CN101391103A - Medicine composition for preventing and treating AIDS viral infection - Google Patents
Medicine composition for preventing and treating AIDS viral infection Download PDFInfo
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- CN101391103A CN101391103A CNA2008101353293A CN200810135329A CN101391103A CN 101391103 A CN101391103 A CN 101391103A CN A2008101353293 A CNA2008101353293 A CN A2008101353293A CN 200810135329 A CN200810135329 A CN 200810135329A CN 101391103 A CN101391103 A CN 101391103A
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Abstract
The invention relates to pharmaceutical composition for preventing and curing the infection of AIDS virus. The components of the composition comprise at least an immunomodulator-immunologic stimulant, at lest a mucosa sorbefacient, human seralbumin and phenylcarbinol, wherein the immunomodulator-immunologic stimulant is recombined human interleukin, interferon, thymin or Toll sample receptor irritant agent, and the mucosa sorbefacient is surface active agent. The pharmaceutical composition of the invention is prepared to aqua or suppository, alleviates the pain caused by the injection of the immunomodulator-immunologic stimulant; greatly improves the security and validity of the use through nontraumatic administration through the mucosa of rectum, has the treating effect exceeding the subcutaneous injection and muscle injection, and has wide applying and generalizing foreground.
Description
Technical field
The present invention relates to the pharmaceutical composition of a kind of prevention and treatment AIDS viral infection, belong to field of pharmaceutical preparations.
Background technology
Since the eighties in 20th century, acquired immune deficiency syndrome (AIDS) (claims acquired immune deficiency syndrome (AIDS) again, AIDS) become the major disease that threatens human health, and number of the infected is the trend that rises year by year.So a famous western medicine expert claims that acquired immune deficiency syndrome (AIDS) is " century plague ".On December 1st, 2003, " China's AIDS is prevented and treated the joint assessment report " by ministry of Health of China and the special topic group associating issue of the United Nations acquired immune deficiency syndrome (AIDS) China shows that China has patients infected hiv about 840,000 at present, acquired immune deficiency syndrome (AIDS) patient about 80,000, be distributed in each provinces, autonomous regions and municipalities of the whole nation, spread all over each stratum of society.
At present anti-AIDS drug is the focus in drug research field, the world, clinical practice more mainly be efabirenz (nucleoside reverse transcriptase inhibitors, NRTI); Protease inhibitor (protease inhibitors, PI) and non-nucleoside reverse transcriptase inhibitor (non-nucleoside reversetranscriptase inhibitors, NNRTI).Lack fidelity (fidelity) because HIV duplicates, often undergo mutation, cause inverase easily to produce drug resistance.At present in the world to the pharmacotherapy trend therapeutic alliance of AIDS, it is HAART, normally a kind of hiv protease inhibitor adds two kinds of ucleosides reversion rate enzyme inhibitors, be used for the treatment of acute or chronic HIV and infect or asynchronous AIDS patient, and use zidovudine to lose efficacy or the nonresponder.Tetrad and several different methods such as different therapies such as six, alternative medicine, intermittent therapy, efficient antiretroviral conjoint therapy have appearred.These medicines and method have following shortcoming: (1) induces the HIV variant that develops immunity to drugs; (2) tool short-term and secular toxic and side effects; (3) can not block the early infection process of HIV.Because the HIV variation is fast, the strain of different regions also may be different, makes the development difficulty of vaccine very big.
At first gone on the market from zidovudine in 1987 by drugs approved by FDA, being used for the treatment of HIV infects and AIDS, from then on anti-AIDS drug development is very fast, since nineteen ninety-five, all have every year 2-3 new varieties to come out, present anti-AIDS medicine has become the fastest class medicine of progress on the antiviral drugs development history.Since 21 century, the sight line of research worker has focused on a lot of new target spots, as the antisense nucleotide medicine, and fusion inhibitor, all kinds of encoding gene antagonisies, the synthetic blocker of novel receptor etc., advantage such as it is obvious that they have drug effect, and specificity is strong, and untoward reaction is low.Novel targets medicine, compound preparation medicine and native compound have become the important research direction of development HIV medicine.
