CN106729658A - A kind of amoxicillin solid dispersion and preparation method thereof - Google Patents

A kind of amoxicillin solid dispersion and preparation method thereof Download PDF

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CN106729658A
CN106729658A CN201710000369.6A CN201710000369A CN106729658A CN 106729658 A CN106729658 A CN 106729658A CN 201710000369 A CN201710000369 A CN 201710000369A CN 106729658 A CN106729658 A CN 106729658A
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amoxicillin
solid dispersion
preparation
lysozyme
utech
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童庆平
黄恒
袁林
孙才汉
孙敏
谷长勤
伍晓雄
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WUHAN XINLIANDA BIOLOGY Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
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    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/429Thiazoles condensed with heterocyclic ring systems
    • A61K31/43Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1611Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
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    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • C12YENZYMES
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    • C12Y302/01Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01017Lysozyme (3.2.1.17)

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Abstract

The invention discloses a kind of amoxicillin solid dispersion and preparation method thereof;The weight percent content of each component of the solid dispersion is as follows:The sulbactam of Amoxicillin 5~20%, 1~5%, lysozyme 0.5~1%, aesculetin 0.5~1%, Utech S 100 1.0~2.0%, sodium hydrogensulfite 0.2~0.5%, PVP 2~5%, balance of DEXTROSE ANHYDROUS.Solid dispersion prepared by the present invention has preparation process is simple, both the drug effect of Amoxicillin had been remained, the drawbacks of avoiding general enteric coated preparations local delivery of drug excessive concentration, lysozyme is added to be even more the antibacterial activity that can improve product, significantly improve bioavilability, the product good palatability for obtaining simultaneously, does not have GI irritation, can greatly promote cure rate.

Description

A kind of amoxicillin solid dispersion and preparation method thereof
Technical field
The invention belongs to veterinary drug technical field, and in particular to a kind of amoxicillin solid dispersion, also relate to A kind of preparation method of amoxicillin solid dispersion.
Background technology
Amoxicillin (Amoxicillin), also known as amoxycillin, is that semi-synthetic acidproof penbritin class resists Raw element.The medicine has a broad antifungal spectrum, sterilizing power is strong, and effect is rapid, to main gram-positive bacteria and some negative bacteriums such as streptococcus, Pasteurella, the staphylococcus that penicillase is not produced, Escherichia coli, salmonella, proteus mirabilis etc. are sensitive, can be extensive Sensitive bacteria infection for treating urethra, respiratory tract and the skin of various animals.At present, it has been used in the quick of pig, ox and poultry Sense bacterium infection.
Amoxicillin is very poor in water stability, and degrade 1-5% per hour;Amoxicillin slightly soluble in water, in 100ml Its solubility is only 0.1 gram in water, and its dissolution rate is less than 80%;Simultaneously traditional Amoxicillin bitter, also with intestines and stomach Excitant, solves the problems, such as stability, solubility and dissolution rate, and good palatability becomes what Wymox research faced Problem.Current Amoxicillin formulation has tablet, powder, parenteral solution, supensoid agent etc., but big multi-form needs multiple dosing to tie up Sufficiently long active drug concentration is held, and repetitively administered can make the increase of administration cost, and cause animal stress reaction.And be suspended Although agent can reach good utilization ratio of drug, however, due to the presence of water in liquid preparation, the stability of its preparation is all the time Shortcomings, injection there is a problem of in-convenience in use and high cost.The absorption site of Amoxicillin is in the upper of intestines and stomach End, in order to overcome its stomach irritation and acid labile, therefore its most preferred dosage form should be a kind of enteric coated preparations, and said preparation is in stomach In there is part to discharge, usual 10%~50%, so can both avoid stimulation of the medicine to stomach, optimal suppression can be reached again Bacteria concentration plays the purpose of rapid-onset.With the wriggling of stomach, remaining part medicine can gradually pass through pylorus and enter in enteron aisle, Dissolved in the presence of the suitable pH value of enteron aisle, discharge medicine, medicine is entered body-internal-circulation system, keep blood concentration Balance.Therefore, a kind of Amoxicillin oral formulations with good palatability, good stability and with double release functions are prepared The edible comfortableness of the medicine will be greatly improved.
