CN101590045A - The medical composition and its use that contains amlodipine and naftopidil - Google Patents
The medical composition and its use that contains amlodipine and naftopidil Download PDFInfo
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- CN101590045A CN101590045A CNA2008101130929A CN200810113092A CN101590045A CN 101590045 A CN101590045 A CN 101590045A CN A2008101130929 A CNA2008101130929 A CN A2008101130929A CN 200810113092 A CN200810113092 A CN 200810113092A CN 101590045 A CN101590045 A CN 101590045A
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Abstract
The invention discloses a kind of purposes of pharmaceutical composition, the compositions that promptly contains acceptable carrier on the naftopidil of amlodipine, pharmaceutical dosage of pharmaceutical dosage and the pharmaceutics in preparation treatment hypertension or/and with prostatic hyperplasia relevant disease medicine in purposes.The invention still further relates to this pharmaceutical composition and be used for preventing, treating and delay the application of the medicine of hypertension and/or benign prostatic hyperplasia relevant disease in preparation.By enforcement of the present invention, the pharmaceutical composition that offers this special-purpose of patient is determined curative effect not only, but also can improve patient's compliance, and the patient is taken medicine conveniently, reduces medical expense, has better market prospect.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains amlodipine and naftopidil, and this pharmaceutical composition is used for preventing, treating and delay the purposes of the medicine of benign prostatic hyperplasia relevant disease or hypertensive patients benign prostatic hyperplasia relevant disease in preparation.The invention belongs to pharmaceutical field.
Background technology
Hypertension is the healthy modal a kind of cardiovascular disease of harm humans, is the great public health problem in the global range.Increased nearly 50% during " eight or five " (1992-1994) during China's middle-aged population hypertension control rate " 95 " (1998), but control rate also only reaches 6.0%[king increases force etc. the evolving trend of Chinese middle-aged population hypertension prevalence and awareness, treatment rate, control rate. and Chinese epidemiology magazine .2004,25 (5): 407-411].(benign prostate hyperplasia BPH) is one of modal disease of elderly men to benign prostate hyperplasia.No.1 Hospital Affiliated to Beijing Medical Univ. after death performed an autopsy on sb to the prostatosis patient more than 40 years old in 1989, found that histology BPH sickness rate rises to 30.5% from 6.6% of Concord Hospital's report in 1936.BPH become one of commonly encountered diseases of clinical Urology Surgery [Gu Fangliu etc. benign prostatic hyperplasia and carcinoma of prostate are in the research of Chinese incidence. Chinese tumor .1997,6 (10): 19].The urinary tract obstruction that BPH the causes phase symptom reason of urinating comprises static factor and kinetic factor.Prostate and bladder neck have abundant alpha-2-adrenoceptor.The outgrowth tuberosity in prostate transitional areas and urethra peripheral region is static factor to the pressure that urethra produces, the mechanical obstruction that mainly refers to urethra, but alpha-adrenergic receptor excitation time, increased the weight of the symptom of urethral obstruction, the tension force of prostate, capsula prostatica, bladder neck increases then for blocking kinetic factor.
Lower urinary tract syndrome (lower urinary tract syndrome, LUTS) for storing up the general designation of the urine phase (zest) and/or (obstructive) symptom of urinating the phase, be the common symptom of gerontal patient [suggestion is recommended by the 5th international scientific committee of international benign prostatic hyperplasia Advisory Board: the assessment of elderly men lower urinary tract symptom and treatment. Chinese magazine of urology surgery .2001,22:564-570]: storage urine phase symptom (also claiming irritation in the past) comprises urgent micturition, frequent micturition, urinary incontinence, symptoms such as nocturia increases, the phase symptom of urinating mainly comprises dysuria, the urine line is thin, the urine back sound of rain pattering, urinary hesitancies etc. are based on dysuria.LUTS has higher incidence in the crowd: 5% child has enuresis nocturna, and 15% women and 7% male adult suffer from the urinary continence disorder disease; In the elderly men more than 70 years old, about 80% people suffers from benign prostatic hyperplasia, and prostate volumes wherein more than half approximately obviously increase, and wherein 50% prostate that increases can cause bladder outlet obstruction (BOO).LUTS can be caused that BPH is that the male patient brings out the topmost factor of LUTS by multiple factor.
