CN100534434C - Sodium hyaluronate carulon fat emulsion formulation and its uses - Google Patents
Sodium hyaluronate carulon fat emulsion formulation and its uses Download PDFInfo
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- CN100534434C CN100534434C CNB2006100428081A CN200610042808A CN100534434C CN 100534434 C CN100534434 C CN 100534434C CN B2006100428081 A CNB2006100428081 A CN B2006100428081A CN 200610042808 A CN200610042808 A CN 200610042808A CN 100534434 C CN100534434 C CN 100534434C
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Abstract
The invention discloses the formulation of sodium hyaluronate aeroseb-D intralipid and the application in preparing medicine treating arthritis. The main components contained in formulation are aeroseb-D or its derivant, lecithin used as emulsion packing material and slow-releasing agent, sodium hyaluronate used as stabilizing agent for emulation, lubricant for soft tissue and bone and joint and anti-inflammation adjuvant, and vitamin E used as antioxidant. The emulation makes use of technology of medicine-delivery by emulation and function of lubricating and disinfecting soft tissue by sodium hyaluronate, and the adhesive degree and stability of emulation is dramatically increased, the slow-releasing property is prolonged, anti-inflammatory action is enhanced, and pain caused by arthritis is effectively reduced. The good bioavailability of said emulation enables complete metabolism in human body and the side effect is little.
Description
Technical field
The present invention relates to a kind of medicine, particularly a kind of sodium hyaluronate carulon fat emulsion formulation, said preparation can be as the medicinal application that is used to prepare treatment of arthritis.
Background technology
(Osteoarthritis is a kind of by the chronic degenerative arthropathy due to the multiple reason OA) to osteoarthritis, is principal character with articular cartilage degeneration, destruction and hyperosteogeny
[1]Its morbidity is relevant with multiple factors such as age, body constitution amount, inflammation, wound, heredity, does not have obvious region and race difference, is one of important cause of disease of disabling of the mankind
[2]Still lack effective radical cure measure and medicine clinically.
Below be the list of references that the inventor provides by retrieval:
[1]Hunter DJ，Felson DT.Osteoarthritis.BMJ.2006.Mar 18；332(7542)：639-42。
[2]Anderson JJ，Felson DT.Factors associated with osteoarthritis of theknee in the first national health and nutrition examination survey(HANES I).Evidence for an association with overweight，race，and physical demands ofwork.Am J Epidemiol，1988，28：179-189。
[3] Chen Tao, Huimin power, Fu Jingguo, Wang Jiucheng, the progress of fat milk pharmaceutical preparation; The up-to-date medical information digest in the world, 2004, (5): 19-22.
[4] Liu Kemin, Chen Weijun.Hyaluronic acid intra-articular injection treatment osteoarthritis.China's experimental surgery magazine, 1993,4:164-165.
[5]Stein A，Yassouridis A，Szopko C，Helmke K，Stein C.Intraarticularmorphine versus dexamethasone in chronic arthritis.Pain.1999，83(3)：525-532。
[6] Zhao Haiying, dexamethasone clinical practice recent developments.The medicine Leader, 1999, (1): 50.
Summary of the invention
The present invention is intended to utilize the collaborative advantage of hyaluronate sodium and fat milk, and preparation can be for clinical treatment and the arthritic dexamethasone pharmaceutical emulsion of control, for prevention and treatment of arthritis provide effective and inexpensive medicine clinically.
In order to realize above-mentioned task, the present invention takes following technical solution:
A kind of sodium hyaluronate carulon fat emulsion formulation is characterized in that, contains in the said preparation that makes:
As the dexamethasone or the dexamethasone derivant of medicine, its consumption is at 0.1～40mgml
-1
As the lecithin of fat milk packaging material, slow releasing agent, its consumption is at (0.1%～10%);
As the hyaluronate sodium of emulsion preparations stabilizing agent, soft tissue and osteoarthrosis lubricant, antiinflammatory adjuvant, its consumption accounts for the 0.001-3% of volumes of formulation ratio;
As the vitamin E of antioxidant, its consumption accounts for the 0-1% of volumes of formulation ratio.
Above-mentioned dexamethasone derivant is the derivative of fatty acid of dexamethasone, or the dexamethasone derivant of other fat-soluble compounds modifications.
The lecithin of above-mentioned fat milk packaging material, slow releasing agent is Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline or synthetic lecithin.
