CN104491849B

CN104491849B - Allicin multiple enteric piece is as the application for preparing treatment myocardial infarction disease medicament

Info

Publication number: CN104491849B
Application number: CN201410622899.0A
Authority: CN
Inventors: 李连达; 李贻奎; 张金艳; 李新霞; 陈坚
Original assignee: XINJIANG AILEXIN PHARMACEUTICAL CO Ltd
Current assignee: Xinjiang Elexin Biotechnology Co ltd
Priority date: 2014-11-08
Filing date: 2014-11-08
Publication date: 2017-12-08
Anticipated expiration: 2034-11-08
Also published as: CN104491849A

Abstract

The present invention relates to the applied technical field of allicin, it is a kind of application of allicin multiple enteric piece as preparation treatment myocardial infarction disease medicament, the present invention passes through " allicin multiple enteric piece gastric infusion, and biochemical indicator inspection is homogenized to obtain to the histopathologic examination of rat heart infarction animal model and blood and heart tissue, as a result show, allicin multiple enteric piece and the drug effect with anti-infarction, and significant dose-dependent relationship is presented between each dosage group, illustrate that allicin multiple enteric piece can effectively prevent and treat myocardial infarction disease, further illustrate that allicin preparation can turn into a kind of new pharmaceutical formulation of efficiently treatment myocardial infarction disease.

Description

Allicin multiple enteric piece is as the application for preparing treatment myocardial infarction disease medicament

Technical field

The present invention relates to the applied technical field of allicin, is that a kind of allicin multiple enteric piece is treated as preparation The application of myocardial infarction disease medicament.

Background technology

Since ancient times, garlic (Allium sativum L) is the generally acknowledged medicine-food two-purpose of different parts of the world, different nationalities Plant.It is B.C., just there is the medicinal note of many garlics in ancient Egypt, ancient Gingko, the archaeological information of ancient Roman and medical literature Carry.Ancient Times in China, garlic are common drugs.《Compendium of Materia Medica》Described in:Garlic " logical the five internal organs, up to all keys, go cold-dampness, and exorcise evil spirits evil, Subduing inflammation ", " only cholera, evil removing is haunt and plague, solves pestilence, removes disease due to noxious agents produced by various parasites, malignant sore, snakeworm, small stream poison ", " journey taken, then scorching wind miasma rain can not Add, eating brave cured poison can not do harm to ".Chen Cangqi is said：" garlic just eats unfavorable mesh, and more foods are bright, and long food makes us serum ".Uygur medicine is discussed Write and record：For treating a variety of diseases such as qi and blood stagnation, sphagitis, apoplexy, hemiplegia, convulsions, joint pain.Dimension doctor's ancient books is recorded One method of Garlic in Treatment hemiplegia：Eat 1, garlic raw within 1st day, increase day by day 1,20 were eaten raw to the 20th day.Hereafter day subtract 1, 39 days are a course for the treatment of, there is special effect.

Modern age, garlic are mainly used as Antibiotics usage.During the World War I, garlic is widely used as anti-corrosion And antimicrobial.In generation nineteen thirty, finds that hundred bright more breaths have antibacterial effect, nineteen thirty-seven synthesis sulfapryidine, nineteen thirty-nine synthesis sulfanilamide (SN) thiophene Azoles, nineteen forty-one synthesis sulphadiazine.Nineteen twenty-eight Fleming finds penicillin（MIT bavins grace in 1938, Florey extraction）Come out. Nineteen sixty instead of after, semi-synthetic, synthetic antibiotic is come out one after another.Various infectious diseases are substantially achieved control.The medicine of garlic With drastically reducing.But hereafter find that a variety of bacterial strains produce resistance, undesirable and a variety of to the effect of fungi to antibiotic The discovery of side effect.Therefore nineteen fifty is among the people to be not off curing the disease using garlic to 1980.Some large hospitals, are steamed using water Steam distillation prepares galic essential oil and parenteral solution, and treatment nosomycosis obtains good efficacy.The discovery of the 1980's, garlic active ingredient pair World's morbidity and mortality highest cardiovascular and cerebrovascular disease has the effect of good.

The botany research of garlic：1st, plant classification belongs to：How to be named in woods for garlic (Allium sativum L.) Age, plant classification method are still incomplete.The morphological feature of garlic with allium, Lycoris, Anemarrhena and lilium relatively, But belong to Liliaceae (Liliaceae) very reluctantly, 1987, the botanist such as Takhtajan was by the green onion in former Liliaceae Category is independent into green onion section, solve the umbel of green onion section and it is similar to Amaryllidaceae by the involucre that bract forms and in its ovary Position flower again and liliaceous ovary epigynous flower identical contradiction, and is received by each authoritative institution, allium is under the jurisdiction of into green onion section (Alliaceae), thus, the ownership of garlic plant classification, should be revised as：" green onion section (Alliaceae) plant garlic (Allium Sativum L.) ", or broad sense Liliaceae；2nd, the kind of garlic：2.1st, the classification of the kind of garlic:Garlic only has one in the whole world Individual kind " Allium sativum L. " saying is inaccurate, it was reported that, (1), form whole world garlic has 600 multi items at present, Credit class (morphology, cytology), Regel (1875) and Vedensky (1968) think A.1ongicuspis be garlic ancestral First, Helm (1956) is classified as 3 mutation：Longicuspis (long plush copper), ophioscordon (snake garlic) and sativum, Kazakova (1971 to 1978) separates two subspecies again:Subtropical (subtropical zone) and Pekinense (Beijing) is altogether 5 kinds, the difference caused by varying environment, many novel species are produced again.By color of the leather, white skin garlic and purple garlic, white skin can be divided into Garlic cold resistance is strong, and general late fall sowing, principal item has 23 kinds, and purple garlic crust aubergine, valve fertilizer, number are few, typically early to sow in spring Kind, (2), Phytochemistry classification principal item has 26 kinds, and, cysteine derivative is the shared Phytochemistry of different cultivars garlic Composition, cysteine-sulfide have important systematics meaning, are divided into three classes：1）, cysteine-sulfide content It is high；2）, cysteine-sulfide content it is low；3）, based on alliin and different alliin (isoalliin), (3), by purposes point Class, Miao Yongxing, a kind of sedge type, head type, seedling a kind of sedge dual-purpose type, the climing dual-purpose type of head a kind of sedge dual-purpose type head seedling, 2.2, molecular biology method Classification (molecular labeling) confirms the original producton location of garlic, and Vavilov (1926), Kazakova (1971) think that the Central Asia is rising for garlic Source center, Etoh (1986), Kotlinska (1991), Kamenetsky (2004) etc. finds that garlic is fertile in Central Asia Tianshan Mountains Archetype, the support Central Asia are the garlic centre of origin, then by the biochemistry and molecule mark such as Pooler (1993) and Hong (1999) Analysis of scoring is verified that the saying that garlic is introduced from foreign countries is inaccurate；3rd, garlic is original, Wu Zhengyi etc., proposes new plant Resource classification system：Xinjiang has the wild economic plant germ plasm resource of Important Economic potentiality, including：The vegetables such as green onion, garlic, fragrant-flowered garlic are wild Raw sibling species, there is the prospect further developed, 1996 to 1998, Xinjiang academy of agricultural sciences Lu Jun Jun etc., collect, investigate, hair Existing a variety of garlics, the display Mountain Ranges of Tian Shan Mountains is the main distributed areas of allium Garlic Germplasm Resources.

