CN101623259A - Amoxicillin lipidosome solid preparation and new application thereof - Google Patents
Amoxicillin lipidosome solid preparation and new application thereof Download PDFInfo
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Abstract
The invention provides an amoxicillin lipidosome solid preparation and a new application thereof. Certain amounts of yolk lecithin, cholesterin, natrium glycocholicum, tween 80 and an active ingredient amoxicillin are combined and are prepared into amoxicillin lipidosome by film dispersion technology, and the amoxicillin lipidosome is mixed with the certain accessories to prepare various solid preparations. The amoxicillin lipidosome solid preparation not only can solve the problems of poor dissolution rate and poor quality stability of the amoxicillin, increases the medical effect and the bioavailability of the preparation, can treat bacterial liver abscess and obtain good invention effect.
Description
Technical field
The present invention relates to a kind of amoxicillin lipidosome and preparation method thereof, the new application of particularly a kind of amoxicillin lipidosome solid preparation and preparation method thereof, and described solid preparation in the treatment bacterial liver abscess.
Background technology
Bacterial liver abscess is common clinically emergency and severe disease infectious disease, and its main pathogenic bacterium are escherichia coli, Klebsiella Pneumoniae, Enterococcus, staphylococcus aureus, anaerobe, and about 20% case is a mixed infection.
Liver communicates with biliary tract and communicates with intestinal whereby, liver is accepted Hepatic artery, pylic dual blood blood supply, because these anatomical features, liver is increased by the chance of bacterial infection, causes that the bacterial origin of liver abscess mainly is: (1) is through biliary system enteric cavity antibacterial retrograde infection.Data shows, accounts for 40%～60% through the biliary tract retrograde infection, and when suffering from biliary tract, (comprising liver inside and outside bile duct stone, biliary tract ascarid, tumor of biliary tract and operation on biliary tract, biliary tract inflammation etc.), the liver infection chance obviously increases.(2) through portal vein Intraabdominal infection (appendicitis, pelvic inflammatory disease) is sent out to liver and cause liver abscess, this once was the main cause of liver abscess.Now seldom through the chance of portal vein hematogenous infection, the secondary liver abscess reaches latent source property liver abscess after also having wound in addition, some scholars think that latent source property liver abscess sickness rate has increase trend, have up to 45%, often with immunologic hypofunction and metabolic disease, Taiwan's scholars is observed the pathogenic bacterium of liver source property liver abscess and portal liver abscess based on escherichia coli and Klebsiella, the pathogenic bacterium of latent source property liver abscess are based on Klebsiella and Enterococcus, it sums up 1990-1996 182 routine bacterial liver abscesss, wherein the pathogenic bacterium of 160 examples are Klebsiellas, and these patients all merge diabetes but do not have biliary tract.
The amoxicillin, its chemical name is: (2S, 5R, 6R)-3, the 3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate, molecular formula: C
16H
19N
3O
5S3H
2O, molecular weight: 419.46, structural formula is:
The amoxicillin is a Penicillin antibiotics, to Streptococcus such as streptococcus pneumoniae, Hemolytic streptococcuss, do not produce aerobic gram positive coccus such as penicillinase staphylococcus, enterococcus faecalis, aerobic gram-negative bacterias such as escherichia coli, proteus mirabilis, Salmonella, hemophilus influenza, Diplococcus gonorrhoeae do not produce the beta lactamase bacterial strain and helicobacter pylori has good antibacterial activity.Bacteria cell wall is synthetic brings into play bactericidal action by suppressing in the amoxicillin, can make antibacterial become spheroid rapidly and dissolves, breaks.
The amoxicillin is slightly soluble in water, and almost insoluble in ethanol, the dissolution of its solid preparation is relatively poor, and quality stability is also very poor, can not reach the prescription of effect duration.A kind of dissolution is good, good stability, the little amoxicillin solid preparation of side effect, becomes the hot issue of present research gradually.
