CN101683526A - Pharmaceutical composition containing angiotensin II receptor antagonist, B vitamins and gingo biloba extract - Google Patents
Pharmaceutical composition containing angiotensin II receptor antagonist, B vitamins and gingo biloba extract Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition containing angiotensin II receptor antagonist (ARB) of therapy dose and one of active metabolites or pharmaceutically acceptable salts thereof, one or several of B vitamins of therapy dose, gingo biloba extract (GbE) of therapy dose and pharmacy acceptable carriers and application of the pharmaceutical composition in preparing pharmaceuticals used for treating, preventing or delaying brain stroke. The pharmaceuticals prepared from the pharmaceutical composition is superior to simple antihypertensive drugs in the aspect of treating, preventing or delaying brain stroke diseases, and oral use becomes more convenient for patients. The invention belongs to the pharmacy field.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains angiotensin ii receptor antagonist (ARB), vitamin B group, Folium Ginkgo extract (GbE) and pharmaceutics acceptable carrier, and this pharmaceutical composition is used for the treatment of, prevents or delays purposes in the apoplexy medicine in preparation.The invention belongs to pharmaceutical field.
Background technology
Apoplexy is that acute brain circulatory disturbance causes limitation or the damaged disease of diffusivity brain function rapidly, as cerebral thrombosis, cerebral embolism, cerebral hemorrhage, subarachnoid hemorrhage etc.Cerebral hemorrhage, cerebral embolism directly cause the cerebral tissue necrosis on the one hand, its occupy-place effect makes pathological changes surrouding brain tissue pressurized, ischemia, anoxia again on the other hand, concurrent diffusivity brain tissue damage, oxygen-derived free radicals produce and increase, the latter is by injured nerve tissue biological film, the inside and outside normal ion distribution of interference cell and influence a series of mechanism such as enzymatic activity and directly cause failure cell degeneration, necrosis.
In causing the risk factor of apoplexy, hypertension is most important and modal reason.Every decline 5～10mmHg of systolic pressure or the every decline 2～5mmHg of diastolic pressure, apoplexy is dangerous to reduce by 30%～40%.Blood pressure lowering therapeutic test cooperative groups (BPLTC) meta-analysis shows, the blood pressure difference of-4/-3mmHg can make the apoplexy relative risk reduce by 23%.
Present clinical antihypertensive drugs commonly used, all the certain problem of also existence more or less at first is that efficacy of antihypertensive treatment has certain limit, and lot of documents report total effective rate only is about 50%～60%, 40%～50% is invalid or curative effect is not remarkable, is difficult to reach the purpose of effective prevention or treatment apoplexy.Moreover the medicine that does not still have effectively prevention or treatment apoplexy clinically.
Summary of the invention
The purpose of this invention is to provide a kind of effective treatment, prevent or delay apoplexy and relevant disease pharmaceutical composition thereof.
For realizing above-mentioned purpose of the present invention, the present invention by the following technical solutions:
A kind of pharmaceutical composition comprises:
(1) a kind of in angiotensin ii receptor antagonist of pharmaceutical dosage (ARB) and active metabolite thereof or its officinal salt;
(2) one or more in the vitamin B group of pharmaceutical dosage;
(3) Folium Ginkgo extract of pharmaceutical dosage (GbE); And
(4) pharmaceutics acceptable carrier.
According to the present invention, described angiotensin ii receptor antagonist comprises Candesartan (candesartan), telmisartan (telmisartan), losartan (losartan), valsartan (valsartan), irbesartan (irbesartan), eprosartan (eprosartan), Tasosartan (tasosartan), Olmesartan (olmesartan) etc.
According to the present invention, described vitamin B group is selected from one or more in folic acid, vitamin B6, the vitamin B12, preferred folic acid.Be to be understood that, vitamin B6 among the present invention comprises the derivant of pyridoxol, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine, pyridoxin phosphate, pyridoxal 5-phosphate, phosphopyridoxamine and above-mentioned substance and metabolism and/or generate the material of this compounds in vivo, the preferred 2mg-50mg of the dosage of vitamin B6 among the present invention, the dosage of the vitamin B6 among the present invention can be replaced to produce equivalent effect with above-mentioned substance; Vitamin B12 among the present invention comprises the derivant of cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine, cyanocobalamin and above-mentioned substance and metabolism and/or generate the material of this compounds in vivo, the preferred 0.001mg-2mg of the dosage of vitamin B12 among the present invention, the dosage of the vitamin B12 among the present invention can be replaced to produce equivalent effect with above-mentioned substance; Folic acid comprises the active metabolite of folic acid, formyl tetrahydrofolic acid, L-methopterin, folic acid officinal salt, folic acid or folic acid officinal salt and metabolism and/or generate the material of folic acid in vivo, the preferred 0.1mg-5mg of the dosage of folic acid among the present invention, the dosage of the folic acid among the present invention can be replaced to produce equivalent effect with above-mentioned substance.
According to the present invention, described Folium Ginkgo extract (GbE) is the dried leaves extract of Ginkgoaceae plant Ginkgo biloba (Ginkgo biloba L.), extracts by the contemporary standard metallization processes to form, and for light yellowish brown flowable powder, inherent fragrance is arranged, bitter in the mouth.Main chemism composition is total flavones (account for 24%, mainly comprise kaempferol, Quercetin and 3 kinds of single flavone of isorhamnetin and derivant thereof) and total lactone (accounting for 6%).
