CN102499936B - Compound telithromycin nanoemulsion oral liquid and preparation method thereof - Google Patents
Compound telithromycin nanoemulsion oral liquid and preparation method thereof Download PDFInfo
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- CN102499936B CN102499936B CN 201110392416 CN201110392416A CN102499936B CN 102499936 B CN102499936 B CN 102499936B CN 201110392416 CN201110392416 CN 201110392416 CN 201110392416 A CN201110392416 A CN 201110392416A CN 102499936 B CN102499936 B CN 102499936B
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Abstract
The invention discloses compound telithromycin nanoemulsion oral liquid. The grain size of the oral liquid ranges from 1nm to 100nm, the compound telithromycin nanoemulsion oral liquid is prepared by raw materials including, by mass percent, from 35 to 45% of surface active agent, from 1 to 5% of cosurfactant, from 4 to 12% of oil phase, from 1 to 3.5% of telithromycin, from 0.1 to 0.3% of bromhexine hydrochloride and the balance deionized water, and the sum of the mass percents of the raw materials is 100%. The telithromycin is the first and the uniquely listed ketolide medicine in the world at present, and has broad-spectrum antibiotic activity, lower selective drug resistance and cross drug resistance with other ketone antibiotics; and after the telithromycin is compatible with the bromhexine hydrochloride, a high treatment effect in terms of treating respiratory tract infection is realized. Compound telithromycin nanoemulsion remarkably increases activities of two types of medicines, is high in safety, simple in preparation and low in energy consumption, can be produced in a batch manner without special equipment, and has a wide market prospect in the field of medicine.
Description
Technical field
[0001] the invention belongs to field of medicaments, relate to a kind of novel form of ketolide antibiotics Ketek, specifically oil-in-water type compound spiramycin nanometer emulsion oral liquid of a kind of transparent and stable and preparation method thereof.
Background technology
[0002] Ketek (Telithromycin) is first antibacterials in semi-synthetic macrolide-lincosamide-streptogramine B (MLSB) family, belong to ketolide antibiotics, design for macrolide drug resistance pathogenic organisms of respiratory tract.Have broad spectrum antibiotic activity, lower selectivity drug resistance and with the cross resistance of other ketone antibiotics.Similar to Macrolide, this compounds is by disturbing synthesizing of bacterioprotein to play a role, but maximum difference is Ketek the ribosomal adhesion of wild type is distinguished strong approximately 10 times and 6 times than erythromycin and clarithromycin, streptococcus pneumoniae, streptococcus pneumoniae, bloodthirsty hemophilus influenza and Mo Lahan bacterium all there are good therapeutic effect, and strong than Macrolidees such as azithromycins.In the situation that Community-acquired respiratory tract pathogenic bacterium are increasing to beta-lactam, most of macrolide antibiotics drug resistance at present, new, an important treatment approach has been opened up in the application of Ketek.As first ketolide antibiotics of drugs approved by FDA (2004), Ketek is that first is also the ketolide medicine of an only listing at present in the world.Be mainly used in following 4 kinds of indications: community acquired pneumonia (CAP), acute bacterial sinusitis (ABS), acute bacterial infection deterioration (ABECB) and patient's the tonsillitis/pharyngitis more than 12 years old of chronic bronchitis patient more than 18 years old.This product has just been created good market achievement with strong growth in U.S. one listing, and the sales volume of 2005 has been turned over 3 times with respect to 6,400 ten thousand dollars of the previous year, up to 1.93 hundred million dollars.Because ketolide antibiotics is unanimously had an optimistic view of by industry, so it gets a good chance of and will affect the market share of whole Macrocyclolactone lactone kind medicine subtlely.But unavoidablely be that for the ketolide medicine, its present price is far above other conventional macrolide medicines, and water insoluble, only can use as oral tablet or capsule, for having dysphagia person or child to use inconvenience.
