CN104224788A - Medicinal composition of indapamide and folic acid and application of medicinal composition - Google Patents
Medicinal composition of indapamide and folic acid and application of medicinal composition Download PDFInfo
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- CN104224788A CN104224788A CN201410514004.1A CN201410514004A CN104224788A CN 104224788 A CN104224788 A CN 104224788A CN 201410514004 A CN201410514004 A CN 201410514004A CN 104224788 A CN104224788 A CN 104224788A
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Abstract
The invention relates to a medicinal composition prepared from indapamide, folic acid and a medicinally available carrier, and application of the composition for preparing a drug for treating hypertension with hyperhomocysteinemia and a disease of homocysteine rising. In the composition, the preferable content of indapamide is 0.625-2.5 mg, and the preferable content of folic acid is 0.4-0.8 mg. The medicinal composition disclosed by the invention has the benefits that indapamide and folic acid can be combined to reduce blood pressure, obviously lower level of homocysteine and raise the level of folic acid, so as to relieve damage of homocysteine to the blood vessel, strengthen targeted organ protection for a hypertension patient, and play a pharmacologic synergistic role. In addition, the medicinal composition can further allow the patient to take medicine conveniently and reduce the medical costs.
Description
Technical field
The present invention relates to the pharmaceutical composition be made up of indopamide and folic acid and the purposes raised at preparation treatment hypertension complicated hyperhomocysteinemiainjury or homocysteine in the medicine of disease thereof.Belong to pharmaceutical field.
Background technology
Hypertension is one of modal chronic disease, also be the topmost risk factor of cardiovascular and cerebrovascular disease, the disabling of the major complications (target organ damage) such as its apoplexy, myocardial infarction, heart failure and chronic kidney disease, fatality rate are high, serious consumption medical resource, brings heavy burden to family and society.Hypertensive major therapeutic goals reduces the generation of cardiovascular complication and dead overall danger to greatest extent, need to treat all reversibility cardiovascular risk factors, subclinical target organ damage and the various and clinical disease deposited [Chinese hypertension prevention and control guide revision committee. Chinese hypertension prevention and control guide 2010. Chinese Journal of Cardiology, 2011; 39 (7): 579 ~ 616].
The conventional antihypertensive drug of China's hypertension prevention and control Guidelines recommend comprises five large classes, that is: calcium antagonist (CCB), angiotensin converting enzyme inhibitor (ACEI), Angiotensin Ⅱ receptor antagonist (ARB), diuretic and beta-blocker, or the compound preparation of the fixed dosage be made up of these medicines.Most hyperpietics need two or more antihypertensive drug to reach the target controlling blood pressure, and two kinds of medicines can prescription or be the compound preparation of fixed dosage separately.International clinical trial proves that drug combination has it to need and is worth, and the dosage of often kind of medicine is little, and the therapeutical effect of medicine has concertedness or is at least added, and untoward reaction can cancel out each other or reduce.
At hypertension prevention and control joint committee of the U.S. [Chobanian AV, et al.The seventh report of Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure:the JNC7Report.JAMA, 2003; 289 (19): 2560 ~ 2572], in the drug combination recommended of heart of Europe association/Society of Hypertension and China 2010 Hypertension Guideline, concerted application of drugs more than half employs diuretic.In hypertension therapeutic, the use of people to diuretic lives through setback.Within 1978, thiazide diuretic was once classified as a line depressor by World Health Organization (WHO), was often applied to separately and treated light, moderate hypertension.But clinical practice finds, long-term or larger dose uses diuretic can cause electrolyte disturbance (as low blood sodium, hypokalemia), and about 30% also impaired glucose tolerance etc. occurs.Therefore, along with the appearance of CCB, ACEI, ARB class antihypertensive, the use of diuretic significantly reduces.But find in clinical practice, antihypertensive drugs based on low-dose diuretic, it may be the basis that other antihypertensive drugs play curative effect that the effective blood volume that it causes reduces, so start again to pay attention to diuretic use [angiocardiology branch of Chinese Medical Association hypertension group. the hypertensive Chinese Consensus of experts of diuretic therapy. Chinese hypertension magazine, 2011; 19 (3): 214 ~ 222].