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist and active metabolite thereof or its officinal salt are selected from Candesartan, telmisartan, losartan, valsartan, irbesartan, eprosartan, Tasosartan, a kind of in Olmesartan and active metabolite thereof or its officinal salt, wherein, Candesartan content is 2mg-12mg, telmisartan content is 10mg-80mg, losartan content is 12.5mg-100mg, valsartan content is 40mg-160mg, irbesartan content is 75mg-300mg, eprosartan content is 30mg-800mg, Tasosartan content is 25mg-200mg, Olmesartan content is 10mg-40mg; Described vitamin B group is selected from a kind of in folic acid, vitamin B6 and the vitamin B12, and wherein the content of folic acid is 0.1mg-5mg, and the content of vitamin B6 is 2mg-50mg, and the content of vitamin B12 is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a candesartan Cilexetil, and content is the amount that is equivalent to the 2mg-12mg Candesartan; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a candesartan Cilexetil, and content is the amount that is equivalent to the 2mg-12mg Candesartan; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a candesartan Cilexetil, and content is the amount that is equivalent to the 2mg-12mg Candesartan; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a telmisartan, and content is 10mg-80mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a telmisartan, and content is 10mg-80mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a telmisartan, and content is 10mg-80mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a Losartan Potassium, and content is the amount that is equivalent to the 12.5mg-100mg losartan; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a Losartan Potassium, and content is the amount that is equivalent to the 12.5mg-100mg losartan; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a Losartan Potassium, and content is the amount that is equivalent to the 12.5mg-100mg losartan; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a valsartan, and content is 40mg-160mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a valsartan, and content is 40mg-160mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a valsartan, and content is 40mg-160mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is an irbesartan, and content is 75mg-300mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is an irbesartan, and content is 75mg-300mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is an irbesartan, and content is 75mg-300mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is an eprosartan, and content is 30mg-800mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is an eprosartan, and content is 30mg-800mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is an eprosartan, and content is 30mg-800mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a Tasosartan, and content is 25mg-200mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a Tasosartan, and content is 25mg-200mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is a Tasosartan, and content is 25mg-200mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is an olmesartan medoxomil, and content is the amount that is equivalent to the 10mg-40mg Olmesartan; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is an olmesartan medoxomil, and content is the amount that is equivalent to the 10mg-40mg Olmesartan; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the pharmaceutical composition provided by the invention, described angiotensin ii receptor antagonist is an olmesartan medoxomil, and content is the amount that is equivalent to the 10mg-40mg Olmesartan; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
According to the present invention, active component in the pharmaceutical composition is the solvent in the compositions, one of them active component comes from a kind of in angiotensin ii receptor antagonist and active metabolite or its officinal salt, second active component is from one or more vitamin B group, and the 3rd active component is Folium Ginkgo extract.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, oral liquid, membrane or patch, what should particularly point out is to contain angiotensin ii receptor antagonist, the pharmaceutical composition of vitamin B group and Folium Ginkgo extract is made tablet or capsule.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., described pharmaceutics acceptable carrier includes excipient and the adjuvant that helps reactive compound is mixed with pharmaceutical formulation when making tablet, compositions as one or more materials of starch, sucrose, dextrin, microcrystalline Cellulose, inorganic salts, lactose, sodium chloride, citric acid and sodium sulfite etc. belongs to this area general knowledge.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into slow releasing preparation, comprise excipient and adjuvant etc.Described excipient and adjuvant have comprised that the adjuvant of slow releasing function is that 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, the hypromellose employing includes the extensive stock of hydroxypropyl methylcellulose (HPMC) such as U.S. many elegant (Methocel) of all size, ethyl cellulose adopts the extensive stock that includes ethyl cellulose (EC), and polyacrylic resin adopts and includes polyacrylic resin II, the acrylic resin of III class or analog such as all size (Eudragit).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into controlled release preparation, comprise that active medicine has reached the adjuvant of controlled release effect.The above-mentioned adjuvant that plays the controlled release effect 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 be adopted 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 natural pigment such as carmine, amaranth, lemon yellow, bright orchid, indigo, brownish red ferrum oxide and synthetic dyestuff or the like; Porogen can adopt sucrose, mannitol, Polyethylene Glycol, titanium dioxide, Pulvis Talci, silicon dioxide etc.; Membrane material can adopt cellulose acetate, ethyl cellulose, hydroxypropyl emthylcellulose acetic acid succinate, 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 contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into slow releasing capsule; controlled release capsule; the capsule that contains micropill or small pieces; contain the pH dependent form capsule of micropill or small pieces etc.; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., coating material comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; the 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 of Oleum Ricini and percentage etc.) with porogen various medicaments adjuvants such as (as PEG6000).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into dosage forms such as granule, oral liquid, membrane, patch.
Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously in identical preparation, also grant diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of second (or additional) active component should not cause active component to unite the loss of the beneficial effect that brings.If grant diseased individuals simultaneously, the chemical compound in the compositions can mix and be present in the same pharmaceutical dosage forms, also can independently exist respectively with same dosage form.If independently exist respectively 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 built-in one or more dosage forms, and operation instructions.In the present invention preferably with a kind of in a kind of, the vitamin B group in the described angiotensin ii receptor antagonist and compound tablet that Folium Ginkgo extract is formed.
Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously in preparation inequality, also grant diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of second (or additional) active component should not cause active component to unite the loss that brings beneficial effect.If grant diseased individuals simultaneously, the chemical compound in the compositions independently exists with different dosage forms, and pharmaceutical composition also can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of built-in one or more dosage forms, and operation instructions.
Another object of the present invention provide in the vitamin B group of a kind of, the pharmaceutical dosage in the angiotensin ii receptor antagonist that contains pharmaceutical dosage and active metabolite or its officinal salt one or more, the pharmaceutical composition of the Folium Ginkgo extract of pharmaceutical dosage and pharmaceutics acceptable carrier in the preparation treatment, prevent or delay purposes in the medicine of apoplexy and relevant disease thereof.Wherein, angiotensin ii receptor antagonist and active metabolite thereof or its officinal salt are selected from a kind of in Candesartan, telmisartan, losartan, valsartan, irbesartan, eprosartan, Tasosartan, Olmesartan and active metabolite thereof or its officinal salt; Vitamin B group is selected from one or more in folic acid, vitamin B6, the vitamin B12, preferred folic acid; Folium Ginkgo extract is a kind of faint yellow flour that extracts from the dried leaves of Ginkgoaceae Ginkgo plant Ginkgo biloba, mainly contains flavone and terpene lactone two big active components.
