CN100446775C - Chonsurid for venous injection administration and its preparing method - Google Patents
Chonsurid for venous injection administration and its preparing method Download PDFInfo
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- CN100446775C CN100446775C CNB2006100389227A CN200610038922A CN100446775C CN 100446775 C CN100446775 C CN 100446775C CN B2006100389227 A CNB2006100389227 A CN B2006100389227A CN 200610038922 A CN200610038922 A CN 200610038922A CN 100446775 C CN100446775 C CN 100446775C
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- Prior art keywords
- chondroitin sulfate
- injection
- acid
- preparation
- administration
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention discloses chondroitin sulfate which can be used for administration in an intravenous injection approach, and a preparation method of chondroitin sulfate. A preparation prepared from a purified chondroitin sulfate not only can be used for intramuscular injection, but also can be used for intravenous administration in the methods that the preparation is added into the infusion liquid of dextrose or physiological saline or is directly pushed and injected, etc. The use of the preparation is greatly convenient, and the pain of the intramuscular injection for administration for many times is reduced. The chondroitin sulfate with the purpose overcomes the defects of low purity and immunogenicity of the injection liquid of the chondroitin sulfate of the prior art. The chondroitin sulfate is directly injected to enter a blood circulation system. The chondroitin sulfate has the advantages of high blood drug concentration, rapid effect taking, favorable therapeutic effect and low side effects.
Description
Technical field
The present invention relates to a kind of high-purity preparing chondroitin sulfates free from foreign meter substantially, and contain this chondroitin sulfate is used for the intravenous route administration as effective ingredient preparation.
Background technology
Chondroitin sulfate (Chondroitin Sulfate, CS) be one of the main component of mammal connective tissue, mainly be distributed in cartilage, bone, tendon, ligament, sarolemma and the blood vessel wall, belong to the macromole acid mucopolysaccharides, industrial is raw material with the cartilage of aquatic products such as the cartilaginous tissues of animals such as pig, cattle, sheep and shark often, utilizes biochemical extraction process technology to make.
Up to the present, a lot of about the patent and the bibliographical information of chondroitin sulfate, but rarely found about the report that chondroitin sulfate extraction crude product is further purified extreme high purity.Because chondroitin sulfate is for extracting gained from biological tissue, the Animal fat of introducing in the production process, albumen, polypeptide and other impurity have become to cause the specificity substance of irritated, haemolysis and irritating property of generation reaction, and therefore the dosage form that chondroitin sulfate is made the direct administration of vein exists huge technical problem.Up to now, without any the report that effectively chondroitin sulfate is used for the direct administration of clinical vein.
Woods state equality research chondroitin sulfate process for refining adopts methods such as oxidation, filtration and precipitation to make with extra care, and satisfies the requirement " food and medicine, 2005,6 " of eye drop.Openly improve production technique of chondroitin sulfate on " Chinese biochemical drug magazine " (2005 1), improve chondroitin sulfate productive rate and content method, adopt useless pancreas slag to clean cartilage, temperature, time and pH value with orthogonal experiment design control enzyme hydrolysis, after absorption foreigh protein removing matter, with salt etc., improved productive rate.
Has delivered with pig larynx, tracheal cartilages and nasal cartilages " Zhengzhou University's journal (medicine) " (2005,01) is the method for the highly purified chondroitin sulfate of feedstock production.Extract pig larynx, tracheal cartilages and nasal cartilages tissue with the dense salt of diluted alkaline, selecting relative molecular mass is 10,000 cross-flow ultrafiltration film carries out purified method preparation, after the ultrafiltration, is that the chondroitin sulfate cellulose content that raw material makes increases by 16.83% and 11.75% respectively with pig larynx tracheal cartilages and nasal cartilages.The new technology that the upright a kind of chondroitin sulfate in high Huajian is produced is a raw material with the bovine nasal cartilage, adopts the method that increases alkali concn extraction, combinative enzyme hydrolysis and concentrate the back alcohol precipitation to inquire into process conditions.Under optimum experimental condition, obtaining chondroitin sulfate is white powder, and its purity reaches 95.2% (" University Of Qingdao's journal (engineering version) " 2003,04).