Chinese patent CN1839832A discloses a kind of amoxicillin pharmaceutical composition and preparation method thereof, be made up of amoxicillin, ascorbic acid, disodium EDTA, the weight ratio of each component is the amoxicillin: ascorbic acid: disodium EDTA=1: 0.002: 0.001～1: 0.1: 0.05.Preparation method is: take by weighing a certain amount of amoxicillin, adding weight is 1/500～1/10 ascorbic acid, 1/1000～1/20 disodium EDTA and 1/4～3/2 adjuvant; Adopt equivalent to increase progressively dilution method, cross 80 mesh sieves the said components mix homogeneously; Dry granulation under 15 ℃～30 ℃ temperature; Pulverized 100 mesh sieves.The quality of the pharmaceutical preparations stability of this method preparation improves, but does not improve the shortcoming of dissolution difference.
Chinese patent CN101390837A discloses a kind of amoxicillin granule and production method thereof, Chinese patent CN101390846A discloses a kind of Biomox and production method thereof, above-mentioned two patents all adopt micronization technology that micronizing is carried out in the raw material amoxicillin, making particle diameter is 500～1000 purpose fine powders, is mixed with corresponding preparation with other adjuvants again.The preparation dissolution of this patent preparation improves, but does not improve the shortcoming of quality stability difference.
The inventor is through long-term conscientious research, beyond thought discovery is applied to contain a kind of novel form liposome of targeting drug delivery system in the solid preparation of amoxicillin, not only can solve the problem of amoxicillin dissolution difference and quality stability difference simultaneously, preparation drug effect and bioavailability have been improved, also can treat bacterial liver abscess, thereby finish the present invention.
Summary of the invention
The object of the present invention is to provide a kind of amoxicillin lipidosome solid preparation, specifically, the combination of Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC, Tween 80 and active component amoxicillin by certain content, adopt the thin film dispersion technology to make amoxicillin lipidosome, and then and certain adjuvant be mixed and made into various solid preparations, solved the problem of dissolution difference and quality stability difference well, improve the drug effect and the bioavailability of preparation, obtained gratifying technique effect.
The technical scheme that the present invention solves is as follows:
The invention provides a kind of amoxicillin lipidosome, make by amoxicillin, Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC and Tween 80, and calculating component by weight is: 1 part of amoxicillin, 2～20 parts of Ovum Gallus domesticus Flavus lecithins, 0.5～10 part in cholesterol, 1～10 part of NaGC, 0.5～12 part of Tween 80, it makes liposome by the method that comprises the steps: (1) is dissolved in amoxicillin, Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC, Tween 80 in the solvent, mix homogeneously makes immobilized artificial membrane except that after desolvating; (2) add buffer salt solution and make the complete aquation of immobilized artificial membrane, become liposome turbid liquor; (3) amoxicillin lipidosome will be got after suspension lyophilization or the spray drying.
As the present invention's one preferred embodiment, above-mentioned described amoxicillin lipidosome calculates component by weight and is: 1 part of amoxicillin, 3～8 parts of Ovum Gallus domesticus Flavus lecithins, 1～6 part in cholesterol, 2～4 parts of NaGCs, 0.5～5 part of Tween 80.
Wherein, above-mentioned described buffer salt solution is the pharmaceutically acceptable buffer salt solution of pH value 4.5～6.0, and for example buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer; The described buffer salt solution of preferred adding is 16～40 weight portions.
The above-mentioned described amoxicillin lipidosome of the present invention, wherein said solvent, can be organic solvent, for example be selected from ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane one or more, preferred described solvent is an isopropyl alcohol.
Above-mentioned described amoxicillin lipidosome wherein, adds buffer salt solution and makes the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying, becomes liposome turbid liquor.
As one of most preferred embodiment of the present invention, above-mentioned described amoxicillin lipidosome, be to make by the method that comprises the steps: (1) is dissolved in amoxicillin, Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC, Tween 80 in the isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane; (2) add buffer salt solution and make the complete aquation of immobilized artificial membrane, reuse tissue mashing machine spares matter emulsifying, makes liposome turbid liquor; (3), promptly get amoxicillin lipidosome with suspension lyophilization or spray drying.
The technical scheme that the present invention solves also comprises:
A kind of amoxicillin solid preparation is made up of above-mentioned described amoxicillin lipidosome and pharmaceutically acceptable other adjuvants, for example can be solid preparations such as granule, tablet, capsule, dispersible tablet, dry suspension.