In the purposes of the present invention, described angiotensin ii receptor antagonist and active metabolite thereof or its officinal salt are selected from Candesartan, telmisartan, losartan, valsartan, irbesartan, eprosartan, Tasosartan, a kind of in Olmesartan and active metabolite thereof or its officinal salt, wherein, Candesartan content is 2mg-12mg, telmisartan content is 10mg-80mg, losartan content is 12.5mg-100mg, valsartan content is 40mg-160mg, irbesartan content is 75mg-300mg, eprosartan content is 30mg-800mg, Tasosartan content is 25mg-200mg, Olmesartan content is 10mg-40mg; Described vitamin B group is selected from folic acid, vitamin B6 and the vitamin B12-kind, wherein the content of folic acid is 0.1mg-5mg, and the content of vitamin B6 is 2mg-50mg, and the content of vitamin B12 is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a candesartan Cilexetil, and content is the amount that is equivalent to the 2mg-12mg Candesartan; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a candesartan Cilexetil, and content is the amount that is equivalent to the 2mg-12mg Candesartan; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a candesartan Cilexetil, and content is the amount that is equivalent to the 2mg-12mg Candesartan; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a telmisartan, and content is 10mg-80mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a telmisartan, and content is 10mg-80mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a telmisartan, and content is 10mg-80mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a Losartan Potassium, and content is the amount that is equivalent to the 12.5mg-100mg losartan; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a Losartan Potassium, and content is the amount that is equivalent to the 12.5mg-100mg losartan; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a Losartan Potassium, and content is the amount that is equivalent to the 12.5mg-100mg losartan; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a valsartan, and content is 40mg-160mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a valsartan, and content is 40mg-160mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a valsartan, and content is 40mg-160mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is an irbesartan, and content is 75mg-300mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is an irbesartan, and content is 75mg-300mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is an irbesartan, and content is 75mg-300mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is an eprosartan, and content is 30mg-800mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is an eprosartan, and content is 30mg-800mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is an eprosartan, and content is 30mg-800mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a Tasosartan, and content is 25mg-200mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a Tasosartan, and content is 25mg-200mg; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is a Tasosartan, and content is 25mg-200mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is an olmesartan medoxomil, and content is the amount that is equivalent to the 10mg-40mg Olmesartan; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is an olmesartan medoxomil, and content is the amount that is equivalent to the 10mg-40mg Olmesartan; Described vitamin B group is a vitamin B6, and content is 2mg-50mg; Described Folium Ginkgo extract content is 40mg-240mg.
In the purposes of the present invention, described angiotensin ii receptor antagonist is an olmesartan medoxomil, and content is the amount that is equivalent to the 10mg-40mg Olmesartan; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
Among the present invention, term " pharmaceutical dosage " is meant that the clinician grants the dosage of medicine to diseased individuals according to the diseased individuals degree that is in a bad way in order to reach effective treatment, prevent or to delay the purpose of disease.Be to be understood that medicine pharmaceutical dosage provided by the invention is not a limitation of the present invention, but to of the present invention preferred, generally, in this dosage preferable range, this medicine can effectively treat, prevent or delay effect disease that the patient takes a disease generation.Diseased individuals is meant the self-existent life entity of suffering from disease, and in the present invention, life entity refers to the mankind especially.Should be appreciated that in the prior art, human pharmaceutical use dosage or pharmaceutical dosage scope can with mammal, as rat, mice etc., converting is fit to pharmaceutical dosage or the dosage range that corresponding animal is suitable for to draw.
Among the present invention, " risk factor of apoplexy " be meant hypertension, diabetes, dyslipidemia, smoking, drink, fat, lack physical training, cerebral arterial stenosis, heart change.Other risk factors have unreasonable use of anticoagulant behind artery dissection, patent foramen ovale, hyperhomocysteinemiainjury, high blood coagulation state, Cerebral Venous Sinus thrombosis, women's hormone replacement therapy, the cerebral thrombosis etc.
Advantage of the present invention is:
The combined effect of angiotensin ii receptor antagonist, vitamin B group and Folium Ginkgo extract be not each active substance each self-applying simply add and, but in treatment, prevent or delay to have aspect apoplexy and the associated conditions thereof significant more effect.That is to say that angiotensin ii receptor antagonist, vitamin B group and Folium Ginkgo extract administering drug combinations have been obtained synergy.Therefore pharmaceutical composition provided by the invention has tangible prevention or delays apoplexy and the beneficial effect of associated conditions on the effective therapeutic effect that brings high blood pressure down, and is treatment preferably, prevents or delay the apoplexy medicine.
The present invention will be further described below in conjunction with the specific embodiment, is not limitation of the invention, all any this areas of carrying out according to content of the present invention be equal to replacement, all belong to protection scope of the present invention.
The specific embodiment
The consumption of the preparation process of following pharmaceutical preparation embodiment and used material of preparation or the used material of preparation is not limited to character express; all formulation methods that contains pharmaceutical composition provided by the invention; all belong to protection scope of the present invention; but concrete experimental technique reference drug preparation quick-reference book is as " pharmaceutical necessities is used and preparation ", " pharmaceutics ", " Biopharmaceutics and Pharmacokinetics " etc.
