CN1262277C - Injection of low molecular weight chondroitin sulfate and its prepn. method - Google Patents
Injection of low molecular weight chondroitin sulfate and its prepn. method Download PDFInfo
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- CN1262277C CN1262277C CN 200310119302 CN200310119302A CN1262277C CN 1262277 C CN1262277 C CN 1262277C CN 200310119302 CN200310119302 CN 200310119302 CN 200310119302 A CN200310119302 A CN 200310119302A CN 1262277 C CN1262277 C CN 1262277C
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Abstract
The present invention discloses an injection of low molecular weight chondroitin sulfate and a preparation method thereof. The low molecular weight chondroitin sulfate injection contains low molecular weight chondroitin sulfate and/or salts thereof whose average molecular weight is in the range of 2, 000 to 10, 000 dalton, and medicinal addition agents can be added into the low molecular weight chondroitin sulfate injection, wherein the contained low molecular weight chondroitin sulfate is prepared by a hyperfiltration technology and a nanofiltration technology. Compared with a common chondroitin sulfate injection, the chondroitin sulfate injection of the present invention has the advantages of low molecular weight, high purity and favorable pharmacological activity.
Description
Technical field
The present invention relates to a kind of low-molecular weight chondroitin sulfate injection and preparation method thereof, specifically, the present invention relates to a kind of molecular weight, 000-10, low-molecular weight chondroitin sulfate injection between 000 dalton and preparation method thereof 2.
Background technology
Chondroitin sulfate be a kind of with animals such as pig, cattle, sheep cartilaginous tissue and the cartilage of aquatic products such as shark be raw material, the macromolecular acid mucopolysaccharides that utilizes biochemical extraction process technology to make.The sodium salt of chondroitin sulfate, potassium salt, calcium salt, zinc salt etc. are widely used in medicine, health promoting product, food, cosmetics, feed for pet etc., for example chondroitin sulfate can be used as hypolipidemic, be used for the clinical treatment hyperlipidemia, the effect that the chondroitin sulfate A sodium injection then has blood fat reducing, the formation of anti-atherogenic speckle, anticoagulant and reduces the body oxygen consumption can be used for the treatment of atheromatosis, angina pectoris, hyperlipidemia etc.Chondroitin sulfate has different physiological roles, plays an important role keeping on tissue and the immune function, can be used to prevent and treat neuropathic pains such as coronary heart disease, treatment migraine, improve senile function of joint degeneration etc.
Commercially available chondroitin sulfate medicine mainly contains now: medicines such as oral dosage form (tablet, capsule), injection, eye drop.The crude drug that all medicines adopt is the water-soluble poly zoarium of bigger chondroitin sulfate A of molecular weight fluctuation range and chondroitin sulfate C, perhaps is the sodium salt of chondroitin sulfate A, chondroitin sulfate C.
The chondroitin sulfate product is normally about 40 with a kind of mean molecule quantity, 000-50, and 000 daltonian water-soluble polymer form exists, and wherein, sulphuric acid is connected on the disaccharide that repeats to combine with ehter bond.The chondroitin sulfate product is generally the mixture of chondroitin sulfate A and these two kinds of main configurations of chondroitin sulfate C.
The production method of chondroitin sulfate mainly contains three kinds: acid degradation, alkaline degradation, enzymatic isolation method, comparatively common with its sodium salt, also can produce chondroitin sulfate potassium salt, calcium salt or zinc salt, as disclosing chondroitin sulfate and production method thereof among CN 99112553.3 and the CN 99112554.1 as required.The chondroitin sulfate molecular weight difference that the different process method is produced, generally 20,000-50 is between 000 dalton.There are big, the shortcomings such as oral absorption is poor, bioavailability is low, curative effect instability of molecular weight fluctuation in common chondroitin sulfate medicine.But up to now,, still there is not clear and definite national drug standards requirement for the molecular weight ranges of chondroitin sulfate medicine.
The production technology of medicinal chondroitin sulfate raw material and technology, usually must obtain the official approval of national drug administrative service division, the mean molecule quantity of resulting chondroitin sulfate pharmaceutical injection raw material is at 5000-50, between 000 dalton, the mean molecule quantity of chondroitin sulfate A is 50,000 dalton, the mean molecule quantity of chondroitin sulfate C is 25,000 dalton.Medicines such as existing chondroitin sulfate A sodium injection are still got by the bigger chondroitin sulfate crude drug preparation of molecular weight fluctuation range.
