somatomedin PDGF-B, the influence of bFGF and relevant oncogene c-sis thereof and c-myc expression.Found that: DDPH can reduce the mitochondrion of renal artery VSMC reducing the SHR blood pressure simultaneously, rough endoplasmic reticulum and ³The H-TdR incorporation, and can reverse VSMC when propagation PDGF-B, the expression enhancing of bFGF antigen and c-sis and c-nyc mRNA.Prompting; DDPH can suppress the VSMC propagation of SHR, and is relevant with the The Molecular Biology Mechanism of somatomedin and oncogene regulation and control.

DDPH is to the influence of pulmonary hypertension induced lung blood vessel remodeling.With surveying methods such as right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), Feugen and elastic fibers complexity, graphical analysis, observation 1-(2, the 6-xylyloxy)-2-(3,4-dimethoxy-ethylamine base) propane hydrochloride salt (DDPH) brings out the influence of Pulmonary Hypertension and lung blood vessel remodeling to monocrotaline (M).The result: 1. DDPH causes that to M the inhibitory action that rat RVSP raises reaches 38.95%.2. RVHI and lung small artery media thickness, M add DDPH (MD) group than M group respectively low 33.49% and 47.28%.3. circular muscle shape pulmonary artery number, the MD group is than M group few 50.81%.4. cells of vascular wall is examined the OD value of DNA, and the MD group is also low by about 50.00% than the M group, can think that DDPH also has the effect that suppresses pulmonary hypertension and lung blood vessel remodeling.

1-(2, the 6-dimethyl phenoxy)-2-(3,4-dimethoxy benzene ethylamino) propane hydrochloride salt pair myocardial hypertrophy rat left ventricle N-ras, the influence that P53 mRNA expresses.Be research 1-(2, the 6-dimethyl phenoxy)-2-(3,4-dimethoxy benzene ethylamino) propane hydrochloride salt (DDPH) is to the reverse effect of myocardial hypertrophy, causes the rat heart muscle hypertrophy model with the narrow ventral aorta method of part, from postoperative wk 4, ig DDPH 25 and 50mgkg ^-1D ^-1, continue 8wk.Postoperative 12wk, each organizes the rat body weight there was no significant difference, but model group heart weight/body weight, left ventricle weighs/weighs apparently higher than matched group whole-heartedly.The N-rasmRNA of model group cardiac muscular tissue expression ratio matched group height, DDPH can reverse above-mentioned variation.Show DDPH can reverse ventral aorta narrow due to myocardial hypertrophy.

Experimental results show that it to answering the therapeutical effect of the arrhythmia effect due to irritating, test also proof has the reverse myocardial hypertrophy, improves valuable pharmacological effects such as blood vessel wall pathological change; Zoopery shows that also it has the pulmonary artery of reduction and portal hypertension effect, and this is very useful to the hypertensive patient who suffers from liver cirrhosis and pulmonary heart disease.

Pharmacology, toxicity and medicine are for experimental results show that this medical instrument has safety preferably.

The data that provided according to the rat acute toxicity test:

LD ₅₀/ Ic ₃₀=1346/31=43.4 shows bigger safety.

Animal (begle Canis familiaris L.) long term toxicity (6 months) experimental results show that: 12mg/kg is a non-toxic, and 4mg/kg is clinical recommended dose, and 12～60mg/kg is a safety range, and 180mg/kg is a toxic dose.In toxic reaction, show as convulsions, twitch, but all can reverse, and be dose dependent.

Micronucleus test, Salmonella reversion test, reproductive toxicity test are all negative.

From acute toxicity, chronic toxicity and the pharmacokinetics test data done, phenoprolamine hydrochloride (DDPH) in the normal dose scope to the vitals of animal, as: the heart, lung, liver, kidney and nervous system, respiratory system etc. are not all found untoward reaction.

Embodiment 1:DDPH slow releasing tablet

Recipe quantity (mg/litre)

DDPH 30～150

Hypromellose (HPMC) is an amount of

Kappa nurse (Carbopol) is an amount of

Lactose (Lactose) is an amount of

Magnesium stearate (M.S) 1%

Hypromellose is a blocker, and its specification can be used K4M, E ₅, K ₁₀₀By just not mixing on year-on-year basis, its consumption is 5～85% of a principal agent amount etc. basic, normal, high viscosity; The kappa nurse also is a blocker, and its specification has 934,971 ... Deng, consumption is 0.5～10% of a principal agent amount; Lactose is diluent and porogen, and its consumption is 5～50% of a principal agent amount, and also available polyethylene ketopyrrolidine, Polyethylene Glycol, sodium chloride etc. are made porogen; Lubricant is a magnesium stearate, and consumption is that dried granule weighs 1%.

With DDPH, Lactose, Caxbopol, section H PMC mix homogeneously, make binding agent system soft material with 4%HPMC 70% alcoholic solution, with 18～28 mesh sieve system wet granulars, in dry below 50 ℃, behind the granulate with tabletting behind the magnesium stearate mixing.

HPMC, the Carbopol of the framework material of this matrix tablet in above-mentioned prescription, be main the composition, also can form by HPMC and ethyl cellulose or polyacrylic resin etc.