The above-mentioned described amoxicillin of the present invention solid preparation, wherein said adjuvant is not particularly limited, can be the pharmaceutical necessities of solid preparation commonly used in the pharmaceutics, specifically make: 1 part of amoxicillin lipidosome, 3～15 parts of filleies, 0.2～2 part of disintegrating agent by following component by weight, 0.1～0.5 part of binding agent, 0～5 part of correctives, 0～0.5 part of aromatic, 0.05～0.3 part of lubricant.
As preferably, wherein:
Described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate;
Described disintegrating agent is selected from one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the dried starch;
Described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, starch slurry, sodium carboxymethyl cellulose, the syrup;
Described correctives is selected from one or more in sucrose, Aspartane, saccharin sodium, the steviosin;
Described aromatic is selected from one or more in Fructus Citri tangerinae essence, strawberry essence, chocolate essence, Herba Menthae essence, the milk flavour;
Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate etc.
Further, the present invention also provides the preparation method of above-mentioned described amoxicillin solid preparation, and it comprises the steps:
(1) amoxicillin lipidosome is pulverized, crossed 80 mesh sieves, standby;
(2) filler, disintegrating agent, correctives are pulverized, crossed 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add binding agent, aromatic system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate;
(4) dried granules is carried out packing or tabletting, make the amoxicillin solid preparation.
The present invention also provides the application of amoxicillin solid preparation in the treatment bacterial liver abscess.
The present invention makes amoxicillin lipidosome by specific adjuvant and supplementary material proportioning, and amoxicillin lipidosome provided by the invention and amoxicillin solid preparation compared with prior art, have beyond thought effect, and major advantage is as follows:
(1) the present invention passes through amoxicillin and suitable excipients and suitable supplementary material proportioning, make solid preparation with conventional pharmaceutic adjuvant again after making amoxicillin lipidosome, can solve the problem of amoxicillin poor stability and dissolution difference simultaneously, improve the drug effect and the bioavailability of preparation, guaranteed product quality;
(2) used Ovum Gallus domesticus Flavus lecithin, cholesterol, Tween 80 and NaGC degradation in vivo, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(3) production technology is simple, and cost is low, can industrial-scale production.
Amoxicillin lipidosome solid preparation provided by the invention carries out stability test and investigates, and accelerated test is 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, and every detection index does not have significant change.
Amoxicillin lipidosome solid preparation provided by the invention carries out acute toxicity test, abnormal toxicity test and heat source check, and is all up to specification, and safety obtains proof.
The specific embodiment
Further specify the present invention by the following examples, but should not be construed as limitation of the present invention.
Embodiment 1
The preparation of amoxicillin lipidosome
Prescription: amoxicillin 125g
Ovum Gallus domesticus Flavus lecithin 375g
Cholesterol 125g
NaGC 250g
Tween 80 62.5g
Preparation technology
(1) 125g amoxicillin, 375g Ovum Gallus domesticus Flavus lecithin, 125g cholesterol, 250g NaGC and 62.5g Tween 80 are dissolved in the 4000ml isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add pH=4.5 acetic acid-sodium-acetate buffer 2000ml, jolting is stirred and is made the complete aquation of immobilized artificial membrane, the even at a high speed matter emulsifying 20min of reuse tissue mashing machine, and rotating speed 15000r/min makes liposome turbid liquor;
(3) with the suspension lyophilization, make amoxicillin lipidosome.
Comparative Examples 1
The preparation of amoxicillin lipidosome
Prescription: amoxicillin 125g
Ovum Gallus domesticus Flavus lecithin 240g
Cholesterol 60g
NaGC 120g
Tween 80 60g
Preparation technology chooses the outer weight portion of component preferable range of the present invention and forms with embodiment 1, makes amoxicillin lipidosome.