The active ingredient of garlic：

1st, garlicin compound：Because some bacterial strains produce drug resistance, and the effect to fungi to antibiotic It is undesirable, among the people to be not off curing the disease using garlic, some large hospitals, galic essential oil and injection are prepared using steam distillation Liquid, treatment nosomycosis obtain good efficacy, and 1972 to 1976, Shanghai Mr. Lang Yijiang etc. was smart from garlic steam distillation Isolated a kind of oily yellow liquid in oil, physicochemical property is more stable, has strong garlic odour, isolated and purified through GC, HPLC, IR, MS etc. are analyzed and identified, and confirm as trisulfide（Alliitridum）, (Lang Yijiang, etc., garlic active ingredient research, medium-height grass Medicine communicates, and 1981;12(1):4), this achievement in research is in domestic and international advanced level, and pharmacological experiment is shown with similar The pharmacological action of garlic composition, Allicin is once named as, standard is named as allicin within 2002；

2nd, after the results of study such as Lang Yijiang deliver 10 years, the state such as moral, U.S., Israel, Japan find, garlic effectively into Divide has the effect of good to world's morbidity and mortality highest cardiovascular and cerebrovascular disease, causes world's extensive concern, starts The climax of garlic research, the experimental results show, alliin (Alliin), allinase (Alliinase) and allicin (Allicin) it is that garlic is anti-infective, prevents and treats the main composition of cardio-cerebrovascular diseases, alliin and allicin is beautiful The multinational pharmacopeia such as state, Britain/European Union are confirmed as garlic and its preparation and differentiated and the leading indicator of assay, and Chinese Pharmacopoeia and Relevant criterion still uses " allicin（Garlicin compound）" index as quality control, thus, formed in the world Two kinds of " medicinal garlic " quality index systems,（1）, alliin（Alliin, CAS：556-27-24）, chemical name:S- allyls Base-Cys sulfoxide (S-Allyl-L-cysteine sulfoxide), mp:163 DEG C to 165 DEG C, [α] D=+ 60o, in vain Color filament crystal.Separated and identified first from garlic by Stoll and Seeback within 1948.It is present in garlic in the form of odorless It is most original in garlic unicorn bud, most important, content highest sulfur-containing amino acid in bulbil.Content has very because of kind and the place of production Big difference (0.3-2.5%)（Note:The U.S.《Chemical abstracts, CA》Society, in order to solve, " multiple compounds are of the same name, or same compound It is several " problem, provided to each compound one coding）,（2), alliin lyase (Alliinase, EC 4.4.1.4 ,CAS:9031-77-0) also known as allinase, Alkylcysteine sulfoxide lyase（S-allyl-L- cysteine sulfoxide lyase）. Belong to dimer glycoprotein, two molecular weight subunits are 51.5 KDa.By N- terminal domains (yellow), P5P With reference to domain (blueness) and C- terminal domains (red) composition, crystallization is in yellow, odorless, isoelectric pH:4.9, to temperature It is sensitive（EC 4.4.1.4：Coding of the international enzyme committee to allinase.First digit 4 represents that the enzyme belongs to the fourth-largest class and (split Synthase);Second digit 4 represents the 4th subclass (Alkylcysteine sulfoxide lyase) of category;Third digit 1 represents the first group of category, fourth digit 4 Represent the sequence number of the discovery enzyme）, (3), allicin (Allicin, CAS:539-86-6), chemical name:The thio Asia of diallyl Sulphonic acid ester (Diallyl thiosulfinate), MW:162.3, BP:28 DEG C (decomposition), are slightly soluble in water, there is garlicky, nineteen forty-four Cavallito and Bailey is isolated from the garlic juice pulverized first, is that the production for closing substrate alliin is split in allinase catalysis Thing, is the most important bioactive ingredients of garlic, but unstable chemcial property, and a few hours are decomposed metamorphic in normal temperature, air.

Allicin (Allitridum, CAS:2050-87-5)：The national drug standards " WS-10001- (HD-0050)- 2002 " are defined as " Ailitridin, containing C to allicin₆H₁₀S₃97%-103% " is should be, Ailitridin, was once named as " garlic New element (Allitride).The national drug standards rename as allicin within 2002.NF（2015 editions）Continue to use.Continue three The content height of the propylene of sulphur two, as the standard for directly judging garlic medicinal material and the quality of the pharmaceutical preparations, " Ailitridin " is named as Allicin, from present（After standard formulation 30 years）From the point of view of, hurry and easy the defects of misunderstanding be present, first, at that time not yet The system research of garlic is completed, second, allicin to be regarded as to the principle active component of garlic, experimenter is misled and is tried using chemistry Agent carries out pharmacodynamics test, replaces garlic vegetable drug with chemical reagent, produces garlic pharmaceutical preparation and plurality kinds of health care product, make China broad masses fail to enjoy plant garlic really medical treatment and health-care effect, the garlic preparation in China is lagged behind the world, Therefore, China garlic relevant criterion should grow with each passing hour, and revise as early as possible.

Allicin, alliin, the chemical constitution of allicin are different：Alliin, allicin and allicin, are chemically tied Structure, chemical abstracts numbering, physicochemical property, bioactivity etc. are three kinds of different compounds, it is necessary to are eliminated the false and retained the true.

Allicin (Allicin, CAS:539-86-6), chemical name:GIUCOSinoate (Diallyl thiosulfinate),MW:162.3, BP:28 DEG C (decomposition), are slightly soluble in water, there is garlicky, nineteen forty-four Cavallito and Bailey It is isolated from the garlic juice pulverized first, it is that the product for closing substrate alliin is split in allinase catalysis, is that garlic is most important Bioactive ingredients, but unstable chemcial property, a few hours are decomposed metamorphic in normal temperature, air.

Allicin is that have moderately toxic chemical industry synthesis product：Allicin (Allitridum), alias：Garlicin Ether, trisulfides two propylene, diallyl trisulfide etc.（Allisatin, Allitrid, Diallyl trisulfide）, it is a kind ofization The reagent of synthesis is learned, once as chemical synthesis intermediate, paint thinner.Yellow flammable liquid, purity:50-99%；Allicin Toxicity level:In (Hazard Class:6.1-b, Poisonous/Toxic Materials), acute toxicity:Mouse oral LD50:100 mg/Kg, intravenous LD50:70mg/kg, Oral Administration in Rats LD50:265mg/kg, hazardous materials transportation number:2810[37]； Hunan Jing Tian scientific ＆ technical corporation produces 1000 tons of synthetic allicin per year, and workshop-sink flows to Xiang River with rainwater, and institute is withered to the greatest extent through part vegetation, Ox is because careless and dead near Chi Liao factories, and the fish of neighbouring Xiang River cultivation, all strange death, several millworkers are through the refined doctor in Hunan Institute is diagnosed as caused DPN of being poisoned.The bioactivity of allicin does not represent the effect of plant garlic and its preparation, experiment It has been shown that, garlic is known as many drug effects, but can not represent the drug effect of plant garlic main component alliin and allicin And the effect of clinical practice, due to the misunderstanding formed for a long time, the active ingredient for replacing Natural Garlic with toxic chemical is made Health food and medicine, make China broad masses fail to enjoy the achievement in research of modern age plant garlic, consumer is caused perhaps More infringements.Therefore, both " Allitridum ", " Allicin " document, pharmacology, toxicity and clinical practice etc. are lumped together, At home and abroad cause many misunderstandings.Also, the active ingredient in the capsulae allitridi or garlicin injection of current clinical practice It is not " Diallytrisin " single component, but one group of mixture.Allicin is free of in fresh garlic, allicin is all people Work synthesizes, and is not the active ingredient of garlic.The chemical constitution of allicin and alliin or allicin is entirely different.By " two Diallyl trisulfide ether " is referred to as " allicin ", is a gross mistake.Make one to take for " active ingredient that allicin is garlic ", Therefore " allicin can extract from fresh garlic " be even more it is a kind of do not have it is valid misread, mislead or guess.Such as Fig. 2, Fig. 3, Fig. 4 institute Show, the chemical constitution of alliin, allicin and allicin can be compared；Further, as shown in Figure 5, it will be appreciated that Alliin, allinase, the relation of allicin and diallyl sulfide (ally sulfides).

Alliin, garlic are sulfur amino acid content highest plants in known edible plant, and wherein alliin accounts for whole More than the 70% of sulfur-containing amino acid, it is sulfur-containing amino acid to have 5% to 6% in the essential amino acid of human body.Body can not synthesize in itself to be contained Sulphur amino acid, it is necessary to from external intake.Alliin is metabolized in vivo, directly participates in the synthesis of glutathione (GSH).Glutathione (GSH) it is a kind of tripeptides, by cysteine (cysteine), glutamic acid (glutamic acid) and glycine (glycine groups Into), there is Immune-enhancing effect (enhancer), the removing toxic substances function such as (detoxifier) and anti-oxidant (antioxidant), so as to send out Drug effect is waved, resists the invasion of pathogen, prevents generation and the adjuvant therapy of tumors of cardiovascular and cerebrovascular disease.