Amlodipine chemical name: 3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate.By L type calcium channel on the vasoactive smooth muscle cell film, suppress calcium ion and stride film intravasation smooth muscle, thereby reduce flow of calcium ions, vascular smooth muscle tension force is descended; Naftopidil chemical name: (±)-1-[4-(2-anisyl) piperazinyl]-3-(1-naphthoxy)-2-propanol, blocking-up α 1 receptor acting, alleviate prostate due to this receptor excitement and urethra the sympathetic nerve sexual tension, to reduce urethra intrinsic pressure, improves the symptoms such as dysuria due to the benign prostate hyperplasia.
Summary of the invention
The object of the present invention is to provide a kind of prevention, treat and delay the pharmaceutical composition of benign prostatic hyperplasia relevant disease or hypertensive patients benign prostatic hyperplasia relevant disease, comprising: acceptable carrier on amlodipine, naftopidil and the pharmaceutics.
In pharmaceutical composition provided by the invention, amlodipine becomes content of the present invention to create as a kind of active component with naftopidil with acceptable carrier mutual group on the pharmaceutics.Amlodipine can exist with the form of chemical compound, also can the medicinal precursor of amlodipine, forms such as amlodipine active metabolite or amlodipine salt exist.The preferred Amlodipine Besylate Tablet of the salt of amlodipine.As the equivalents of amlodipine, above-mentioned substance is also in the scope of protection of present invention.
In pharmaceutical composition provided by the invention, amlodipine content is 1～20mg, and preferred 2.5mg～10 benzenesulfonic acid mg is more preferably 5mg～10mg.The content and the amlodipine content of the medicinal precursor of amlodipine, amlodipine active metabolite or amlodipine salt can be equal to replacement.
In pharmaceutical composition provided by the invention, naftopidil becomes content of the present invention to create as a kind of active component with amlodipine with acceptable carrier mutual group on the pharmaceutics.Naftopidil can exist with the form of chemical compound, also can the medicinal precursor of naftopidil, forms such as naftopidil active metabolite, naftopidil salt or naftopidil esters exist.As the equivalents of naftopidil, above-mentioned substance is also in the scope of protection of present invention.
In pharmaceutical composition provided by the invention, naftopidil content is 12.5mg～100mg, preferred 25mg～50mg.The content and the naftopidil content of the medicinal precursor of naftopidil, naftopidil active metabolite, naftopidil salt or naftopidil esters can be equal to replacement, preferred hydrochloric acid naftopidil.
At a preferred composition provided by the invention, the content of amlodipine is 5mg, and naftopidil content is 25mg, or 50mg.
The dosage form of this pharmaceutical composition includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, the single chamber controlled release tablet, two chambers controlled release tablet, the pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/the position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, the capsule that contains micropill or small pieces, the pH dependent form capsule that contains micropill or small pieces, granule, oral liquid, dosage form such as membrane or patch, what should particularly point out is that the pharmaceutical composition that will contain naftopidil and amlodipine is made tablet, capsule or granule.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into oral formulations, comprise tablet, capsule, granule etc., described pharmaceutically acceptable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when making tablet, compositions as one or more materials of starch, microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, Icing Sugar, glucose, sodium chloride, cysteine, citric acid and sodium sulfite etc. belongs to this area general knowledge.
Find through a large amount of experiments, the pharmaceutical composition that amlodipine and naftopidil are formed has unexpected effect to treatment benign prostatic hyperplasia relevant disease, therefore, the invention provides the pharmaceutical composition that contains acceptable carrier on amlodipine, naftopidil and the pharmaceutics is used for preventing, treating and delay the medicine of benign prostatic hyperplasia relevant disease in preparation purposes.
