CN1452981A - Herpes virus treating medicine composition and its production process - Google Patents
Herpes virus treating medicine composition and its production process Download PDFInfo
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Abstract
The present invention is one kind of medicine composition for treating herpesvirus disease and its production process. The composition includes Hypericum perforatum extractive 50-80 wt% and lysine hydrochloride 20-50 wt%. it is used to suppress herpesvirus infection and raising body's immunity to reach the aim of resisting HSV-1, CMV and HIV. It has no obvious side effect, and is one ideal kind of medicine for treating herpesvirus infection.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition for the treatment of herpesvirus, particularly be added with the pharmaceutical composition and the production method thereof of the treatment herpesvirus of Chinese medicine.
Background technology
Herpesvirus (Herpes-virus) is a group median size, structural similarity, the tunicary distrand DNA virus of finding at animal and human's apoplexy due to endogenous wind.Have now found that more than 100 kinds.Wherein, herpes simplex virus (Herpes Simples Viruses, HSV) and varicella zoster virus (Varicella-zoster virus VZV) is common infectious agent.HSV infects relevant with more than 10 kind of diseases such as congenital malformation, miscarriage, cervical cancer, encephalitis, newborn child's illness, sexually transmitted disease (STD)s.VZV infects can cause herpes zoster.
Known herpes simplex virus (Herpes Simples Viruses, HSV) and varicella zoster virus (Varicella-zoster virus, VZV) relevant with acquired immune deficiency syndrome (AIDS) (HIV), according to relevant document introduction, often usually be subjected to herpesvirus infection and pathogenic in acquired immune deficiency syndrome (AIDS) HIV (+) carrier, in the treatment of acquired immune deficiency syndrome (AIDS), recognize, herpesvirus infection reaches to cause a disease in HIV (+) carrier two characteristics: the one, and the incidence of infection height, the 2nd, clinical symptoms is serious, the course of disease is long, outbreak repeatedly, prognosis mala.
Stavrianeas etc. have reported in 1988 to 1996 the Greece HIV of Andreas Sygros hospital (+) carriers the herpesvirus infection situation of causing a disease.359 people suffer from the herpesvirus infection disease in 690 HIV (+) carrier, and sickness rate is up to 52.03%.Wherein 101 people infect for HSV, and 110 people infect for VSV, and 97 people infect for EBV, and 51 people are cmv infection.HSV mainly infects genitals and crissum (77/101), accounts for HSV the infected 76.2%.Wherein 18 HSV the infecteds show as the prolonged ulcer that does not heal of infection site.4 examples show as the hypertrophic infringement in the herpes zoster that the VZV infection causes, 7 routine hemorrhagic necrosis infringements, and 11 examples are shown effect repeatedly and are reached 31 times, and 6 routine skin lesion are many dermatotomes.Cmv infection and CD
4 +The T lymphocyte level is lowly relevant, all cmv infection person GD
4 +T lymphocyte＜100/ul.And in 97 EBV the infecteds, 96 people show as the oral cavity hairy leukoplakia, and (Oral hairy lenukoplakia, OHL), 1 people shows as the Burkitt lymphoma
[3]
Many HIV sufferers all are associated with extensive skin of HSV or mucosal infections.This class HSV infects and not only to be difficult to diagnosis, and may be with the AIDS sick rate relevant with mortality rate.Garcia-Plata etc. have reported that 1 44 years old HIV (+) plasma specific HSV-2 antibody positive rate accounts for 35.7%, then account for 82.7% in HIV (+) sample, show that HIV and HSV-2 have significant correlation.Therefore he proposes to control that HSV-2 infects may be to reduce the good method that HIV propagates in the crowd
[5]Mwansasu has detected the routed soup of 70 genital ulcer patients of Tanzania and has organized HSV-1, HSV-2 and HIV infection conditions.The result detects HSV-2 DNA in 64% case, but does not detect the existence of HSV-1DNA.The positive rate of HSV-2 and HIV antibody accounts for 79.7% and 42% respectively, also points out between HSV-2 and the HIV relevant.
VZV infects and show as herpes zoster more in normal population, and the VZV infection causes choroid and retinitis person generally to be detected in acquired immune deficiency syndrome (AIDS), (Progressive outerretinal necerosis, PORN) syndrome is wherein one type to radical property periphery retinal necrosis.The PORN disease progression is rapid, and a few days to several weeks are just as blind as a bat, and does not have effective Therapeutic Method.
After B cell lymphoid hyperplasia (B-cell lymphoid proliferarions) betided former or acquired immunity dysfunction due to EBV infected.In HIV the infected, EBV B cell lymphoma (B-ecll lymphoma) pilosity of being correlated with is born in serious immunosuppressant patient.Have 30F%～70% relevant with EBV in the case of HIV (+) carrier trouble Burkiff lymphoma (Burkitt lymphoma), prompting EBV plays an important role in aids patient trouble lymphoma process.
HHV-6 separated from lymphoproliferative diseases (lymphoproliferativediseasea) patient and blood lymphocytes first in 1986 and obtains.Human HHV-6 primary infection mostly occurred in the Childhood, hid in lymphoid tissue then.It is generally acknowledged when immunity of organism is low and activate once more that clinical manifestation is heating, hepatitis, encephalitis and interstitial pneumonia.Ranger-Rogez etc. comprise HIV sufferers, the asymptomatic person of HIV (+) and HIV (-) person to 1085, detect HHV-6 antibody, and the result shows that HHV-6 antibody positive rate and HIV (+) and the HIV stage that catches has nothing to do.
A kind of new nerpes vinrus hominis of nineteen ninety, HHV-7 separates obtaining from normal adults CD4-T lymphocyte.Similar with HHV-6, the multiple body life of human HHV-7 primary infection was hidden in lymphoid tissue then in the Childhood.Results of study such as Kempf show.It is the activatory reason of HHV-7 that the HIV infection causes immunity of organism to suppress.
HHV-8 is newfound a kind of herpesvirus, be considered to Kaposi ' s sarcoma (Kaposi ' s sarcoma, KS) the cause of disease, therefore have another name called the relevant herpesvirus of Kaposi ' s sarcoma (Kaposi ' s sarcoma-associatedherpesvirus, KSHV).HHV-8 unlike other herpesvirus in healthy people ubiquity, the HHV-8 infection rate is 20%～50% in HIV-1 (+) carrier, is higher than healthy population
[12]Measure in the HIV sufferers peripheral blood and measure HHV-8IgG antibody in HHV-8 or the serum, the generation of prompting KS.HHV-8 is also relevant with the generation of HIV sufferers body cavity B cell lymphoma.
In a word, human infection's herpesvirus is very general, but mostly is inapparent infection or the primary infection symptom is lighter.After the primary infection, herpesvirus is dived shape in corresponding histiocyte, stimulates when body suffers some, and particularly the latent virus activation causes disease during the body cell immune function depression.The HIV specificity is attacked CD
4 +The T lymphocyte, the body cell immunologic function is badly damaged, make the herpesvirus activation of hiding cause disease or just body be easy to infect herpesvirus, and can cause serious herpesvirus infection disease.People such as Bagdades find that HSV infects ulcer and the CD that causes in HIV (+) carrier
4 +The T lymphocyte is low-level to be closely related, and points out out getting in touch of HIV (+) carrier HSV infection and cellular immune level.