Solid dispersion technology is that medicine is dispersed in solid carrier in forms such as particulate, crystallite or molecular staties One new formulation technology.
Lysozyme (lysozyme), hydrolyzes also known as muramidase (muramidase) or N- acetyl mureins glycan Enzyme (N-acetylmuramide lycanohydrlase), is that one kind is widely present in milk, saliva, tears, egg and fish Native enzyme in ovum, with Efficient antibacterial, sterilization, antiviral bioactivity.It can decompose killing such as staphylococcus The gram positive bacterias such as category, streptococcus.Can be as a kind of sterilized and nourishing additive agent, in medicine, food and biochemical field Extensive use, wide market.Due to the more prominent high efficiency in terms of the pharmacological effects such as antiviral, bactericidal antiphlogistic of the enzyme and Popularity, the focus as biomedicine field research.
The content of the invention
It is how western that one kind of offer in view of the shortcomings of the prior art of the invention can improve animal welfare, eutherapeutic hydrochloric acid for animals Ring element solid dispersion.
It is a further object to provide the preparation method of above-mentioned veterinary doxycycline hydrochloride solid dispersion.
The technical scheme is that:A kind of amoxicillin solid dispersion, its component and percentage by weight are:Ah The sulbactam of Amdinocillin 5~20%, 1~5%, lysozyme 0.5~1%, aesculetin 0.5~1%, Utech S-100 1.0~ 2.0%, sodium hydrogensulfite 0.2~0.5%, PVP 2~5%, balance of DEXTROSE ANHYDROUS.
Preferably, said components and percentage by weight are:Amoxicillin 10%, sulbactam 2%, lysozyme 1.0%, the bark of ash B prime 1.0%, Utech S-100 1.5%, sodium hydrogensulfite 0.4%, PVP 3%, balance of DEXTROSE ANHYDROUS.
A kind of preparation method of amoxicillin solid dispersion, comprises the following steps:
( 1)By Utech S-100 dissolvings in ethanol, stirring is presented clear solution after 30~60 minutes;
( 2)Sodium hydrogensulfite, Amoxicillin and sulbactam are added, is sheared 30 minutes into high speed shear homogenizer;
( 3)It is transferred in vacuum drying chamber again, temperature is maintained at 60 DEG C to drying, and takes out, and grinds 80 mesh sieves, obtains carrier Core layer;
( 4)Then PVP, lysozyme, aesculetin and the DEXTROSE ANHYDROUS of recipe quantity are put into respectively, use suitable after being well mixed Amount pure water granulation;
( 5)60 DEG C of dryings, whole grain obtains final product amoxicillin solid dispersion.
Preferably, the weight of above-mentioned ethanol is 10~100 times of Utech S-100.
Preferably, the weight of above-mentioned ethanol is 20 times of Utech S-100.
Preferably, the consumption of above-mentioned pure water accounts for 2%~5% ratio of the amoxicillin solid dispersion gross weight.
Preferably, the consumption of above-mentioned pure water accounts for 3% ratio of the amoxicillin solid dispersion gross weight.
Due to Amoxicillin bitter, palatability is bad;On the other hand, Amoxicillin is unstable under one's belt, degradable and right Stomach lining has excitant, and the ill symptomses such as apocleisis, the Nausea and vomiting of livestock and poultry can be caused in administration process.The present invention is used The Amoxicillin of solid dispersion technology is water-soluble to be increased, and bioavilability is improved, while masking the bitter taste and thorn of Amoxicillin Swash property, increased palatability, the double delivery systmes of creative invention, said preparation has part to discharge under one's belt, usual 10%~ 50%, stimulation of the medicine to stomach so can have both been avoided, the mesh that optimal Mlc plays rapid-onset can be reached again 's.With the wriggling of stomach, remaining part medicine can gradually pass through pylorus and enter in enteron aisle, in the effect of the suitable pH value of enteron aisle Lower dissolving, discharges medicine, medicine is entered body-internal-circulation system, keeps the balance of blood concentration.