Allinase (allinnase), also known as " Alkylcysteine sulfoxide lyase ", there is the catalysis of mild condition to split cooperation use the C-S keys of compound, There is certain effect for preventing and treating " homocysteine hypercalcinuria ".Homocysteine (homocysteine, Hcy) is horizontal in blood Rise, be the morbidity of the vascular conditions such as atherosclerosis a hazards, and with Atheromatosis feelings in bright Aobvious dose-dependence.And blood vessel endothelium dysfunction caused by Hcy mass formed by blood stasis is in atherosclerosis early stage pathogenic process Important initiating link.Allinase is likely to become " future " medicine of preventing and treating homocysteine hypercalcinuria.Unfortunately, current majority is ground " allicin of the person of studying carefully to be not present in fresh garlic（Diallytrisin）" it is used as research object.

American Pharmacopeia and European Union's pharmacopeia confirm that the principle active component of garlic (Alliium sativum L.) is：1., garlic Propylhomoserin (Alliin), chemical name：SACS (S-Allyl-L-cysteine);2., allinase (Alliinase, EC 4.4.1.4), also known as alliin lyase (Alliin lyase)；3., allinase catalytic pyrolysis alliin production Raw allicin (Allicin) chemical name:GIUCOSinoate (Diallyl thiosulfinate), due to The extraction of allicin and preparation technique are very difficult and complicated, therefore research and develop allicin system safely, effectively, quality controllable Agent turns into the study hotspot of pharmacy man of various countries.

After fresh garlic is cut or smashed to pieces, alliin therein is met with allinase, and rapid catalytic reaction is generated into allicin, Allicin is unstable with the physicochemical property in air at normal temperatures, therefore alliin, allinase and preparation are extracted from fresh garlic " alliin+allinase " solid pharmaceutical preparation and allicin parenteral solution are very difficult.The present invention is related to and uses six patents of invention altogether Technology：

（1）, from fresh garlic extract alliin production technology refer to Publication No. 1425650 Chinese patent literature；

（2）, from fresh garlic extract allinase production technology refer to Publication No. 1424397 Chinese patent literature；

（3）, alliin reference substance preparation method refer to Publication No. 101560174 Chinese patent literature；

（4）, the infectious disease such as a kind of anti-helicobacter pylori and Candida albicans alliin/alliinase dualistic drug-releasing multilayer tablet With reference to the Chinese patent literature of Publication No. 101549152；

The schematic diagram that allinase catalytic pyrolysis alliin produces allicin (potential allicin) is as shown in Figure 1：

Quantitative relation formula such as allinase catalytic pyrolysis alliin generation allicin in Fig. 1 can be seen that two molecule alliins One molecule allicin, i.e. 354.4 grams of alliin (2 [C are generated by allinase catalytic pyrolysis₆H₁₁NO₃S] = 2×177.2= 354.4) 162.3 grams of ([C of allicin can be generated₆H₁₀OS₂]=162.3)。

Relation between potential allicin amount and alliin amount is expressed from the next：

Potential allicin amount=alliin amount × C ×（162.3/354.4）

In formula：C represents alliin purity.

Numerous studies show that allicin plays an important role in the antimicrobial acivity of garlic.To angiocardiopathy In terms of prevention and treatment, garlic has reducing blood lipid, antithrombotic, hypotensive and preventing and treating atherosclerosis and other effects, mechanism of action It is derived from the organic sulfur compound I of garlic）By suppressing a kind of enzyme-HMG-CoA very important during cholesterol biosynthesis also Protoenzyme suppresses cholesterol biosynthesis；ⅱ）Platelet aggregation can be suppressed；ⅲ）Suppression plays important in angiocardiopathy pathology Effect the enzyme for causing inflammation, i.e. epoxidase and lipoxygenase activity, reduce nitric oxide synthetase（iNOS）Derivant exists Inflammatory leukocytes（Macrophage）In expression；ⅳ）Suppress propagation and the transfer of vascular smooth muscle cells；V）It can synthesize important Vascular cell in antioxidant-glutathione and have antioxidation activity.

Drawn according to France and clap thunder（Rabelais ）University I. Arnault and J. Auger etc. 2004 is to European countries 11 commercialization garlic products using garlic powder as active component（2 × Austria, 1 × Germany, 2 × Italy, 3 × Sweden, 1 × Britain, wherein only German examined product has medicine qualification）The analysis of progress, the results showed that, most of garlic powder products into Divide and greatly differed from each other with what their manufacturers declared.Neither one product stability reaches 90% limit mark of medicine code requirement Standard, most products have dropped to less than the 50% of assessment values.

So in order to prevent and treat critical illness, clinical requirement active ingredient reaches high content to ensure curative effect.Therefore, beautiful, The scholar of a small number of developed countries such as moral, Israel, France starts using cryogenic freezing, vacuum drying, ion exchange, film point From etc. advanced technology, spend great effort research and development " the efficient novel formulation of garlic ".But development is still at present, both at home and abroad still Released without " the efficient novel formulation of garlic " product.

The content of the invention

The application of myocardial infarction disease medicament is treated as preparation the invention provides a kind of allicin multiple enteric piece, The deficiency of above-mentioned prior art is overcome, it can effectively solve to there is no " the efficient novel formulation of garlic " product and at present treatment both at home and abroad The problem of myocardial infarction effect of drugs is not ideal.

The technical scheme is that realized by following measures：A kind of allicin multiple enteric piece is as preparation Treat the application of myocardial infarction disease medicament.

Here is the further optimization and/or improvements to foregoing invention technical scheme：

Above-mentioned treatment myocardial infarction disease medicament is allicin multiple enteric piece.

Above-mentioned allicin multiple enteric piece is obtained by following preparation methods：The first step, the preparation of alliin layer：By weight Number score also known as take I 55.8 parts to 68.2 parts of filler, I 3 parts to 5 parts of adhesive, interior plus I 1.8 parts to 3.3 parts of disintegrant, Additional I 1.8 parts to 3.3 parts of disintegrant, I 1.8 parts to 2.2 parts of glidant, I 0.9 parts of lubricant to 1.1 parts and alliin 112.5 Part is to 137.5 parts and crushes respectively, is mixed after alliin, filler I, adhesive I, interior plus disintegrant I are well mixed Material I, in adding the ethanol water 100ml to 600ml that volume fraction is 10% to 99% ratio in every kilogram of compound I to mixed The ethanol water for adding that fraction is 10% to 99% in material I is closed, is stirred to obtain softwood I while adding ethanol water, Softwood I is crossed into 10 mesh to 120 eye mesh screens and obtains wet grain I, wet grain I is dried in vacuo at a temperature of 0 DEG C to 60 DEG C and done Particle I, dry particl I cross 10 mesh to 120 eye mesh screens carry out whole grain, then added into the dry particl after whole grain additional disintegrant I, Standby grain I is obtained after glidant I and lubricant I are well mixed；

Second step, the preparation of allinase layer：Score also known as takes II 55.8 parts to 68.2 parts of filler, adhesive in parts by weight II 5.4 parts to 6.6 parts, interior plus II 3.15 parts to 3.85 parts of disintegrant, II 3.15 parts to 3.85 parts of additional disintegrant, glidant II 2.7 parts to 3.3 parts, II 0.9 parts to 1.1 parts of lubricant and vigor are more than or equal to 1000IU/g 112.5 parts to 137.5 parts of allinase And crush respectively, compound II is obtained after allinase, filler II, adhesive II, interior plus disintegrant II are well mixed, by every thousand The ratio that the ethanol water 100ml to 600ml that fraction is 10% to 99% is added in gram compound II adds into compound II Fraction is 10% to 99% ethanol water, is stirred to obtain softwood II while adding ethanol water, by the mistake of softwood II 10 mesh to 120 eye mesh screens obtain wet grain II, and wet grain II is dried in vacuo at a temperature of 0 DEG C to 60 DEG C to obtain dry particl II, Dry particl II crosses 10 mesh to 120 eye mesh screens and carries out whole grain, and additional disintegrant II is then added into the dry particl after whole grain, helps stream Standby grain II is obtained after agent II and lubricant II are well mixed；

3rd step, the preparation of separation layer：Score also known as takes III 68.04 parts to 83.16 parts of filler, bonding in parts by weight III 2.16 parts to 2.64 parts of agent, interior plus III 0.9 parts to 1.1 parts of III 0.9 parts to 1.1 parts of disintegrant and additional disintegrant and difference powder It is broken, compound III is obtained after filler III, adhesive III and interior plus disintegrant III are well mixed, by every kilogram of compound III Add fraction be 10% to 99% ethanol water 100ml to 600ml ratio added into compound III fraction be 10% to 99% ethanol water, it is stirred to obtain softwood III while adding ethanol water, softwood III is crossed into 10 mesh to 120 mesh Screen cloth obtains wet grain III, wet grain III is dried in vacuo at a temperature of 0 DEG C to 60 DEG C to obtain dry particl III, dry particl III crosses 10 Mesh to 120 eye mesh screens carry out whole grain, then added into the dry particl after whole grain additional disintegrant III it is well mixed after obtain it is standby Grain III；

4th step, tabletting:By standby grain I, standby grain II and standby grain III according to required tablet format according to standby grain I, standby grain III Be pressed into the tablet of 3 synusia by 3 times with the sequencing of standby grain II, and the piece for adjusting every tablet of tablet weigh to 0.45g to 0.55g, hardness to 3kg to 15kg；

5th step, parcel enteric coating obtains allicin multiple enteric piece outside the tablet obtained in upper step.