Multinomial clinical and experimental result demonstration, HHV-6 also is one that the course of disease developed after HIV infected and promotes the factor.Be different from other cofactor (as HSV, CMV and ESV etc.) that HIV infects, HHV-6 can attack CD
4 +The T lymphocyte, and influence the HIV infection morbidity by number of mechanisms, it may mechanism have:
1.HHV-6 several immunocytes of direct infection or interference body comprise CD
4 +T lymphocyte, natural killer cell (naturekiller cell, NK cell), part bone-marrow-derived lymphocyte and mononuclear phagocyte weaken body immune system antiviral function.
2.HHV-6 and HIV can be at CD
4 +The T lymphocyte duplicates jointly, but (long terminal repeat LTR) strengthens HIV and expresses the long terminal repeat of HHV-6 trans-activation HIV, quickens host cell death.
3.HHV-6 can raise CD
4Molecule is at CD
4 +The expression of cell can also induce CD4mRNA and albumen at CD
4 -The expression of cell comprises NK cell, ripe CD
4 -CD
8 +T lymphocyte and CD
4 -δ Y lymphocyte.Therefore, HHV-6 can broadening HIV permissive cell scope, strengthens HIV sending out in vivo.
4.HHV-6 can also stimulate the expression of some inflammatory cytokine, as interferon a (interterona, IFNa), tumor necrosis factor a (rumor necrosis factora, TNFa), interleukin 1 β (inrerleukin 1 β, IL1 β) etc.These inflammatory factors are in the external expression that can influence HIV, and may be one of acquired immune deficiency syndrome (AIDS) and relevant disease pathogenesis thereof.
In sum, it lowly is the main cause of herpesvirus infection, recurrence that the HIV infection causes body's immunity, and herpesvirus (removing HHV-7) increases the probability that HIV propagates as cofactor, promotes acquired immune deficiency syndrome (AIDS) to fall ill, and quickening the course of disease also influences prognosis.Therefore must pay attention to the control that HIV sufferers merges herpesvirus infection.
The present antiviral drugs that the control of acquired immune deficiency syndrome (AIDS) merging herpesvirus infection is mainly used comprises (one) nucleoside medicine: one on behalf of acyclovir (Acyclovir, ACV treatment HSV and VZV infect); (two on behalf of ganciclovir (Ganciclovir, treatment cmv infection), valaciclovir (Valaciclovir); Three on behalf of famciclovir (Famciclovir, treatment VZV infects); (2) non-nucleoside medicine: foscarnet sodium (foscarnet sodium), plain Li Fuding (Sorivudine, treatment HSV infects); (3) biological antiviral drugs: interferon (Interferon).
But drug resistance has appearred in the above-mentioned medicine that has recently, and the toxic and side effects that has is bigger, costs an arm and a leg.Therefore, the medical science men are also constantly seeking the new safe and effective antiviral agents of exploitation.
According to the document introduction, many Chinese herbal medicine or Chinese medicine preparation be glycyrrhizin, trichosanthin, Radix Scutellariae, Cortex Mori, Bulbus Allii, mushroom, Fructus Caricae, Radix Ginseng, Fructus Momordicae charantiae, SHUANGHUANLIAN, Herba Violae, Radix Bupleuri, Radix Salviae Miltiorrhizae, Spica Prunellae, Herba Hedyotidis Diffusae, Rhizoma Coptidis, Flos Lonicerae, Radix Arnebiae (Radix Lithospermi), Herba Andrographis, the Radix Pulsatillae, Radix Saposhnikoviae, Ganoderma for example.The Radix Astragali, Radix Isatidis, Herba Taxilli, Herba Epimedii, Radix Sophorae Flavescentis, Herba Sidae Rhombifoliae soup, Liujunzi Tang, Radix Paeoniae Rubra preparation, GUIPI TANG, BUZHONG YIQI TANG etc., big potentiality are being arranged aspect adjusting body's immunity and antiviral, prevention and the treatment acquired immune deficiency syndrome (AIDS), can strengthen the lymphocyte vigor, improve the AIDS symptom, prolong life cycle and reduction and carry the sickness rate of examining important function is arranged.
But how from treatment herpes disease, by suppressing herpesvirus infection, recurrence, the human body immunity improving function reaches and has anti-HSV-1, and the effect purpose of CMV and HIV remains viral physician's research topic.
Technology contents
The inventor is in secular scientific research, compare by pharmacology, pharmacodynamics some Chinese herbal medicine, and screened some natural antiviral drugs, find that Herba Hyperici perforati is to lead and the medicine that adds after some aminoacid combinations has anti-HSV-1, the effect of CMV and HIV.
Technical scheme of the present invention is as follows:
The pharmaceutical composition of treatment herpesvirus comprises Herba Hyperici perforati and lysine hydrochloride, and its composition and weight percentage are:
Herba Hyperici perforati extract 50-80%
Lysine hydrochloride 20-50%
Above-described Herba Hyperici perforati extract contains hypericin 2-5%, after its extracting method can adopt hot-water soak 2h about 50 ℃, adds 0.5%NaOH, with 75% methanol under 0.05Mpa 78 ℃ extract 3-5 time, each 1.5h, the solvent amount is 5 times, concentrate drying under 80 ℃ of conditions; Also can adopt 80% ethanol is solvent, pinch goes out the anthracene derivant in the Herba Hyperici perforati, the reuse adsorbent resin, and the binding silica gel chromatography is separated hypericin, obtains content and be 4.26% hypericin product; The document introduction that has is extracted hyperin with 95% ethanol as solvent, adds a small amount of (NH when concentrating
4)
2SO
4, be to concentrate under the condition of 34～8kPa in vacuum, adopt spray-dired method to obtain, also can extract and obtain with other method of document introduction.
Above-described lysine hydrochloric acid salt content is more than 95%.
The preparation that described pharmaceutical composition is made comprises tablet, capsule, pill, granule, mixture, syrup.
The production method of pharmaceutical composition of the present invention is as follows:
1, the production method of tablet: with Herba Hyperici perforati extract, lysine hydrochloride, make particle drying, add disintegrating agent, lubricant with excipient, tabletting, or directly pack, or sugar coating, or the bag film-coat promptly obtains product.
The described excipient of above tablet is starch and derivant thereof, dextrin, calcium hydrogen phosphate etc.; Described disintegrating agent is sodium carboxymethyl cellulose, hydroxypropyl cellulose etc.; Described lubricant is a magnesium stearate etc.; Described sugar coating material is sucrose, Pulvis Talci, gelatin, pigment, river wax etc.; Described thin film coating material is stomach dissolution type water, pure coating material etc.Wherein the weight content of excipient, disintegrating agent, lubricant, coating material consumption is respectively: 5～75%, 0.5～20%, 0.5～2.0%, 2～45%.
2, the production method of capsule: Herba Hyperici perforati extract, lysine hydrochloride are added excipient and disintegrating agent and make it dry, in incapsulating then, obtain product.
