CN1315532C - Compound lysoamidase spray agent and preparing method - Google Patents
Compound lysoamidase spray agent and preparing method Download PDFInfo
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- CN1315532C CN1315532C CNB200410067265XA CN200410067265A CN1315532C CN 1315532 C CN1315532 C CN 1315532C CN B200410067265X A CNB200410067265X A CN B200410067265XA CN 200410067265 A CN200410067265 A CN 200410067265A CN 1315532 C CN1315532 C CN 1315532C
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- lysoamidase
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Abstract
The present invention relates to a compound lysoamidase spray and a preparation method thereof. The compound lysoamidase spray disclosed by the present invention contains 0.1% to 1.0% of lysoamidase as an active component, 0.1 to 10.0% of antioxidant and 0.1 to 10.0% of antioxygen synergist, and a buffer solution with pH of 3.0 to 9.0 is used as a solvent. The formula of the present invention solves the stability problem of compound lysoamidase in a water solution, and the provided spray preparation has the advantages of convenient use, obvious antibacterial effect and stable quality.
Description
Technical field
The invention belongs to technical field of medicine.Be specifically related to compound lysoamidase spray agent and preparation method.
Background technology
Lysoamidase is a kind of novel antibiotic enzyme external used medicine medical or for animals that obtains from a kind of culture fluid of pseudomonas bacillus, has very strong bacterolysis and protein dissolution ability.The easy moisture absorption of Lysoamidase powder, do not have smell, tasteless.Soluble in water, in ethanol and chloroform, do not dissolve.Lysoamidase is made of the albumen of 90% polysaccharide and 10% that (polysaccharide is electronegative, has numerously in N-acetyl-glucosamine, and the cellular construction that N-acetylated mannan alditol and N-acetyl galacturonic acid three constitute is formed.Protein part is made up of nearly 20 kinds of different albumen, and bacteriolyze albumen is wherein arranged, as phosphoric acid (ester) enzyme and protease).The original main dosage form of Lysoamidase is a lyophilized powder, can be used as surgery local application, and application method mainly contains: the filling wound, irrigate, and gargle soak.Medical science and biological experiment confirm: some lysozyme has proteolytic activity among the Lysoamidase, can remove wound rots to organize, the downright bad part of suppurative wound is come off rapidly, have simultaneously and promote immunity and quicken epitheliogenic effect, the endopeptidase that in hydrolysis staphylococcus aureus process, plays a major role a kind of lysozyme that comes to this with proteinase activity.Under proper condition, Lysoamidase dry powder can be preserved 3 years.
Lysoamidase can destroy the cell wall that antibiosis is have the gram positive bacteria (as: staphylococcus, streptococcus) of resistance, and is the most effective to staphylococcus aureus.Lysoamidase and polymyxin B are compound, can wider antibacterial action be arranged to gram negative bacteria, for example: actinomyces pseudonecrophorus, bacteroid, escherichia coli, pseudomonas putida, bacillus pyocyaneus, Salmonella, common degeneration bacterium, degeneration bacillus.
Lysoamidase in the clinical experiment process, be mainly used in after suppurative fistula, mastitis, the operation before stomach wall and lower limb wound and by the acute soft tissue that the pathogenic staphylococcus that antibiosis is have resistance causes suppurate (as cellulitis, abscess, suppurative cellulites).To above-mentioned all situations, Lysoamidase demonstrates good effect: compare with the matched group of being treated by conventional medicament, treatment time has shortened 2 times.In the clinical trial,, show bacteriolyze, removing the necrotic tissue and tissue regeneration promoting effect equally with Lysoamidase and the compound treatment that is used for oral disease of polymyxin B.Suppurative wound and burn, the dermatosis (folliculitis, furunculosis, other forms of pyoderma) that the suppuration inflammation is arranged, post-surgical trauma, scald, trophic ulcer, mastitis and endometritis, periodontal tissue and oral disease, pulpitis, periodontitis, central osteomyelitis, oral mucosa cavity, throat pain, naso-pharynageal disease.
But because Lysoamidase is unstable in aqueous solution, feasible formulation development for it is restricted, and uses also to be affected.
Summary of the invention
Technical problem to be solved by this invention is to solve the stability problem of composite lysozyme Lysoamidase in aqueous solution, provide a kind of easy to use, antibacterial effect is obvious, stay-in-grade Lysoamidase spray.
Compound lysoamidase spray agent disclosed by the invention contains 0.1%～1.0% active component Lysoamidase, 0.05～10.0% antioxidant and 0.05～10.0% antioxidant synergist, and is solvent with pH for the 3.0-9.0 buffer.