Indopamide (also known as indapamide, Indapamide) is a kind of thiazine sample diuretic, and Indolinyl derivative, has diuresis and calcium antagonism, for a kind of newly, stronger long-acting depressor.Indopamide is lax vascular smooth muscle by retardance Ca2+ influx, peripheral vascular resistance is declined, produce pressure reduction effect, and by suppressing distal renal tubular cortex dilution section absorb water and eletrolytes again and play diuresis, therefore the side effect such as long-term taking also can produce hypokalemia, hypochloremic alkalosis, blood uric acid increase.Therefore, the clinical Benefit/Hazard ratio of hyperpietic's prolonged application indopamide needs to be further improved.
Survey data shows, and China about 75% hyperpietic often merges hyperhomocysteinemiainjury, has people that the hypertension of this type is referred to as H type hypertension.Epidemiological study is pointed out, homocysteine (homocysteine in blood, being called for short Hcy) level raises or folate level reduction raises relevant [Sun Y with the danger of coronary heart disease, apoplexy, et al.Use of serum homocysteine to predict stroke, coronary heart disease and death in Ethnic Chinese:a 12-year prospective cohort study.Circ J.2009; 73:1423-1430].As aforementioned, the object of hypertension therapeutic mainly reduces the danger of cardiovascular complication, therefore target control treatment is no doubt important, but target-organ protection is final goal, needs to intervene various cardiovascular risk factors, target organ damage or cohesive disease.Therefore, improve indopamide further to the target organ protection function of hyperpietic, reduce the cardiovascular event risk that H type hypertension causes, there is important clinical meaning and social meaning.
Summary of the invention
The object of the invention is to overcome the deficiency that indopamide exists when treating H type hypertension, provide a kind of target-organ protection and reduce cardiovascular event dangerous in better and pharmaceutical composition that side effect does not increase.
For achieving the above object, the present invention intends by the following technical solutions:
A kind of pharmaceutical composition, constituent is
(1) indopamide of pharmaceutical dosage;
(2) folic acid (folic acid) of pharmaceutical dosage; And
(3) acceptable carrier on pharmaceutics.
Above-mentioned " pharmaceutical dosage " refers to the amount of pharmacological action with collaborative, prevention or treatment.
In compositions of the present invention, the content of indopamide is 0.2mg ~ 5mg, and its better content is 0.625mg ~ 2.5mg.
In compositions of the present invention, described folate content is 0.2 ~ 5mg, and its better content is 0.4 ~ 0.8mg.
According to the present invention, active component in pharmaceutical composition is the solvent in compositions, one of them active component is indopamide, another active component is folic acid, the dosage form of this pharmaceutical composition includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, single chamber controlled release tablet, two rooms controlled release tablet, 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/position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, capsule containing micropill or small pieces, pH dependent form capsule containing micropill or small pieces, oral liquid, membrane or patch, should it is emphasized that, pharmaceutical composition containing indopamide and folic acid is made tablet or capsule.
Also containing pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., when making tablet, described pharmaceutically suitable carrier comprises the excipient and accessory drugs that contribute to reactive compound being mixed with pharmaceutical formulation, as the compositions of one or more materials of microcrystalline Cellulose, inorganic salts, lactose, sodium chloride, citric acid and sodium sulfite etc., belong to this area general knowledge.
Also containing pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into slow releasing preparation, comprise excipient and adjuvant etc.The adjuvant that described excipient and adjuvant have comprised slow releasing function be the solubility/insoluble salt of hydroxypropyl methylcellulose and/or ethyl cellulose and/or polyacrylic resin class and/or polycarboxy ethene and/or alginic acid and/or ethyl cellulose and/or other play the adjuvant of slow releasing function, hypromellose adopts the many shows of the extensive stock U.S. as all size (Methocel) including hydroxypropyl methylcellulose (HPMC), ethyl cellulose adopts the extensive stock including ethyl cellulose (EC), polyacrylic resin adopts and includes polyacrylic resin Ⅱ, III class or analog are as the acrylic resin (Eudragit) of all size.
