CN1438032A - Compound preparation for dissolving staphyloase and preparation method - Google Patents
Compound preparation for dissolving staphyloase and preparation method Download PDFInfo
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- CN1438032A CN1438032A CN 03103476 CN03103476A CN1438032A CN 1438032 A CN1438032 A CN 1438032A CN 03103476 CN03103476 CN 03103476 CN 03103476 A CN03103476 A CN 03103476A CN 1438032 A CN1438032 A CN 1438032A
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- Prior art keywords
- lysozyme
- preparation
- staphylococcus
- lysostaphin
- antibacterial
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- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 claims abstract description 66
- 235000010335 lysozyme Nutrition 0.000 claims abstract description 66
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discloses a lysostaphin compounded preparation. Said preparation comprises bacteria-killing effective quantity of lysostaphin and lysozyme. Said lysostaphin compounded preparation has higher bacteria-killing effect as compared with single lysostaphin, not only has the strong bacteria-killing action for Gram-positive bacterium and Gram-negative bacterium, but also has the good effect for killing the fungi of Candida albicans and red trichophyton, etc. It has high bacteria-killing activity and stability, does not produce drug resistance, and has no toxic side effect.
Description
Technical field
The present invention relates to a kind of biological sterilization preparations, relate in particular to complex preparation of a kind of staphylococcus lysozyme and preparation method thereof.
Background technology
At present, courses of infection clinically is quite serious, and it has become a big killer who threatens human health over nearly 20 years.And increasing antibacterial can be resisted antibiotic treatment, thereby public health has been caused serious threat.In the U.S., the life that lost because of drug resistant bacterial infections in 1998 is than also many on Vietnam battlefield.Once easy just can be by the pathogenic bacteria of antibiotic kills as staphylococcus aureus, streptococcus pneumoniae, bacillus pyocyaneus, Candida albicans, escherichia coli etc., the more and more fierceness that becomes because having produced drug resistance now makes the people more and more at a loss what to do.And drug resistance staphylococcus aureus wherein is wherein active molecule, the infection that causes by it, not only curative effect is not good enough or invalid fully under conventional therapy, can also change simultaneously the ecological ragime of patient's normal flora, thereby cause extra misery to patient, increase financial burden and misfortune.
In the face of more and more serious courses of infection, what widely apply clinically at present is the chemical classes therapeutic agent, mainly is antibiotic, but be extensive use of along with antibiotic, many unfavorable factors constantly occur, the drug tolerant bacteria that thereupon occurs is more and more on the one hand, eliminate them and become more and more difficult; The side effect that brings of antibiotic is quite serious on the other hand, has all caused certain injury for patient's body and mind.Therefore, medical circle is being sought a kind of alternative antibiotic always, can play bactericidal effect, but is difficult for producing the biocide preparation of endurance strain.
According to patent both domestic and external and document, staphylococcus lysozyme can be used to treat all kinds of staphy lococcus infections, particularly at the drug resistance staphylococcus aureus.Simple staphylococcus lysozyme only has killing effect to part gram positive bacterias such as staphylococcuses, and the traumatic infection mixed infection of multiple pathogen often, moreover have much is gram negative bacteria, as the common bacillus pyocyaneus of burn wound, escherichia coli etc., common anaerobe such as Hemolytic streptococcus in the oral cavity, the still fungal infection that has is as Candida albicans, trichophyton.
Patent:
(1) compositions of CN1353602A treatment staphy lococcus infection and method this technology on March 3rd, 2000 are staphylococcus lysozyme or other staphylococcus agent by aureus cell wall Peptidoglycan cross-bond, as staphylococcus lysozyme and a kind ofly can effectively suppress staphylococcic antibiotic administering drug combinations, can suppress the infection due to the staphylococcus of one or more staphylococcus lysozymes or the tolerance of cell wall living antibiotics.