Wherein antioxidant mainly is selected from antioxidant such as sulfur-containing compound, enediol class, amino acids, comprise: thiourea, thioglycerol, 5-sulfo--D-glucose, tocopherol, natrium malicum, sodium L-ascorbate-2-phosphate, L-glutathion, L-cysteine L-methionine, L-leucine and bovine albumin etc., have prior to oxidation of drug, suppress the effect of free radical chain reaction.
Antioxidant synergist is selected from metal-chelator, organic acid and amino acids, have and the complexation of trace metal catalyst, thereby the pH value that perhaps reduces solution reduces oxidation potential, perhaps reduces the stability of oxygen in the solution and the effect of content.Comprise: diethylamine tetraacethyl sodium salt, diethylamine tetraacethyl calcium salt, succinic acid, fumaric acid, tartaric acid, citric acid, glycine, cysteine and tryptophan etc.
The pH3.0-9.0 buffer is selected from sodium dihydrogen phosphate+sodium hydrogen phosphate buffer, sodium hydrogen phosphate+citrate buffer solution, sodium hydrogen phosphate+potassium phosphate buffer, Tris+ hydrochloride buffer, potassium dihydrogen phosphate+sodium hydrate buffer solution, glycine+sodium hydrate buffer solution and sodium carbonate+sodium bicarbonate etc.The soluble inorganic salt ion such as the K that contain in the buffer
+, Ca
2+, Na
+, PO
4 3-Deng, have the bacteriostatic activity that strengthens medicine, be equivalent to the effect of activator.
According to the use position difference of spray, in preparation, can also add other auxiliary elements, as diluent, flavoring agent etc.
Another technical problem to be solved by this invention is to provide the preparation method of above-mentioned compound lysoamidase spray agent.
The method of the invention comprises the following steps:
(1) preparation pH3.0-9.0 buffer;
(2) add composite lysozyme Lysoamidase in buffer, the w/v of composite lysozyme and buffer is about 1: 100-1000w/v, stir and make it dissolving, homodisperse;
(3) add antioxidant, antioxidant synergist and other adjuvants, fully stir and make its dissolving;
(4) filter the packing spray container completely of going into to sterilize, low temperature 4-6 ℃ preservation.
The spray dosage is little, and the dosage size is scalable easy to control, convenient drug administration, and be different from aerosol, and do not add propellant, do not need pressure vessel, technology is simple, compliance with environmental protection requirements.
To body surface, mucosa and cavity/canal drug administration, topical therapeutic can be applied to spray, whole body therapeutic can be applied to again.The blood capillary of nasal cavity, oral cavity and other tract mucosas is abundant, after medicine is absorbed, directly enters blood circulation, can avoid the destruction of enzyme in the gastrointestinal tract and liver to the first-pass effect of medicine, helps bioavailability and improves.
Lysoamidase spray of the present invention is according to the oral hygiene principle design, and effective ingredient infiltrates interior tissue by local lesion's spraying, has ultra-fine shape spraying, and penetration can directly act on wound surface by force, and lasting medicine is concentrated, instant effect.Can be effectively press down antibacterials such as the staphylococcus aureus that causes pharyngolaryngitis, tonsillitis, oral ulcer, gingivitis, periodontitis, pericoronitis, papillary gingivitis extremely, Hemolytic streptococcus, streptococcus pneumoniae, big enterococcus, Candida albicans, fungus anaerobe, the sterilizing rate height.But said preparation has specificity kills noxious bacteria in the oral cavity, the protection profitable strain, and life-time service can not produce drug resistance; Safety non-toxic is non-stimulated to mucosa simultaneously, and long-term frequent use is without any side effects; Also have bactericidal antiphlogistic, resist various infection, human body immunity improving power is quickened wound healing, the function of tissue repair.
Carry out antibiotic comparative test with compound lysoamidase spray agent of the present invention and cephalosporins medicine, the result shows that the fungistatic effect of compound lysoamidase spray agent of the present invention is better than the first generation cephalosporins medicine cefalexin of present Shanghai consumption maximum.
Stability test shows, compound lysoamidase spray agent formulation products of the present invention can be stablized and stored 1 year, and the preparation that does not add antioxidant is tired obvious reduction is just arranged January, in the time of 1 year without any bacteriostatic activity.
