CN1748785A - Water solution preparation of reducing type glutathione, its preparing method and use - Google Patents
Water solution preparation of reducing type glutathione, its preparing method and use Download PDFInfo
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- CN1748785A CN1748785A CN 200510102989 CN200510102989A CN1748785A CN 1748785 A CN1748785 A CN 1748785A CN 200510102989 CN200510102989 CN 200510102989 CN 200510102989 A CN200510102989 A CN 200510102989A CN 1748785 A CN1748785 A CN 1748785A
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Abstract
The aqua preparation consists of reduced glutathione, medicinal supplementary material and water, and each preparation unit may contain reduced glutathione in 0.01-100g and have volume of 0.1-500 ml. The supplementary material may be selected from mannitol, polyglycerin and other carbohydrate, cyclodextrin, amino acids, etc. The preparation process of the reduced glutathione aqua preparation includes compounding liquid, sterilizing, packing, sealing and other steps. It has the features of high stability and easy preparation, has the structure and activity of reduced glutathione well maintained, and may be in injection, spray, drop and other acceptable aqua preparation forms. The reduced glutathione aqua preparation has wide medicinal application foreground in preventing and treating poisoning, radiation sickness, liver disease, allergic disease, eye disease and senility disease.
Description
The present invention relates to medicine and formulation art thereof.The core of invention has been to provide a kind of novel formulation, its preparation method of reduced glutathion and has been used for preventing and treating application in the medicine of poisoning, Radiation sickness, hepatic disease, anaphylactic disease, ophthalmic diseases and old and feeble sexually transmitted disease (STD) disease in preparation.
Glutathion be belong to contain sulfydryl, the small-molecule peptide material, have antioxidation and integrate Detoxication.Glutathion extensively is present in the animal and plant cells, and content is more in liver and erythrocyte.Now, can be by chemosynthesis or fermentative Production.
Glutathion has reduced form (G-SH) and two kinds of forms of oxidized form (G-S-S-G), accounts for the overwhelming majority with reduced glutathion under physiological condition.Change between glutathion reductase catalysis amphitypy.The NADPH that the coenzyme of this enzyme provides for phosphoric acid sugar bypass metabolism.
Glutathion is the prothetic group of Triose phosphate dehydrogenase, is again the coenzyme of aldoketonutase and phosphotriose dehydrogenase, participates in tricarboxylic cycle and carbohydrate metabolism in the body, makes human body obtain high-energy.
Sulfydryl on the glutathion cysteine is its active group (so glutathion often be abbreviated as G-SH), easily and heavy metallic salt complexations such as iodoacetic acid, mustard gas (a kind of poison), lead, hydrargyrum, arsenic, and has had the integration Detoxication.Glutathion (the especially glutathion in the hepatocyte) has very important physiological action and integrates Detoxication exactly, can combine with some drugs (as acetaminophen), toxin (as free radical, heavy metal) etc., participate in biotransformation, thereby deleterious poisonous substance in the body is converted into harmless material, excretes external.
Another major physiological effect of glutathion is as a kind of important antioxidants in the body, and it can dispose the intravital free radical of people, and cleaning and purification human internal environment pollute, thereby has promoted people's physical and mental health.Because reduced glutathion itself is subject to some material oxidation,, thereby allow protein and enzyme equimolecular bring into play its physiological function so it can protect sulfydryl in numerous protein and the enzyme equimolecular not by as harmful substance oxidations such as free radicals in vivo.
The content of glutathion is a lot of in the human erythrocyte; this is in reducing condition to proteinic sulfydryl on the protection erythrocyte membrane; prevent that haemolysis is significant; but also can protect hemoglobin not to be subjected to oxidations such as hydrogen peroxide or free radical, thereby make it continue normally to transport the ability of oxygen in performance.The part hemoglobin is under the effect of oxidants such as hydrogen peroxide in the erythrocyte, and wherein oxidation of divalent is a ferric iron, makes hemoglobin change metahemoglobin into, thereby has lost band oxygen ability.Reduced glutathion can be directly combines with oxidant such as hydrogen peroxide, generates water and oxidized form of glutathione, also metahemoglobin can be reduced to hemoglobin.