Above-mentioned filler I be starch, Icing Sugar, maltodextrin, lactose, amylum pregelatinisatum, microcrystalline cellulose, inorganic salts and One or more of mannitol；Or/and adhesive I is starch slurry, sodium carboxymethylcellulose, HPMC, hydroxypropyl One or more of sodium carboxymethylcellulose pyce, methylcellulose, ethyl cellulose and polyvinylpyrrolidone；Or/and interior plus disintegration Agent I is sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol etc., natrium carbonicum calcinatum, glycine, change One or more of property starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate； Or/and additional disintegrant I is sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol etc., anhydrous carbon Sour sodium, glycine, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate One or more of；Or/and glidant I is silica, talcum powder, the one or more in superfine silica gel powder, lubricant I is Magnesium stearate, polyethylene glycol, magnesium laurylsulfate, zinc stearate, odium stearate, sucrose fatty ester, calcium phosphate, stearic acid, One or more of calcium silicates and alumina silicate；Or/and filler II is starch, Icing Sugar, maltodextrin, lactose, compressibility shallow lake One or more of powder, microcrystalline cellulose, inorganic salts and mannitol；Or/and adhesive II is starch slurry, carboxymethyl cellulose Plain sodium, HPMC, hydroxypropyl methyl cellulose sodium, methylcellulose, ethyl cellulose and polyvinylpyrrolidone One or more of；Or/and interior plus disintegrant II is sodium carboxymethyl starch, dried starch, gas-producing disintegrant, cross-linked carboxymethyl fibre Tie up plain sodium etc., natrium carbonicum calcinatum, glycine, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, carbon One or more of sour potassium and potassium dihydrogen phosphate；Or/and additional disintegrant II is sodium carboxymethyl starch, dried starch, effervesce disintegration Agent, Ac-Di-Sol etc., natrium carbonicum calcinatum, glycine, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, carboxylic One or more of methylcellulose calcium, potassium carbonate and potassium dihydrogen phosphate；Or/and glidant II be silica, talcum powder, One or more of superfine silica gel powder；Or/and lubricant II be magnesium stearate, polyethylene glycol, magnesium laurylsulfate, zinc stearate, One or more of odium stearate, sucrose fatty ester, calcium phosphate, stearic acid, calcium silicates and alumina silicate；Or/and filler III For one or more of starch, Icing Sugar, maltodextrin, lactose, amylum pregelatinisatum, microcrystalline cellulose, inorganic salts and mannitol； Or/and adhesive III is starch slurry, sodium carboxymethylcellulose, HPMC, hydroxypropyl methyl cellulose sodium, methyl One or more of cellulose, ethyl cellulose and polyvinylpyrrolidone；Or/and interior plus disintegrant III is CMS Sodium, dried starch, gas-producing disintegrant, Ac-Di-Sol etc., natrium carbonicum calcinatum, glycine, converted starch, tartaric acid, One or more of aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate；Or/and additional disintegration Agent III be sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol etc., natrium carbonicum calcinatum, glycine, In converted starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate it is a kind of with On.

In the above-mentioned first step, count in parts by weight, filler I is 58.2 parts, adhesive I is 4 parts, interior plus disintegrant I is 2.5 parts, additional disintegrant I be 2.5 parts, glidant I be 2 parts, lubricant I is 1 part and alliin is 125 parts；Or/and second In step, count in parts by weight, filler II is 58.2 parts, adhesive II is 6 parts, interior plus disintegrant II is 3.5 parts, additional disintegration Agent II is 3.5 parts, glidant II is 3 parts, lubricant II is 1 part and allinase of the vigor more than or equal to 1000IU/g is 125 parts； Or/and the 3rd in step, count in parts by weight, filler III is 75 parts, adhesive III is 2.5 parts, interior plus III 1 parts of disintegrant and Additional disintegrant III is 1 part.

In the above-mentioned first step, softwood I is crossed into 40 eye mesh screens and obtains wet grain I, wet grain I is carried out into vacuum at a temperature of 30 DEG C does Dry to obtain dry particl I, dry particl I crosses 40 eye mesh screens and carries out whole grain；Or/and in second step, softwood II is crossed into 40 eye mesh screens and obtained Wet grain II, wet grain II is dried in vacuo at a temperature of 30 DEG C to obtain dry particl II, it is whole that dry particl II crosses the progress of 40 eye mesh screens Grain；Or/and softwood III is crossed into 40 eye mesh screens and obtains wet grain III, wet grain III is dried in vacuo at a temperature of 30 DEG C and done Particle III, dry particl III cross 40 eye mesh screens and carry out whole grain；In 4th step, adjust the piece weight of every tablet of tablet to 0.5g, hardness to 8kg。

The preparation method of above-mentioned allicin multiple enteric piece refers to the Chinese patent literature of Publication No. 101549152.

The present invention passes through " allicin multiple enteric piece gastric infusion, and the pathologic group to rat heart infarction animal model Knit inspection and blood and heart tissue is homogenized to obtain biochemical indicator inspection, as a result show, allicin multiple enteric piece has anti- The drug effect of myocardial infarction, and significant dose-dependent relationship is presented between each dosage group, illustrate allicin multiple enteric piece Myocardial infarction disease can be effectively prevented and treated, further illustrates that allicin preparation can turn into a kind of efficiently treatment myocardial infarction disease The new pharmaceutical formulation of disease.

Brief description of the drawings

Fig. 1 is the relational expression schematic diagram that allinase catalytic pyrolysis alliin produces allicin in the present invention.

Fig. 2 is alliin chemical constitution schematic diagram in the present invention.

Fig. 3 is allicin chemical constitution schematic diagram in the present invention.

Fig. 4 is allicin chemical constitution schematic diagram in the present invention.

Fig. 5 is the pass of alliin in the present invention, allinase, allicin and diallyl sulfide (ally sulfides) It is schematic diagram.

Fig. 6 is to influence schematic diagram to rat model of myocardial infarction myocardial infarct size for reagent product in the present invention.

Fig. 7 is sham-operation group myocardial histopathology morphological change schematic diagram in the present invention.

Fig. 8 is model group myocardial histopathology morphological change schematic diagram in the present invention.

Fig. 9 is alliin+allinase low dose group myocardial histopathology morphological change schematic diagram in the present invention.

Figure 10 is alliin+allinase middle dose group myocardial histopathology morphological change schematic diagram in the present invention.

Figure 11 is alliin+allinase high dose myocardial histopathology morphological change schematic diagram in the present invention.

Figure 12 is the heart tissue materials position view that biochemical indicator is determined in the present invention.

Embodiment

The present invention is not limited by following embodiments, can technique according to the invention scheme and actual conditions it is specific to determine Embodiment.

With reference to embodiment, the invention will be further described：

Embodiment 1, the allicin multiple enteric piece is as the application for preparing treatment myocardial infarction disease medicament.

Embodiment 2, as the preferred of above-described embodiment, treatment myocardial infarction disease medicament is allicin multiple enteric Piece.