Shanghai University's school of life and health sciences has proposed the new technology that two enzymes are produced chondroitin sulfate, and steady quality and yield are improved, and Wang Shizhong has adopted that chondroitin sulfate becomes proteoglycan with protein bound in the cartilage, and combines with collagen protein.Adopt first high temperature steaming, after add dilute alkali to combine and extract this medicine with enzymolysis, behind the TCA precipitating proteins, Kaolin absorption, the reuse chloroform is stripped continuously, makes product quality reach top grade pure (" Acta Pharmaceutica Sinica " 1980,03).
CN1733809A has reported a kind of low-molecular-weight chondroitin sulfate preparation method, utilize commercial sulfuric acid chrondroitin crude product, through chondroitin sulfate enzymatic degradation, ultrafilter membrane concentrate, 95% special process such as alcohol crystal obtain the chondroitin sulfate that molecular weight is the molecular weight between 10000～15000 dalton.The CN1699428A invention has related to a kind of preparing chondroitin sulfates, passes through steaming and decocting processing, insulation or gentle leaching, enzymolysis, crosses methods such as filtering albumen, ultrafiltration purification, vacuum concentration, spray drying treatment.CN1654670A comprises the material processing, the higher chondroitin sulfate of content that lixiviate, filter and remove residue, the spissated step of filtrate obtain.
All these above-mentioned academic report or publication methods, it is very limited that the purity of the product of gained and yield are improved, therefore these products exist quite high impurity to cause irritated, haemolysis and the reaction of irritating property of generation and influence the clinical use of chondroitin sulfate, the raw material of all these products is applied to the pharmacy aspect at present, all can only be used for oral or intramuscular injection.
Chondroitin sulfate is the mixture of chondroitin sulfate A, two kinds of configurations of chondroitin sulfate C, has different physiological roles, of many uses, mainly be used in the treatment headache, neuropathic pains such as migraine, coronary heart disease, angina pectoris, play an important role keeping on tissue and the immune function, also can be used for anti-curing arthritis, improve veteran form function of joint degeneration etc.
At present the chondroitin sulfate preparation is all existing at home and abroad produces, the domestic injection type that has gone on the market, its clinical administration approach is intramuscular injection, one time 1, every day 1～2 time.Because its purity is low, there is certain limitation in route of administration, at all kinds of neuropathic pains with need fast or use during the disease of continued treatment all to be very limited.
The present invention relates to a kind of high-purity preparing chondroitin sulfates, and contain this chondroitin sulfate is used for the intravenous route administration as effective ingredient preparation, preclinical test shows, highly purified chondroitin sulfate is because its content improves, molecular weight concentrates on 30,000～50,000, impurity is few relatively, the preparation of making has reduced stimulation by the intravenous route administration and toxic and side effects, activity and curative effect are improved, and has also enlarged route of administration simultaneously, increases patient's compliance.Directly enter blood circulation by the direct administration of intravenous route without absorption process, increase curative effect, shortened onset time, made things convenient for clinical use, reduced the misery of frequent injection, and, can not produce allergy, haemolysis and the reaction of irritating property owing to removed impurity.
Summary of the invention
Order of the present invention is to provide highly purified chondroitin sulfate.
Another object of the present invention is to provide above-mentioned preparing chondroitin sulfates, Zhi Bei chondroitin sulfate by this method, and molecular weight distribution is 30,000～50,000 dalton.
Another purpose of the present invention is the chondroitin sulfate preparation that is to be provided for this route of administration of intravenous injection.
The present invention is by improving the purity of chondroitin sulfate raw material, its molecular weight ranges is controlled, raising is to the quality control standard of chondroitin sulfate preparation, impurities is carried out strict control, reduce the generation of clinical side reaction, and, prepare the chondroitin sulfate preparation that can be used for the intravenous administration approach safely and effectively by the preclinical test confirmation.
The present invention is as follows:
Can supply the chondroitin sulfate of intravenous route administration:
The content of its chondroitin sulfate is greater than 96%,
The advantage of this method is that the molecular weight ranges of acquisition chondroitin sulfate is 30,000～50,000 dalton, and the dispersion of distribution (Mw/Mn) should be less than 1.8.This has increased drug effect significantly, has reduced side effect, makes things convenient for the patient to use.