At present, manually developed the glutathion medicine, be widely used in clinical, except that utilizing its sulfydryl with the toxin poisonings such as chelating heavy metal, fluoride, mustard gas, also be used in hepatitis, hemolytic disease and keratitis, cataract and retinal diseases etc., as the medicine of auxiliary treatment.Following disease is treated and prevented to the clinical practice glutathion:
(1) detoxifcation: the poisoning to acrylonitrile, fluoride, mustard gas, carbon monoxide, heavy metal, organic solvent, arsenical (as Chinese medicine pyrrole frost, male sulphur etc.), lead, hydrargyrum, sulfur, phosphorism etc. all has Detoxication.
(2) Radiation sickness and radiation protection: be used for radiation cure, radiopharmaceutical or because the myeloid tissue inflammation of using leukopenia that tumour medicine causes and causing owing to lonizing radiation, this product all can be improved its symptom, and has effects such as radioprotective, Exposure to Sunlight.Simultaneously, this product also can be used to treat because of diseases such as the scleroderma that radiotherapy causes, dermatomyositis, lupus erythematosus, and to being subjected to the personnel of ionizing radiation, also injectable this product is as preventive measure.
(3) the liver protecting: comprise the liver injury that viral, drug toxicity, ethanol toxicity and other chemical substance toxicity cause.
(4) antiallergic: can correct the imbalance of acetylcholine, acetylcholine esterase, thereby eliminate because the caused allergic symptom of this imbalance.Can be used for the treatment of autoimmune diseasees such as lupus erythematosus, scleroderma, dermatomyositis, arthritis.
(5) improve the course of disease and the symptom of some disease: to leukopenia, various hypoxemia (as acute anemia, adult respiratory distress syndrome, septicemia etc.), nausea and vomiting, painful abdominal mass symptom and because other symptoms that hepatic disease causes all have the improvement effect such as itch.Simultaneously, to diabetic complication such as retinal diseases, peripheral nerve disease etc., the improvement effect is arranged all.
(6) skin maintenance skin protection: glutathion is a medicine commonly used clinically at present, and the cosmeceutical that can be used as again clinically uses.Because glutathion can the intravital free radical of chelating, extracellular toxin in the heavy metal etc., prevents cutaneous pigmentation, prevents that new melanin from forming and reducing its oxidation, so all have good skin care, an effect of beauty treatment with still outer in it.
(7) increase vision and ophthalmic diseases: promote the metabolism of ocular tissue, can suppress the instability of crystal proteins sulfydryl, thereby can be used for keratitis, cornea wound etc., and can prevent the development of cataract and retinal diseases.Should before entering the geratic period, promptly begin often to take this type of antioxidant to this class disease, often inject this product in other words, can play preventive effect.The effect of good increase vision is also arranged simultaneously.
(8) anti-aging effects: when body aging, free radical of all kinds generates and increases in the body, and free radical is one of endotoxin important in the human body as human body waste.Because glutathion can be removed extracellular toxin in free radical, the heavy metal etc., thereby this product is applicable to slow down aging and has good effect.
In a word, the glutathion side effect is little, even heavy dose of, life-time service also seldom has untoward reaction.Glutathion is rapid-action by drug administration by injection, curative effect is clear and definite, is a kind of integration antidote that is well worth doing.Because the chemical nature of glutathion is a small-molecular peptides, so its external is easy permeate through cell membranes and by skin absorbs, and external is a produce effects very as cosmetics for it, and its skin protection curative effect is splendid.Simultaneously, glutathion is as small-molecular peptides, and its for oral administration need not can absorption by digestion is so the glutathion oral administration is effective.Therefore, prevent or when treating, can realize the number of ways administration, for example injection, oral, eye drip, smear, spray or the like at the utilization glutathion.Pharmacological action that it is clear and definite and potential multiple administering mode make this material prospect in medicine more wide.
