CN102743350B - Methionine vitamin B1Injection composition and its preparing method - Google Patents
Methionine vitamin B1Injection composition and its preparing method Download PDFInfo
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- CN102743350B CN102743350B CN201210265065.XA CN201210265065A CN102743350B CN 102743350 B CN102743350 B CN 102743350B CN 201210265065 A CN201210265065 A CN 201210265065A CN 102743350 B CN102743350 B CN 102743350B
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Abstract
The invention provides methionine vitamin B1The composition injection contains methionine 5-20 weight portions and vitamin B11 part by weight; it may also contain antioxidant Vc or cysteine; the invention also provides the process for preparing the above injection, heating water for injection to 40-70 deg.C, adding methionine to dissolve, cooling the solution to 30 deg.C, and adding vitamin B1Stirring for dissolving, adjusting pH, adding active carbon, filtering, bottling the filtrate, and lyophilizing; methionine and vitamin B of the present invention1The quality of the injection product of the composition is superior to that of the similar products, the impurity content is low, and the product stability is good.
Description
Technical field
The present invention relates to a kind of methionyl vitamin B
1Composite injection, and the preparation method of this injection belong to field of pharmaceutical preparations.
Background technology
Methionyl is one of needed by human eight seed amino acids, can not synthesize in human body, must rely on external source to replenish.Methionine is combined into S-adenosine propylhomoserin with ATP in human body, can promote the liver plasma membrane phospholipid methylation, reduces intrahepatic cholestasis, turns the sulfenyl effect and strengthens; Be conducive to hepatocyte and recover normal physiological function, promote that jaundice disappears and liver function recovery; Supply with methyl, promote the synthetic of choline, the fat of the latter and liver is combined into lecithin, and effect for reducing fat is arranged, the liver lipid metabolism of promotion is arranged and protect the liver, the effect such as detoxifcation, the running of promotion body fat metabolism, the effect that prevents the sedimentation of fat.
Vitamin B
1Be combined into cocarboxylase with pyrophosphoric acid in vivo, the oxidative deamination of acetone acid and α-ketoglutaric acid reaction in the involved in sugar metabolism is that carbohydate metabolism institute is essential.During shortage, the oxidation formation acetone acid that is obstructed, the human body energy supply is piled up and affected to lactic acid.Its feature is mainly manifested in the nucleus cardiovascular system, the multiple peripheral neuritis of sensory nerve and nervus motorius all effected occurs, shows as the symptoms such as paraesthesia, neuralgia, myasthenia of limbs and muscular soreness and atrophy.The cardiovascular aspect increases due to acetone acid and lactic acid, makes the small artery expansion, and diastolic pressure descends, and the myocardial metabolism imbalance is therefore be prone to cardiopalmus, tachypnea, uncomfortable in chest, cardiac hypertrophy, liver is congested and the symptom of the lower cardiac dysfunction such as swollen on every side.The digestive tract aspect shows as appetite and descends and to cause weak and weight loss etc.
The methionine plain B that supports one's family
1The purposes of compositions is:
One, hepatopathy: as various acute, chronic hepatitis, liver cirrhosis, fatty liver and intrahepatic cholestasis; Two, the application of cardiovascular disease; Three, the preoperative and postoperative of surgical patient is used; Four, the application during the tumour patient Radiotherapy chemotherapy; Five, take in malabsorption and Chronic consumptions patient; Six, the treatment of ethanol, barbiturate, heavy metal poisoning.
But present existing methionine and vitamin B
1The injection of compositions exists some defectives: as stable not, thereby easily occuring, degraded makes drug effect reduction etc. in storage, transportation, and especially not soluble for methionine, and vitamin B
1The unfavorable characteristics of easy oxidation, prior art is at methionine and vitamin B
1Add cosolvent, antioxidant for example sulphite or sodium pyrosulfite in composite injection, and the needed proppant of freeze-dried powder for example mannitol, sorbitol, glucose or dextran, these disclosed methionine and vitamin Bs
1Composite freeze-dried powder agent or stability are bad, the pharmaceutic adjuvant large usage quantity, although added a certain amount of sodium sulfite or sodium pyrosulfite can prevent product generation oxidation reaction, but introduced sulfurous acid, thereby brought some side effect such as related substance increases, the interior Quality Down of shelf life of products, potential safety hazard.
Summary of the invention
the objective of the invention is for the deficiencies in the prior art, a kind of methionine-vitamin B 1 composite injection and preparation method thereof is provided, when bringing useful assosting effect due to adjuvant, the side effect that is difficult to expect that also inevitably brings, therefore, the inventor follow can prepare stable and controllable for quality, on the basis of the product that meets clinical needs, the kind of adjuvant, the more few better principle of consumption, the data result that obtains through great many of experiments shows, the most multiplex a kind of adjuvant of compositions of the present invention, can reach satisfied preparation especially effect and the expection purpose of lyophilized injectable powder.
In addition, can greatly improve the methionine plain B that supports one's family by preparation method of the present invention
1The stability of composite injection, preparation are no matter to be in preparation, packing or freeze-drying process, related substance all without obviously increase, content is also without obviously decline, the methionine of the preparation plain B that supports one's family
1Composite injection has good stability in transportation and storage process, during clinical use, compatibility solution can be placed the long period, make clinical use become convenient, also greatly having reduced simultaneously increases because of impurity (related substance) the curative effect problem that the hidden danger brought to patient's drug safety and content descend and brings to the patient.
The invention provides a kind of methionine plain B that supports one's family
1Composite injection, its side effect is little, has good stability.
The invention provides a kind of methionine plain B that supports one's family
1Composite injection, said composition contain methionine 5-20 weight portion, vitamin B
11 weight portion.
The above-mentioned methionine plain B that supports one's family
1Composite injection, it is mainly freeze-dried powder or liquid drugs injection, and in the present invention, preferably this injection is freeze-dried powder.
The above-mentioned methionine of the present invention and vitamin B
1Composite injection is on stable and controllable for quality, the basis that meets clinical needs, be down to kind, the consumption of adjuvant minimum as far as possible, having realized not adding adjuvant in composite injection can obtain indices and reach the especially product of freeze-dried powder standard-required of injection fully, the data result that obtains through great many of experiments shows, methionine of the present invention and vitamin B
1The composite injection product quality is better than like product, and impurity (related substance) content is low, and product stability is good, reaches the promising result and the expection purpose that meet the injection requirement.
Methionine of the present invention and vitamin B
1Composite injection preferably contains methionine 10 weight portions, vitamin B for being preferably lyophilized injectable powder in said composition
11 weight portion.
Methionine of the present invention and vitamin B
1Composite injection also contains antioxidant 0.01-0.05 weight portion, and this antioxidant is Vc or cysteine.