The specific embodiment
Embodiment 1
Lysoamidase 50,000IU (about 300mg)
Sodium L-ascorbate-2-phosphate 1.5g
Tartaric acid 0.28g
Mentholum 0.1g
Aspartame 0.15g
Natrium malicum 0.5g
Preparation 0.01M, the phosphate buffer of PH8.0 (100ml) (sodium dihydrogen phosphate+sodium hydrogen phosphate); (50,000IU), stirring makes it dissolving, homodisperse to add composite lysozyme Lysoamidase; Add sodium L-ascorbate-2-phosphate, natrium malicum, tartaric acid, Mentholum and aspartame, stir accelerate dissolution, make into stable system, filter the packing spray container completely of going into to sterilize, low temperature 4-6 ℃ preservation.
Embodiment 2
Lysoamidase 50,000IU(300mg)
Thiourea 3.8g
Diethylamine tetraacethyl sodium salt 0.5g
Fructus Citri Limoniae oil 0.18g
Sweetleaf centautin 0.15g
The phosphate buffer 100ml (sodium hydrogen phosphate+potassium dihydrogen phosphate) of preparation PH6.8; Add composite lysozyme Lysoamidase, stir and make it dissolving, homodisperse; Add thiourea, diethylamine tetraacethyl sodium salt, Fructus Citri Limoniae oil and sweetleaf centautin, make solution, stir accelerate dissolution, make into stable system, filter, the packing spray container completely of going into to sterilize, low temperature 4-6 ℃ preservation.
Embodiment 3
Lysoamidase 50,000IU
L-glutathion 2.5g
Citric acid 1.2g
Oleum Rosae Rugosae 0.28g
Sweetleaf centautin 0.3g
Bovine albumin 0.5g
The Tris buffer 100ml (Tris+ hydrochloride buffer) of preparation PH5.0; Add composite lysozyme Lysoamidase, stir and make it dissolving, homodisperse; Add L-glutathion, citric acid, Oleum Rosae Rugosae, sweetleaf centautin and bovine albumin, make solution, stir accelerate dissolution, make into stable system, filter, the packing spray container completely of going into to sterilize, low temperature 4-6 ℃ preservation.
Embodiment 4 Lysoamidase spray antibacterial tests
Lysoamidase antibacterials sensitization test:
For colon bacillus (ATCC52922) minimal inhibitory concentration: 0.0625mg/ml
For Pseudomonas aeruginosa (ATCC27853) minimal inhibitory concentration: 0.0625mg/ml
Embodiment 5 stability tests
| Numbering | (MIC) | 0 month | January | February | March | June | December |
| 0201 | mg/ml | 0.005 | 0.038 | 0.038 | 0.038 | 0.038 | - |
| 0213 | mg/ml | 0.010 | 0.005 | 0.005 | 0.005 | 0.010 | 0.010 |
Wherein: MIC is a minimum inhibitory concentration
*The stability observing condition is 4 ℃, humidity 75%.
*0201:Lysoamidase directly is dissolved in phosphate buffer, carries out stability observing, adopts MIC (minimal inhibitory concentration is as detecting index)
*0213: preparation of the present invention, Lysoamidase is dissolved in phosphate buffer, and adds antioxidant, antioxidant synergist etc., carries out stability observing.
Conclusion: preparation of the present invention is deposited 1 year steady quality under 4 ℃, obviously is better than not adding antioxidant, antioxidant synergist preparation.
Claims (7)
1, compound lysoamidase spray agent is characterized in that this spray contains 0.1%～1.0% active component Lysoamidase, 0.1～10.0% antioxidant and 0.1～10.0% antioxidant synergist, and is solvent with pH for the 3.0-9.0 buffer.
2, compound lysoamidase spray agent according to claim 1 is characterized in that wherein said antioxidant is selected from sulfur-containing compound, enediol class, amino acids antioxidant.
3, compound lysoamidase spray agent according to claim 2 is characterized in that wherein said antioxidant is selected from thiourea, thioglycerol, 5-sulfo--D-glucose, tocopherol, natrium malicum, sodium L-ascorbate-2-phosphate, L-glutathion, L-cysteine L-methionine, L-leucine and bovine albumin.
4, compound lysoamidase spray agent according to claim 1 is characterized in that wherein said antioxidant synergist is selected from metal-chelator, organic acid and amino acids.
5, compound lysoamidase spray agent according to claim 4 is characterized in that wherein said antioxidant synergist is selected from diethylamine tetraacethyl sodium salt, diethylamine tetraacethyl calcium salt, succinic acid, fumaric acid, tartaric acid, citric acid, glycine, cysteine and tryptophan.
6, compound lysoamidase spray agent according to claim 1 is characterized in that wherein said pH3.0-9.0 buffer is selected from sodium dihydrogen phosphate+sodium hydrogen phosphate buffer, sodium hydrogen phosphate+citrate buffer solution, sodium hydrogen phosphate+potassium phosphate buffer, Tris+ hydrochloride buffer, potassium dihydrogen phosphate+sodium hydrate buffer solution, glycine+sodium hydrate buffer solution and sodium carbonate+sodium bicarbonate.