But in fact, the biological activity of chondroitin sulfate is different and different with molecular weight, and its pharmacologically active and molecular weight have confidential relation.U.S. Pat 3,405 discloses in 120, when the mean molecule quantity of chondroitin sulfate 2,000-6, during 000 dalton, its pharmacologically active is the strongest, has better therapeutic to preventing and treating atherosclerosis, rheumatic inflammation and wound healing etc.So low-molecular-weight chondroitin sulfate has better clinical effect than the chondroitin sulfate of common molecular weight.
Prior art discloses the multiple method for preparing low-molecular weight chondroitin sulfate, for example U.S. Pat 3, enzymatic isolation method among ion-exchange-resin process among acid-hydrolysis method in 405,120, Japan special permission 70-04734 and the 74-30817 and the Japan special permission 73-14078 etc.Though these methods all can prepare low-molecular-weight chondroitin sulfate, but be not further purified separation steps in its preparation method, as US3,405, sour decomposition of the mixture in 120 precipitates not carrying out just adding ethanol under the isolating prerequisite, thereby prepared product purity is not high, is unsuitable for preparing the medicine of injection type.
Because at present there is not the Technology of producing low-molecular weight chondroitin sulfate in China, and the separating and purifying technology of low-molecular-weight chondroitin sulfate both domestic and external do not reach a standard as yet, and therefore the injection listing of this medicine is not arranged always.At present, there is not molecular weight to be lower than 10,000 daltonian products in the chondroitin sulfate of selling on the China market.Low-molecular-weight chondroitin sulfate is better than the pharmacologically active of the uncertain common chondroitin sulfate of molecular weight, and easier absorption.Therefore, necessaryly develop a kind of method for preparing low-molecular-weight chondroitin sulfate, and low-molecular-weight chondroitin sulfate is made the appropriate drug dosage form.
Summary of the invention
One of purpose of the present invention provides a kind of low-molecular weight chondroitin sulfate injection.
In low-molecular weight chondroitin sulfate injection of the present invention (or claiming injection), the mean molecule quantity of contained low-molecular weight chondroitin sulfate is 2,000-10,000 dalton, it can be selected from chondroitin sulfate A, the sodium salt of chondroitin sulfate A, the potassium salt of chondroitin sulfate A, the calcium salt of chondroitin sulfate A, the zinc salt of chondroitin sulfate A, the iron salt of chondroitin sulfate A, the magnesium salt of chondroitin sulfate A, the aluminum salt of chondroitin sulfate A, chondroitin sulfate C, the sodium salt of chondroitin sulfate C, the potassium salt of chondroitin sulfate C, the calcium salt of chondroitin sulfate C, the zinc salt of chondroitin sulfate C, the iron salt of chondroitin sulfate C, the magnesium salt of chondroitin sulfate C and in the chondroitin sulfate C one or more; This injection is an aqueous injection, and can contain pharmaceutically acceptable additives.
Preferably, in the low-molecular weight chondroitin sulfate injection of the present invention, the mean molecule quantity of contained low-molecular weight chondroitin sulfate is 2,000-8,000 dalton.
Among the present invention, low-molecular weight chondroitin sulfate is preferably selected from one or more in the calcium salt of the potassium salt of the sodium salt of the calcium salt of the potassium salt of the sodium salt of chondroitin sulfate A, chondroitin sulfate A, chondroitin sulfate A, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate C, chondroitin sulfate C and chondroitin sulfate C; More preferably, low-molecular weight chondroitin sulfate is selected from one or more in the sodium salt of sodium salt, chondroitin sulfate C and chondroitin sulfate C of chondroitin sulfate A, chondroitin sulfate A.
In the low-molecular weight chondroitin sulfate injection of the present invention, the additives that added are to be selected from sodium chloride, glucose, fructose and the lactose one or more, excipient substance such as the antioxidant, isoosmotic adjusting agent, solubilizing agent, antibacterial, local anesthetic, buffer agent that also can comprise other, also can be as required, add other additives, for example, contain in the prescription, can add local anesthetic the irritant material of blood vessel; The material that contains easy oxidation can add antioxidant such as sodium sulfite, sodium sulfite; Contain the material that easily becomes sour and to add antibacterial such as benzyl alcohol, phenol, phenylmercuric nitrate.
