CN102145172A - Composition for improving absorbance of aminoglycoside drug - Google Patents
Composition for improving absorbance of aminoglycoside drug Download PDFInfo
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- CN102145172A CN102145172A CN2011100281139A CN201110028113A CN102145172A CN 102145172 A CN102145172 A CN 102145172A CN 2011100281139 A CN2011100281139 A CN 2011100281139A CN 201110028113 A CN201110028113 A CN 201110028113A CN 102145172 A CN102145172 A CN 102145172A
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Abstract
The invention provides a composition for improving the absorbance of aminoglycoside drug, which has greatly-improved absorbance in organisms and exhibits effective pharmacological action. The composition contains 0.1 to 5% absorption enhancer, which is one or more of medium chain sodium aliphatate salt and cholic acid salts; 5 to 20% of aminoglycoside drug, and the balance of pharmaceutically acceptable auxiliaries. Oral administration of the aminoglycoside drug results in quite little absorption of the aminoglycoside drug, and clinical oral drug is used only as the drug for enteric infection. According to the invention, as the absorption enhancer is added, the applicable scope of the aminoglycoside drug is widened, and oral administration can reach the purpose of treating general infection.
Description
Technical field
The present invention relates to a kind of compositions that improves the aminoglycoside medicaments trap, described compositions can present pharmacological action in vivo effectively by oral.
Background technology
Aminoglycoside antibiotics is the glycoside antibiotic that is formed by connecting by oxo bridge by amino sugar and aminocyclitol.Aminoglycoside medicaments by sources can be divided three classes: the first kind is to obtain in the culturing filtrate by streptomyces, spends mycin, kanamycin, bekanamycin, tobramycin, ribostamycin etc. as streptomycin, dihydrostreptomycin, neomycin, paromomycin, lining.The antibiotic that second class is produced by micromonospora is as gentamycin, sisomicin, spectinomycin, aburamycin, micronomicin.The 3rd class is semi-synthetic aminoglycoside medicine, as celebrates big-micronomicin, dibekacin, amikacin, netilmicin etc.
The common trait that aminoglycoside antibiotics has is that pharmacokinetics seldom is absorbed after oral, and it is about 3% that complete intestinal mucosa can only absorb, and the absorbtivity through mucosa ulcer or abrasion or that inflammation is arranged is arranged increases slightly.This type of medicine major part is discharged without changing with feces, and many gram negative bacillis such as escherichia coli, Klebsiella, Proteus, Enterobacter, Salmonella, Shigella, Brucella, p pestic genus etc. are also had an antibacterial action.Because the aminoglycoside medicaments oral absorption is poor, can be distributed to body tissue rapidly behind the quiet notes, wherein liver, kidney concentration are the highest, concentrate in nucleated cell, and be higher at the leukocyte intensive amount, is difficult for seeing through blood brain barrier; Metabolism is few, and 12%～25% by kidney in 24 hours, and 50%～90% by discharging in the bile.The oral absorbability of aminoglycoside is not only to the performance of its pharmacodynamic action in the clinical practice, and to the manifesting of post antibiotic effect, all significant.
Improve method that drug oral absorbs change the mucous viscosity in small intestinal surface, improve the mobile of film and impel the dissolving of film component.0.2-20mmol/L surfactant can change mucous rheological property, reduce mucous viscosity and elasticity, improve the permeability of oral drugs.Surfactant can impel the film component dissolving, passes, inserts lipid bilayer when low concentration, promotes drug absorption, but also destroys intestinal epithelial cell simultaneously, but destructive intestinal epithelial cell can the reversible recovery of very fast energy after drug withdrawal.Different surfactants sees through the effect difference to the intestinal capsule of aminoglycoside medicaments, and it is the most remarkable that medium-chain fatty acid sodium salt and cholic acid salt improve, for the oral administered dosage form development provides reference frame.
Summary of the invention
In order to solve the low problem of aminoglycoside medicaments oral absorbability, pass through oral absorption promotion degree mensuration, Study of cytotoxicity, the laboratory animal toxic and side effects is observed, the invention provides a kind of compositions that improves the aminoglycoside medicaments trap, compositions of the present invention is by the absorption enhancer of 0.1～5% (W/W), and the aminoglycoside medicaments of 5～20% (W/W) and adjuvant are formed.
