CN110227071B - Compound borneol antibacterial agent - Google Patents
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- CN110227071B CN110227071B CN201910716008.0A CN201910716008A CN110227071B CN 110227071 B CN110227071 B CN 110227071B CN 201910716008 A CN201910716008 A CN 201910716008A CN 110227071 B CN110227071 B CN 110227071B
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- A61K31/01—Hydrocarbons
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- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
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Abstract
The present invention provides a kind of compound borneol antibacterial agents, belong to pharmaceutical preparations technology field.A kind of compound borneol antibacterial agent, is calculated by mass percentage, including following component and proportion: Bronyl acetate 85-90%, limonene 2.5-5%, borneol 5-10%, gaultherolin 1-1.5%.Antibacterial agent provided by the invention, antibacterial and bactericidal effect is significant, can be used in inhibiting and killing staphylococcus aureus, Candida albicans, Escherichia coli, has broad-spectrum antibacterial property, applicability is wide.Antibacterial agent of the invention can treat infective factors caused by a variety of fungies or bacterium etc., alleviate wound infection, and non-toxic, nonirritant to skin, safely and effectively.
Description
Technical field
The invention belongs to pharmaceutical preparations technology fields, and in particular to a kind of compound borneol antibacterial agent.
Background technique
Borneol (Borneol), also known as borneol, including three kinds of d-Bomeol, L-Borneol and isoborneol isomers.Borneol is made
For the representative medicine of drugs of causing resuscitation by administering aromatic drugs, play important walking alone makes to act on assistant.Currently, existing for the antibacterial of borneol both at home and abroad
Many research reports are carrying out external bacteriostatic experiment to 14 kinds of common causative bacterial strains, discovery borneol to staphylococcus aureus,
Resistant Staphylococcus aureus and staphylococcus albus have apparent bacteriostasis, there is bacteriostasis in low concentration, highly concentrated
There is bactericidal effect when spending, fungistatic effect increases with action time and is enhanced, weaken with the reduction of drug concentration (Unlu M,
Daferera D, Donmez E, Polissiou M, Tepe B, Sokmen A. Compositions and the in
vitro antimicrobial activities of the essential oils of Achillea setacea and
Achillea teretifolia[J].J Ethnopharmacol,2002;83:117–21;Try to gain family's bowl, Yang Shenghua, Sun Yumei
The research [J] of the vitro antibacterial activity of equal borneol and isoboeneol, West China pharmaceutical journal, 1989,4 (l): 20-22.;Huang Xiaomin,
3 kinds of dosage form antibacterial activity in vitro research [J] Jiangxi College of Traditional Chinese Medicine journals of the such as Liao Lingjun, Zeng Songrong MEIHUA BINGPIAN, 2005,17
(1): 63-65.), meanwhile, borneol shows good result to antimycotic, from otitis media suppurative patient's external auditory canal secretion
The fungal bacterial strains such as black aspergillus are isolated, are observed by Electronic Speculum, aspergillus niger cell membrane, cytoplasm are destroyed out under borneol effect
Now a large amount of electronics blank areas (ETA), mitochondria deformation, mycelia shrinkage, torsional deformation cause fungi to dissolve dead (Chang Songping, Lee
Clinical application [J] Chinese medicine of influence and treatment otitis media suppurative of the borneol such as beautiful spring to fungal cell's ultra microstructure is miscellaneous
Will, 2000,25 (5): 306-308.).
Limonene (Limonene), the monocyclic monoterpene being widely present in plant, crude limonene is with D- limonene, DL-
Limonene, 3 kinds of isomers of L-citrene form be present in plant volatile oil, be often used as food additives.Foreign countries also have
Limonene is used as food preservative by document, and is studied its fungistatic effect.Studies in China discovery, limonene is to beer
Yeast, Saccharomyces cerevisiae, aspergillus niger have bacteriostasis, and fungistatic effect is substantially better than potassium sorbate and sodium benzoate, but to gold
Staphylococcus aureus does not have obvious bacteriostasis, and (Wang Xuemei, Chen Hui, Li Xuejiao wait natural activity monoterpene-limonene antibacterial
Performance study [J] Jilin Auto Industry, 2010,32 (1): 24-28.).
Bronyl acetate, also known as borneolacetate are colourless liquid and crystalline solid, have antidiarrheal, analgesia, inhibit intestines flat
The effects of sliding muscle spasmus, wherein analgesic activity is more obvious.Meanwhile Bronyl acetate is also room spray fragrance, bath perfume
The important component of material, talcum powder.