Below the high-purity preparing chondroitin sulfates is described in detail.
Adopting the chondroitin sulfate crude product of biological extraction is raw material, caustic-alkali aqueous solution heat treated 1h～2h through 10～20% (mass ratioes), temperature is controlled at 25～35 ℃, then gained liquid is carried out solid-liquid separation, with the solid-state aqueous solutions of organic acids that is partially dissolved in of gained, be more than 10 to wherein adding ethanol and caustic alkali to pH, the generation precipitation, with this washing of precipitate, drying, obtain the precipitation of chondroitin sulfate.
With precipitation, the dissolving of previous step gained, be mixed with 0.1～10% (w/v) solution, carry out ultrafiltration purification.Described ultrafiltration purification process, its molecular weight that dams is 30,000～50,000.
Raw material of the present invention is to extract the chondroitin sulfate that is distributed in cartilage, bone, tendon, ligament, sarolemma and the blood vessel wall by the whole bag of tricks, belong to the macromole acid mucopolysaccharides, the cartilage that extracts on the biology usually with aquatic products such as the cartilaginous tissues of animals such as pig, cattle, sheep and sharks is a raw material, utilizes biochemical extraction process technology to make.
When utilizing this chondroitin sulfate crude product for raw material, purity there is not special requirement, this is the another advantage that the present invention has: different purity chondroitin sulfate crude product is purified, can obtain highly purified product.
The caustic-alkali aqueous solution heat treated is for macromolecular polysaccharide in the polysaccharide is hydrolyzed to micromolecular polysaccharide, so the concentration of caustic-alkali aqueous solution is very important to the scope of the molecular weight that improves polysaccharide, and preferred range is 10～20%, and more preferably scope is 12～16%.
The caustic solution that the present invention uses, reactor can be: stainless steel ware, porcelain.Heat treated can be carried out under normal pressure, also can carry out under the environment of pressurization or decompression.
Certainly the time of caustic alkali heat treated is also very important to the scope of polysaccharide molecular weight, heat time heating time, length can cause that the polysaccharide molecule hydrolysis is complete, did not reach needed molecular weight ranges, and the time too weak point can cause hydrolysis incomplete, yield reduces, and therefore preferred time range is 1～2h.
In the present invention, the organic acid that is used to dissolve chondroitin sulfate is that pharmaceutical field is commonly used, includes but not limited in citric acid, malic acid, tartaric acid, oxalic acid, succinic acid, lactic acid and the acetic acid one or more.Wherein preferred organic acid is citric acid, malic acid and their mixture.
Viscosity increases, and can make later step process difficulty, therefore regulates distilled water, organic acid adding method, and its viscosity is reduced, and this is very important.
The concentration of medicinal liquid is very big to the influence of ultrafiltration, and suitable concentration can be accelerated the process of ultrafiltration, and makes that the molecular weight ranges of resultant chondroitin sulfate is little, and in this course, general 1～25% medicinal liquid all can carry out ultrafiltration, and preferred liquor strength is 1～10%.Its of selected ultrafiltration purification equipment molecular weight that dams is 30,000～50,000.
Through the chondroitin sulfate of such process preparation, the molecular weight ranges that it is characterized in that described chondroitin sulfate is 30,000～50,000 dalton.
Confirm by animal experiment, chondroitin sulfate 30,000～50,000 daltonian molecular weight can obviously reduce some side reactions, improves pharmaceutically-active performance, concrete following test meeting is described in detail this.
In addition, assay for chondroitin sulfate, adopted a kind of new method, domestic method of quality control to chondroitin sulfate mainly is the hydrolysis colorimetry at present, after hydrolysis, produce glucuronic acid and aminohexose, promptly be based upon aminohexose and measure Elson-Morgn method on the basis and the carbazole method on the glucuronic acid basis, formality is loaded down with trivial details and repeatability is relatively poor, can not fine reflection chondroitin sulfate cellulose content, thereby the raw material of chondroitin sulfate and the quality raising of preparation are restricted, and the purity of domestic most of chondroitin sulfate raw material can only reach 80～90%.The present invention adopts cetylpyridinium chloride solution (CPC) titration method to control its content in to the chondroitin sulfate quality testing, and content is greater than 96%.Adopt electrophoresis method to control its its related substances, content should be less than 2.0%, and described related substance is meant differential protein and anaphylactogen.