Above-mentioned low-molecular weight chondroitin sulfate injection can comprise that low-molecular-weight chondroitin sulfate B etc. does not have too big effect to the performance drug effect and can not produce the material of toxic and side effects, but does not preferably contain this type of material.
In above-mentioned low-molecular weight chondroitin sulfate injection, the low-molecular weight chondroitin sulfate that is adopted is to prepare with the method that comprises the steps:
(1) chondroitin sulfate with common molecular weight carries out acid hydrolysis;
(2) product behind the above-mentioned acid hydrolysis carries out the alkali neutralization, is adjusted under the alkali condition of pH=8-11, carries out centrifugalize then, removes the precipitation of foreigh protein removing;
(3) transfer pH to neutral the supernatant of above-mentioned steps (2) gained, carry out ultrafiltration then, hold back chondroitin sulfate and the impurity of removing macromolecule;
(4) filtrate of step (3) gained is carried out nanofiltration and concentrate, remove small molecular weight impurity.Another object of the present invention provides a kind of method for preparing the low-molecular weight chondroitin sulfate injection.
The method that the present invention prepares the low-molecular weight chondroitin sulfate injection comprises the steps:
(1) chondroitin sulfate with common molecular weight carries out acid hydrolysis;
(2) product behind the above-mentioned acid hydrolysis carries out the alkali neutralization, is adjusted under the alkali condition of pH=8-11, carries out centrifugalize then, removes the precipitation of foreigh protein removing;
(3) transfer pH to neutral the supernatant of above-mentioned steps (2) gained, adopt ultrafilter membrane to carry out single-stage ultrafiltration or multi-ultrafiltration then, hold back and remove mean molecule quantity greater than 10,000 daltonian chondroitin sulfate and impurity;
(4) filtrate of step (3) gained is carried out nanofiltration with NF membrane and concentrate, hold back and remove mean molecule quantity less than 2,000 daltonian chondroitin sulfate and impurity;
(5) concentrated solution with step (4) gained carries out spray drying or adds ethanol carrying out crystalline deposit, obtains low-molecular weight chondroitin sulfate;
(6) low-molecular weight chondroitin sulfate that makes in the step (5) is dissolved in the water for injection, and adds the injection active carbon, heat tracing filters decarburization then, fill, seals, and promptly makes the low-molecular weight chondroitin sulfate injection.
In the said method, the chondroitin sulfate of the common molecular weight in the step (1) can be commercially available chondroitin sulfate.If what adopt is commercially available chondroitin sulfate crude product, then can directly carry out acid hydrolysis.Certainly, also can directly set out, obtain the chondroitin sulfate crude product by methods such as alkali liquor extraction, enzymolysis earlier, carry out acid hydrolysis again by the animal cartilage tissue.Like this, before acid hydrolysis, can comprise steps such as alkali liquor extraction and/or enzymolysis, but these steps are optional.
The employed acid of acid hydrolysis can be to be selected from a kind of in hydrochloric acid, sulphuric acid, nitric acid and the oxalic acid in the above-mentioned steps (1), and preferably selects the higher acid of concentration for use, and for example selecting concentration for use is the acid of 0.1-1N.Acid-hydrolyzed effect is to obtain low-molecular-weight chondroitin sulfate.If carry out acid hydrolysis with commercial sulfuric acid chrondroitin crude product, then the acid hydrolysis temperature can be controlled in the 40-90 ℃ of scope, is preferably 60-80 ℃.Hydrolysis time generally can be controlled in 3-12 hour, is preferably 8-10 hour.
In fact, step (1) can also adopt additive method, for example ion-exchange-resin process, enzymatic isolation method etc. except adopting acid-hydrolysis method.
In the above-mentioned steps (2), earlier the pH value of step (1) acid hydrolysis products is transferred to the faintly acid scope and can stop acid hydrolytic reaction with alkaline matter, used alkaline matter can be sodium hydroxide, potassium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate etc., is preferably weak base such as sodium bicarbonate, sodium bicarbonate; Then, continue to be adjusted under the alkali condition of pH=8-11, carry out centrifugalize then, remove the precipitation of foreigh protein removing.During centrifugalize, preferably use continuous flow centrifuge to carry out the separation of foreign protein.Compare with traditional filter cloth, manger Filtration, this separate mode effective, loss is low, production efficiency is high.