Above-mentioned composition of the present invention is preferably by methionine 5-20 weight portion, vitamin B
11 weight portion and antioxidant 0.01-0.05 weight portion form; This antioxidant is Vc or cysteine.With vitamin B
1Be that 1 weight portion is the benchmark meter, cysteine is the 0.01-0.05 weight portion.More preferably with methionine 10 weight portions, vitamin B
11 weight portion meter, cysteine are the 0.01-0.05 weight portion.
The side effect that is difficult to expect that too much inevitably brings due to adjuvant, therefore, the methionine that the present invention obtains and vitamin B
1Composite injection is down to kind, the consumption of adjuvant minimumly on stable and controllable for quality, the basis that meets clinical needs as far as possible, considers that to utilize technique to overcome methionine fully not soluble, and vitamin B
1Although the unfavorable factors such as easy oxidation are feasible, experimental results show that repeatability and exploitativeness are all good, for further the protection product is not oxidized, the present invention adopts a kind of adjuvant, and namely antioxidant Vc or cysteine, strengthened the protection of anti-oxidation.The data result that obtains through great many of experiments shows, methionine of the present invention and vitamin B
1The composite injection quality is better than like product, and impurity (related substance) content is low, and product stability is good, reaches the promising result and the expection purpose that meet the injection requirement.
In the selection of antioxidant, the present invention has passed through a large amount of examination experiments, finally be defined as Vc or cysteine, this selection to the benefit that product brings is: well-known, Vc or cysteine all have stronger anti-oxidation characteristics, experimental results show that, in composite injection of the present invention, on the one hand, the Vc of minute quantity or cysteine can reach the antioxidative effect, on the other hand, the main component of present composition injection is methionine and vitamin B
1It belongs to aminoacid and vitamins, Vc belongs to vitamin, cysteine belongs to aminoacid, cysteine is similar to methionine, although it is not soluble in water, but only need to adopt the water for injection that is heated to uniform temperature to dissolve in preparation technology, can solve well this difficult problem, and the material that generates after the cysteine oxidation is cystine, it also belongs to aminoacid, do not introduce other impurity in the processes such as preparation, lyophilizing, placement, more avoided generation intermediate product impurity, therefore, methionine of the present invention and vitamin B
1Composite injection quality, stability all significantly are better than like product and prior art products.
The present invention also provides above-mentioned methionine and vitamin B
1The preparation method of composite injection, it is:
(1) first with the water for injection dissolving methionine of 40 ℃-70 ℃, obtain methionine solution, the amount of this water for injection is below 80% of solution total amount;
(2) methionine solution that (1) is obtained is down to room temperature (below 30 ℃), vitaminize B in solution
1Mixed dissolution obtains the methionine plain B that supports one's family
1Solution;
(3) methionine that (2) the is obtained plain B that supports one's family
1Solution is adjusted to pH4.0～4.5, and the supplementary injection water adds needle-use activated carbon to solution total amount (for example, approximately 1000mL), filters, and this activated carbon dosage is the 0.1-0.2%(g/ml of solution total amount);
(4) the solution embedding after the filtration that (3) is obtained or bottling postlyophilization obtain described methionyl vitamin B
1Composite injection.
The effect of needle-use activated carbon is to adsorb thermal source in supplementary material, impurity etc., and consumption is very few, and in final products, impurity content is too high, and the clarity of final products is defective.Through screening, finally selecting concentration is 0.05% active carbon.The screening experiment of active carbon is normal experiment, owes to give herein, can replenish at any time evidence when needing.
Needle-use activated carbon stirred 15 minutes after filtering, and filtered decarburization, and with 0.22 μ m degerming microporous filter membrane fine straining, thoroughly to remove the pyrogen in the powder pin, then sterilizing room is advanced in filter with medicinal liquid, and half plug is pressed in fill, puts into the lyophilizing cabinet, lyophilization.Lyophilization is the key of freeze-dried powder success or failure, has directly affected the various performances of product; The present invention has done significant improvement to Freeze Drying Technique just, just makes the so simple methionine of adjuvant and vitamin B
1The composite freeze-dried powder agent is able to successfully.
Because this product adjuvant used is simple, adjuvant does not have the effect of freeze-dried powder proppant, therefore, if expect all qualified freeze-drying prods of indices, must carry out all groping to processing step and improve, and just can reach satisfied effect.To this, the inventor has paid a large amount of effort, finally obtains following selection process.
Product of the present invention is preferably methionine and vitamin B
1Composite freeze-dried powder, its preparation method is:
(1) first with the water for injection dissolving methionine of 40 ℃-70 ℃, obtain methionine solution, the amount of this water for injection is below 80% of solution total amount;
(2) methionine solution that (1) is obtained is down to room temperature (below 30 ℃), vitaminize B in solution
1Mixed dissolution obtains the methionine plain B that supports one's family
1Solution;
(3) methionine that (2) the is obtained plain B that supports one's family
1Solution is adjusted to pH4.0～4.5, and the supplementary injection water adds needle-use activated carbon to solution total amount (for example, approximately 1000mL), filters, and this activated carbon dosage is the 0.1-0.2%(g/ml of solution total amount);
(4) the solution bottling after the filtration that (3) is obtained enters following cryodesiccated step;
(1) pre-freeze is placed on the solution bottling in freezing cabinet and is cooled to-3 ℃ ~-5 ℃, is incubated 1-2 hour, then is cooled to-40 ℃, is incubated freezing 2-3 hour;
(2) distillation, then be cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-8 ℃ ~-5 ℃ at 10 ~ 12 hours, keep-8 ℃ ~-5 ℃ 6 hours;
(3) drying is warming up to 0 ℃, is incubated 1 hour, with 6-7 hour cascade raising temperature to 40 ℃ ~ 45 ℃, is incubated 3-5 hour, lyophilization;
(4) vacuum tamponade, after lyophilization is complete, the nitrogen of wadding warp aseptic filtration in freeze drying box again, in the process of filling nitrogen, at least twice is evacuated to 8-10Pa, keep vacuum and nitrogen environment in freeze drying box, then automatically tamponade under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
One of innovative point of the present invention is, utilizes technique to overcome defective and the unfavorable factor of material itself, that is, utilize the process of improvement to solve the not soluble and vitamin B of methionine
1The difficult problem of easy oxidation, having met or exceeded prior art adopts and adds for example solubilising, the antioxidative effect that realize of cosolvent, antioxidant of multiple auxiliary materials, avoided to greatest extent that prior art adds that the related substance that adjuvant too much brings increases, Quality Down in shelf life of products, had the drawback such as potential safety hazard, guaranteed drug quality and drug safety.