Also containing pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into controlled release preparation, comprise the adjuvant of active medicine and a controlled-release function.The adjuvant of above-mentioned controlled-release function is polyoxyethylene and/or hypromellose and/or ethyl cellulose and/or sodium chloride and/or lactose and/or mannitol and/or fructose and/or glucose and/or sucrose or low-substituted hydroxypropyl cellulose and/or cross-linking sodium carboxymethyl cellulose and/or crospolyvinylpyrrolidone and/or cellulose acetate.Above-mentioned adjuvant is pharmaceutical carrier, expanding material, permeation-promoter, solubilizing agent, binding agent, wetting agent, lubricant, coloring agent, porogen, membrane material, antiplastering aid, plasticizer, lucifuge agent, solvent.Pharmaceutical carrier, expanding material can adopt polyoxyethylene, hypromellose, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, Glyceryl Behenate class etc.; Permeation-promoter can adopt sodium chloride, lactose, mannitol etc.; Solubilizing agent can adopt sodium lauryl sulphate or poloxamer etc.; Binding agent can adopt polyvinylpyrrolidone, hypromellose, chitosan, sodium alginate, methylcellulose, ethyl cellulose, starch slurry, arabic gum, gelatin, sucrose, polyvinyl alcohol etc.; Wetting agent can adopt the ethanol-water solution of dehydrated alcohol, water, various concentration; Lubricant can adopt stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin etc.; Coloring agent can adopt the natural pigment and synthetic dyestuff etc. such as carmine, amaranth, lemon yellow, bright orchid, indigo, brownish red ferrum oxide; Porogen can adopt sucrose, mannitol, Polyethylene Glycol, titanium dioxide, Pulvis Talci, silicon dioxide etc.; Membrane material can adopt cellulose acetate, ethyl cellulose, HPMCAS, beautiful jade Cellulose Acetate Phthalate, poly-phthalic acid vinyl acetate cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose etc.; Solvent can adopt acetone, dehydrated alcohol, ethanol, water etc.
Also containing pharmaceutics acceptable carrier in said composition, can be made into sublingual lozenge, oral cavity quick disintegrating slice or dispersible tablet etc.; Comprise excipient and adjuvant etc.Described excipient and adjuvant have mannitol, sorbitol, maltose alcohol, low substituted hydroxy-propyl methylcellulose, microcrystalline Cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, process agar, cyclodextrin, glycyrrhizic acid, stevioside, citric acid, Oleum menthae, eucalyptus oil, Oleum Caryophylli, Fructus Citri Limoniae oil, citrus seed oil and some other correctives etc. with microcapsule parcel.
Also containing pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into enteric coatel tablets or enteric coated capsule etc., comprise excipient and adjuvant etc., described excipient and adjuvant have starch, microcrystalline Cellulose, inorganic salts, hydroxypropyl emthylcellulose, ethyl cellulose, polyacrylic resin class, polycarboxy ethene, solubility/insoluble the salt of alginic acid, octadecanol, stearic acid, sodium chloride, cysteine, the compositions of one or more materials of citric acid and sodium sulfite etc., enteric-coating material comprises: Lac, CAP, crylic acid resin (as Eudragit L and S type etc.), polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate, succinic acid acetic acid hydroxypropyl methylcellulose, and plasticizer is (as diethyl phthalate, Polyethylene Glycol, propylene glycol, glycerol triacetate, dimethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, CitroflexA-2, the acetylated monoglycerides etc. of Oleum Ricini and various percentage ratio) with the various medicaments adjuvant such as porogen (as PEG6000).