Have tens kinds of new drugs at present at least in development, yet unfortunately these new drugs are the same with existing therapy, still just act on the enzyme-reverse transcriptase and the protease of virus, rather than the cell of viral infection.The treatment acquired immune deficiency syndrome (AIDS) is many based on Western medicine, generally just a bit play a role at certain of HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) structure, and HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) adaptive capacity is strong in vivo, variation is fast, cause can't producing gratifying effect with single Western medicine.In fact the top so-called HAART of mentioning is exactly with several HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) to be killed or inhibiting Western medicine mixing use, makes HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) can't occur variation and performance therapeutical effect in a short time.But this Therapeutic Method can only play a role within a certain period of time, and big to the toxic and side effects of body, costs an arm and a leg, and is difficult to popularize.After some patients stop Drug therapy, virus load can rebound than higher level before the treatment, in a word, because the toxicity of medicine, the difficulty of lasting treatment is passed and the drug resistance strain that occurs in time, lacks the new target position for the treatment of HIV, and in the treatment to the reasons such as immunoreation reduction of HIV, we must search out the medicine of defeating this fearful disease.
HIV invades the CD4+ cell, causes the loss of carrying out property of CD4+ cell, and cause opportunistic infection and fall ill, so that dead.Characteristics of incidence according to acquired immune deficiency syndrome (AIDS) should be considered immunization therapy.But the drug candidate of immunization therapy is a lot, and the pharmaceutical composition formed mutually of interworking and suitable dosage form thereof are prevented and treated AIDS viral infection and do not see relevant report mutually to select which type of immunotherapy medicaments and which type of medicine and other drug for use.
Summary of the invention
The object of the present invention is to provide the pharmaceutical composition of a kind of prevention and treatment AIDS viral infection, this pharmaceutical composition has good synergism, by rectal mucosal non-invasive administration, the safety and the effectiveness of its use have been improved greatly, considerably beyond through antiviral therapy effect subcutaneous or that intramuscular injection produces, have and use widely and promotion prospect.
For achieving the above object, the present invention adopts following technical scheme:
The pharmaceutical composition of a kind of prevention and treatment AIDS viral infection, it is characterized in that: joining of described compositions comprises at least a immunomodulator-immunostimulant mutually, at least a mucosa absorption promoter, and human serum albumin and benzyl alcohol.
HIV invades the CD4+ cell, causes the loss of carrying out property of CD4+ cell, and cause opportunistic infection and fall ill, so that dead.Characteristics of incidence according to acquired immune deficiency syndrome (AIDS) should be considered immunization therapy.The inventor finds but pharmaceutical composition that at least a immunomodulator-immunostimulant and at least a mucosa absorption promoter are formed has and significantly joins mutually and synergism that through a large amount of test is unexpected patients infected hiv is had the obvious treatment effect.Mucosa absorption promoter helps mucous membrane of rectum and absorbs, but prolong drug expands the intercellular substance of opening the mucous membrane of rectum epithelium in the time that mucous membrane of rectum stops, and promotes the momentary expansion of rectum capillary tube, promotes the absorption of mucosa, helps increasing bioavailability of medicament.
Among the present invention, described immunomodulator-immunostimulant comprises recombinant human interleukin, interferon, thymosin or Toll sample receptor stimulators; Described mucosa absorption promoter is surfactant.
Among the present invention, select one or more and mucosa absorption promoter in recombinant human interleukin, interferon, thymosin or the Toll sample receptor stimulators for use---surfactant has good mutual effect and the synergism of joining, and patients infected hiv is had the good curing effect.
Among the present invention, described recombinant human interleukin is recombinant human interleukin--2, recombinant human interleukin-7 or recombinant human interleukin-X; Described interferon is recombinant human interferon alpha 2 b or recombinant human interferon alpha 1 b; Described thymosin is a human thymosin alfa 1; Described Toll sample receptor stimulators is the TLR-3 stimulant.
The recombinant human interleukin--2 has the effect that enhancing human body immunity is regulated, and patient T lymphocyte number is increased.
Recombinant interferon is a class broad-spectrum antiviral and immune modulator matter, is widely used in antiviral therapy.
Thymosin alpha 1 has been known as specificity and has regulated immune imbalance state, the most effective immune molecule of enhancing immunity.Its immunologic competence comprises: the special T cellular immunization of (1) enhancing body reserve capabillity.The only guaranteed liberal quantity of T cell could produce special, scavenging action efficiently when virus, tumor invasion.One of action target spot of Thymosin alpha 1 is just in the maturation process of T cell; (2) transfer specific cellular immunity, humoral immunization, strengthen macrophage function, removing antigen (virus, antibacterial, tumor etc.), final effect effectively suppress immune system and removing exotic disease substance for promoting specific cellular immunity and humoral immunization process; (3) recover low, immune, the humoral immune function of damaged cells.