Bisolvon has another name called bromhexine hydrochloride, bromhexine, bromobenzyl ring amine, bromine amine, belongs to the mucus regulator, has stronger mucolytics effect, impels the lysosome of mucous secreting cell to disengage, and makes the sticking sugared Study On Fiber Differentiation cracking of apoplexy due to phlegm; Also can suppress the synthetic of acidoglycoprotein in mucous gland and goblet cell, make it to secrete the lower micro-molecule glucoprotein of viscosity, thereby make sputum be convenient to discharge, keep respiratory tract smooth and easy.Bisolvon is used for the sticking expectorant such as bronchitis, asthma, emphysema and is difficult for the diseases such as expectoration.Being the specific drug that promotes that sticking expectorant produces and liquefies due to bromhexine, though gone on the market for many years, is still the drug of first choice of the common infectious cough for the treatment of.Bisolvon is slightly soluble in water, only can orally use, and the drug absorption rate is low, and stripping quantity is unstable, and for having dysphagia person or child to use inconvenience.
Summary of the invention
The objective of the invention is the problem and blemish for prior art, the compound telithromycin nanoemulsion oral liquid that a kind of dissolubility is good, bioavailability is high, physical property is stable is provided.
The technical method of realizing the foregoing invention purpose is a kind of oil-in-water type compound Ketek nanometer emulsion oral liquid, is made by the raw material of following mass percent:
Surfactant 35%～45%, cosurfactant 1%～5%, oil phase 4%～12%, Ketek 1%～3.5%, Bisolvon 0.1%～0.3%, surplus are deionized water, and the mass percent sum of above-mentioned raw materials is 100%.
The formula optimization mass percent scope of preparation medicine of the present invention is:
Surfactant 37%～43%, cosurfactant 2%～4%, oil phase 5%～10%, Ketek 1.5%～3%, Bisolvon 0.12%～0.24%, surplus are deionized water, and the mass percent sum of above-mentioned raw materials is 100%.
The formula best in quality percentage ratio of preparation medicine of the present invention is:
Surfactant 39.5%, cosurfactant 3%, oil phase 7.8%, Ketek 2%, Bisolvon 0.2%, deionized water 47.5%.
Described surfactant is one or more the mixture in EL-40, RH-40, tween 80 and PLURONICS F87.
Described cosurfactant is one or more the mixture in dehydrated alcohol, 1,2-PD, glycerol and Polyethylene Glycol-600.
Described oil phase is one or more mixture of butyl acetate, cinnamic aldehyde, carvacrol, glyceryl triacetate and ethyl acetate.
The present invention selects the nonionic surfactant of avirulence and good biocompatibility in the selection of surfactant.Nonionic surfactant is more stable in solution, is not subject to the impact of strong electrolyte, inorganic salts, also is not subject to the impact of soda acid, and good with the compatibility of other surfactants, haemolysis is less.Available surfactant has: one or more mixture in EL-40, RH-40, tween 80 and PLURONICS F87.
Cosurfactant makes drug loading further increase for the good solubility of Ketek and Bisolvon except the stabilized nanoscale breast.
The present invention is according to when the required surfactant HLB value of emulsifying oil phase is close with surfactant, the principle that formed emulsion is stable, the oil phase of selecting are one or more mixture of butyl acetate, cinnamic aldehyde, carvacrol, glyceryl triacetate and ethyl acetate.
A further object of the invention is to provide the preparation method of above-mentioned compound telithromycin nanoemulsion oral liquid, it is characterized in that: comprise the following steps:
(1) take surfactant, cosurfactant, oil phase, Ketek, Bisolvon, the deionized water of formula proportion, standby;
(2) with surfactant and cosurfactant mixing, then add oil phase, mixing;
(3) add Ketek, mixing;
(4) add Bisolvon, mixing;
(4) slowly add deionized water under room temperature, and the limit adds the deionization waterside and stirs, until form clear, colourless or little yellow, viscosity is little and the liquid of good fluidity, and get final product.
The present invention is with Ketek and Bisolvon drug combination, neither drug effect is simple addition quantitatively, neither mechanically offset each other by toxicity, but by the medicine reasonable compatibility, complementary and the collaborative effect of performance, produce the whole synthesis effect on the pharmacology.When utilizing the antibiotic therapy tract bacterial, reality has increased the viscosity of sputum, and sputum is discharged not smooth, usually increases the weight of the state of an illness, in actual therapeutic, must use the mucus regulator to increase antibacterial effect.