Aesculetin is in itself a kind of antimicrobial, has inhibitory action to shigella dysenteriae, can be used to treat acute bacillary dysentery, and have Relieving asthma, phlegm-dispelling functions.Simultaneously as adjuvant, the mechanism for strengthening immune response is the physical form by changing antigen, and extension is anti- Original retention time in body;Submission ability of the stimulation MNP to antigen;Stimulate lymphocyte differentiation, increase and expand Immune response ability.
Lysozyme is the nospecific immunity factor important in organism, with antibacterial, antiviral, strengthen immunity and rush Enter the multi-functionals such as wound tissue's reparation.From the point of view of lysozyme practical application effect, often than laboratory good antimicrobial effect very It is many.Its main cause is:Lysozyme has good biocompatibility, not only direct hydrolysis malignant bacteria cell membrane, Er Qiehe Other multi-element biologic agents in combination effect in animal body, presses down bactericidal, neutralizes a toxin, and builds up health, and promotes growth;Secondly, Environment meets the best use of condition of lysozyme just in animal body.And under lab, do not possess also and preferably embody molten The simulated experiment of effect in bacterium enzyme animal body.
The present invention selection Amoxicillin and lysozyme perfect adaptation, can reach the effect of low dosage curative effect high, be coated with Ah not XiLin, reduces destruction of the hydrochloric acid in gastric juice to Amoxicillin, while sustained release is formed in enteron aisle absorbing, blood concentration is maintained for a long time and controls Treatment amount;Coating Amoxicillin, effectively reduces the bitter taste of medicine, increased the palatability of product.Hydrochloric acid in gastric juice is reduced simultaneously to Ah not The destruction in XiLin, dissolves fast, stable in properties in water, and degradation speed is slow.Just lost after about 4 hours in water general Amoxicillin Effect, and this product activity that 24 hours still maintain 85% in water.Sustained release is formed in enteron aisle simultaneously to absorb, and makes blood concentration long Phase maintains therapeutic dose, while having conciliation immunologic function, recovers macrophage immunity activity.
Being combined with lysozyme coating and solid dispersion technology for the invention, significantly improves Amoxicillin Stability, improves bioavilability, reaches the effect of double releases, does not have gastrointestinal irritation, good palatability, while reducing poison Side effect.
Compared to existing technology, the beneficial effects of the present invention are:
(1) solid dispersion technology is used with the effect of covering of the bag using carrier, delays the hydrolysis and oxidation of Amoxicillin, improve medicine Stability;Double delivery systmes, can both reach the purpose that optimal Mlc plays rapid-onset, turn avoid general enteric The drawbacks of preparation local delivery of drug excessive concentration;Cover adverse drug smell and excitant;Good dispersion, greatly accelerates the molten of medicine Go out, improve the bioavilability of medicine, make a kind of quick-acting, efficient preparation;
(2) solid dispersion of bacteriolyze ferment treatment, due to the coated synergistic effect of lysozyme, the antibacterial activity of Amoxicillin is improved 4 times, palatability is in good taste, does not have the sensation of bitter, and is very beneficial to pipe intestinal protection and nutrient absorption, solve antibiotic not by Hydrochloric acid in gastric juice destruction, protective rate 98%, to gastrointestinal mucosa without destruction, while solid disperses, duration of efficacy is long, improves medicine Absorption and bioavilability, with reconcile immunologic function, recover macrophage immunity activity;(3) with Amoxicillin, the bark of ash B prime and lysozyme are the compound preparation of main component, overcome that existing single preparations of ephedrine compound preparation effect is poor, consumption is big, remain Shortcoming high;Amoxicillin and two kinds of Drug combinations of aesculetin, can greatly improve drug susceptibility, with single drug Compare, dosage and times for spraying is greatly decreased, while improving curative effect of medication, reduce the dosage of antibiotic, reduce Medicine remains risk to the toxic and side effect and medicine of animal using the potential drug that process may occur, and in field of veterinary has good Good application prospect;
(4) addition sulbactam can effectively suppress the activity of beta-lactamase, solve the resistance problems of Amoxicillin;Match somebody with somebody Close aesculetin synergistic effect, and have relieving asthma, phlegm-dispelling functions;
(5) relative to injection, high cost, in-convenience in use, solid dispersion can be used with spice or drinking-water, using simple, Beneficial to large-scale cultivation.