Above-mentioned absorption enhancer is one or more in medium-chain fatty acid sodium salt, the cholate.
Above-mentioned medium-chain fatty acid sodium salt can be one or more in sodium caprylate, Capric acid sodium salt, sodium laurate and the enuatrol.
Above-mentioned cholate can be one or more in sodium deoxycholate, SODIUM CHENODIOL, NaGC and the sodium taurocholate.
Above-mentioned aminoglycoside medicaments can be streptomycin, dihydrostreptomycin, neomycin, paromomycin, lining spend mycin, kanamycin, bekanamycin, tobramycin, ribostamycin, gentamycin, sisomicin, spectinomycin, aburamycin, micronomicin (sagamicin) celebrating big-in micronomicin, dibekacin (dibekacin), amikacin (amikacin), netilmicin (netilmicin) one or more.
Last compositions can be that the pharmacology goes up acceptable arbitrary dosage form, comprises powder, pre-mixing agent, granule, tablet, effervescent tablet, capsule.
The invention has the beneficial effects as follows:
Compositions of the present invention has that short Absorption is obvious, toxic and side effects is low, it is wide to be suitable for the medicine scope, and result of use is not subjected to the influence of conventional formulation technology.Clearly propose compositions in the invention, well solved the low problem of aminoglycoside medicaments oral absorbability that always exists at the aminoglycoside medicaments trap.Primary raw material of the present invention is the food additive of country's permission, so its safe, stay in grade has no side effect to people and animals, has very high application, promotional value.
The specific embodiment
Following examples are that ability technical staff should be appreciated that following description shall not be applied to restriction protection scope of the present invention in order to the explanation preferred embodiment of the invention.
Embodiment 1: a kind of raising gentamycin sulfate oral absorbability compositions
Prescription:
Compound method:
With anhydrous glucose Capric acid sodium salt, NaGC are carried out carrying out the mixing of all supplementary materials after the equivalent gradient mixes 6 times respectively, fully behind the mix homogeneously, the pharmaceutical composition of powder.
Embodiment 2: a kind of raising kanamycin sulfate oral absorbability composition granule
Carry out the preparation of granule by following technology:
(1) takes by weighing Capric acid sodium salt, sodium laurate, sodium taurocholate, adopt the equivalent dilution method dilution 3 times of progressively increasing with starch respectively, obtain three kinds of mixture after mixing, stirring;
(2) with above-mentioned three kinds of mixture and remaining starch, anhydrous glucose, kanamycin sulfate in mixer, mixed 30 minutes, mixture B;
(3) take by weighing PVP molten with ethanol in, mix homogeneously obtains mixture C;
(4) mixture C is slowly poured among the mixture B, done and wetly to granulate with 14 mesh sieves when suitable, behind the particle drying, carry out granulate, promptly get a kind of composition grain that improves kanamycin sulfate drug absorption degree with 16 mesh sieves.
Embodiment 3: the short Absorption of compositions is investigated
To 20 on an empty stomach 60 age in days piglets of states give the product of embodiment 1,4mg/kg body weight (in gentamycin), drinking-water is thrown something and fed, this is a test group; Matched group gives the gentamycin sulfate soluble powder (5%) of Shandong manufacturer production, 4mg/kg body weight (in gentamycin), and drinking-water is thrown something and fed.Measure the blood drug level of different time, the results are shown in shown in the accompanying drawing 1, from accompanying drawing 1, can draw, add absorption enhancer after, gentamycin sulfate 1h after the administration just can detect absorption, administration reached peak value after 3 hours, and will compare the photograph medicine and exceed more than 2 times.According to the pharmacokinetic parameter of two medicines of blood drug level calculating, meansigma methods sees the following form shown in 1.
The pharmacokinetic parameters of medicine relatively behind the table 1 adding absorption enhancer
AUC
10hr: average lower area of blood concentration-time curve (ng/mLh) in 0-10 hour, the highest blood level of Cmax (ng/mL) MRT: mean residence time (hr)
Can confirm that by table 1 by the adding of absorption enhancer, gastral absorbent properties improve in the gentamycin sulfate, can make the more effective performance pharmacological action of this pharmacological active substance.