Embodiment 3, as the preferred of above-described embodiment, allicin multiple enteric piece is obtained by following preparation methods：The One step, the preparation of alliin layer：Score also known as takes I 55.8 parts to 68.2 parts of filler, I 3 parts to 5 of adhesive in parts by weight Part, interior plus I 1.8 parts to 3.3 parts of disintegrant, I 1.8 parts to 3.3 parts of additional disintegrant, I 1.8 parts to 2.2 parts of glidant, lubricant I 0.9 parts to 1.1 parts and 112.5 parts to 137.5 parts of alliin simultaneously crush respectively, by alliin, filler I, adhesive I, it is interior plus Compound I is obtained after disintegrant I is well mixed, by the ethanol water that addition volume fraction is 10% to 99% in every kilogram of compound I Solution 100ml to 600ml ratio adds the ethanol water that fraction is 10% to 99% into compound I, and it is water-soluble to add ethanol It is stirred to obtain softwood I while liquid, softwood I is crossed into 10 mesh to 120 eye mesh screens obtains wet grain I, by wet grain I at 0 DEG C to 60 It is dried in vacuo to obtain dry particl I at a temperature of DEG C, dry particl I crosses 10 mesh to 120 eye mesh screens and carries out whole grain, then to after whole grain Dry particl in add additional disintegrant I, glidant I and lubricant I it is well mixed after obtain standby grain I；

Embodiment 4, as the preferred of above-described embodiment, filler I is starch, Icing Sugar, maltodextrin, lactose, compressibility One or more of starch, microcrystalline cellulose, inorganic salts and mannitol；Or/and adhesive I is starch slurry, carboxymethyl cellulose Plain sodium, HPMC, hydroxypropyl methyl cellulose sodium, methylcellulose, ethyl cellulose and polyvinylpyrrolidone One or more of；Or/and interior plus disintegrant I is sodium carboxymethyl starch, dried starch, gas-producing disintegrant, cross-linked carboxymethyl fiber Plain sodium etc., natrium carbonicum calcinatum, glycine, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, carbonic acid One or more of potassium and potassium dihydrogen phosphate；Or/and additional disintegrant I be sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol etc., natrium carbonicum calcinatum, glycine, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, carboxymethyl One or more of cellulose calcium, potassium carbonate and potassium dihydrogen phosphate；Or/and glidant I is silica, talcum powder, micro mist silicon One or more in glue, lubricant I are magnesium stearate, polyethylene glycol, magnesium laurylsulfate, zinc stearate, odium stearate, sugarcane One or more of sugar fatty acid ester, calcium phosphate, stearic acid, calcium silicates and alumina silicate；Or/and filler II is starch, sugar One or more of powder, maltodextrin, lactose, amylum pregelatinisatum, microcrystalline cellulose, inorganic salts and mannitol；It is or/and viscous Mixture II is starch slurry, sodium carboxymethylcellulose, HPMC, hydroxypropyl methyl cellulose sodium, methylcellulose, second One or more of base cellulose and polyvinylpyrrolidone；Or/and interior plus disintegrant II be sodium carboxymethyl starch, dried starch, It is gas-producing disintegrant, Ac-Di-Sol etc., natrium carbonicum calcinatum, glycine, converted starch, tartaric acid, aluminium-magnesium silicate, micro- One or more of brilliant wax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate；Or/and additional disintegrant II is carboxymethyl Sodium starch, dried starch, gas-producing disintegrant, Ac-Di-Sol etc., natrium carbonicum calcinatum, glycine, converted starch, winestone One or more of acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate；Or/and glidant II is one or more of silica, talcum powder, superfine silica gel powder；Or/and lubricant II is magnesium stearate, polyethylene glycol, the moon One in cinnamic alcohol magnesium sulfate, zinc stearate, odium stearate, sucrose fatty ester, calcium phosphate, stearic acid, calcium silicates and alumina silicate More than kind；Or/and filler III is starch, Icing Sugar, maltodextrin, lactose, amylum pregelatinisatum, microcrystalline cellulose, inorganic salts One or more of with mannitol；Or/and adhesive III is starch slurry, sodium carboxymethylcellulose, HPMC, hydroxyl One or more of propyl methocel sodium, methylcellulose, ethyl cellulose and polyvinylpyrrolidone；Or/and it is interior plus Disintegrant III is sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol etc., natrium carbonicum calcinatum, sweet ammonia One kind in acid, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate More than；Or/and additional disintegrant III be sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol etc., Natrium carbonicum calcinatum, glycine, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and phosphoric acid One or more of potassium dihydrogen.

Embodiment 5, as the preferred of above-described embodiment, in the first step, count in parts by weight, filler I is 58.2 parts, viscous Mixture I is 4 parts, interior plus disintegrant I is 2.5 parts, additional disintegrant I is 2.5 parts, glidant I is 2 parts, lubricant I be 1 part and Alliin is 125 parts；Or/and in second step, count in parts by weight, filler II is 58.2 parts, adhesive II is 6 parts, it is interior plus Disintegrant II is 3.5 parts, additional disintegrant II is 3.5 parts, glidant II is 3 parts, lubricant II is that 1 part and vigor are more than or equal to 1000IU/g allinase is 125 parts；Or/and the 3rd in step, count in parts by weight, filler III is 75 parts, adhesive III is 2.5 parts, interior plus III 1 parts of disintegrant and additional disintegrant III are 1 part.

Embodiment 6, as the preferred of above-described embodiment, in the first step, count in parts by weight, filler I is 58.2 parts, viscous Mixture I is 4 parts, interior plus disintegrant I is 2.5 parts, additional disintegrant I is 2.5 parts, glidant I is 2 parts, lubricant I be 1 part and Alliin is 125 parts；Or/and in second step, count in parts by weight, filler II is 58.2 parts, adhesive II is 6 parts, it is interior plus Disintegrant II is 3.5 parts, additional disintegrant II is 3.5 parts, glidant II is 3 parts, lubricant II is that 1 part and vigor are more than or equal to 1000IU/g allinase is 125 parts；Or/and the 3rd in step, count in parts by weight, filler III is 75 parts, adhesive III is 2.5 parts, interior plus III 1 parts of disintegrant and additional disintegrant III are 1 part.

Embodiment 7, as the preferred of above-described embodiment, in the first step, softwood I crossed into 40 eye mesh screens and obtains wet grain I, will be wet Grain I is dried in vacuo to obtain dry particl I at a temperature of 30 DEG C, and dry particl I crosses 40 eye mesh screens and carries out whole grain；Or/and second step In, softwood II is crossed into 40 eye mesh screens and obtains wet grain II, wet grain II is dried in vacuo at a temperature of 30 DEG C to obtain dry particl II, Dry particl II crosses 40 eye mesh screens and carries out whole grain；Or/and softwood III is crossed into 40 eye mesh screens and obtains wet grain III, by wet grain III at 30 DEG C At a temperature of be dried in vacuo to obtain dry particl III, dry particl III crosses 40 eye mesh screens and carries out whole grain；In 4th step, every tablet of medicine is adjusted The piece of piece is heavy to 0.5g, hardness to 8kg.

Embodiment 8, as the preferred of above-described embodiment, the preparation method of allicin multiple enteric piece refers to Publication No. 101549152 Chinese patent literature, according to the allicin multiple enteric piece in the present invention other method or Publication No. Allicin multiple enteric piece prepared by the method for 101549152 Chinese patent literature quite contains potential allicin per 10mg 3.71mg, allicin multiple enteric piece meet relevant criterion through spectrum and chromatography quality.

Analysis detection is carried out to drug effect of the allicin multiple enteric piece in terms of myocardial infarction disease is treated below:

1st, animal model and packet

Model group：Using male, to 220gwistar rats as experimental animal, 3.5% is injected intraperitoneally with 10mL/kg by 180g again Chloral hydrate anesthesia, lie on the back and be fixed on rat plate；In rats with left the 4th, 5 intercostal incisions, thoracic cavity is opened, tears pericardium, gently Press thorax extrusion heart, with No. 0 surgical thread under left auricle of heart following coronary artery occlusion left anterior descending branch at 2mm, heart is put back to immediately Thoracic cavity, close otch, skin suture.

Sham-operation group：Only threading does not ligature.Using male, 180g is weighed to 220gwistar rats as experimental animal, with 10mL/ 3.5% chloral hydrate anesthesia is injected intraperitoneally in kg, lies on the back and is fixed on rat plate；In rats with left the 4th, 5 intercostal incisions, chest is opened Chamber, pericardium is torn, it is light to press thorax extrusion heart, threaded with No. 0 surgical thread under left auricle of heart at 2mm, heart is put back into chest immediately Chamber, close otch, skin suture.