(2) CN1269727A only containing lysostaphin or containing lysostaphin and antibiotic pharmaceutical composition on July 21st, 1998 for the treatment staphy lococcus infection
Though above patented technology has certain germicidal efficacy, only be to be used for resisting staphy lococcus infection, fungicidal spectrum is limited.And poor stability, and if staphylococcus lysozyme and antibiotic share, antibiotic still exists to the side effect such as zest of body, and can not well solve drug resistant bacterial infections, thereby can not reach optimum efficiency.
Summary of the invention
Complex preparation that provides a kind of staphylococcus lysozyme and preparation method thereof is provided technical problem to be solved by this invention, and narrow to solve antibacterial fungicidal spectrum of the prior art, toxic and side effects is big, easily produces chemical sproof shortcoming.
The invention provides a kind of complex preparation of staphylococcus lysozyme, said preparation comprises the staphylococcus lysozyme and the lysozyme of the effective dose that sterilizes, and its preferred weight ratio is:
Staphylococcus lysozyme: lysozyme=1: 200～400.
Staphylococcus lysozyme wherein is one or more in agriotype, reorganization generation, mutant or any reorganization that contains the glycine cross-bond that keeps the staphylococcus whole cell peptidoglycan or the relevant enzyme; Lysozyme is one or more in bacterial cell wall lyase, yeast cell wall lyase, the mycete cell wall lyase.Used staphylococcus lysozyme is to be produced by gene recombinaton, and bacillus subtilis is excretory.Used lysozyme be by extract in the Ovum Gallus domesticus album or gene recombinaton produce.
Also comprise in this complex preparation in the protein stabilizing agent of total formulation weight amount 0.2-60% and the ionic compound of 0.5-20%.
The protein stabilizing agent of being addressed comprises medicinal macromolecular compounds such as polyethylene glycol substances or chitosan, chitin, N-acetyl-D-amino, can wrap up protein or polypeptide, avoids the destruction of other materials, thereby strengthens the stability of protein or polypeptide;
The ionic compound of being addressed is K
+, Na
+, Mg
2+, PO
4 3-, Cl
-In any two kinds of aniones and cationic combination, as NaCl, KCl etc. can assist the stability that strengthens this complex preparation, and can regulate its acid-base value, make it to be applicable to the wound surface or the mucosa of different parts.
The polyethylene glycol substances of being addressed comprises it being in PEG400, cetomacrogol 1000, Polyethylene Glycol 1 500, Macrogol 4000 or the polyethylene glycol 6000 one or more.
In order to strengthen this complex preparation sterilizing power, enlarge fungicidal spectrum, also comprise antibacterial in total formulation weight amount 0-20%.Wherein antibacterial is meant chlorhexidine acetate, bacteriostatic peptide or the Chinese medicine extract of bactericidal action is arranged, as sativin, thymol, catechol, tomatidine, emodin etc.
This complex preparation also comprises the antistaling agent in total formulation weight amount 0.1-20%, and antistaling agent is one or more in parabens or the sodium benzoate.
This complex preparation also comprises the ephedrine in total formulation weight amount 0-20%, and ephedrine is the smooth muscle contraction agent, is used for wound surface, can promote wound healing; Also can be used for nasal cavity, promote mucosa to absorb.
According to the present invention, preferred component and weight percent content are:
Staphylococcus lysozyme 0.00001-20%
Lysozyme 0.0001-85%
Protein stabilizing agent 0.2-60%
Ionic compound 0.5-20%
Antibacterial 0-20%
Antistaling agent 0.1-20%
Ephedrine 0-20%.
Preferred component and weight percent content are:
Staphylococcus lysozyme 0.1-20%
Lysozyme 50-85%
Protein stabilizing agent 0.2-30%
Ionic compound 0.5-20%
Antibacterial 1-20%
Antistaling agent 0.1-20%
Ephedrine 0-20%.
The preparation method of preparation of the present invention can adopt conventional physical mixed, and each component is mixed in proportion, and fill is put in storage in plastics or vial then, and room temperature preservation gets final product.
Each compound that is produced not only bactericidal effect is much higher than staphylococcus lysozyme, and 10-40 is doubly to the simple superposition of three's bactericidal effect; The fungicidal spectrum of each complex also obviously enlarges, and all can reach very strong killing action to gram positive bacteria and gram negative bacteria, and funguses such as Candida albicans and trichophyton are also had good killing effect.