Be limited to the restriction of indexs such as stability, have only the injectable powder and the tablet of reduced glutathion in the market, the former needs to dissolve in use, has also increased the chance of medicine pollution when having increased operating procedure; Also to be increased in the time of staying in the digestive tract after the latter is oral, may cause degraded through absorbing after the dissolving.The present invention has formulated the aqueous solution preparation of reduced glutathion just at the single situation of present reduced glutathion dosage form, has solved the stability problem of reduced glutathion in aqueous solution.This aqueous solution preparation of invention can be prepared into dosage forms such as injection, oral liquid, drop, spray, has characteristics easy to use.This is a main purpose of the present invention.
Mentality of designing of the present invention, research contents and technical scheme:
Main contents of the present invention comprise development, study on the stability and three parts of pharmaceutical research of preparation process.Wherein, the stability of reduced glutathion in aqueous solution preparation is the problem that needs emphasis to solve.
According to the requirement of human aqueous solution preparation research, this solution type preparation should be a solution clear and bright, safe, harmless, good stability.Solvent can be that aqueous also can be non-aqueous, and what aqueous solvent was the most frequently used is water for injection.According to the characteristics of active medicine, can select various pharmaceutic adjuvants, as osmotic pressure regulator, solubilizing agent, antioxidant, cosolvent, pH value regulator or the like.Consider the convenience of clinical use, we select for use water as solvent.In conjunction with the characteristics of reduced glutathion, we mainly consider to have used following adjuvant: osmotic pressure regulator, pH value regulator, solubilizing agent, antioxidant and antiseptic.
Optionally osmotic pressure regulator can be but be not limited only to inorganic salts chemical compound such as sodium chloride; Optionally the pH value regulator can be but be not limited only to phosphate buffer, acetate buffer solution, citrate buffer solution etc.; Optionally solubilizing agent or cosolvent can be but be not limited only to 20 kinds of human amino acids such as glycine and salt (as cysteine, leucine, methionine etc.) thereof, various cyclodextrin, glycerol carbohydrate, various cyclodextrin, low molecular dextran, poloxamers or the like such as (perhaps sorbitol, Polyethylene Glycol, propylene glycol); Optionally antioxidant can be but be not limited only to ethylenediaminetetraacetic acid and salt thereof, ascorbic acid, citric acid, cysteine, glutathion, methionine or the like; Available antiseptic can be but be not limited only to cinnamyl alcohol, formic acid or the like.
Show that through a large amount of orthogonal tests above-mentioned adjuvant has good stablizing effect to reduced glutathion.Wherein, preferred pH value regulator is that phosphate buffer, preferred solubilizing agent are cyclodextrin compounds, and preferred osmotic pressure regulator is a sodium chloride, and preferred anti-oxidants is the EDTA disodium.
In prescription aspect reduced glutathion and the supplementary product consumption composition, reduced glutathion can be 0.01-100g in the unit formulation, for example 0.3,0.6,1.2,1.5,1.8,3,10,20,50g/ props up.The volume of unit formulation can be 0.1-500ml, for example 0.1,0.5,1,2,5,10,20,50,100,250,500ml.
A preferred prescribed regimen is: the disodiumedetate (EDTA) of 0.3-10g reduced glutathion, 5-50mmol/L phosphate buffer, 0.5-10mmol/L, the sodium chloride of 0.5-5%.Preferred on this basis scheme is: the disodiumedetate (EDTA) of 0.3-3g reduced glutathion, 10-30mmol/L phosphate buffer, 0.5-2mmol/L, the sodium chloride of 0.5-2%.Most preferred scheme is: the disodiumedetate (EDTA) of 0.6g reduced glutathion, 20mmol/L phosphate buffer, 1mmol/L, 0.7% sodium chloride, being prepared into specification is the preparation that 0.6g: 1ml/ props up.
Another preferred prescribed regimen is: the disodiumedetate (EDTA) of 0.3-10g reduced glutathion, 5-50mmol/L phosphate buffer, 0.5-10mmol/L, the sodium chloride of 0.5-5%, 0.1-10% hydroxypropyl beta cyclodextrin.On this basis, preferred component solutions is: the disodiumedetate (EDTA) of 0.3-3g reduced glutathion, 10-30mmol/L phosphate buffer, 0.5-2mmol/L, the sodium chloride of 0.5-2%, 0.5-5% hydroxypropyl beta cyclodextrin.Most preferred component solutions is: the disodiumedetate (EDTA) of 0.6g reduced glutathion, 20mmol/L phosphate buffer, 1mmol/L, 0.7% sodium chloride, 2% hydroxypropyl beta cyclodextrin, being prepared into specification is the preparation that 0.6g: 1ml/ props up.