Alliin/allinase low dose group：Using male, 180g is weighed to 220gwistar rats as experimental animal, with 10mL/kg 3.5% chloral hydrate anesthesia is injected intraperitoneally, lies on the back and is fixed on rat plate；In rats with left the 4th, 5 intercostal incisions, thoracic cavity is opened, Tear pericardium, it is light to press thorax extrusion heart, with No. 0 surgical thread under left auricle of heart following coronary artery occlusion left anterior descending branch at 2mm, immediately Heart is put back into thoracic cavity, closes otch, hereinafter referred to as skin suture, low dose group；

Alliin/allinase middle dose group：Using male, 180g is weighed to 220gwistar rats as experimental animal, with 10mL/kg 3.5% chloral hydrate anesthesia is injected intraperitoneally, lies on the back and is fixed on rat plate；In rats with left the 4th, 5 intercostal incisions, thoracic cavity is opened, Tear pericardium, it is light to press thorax extrusion heart, with No. 0 surgical thread under left auricle of heart following coronary artery occlusion left anterior descending branch at 2mm, immediately Heart is put back into thoracic cavity, closes otch, hereinafter referred to as skin suture, middle dose group；

Alliin/allinase high dose group：Using male, 180g is weighed to 220gwistar rats as experimental animal, with 10mL/kg 3.5% chloral hydrate anesthesia is injected intraperitoneally, lies on the back and is fixed on rat plate；In rats with left the 4th, 5 intercostal incisions, thoracic cavity is opened, Tear pericardium, it is light to press thorax extrusion heart, with No. 0 surgical thread under left auricle of heart following coronary artery occlusion left anterior descending branch at 2mm, immediately Heart is put back into thoracic cavity, closes otch, hereinafter referred to as skin suture, high dose group.

2nd, animal model detects

（1）, Electrocardiography：Each group animal carries out Electrocardiography in postoperative 1 hour, and the elevated animal of ST sections is included into reality Test system.Each group animal is administered in next day, and detection electrocardiogram is repeated in the stipulated time.

（2）, B ultrasound detection：By detecting left ventricular end diastolic anterior wall thickness（LVAWd）With rear wall thickness（LVPWd）, relax Open latter stage（LVIDd）With end-systole left ventricular interior diameter（LVIDs）, diastasis and end-systole bulk of left ventricle（LVEDV, LVESV）, LVEF (EF), shortening fraction (FS) and stroke output (SV) are to detect each race's model group animal model No success.

（3）, myocardial infarction area detection：Take out the heart of every group of mouse, normal saline flushing chambers of the heart remained blood, with filter Paper is weighed after blotting surplus liquid；Parallel coronary artery ditch under self-ligating line, ventricle is uniformly cut into uniform thickness 5, weighed respectively After be placed in 0.2% nitro blue tetrazolium normal temperature and dye 2-3min, scanner scans five myocardium positive and negative, swept respectively Trace designs picture；With the infarcted region of multi-media color Pathologic image analysis every myocardium bilateral of systematic survey, the ventricle gross area, stalk are calculated Plug area's gross area and infarct area account for ventricle area percentage.

B ultrasound is detected and myocardial infarction area testing result is shown, if sham-operation group Non Apparent Abnormality and model group cardiac muscle are thin Born of the same parents' structure disturbance, vacuole deformation, swelling, myocardial fibrosis, inflammatory cell infiltration, show modeling success.

3rd, medication

Low dose group, middle dose group and high dose group difference oral administration gavage allicin multiple enteric piece, low dose group：Mouthful Take allicin multiple enteric piece/day/kg of the gavage containing potential allicin 0.75mg；Middle dose group：Oral administration gavage is containing potential Allicin 1.5mg allicin multiple enteric piece/day/kg；High dose group：Oral administration gavage contains potential allicin 3.0mg Allicin multiple enteric piece/day/kg.Continuous 7 days.1 hour materials checks after last dose.

4th, inspection and interpretation of result

4.1st, influence of the allicin multiple enteric piece to myocardial infarction model myocardial infarct size：Core dirty relevant portion, use Cold saline washes away crimson blood, is put in neutral formalin, is dehydrated, embedding, HE dyeing, carries out histopathology, takes The myocardial infarct size average value of low dose group, middle dose group and high dose group is as alliin+allinase administration group, with model group ratio Compared with being shown in Table 1 and Fig. 6, the myocardial infarction area of alliin+allinase administration group rat has significantly it can be seen from table 1 and Fig. 6 Reduce and decline（P＜ 0.01）, illustrate that allicin multiple enteric piece has the effect of preferable to myocardial infarction.

4.2nd, influence (× 100) of the allicin multiple enteric piece to Rat of Myocardial Infarction myocardial pathology

Heart is taken out, ventricle is equably cut 5 by parallel coronary artery ditch under self-ligating line, and normal temperature contaminates in 0.2%N-BT Color, electron-microscope scanning.With sham-operation group myocardial histopathology fractionation integrate compared with, model group, high dose group, middle dose group, Low dose group difference has pole conspicuousness (P ＜ 0.01)；Compared with model group myocardial histopathology fractionation integrates, sham-operation Group, high dose group, middle dose group difference have pole conspicuousness (P ＜ 0.01), low dose group no significant difference (P ＞ 0.05)； Compared with low dosage, high dose group difference has pole conspicuousness (P ＜ 0.01), middle dose group no significant difference（The ＞ of P=0.056 0.05）；Compared with middle dosage, high dose group no significant difference（P=0.106）.

With reference to pathology of hepar grade scale, myocardial histopathology hierarchical table is established, pathology is carried out to cardiac muscular tissue Classification, integration：Myocardial tissue structure is normal, without obvious denaturation, necrosis and inflammatory cell infiltration, is designated as 0 point；Cardiac bistiocyte Structure is still normal, it is seen that obvious deformation, oedema, is designated as 1 point；There is obvious inflammatory cell infiltration in cardiac muscular tissue, is designated as 2 Point；There is a small amount of fibrosis phenomenon in cardiac muscular tissue, obvious meronecrosis occurs, with inflammatory cell infiltration, is designated as 3 points；The heart There is obvious fibrosis phenomenon in muscular tissue, with inflammatory cell infiltration, is designated as 4 points, as shown in table 2.

4.3rd, the form of pathological section

Sham-operation group Non Apparent Abnormality, as shown in Figure 7；Model group myocardial ultramicrostructure is disorderly, vacuole deformation, swelling, the heart Myofibrosis, inflammatory cell infiltration, show modeling success, as shown in Figure 8；Low dose group, the fibrosis compared with model group It has been mitigated that, a small amount of normal myocardium tissue occur, as shown in Figure 9；Middle dose group, fibrosis are further compared with model group Mitigate, half cardiac muscular tissue tends to be normal in the visual field, as shown in Figure 10；High dose, do not occur the heart in the visual field compared with model group Myofibrosis phenomenon, most of cardiac muscle cell tend to be normal, and it is as shown in figure 11 inflammatory cell infiltration phenomenon only occur.It can draw Conclusion:Allicin multiple enteric piece can be effective against myocardial infarction, and significant dose-dependant is presented between each dosage group Sexual intercourse.As shown in table 3, table 4.

4.4th, influence of the allicin multiple enteric piece to Rat of Myocardial Infarction serum GOT, LDH

2 hours after last dose, rat with 10mL/kg be injected intraperitoneally 3.5% chloral hydrate anesthesia, abdominal aortic blood, Serum is prepared, second is carried out and detects the biochemical indicators such as GOT and LDH.

Compared with sham-operation group, model group LDH is significantly raised the biochemical indicators such as GOT, LDH, and difference has pole conspicuousness； Compared with model group, each dosage group LDH of alliin+allinase is significantly reduced, and significant dose-dependent relationship be present.It is shown in Table 5 It is shown.

4.5th, allicin multiple enteric piece to Rat of Myocardial Infarction myocardial tissue oxidizing stress index influence

Cored dirty relevant portion according to Figure 12, wash away crimson blood with cold saline, 10% homogenate is made, centrifuged, take supernatant By related kit technical method, SOD activity, MDA contents in cardiac muscular tissue are determined, calculates SOD/MDA ratios, GSH-px lives Property.