Fat milk (lipid emulsion or fat emulsion) is a development in recent years novel pharmaceutical formulation faster, has very high clinical and economic worth
[3]Fat milk is stable oil-in-water type (O/W) Emulsion made from vegetable oil (main component is a fatty acid triglycercide), phospholipid emulsifier, isotonic agent and water for injection, can supply vein or muscle local injection, can be fully by organism metabolism and utilization.The security performance of fat milk is good, and is non-stimulated, is one of widely used novel form in the clinical treatment.The particle diameter of fat milk is little and be evenly distributed, and good stability has multi-functional targeted drug and carries, and can obviously reduce the toxic and side effects of medicine, reduces the zest of medicine, improves bioavailability, and has the long-acting slow-release effect.
Hyaluronate sodium (sodium hyaluronate) is the exogenous biomaterial of a kind of macromolecule polysaccharide body that is alternately formed repeatedly by N-acetyl glucosamine aldehydic acid, viscoelasticity, plasticity and excellent biological compatibility with height are having obvious effect aspect Film with Preventing Adhesion and the reparation soft tissue.Hyaluronate sodium can form unordered fibrillar meshwork structure and be isolated in tissue surface, forms insulating space, produces biological barrier, therefore can hinder exogenous histiocyte near injury region, thereby suppresses adhesion.Inflammation serous coat and normal serous coat are isolated.It can also suppress granulocytic migration and activity, stimulates the macrophage effect, suppresses scorching card reaction, reduces the formation of tissue adhesion.The complex of hyaluronate sodium and protein shape covers articular surface, and the protection articular cartilage plays lubricated, cushioning effect
[4]Can combine simultaneously or cause macromolecular substances bitterly and combine, alleviate or eliminate arthralgia with some with pain receptor.The articular cartilage degeneration that inflammatory mediators such as effective inhibition Kallidin I cause prevents joint accretion, contracture.Be the ideal lubricant of osteoarthritis, surgery, gynecological, bone surgery, the antitack agent that operation on tendon is good.
Dexamethasone belongs to adrenal cortex hormones drug, and antiinflammatory and anti-immunization are arranged.Under general dosage, hormone is mainly by suppressing the synthetic antiinflammatory action that reaches of prostaglandin.It can reduce the permeability of blood capillary, suppresses inflammatory infiltration and oozes out, and can make the edema extinction of intercellular substance, alleviates arthralgia.In chronic inflammatory disease and acutely inflamed later stage, hormone can be suppressed to the shape of fibrocellular hypertrophy and granulation tissue
[5]Become, thus the cicatrix and the adhesion that reduce inflammation and cause.Hormone still is helpful for the inflammation of control rheumatoid arthritis in active stage.But long-range medication or the medication of super large dosage can cause serious adverse such as Ke Xing (cushing ' s) syndrome, the upper arm or ischemic necrosis of femoral head, osteoporosis or fracture (comprising vertebral compression fracture, long bone pathologisch Bruch), myasthenia, amyotrophy, hypokalemia syndrome, GI irritation (feel sick, vomiting), pancreatitis, peptic ulcer or intestinal perforation
[6]
Dexamethasone is prepared into the hyaluronate sodium fat emulsion formulation, can keeps the high concentration of medicine, prevented that medicine from entering blood, promptly reduced the toxic and side effects that the whole body administration causes, strengthened partial therapeutic effect again at injection site.The dexamethasone that is dissolved in the soybean oil can slowly be diffused into inflammation part, has played the effect of slow release, can significantly reduce the action time of medication number of times and prolong drug.Can improve the stability of pharmaceutical preparation and add hyaluronate sodium, increase the adhesive force of medicine, can improve the therapeutic effect of medicine at articular cavity.
In sum, the present invention combines fat emulsion formulation and passs medicine technology and hyaluronate sodium to the physical chemistry function of treatment of arthritis, has following five big advantages:
(1) the present invention can avoid using the cosolvent that side effect is arranged with slightly solubility and fat-soluble dexamethasone or dexamethasone derivant drug encapsulation in fat emulsion formulation;
(2) drug encapsulation can increase absorption, the enhancing drug effect of medicine in fat emulsion formulation;
(3) fat emulsion formulation has slow releasing function, action time that can prolong drug;
(4) add hyaluronate sodium and can improve the stability of pharmaceutical preparation, increase the adhesive force of medicine at articular cavity;
(5) can help and improve the local positioning release of medicine, thereby improve the therapeutic effect of medicine.Avoided whole body administration or medicine to enter the toxic and side effects that blood causes.