Gaultherolin, also known as Methyl Salicylate are a kind of colourless or light yellow or pale yellow red, transparent oil
Shape liquid has strong wintergreen fragrance.
Currently, as antibiotic is widely used in controlling in the aspect of disease caused by all kinds of bacteriums and pathogenic microorganisms
Treat, germ also gradually shows the drug resistance of antibiotic, it is, thus, sought for effectively, the antibacterial agent of wide spectrum.
Up to now, not yet there is the compound externally used antimicrobial of gaultherolin, borneol, limonene, Bronyl acetate, borneol
The relevant report of preparation.
Summary of the invention
For above situation, the present invention provides a kind of compound borneol antibacterial agents, select natural component present in plant
Compounded combination, composition can inhibit and kill the antibacterial agent of germ, and the antibacterial effect of the antibacterial agent is significant, have antibacterial wide spectrum
Property.
Technical scheme is as follows:
The present invention provides a kind of compound borneol antibacterial agents, are calculated by mass percentage, including following component and proportion: second
Sour borneol acetate 85-90%, limonene 2.5-5%, borneol 5-10%, gaultherolin 1-1.5%.
Further, the compound borneol antibacterial agent, is calculated by mass percentage, including following component and proportion: acetic acid
Borneol acetate 88%, limonene 2.5%, borneol 8%, gaultherolin 1.5%.
Further, the compound borneol antibacterial agent, the borneol are selected from natural borneol.
Further, the auxiliary material for allowing to be added can be added according to actual needs on pharmaceutical preparation in the compound borneol antibacterial agent
Any one external application pharmaceutical preparation dosage form is made with auxiliary agent;Preferred dosage form is ointment, lotion, emulsifiable paste.
The present invention compared to the prior art, the beneficial effect is that:
1, antibacterial agent provided by the invention, antibacterial and bactericidal effect are significant, be able to suppress and kill staphylococcus aureus,
Candida albicans, Escherichia coli have broad-spectrum antibacterial property, and applicability is wide, can overcome the drug resistance of antibiotic antibacterial.
2, antibacterial agent of the invention selects various ingredients mixing, can be to feel caused by a variety of fungies of external curing or bacterium etc.
Metachromia skin disease alleviates wound infection, and non-toxic, nonirritant to skin, safely and effectively, bacteriostasis antibiosis effect and borneol
Single medicine is compared, better effect, and dosage is less.
Specific embodiment
Combined with specific embodiments below, the present invention is further described.
The formula of embodiment one and preparation preparation
1 compound borneol antibacterial ointment of preparation
Formula:
Main ingredient: Bronyl acetate 8.5g, limonene 0.4g, borneol 1g, gaultherolin 0.1g;
Matrix: 90g vaseline, 10g lanolin;
Ointment formulation process:
(1) main ingredient of recipe ratio is weighed respectively, and borneol therein is finely ground;
(2) respectively weighing weight is the vaseline and lanolin for being formulated half amount, and vaseline and lanolin is ground well obtained
Ointment bases;
(3) by Bronyl acetate by equal increments in the form of be added in ointment bases, grind well, and then by borneol, lemon
Lemon alkene, gaultherolin are successively added separately in ointment bases, are ground well;
(4) continue that remaining vaseline and lanolin are added thereto, grind well up to compound borneol antibacterial ointment, sealing
Afterwards in shady place save or it is stored refrigerated.
2 compound borneol antimicrobial lotion of preparation
Formula:
Main ingredient: Bronyl acetate 8.8g, limonene 0.25g, borneol 0.8g, gaultherolin 0.15g;
Solvent: ethyl alcohol
Lotion preparation process:
It is mixed after weighing the main ingredient of recipe ratio, and ethanol in proper amount solution is added thereto, be configured to content of dispersion 0.1g/ml-
The solution of 0.2g/ml to get compound borneol antimicrobial lotion, after sealing in shady place save or it is stored refrigerated.
3 compound borneol antibacterial cream of preparation
Formula:
Main ingredient: Bronyl acetate 9g, limonene 0.4g, borneol 0.5g, gaultherolin 0.1g;
Matrix: glycerin monostearate 2.8g, stearic acid 9.6g, albolene 2.4g, atoleine 2g, glycerol 2.4g,
Distilled water 80g, dodecyl sodium sulfate 0.1g, ethylparaben 0.01g.