(Tolllike receptors, TLRs) family is in the identification of pathogen with activate and bringing into play important effect aspect the natural immunity for Toll sample receptor.Activating TLRs not only can the inducing natural immunne response, and helps the generation of specific immune response, thereby TLRs is the bridge between the natural immunity and the acquired immunity.TLRs monitors and the various PAMPs of identification as autarcetic eyes, is the first road barrier of body opposing infectious disease.The mankind TLR-1-10 is arranged, wherein TLR-3 relates to antiviral innate immunity mechanism, the stimulant of TLR-3 has (seeing Sigma reagent catalogue) such as poly1:C, some company is developing new TLR-3 stimulant, as: HemispherxBiopharma company (AMEX:HEB) declares formally to submit the detailed answer for the treatment of 14 problems of chronic fatigue syndrome (" CFS ") about experimental drug Ampligen (r) to FDA.The problem that FDA proposes is crossed over clinical and preclinical topic.Except the topical application skin cancer, the agreement .PolyI:poly C12U (Ampligen (r)) that the chemical compound that does not still have at present a kind of TLR type obtains FDA is a kind of experimental medicine, is a class RNA, in the hope of can commercialization.
Above-mentioned immunostimulant-immunomodulator and surfactant have good mutual effect and the synergism of joining, and patients infected hiv is had the good curing effect.
Above-mentioned surfactant comprises one or more in sodium glycocholate salt, saponin, chitosan, glycocholic acid sodium salt, 9-lauryl ether (BL-9), L glycocholate or the PS.
Among the present invention, described pharmaceutical composition also comprises phosphate buffered solution, to guarantee the stability of required pH value.Join mutually according to different prescriptions, the pH value of the phosphate buffered solution that has is 5.0-7.4, and the pH value of the phosphate buffered solution that has is 7.2-7.4.
Among the present invention, the dosage form of described pharmaceutical composition is water preparation or suppository.The method that pharmaceutical composition of the present invention is used always according to those skilled in the art prepares water preparation or suppository, because intestinal mucosa is rich in lymphoid tissue, rich blood vessel, medicine can be absorbed rapidly by mucous membrane of rectum, about 50% first without liver, directly enter blood, the serious side reaction of avoiding active medicine to cause; More, can make the bigger therapeutic effect of medicine performance because the intestinal lymphoid tissue is abundant.
Compared with prior art, the present invention has following beneficial effect:
(1) has between the pharmaceutical composition of the present invention and significantly join mutually and synergism, patients infected hiv is had the good curing effect;
(2) pharmaceutical composition of the present invention helps the mucous membrane of rectum absorption, but prolong drug expands the intercellular substance of opening the mucous membrane of rectum epithelium in the time that mucous membrane of rectum stops, and promotes the momentary expansion of rectum capillary tube, promote the absorption of mucosa, help increasing bioavailability of medicament;
(3) pharmaceutical composition of the present invention can be absorbed rapidly by mucous membrane of rectum, and about 50% first without liver, directly enters blood, the serious side reaction of avoiding active medicine to cause; More, can make the bigger therapeutic effect of medicine performance because the intestinal lymphoid tissue is abundant;
(4) medicine of the present invention demonstrates good curative effect through clinical trial to patients infected hiv, and safety, and reliable, side effect is little, and the patient is easy to accept.
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1
Use special per anum mucous membrane of rectum administrator according to the anorectal anatomical structure:
Adopt 2 milliliters of (or 5ml) asepsis injectors, without syringe needle, replace the most advanced and sophisticated slick and sly sub warhead to be about 3.5 centimetres, internal diameter is tiny, and is similar with small size syringe needle internal diameter.
Have 1 milliliter of medicinal liquid of 2 milliliters of (or 5ml) syringes (rectal device) prepackage of the most advanced and sophisticated slick and sly sub warhead that is about 3.5 centimetres, directly per anum injects rectum, after the injection, lies in bed 10 minutes.
