CN104043112B - A kind of ointment pharmaceutical composition containing recombinanthumaninterferonα-2b (pseudomonas) - Google Patents
A kind of ointment pharmaceutical composition containing recombinanthumaninterferonα-2b (pseudomonas) Download PDFInfo
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- CN104043112B CN104043112B CN201410310586.1A CN201410310586A CN104043112B CN 104043112 B CN104043112 B CN 104043112B CN 201410310586 A CN201410310586 A CN 201410310586A CN 104043112 B CN104043112 B CN 104043112B
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- human interferon
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Abstract
The present invention relates to field of pharmaceutical preparations, particularly one contains ointment pharmaceutical composition and the preparation thereof of recombinant human interferon alpha 2 b (pseudomonas).Pharmaceutical composition of the present invention, comprises following composition: recombinant human interferon alpha 2 b stock solution 3.75 × 10
8iU-7.5 × 10
8iU, human albumin 10-20g, sodium carboxymethyl cellulose 60-70g, glycerol 3700-3800g, sodium lauryl sulphate 8-12g, citric acid 15-20g, sodium citrate 70-75g, chlorogenic acid 8-12g, purified water is settled to 5kg.
Description
Technical field:
The present invention relates to field of pharmaceutical preparations, particularly one contains ointment pharmaceutical composition and the preparation thereof of recombinant human interferon alpha 2 b (pseudomonas).
Background technology:
Group human interferon-alpha-2 b has broad-spectrum antiviral, antitumor, antiproliferative effect and improves the effects such as immunologic function.Interferon and cell surface receptor zygotic induction cell produce multiple antiviral protein, suppress virus at propagated in cells, improve immunologic function to comprise and strengthen the phagocytic function of macrophage, strengthen the function of lymphocyte to the cytotoxicity of target cell and NK cell sexual cell.
Recombinant human interferon alpha 2 b ointment
Main component: recombinant human interferon alpha 2 b.
Function cures mainly: be mainly used in treating the condyloma acuminatum that caused by human papillomavirus, also can be used for treating the herpes labialis and genital herpes that are caused by herpes simplex virus.
Usage and dosage: be coated with affected part, every day 4 times.Condyloma acuminatum medication 6-8 week, or follow the doctor's advice.Herpes labialis and genital herpes continuous use 1 week, or follow the doctor's advice.
Effect duration: 24 months
Side effect: stimulation, allergy and other systemic adverse reactions individuals patients generally can not be caused occasionally can to occur pruritus, causalgia etc.
Therapeutic Characteristics:
Recombinant human interferon alpha 2 b ointment is mainly used in treating the condyloma acuminatum caused by human papillomavirus, and (condyloma acuminatum infects by human papillomavirus (HPV) a kind of sexually transmitted disease (STD) caused.Main Types be HPV1,2,6,11,16,18,31,33 and 35 types etc., wherein HPV16 may be relevant with the generation of women's cervical cancer with 18 type Long-term Infections.Human papillomavirus (HumanPapillomavirus, HPV) is the DNA viruses of a kind of molecule less (diameter 55nm), biologically belongs to Papovavirus section.Known human papillomavirus has 100 Multi-genotypes, wherein has more than 30 kind meetings to infect skin and the mucosa of human reproduction's organ, causes various disease.) also can be used for treating the herpes labialis that caused by herpes simplex virus and genital herpes.
Multiple report is had to recombinant human interferon alpha 2 b ointment in prior art, the present invention finds, existing recombinant human interferon alpha 2 b ointment has skin irritation under partial picture in use, even cause pain, be unfavorable for the use of medicine, the present invention has carried out further research to formula for this reason, find chlorogenic acid to join in formula to be prepared into ointment formulation together with recombinant human interferon alpha 2 b, skin irritation alleviates greatly, the rate of release of medicine can be accelerated simultaneously, be conducive to the absorption of medicine and the use of preparation.