Also containing pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into delayed-release tablet or timing (position) releasing piece, comprise excipient and adjuvant, described excipient and adjuvant have starch, microcrystalline Cellulose, inorganic salts, hydroxypropyl emthylcellulose, ethyl cellulose, polyacrylic resin class, polycarboxy ethene, solubility/insoluble the salt of alginic acid, octadecanol, stearic acid, sodium chloride, cysteine, the compositions of one or more materials of citric acid and sodium sulfite etc., the coating material that a described delayed release or timing (position) discharge comprises: Lac, CAP, ethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, crylic acid resin (as Eudragit L and S type etc.), polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate, succinic acid acetic acid hydroxypropyl methylcellulose, polyvinyl acetate phthalic acid ester, and plasticizer is (as diethyl phthalate, Polyethylene Glycol, propylene glycol, glycerol triacetate, dimethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, CitroflexA-2, the acetylated monoglycerides etc. of Oleum Ricini and various percentage ratio) with porogen (as PEG1000, PEG4000, the various medicaments adjuvant such as PEG6000).
Also containing pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into slow releasing capsule, controlled release capsule, the capsule containing micropill or small pieces, the pH dependent form capsule etc. containing micropill or small pieces, comprise excipient and adjuvant, described excipient and adjuvant have starch, microcrystalline Cellulose, inorganic salts, hydroxypropyl emthylcellulose, ethyl cellulose, polyacrylic resin class, polycarboxy ethene, solubility/insoluble the salt of alginic acid, octadecanol, stearic acid, sodium chloride, cysteine, the compositions of one or more materials of citric acid and sodium sulfite etc., coating material comprises: Lac, CAP, ethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, crylic acid resin (as Eudragit L and S type etc.), polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate, succinic acid acetic acid hydroxypropyl methylcellulose, polyvinyl acetate phthalic acid ester, and plasticizer is (as diethyl phthalate, Polyethylene Glycol, propylene glycol, glycerol triacetate, dimethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, CitroflexA-2, the acetylated monoglycerides etc. of Oleum Ricini and various percentage ratio) with the various medicaments adjuvant such as porogen (as PEG6000).
Also containing pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into the dosage forms such as granule, oral liquid, membrane, patch.When making patch membrane, described pharmaceutically acceptable carrier comprises the excipient and adjuvant that contribute to reactive compound being mixed with pharmaceutical formulation; as polyvinyl alcohol, Triafol T, ethylene-vinyl acetate copolymer, polyvinylpyrrolidone, polyacrylamide, polybutene class pressure sensitive adhesive, crylic acid resin pressure sensitive adhesive, silicone pressure sensitive adhesive etc.; and the back lining materials such as polrvinyl chloride, polyethylene, aluminium foil, polypropylene, polyester, the compositions of one or more materials of the protecting film such as polyethylene, polystyrene, polypropylene etc.
Compound in pharmaceutical composition provided by the invention can grant diseased individuals in identical preparation simultaneously, also in succession grants diseased individuals discriminably.If in succession grant diseased individuals, then the loss of the beneficial effect that the delay that second (or additional) active component is granted should not cause active ingredient combination to bring.If grant diseased individuals simultaneously, the compound in compositions can mix and is present in same pharmaceutical dosage forms, also independently can exist with same dosage form.If independently exist with same dosage form, then pharmaceutical composition can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of one or more dosage forms built-in and operation instructions thereof.Select the compound tablet of indopamide and folic acid composition in the present invention.
Another object of the present invention is to provide the purposes of compositions in the medicine preparing treatment hypertension complicated height Hcy mass formed by blood stasis or Hcy rising disease containing indopamide and folic acid.
Beneficial effect of the present invention: there is no the special-purpose medicaments for the treatment of high Hcy mass formed by blood stasis clinically at present; indopamide and folic acid share not only can blood pressure lowering, but also significantly can reduce plasma Hcy level and promote plasma folic acid level; thus alleviate Hcy to the damage of blood vessel; strengthen target-organ protection; the two has pharmacology's synergism, and fills up the blank that high Hcy mass formed by blood stasis medicine is treated by China.