Above-mentioned preparation prescription can be prepared by following technology:
(1) under 100 grades of laminar flows, takes by weighing required sodium chloride, 12 water sodium hydrogen phosphates, 2 water sodium dihydrogen phosphate disodiumedetates, in the suitable container of packing into, add the amount of calculation sterilized water for injection dissolving is used immediately by inventory.
(2) the recipe quantity reduced glutathion is added buffer, shake up after the dissolving, ultrafiltration post ultrafiltration depyrogenation, the filter that the reuse high pressure steam sterilization is crossed (the double-deck filter membrane of 0.22 μ m, 0.45 μ m) filtration sterilization is sealed, and prepares packing.
(3) adjust dosage with sterilized water for injection earlier before the packing, after dose titration is qualified, the liquid packing of changing dressings.After jumping a queue entirely, medicine bottle is sent into the bottle track, carry out gland.
(4) start Cover-rolling machine, medicine bottle is with the rotating disk injection, and aluminium lid adds on the medicine bottle through track, and is locked by head.Rolling lid back aluminium lid should be tightly, neat in edge.
So far, the design and the research of preparation process thereof has been finished in our invention, begins to investigate stability of formulation.Experiment with sample from the prepared product of embodiment 1.
According to corresponding research requirement, we have mainly investigated the clarity of appearance character, pH value, solution and color, related substance, content, clarity test, bacterial endotoxin and aseptic stability study.Influence factor's test, accelerated test and long term test have mainly been carried out.
It is high temperature and strong illumination that the influence factor tests main investigation factor.
Strong illumination experiment: test sample is placed in the clarity detector, is to place 10 days under the condition of 4000lx ± 500lx in intensity of illumination, in sampling in the 5th and the 10th day, detects by stable high spot reviews project, and compares with 0 day.Result such as table 1.The result shows that this product pH value after illumination obviously descends, and related substance increases, and content obviously descends, and all other indexs do not have significant change, so this product answers shading to preserve.
Table 1 exposure experiments to light study on the stability result
| Lot number | Time (my god) | The investigation project | |||||
| Appearance character | The pH value | Clarity | Clarity and color | Related substance (%) | Content (%) | ||
| 01 | 0 | Achromatism and clarity | 6.84 | Up to specification | Clarify colourless | 0.26 | 99.41 |
| 5 | Achromatism and clarity | 5.48 | Up to specification | Clarify colourless | 0.91 | 85.29 | |
| 10 | Achromatism and clarity | 5.20 | Up to specification | Clarify colourless | 1.78 | 79.11 | |
High temperature experiment: test sample is placed glass dish, placed 10 days down at 60 ℃ respectively, during this period,, detect by stable high spot reviews project respectively at sampling in the 5th and the 10th day, and with 0 day relatively.Testing result sees Table 2.
Table 2 hot test study on the stability result (60 ℃)
| Lot number | Time (my god) | The investigation project | |||||
| Appearance character | The pH value | Clarity | The clarity of solution and color | Related substance (%) | Content (%) | ||
| 01 | 0 | Achromatism and clarity | 6.94 | Up to specification | Clarify colourless | 0.25 | 99.20 |
| 5 | Achromatism and clarity | 6.25 | Up to specification | Clarify colourless | 3.01 | 81.56 | |
| 10 | Achromatism and clarity | 6.01 | Up to specification | Clarify colourless | 5.62 | 74.09 | |
60 ℃ of experimental results of high temperature show: this product is behind 60 ℃ of high temperature 10 days, and pH value obviously descends, and related substance obviously increases, and content obviously descends, and all other indexs do not have significant change.Carry out 40 ℃ of tests of high temperature according to above some variation event.See Table 3.