For this reason, the invention provides a kind of ointment pharmaceutical composition containing recombinant human interferon alpha 2 b (pseudomonas) and preparation method thereof, medicine of the present invention comprises following composition: recombinant human interferon alpha 2 b, human albumin, glycerol, sodium carboxymethyl cellulose, citric acid, sodium citrate, sodium lauryl sulphate, chlorogenic acid.
Summary of the invention
The invention provides a kind of pharmaceutical composition containing recombinant human interferon alpha 2 b (pseudomonas), its formula is composed as follows:
Prescription: every 1000
Preferably, prescription: every 1000 (5g/ props up, and 10g/ props up)
Preparation method
Get citric acid and the sodium citrate of recipe quantity, dissolve by recipe quantity purified water, measure buffer solution ph within the scope of 4.8-5.2 → with half buffer solution recipe quantity sodium lauryl sulphate, stirring and dissolving, stir (solution 1); By the glycerol of the interferon stock solution of second half buffer and recipe quantity human albumin (20%) and recipe quantity, chlorogenic acid mix homogeneously (solution 2) → add about total amount 1/2-2/3, after adding recipe quantity sodium carboxymethyl cellulose again, then surplus glycerol → stirring is added, emulsifying → add solution 1 in emulsion tank, expand → in emulsion tank, add solution 2, stir → embedding → packaging → finished product.
The depside that chlorogenic acid (Chlorogenicacid) is made up of caffeic acid (Caffeicacid) and quinic acid (Quinicacid), different name chlorogenic acid, chemical name 3-O-caffeoyl Kui acid (3-O-caffeoylquinicacid) molecular formula: C
16h
18o
9, molecular weight: 354.30 is plant a kind of benzene-like compounds through shikimic acid pathway generation in aerobic respiration process.Chlorogenic acid is extensively present in high dicotyledon and pteridophyta, mainly richly be that in Caprifoliaceae Lonicera (Lonicera), Compositae artemisia (Artemisia) plant, the plant that wherein content is higher is mainly the Cortex Eucommiae, Flos Lonicerae, Helianthi, the wood that continues, coffee, cocoa tree etc.Chlorogenic acid has biological activity widely, and modern science has been deep into multiple fields such as food, health care, medicine and daily-use chemical industry to the bioactive research of chlorogenic acid.Chlorogenic acid is a kind of important bioactive substance, has antibacterial, antiviral, increases the effects such as leukocyte, hepatic cholagogic, antitumor, blood pressure lowering, blood fat reducing, scavenging free radicals and stimulating central nervous system system.
The present invention finds in research chlorogenic acid injection process, it can reduce skin heart zest and local pain, through screening, the present invention simultaneously finds that the use amount of chlorogenic acid is at 10mg, this dosage can not produce any side effect, but can play the effect of auxiliary recombinant human interferon alpha 2 b (pseudomonas).
Below by way of experimental data, beneficial effect of the present invention is described:
Contrast experiment:
The indices of recombinant human interferon alpha 2 b ointment (pseudomonas) sample investigated embodiment 1 and the comparative example not adding chlorogenic acid and gone on the market
Whether add the impact of chlorogenic acid on vitro release to see the following form:
Skin irritation test method
Select white rabbit 12, male and female half and half.In first 1 day of administration by family's rabbit back spinal column both sides electric haircutting scissors unhairing, unhairing area is about 150cm
2(15cm*10cm).Rabbit is divided into 3 groups, often organizes 4, each 2 of male and female.Take consubstantiality left and right sides self-contrast method experimental observation.Be set to embodiment 1 sample (adding chlorogenic acid) group, comparative example 1 sample (not adding chlorogenic acid) group, recombinant human interferon alpha 2 b (pseudomonas) sample sets of going on the market respectively.Recombinant human interferon alpha 2 b ointment is coated with and puts on the skin in test rabbit left dorsal unhairing district, and unhairing district puts the emulsifiable paste matrix of same dose on the skin in contrast with method painting on the right side of back.Be covered in coating position with layer antiseptic gauze after emulsifiable paste or emulsifiable paste matrix are put in painting on the skin, fixed with adhesive plaster.To 3 groups of rabbit medication every day 1 time, continuous 7d, observes 7d after drug withdrawal again.Except the skin erythema examining and record every day when every day changes dressings and edema situation, also should observe painting and put position on the skin and whether have the situations such as pigmentation, petechia, pachylosis or epidermatic atrophy.Carry out skin irritation evaluation.
