CN102743350A - Methionine vitamin B1Injection of composition - Google Patents
Methionine vitamin B1Injection of composition Download PDFInfo
- Publication number
- CN102743350A CN102743350A CN201210265065XA CN201210265065A CN102743350A CN 102743350 A CN102743350 A CN 102743350A CN 201210265065X A CN201210265065X A CN 201210265065XA CN 201210265065 A CN201210265065 A CN 201210265065A CN 102743350 A CN102743350 A CN 102743350A
- Authority
- CN
- China
- Prior art keywords
- solution
- methionine
- injection
- freeze
- hour
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 isThe stability is good.
Description
Technical field
The present invention relates to a kind of methionyl vitamin B
1Composite injection, and the method for preparing 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 the 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 methylationization, reduces intrahepatic cholestasis, changes the sulfenyl effect and strengthens; Help 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, effect such as detoxifcation, the metabolic running of promotion body fat, 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 KG reaction in the involved in sugar metabolism is that carbohydate metabolism institute is essential.During shortage, the oxidation formation acetone acid that is obstructed, lactic acid are piled up also influences the human body energy supply.Its characteristic mainly shows the nucleus cardiovascular system, the multiple peripheral neuritis of sensory nerve and nervus motorius all effected occurs, shows as symptoms such as paraesthesia, neuralgia, myasthenia of limbs and muscular soreness and atrophy.The cardiovascular aspect makes the small artery expansion because acetone acid and lactic acid increase, and diastolic pressure descends, the myocardial metabolism imbalance, so be prone to cardiopalmus, tachypnea, uncomfortable in chest, cardiac hypertrophy, liver is congested and on every side under the symptom of cardiac dysfunction such as swell.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: like 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, tumour patient put, the application during 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: stable as inadequately, thereby taking place easily, degraded makes drug effect reduction etc. in storage, transportation, and especially be difficult for dissolving to 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 the 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; Can prevent product generation oxidation reaction though added a certain amount of sodium sulfite or sodium pyrosulfite; But introduced sulfurous acid, thereby brought some side effect such as related substance increases, the interior downgrade of shelf life of products, potential safety hazard.
Summary of the invention
The objective of the invention is deficiency to prior art; A kind of methionine-vitamin B 1 composite injection and preparation method thereof is provided, when bringing useful assosting effect owing to adjuvant, the side effect that is difficult to expect that also brings inevitably; Therefore; The inventor follows and can prepare on the basis of stable and controllable for quality, the product that meets clinical needs, the few more good more principle of the kind of adjuvant, consumption, and the data results that obtain through a large amount of experiments show; Compositions of the present invention is used a kind of adjuvant at most, can reach satisfied the preparation especially effect and the intended purposes of lyophilized injectable powder.
In addition, can improve the methionine plain B that supports one's family greatly through method for preparing of the present invention
1The stability of composite injection, preparation are no matter to be that related substance does not all have obvious increase, content and do not have obvious decline yet in preparation, packing or the freeze-drying process, the methionine of the preparation plain B that supports one's family
1Composite injection has good stability in transportation and storage process; Compatibility solution can be placed the long period during clinical use; Make clinical use become convenient, also having reduced greatly simultaneously increases the curative effect problem of descending and bringing to the patient for hidden danger that patient's drug safety brings and content because of impurity (related substance).
The present invention provides a kind of methionine plain B that supports one's family
1Composite injection, its side effect is little, has good stability.
The present 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 a freeze-dried powder.
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; Reduce to kind, the consumption of adjuvant minimum as far as possible; Having realized in composite injection, not adding adjuvant can obtain each item index and reach the especially product of freeze-dried powder standard-required of injection fully; The data result that obtains through a large amount of experiments shows methionine of the present invention and vitamin B
1The composite injection product quality is superior to like product, and impurity (related substance) content is low, and product stability is good, reaches the promising result and the intended purposes 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 the 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 are formed; 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.
Since the side effect that is difficult to expect that adjuvant too much brings inevitably, therefore, methionine that the present invention obtains and vitamin B
1Composite injection is reduced 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 utilizing technology to overcome methionine fully is difficult for dissolving, and vitamin B
1Although unfavorable factors such as easy oxidation are feasible, experiment proof repeatability and exploitativeness are all good, and not oxidized in order further to protect product, the present invention adopts a kind of adjuvant, and promptly antioxidant Vc or cysteine have been strengthened the protection of anti-oxidation.The data result that obtains through a large amount of experiments shows methionine of the present invention and vitamin B
1The composite injection quality is superior to like product, and impurity (related substance) content is low, and product stability is good, reaches the promising result and the intended purposes that meet the injection requirement.
