CN100528160C - An antibacterial rifampicin nanoemulsion and preparation method thereof - Google Patents
An antibacterial rifampicin nanoemulsion and preparation method thereof Download PDFInfo
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- CN100528160C CN100528160C CNB2006100430503A CN200610043050A CN100528160C CN 100528160 C CN100528160 C CN 100528160C CN B2006100430503 A CNB2006100430503 A CN B2006100430503A CN 200610043050 A CN200610043050 A CN 200610043050A CN 100528160 C CN100528160 C CN 100528160C
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- rifampicin
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Abstract
The invention discloses an antibiotic medicament of Rifampin nano emulsion, which comprises (by weight percent) Rifampin 0.05-0.20%, fluid wax 1.99-19.98%, Twain-80 3.98-26.64%, Span-80 1.99-13.32%, distilled water 50.00-90.00%. Its preparation includes the steps of mixing, homogenizing, charging distilled water and stirring.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of novel form of antibiotic medicine, be specifically related to a kind of antibacterial rifampicin nanoemulsion and preparation method thereof.
Background technology
Rifampicin is a class broad-spectrum antibiotic medicine, because its antibacterial action to tubercule bacillus is strong, is widely used in treatment lungy clinically.In recent years, it is found that this medicine also obtained effect preferably in the treatment of non-tuberculosis disease, for example diseases such as bacillary dysentery, intractable diarrhoea, chronic suppurative otitis media, oral ulcer, psoriasis, impetigo.Rifampicin is a kind of medicine that is insoluble in water, so rifampicin is mainly tablet and capsule clinically.Though this medicine is strong to the penetration power of human body, better by oral absorbance, must could arrive diseased region through liver, so the directionality release action is poor.At present, the external preparation of rifampicin mainly contains eye drop, [, but because rifampicin easy oxidation deterioration in water, so its less stable.
Summary of the invention
The object of the present invention is to provide a kind of antibacterial rifampicin nanoemulsion that is suitable for clinical practice.This medicine is active ingredient rifampicin and carrier nano-emulsion to be organically combined be prepared from, and solved the characteristic that rifampicin is insoluble in water, improved its effect of drugs, has good stability, absorbs rapidly, to the bland advantage of body.
The purpose that realizes foregoing invention is that scheme is a kind of antibacterial rifampicin nanoemulsion, and each amounts of components is for all to have effect preferably in following weight percentage ranges:
Rifampicin 0.05%～0.20%
Liquid paraffin 1.99%～19.98%
Tween 80 3.98%～26.64%
Arlacel-80 1.99%～13.32%
Distilled water 50.00%～90.00%
The formula optimization weight percentage ranges of preparation medicine of the present invention is:
Rifampicin 0.05%～0.15%
Liquid paraffin 3.97%～19.94%
Tween 80 7.94%～26.59%
Arlacel-80 3.97%～13.29%
Distilled water 50.00%～80.00%
The optimum weight hundred of medicine of the present invention is than being:
Rifampicin 0.10%
Liquid paraffin 8.97%
Tween 80 13.95%
Arlacel-80 6.98%
Distilled water 70.00%
Another object of the present invention provides the preparation method of antibacterial rifampicin nanoemulsion, may further comprise the steps:
1) it is standby to take by weighing each drug component rifampicin, liquid paraffin, tween 80, Arlacel-80, distilled water;
2) at normal temperatures and pressures, after rifampicin, liquid paraffin, tween 80 and the Arlacel-80 mixing with described weight, put and stir homogenizing 30min on the constant temperature blender with magnetic force, slowly drip distilled water then in mixture, the limit edged stirs, and the system viscosity is less during beginning, adding along with water, it is sticky that system can become, and continues to drip and constantly stir, after the amount of water reaches certain value, system again can be thinning, can form the rifampicin nano-emulsion this moment, then water is added to q.s, promptly gets the present invention.
The present invention also has a purpose that the another kind of preparation method of antibacterial rifampicin nanoemulsion is provided, and may further comprise the steps:
1) it is standby to take by weighing each drug component rifampicin, liquid paraffin, tween 80, Arlacel-80, distilled water;
2) at normal temperatures and pressures, with liquid paraffin, tween 80 and the Arlacel-80 of described weight mix homogeneously by a certain percentage, slowly drip distilled water then in this mixture, the limit edged stirs, and the system viscosity is less during beginning, adding along with water, it is sticky that system can become, and continues to drip and constantly stir, after the amount of water reaches certain value, system again can be thinning, and can form the blank Emulsion of O/W type (oil-in-water type) this moment.After water is added to q.s, in this blank Emulsion, add the rifampicin of described weight, put and stir homogenizing 30min on the constant temperature blender with magnetic force, rifampicin is fully dissolved, can form the rifampicin nano-emulsion this moment.