Embodiment 2
One of composition components:
Every milliliter contains:
1. recombinant human interleukin--2 (5,000,000 unit)
2. chitosan 0.5%, and molecular weight is 150kD, and is deacetylated more than 85%
3. the glycocholic acid sodium salt 1%
4. the human serum albumin 2%
5. benzyl alcohol 0.5%
Embodiment 3
Two of composition components:
Every milliliter contains:
1. recombinant human interferon alpha 2 (1,000 ten thousand unit)
2. recombinant human interleukin--2 (5,000,000 unit)
3. saponin 1%
4. chitosan 0.5%
5. the human serum albumin 2%
6. benzyl alcohol 0.5%
7.40mM its pH5.5 of phosphate solution buffer
Embodiment 4
Three of composition components
Every milliliter contains:
1. recombinant human interleukin--2 (5,000,000 unit)
2.1.6 milligram human thymosin alfa 1
3. chitosan 0.51%
4. the glycocholic acid sodium salt 1%
5. the human serum albumin 2%
6. benzyl alcohol 0.5%
7.40mM its pH7.2-7.4 of phosphate solution buffer
Embodiment 5
Four of composition components
Every milliliter contains:
1. recombinant human interleukin--2 (5,000,000 unit)
2. recombinant human interferon alpha 2 b or α 1b (1,000 ten thousand unit)
3.9-lauryl ether (BL-9)
4. chitosan 0.5%
5. the human serum albumin 2%
6. benzyl alcohol 0.5%
7.40mM its pH7.0 of phosphate solution buffer
Embodiment 6
Five of composition components:
Every milliliter contains:
1.2 milligram human thymosin alfa 1
2. recombinant human interleukin-7 (or X) (5,000,000 unit)
3.30mmol/L glycocholate
4. PS 1%
5. the human serum albumin 2%
6. benzyl alcohol 0.5%
7.40mM its pH7.2-7.4 of phosphate solution buffer
Embodiment 7
Six of composition components
Every milliliter contains:
1.TLR-3 stimulant (PolyI:C and derivant thereof)
2. recombinant human interferon alpha 2 b or α 1b (1,000 ten thousand unit)
3.9-lauryl ether (BL-9) 0.5%
4. the human serum albumin 2%
5. benzyl alcohol 0.5%
6.40mM its pH7.2-7.4 of phosphate solution buffer
Embodiment 8
The manufacturing process of recombinant human interferon alpha 2 or interleukin:
This manufacturing process is to formulate in conjunction with this product characteristics according to " the human recombinant DNA Part Quality Control main points " of [defending No. 37 literary composition approval of pharmaceutical control and administration word (90)].The strain system that is used to make this product will have the pBV220 plasmid transformation escherichia coli DH5 α strain of human interferon gene or human interleukin.Ferment with 80 liters of fermentation tanks.Must carry out a slack tank sterilization before each fermentation.The culture medium of fermentation usefulness is improved LB culture medium, with the distilled water preparation, does not wherein contain any antibiotic, carries out reality jar sterilization after the preparation.It is 100ug/ml that adding ampicillin in sterilization back makes its final concentration.The engineering bacteria cultivation temperature is 30.0 ± 0.1 ℃, cultivates 4-6 hour, is warmed up to 42 ℃ of express recombinant human interferon-alpha-2 bs again.Time 4-6 hour.With centrifugal method collection bacterium, ultrasonic at the ice bath environment, broken bacterium.Centrifugal collection inclusion body, degeneration, renaturation, through behind a series of chromatographies, with 0.22 μ m membrane filtration degerming, the specific activity of recombinant human interferon alpha 2 is not less than 1 * 108IU/mg albumen, the recombination human interleukin specific activity is not less than 1 * 107IU/mg albumen, and it is qualified to judge.Purity reaches more than 95%.
Embodiment 9
The processing technology of prepackage type rectally water preparation:
Will be at the immunomodulator/stimulant of GMP Workshop Production, analytically pure promotion mucosa absorption stimulant, the human albumin of code is produced in the SFDA approval that has by the GMP Workshop Production, the analytical pure benzyl alcohol, phosphate buffer, join mutually by above-mentioned prescription content after, use the automatic packer packing, rectal cannula and packing are installed in 1 milliliter of every syringe cylinder prepackage then automatically.
Embodiment 10
The processing technology of anal orifice and rectal intestine mucosa suppository:
45 milliliters of glycerol, gelatin 20 grams, 8 milliliters of aquae destillatas, mix homogeneously is at room temperature placed 3-5 day, the 1210C high pressure, 30 minutes, when being cooled to 560C with immunomodulator/stimulant, the mucosa absorption stimulant, albumin, benzyl alcohol, phosphate buffer, the control dosage is 1.0-1.5 milliliter (wants the proteinic formulation dosage of calculated activity/3.5 milliliters), add 0.7 milliliter of dimethyl Asia (DMSO) again, then stamper packing automatically.
Embodiment 11
The PRELIMINARY RESULTS that the pharmaceutical composition of employing the foregoing description 2 carries out clinical trial is as follows:
Purpose is inquired into the curative effect of above-mentioned composition by mucous membrane of rectum drug treatment HIV/AIDS patient.
Method gives the pharmaceutical composition (including IL-2400-800 ten thousand units) of the foregoing description 2 by mucous membrane of rectum, and is weekly, 1 month course of treatment.