1% concentration composite lysostaphin formulation soln detects through Shanghai City preventive medicine academy, act on skin surface 2-10 minute after testing and can kill gonococcus, staphylococcus aureus, Candida albicans, bacillus pyocyaneus, escherichia coli, Hemolytic streptococcus etc. rapidly, killing rate reaches 99.9%.Characteristics such as it is good to have bactericidal effect, non-stimulated.
The antibacterial of strain more than 400 that clinical each section is collected has carried out the sterilization experiment that presses down of said preparation.Experimental result shows: 1% concentration composite lysostaphin formulation soln is to common clinically staphylococcus aureus, and staphylococcus epidermidis, Diplococcus pneumoniae, D group enterococcus, tetracoccus, product monokaryon Listerella, streptococcus and stomach Helicobacter pylori, escherichia coli, bacillus pyocyaneus etc. all have tangible inhibitory or killing effect.
Pure staphylococcus lysozyme is very unstable at normal temperatures, contains the stabilizing agent and the synergist of multiple our screening in the composite composite lysostaphin, and stability greatly strengthens, and makes it applicable to industrial-scale production.
Staphylococcus lysozyme and composite lysostaphin enzyme are lived stability experiment relatively, preserve 3 months (being equivalent to room temperature preserved 2 years) through 37 ℃, see Table 1, table 2.
The activity ratio before and after 37 ℃ of placements in 3 months of table 1 staphylococcus lysozyme
| Enzymatic activity (U/mg) before staphylococcus lysozyme is placed | 37 ℃ of 3 months placement back enzymatic activitys (U/mg) of staphylococcus lysozyme | Rate of descent (%) | |
| ?1 | ?566 | ?301 | ?46.8 |
| ?2 | ?568 | ?299 | ?47.3 |
| ?3 | ?560 | ?290 | ?48.2 |
| Meansigma methods | ?47.4 |
The dissolving staphylococcal bacteria activity ratio before and after 37 ℃ of placements in 3 months of table 2 composite lysostaphin
| Enzymatic activity (U/g) before composite lysostaphin is placed | 37 ℃ of 3 months placement back enzymatic activitys (U/g) of composite lysostaphin | Rate of descent (%) | |
| ?1 | ?1000 | ?960 | ?4.00 |
| ?2 | ?1020 | ?967 | ?5.20 |
| ?3 | ?1015 | ?967 | ?4.73 |
| Meansigma methods | ?4.64 |
Staphylococcus lysozyme enzyme in the composite lysostaphin purer staphylococcus lysozyme height of stability of living as seen from the above table.
Experiment also proves the composite lysostaphin preparation to endurance strain, and as feeling most thorny methicillin-resistant staphylococcus aureus on the present clinical medicine, drug resistance Diplococcus pneumoniae, the killing effect of having a liking for the narrow food sporangium of Fructus Hordei Germinatus more are better than common antibiotics.
Its basic characteristics are:
1. fungicidal spectrum is wide than staphylococcus lysozyme.Can not only effectively kill staphylococcus, staphylococcus, Candida albicans, bacillus pyocyaneus, escherichia coli, Diplococcus pneumoniae, D group enterococcus, tetracoccus, product monokaryon Listerella, streptococcus, anaerobe, have a liking for common malignant bacterias such as the narrow food sporangium of Fructus Hordei Germinatus, gonococcus, stomach Helicobacter pylori are also had very strong killing action.To some drug tolerant bacterias, also demonstrate extremely strong bactericidal effect in addition as drug resistance staphylococcus aureus, drug resistance Diplococcus pneumoniae etc.
2. bactericidal activity and stability are much higher than staphylococcus lysozyme.Because composite lysostaphin is to be main component with the staphylococcus lysozyme, being equipped with compositions such as lysozyme, above-mentioned micromolecular compound and stabilizing agent, synergist is composited, have bigger stability than pure staphylococcus lysozyme, prove that after tested this product can be preserved 2 years at normal temperatures.