More than preparation capsule described excipient is starch and derivant thereof, calcium hydrogen phosphate, magnesium stearate, differential silica gel etc.Weight 20～80%.
3, the production method of pill: Herba Hyperici perforati extract, lysine hydrochloride are added excipient, pill.1. make concentrated pill; 2. add excipient weight 10～100%, Mel, make water-honeyed pill, big honeyed pills, concentrated pill.
4, the production method of granule: in the concentrated solution that above-mentioned production obtains, add excipient, and make granule, make it dry, obtain product.
The composition and the content that add excipient: sucrose 50～95%, lactose 50～90%, dextrin 50～70%.
5, the production method of mixture:, promptly obtain product with Herba Hyperici perforati extract, lysine hydrochloride and correctives, antiseptic solution mix homogeneously.
The correctives and the content thereof that add: sucrose (or Mel) 10～60%, potassium sorbate preservative 0.1～1%, ethyl hydroxybenzoate 0.1～0.3%.
6, the production method of syrup:, promptly obtain product with Herba Hyperici perforati extract, lysine hydrochloride and sucrose, antiseptic solution mix homogeneously.
The sucrose amount that adds is 60～70%, potassium sorbate preservative 0.1～1%, ethyl hydroxybenzoate 0.1～0.3%.
The antiinflammatory action mechanism of pharmaceutical composition of the present invention with and outstanding substantive distinguishing features and obvious improvement be:
Herba Hyperici perforati is Guttiferae Hypericum (Hyprzeum L) plant Herba Hyperici perforati (disease such as it mainly is used to antidepressant, astringing to arrest bleeding, controls haematemesis for Hypericum perforatumLinn, herb EHPL), traumatic hemorrhage, toxic swelling and pain relieving.External in recent years discovers, hypericin is the main effective ingredient in the Herba Hyperici perforati in the extract, can treat hepatitis A, hepatitis B, rheumatic ostalgia etc.The document introduction that has, hypericin still are a kind of promising endogenous photosensitizers, can be applicable to the photochemodiagnosis and the treatment of tumor, have the effect of significant anti-DNA, RNA viruses.Meruelo D etc. studies show that hypericin contained in the Herba Hyperici perforati and pseudohypericin all have antiretroviral (as a HIV) effect with external in vivo.Experimental results show that hypericin also has inhibitory action to HSV-1, HSV-1, parainfluenza virus, vaccinia virus, herpes Stomatovirus external.
Lysine hydrochloride is a L-lysine, another name L-glycoleucine, L-pine propylhomoserin, L-2, the hydrochlorate of 6-diaminocaproic acid, outward appearance is white or near-white, free flowable crystalline powder, the visible impurity of no naked eyes, lysine hydrochloride is more stable usually, high temperature easily lumps down, relative humidity is stable below 60%, then generates dihydrate more than 60%, alkali condition and directly then decomposition of heating in the presence of reducing sugar, soluble in water, it is neutral to subacidity, with phosphoric acid that aqueous solution is, hydrochloric acid, sodium hydroxide, ion exchange resin etc. heat together, can play racemization.
The inventor is also through retrieval, understand the progress of Herba Hyperici perforati domestic and international research and treatment disease, and the open source literature that retrieves relevant Herba Hyperici perforati has following: 1, " homemade Herba Hyperici perforati The Chemical Constituents ", Yin Zhi fine jade leaf literary talent, (China Medicine University) " China Medicine University's journal ".The chemical constituent that 2002,33 (4) [digests] produce Herba Hyperici perforati to China Guizhou has been carried out the chemical research than system.Utilize various chromatographic techniques to carry out separation and purification, carry out structure through physics and chemistry constant and Spectrum Analysis etc. and identify.Separate and obtain 8 chemical compounds: Quercetin (quercetin, I), skin glycosides (quercitrin, II), and kaempferol (kaempferol, III), 1, and the 7-dihydric xanthenone (1,7-dihydroxyxanthone, IV), kielcorin (5-hydroxymethyl-6-guaiacyl-2,3:3 ', 2 ', 4 '-methoxy-xanthone-1,4-dioxane, V), emodin (emodin, VI), 2,5-dimethyl-7-hydroxyl chromone (2,5-dimethyl-7-hydroxychromone, VII), and vanillic acid (vanillic acid, VII).Conclusion: compound IV, VII obtains for separating from Herba Hyperici perforati first with VIII.2, " research of Herba Hyperici perforati extract antidepressant effect " author, (Shenyang Pharmaceutical University, the attached first clinical hospitals of Chinese Medical Sciences University) such as Xu Jing, Cai Shuan, " Pharmacology and Clinics of Chinese Materia Medica ".2002,18 (5), [digest] purpose: the research Herba Hyperici perforati extract is to the depression effect of mice.Method: chosen and forced mouse swimming test, mouse tail suspention stress be tested, the experimental index such as inhibition symptom due to the antagonism reserpine.The result: Herba Hyperici perforati extract 150mg/kg, 300mg/kg significantly shorten the dead time of compeling swimming mice and tail suspention mice; Significantly body temperature decline effect and the effect of mice blepharoptosis due to the antagonism reserpine.Conclusion: Herba Hyperici perforati extract has certain antidepressant effect.3, " the new antifungal flavonoid glycoside in the Herba Hyperici perforati ", author, (Nanjing Normal University, Nanjing University) " Botany Gazettes " such as Lu Yan flower Zhang Zhen.2002，44(6)。[digest] separates from 80% ethanol extraction of Herba Hyperici perforati (Hypericum perforatum L.) aerial parts and obtains 1 new flavonoid glycoside and 6 known flavone compounds.Adopt infrared spectrum; ultraviolet spectra; the structure that spectroscopic technique such as mass spectrum and NMR (Nuclear Magnetic Resonance) spectrum records the neoflavone glycosides is 6 " O-acetyl group Quercetin-3-O-β-D-Azloglycoside (1; 6 "-O-acetyl quercetin3-O-β-D-alloside); 6 known compounds are accredited as Quercitroside (quercitrin) respectively, hyperin (hyperoside), avicularin (avicularin); rutin (rutin), Quercetin (quercetin) and kaempferol (kaemfero10.The extracorporeal antifungal activity experiment shows, neoflavone glycosides (1), Quercitroside and Quercetin have certain inhibitory action to phytopathogen Helminthosporium sativum Pamel King et Bakke, and three's minimal inhibitory concentration (MIC) is respectively: 25,50 and 50 μ g/mL.In addition, 1 and Quercitroside the growth of standing grain redness of the skin or complexion fusarium (Fusarium graminearum Schw.) is also had inhibitory action (the MIC value is 100 μ g/mL).4, " Herba Hyperici perforati active component research new development ", (Wuhan University, Chongqing business school) " Chinese herbal medicine " such as Li Hong, Jiang Huaichun.2001，32(7)。[digest] introduced the active component of Herba Hyperici perforati, the research new development of pharmacological action such as antidepressant, antitumor, antiviral and side effect.5, " progress of Herba Hyperici perforati and Countermeasures for Sustainable Development ", Lee understands peaceful king and deposits lotus (Hanzhong Normal College) " Hanzhong Normal College's journal: from section's version ".2000,18 (1) [digest] Herba Hyperici perforati is except that being used as medicine as traditional Chinese crude drug, and its active component is at the treatment depression, and hepatitis and acquired immune deficiency syndrome (AIDS) and aspect such as anticancer have and important utilize prospect and by extensive concern.This paper has summarized the crude drug microscopical identification feature of Herba Hyperici perforati, the research of effective ingredient, the progress of aspects such as pharmacology and clinical trial.Inquired into the countermeasure of sustainable development simultaneously.6, " pharmacognostical study of Herba Hyperici perforati ", thunder state lotus Wang Ji great waves (ShanXi Chinese Medicine Academy) " ShanXi Chinese Medicine Academy journal ".1999，22(6)。[digest] is effectively new for seeking and studying, nontoxic, safe and reliable, the particularity analgesic of non-narcotic, the author is very abundant to area, Qinling Mountains data, and the plant Herba Hyperici perforati that is rich in hyperin has made to be the pharmacognostical study of system first, for the development and utilization of this medicine provides reliable evaluation and research data.7, " progress of hypericin ", the skilful Li Gaohong of beam becomes (Peking University), " Chinese herbal medicine ".1999，30(9)。[digest] summarizes hypericin in antidepressant, antiviral, and to the photochemical therapy of cancer, the newest research results of aspects such as immunity is for developing new drug provides reference.