Table 3 hot test study on the stability result (40 ℃)
| Lot number | Time (my god) | The investigation project | |||||
| Appearance character | The pH value | Clarity | The clarity of solution and color | Related substance (%) | Content (%) | ||
| 01 | 0 | Achromatism and clarity | 6.89 | Up to specification | Clarify colourless | 0.22 | 99.41 |
| 5 | Achromatism and clarity | 6.57 | Up to specification | Clarify colourless | 0.74 | 93.45 | |
| 10 | Achromatism and clarity | 6.43 | Up to specification | Clarify colourless | 1.35 | 91.76 | |
40 ℃ of experimental results of high temperature show: this product is behind 40 ℃ of high temperature 10 days, and pH value descends, and related substance increases, and content descends, according to above some change so carry out 25 ℃ of tests.Met and saw Table 4.
25 ℃ of tests of table 4 study on the stability result
| Lot number | Time (my god) | The investigation project | |||||
| Appearance character | The pH value | Clarity | The clarity of solution and color | Related substance (%) | Content (%) | ||
| 01 | 0 | Achromatism and clarity | 6.87 | Up to specification | Clarify colourless | 0.23 | 99.52 |
| 5 | Achromatism and clarity | 6.80 | Up to specification | Clarify colourless | 0.68 | 98.63 | |
| 10 | Achromatism and clarity | 6.71 | Up to specification | Clarify colourless | 1.55 | 97.93 | |
Show in result under 25 ℃ of experiment conditions: this product is after 25 ℃ of conditions are placed 10 days, and pH value descends, and related substance slightly increases, and content has decline slightly; Belong to the preparation responsive especially to temperature so can determine this product, accelerated tests can be carried out under the condition of RH 60 ± 10% 25 ℃ ± 2 ℃ of temperature; Long-term experiment can carry out under 2 ℃ of-10 ℃ of conditions of temperature.
Accelerated test: this product packing is placed 25 ℃ ± 2 ℃ of temperature, in the environment of RH 60 ± 10%, placed 6 months, respectively at 1st month, 2 months, 3 months, 6 samplings at the end of month detected by stable high spot reviews project.Result of the test sees Table 5.
Table 5 accelerated test is investigated result's (25 ℃ ± 2 ℃, RH60 ± 10%)
| Lot number | Month | The investigation project | ||||||
| Appearance character | PH value | Clarity | Related substance (%) | Endotoxin | Aseptic | Content (%) | ||
| 02 | 0 | Achromatism and clarity | 6.89 | Up to specification | 0.24 | Up to specification | Up to specification | 100.00 |
| 1 | Achromatism and clarity | 6.24 | Up to specification | 4.77 | - | - | 94.43 | |
| 2 | The solution muddiness | 5.60 | The solution muddiness | 8.19 | - | - | 86.09 | |
| 3 | The solution muddiness | 5.09 | The solution muddiness | 13.65 | - | - | 80.32 | |
| 6 | The solution muddiness | 4.85 | The solution muddiness | 21.32 | - | - | 75.89 | |
Accelerated test result shows that the reduced glutathion aqueous solution was placed 6 months with this understanding, and pH value descends, and related substance increases, and content descends and illustrates that this product belongs to the preparation responsive especially to temperature, need put cold place and preserve.
Long term test: this product packing is placed under 2 ℃ of-10 ℃ of conditions of temperature, placed 6 months, sampling in per 3 months once detected by stable high spot reviews project respectively at 0 month, 3 months, 6 months.After 9 months, continued to investigate respectively at 12 months, 18 months, 24 months, 36 months.Result of the test sees Table 6.
Table 6 long term test is investigated result's (2 ℃-10 ℃)
| Lot number | Month | The investigation project | |||||||
| Appearance character | Clarity and color | PH value | Purity (%) | Related substance (%) | Endotoxin | Aseptic | Content (%) | ||
| 02 | 0 | Achromatism and clarity | Clarify colourless | 6.78 | 97.33 | 0.21 | Up to specification | Up to specification | 99.85 |
| 3 | Achromatism and clarity | Clarify colourless | 6.76 | 97.18 | 0.28 | Up to specification | Up to specification | 99.74 | |
| 6 | Achromatism and clarity | Clarify colourless | 6.74 | 97.05 | 0.30 | Up to specification | Up to specification | 99.70 | |
| 03 | 0 | Achromatism and clarity | Clarify colourless | 6.82 | 97.65 | 0.23 | Up to specification | Up to specification | 99.57 |
| 3 | Achromatism and clarity | Clarify colourless | 6.77 | 97.12 | 0.31 | Up to specification | Up to specification | 99.46 | |
| 6 | Achromatism and clarity | Clarify colourless | 6.75 | 96.98 | 0.35 | Up to specification | Up to specification | 99.21 | |
The result shows that the reduced glutathion aqueous solution was placed 6 months under the long term test condition, every index does not all have obvious change, illustrates that this product has good stability.