Find through a large amount of experiments, the pharmaceutical composition that amlodipine and naftopidil are formed has unexpected effect to treatment hypertension companion benign prostatic hyperplasia: pharmaceutical composition provided by the invention has obvious synergism, one of its synergism is collaborative hypotensive effect, and its blood pressure lowering amplitude is respectively greater than the blood pressure lowering amplitude of two single medications; Two of its potentiation is the collaborative benign prostate hyperplasia shape effect that improves, and it improves the remarkable respectively effect of improvement respectively greater than two single medications of benign prostate hyperplasia shape effect.Therefore, the invention provides the pharmaceutical composition that contains acceptable carrier on amlodipine, naftopidil and the pharmaceutics is used for preventing, treating and delay the medicine of hypertensive patients benign prostatic hyperplasia relevant disease in preparation purposes.
In the present invention, the prostatic hyperplasia relevant disease comprises lower urinary tract syndrome, the lower urinary tract syndrome that prostatic hyperplasia, prostatic hyperplasia occur together.Prostatic hyperplasia and lower urinary tract syndrome connect each other on symptom, and the lower urinary tract syndrome that prostatic hyperplasia occurs together is complex interactions causes between prostate and bladder excitation, blocks symptom.The lower urinary tract syndrome that prostatic hyperplasia, prostatic hyperplasia occur together, lower urinary tract syndrome are complementary three diseases, are referred to as the prostatic hyperplasia relevant disease.
In such use provided by the invention, amlodipine becomes content of the present invention to create as a kind of active component with naftopidil with acceptable carrier mutual group on the pharmaceutics.Amlodipine can exist with the form of chemical compound, also can the medicinal precursor of amlodipine, forms such as amlodipine active metabolite or amlodipine salt exist.The preferred Amlodipine Besylate Tablet maleate of the salt of amlodipine.As the equivalents of amlodipine, above-mentioned substance is also in the scope of protection of present invention.
In such use provided by the invention, amlodipine content is 1～20mg, and preferred 2.5mg～10mg is more preferably 5mg～10mg.The content and the amlodipine content of the medicinal precursor of amlodipine, amlodipine active metabolite or amlodipine salt can be equal to replacement.
In such use provided by the invention, naftopidil becomes content of the present invention to create as a kind of active component with amlodipine with acceptable carrier mutual group on the pharmaceutics.Naftopidil can exist with the form of chemical compound, also can the medicinal precursor of naftopidil, forms such as naftopidil active metabolite, naftopidil salt or naftopidil esters exist.As the equivalents of naftopidil, above-mentioned substance is also in the scope of protection of present invention.
In such use provided by the invention, naftopidil content is 12.5mg～100mg, preferred 25mg～50mg.The content and the naftopidil content of the medicinal precursor of naftopidil, naftopidil active metabolite, naftopidil salt or naftopidil esters can be equal to replacement, preferred hydrochloric acid naftopidil.
The invention has the beneficial effects as follows: pharmaceutical composition provided by the invention has obvious potentiation, one of its potentiation is to work in coordination with and improves the effect of benign prostate hyperplasia shape, and it improves the respectively improvement effect of benign prostate hyperplasia shape effect greater than two single medications.Further, the present invention also provides pharmaceutical composition that above-mentioned amlodipine and naftopidil form to be used for preventing, treating and delay the purposes of the medicine of hypertensive patients benign prostatic hyperplasia relevant disease in preparation, for the patient of hypertensive patients benign prostatic hyperplasia provides a kind of feasible medicine.By enforcement of the present invention, the pharmaceutical composition that offers this special-purpose of patient can improve patient's compliance, and the patient is taken medicine conveniently, reduces medical expense, has better market prospect.
The specific embodiment
Embodiment 1Preparation contains the compound amlodipine naftopidil sheet of 2.5mg amlodipine and 25mg naftopidil
Prescription: amlodipine 2.5g
Naftopidil 25g
Lactose 50g
Microcrystalline Cellulose 50g
Starch 10g
Carboxymethyl starch sodium 30g
Magnesium stearate 1g
Preparation method: will contain 2.5g amlodipine (Amlodipine Besylate Tablet, available from pfizer inc (DaLian, China), its consumption is converted into the amount of the Amlodipine Besylate Tablet that contains the 5g amlodipine according to the molecular weight of the molecular weight of Amlodipine Besylate Tablet and amlodipine), 25g naftopidil (hydrochloric acid naftopidil, available from Anhui BBCA Pharmaceuticals Co., Ltd.), the 50g lactose, 50g Celluloasun Microcrystallisatum and 10g starch are pulverized the back uniform mixing, make soft material with 10% polyvidone alcoholic solution, granulate, dry, granulate, with water content is about 3% granule and magnesium stearate mix homogeneously, with the tablet machine compacting in flakes.Every contains amlodipine 2.5mg, naftopidil 25mg in 1000 compound tablet making, and its mass ratio is 1: 10.