As shown in table 6, compared with sham-operation group, each group rat heart muscle tissue SOD reduces, wherein, model group, low dosage Group significantly reduces, and difference has conspicuousness (P ＜ 0.05)；Compared with model group, each group rat heart muscle tissue SOD significantly rises Height, difference are respectively provided with conspicuousness (P ＜ 0.01).

Compared with sham-operation group, each group rat heart muscle tissue MDA contents significantly raise, and difference is respectively provided with conspicuousness (P ＜ 0.01)；Compared with model group, each group rat heart muscle tissue MDA is significantly reduced, and difference is respectively provided with conspicuousness (P ＜ 0.01).

Compared with sham-operation group, each group rat heart muscle tissue GSH-Px contents reduce, wherein, model group, low dose group, Middle dose group significantly reduces, and difference has conspicuousness (P ＜ 0.05 or P ＜ 0.01)；Compared with model group, each group rat heart muscle group GSH-Px is knitted significantly to raise, wherein, sham-operation group, high dose group difference have conspicuousness (P ＜ 0.05 or P ＜ 0.01).

4.6th, influence of the allicin multiple enteric piece to Rat of Myocardial Infarction cardiac muscular tissue mitochondrial function index

Cored dirty relevant portion according to Figure 12, wash away crimson blood with cold saline, 10% homogenate is made, centrifuged, take supernatant By related kit technical method, SDH, ICDH, α-KGDH and Ca in cardiac muscular tissue are determined²⁺-Mg²⁺- ATP enzyme vigor.

As shown in table 7, compared with sham-operation group, each group rat heart muscle tissue SDH levels significantly reduce, wherein, model Group, low dose group difference have conspicuousness (P ＜ 0.05 or P ＜ 0.01)；Compared with model group, each group rat heart muscle tissue SDH Significantly rise, difference are respectively provided with conspicuousness (P ＜ 0.05 or P ＜ 0.01).

Compared with sham-operation group, each group rat heart muscle tissue ICDH levels significantly reduce, wherein, model group, middle dosage Group, low dose group difference have conspicuousness (P ＜ 0.01)；Compared with model group, each group rat heart muscle tissue ICDH significantly rises Height, wherein, sham-operation group, middle dose group, high dose group difference are respectively provided with conspicuousness (P ＜ 0.01).

Compared with sham-operation group, each group rat heart muscle tissue α-KGDH levels significantly reduce, and difference is respectively provided with conspicuousness (P ＜ 0.01)；Compared with model group, each group rat heart muscle tissue α-KGDH are significantly raised, wherein, sham-operation group difference has Conspicuousness P ＜ 0.01).

Compared with sham-operation group, each group rat heart muscle tissue Ca²⁺-Mg²⁺- ATP levels significantly reduce, wherein, model Group, low dose group difference are respectively provided with conspicuousness (P ＜ 0.01)；Compared with model group, each group rat heart muscle tissue Ca²⁺-Mg²⁺- ATP levels significantly raise, wherein, model group, middle dose group, high dose group difference have conspicuousness (P ＜ 0.05 or P ＜ 0.01)。

It can be drawn by above-mentioned experimentation and result：By " allicin multiple enteric piece gastric infusion, and to big The histopathologic examination of mouse heart infarction animal model and blood and heart tissue are homogenized to obtain biochemical indicator inspection, as a result show, greatly Allicin multiple enteric piece and the drug effect with anti-infarction, and significant dose dependent is presented between each dosage group and closes System, illustrates that allicin multiple enteric piece can effectively prevent and treat myocardial infarction disease.

Claims

1. a kind of allicin multiple enteric piece is as the application for preparing treatment myocardial infarction disease medicament, the allicin multilayer Enteric coatel tablets are obtained by following preparation methods：The first step, the preparation of alliin layer：Score also known as takes filler I in parts by weight 55.8 parts to 68.2 parts, I 3 parts to 5 parts of adhesive, interior plus I 1.8 parts to 3.3 parts of disintegrant, I 1.8 parts to 3.3 of additional disintegrant 112.5 parts to 137.5 parts of part, I 1.8 parts to 2.2 parts of glidant, I 0.9 parts to 1.1 parts of lubricant and alliin simultaneously crush respectively, Compound I is obtained after alliin, filler I, adhesive I, interior plus disintegrant I are well mixed, is added by every kilogram of compound I Enter the ethanol water 100ml to 600ml that volume fraction is 10% to 99% ratio added into compound I fraction be 10% to 99% ethanol water, it is stirred to obtain softwood I while adding ethanol water, softwood I is crossed into 10 mesh to 120 mesh sieves Net obtains wet grain I, wet grain I is dried in vacuo at a temperature of 0 DEG C to 60 DEG C to obtain dry particl I, dry particl I crosses 10 mesh extremely 120 eye mesh screens carry out whole grain, and additional disintegrant I, glidant I and lubricant I are then added into the dry particl after whole grain and is mixed Standby grain I is obtained after uniformly；

Second step, the preparation of allinase layer：Score also known as takes II 55.8 parts to 68.2 parts of filler, adhesive II in parts by weight 5.4 parts to 6.6 parts, interior plus II 3.15 parts to 3.85 parts of disintegrant, II 3.15 parts to 3.85 parts of additional disintegrant, glidant II 2.7 parts to 3.3 parts, II 0.9 parts to 1.1 parts of lubricant and vigor are more than or equal to 1000IU/g 112.5 parts to 137.5 parts of allinase And crush respectively, compound II is obtained after allinase, filler II, adhesive II, interior plus disintegrant II are well mixed, by every thousand The ratio that the ethanol water 100ml to 600ml that fraction is 10% to 99% is added in gram compound II adds into compound II Fraction is 10% to 99% ethanol water, is stirred to obtain softwood II while adding ethanol water, by the mistake of softwood II 10 mesh to 120 eye mesh screens obtain wet grain II, and wet grain II is dried in vacuo at a temperature of 0 DEG C to 60 DEG C to obtain dry particl II, Dry particl II crosses 10 mesh to 120 eye mesh screens and carries out whole grain, and additional disintegrant II is then added into the dry particl after whole grain, helps stream Standby grain II is obtained after agent II and lubricant II are well mixed；

3rd step, the preparation of separation layer：Score also known as takes III 68.04 parts to 83.16 parts of filler, adhesive III in parts by weight 2.16 parts to 2.64 parts, interior plus III 0.9 parts to 1.1 parts of III 0.9 parts to 1.1 parts of disintegrant and additional disintegrant and crush respectively, Compound III is obtained after filler III, adhesive III and interior plus disintegrant III are well mixed, is added by every kilogram of compound III Entering the ethanol water 100ml to 600ml that fraction is 10% to 99% ratio, fraction is added into compound III is 10% to 99% Ethanol water, add ethanol water while be stirred to obtain softwood III, by softwood III cross 10 mesh to 120 eye mesh screens Wet grain III is obtained, wet grain III is dried in vacuo at a temperature of 0 DEG C to 60 DEG C to obtain dry particl III, dry particl III crosses 10 mesh extremely 120 eye mesh screens carry out whole grain, are then added into the dry particl after whole grain after additional disintegrant III is well mixed and obtain standby grain III；

4th step, tabletting:By standby grain I, standby grain II and standby grain III according to required tablet format according to standby grain I, standby grain III and standby The sequencing of grain II is pressed into the tablet of 3 synusia by 3 times, and the piece for adjusting every tablet of tablet weighs to 0.45g to 0.55g, be hard Degree is to 3kg to 15kg；

2. allicin multiple enteric piece according to claim 1 should as preparation treatment myocardial infarction disease medicament With, it is characterised in that treatment myocardial infarction disease medicament is allicin multiple enteric piece.