Embodiment 1: preparation compound candesartan cilexetil folic acid gingko leaf slow-releasing table (1000 amounts)
Prescription:
Candesartan 4g
Folic acid 0.2g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
Hydroxypropyl emthylcellulose (K15-M) 50g
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) getting the folic acid of the candesartan Cilexetil that is equivalent to 4g Candesartan amount and recipe quantity and Folium Ginkgo extract crosses behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, hydroxypropyl emthylcellulose (K15-M) mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-30,95% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay, aluminium-plastic bubble plate packing.
Embodiment 2～9: the preparation of the compound candesartan cilexetil folic acid gingko leaf slow-releasing table of different content proportioning
Preparation method is identical with embodiment 1, makes slow releasing tablet according to the granule that prescription shown in the table 1 obtains.
Table 1 embodiment 2～9 extended release tablet formulations are formed
Embodiment 10: preparation compound candesartan cilexetil folic acid vitamin B12 Folium Ginkgo (1000 amounts)
Prescription:
Candesartan 8g
Folic acid 0.8g
Vitamin B12 2g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
Low-substituted hydroxypropyl cellulose 20g
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) to cross 100 sieve backs respectively standby by equivalent incremental method mix homogeneously for folic acid, vitamin B12 and the Folium Ginkgo extract of getting the candesartan Cilexetil that is equivalent to 8g Candesartan amount and recipe quantity;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-30,95% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay, aluminium-plastic bubble plate packing.
Embodiment 11: preparation compound recipe telmisartan folic acid Folium Ginkgo (1000 amounts)
Prescription:
Telmisartan 40g
Folic acid 0.8g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
Low-substituted hydroxypropyl cellulose 20g
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) it is standby by equivalent incremental method mix homogeneously that telmisartan, folic acid and the Folium Ginkgo extract of getting recipe quantity crossed 100 sieve backs respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-3095% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay, aluminium-plastic bubble plate packing.
Embodiment 12～19: the preparation of the compound recipe telmisartan folic acid Folium Ginkgo of different content proportioning
Preparation method is identical with embodiment 11, makes tablet according to the granule that prescription shown in the table 2 obtains.
Table 2 embodiment 12～19 tablet formulations are formed
Embodiment 20: preparation compound recipe telmisartan folic acid vitamin B6 gingko leaf slow-releasing table (1000 amounts)
Prescription:
Telmisartan 40g
Folic acid 0.8g
Vitamin B6 10g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
Hydroxypropyl methylcellulose (K15-M) 50g
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) telmisartan, folic acid, vitamin B6 and the Folium Ginkgo extract of getting recipe quantity crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, hydroxypropyl methylcellulose (K15-M) mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-3095% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay, aluminium-plastic bubble plate packing.
Embodiment 21: preparation compound recipe Losartan Potassium folic acid gingko leaf slow-releasing table (1000 amounts)
Prescription:
Losartan 50g
Folic acid 0.8g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
Hydroxypropyl cellulose (K15-M) 50g
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) getting the folic acid of the Losartan Potassium that is equivalent to 50g losartan amount and recipe quantity and Folium Ginkgo extract crosses behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, hydroxypropyl emthylcellulose (K15-M) mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-30,95% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay, aluminium-plastic bubble plate packing.
Embodiment 22: preparation compound valsartan vitamin B6 Folium Ginkgo (1000 amounts)
Prescription:
Valsartan 80g
Vitamin B6 10g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
Low-substituted hydroxypropyl cellulose 30g
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) valsartan, vitamin B6 and the Folium Ginkgo extract of getting recipe quantity crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-30,95% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay, aluminium-plastic bubble plate packing.
Embodiment 23: preparation compound valsartan vitamin B12 Folium Ginkgo controlled release tablet (1000 amounts)
Prescription:
Valsartan 80g
Vitamin B12 2g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
Low-substituted hydroxypropyl cellulose 20g
Cellulose acetate 80g
PEG-1500??????????????????????????20g
Acetone 2000ml
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) valsartan, vitamin B12 and the Folium Ginkgo extract of getting recipe quantity crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-3095% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay;
(6) cellulose acetate and PEG-1500 are dissolved in the acetone, become suspension, stir and make muddy coating;
(7) aluminium-plastic bubble plate packing.
Embodiment 24: preparation compound recipe irbesartan folic acid Folium Ginkgo controlled release tablet (1000 amounts)
Prescription:
Irbesartan 75g
Folic acid 0.8g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 35g
Carboxymethyl starch sodium 20g
Low-substituted hydroxypropyl cellulose 20g
Cellulose acetate 80g
PEG-1500????????????????????????????20g
Acetone 2000ml
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) irbesartan, folic acid and the Folium Ginkgo extract of getting recipe quantity crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-3095% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay;
(6) cellulose acetate and PEG-1500 are dissolved in the acetone, become suspension, stir and make muddy coating;
(7) aluminium-plastic bubble plate packing.
Embodiment 25: preparation compound recipe Tasosartan folic acid Folium Ginkgo controlled release tablet (1000 amounts)
Prescription:
Tasosartan 100g
Folic acid 0.8g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 20g
Carboxymethyl starch sodium 20g
Low-substituted hydroxypropyl cellulose 20g
Cellulose acetate 80g
PEG-1500????????????????????????????20g
Acetone 2000ml
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) Tasosartan, folic acid and the Folium Ginkgo extract of getting recipe quantity crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-30,95% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay;
(6) cellulose acetate and PEG-1500 are dissolved in the acetone, become suspension, stir and make muddy coating;
(7) aluminium-plastic bubble plate packing.