The specific embodiment
The present invention verifies the sodium hyaluronate carulon fat emulsion formulation amount ranges of listed medicine in prescription of filling a prescription.Under technology of the present invention and condition, when fat milk prescription except the lecithin consumption according to amount of drug the corresponding adjustment, other components and consumption are maintained fixed constant, dexamethasone or dexamethasone derivant amount of drug are at 0.1～40mgml
-1Arbitrary consumption in the scope all guarantees to make stable final products.Though content of medicines is at 0.1mgml in principle
-1Below can make stable fat emulsion formulation, but its drug level does not reach effective medicinal concentration, has not had clinical meaning, so do not investigated in an embodiment yet.
One, sodium hyaluronate carulon fat emulsion formulation prepares embodiment
1, the fat emulsion formulation of variable concentrations medicine (only being example) with the dexamethasone palmitate
Embodiment 1:
Preparation (the 0.1mgml of low content dexamethasone palmitate fat milk
-1Dexamethasone palmitate)
Prescription:
| Dexamethasone palmitate | 100mg |
| Soybean oil (injection) | 99.0g |
| Lecithin (injection) | 12g |
| Vitamin E (injection) | 20ml |
| Hyaluronate sodium | 10ml |
| Glycerol | 22g |
| Water for injection | Add to 1000ml |
Get soybean oil 99g, add lecithin 12g, under the condition of nitrogen protection, be heated to 75 ℃, stir about 10min fully dissolves lecithin, adds dexamethasone palmitate 100mg and 20ml vitamin E then, the dissolving mixing.Other gets water for injection 800ml, adds glycerol 22g.Under the condition of nitrogen protection, dexamethasone palmitate phospholipid oil solution is added in the glycerine water solution, make colostrum, add the 10ml hyaluronate sodium then, mixing, and regulate total amount to 1000ml.High pressure homogenizer homogenizing 7-8 time, homogenization pressure are 100MPa, to particle size range at 180nm-300nm, regulate pH 7.0-8.0, filter, packing feeds nitrogen, sealing.115 ℃ of sterilization 30min, after lamp inspection was qualified, packing was in storage below 25 ℃.
Embodiment 2:
Preparation (the 40mgml of high-load dexamethasone palmitate fat milk
-1Dexamethasone palmitate)
Prescription:
| Dexamethasone palmitate | 40g |
| Soybean oil (injection) | 99.0g |
| Lecithin (injection) | 12g |
| Vitamin E (injection) | 20ml |
| Hyaluronate sodium | 10ml |
| Glycerol | 22g |
| Water for injection | Add to 1000ml |
Get soybean oil 99g, add lecithin 12g, under the condition of nitrogen protection, be heated to 75 ℃, stir about 10min fully dissolves lecithin, adds dexamethasone palmitate 40g and 20ml vitamin E then, the dissolving mixing.Other gets water for injection 800ml, adds glycerol 22g.Under the condition of nitrogen protection, dexamethasone palmitate phospholipid oil solution is added in the glycerine water solution, make colostrum, add the 10ml hyaluronate sodium then, mixing, and regulate total amount to 1000ml.High pressure homogenizer homogenizing 7-8 time, homogenization pressure are 100MPa, to particle size range at 180nm-300nm, regulate pH 7.0-8.0, filter, packing feeds nitrogen, sealing.115 ℃ of sterilization 30min, after lamp inspection was qualified, packing was in storage below 25 ℃.
Embodiment 3:
Preparation (the 5mgml of low content dexamethasone palmitate fat milk
-1Dexamethasone palmitate)
| Dexamethasone palmitate | 500mg |
| Soybean oil (injection) | 99.0g |
| Lecithin (injection) | 12g |
| Vitamin E (injection) | 20ml |
| Hyaluronate sodium | 10ml |
| Glycerol | 22g |
| Water for injection | Add to 1000ml |
Preparation method is with embodiment 2.