Embodiment 4: the safety of compositions is investigated
The toxicity of promoter is the problem that needs high spot reviews in the formulation development, because after promoter upsets the intestinal mucosal barrier layer, intestinal endotoxin and other chemical substance might be absorbed and enter blood circulation and cause side reaction.The toxicity of intestinal absorption promoter is used the lactic acid dehydrogenase changes of contents always, the intestinal mucosa morphological change is estimated, therefore the present invention has also carried out lactic acid dehydrogenase changes of contents mensuration in test group and the matched group Intestinum Sus domestica circulation fluid, has observed the intestinal mucosa morphological change with paraffin section.
4.1 (Lactate dehydrogenase LDH) can generate acetone acid by catalysis lactic acid to lactic acid dehydrogenase, and acetone acid and 2,4 dinitrophenyl hydrazine reaction generate the acetone acid dinitrophenylhydrazone, are brownish red in alkaline solution, can obtain enzyme activity by colorimetric.According to the test kit step, be vertical coordinate with absolute absorption degree OD value, the LDH unit of activity is that abscissa carries out linear regression, gets standard curve equation: A=0.0002C+0.0071 (r=0.9997), the curve linear relation is good.
Each 20 μ L of specimen that the lactic acid dehydrogenase assay is obtained at body intestinal circulation experiment in the sample carry out according to the test kit step, record absolute absorption degree OD value, and the substitution normal equation calculates its LDH vigor, and measurement result sees the following form shown in 2.As seen from Table 2 along with the increase of intestinal perfusion time, the content of LDH is also in continuous increase in each experimental group intestinal circulation fluid, content and the blank group of LDH do not have significant difference (P＞0.05) in embodiment 1 sample sets, the contrast medicine group intestinal circulation fluid, execute example 1 sample sets, contrast medicine group is compared also no difference of science of statistics (P＞0.05), illustrates that gentamycin sulfate and absorption enhancer do not have obvious damaging action to intestinal cell.
The vigor of LDH in the table 2 Intestinum Sus domestica circulation fluid (x ± S, n=5)
4.2 intestinal mucosa morphological observation
This experiment is observed short absorbent SC to the morphologic influence of intestinal mucosa by preparation Intestinum Sus domestica mucosa pathological section specimen.
The evaluation methodology the most intuitively of intestinal mucosa toxicity is with the variation of mucous membrane tissue structure and the metamorphosis of surperficial cilium after the microscopic examination administration.According to the stimulation of absorption enhancer, absorption enhancer is respectively 3 ranks to the stimulation of mucosa: slight, moderate and severe to mucosa.Judgment criteria is as follows: 1. slight: the mucosal epithelium cell is complete, a small amount of cell infiltration under the mucosa, and goblet cell density increases; 2. moderate: mucosal epithelium cellular edema, cell infiltration under the mucosa; 3. severe: the mucosal epithelium cytopathy is downright bad or come off a large amount of cell infiltration.
Intestinal mucosa morphology experimental result shows that along with the prolongation of the time of testing, blank group, embodiment 1 sample sets, contrast medicine group intestinal mucosa all have obvious impairment.In complete, the fine hair marshalling of experiment 0 minute moment intestinal mucosa; A small amount of eosinophilic granulocyte and lymphocytic infiltration were arranged under the visible mucosa in the time of 30 minutes.Visible a small amount of cell infiltration in the time of 60 minutes, goblet cell increases; Microvillus is sparse, misaligned in the time of 90 minutes, and mucosal epithelium cellular edema, cell infiltration are obvious, the local mucosa degeneration necrosis and the situation that comes off, and visible intestinal mucosa is moderate to the severe stimulation.Compare with the blank group, embodiment 1 sample sets, contrast medicine group group all do not have the performance that obviously increases the weight of the intestinal mucosa damage.
Description of drawings:
During the short Absorption of Fig. 1: embodiment 3 compositionss was investigated: after pig oral embodiment 1 product of difference and the market reference product, the average blood drug level in the serum over time.
Claims (6)
1. a compositions that improves the aminoglycoside medicaments trap is characterized in that described compositions comprises the absorption enhancer of 0.1～5% (W/W), the aminoglycoside medicaments of 5～20% (W/W), and surplus is an acceptable accessories.