In the above-mentioned steps (3), the effect of ultrafiltration is the macromole impurity of removing in the low-molecular weight chondroitin sulfate, for example protein, polysaccharide etc., and the nonconforming chondroitin sulfate of molecular cut off.So-called ultrafiltration (being called for short UF) is meant with pressure to be motive force, utilizes the different apertures of ultrafilter membrane that liquid is carried out isolating physics screening process.The molecular cut off of ultrafiltration (CWCO) is generally 6,000 to 500,000 dalton.In fact, ultrafiltration and nanofiltration (NF) all belong to membrane separation technique, promptly utilizing the difference of diffusion barrier to each components selection osmosis performance in the mixture, is that motive force is to bi-component or the blended gas of multicomponent or liquid separates, the method for classification, purification and enrichment with outside energy or chemical potential difference.The filter membrane that ultrafiltration is used can be held back the impurity of different molecular weight size, and the average molecular weight range of holding back is 3, and 000-50 is about 000 dalton.Because the molecular weight ranges of low-molecular weight chondroitin sulfate is 2,000-10,000 dalton, and the mean molecule quantity of protein, polysaccharide is usually greater than 10,000 dalton, therefore, removing impurity, preferably to adopt interception be 10,000 daltonian filter membranes.In addition, comparatively serious because the viscosity of low-molecular weight chondroitin sulfate is bigger to the pollution of ultrafilter membrane, therefore, preferably adopt polyacrylonitrile film, sulfuration polysulfone membrane etc.
Ultrafiltration in the above-mentioned steps (3) can be single-stage ultrafiltration or multi-ultrafiltration.Three grades of ultrafiltration of preferred employing are held back and are removed mean molecule quantity greater than 8,000 daltonian chondroitin sulfate and impurity.
Nanofiltration in the above-mentioned steps (4) can be played effect concentrated, that remove small molecular weight impurity such as salt.So-called nanofiltration (being called for short NF) is meant that the aperture of diffusion barrier is in nanoscale, is suitable for the isolated molecule amount 200～2,000, molecular dimension is about the membrane process of the dissolved constituent of 1nm.The transmembrane pressure that the NF membrance separation needs is generally 0.5～2.0MPa, hangs down 0.5～3MPa than reach the pressure reduction that same infiltration energy institute must apply with reverse osmosis membrane.According to operating pressure and stall limit, can NF be come between reverse osmosis and the ultrafiltration qualitatively, also there is the people NF to be called " low pressure reverse osmosis " or " loose reverse osmosis ".The NF technical development is very fast, and the NF membrane module is in the mid-80 commercialization.The interception capacity of nanofiltration can be held back mean molecule quantity at 200-2, the material about 000 dalton greater than ultrafiltration.Compare with reverse osmosis with ultrafiltration, the advantage of nanofiltration is the Organic substance that can hold back through that part of small-molecular weight of ultrafilter membrane, the inorganic salt that the reverse osmosis membrane of dialysing is again held back---promptly concentrate and carry out synchronously with desalination; And under equal impressed pressure, the flux of nanofiltration is more much bigger than reverse osmosis; When flux one regularly, the required pressure of nanofiltration is more much lower than the reverse osmosis.So substitute reverse osmosis with the nanofiltration method, " concentrating " process can be carried out more effectively and quickly, and reaches bigger " concentrating " multiple.Adopt ultrafiltration merely, do not reach the purpose of desalination even multi-ultrafiltration also can only play spissated effect, and concentrating efficiency is low.Therefore, the present invention adopts that the method for nanofiltration concentrates, desalination, and is more more effective, easy, quick than ultrafiltration, improved the efficient of suitability for industrialized production greatly.
Preferably, it is to hold back to remove mean molecule quantity less than 2,000 daltonian chondroitin sulfate and impurity that the nanofiltration in the above-mentioned steps (4) concentrates, and especially removes small molecular weight impurity, inorganic salt and moisture.