Below in conjunction with detailed description of the invention, the present invention will be further described, not limitation of the invention, and the equivalent replacement of all any this areas of carrying out according to content of the present invention, all belongs to protection scope of the present invention.
Detailed description of the invention
Embodiment 1: prepare indopamide/folic acid (1.25mg/0.4mg) sheet (1000)
Formula forms:
Preparation technology:
Folic acid is mixed homogeneously with indopamide equal increments, adds lactose, microcrystalline Cellulose, pregelatinized Starch mix homogeneously, soft material is made with 10% appropriate polyvidone alcoholic solution, granulation, dry, granulate, by water content be about 3% granule mix homogeneously with appropriate magnesium stearate, make 1000 and get final product according to a conventional method.
Embodiment 2: prepare indopamide/folic acid (2.5mg/0.8mg) sheet (1000)
Formula forms:
Preparation technology is with embodiment 1.
Embodiment 3: prepare indopamide/folic acid (2.5mg/0.8mg) capsule (1000)
Formula forms:
Preparation technology:
According to prescription proportioning, get lactose, microcrystalline Cellulose, carboxymethylstach sodium in about 100 DEG C difference drying about 2 hours, carboxymethylstach sodium crosses 100 mesh sieves, and lactose, microcrystalline Cellulose cross 80 mesh sieves; After crude drug being crossed 100 mesh sieves with above-mentioned adjuvant mixture by mixing homogeneously, granulate, then mix homogeneously, with No. 3 capsule fills with appropriate mountain acid glyceride of healing.Make 1000 and get final product.
Embodiment 4: compound recipe indopamide folic acid is to the curative effect of H type hypertensive rat model
One, method
Animal Model: spontaneous hypertensive rat (SHR) is purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center, after 8 week age, rat blood pressure raises, and significantly raises after 10 week age, surveys rat blood pressure 1 week, get the rat of blood pressure stabilization for experiment, body weight is 210 ~ 260g about.The grouping of SHR rat and dosage are in table 1, and wherein SHR matched group (n=13) gives chow diet, and other group gives homomethionin feedstuff (modeling of high Hcy mass formed by blood stasis), measure the forward and backward each time period blood pressure of rat administration respectively.
Grouping and administration: each group gives indopamide (0.25mg/kg), folic acid (0.08mg/kg), indopamide+folic acid (0.25mg+0.08mg/kg), gastric infusion, every day 1 time, continuous 6 weeks respectively.All the other two group model groups and normal group give normal saline respectively.After last administration, Biochemical Indexes is carried out in ventral aorta blood sampling.
Two, result
Result shows, compares with SHR matched group, and other methionine feed group Hcy all significantly raises, prompting H type hypertension modeling success.Indopamide group hypotensive effect is obvious, but Hcy is not made significant difference, folic acid group is without remarkable hypotensive effect, but can significantly reduce Hcy level, indopamide+folic acid group blood pressure lowering, to fall Hcy effect all remarkable, and fall Hcy effect and be better than folic acid group, show that indopamide+folic acid has cooperative effect falling on Hcy.In table 1,2.
Table 1 indopamide+folic acid is to the hypotensive activity (x ± s) of H type Hypertensive Rats
Note: compare with matched group,
*p<0.05,
*p<0.01
Table 2 indopamide+folic acid is to the Hcy effect of falling (x ± s) of H type Hypertensive Rats
Note: compare with SHR matched group baseline,
*p<0.05; Compare with indopamide group,
▲p<0.01, compares with folic acid group,
☆p<0.05.