Local pain experimental technique
Randomly draw from the Healthy People of voluntary participation experimental study 60 example, men and women half and half, age 25-55 year.Be divided into 3 groups at random, often organize 20 people.Be set to embodiment 1 sample (adding chlorogenic acid) group, comparative example 1 sample (not adding chlorogenic acid) group, recombinant human interferon alpha 2 b (pseudomonas) sample sets of going on the market respectively.Being coated with by recombinant human interferon alpha 2 b ointment puts on the skin after subjects skin, use visual analogue scale (visual arna loguescale, VAS) evaluate patient pain condition, i.e. ruler method, be also called linear visual analogue scales: the linear scale that 10cm is long puts on 0 and 10 printed words, represent different pain degrees, numeral larger expression pain degree is stronger.First explain that 0 point of expression is painless to patient before using, 10 points represent the most bitterly, and 1-10 represents slight to severe pain.Allow patient oneself iris out on line relevant position that one can represent its pain degree, is then gone out the numeral of pain, respectively record, and carries out statistical analysis with ruler measurement by estimator.
Vitro release test method
Get healthy mice, use 8%Na
2s solution unhairing, disconnected neck is put to death, and gets skin of back, scrapes off subcutaneus adipose tissue and adhesion thing, and distilled water flushing is clean, soaks 30min with normal saline, for subsequent use.The recombinant human interferon alpha 2 b emulsifiable paste prepared is smoothened on external Corium Mus, makes Corium Mus lower floor close contact bubble removing side by side.Use Franz diffusion cell, take normal saline as acceptable solution in acceptance pool, in receiving chamber, fill it up with acceptable solution, water bath heat preservation 37 DEG C, built-in stirrer is with 100rmin
-1speed stirs, and respectively at Isosorbide-5-Nitrae, 8,12,24,48,72h extracts 1mL receiving liquid in receiving chamber, and supplements equal-volume normal saline rapidly, measures the biologic activity of recombinant human interferon alpha 2 b.
Accelerate 3 months medicine assay experimental techniques
The sample getting 3 batches at random carries out accelerated test, is placed on and commercially produces in the same or analogous packing container of product, and experimental condition is 25 DEG C ± 2 DEG C/RH75% ± 5%, and the investigation time is 3 months.Cytopathic-effect inhibition assay is adopted to measure the biologic activity of recombinant human interferon alpha 2 b.Method And Principle: make two WISH cell adherent growth in the medium, go down to posterity by (1:2) ~ (1:4), 2 ~ 3 times weekly, grow in complete culture solution.Get cultured cells and discard culture fluid. wash 2 digestion and collecting cells afterwards with PBS, be mixed with every 1ml containing 2.5*10 with complete culture solution
5~ 3.5*10
5the cell suspension of individual cell, is inoculated in 96 porocyte culture plates, every hole 100 μ l, in 37 DEG C, cultivate 4 ~ 6 hours under 5% carbon dioxide conditions; The standard solution prepared and need testing solution are moved in the culture plate of inoculation WISH cell, every hole adds people 10 μ l, in 37 DEG C, cultivate 18 ~ 24 hours under 5% carbon dioxide conditions, discard the supernatant in Tissue Culture Plate, the vesicular stomatitis virus (VSV ,-70 DEG C of preservations) preserved is diluted to about 100CCID with counteracting toxic substances culture fluid
50, every hole 100 μ l, in 37 DEG C, cultivate 50% pathological changes point of 24 hours < microscopic criteria product solution under 5% carbon dioxide conditions at 1IU/ml); Then the supernatant in Tissue Culture Plate is discarded, every hole adds dyeing liquor 50 μ l, room temperature carefully washes away dyeing liquor with flowing water after placing 30 minutes, and blots residual moisture, every hole adds destaining solution 100 μ l, room temperature is placed 3 ~ 5 minutes, after mixing, is reference wavelength by microplate reader with 630nm, absorbance is determined, record measurement result at wavelength 5700nm Chu Measuring.Test data adopts computer program or four parametric regression computing methods to process, and is calculated as follows result:
Test sample biologic activity (IU/ml)=P
t* (D
s* E
%)/(D
t* E
t)
(biologic activity acceptability limit: 80.0%-150.0%)
Detailed description of the invention:
Embodiment 1
Prescription: every 1000 (5g/ props up, and 10g/ props up)
Preparation method
Get citric acid and the sodium citrate of recipe quantity, dissolve by recipe quantity purified water, measure buffer solution ph within the scope of 4.8-5.2 → with half buffer solution recipe quantity sodium lauryl sulphate, stirring and dissolving, stir (solution 1); By the glycerol of the interferon stock solution of second half buffer and recipe quantity human albumin (20%) and recipe quantity, chlorogenic acid mix homogeneously (solution 2) → add about total amount 1/2-2/3, after adding recipe quantity sodium carboxymethyl cellulose again, then surplus glycerol → stirring is added, emulsifying → add solution 1 in emulsion tank, expand → in emulsion tank, add solution 2, stir → embedding → packaging → finished product.
Comparative example 1
Prescription: every 1000 (5g/ props up, and 10g/ props up)
Preparation method
Get citric acid and the sodium citrate of recipe quantity, dissolve by recipe quantity purified water, measure buffer solution ph within the scope of 4.8-5.2 → with half buffer solution recipe quantity sodium lauryl sulphate, stirring and dissolving, stir (solution 1); By the glycerol of the interferon stock solution mix homogeneously (solution 2) of second half buffer and recipe quantity human albumin (20%) and recipe quantity → add about total amount 1/2-2/3, after adding recipe quantity sodium carboxymethyl cellulose again, then surplus glycerol → stirring is added, emulsifying → add solution 1 in emulsion tank, expand → in emulsion tank, add solution 2, stir → embedding → packaging → finished product.
Claims (3)
1. the pharmaceutical composition containing recombinant human interferon alpha 2 b, it is characterized in that, formula is as follows: every 1000,5g/ props up,
2. the pharmaceutical composition containing recombinant human interferon alpha 2 b, it is characterized in that, formula is as follows: every 1000,5g/ props up,
3. the pharmaceutical composition containing recombinant human interferon alpha 2 b, it is characterized in that, formula is as follows: every 1000,10g/ props up,
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001015736A3 (en) * | 1999-08-27 | 2003-05-22 | Maxygen Aps | Interferon-beta conjugates |
| CN1672731A (en) * | 2004-03-26 | 2005-09-28 | 天津药物研究院 | Interferon spray for lung administration and its prepn process |
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2014
- 2014-07-01 CN CN201410310586.1A patent/CN104043112B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001015736A3 (en) * | 1999-08-27 | 2003-05-22 | Maxygen Aps | Interferon-beta conjugates |
| CN1672731A (en) * | 2004-03-26 | 2005-09-28 | 天津药物研究院 | Interferon spray for lung administration and its prepn process |
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Inventor after: Pang Rui Inventor after: Qin Weiying Inventor after: Xu Yu Inventor after: Li Mingyue Inventor after: Chen Yujun Inventor after: Zhao Haidan Inventor after: Zheng Liyun Inventor after: Duan Zhiqiang Inventor after: Wang Qing Inventor after: Bai Yu Inventor after: Liu Wenbin Inventor after: Han Jie Inventor before: Pang Rui Inventor before: Qin Weiying Inventor before: Xu Yu Inventor before: Li Mingyue Inventor before: Chen Yujun Inventor before: Zhao Haidan Inventor before: Zheng Liyun Inventor before: Duan Zhiqiang Inventor before: Wang Qing Inventor before: Bai Yu Inventor before: Liu Wenbin Inventor before: Han Jie |
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