CN1321692C - Medicinal composition for treating arthritis - Google Patents
Medicinal composition for treating arthritis Download PDFInfo
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- CN1321692C CN1321692C CNB2005100903659A CN200510090365A CN1321692C CN 1321692 C CN1321692 C CN 1321692C CN B2005100903659 A CNB2005100903659 A CN B2005100903659A CN 200510090365 A CN200510090365 A CN 200510090365A CN 1321692 C CN1321692 C CN 1321692C
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- trypsin inhibitor
- human urine
- pharmaceutical composition
- hyaluronate sodium
- urine trypsin
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Abstract
The present invention relates to a medical composition for treating arthritis, and especially for treating osteoarthritis and rheumatoid arthritis. A medicinal preparation prepared from urinary trypsin inhibitor (ulinastatin) and hyaluronic acid according to a proper proportion can be frozen-drying powder injections or injection liquid for partial injection or intravenous injection. The medical composition can also comprise additives, such as mannitol, dextran, glycine, etc.
Description
Technical field
The present invention relates to the pharmaceutical composition of treatment of arthritis, particularly contain human urine trypsin inhibitor and hyaluronic compositions.
Background technology
The present invention relates to two kinds of medicines--human urine trypsin inhibitor and hyaluronic acid; Relate to two sick kinds--osteoarthritis and rheumatoid arthritis.Corresponding field prior art situation is described below respectively.
(ulinastatin ulinastatin), is a kind of protease inhibitor of separation and purification from Urina Hominis to human urine trypsin inhibitor, the glycoprotein of molecular weight 67000D for Urinary Trypsin Inhibitor, UTI.This albumen is a kind of wide spectrum hydrolase inhibitor, to comprising multiple hydrolytic enzyme such as trypsin, elastoser, hyaluronidase inhibitory action is arranged.With this material is the therapeutic use that the pharmaceutical preparation injection ulinastatin of active component is mainly used in acute pancreatitis, acute circulatory failure, systemic inflammatory reaction etc.
Hyaluronic acid (claims glass acid again, Hyaluronic acid) is a kind of linear polysaccharide of uniqueness, be distributed in widely in the extracellular matrix of animal and human's body connective tissue, be to repeat crosslinked and macromolecule aminoglycan that form by N-acetylglucosamine and D-glucuronic acid, exist so that the form of free chain is free in vivo, stronger water absorption and height viscosity are arranged.Molecular weight is 10
5～10
7The pharmaceutically used hyaluronate sodium that is generally is mainly used in ophthalmology viscosurgery, treatment arthrosis, soft tissue repair and as fields such as pharmaceutical carriers.Because of its good moisture preserving also is used widely in cosmetics.
Osteoarthritis (OA) is one group to be had different etiology but the disease of similar biology, morphology and Clinical symptoms is arranged, and is one of the most common and most important joint disease, and the old people falls ill outstanding many.Rheumatoid arthritis claims rheumatoid (RA) again, is the chronic systemic inflammatory disease that a kind of cause of disease is not understood as yet fully, belongs to the autoimmune inflammatory diseases, is a kind of common and obstinate chronic arthritis.Two class arthritis disability rate height, and lack effective treatment means.Obviously risings of inflammatory mediator such as intraarticular interleukin-1, disorganization or degraded aggravation, therefore, the medicine of conventional clinically some anti-inflammatory responses of use is used for this class treatment of diseases.
Hyaluronate sodium is the normal composition of knuckle synovia, except lubrication, also to the nutritious effect of articular cartilage.Discover that get involved hyaluronic concentration in the knuckle synovia, molecular weight, viscoelasticity of osteoarthritis, traumatic arthritis, rheumatoid arthritis people all is lower than normally.At arthritic this pathogenesis; modern medicine has been set up the method to intraarticular injection macromolecule hyaluronic acid solution treatment osteoarthritis; can recover the viscoelasticity of joint tissue; rebuild the protective effect of hyaluronic acid to joint tissue; alleviate synovial membrane inflammation; improve function of joint, alleviate patient's pain.Find that simultaneously the hyaluronic acid curative effect of different molecular weight is variant, the hyaluronic acid of higher molecular weight is better than the relatively low person of molecular weight.Its reason is that the hyaluronic acid degradation of higher molecular weight is slow relatively, and action time is longer.Therefore, delaying the process that hyaluronic acid is degraded in articular cavity, is an approach that improves hyaluronic acid preparation treatment of arthritis curative effect.