Embodiment 2
The preparation of amoxicillin lipidosome
Prescription: amoxicillin 250g
Ovum Gallus domesticus Flavus lecithin 2000g
Cholesterol 1500g
NaGC 1000g
Tween 80 1250g
Preparation technology
(1) 250g amoxicillin, 2000g Ovum Gallus domesticus Flavus lecithin, 1500g cholesterol, 1000g NaGC and 1250g Tween 80 are dissolved in the 18000ml isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add pH=6.0 citric acid-sodium citrate buffer 10000ml, jolting is stirred and is made the complete aquation of immobilized artificial membrane, the even at a high speed matter emulsifying 10min of reuse tissue mashing machine, and rotating speed 13000r/min makes liposome turbid liquor;
(3) with the suspension spray drying, make amoxicillin lipidosome.
Comparative Examples 2
The preparation of amoxicillin lipidosome (preparation technology's difference)
Prescription: amoxicillin 250g
Ovum Gallus domesticus Flavus lecithin 2000g
Cholesterol 1500g
NaGC 1000g
Tween 80 1250g
Preparation technology
(1) 2000g Ovum Gallus domesticus Flavus lecithin, 1500g cholesterol, 1000g NaGC are dissolved in the 12000ml isopropyl alcohol;
(2) 250g amoxicillin and 1250g Tween 80 are dissolved in pH=6.0 citric acid-sodium citrate buffer 8000ml;
(3) with the two mixing, stir, form w/o type Emulsion, the heated and stirred evaporation, when mixture reaches the thickness state, add pH=6.0 citric acid-sodium citrate buffer 2000ml again, continue the heated and stirred evaporation and remove isopropyl alcohol, ultrasonic 15min, be transferred to jolting in the tissue mashing machine, at a high speed even matter emulsifying 10min, rotating speed 13000r/min makes liposome turbid liquor;
(3) with the suspension spray drying, make amoxicillin lipidosome.
Embodiment 3
The preparation of amoxicillin lipidosome
Prescription: amoxicillin 125g
Ovum Gallus domesticus Flavus lecithin 625g
Cholesterol 500g
NaGC 375g
Tween 80 250g
Preparation technology
(1) 125g amoxicillin, 620g Ovum Gallus domesticus Flavus lecithin, 500g cholesterol, 375g NaGC and 250g Tween 80 are dissolved in the 7500ml isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add pH=5.2 sodium dihydrogen phosphate-sodium hydrogen phosphate buffer 3000ml, jolting is stirred and is made the complete aquation of immobilized artificial membrane, the even at a high speed matter emulsifying 20min of reuse tissue mashing machine, and rotating speed 12000r/min makes liposome turbid liquor;
(3) with the suspension spray drying, make amoxicillin lipidosome.
Embodiment 4
The preparation of amoxicillin granules
Amoxicillin lipidosome (in the amoxicillin) 12.5g
Starch 80g
Dextrin 30g
Sucrose 55g
Aspartane 1.25g
30 POVIDONE K 30 BP/USP 30 2.5g
Strawberry essence 2.0g
Preparation technology
(1) liposome that will contain the 12.5g amoxicillin is pulverized, and crosses 80 mesh sieves, and is standby;
(2) take by weighing 80g starch, 30g dextrin, 55g sucrose and 1.25g Aspartane, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 5% 30 POVIDONE K 30 BP/USP
3080% alcoholic solution 50ml and 2.0g strawberry essence system soft material are crossed 20 mesh sieves and are granulated, 60 ℃ of oven dry, and 18 mesh sieve granulate get amoxicillin granules;
(4) with the dried granules packing, make amoxicillin granule.
Embodiment 5
The preparation of amoxicillin sheet
Amoxicillin lipidosome (in the amoxicillin) 12.5g
Starch 45g
Microcrystalline Cellulose 52g
Low-substituted hydroxypropyl cellulose 8g
Hypromellose 1g
Magnesium stearate 1.4g
Pulvis Talci 2.8g
Preparation technology
(1) liposome that will contain the 12.5g amoxicillin is pulverized, and crosses 80 mesh sieves, and is standby;
(2) take by weighing 45g starch, 52g microcrystalline Cellulose, 8g low-substituted hydroxypropyl cellulose, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 2% hypromellose, 50% alcoholic solution 50ml system soft material, to cross 20 mesh sieves and granulate, 55 ℃ of oven dry add 1.4g magnesium stearate and 2.8g Pulvis Talci mix homogeneously, and 18 mesh sieve granulate get amoxicillin granules;
(4), make the amoxicillin sheet with the dried granules tabletting.