In the selection of antioxidant, the present invention has passed through a large amount of examination experiments, finally confirms as Vc or cysteine; This selection to the benefit that product brings is: well-known, Vc or cysteine all have stronger anti-oxidation characteristics, the experiment proof; 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
1, it belongs to aminoacid and vitamins, and Vc belongs to vitamin; Cysteine belongs to aminoacid, and cysteine is similar with methionine, though not soluble in water; But in preparation technology, only need to adopt the water for injection that is heated to uniform temperature to dissolve, can solve this difficult problem well, and the material that generates after the cysteine oxidation is a cystine; It also belongs to aminoacid, in processes such as preparation, lyophilizing, placement, does not introduce other impurity, has more avoided generation intermediate product impurity; Therefore, methionine of the present invention and vitamin B
1Composite injection quality, stability all significantly are superior to like product and prior art products.
The present invention also provides above-mentioned methionine and vitamin B
1The method for preparing of composite injection, it is:
(1) earlier with 40 ℃-70 ℃ water for injection dissolving methionine, 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 reduced 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, replenishes water for injection to solution total amount (for example, about 1000mL), adds needle-use activated carbon, filters, and this amount of activated is the 0.1-0.2% (g/ml) of solution total amount;
(4) 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 the supplementary material, impurity etc., and consumption is very few, and impurity content is too high in the final products, 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 a normal experiment, owes to give here, can replenish evidence at any time 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, sterilizing room is advanced in filter then with medicinal liquid, and half plug is pressed in fill, puts into the lyophilizing cabinet, lyophilization.Lyophilization is the freeze-dried powder key of success, has directly influenced the various performances of product; The present invention has done significant improvement to Freeze Drying Technique just, just makes so simple methionine of adjuvant and vitamin B
1The composite freeze-dried powder agent is able to success.
Because the used adjuvant of this product is simple, adjuvant does not have the effect of freeze-dried powder proppant, therefore, if expect the freeze-drying prods that each item index is all qualified, 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, obtains following selection process finally.
Product of the present invention is preferably methionine and vitamin B
1Composite freeze-dried powder, its preparation method is:
(1) earlier with 40 ℃-70 ℃ water for injection dissolving methionine, 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 reduced 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, replenishes water for injection to solution total amount (for example, about 1000mL), adds needle-use activated carbon, filters, and this amount of activated is the 0.1-0.2% (g/ml) of solution total amount;
(4) the solution bottling after the filtration that (3) is obtained, cryodesiccated step below the entering;
(5) pre-freeze is placed on solution bottling in the freezing cabinet and is cooled to-3 ℃～-5 ℃, is incubated 1-2 hour, is cooled to-40 ℃ again, is incubated freezing 2-3 hour;
(6) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is warming up to-8 ℃～-5 ℃ at 10～12 hours, keep-8 ℃～-5 ℃ 6 hours;
(7) 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;
(8) vacuum tamponade, after lyophilization finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 8-10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said methionine plain B that supports one's family
1The freeze-dried powder of compositions.
One of innovative point of the present invention is, utilizes technology to overcome the defective and the unfavorable factor of material itself, that is, utilize the process of improvement to solve methionine and be difficult for dissolving and vitamin B
1The difficult problem of easy oxidation; Having met or exceeded prior art adopts and adds the for example solubilising, the antioxidative effect that realize of cosolvent, antioxidant of multiple adjuvant; Avoided to greatest extent that prior art adds that the related substance that adjuvant too much brings increases, downgrade in the shelf life of products, had drawback such as potential safety hazard, guaranteed drug quality and drug safety.
Innovative point that the present invention is above-mentioned and beneficial effect are realized through two steps:
First substep dissolved substance component is to reach the quick-dissolving purpose of indissoluble component.Dissolve the methionine of indissoluble under the room temperature earlier with the water for injection of heating; General 40 ℃-70 ℃ water for injection gets final product; The influence that the relation of this account temperature and rate of dissolution and temperature raise technology and product are brought, the preferred 40-50 of the present invention ℃ water for injection dissolving methionine is after dissolving fully; Solution is reduced to room temperature, adds vitamin B
1Mixed dissolution.