Summary of the invention
The purpose of this invention is to provide a kind of pharmaceutical composition, in this compositions, hyaluronate sodium is under the effect of other component, and its pharmacological action is strengthened and prolonged, and the curative effect of treatment of arthritis is improved.
The technical scheme that realizes the object of the invention is, with human urine trypsin inhibitor (Urinary TrypsinInhibitor, UTI, ulinastatin, ulinastatin) be mixed with pharmaceutical composition with hyaluronate sodium, be applied to arthritis, particularly the treatment of osteoarthritis and rheumatoid arthritis.
The ratio range of human urine trypsin inhibitor and hyaluronate sodium is: hyaluronate sodium (molecular weight 300,000～1,000 ten thousand) 1mg joins human urine trypsin inhibitor 0.01～2,000,000 units;
The optimum ratio of going into urinary trypsin inhibitor and hyaluronate sodium is that hyaluronate sodium (molecular weight 300,000～1,000 ten thousand) 1mg joins human urine trypsin inhibitor 0.25～100,000 units;
The best proportioning of human urine trypsin inhibitor and hyaluronate sodium is that hyaluronate sodium (molecular weight 300,000～1,000 ten thousand) 1mg joins human urine trypsin inhibitor 10,000 units.
Pharmaceutical composition of the present invention contains the human urine trypsin inhibitor and the hyaluronate sodium as active component for the treatment of effective dose, is equipped with pharmaceutically acceptable auxiliaries, is made into various suitable dosage forms, comprises lyophilized injectable powder and injection liquor, for clinical use.
Through the preparation of local injection administration, generally be solid sterilization composition form.These compositionss can also contain additive, particularly mannitol, dextran, glycine etc.It is a kind of or add several simultaneously to add it.Be dissolved in during use in sterile saline or other injection sterile medium.
Sterilization composition through intravenous administration also can be an aqueous solution, and these compositionss can also contain additive, particularly mannitol, sodium chloride, glucose etc.It is a kind of or add several simultaneously to add it.
Using the arthritic dosage of medicine composite for curing of the present invention decides according to the order of severity, the treatment of the state of an illness blanking time.The each usual amounts of adult's articular cavity inner injecting and administering is equivalent to human urine trypsin inhibitor 0.1～50,000 units, hyaluronate sodium (molecular weight 300,000～1,000 ten thousand) 1～3mg, and administration is 1～2 time weekly.
Human urine trypsin inhibitor and hyaluronic acid are used in combination, and human urine trypsin inhibitor has anti-inflammatory effect, and hyaluronic acid has protective effect to the joint, both advantage additions, and curative effect improves.Simultaneously, human urine trypsin inhibitor also plays inhibitory action to hyaluronidase, thereby delays hyaluronic acid in IA degradation process, makes drug effect permanent, can reduce the medication number of times, reduces the curative effect difference that is caused because of the hyaluronan molecule quantitative changeization.Compare with numerous anti-inflammatory response medicines, human urine trypsin inhibitor does not have apparent side effect, uses safer.Experiment shows, uses the effectively development of inhibition test animal rheumatoid arthritis and osteoarthritis of pharmaceutical composition of the present invention, than using simple human urine trypsin inhibitor and using simple hyaluronic acid curative effect to have made marked progress.
The specific embodiment
Embodiment 1 preparation human urine trypsin inhibitor (UTI) solution
Get ulinastatin 2,500 ten thousand units, add 5 gram mannitol and the dissolving of an amount of water for injection, regulate PH to neutral, add injection water to 1000 milliliter, aseptic filtration is in 1000 ampoule bottles of packing, promptly.
Embodiment 2 preparation sodium hyaluronate solutions
2 gram hyaluronate sodiums are dissolved in an amount of injection normal saline, regulate pH to neutral, add the injection normal saline to 200ml, and aseptic filtration is in 1000 pre-charge injectors of packing, promptly.