2, the fat emulsion formulation of variable concentrations hyaluronate sodium (only being example) with the dexamethasone palmitate
Embodiment 4:
Low content sodium hyaluronate carulon fat emulsion formulation (0.001%v/v hyaluronate sodium)
Prescription:
| Dexamethasone palmitate | 500mg |
| Soybean oil (injection) | 99.0g |
| Lecithin (injection) | 12g |
| Vitamin E (injection) | 20ml |
| Hyaluronate sodium | 1ml |
| Glycerol | 22g |
| Water for injection | Add to 1000ml |
Get soybean oil 99g, add lecithin 12g, under the condition of nitrogen protection, be heated to 75 ℃, stir about 10min fully dissolves lecithin, adds dexamethasone palmitate 500mg and 20ml vitamin E then, the dissolving mixing.Other gets water for injection 800ml, adds glycerol 22g.Under the condition of nitrogen protection, dexamethasone palmitate phospholipid oil solution is added in the glycerine water solution, make colostrum, add the 1ml hyaluronate sodium then, mixing, and regulate total amount to 1000ml.High pressure homogenizer homogenizing 7-8 time, homogenization pressure are 100MPa, to particle size range at 180nm-300nm, regulate pH 7.0-8.0, filter, packing feeds nitrogen, sealing.115 ℃ of sterilization 30min, after lamp inspection was qualified, packing was in storage below 25 ℃.
Embodiment 5:
The preparation of high-load sodium hyaluronate carulon fat emulsion (3%v/v hyaluronate sodium)
Prescription:
| Dexamethasone palmitate | 40g |
| Soybean oil (injection) | 99.0g |
| Lecithin (injection) | 12g |
| Vitamin E (injection) | 20ml |
| Hyaluronate sodium | 30ml |
| Glycerol | 22g |
| Water for injection | Add to 1000ml |
Get soybean oil 99g, add lecithin 12g, under the condition of nitrogen protection, be heated to 75 ℃, stir about 10min fully dissolves lecithin, adds dexamethasone palmitate 40g and 20ml vitamin E then, the dissolving mixing.Other gets water for injection 800ml, adds glycerol 22g.Under the condition of nitrogen protection, dexamethasone palmitate phospholipid oil solution is added in the glycerine water solution, make colostrum, add the 30ml hyaluronate sodium then, mixing, and regulate total amount to 1000ml.High pressure homogenizer homogenizing 7～8 times, homogenization pressure are 100MPa, to particle size range at 180nm～300nm, regulate pH 7.0-8.0, filter, packing feeds nitrogen, sealing.115 ℃ of sterilization 30min, after lamp inspection was qualified, packing was in storage below 25 ℃.
Two, sodium hyaluronate carulon fat emulsion agent topical is to the arthritic experimentation of Os Leporis seu Oryctolagi
2.1 sodium hyaluronate carulon fat emulsion agent topical is to the arthritic therapeutical effect of Os Leporis seu Oryctolagi
2.1.1 material and method
Animal:
40 of healthy male New Zealand rabbits, body weight 2-3Kg; The 6-8 monthly age; Be divided into normal group, model group, carulon fat emulsion agent group and sodium hyaluronate carulon fat emulsion agent group at random, every group each 10.
Reagent:
Interleukin-11 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF-α) and matrix metalloproteinase 3 (MMP-3) test kit are produced by U.S. DSL.Malonaldehyde (MDA), superoxide dismutase (SOD) and Coomassie brilliant blue protein reagent box build up bio-engineering research by Nanjing to be provided.Set up the Hulth model:
List of references (Wu Haishan, Qian Qirong, Gu Qisheng: the arthritic experimentation of intra-articular injection hyaluronate sodium prevention Os Leporis seu Oryctolagi.Chinese journal of orthopedics, 1996,16:37-39.), with 3% pentobarbital sodium 30mg/Kg intravenous anesthesia, a picked at random left side/right knee joint operation.Do the kneecap inner incision, cut off forward and backward ligamentaum cruciatum, the excision medial meniscus also cuts off medial collateral ligament, notices that the protection articular cartilage face is injury-free, the layer-by-layer suture otch.Postoperative is not fixedly hindered limb, sub-cage rearing.
Medication:
At that time respectively at the agent of intra-articular injection carulon fat emulsion and each 1ml of sodium hyaluronate carulon fat emulsion agent, wherein the sodium hyaluronate carulon fat emulsion agent contains hyaluronate sodium 1% (volume ratio) and dexamethasone 4mgml to the administration treated animal in postoperative
-1The carulon fat emulsion agent contains dexamethasone 4mgml
-1Thereafter 1 week of every interval injects once, until execution.Matched group is then injected the equivalent normal saline.