A kind of compound telithromycin nanoemulsion oral liquid of the present invention be applicable to due to streptococcus pneumoniae, micrococcus scarlatinae, staphylococcus, mycoplasma, chlamydia and legionella etc. light, in, severe infection, be mainly used in treating respiratory tract infection, comprise community acquired pneumonia (CAP), the acute aggravation of chronic bronchitis (AECB), acute antritis (AMS), pharyngitis and tonsillitis.Usage: oral, each 10 g, every day 2 times.
The present invention detects through transmission electron microscope, and droplet diameter distribution is between 10～100 nm, and outward appearance is yellow or colourless transparent liquid, has good stability:
1. ageing stability
When ageing stability referred to that nanometer emulsion oral liquid is preserved under room temperature nature change condition, outward appearance in time
The degree that extends and change.This compound telithromycin nanoemulsion oral liquid is transparent lastingly, does not find muddy or precipitation, illustrates that its ageing stability is good.
2. heat storage stability
This compound telithromycin nanoemulsion oral liquid is placed in test tube, and sealing is placed in 37 ℃ of constant water bath box and stores 14 days, and this liquid appearance after storage is transparent.
3. anti-freeze-stable
This compound telithromycin nanoemulsion oral liquid in-4 ℃ of one weeks of preservation, is returned to room temperature after taking-up.This compound telithromycin nanoemulsion oral liquid becomes solid in the time of-4 ℃, return to after room temperature it and return to transparently, and places after a week still transparently, illustrates that this nanometer emulsion freezing-resistance is good.
4. accelerated stability
This compound telithromycin nanoemulsion oral liquid is placed in test tube, and sealing is in centrifugal 20 min of 15000 r/min, not layering, still clear.
A kind of compound telithromycin nanoemulsion oral liquid of the present invention compared with prior art has the following advantages:
1) compound nanometer emulsion of the present invention drips particle diameter less than 100 nm, the fat-soluble height of medicine, medicine are crossed the cell wall of antibacterial by the carrier very permeable, directly antibiotic the or sterilizing function of performance in thalline, improve greatly the drug effect of Ketek, thereby reduced the intake of medicine;
2) compound nanometer emulsion oral absorption of the present invention can be avoided first pass effect of hepar, reduces drug dose, reduces drug toxicity;
3) compound recipe of the present invention can efficient, sterilization expectoration, for the treatment lower respiratory infection, the effect of getting twice the result with half the effort is arranged especially;
4) thermodynamic stability is good, and bin stability is high, the outward appearance clear, and the emulsion droplet dispersion is good, and any inhomogeneities or precipitate all easily are found, and sensible quality improves;
5) antiseptic property improves, and decentralized photo liquid is smaller, can prevent the intrusion of antibacterial;
6) but this product infinite dilution can add in drinking-water and take, add the sweeting agents such as sucrose also not affect its drug effect;
7) preparation technology is simple, is fit to large-scale production.
The specific embodiment
Below further set forth the beneficial effect of medicine of the present invention by pharmacodynamics test and contrast test.(nano-emulsion formula used is the formula optimum weight percentage ratio of preparation medicine of the present invention: surfactant 39.5%, cosurfactant 3%, oil phase 7.8%, Ketek 2%, Bisolvon 0.2%, deionized water 47.5%)
Test example 1The test of compound telithromycin nanoemulsion oral liquid antibacterial activity in vitro
inoculate respectively streptococcus pneumoniae on different culture medium, micrococcus scarlatinae, staphylococcus aureus, Haemophilus influenzae, the mucositis catarrhalis, mycoplasma, chlamydia, legionella, escherichia coli, (above strain provides by my school Microbiological Lab), at 37 ℃, slowly drip 0.2% on culture medium after cultivating 24 h, 0.5%, 1% compound telithromycin nanoemulsion oral liquid, compound recipe Ketek suspension (identical with Ketek and Bisolvon content in 0.5% compound telithromycin nanoemulsion oral liquid), each 1 ml of compound erythromycin suspension (identical with Ketek and Bisolvon content in 0.5% compound telithromycin nanoemulsion oral liquid) suspension, cultivate through 12 h, observe antibacterial situation, the results are shown in Table 1.