The room temperature of mentioning among the present invention is generally below 30 ℃, also comprises 30 ℃, for example can be 15～30 ℃.
It two is vacuum tamponades, and automatic tamponade under starvation fully and the environment that guarantees vacuum simultaneously too can the antioxidative effect even realized not having the antioxidant existence.After lyophilization, the nitrogen of wadding warp aseptic filtration in freeze drying box, at least twice is evacuated to 8-10Pa in the process of filling nitrogen, keeps vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then.
Methionine that the present invention obtains and vitamin B
1Composite injection can add any adjuvant, and utilize technology to overcome methionine fully and be difficult for dissolving, and vitamin B
1Unfavorable 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 technology goes out is loose, and it is better than the like product solubility with proppant for the experiment proof, and repeatability and exploitativeness are all good.
But for further the protection product is not oxidized; The intermediate product that generates in impurity of considering not introduce conventional antioxidant simultaneously and being brought and the antioxidation process does not bring impurity yet; 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, in the said step of above-mentioned method for preparing (1),, add the cysteine of antioxidant 0.01～0.05 weight portion simultaneously again with 40 ℃～70 ℃ water for injection dissolving methionine; Perhaps, in said step (2), vitaminize B
1The blended Vc that adds antioxidant 0.01～0.05 weight portion simultaneously, mixed dissolution.
The present invention also provides a kind of methionine and vitamin B
1The method for preparing of composite injection, it is:
(1) earlier with 40 ℃-70 ℃ water for injection dissolving methionine, 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 reduces to room temperature (promptly 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, replenishes water for injection to solution total amount (for example 1000mL), adds needle-use activated carbon, filters the 0.1-0.2% (g/ml) that this needle-use activated carbon consumption is the solution total amount;
(4) the solution bottling postlyophilization after the filtration that (3) is obtained; Described lyophilization is:
A, pre-freeze are placed on solution bottling in the freezing cabinet and are cooled to-3～-5 ℃, are incubated 1-2 hour, reduce to-40 ℃ again, are incubated freezing 2-3 hour;
B, distillation are cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 8-10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said 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 method for preparing of composite injection, it is:
(1) earlier with 40 ℃-70 ℃ water for injection dissolving methionine, 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 reduces to room temperature (promptly 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, replenishes water for injection to solution total amount (about 1000mL), adds needle-use activated carbon, filters the 0.1-0.2% (g/ml) that this needle-use activated carbon consumption is the solution total amount;
(4) the solution bottling postlyophilization after the filtration that (3) is obtained; Described lyophilization is:
A, pre-freeze are placed on solution bottling in the freezing cabinet and are cooled to-3 ℃～-5 ℃, are incubated 1-2 hour, are cooled to-40 ℃ again, are incubated freezing 2-3 hour;
B, distillation are cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 8-10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said 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
1The composite injection prescription is more reasonable, does not add proppant and can make all good lyophilized formulations product 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 improved methionine and vitamin B greatly
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 control technological operation step can reach the antioxidative effect of the like product that has added antioxidant in the prior art.Experiment this process repeatability of proof and exploitativeness are good, are 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 have the extra impurity that brings 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 under vacuum, to distil in order to fix product.As do not freeze reality fully, and it is external that product can emit bottle outlet during evacuation, causes the spray bottle, and final products do not have certain shape, belong to waste product; If temperature is crossed to hang down and is wasted energy again, prolong the subsequent technique operating time without reason, the design of pre-freeze has determined the quality of dry run and freeze-drying prods to a great extent.