Emulsifiable paste preparation process:
(1) each main ingredient is weighed, and borneol therein is finely ground;
(2) stearic acid, glycerin monostearate, atoleine, albolene are co-located in dry beaker, heating water bath
To 70-80 DEG C, make fine melt;
(3) glycerol and distilled water are set altogether in another beaker, heating water bath is to 80-90 DEG C, then dodecane is added thereto
Base sodium sulphate and ethylparaben, make fine melt;
(4) water phase is slowly added in oily phase under isothermal, it is stirring while adding, until condensing to get emulsifiable paste matrix;
(5) Bronyl acetate, borneol, limonene, gaultherolin are added rapidly in matrix respectively, stir evenly to get
Compound borneol antibacterial cream, after sealing in shady place save or it is stored refrigerated.
Two Antimicrobial test of embodiment
1 experimental strain
Staphylococcus aureus (Staphylococusaureus, ATCC6538),
Candida albicans (Candida albicans, ATCC10231),
Escherichia coli (Escherichia coli (Migula) Castellani et Chulmers, ATCC8099);
2 drugs and reagent
Sodium chloride (analyzing pure AR), tryptone, yeast extract, agar powder, PBS buffer
Culture medium: beef extract soup fluid nutrient medium: the preparation of self-control-beef extract soup fluid nutrient medium (bacteria culture media):
Beef extract 2.0g, peptone 2.0g, sodium chloride 1.0g are weighed, is put into beaker, after adding a small amount of distilled water heating fusing, then
Add distilled water to 200ml, then adjusts its pH value to 7.4-7.6 with 20g/dl sodium hydroxide solution, filtered with filter paper, with three
Angle flask packaged, with 103.4kPa sterilizing 20 minutes.
Liquid Sabouraud' smedium (SD) (fungi culture medium): it is purchased from institute of microbiology, Guangdong Academy of Sciences, then
In 115 DEG C high pressure sterilization 15 minutes it is spare.
Equipment: test tube, pipette, rack for test tube, small conical flask, oese, 50 μ L and 100 μ L sample injectors, clean work
Make platform, small electrothermal sterilizer, biochemical cultivation case.
Reagent: 1mol/L hydrochloric acid;200g/L sodium hydroxide solution;Methanol.
3 antibacterial agents and positive control
Borneol (B);
Bronyl acetate (CB);
Gaultherolin (S);
Limonene (N);
Compound borneol antibacterial agent (FB), by Bronyl acetate 8.8g, limonene 0.25g, borneol 0.8g, gaultherolin
0.15g is formed after mixing;
800,000 unit of Benzylpenicillin sodium salt (BS);
Ketoconazole (KCZ);
Compound beclomethasone camphor emulsifiable paste (BZ);
Under sterile working, the original of content of dispersion 10mg/ml is made respectively with methanol dissolution and constant volume in each antibacterial agent and reference material
Liquid, 4 DEG C of refrigerators are protected from light and are sealed, spare.
4 experimental methods
The experiment of 1 anti-Staphylococcus aureus of example
12, every row's test tube, number 1-12,7 row's test tube in total, using medical fluid doubling dilution diluent in test tube
Liquid, i.e. broth dilution method.By the borneol stoste of 10mg/ml, the Bronyl acetate stoste of 10mg/ml, 10mg/ml compound borneol
Antimicrobial stock solution, the Benzylpenicillin sodium salt stoste of 10mg/ml, the gaultherolin stoste of 10mg/ml, the limonene stoste of 10mg/ml,
After each personal beef extract soup fluid nutrient medium dilution of the compound beclomethasone camphor emulsifiable paste stoste of 10mg/ml, concentration is 1280 μ g/
Ml, the culture solution 2ml containing different antibacterial medical fluids after above-mentioned dilution is respectively added respectively in 1, No. 2 test tube of every row later,
Then, 2ml liquid is sucked out into No. 3 test tube after mixing in No. 2 test tubes again, and No. 3 test tubes are sucked into 2ml liquid 4 after mixing again
In test tube, so in turn two-fold dilution is to No. 10 test tubes, and so far, the antibacterial medical fluid of No. 1-11 each pipe of every row is diluted to concentration
For 1280 μ g/ml, 640 μ g/ml, 320 μ g/ml, 160 μ g/ml to 2.5 μ g/ml, respectively it is added in row's 1-11 test tube fresh golden yellow
(quantity of microorganism inoculated of each test tube is about 2.5 × 10 to color staphylococcus bacteria suspension4CFU/ml), steamed beef soup respectively is added in No. 12 test tubes of row
Culture solution 2ml is all placed in constant incubator as blank control, the above test tube and cultivates 18h at 37 DEG C.
