CN1055249C - Analgesia medicine and its mfg. method - Google Patents
Analgesia medicine and its mfg. method Download PDFInfo
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- CN1055249C CN1055249C CN98103220A CN98103220A CN1055249C CN 1055249 C CN1055249 C CN 1055249C CN 98103220 A CN98103220 A CN 98103220A CN 98103220 A CN98103220 A CN 98103220A CN 1055249 C CN1055249 C CN 1055249C
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Abstract
The present invention provides an anodyne (Anshuling) and a preparation method thereof. Vaccinia viruses are inoculated to white rabbits, and active preparation is extracted from the variole skin tissues of the white rabbits through the steps of solvent extraction, acid treatment, alkali treatment, adsorption, elution, concentration, etc. The active preparation is mixed with pharmaceutic adjuvant, so the anodyne of the present invention is obtained. The anodyne of the present invention has strong analgesic effect and minimal side effect.
Description
The present invention relates to a kind of analgesic and its manufacture method.With virus vaccinicum (vaccinia virus) inoculation White Rabbit, through solvent extraction, acid treatment, alkali treatment, absorption and eluting and step such as concentrate and prepare active ingredient from the pox skin histology of sending out of this White Rabbit, with this active ingredient and pharmaceutic adjuvant combination, promptly obtain analgesic of the present invention then.
Analgesic mainly is that a class acts on the central nervous system, and selectivity suppresses the medicine that the pain sensation does not influence its sensation simultaneously.Opium sample alkaloid and synthetic substitute thereof are typical central action analgesic, and their analgesic activity is stronger, but side effect is also comparatively serious, are easy to generate addiction, toleration and respiration inhibition etc. after using repeatedly.At present, also there is not a kind of analgesic activity strong clinically, and the minimum analgesic of side effect.
Therefore, it is strong to the purpose of this invention is to provide a kind of analgesic activity, and the minimum analgesic of side effect and the manufacture method of this analgesic.
Analgesic of the present invention contains active ingredient and pharmaceutic adjuvant, wherein said active ingredient contains aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine, and contain urocanic acid, uracil, the fast cry of certain animals of inferior Huang, xanthine, thymus pyrimidine, more than the content range of various materials be respectively (μ g/ml): aspartic acid 0.2-0.5, threonine 0.1-0.4, serine 0.3-0.8, glutamic acid 0.7-1.4, glycine 0.3-0.7, alanine 0.4-0.9, valine 0.1-0.4, isoleucine 0.1-0.3, leucine 0.1-0.4, tyrosine 0.2-0.6, phenylalanine 0.1-0.4, lysine 0.05-0.2, histidine 0.1-0.4, urocanic acid 12.0-22.5, uracil 6.5-12.1, hypoxanthine 0.7-1.4, xanthine 5.4-10.2, thymus pyrimidine 1.3-2.5; Said preparation is colourless or light yellow liquid, pH value is 7.0-8.0, has uv absorption at 265-275nm, ninhydrin reaction is positive, and range protein detects negative, and 3,5-orcin-hydrochloric acid reaction is positive, the arsenomolybdate method dye-forming reaction is positive, and this active ingredient is prepared by following steps: a) inoculate White Rabbit with virus vaccinicum (Vaccinum variolae) lister, collect the skin histology of having smallpox; B) tissue that will collect is cut into small pieces, and doubly measures 2% the phenol solution of (weight) to wherein adding 2.5-3.5, soaks, and is centrifugal and filter, and obtains solution A; C) solution A is transferred to faintly acid, boil the centrifugal and filtration in back, obtain solution B; D) solution B is transferred to alkalescence, boil after-filtration, obtain solution C; E) solution C is transferred to faintly acid, to wherein adding adsorbent, after the immersion, filter, water eluting adsorbent obtains solution D under alkaline environment; F) solution D is transferred to faintly acid, the heating postcooling obtains solution E; G) decompression concentrated solution E and filtration.
Preferably, this active ingredient is prepared by following steps: a) with virus vaccinicum lister inoculation White Rabbit, collect the skin histology of having smallpox; B) collected tissue is cut into small pieces, 2% phenol solution to wherein adding 3 times of amounts (weight) soaked 72 hours, centrifugal and filter after, obtain solution A; C) pH value with solution A transfers to 5.0, boils centrifugal and filtration after 30 minutes, obtains solution B; D) pH value with solution B transfers to 9.2, boils 30 minutes after-filtration, obtains solution C; E) pH value with solution C transfers to 4.5, to wherein adding active carbon, soaks after 4 hours, filters, and washes the deactivation charcoal under pH11.0 with water, obtains solution D; F) pH value with solution D transfers to 6.0, is heated to 121 ℃, is cooled to below 40 ℃, obtains solution E; G), filter then at 60 ℃ of following decompression concentrated solution E.