The test of table 1 compound telithromycin nanoemulsion oral liquid antibacterial activity in vitro
The result of table 1 has clearly show: 1) antibacterial activity along with the increase compound telithromycin nanoemulsion oral liquid of concentration also increases, and when dosage is very low, drug effect is just arranged.And the compound recipe Ketek suspension antibacterial activity of the same dosage of matched group is obviously effective not as compound telithromycin nanoemulsion oral liquid, and the compound erythromycin suspension antibacterial effect activity of same dosage is poorer.2) strain of this experiment setting is all common respiratory tract infection bacterium, and the some of them strain is comparatively obstinate, and the treatment of conventional medicine does not usually have good effect.Ketek is as the ketolide new drug, add be packaged into nano-emulsion after drug effect be multiplied, brought into play good sterilization and bacteriostasis effect for these obstinate strains the time, have wide market prospect.("-" expression is invalid, and "+" expression effectively)
Test example 2Compound telithromycin nanoemulsion oral liquid and other preparation for treating Piglet s colibacillosis
40 patients (18 of male patients, 22 of female patients to respiratory system infection disease, 19～62 years old age, 43.3 years old mean age) compare treatment with compound telithromycin nanoemulsion oral liquid, Roxithromycin Tablets and Amoxicillin Capsules under Isodose, the compound telithromycin nanoemulsion oral liquid total effective rate is 100%; The Roxithromycin Tablets total effective rate is 87.71%; The Amoxicillin Capsules total effective rate is 88.93%.It is very fast that wherein compound telithromycin nanoemulsion oral liquid produces drug effect, takes short treating period, is easy to take.
Below the embodiment that provides by the inventor further set forth the preparation method of a kind of compound telithromycin nanoemulsion oral liquid of the present invention.
Embodiment 1
Preparation method:
(1) take surfactant, cosurfactant, oil phase, Ketek, Bisolvon, the deionized water of formula proportion, standby;
(2) with surfactant and cosurfactant mixing, then add oil phase, mixing;
(3) add Ketek, mixing;
(4) add Bisolvon, mixing;
(4) slowly add deionized water under room temperature, and the limit adds the deionization waterside and stirs, until form clear, colourless or little yellow, viscosity is little and the liquid of good fluidity, claims that its weight is 100 g.
Fill a prescription as follows: tween 80 9.5 g, RH-40 30 g, dehydrated alcohol 2.7 g, PEG-600 0.3 g, butyl acetate 7 g, cinnamic aldehyde 0.8 g, Ketek 2 g, Bisolvon 0.2 g, deionized water 47.5 g amount to 100 g.
Embodiment 2
Tween 80 30 g, EL-40 5 g, dehydrated alcohol 4.5 g, 1,2-PD 0.5 g, ethyl acetate 3 g, carvacrol 1 g, Ketek 1 g, Bisolvon 0.3 g, deionized water 54.7 g.
Embodiment 3
Tween 80 40 g, PLURONICS F87 5 g, dehydrated alcohol 1 g, butyl acetate 7 g, cinnamic aldehyde 0.8 g, glyceryl triacetate 2.6 g, Ketek 3.5 g, Bisolvon 0.1 g, deionized water 40 g.
Embodiment 4
Tween 80 35 g, RH-40 5 g, dehydrated alcohol 1.2 g, glycerol 0.3 g, butyl acetate 10 g, glyceryl triacetate 2 g, Ketek 1.5 g, Bisolvon 0.12 g, deionized water 44.88 g.
Embodiment 5
Tween 80 35 g, PLURONICS F87 2 g, dehydrated alcohol 3.7 g, PEG-600 0.3 g, ethyl acetate 4.2 g, cinnamic aldehyde 0.8 g, Ketek 1.2 g, Bisolvon 0.24 g, deionized water 52.56 g.
Embodiment 6
Tween 80 35 g, RH-40 8 g, dehydrated alcohol 0.7 g, PEG-600 0.3 g, butyl acetate 7 g, cinnamic aldehyde 1 g, glyceryl triacetate 2 g, Ketek 3 g, Bisolvon 0.15 g, deionized water 42.85 g.