Observation index:
(1) tectology changes, and by grouping before the art, puts to death animal in 12 weeks of postoperative, dissect knee joint immediately, under operating microscope, observe, reference literature (Wu Haishan, Qian Qirong, Gu Qisheng: the arthritic experimentation of intra-articular injection hyaluronate sodium prevention Os Leporis seu Oryctolagi.Chinese journal of orthopedics, 1996,16:37-39.) grading method of osteoarthritis is divided into the I degree with its cartilage degeneration degree: cartilage surface is softening but level and smooth; The II degree: the cartilage attenuation fubril pencil occurs and becomes; The III degree: the obvious fiber bundle-like of cartilage becomes; The IV degree: the abrasiveness fiber bundle-like becomes companion's subchondral bone to be exposed and osteosclerosis.
(2) Mankin ' s scoring: getting in the femur condyle articular cartilage specimen, to carry out routine fixing, decalcification, and paraffin embedding, section, HE dyes, and observes under optical microscope.And press Mankin ' s standards of grading scorings (document: Mankin HJ, Dorfman H, Lippielo L, et al.Biochemical andmetabolic abnormalities in articular cartilage from osteoarthritic human hips.II.Correlation of morphology with biochemical and metabolic data.J Bone JointSurg, 1971,53:523-531).(3) biochemical indicator: 1. il-1 (IL-1) in the knuckle synovia; 2. interleukin-6 (IL-6); 3. tumor necrosis factor (TNF-α); 4. matrix metalloproteinase 3 (MMP-3); More than four get the centrifugal back of knuckle synovia sample, adopt double antibodies sandwich ELISA method, measure respectively.5. superoxide dismutase (SOD) determination of activity in the synovial membrane: 10% tissue homogenate is made by the synovial tissue of being excised, and pyrogallol method is measured the SOD activity.6. malonaldehyde (MDA) is measured: get blood 50 μ l, the spectrophotometry contents of mda of thiobarbituricacid (TBA) through auricular vein before the sacrifice of animal.
Statistical procedures:
(x ± s) expression carries out the t check of independent sample mean to data with SPSS 11.0 statistics softwares with mean ± standard deviation.
2.1.2 result
2.1.2.1 tectology changes
Reach substantially under the operating microscope and observe, 10 animal calibration of model group result is 7 of 3 IV degree of III degree, shows the model copy success.Compare with model group, the cartilage degeneration degree of sodium hyaluronate carulon fat emulsion agent treatment group and dexamethasone fat emulsion preventative surfactant treatment group significantly reduces, compare with the cartilage degeneration degree of carulon fat emulsion agent treatment group, sodium hyaluronate carulon fat emulsion agent treatment group produce effects is more obvious, sees Table 1.
Table 1 is through sodium hyaluronate carulon fat emulsion agent treatment, and rabbit OA model tectology is graded
| Group | Normally | I | II | III | IV |
| Normally | 10 | ||||
| Model | 3 | 7 | |||
| The carulon fat emulsion agent | 1 | 5 | 4 | ||
| The sodium hyaluronate carulon fat emulsion agent | 3 | 6 | 1 |
2.1.2.2 om observation
Adopt the score of Mankin ' s rank scores method, model group must be divided into (5.94 ± 1.02) and normal control group (0.48 ± 0.08) scoring level significantly raise (P＜0.01).Compare with model group, the scoring (3.64 ± 0.81) of sodium hyaluronate carulon fat emulsion agent group score (2.01 ± 0.72) carulon fat emulsion agent group obviously reduces (P＜0.01) respectively, and the scoring of sodium hyaluronate carulon fat emulsion agent group significantly is lower than carulon fat emulsion agent group (P＜0.01), shows that the sodium hyaluronate carulon fat emulsion agent is to the more significant effect of rabbit OA model tool.
2.1.2.3 osteoarthrosis synovial fluid and blood parameters are measured
Sodium hyaluronate carulon fat emulsion agent group is compared with malonaldehyde (MDA) level in the interior il-1 (IL-1) of the knuckle synovia of model group, interleukin-6 (IL-6), tumor necrosis factor (TNF-α), matrix metalloproteinase 3 (MMP-3) content and the blood with carulon fat emulsion agent group, significantly reduce (P＜0.05), superoxide dismutase (SOD) activity significantly improves (P＜0.05) in the synovium of joint simultaneously, and the effect of sodium hyaluronate carulon fat emulsion agent group is more remarkable, sees Table 2,3.