After obtaining said active ingredient, this active ingredient and pharmaceutic adjuvant combination can be obtained analgesic of the present invention.This analgesic can be the various dosage forms that are suitable for clinical use, comprises injection, tablet, ointment, capsule, granule etc., preferably injection.Said pharmaceutic adjuvant comprises various pharmaceutic adjuvants.In injection, adjuvant can be a distilled water for injection, and normal saline, injection vegetable oil, glucose injection, propylene glycol, Polyethylene Glycol etc. can also be various stabilizing agents, emulsifying agent etc.; In tablet, capsule and granule, adjuvant can be excipient such as starch, lactose, mannitol, bonding agent such as crystalline cellulose, arabic gum, corn starch, gelatin, polyethylene, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, Polyethylene Glycol, potato starch are decided disintegrating agent, lubricant such as Pulvis Talci, magnesium stearate, wetting agent such as glycerol etc.In ointment, adjuvant can be substrate such as fatty oil, paraffin, lanoline, vaseline, ethylene glycol, glycerol etc.
Pharmacology and clinical trial show that analgesic of the present invention has analgesic activity to multiple disease.These diseases comprise pain that the having an intense pain of various neuralgias, lumbago, biliary colic, angina pectoris, arterial thrombosis pain, wound empyrosis etc., intra-operative and postoperative pain, peptic ulcer disease pain, dysmenorrhea, puerperal uterine contraction pain, headache, various tumor cause etc.Analgesic of the present invention can also improve immunologic function.In addition, analgesic of the present invention has minimum side effect.
Adopt the low vegetative dystonie model of analgesia threshold value, what the emergent attitude Mus that stimulates with specific room temperature carried out studies show that, no matter be the Thamr-Smith method of using thermostimulation, still the Randall-Selitto method of mechanical compression stimulation confirms that all analgesic of the present invention has significant analgesia role to the vegetative dystonie model mouse.
With analgesic of the present invention 20 Pruritus dermatoses patients are tested subcutaneous injection analgesic of the present invention, 1 day 1 ampoule (3 milliliters) clinically, 1 week, 2 weeks of administration were when administration finished more than 3 times, improvement and moderate improver account for 70% fully, are 95% more than slight the improvement.Muscle and subcutaneous clinical experiment to 29 routine lumbago patients show serviceability and the safety that has also shown analgesic of the present invention.
With the inflammation relevant with immune function is index, take all factors into consideration 48 hours homology PCA inhibitory action, and anticomplementary activity studies show that to the active function of macrophage, analgesic of the present invention can promote the macrophage activation effect effectively, obviously suppress the homology PCA reactions in 48 hours that cause as the IgE antibody of the mice of I allergic reaction type model, and can suppress the model anticomplementary activity as the II allergic reaction type, its effect is linear with consumption.Hence one can see that, and analgesic of the present invention has the effect of the inflammation that suppresses relevant with immune function, can improve immunologic function.
Mice and rat are carried out disposable oral, abdominal cavity and subcutaneous administration has been determined its acute toxicity with analgesic of the present invention.Abdominal cavity and subcutaneous administration 6,000 units/kg, oral administration 10,000 units/kg in 14 days observation period, have only an example to confirm as death in subcutaneous group of male Mus, and other administration group is all survived.Routine male Mus death in 5 days after administration is not found special abnormality to the dissection of this death Mus in the subcutaneous administration group, therefore can not think because of drug influence death.With analgesic of the present invention with 30,60 and continuous 28 days of 120 units/kg to the rat abdominal cavity administration, all occur death in any one group, urine examination, ophthalmologic examination, blood chemical examination, histopathologic examination and dissection all illustrate and do not exist because the variation that the administration of analgesic of the present invention causes.These illustrate that analgesic toxicity of the present invention is very little.
The antigenicity experiment of adopting Cavia porcellus and white mice to carry out shows that analgesic of the present invention does not have antigenicity.With the rabbit is experimental subject, adopts the mode of infiltration injecting, shows that with ading up to according to the security test of carrying out of naked eyes and the viewed total scar of histopathology analgesic of the present invention is very low to the local toxicological effect of tame rabbit muscle.
At Slc:ddy is 1 subcutaneous injection analgesic of the present invention of organogenesis's (being equivalent to pregnant 6-15 days) 1 day of SPF mice, dosage is respectively 1.2,12 is 120 units/kg, has studied the influence of analgesic of the present invention to animal, fetus and young baby thus.The result shows that administration does not influence gestation and the general state of age of sucking, body weight and appetite, puerperal inleakaging state and dissecting check all not have to find with inject checking matter relevant unusually.Do not find that fetus is unusual because of the specificity of injection the checking matter appearance, skeleton and the organ morphology that cause.Viability, body weight change, appearance to the young baby behind the injection checking matter broken up, various functions, behavior and reproduction function when weaning all do not have influence.