Embodiment 2Preparation contains the compound amlodipine naftopidil capsule of 2.5mg amlodipine and 50mg naftopidil.
Prescription: amlodipine 2.5g
Naftopidil 50g
Lactose 100～200g
Carboxymethyl starch sodium 15～25g
10% polyvidone aqueous solution is an amount of
Magnesium stearate 1%
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get the Amlodipine Besylate Tablet that is equivalent to 2.5g amlodipine amount, naftopidil 50g is according to equivalent incremental method mix homogeneously, add 100～200g lactose, 15～25g carboxymethyl starch sodium (the definite consumption of adjuvant is adjusted according to the active medicine consumption), according to equivalent incremental method uniform mixing, make soft material with 10% polyvidone alcoholic solution, 20 mesh sieves are granulated, 60 ℃ of dry about 2h, 20 mesh sieve granulate, controlling particulate water content is 2-3%, with dried granule and recipe quantity magnesium stearate mix homogeneously, semi-finished product detect, and measure content, the Capsules of packing into promptly gets 1000 capsules.Note lucifuge in the preparation process.The qualified back of product inspection aluminium-plastic bubble plate packing keeps in Dark Place.Every contains 2.5mg amlodipine and 50mg naftopidil in the compound capsule of making.
Embodiment 3Preparation contains the compound amlodipine naftopidil granule of 2.5mg amlodipine and 75mg naftopidil
Prescription: amlodipine 2.5g
Naftopidil 75g
Lactose 850～950g
Carboxymethyl starch sodium 10～20g
Arabic gum 2g
10% polyvidone aqueous solution is an amount of
Orange flavor 2g
Aspartame 5g
Polyethylene Glycol 1%
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get the Amlodipine mesylate that is equivalent to 2.5g amlodipine amount, naftopidil 75g is according to equivalent incremental method mix homogeneously, add 850～950g lactose, 10～20g carboxymethyl starch sodium (the definite consumption of adjuvant is adjusted according to the active medicine consumption), according to equivalent incremental method uniform mixing, make soft material with 10% polyvidone alcoholic solution, 18 mesh sieves are granulated, 60 ℃ of dry about 2h, 16 mesh sieve granulate, controlling particulate water content is below 2%, with dried granule and recipe quantity orange flavor, aspartame, the magnesium stearate mix homogeneously, semi-finished product detect, and measure content, and the aluminum bag of packing into promptly gets 1000 bags.Note lucifuge in the preparation process.Every bag contains amlodipine 5mg and naftopidil 75mg in the compound granular agent of making.
Embodiment 4Preparation contains the compound amlodipine naftopidil sheet of 5mg amlodipine and 25mg naftopidil
Prescription: amlodipine 5g
Naftopidil 25g
Lactose 50g
Microcrystalline Cellulose 50g
Starch 10g
Carboxymethyl starch sodium 30g
Magnesium stearate 1g
Preparation method is identical with embodiment 1.Every contains amlodipine 5mg, naftopidil 25mg in 1000 compound tablet making, and its mass ratio is 1: 5.
Embodiment 5Preparation contains the compound amlodipine naftopidil sheet of 5mg amlodipine and 50mg naftopidil
Prescription: amlodipine 5g
Naftopidil 50g
Lactose 50g
Microcrystalline Cellulose 50g
Starch 10g
Carboxymethyl starch sodium 30g
Magnesium stearate 1g
Preparation method is identical with embodiment 1.Every contains amlodipine 5mg, naftopidil 50mg in 1000 compound tablet making, and its mass ratio is 1: 10.