Embodiment 3 preparation human urine trypsin inhibitor and hyaluronate sodium composite preparations
2 gram hyaluronate sodiums are added in the 5000000 unit human urine trypsin inhibitors, regulate pH to neutral, add the injection normal saline to 200ml, aseptic filtration is in 1000 pre-charge injectors of packing, promptly.
Embodiment 4 medicines of the present invention are to the treatment experiment of experimental rheumatoid arthritis rat
Laboratory animal and disease model: 40 of SD rats, male and female half and half, body weight 160～180g is equally divided into four groups (test group, hyaluronic acid group, UTI group, matched groups), 10 every group at random.The carrageenin 50ul/ of injection 1% only causes inflammation under the right back sufficient plantar aponeurosis of rat, sets up the rheumatoid arthritis rat model.
Grouping and medication: test group causes the composite preparation 0.1ml that contained hyaluronate sodium and human urine trypsin inhibitor in scorching back second day when each intraarticular injection of rat is according to the preparation of the embodiment of the invention 3 methods, per 7 days 1 time, twice totally; The corresponding sodium hyaluronate solution 0.1ml that gives by the preparation of the embodiment of the invention 2 methods of hyaluronic acid group; The corresponding UTI solution 0.1ml that gives by the preparation of the embodiment of the invention 1 method of UTI group; Model control group is with physiologic saline for substitute.Adopted volumetric method measurements to cause scorching foot (constitutional) before medication and after the medication on the the 6th, 12,18 day and to the volume of parapodum (Secondary cases), calculating swelling degree and inhibitory rate of intumesce.The results are shown in Table 1, table 2.
The influence of table 1 pair rat arthritis constitutional pathological changes (n=10, x ± s)
| Group | The 6th day | The 12nd day | The 18th day |
| Experimental group hyaluronic acid group UTI organizes matched group | 15.7±9.2 24.6±8.3 25.1±7.6 42.5±8.3 | 16.7±8.1 26.7±10.0 27.5±11.2 46.3±10.1 | 16.5±7.4 27.3±10.2 27.5±11.4 45.1±9.3 |
The influence of table 2 pair rat arthritis Secondary cases pathological changes (n=10, x ± s)
| Group | The 6th day | The 12nd day | The 18th day |
| Experimental group hyaluronic acid group UTI organizes matched group | 0.5±0.5 1.3±0.3 1.1±0.5 6.3±1.2 | 1.8±0.6 3.2±1.6 2.5±0.8 10.4±3.2 | 1.8±0.7 6.1±2.2 5.5±1.8 12.5±4.3 |
Experimental result shows, use pharmaceutical composition that the present invention contains hyaluronate sodium and human urine trypsin inhibitor simultaneously and can effectively suppress the development of constitutional and Secondary cases rat arthritis, its curative effect obviously is better than using simple hyaluronate sodium and uses simple human urine trypsin inhibitor.
Embodiment 5 medicines of the present invention are to the treatment experiment of experimental osteoarthritis rabbit
Laboratory animal and disease model: 20 of healthy adult male rabbits, body weight 2.5～3.5kg, single cage standardization forage feed.Set up osteoarthritis Rabbit Model [Colombo C etal, Arthritis Rhet, 1983,26 (7): 875] with reference to the Colombo method.24 animals are divided into 4 groups (test group, hyaluronic acid group, UTI group, matched groups), 5 every group at random after the modeling.
Grouping and medication: the 6th day begins to carry out therapeutic test after the modeling, observes for 26 weeks continuously.Test group contains the combination preparation 0.1ml of hyaluronate sodium and human urine trypsin inhibitor, per 7 days 1 time, totally six times when the rabbit intraarticular injection is by the preparation of the embodiment of the invention 3 methods; The corresponding sodium hyaluronate solution 0.1ml that gives by the preparation of the embodiment of the invention 2 methods of hyaluronic acid group; The corresponding UTI solution 0.1ml that gives by the preparation of the embodiment of the invention 1 method of UTI group; The injection normal saline of matched group injection equal volume.
The result: matched group groove sample pathological changes occurs in cartilage heavy burden district during 16 weeks, and the surface is the graininess projection, and the dark yellow muddiness of color and luster had hyperosteogeny to form in the 19th week, and the non-heavy burden of the 25th all cartilages district is uneven, local cartilage defect.Hyaluronic acid group and UTI group, test group whole 26 all interior forms do not have significant change.