The answer test explanation analgesic of the present invention that carries out with antibacterial (salmonella typhimurium TA100, TA98, TA1535, TA1537 and escherichia coli WP2uvrA) does not have the induce variation effect to genetic factor.The chromosomal abnormality test of carrying out with mammal cultured cell (CHL) shows that analgesic of the present invention does not have the induce variation effect to chromosome.With ICR (Crj:CD-1) is that the small nut test that male mice carries out shows that analgesic of the present invention does not have the induce variation effect to chromosome.
Below further specify the present invention with embodiment.The antigen that embodiment 1 preparation is used to inoculate
With 2.5 kilograms of body weight, 3 centimetres in testis and blocky adult healthy Japan large ear rabbit are as the buck of antigen subculture.With 70% cotton ball soaked in alcohol sterilization scrotum, with antigen Smallpox Vaccine (vaccinumvariolae) lister (dry variola vaccine, National Institutes of Health,Japan (Tokyo product Chuan Qu goes up big rugged 2-10-35) is produced) dissolving, shake up, extract 0.2 milliliter with 1 milliliter of needle tubing, central internal layer injection to a rabbit testis, postvaccinal rabbit is put into special-purpose rabbit house, guarantee drinking-water and supply of forage fully, observe every day and reached optimum state (orchioscirrhus, swelling and purpling) in twice, the 4 day.Firmly break cervical vertebra,, cut off scrotum, remove the testis connective tissue with 70% cotton ball soaked in alcohol sterilization scrotum periphery.Clean through normal saline (0.9%) cutting the testis of adopting, again through 2 PBS (-) (sodium chloride 80 grams, potassium chloride 2 grams, sodium dihydrogen phosphate 11.5 gram, dihydrogen phosphate dihydrate potassium 2 grams add injection water to 10 liter) twice of solution flushing, dry, weigh, put into the special container that ice cube is housed, finally put into-80 ℃ ultra cold storage freezer and preserve.To organize (testis) to take out refrigerator softening 1 hour, under low temperature (4 ℃), grind, with 1: 1 and EAGLE ' S culture medium (Eagle ' s powder 9.4 grams, 10% sodium bicarbonate 12.5-22.0 milliliter, 10 milliliters of glutamine, 1 liter of injection water) mix, after the packing, the ultra cold storage freezer of putting into-80 ℃ freezed 1 hour, took out in 37 ℃ water bath again and thawed, 3 times repeatedly.Then, carry out low-temperature centrifugation (4 ℃, 3500rpm, 20 minutes).Being packed as 10 milliliters one ultra cold storage freezer of putting into-80 ℃ preserves.Embodiment 2 preparation active ingredients
Take out antigen from-80 ℃ ultra cold storage freezer, the incubator of putting into 30 ℃ slowly dissolves it.5 milliliters (every milliliter contains 10 to extract the antigen for preparing by embodiment 1 with one 10 milliliters needle tubings
7-10
8Individual virus), inject 500 milliliters PBS (-) solution, shake up, obtain injection antigen.The hair of ripe large ear rabbit (2.75 kilograms) back of a health is cut off, cut plucked position with 75% cotton ball soaked in alcohol wiping.With above this rabbit of injection antigen intradermal injection that makes, every 1.5 centimetres of injection one pins, every row injects 11 points from left to right, and each marginal not is penetrated 5 rows, and every pin contains 0.2 milliliter of antigen amount, notes water-tight, empty beating not, does not annotate and wears skin.To inject antigenic rabbit raised 4 days.It is good to send out pox, color by ruddy transfer to purplish red, pachyderma, subcutaneous have an edema, the buttocks edema is obvious.Put to death rabbit with the cervical vertebra dislocation method, finish in 15 minutes and adopt skin.Use the plastic bag packaging rabbit, leave in-80 ℃ the refrigerator-freezer standby immediately.Rabbit (20 * 20 centimetres, 200 grams) is cut into 1 square centimeter fritter, to 2% phenol solution that wherein adds 3.5 times of amounts (weight).In this solution, fed nitrogen 3 minutes, make its bubbling, then sealing.Be placed on 4 ℃ of environment following 72 hours, liquid becomes after the emulsion centrifugal, takes out supernatant, with No. 5 filter paper filterings, obtains brown solution A; In solution A, fed nitrogen 3 minutes, and made its bubbling, the pH value of this solution is transferred to 5.0, in water-bath, boiled 30 minutes, be cooled to 28 ℃ immediately with 1M hydrochloric acid, then centrifugal, use filter paper low pressure filtering supernatant then No. 5, obtain solution B; In solution B, fed nitrogen 3 minutes, and made its bubbling, pH value of filtrate is transferred to 9.2, in water-bath, boiled 30 minutes, be cooled to 28 ℃ immediately, hang down press filtration with No. 5 filter paper and 0.45 μ m filter membrane then, obtain solution C with the 1M sodium hydroxide; In solution C, fed nitrogen 3 minutes, make its bubbling, with 1M hydrochloric