The rifampicin nano-emulsion that the present invention comprised is made up of rifampicin, liquid paraffin, tween 80, Arlacel-80 and distilled water, outward appearance is the kermesinus transparency liquid, viscosity is less, good stability, not stratified through high speed centrifugation, detect through transmission electron microscope, its liquid-drop diameter size is between 10～100nm.
The present invention is mainly as skin and mucosa delivery, and concrete purposes is as follows:
1) the rifampicin nano-emulsion of low concentration can be made into rifampicin eye drop, is used for the treatment of diseases such as trachoma, hordeolum, conjunctivitis, keratitis.
2) the rifampicin nano-emulsion of concentration can be made into rifampicin liniment, spray in, is used for the treatment of the various skin disease, as psoriasis, impetigo etc.
3) the rifampicin nano-emulsion of high concentration adding penetrating agent can be made into the Transdermal absorption administration, and the treatment internal disease is as bacillary dysentery, intractable diarrhoea, enteritis etc.
Innovation part of the present invention is that the antibiotic medicine rifampicin that will be insoluble in water is solubilized in the Emulsion system, has made the rifampicin nano-emulsion.This rifampicin nano-emulsion has good stability, and antibacterial action is strong, absorbs rapidly, to advantages such as the body zest are little.
The specific embodiment
Below further set forth the beneficial effect of medicine of the present invention by testing example, these are tested examples and have comprised that medicine stability test of the present invention, pharmacodynamics test and clinical observation on the therapeutic effect test.
Test example 1 antibacterial rifampicin nanoemulsion stability experiment
1, test material
Antibacterial rifampicin nanoemulsion of the present invention
2, test method
(1) centrifugal acceleration test
Get the rifampicin nano-emulsion of the present invention that makes in right amount in centrifuge tube, sealing orifice is put in the high speed centrifuge, with the centrifugal 20min of 10000rpm.Observe outward appearance of the present invention and whether change, and at the bottom of centrifuge tube, have or not drug precipitation.
(2) light stability test
Antibacterial rifampicin nanoemulsion of the present invention is packed in the vial, and sealing places under the daylight, and light at room temperature is according to 10d, in 1d, 3d, 5d, 10d sampling.Observe outward appearance of the present invention and whether change, measure rifampicin medicine content.
(3) temperature stability test
The flat nano-emulsion antibiotic medicine of good fortune of the present invention is sub-packed in several vials, places after the sealing and place the investigation 3 months that keeps sample under 4 ℃, 25 ℃, the 37 ℃ conditions, every 10d sampling is observed.Observe outward appearance of the present invention and whether change, measure rifampicin medicine content.
3, result of the test
The centrifugal stability test result of antibacterial rifampicin nanoemulsion of the present invention shows: the present invention is through the centrifugal 20min of 10000rpm, and outward appearance is still transparent, does not see physical changes such as layering, flocculation, and not seeing at the bottom of centrifuge tube has drug precipitation.
The light stability result of the test of antibacterial rifampicin nanoemulsion of the present invention shows: the present invention is at room temperature in daylight, and outward appearance is still transparent, does not see physical changes such as layering, flocculation, and rifampicin medicine content has downward trend slightly.
The temperature stability result of the test of antibacterial rifampicin nanoemulsion of the present invention shows: the present invention placed 3 months under 4 ℃, 25 ℃, 37 ℃ conditions, outward appearance is still transparent, do not see physical changes such as layering, flocculation, rifampicin medicine content has downward trend slightly.
Test example 2 antibacterial rifampicin nanoemulsion extracorporeal bacteria inhibitor tests
1, test material
Be subjected to the reagent thing: the rifampicin methanol solution of antibacterial rifampicin nanoemulsion of the present invention, 1mg/mL.
Test strain and culture medium: plain agar culture plate (self-control), common nutrient broth (self-control), staphylococcus aureus, escherichia coli, streptococcus (Microbiological Lab provides by this school).
2, test method:
(1) preparation of susceptibility sheet
Select qualitative filter paper for use, make the circular filter paper sheet that diameter is 8mm with card punch, carry out 121 ℃ of 30min of high pressure steam sterilization then, the reuse thermostatic drying chamber carries out drying for standby.