Differential protein in the chondroitin sulfate and anaphylactogen material are to cause clinical and the main cause pharmacology side reaction, by this preparation method, can reach the level (＜2%) that does not contain albumen and anaphylactogen substantially, as shown in table 1 below, the 4 batches of different chondroitin sulfate are through the amount (in protein content) of albumen behind the purification and anaphylactogen.
Table 1 preparation method of the present invention compares the removal of albumen and anaphylactogen
| The albumen of raw material crude product and amount of allergen (%) | The albumen of highly finished product and amount of allergen (%) | |
| 1 | 18.5 | 1.9 |
| 2 | 9.7 | 1.6 |
| 3 | 13.1 | 1.6 |
| 4 | 6.5 | 1.3 |
Self-evident, high-purity chondroitin sulfate provided by the invention can pass through oral cavity or parenteral.Especially, oral formulations comprises granule, powder, tablet (comprising sugar coated tablet), pill, capsule, syrup, Emulsion and suspending agent.Parenteral formulation comprise injection (for example subcutaneous injection, intravenous injection, intramuscular injection, peritoneal injection), drop, external preparation (for example, nasal cavity preparation, percutaneous preparation, and ointment), and suppository (for example, rectal suppository and vaginal suppository).Can use this area method commonly used, add pharmaceutically acceptable carrier and prepare above-mentioned preparation.
Pharmaceutically acceptable carrier comprises excipient, binding agent, diluent, additive, aromatic, buffer agent, thickening agent, coloring agent, stabilizing agent, emulsifying agent, dispersant, suspending agent and antiseptic.Can use following carrier, for example magnesium carbonate, magnesium stearate, Talcum, sugar, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose, sodium carboxymethyl cellulose, low melt wax, cocoa butter.
But especially goodly, outstanding advantage of the present invention is to provide a kind of intravenous administration formulation of the chondroitin sulfate that can't prepare according to prior art.But the preparation chondroitin sulfate of injection for intravenous administration comprises injection, injection powder pin, sodium chloride transfusion, glucose infusion liquid solution-type injection and other and can be used for the micelle or the particulate delivery system of intravenous drip.
Existing chondroitin sulfate ejection preparation clinical application approach only has intramuscular injection a kind of, using the technical problem that is restricted at all kinds of neuropathic pains with when needing the disease of treatment fast, the present invention provides a kind of chondroitin sulfate preparation of can injection for intravenous using for the patient.Certainly the preparation of the chondroitin sulfate preparation of the present invention's preparation equally also can carry out muscle or subcutaneous injection.
When using chondroitin sulfate of the present invention as active component, can make different form of medication as required, be applied to intravenous injection with the intravenous injection administration.Make these different form of medication, can be extensive use of known in the past carrier in this area and reagent.For example: one or more in the excipient of freeze-dried powder such as mannitol, lactose, fructose, glucose sugar, the arabinose), antioxidant (as in sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, methionine, Calcium Disodium Versenate, phosphoric acid, the citric acid etc. one or more), and regulate isoosmotic glucose, sodium chloride, sorbitol etc., regulate organic acid or the organic base (lactic acid, hydrochloric acid, malic acid, sodium hydroxide etc.) of pH.If desired, can also add for example solubilizing agent (for example, sodium salicylate and sodium acetate), stabilizing agent (for example, the human serum albumin), soothing agent (for example Benzalkonii Chloridum and procaine hydrochloride).
When using chondroitin sulfate of the present invention as active component with the intravenous injection administration, effectively between dosage range 10～200mg, this point is being confirmed in the preclinical test subsequently, the content in preparation (weight ratio) 0.1%～50%,, preferred 0.5～20%.