acid pH value of filtrate is transferred to 4.5, in solution C, fed nitrogen 3 minutes, make its bubbling, to wherein adding 40 gram active carbons, soaked 4 hours with constantly stirring down in 30 ℃, stop to stir, it was left standstill 30 minutes, take out the supernatant, under nitrogen environment, hang down press filtrations with No. 5 filter paper, soak with injection water (pH8.0) then and clean active carbon, under nitrogen environment,, discard filtrate collection and store active carbon with No. 5 low press filtrations of filter paper, the vessel of carrying active charcoal are added in 400 milliliters of injection waters, feed nitrogen and make its bubbling, with the lM sodium hydroxide pH is transferred to 11.0, continuous stirring 4 hours.Under nitrogen environment,, clean active carbon with 40 milliliters of injection waters again, obtain solution D with 0.45 μ m membrane filtration; With 1M hydrochloric acid pH is transferred to 6.0, to wherein feeding nitrogen and sealing up for safekeeping in container.Fed nitrogen 5 minutes in container, make its bubbling, sealed container is heated to 12l ℃, keeps 20 minutes, is cooled to then below 40 ℃, obtains solution E; With solution E suction distilling under reduced pressure device, make the air in the distilling under reduced pressure device be replaced with nitrogen, be 5 milliliters at 60 ℃ of following distilling under reduced pressure to volume, with No. 5 filter paper filterings,, obtain 5 milliliters of active ingredients then with 0.2 μ m membrane filtration.This active ingredient contains aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine, and contain urocanic acid, uracil, hypoxanthine, xanthine, thymus pyrimidine, more than the content of various materials be respectively (μ g/ml): aspartic acid 0.3, threonine 0.2, serine 0.5, glutamic acid 1.1, glycine 0.5, alanine 0.6, valine 0.3, isoleucine 0.1, leucine 0.3, tyrosine 0.4, phenylalanine 0.2, lysine 0.1, histidine 0.2, urocanic acid 18.2, uracil 9.5, hypoxanthine 1.1, xanthine 8.6, thymus pyrimidine 2.0.Said preparation is a colourless liquid, and pH value is about 7.5, has uv absorption at 265-275nm, and ninhydrin reaction is positive, and range protein detects negative, 3, and 5-orcin-hydrochloric acid reaction is positive, and the arsenomolybdate method dye-forming reaction is positive.Embodiment 3 preparation active ingredients
Take out antigen from-80 ℃ ultra cold storage freezer, the incubator of putting into 30 ℃ slowly dissolves it.5 milliliters (every milliliter contains 10 to extract the antigen for preparing by embodiment 1 with one 10 milliliters needle tubings
7-10
8Individual virus), inject 500 milliliters PBS (-) solution, shake up, obtain injection antigen.The hair of ripe large ear rabbit (2.5 kilograms) back of a health is cut off, cut plucked position with 75% cotton ball soaked in alcohol wiping.With above this rabbit of injection antigen intradermal injection that makes, every 1.5 centimetres of injection one pins, every row injects 10 points from left to right, and each marginal not is penetrated 5 rows, and every pin contains 0.2 milliliter of antigen amount, notes water-tight, empty beating not, does not annotate and wears skin.To inject antigenic rabbit raised 3 days.It is good to send out pox, color by ruddy transfer to purplish red, pachyderma, subcutaneous have an edema, the buttocks edema is obvious.Put to death rabbit with the cervical vertebra dislocation method, finish in 15 minutes and adopt skin.Use the plastic bag packaging rabbit, leave in-80 ℃ the refrigerator-freezer standby immediately.Rabbit (18 * 18 centimetres, 180 gram) is cut into 1 square centimeter fritter, to 2% the phenol solution that wherein adds 2.5 times of amounts (weight).In this solution, fed nitrogen 3 minutes, make its bubbling, then sealing.Be placed on 4 ℃ of environment following 70 hours, liquid becomes after the emulsion centrifugal, takes out supernatant, with No. 5 filter paper filterings, obtains brown solution A; In solution A, fed nitrogen 3 minutes, and made its bubbling, the pH value of this solution is transferred to 4.5, in water-bath, boiled 30 minutes, be cooled to 26 ℃ immediately with 1M hydrochloric acid, then centrifugal, use filter paper low pressure filtering supernatant then No. 5, obtain solution B; In solution B, fed nitrogen 3 minutes, and made its bubbling, pH value of filtrate is transferred to 8.7, in water-bath, boiled 30 minutes, be cooled to 26 ℃ immediately, hang down press filtration with No. 5 filter paper and 0.45 μ m filter membrane then, obtain solution C with the 1M sodium hydroxide; In solution C, fed nitrogen 3 minutes, make its bubbling, with 1M hydrochloric acid pH value of filtrate is transferred to 4.0, in solution C, fed nitrogen 3 minutes, make its bubbling, to wherein adding 30 gram active carbons, soaked 4 hours with constantly stirring down in 25 ℃, stop to stir, it was left standstill 30 minutes, take out the supernatant, under