Embodiment 6Preparation contains the compound amlodipine naftopidil sheet of 5mg amlodipine and 75mg naftopidil
Prescription: amlodipine 5g
Naftopidil 75g
Lactose 50g
Microcrystalline Cellulose 50g
Starch 10g
Carboxymethyl starch sodium 30g
Magnesium stearate 1g
Preparation method is identical with embodiment 1.Every contains amlodipine 5mg, naftopidil 75mg in 1000 compound tablet making, and its mass ratio is 1: 15.
Embodiment 7Preparation contains the compound amlodipine naftopidil sheet of 10mg amlodipine and 25mg naftopidil
Prescription: amlodipine 10g
Naftopidil 25g
Lactose 50g
Microcrystalline Cellulose 50g
Starch 10g
Carboxymethyl starch sodium 30g
Magnesium stearate 1g
Preparation method is identical with embodiment 1.Every contains amlodipine 10mg, naftopidil 25mg in 1000 compound tablet making, and its mass ratio is 1: 2.5.
Embodiment 8Preparation contains the compound amlodipine naftopidil sheet of 10mg amlodipine and 50mg naftopidil
Prescription: amlodipine 10g
Naftopidil 50g
Lactose 50g
Microcrystalline Cellulose 50g
Starch 10g
Carboxymethyl starch sodium 30g
Magnesium stearate 1g
Preparation method is identical with embodiment 1.Every contains amlodipine 10mg, naftopidil 50mg in 1000 compound tablet making, and its mass ratio is 1: 5.
Embodiment 9Preparation contains the compound amlodipine naftopidil sheet of 10mg amlodipine and 75mg naftopidil
Prescription: amlodipine 10g
Naftopidil 75g
Lactose 50g
Microcrystalline Cellulose 50g
Starch 10g
Carboxymethyl starch sodium 30g
Magnesium stearate 1g
Preparation method is identical with embodiment 1.Every contains amlodipine 10mg, naftopidil 75mg in 1000 compound tablet making, and its mass ratio is 1: 7.5.
Embodiment 10The compound amlodipine naftopidil is to the effect of BPH rat model
Animal and grouping SPF level male SD rat are divided into 5 groups, promptly blank (sham operated rats), model group, amlodipine group (0.5mg/kg), naftopidil group (2.5mg/kg), the amlodipine+naftopidil group (0.5mg/kg+2.5mg/kg) organized.By operation or the index determining progress of 5 rats every day, totally 5 groups of rats are divided into 20 batches of sequential carrying out.After modelling and administration model group, amlodipine group, naftopidil group, the compound recipe group rats by intraperitoneal injection 3.5% chloral hydrate 350mg/kg anesthesia, aseptic condition is extractd bilateral testes (castration) down, intramuscular injection penicillin 20,000 U/kg, for three days on end, castration operation only begins testosterone propionate 0.5mg/ that subcutaneous injection is dissolved in olive oil after 7 days, every day 1 time, continuous 21 days.Each administration group subcutaneous injection testosterone propionate was pressed 1ml100g after 7 days
-1The body weight gastric infusion, every day 1 time, continuous 14 days; Blank group and model group are irritated appearance normal saline such as stomach respectively.
Intrinsic pressure and the urine quantity measuring method of rat bladder is respectively organized 1.5 hours pneumoretroperitoneums of rat last administration and is injected 20% urethane (1gkg
-1) anesthesia, vertically cut on pubic arch top, expose bladder, at duck eye of bladder top thorn, insert the internal and external casing conduit, a conduit (trocar sheath, diameter 1.2mm) lead the physiology recording system by pressure receptor with PC-Lab links to each other more, another root conduit (inner sleeve, diameter 0.61mm) links to each other with the constant speed syringe pump and constant speed is paid close attention to normal saline, and rate of flooding is 2mlh
-1Each rat is write down indexs such as each urodynamics parameter and single voided volume respectively after in stable condition 0.5 hour.
Rat prostate assessment of indices rat is won its prostate veutro leaf, coagulation gland and dorsal part leaf respectively, and takes by weighing weight in wet base after measuring and finishing, and calculates the prostate index after the merging full weight as follows: prostate index=prostate weight in wet base (mg)/body weight (g)
The data statistics data represent that with Mean ± SD each is organized and relatively adopts variance analysis between each index.