Specific embodiment
Specific embodiment of the invention is illustrated with reference to specific embodiment, but following examples are used only in detail The present invention is illustrated, the scope of the present invention is limited never in any form.
Embodiment 1
A kind of amoxicillin solid dispersion, component and correspondence percentage by weight are:Amoxicillin 5%, sulbactam 1%, Lysozyme 0.5%, aesculetin 0.5%, Utech S-100 1.0%, sodium hydrogensulfite 0.2%, PVP 2%, balance of anhydrous Portugal Grape sugar.
The preparation method of the amoxicillin solid dispersion, concretely comprises the following steps:Full dose Utech S-100 is dissolved in In 10 times of ethanol of weight, stirring is presented clear solution after 30 minutes, adds sodium hydrogensulfite, Amoxicillin and sulbactam, After being sheared 30 minutes into high speed shear homogenizer, it is transferred in vacuum drying chamber, temperature is maintained at 60 DEG C to drying, and takes out, and grinds The broken mistake 80 that is milled mesh sieve, obtains carrier core layer.Then the input PVP of recipe quantity, lysozyme, aesculetin and anhydrous respectively Glucose, is pelletized after being well mixed with appropriate purified water, 60 DEG C of dryings, and whole grain obtains final product graininess amoxicillin solid point Powder.
The consumption of above-mentioned pure water accounts for 2% ratio of graininess amoxicillin solid dispersion gross weight.
Embodiment 2
A kind of amoxicillin solid dispersion, component and correspondence percentage by weight are:Amoxicillin 10%, sulbactam 2%, Lysozyme 0.8%, aesculetin 0.8%, Utech S-100 1.5%, sodium hydrogensulfite 0.4%, PVP 3%, balance of anhydrous Portugal Grape sugar.
The preparation method of the amoxicillin solid dispersion, concretely comprises the following steps:Full dose Utech S-100 is dissolved in In 20 times of ethanol of weight, stirring is presented clear solution after 40 minutes, adds sodium hydrogensulfite, Amoxicillin and sulbactam, After being sheared 30 minutes into high speed shear homogenizer, it is transferred in vacuum drying chamber, temperature is maintained at 60 DEG C to drying, and takes out, and grinds The broken mistake 80 that is milled mesh sieve, obtains carrier core layer.Then the input PVP of recipe quantity, lysozyme, aesculetin and anhydrous respectively Glucose, is pelletized after being well mixed with appropriate purified water, 60 DEG C of dryings, and whole grain obtains final product graininess amoxicillin solid point Powder.
The consumption of above-mentioned pure water accounts for 3% ratio of graininess amoxicillin solid dispersion gross weight.
Embodiment 3
A kind of amoxicillin solid dispersion, component and correspondence percentage by weight are:Amoxicillin 10%, sulbactam 2%, Lysozyme 1.0%, aesculetin 1.0%, Utech S-100 1.5%, sodium hydrogensulfite 0.4%, PVP 3%, balance of anhydrous Portugal Grape sugar.