nitrogen environment, hang down press filtrations with No. 5 filter paper, soak with injection water (pH8.0) then and clean active carbon, under nitrogen environment,, discard filtrate collection and store active carbon with No. 5 low press filtrations of filter paper, the vessel of carrying active charcoal are added in 360 milliliters of injection waters, feed nitrogen and make its bubbling, with the 1M sodium hydroxide pH is transferred to 10.5, continuous stirring 4 hours.Under nitrogen environment,, clean active carbon with 45 milliliters of injection waters again, obtain solution D with 0.45 μ m membrane filtration; With 1M hydrochloric acid pH is transferred to 5.5, to wherein feeding nitrogen and sealing up for safekeeping in container.Fed nitrogen 5 minutes in container, make its bubbling, sealed container is heated to 120 ℃, keeps 20 minutes, is cooled to then below 40 ℃, obtains solution E; With solution E suction distilling under reduced pressure device, make the air in the distilling under reduced pressure device be replaced with nitrogen, be 5 milliliters at 70 ℃ of following distilling under reduced pressure to volume, with No. 5 filter paper filterings,, obtain 2 milliliters of active ingredients then with 0.2 μ m membrane filtration.This active ingredient contains aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine, and contain urocanic acid, uracil, hypoxanthine, xanthine, thymus pyrimidine, more than the content of various materials be respectively (μ g/ml): aspartic acid 0.2, threonine 0.4, serine 0.3, glutamic acid 1.4, glycine 0.7, alanine 0.4, valine 0.1, isoleucine 0.3, leucine 0.4, tyrosine 0.6, phenylalanine 0.1, lysine 0.05, histidine 0.4, urocanic acid 12.0, uracil 12.1, hypoxanthine 1.4, xanthine 5.4, thymus pyrimidine 1.3.Said preparation is a colourless liquid, and pH value is 7.0, has uv absorption at 265-275nm, and ninhydrin reaction is positive, and range protein detects negative, 3, and 5-orcin-hydrochloric acid reaction is positive, and the arsenomolybdate method dye-forming reaction is positive.Embodiment 4 preparation active ingredients
Take out antigen from-80 ℃ ultra cold storage freezer, the incubator of putting into 30 ℃ slowly dissolves it.5 milliliters (every milliliter contains 10 to extract the antigen for preparing by embodiment 1 with one 10 milliliters needle tubings
7-10
8Individual virus), inject 500 milliliters PBS (-) solution, shake up, obtain injection antigen.The hair of ripe large ear rabbit (3 kilograms) back of a health is cut off, cut plucked position with 75% cotton ball soaked in alcohol wiping.With above this rabbit of injection antigen intradermal injection that makes, every 1.5 centimetres of injection one pins, every row injects 12 points from left to right, and each marginal not is penetrated 5 rows, and every pin contains 0.2 milliliter of antigen amount, notes water-tight, empty beating not, does not annotate and wears skin.To inject antigenic rabbit raised 4 days.It is good to send out pox, color by ruddy transfer to purplish red, pachyderma, subcutaneous have an edema, the buttocks edema is obvious.Put to death rabbit with the cervical vertebra dislocation method, finish in 15 minutes and adopt skin.Use the plastic bag packaging rabbit, leave in-80 ℃ the refrigerator-freezer standby immediately.Rabbit (22 * 22 centimetres, 220 grams) is cut into 1 square centimeter fritter, to 2% phenol solution that wherein adds 2 times of amounts (weight).In this solution, fed nitrogen 3 minutes, make its bubbling, then sealing.Be placed on 4 ℃ of environment following 72 hours, liquid becomes after the emulsion centrifugal, takes out supernatant, with No. 5 filter paper filterings, obtains brown solution A; In solution A, fed nitrogen 3 minutes, and made its bubbling, the pH value of this solution is transferred to 5.5, in water-bath, boiled 30 minutes, be cooled to 30 ℃ immediately with 1M hydrochloric acid, then centrifugal, use filter paper low pressure filtering supernatant then No. 5, obtain solution B; In solution B, fed nitrogen 3 minutes, and made its bubbling, pH value of filtrate is transferred to 9.7, in water-bath, boiled 30 minutes, be cooled to 30 ℃ immediately, hang down press filtration with No. 5 filter paper and 0.45 μ m filter membrane then, obtain solution C with the 1M sodium hydroxide; In solution C, fed nitrogen 3 minutes, make its bubbling, with 1M hydrochloric acid pH value of filtrate is transferred to 4.8, in solution C, fed nitrogen 3 minutes, make its bubbling, to wherein adding 44 gram active carbons, soaked 4 hours with constantly stirring down in 35 ℃, stop to stir, it was left standstill 30 minutes, take out the supernatant, under nitrogen environment, hang down press filtrations with No. 5 filter paper, soak with injection water (pH8.0) then and clean active carbon, under nitrogen environment,, discard filtrate collection and store active carbon with No. 5 low press filtrations of filter paper, the vessel