The innovative point that the present invention is above-mentioned and beneficial effect are realized by two steps:
First substep dissolved substance component is to reach the instant purpose of Their Insoluble Components.First dissolve the methionine of indissoluble under room temperature with the water for injection of heating, the water for injection of general 40 ℃-70 ℃ gets final product, this considers the impact that the relation of temperature and rate of dissolution and temperature raise technique and product are brought, the water for injection dissolving methionine of the preferred 40-50 of the present invention ℃, fully after the dissolving, solution is down to room temperature, adds vitamin B
1Mixed dissolution.
The room temperature of mentioning in the present invention is generally below 30 ℃, also comprises 30 ℃, for example can be 15 ~ 30 ℃.
It two is vacuum tamponades, at starvation fully with guarantee simultaneously tamponade automatically under the environment of vacuum, and too can the antioxidative effect without the antioxidant existence even realized.After lyophilization, the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 8-10Pa, keeps vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition.
The methionine that the present invention obtains and vitamin B
1Composite injection can add any adjuvant, utilizes technique to overcome methionine fully not soluble, and vitamin B
1The unfavorable factors such as easy oxidation, the product appearance that obtains is loose block, clarity and solubility have also reached best requirement, and utilize the control technological operation to reach the antioxidative effect.Outstanding feature is, the product architecture that the lyophilizing of this technique goes out is loose, experimental results show that it is better than the like product solubility with proppant, and repeatability and exploitativeness are all good.
But for further the protection product is not oxidized; consider simultaneously not introduce the intermediate product that generates in impurity that conventional antioxidant brings and antioxidation process and also do not bring impurity; guarantee the stability of product quality; in a preferred embodiment; the present invention has added a kind of antioxidant Vc or cysteine, strengthens the antioxidative effect.
That is, with the water for injection dissolving methionine of 40 ℃ ~ 70 ℃, add again the cysteine of antioxidant 0.01 ~ 0.05 weight portion simultaneously in the described step of above-mentioned preparation method (1); Perhaps, in described step (2), vitaminize B
1The Vc that adds antioxidant 0.01 ~ 0.05 weight portion when mixing, mixed dissolution.
The present invention also provides a kind of methionine and vitamin B
1The preparation method of composite injection, it is:
(1) first with the water for injection dissolving methionine of 40 ℃-70 ℃, add the cysteine of 0.01 ~ 0.05 weight portion simultaneously again, obtain solution a, the amount of this water for injection is below 80% of solution total amount;
(2) the solution a that (1) is obtained is down to room temperature (namely below 30 ℃), vitaminize B in solution
1Mixed dissolution obtains the methionine plain B that supports one's family
1Solution;
(3) methionine that (2) the is obtained plain B that supports one's family
1Solution is adjusted to pH4.0～4.5, and the supplementary injection water adds needle-use activated carbon to solution total amount (for example 1000mL), filters, and this needle-use activated carbon consumption is the 0.1-0.2%(g/ml of solution total amount);
(4) the solution bottling postlyophilization after the filtration that (3) is obtained; Described lyophilization is:
A, pre-freeze are placed on the solution bottling in freezing cabinet and are cooled to-3 ~-5 ℃, are incubated 1-2 hour, then are down to-40 ℃, are incubated freezing 2-3 hour;
B, distillation, then be cooled to-45 ℃, evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-8 ℃ ~-5 ℃ at 10 ~ 12 hours, keep-8 ℃ ~-5 ℃ 6 hours;
C, drying are warming up to 0 ℃, are incubated 1 hour, with 6-7 hour cascade raising temperature to 40 ℃ ~ 45 ℃, are incubated 3-5 hour, lyophilization;
D, vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 8-10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
The present invention also provides another kind of methionine and vitamin B
1The preparation method of composite injection, it is:
(1) first with the water for injection dissolving methionine of 40 ℃-70 ℃, obtain solution a, the amount of this water for injection is below 80% of solution total amount;
(2) the solution a that (1) is obtained is down to room temperature (namely below 30 ℃), vitaminize B in solution
1And the Vc mixed dissolution of antioxidant 0.01 ~ 0.05 weight portion, obtain the methionine plain B that supports one's family
1Solution;
(3) methionine that (2) the is obtained plain B that supports one's family
1Solution is adjusted to pH4.0～4.5, and the supplementary injection water adds needle-use activated carbon to solution total amount (approximately 1000mL), filters, and this needle-use activated carbon consumption is the 0.1-0.2%(g/ml of solution total amount);
(4) the solution bottling postlyophilization after the filtration that (3) is obtained; Described lyophilization is:
A, pre-freeze are placed on the solution bottling in freezing cabinet and are cooled to-3 ℃ ~-5 ℃, are incubated 1-2 hour, then are cooled to-40 ℃, are incubated freezing 2-3 hour;
B, distillation, then be cooled to-45 ℃, evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-8 ℃ ~-5 ℃ at 10 ~ 12 hours, keep-8 ℃ ~-5 ℃ 6 hours;
C, drying are warming up to 0 ℃, are incubated 1 hour, with 6-7 hour cascade raising temperature to 40 ℃ ~ 45 ℃, are incubated 3-5 hour, lyophilization;
D, vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 8-10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
Technical scheme of the present invention has following advantage:
1, the methionine provided by the invention plain B that supports one's family
1Composite injection prescription is more reasonable, does not add proppant and can make all good lyophilized formulations products of outward appearance, clarity and solubility;
2, methionine provided by the invention and vitamin B
1Composite injection has been avoided the generation of introducing impurity (related substances) because do not add the lyophilizing proppant, has greatly improved methionine and vitamin B
1The stability of composite injection has further improved the drug safety reliability;
3, the methionine provided by the invention plain B that supports one's family
1Composite injection on the basis of not adding the lyophilizing proppant, only utilizes and controls the antioxidative effect that the technological operation step can reach the like product that has added antioxidant in the prior art.Experimental results show that this process repeatability and exploitativeness are good, be fit to suitability for industrialized production;
4, the methionine provided by the invention plain B that supports one's family
1Composite injection has preferably added a kind of antioxidant Vc or cysteine, to strengthen the antioxidative effect.Avoided adding the impurity that conventional antioxidant brings, the intermediate product that antioxidant of the present invention generates in antioxidation process does not additionally bring impurity to product composition yet, improve quality, guaranteed the stability of product quality, further improved clinical safety in utilization.
The purpose of pre-freeze is to make it to distil under vacuum in order to fix product.As do not have fully charge real, and it is external that during evacuation, product can emit bottle outlet, causes the spray bottle, and final products do not have certain shape, belong to waste product; Waste energy again if temperature is too low, extend without reason the subsequent technique operating time, the design of pre-freeze has determined the quality of dry run and freeze-drying prods to a great extent.