Experimental rabbits is made Anatomical Observation, the perusal articular surface after the 26th week.The results are shown in, 5 rabbit articular surfaces of matched group are rough, tarnish, and cartilage is opaque, visible large stretch of damaged and neoplasm; Hyaluronic acid group and UTI group, articular surface is rough, and color and luster is dark, and the cartilage transparency is low, and tiny damaged and a little neoplasm is arranged; And the test group articular surface is smooth, and is glossy, and cartilage is transparent, do not have obviously damaged and neoplasm.
Experimental result shows, uses UTI or hyaluronic acid separately, all can effectively suppress the development of rabbit osteoarthritis, and it is the most obvious to use the effect of the medicine composite for curing that the present invention contains hyaluronate sodium and human urine trypsin inhibitor simultaneously.
Claims (7)
1. pharmaceutical composition that is used for the treatment of osteoarthritis and rheumatoid arthritis, it is characterized in that it is with the pharmaceutical preparation by following consumption proportion preparation of human urine trypsin inhibitor and hyaluronate sodium: the hyaluronate sodium 1mg of molecular weight 300,000-1,000 ten thousand joins human urine trypsin inhibitor 0.01-200 ten thousand units.
2. pharmaceutical composition according to claim 1 is characterized in that, human urine trypsin inhibitor and hyaluronate sodium proportioning are: the hyaluronate sodium 1mg of molecular weight 300,000-1,000 ten thousand joins human urine trypsin inhibitor 0.25-10 ten thousand units.
3. pharmaceutical composition according to claim 2 is characterized in that, human urine trypsin inhibitor and hyaluronate sodium proportioning are: the hyaluronate sodium 1mg of molecular weight 300,000-1,000 ten thousand joins human urine trypsin inhibitor 10,000 units.
4. according to the described pharmaceutical composition of the arbitrary claim of claim 1-3, it is characterized in that the pharmaceutical preparation of being prepared is lyophilized injectable powder or injection liquor.
5. according to the described pharmaceutical composition of the arbitrary claim of claim 1-3, it is characterized in that the pharmaceutical preparation of being prepared is aqueous solution.
6. pharmaceutical composition according to claim 4 is characterized in that, also contains wherein one or more of mannitol as additive, dextran, glycine in the compositions.
7. pharmaceutical composition according to claim 4 is characterized in that, also contains wherein one or more of mannitol as additive, sodium chloride, glucose in the compositions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100903659A CN1321692C (en) | 2005-08-16 | 2005-08-16 | Medicinal composition for treating arthritis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100903659A CN1321692C (en) | 2005-08-16 | 2005-08-16 | Medicinal composition for treating arthritis |
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| CN1751740A CN1751740A (en) | 2006-03-29 |
| CN1321692C true CN1321692C (en) | 2007-06-20 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101954072A (en) * | 2010-10-08 | 2011-01-26 | 广东天普生化医药股份有限公司 | Use of ulinastatin in preparation of drugs for treating rheumatoid arthritis and pharmaceutical composition thereof |
| CN105833258A (en) * | 2016-06-16 | 2016-08-10 | 扬州市第人民医院 | Application of ulinastatin to preparation of medicine for preventing and treating granulosis |
| CN114681411A (en) * | 2022-04-15 | 2022-07-01 | 臻赫医药(杭州)有限公司 | Biological gel preparation, preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1131675A (en) * | 1994-12-22 | 1996-09-25 | 赫尔克里斯有限公司 | Grosslinked acidic polysaccharides and their uses |
| JP2004208604A (en) * | 2002-12-27 | 2004-07-29 | Seikagaku Kogyo Co Ltd | New method for measuring enzyme activity |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1131675A (en) * | 1994-12-22 | 1996-09-25 | 赫尔克里斯有限公司 | Grosslinked acidic polysaccharides and their uses |
| JP2004208604A (en) * | 2002-12-27 | 2004-07-29 | Seikagaku Kogyo Co Ltd | New method for measuring enzyme activity |
Non-Patent Citations (1)
| Title |
|---|
| 间α胰蛋白酶抑制剂与胞外间质 赵明等，生物化学与生物物理进展，第24卷第3期 1997 * |
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