Get 5 sterilization plates respectively, in 5 plates, add the rifampicin nano-emulsion of 2mg/mL, 1.5mg/mL, 1mg/mL, a 0.5mg/mL4 variable concentrations and the rifampicin methanol solution of 1mg/mL respectively, the filter paper of sterilizing-drying being crossed with the ophthalmology tweezers immerses in each plate one by one then, in order to avoid filter paper stacks, make medicinal liquid be difficult to immerse fully.Put in 4 ℃ of refrigerators behind the 24h, carefully filter paper is moved in the other sterilization plate, put drying for standby in 60 ℃ of thermostatic drying chambers.
(2) extracorporeal bacteria inhibitor test
Depletion Staphylococcus aureus, escherichia coli and streptococcus are inoculated in respectively in the common nutrient broth, put and carry out the 24h cultivation in 37 ℃ of constant incubators.Difference depletion Staphylococcus aureus, escherichia coli and streptococcic 24h broth culture, evenly coat on the plain agar flat board with the sterilization cotton swab, respectively be coated with 5 Zhang Ping's plates, the susceptibility sheet that will be prepared by the rifampicin methanol solution of 2mg/mL, 1.5mg/mL, 1mg/mL, 0.5mg/mL rifampicin nano-emulsion and 1mg/mL is attached on the different flat boards then, 4 identical susceptibility sheets of each dull and stereotyped subsides are put in 37 ℃ of constant incubators and are cultivated 24h.Observe antibacterial situation and measure the size of inhibition zone.
3, result of the test
The result shows: the susceptibility sheet by antibacterial rifampicin nanoemulsion preparation of the present invention has higher bacteriostasis than the susceptibility sheet by the preparation of rifampicin methanol solution.See Table 1
Table 1 extracorporeal bacteria inhibitor test result
The test of test example 3 antibacterial rifampicin nanoemulsion Transdermal absorption
1, test material
Be subjected to the reagent thing: antibacterial rifampicin nanoemulsion of the present invention, the present invention add 5% azone (penetrating agent), complex rifampin liniment (lot number: 981026, Shandong animal health product factory produces).
Experimental animal: 10 of Kunming kind healthy mices, body weight 20.0 ± 2.0g.
2, test method
Sodium sulfide solution with 20% loses hair or feathers to the abdominal part of white mice, wipes hair gently with cotton balls behind the 15min, observes depilation situation and congested degree, observes behind the 2h, and, hyperemia clean to lose hair or feathers less, undamaged skin is good.
The disconnected neck of white mice is put to death, peel off skin of abdomen, remove clean subcutaneous fat, clean with normal saline, put in the normal saline and put into refrigerator cold-storage and preserve, use in the week, Corium Mus must not have any damage before the test.
Blot skin surface moisture with filter paper, skin placed on the Franz diffusion cell, horny layer up, fixedly diffusion cell and reception tank.In reception tank, fill the phosphate buffer of pH 7.0, make skin contact electromagnetic agitation, 32 ℃ of waters bath with thermostatic control, preheating 20min with reception liquid.
That draws 1mL is subjected to the reagent thing, is evenly coated on the isolated skin.After adding sample 2,4,6,8,10,12,14,16,18h receives liquid 5mL (adding the phosphate buffer 5mL of pH7.0 subsequently) from accurate absorption of Franz diffusion cell sample tap respectively, the phosphate buffer of pH7.0 is blank, measure trap, substitution standard curve Equation for Calculating rifampicin concentration in (474 ± 2) nm wavelength place.
Because continuous sampling is also added new phosphate buffer in the reception tank at every turn, the numerical value of survey is little than actual value, so use updating formula to calculate rifampicin accumulation releasing medicine through skin penetration amount
(18 is long-pending for receiving liquid, and 5 is each sample volume).
3, result of the test
The result shows: prepared antibacterial rifampicin nanoemulsion of the present invention is compared with the complex rifampin liniment, its skin permeation rate is apparently higher than the complex rifampin liniment, add penetrating agent in the rifampicin nano-emulsion, the skin permeation rate of rifampicin nano-emulsion can be greatly enhanced again.See Table 2
Table 2 Transdermal absorption result of the test
Test example 4 antibacterial rifampicin nanoemulsions are to the rabbit irritation test
1, test material
Be subjected to the reagent thing: antibacterial rifampicin nanoemulsion of the present invention, complex rifampin liniment (lot number: 981026, Shandong animal health product factory produces), rifampicin eye drop (by the self-control of pharmacopeia prescription).
Experimental animal: 18 of rabbit, male and female half and half, body weight (2.0 ± 0.2) Kg, provide by experimental animal center, this school.