Lysine and derivant thereof are treated disease separately at the Chinese science and technology periodical with following disclosed documents are arranged in Chinese patent: 1, the clinical observation of [autograph] theophylline-lysine treatment bronchial asthma and asthmatic bronchitis [periodical name] clinical department of internal medicine magazine.1995,12 (4) [digest] authors adopt the curative effect and the side effect of the oral theophylline-lysine of double-blind method comparative study and aminophylline treatment bronchial asthma and asthmatic bronchitis, the result shows: theophylline-lysine is relievingd asthma, cough-relieving and to improve the spasm effect of stingy road similar to aminophylline, and side effect reduces than ammonia tea, is a kind of bronchodilator preferably; 2, [autograph] Benzydalysine eye drop is observed [periodical name] ophthalmology new development to experimental cataractous therapeutical effect.1997,17 (3); 3, [autograph] L-lysine is to effect [periodical name] the Affiliated Hospital of Qingdao University journal of rat brain damage.2001，37(4)。[digest] purpose research L-lysine is to the effect of rat closed injury of brain.Method adopts the falling bodies method to cause the rat closed injury of brain, and the L-of disposable celiac injection at once lysine is observed the influence of L-lysine to brain injury rat brain edema, case fatality rate after the wound; Adopt the downright bad neuron count method in specific region under the light microscopic, observe of the effect of L-lysine cortex and the infringement of Hippocampus CA-1 neuron.L-lysine group (621.5mg/kg and 310.8mg/kg) compares with matched group (NS group) as a result, can significantly reduce relevant brain district degeneration, downright bad neuronic quantity (H=10.35,13.84, t=2.16～9.25, P＜0.05,0.01), significantly alleviate cerebral edema (F=3.52, q=4.04～11.37, P＜0.01), 621.5mg/kg L-lysine can significantly reduce the case fatality rate (P=0.009) of rat behind the brain injury simultaneously.Conclusion L-lysine has the certain protection effect to brain injury.4, Chinese patent＜application number〉01111316＜notification number〉1365665＜denomination of invention〉be used for the pharmaceutical composition＜digest that contains Ascorbate and lysine with the extracellular substrate degeneration relevant disease〉disclose a kind of prevention and treatment and extracellular matrix degradation diseases associated or morbid state as included but not limited to degenerative disorders, particularly the compositions of atherosclerosis, cancer, infection or other inflammatory diseasess comprises lysine, proline, Ascorbate and derivant thereof and synthetic analog and vitamin, provitamin and trace element.5, Chinese patent＜application number〉96116212＜denomination of invention〉a kind of medicine＜digest for the treatment of cerebrovascular〉the invention discloses sick new drug---the Styracol tablet of a kind of resisting cerebrovascular, mainly form by paeonol, ligustrazine, lysine, Margarita powder, vitamin E etc., it can improve cerebral blood flow behind the cerebral infarction, the various syndromes such as disturbance of consciousness that occur behind ischemic cerebrovascular that the treatment a variety of causes causes and the craniocerebral trauma.6, Chinese patent＜application number〉95109783＜Granted publication day〉2000 years 05 month 03 day＜denominations of invention〉a kind of pharmaceutical composition for the treatment of craniocerebral trauma and syndrome thereof, the present invention is a kind of pharmaceutical composition for the treatment of craniocerebral trauma and syndrome thereof, and its main component is lysine hydrochloride, vitamin B6, vitamin B 1 and calcium gluconate.6, Chinese patent＜application number〉93103380＜denomination of invention〉the L-lysine hydrochloric acid is at the application＜digest of preparation in the haemostatic medicament〉the invention discloses a kind of hemostasis new drug (agent of body-building crude granule), the main component of this hemostasis new drug is the L-lysinate, can treat some organ hemorrhage of human body with this haemostatic medicament, as metrorrhagia, operation back abnormal bleeding, spitting of blood, hematuria etc., thus the new purposes of L-lysine opened up.7, Chinese patent＜application number〉93102915＜denomination of invention〉L-lysine hydrochloride is used to prepare the application＜digest of treatment craniocerebral trauma medicine〉the invention provides the new purposes of L-lysine and its esters, promptly treat the medicine of craniocerebral injury with L-lysine, it is reached more than 90% by the effective percentage of mechanical injuries, cerebrovascular, cerebral hypoplasia, climacteric syndrome to treatment cranium brain, further widened the new purposes of L-lysine.
Chinese patent＜application number wherein〉the 95109783,93103380, the 93102915th, the inventor (original unit: innovation and creation Guangxi Nanning Yijiang Pharmaceutical Factory).
Obtaining proof from above-mentioned literature to, Herba Hyperici perforati aspect some disease of treatment, especially the research of antidepressant effect is more, but unexposed its using method, does not also see that the open source literature that has Herba Hyperici perforati extract and other medicines to be made into compositions reports; Lysine at treatment craniocerebral injury, treatment human body some organ hemorrhage, improve cerebral infarction after aspect such as cerebral blood flow more research has also been arranged, and formed drug products and on market, sold, but do not find lysine at the medicinal report of treatment aspect the herpes yet, do not see the open source literature report that Herba Hyperici perforati and lysine is combined into medicine yet.
The inventor in Herba Hyperici perforati and lysine being combined into the process that medicine studies to its pharmacology, pharmacodynamics and clinical trial, find that this pharmaceutical composition xylol induced mice ear swelling, cotton balls oxter are buried and bring out granulation tissue hyperplasia in various degree inhibitory action is all arranged, but acute inflammation is had the highly significant meaning, and the bacteriostasis result of the test points out this medicine that some pathogenic bacterias such as staphylococcus aureus are had inhibitory action; Acute inflammation, chronic hyperplastic inflammation effect are proportionate.The mechanism of action of thinking may be relevant with its antiinflammatory, antibacterial, antibacterial action and anti-infectious function.