Embodiment 5: compound recipe indopamide folic acid is to the target organ protection function of Two-kidney One-clip (2K1C) Hypertensive Rats
One, method
(1) 2K1C hypertensive rat model prepares chloral hydrate (320mg/kg) intraperitoneal injection of anesthesia Wistar rat (male and female half and half, 150 ~ 180g), abdominal cavity is opened along abdomen median line, be separated left renal artery, the narrow rat left renal artery of 0.2mm silver brain clip, gets contractive pressure >=140mmHg person for postoperative 8 ~ 10 weeks for Hypertensive Rats.(2) 2K1C rat 56 is got in grouping and administration, divide equally 4 groups, often organize 14, for model control group, indopamide (0.25mg/kg) group, indopamide+folic acid (0.25+0.04mg/kg), folic acid (0.04mg/kg) group, separately get 14 normal rats as Normal group.Every day gastric infusion 1 time, Normal group, hypertension group such as to give at the capacity distilled water, successive administration 26 weeks.(3) Testing index 1. pressure value: adopt tail cover method, before measuring administration respectively with 179 type non-damage toy blood pressure measuring instrument, administration the 1st, 5,9,13,18,22,26 weeks rat blood pressures, each mensuration 3 times, averages.2. endothelial function: 26 weekends, gets blood by test kit description, measures Plasma Nitric Oxide (NO), Endothelin (ET) level.3. renal function: 26 weekends, collects urine, and survey urine protein, 24h urinate α
1microglobulin, urine creatine.4. pathologic finding: to core, the internal organs such as kidney, spleen, brain, 10% formalin is fixed, paraffin embedding, section, and HE dyes, light microscopy checking.(4) statistical analysis calculates each group of mean and standard deviation respectively, and administration group and matched group carry out t inspection.
Two, result
(1) impact of indopamide+folic acid on hypertensive rat blood pressure is compared with normal group, and model group rats blood pressure significantly raises, and folic acid group blood pressure slightly reduces, and wherein within the 5th, 9 week, has significant difference.Indopamide group, indopamide+folic acid group rat blood pressure significantly reduces, and comparing with model group has significant difference.Compare with indopamide group, indopamide+folic acid group blood pressure reduces further, and wherein the 9th, 13,18,22,26 week time point compares significant difference.Show that folic acid is alone and have slight hypotensive effect, indopamide significantly can reduce rat blood pressure, and folic acid and indopamide share for a long time, strengthens the hypotensive effect of renal hypertensive rat.
(2) impact of indopamide+folic acid on Hypertensive Rats blood plasma NO, ET level is compared with normal rats, and hypertension group rat plasma NO level significantly reduces, and ET level significantly raises.Compare with hypertension model group, folic acid group, indopamide group rat plasma NO rising, ET reduce.Indopamide+folic acid group rat plasma NO raises further; ET reduces further, and show that renal hypertensive rat has occurred that inner skin cell function damages, indopamide, folic acid on rats inner skin cell function have protective effect; both share and this protective effect are strengthened, in table 3.
Table 3 indopamide+folic acid is on the impact (X ± SD) of Hypertensive Rats blood plasma NO, ET level
Compare with normal group,
*p<0.01; Compare with model group,
▲p<0.05,
▲ ▲p<0.01; Compare with indopamide group,
★p<0.05
(3) indopamide+folic acid affects twenty-four-hour urine α to Hypertensive Rats renal function
1microglobulin is the label reflecting early stage injury of renal tubular.Compare with normal rat, Hypertensive Rats urine 24h α
1-microglobulin, urine protein significantly raise.Indopamide group rat urine 24h α
1-microglobulin, urine protein reduce, and folic acid is alone to be had no significant effect renal hypertensive rat renal function.Indopamide+folic acid group rat urine 24h α
1-microglobulin, urine protein reduce further; compare with indopamide group that there were significant differences; show that renal hypertensive rat occurs that Renal function in early period damages; the renal function injury of indopamide to Hypertensive Rats has protective effect; folic acid and indopamide share, and strengthen the protecting renal function effect of renal hypertensive rat.In table 4 ~ 5.