3. be difficult for producing drug resistance.As the staphylococcus lysozyme and the lysozyme of main active, have unique sterilization mechanism, staphylococcus lysozyme is by the glycine key in the narrow spectrum cut-out muramyl peptide polysaccharide, reaches the effect of quick kill pathogenic organisms; Lysozyme then can act on β-1,4 glycosidic bond or β-1,3 glucosan in the cell wall, makes it fracture.It is composite that two kinds of enzymes carry out in certain proportion, synergism, and dual cracking bacteria cell wall, thereby antibacterial is difficult for it is produced drug resistance.
4. body is had no side effect.Staphylococcus lysozyme and lysozyme are protein product, and skin and mucosa are produced to stimulate, and body is not produced any type of toxic and side effects, and can thoroughly degrade by metabolism, do not have residual, can enrichment.
Added that compound enzymic preparation of the present invention can be used for treating abscess, tinea, ulcer, decubital ulcer, burn, scalds, burns, furuncle, incised wound, oral ulcer, vaginitis, all kinds of oral disease, respiratory tract disease and the acute or chronic gastritis that causes by bacterial infection, the bacterial disease of all kinds of inflammations of external auditory canal, otitis media, keratitis, orbital cellulitis, conjunctivitis, hordeolum, acute and chronic rhinitis, sinusitis, prevention of STD, Aquatic product, prevent and treat acne, all kinds of by antibacterial, fungus-caused skin of face illness etc.; The debridement and the wound dressing that also can be used for preoperative and postoperative in the various surgical operations such as surgery, department of obstetrics and gynecology, urology department, the department of stomatology; Can be used for removing adherent antibacterial on the contact lens.
The specific embodiment
Embodiment 1 makes 100 gram composite lysostaphin preparation proportionings: the coccus enzyme 0.001g of Portugal, molten Portugal lysozyme 53g chlorhexidine acetate 1g potassium phosphate 8g sodium chloride 12g chitin 25.9g
Method: in sterilizing room,, add successively in proportion in the clean glass or rustless steel container, stir gently by described each component that takes by weighing of last table, fully mixed evenly after, fill in plastics or vial, warehouse-in, room temperature preservation gets final product.
This proportioning can be used for making mucocutaneous germ killing drugs, and additive capacity is 1-20%.Add the mucocutaneous germ killing drugs of this proportioning, can kill gonococcus, staphylococcus aureus, Candida albicans, bacillus pyocyaneus, escherichia coli of skin, mucomembranous surface etc. in 2-10 minute, killing rate reaches 99.9%.Can treat abscess, tinea, ulcer, decubital ulcer, burn, scald, burn, furuncle, acne, incised wound, oral ulcer, pharyngolaryngitis, gingivitis, vaginitis, prevention of STD, be used for various surgical operations such as surgery, department of obstetrics and gynecology, urology department, the department of stomatology, the debridement of preoperative and postoperative and wound dressing.
Embodiment 2 makes 100 gram composite lysostaphin preparation proportionings: the coccus enzyme 0.01g of Portugal, molten Portugal lysozyme 52g sodium benzoate 1g potassium phosphate 9g sodium chloride 12g chitosan 26g
Method: in sterilizing room,, add successively in proportion in the clean glass or rustless steel container, stir gently by described each component that takes by weighing of last table, fully mixed evenly after, fill in plastics or vial, warehouse-in, room temperature preservation gets final product.
This proportioning is used for food fresh keeping, and additive capacity is 1-20%.
Add the food of this proportioning, can prolong the shelf-life of fresh food, can prolong the shelf-life of milk, seafood.
Embodiment 3 makes 100 gram composite lysostaphin preparation proportionings: the coccus enzyme 0.1g of Portugal, molten Portugal lysozyme 52g bacteriostatic peptide 1g potassium phosphate 9g sodium chloride 12g chitosan 25.9g
Method: in sterilizing room,, add successively in proportion in the clean glass or rustless steel container, stir gently by described each component that takes by weighing of last table, fully mixed evenly after, fill in plastics or vial, warehouse-in, room temperature preservation gets final product.