Embodiment 2:DDPH film control sheet

Recipe quantity (milligram/sheet)

DDPH 30～150

Lactose 7～36

Polyvinylpyrrolidone (PVP) is an amount of

HPMC 14～65

Magnesium stearate (M.S) 1%

The ethyl cellulose coating solution:

Ethyl cellulose (EC) 2g

Diethyl phthalate (DEP) 0.5g

95% ethanol 100ml

Magnesium stearate 1g

With DDPH, Lactose, HPMC mixing, cross 28 mesh sieve system wet granulars with 5～10%PVP alcoholic solution system soft material, dry below 50 ℃, add M.S mixing tabletting behind the granulate, with EC coating solution coating, meet the controlled release requirement to dissolution test, the weightening finish of clothing film is about 5～8% usually.

Embodiment 3:DDPH osmotic pump tablet

Recipe quantity (milligram/sheet) amount

DDPH 30～150 5～10%HPMC alcohol liquid

Lactose 7～36 magnesium stearate 1%

Sodium chloride 10～70

Coating solution:

Cellulose acetate 3～5g

Polyethylene Glycol ₄₀₀(PEG ₄₀₀) 1～2g

Diethyl phthalate (DEP) 1g

Ethanol 20ml

Acetone 80ml

With DDPH, lactose, sodium chloride mixing,, cross 28 mesh sieves and granulate with 5～10%HPMC alcohol liquid system soft material, dry, granulate add M.S mixing tabletting, with cellulose acetate coating solution coating below 50 ℃, make thickness reach 40～100 μ m, laser boring, making the aperture is 0.5～1.0mm.

Embodiment 4:DDPH sustained-release micro-pill capsules

Recipe quantity (milligram/grain) coating solution:

DDPH 30～150 EC 2g

Starch 30～150 DEP 0.5g

Dextrin 60～300 M.S 1g

Sodium lauryl sulphate (SLS) 2～12 95% ethanol 100ml

Polyvinylpyrrolidine (PVP) 3～150

Starch, dextrin are made celphere (also available sucrose or microcrystalline Cellulose pill flower) earlier, make with the mixed powder that adds DDPH, sodium lauryl sulfate, polyvinylpyrrolidone and an amount of dextrin behind the moistening celphere of 40～80% ethanol and to contain fragrant plain ball, dry below 50 ℃, wrap EC clothing film again, about drying below 5～8%, 50 ℃ that increases weight back is encapsulated.

Embodiment 5 amounts (milligram/grain)

DDPH 30～150

SLS 0.8～48

PVP 3～150

HPMC 2～130

Starch 30～150

40～80% ethanol are an amount of

With DDPH, SLS, PVP, HPMC, starch mixing, make wetting agent with 40～80% ethanol, make the matrix type micropill.

Embodiment 6:DDPH slow releasing capsule

Recipe quantity (milligram/grain)

DDPH 30～150

HPMC 2～15

Lactose 7～36

4%EC ethanol liquid is an amount of

M.S 1％

With DDPH, Lactose, HPMC mixing, with 4%EC alcohol liquid system soft material, cross 18 mesh sieves and granulate, drying below 50 ℃, granulate adds behind the M.S mixing encapsulated.

Embodiment 7:DDPH percutaneous controlled-release membrane

Recipe quantity (milligram/paster)

DDPH 30～500

Azone (Ayonl) 0.3～25

Propylene glycol (PG) 1～10

EC 1～5

95% ethanol is an amount of

DDPH is dissolved in an amount of 95% ethanol, adds EC and be stirred to moltenly, add Azse, PG mixing, pour into and be fixed with on the mould circle mouth backing material, dry below 50 ℃, take out the mould circle, be coated with pressure sensitive adhesive in the turnover of medicine film, cover sticking paper, the dress aluminium plastic packaging bag seals.Medicine film (paster) diameter is 10～20cm ²

Prescription of embodiment 8:DDPH tablet and preparation method thereof

Prescription: 1000 consumptions

DDPH： 50g

Microcrystalline Cellulose 40g

Hydroxymethyl starch is received 5g

15% starch mixes slurry with 2% sodium lauryl sulphate suitable

Magnesium stearate 1% (W/W)

Method for making: get DDPH by recipe quantity mark and cross sieve No. 10, microcrystalline Cellulose, hydroxymethyl starch are received mixing, add sodium lauryl sulphate and make soft material with the slurry that mixes of starch, and No. 2 nylon mesh granulations in 60 ℃ of dryings 4 hours, add 1% magnesium stearate mixing, tabletting behind the granulate.

The prescription and the preparation method of embodiment 9:DDPH hard capsule

Prescription: 1000 consumptions of 1000 consumptions

DDPH 50g 30g

Microcrystalline Cellulose: 10～40g, 10～50g

Sodium Hydroxymethyl Stalcs: 5g 5g

Starch: 4～34g, 14～54g

Magnesium stearate 1g 1g

Method for making: took by weighing the DDPH fine powder of No. 10 sieves by recipe quantity, microcrystalline Cellulose (cross No. 5 sieve), Sodium Hydroxymethyl Stalcs (crossing sieve No. 5), starch (crossing sieve No. 5) mix homogeneously, the magnesium stearate fine powder that will cross No. 6 sieves again adds mixing, adorns capsule No. 4.

Claims (1)

1, the application of phenoprolamine hydrochloride in preparation treatment benign prostatic hyperplasia medicine.