Outstanding substantive distinguishing features of the present invention and obvious improvement are:
1, safety
We recognize from open source literature, and the toxicity work of Herba Hyperici perforati extract is mice, and animals such as rat and dog have carried out reaching the test in 26 weeks on one's body.Maximum test dose is 5000mg/kg, and tolerance dose is not 900mg/kg every day at first.LD
50Greater than maximal dose.All test ends show gene poison and mutagenesis.13 male normal persons take every day 900,1800 and 3600mg pass through in the leaf Fructus Forsythiae extract test, every day, 900mg was the safe and effective dosage that most of clinical trials are adopted.In the clinical trial that we carry out, proved that also the people takes the safety of Herba Hyperici perforati extract.
2, the effectiveness of analgesia and antiinflammation
After the combination of Herba Hyperici perforati extract of the present invention and lysine hydrochloride the effect of obvious treatment herpes is arranged, and use Herba Hyperici perforati extract separately or use lysine hydrochloride not reach effect after compound separately.
3, to other adjuvant treatment effect of human body
After Herba Hyperici perforati extract and lysine hydrochloride are composite, demonstrate this pharmaceutical composition and not only have the sick effect of treatment herpes, suppress herpesvirus infection, recurrence, the human body immunity improving function, reach and have anti-HSV-1, the effect of CMV and HIV, and also have antidepressant, antineoplastic effect, can also replenish the part vitamin that human body lacks.
The specific embodiment
Embodiment 1
Get Herba Hyperici perforati extract 500g, lysine hydrochloride 500g (hypericin content 2-5% in the Herba Hyperici perforati extract wherein, the lysine hydrochloric acid salt content is more than 95%), mix with 5～75% starch or starch derivatives, dextrin, calcium hydrogen phosphate, make granule, dry, add 0.5～20% sodium carboxymethyl cellulose, hydroxypropyl cellulose, lubricant 0.5～2.0% magnesium stearate, tabletting, or directly pack, or sugar coating, or the bag film-coat promptly obtains product.
Embodiment 2
Get Herba Hyperici perforati extract 750g, lysine hydrochloride 250g, mix with 5～75% starch or starch derivatives, dextrin, calcium hydrogen phosphate, make granule, drying adds 0.5～20% sodium carboxymethyl cellulose, hydroxypropyl cellulose, lubricant 0.5～2.0% magnesium stearate, tabletting, or directly pack, or sugar coating, or the bag film-coat promptly obtains product.
Embodiment 3
Get Herba Hyperici perforati extract 800g, lysine hydrochloride 200g makes granule with 5～75% starch or starch derivatives, dextrin, calcium hydrogen phosphate, and drying adds fluidizer differential silica gel, and is encapsulated, promptly obtains product.
Embodiment 4
Get Herba Hyperici perforati extract 500g, lysine hydrochloride 250g makes granule with 5～75% starch or starch derivatives, dextrin, calcium hydrogen phosphate, and drying adds fluidizer differential silica gel, and is encapsulated, promptly obtains product.
Embodiment 5
Get Herba Hyperici perforati extract 700g, lysine hydrochloride 300g makes concentrated pill, water-honeyed pill, big honeyed pills, promptly obtains product with excipient sucrose 100g, lactose 100g, dextrin 300g.
Embodiment 6
Get Herba Hyperici perforati extract 650g, lysine hydrochloride 350g, 30g makes concentrated pill, water-honeyed pill, big honeyed pills, promptly obtains product with excipient sucrose 200g, lactose 100g, dextrin 200g.
Embodiment 7
Get Herba Hyperici perforati extract 800g, lysine hydrochloride 350g adds sucrose 500g, dextrin 500g, makes granule, and drying obtains product.
Embodiment 8
Get Herba Hyperici perforati extract 750g, lysine hydrochloride 250g mixes with sucrose 10～55%, potassium sorbate preservative 0.1～1%, ethyl hydroxybenzoate 0.1～0.3%, makes mixture.
Embodiment 9
Get Herba Hyperici perforati extract 650g, lysine hydrochloride 630g is 60～70% with the sucrose amount, potassium sorbate preservative 0.1～1%, ethyl hydroxybenzoate 0.1～0.3% merge, and makes syrup.
The relevant clinical trial of the present invention, pharmacology, pharmacodynamics situation:
One, the external anti-herpesvirus experimentation of Herba Hyperici perforati extract and lysine hydrochloride
Test unit, Department Of Medicine, Peking University's europathology research department
Test period: in JIUYUE, 2002-2003 year January
Summary purpose: estimate Herba Hyperici perforati extract, lysine hydrochloride separately and unite the cytotoxicity and the herpesvirus resisting activity of use.Method: adopt cytopathic effect method (CPE), measure Herba Hyperici perforati extract, lysine hydrochloride separately and unite the cytotoxicity of use to Vero cell and 2BS cell, and to the antiviral activity of herpes simplex virus I-type (HSV-1) and varicella zoster virus (VZV).The result: lysine hydrochloride, Herba Hyperici perforati extract separately or unite use external to HSV-1 and VZV performance antiviral activity in various degree, minimum effective drug concentration (MIC), medium effective concentration (IC
50) scope is respectively 9.7 μ g/mL～39.0 μ g/mL, 6.8 μ g/mL～27.5 μ g/mL are with positive control drug ribavirin MIC, IC
50Close.Conclusion: Herba Hyperici perforati extract, lysine hydrochloride are separately or unite use and have anti-HSV-1 and a VZV effect external.
Key word: Herba Hyperici perforati extract; Lysine hydrochloride; Herpes simplex virus; Varicella zoster virus; Cytopathic effect.
Herpesvirus (Herpes-virus) is a group median size, structural similarity, the tunicary distrand DNA virus of finding at animal and human's apoplexy due to endogenous wind.Have now found that more than 100 kinds.Wherein, herpes simplex virus (Herpes Simples Viruses, HSV) and varicella zoster virus (Varicella-zoster virus VZV) is common infectious agent.HSV infects relevant with more than 10 kind of diseases such as congenital malformation, miscarriage, cervical cancer, encephalitis, newborn child's illness, sexually transmitted disease (STD)s.But VZV infects this plays herpes zoster.(acyclovir ACV) occurred drug resistance, and toxic and side effects is bigger, costs an arm and a leg owing to classical antiviral agents acycloguanosine.Seek the new safe and effective antiviral agents of exploitation and become focus.
Herba Hyperici perforati (Hypericum perforatum L) has another name called Herba Hyperici perforati (St.John ' s wort), is the Guttiferae hypericum, all herbal medicine, and can clear away heart-fire makes eye bright, and regulating menstruation and activating blood, hemostasia and promoting granulation, detoxicating, relieving inflammation extensively distribute in China Qin crust area
[2]Herba Hyperici perforati also has antiviral, analgesia, antiinflammatory, multiple pharmacological effect such as antibiotic, and safe.
Lysine is one of 8 seed amino acids of needed by human.Bibliographical information, the oral lysine of herpesvirus infection patient (1000mg/d～3000mg/d) can prevent herpes recurrence or minimizing recurrence frequency, relief of symptoms, the shortening course of disease.Ehal M etc. notices that the peptide class that major part has an anti-herpesvirus effect all is rich in lysine.