The preparation method of the amoxicillin solid dispersion, concretely comprises the following steps:By total amount Utech S-100 dissolvings In 50 times of ethanol of weight, stirring is presented clear solution after 40 minutes, adds sodium hydrogensulfite, Amoxicillin and Sulbactam Sodium, after being sheared 30 minutes into high speed shear homogenizer, is transferred in vacuum drying chamber, and temperature is maintained at 60 DEG C to drying, and takes out, 80 mesh sieves were ground, carrier core layer was obtained.Then PVP, lysozyme, aesculetin and the nothing of recipe quantity are put into respectively Water glucose, is pelletized after being well mixed with appropriate purified water, and 60 DEG C of dryings, whole grain obtains final product graininess amoxicillin solid Dispersant.
The consumption of above-mentioned pure water accounts for 3% ratio of graininess amoxicillin solid dispersion gross weight.
Embodiment 4
A kind of amoxicillin solid dispersion, component and correspondence percentage by weight are:Amoxicillin 20%, sulbactam 5%, Lysozyme 1.0%, aesculetin 1.0%, Utech S-100 2.0%, sodium hydrogensulfite 0.5%, PVP 5%, balance of anhydrous Portugal Grape sugar.
The preparation method of the amoxicillin solid dispersion, concretely comprises the following steps:By total amount Utech S-100 dissolvings In 100 times of ethanol of weight, stirring is presented clear solution after 60 minutes, adds sodium hydrogensulfite, Amoxicillin and Sulbactam Sodium, after being sheared 30 minutes into high speed shear homogenizer, is transferred in vacuum drying chamber, and temperature is maintained at 60 DEG C to drying, and takes out, 80 mesh sieves were ground, carrier core layer was obtained.Then PVP, lysozyme, aesculetin and the nothing of recipe quantity are put into respectively Water glucose, is pelletized after being well mixed with appropriate purified water, and 60 DEG C of dryings, whole grain obtains final product graininess amoxicillin solid Dispersant.
The consumption of above-mentioned pure water accounts for 5% ratio of gross weight.
The present invention is further described or illustrated by the following examples, but is not intended to limit the invention.
Dissolution Rate Testing, is tested using the sample of embodiment 2.
Dissolving-out method:Basket method(Annex page 114 first method of Chinese veterinary pharmacopoeia 2010 edition);
Leaching condition:Dissolution medium is 0.1mol/L hydrochloric acid solution 900ml, and rotating speed is 50 revs/min;
Sample time:Sampled respectively at the 5th, 10,20,30,40,60,90 and 120 minutes;
Detection method:UV-VIS spectrophotometry(Appendix 26 page of Chinese veterinary pharmacopoeia 2010 edition), at 345nm wavelength Mensuration absorbance;
Detecting instrument:Spectrophotometry instrument, model:752N types
Result see the table below 1:The dissolution test result of table 1
Even from Dissolution experiments as can be seen that being stirred 120 minutes in 0.1mol/L hydrochloric acid solutions, dissolution rate only has 34.1%, meet the requirement of release 10%~50% in stomach.
Effect judges
Test therapeutic effect observation 1. of 1 embodiment 3 to swine influenza and select Experimental agents:Described in the embodiment of the present invention 3 Amoxicillin solid dispersion.2. animal subject:There is following symptom in certain age in days piglet of pig farm 20, sick pig:Flu hair Heat, spray nose are sneezed, submandibular lymph nodes enlargement, schneiderian membrane flush swelling, and nose stream serosity, mucus or purulence nose liquid are exhaled Difficult, cough and asthma is inhaled, is popular pig according to comprehensive diagnos such as epidemiology, clinical symptoms, microbiology and Serological testing Sexuality emits.Random selection 200,4 groups of average mark.
(1)Blank group:Do not carry out any treatment;
(2)Experimental group:Using solid dispersion described in the mixed feeding embodiment of the present invention 3,200g/ tons of feed is used in conjunction 5 days.