Embodiment 7
Tween 80 25 g, EL-40 15 g, dehydrated alcohol 1.7 g, PEG-600 0.3 g, butyl acetate 7 g, carvacrol 1 g, Ketek 1.5 g, Bisolvon 0.2 g, deionized water 48.3 g.
Embodiment 8
Tween 80 40 g, RH-40 2 g, dehydrated alcohol 3.7 g, PEG-600 0.3 g, butyl acetate 8 g, cinnamic aldehyde 1 g, glyceryl triacetate 1 g, Ketek 2.5 g, Bisolvon 0.24 g, deionized water 41.26 g.
Claims (5)
1. a compound telithromycin nanoemulsion oral liquid, is characterized in that, made by the raw material of following mass percent:
Surfactant 35%～45%, cosurfactant 1%～5%, oil phase 4%～12%, Ketek 1%～3.5%, Bisolvon 0.1%～0.3%, surplus are deionized water, and the mass percent sum of above-mentioned raw materials is 100%;
Described surfactant is one or more the mixture in EL-40, RH-40, tween 80 and PLURONICS F87;
Described cosurfactant is one or more the mixture in dehydrated alcohol, 1,2-PD, glycerol and Polyethylene Glycol-600;
Described oil phase is one or more mixture of butyl acetate, cinnamic aldehyde, carvacrol, glyceryl triacetate and ethyl acetate.
2. compound telithromycin nanoemulsion oral liquid according to claim 1, is characterized in that, made by the raw material of following mass percent:
Surfactant 37%～43%, cosurfactant 2%～4%, oil phase 5%～10%, Ketek 1.5%～3%, Bisolvon 0.12%～0.24%, surplus are deionized water, and the mass percent sum of above-mentioned raw materials is 100%.
3. compound telithromycin nanoemulsion oral liquid according to claim 1, is characterized in that, made by the raw material of following mass percent:
Surfactant 39.5%, cosurfactant 3%, oil phase 7.8%, Ketek 2%, Bisolvon 0.2%, deionized water 47.5%.
4. compound telithromycin nanoemulsion oral liquid according to claim 1, it is characterized in that: the particle diameter of this oral liquid is 1～100 nm.
5. the preparation method of compound telithromycin nanoemulsion oral liquid claimed in claim 1 is characterized in that: comprise the following steps:
(1) take surfactant, cosurfactant, oil phase, Ketek, Bisolvon, the deionized water of formula proportion, standby;
(2) with surfactant and cosurfactant mixing, then add oil phase, mixing;
(3) add Ketek, mixing;
(4) add Bisolvon, mixing;
(4) slowly add deionized water under room temperature, and the limit adds the deionization waterside and stirs, until form clear, colourless or little yellow, viscosity is little and the liquid of good fluidity, and get final product.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931130A (en) * | 2006-09-18 | 2007-03-21 | 西北农林科技大学 | Nanometer emulsion oral liquid of andrographolide and its prepn process |
| CN101066245A (en) * | 2007-05-25 | 2007-11-07 | 朱芳海 | Orally taken emulsion and its prepn |
| CN101180064A (en) * | 2005-02-25 | 2008-05-14 | 艾文蒂斯药品公司 | Solid pharmaceutical composition with telithromycin |
| CN102166233A (en) * | 2011-04-06 | 2011-08-31 | 西北农林科技大学 | Oil-in-water type sea buckthorn oil nano-emulsion oral liquid and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180064A (en) * | 2005-02-25 | 2008-05-14 | 艾文蒂斯药品公司 | Solid pharmaceutical composition with telithromycin |
| CN1931130A (en) * | 2006-09-18 | 2007-03-21 | 西北农林科技大学 | Nanometer emulsion oral liquid of andrographolide and its prepn process |
| CN101066245A (en) * | 2007-05-25 | 2007-11-07 | 朱芳海 | Orally taken emulsion and its prepn |
| CN102166233A (en) * | 2011-04-06 | 2011-08-31 | 西北农林科技大学 | Oil-in-water type sea buckthorn oil nano-emulsion oral liquid and preparation method thereof |
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