Can resist the generally acknowledged reason of HSV to be for lysine, duplicating of virus must have enough arginine, and lysine disturbs the arginine utilization, thereby suppresses the recurrence of herpes simplex and herpes zoster, even the outbreak symptom is also lighter, the course of disease is shorter.The existing clinical treatment that is mainly used in herpes zoster and cold sore, recommended dose is three times on the one, each 1000mg.
Although clinical report is many, lack the experimental basis of Herba Hyperici perforati extract and the effect of lysine anti-herpesvirus so far.The purpose of this experiment is by estimating Herba Hyperici perforati extract, lysine hydrochloride separately and unite the cytotoxicity and the herpesvirus resisting activity of use, clinical separately or unite to use experimental basis is provided for it, for exploitation treatment virus infective medicament provides experiment basis.1.1 material 1.1.1 medicine and instrument: (Guangxi Nanning Yongjiang Pharmacy Co., Ltd. produces lysine hydrochloride, lot number: 010605), (Guangxi Nanning Yongjiang Pharmacy Co., Ltd. provides Herba Hyperici perforati extract, product batch number: 1605795, hypericin content 3 ‰, brown bottle keeps in Dark Place), and ribavirin injection (0.1g/mL, Suzhou No.6 Pharmaceutical Factory produces, lot number: 00023), dimethyl sulfoxide (Sigma company produces for dimethylsulfoxide, DMSO).96 holes trace Tissue Culture Plate, CO
2Incubator, superclean bench, inverted microscope.1.1.2 experiment grouping: experiment is divided into 2: 1 groups of (1) lysine hydrochloride groups, (2) Herba Hyperici perforati extract group, (3) Herba Hyperici perforati extract+1: 1 group of lysine hydrochloride weight ratio, (4) Herba Hyperici perforati extract+1: 2 group of lysine hydrochloride weight ratio, (5) Herba Hyperici perforati extract+lysine hydrochloride weight ratio.Each group medicine is dissolved in Eagle ' s cell culture maintenance medium (containing 10%DMSO), is mixed with 5mg/mL concentration, centrifuging and taking supernatant, the sterilization of sterilizing room membrane filtration.(6) positive controls: ribavirin group (Eagle ' the s cell culture maintenance medium that does not contain DMSO is diluted to 5mg/mL concentration), (7) blank group: Eagle ' s cell culture maintenance medium (containing 10%DMSO).1.1.3 Strain: herpes simplex virus I-type (HSV-1) lot number: 2002320, varicella zoster virus (VZV) lot number: 2002216, provide by Virology Inst., Chinese Academy of Preventive Medical Science.1.1.4 cell strain: African green monkey kidney cell (Green monkey kidney cells, Vero cell), human embryonic lung diploid fibroblast (2BS cell) 10-13 is provided by Virology Inst., Chinese Academy of Preventive Medical Science for cell.1.1.5Eagle ' test material such as s cell culture maintenance medium, provide by China Preventive Medicial Science Institute's virological investigation.1.2 method 1.2.1 medicine is to the toxicity test of Vero cell and 2BS cell
(cytopathic effect, CPE), Vero cell and 2BS cell are with 4 * 10 to adopt the cytopathic effect method
5/ mL inoculates 96 well culture plates, 37 ℃, 5%CO2 are cultivated 24h, add checking medicine and positive control medicine 5000 μ g/mL～39 μ g/mL respectively, 1: 10～1: 160 (being equivalent to DMSO concentration 1.0%～0.063%) of blank (containing 10%DMSO), every concentration is inoculated 4 holes, every hole 100 μ L.Establish the normal cell contrast simultaneously.Put 37 ℃, 5%CO
2Cultivate 5～7d.Every 24h is the observation of cell metamorphosis under inverted microscope, and the record cellular morphology changes: be changed to below 25%+, 26%～50% is changed to ++, 51%～75% is +++, 76%～100% is changed to ++ ++.Use the Reed-Muench method, calculate medicine median toxic concentration (TD
50) and maximal non-toxic concentration (TD
0).1.2.2 in the Vero cell culture to the mensuration of HSV-1 virus virulence
Adopt viral CPE method, the Vero cell is with 4 * 10
5/ mL inoculates 96 well culture plates, 37 ℃, 50%CO
2Cultivate 24h, add the HSV-1 of original concentration, 1: 10～1: 10
6, 6 concentration of 10 times of dilutions, every concentration 4 holes, every hole 100 μ L.If normal cell contrast.37 ℃, 50%CO
2Cultivate 5～7d.The observation of cell form is used the Reed-Muench method, calculates the HSV-1 half and infects concentration (TCID
50).1.2.3 in the 2BS cell culture to the mensuration of VZV virus virulence
Adopt viral CPE method, the 2BS cell is with 4 * 10
5/ mL inoculates 96 well culture plates, 37 ℃, 50%CO
2Cultivate 24h, add the VZV of original concentration, 1: 10～1: 80,4 concentration of 2 times of dilutions, every concentration 4 holes, every hole 100 μ L.If normal cell contrast.37 ℃, 50%CO
2Cultivate 5～7d.The observation of cell form is used the Reed-Muench method, calculates viral half and infects concentration (TDID
50).1.2.4 medicine in the Vero cell culture to the inhibition test of HSV-1
Adopt viral CPE method, the Vero cell is with 4 * 10
5/ mL inoculates 96 well culture plates, 37 ℃, 50%CO
2Cultivate 24h, add the 100TCID of HSV-1
50Viral liquid, every hole 100 μ L, 37 ℃, 50%CO
2Cultivate 1h and make its absorption, discard viral liquid then.Add the checking medicine respectively, the maximal non-toxic concentration (TD of choice of drug pair cell
0), each administration group 625 μ g/mL～4.88 μ g/mL, 1: 40～1: 5120 (being equivalent to DMSO concentration 0.25%～0.002%) of blank group (containing 10%DMSO), 8 concentration of 2 times of dilutions, every concentration 4 holes, every hole 100 μ L.Ribavirin injection is 935 μ g/mL～7.3 μ g/mL, 8 concentration of 2 times of dilutions, every concentration 4 holes, every hole 100 μ L.Establish the contrast of virus control and normal cell simultaneously, 37 ℃, 50%CO
2Cultivate 5～7d, every 24h inverted microscope is observed viral CPE down, finishes test when becoming and occur " ++ +～++ ++ " to the virus control cell.Same test triplicate is averaged, and utilizes mean value computation medicine medium effective concentration (IC
50), minimum effective drug concentration (MIC) and therapeutic index (TI).1.2.5 medicine in the 2BS cell culture to the inhibition test of VZV
Adopt viral CPE method, the 2BS cell is with 4 * 10
5/ mL inoculates 96 well culture plates, 37 ℃, 50%CO
2Cultivate 24h, add the 100TCID of VZV
50Viral liquid, every hole 100 μ L, 37 ℃, 50%CO
2Absorption 1h discards viral liquid.All the other experimental procedures are described with 1.2.4, obtain medicine medium effective concentration (IC
50), minimum effective drug concentration (MIC) and therapeutic index (TI).The toxic action of 2 results, 2.1 medicine pair cells
Normal Vero cell and the tolerant drug level of 2BS cell are shown in table-1.TD
50Represent the medicine median toxic concentration, TD
0Represent medicine maximal non-toxic concentration.Because Herba Hyperici perforati extract is water insoluble, each organizes medicine all with Eagle ' s cell culture maintenance medium (the being blank) preparation that contains 10%DMSO.DMSO has certain cytotoxicity, thus the blank group be diluted to 1: 40 (containing 0.25%DMSO) just to normal Vero cell and 2BS cell free of toxic effects.To compare with blank, each test group medicine is being diluted to 1: 8 (containing 1.25%DMSO)～reach TD 1: 32 (containing 0.31%DMSO) during scope