Embodiment 26: preparation compound recipe olmesartan medoxomil folic acid Folium Ginkgo controlled release tablet (1000 amounts)
Prescription:
Olmesartan 40g
Folic acid 0.8g
Folium Ginkgo extract 80g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
Low-substituted hydroxypropyl cellulose 20g
Cellulose acetate 80g
PEG-1500????????????????????????????20g
Acetone 2000ml
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) getting the folic acid of the olmesartan medoxomil that is equivalent to 40g Olmesartan amount and recipe quantity and Folium Ginkgo extract crosses behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-30,95% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay;
(6) cellulose acetate and PEG-1500 are dissolved in the acetone, become suspension, stir and make muddy coating;
(7) aluminium-plastic bubble plate packing.
Embodiment 27: preparation compound candesartan cilexetil folic acid Folium Ginkgo capsule (1000 amounts)
Prescription:
Candesartan 4g
Folic acid 0.2g
Folium Ginkgo extract 80g
Lactose 30
Microcrystalline Cellulose 15g
Starch 20g
Carboxymethyl starch sodium 5g
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) getting the folic acid of the candesartan Cilexetil that is equivalent to 4g Candesartan amount and recipe quantity and Folium Ginkgo extract crosses behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) with other adjuvant respectively at 70 ℃ of dry about 2h after, mistake 100 mesh sieves;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, lactose, the starch mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-30,95% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, the Capsules of packing into behind the assay, aluminium-plastic bubble plate packing.
Embodiment 28～35: the preparation of the compound candesartan cilexetil folic acid Folium Ginkgo capsule of different content proportioning
Preparation method is identical with embodiment 27, makes capsule according to the granule that prescription shown in the table 3 obtains.
Table 3 embodiment 28～35 capsule prescriptions are formed
Embodiment 36～44: the preparation of the compound recipe telmisartan folic acid Folium Ginkgo capsule of different content proportioning
Preparation method is identical with embodiment 27, makes capsule according to the granule that prescription shown in the table 4 obtains.
Table 4 embodiment 36～44 capsule prescriptions are formed
| 5% 30 POVIDONE K 30 BP/USP-30 | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount |
| Magnesium stearate | ??1％ | ??1％ | ??1％ | ??1％ | ??1％ | ??1％ | ??1％ | ??1％ | ??1％ |
Embodiment 45: preparation compound candesartan cilexetil folic acid Folium Ginkgo granule (1000g amount, 1g/ bag)
Prescription:
Candesartan 4g
Folic acid 0.2g
Folium Ginkgo extract 80g
Soluble starch 200g
Cane sugar powder 600g
Carboxymethyl starch sodium 55g
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) getting the folic acid of the candesartan Cilexetil that is equivalent to 4g Candesartan amount and recipe quantity and Folium Ginkgo extract crosses behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) with other adjuvant respectively at 70 ℃ of dry about 2h after, mistake 100 mesh sieves;
(3) get carboxymethyl starch sodium, soluble starch, the cane sugar powder mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-30,95% alcoholic solution and make soft material in right amount, 20 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 18 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, pack behind the assay.
Embodiment 46: preparation compound recipe telmisartan folic acid Folium Ginkgo granule (1000g amount, 1g/ bag)
Prescription:
Telmisartan 40g
Folic acid 0.2g
Folium Ginkgo extract 80g
Soluble starch 200g
Cane sugar powder 600g
Carboxymethyl starch sodium 55g
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) telmisartan, folic acid and the Folium Ginkgo extract of getting recipe quantity crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) with other adjuvant respectively at 70 ℃ of dry about 2h after, mistake 100 mesh sieves;
(3) get carboxymethyl starch sodium, soluble starch, the cane sugar powder mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-3095% alcoholic solution and make soft material in right amount, 20 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 18 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, pack behind the assay.
Embodiment 47: Candesartan/folic acid/Folium Ginkgo extract (GbE) compositions is to the protective effect research of traumatic brain injury (TBI) back neurocyte and function thereof
75 male SD rats, body weight 250～280g is divided into false damage group, TBI group, Candesartan+folic acid group, Folium Ginkgo group, Candesartan+folic acid+GbE group, 15 every group at random.
Animal model preparation: animal is weighed after pneumoretroperitoneum injects 3.5% chloral hydrate 350mg/kg anesthesia, removes the hair of rat head skin, and routine disinfection cuts scalp, long incision 2cm along median line.Be drilled in 3.5mm behind the bregma with dentistry, the other 2.5mm in center line right side place brill is opened skull, as the center, stings out the circular bone window that diameter is 5mm with mosquito clamp, peels off periosteum and keeps cerebral dura mater complete.Rat is lain against on the bump platform, and the bone window is aimed at the passivity screw terminal, freely falls from the 50cm eminence is vertical with the heavy counterweight of 50g, and the bottom by bump passivity screw acts on the right parietal lobe cerebral tissue, causes the local brain contusion of right parietal lobe.After the gelfoam hemostasis, bone wax sealing bone window.Sew up scalp then, animal is put back in the cage observe, and respectively at hindering back 7d sacrificed by decapitation animal.False damage group is only cut the scalp window that opens seam, and does not cause brain injury.
Rat uses Candesartan+folic acid (0.8mg/kg/d+0.08mg/kg/d), GbE (8.0mg/kg/d) and Candesartan+folic acid+GbE (0.8mg/kg/d+0.08mg/kg/d+8.0mg/kg/d) to irritate stomach after hindering immediately respectively, false damage group and TBI group are then irritated stomach with normal saline, every day 1 time, successive administration 7 days.After 7 days, each treated animal quantity is: 15 of false damage groups, 14 of TBI groups, candesartan Cilexetil+14 of folic acid groups, 14 of Folium Ginkgo groups, candesartan Cilexetil+folic acid+GbE organize 15.