Bottled freeze-dried products be mainly by with freeze dryer in shelf complete exchange heat, at the bottom of shelf temperature, in medicine and freeze dryer, the temperature difference of shelf is large, and rate of temperature fall is faster, and the degree of supercooling of solution and degree of supersaturation are larger, the granularity of critical crystallization is little, nucleation rate is faster, can form easily the less thin ice crystal of the more size of granule, after thin ice crystal distillation, the void size that forms in material is less, and after lyophilizing, solubility is good.Otherwise if not cooling in advance, rate of temperature fall can form oarse-grained ice crystal soon, forms the aqueous vapor discharge channel after the ice crystal distillation, and the void size that forms in material is larger, and after lyophilizing, the product solubility is poor.The design cryogenic temperature is-40 ℃.Freeze drying box is cooled in advance-40 ℃, purpose is to strengthen the temperature difference of medicine and shelf.
In test, the inventor finds, if bottled medicinal liquor is placed directly in advance on the dividing plate that is cooled to-40 ℃, when the large environment borehole cooling of the temperature difference, it is poor that the medicinal liquid up and down two parts in bottle can produce thermograde, in the process that an ice face advances from bottom to top, in solution, upwards migration of solute, cause the solute of upper epidermis often more, and density is higher, and lower bottom density is less, short texture.Thus, in the design of pre-freeze, solution is placed in the freeze drying box of the fridge that is cooled to-40 ℃, be incubated freezing 2-3 hour, although because the design cryogenic temperature is lower, shorten to a great extent crystallization time, shortened equally the solute migration time, greatly improved the atrophy situation that causes due to density variation.
in order to reach better effect, the present invention preferably adopts staging pre-freeze, soon medicinal liquid first is placed in the lyophilizing cabinet from room temperature and is cooled to-3 ℃ ~-5 ℃, kept temperature 1-2 hour, this process, make temperature autobalance in medicinal liquid, eliminate thermograde, then, again medicinal liquid is cooled to-40 ℃, freezing 2-3 hour, can reducing like this medicinal liquid up and down two parts in bottle, can to produce thermograde poor, to such an extent as to and make enough large medicinal liquid whole crystallizations of moment of boring energy accumulation, prepared product solubility is splendid, outward appearance is full, color even, hole is fine and close, than the outward appearance that adopts direct pre-freeze method product, clarity and stability are all better.
The distillation phase can be except the moisture of 90% left and right.During distillation, the upper materials drying that will take the lead in, too fast if its temperature rises, might reach the temperature of caving in, porous skeleton stiffness degradation, coming off appears in the granule in drying layer, can seal the micro channel of drying nest, stops the carrying out of distillation, rate of sublimation is slowed down, even make underclad portion atrophy slightly, affect the content of goods residual moisture, cause solubility, stability and clarity variation simultaneously.Temperature retention time is unsuitable long, the small crystals that produces due to the medicinal liquid quick freezing has very high surface energy, when heating, recrystallize might occur; mutually combining between little ice crystal forms large ice crystal; make its surface to volume ratio reach minimum; large ice crystal makes the dried frozen aquatic products outward appearance bad, and solubility is poor.Therefore, the choice relation of sublimation temperature is to the speed of distillation, and excessive temperature or cross distillation for a long time or be incubated all has adverse effect to product.Different medicinal liquids are according to the difference of its physical and chemical performance, and the sublimation temperature of suitable this medicinal liquid lyophilizing and distillation time and temperature retention time are also different.The inventor proves by replica test: time and temperature design that the present invention selects sublimation stage to adopt can make the methionine of the present invention plain B that supports one's family
1Composite freeze-dried powder agent solubility, stability and clarity all reach optimization.through the contrast experiment, different sublimation temperature in design medicinal liquid freeze-dry process, different distillation time and different temperature retention times, after carrying out lyophilizing respectively, again with sodium chloride or glucose solution dissolving, by in different sublimation temperatures, repeatedly contrast the clarity after freeze-drying prods dissolves between different distillation time and different temperature retention times, solubility, carry out again the assay of related substances, experiment show sublimation stage, be cooled to-45 ℃, evacuation reaches 10Pa and keeps heating up under vacuum, be warming up to-8 ℃ ~-5 ℃ at 10 ~ 12 hours, keep-8 ℃ ~-5 ℃ about 6 hours, the final products that obtain in this scope, its clarity is best, solubility is best, related substances (being impurity) content is also minimum.Because experimental technique and detection method are the normal experiment method, can be referring to associated materials such as pharmacopeia or ministry standards, therefore, contrast experiment's operational approach and concrete data result are owed to give herein, can replenish at any time evidence when needing.Obviously be better than like product.
Although pressure is low is conducive to the distillation of ice in product, when too low, unfavorable to conducting heat, product is difficult for obtaining heat, the rate of sublimation reduction due to pressure.When pressure is too high, the product caloric receptivity will reduce, and in product, the rate of sublimation of ice slows down, and all can cause the lyophilizing failure.Therefore, pressure is set as 8 ~ 10Pa, not only has been beneficial to heat transfer but also has been beneficial to the carrying out of distillation, also can relatively shorten time distillation phase.
Distil complete, because also there is the moisture of 10% left and right in product, reach qualified remaining water content in order to make product, must be further dry to product, that is, enter drying stage.Dry run is incubated 1 hour for being warming up to 0 ℃, and 6-7 hour cascade raising temperature to 40 ~ 45 ℃ are incubated 3-5 hour.
The present invention adopts above-mentioned formula, through above-mentioned process, and the methionine that the makes plain B that supports one's family
1The composite freeze-dried powder product appearance is full, and solubility is good, and is best in quality, and is suitable for suitability for industrialized production.
Freeze-dried powder composition and method of making the same of the present invention can improve the methionine plain B that supports one's family greatly
1No matter the stability of composite injection be the methionine plain B that supports one's family in configuration, packing or freeze-drying process
1The related substance of composite injection all also descends without obvious without increase, content, this lyophilized injectable powder has good stability in transportation and storage process, during clinical use, compatibility solution can be placed the long period, make clinically to become convenient, also greatly having reduced simultaneously increases because of impurity (related substance) the curative effect problem that the hidden danger brought to patient's drug safety and content descend and brings to the patient.
The specific embodiment
The present invention is further described below in conjunction with embodiment.
The freeze dryer that following examples adopt is the LYO-20 freezer dryer.Acid or alkali that the adjusting pH value adopts are 1mol/L hydrochloric acid solution or saturated sodium hydroxide solution.