0, contained DMSO concentration is higher than pair cell non-toxic concn 0.25%, illustrates that the toxic effect of medicine group might partly or entirely come from solvent DMSO, its actual TD
50, TD
0Should be greater than measured value.And the positive control ribavirin needs with Eagle ' the s cell culture maintenance medium dilution that does not contain DMSO, is the medicine actual concentration so record toxicity.2.2 in Vero and 2BS cell culture to HSV-1 and VZV virus virulence measurement result (TCID
50)
Observe CPE, calculate the median infective dose (TCID of HSV-1
50) be 1: 10
6, the median infective dose (TCID of VZV
50) 1: 28.Promptly inoculating every hole 0.1mL titre is 1: 10
6HSV-1 can make the 50%Vero cell that obvious pathological changes takes place, the VZV that inoculates every hole 0.1mL titre and be 1: 28 can make the 50%2BS cell that obvious pathological changes takes place.2.3 medicine laugh at virus function 2.3.1 medicine inhibition test result to HSV-1 virus in the Vero cell culture
The result is as shown in table 2, when HSV-1 virus with 100TCID
50After concentration infected normal Vero cell, each was organized trial drug and all shows antivirus action in various degree.Minimum effective drug concentration (MIC) scope does not wait medium effective concentration (IC from 9.7 μ g/ml～19.5 μ g/ml
50) scope do not wait from 6.8 μ g/ml～27.5 μ g/ml.2.3.2 medicine in the 2BS cell culture to the inhibitory action of VZV virus
The result is as shown in table 2, when VZV virus with 100TCID
50After concentration infected normal cell, each was organized trial drug and all shows antivirus action in various degree, and minimum effective drug concentration (MIC) scope does not wait medium effective concentration (IC from 9.7 μ g/ml～39.0 μ g/ml
50) scope do not wait from 6.8 μ g/ml～19.0 μ g/ml.3 discuss
HSV the incidence of infection sharply increases in recent years, and 60%～90%HSV carrier is arranged among the crowd, the serious threat human health
[8]Herpes zoster is the painful diseases that VZV causes, its the most common and make us most because of the complication of disturbing be herpes post herpetic neuralgia (postherpetic neuralgia PHN), especially the gerontal patient sees more, normal lasting several months or several years, show as and continue and/or pain is brought out in intermittent spontaneous stimulation, for example hyperpathia, allodynia.The consequence of pain comprises fatigue, sleep barrier loss of appetite, depression, social withdrawal, influence daily life reduces quality of life
[9]
Although nucleoside analog such as nitrine cytidine (zidovudine, AZT), dideoxyinosine (ddI), dideoxycytidine (ddC), ACV be widely used in as antiviral agents clinical, serious adverse
[10]With viral drug resistance strain
[1]Appearance make new low toxicity, the high-efficient antiviral medicament of development very urgent.The natural drug wide material sources, untoward reaction is less, and its antivirus action comes into one's own day by day.
Herba Hyperici perforati extract (standard is for containing 3 ‰ hypericins) is extensive use of as anti-strongly fragrant medicine, and clinical patients has good tolerability to it.After the medication, the incidence rate of its side effect is similar to placebo.Use in the U.S. even as food supplement.The Herba Hyperici perforati extract pharmacological action is extensive, has multinomial pharmacological actions such as analgesia, antiinflammatory, antibiotic, antitumor.Meruelo D etc. studies show that hypericin contained in the Herba Hyperici perforati and pseudohypericin all have antiretroviral (as a human immunodeficiency virus HIV) effect with external in vivo
[12]Experimental results show that hypericin also has inhibitory action to HSV-1, HSV-2, parainfluenza virus, vaccinia virus, herpes Stomatovirus external
[13]
Lysine is a kind of physiological material, and is safe, uses as food additive.More existing clinically reports with lysine treatment herpesvirus infection, consumption is up to 3000mg every day.
In order to study these two kinds of safety of Herba Hyperici perforati extract and lysine, low cytotoxic drug in external anti-herpesvirus effect, this experiment attacks Vero with HSV-1 and VZV attack 2BS cell is a model, use separately by CPE method research lysine hydrochloride, Herba Hyperici perforati extract, and cytotoxicity and external anti-HSV-1, the VZV effect when uniting use in 1: 1,1: 2,2: 1 with weight ratio of lysine hydrochloride and Herba Hyperici perforati extract.As a whole, minimum effective drug concentration (MIC), medium effective concentration (IC
50) scope is respectively 9.7 μ g/ml～39.0 μ g/ml, 6.8 μ g/ml～27.5 μ g/ml are with positive control drug ribavirin MIC, IC
50Close.
Lysine hydrochloride, Herba Hyperici perforati extract measured in the experiment use separately, and lysine hydrochloride and Herba Hyperici perforati extract when uniting use in 1: 1,1: 2,2: 1 with weight ratio cytotoxicity be higher than ribavirin.May be because the checking medicine disposes with the culture fluid that contains 10%DMSO, and ribavirin need with the culture fluid configuration that does not contain DMSO.The measurement result of blank group shows, when DMSO concentration is higher than 0.25% to normal Vero cell and the toxic effect of 2BS cell.So the toxicity difference of checking medicine and ribavirin pair cell might partly or entirely come from the effect of solvent DMSO, and the safety of medicine reality is high shown in the experiment.
In sum, Herba Hyperici perforati extract, lysine hydrochloride are separately or unite use and have a herpesvirus resisting activity external, Herba Hyperici perforati extract, lysine use in conjunction also provide new thinking for research treatment disease of viral infection (as herpes post herpetic neuralgia PHN), remain further to be furtherd investigate.
Two, pharmacological research
The pharmacology of Department Of Medicine, Peking University system and europathology research department have also carried out pharmacological research to pharmaceutical composition of the present invention in JIUYUE, 2002-2003 year January, and pharmacological research has been done following project altogether:
1, Herba Hyperici perforati extract, lysine hydrochloride compositions are used the neurobehavioral influence of mice, kind is ICR, male and female half and half, totally 60, whether to central nervous system of mice have inhibitory action, experimental result shows that high dose (2000mg/kg) and middle dosage (1000mg/kg) do not have influence to the general neural mental act of mice if observing gastric infusion.
2, Herba Hyperici perforati extract, lysine hydrochloride compositions are used the influence to the mice autonomic activities, kind is ICR, male and female half and half, totally 60, whether to central nervous system of mice have inhibitory action, experimental result shows that high dose (2000mg/kg) and middle dosage (1000mg/kg) have obvious sedation to mice if observing gastric infusion.