It is 1-40% that this proportioning is used to make the oral drugs additive capacity.Add the oral drugs of this proportioning, can treat all kinds of oral disease, respiratory tract disease and the acute or chronic gastritis that cause by bacterial infection.
Embodiment 4 makes 100 gram composite lysostaphin preparation proportionings: the coccus enzyme 0.5g of Portugal, molten Portugal lysozyme 46g thymol 15g potassium phosphate 14g sodium chloride 12.5g Polyethylene Glycol 12g
Method: in sterilizing room,, add successively in proportion in the clean glass or rustless steel container, stir gently by described each component that takes by weighing of last table, fully mixed evenly after, fill in plastics or vial, warehouse-in, room temperature preservation gets final product.
This proportioning is used to make the otitis disease drug, and additive capacity is 1-20%; Add the auditory meatus medicine of this proportioning, can treat all kinds of inflammations of external auditory canal, otitis media.Be used to make ophthalmic remedy, additive capacity is 1-20%; The opthalmological that adds prescription four can be used for treating keratitis, orbital cellulitis, conjunctivitis, hordeolum; Be used to remove adherent antibacterial on the recessive glasse.Be used for the aquatic product fishery medicine, additive capacity is 15-40%; Can be used for treating the bacterial disease of Aquatic product.Be used to make cosmetics, additive capacity is 1-20%, can be used for preventing and treating acne, treats all kinds of by antibacterial, fungus-caused skin of face illness.
Embodiment 5 makes 100 gram composite lysostaphin preparation proportionings: the coccus enzyme 1g of Portugal, molten Portugal lysozyme 58g ephedrine 15g potassium phosphate 14g sodium chloride 12g
Method: in sterilizing room,, add successively in proportion in the clean glass or rustless steel container, stir gently by described each component that takes by weighing of last table, fully mixed evenly after, fill in plastics or vial, warehouse-in, room temperature preservation gets final product.
This prescription can be used for making the nasal inflammation medicine, and additive capacity is 1-20%, can treat acute and chronic rhinitis, sinusitis.
Claims (10)
1. a lysostaphin compounded preparation is characterized in that said preparation comprises the complex preparation that the invention provides a kind of staphylococcus lysozyme, and said preparation comprises the staphylococcus lysozyme and the lysozyme of the effective dose that sterilizes.
2. complex preparation according to claim 1 is characterized in that, the weight ratio of staphylococcus lysozyme and lysozyme is:
Staphylococcus lysozyme: lysozyme=1: 200～400.
3. complex preparation according to claim 1 and 2, it is characterized in that described staphylococcus lysozyme is one or more in agriotype, reorganization generation, mutant or any reorganization that contains the glycine cross-bond that keeps the staphylococcus whole cell peptidoglycan or the relevant enzyme; Described lysozyme is one or more in bacterial cell wall lyase, yeast cell wall lyase, the mycete cell wall lyase.
4. complex preparation according to claim 1 and 2 is characterized in that, said preparation also comprises in staphylococcus lysozyme and the protein stabilizing agent of lysozyme gross weight 0.2-60% and the ionic compound of 0.5-20%; Protein stabilizing agent is one or more in polyethylene glycol substances or chitosan, chitin, the N-acetyl-D-amino; Ionic compound is K
+, Na
+, Mg
2+, PO
4 3-, Cl
-In any two kinds of aniones and cationic combination.
5. complex preparation according to claim 1 and 2 is characterized in that, said preparation also comprises the antibacterial in staphylococcus lysozyme and lysozyme gross weight 0-20%; Antibacterial is one or more in chlorhexidine acetate, bacteriostatic peptide, sativin, thymol, catechol, tomatidine or the emodin.
6. complex preparation according to claim 1 and 2, it is characterized in that, said preparation comprises that also described antistaling agent is one or more in parabens or the sodium benzoate in the antistaling agent of staphylococcus lysozyme and lysozyme gross weight 0.1-20%.
7. complex preparation according to claim 1 and 2 is characterized in that, said preparation also comprises the ephedrine in staphylococcus lysozyme and lysozyme gross weight 0-20%.