Embodiment 6
The preparation of amoxicillin dispersible tablet
Amoxicillin lipidosome (in the amoxicillin) 12.5g
Mannitol 50g
Lactose 48g
Carboxymethylstach sodium 12g
Polyvinylpolypyrrolidone 10g
30 POVIDONE K 30 BP/USP 30 2g
Aspartane 3.2g
Magnesium stearate 1.5g
Preparation technology
(1) liposome that will contain the 12.5g amoxicillin is pulverized, and crosses 80 mesh sieves, and is standby;
(2) take by weighing 50g mannitol, 48g lactose, 12g carboxymethylstach sodium, 10g polyvinylpolypyrrolidone and 3.2g Aspartane, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 5% 30 POVIDONE K 30 BP/USP
3080% alcoholic solution system soft material is crossed 20 mesh sieves and is granulated, and 55 ℃ of oven dry add 1.5g magnesium stearate mix homogeneously, and 18 mesh sieve granulate get amoxicillin granules;
(4) with the dried granules tabletting, make amoxicillin dispersible tablet.
Embodiment 7
The preparation of Amoxicillin Capsules
Amoxicillin lipidosome (in the amoxicillin) 12.5g
Starch 46g
Microcrystalline Cellulose 55g
30 POVIDONE K 30 BP/USP 30 1.5g
Magnesium stearate 1.4g
Preparation technology
(1) liposome that will contain the 12.5g amoxicillin is pulverized, and crosses 80 mesh sieves, and is standby;
(2) take by weighing 46g starch, 55g microcrystalline Cellulose, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 3% 30 POVIDONE K 30 BP/USP
3060% alcoholic solution system soft material is crossed 20 mesh sieves and is granulated, and 60 ℃ of oven dry add 1.4g magnesium stearate mix homogeneously, and 18 mesh sieve granulate get amoxicillin granules;
(4) with the dried granules packing, make Amoxicillin Capsules.
Test example 1
The mensuration of envelop rate
Get the Liposomal formulation of embodiment 1-3 and Comparative Examples 1-2 preparation, the total content that high performance liquid chromatography detects the amoxicillin is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, soak more than the swelling 12h with the pH6.8 phosphate buffer, pack in the chromatographic column (200 * 10mm) into, with above-mentioned phosphate buffer flushing balance, getting the amoxicillin lipidosome that embodiment 1-3 and Comparative Examples 1-2 obtain respectively is dissolved in water, make the solution that every 1ml contains the about 0.5mg in amoxicillin, get solution 1.5ml adding chromatography respectively and live the top, with phosphate buffer 50ml eluting, flow velocity 1.2ml/min, the eluent of collecting adds rupture of membranes agent (ethanol: 50ml benzyl alcohol=6: 1), mixing, the content M of high performance liquid chromatography detection amoxicillin
1
Envelop rate %=M
1/ M * 100%.
Table 1 entrapment efficiency determination result
By above result as can be known, the liposome encapsulation that the present invention makes is very high, meets the actual production requirement substantially; The liposome encapsulation that the Comparative Examples of the Comparative Examples of proportioning and Different Preparation makes and the scope of the invention is write out a prescription outward is very low, has compared tangible gap with embodiment, is not suitable for production requirement.
Test example 2
The detection of particle diameter
Get the liposome of embodiment 1-3 and Comparative Examples 1-2 preparation, adopt micro-image analyzer to measure the particle size distribution of liposome, result such as table 2:
Table 2 particle diameter testing result
By above result as can be known, the liposome that embodiment 1-3 makes shows spherical, ellipticity, and particle diameter is even, and scope is 100-200nm; The liposome shape that Comparative Examples 1-2 makes is indefinite, not of uniform size, and particle diameter is inhomogeneous, and scope is 400-800nm.