Table 2 is treated through the sodium hyaluronate carulon fat emulsion agent, the variation of IL-1, IL-6, TNF-α, MMP-3 in the rabbit OA model knuckle synovia
| Group | IL-1 (ng·L -1) | IL-6 (ng·L -1) | TNF-α (ng·L -1) | MMP-3 (μg·L -1) |
| Normally | 9.84±0.33 | 10.21±0.24 | 11.98±0.66 | 11.08±0.42 |
| Model | 15.67±0.43 ＊ | 16.37±0.57 | 23.07±.035 | 18.22±0.20 |
| The carulon fat emulsion agent | 12.34±0.63 | 13.11±0.39 ＊ | 14.98±0.68 ＊ | 14.29±0.33 ＊ |
| The sodium hyaluronate carulon fat emulsion agent | 10.55±0.31 ＊＊ | 11.08±0.41 ＊＊ | 12.55±0.38 ＊＊ | 12.04±0.11 ＊＊ |
Annotate: compare with model group,
*P＜0.01; Compare with model group,
*P＜0.01; Compare with carulon fat emulsion agent group,
*P＜0.05.
Table 3 is through sodium hyaluronate carulon fat emulsion agent treatment, the variation of rabbit OA model synovium of joint SOD vigor and blood MDA level
| Group | MDA(mmol·L -1) | SOD(μ·mg -1·pro) |
| Normally | 1.62±0.22 | 128.60±6.37 |
| Model | 3.32±0.37 | 54.13±5.28 |
| The carulon fat emulsion agent | 2.39±0.44 ＊ | 89.59±7.01 ＊ |
| The sodium hyaluronate carulon fat emulsion agent | 1.70±0.24 ＊＊ | 111.69±4.88 ＊＊ |
Annotate: compare with model group,
*P＜0.01; Compare with model group,
*P＜0.01; Compare with carulon fat emulsion agent group,
*P＜0.05.
2.1.3 conclusion
(Osteoarthritis is a kind of by the chronic degenerative arthropathy due to the multiple reason OA) to osteoarthritis, and clinical manifestation is articular cartilage degeneration, destruction and hyperosteogeny, still lacks effective radical cure measure and medicine at present.Often adopt the hyaluronic acid intra-articular injection to treat clinically, can alleviating pain, mitigation symptoms.Hyaluronic acid is a kind of mucopolysaccharide; in the B emiocytosis of intraarticular by synovial membrane; it is in the knuckle synovia and the interior important component of cartilage matrix; protection and keeping of synovial fluid lubricated, cartilage to synovium of joint all produce important function (document: Peyron JG; Balazs ES.Preliminaryclinical assessment of Nahyaluronate injection into human arthritic joint.Pathologic Biology; 1974,74:731).Studies show that the dexamethasone intra-articular injection also has therapeutical effect to OA.Dexamethasone belongs to adrenal cortex hormones drug, and antiinflammatory and immunosuppressive action are arranged.Mainly by suppressing the synthetic antiphlogistic effects that reaches of prostaglandin.It can reduce the permeability of blood capillary, suppresses inflammatory infiltration and oozes out, and can make the edema extinction of intercellular substance, reaches the purpose of prevention and treatment OA.The sodium hyaluronate carulon fat emulsion agent of adopting in the experiment is dexamethasone to be encapsulated in add hyaluronate sodium in the fat emulsion formulation simultaneously, and preparation has increased drug synergism, makes the absorption increase of principal agent, drug effect strengthen, and have slow releasing function.Owing to improved the adhesive force of medicine at articular cavity, can promote the local positioning release of medicine, avoid medicine to enter the toxic and side effects that blood causes.
This experiment adopts the Hulth method to set up rabbit knee joint OA model.Use sodium hyaluronate carulon fat emulsion agent intra-articular injection, to observe its influence and Mankin ' s rank scores situation to the rabbit knee tectology, experimental result shows, compare with model group, sodium hyaluronate carulon fat emulsion agent and carulon fat emulsion agent all make rabbit knee joint OA model cartilage degeneration degree significantly reduce, drug effect with sodium hyaluronate carulon fat emulsion agent group and carulon fat emulsion agent group compares simultaneously, finds that sodium hyaluronate carulon fat emulsion agent group is to suppressing the more significant effect of rabbit OA model cartilage degeneration tool.