2, test method
Get 18 of rabbit, be divided into 6 groups at random.Give the complex rifampin liniment for the 1st group, the 2nd group of rifampicin nano-emulsion of giving 2mg/mL, the 3rd group of rifampicin nano-emulsion of giving 1.5mg/mL, the 4th group of rifampicin nano-emulsion of giving 1mg/mL, the 5th group of rifampicin nano-emulsion of giving 0.5mg/mL given rifampicin eye drop for the 6th group.
(1) skin irritation test
For each group rabbit, 24h before the administration, the rabbit back both sides of being in are with sodium sulfide each 5cm * 10cm that respectively loses hair or feathers.Adopt about consubstantiality self to contrast, depilation district in left side is coated with the rifampicin nano-emulsion, and right side depilation district is coating not, behind the administration 24h, remove left drug with warm water, respectively at 1h, 24h, 48h, 72h perusal after removing, and the record place of smearing has or not situations such as erythema and edema.
(3) eye irritant test
Each is organized rabbit and is placed in the fixed case, and eyelid is pulled into annular, and pushes down nasolacrimal duct with finger, in case medicinal liquid flows in the nasolacrimal duct.Adopt about consubstantiality self to contrast, the left side eyes drip the rifampicin nano-emulsion, and the right side eyes do not drip medicine.Each organizes rabbit when dripping the medicinal liquid of variable concentrations, drips 0.1ml at every turn, lets go behind the 1min and appoints medicinal liquid to flow out naturally.In administration 30min, check 1 tear secretion every 5min, behind administration 30min, open eyelid gently every 1h, observe the reaction of conjunctiva, and have or not irritative symptoms such as tangible hyperemia, stream rushing, photophobia, edema.
3, result of the test
The result shows: prepared antibacterial rifampicin nanoemulsion of the present invention to the skin of rabbit and mucous membrane irritation all less than the complex rifampin liniment, concentration be the rifampicin nano-emulsion of 1mg/mL and 0.5mg/mL to the rabbit eye irritation all less than rifampicin eye drop.See Table 3
Table 3 rabbit irritation test result
(+++strong stimulation ++ medium stimulation+weak stimulation-non-stimulated)
Further specify the preparation method of product of the present invention below in conjunction with specific embodiment.
1 first kind of preparation method of embodiment
1) take by weighing each drug component rifampicin 0.20g, liquid paraffin 14.94g, tween 80 23.24g, Arlacel-80 11.62g, standby;
2) at normal temperatures and pressures, after rifampicin, liquid paraffin, tween 80 and the Arlacel-80 mixing with described weight, put and stir homogenizing 30min on the constant temperature blender with magnetic force, slowly in mixture, drip distilled water then, the limit edged stirs, the system viscosity is less during beginning, and along with the adding of water, it is sticky that system can become, continue to drip and constantly stir, when the amount of water is added to 50g, can form the rifampicin nano-emulsion, this moment, the system viscosity was less.
The rifampicin nano-emulsion concentration of this formulation is 2mg/mL, and water content is 50%, and viscosity is higher relatively, to the skin nonirritant, can add penetrating agent and make transdermal patch, treatment bacillary dysentery, diseases such as intractable diarrhoea, enteritis.
2 second kinds of preparation methoies of embodiment
At normal temperatures and pressures, take by weighing liquid paraffin 14.94g according to embodiment 1 prescription, tween 80 23.24g, Arlacel-80 11.62g with its mix homogeneously, slowly drips distilled water then in this mixture, the limit edged stirs, the system viscosity is less during beginning, and along with the adding of water, it is sticky that system can become, continue to drip and constantly stir, water is added to 50.00g, and can form the blank Emulsion of O/W type (oil-in-water type) this moment, takes by weighing rifampicin 0.20g by embodiment 1 prescription then, it is joined in the blank emulsion bases, put and stir homogenizing 30min on the constant temperature blender with magnetic force, rifampicin is fully dissolved, can form the rifampicin nano-emulsion this moment.
Embodiment 3
Component unit/g
Rifampicin 0.20g
Liquid paraffin 11.92g
Tween 80 11.92g
Arlacel-80 5.96g
Distilled water 70.00g
With first kind of preparation method, this prepared rifampicin nano-emulsion concentration of filling a prescription also is 2mg/mL, and water content is 70%, and viscosity is less relatively, to the skin nonirritant, can be made into liniment, spray, diseases such as treatment psoriasis, impetigo, acne, furuncle and phyma.