Test example 3
Stability test
Get amoxicillin lipidosome preparation and sheet (North China Pharmaceutical Group Preparation Co., Ltd.'s production of listing preparation amoxicillin that embodiment 4-7 makes, lot number 20081022), under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carrying out accelerated test investigates, compare dissolution and stability, the result is as follows:
Table 3 accelerated test is investigated
By above result as can be known, the sample dissolution of embodiment of the invention 4-7 is higher than about 81% of listing tablet far away all more than 90%, illustrates that the amoxicillin lipidosome that the present invention makes has improved its dissolubility, thereby has improved bioavailability accordingly.After the accelerated test 6 months, significant change does not take place in sample dissolution, content and the related substance of embodiment of the invention 4-7, and listing formulation content and dissolution decline are bigger, and related substance raises obviously, illustrates that the amoxicillin lipidosome that the present invention makes has improved its stability of formulation.
Test example 4
Clinical trial
1, diagnostic criteria
(1) heating.(2) right hypochondrial region, nauseating, weak, appetite is poor.(3) pain is kowtowed in the hepatic region.(4) the tip blood picture increases＞10 * 109/L.(5) abnormal liver function.(6) the space occupying lesion kitchen range that fluidity is arranged in B ultrasonic or the CT examination liver or do not liquefy fully.
More than any 1 add the 6th, and except hepatocarcinoma and noninfectious disease.182 selected routine patients all meet above requirement and are diagnosed as bacterial liver abscess, are divided into 3 groups at random: 61 people of observation group, male 38 examples, women 23 examples, 57.3 ± 3.5 years old mean age; Matched group 60 people, male 35 examples, women 25 examples, 52.5 ± 2.9 years old mean age; Listing sample sets 61 people, male 39 examples, women 22 examples, 54.6 ± 5.6 years old mean age, three groups all have comparability at aspects such as age, sex, disease type and the state of an illness.
2, Therapeutic Method
Observation group gives the each 0.5g of amoxicillin lipidosome granule of the embodiment of the invention 4 preparations, twice of every day; Quiet ampicillin 2.5g of matched group, twice of every day; The listing sample sets gives North China Pharmaceutical Group Preparation Co., Ltd.'s production amoxicillin sheet (lot number 20081022), and a 0.5g, is ten days the course of treatment at every day twice.
3, observation index
1. body temperature changes; 2. symptom of digestive tract: right hypochondrial region, feel sick, the appetite situation; 3. pain is kowtowed in the hepatic region; 4. tip hemogram; 5. liver function; 6. liver B ultrasonic or CT influence changes; 7. adverse effect.
4, therapeutic evaluation
" antibacterials clinical research guideline " that the evaluation of clinical curative effect standard is issued by Ministry of Public Health divides recovery from illness, produce effects, progress and invalid 4 grades of evaluations.Recovery from illness: symptom, sign, lab index and liver image recover normal; Produce effects: the state of an illness is clearly better, but has 1 not recover normal fully in above-mentioned 4; Progressive: the state of an illness takes a turn for the better to some extent, but not obvious; Invalid: medication after 10 days the state of an illness do not have and alleviate.Recovery from illness and produce effects add up to effectively.
5, clinical test results
(1), the results are shown in Table 4 after three groups of liver abscess patient treatments of clinical efficacy through a course of treatment, 35 people that fully recover of observation group wherein, total effective rate is 86.88%; The matched group recovery from illness is 20 people, and total effective rate is 63.33%; Listing sample sets 30 people that fully recover, total effective rate is 73.33%.Observation group compares cure rate and total effective rate and all has tangible significance, P＜0.05 with matched group; Observation group compares with the listing sample sets simultaneously, also has significance, P＜0.05 on cure rate and total effective rate.
Three groups of clinical efficacies of table 4 relatively
Annotate: compare with matched group: ★ P＜0.05; Compare with the listing sample: △ P＜0.05.
(2), in observation group's 61 examples, positive bacterial culture has 46 examples to bacteriology checking before the treatment, wherein turns out escherichia coli 30 examples as a result, staphylococcus aureus 16 examples, 40 routine antibacterial culturing are turned out cloudy after the medication, 6 examples are still positive, but clinical symptoms and sign are clearly better; The matched group positive bacterial culture has 41 examples, wherein turns out escherichia coli 28 examples, staphylococcus aureus 13 examples, and 29 routine antibacterial culturing are turned out cloudy after the medication, and 11 examples are still positive; Listing sample sets positive bacterial culture has 43 examples, wherein turns out escherichia coli 34 examples, staphylococcus aureus 9 examples, and 35 routine antibacterial culturing are turned out cloudy after the medication, and 8 examples are still positive.Three groups of bacteria clearance are respectively 86.96%, 73.17%, 81.39%.