Bottled freeze-dried products mainly be through with freeze dryer in shelf accomplish exchange heat, at the bottom of the shelf temperature, the temperature difference of shelf is big in medicine and the freeze dryer; Rate of temperature fall is fast more, and the degree of supercooling of solution and degree of supersaturation are bigger, and critical crystalline granularity is then little; Nucleation rate is fast more, can form the less thin ice crystal of the more size of granule easily, after the thin ice crystal distillation; The void size that forms in the material is less, and solubility is good after the lyophilizing.Otherwise if not cooling in advance, rate of temperature fall can form oarse-grained ice crystal soon, and ice crystal distillation back forms the aqueous vapor discharge channel, and the void size that forms in the material is bigger, and the product solubility is poor after the lyophilizing.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 be placed directly in bottled medicinal liquor in advance on the dividing plate that is cooled to-40 ℃; When cooling under the big environment of the temperature difference, the medicinal liquid in the bottle up and down two parts can to produce thermograde poor, in the propulsive from bottom to top process of an ice face; Upwards migration of solute causes the solute of upper epidermis often more in the solution, and density is higher; And bottom density is less down, 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; Though because the design cryogenic temperature is lower; Shortened crystallization time to a great extent, shortened the solute migration time equally, improved greatly because the atrophy situation that density variation causes.
In order to reach better effect, the present invention preferably adopts staging pre-freeze, is about to medicinal liquid and places lyophilizing cabinet internal cooling to-3 ℃～-5 ℃ earlier from room temperature; Kept temperature 1-2 hour, this process makes temperature autobalance in the medicinal liquid; Eliminate thermograde, then, again medicinal liquid is cooled to-40 ℃; Freezing 2-3 hour, can reduce like this in the bottle medicinal liquid up and down two parts can to produce thermograde poor, to such an extent as to and make enough medicinal liquid whole crystallizations of moment greatly of boring energy accumulation; Prepared product solubility is splendid, and outward appearance is full, color even, hole fine and close, and is all better than the outward appearance, clarity and the stability that adopt direct pre-freeze method product.
The distillation phase can be removed about 90% moisture.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 rigidity reduces, and coming off appears in the granule in the drying layer; Can seal the micro channel of drying nest, stop the carrying out of distillation, rate of sublimation is slowed down; Even make underclad portion atrophy slightly, and influence the content of goods residual moisture, cause solubility, stability and clarity variation simultaneously.Temperature retention time is unsuitable long; Because the small crystals that the medicinal liquid quick freezing produces has very high surface energy; When heating, recrystallize might take place, mutually combining between the little ice crystal forms big ice crystal, makes its surface to volume ratio reach minimum; Big 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 it is also different with distillation time and temperature retention time to be fit to the freeze dried sublimation temperature of this medicinal liquid.The inventor proves through 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 the design medicinal liquid freeze-dry process, different distillation time and different temperature retention times, carry out lyophilizing respectively after, reuse sodium chloride or glucose solution dissolving; Through the clarity after contrasting the freeze-drying prods dissolving repeatedly between different sublimation temperatures, different distillation time and the different temperature retention time, solubility, carry out the assay of related substances again; Experiment show sublimation stage, be cooled to-45 ℃, evacuation reaches 10Pa and keeps heating up under the 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 owes to give with concrete data result here, can replenish evidence at any time when needing.Obviously be superior to like product.
Help the distillation of ice in the product though pressure is low, because pressure is when too low, unfavorable to conducting heat, product is difficult for obtaining heat, the rate of sublimation reduction.When pressure is too high, the product caloric receptivity will reduce, and the rate of sublimation of ice slows down in the product, all can cause the lyophilizing failure.Therefore, pressure is set at 8～10Pa, not only has been beneficial to the transmission of heat but also has been beneficial to the carrying out of distillation, also can shorten time distillation phase relatively.
Distillation finishes, because also there is the moisture about 10% in the product, reaches qualified remaining water content in order to make product, must be further dry to product, that is, get into 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 prescription, 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 the freeze-drying process
1The related substance of composite injection does not all have increase, content and does not have obvious decline yet; This lyophilized injectable powder has good stability in transportation and storage process; Compatibility solution can be placed the long period during clinical use; Make clinically to become convenient, also having reduced greatly simultaneously increases the curative effect problem of descending and bringing to the patient for hidden danger that patient's drug safety brings and content because of impurity (related substance).
The specific embodiment
Below in conjunction with embodiment the present invention is further specified.