To visually observe liquid without muddy or precipitating, the unconverted drug highest dilution of color, that is, it is visible by naked eyes thin
The lowest concentration of drug of bacterium growth is as drug to the minimum inhibitory concentration (MIC) of the bacterial strain.
By the above-mentioned meat soup 0.05ml streak inoculation being visible by naked eyes in the test tube of bacterial growth in nutrient agar plate
On, it is incubated for 24 hours in 35 DEG C of incubators, the nutrient agar plate that 35 DEG C are incubated for 24 hours is taken out, is born with sterile on plate
Terminal of the long lowest concentration of drug (highest dilution) as minimum bactericidal concentration (MBC).As a result it see the table below 1.
The experiment of 2 anti-candida albicans of example
Except the strain staphylococcus aureus of addition is replaced with Candida albicans, by the Benzylpenicillin sodium salt stoste of 10mg/ml
Except the ketoconazole stoste for replacing with 10mg/ml, remaining is identical as the anti-Staphylococcus aureus experimental method of example 1, as a result sees
The following table 1.
The experiment of the anti-Escherichia coli of example 3
Except the strain staphylococcus aureus of addition is replaced with Escherichia coli, remove 10mg/ml Benzylpenicillin sodium salt stoste,
Benzylpenicillin sodium salt, the experiment of compound beclomethasone camphor emulsifiable paste anti-microbial property, are kept to 5 row's tube assays, the anti-golden yellow of remaining and example 1
Staphylococcus experimental method is identical, as a result see the table below 1.
1 antibacterial measurement result of table
Note: borneol (B), compound borneol antibacterial agent (FB), Benzylpenicillin sodium salt (BS), ketoconazole (KCZ), compound beclomethasone camphor tree
Brain emulsifiable paste (BZ), gaultherolin (S), limonene (N);
As it can be seen from table 1 compound borneol antibacterial agent provided by the invention to staphylococcus aureus, Candida albicans and
Escherichia coli this 3 kinds of common causative strains play the role of inhibition and killing, and the inhibition of fungistatic effect and antibiotic and kill
Going out, it is close or more excellent to act on.Component compatibility provided by the invention, compared to other one-components such as borneol, Bronyl acetate right
On the fungistatic effect of staphylococcus aureus, Candida albicans and Escherichia coli, be more good fungistatic effect is all had, is shown
The superiority of compounding ingredients of the invention on fungistatic effect and broad-spectrum antibacterial property.
The external toxicological experiment of embodiment three
1 skin irritation test of example
1 experimental animal
Large ear rabbit, all-male, 3.0 ± 0.2Kg of weight are provided by Jiangxi Prov. Medicine Inst.In laboratory before experiment
Interior observation is fed one week.By group sub-cage rearing, 1, every cage, ad lib water inlet when test.20 ± 4 DEG C of animal feeding room temperature,
Relative humidity is 50% ± 10%.
2 experimental methods
Using androgynous own control, compound borneol antibacterial agent is observed to the irritation effect of damaged skin and intact skin.
1. grouping: taking large ear rabbit similar in 12 weight at random, be divided into 2 groups, every group 6, half male and half female is distinguished
For intact skin group and damaged skin group.
2. experimental method: in first 1 day of experiment, giving large ear rabbit preserved skin, its back backbone two sides is lost hair or feathers, area accounts for entirely
Body 10% or so.Experimental day sterilizes damaged skin group alcohol to hair removal section, white in big ear with lidocaine hydrochloride solution
Rabbit back does 2 local anaesthesia positions at random.After five minutes, hair-fields is being gone to make 2 well stroke wounds with scalpel, with slight oozing of blood
For standard, left and right sides skin lesion degree is consistent as far as possible.After blood flow stopping, hair-fields is gone to coat 1ml's on the left of groups of animals
Compound borneol antibacterial ointment (preparation 1 is prepared in the example 1 in above-described embodiment one), right side is to equivalent matrix (with above-mentioned reality
Applying the example 1 in example one, to be prepared preparation 1 identical, except being added without any main ingredient).It is wrapped up and is fixed with sterile gauze, sub-cage rearing.
Intact skin group similarly uses androgynous own control.Wash away drug with warm water after 24 hours, after removing drug 1h, 12h,
For 24 hours, 48h, 72h, 4d, 5d observe medicine-feeding part situations such as whether there is or not erythema oedema.According to " study of tcm new drug guide (pharmacy, medicine
Reason, toxicity) " in skin wound repair standards of grading evaluated, and calculate average value, the results are shown in Table 2.