7 routine HIV/AIDS patients participate in this treatment as a result, all are the male, and in age 18-40 year, wherein 3 examples are being accepted antiretroviral therapy.7 routine patient CD4+T cell number do not have obvious change after treating January, but obviously decline appears in 4 routine patient's virus loads, and fall is about 0.4-2.0log.Evident in efficacy.Clinical symptoms is obviously improved behind the 7 routine patient treatments, and muscle power is obviously recovered, and two routine patient's erythra partly disappear, and similar immunologic reconstitution syndrome appears in 1 example.
The conclusion clinical trial shows that above-mentioned composition demonstrates good curative effect by the mucous membrane of rectum drug treatment to HIV/AIDS patient.And safety, reliable, side effect is little, and the patient is easy to accept.
The pharmaceutical composition of other embodiments of the invention carries out above-mentioned clinical trial, has similar substantially result.
Claims (7)
1, the pharmaceutical composition of a kind of prevention and treatment AIDS viral infection, it is characterized in that: joining of described compositions comprises at least a immunomodulator-immunostimulant mutually, at least a mucosa absorption promoter, and human serum albumin and benzyl alcohol.
2, pharmaceutical composition according to claim 1 is characterized in that: described immunomodulator-immunostimulant comprises recombinant human interleukin, interferon, thymosin or Toll sample receptor stimulators; Described mucosa absorption promoter is surfactant.
3, pharmaceutical composition according to claim 2 is characterized in that: described recombinant human interleukin is recombinant human interleukin--2, recombinant human interleukin-7 or recombinant human interleukin-X; Described interferon is recombinant human interferon alpha 2 b or recombinant human interferon alpha 1 b; Described thymosin is a human thymosin alfa 1; Described Toll sample receptor stimulators is the TLR-3 stimulant.
4, pharmaceutical composition according to claim 3 is characterized in that: described surfactant comprises one or more in sodium glycocholate salt, saponin, chitosan, glycocholic acid sodium salt, 9-lauryl ether, L glycocholate or the PS.
5, pharmaceutical composition according to claim 4 is characterized in that: described pharmaceutical composition also comprises phosphate buffered solution.
6, pharmaceutical composition according to claim 5 is characterized in that: the pH value of described phosphate buffered solution is 5.0-7.4 or 7.2-7.4.
7, according to any described pharmaceutical composition of claim 1-5, it is characterized in that: the dosage form of described pharmaceutical composition is water preparation or suppository.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200810135329 CN101391103B (en) | 2008-07-31 | 2008-07-31 | Medicine composition for preventing and treating AIDS viral infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200810135329 CN101391103B (en) | 2008-07-31 | 2008-07-31 | Medicine composition for preventing and treating AIDS viral infection |
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| CN101391103A true CN101391103A (en) | 2009-03-25 |
| CN101391103B CN101391103B (en) | 2013-07-24 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103877566A (en) * | 2013-11-13 | 2014-06-25 | 南京洲邦生物科技有限公司 | Swine broad-spectrum immune enhancement preparation and preparation method thereof |
| CN106577642A (en) * | 2016-11-29 | 2017-04-26 | 上海师范大学 | Pesticide spraying additive, preparation method, and application thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1014584B (en) * | 1989-12-30 | 1991-11-06 | 白璋华 | Process for prodeucing of composition for curing disease of immune function lack |
| WO1996001318A1 (en) * | 1994-07-05 | 1996-01-18 | Steeno Research Group A/S | Immunomodulators |
| ES2448466T3 (en) * | 1997-04-15 | 2014-03-14 | Ohr Pharmaceutical, Inc. | Preparation of Product R and product thus obtained |
| CN1269840C (en) * | 2003-06-30 | 2006-08-16 | 美国福源集团 | Human interferon analogue with long-lasting biological effects |
| CN100425288C (en) * | 2005-01-28 | 2008-10-15 | 北京金迪克生物技术研究所 | Nasal cavity spraying inactivated influenza virus vaccine and its prepn process |
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2008
- 2008-07-31 CN CN 200810135329 patent/CN101391103B/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103877566A (en) * | 2013-11-13 | 2014-06-25 | 南京洲邦生物科技有限公司 | Swine broad-spectrum immune enhancement preparation and preparation method thereof |
| CN106577642A (en) * | 2016-11-29 | 2017-04-26 | 上海师范大学 | Pesticide spraying additive, preparation method, and application thereof |
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| Publication number | Publication date |
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| CN101391103B (en) | 2013-07-24 |
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