The freeze dryer that following examples adopted is the LYO-20 freezer dryer.Regulating acid or the alkali that pH value adopted is 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
Method for preparing:
1, water for injection is heated to 40-50 ℃, adds methionine, stirs to make to be dissolved to the solution clarification;
2, the solution temperature that obtains of step 1 is reduced to 30 ℃, adds vitamin B again
1, stirring makes and is dissolved to the solution clarification;
3, be adjusted to pH4.5; Replenish water for injection to solution total amount, 0.2% (g/ml) that presses the solution total amount adds 767 type injection-use activated carbons, stirs, and leaves standstill 30 minutes, filters;
4, the solution embedding after the filtration obtains 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
Method for preparing:
1, water for injection is heated to 40-50 ℃, adds methionine, stirs to make to be dissolved to the solution clarification;
2, the solution temperature that obtains of step 1 is reduced to 30 ℃, adds vitamin B again
1, stirring makes and is dissolved to the solution clarification;
3, be adjusted to pH4.4; Replenish water for injection to solution total amount, add 767 type injection-use activated carbons, it is 0.2% (g/ml) of solution total amount, stirs, and leaves standstill 30 minutes, filters;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is following:
(1) pre-freeze is placed on solution bottling in the freezing cabinet and is cooled to-5 ℃, is incubated 1-2 hour, is cooled to-40 ℃ again, is incubated freezing 2-3 hour;
(2) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said 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
Method for preparing:
1, water for injection is heated to 60 ℃, adds methionine, stirs to make to be dissolved to the solution clarification;
2, the solution of step 1 is cooled to 25 ℃, adds vitamin B
1, stirring makes and is dissolved to the solution clarification;
3, be adjusted to pH4.3; Replenish water for injection to solution total amount, add injection-use activated carbon, stir, left standstill 30 minutes, filter by solution total amount (promptly preparing cumulative volume) 0.1% (g/ml);
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is following:
(1) pre-freeze is placed on solution bottling in the freezing cabinet and is cooled to-5 ℃, is incubated 2 hours, is cooled to-40 ℃ again, is incubated freezing 3 hours;
(2) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said 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
Method for preparing:
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 reduced to 30 ℃, adds vitamin B again
1, stirring makes and is dissolved to the solution clarification;
3, be adjusted to pH4.0; Replenish water for injection to solution total amount, add 767 type injection-use activated carbons, stir, left standstill 30 minutes, filter by solution total amount (promptly preparing cumulative volume) 0.1% (g/ml);
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is following:
(1) pre-freeze is placed on solution bottling in the freezing cabinet and is cooled to-3 ℃, is incubated 1 hour, is cooled to-40 ℃ again, is incubated freezing 2 hours;
(2) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 8Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said 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
Method for preparing:
1, water for injection is heated to 70 ℃, adds methionine and cysteine, stirs to make to be dissolved to the solution clarification;
2, the solution temperature that obtains of step 1 is reduced to 30 ℃, adds vitamin B again
1, stir and make dissolving;
3, be adjusted to pH4.0; Replenish water for injection to solution total amount, add 767 type injection-use activated carbons, stir, left standstill 30 minutes, filter by solution total amount (promptly preparing cumulative volume) 0.2% (g/ml);
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is following:
(1) pre-freeze with being cooled to-4 ℃ earlier after the solution bottling, places in the freezing cabinet that is cooled to-40 ℃ then, is incubated freezing 2 hours;
(2) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said 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
Method for preparing:
1, water for injection is heated to 45 ℃, adds methionine, adds the antioxidant cysteine more simultaneously and makes its dissolving obtain solution;
2, the solution temperature that obtains of step 1 is reduced to 30 ℃, adds vitamin B again
1, stirring makes and is dissolved to the solution clarification;
3, be adjusted to pH4.5; Replenish water for injection to solution total amount, add 767 type injection-use activated carbons, stir, left standstill 30 minutes, filter by solution total amount (promptly preparing cumulative volume) 0.2% (g/ml);
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is following:
(1) pre-freeze is placed on solution bottling in the freezing cabinet and is cooled to-3 ℃, is incubated 2 hours, is cooled to-40 ℃ again, is incubated freezing 3 hours;
(2) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 8Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said 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
Method for preparing:
1, water for injection is heated to 50 ℃, adds methionine, stirs to make to be dissolved to the solution clarification;
2, the solution temperature that obtains of step 1 is reduced to 30 ℃, adds vitamin B again
1And the Vc stirring makes dissolving;
3, be adjusted to pH4.0; Replenish water for injection to solution total amount, add 767 type injection-use activated carbons, stir, left standstill 30 minutes, filter by solution total amount (promptly preparing cumulative volume) 0.1% (g/ml);
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is following:
(1) pre-freeze is placed on solution bottling in the freezing cabinet and is cooled to-5 ℃, is incubated 1 hour, is cooled to-40 ℃ again, is incubated freezing 2 hours;
(2) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then 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
Method for preparing:
1, water for injection is heated to 45 ℃, adds methionine, adds the antioxidant cysteine more simultaneously and makes its dissolving obtain solution;
2, the solution temperature that obtains of step 1 is reduced to 30 ℃, adds vitamin B again
1, be stirred to the solution clarification;
3, be adjusted to pH4.0～4.5; Replenish water for injection to solution total amount, 0.2% (g/ml) that presses the solution total amount adds 767 type injection-use activated carbons, stirs, and leaves standstill 30 minutes, filters;
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is following:
(1) pre-freeze is placed on solution bottling in the freezing cabinet and is cooled to-5 ℃, is incubated 2 hours, is cooled to-40 ℃ again, is incubated freezing 3 hours;
(2) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said 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
Method for preparing:
1, water for injection is heated to 45 ℃, adds methionine, stirs to make to be dissolved to the solution clarification;
2, the solution temperature that obtains of step 1 is reduced to 30 ℃, adds vitamin B again
1And the Vc stirring makes dissolving;
3, be adjusted to pH4.0; Replenish water for injection to solution total amount, add 767 type injection-use activated carbons, stir, left standstill 30 minutes, filter by solution total amount (promptly preparing cumulative volume) 0.1% (g/ml);
4, lyophilization is carried out in the bottling of the solution after the filtration, and step is following:
(1) pre-freeze is placed on solution bottling in the freezing cabinet and is cooled to-5 ℃, is incubated 1-2 hour, is cooled to-40 ℃ again, is incubated freezing 2-3 hour;
(2) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said 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 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 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 here.
Experimental example 2: stability experiment
Investigate: outward appearance, clarity of solution and color, moisture, related substance, clarity, content.
Test basis: NF and State Food and Drug Administration's national drug standards.
Test method: get the product of the embodiment of the 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; Respectively sampling when 0 day, 5 days and 10 days; Observing face shaping has no change, and indexs such as the clarity of inspection acidity, solution and color, moisture, related substance, clarity, content compare with 0 day numerical value.
The illumination result sees table 2, and humidity result sees table 3～table 6.
What compare experiment simultaneously is commercially available methionine-vitamin B 1 freeze-dried powder (promptly adding the methionine-vitamin B 1 freeze-dried powder of proppant mannitol, antioxidant sulphite or sodium pyrosulfite), and contrast and experiment is seen 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, no foreign body | Clear and bright, no foreign body | Clear and bright, no foreign body |
| 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, no foreign body | Clear and bright, no foreign body | Clear and bright, no foreign body |
| 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, no foreign body | Clear and bright, no foreign body | Clear and bright, no foreign body |
| 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, no foreign body | Clear and bright, no foreign body | Clear and bright, no foreign body |
| The clarity of solution and change color | 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, no foreign body | Clear and bright, no foreign body | Clear and bright, no foreign body |
| The clarity of solution and change color | 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, no foreign body | Clear and bright, no foreign body | Clear and bright, no foreign body |
| Acidity | 4.60 | 4.63 | 4.65 |
| The clarity of solution and change color | 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, no foreign body | Clear and bright, no foreign body | Clear and bright, no foreign body |
| The clarity of solution and change color | 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 |
The result shows, the methionine of the present invention plain B that supports one's family
1The aqueous solution of lyophilized injectable powder is at above-mentioned various experimental condition held 10 days, each item index, vitamin B
1With the content bacterium of methionine, all do not have a significant change.And at moisture, related substance (impurity) content and methionine content and vitamin B
1The content aspect obviously is superior to 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. lyophilizing effect comparative experimentss
(like product of write out a prescription a), sorbitol (prescription b) being made proppant carries out the experiment of lyophilizing effect according to the embodiment of the invention 2 and 6 methods to the product that embodiment 2,6 is obtained, and the result sees table 7. with selecting mannitol for use
Table 7. lyophilizing 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 | Be prone to molten, clear and bright, microgranule arranged |
The result shows, the methionine of the present invention plain B that supports one's family
1The lyophilizing effect of lyophilized injectable powder and solubility all are superior to selecting for use the mannitol (like product of write out a prescription a), sorbitol (prescription b) being made proppant.