(3), among the 61 routine patients of untoward reaction observation group, blood, routine urinalysis before and after the medication, liver, the equal no change of renal function do not have uncomfortable symptom.Diarrhoea appears in matched group 5 examples, disappears after the drug withdrawal.
In sum, determined curative effect in the amoxicillin lipidosome solid preparation treatment bacterial liver abscess process of the present invention's preparation, untoward reaction is few, than prior art products better effect is arranged.
Claims (10)
1, a kind of amoxicillin lipidosome, it is characterized in that making by amoxicillin, Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC and Tween 80, and calculating component by weight is: 1 part of amoxicillin, 2～20 parts of Ovum Gallus domesticus Flavus lecithins, 0.5～10 part in cholesterol, 1～10 part of NaGC, 0.5～12 part of Tween 80, make liposome by the method that comprises the steps: (1) is dissolved in amoxicillin, Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC, Tween 80 in the solvent, mix homogeneously makes immobilized artificial membrane except that after desolvating; (2) add buffer salt solution and make the complete aquation of immobilized artificial membrane, become liposome turbid liquor; (3) amoxicillin lipidosome will be got after suspension lyophilization or the spray drying.
2, amoxicillin lipidosome according to claim 1 is characterized in that calculating by weight component and is: 1 part of amoxicillin, 3～8 parts of Ovum Gallus domesticus Flavus lecithins, 1～6 part in cholesterol, 2～4 parts of NaGCs, 0.5～5 part of Tween 80.
3, according to the described amoxicillin lipidosome of claim 1-2, wherein said buffer salt solution is the pharmaceutically acceptable buffer salt solution of pH value 4.5～6.0, and for example buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer; The described buffer salt solution of preferred adding is 16～40 weight portions.
4, according to the described amoxicillin lipidosome of claim 1-3, wherein said solvent is an organic solvent, for example be selected from ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane one or more, preferred solvent is an isopropyl alcohol.
5, according to the described amoxicillin lipidosome of claim 1-4, wherein, add buffer salt solution and make the complete aquation of immobilized artificial membrane, reuse tissue mashing machine spares matter emulsifying, becomes liposome turbid liquor.
6, a kind of amoxicillin solid preparation is characterized in that being made up of each described amoxicillin lipidosome of claim 1-5 and pharmaceutically acceptable other adjuvants; Preferred described amoxicillin solid preparation is granule, tablet, capsule, dispersible tablet or dry suspension.
7, amoxicillin according to claim 6 solid preparation, it is characterized in that described solid preparation is to be made by following component by weight: 1 part of amoxicillin lipidosome, 3～15 parts of filleies, 0.2～2 part of disintegrating agent, 0.1～0.5 part of binding agent, 0～5 part of correctives, 0～0.5 part of aromatic, 0.05～0.3 part of lubricant.
8, amoxicillin according to claim 7 solid preparation, wherein: described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate; Perhaps described disintegrating agent is selected from one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the dried starch; Perhaps described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, starch slurry, sodium carboxymethyl cellulose, the syrup; Perhaps described correctives is selected from one or more in sucrose, Aspartane, saccharin sodium, the steviosin; Perhaps described aromatic is selected from one or more in Fructus Citri tangerinae essence, strawberry essence, chocolate essence, Herba Menthae essence, the milk flavour; Perhaps described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate etc.
9, a kind of method for preparing the described amoxicillin of claim 6-8 solid preparation, it comprises the steps: (1) with the amoxicillin lipidosome pulverizing, 80 mesh sieves are standby excessively; (2) filler, disintegrating agent, correctives are pulverized, crossed 80 mesh sieves, mix, standby; (3) with above-mentioned supplementary material mix homogeneously, add binding agent, aromatic system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate; (4) dried granules is carried out packing or tabletting, make the amoxicillin solid preparation.
10, be used for the treatment of application in the bacterial liver abscess medicine according to the described amoxicillin of claim 6-8 solid preparation in preparation.
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