of carrying active charcoal are added in 440 milliliters of injection waters, feed nitrogen and make its bubbling, with the 1M sodium hydroxide pH is transferred to 11.5, continuous stirring 4 hours.Under nitrogen environment,, clean active carbon with 50 milliliters of injection waters again, obtain solution D with 0.45 μ m membrane filtration; With 1M hydrochloric acid pH is transferred to 6.5, to wherein feeding nitrogen and sealing up for safekeeping in container.Fed nitrogen 5 minutes in container, make its bubbling, sealed container is heated to 121 ℃, keeps 20 minutes, is cooled to then below 45 ℃, obtains solution E; With solution E suction distilling under reduced pressure device, make the air in the distilling under reduced pressure device be replaced with nitrogen, be 5 milliliters at 55 ℃ of following distilling under reduced pressure to volume, with No. 5 filter paper filterings,, obtain 4 milliliters of active ingredients then with 0.2 μ m membrane filtration.This active ingredient contains aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine, and contain urocanic acid, uracil, hypoxanthine, xanthine, thymus pyrimidine, more than the content of various materials be respectively (μ g/ml): aspartic acid 0.5, threonine 0.1, serine 0.8, glutamic acid 0.7, glycine 0.3, alanine 0.9, valine 0.4, isoleucine 0.1, leucine 0.1, tyrosine 0.2, phenylalanine 0.4, lysine 0.2, histidine 0.1, urocanic acid 22.5, uracil 6.5, hypoxanthine 0.7, xanthine 10.2, thymus pyrimidine 2.5.Said preparation is a light yellow liquid, and pH value is 8.0, has uv absorption at 265-275nm, and ninhydrin reaction is positive, and range protein detects negative, 3, and 5-orcin-hydrochloric acid reaction is positive, and the arsenomolybdate method dye-forming reaction is positive.Embodiment 5 preparation injections
Adopt following prescription, the method for preparing injection according to routine prepares injection:
5 milliliters of the active ingredients that is obtained among the embodiment 2
Sodium chloride 2.6 grams
300 milliliters of distilled water for injection.Embodiment 6 preparation injections
Adopt following prescription, the method for preparing injection according to routine prepares injection:
5 milliliters of the active ingredients that is obtained among the embodiment 3
Sodium chloride 2.52 grams
280 milliliters of distilled water for injection.Embodiment 7 preparation injections
Adopt following prescription, the method for preparing injection according to routine prepares injection:
5 milliliters of the active ingredients that is obtained among the embodiment 4
Sodium chloride 2.79 grams
310 milliliters of distilled water for injection.Embodiment 8 preparation tablets
Adopt following prescription, the method for preparing injection according to routine prepares tablet:
50 milliliters of the active ingredients that embodiment 2 is obtained
125 milligrams of lactose
Crystalline cellulose 20 grams
5 milligrams of magnesium stearate.
Claims (10)
1. analgesic, this analgesic contains active ingredient and pharmaceutic adjuvant, wherein said active ingredient contains aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine, and contains urocanic acid, uracil, hypoxanthine, xanthine, thymus pyrimidine; Said preparation is colourless or light yellow liquid, and pH value is 7.0-8.0, has uv absorption at 265-275nm, and ninhydrin reaction is positive, and range protein detects negative, 3, and 5-orcin-hydrochloric acid reaction is positive, and the arsenomolybdate method dye-forming reaction is positive.
2. according to the analgesic of claim 1, the content range of various materials is respectively (μ g/ml) in the wherein said active ingredient: aspartic acid 0.2-0.5, threonine 0.1-0.4, serine 0.3-0.8, glutamic acid 0.7-1.4, glycine 0.3-0.7, alanine 0.4-0.9, valine 0.1-0.4, isoleucine 0.1-0.3, leucine 0.1-0.4, tyrosine 0.2-0.6, phenylalanine 0.1-0.4, lysine 0.05-0.2, histidine 0.1-0.4, urocanic acid 12.0-22.5, uracil 6.5-12.1, hypoxanthine 0.7-1.4, xanthine 5.4-10.2, thymus pyrimidine 1.3-2.5.
3. according to the analgesic of claim 1 or 2, wherein said active ingredient is prepared by following steps: a) inoculate White Rabbit with virus vaccinicum (Vaccinum variolae) lister, collect the skin histology of having smallpox; B) tissue that will collect is cut into small pieces, and 2% phenol solution to adding wherein that 2.5-3.5 doubly measures soaks, and is centrifugal and filter, and obtains solution A; C) solution A is transferred to faintly acid, boil the centrifugal and filtration in back, obtain solution B; D) solution B is transferred to alkalescence, boil after-filtration, obtain solution C; E) solution C is transferred to faintly acid, to wherein adding adsorbent, after the immersion, filter, water eluting adsorbent obtains solution D under alkaline environment; F) solution D is transferred to faintly acid, the heating postcooling obtains solution E; G) decompression concentrated solution E and filtration.