The objective of the invention is to realize by following method: adopting the chondroitin sulfate crude product of biological extraction is raw material, caustic-alkali aqueous solution heat treated 1h～2h through 10～20% (mass ratioes), temperature is controlled at 25～35 ℃, then gained liquid is carried out solid-liquid separation, with the solid-state aqueous solutions of organic acids that is partially dissolved in of gained, be more than 10 to wherein adding ethanol and caustic alkali to pH, the generation precipitation, with this washing of precipitate, drying, obtain the precipitation of chondroitin sulfate.With the resolution of precipitate of previous step gained, be mixed with 0.1～10% (w/v) solution, carry out ultrafiltration purification.Describedly be used for intravenous chondroitin sulfate, adopt cetylpyridinium chloride solution titration method (operating process of this method of next section explanation or the document of this method of record is provided) to control its content, content is greater than 96%.Electrophoresis method is controlled its impurity content less than 2%.
Embodiment:
Following examples are for more detailed description chondroitin sulfate preparation method of the present invention and some dosage forms of being comprised as the intravenous injection approach, and should not be considered as the present invention is made any restriction.
Embodiment 1
The chondroitin sulfate crude product of biological extraction is 60.0g, the caustic-alkali aqueous solution 3.0L that adds 12% (mass ratio), dissolving, heating 1.5h handle, temperature is controlled at 30 ℃, then gained liquid is carried out solid-liquid separation, with the solid-state aqueous citric acid solution that is partially dissolved in of gained, to wherein add ethanol 50ml, caustic alkali 8.5ml to pH is more than 10, produce precipitation 43.2g,, obtain the precipitation 40.6g of chondroitin sulfate this washing of precipitate, drying.
The gained precipitation is added water 2L, and stirring and dissolving is carried out ultrafiltration purification.Described ultrafiltration purification process, its molecular weight that dams is 30,000-50,000, promptly get chondroitin sulfate highly finished product solution, the content of chondroitin sulfate highly finished product is more than 98.9% (CPC method mensuration) after measured.The content of other impurity such as albumen is less than 2%.
Purified chondroitin sulfate is added an amount of water for injection, and regulating pH value is about 6.0, is prepared into injection according to the conventional method of injection.
Embodiment 2
The chondroitin sulfate crude product of biological extraction is 60.0g, the caustic-alkali aqueous solution 3.5L that adds 12% (mass ratio), dissolving, heating 1.0h handle, temperature is controlled at 35 ℃, then gained liquid is carried out solid-liquid separation, with the solid-state lactic acid aqueous solution that is partially dissolved in of gained, to wherein add ethanol 60ml, caustic alkali 9.5ml to pH is more than 10, produce precipitation 41.2g,, obtain the precipitation 40.8g of chondroitin sulfate this washing of precipitate, drying.
With precipitation add water 3L, stirring and dissolving is carried out ultrafiltration purification.Described ultrafiltration purification process, its molecular weight that dams is 35,000～45,000, promptly gets chondroitin sulfate highly finished product solution, after measured the content of chondroitin sulfate highly finished product more than 99.1% (CPC method) measure.The content of other impurity such as albumen is less than 1.5%.
Purified chondroitin sulfate is added an amount of water for injection and excipient, and the regulator solution pH value is about 6.0, is prepared into freeze-dried powder according to the conventional method of injection.
Embodiment 3
The chondroitin sulfate crude product of biological extraction is 60.0g, the caustic-alkali aqueous solution 3.0L that added 20% (mass ratio), dissolving, heating 1.0h handle, temperature is controlled at 25 ℃, then gained liquid is carried out solid-liquid separation, with the solid-state aqueous solution of malic acid that is partially dissolved in of gained, to wherein add ethanol 50ml, caustic alkali 8.5ml to pH is more than 10, produce precipitation 43.7g,, obtain the precipitation 41.2g of chondroitin sulfate this washing of precipitate, drying.
With precipitation add water 2L, stirring and dissolving is carried out ultrafiltration purification.Described ultrafiltration purification process, its molecular weight that dams is 40,000～50,000, promptly gets chondroitin sulfate highly finished product solution, the content of chondroitin sulfate highly finished product is more than 99.1% (CPC method mensuration) after measured.The content of other impurity such as albumen is less than 2%.
Purified chondroitin sulfate is added an amount of water for injection and excipient, and the sodium chloride of milliosmolaritys such as adding, regulator solution pH value are about 7.0, prepare chondroitin sulfate according to the conventional method of injection and become sodium chloride injection.