Experimental result
To BPH rat model body weight, prostate weight in wet base and prostate is exponential influence modeling after, each organizes the rat body weight no significant difference.The model group rat is compared with blank group, and prostate weight in wet base and prostate index all significantly raise, and shows BPH model modeling success.Amlodipine, naftopidil list with and amlodipine, naftopidil combination prostate weight in wet base and prostate index are not all had obvious influence, illustrate that two single medicines and combination are not to play a role by dwindling prostate volume.The results are shown in Table 1.
Table 1 amlodipine naftopidil compositions is to the influence of BPH rat model body weight, prostate weight in wet base and prostate index (PI) (x ± s)
Compare * * P＜0.01 with model group
2. BPH rat model urination time, the influence of the blanking time of urinating are compared with blank group, model group urination time significant prolongation, significantly shorten the blanking time of urinating.With model group relatively, amlodipine group significant prolongation blanking time of urinating, urination time has certain shortening; Naftopidil group urination time significantly shortens, significant prolongation blanking time of urinating; Amlodipine+naftopidil group rat urine time significantly shortens, and has further than two single medicine groups and significantly improves.Amlodipine+naftopidil group rat urine significant prolongation blanking time has significant significant difference than two single medicine group exercising results.See Table 2.
Table 2 amlodipine naftopidil compositions is to BPH rat urine time and the influence of urinating blanking time (x ± s)
Compare * P＜0.05, * * P＜0.01 with model group; Compare #P＜0.05 with the amlodipine group;
Compare ， $P＜0.05 with the naftopidil group
To BPH rat urine point press, the voltage crest of urinating value and single voided volume influence model group and blank group relatively, urinate and press and the voltage crest value of urinating all significantly raises.Compare with model group, amlodipine group, naftopidil group rat urine point are pressed and the voltage crest value of urinating all significantly reduces; Compare with amlodipine group, naftopidil group, amlodipine+naftopidil group rat urine point is pressed and the voltage crest value of urinating further significantly reduces, and the result has significant significant difference.
Compare with model group, amlodipine group, naftopidil group rat single voided volume significantly do not increase (P＞0.05); Amlodipine+naftopidil group rat single voided volume significantly increases (P＜0.01).Compare with amlodipine group, naftopidil group, amlodipine+naftopidil group rat single voided volume further increases.See Table 3.
Table 3 amlodipine naftopidil compositions is pressed by BPH rat urine point and the influence of the voltage crest value of urinating (x ± s)
Compare * P＜0.05, * * P＜0.01 with model group; Compare #P＜0.05 with the amlodipine group;
Compare ， $P＜0.05 with the naftopidil group
Embodiment 11 compound recipe naftopidil amlodipines merge the effect of BPH to spontaneous hypertensive rat
Animal and grouping spontaneously hypertensive (SHR) rat are divided into 5 groups, promptly blank (sham operated rats), model group, amlodipine group (0.5mg/kg), naftopidil group (5mg/kg), the amlodipine+naftopidil group (0.5mg/kg+5mg/kg) organized.By operation or the index determining progress of 5 rats every day, totally 5 groups of rats are divided into 20 batches of sequential carrying out.After modelling and administration model group, amlodipine group, naftopidil group, the compound recipe group rats by intraperitoneal injection 3.5% chloral hydrate 350mg/kg anesthesia, aseptic condition is extractd bilateral testes (castration) down, intramuscular injection penicillin 20,000 U/kg, for three days on end, castration operation only begins testosterone propionate 0.5mg/ that subcutaneous injection is dissolved in olive oil after 7 days, every day 1 time, continuous 21 days.Each administration group subcutaneous injection testosterone propionate was pressed 1ml100g after 7 days
-1The body weight gastric infusion, every day 1 time, continuous 14 is big; Blank group and model group are irritated appearance normal saline such as stomach respectively.