Experimental example 4. stable comparative experimentss
Select for use mannitol (be called for short a), the like product of sorbitol+sodium pyrosulfite (being called for short b) sample as a comparison, the product that obtains with the embodiment of the invention 2 (hereinafter to be referred as A), embodiment 6 (hereinafter to be referred as B) carries out the stability experiment contrast, the result sees 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 shows that 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 superior to selecting for use the similar freeze-dried powder of mannitol, sorbitol+sodium pyrosulfite.
The present invention is not limited to above-mentioned embodiment, and other any identical with the present invention or akin products that anyone draws under enlightenment of the present invention all are not precluded within outside protection scope of the present invention.
Claims (10)
1. a methionine plain B that supports one's family
1Composite injection is characterized in that, said composition contains methionine 5-20 weight portion, vitamin B
11 weight portion.
2. composite injection as claimed in claim 1 is characterized in that, the said composition injection is freeze-dried powder or liquid drugs injection.
3. composite injection as claimed in claim 1 is characterized in that the said composition injection is a freeze-dried powder, contains methionine 10 weight portions, vitamin B
11 weight portion.
4. like claim 1 or 2 or 3 described composite injections, it is characterized in that the said composition injection also contains antioxidant, this antioxidant is Vc or cysteine 0.01-0.05 weight portion.
5. composite injection as claimed in claim 4 is characterized in that, said composition is by methionine 5-20 weight portion, vitamin B
11 weight portion and antioxidant 0.01-0.05 weight portion are formed; This antioxidant is Vc or cysteine.
6. the method for preparing of the said composite injection of claim 1 is characterized in that, this method is:
(1) earlier with 40 ℃-70 ℃ water for injection dissolving methionine, 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 reduced 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, replenishes water for injection to solution total amount, adds needle-use activated carbon, filters, and this amount of activated is the 0.1-0.2% (g/ml) of solution total amount;
(4) solution embedding after the filtration that (3) is obtained or bottling postlyophilization obtain described methionyl vitamin B
1Composite injection.
7. method for preparing as claimed in claim 6 is characterized in that, the described lyophilization of step in this method (4) is:
(1) pre-freeze is placed on solution bottling in the freezing cabinet and is cooled to-3 ℃～-5 ℃, is incubated 1-2 hour, is cooled to-40 ℃ again, is incubated freezing 2-3 hour;
(2) distillation is cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 8-10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said methionine plain B that supports one's family
1The freeze-dried powder of compositions.
8. method for preparing as claimed in claim 6 is characterized in that, with 40 ℃～70 ℃ water for injection dissolving methionine, adds the cysteine of antioxidant 0.01～0.05 weight portion simultaneously again in the said step (1); Perhaps, in said step (2), vitaminize B
1The blended Vc that adds antioxidant 0.01～0.05 weight portion simultaneously, mixed dissolution.
9. method for preparing as claimed in claim 8 is characterized in that, this method is:
(1) earlier with 40 ℃-70 ℃ water for injection dissolving methionine, 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 reduces 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, replenishes water for injection to solution total amount, adds needle-use activated carbon and filters, and this amount of activated 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 solution bottling in the freezing cabinet and are cooled to-3 ℃～-5 ℃, are incubated 1-2 hour, are cooled to-40 ℃ again, are incubated freezing 2-3 hour;
B, distillation are cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 8-10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said methionine plain B that supports one's family
1The freeze-dried powder of compositions.