4. according to the analgesic of claim 3, wherein said active ingredient is prepared by following steps: a) with virus vaccinicum lister inoculation White Rabbit, collect the skin histology of having smallpox; B) collected tissue is cut into small pieces, 2% phenol solution to wherein adding 3 times of amounts soaked 72 hours, centrifugal and filter after, obtain solution A; C) pH value with solution A transfers to 5.0, boils centrifugal and filtration after 30 minutes, obtains solution B; D) pH value with solution B transfers to 9.2, boils 30 minutes after-filtration, obtains solution C; E) pH value with solution C transfers to 4.5, to wherein adding active carbon, soaks after 4 hours, filters, and washes the deactivation charcoal under pH11.0 with water, obtains solution D; F) pH value with solution D transfers to 6.0, is heated to 121 ℃, is cooled to below 40 ℃, obtains solution E; G), filter then at 60 ℃ of following decompression concentrated solution E.
5. a production is according to the method for the analgesic of claim 1 or 2 or 3, and this method may further comprise the steps: a) with virus vaccinicum lister inoculation White Rabbit, collect the skin histology of having smallpox; B) tissue that will collect is cut into small pieces, and 2% phenol solution to adding wherein that 2.5-3.5 doubly measures soaks, and is centrifugal and filter, and obtains solution A; C) solution A is transferred to faintly acid, boil the centrifugal and filtration in back, obtain solution B; D) solution B is transferred to alkalescence, boil after-filtration, obtain solution C; E) solution C is transferred to faintly acid, to wherein adding adsorbent, after the immersion, filter, water eluting adsorbent obtains solution D under alkaline environment; F) solution D is transferred to faintly acid, the heating postcooling obtains solution E; G) decompression concentrated solution E and filtration obtain active ingredient; H) with active ingredient and pharmaceutic adjuvant combination.
6. according to the method for claim 5, this method may further comprise the steps: a) with virus vaccinicum lister inoculation White Rabbit, collect the skin histology of having smallpox; B) collected tissue is cut into small pieces, 2% phenol solution to wherein adding 3 times of amounts soaked 72 hours, centrifugal and filter after, obtain solution A; C) pH value with solution A transfers to 5.0, boils centrifugal and filtration after 30 minutes, obtains solution B; D) pH value with solution B transfers to 9.2, boils 30 minutes after-filtration, obtains solution C; E) pH value with solution C transfers to 4.5, to wherein adding active carbon, soaks after 4 hours, filters, and washes the deactivation charcoal under pH11.0 with water, obtains solution D; F) pH value with solution D transfers to 6.0, is heated to 121 ℃, is cooled to below 40 ℃, obtains solution E; G) at 60 ℃ of following decompression concentrated solution E, filter then, obtain active ingredient; H) with active ingredient and pharmaceutic adjuvant combination.
7. active ingredient, it contains aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine, and contains urocanic acid, uracil, hypoxanthine, xanthine, thymus pyrimidine; Said preparation is colourless or light yellow liquid, and pH value is 7.0-8.0, has uv absorption at 265-275nm, and ninhydrin reaction is positive, and range protein detects negative, 3, and 5-orcin-hydrochloric acid reaction is positive, and the arsenomolybdate method dye-forming reaction is positive.
8. according to the active ingredient of claim 7, wherein the content range of said various materials is respectively (μ g/ml): aspartic acid 0.2-0.5, threonine 0.1-0.4, serine 0.3-0.8, glutamic acid 0.7-1.4, glycine 0.3-0.7, alanine 0.4-0.9, valine 0.1-0.4, isoleucine 0.1-0.3, leucine 0.1-0.4, tyrosine 0.2-0.6, phenylalanine 0.1-0.4, lysine 0.05-0.2, histidine 0.1-0.4, urocanic acid 12.0-22.5, uracil 6.5-12.1, hypoxanthine 0.7-1.4, xanthine 5.4-10.2, thymus pyrimidine 1.3-2.5.
9. according to the active ingredient of claim 8, it is prepared by following steps: a) inoculate White Rabbit with virus vaccinicum (Vaccinum variolae) lister, collect the skin histology of having smallpox; B) tissue that will collect is cut into small pieces, and 2% phenol solution to adding wherein that 2.5-3.5 doubly measures soaks, and is centrifugal and filter, and obtains solution A; C) solution A is transferred to faintly acid, boil the centrifugal and filtration in back, obtain solution B; D) solution B is transferred to alkalescence, boil after-filtration, obtain solution C; E) solution C is transferred to faintly acid, to wherein adding adsorbent, after the immersion, filter, water eluting adsorbent obtains solution D under alkaline environment; F) solution D is transferred to faintly acid, the heating postcooling obtains solution E; G) decompression concentrated solution E and filtration.