Observe animal and generally show body weight; Blance test [document: Dixon CE, Lyeth BG, Povlishock JT, etal.Afluid percussion model of experimental brain injury in the rat.Neurosurgery, 1987,67 (1): 110-119], keep away dark avoidance test [list of references Miyamoto M.lesioning of the rat basalforebrain leads to memory impaiments in passive and active avoidance tasks.BrainRes.1985,328 (1): 97-104], brain water content (method: 7d after wound, get each treated animal, respectively with 3.5% chloral hydrate anesthesia, sacrificed by decapitation, open cranium and get brain, get a side cerebral tissue, the opposite side cerebral tissue is for surveying the inspection of other indexs, behind the bloodstain of filter paper exhaustion brain surface, get and hinder the side cerebral tissue, analytical balance claims weight in wet base to be placed on the interior roasting 48h of 105 ℃ of thermostatic drying chambers to constant weight, pressing the Elliot formula after the title dry weight calculates: brain water content (%)=(weight in wet base-dry weight)/weight in wet base * 100%), (the method: the about 100-200mg of cerebral tissue that gets above-mentioned damage zone of the variation of MDA and NO in the cerebral tissue, weigh, place normal saline, fully homogenate becomes brain tissue homogenate's liquid of 10% on ice, 4 ℃ of centrifugal 10min of 13000r/min, get supernatant in-20 ℃ of preservations, for MDA and NO assay.MDA content adopts improvement thiobarbituricacid (TBA) method to measure, and the NO assay builds up the test kit description operation that bio-engineering research provides by Nanjing).
Pathological observation: for above-mentioned each treated animal, open breast, expose heart, cut off the right auricle, pour into the 200ml heparin-saline fast from left ventricle after, pour into the about 300ml of 4% neutral paraformaldehyde phosphate buffer again.Open cranium and get brain, put into fixedly 12h of fixative back.Conventional H E dyeing, light microscopic is observed down: neuronal cell is arranged; Blood vessel external series gap, cerebral tissue.
Statistical method adopts SPSS 12.0 software processes, and data are used
The t check is relatively adopted in expression between group, there is statistical significance P＜0.05.
The result:
General state is observed: wound is preceding, wound back rat body weight does not have group difference (P＞0.05).Hinder back 3-4h animal and revive, movable few.Hindering back rat next day all can ad lib, drinking-water, no quadriplegia, and activity is limited but less.Behind the 2d, to compare difference not obvious before the diet of rat and the damage, and movable number of times increases.
The blance test result: there was significant difference (P＜0.05) in the equilibration time result between each time point TBI group and false damage group and treatment group and TBI organized behind the TBI, and decline in various degree appears in the balance exercise of rat, coordination function behind the TBI.EGb can improve rat and hinder back balance campaign, coordination function.Share with Candesartan and folic acid, the improvement effect obviously is better than folk prescription and compound recipe group.See Table 5.
Table 5 Candesartan+folic acid+Folium Ginkgo is to the influence of TBI rat equilibration time (second)
(7d)
Annotate: compare * P＜0.05 with vacation damage group; Compare #P＜0.05 with the TBI group; Compare ， ﹠amp with folk prescription and compound recipe group; P＜0.05.
Keep away dark avoidance test result: 7d time point and false damage group compare, and the TBI model group is avoided dark avoidance test all obviously shortenings incubation period, shows that TBI can cause the decline of rat passive learning memory ability.Candesartan+folic acid+GbE has treated the back significant prolongation time of being detained, and effect obviously is better than folk prescription and compound recipe group.See Table 6.
Table 6 Candesartan+folic acid+Folium Ginkgo is kept away dark avoidance test incubation period (second) influence to rat
(7d)
Annotate: compare * P＜0.05 with vacation damage group; Compare #P＜0.05 with the TBI group; Compare ， ﹠amp with folk prescription and compound recipe group; P＜0.05.
The variation of damage back rat cerebral tissue water content: damage back 7d, hinder the more false damage group of side hemisphere brain water content and significantly raise, brain water content obviously reduces after Candesartan+folic acid+GbE treatment, sees Table 7.
Table 7 damage back different time is respectively organized rat and is hindered the variation of side brain water content
Annotate: with vacation damage group ratio, * * P＜0.01; With model group ratio, △ P＜0.05.
The variation of MDA and NO in the rat cerebral tissue: hinder back 7d, the model group rat hinders in the side cerebral hemisphere the more false damage group of content of MDA and NO significantly raise (P＜0.01), after each treatment group treatment, the content of MDA and NO significantly reduces (P＜0.05), especially the most obvious with the effect of treatment group 3 after Candesartan+folic acid+GbE treatment, see Table 8.
Table 8 is hindered back 7d and is respectively organized the content that rat hinders MDA and NO in the side cerebral tissue
Annotate: with vacation damage group ratio, * * P＜0.01; With model group ratio, △ P＜0.05.
Pathological observation is the result dye through HE, false damage group neuronal cell queueing discipline; The broadening of TBI group visible vessels external series gap, the neuron irregular arrangement, endochylema is bright, nuclear membrane obscure boundary, the visible a large amount of RCOs of cerebral tissue; Treatment group neuronal degeneration is lighter relatively, and ECS is less, and neuron endochylema, nuclear membrane are clear relatively, and the blood vessel external series gap is less.
Embodiment 48: telmisartan/folic acid/Folium Ginkgo extract (GbE) compositions is to the treatment research of cat acute cerebral infarction
40 healthy domestic cats are equally divided into 4 groups at random: A organizes (normal saline matched group), and B organizes (telmisartan+folic acid group), and C organizes (GbE group), and D organizes (telmisartan/folic acid/Folium Ginkgo extract group).The B group is treated with telmisartan 1.0mg/kg+ folic acid 0.02mg/kg every day; The C group is treated with GbE 2.0mg/kg every day; The D group is treated (using telmisartan 1.0mg/kg, folic acid 0.02mg/kg, GbE 2.0mg/kg every day) with telmisartan+folic acid+GbE group; The A group is 5ml 0.85%NaCl filling every day stomach, each treatment group successive administration 7 days.