10. method for preparing as claimed in claim 8 is characterized in that, this method is:
(1) earlier with 40 ℃-70 ℃ water for injection dissolving methionine, 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 reduces 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, replenishes water for injection to solution total amount, adds needle-use activated carbon, filters, and this amount of activated 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 going in the freezing cabinet after the solution bottling, are cooled to-3 ℃～-5 ℃ earlier, keep 1-2 hour, cool the temperature to-40 ℃ again, are incubated freezing 2-3 hour;
B, distillation are cooled to-45 ℃ again, and evacuation when vacuum arrives 10Pa, keeps vacuum 10Pa, heats up, and is 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 finishes, the nitrogen of wadding warp aseptic filtration in freeze drying box again; At least twice is evacuated to 8-10Pa in the process of filling nitrogen; Keep vacuum and nitrogen environment in the freeze drying box, automatic tamponade under vacuum condition then obtains the said methionine plain B that supports one's family
1The freeze-dried powder of compositions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210265065.XA CN102743350B (en) | 2012-07-30 | 2012-07-30 | Methionine vitamin B1Injection composition and its preparing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210265065.XA CN102743350B (en) | 2012-07-30 | 2012-07-30 | Methionine vitamin B1Injection composition and its preparing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102743350A true CN102743350A (en) | 2012-10-24 |
| CN102743350B CN102743350B (en) | 2013-06-19 |
Family
ID=47024087
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210265065.XA Active CN102743350B (en) | 2012-07-30 | 2012-07-30 | Methionine vitamin B1Injection composition and its preparing method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102743350B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412896A (en) * | 2016-01-06 | 2016-03-23 | 鲁南制药集团股份有限公司 | Method for avoiding reduction of vitamin B1 content in Anshen Bunao syrup |
| CN110302150A (en) * | 2019-08-07 | 2019-10-08 | 成都市海通药业有限公司 | Methionine-vitamin B 1 injection and its preparation method |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2012
- 2012-07-30 CN CN201210265065.XA patent/CN102743350B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412896A (en) * | 2016-01-06 | 2016-03-23 | 鲁南制药集团股份有限公司 | Method for avoiding reduction of vitamin B1 content in Anshen Bunao syrup |
| CN110302150A (en) * | 2019-08-07 | 2019-10-08 | 成都市海通药业有限公司 | Methionine-vitamin B 1 injection and its preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102743350B (en) | 2013-06-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100484525C (en) | Pantoprazole sodium freeze-dried powder injection and preparing method thereof | |
| CN102106833B (en) | Pemetrexed disodium freeze-dried powder injection and preparation method thereof | |
| CN100506217C (en) | Ambroxol hydrochloride freeze-dried powder injection and preparing method thereof | |
| CN100560062C (en) | A kind of clindamycin phosphate freeze-dried powder needle and preparation method thereof | |
| CN101627996B (en) | Rabeprazole sodium composition and preparation method thereof | |
| CN102327238A (en) | Levocarnitine composition for injection and preparation method of levocarnitine composition | |
| CN101711746B (en) | Ganciclovir freeze-dry preparation for injection and preparation method thereof | |
| CN105078906A (en) | Urokinase-containing pharmaceutical lyophilized preparation and preparation method thereof | |
| CN102247373B (en) | Composition of methionine vitamin B1 compound | |
| CN102743350B (en) | Methionine vitamin B1Injection composition and its preparing method | |
| CN102091046B (en) | Fludarabine phosphate freeze-dried powder injection and preparation method thereof | |
| CN101181243A (en) | Adenosine cyclophosphate freeze-dry preparations and preparation method thereof | |
| CN102743351B (en) | Pantoprazole sodium freeze-dried medicinal composition and preparation method thereof | |
| CN101683356A (en) | Water-soluble vitamin preparation for injection and preparation method thereof | |
| CN103417474B (en) | Calcium dibutyacyladenosine cyclophosphate-containing composition for injection | |
| CN102657663B (en) | Fat-soluble composite vitamin I composition freeze-dried powder injection and preparation method thereof | |
| CN101195582A (en) | Cinnamic amide derivant | |
| CN100496464C (en) | Folic acid freeze-dried injection and preparation thereof | |
| CN104697298B (en) | A kind of lyophilizing technique of water soluble vitamins | |
| CN102512382B (en) | Esomeprazole sodium pharmaceutical composition for injection | |
| CN102166198A (en) | Stable naloxone hydrochloride freeze-dry preparation and preparation method thereof | |
| CN108175750A (en) | A kind of freeze-drying method of azithromycin injection | |
| CN101810620B (en) | Methionine-vitamin B1 composite injection and preparation method thereof | |
| CN102846563A (en) | Injection composition of pemetrexed disodium and preparation method of injection composition | |
| CN107616967A (en) | A kind of double auxiliary material injection esomeprazole sodium freeze-dried powder injections |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
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 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| TR01 | Transfer of patent right |
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 |
|
| TR01 | Transfer of patent right |