Embodiment 1: the methionine plain B that supports one's family
1Composite injection
Methionine 10 weight portions
Vitamin B
11 weight portion
Preparation method:
1, water for injection is heated to 40-50 ℃, adds methionine, is stirred to dissolve to solution to clarify;
2, the solution temperature that obtains of step 1 is down to 30 ℃, then adds vitamin B
1, be stirred to dissolve to solution and clarify;
3, be adjusted to pH4.5; The supplementary injection water is to the solution total amount, by the 0.2%(g/ml of solution total amount) add 767 type injection-use activated carbons, stir, standing 30 minutes, filter;
4, the solution embedding after the filtration, obtain the methionyl vitamin B 1 composite injection.
Embodiment 2: the methionine plain B that supports one's family
1Composite freeze-dried powder
Methionine 10 weight portions
Vitamin B
11 weight portion
Preparation method:
1, water for injection is heated to 40-50 ℃, adds methionine, is stirred to dissolve to solution to clarify;
2, the solution temperature that obtains of step 1 is down to 30 ℃, then adds vitamin B
1, be stirred to dissolve to solution and clarify;
3, be adjusted to pH4.4; The supplementary injection water adds 767 type injection-use activated carbons to the solution total amount, and it is the 0.2%(g/ml of solution total amount), stir, standing 30 minutes, filter;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is as follows:
(1) pre-freeze is placed on the solution bottling in freezing cabinet and is cooled to-5 ℃, is incubated 1-2 hour, then is cooled to-40 ℃, is incubated freezing 2-3 hour;
(2) distillation, then be cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-5 ℃ at 10 ~ 12 hours, keep-5 ℃ 6 hours;
(3) drying is warming up to 0 ℃, is incubated 1 hour, with 6-7 hour cascade raising temperature to 45 ℃, is incubated 3 hours, lyophilization;
(4) vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
Embodiment 3: the methionine plain B that supports one's family
1Composite freeze-dried powder
Methionine 15 weight portions
Vitamin B
11 weight portion
Preparation method:
1, water for injection is heated to 60 ℃, adds methionine, is stirred to dissolve to solution to clarify;
2, the solution of step 1 is cooled to 25 ℃, adds vitamin B
1, be stirred to dissolve to solution and clarify;
3, be adjusted to pH4.3; The supplementary injection water is to the solution total amount, by solution total amount (namely preparing cumulative volume) 0.1%(g/ml) add injection-use activated carbon, stir, standing 30 minutes, filter;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is as follows:
(1) pre-freeze is placed on the solution bottling in freezing cabinet and is cooled to-5 ℃, is incubated 2 hours, then is cooled to-40 ℃, is incubated freezing 3 hours;
(2) distillation, then be cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-5 ℃ at 12 hours, keep-5 ℃ 6 hours;
(3) drying is warming up to 0 ℃, is incubated 1 hour, with 6 hours cascade raising temperatures to 40 ℃, is incubated 3 hours, lyophilization;
(4) vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
Embodiment 4: the methionine plain B that supports one's family
1Composite freeze-dried powder
Methionine 5 weight portions; Vitamin B
11 weight portion; Cysteine 0.02 weight portion
Preparation method:
1, water for injection is heated to 40 ℃, adds methionine and cysteine, stirs, and makes to be dissolved to the solution clarification;
2, the solution temperature that obtains of step 1 is down to 30 ℃, then adds vitamin B
1, be stirred to dissolve to solution and clarify;
3, be adjusted to pH4.0; The supplementary injection water is to the solution total amount, by solution total amount (namely preparing cumulative volume) 0.1%(g/ml) add 767 type injection-use activated carbons, stir, standing 30 minutes, filter;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is as follows:
(1) pre-freeze is placed on the solution bottling in freezing cabinet and is cooled to-3 ℃, is incubated 1 hour, then is cooled to-40 ℃, is incubated freezing 2 hours;
(2) distillation, then be cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-8 ℃ at 10 hours, keep-8 ℃ 6 hours;
(3) drying is warming up to 0 ℃, is incubated 1 hour, with 6 hours cascade raising temperatures to 45 ℃, is incubated 3 hours, lyophilization;
(4) vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 8Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
Embodiment 5: the methionine plain B that supports one's family
1Composite freeze-dried powder
Methionine 10 weight portions
Vitamin B
11 weight portion
Cysteine 0.03 weight portion
Preparation method:
1, water for injection is heated to 70 ℃, adds methionine and cysteine, is stirred to dissolve to solution to clarify;
2, the solution temperature that obtains of step 1 is down to 30 ℃, then adds vitamin B
1, be stirred to dissolve;
3, be adjusted to pH4.0; The supplementary injection water is to the solution total amount, by solution total amount (namely preparing cumulative volume) 0.2%(g/ml) add 767 type injection-use activated carbons, stir, standing 30 minutes, filter;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is as follows:
(1) pre-freeze with first being cooled to-4 ℃ after the solution bottling, then is placed in the freezing cabinet that is cooled to-40 ℃, is incubated freezing 2 hours;
(2) distillation, then be cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-6 ℃ at 10 hours, keep-6 ℃ 6 hours;
(3) drying is warming up to 0 ℃, is incubated 1 hour, with 6 hours cascade raising temperatures to 40 ℃, is incubated 4 hours, lyophilization;
(4) vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
Embodiment 6: the methionine plain B that supports one's family
1Composite freeze-dried powder
Methionine 10 weight portions
Vitamin B
11 weight portion
Cysteine 0.01 weight portion
Preparation method:
1, water for injection is heated to 45 ℃, adds methionine, adds the antioxidant cysteine to make its dissolving obtain solution simultaneously again;
2, the solution temperature that obtains of step 1 is down to 30 ℃, then adds vitamin B
1, be stirred to dissolve to solution and clarify;
3, be adjusted to pH4.5; The supplementary injection water is to the solution total amount, by solution total amount (namely preparing cumulative volume) 0.2%(g/ml) add 767 type injection-use activated carbons, stir, standing 30 minutes, filter;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is as follows:
(1) pre-freeze is placed on the solution bottling in freezing cabinet and is cooled to-3 ℃, is incubated 2 hours, then is cooled to-40 ℃, is incubated freezing 3 hours;
(2) distillation, then be cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-5 ℃ at 12 hours, keep-5 ℃ 6 hours;
(3) drying is warming up to 0 ℃, is incubated 1 hour, with 6 hours cascade raising temperatures to 40 ℃, is incubated 3 hours, lyophilization;
(4) vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 8Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
Embodiment 7: the methionine plain B that supports one's family
1Composite freeze-dried powder
Methionine 10 weight portions
Vitamin B
11 weight portion
Vc (antioxidant) 0.02 weight portion
Preparation method:
1, water for injection is heated to 50 ℃, adds methionine, is stirred to dissolve to solution to clarify;
2, the solution temperature that obtains of step 1 is down to 30 ℃, then adds vitamin B
1And Vc is stirred to dissolve;
3, be adjusted to pH4.0; The supplementary injection water is to the solution total amount, by solution total amount (namely preparing cumulative volume) 0.1%(g/ml) add 767 type injection-use activated carbons, stir, standing 30 minutes, filter;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is as follows:
(1) pre-freeze is placed on the solution bottling in freezing cabinet and is cooled to-5 ℃, is incubated 1 hour, then is cooled to-40 ℃, is incubated freezing 2 hours;
(2) distillation, then be cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-6 ℃ at 10 ~ 12 hours, keep-6 ℃ 6 hours;
(3) drying is warming up to 0 ℃, is incubated 1 hour, with 6 hours cascade raising temperatures to 40 ℃, is incubated 4 hours, lyophilization;
(4) vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the methionine plain B that supports one's family
1The lyophilized injectable powder of compositions.