Intrinsic pressure and the urine quantity measuring method of rat bladder is respectively organized rat art time 1.5 hours pneumoretroperitoneums of administration and is injected 20% urethane (1gkg
-1) anesthesia, vertically cut on pubic arch top, expose bladder, at duck eye of bladder top thorn, insert the internal and external casing conduit, a conduit (trocar sheath, diameter 1.2mm) lead the physiology recording system by pressure receptor with PC-Lab links to each other more, another root conduit (inner sleeve, diameter 0.61mm) links to each other with the constant speed syringe pump and constant speed is paid close attention to normal saline, and rate of flooding is 2mlh
-1Each rat is write down indexs such as each urodynamics parameter and single voided volume respectively after in stable condition 0.5 hour.
Rat prostate assessment of indices rat is won its prostate veutro leaf, coagulation gland and dorsal part leaf respectively, and takes by weighing weight in wet base after measuring and finishing, and calculates the prostate index after the merging full weight as follows: prostate index=prostate weight in wet base (mg)/body weight (g)
The data statistics data represent that with Mean ± SD each is organized and relatively adopts variance analysis between each index.
Experimental result
To SHR merge BPH rat body weight, prostate weight in wet base and prostate index (PI) influence modeling after, each organizes the rat body weight no significant difference.The model group rat is compared with blank group, and prostate weight in wet base and prostate index all significantly raise, and shows that SHR merges BPH rat model modeling success.Amlodipine, naftopidil list with and amlodipine, naftopidil combination prostate weight in wet base and prostate index are not all had obvious influence, illustrate that two single medicines and combination are not to play a role by dwindling prostate volume.The results are shown in Table 4.
Table 4 amlodipine naftopidil compositions merges the influence (x ± s) of BPH rat body weight, prostate weight in wet base and prostate index (PI) to SHR
Compare * * P＜0.01 with model group
2. SHR is merged the model group that influences of BPH rat urine time, the blanking time of urinating and compare with blank group, the urination time significant prolongation, significantly shorten the blanking time of urinating.With model group relatively, amlodipine group, naftopidil group rat urine time significantly shorten, amlodipine group significant prolongation blanking time of urinating.Compare with amlodipine group, naftopidil group, amlodipine+naftopidil group rat urine time further shortens, the blanking time of urinating further significant prolongation; Wherein urinate blanking time index and two single medicine groups significant difference is relatively arranged.See Table 5.
Table 5 amlodipine naftopidil compositions is to BPH rat urine time and the influence of urinating blanking time (x ± s)
Compare * P＜0.05, * * P＜0.01 with model group; Compare #P＜0.05 with the amlodipine group;
Compare ， $P＜0.05 with the naftopidil group
3. SHR is merged that BPH rat urine point is pressed and the voltage crest value of urinating influence model group and blank group relatively, urinate and press and all significantly risings of voltage crest value of urinating.Compare with model group, amlodipine group, naftopidil group rat urine point are pressed and the voltage crest value of urinating significantly reduces.Compare with amlodipine group, naftopidil group, amlodipine+naftopidil group rat urine point is pressed and the voltage crest value of urinating further significantly reduces, and than two single medicine groups significant significant difference is arranged.Compare with model group, amlodipine group, naftopidil group rat single voided volume are increase trend, compare with amlodipine group, naftopidil group, amlodipine+naftopidil group rat single voided volume further increases, and has compared significant difference with the amlodipine group.See Table 6.
Table 6 amlodipine naftopidil compositions is pressed by BPH rat urine point and the influence of the voltage crest value of urinating (x ± s)
Compare * P＜0.05, * * P＜0.01 with model group; Compare #P＜0.05 with the amlodipine group;
Compare ， $P＜0.05 with the naftopidil group
4, before the influence that SHR is merged the BPH rat blood pressure and the medicine blood pressure relatively, each administration group blood pressure is significantly reduction all; The amlodipine antihypertensive effect significantly is better than the naftopidil group; Amlodipine+naftopidil group antihypertensive effect significantly is better than amlodipine group or naftopidil group, and shows tangible significant difference.The results are shown in Table 7.