Embodiment 4
The chondroitin sulfate crude product of biological extraction is 60.0g, the caustic-alkali aqueous solution 4.0L that adds 13% (mass ratio), dissolving, heating 1.5h handle, temperature is controlled at 25C, then gained liquid is carried out solid-liquid separation, with the solid-state aqueous solutions of organic acids that is partially dissolved in of gained, to wherein add ethanol 50ml, caustic alkali 8.5ml to pH is more than 10, produce precipitation 40.8g,, obtain the precipitation 38.4g of chondroitin sulfate this washing of precipitate, drying.
With precipitation add water 2L, stirring and dissolving is carried out ultrafiltration purification.Described ultrafiltration purification process, its molecular weight that dams is 30,000～40,000, promptly gets chondroitin sulfate highly finished product solution, after measured the content 99.3% of chondroitin sulfate highly finished product (CPC method mensuration).The content of other impurity such as albumen is less than 2%.
Purified chondroitin sulfate is added an amount of water for injection and excipient, and the sodium chloride of milliosmolaritys such as adding, regulator solution pH value are about 7.0, prepare chondroitin sulfate according to the conventional method of injection and become sodium chloride injection.
Intravenous route administration chondroitin sulfate provided by the present invention is prepared into preparation and commercially available common chondroitin sulfate injection relatively, and onset is rapid, and pharmacological toxicology and safety testing result show its security and stability height, and be little to vein irritating.
(1) pharmacodynamics test
By animal experiment study, detect the influence of chondroitin sulfate, the influence that rat suppository is formed and to the antiinflammatory action of rat and mice to rabbit coagulation function and hemorheology index.Preparation that can intravenous chondroitin sulfate of the present invention, containing purity by intravenous injection is 96% above chondroitin sulfate 20～100mg.
The result shows, observe chondroitin sulfate to rabbit coagulation function and hemorheological influence, with 56.0,28.0 and the dosage intravenous injection administration of 14.0mg/kg (people's usual amounts 8,4 and 2 times), coagulation function be can obviously improve, prothrombin time (PT), thrombin time (TT), part thrombokinase time (APTT) and plasma fibrinogen (FIB) time prolonged; Obviously improve the hemorheology index, the results are shown in Table 2～3.
To the influence that rat suppository forms, show that chondroitin sulfate is inhibited to the platelet aggregation of rat by thrombosis method detection of drugs, the results are shown in Table 4.
By the antiinflammatory action of rat footpad swelling method and mice ear method detection of drugs, show that chondroitin sulfate has tangible antiinflammatory action.Result of the test shows that chondroitin sulfate has the coagulation function of improvement, improves hemorheology index, suppresses platelet aggregation and antiinflammatory action.
Table 2. chondroitin sulfate is to the influence of rabbit coagulation function
Table 3. chondroitin sulfate is to the influence of rabbit hemorheology index
N=8,
#Compare with matched group the same period P＜0.05; * P=0.05, with before the administration relatively
Table 4. chondroitin sulfate is to the influence of mouse platelets agglutination
(2) general pharmacology test
General pharmacology is learned research and is meant the pharmacological action in addition of observation main pharmacodynamics, mainly observes spiritual nervous system, respiratory system and three aspects of cardiovascular system, and using for clinical drug provides the safety foundation.
The experiment of spirit nervous system shows chondroitin sulfate 240,480 and 960mgkg
-1Each dosage group does not have obvious influence to mice coordination exercise and behavior classification, and each organizes the mice scoring all in normal range; To not having obvious influence by the pentobarbital sodium in mice sleep time; The mice general activity also there is not obvious influence, phenomenons such as each experimental group animal there is no movable blunt, posture abnormal gait, shouts, jumps, enrages, drowsiness, perpendicular hair, each dosage of prompting chondroitin sulfate does not have obvious influence to animal spirit nervous system, the results are shown in Table 5～7.
Cardiovascular and respiratory system experiment show, normally anaesthetize domestic cat, lumbar injection 71.5,143 and 286mgkg
-1Chondroitin sulfate, before and after the administration relatively and with matched group relatively, blood pressure, electrocardio, respiratory frequency and the degree of depth there are no significant difference, the prompting chondroitin sulfate does not have obvious influence to domestic cat cardiovascular and respiratory system, the results are shown in Table 8～12.