Animal model is made: adopt left side eye socket approach to make the middle cerebral artery ischemia-reperfusion injury model.Domestic cat is anaesthetized successfully, conventional preserved skin around the left eye, sterilization, shop aseptic operation list.At first enlarge palpebral fissure slightly along the left eye outer canthus, cut conjunctiva at upper tarsal conjunctiva and bulbar conjunctiva intersection. successively go deep into chorista to the socket of the eye rear wall, peel off tissue between eyeball and the socket of the eye wall along the socket of the eye rear wall, remove fatty tissue behind crystalline lens, vitreous body and the ball, expose canalis opticus.Open the about 7mm of a size * 9mm bone window on the other temporo of canalis opticus top and expose cerebral dura mater, carefully cut off cerebral dura mater, expose middle cerebral artery M2 section, press from both sides near section that closes finding middle cerebral artery M2 section with the fiber vascular clamp with little eye scissors.Eye socket shop wet gauze was decontroled vascular clamp after 2 hours, carefully sewed up cerebral dura mater, the cured filling bone of medical bone window bony defect, and eye socket is filled in the gauze pressurization of using gentamycin to soak, uses the silk suture eyelid.After modelling is finished, again after the perfusion at once diffusion-weighted imaging (DWI) show the high signal in middle cerebral artery blood supply district, and signal raises gradually, thinks that then animal model makes successfully.Postoperative dynamically carries out T, WI, 1I2WI, FLAIR, DWI sequence scanning, and carry out neurological deficits score.
Neurological deficits score: according to Philip cat cerebral ischemia function of nervous system standards of grading.From consciousness, motion, sensation, vision, posture, balance six aspects, 40 laboratory animals were carried out neurological deficits score in postoperative the 7th day.Wherein 2 animal deads replenish 2 in addition and carry out the postorder laboratory observation.
Clinical manifestation: the neurological deficit symptom all occurs behind each treated animal recovery from anesthesia of postoperative, show as in various degree the head layback, the contralateral limbs paralysis is twitched and is turn-taked.Each treatment group (B, C, D group) impaired symptom of function of nervous system that animal showed is lighter, and it is shorter to recover time-histories.And heavier nerve damage symptom appears in matched group (A group) animal, and recovery time is longer.Postoperative carried out neurological deficits score in 7 days respectively.The factor analysis statistical result showed is single can both to make function of nervous system's scoring lower with telmisartan or list with GbE, but telmisartan+folic acid+GbE group treatment group neurological functional recovery is better than the single drug group, three's use in conjunction has good synergism, and (P＜0.05=sees Table 9.
Different group Philip ' s score function of nervous system is relatively after 7 days for table 9
Conclusion: telmisartan+folic acid+GbE therapeutic alliance cat acute cerebral infarction is better than the single drug group, and the three has synergism.Embodiment 49: valsartan/folic acid/Folium Ginkgo extract (GbE) compositions is to the influence of apoplexy susceptible type spontaneous hypertensive rat (SHRsp) cerebrovascular structure
With 6 ages in week male SHRsp be divided into model group (9), valsartan+folic acid group (9) at random, GbE group (9) and valsartan+folic acid+GbE organizes (8), all raises high protein feed, drinks 1.5%NaCl since the 8th all ages.86 week male normal arterial pressure rats in age (WKY) are raised normal diet as the normal control group, the drink tap water.Valsartan group+folic acid group is irritated stomach with valsartan 0.8mg/kg+ folic acid 0.08mg/kg every day, the GbE group is irritated stomach with GbE 8mg/kg every day, valsartan+folic acid+GbE group is irritated stomach with valsartan 0.8mg/kg, folic acid 0.08mg/kg, GbE 8.0mg/kg every day, irritate stomach with 1ml/100g0.85%NaCl all the other two groups of every days, feeds 18 all backs sacrificed by decapitation.
Every morning marks according to rat brain apoplexy clinical manifestation standards of grading: 1 minute: movable lacking-quantity of motion slightly reduces or is slight excited; 2 minutes: activity seldom-quantity of motion obviously reduce or excitation excited; 3 minutes: prostrate motionless-can not walk the melancholy symptom; 4 minutes: paralyse-can not stand any side or bilateral limb paralysis.
The back drug withdrawal of 18 weeks, row aorta intubate behind the rat anesthesia, the perfusion of 2.5% glutaraldehyde is fixing, broken end is got brain, separates skull base arterial ring and intraparenchymatous small artery of brain and arteriole, separates skull base arterial ring and intraparenchymatous small artery of brain and arteriole under operating microscope, 2.5% glutaraldehyde is fixed, Epon 812 embeddings, semithin section, Toluidine blue staining.Semithin section adopts CMIAS series 2 multi-functional true color pathological image analysis systems to measure the media thickness of blood vessel, tube chamber radius, middle film cross-sectional area, tube chamber cross-sectional area etc., calculates the ratio of media thickness/tube chamber radius, and 10 blood vessels are surveyed in every section.The results are shown in Table 10.
All data all with
Expression is analyzed with the SPSS statistical software, the relatively employing one factor analysis of variance of a plurality of sample averages, and the q that relatively adopts in twos of a plurality of sample averages checks.
Table 10 is respectively organized rat brain tremulous pulse morphometric and stereologic analysis
Annotate: compare * P＜0.05, * * P＜0.01 with the normal control group; Compare ##P＜0.01 with model group.