Table 7 amlodipine naftopidil compositions merges the influence (x ± s) of BPH rat blood pressure to SHR
Compare with model group,
*P＜0.01; Compare #P＜0.05 with the amlodipine group; Compare ， $P＜0.05 with the naftopidil group
In embodiment 10 and the every index of 11 urodynamicss, the rat urine time shortens, a pressure drop of urinating is low mainly to have reflected the improvement of medicine to bladder outlet obstruction (BOO) symptom (BOO) with the increase of single voided volume, the prolongation of urinating blanking time has mainly reflected the inhibition of medicine to being overexcited property of detrusor of bladder (OAB), the reduction of the voltage crest of urinating value has reflected the medicine improvement that block at the bladder outlet position when urinating on the one hand, has also reflected the inhibition to being overexcited property of body of bladder smooth muscle on the other hand.
This result of study shows: amlodipine, naftopidil list use the SD rat that suffers from BPH or the SHR rat urine point of suffering from BPH is pressed and the voltage crest value of urinating all has clear and definite improvement effect, amlodipine naftopidil combination demonstrates the improvement effect than the more remarkable improvement of single medicine group, the prompting compound recipe to BPH cause block symptom and irritation all can further improve.
Simultaneously, SD rat that suffers from BPH or the SHR rat urine time of suffering from BPH can be significantly shortened in the combination of amlodipine naftopidil, and significant prolongation is urinated blanking time.Compare with amlodipine or naftopidil with single, the combination of amlodipine naftopidil has further improvement significantly to act on to each index, the prolongation of significance is particularly all arranged than amlodipine, naftopidil list medicine group on index blanking time of urinating, also further reacted amlodipine naftopidil combination and not only blocked aspect the symptom, and demonstrated tangible effect characteristics aspect the bladder excessive activities irritation improving in improvement.Simultaneously, the SHR rat single voided volume that the combination of amlodipine naftopidil can obviously increase the SD rat that suffers from BPH or suffer from BPH is compared with amlodipine or naftopidil with single, demonstrates more obvious advantage.When improving the BPH symptom, the amlodipine naftopidil makes up than two medicines respectively singly with bringing high blood pressure down more significantly.
In sum, the combination of amlodipine naftopidil is compared with amlodipine or naftopidil list medicine group, can control or improve blocking and bladder excessive activities irritation and blood pressure that BPH causes further, comprehensively and effectively, significantly is better than the action effect of single medicine.
Claims (9)
1. a pharmaceutical composition contains acceptable carrier on amlodipine, naftopidil and the pharmaceutics.
2. according to the pharmaceutical composition described in the claim 1, it is characterized in that: described amlodipine content is 1～10mg, preferred 5～10mg.
3. according to the pharmaceutical composition described in the claim 1, it is characterized in that: described naftopidil content is 12.5～100mg, preferred 25～50mg.
4. pharmaceutical composition according to claim 1 is characterized in that the pharmacy dosage form of described pharmaceutical composition is an oral formulations, comprises tablet, capsule or granule.
5. the pharmaceutical composition that contains acceptable carrier on amlodipine, naftopidil and the pharmaceutics is used for preventing, treating and delay the purposes of the medicine of benign prostatic hyperplasia relevant disease in preparation.
6. the pharmaceutical composition that contains acceptable carrier on amlodipine, naftopidil and the pharmaceutics is used for preventing, treating and delay the purposes of the medicine of hypertensive patients benign prostatic hyperplasia relevant disease in preparation.
7. according to each described purposes in claim 5 or 6, it is characterized in that: described prostatic hyperplasia relevant disease comprises lower urinary tract syndrome, the lower urinary tract syndrome that prostatic hyperplasia, prostatic hyperplasia occur together.
8. purposes according to claim 7 is characterized in that: described amlodipine content is 1～10mg.
9. purposes according to claim 7 is characterized in that: described naftopidil content is 25～100mg.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101130929A CN101590045A (en) | 2008-05-27 | 2008-05-27 | The medical composition and its use that contains amlodipine and naftopidil |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008101130929A CN101590045A (en) | 2008-05-27 | 2008-05-27 | The medical composition and its use that contains amlodipine and naftopidil |
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| CNA2008101130929A Pending CN101590045A (en) | 2008-05-27 | 2008-05-27 | The medical composition and its use that contains amlodipine and naftopidil |
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Open date: 20091202 |