The stability test conclusion: show by influence factor's result of the test, the reduced glutathion aqueous solution in illumination, transfer postpone in 40 ℃, 25 ℃ conditions of high temperature (60 ℃) and find that pH value descends, content descends, related substance increases; Placed 6 months in accelerated test condition (25 ℃ ± 2 ℃, RH60 ± 10%), pH value descends, and content descends, and related substance increases, and places 6 months in long term test condition (2 ℃-10 ℃), and every index does not all have obvious change.Determine that this product should be in shading, Leng Chu (2-10 ℃) preservation.02 batch sample long term test purity test the results are shown in accompanying drawing 1,2,3, is respectively this batch sample 0,3,6 month result.
Another part content of the present invention is to investigate the pharmacology of described aqueous solution ejection preparation.The main purpose of pharmaceutical research is the biological activity of more this dosage form and existing reduced glutathion injectable powder type.Reduced glutathion has physiological function widely, and this is not the problem that the present invention will illustrate.What we need solve only is the activity whether novel formulation provided by the invention has reduced glutathion, infers said preparation when the indication of treatment reduced glutathion and the equivalence of existing preparation with this, and determines the said preparation practicality with this.We have adopted following test for this reason:
Reduced glutathion is active influence test to antioxidase:
1 material male Wistar rat (Military Medical Science Institute's animal center), GST, SOD, MDA test kit (bio-engineering research institute is built up in Nanjing) etc.No. 01 sample, the reduced glutathion lyophilized powder (trade name: Gu Lading) of embodiment of the invention preparation.
2 methods
Modelling: 58 Wistar ♂ rats, body constitution amount 240-320g is divided into 3 groups at random.Matched group (10): give 500g/L Glucose Liquid 20mL/kg
-1/ d
-1With Semen Maydis oil 2g/kg
-1/ d
-1Damage group (15): administration by gavage gives Semen Maydis oil 2g/kg
-1/ d
-1, add 400g/L ethanol 4g/kg
-1/ d
-1Be total to 3d, 8g/kg
-1/ d
-1Be total to 10d, 10g/kg
-1/ d
-1Be total to 10d.No. 01 medication therapy groups (15): and the damage group between equivalent Semen Maydis oil+ethanol irritate on the basis of stomach, irritate stomach and give medicine 0.1g/kg No. 01
-1/ d
-1Paddy is drawn and decides treatment group (15): and the damage group between equivalent Semen Maydis oil+ethanol irritate on the basis of stomach, irritate stomach and give paddy and draw and decide 0.1g/kg
-1/ d
-1After the 23d modeling finished, all rat was respectively organized in execution.Remain 8 of matched groups altogether, 8 of damage groups, 10 of No. 01 medication therapy groups, paddy is drawn and decides 9 of treatment groups.Get serum, blood plasma (100g/L EDTA anticoagulant) carries out related detection.Measure serum AST, ALT, measure blood plasma MDA level, GST and SOD activity respectively.
Experimental data mean ± standard deviation (mean ± SD) expression.Relevant initial data is handled with the SPSS statistical software, carries out variance analysis, with P＜0.05 for significant difference is arranged.
Table 7.AST, ALT, GST, SOD and MDA measurement result (mean ± standard deviation)
| Group | Matched group (n=9) | Damage group (n=7) | No. 01 sample | Gu Lading (n=10) |
| AST(IU/L) | 138.68±22.147 | 195.49±26.21 a | 140.09±15.98 d | 142.12±17.36 d |
| ALT(IU/L) | 46.56±8.25 | 60.37±5.81 a | 49.30±5.45 | 51.90±7.65 |
| Blood plasma GST (U/mL) | 12.36±3.05 | 18.67±2.65 b | 16.53±2.12 b | 16.32±2.10 b |
| Plasma SOD (NU/mL) | 59.69±6.26 | 42.65±6.64 a | 56.30±4.93 d | 56.48±5.03 d |
| Blood plasma MDA (nmoL/mL) | 6.42±0.60 | 6.19±0.52 | 5.85±1.24 | 5.79±1.36 |
aP＜0.05,
bP＜0.01vs matched group;
dP＜0.01vs damage group.