Embodiment 4
Component unit/g
Rifampicin 0.10g
Liquid paraffin 8.97g
Tween 80 13.95g
Arlacel-80 6.98g
Distilled water 70.00g
With first kind of preparation method, the rifampicin nano-emulsion concentration of this formulation is 1mg/mL, water content is 70%, viscosity is less relatively, to skin and the equal nonirritant of mucosa, can be made into liniment, spray, [etc., diseases such as treatment dermatitis, oral ulcer, pharyngitis, suppurative otitis media, eczema of external ear.
Embodiment 5
Component unit/g
Rifampicin 0.05g
Liquid paraffin 8.98g
Tween 80 13.98g
Arlacel-80 6.99g
Distilled water 70.00g
With first kind of preparation method, the rifampicin nano-emulsion concentration of this formulation is 0.5mg/mL, and water content is 70%, viscosity is less relatively, to the equal nonirritant of skin, mucosa and eye, can be made into eye drop, diseases such as treatment trachoma, hordeolum, conjunctivitis, keratitis.
Embodiment 6
Component unit/g
Rifampicin 0.05g
Liquid paraffin 3.98g
Tween 80 3.98g
Arlacel-80 1.99g
Distilled water 90.00g
With first kind of preparation method, the rifampicin nano-emulsion concentration of this formulation is 0.5mg/mL, and water content is 90%, viscosity approaches water, to the equal nonirritant of skin, mucosa and eye, can be made into eye drop, diseases such as treatment trachoma, hordeolum, conjunctivitis, keratitis.
Claims (6)
1. a rifampicin nano-emulsion antibiotic medicine is characterized in that, is the nano-emulsion of being made by following weight percentages:
Rifampicin 0.05%～0.20%, liquid paraffin 1.99%～19.98%, tween 80 3.98%～26.64%, Arlacel-80 1.99%～13.32%, distilled water 50.00%～90.00%.
2. ask according to right and want 1 described antibacterial rifampicin nanoemulsion, wherein the percentage by weight of each raw material is:
Rifampicin 0.05%～0.15%, liquid paraffin 3.97%～19.94%, tween 80 7.94%～26.59%, Arlacel-80 3.97%～13.29%, distilled water 50.00%～80.00%.
3. ask according to right and want 1 described antibacterial rifampicin nanoemulsion, wherein the percentage by weight of each raw material is:
Rifampicin 0.10%, liquid paraffin 8.97%, tween 80 13.95%, Arlacel-80 6.98%, distilled water 70.00%.
4. according to the described antibacterial rifampicin nanoemulsion of claim 1, it is characterized in that described medicine liquid-drop diameter size is between 10～100nm.
5. the preparation method of the described medicine of claim 1 is characterized in that, it comprises the following steps:
1) it is standby to take by weighing each drug component rifampicin, liquid paraffin, tween 80, Arlacel-80, distilled water;
2) rifampicin, liquid paraffin, tween 80 and the Arlacel-80 of described weight being pressed formula proportion mixes, homogenizing 30min, slowly in mixture, drip distilled water then, the limit edged stirs, system can occur by rare change sticky in this process, sticky thinning a series of variations are arranged, until forming the rifampicin nano-emulsion at last again.
6. the preparation method of the described medicine of claim 1 is characterized in that, it comprises the following steps:
1) it is standby to take by weighing each drug component rifampicin, liquid paraffin, tween 80, Arlacel-80, distilled water;
2) with liquid paraffin, tween 80 and the Arlacel-80 mix homogeneously of described weight, slowly in mixture, drip distilled water then, the limit edged stirs, until forming blank emulsion bases, rifampicin with described weight joins in this blank emulsion bases then, stir homogenizing 30min, rifampicin is fully dissolved, can form the rifampicin nano-emulsion.
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| CN100528160C true CN100528160C (en) | 2009-08-19 |
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| EA021117B1 (en) * | 2010-12-27 | 2015-04-30 | Ооо "Научно-Производственный Комплекс "Наносистема" | Method for producing a water-soluble pharmaceutical composition of an antibiotic from the group consisting of rifamycins, and pharmaceutical composition for treating tuberculosis and diseases associated with helicobacter pylori |
| CN109288839A (en) * | 2018-10-30 | 2019-02-01 | 郭长安 | Application of the tuberculosis chemotherapeutics in curing psoriasis |
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Non-Patent Citations (2)
| Title |
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| 地塞米松眼用微乳的研究. 林艳琼等.中国药学杂志，第41卷第5期. 2006 |
| 地塞米松眼用微乳的研究. 林艳琼等.中国药学杂志，第41卷第5期. 2006 * |
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