In the above-mentioned steps (5), the low-molecular weight chondroitin sulfate concentrated solution that obtains by nanofiltration can convection drying, carries out drying as adopting nebulization; Also can in concentrated solution, add ethanol organic solvents such as (2-8 doubly) and carry out crystalline deposit, carry out drying then.If select for use Ethanol Method to precipitate, then concentration of ethanol is preferably 95%.Preferably adopt vacuum drying when dry.Compare with traditional ethanol precipitation, crystallization, drying process, spray drying method has that production efficiency height, loss are low, product does not have that ethanol is residual, moisture is easy to control, be convenient to advantage such as suitability for industrialized production.
In the step (6) of said method, low-molecular weight chondroitin sulfate can directly add the injection water and dissolve, and also can earlier and add the dissolving of injection water behind the solubilizing agent mixing again.If also have the other drug composition in the injection except low-molecular weight chondroitin sulfate, for example: glucose, sodium chloride then can join them in the solution together and makes its dissolving.Certainly, can also add other medicinal additive as required.
In the step (6) of said method, the main purpose that adds the injection active carbon is decolouring, can certainly adopt other discoloration method.Because low-molecular weight chondroitin sulfate is a kind of mucopolysaccharide, the temperature that therefore adds heat decoloring is unsuitable too high, is preferably 60-70 ℃; Bleaching time is also unsuitable long, is preferably 15-30 minute.
In the step (6) of said method, the used device of filtering decarbonization can be husky filter stick, glass sintered filter funnel etc.
In the step (6) of above-mentioned method, can be to the container of the peace bottle of all size or other styles with the low-molecular weight chondroitin sulfate fill, for example penicillin bottle, infusion bottle etc.
In the step (6) of said method, can carry out clarity of injection, pyrogen, quality examination such as aseptic by officinal regulation.
Because the present invention utilizes different ultrafilter membrane of molecular cut off and NF membrane, therefore can isolate the low-molecular weight chondroitin sulfate product of various different molecular weights easily as required, for example mean molecule quantity is 2,000-4,000,4,000-6,000,6,000-8,000,8,000-10,000 daltonian low-molecular weight chondroitin sulfate product, thus can prepare the low-molecular weight chondroitin sulfate injection of various different molecular weights easily.
The present invention adopts ultrafiltration, Nanofiltering membrane grading purification chondroitin sulfate, has characteristics such as efficient, energy-conservation, pollution-free, and the product quality height, dried agent content even can reach more than 99%.
Below in conjunction with embodiment, further specify the present invention, but the present invention is not limited to these embodiment, any on essence spirit of the present invention improvement or substitute, still belong to scope required for protection in claims of the present invention.
The specific embodiment
The preparation of embodiment 1 low-molecular weight chondroitin sulfate
1300 liters of deionized waters are placed in the interlayer retort, be heated to 65 ℃, add 30 kilograms of commercial sulfuric acid chrondroitin (mean molecule quantities 59,000 dalton) crude product, stirring and dissolving, solution adds 26 liters of 36% hydrochloric acid, add deionized water to 1500 liter, make the concentration of hydrochloric acid of solution be about 0.2N.Insulation and stirring reaction are after 10 hours, and cooling adds 4% sodium hydrate aqueous solution rapidly, and the pH value that makes solution removes the precipitation of foreigh protein removing then with continuous flow centrifuge about 9.0.The supernatant of gained filters with ultrafilter membrane, and the reuse NF membrane concentrates, and concentrated solution carries out spray drying, obtains 27.6 kilograms of white low-molecular weight chondroitin sulfates (mean molecule quantity 3700 dalton).
The preparation of embodiment 2 low-molecular weight chondroitin sulfates
1300 liters of deionized waters are placed in the interlayer retort, be heated to 80 ℃, add 30 kilograms of commercial sulfuric acid chrondroitin (mean molecule quantities 51,000 dalton) crude product, stirring and dissolving, solution adds 13.5 kilograms of oxalic acid, add deionized water to 1500 liter, make the concentration of hydrochloric acid of solution be about 0.1N.Insulation and stirring reaction are after 12 hours, and cooling adds 16 kilograms of calcium carbonate rapidly, and behind the separation calcium oxalate precipitation, the pH value that makes solution removes the precipitation of foreigh protein removing then with continuous flow centrifuge about 9.5.The supernatant ultrafiltration membrance filter of gained, NF membrane concentrates, and concentrated solution carries out spray drying, obtains 22.8 kilograms of white low-molecular weight chondroitin sulfates (mean molecule quantity 6300 dalton).