The scoring of normal control group apoplexy is 0.11 ± 0.12, and model group apoplexy scoring (3.41 ± 0.47) is organized (0.36 ± 0.31) apparently higher than valsartan+folic acid group (0.72 ± 0.16), GbE group (0.76 ± 0.14) and valsartan+folic acid+GbE; Compare with valsartan+folic acid group, valsartan+folic acid+GbE group rat brain apoplexy scoring further reduces, and significant difference is arranged.
Structure under the cerebral arteries light microscopic: normal control group middle cerebral artery structure is normal, and film obviously thickens in the model group middle cerebral artery, and valsartan+folic acid group, GbE group and valsartan+folic acid+GbE organize all not have obviously and thicken.
This research shows cerebrovascular om observation of SHRsp and morphometric and stereologic analysis result: the ratio of model group cerebral arteries media thickness/tube chamber radius is apparently higher than the normal control group; Valsartan+folic acid, GbE group and valsartan+folic acid+GbE all can significantly reduce the ratio and the apoplexy clinical manifestation scoring of SHRsp cerebral arteries media thickness/tube chamber radius, reduce apoplexy incidence rate and mortality rate, wherein with valsartan+folic acid+GbE most pronounced effects.
Claims (9)
1. pharmaceutical composition, contain:
1) angiotensin ii receptor antagonist of pharmaceutical dosage and active metabolite thereof or its officinal salt;
2) vitamin B group of pharmaceutical dosage;
3) Folium Ginkgo extract of pharmaceutical dosage; And
4) pharmaceutics acceptable carrier.
2. the pharmaceutical composition described in the claim 1 is characterized in that: described angiotensin ii receptor antagonist and active metabolite thereof or its officinal salt are selected from a kind of in Candesartan, telmisartan, losartan, valsartan, irbesartan, eprosartan, Tasosartan, Olmesartan and active metabolite thereof or its officinal salt; Described vitamin B group is selected from one or more in folic acid, vitamin B6, the vitamin B12; Described Folium Ginkgo extract is the dried leaves extract of Ginkgoaceae plant Ginkgo biloba, extract by the contemporary standard metallization processes to form, main chemism composition be total flavones account for 24% and total lactone account for 6%.
3. the pharmaceutical composition described in the claim 2, it is characterized in that: described Candesartan content is that 2mg-12mg, telmisartan content are that 10mg-80mg, losartan content are that 12.5mg-100mg, valsartan content are that 40mg-160mg, irbesartan content are that 75mg-300mg, Tasosartan content are that 25mg-200mg, Olmesartan content are 10mg-40mg; The content of described folic acid is 0.1mg-5mg, and the content of vitamin B6 is 2mg-50mg, and the content of vitamin B12 is 0.001mg-2mg; The content of described Folium Ginkgo extract is 40mg-240mg.
4. the pharmaceutical composition described in the claim 1, it is characterized in that: described angiotensin ii receptor antagonist and active metabolite thereof or its officinal salt are candesartan Cilexetil, content is the amount that is equivalent to the 2mg-12mg Candesartan; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
5. the pharmaceutical composition described in the claim 1, it is characterized in that: described angiotensin ii receptor antagonist and active metabolite thereof or its officinal salt are candesartan Cilexetil, content is the amount that is equivalent to the 2mg-12mg Candesartan; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
6. the pharmaceutical composition described in the claim 1, it is characterized in that: described angiotensin ii receptor antagonist and active metabolite thereof or its officinal salt are telmisartan, content is 10mg-80mg; Described vitamin B group is a folic acid, and content is 0.1mg-5mg; Described Folium Ginkgo extract content is 40mg-240mg.
7. the pharmaceutical composition described in the claim 1, it is characterized in that: described angiotensin ii receptor antagonist and active metabolite thereof or its officinal salt are telmisartan, content is 10mg-80mg; Described vitamin B group is a vitamin B12, and content is 0.001mg-2mg; Described Folium Ginkgo extract content is 40mg-240mg.
8. each described pharmaceutical composition in the claim 1 to 7, it is characterized in that: this pharmaceutical composition can be made into conventional tablet, slow releasing tablet, controlled release tablet, granule, conventional capsule, slow releasing capsule, controlled release capsule.
In the claim 1 to 8 each described pharmaceutical composition in preparation treatment, prevent or delay purposes in the medicine of apoplexy.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103083367A (en) * | 2011-11-01 | 2013-05-08 | 上海交通大学医学院附属第三人民医院 | Losartan ginkgo leaf compound preparation and preparation method thereof |
| CN114832111A (en) * | 2018-03-21 | 2022-08-02 | 成都百裕制药股份有限公司 | Pharmaceutical composition for preventing and/or treating hypertension |
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| CN1286844C (en) * | 2004-07-28 | 2006-11-29 | 安徽省生物医学研究所 | Medicinal composition containing angiotensin II receptor antagonist and vitamin B |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103083367A (en) * | 2011-11-01 | 2013-05-08 | 上海交通大学医学院附属第三人民医院 | Losartan ginkgo leaf compound preparation and preparation method thereof |
| CN103083367B (en) * | 2011-11-01 | 2015-05-20 | 上海交通大学医学院附属第三人民医院 | Losartan ginkgo leaf compound preparation and preparation method thereof |
| CN114832111A (en) * | 2018-03-21 | 2022-08-02 | 成都百裕制药股份有限公司 | Pharmaceutical composition for preventing and/or treating hypertension |
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Address after: 100176 Beijing economic and Technological Development Zone, West Beijing Road, No. 18, block C, room 216 Co-patentee after: SHENZHEN AUSA PHARMED Co.,Ltd. Patentee after: Beijng Aosa Medical Research Center, Inc. Address before: 100176 room A403, 14 Zhonghe street, Beijing economic and Technological Development Zone Co-patentee before: SHENZHEN AUSA PHARMED Co.,Ltd. Patentee before: Beijng Aosa Medical Research Center, Inc. |
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