Embodiment 8: the methionine plain B that supports one's family
1Composite freeze-dried powder
Methionine 10 weight portions
Vitamin B
11 weight portion
Cysteine 0.05 weight portion
Preparation method:
1, water for injection is heated to 45 ℃, adds methionine, adds the antioxidant cysteine to make its dissolving obtain solution simultaneously again;
2, the solution temperature that obtains of step 1 is down to 30 ℃, then adds vitamin B
1, be stirred to the solution clarification;
3, be adjusted to pH4.0～4.5; The supplementary injection water is to the solution total amount, by the 0.2%(g/ml of solution total amount) add 767 type injection-use activated carbons, stir, standing 30 minutes, filter;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is as follows:
(1) pre-freeze is placed on the solution bottling in freezing cabinet and is cooled to-5 ℃, is incubated 2 hours, then is cooled to-40 ℃, is incubated freezing 3 hours;
(2) distillation, then be cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-8 ℃ at 12 hours, keep-8 ℃ 6 hours;
(3) drying is warming up to 0 ℃, is incubated 1 hour, is warming up to 40 ℃ in 6 hours, is incubated 2 hours;
(4) vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
Embodiment 9: the methionine plain B that supports one's family
1Composite freeze-dried powder
Methionine 10 weight portions
Vitamin B
11 weight portion
Vc (antioxidant) 0.05 weight portion
Preparation method:
1, water for injection is heated to 45 ℃, adds methionine, is stirred to dissolve to solution to clarify;
2, the solution temperature that obtains of step 1 is down to 30 ℃, then adds vitamin B
1And Vc is stirred to dissolve;
3, be adjusted to pH4.0; The supplementary injection water is to the solution total amount, by solution total amount (namely preparing cumulative volume) 0.1%(g/ml) add 767 type injection-use activated carbons, stir, standing 30 minutes, filter;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is as follows:
(1) pre-freeze is placed on the solution bottling in freezing cabinet and is cooled to-5 ℃, is incubated 1-2 hour, then is cooled to-40 ℃, is incubated freezing 2-3 hour;
(2) distillation, then be cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-6 ℃ at 10 ~ 12 hours, keep-6 ℃ 6 hours;
(3) drying is warming up to 0 ℃, is incubated 1 hour, is warming up to 40 ℃ in 6 hours, is incubated 4 hours;
(4) vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.Experimental example 1
Get the product that the embodiment of the present invention 2 obtains, be divided into 3 batches, carry out the quality inspection under the freeze-drying prods continuous item, comprise identification, inspection related substance etc. and assay, result such as table 1.
Table 1. quality testing result
The product that the embodiment of the present invention 3 ~ 9 is obtained has carried out the correlated quality check according to the project of experimental example 1, result and experimental example 1 come to the same thing or close, because length is limited, repeat no more herein.
Experimental example 2: stability experiment
Investigate: outward appearance, clarity of solution and color, moisture, related substance, clarity, content.
Test basis: state-promulgated pharmacopoeia and State Food and Drug Administration's national drug standards.
Test method: get the product of the embodiment of the present invention 2, under the condition as for the influence factor, the influence factor is: illumination 4500LX, temperature: 40 ℃ and 60 ℃; High humidity RH75% and RH92.5% observed 10 days, sampling when 0 day, 5 days and 10 days respectively, and observing face shaping has unchangedly, checks the indexs such as acidity, Clarity and colour of solution, moisture, related substance, clarity, content, compares with the numerical value of 0 day.
Illumination the results are shown in Table 2, and humidity the results are shown in Table 3 ~ table 6.
What compare simultaneously experiment is commercially available methionine-vitamin B 1 freeze-dried powder (namely adding the methionine-vitamin B 1 freeze-dried powder of proppant mannitol, antioxidant sulphite or sodium pyrosulfite), and contrast and experiment sees Table 5a and table 6a.
Table 2. methionine-vitamin B 1 composite injection influence factor result of the test (illumination factor)
| 0 day | 5 days | 10 days | |
| Face shaping | The white loose block | The white loose block | The white loose block |
| Clarity | Clear and bright, foreign | Clear and bright, foreign | Clear and bright, foreign |
| Clarity of solution and change color | Qualified | Qualified | Qualified |
| Moisture (%) | 0.15 | 0.18 | 0.15 |
| Related substance (%) | 0.05 | 0.07 | 0.15 |
| Methionine content (%) | 100.15 | 100.04 | 100.01 |
| Vitamin B 1Content (%) | 100.06 | 99.91 | 99.99 |
Table 3. methionine-vitamin B 1 composite injection influence factor result of the test (40 ℃ of humidity factors)
| 0 day | 5 days | 10 days | |
| Face shaping | The white loose block | The white loose block | The white loose block |
| Clarity | Clear and bright, foreign | Clear and bright, foreign | Clear and bright, foreign |
| Clarity of solution and change color | Qualified | Qualified | Qualified |
| Moisture (%) | 0.05 | 0.04 | 0.03 |
| Related substance (%) | 0.02 | 0.08 | 0.18 |
| Methionine content (%) | 100.03 | 100.02 | 99.97 |
| Vitamin B 1Content (%) | 100.20 | 99.29 | 99.87 |
The table 4. methionine plain B that supports one's family
1Composite injection influence factor result of the test (60 ℃ of temperature factors)
| 0 day | 5 days | 10 days | |
| Face shaping | The white loose block | The white loose block | The white loose block |
| Clarity | Clear and bright, foreign | Clear and bright, foreign | Clear and bright, foreign |
| The clarity of solution and change color | Qualified | Qualified | Qualified |
| Moisture (%) | 0.03 | 0.04 | 0.09 |
| Related substance (%) | 0.05 | 0.11 | 0.12 |
| Methionine content (%) | 101.05 | 100.11 | 99.98 |