Table 5 chondroitin sulfate is to the influence of mice pole-climbing ability
Table 6 chondroitin sulfate is to the fractionated influence of mice Irwin behavior
Table 7 chondroitin sulfate is to the influence of mouse sleep time
Table 8 chondroitin sulfate is to the influence of cat heart rate
Table 9 chondroitin sulfate is to the influence of cat mean arterial pressure
Table 10 chondroitin sulfate to the influence of cat respiratory frequency (unit: inferior/min, X ± SD, n=6)
Table 11 chondroitin sulfate is to the influence of the T ripple of cat electrocardiogram
Table 12 chondroitin sulfate is to the influence of cat respiratory depth
In sum, each dosage of chondroitin sulfate does not all have obvious influence to animal spirit nervous system, respiratory system, cardiovascular system, shows that this product has higher safety.
(3) acute toxicity test
The rodent mice has been carried out acute toxicity test.By the various toxic reactions behind the detection mice disposable celiac drug administration by injection, the LD of measuring and calculating this product
50And fiducial limit.With the maximum concentration of ordinary dissolution 400mg/ml and the maximum administration volume 50ml/kg of chondroitin sulfate, the disposable celiac drug administration by injection is not seen the overt toxicity reaction, and is failed to cause animal subject death, the results are shown in Table shown in 13.
Table 13 animal subject body weight and variation (unit: g)
(4) long term toxicity test
Non-rodent dog has been carried out long term toxicity test.By observing the various reactions that dog intravenously administrable 26 all bodies are taken place, with the assessment safety.High, medium and low dosage group dosage is respectively 400,200 and 100mgkg
-1D
-1, add totally 4 groups of matched groups, every group of 8 animals.Administration mid-term, when the administration phase finishes and convalescent period cut open animal extremely when finishing, observe the general situation (comprising the mental status, reaction, behavioral activity, food-intake and body weight change) of animal subject, and carry out the histological examination of electrocardiogram, blood cell index, blood biochemical index, routine urianlysis and each important organ.The result shows, does not see obvious retardance toxic reaction.
The rodent rat is carried out long term toxicity test, divided matched group (equivalent distilled water), low dose group (350.0mgkg
-1), middle dosage group (700.0mgkg
-1) and high dose group (1400.0mgkg
-1), 40 of every treated animals, male and female half and half.EXPERIMENTAL DESIGN was 26 weeks, administration mid-term, when the administration phase finishes and 2 weeks cutd open animal extremely when convalescent periods finish.Observe the various reactions that body took place after the rat vein administration, with the safety of assessment this product.Observed the general situation of animal in the test, blood cell is learned and haemobiochemistry index, gross anatomy and histopathology index.The result shows that the long-term chondroitin sulfate of rodent rats by intraperitoneal injection does not have obvious retardance toxic reaction
(5) safety testing
Undertaken in the evaluation of chondroitin sulfate intravenous fluid safety testing by China Medicine University at one, comprising vein irritating test, sensitization test (STT) and hemolytic test, and and the listing common chondroitin sulfate injection compare test, the result shows, said preparation meets the intravenous drip requirement, and safety is significantly higher than common chondroitin sulfate injection.
(1) vein irritating test
Annotate the chondroitin sulfate injection to rabbit right, left auricular vein respectively with sterile working's method and (be mixed with 0.6mg/ml solution (dosage is 6ml/3.6mg/kg) and equivalent 20% glucose injection with 20% glucose injection by clinical working concentration, vein is injected 3 times continuously, once a day.The result shows: do not find that the chondroitin sulfate injection has the obvious stimulation effect, compare with 20% glucose injection, do not see vascular endothelial cell swelling, degeneration, necrosis, no obvious thrombosis in the tube chamber.
(2) hemolytic test
The injection hemolytic test shows, when in vitro final concentration is 2mg/ml rabbit is not caused haemolysis and agglutination, at 3h haemolysis is arranged and concentration is the commercial preparation of 0.4mg/ml, haemolysis just occurs at 60min, result such as table 14～15 in the concentration of 2mg/ml.