The preparation of embodiment 3 low-molecular weight chondroitin sulfates
650 liters of deionized waters are placed in the interlayer retort, be heated to 73 ℃, add 40 kilograms of commercial sulfuric acid chrondroitin (mean molecule quantities 51,000 dalton), stirring and dissolving, solution adds 11.2 liters of 36% hydrochloric acid, add deionized water to 1500 liter, make the concentration of hydrochloric acid of solution be about 0.2N.Insulation and stirring reaction are after 8.5 hours, and cooling adds 6.8 kilograms of sodium carbonate rapidly, and the pH value that makes solution removes the precipitation of foreigh protein removing then with continuous flow centrifuge about 10.0.The supernatant ultrafiltration membrance filter of gained, NF membrane concentrates, and concentrated solution carries out spray drying, obtains 37 kilograms of white low-molecular weight chondroitin sulfates (mean molecule quantity 4400 dalton).
The preparation of embodiment 4 low-molecular weight chondroitin sulfates
According to a conventional method by the animal cartilage of pulverizing, after alkaline extraction, acid neutralization, enzyme hydrolysis, the hydrochloric acid of adding 36%, the acidity that makes solution is at 0.1-5N, under 35-95 ℃ condition, acid hydrolysis 3-12 hour, add pH value that alkali makes solution about 10.5, remove the precipitation of foreigh protein removing then with continuous flow centrifuge.The supernatant of gained carries out ultrafiltration, removes macromole impurity, after carrying out nanofiltration again and concentrating, carries out spray drying at last, obtains mean molecule quantity less than 10,000 daltonian low-molecular weight chondroitin sulfate products.
The preparation of embodiment 5 low-molecular weight chondroitin sulfate injections
Injection prescription: per 1000 consumptions
Low-molecular weight chondroitin sulfate (by anhydride) 80g
Water for injection adds to 2L
Its preparation method is: low-molecular weight chondroitin sulfate is fed intake by 105% of recipe quantity, be dissolved in water, add water to volume, mixing, 60-70 ℃ and insulation add 0.1% injection active carbon, and 60-70 ℃ adds insulation about 20 minutes, the glass sintered filter funnel filters decarburization, fill is sealed, 115 ℃ of pressure sterilizings 30 minutes, quality examination promptly gets the low-molecular weight chondroitin sulfate injection of 2ml.
The preparation of embodiment 6 low-molecular weight chondroitin sulfate injections
Injection prescription: per 1000 consumptions
Low-molecular weight chondroitin sulfate (by anhydride) 100g
Sodium chloride 900g
Water for injection adds to 100L
Its preparation method is: low-molecular weight chondroitin sulfate is fed intake by 105% of recipe quantity, be dissolved in water, add the sodium chloride dissolving, add water to volume, mixing, 60-70 ℃ and insulation; Add 0.3% injection active carbon, 60-70 ℃ adds insulation about 20 minutes, and husky filter stick filters decarburization, and fill is sealed, 120 ℃ of pressure sterilizings 30 minutes, and quality examination promptly gets the low-molecular weight chondroitin sulfate injection of 100ml.
The preparation of embodiment 7 low-molecular weight chondroitin sulfate injections
Injection prescription: per 1000 bottles of consumptions
Low-molecular weight chondroitin sulfate (by anhydride) 100g
Glucose 500g
Water for injection adds to 250L
Its preparation method is: the principal agent low-molecular weight chondroitin sulfate is fed intake by 105% of recipe quantity, be dissolved in water, add the glucose dissolving, add water to volume, mixing, 60-70 ℃ and insulation, add 0.5% injection active carbon, 60-70 ℃ adds insulation about 20 minutes, and Sha Xin filters decarburization, fill is sealed; 120 ℃ of pressure sterilizings 30 minutes, quality examination, the low-molecular weight chondroitin sulfate glucose injection agent that promptly gets 250ml.