| Vitamin B 1Content (%) | 100.08 | 99.89 | 99.95 |
Table 5. methionine-vitamin B 1 freeze-dried powder influence factor result of the test (humidity factor RH75%)
| 0 day | 5 days | 10 days | |
| Face shaping | The white loose block | The white loose block | The white loose block |
| Clarity | Clear and bright, foreign | Clear and bright, foreign | Clear and bright, foreign |
| Clarity and colour of solution changes | Qualified | Qualified | Qualified |
| Moisture (%) | 0.05 | 0.04 | 0.11 |
| Related substance (%) | 0.05 | 0.11 | 0.16 |
| Methionine content (%) | 99.99 | 100.10 | 100.05 |
| Vitamin B 1Content (%) | 100.00 | 99.98 | 100.06 |
Table 5a. commercially available methionine-vitamin B 1 freeze-dried powder influence factor's result of the test (humidity factor RH75%)
| 0 day | 5 days | 10 days | |
| Face shaping | The white loose block | The white loose block | The white loose block |
| Clarity | Clear and bright, foreign | Clear and bright, foreign | Clear and bright, foreign |
| Clarity and colour of solution changes | Qualified | Qualified | Qualified |
| Moisture (%) | 0.35 | 0.40 | 0.41 |
| Related substance (%) | 0.15 | 0.25 | 0.36 |
| Methionine content (%) | 99.85 | 97.02 | 95.25 |
| Vitamin B 1Content (%) | 100.28 | 93.61 | 93.56 |
Table 6. methionine-vitamin B 1 freeze-dried powder influence factor result of the test (humidity factor RH92.5%)
| 0 day | 5 days | 10 days | |
| Face shaping | The white loose block | The white loose block | The white loose block |
| Clarity | Clear and bright, foreign | Clear and bright, foreign | Clear and bright, foreign |
| Acidity | 4.60 | 4.63 | 4.65 |
| Clarity and colour of solution changes | Qualified | Qualified | Qualified |
| Moisture (%) | 0.06 | 0.08 | 0.12 |
| Related substance (%) | 0.04 | 0.12 | 0.12 |
| Methionine content (%) | 100.05 | 100.02 | 99.99 |
| Vitamin B 1Content (%) | 100.08 | 99.99 | 99.96 |
Table 6a. commercially available methionine-vitamin B 1 freeze-dried powder influence factor's result of the test (humidity factor RH92.5%)
| 0 day | 5 days | 10 days | |
| Face shaping | The white loose block | The white loose block | The white loose block |
| Clarity | Clear and bright, foreign | Clear and bright, foreign | Clear and bright, foreign |
| Clarity and colour of solution changes | Qualified | Qualified | Qualified |
| Moisture (%) | 0.15 | 0.28 | 0.32 |
| Related substance (%) | 0.15 | 0.25 | 0.36 |
| Methionine content (%) | 99.85 | 93.12 | 93.25 |
| Vitamin B 1Content (%) | 100.28 | 95.61 | 91.56 |
Result shows, the methionine of the present invention plain B that supports one's family
1The aqueous solution of lyophilized injectable powder was placed 10 days under above-mentioned various experimental conditions, indices, vitamin B
1With the content bacterium of methionine, all without significant change.And at moisture, related substance (impurity) content and methionine content and vitamin B
1The content aspect obviously is better than commercial like product methionine-vitamin B 1 freeze-dried powder (having added the methionine-vitamin B 1 freeze-dried powder of proppant mannitol, antioxidant sulphite or sodium pyrosulfite), what product impurity of the present invention is few, antioxidant effect is remarkable, and product quality is more stable.
Experimental example 3. effect comparative experimentss
(like product of write out a prescription a), sorbitol (prescription b) being made proppant carries out the effect experiment according to the embodiment of the present invention 2 and 6 methods to the product that embodiment 2,6 is obtained, and the results are shown in Table 7. with selecting mannitol
Table 7. effect comparative experiments result
| Embodiment 2 | Embodiment 6 | Prescription a | Prescription b | |
| Methionine | 2.00g | 2.00g | 2.00g | 2.00g |
| Vitamin B 1 | 0.2g | 0.2g | 0.2g | 0.2g |
| Water for injection adds to | 50ml | 50ml | 50ml | 50ml |
| The freeze-dried products apparent condition | Loose | Loose | Loosen, have and subside | Loose, block, crackle arranged |
| The redissolution situation | Yi Rong, clear and bright solution | Yi Rong, clear and bright solution | Yi Rong, more clear and bright | More molten, clear and bright, microgranule arranged |
Result shows, the methionine of the present invention plain B that supports one's family
1The effect of lyophilized injectable powder and solubility all are better than selecting the mannitol (like product of write out a prescription a), sorbitol (prescription b) being made proppant.
The stable comparative experiments of experimental example 4.
Select mannitol (be called for short a), the like product of sorbitol+sodium pyrosulfite (being called for short b) is as a comparison sample, with embodiment of the present invention 2(hereinafter to be referred as A), embodiment 6(is hereinafter to be referred as B) product that obtains carries out the stability experiment contrast, the results are shown in Table 9 to table 13.
The stable comparative test of table 9. (illumination factor)
Table 10: stable comparative test (40 ℃ of temperature)
The stable comparative test result of table 11. (temperature: 60 ℃)
The stable comparative test result of table 12. (high humidity RH75%)
Table 13: stable comparative test result (high humidity RH92.5%)
The result demonstration, the freeze-dried powder stability of adding sodium pyrosulfite and mannitol is slightly better than the freeze-drying prods that only adds mannitol, but related substance is not as the latter; The methionine of the present invention plain B that supports one's family
1The related substance of lyophilized injectable powder, stability all are better than selecting the similar freeze-dried powder of mannitol, sorbitol+sodium pyrosulfite.
The present invention is not limited to above-mentioned embodiment, and other any or akin products identical with the present invention that anyone draws under enlightenment of the present invention all are not precluded within outside protection scope of the present invention.