3. allicin multiple enteric piece according to claim 1 or 2 is as preparation treatment myocardial infarction disease medicament Using, it is characterised in that filler I is one in starch, Icing Sugar, maltodextrin, microcrystalline cellulose, inorganic salts and mannitol More than kind；Or/and adhesive I is starch slurry, sodium carboxymethylcellulose, HPMC, hydroxypropyl methyl cellulose One or more of sodium, methylcellulose, ethyl cellulose and polyvinylpyrrolidone；Or/and interior plus disintegrant I is carboxylic first Base sodium starch, dried starch, gas-producing disintegrant, Ac-Di-Sol, natrium carbonicum calcinatum, glycine, converted starch, winestone One or more of acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate；Or/and additional collapse Solution agent I is sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol, natrium carbonicum calcinatum, glycine, change One or more of property starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate； Or/and glidant I is silica, talcum powder, the one or more in superfine silica gel powder, lubricant I is magnesium stearate, poly- second Glycol, magnesium laurylsulfate, zinc stearate, odium stearate, sucrose fatty ester, calcium phosphate, stearic acid, calcium silicates and alumina silicate One or more of；Or/and filler II is in starch, Icing Sugar, maltodextrin, microcrystalline cellulose, inorganic salts and mannitol More than one；Or/and adhesive II is starch slurry, sodium carboxymethylcellulose, HPMC, hydroxypropyl methyl fibre Tie up one or more of plain sodium, methylcellulose, ethyl cellulose and polyvinylpyrrolidone；Or/and interior plus disintegrant II is Sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol, natrium carbonicum calcinatum, glycine, converted starch, One or more of tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate；Or/and outside Add disintegrant II for sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol, natrium carbonicum calcinatum, sweet ammonia One kind in acid, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate and potassium dihydrogen phosphate More than；Or/and glidant II is one or more of silica, talcum powder, superfine silica gel powder；Or/and lubricant II is hard Fatty acid magnesium, polyethylene glycol, magnesium laurylsulfate, zinc stearate, odium stearate, sucrose fatty ester, calcium phosphate, stearic acid, silicon One or more of sour calcium and alumina silicate；Or/and filler III be starch, Icing Sugar, maltodextrin, lactose, amylum pregelatinisatum, One or more of microcrystalline cellulose, inorganic salts and mannitol；Or/and adhesive III is starch slurry, carboxymethyl cellulose In sodium, HPMC, hydroxypropyl methyl cellulose sodium, methylcellulose, ethyl cellulose and polyvinylpyrrolidone More than one；Or/and interior plus disintegrant III is sodium carboxymethyl starch, dried starch, gas-producing disintegrant, cross-linked carboxymethyl fiber Plain sodium, natrium carbonicum calcinatum, glycine, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, calcium carboxymethylcellulose, potassium carbonate One or more of with potassium dihydrogen phosphate；Or/and additional disintegrant III be sodium carboxymethyl starch, dried starch, gas-producing disintegrant, Ac-Di-Sol, natrium carbonicum calcinatum, glycine, converted starch, tartaric acid, aluminium-magnesium silicate, microwax, carboxymethyl are fine Tie up one or more of plain calcium, potassium carbonate and potassium dihydrogen phosphate.

4. allicin multiple enteric piece according to claim 1 or 2 is as preparation treatment myocardial infarction disease medicament Using, it is characterised in that in the first step, count in parts by weight, filler I is 58.2 parts, adhesive I is 4 parts, interior plus disintegrant I For 2.5 parts, additional disintegrant I be 2.5 parts, glidant I is 2 parts, lubricant I is 1 part and alliin is 125 parts；Or/and the In two steps, count in parts by weight, filler II is 58.2 parts, adhesive II is 6 parts, interior plus disintegrant II is 3.5 parts, additional is collapsed Solution agent II is 3.5 parts, glidant II is 3 parts, lubricant II is 1 part and allinase of the vigor more than or equal to 1000IU/g is 125 parts； Or/and the 3rd in step, count in parts by weight, filler III is 75 parts, adhesive III is 2.5 parts, interior plus III 1 parts of disintegrant and Additional disintegrant III is 1 part.

5. allicin multiple enteric piece according to claim 3 should as preparation treatment myocardial infarction disease medicament With, it is characterised in that in the first step, count in parts by weight, filler I is 58.2 parts, adhesive I is 4 parts, interior plus disintegrant I is 2.5 parts, additional disintegrant I be 2.5 parts, glidant I be 2 parts, lubricant I is 1 part and alliin is 125 parts；Or/and second In step, count in parts by weight, filler II is 58.2 parts, adhesive II is 6 parts, interior plus disintegrant II is 3.5 parts, additional disintegration Agent II is 3.5 parts, glidant II is 3 parts, lubricant II is 1 part and allinase of the vigor more than or equal to 1000IU/g is 125 parts； Or/and the 3rd in step, count in parts by weight, filler III is 75 parts, adhesive III is 2.5 parts, interior plus III 1 parts of disintegrant and Additional disintegrant III is 1 part.

6. allicin multiple enteric piece according to claim 1 or 2 is as preparation treatment myocardial infarction disease medicament Using, it is characterised in that in the first step, softwood I is crossed into 40 eye mesh screens and obtains wet grain I, wet grain I is carried out very at a temperature of 30 DEG C Sky is dried to obtain dry particl I, and dry particl I crosses 40 eye mesh screens and carries out whole grain；Or/and in second step, softwood II is crossed into 40 eye mesh screens Wet grain II is obtained, wet grain II is dried in vacuo at a temperature of 30 DEG C to obtain dry particl II, dry particl II is crossed 40 eye mesh screens and entered Row whole grain；Or/and softwood III is crossed into 40 eye mesh screens and obtains wet grain III, wet grain III is carried out being dried in vacuo at a temperature of 30 DEG C To dry particl III, dry particl III crosses 40 eye mesh screens and carries out whole grain；In 4th step, the piece for adjusting every tablet of tablet is heavy to 0.5g, hardness To 8kg.

7. allicin multiple enteric piece according to claim 3 should as preparation treatment myocardial infarction disease medicament With, it is characterised in that in the first step, softwood I is crossed into 40 eye mesh screens and obtains wet grain I, wet grain I is subjected to vacuum at a temperature of 30 DEG C Dry particl I is dried to obtain, dry particl I crosses 40 eye mesh screens and carries out whole grain；Or/and in second step, softwood II is crossed into 40 eye mesh screens and obtained To wet grain II, wet grain II is dried in vacuo at a temperature of 30 DEG C to obtain dry particl II, dry particl II is crossed 40 eye mesh screens and carried out Whole grain；Or/and softwood III is crossed into 40 eye mesh screens and obtains wet grain III, wet grain III is dried in vacuo to obtain at a temperature of 30 DEG C Dry particl III, dry particl III cross 40 eye mesh screens and carry out whole grain；In 4th step, adjust the piece weight of every tablet of tablet to 0.5g, hardness to 8kg。

8. allicin multiple enteric piece according to claim 4 should as preparation treatment myocardial infarction disease medicament With, it is characterised in that in the first step, softwood I is crossed into 40 eye mesh screens and obtains wet grain I, wet grain I is subjected to vacuum at a temperature of 30 DEG C Dry particl I is dried to obtain, dry particl I crosses 40 eye mesh screens and carries out whole grain；Or/and in second step, softwood II is crossed into 40 eye mesh screens and obtained To wet grain II, wet grain II is dried in vacuo at a temperature of 30 DEG C to obtain dry particl II, dry particl II is crossed 40 eye mesh screens and carried out Whole grain；Or/and softwood III is crossed into 40 eye mesh screens and obtains wet grain III, wet grain III is dried in vacuo to obtain at a temperature of 30 DEG C Dry particl III, dry particl III cross 40 eye mesh screens and carry out whole grain；In 4th step, adjust the piece weight of every tablet of tablet to 0.5g, hardness to 8kg。

9. allicin multiple enteric piece according to claim 5 should as preparation treatment myocardial infarction disease medicament With, it is characterised in that in the first step, softwood I is crossed into 40 eye mesh screens and obtains wet grain I, wet grain I is subjected to vacuum at a temperature of 30 DEG C Dry particl I is dried to obtain, dry particl I crosses 40 eye mesh screens and carries out whole grain；Or/and in second step, softwood II is crossed into 40 eye mesh screens and obtained To wet grain II, wet grain II is dried in vacuo at a temperature of 30 DEG C to obtain dry particl II, dry particl II is crossed 40 eye mesh screens and carried out Whole grain；Or/and softwood III is crossed into 40 eye mesh screens and obtains wet grain III, wet grain III is dried in vacuo to obtain at a temperature of 30 DEG C Dry particl III, dry particl III cross 40 eye mesh screens and carry out whole grain；In 4th step, adjust the piece weight of every tablet of tablet to 0.5g, hardness to 8kg。