2 compound borneol antibacterial agent of table is to skin irritation test result
Observation indicate that applying the intact skin after compound borneol antibacterial agent provided by the invention and damaged skin group
Left and right lateral areas does not occur phenomenon in obvious erythema and water, and also non-pigment is calm and blutpunkte at coating position, in addition, from table 2
As can be seen that compound borneol antibacterial agent provided by the invention is to no skin irritation.
The experiment of 2 skin hypersensitivity of example
1. grouping: large ear rabbit, 3.0 ± 0.2Kg of weight are provided by Jiangxi Prov. Medicine Inst.In laboratory before experiment
Interior observation is fed one week.By group sub-cage rearing, 1, every cage, ad lib water inlet when test.20 ± 4 DEG C of animal feeding room temperature,
Relative humidity is 50% ± 10%.
Large ear rabbit similar in 18 weight is taken at random, respectively 3 groups, every group 6, it is multiple to be respectively as follows: A group-for half male and half female
Square borneol antibacterial agent (preparation 1 is prepared in the example 1 in above-described embodiment one), B group-matrix is (with the example 1 in above-described embodiment one
It is identical that preparation 1 is prepared, except being added without any main ingredient), C group-control group (1% sensitization concentration 2,4-dinitrochlorobenzene solution).
2. experimental method: in preceding 1 day of administration, large ear rabbit preserved skin is given, by the depilation of its back left of spine, every side 3 ×
3cm2.It is each to smear compound borneol antibacterial agent, matrix, 1%DNCB to unhairing area on the left of A, B, C group animal respectively for experimental day
0.2ml is wrapped up with gauze and is fixed, sub-cage rearing.After administration 6 hours, homologue is washed away.In the 7th day of experiment and the 14th day with
Same method is respectively repeated 1 times, and amounts to 3 stimulations.14 days after the last administration, using same method, on the right side of each group white rabbit
It loses hair or feathers and smears respective handling object.Tested material is removed after 6 hours, immediately observe skin allergy situation, after removing drug 1,
24, continue within 48,72 hours to observe skin allergy situation, while paying attention to observing whether animal has asthma, astasia or shock etc.
Serious systemic allergic phenomenon.
Experimental result is commented according to cutaneous anaphylaxis degree in " study of tcm new drug guide (pharmacy, pharmacology, toxicity) "
Minute mark standard is evaluated, and the results are shown in Table 3.
3 compound borneol antibacterial agent of table is to skin allergy test result
Observation indicate that smear the white rabbit two sides skin after compound borneol antibacterial agent provided by the invention do not occur it is red
Spot oedema phenomenon, from table 3 it can also be seen that compound borneol antibacterial agent provided by the invention to skin without sensitization.
In conclusion the antibacterial bacteriostatic effect of compound borneol antibacterial agent provided by the invention is good, broad-spectrum antibacterial property can be outer
With safe and non-toxic to no skin irritation, without anaphylaxis.
The above only expresses the preferred embodiment of the present invention, and the description thereof is more specific and detailed, but can not be because
This and be interpreted as limitations on the scope of the patent of the present invention.It should be pointed out that for those of ordinary skill in the art, In
Under the premise of not departing from present inventive concept, several deformations can also be made, improves and substitutes, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (5)
1. compound borneol antibacterial agent, is calculated by mass percentage, including following component and proportion: Bronyl acetate 85-90%, lemon
Lemon alkene 2.5-5%, borneol 5-10%, gaultherolin 1-1.5%.
2. compound borneol antibacterial agent according to claim 1, is calculated by mass percentage, including following component and proportion:
Bronyl acetate 88%, limonene 2.5%, borneol 8%, gaultherolin 1.5%.
3. compound borneol antibacterial agent according to claim 1, the borneol is selected from natural borneol.
4. compound borneol antibacterial agent according to claim 1, can be added according to actual needs allows to be added on pharmaceutical preparation
Auxiliary material any one external application pharmaceutical preparation dosage form is made.
5. compound borneol antibacterial agent according to any one of claims 1-4, dosage form is ointment, lotion.
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WO2004035723A1 (en) * | 2002-10-12 | 2004-04-29 | Reckitt Benckiser Inc | Disinfectant cleaning compositions |
CN108690724A (en) * | 2018-05-11 | 2018-10-23 | 山东大学 | A kind of application of ford dutchmanspipe root or herb volatile oil in preparing anti-curing cancers and/antibacterial product |
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