Claims (4)
1. a methionine plain B that supports one's family
1Composite injection is characterized in that, the said composition injection is freeze-dried powder, by methionine 5-20 weight portion, vitamin B
11 weight portion and antioxidant 0.01-0.05 weight portion form, and this antioxidant is Vc or cysteine;
This freeze-dried powder is made by following preparation method:
(1) first with the water for injection dissolving methionine of 40 ℃-70 ℃, obtain methionine solution, the amount of this water for injection is below 80% of solution total amount;
(2) methionine solution that (1) is obtained is down to room temperature, vitaminize B in solution
1Mixed dissolution obtains the methionine plain B that supports one's family
1Solution;
Described antioxidant in the water for injection dissolving methionine while of step (1) with 40 ℃ ~ 70 ℃, adds the cysteine of antioxidant 0.01 ~ 0.05 weight portion; Perhaps, in described step (2), vitaminize B
1The Vc that adds antioxidant 0.01 ~ 0.05 weight portion when mixing, mixed dissolution;
(3) methionine that (2) the is obtained plain B that supports one's family
1Solution is adjusted to pH4.0～4.5, and the supplementary injection water adds needle-use activated carbon to the solution total amount, filters, and this activated carbon dosage is the 0.1-0.2%(g/ml of solution total amount);
(4) the solution bottling postlyophilization after the filtration that (3) is obtained obtains described methionyl vitamin B
1Composite injection;
The described lyophilization of step in the method (4) is:
Pre-freeze is placed on the solution bottling in freezing cabinet and is cooled to-3 ℃ ~-5 ℃, is incubated 1-2 hour, then is cooled to-40 ℃, is incubated freezing 2-3 hour;
Distillation then is cooled to-45 ℃, and evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-8 ℃ ~-5 ℃ at 10 ~ 12 hours, keep-8 ℃ ~-5 ℃ 6 hours;
Drying is warming up to 0 ℃, is incubated 1 hour, with 6-7 hour cascade raising temperature to 40 ℃ ~ 45 ℃, is incubated 3-5 hour, lyophilization;
The vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 8-10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
2. composite injection as claimed in claim 1, is characterized in that, the said composition injection is freeze-dried powder, by methionine 10 weight portions, vitamin B
11 weight portion and antioxidant 0.01-0.05 weight portion form, and this antioxidant is Vc or cysteine.
3. composite injection as claimed in claim 1, is characterized in that, described preparation method is:
(1) first with the water for injection dissolving methionine of 40 ℃-70 ℃, add the cysteine of antioxidant 0.01 ~ 0.05 weight portion simultaneously again, obtain solution a, the amount of this water for injection is below 80% of solution total amount;
(2) the solution a that (1) is obtained is down to room temperature, vitaminize B in solution
1Mixed dissolution obtains the methionine plain B that supports one's family
1Solution;
(3) methionine that (2) the is obtained plain B that supports one's family
1Solution is adjusted to pH4.0-4.5, and the supplementary injection water adds needle-use activated carbon to filter to the solution total amount, and this activated carbon dosage is the 0.1-0.2%(g/ml of solution total amount);
(4) the solution bottling postlyophilization after the filtration that (3) is obtained; Described lyophilization is:
A, pre-freeze are placed on the solution bottling in freezing cabinet and are cooled to-3 ℃ ~-5 ℃, are incubated 1-2 hour, then are cooled to-40 ℃, are incubated freezing 2-3 hour;
B, distillation, then be cooled to-45 ℃, evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-8 ℃ ~-5 ℃ at 10 ~ 12 hours, keep-8 ℃ ~-5 ℃ 6 hours;
C, drying are warming up to 0 ℃, are incubated 1 hour, with 6-7 hour cascade raising temperature to 40 ℃ ~ 45 ℃, are incubated 3-5 hour, lyophilization;
D, vacuum tamponade, after lyophilization is complete, the nitrogen of wadding warp aseptic filtration in freeze drying box again, in the process of filling nitrogen, at least twice is evacuated to 8-10Pa, keep vacuum and nitrogen environment in freeze drying box, then automatically tamponade under vacuum condition obtains the freeze-dried powder of described methionine-vitamin B 1 composite.
4. composite injection as claimed in claim 1, is characterized in that, described preparation method is:
(1) first with the water for injection dissolving methionine of 40 ℃-70 ℃, obtain solution a, the amount of this water for injection is below 80% of solution total amount;
(2) the solution a that (1) is obtained is down to room temperature, vitaminize B in solution
1And the Vc mixed dissolution of antioxidant 0.01 ~ 0.05 weight portion, obtain the methionine plain B that supports one's family
1Solution;
(3) methionine that (2) the is obtained plain B that supports one's family
1Solution is adjusted to pH4.0～4.5, and the supplementary injection water adds needle-use activated carbon to the solution total amount, filters, and this activated carbon dosage is the 0.1-0.2%(g/ml of solution total amount);
(4) the solution bottling postlyophilization after the filtration that (3) is obtained; Described lyophilization is:
A, pre-freeze with entering in freezing cabinet after the solution bottling, first are cooled to-3 ℃ ~-5 ℃, keep 1-2 hour, then cool the temperature to-40 ℃, are incubated freezing 2-3 hour;
B, distillation, then be cooled to-45 ℃, evacuation when vacuum arrives 10Pa, kept vacuum 10Pa, heats up, and was warming up to-8 ℃ ~-5 ℃ at 10 ~ 12 hours, keep-8 ℃ ~-5 ℃ 6 hours;
C, drying are warming up to 0 ℃, are incubated 1 hour, with 6-7 hour cascade raising temperature to 40 ℃ ~ 45 ℃, are incubated 3-5 hour, lyophilization;
D, vacuum tamponade, after lyophilization is complete, then the nitrogen of wadding warp aseptic filtration in freeze drying box, in the process of filling nitrogen, at least twice is evacuated to 8-10Pa, keep vacuum and nitrogen environment in freeze drying box, then tamponade automatically under vacuum condition obtains the described methionine plain B that supports one's family
1The freeze-dried powder of compositions.
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|---|---|---|---|---|
| WO2007061529A1 (en) * | 2005-11-18 | 2007-05-31 | Scidose Llc. | Lyophilization process and products obtained thereby |
| CN101810620A (en) * | 2009-11-19 | 2010-08-25 | 罗诚 | Methionine-vitamin B1 composite injection and preparation method thereof |
| CN102247372A (en) * | 2011-04-12 | 2011-11-23 | 宁辉 | Methionine-containing medicinal composition and preparation method thereof |
| CN102247373A (en) * | 2011-08-02 | 2011-11-23 | 周晓东 | Composition of methionine vitamin B1 compound |
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| CN102743350A (en) | 2012-10-24 |
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Application publication date: 20121024 Assignee: Wuhan Renfu Pharmaceutical Co., Ltd. Assignor: Liu Shiling Contract record no.: 2013990000432 Denomination of invention: Methionine-vitamin B1 composite injection and preparation method thereof Granted publication date: 20130619 License type: Common License Record date: 20130725 |
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Effective date of registration: 20220512 Address after: 430073 No. 01, floor 6, unit 1, north main building, National Geospatial Information Industry base, No. 5-2, wudayuan Road, Donghu New Technology Development Zone, Wuhan City, Hubei Province Patentee after: Wuhan Tian Tian medical science and Technology Co.,Ltd. Address before: 430071 room 602, unit 2, building 6, Xinghai Hongcheng, No. 58, Minzhu Second Road, Hongshan District, Wuhan City, Hubei Province Patentee before: Liu Shiling |