8. lysostaphin compounded preparation as claimed in claim 1 or 2 is characterized in that the component of said preparation and weight percent content are as follows:
Staphylococcus lysozyme 0.00001-20%
Lysozyme 0.0001-85%
Protein stabilizing agent 0.2-60%
Ionic compound 0.5-20%
Antibacterial 0-20%
Antistaling agent 0.1-20%
Ephedrine 0-20%.
9. lysostaphin compounded preparation as claimed in claim 8 is characterized in that the component of said preparation and weight percent content are as follows:
Staphylococcus lysozyme 0.1-20%
Lysozyme 50-85%
Protein stabilizing agent 0.2-30%
Ionic compound 0.5-20%
Antibacterial 1-20%
Antistaling agent 0.1-20%
Ephedrine 0-20%.
10. the preparation method as each described lysostaphin compounded preparation of claim 1～9 is characterized in that each component is mixed in proportion.
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| CNB031034764A CN100450546C (en) | 2002-01-28 | 2003-01-27 | Compound preparation for dissolving staphyloase and preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02110672 CN1367018A (en) | 2002-01-28 | 2002-01-28 | Compound preparation of staphylococcolysis enzyme and its preparation method and application |
| CN02110672.X | 2002-01-28 | ||
| CNB031034764A CN100450546C (en) | 2002-01-28 | 2003-01-27 | Compound preparation for dissolving staphyloase and preparation method |
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| CN100450546C CN100450546C (en) | 2009-01-14 |
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| CN100388949C (en) * | 2005-08-09 | 2008-05-21 | 上海高科联合生物技术研发有限公司 | Lysostaphin freeze-dried powder for preventing and treating bovine endometritis |
| CN100431419C (en) * | 2003-10-16 | 2008-11-12 | 上海高科生物工程有限公司 | Biological agent for foot disinfection |
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| CN109310087A (en) * | 2016-06-30 | 2019-02-05 | 贴近科学Ip控股私人有限公司 | Antimicrobial compositions and methods of using the same |
| CN113440645A (en) * | 2021-06-29 | 2021-09-28 | 西安汇朴成医疗科技有限公司 | Composite lysozyme liquid dressing for wound surface and preparation method thereof |
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| CN1132517C (en) * | 2000-06-08 | 2003-12-31 | 上海高科生物工程有限公司 | Compound lysostaphin enzyme disinfectant |
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- 2003-01-27 CN CNB031034764A patent/CN100450546C/en not_active Expired - Lifetime
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| CN1911442B (en) * | 2005-08-09 | 2010-06-30 | 上海高科联合生物技术研发有限公司 | Lysostaphin freeze dried powder used for preventing and treating trauma surface infestation |
| CN102552888A (en) * | 2010-12-10 | 2012-07-11 | 上海高科联合生物技术研发有限公司 | Suppository for treating mammal endometritis |
| CN102671190A (en) * | 2012-04-26 | 2012-09-19 | 安徽省芬格欣普蓝生物药业有限公司 | Enzymic preparations for improving human body immunity and enhancing gastrointestinal and respiratory functions |
| CN109310087A (en) * | 2016-06-30 | 2019-02-05 | 贴近科学Ip控股私人有限公司 | Antimicrobial compositions and methods of using the same |
| CN113440645A (en) * | 2021-06-29 | 2021-09-28 | 西安汇朴成医疗科技有限公司 | Composite lysozyme liquid dressing for wound surface and preparation method thereof |
| CN116831941A (en) * | 2023-08-18 | 2023-10-03 | 江苏雪豹日化有限公司 | Lysozyme toothpaste capable of freshening breath and preparation method thereof |
| CN117717612A (en) * | 2023-12-19 | 2024-03-19 | 中山自然说生物科技有限公司 | Privacy care composition and preparation method and application thereof |
| CN117717492A (en) * | 2023-12-19 | 2024-03-19 | 中山自然说生物科技有限公司 | Biological agent for repairing armpit microecology and preparation method and application thereof |
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