3, Herba Hyperici perforati extract, lysine hydrochloride compositions are used the influence to the mice enterokinesia, kind is ICR, male and female half and half, totally 60, with CMC relatively, whether to mouse intestinal function influential, experimental result shows that high dose (2000mg/kg) and middle dosage (1000mg/kg) are to the not obviously influence of mice gastrointestinal if observing gastric infusion.
4, Herba Hyperici perforati extract, lysine hydrochloride compositions are to rat LD
50, kind is the SD rat, male and female half and half, totally 50, be divided into 3 groups, matched group is with 0.25% CMC, observes the mortality rate behind the gastric infusion, experimental result shows that female group dead 90%, male 20% of maximal dose (14000mg/kg) and middle dosage (7072mg/kg) mortality rate are 0.
5, Herba Hyperici perforati extract, lysine hydrochloride compositions are used the electric convulsive influence of mouse anti, kind is ICR, male and female half and half, totally 60, with CMC relatively, sent a telegraph convulsions in 3 seconds with the 110V alternating current, whether maximum electrofit has or not obvious influence to mouse anti to observe gastric infusion, experimental result show high dose (2000mg/kg) and middle dosage (1000mg/kg) to the mouse anti maximum electrofit do not have.
6, Herba Hyperici perforati extract, lysine hydrochloride compositions are used domestic cat heart rate and Electrocardiographic influence, kind is a domestic cat, male and female are regardless of, totally 34, matched group is with 0.25% CMC, observe gastric infusion to domestic cat heart rate and Electrocardiographic variation, experimental result shows that high dose (600mg/kg) and middle dosage (300mg/kg) do not have significant change to domestic cat heart rate and electrocardiogram.
7, Herba Hyperici perforati extract, lysine hydrochloride compositions are used the influence that domestic cat is breathed, kind is a domestic cat, male and female are regardless of, totally 34, matched group is with 0.25% CMC, observe the variation of gastric infusion to domestic cat respiratory frequency and amplitude of respiration, experimental result shows that high dose (600mg/kg) and middle dosage (300mg/kg) do not have significant change to domestic cat heart rate and electrocardiogram.
8, Herba Hyperici perforati extract, lysine hydrochloride compositions are used the influence to the domestic cat blood pressure, kind is a domestic cat, male and female are regardless of, totally 34, matched group is observed the variation of gastric infusion to domestic cat respiratory frequency and amplitude of respiration with 0.25% CMC, and experimental result shows, observed 240 minutes, high dose (600mg/kg) and middle dosage (300mg/kg) do not have significant change to the domestic cat blood pressure.
Claims (9)
1, a kind of pharmaceutical composition with treatment herpesvirus is characterized in that it comprises Herba Hyperici perforati extract and lysine hydrochloride, and its composition and weight content are as follows:
Herba Hyperici perforati extract 50-80%
Lysine hydrochloride 20-50%
2, the pharmaceutical composition of treatment herpesvirus according to claim 1 is characterized in that: the Radix Hyperici Monogyni (Herba Hyperici Monogyni) content of Herba Hyperici perforati extract is 2-5%; The lysine hydrochloric acid salt content is more than 95%.
3, pharmaceutical composition according to claim 1 is characterized in that: described pharmaceutical composition can be made tablet, capsule, pill, granule, mixture, syrup.
4, a kind of production method with pharmaceutical composition of treatment herpesvirus, it is characterized in that: the production method that this pharmaceutical composition is made tablet is: with Herba Hyperici perforati extract, lysine hydrochloride, make particle drying with excipient, add disintegrating agent, lubricant, tabletting, or directly pack, or sugar coating, or the bag film-coat promptly obtains product;
Described excipient is starch and derivant thereof, dextrin, calcium hydrogen phosphate etc.; Described disintegrating agent is sodium carboxymethyl cellulose, hydroxypropyl cellulose etc.; Described lubricant is a magnesium stearate etc.; Described sugar coating material is sucrose, Pulvis Talci, gelatin, pigment, river wax etc.; Described thin film coating material is stomach dissolution type water, pure coating material etc.Wherein the weight content of excipient, disintegrating agent, lubricant, coating material consumption is respectively: 5～75%, 0.5～20%, 0.5～2.0%, 2～45%.
5, a kind of production method with pharmaceutical composition of treatment herpesvirus, it is characterized in that: the production method that this pharmaceutical composition is made capsule is: Herba Hyperici perforati extract, lysine hydrochloride are added excipient, with disintegrating agent and make it dry, in incapsulating then, obtain product;
The described excipient of described preparation capsule is starch and derivant thereof, calcium hydrogen phosphate, magnesium stearate, differential silica gel etc.Weight 20～80%.
6, a kind of production method with pharmaceutical composition of treatment herpesvirus, it is characterized in that: this pharmaceutical composition is made the production method of pill: Herba Hyperici perforati extract, lysine hydrochloride are added excipient, pill.1. make concentrated pill; 2. add excipient weight 10～100%, Mel, make water-honeyed pill, big honeyed pills, concentrated pill.
7, a kind of production method with pharmaceutical composition of treatment herpesvirus, it is characterized in that: this pharmaceutical composition is made the production method of granule: add excipient in the concentrated solution that above-mentioned production obtains, and make granule, make it dry, obtain product;
The composition of the excipient of described granule and content: sucrose 50～95%, lactose 50～90%, dextrin 50～70%.
8, a kind of production method with pharmaceutical composition of treatment herpesvirus, it is characterized in that: this pharmaceutical composition is made the production method of mixture: with Herba Hyperici perforati extract, lysine hydrochloride and correctives, antiseptic solution mix homogeneously, promptly obtain product;
The correctives of described mixture and content thereof: sucrose (or Mel) 10～60%, potassium sorbate preservative 0.1～1%, ethyl hydroxybenzoate 0.1～0.3%.
9, a kind of production method with pharmaceutical composition of treatment herpesvirus, it is characterized in that: this pharmaceutical composition is made the production method of syrup: with Herba Hyperici perforati extract, lysine hydrochloride and sucrose, antiseptic solution mix homogeneously, promptly obtain product.
Described sucrose addition is 60～70%, potassium sorbate preservative 0.1～1%, ethyl hydroxybenzoate 0.1～0.3%.
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| CN1330330C (en) * | 2005-12-31 | 2007-08-08 | 天津生机集团 | Antivirus medicinal composition, preparation method and use |
| CN105935443A (en) * | 2016-01-08 | 2016-09-14 | 新昌县大成生物科技有限公司 | Pharmaceutical composition for treating diabetic cataract |
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| DE19646977A1 (en) * | 1995-09-29 | 1998-01-15 | Schwabe Willmar Gmbh & Co | Stable dry extract of Hypericum perforatum L., Saint John's wort |
| CN1452979A (en) * | 2003-05-17 | 2003-11-05 | 广西化工生物技术研究所 | Medicine composition with anti-inflammatory effect and its production process |
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| CN105935443A (en) * | 2016-01-08 | 2016-09-14 | 新昌县大成生物科技有限公司 | Pharmaceutical composition for treating diabetic cataract |
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