2. a kind of compositions that improves the aminoglycoside medicaments trap according to claim 1 is characterized in that described absorption enhancer is selected from one or more in medium-chain fatty acid sodium salt, the cholate.
3. a kind of compositions that improves the aminoglycoside medicaments trap according to claim 1 and 2 is characterized in that described medium-chain fatty acid sodium salt is selected from one or more in sodium caprylate, Capric acid sodium salt, sodium laurate and the enuatrol.
4. a kind of compositions that improves the aminoglycoside medicaments trap according to claim 1 and 2 is characterized in that described cholate is selected from one or more in sodium deoxycholate, SODIUM CHENODIOL, NaGC and the sodium taurocholate.
5. a kind of compositions that improves the aminoglycoside medicaments trap according to claim 1, it is characterized in that described aminoglycoside medicaments be selected from streptomycin, dihydrostreptomycin, neomycin, paromomycin, lining spend mycin, kanamycin, bekanamycin, tobramycin, ribostamycin, gentamycin, sisomicin, spectinomycin, aburamycin, micronomicin, celebrating big-in the micronomicin, dibekacin, amikacin, netilmicin one or more.
6. according to claim 1 or 2 or 3 or 4 or 5 described a kind of compositionss that improve the aminoglycoside medicaments trap, it is characterized in that said composition can make powder, pre-mixing agent, granule, tablet, effervescent tablet, capsule.
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| CN201110028113A CN102145172B (en) | 2011-01-28 | 2011-01-28 | Composition for improving absorbance of aminoglycoside drug |
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| CN201110028113A CN102145172B (en) | 2011-01-28 | 2011-01-28 | Composition for improving absorbance of aminoglycoside drug |
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| CN102145172B CN102145172B (en) | 2012-09-26 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105617353A (en) * | 2016-01-04 | 2016-06-01 | 李志海 | Oral administration composition of colistin |
| CN109007819A (en) * | 2018-07-25 | 2018-12-18 | 广州正广生物科技有限公司 | Anti- saccharification product of one kind and preparation method thereof |
| CN114668770A (en) * | 2021-10-25 | 2022-06-28 | 中山大学 | Application of neomycin in preparation of medicament for treating infectious spleen and kidney necrosis |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1649513A (en) * | 2002-03-12 | 2005-08-03 | 科学与工业研究会 | Bioavailability/bioefficacy enhancing activity of cuminum cyminum and extracts and fractions thereof |
| WO2005105050A1 (en) * | 2004-04-28 | 2005-11-10 | Procarrier, Inc. | Oral formulation for delivery of poorly absorbed drugs |
| WO2010032140A2 (en) * | 2008-09-17 | 2010-03-25 | Chiasma Inc. | Pharmaceutical compositions and related methods of delivery |
-
2011
- 2011-01-28 CN CN201110028113A patent/CN102145172B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1649513A (en) * | 2002-03-12 | 2005-08-03 | 科学与工业研究会 | Bioavailability/bioefficacy enhancing activity of cuminum cyminum and extracts and fractions thereof |
| WO2005105050A1 (en) * | 2004-04-28 | 2005-11-10 | Procarrier, Inc. | Oral formulation for delivery of poorly absorbed drugs |
| WO2010032140A2 (en) * | 2008-09-17 | 2010-03-25 | Chiasma Inc. | Pharmaceutical compositions and related methods of delivery |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105617353A (en) * | 2016-01-04 | 2016-06-01 | 李志海 | Oral administration composition of colistin |
| CN109007819A (en) * | 2018-07-25 | 2018-12-18 | 广州正广生物科技有限公司 | Anti- saccharification product of one kind and preparation method thereof |
| CN109007819B (en) * | 2018-07-25 | 2022-08-05 | 广州正广生物科技有限公司 | Anti-saccharification product and preparation method thereof |
| CN114668770A (en) * | 2021-10-25 | 2022-06-28 | 中山大学 | Application of neomycin in preparation of medicament for treating infectious spleen and kidney necrosis |
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| Publication number | Publication date |
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| CN102145172B (en) | 2012-09-26 |
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