The preparation of embodiment 8 low-molecular weight chondroitin sulfate injections
Injection prescription: per 1000 bottles of consumptions
Low-molecular weight chondroitin sulfate (by anhydride) 100g
Chlorination 450g
Fructus Vitis viniferae 500g
Water for injection adds to 500L
Its preparation method is: the principal agent low-molecular weight chondroitin sulfate is fed intake by 105% of recipe quantity, be dissolved in water, add sodium chloride, glucose dissolving, add water to volume, mixing, 60-70 ℃ and insulation, add 0.1% injection active carbon, 60-70 ℃ adds insulation about 20 minutes, and Sha Xin filters decarburization, fill, seal, 115 ℃ of pressure sterilizings 30 minutes, quality examination promptly gets the low-molecular weight chondroitin sulfate glucose sodium chloride injection of 500ml.
Claims (4)
1, a kind of preparation method of low-molecular weight chondroitin sulfate injection, this method comprises the steps:
(1) chondroitin sulfate with common molecular weight carries out acid hydrolysis;
(2) product behind the above-mentioned acid hydrolysis is carried out the alkali neutralization, be adjusted under the alkali condition of pH=8-11, carry out centrifugalize then, remove the precipitation of foreigh protein removing;
(3) transfer pH to neutral the supernatant of above-mentioned steps (2) gained, adopt ultrafilter membrane to carry out single-stage ultrafiltration or multi-ultrafiltration then, hold back and remove mean molecule quantity greater than 10,000 daltonian chondroitin sulfate and impurity;
(4) filtrate of step (3) gained is carried out nanofiltration with NF membrane and concentrate, hold back and remove mean molecule quantity less than 2,000 daltonian chondroitin sulfate and impurity;
(5) concentrated solution with step (4) gained carries out spray drying or adds ethanol carrying out crystalline deposit, obtains low-molecular weight chondroitin sulfate;
(6) low-molecular weight chondroitin sulfate that makes in the step (5) is dissolved in the water for injection, and adds the injection active carbon, heat tracing filters decarburization then, fill, seals, and promptly makes the low-molecular weight chondroitin sulfate injection.
2, the preparation method of low-molecular weight chondroitin sulfate injection as claimed in claim 1 is characterized in that, the employed acid of acid hydrolysis is to be selected from a kind of in hydrochloric acid, sulphuric acid, nitric acid and the oxalic acid in the step (1).
3, the preparation method of low-molecular weight chondroitin sulfate injection as claimed in claim 1 is characterized in that, the centrifugalize described in the step (2) is carried out in continuous flow centrifuge.
4, the preparation method of low-molecular weight chondroitin sulfate injection as claimed in claim 1, it is characterized in that, ultrafiltration described in the step (3) is to adopt ultrafilter membrane to carry out three grades of ultrafiltration, holds back and removes mean molecule quantity greater than 8,000 daltonian chondroitin sulfate and impurity.
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| CN 200310119302 CN1262277C (en) | 2003-05-07 | 2003-12-03 | Injection of low molecular weight chondroitin sulfate and its prepn. method |
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| CN03114374.1 | 2003-05-07 | ||
| CNA031143741A CN1470245A (en) | 2003-05-07 | 2003-05-07 | Low-molecular-weight chondroitin sulfate injecta and its preparation method |
| CN 200310119302 CN1262277C (en) | 2003-05-07 | 2003-12-03 | Injection of low molecular weight chondroitin sulfate and its prepn. method |
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| CN1262277C true CN1262277C (en) | 2006-07-05 |
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Cited By (1)
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| EP4053290A4 (en) * | 2019-11-01 | 2024-01-17 | Nanjing Hanxin Pharmaceutical Tech Co Ltd | Low molecular weight chondroitin sulfate, composition containing same, and preparation method therefor and use thereof |
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| CN107936139A (en) * | 2016-10-12 | 2018-04-20 | 山东万邦赛诺康生化制药股份有限公司 | A kind of preparation process of dermatan sulfate |
| CN109431986A (en) * | 2018-12-17 | 2019-03-08 | 江西润泽药业有限公司 | Chondroitin sulfate injection and preparation method thereof |
| WO2021179319A1 (en) * | 2020-03-13 | 2021-09-16 | 南京汉欣医药科技有限公司 | Composition containing hydrolyzed chondroitin sulfate for preventing and treating osteoarthropathy |
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| EP4053290A4 (en) * | 2019-11-01 | 2024-01-17 | Nanjing Hanxin Pharmaceutical Tech Co Ltd | Low molecular weight chondroitin sulfate, composition containing same, and preparation method therefor and use thereof |
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