The result shows, reduced glutathion aqueous solution provided by the invention and traditional injectable powder have that antioxidase is the function of content in the same control agent.
In sum, the invention provides the novel form of a reduced glutathion, this dosage form manufacturing technique is more easy to use than existing injectable powder and solid preparation, is easy to amplify on producing, and is with the obvious advantage, is convenient to the realization of industrialization; Simultaneously, aspect biological activity and preparation stability, this aqueous solution dosage form good stability can long term storage, and it is active identical with existing injectable powder.Therefore the present invention has embodied the patent key element of novelty, creativeness and practicality well.
For the implementation process of this patent is described better, we are listed below embodiment.Need to prove that cited embodiment is one of imbody of thinking of the present invention and spirit, is not the scope restriction to the patent of invention description, more is not the refinement to claim.Under thinking of the present invention instructed, the aqueous products (injection, spray, drop, oral liquid etc.) of the reduced glutathion that any this patent is described all should be included in the scope of this patent.
The preparation of embodiment 1, the described pharmaceutical preparation of claim 7
Sodium chloride 7.0g, sodium hydrogen phosphate (containing 12 water of crystallization) 4.37g, sodium dihydrogen phosphate (containing 2 water of crystallization) 1.22g, disodiumedetate 0.64g, reduced glutathion 600g decided in accurate title, be dissolved in water for injection, fixed molten at last to 1000ml, be distributed into 1000 with the 2ml cillin bottle.Final specification is that 0.6g/ props up.According to this 3 batches of production sample of writing out a prescription altogether, numbering is respectively 01,02,03.Operation sequence is described execution to specifications.
The preparation of embodiment 2, the described pharmaceutical preparation of claim 10
Sodium chloride 7.0g, sodium hydrogen phosphate (containing 12 water of crystallization) 4.37g, sodium dihydrogen phosphate (containing 2 water of crystallization) 1.22g, disodiumedetate 0.64g, reduced glutathion 600g, hydroxypropyl beta cyclodextrin 20g decided in accurate title, be dissolved in water for injection, fixed molten at last to 1000ml, be distributed into 1000 with the 2ml cillin bottle.Final specification is that 0.6g/ props up.According to this 1 batch of production sample of writing out a prescription altogether, numbering 04.Operation sequence is described execution to specifications.
Claims (14)
1, a kind of aqueous solution preparation of reduced glutathion.
2, the described preparation of claim 1 is characterized in that being made up of reduced glutathion, suitable pharmaceutic adjuvant and water.
3, the described preparation of claim 2, the content that it is characterized in that reduced glutathion can be that 0.01-100g/ props up, for example 0.3,0.6,1.2,1.5,1.8,3,10,20,50g/ props up.
4, the described preparation of claim 3, its pharmaceutic adjuvant can be selected for use but be not limited only to one or several combination in buffering such as 20 kinds of human amino acids such as glycerol saccharide compound, various cyclodextrin, glycine etc. such as (perhaps mannitol, sorbitol, Polyethylene Glycol), low molecular dextran, poloxamer, phosphate (perhaps acetate, citrate) salt, ethylenediaminetetraacetic acid and salt thereof or the like.
5, the described preparation of claim 4, one of them preferred ingredients scheme is: the disodiumedetate (EDTA) of 0.3-10g reduced glutathion, 5-50mmol/L phosphate buffer, 0.5-10mmol/L, the sodium chloride of 0.5-5%.
6, the described preparation of claim 5, its preferred component solutions is: the disodiumedetate (EDTA) of 0.3-3g reduced glutathion, 10-30mmol/L phosphate buffer, 0.5-2mmol/L, the sodium chloride of 0.5-2%.