7, the preparation method of compound lysoamidase spray agent according to claim 1 is characterized in that this method comprises the following steps:
(1) preparation pH3.0-9.0 buffer;
(2) add composite lysozyme Lysoamidase in buffer, the w/v of composite lysozyme and buffer is about 1: 100-1000w/v, stir and make it dissolving, homodisperse;
(3) add antioxidant, antioxidant synergist and other adjuvants, fully stir and make its dissolving;
(4) filter the packing spray container completely of going into to sterilize, low temperature 4-6 ℃ preservation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410067265XA CN1315532C (en) | 2004-10-19 | 2004-10-19 | Compound lysoamidase spray agent and preparing method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410067265XA CN1315532C (en) | 2004-10-19 | 2004-10-19 | Compound lysoamidase spray agent and preparing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1616092A CN1616092A (en) | 2005-05-18 |
| CN1315532C true CN1315532C (en) | 2007-05-16 |
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| CNB200410067265XA Expired - Fee Related CN1315532C (en) | 2004-10-19 | 2004-10-19 | Compound lysoamidase spray agent and preparing method |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103203014B (en) * | 2013-03-06 | 2015-02-25 | 哈尔滨础润医疗器械有限责任公司 | Preparation method of blended functional surgical irrigating fluid |
| CN103830180B (en) * | 2014-03-27 | 2016-03-02 | 山东司邦得制药有限公司 | A kind of lisozima mouth sprays and preparation method thereof |
| EP3478066A1 (en) * | 2016-06-30 | 2019-05-08 | Next Science IP Holdings Pty Ltd | Antimicrobial compositions and methods employing same |
| CN117442702A (en) * | 2022-01-26 | 2024-01-26 | 陕西师范大学 | Antibacterial liquid with controllable-size protein-based nanoparticles |
| CN117643311B (en) * | 2023-12-01 | 2024-09-27 | 北京舜雷科技有限公司 | Composition, preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2139348C1 (en) * | 1997-10-06 | 1999-10-10 | Институт биохимии и физиологии микроорганизмов им.Г.К.Скрябина РАН | Agent for lysis of cells of gram-positive and gram-negative microorganisms |
| CN1390135A (en) * | 1999-09-14 | 2003-01-08 | 新眼界诊断公司 | Topical treatment of streptococcal infections |
| CN1390535A (en) * | 2002-07-30 | 2003-01-15 | 上海宇盛科技有限公司 | Effervescent table for cleaning oral cavity |
-
2004
- 2004-10-19 CN CNB200410067265XA patent/CN1315532C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2139348C1 (en) * | 1997-10-06 | 1999-10-10 | Институт биохимии и физиологии микроорганизмов им.Г.К.Скрябина РАН | Agent for lysis of cells of gram-positive and gram-negative microorganisms |
| CN1390135A (en) * | 1999-09-14 | 2003-01-08 | 新眼界诊断公司 | Topical treatment of streptococcal infections |
| CN1390535A (en) * | 2002-07-30 | 2003-01-15 | 上海宇盛科技有限公司 | Effervescent table for cleaning oral cavity |
Non-Patent Citations (6)
| Title |
|---|
| 抗氧化剂抗衰老的应用现状及存在部题 李勤劳，张恩户，刘敏，赵子剑，陕西中医学院学报，第26卷第6期 2003 * |
| 抗氧化剂抗衰老的应用现状及存在部题 李勤劳，张恩户，刘敏，赵子剑，陕西中医学院学报，第26卷第6期 2003;撇菌剂及其抗菌机理 夏金兰，王春，刘新星，中南大学学报(自然科学版)，第35卷第1期 2004;溶菌酶的研究进展 荣晓花，凌沛学，中国生化药物杂志，第20卷第6期 1999;深菌酶及其应用 叶丹，连宾，贵州科学，第21卷第3期 2003;深菌酶及在食品中的应用 李冬梅，食品工业，第3期 1999 * |
| 撇菌剂及其抗菌机理 夏金兰，王春，刘新星，中南大学学报(自然科学版)，第35卷第1期 2004 * |
| 深菌酶及其应用 叶丹，连宾，贵州科学，第21卷第3期 2003 * |
| 深菌酶及在食品中的应用 李冬梅，食品工业，第3期 1999 * |
| 溶菌酶的研究进展 荣晓花，凌沛学，中国生化药物杂志，第20卷第6期 1999 * |
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