Table 14 chondroitin sulfate injection of the present invention hemolytic test table (5% glucose injection)
The common chondroitin sulfate injection of table 15 hemolytic test table (5% glucose injection)
Annotate :-haemolysis not; + complete hemolysis
(3) sensitivity test
Observe two kinds of chondroitin sulfate injection (the inventive method preparation and common chondroitin sulfate injection) Cavia porcellus is had or not anaphylaxis, for data for clinical drug use provides foundation.Get 18 of healthy guinea pigs, be divided into 3 groups at random, 6 every group (male and female half and half).Be divided into negative control group (20% glucose injection sensitization, and attack with this injection), positive controls (Ovum Gallus domesticus album sensitization with 4%, and attack with this reagent), be subjected to reagent group (with the chondroitin sulfate injection sensitization of 0.6mg/ml, and attack with this medicine).
The above-mentioned medicinal liquid 0.5ml/ of every group of lumbar injection at first the next day only injects 3 times altogether.Then every group of Cavia porcellus is divided into two groups, wherein a group Cavia porcellus the 14th day by forelimb intravenous injection original liquid 1ml/ only behind first time lumbar injection medicinal liquid; The 21st day by forelimb intravenous injection original liquid 1ml/ only behind first time lumbar injection medicinal liquid for another group Cavia porcellus.Observe the Cavia porcellus symptoms of allergic in 30 minutes after the intravenous injection, and mark by table 2 standards of grading.
Be subjected to reagent according to two group Cavia porcelluss of the chondroitin sulfate injection of this patent method preparation respectively at attacking with original liquid in the 14th day and the 21st day behind the first time lumbar injection medicinal liquid, anaphylaxis does not all take place; And the positive controls Cavia porcellus occurs dyspnea in injecting in back 1 minute, and tic is fallen down, and is then dead, and Cavia porcellus death all occurs in injects in back 1-2 minute.In addition, anaphylaxis does not all take place in 6 Cavia porcelluss of negative control group yet, slight anaphylaxis takes place respectively at attacking with original liquid in the 14th day and the 21st day behind the first time lumbar injection medicinal liquid in the two group Cavia porcelluss that are subjected to the common chondroitin sulfate injection of reagent; The results are shown in Table 16～17.
Under this experimental condition, show that the chondroitin sulfate injection according to the present invention's preparation does not have sensitization to the animal subject Cavia porcellus, and commercially available common chondroitin sulfate has certain sensitization.
The standards of grading of table 16 systemic anaphylaxis
The anaphylactic reaction result of the test of two kinds of chondroitin sulfate injection of table 17
These vein irritating tests, sensitization test (STT) and hemolytic test, the result meets the intravenous drip requirement after showing that the chondroitin sulfate for preparing according to the inventive method is prepared into preparation, and safety is significantly higher than common chondroitin sulfate injection.
Claims (4)
1, a kind of preparing chondroitin sulfates that can be used for the intravenous route administration, it is characterized in that: the caustic-alkali aqueous solution that in the chondroitin sulfate crude product, adds 10～20% quality, 25～35 ℃ of heat treated 1h～2h, then gained liquid is carried out solid-liquid separation, gained is solid-state be partially dissolved in aqueous solutions of organic acids after, is more than 10 to wherein adding ethanol and caustic alkali to pH, and the generation precipitation is with this washing of precipitate, dry, obtain the precipitation of chondroitin sulfate, with the resolution of precipitate of gained, be mixed with the solution of 1～25% w/v again, carry out ultrafiltration purification, the molecular weight that dams in the ultrafiltration purification process is 30,000～50,000, promptly.
2, preparing chondroitin sulfates as claimed in claim 1, the molecular weight ranges that it is characterized in that the described chondroitin sulfate that dams is 35,000～45,000 dalton, the dispersion of distribution is less than 1.8.
3, as the preparing chondroitin sulfates in the claim 1, wherein the quality of caustic alkali is 12～16% than concentration.
4, as the preparing chondroitin sulfates in the claim 1, wherein organic acid comprises one or more in citric acid, malic acid, tartaric acid, oxalic acid, succinic acid, lactic acid and the acetic acid.
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| 《硫酸软骨素的提取和纯化分离技术》. 李鑫等.天然产物研究与开发，第16卷第6期. 2004 |
| 《硫酸软骨素的提取和纯化分离技术》. 李鑫等.天然产物研究与开发，第16卷第6期. 2004 * |
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