7, the described preparation of claim 5, its most preferred scheme is: the disodiumedetate (EDTA) of 0.6g reduced glutathion, 20mmol/L phosphate buffer, 1mmol/L, 0.7% sodium chloride, being prepared into specification is the preparation that 0.6g:1ml/ props up.
8, the described preparation of claim 4, its another preferred ingredients scheme is: the disodiumedetate (EDTA) of 0.3-10g reduced glutathion, 5-50mmol/L phosphate buffer, 0.5-10mmol/L, the sodium chloride of 0.5-5%, 0.1-10% hydroxypropyl beta cyclodextrin.
9, the described preparation of claim 8, its preferred component solutions is: the disodiumedetate (EDTA) of 0.3-3g reduced glutathion, 10-30mmol/L phosphate buffer, 0.5-2mmol/L, the sodium chloride of 0.5-2%, 0.5-5% hydroxypropyl beta cyclodextrin.
10, the described preparation of claim 8, its most preferred prescribed regimen is: the disodiumedetate (EDTA) of 0.6g reduced glutathion, 20mmol/L phosphate buffer, 1mmol/L, 0.7% sodium chloride, 2% hydroxypropyl beta cyclodextrin, being prepared into specification is the preparation that 0.6g:1ml/ props up.
11, claim 1,2,3,4,5,6,8,9 described preparations, its unit formulation volume can be 0.1-500ml.
12, claim 1,2,3,4,5,6,7,8,9,10,11 described preparations can make by steps such as dosing, degerming, packing, glands.
13, claim 1,2,3,4,5,6,7,8,9,10,11,12 described preparations can be processed into injection, spray, drop, oral liquid and other acceptable aqueous solution dosage form.
14, claim 1,2,3,4,5,6,7,8,9,10,11,12,13 described preparations are used for preventing and treating the application of the medicine of poisoning, Radiation sickness, hepatic disease, anaphylactic disease, ophthalmic diseases and old and feeble sexually transmitted disease (STD) disease in preparation.
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| CN 200510102989 CN1748785A (en) | 2005-09-16 | 2005-09-16 | Water solution preparation of reducing type glutathione, its preparing method and use |
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| CN 200510102989 CN1748785A (en) | 2005-09-16 | 2005-09-16 | Water solution preparation of reducing type glutathione, its preparing method and use |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102100904A (en) * | 2011-01-25 | 2011-06-22 | 成都卓阳生物科技有限公司 | Reduced glutathione percutaneous absorption preparation and preparation method thereof |
| CN102329370A (en) * | 2011-09-22 | 2012-01-25 | 山东金城医药化工股份有限公司 | Method for preparing reduced glutathione monosodium salts |
| CN101745095B (en) * | 2010-01-28 | 2012-10-10 | 广州白云山天心制药股份有限公司 | Composition of reduced glutathione and sodium carbonate or sodium bicarbonate |
| CN104955468A (en) * | 2013-01-21 | 2015-09-30 | 协和发酵生化株式会社 | Nitric oxide concentration elevating agent |
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2005
- 2005-09-16 CN CN 200510102989 patent/CN1748785A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101745095B (en) * | 2010-01-28 | 2012-10-10 | 广州白云山天心制药股份有限公司 | Composition of reduced glutathione and sodium carbonate or sodium bicarbonate |
| CN102100904A (en) * | 2011-01-25 | 2011-06-22 | 成都卓阳生物科技有限公司 | Reduced glutathione percutaneous absorption preparation and preparation method thereof |
| CN102100904B (en) * | 2011-01-25 | 2013-04-24 | 成都卓阳生物科技有限公司 | Reduced glutathione percutaneous absorption preparation and preparation method thereof |
| CN102329370A (en) * | 2011-09-22 | 2012-01-25 | 山东金城医药化工股份有限公司 | Method for preparing reduced glutathione monosodium salts |
| CN104955468A (en) * | 2013-01-21 | 2015-09-30 | 协和发酵生化株式会社 | Nitric oxide concentration elevating agent |
| US11654125B2 (en) | 2013-01-21 | 2023-05-23 | Kyowa Hakko Bio Co., Ltd. | Agent for elevating nitric oxide concentration |
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