IL-1, IL-6, TNF-α and MMP-3 are the major protein prime factors that body immune system is regulated bone metabolism, it is the important medium (document: Mathieu P.Interleukin-1:Its role that participates in the knee joint OA morbidity process, Its dosage, the difficulties in advances in arthritis.Results of a " pilot " study with diacerheine (ART so) in gonarthrosis.Rev Prat 1999; (Suppl13): S15-18; Guo's generation silk ribbon for holding a jade seal through its nose, gonadal hormone and cytokine and osteoarthritis and osteoporotic relation. foreign medical science endocrine fascicle 2003; 23 (2), 98-100; Cawston T, Billillgton C, CleaverC, et al.There gulation of MMPs and TIMOs in cartilage turnover.Ann NYAcad Sci 1999; 87 (8), 120-129).Experiment shows that by above every index of detection model group and treatment group sodium hyaluronate carulon fat emulsion agent and carulon fat emulsion agent all can obviously reduce IL-1, IL-6, TNF-α, MMP-3 level in the rabbit knee OA model knuckle synovia.Further the contrast experiment finds that the sodium hyaluronate carulon fat emulsion agent compares with the carulon fat emulsion agent and have more significant pharmacologically active.
MDA, SOD are the pairing indexs commonly used that detects body oxygen-derived free radicals level, MDA content height reflects the order of severity that body cell is attacked by free radical again indirectly, and SOD vigor height reflects body removing oxygen-derived free radicals ability indirectly, SOD is the high-efficiency scavenging agent of oxygen-derived free radicals in the body, suppress peroxidization, participate in the anti-infectious immunity mechanism of body, the inflammation-inhibiting reaction is so its activity influence the inflammation development.The sodium hyaluronate carulon fat emulsion agent can obviously reduce malonaldehyde (MDA) level in the rabbit knee OA model blood, significantly improves superoxide dismutase in the animal pattern synovium of joint (SOD) activity simultaneously.And the effect significance is better than the carulon fat emulsion agent.
In view of the above, the applicant thinks: the sodium hyaluronate carulon fat emulsion agent has therapeutical effect and is better than the carulon fat emulsion agent OA.Sodium hyaluronate carulon fat emulsion agent intra-articular injection not only can improve the hyaluronic absolute content of intraarticular; bring into play its effect in the cartilage matrix metabolism; and can simulate the physical action of knuckle synovia, the protection articular cartilage is slowed down the generation of regression.But inflammation-inhibiting also simultaneously, blocking-up participates in important medium and the reaction thereof in the OA morbidity process, thereby reaches the purpose of prevention and treatment OA.In addition, because said preparation has excellent biological compatibility, metabolism fully in vivo, and side effect is slight.Therefore being applied as of this novel formulation prevents and treats OA a kind of new approach is provided.
Claims (2)
1. the sodium hyaluronate carulon fat emulsion formulation of a treatment of arthritis is characterized in that, the prescription that makes this sodium hyaluronate carulon fat emulsion formulation consists of:
Dexamethasone palmitate: 100mg～40g, injection soybean oil: 99.0g, injection lecithin: 12g, injection vitamin E: 20ml, hyaluronate sodium: 10ml, glycerol: 22g, adding injection water to fat emulsion formulation cumulative volume is 1000ml.
2. the preparation method of the sodium hyaluronate carulon fat emulsion formulation of the described treatment of arthritis of claim 1 is characterized in that:
Get soybean oil 99g, add lecithin 12g, under the condition of nitrogen protection; be heated to 75 ℃, stir about 10min fully dissolves lecithin, adds dexamethasone palmitate and 20ml vitamin E then; dissolving is even, and other gets water for injection 800ml, adds glycerol 22g; under the condition of nitrogen protection; dexamethasone palmitate phospholipid oil solution is added in the glycerine water solution, make colostrum, add the 10ml hyaluronate sodium then; mixing; adding injection water to fat emulsion formulation cumulative volume is 1000ml, and high pressure homogenizer homogenizing 7-8 time, homogenization pressure are 100Mpa; to particle size range at 180nm-300nm; regulate pH7.0-8.0, filter packing; feed nitrogen; sealing, 115 ℃ of sterilization 30min are after lamp inspection is qualified; packing is at storage below 25 ℃.
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