Table 4 indopamide+folic acid administration 26 weeks urinates α to Hypertensive Rats
1the impact (X ± SD) of-microglobulin
Compare with normal group,
*p<0.01; Compare with model group,
▲ ▲p<0.01; Compare with indopamide group,
★p<0.05,
★ ★p<0.01
The table 5 indopamide+impact of folic acid successive administration 26 weeks on Hypertensive Rats urinaryalbumin (X ± SD)
Compare with normal group,
*p<0.01; Compare with model group,
▲p<0.05,
▲ ▲p<0.01; Compare with indopamide group,
★p<0.05,
★ ★p<0.05
(4) the histopathological examination normal rats heart, kidney, brain, spleen are showed no obvious change.Model group rats cardiac myocyte hypertrophy, thicker, elongated, core is engrain greatly, and part myocardial cell has cellular edema (showing as cloudy swelling or hydropic degeneration), minority animal coronary atherosclerosis; The kidney major part glomerule fibrosis of being pressed from both sides, vitreous degeneration or blood capillary ball are lobulated, sacculus parietal layer epithelial proliferation, and corresponding renal tubules atrophy, even disappears; Part glomerule compensatory hypertrophy, tubular ectasia; Arteriole and arteriolosclerosis, interstitial fibers hamartoplasia, lymphocytic infiltration; Opposite side nephropathy is not obvious, and glomerule is slightly loose; Spleen central artery vitreous degeneration; The brain arteriolosclerosis of Some Animals, minority is shown in capillary proliferation.The above-mentioned pathological changes of administration group rat all has and alleviates in various degree: the target organ damage of alone folic acid to renal hypertensive rat has slight protective effect; the target organ damage of indopamide to Hypertensive Rats has protective effect, and folic acid and indopamide share and strengthen further the target organ protection function of renal hypertensive rat.
Claims (5)
1. a pharmaceutical composition, constituent is:
(1) indopamide of pharmaceutical dosage;
(2) folic acid of pharmaceutical dosage; And
(3) acceptable carrier on pharmaceutics.
2. compositions according to claim 1, is characterized in that: the content of described indopamide is 0.2mg ~ 5mg, preferred 0.625mg ~ 2.5mg.
3. compositions according to claim 1, is characterized in that: the content of described folic acid is 0.2mg ~ 5mg, preferred 0.4mg ~ 0.8mg.
4. the compositions according to any one of claims 1 to 3, is characterized in that: said composition can be made into conventional tablet, conventional capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, slow releasing capsule, controlled release capsule, the capsule containing micropill or small pieces, pH dependent form capsule, granule, oral liquid, membrane, the patch dosage forms containing micropill or small pieces.
5. the compositions according to any one of Claims 1-4 raises the purposes in the medicine of disease at preparation treatment hypertension complicated hyperhomocysteinemiainjury or homocysteine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110237258A (en) * | 2018-03-09 | 2019-09-17 | 深圳奥萨制药有限公司 | For treating the pharmaceutical composition of hypertension |
| CN112569356A (en) * | 2019-09-30 | 2021-03-30 | 深圳奥萨制药有限公司 | A pharmaceutical composition containing diuretic |
| CN112569357A (en) * | 2019-09-30 | 2021-03-30 | 深圳奥萨制药有限公司 | Composition of dual endothelin receptor antagonists and diuretic |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101590040A (en) * | 2008-05-30 | 2009-12-02 | 北京奥萨医药研究中心有限公司 | The composition and use thereof that contains indopamide and vitamin B group |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101590040A (en) * | 2008-05-30 | 2009-12-02 | 北京奥萨医药研究中心有限公司 | The composition and use thereof that contains indopamide and vitamin B group |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110237258A (en) * | 2018-03-09 | 2019-09-17 | 深圳奥萨制药有限公司 | For treating the pharmaceutical composition of hypertension |
| CN112569356A (en) * | 2019-09-30 | 2021-03-30 | 深圳奥萨制药有限公司 | A pharmaceutical composition containing diuretic |
| CN112569357A (en) * | 2019-09-30 | 2021-03-30 | 深圳奥萨制药有限公司 | Composition of dual endothelin receptor antagonists and diuretic |
| CN112569356B (en) * | 2019-09-30 | 2023-02-07 | 深圳奥萨制药有限公司 | A pharmaceutical composition containing diuretic |
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Application publication date: 20141224 |