10. according to the active ingredient of claim 9, it is prepared by following method: a) with virus vaccinicum lister inoculation White Rabbit, collect the skin histology of having smallpox; B) collected tissue is cut into small pieces, 2% phenol solution to wherein adding 3 times of amounts soaked 72 hours, centrifugal and filter after, obtain solution A; C) pH value with solution A transfers to 5.0, boils centrifugal and filtration after 30 minutes, obtains solution B; D) pH value with solution B transfers to 9.2, boils 30 minutes after-filtration, obtains solution C; E) pH value with solution C transfers to 4.5, to wherein adding active carbon, soaks after 4 hours, filters, and washes the deactivation charcoal under pH11.0 with water, obtains solution D; F) pH value with solution D transfers to 6.0, is heated to 121 ℃, is cooled to below 40 ℃, obtains solution E; G), filter then at 60 ℃ of following decompression concentrated solution E.
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| CN98103220A CN1055249C (en) | 1998-07-15 | 1998-07-15 | Analgesia medicine and its mfg. method |
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| CN98103220A CN1055249C (en) | 1998-07-15 | 1998-07-15 | Analgesia medicine and its mfg. method |
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| CN1055249C true CN1055249C (en) | 2000-08-09 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004060381A1 (en) * | 2002-10-31 | 2004-07-22 | Vanworld Pharmaceutical (Rugao) Company Limited | Rabbit skin comprising biological active substance and its use |
| CN101732348B (en) * | 2008-11-11 | 2015-01-14 | 威世药业（如皋）有限公司 | Application of varicella vaccine inflammation induced rabbit fur extractive in preparing medicaments for treating acute cerebrovascular diseases |
| WO2020248240A1 (en) | 2019-06-14 | 2020-12-17 | 俊熙有限公司 | Use of extract from rabbit skin inflamed by vaccinia virus in treatment of cancer |
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| US7148012B2 (en) * | 2002-10-31 | 2006-12-12 | Nippon Zoki Pharmaceutical Co., Ltd. | Therapeutic agent for fibromyalgia |
| JP3818657B2 (en) * | 2004-12-01 | 2006-09-06 | 日本臓器製薬株式会社 | Dried product and production method thereof |
| CN1613305B (en) * | 2004-12-06 | 2011-01-12 | 威世药业（如皋）有限公司 | Active agent containing biological active substances from cony fur |
| JP5937089B2 (en) | 2010-10-14 | 2016-06-22 | 日本臓器製薬株式会社 | Method for promoting collagen and proteoglycan synthesis in chondrocytes |
| CN103357006B (en) | 2012-10-10 | 2014-10-15 | 日本脏器制药株式会社 | Method for examining preparation containing extractive |
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| KR102182240B1 (en) * | 2013-04-30 | 2020-11-24 | 니폰 조키 세야쿠 가부시키가이샤 | Extract, and preparation containing said extract |
| CN105663166B (en) * | 2016-03-02 | 2020-04-17 | 中国人民解放军疾病预防控制所 | Bioactive preparation of specific anti-smallpox virus infection model strain and application thereof |
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| JP2022536582A (en) | 2019-04-17 | 2022-08-18 | ▲諾▼希生物▲薬▼物▲開▼▲発▼有限公司 | Use of an extract from rabbit skin inflamed by vaccinia virus in the treatment of hematopoietic injury |
| WO2020211005A1 (en) * | 2019-04-17 | 2020-10-22 | 骏运投资有限公司 | Use of vaccinia virus-induced inflammatory rabbit skin extract for prevention or treatment of pain |
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| JPS6244178A (en) * | 1985-08-22 | 1987-02-26 | Chiba Pref Gov | Recombinant vaccinia virus |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004060381A1 (en) * | 2002-10-31 | 2004-07-22 | Vanworld Pharmaceutical (Rugao) Company Limited | Rabbit skin comprising biological active substance and its use |
| US8900639B2 (en) | 2002-10-31 | 2014-12-02 | Vanworld Pharmaceutical (Rugao) Company Limited | Process for obtaining a rabbit skin comprising biological active substances |
| CN101732348B (en) * | 2008-11-11 | 2015-01-14 | 威世药业（如皋）有限公司 | Application of varicella vaccine inflammation induced rabbit fur extractive in preparing medicaments for treating acute cerebrovascular diseases |
| WO2020248240A1 (en) | 2019-06-14 | 2020-12-17 | 俊熙有限公司 | Use of extract from rabbit skin inflamed by vaccinia virus in treatment of cancer |
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| CN1205233A (en) | 1999-01-20 |
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