(3)Amoxicillin control group:Using commercially available 10% Amoxicillin pulvis, 200g/ tons of feed is used in conjunction 5 days
(4)Lysozyme control group:Lysozyme solid dispersion is made by oneself using mixed feeding(Lysozyme 1.0%, aesculetin 1.0%, especially Strange S-100 2.0%, sodium hydrogensulfite 0.5%, PVP 5%, balance of DEXTROSE ANHYDROUS), 500g/ tons of feed be used in conjunction 5 days. The clinical sign of observation and recording laboratory animal, judges therapeutic effect in five days.3. index of assessment of curative effect cure rate:Clinical condition Shape disappears, and spirit, appetite etc. recover normal, and category is cured, and curing number according to each group animal calculates cure rate.
It is efficient:The animal and symptom cured after being treated through medication have obvious alleviator, are judged to effectively.It is invalid Rate:Through medication treat after clinical symptoms do not disappear, the state of an illness do not take a turn for the better and treat during died because originally dying of illness be accordingly to be regarded as it is invalid, Statistics invalid number, calculates inefficiency.
4. result see the table below 2;
Therapeutic effect of the embodiment of the present invention 3 of table 2 to swine influenza:
As seen from the above table, the embodiment of the present invention 3 is all remarkably higher than Ah not to the treatment cure rate and effective percentage of swine influenza XiLin control group and lysozyme control group and blank control group, and inefficiency is substantially less than other three groups.Result shows, of the invention Swine influenza can effectively be treated.And it is observed that after the pig treatment of implementation group, clinical symptom disappearance, appetite and spiritual shape State etc. is significantly better than that Amoxicillin control group and lysozyme control group.
Above test result indicate that, Amoxicillin and lysozyme, the compatibility application of aesculetin are remarkably improved animal disease The cure rate of disease, good palatability.

Claims (7)

1. a kind of amoxicillin solid dispersion, it is characterised in that its component and percentage by weight are:Amoxicillin 5~ 20%, 1~5% sulbactam, lysozyme 0.5~1%, aesculetin 0.5~1%, Utech S-100 1.0~2.0%, sulfurous acid Hydrogen sodium 0.2~0.5%, PVP 2~5%, balance of DEXTROSE ANHYDROUS.
2. amoxicillin solid dispersion is planted according to claim 1, it is characterised in that the component and weight hundred Point ratio is:Amoxicillin 10%, sulbactam 2%, lysozyme 1.0%, aesculetin 1.0%, Utech S-100 1.5%, sulfurous acid Hydrogen sodium 0.4%, PVP 3%, balance of DEXTROSE ANHYDROUS.
3. the preparation method of amoxicillin solid dispersion is planted according to claim 1, it is characterised in that including such as Lower step:
( 1)By Utech S-100 dissolvings in ethanol, stirring is presented clear solution after 30-60 minutes;
( 2)Sodium hydrogensulfite, Amoxicillin and sulbactam are added, is sheared 30 minutes into high speed shear homogenizer;
( 3)It is transferred in vacuum drying chamber again, temperature is maintained at 60 DEG C to drying, and takes out, and grinds 80 mesh sieves, obtains carrier Core layer;
( 4)Then PVP, lysozyme, aesculetin and the DEXTROSE ANHYDROUS of recipe quantity are put into respectively, use suitable after being well mixed Amount pure water granulation;
( 5)60 DEG C of dryings, whole grain obtains final product amoxicillin solid dispersion.
4. preparation method according to claim 3, it is characterised in that the weight of the ethanol for Utech S-100 10~ 100 times.
5. the preparation method according to claim 3 or 4, it is characterised in that the weight of the ethanol is the 20 of Utech S-100 Times.
6. the preparation method according to claim 3 or 4, it is characterised in that the consumption of the pure water accounts for the compound Ah Moses 2%~5% ratio of woods solid dispersion gross weight.
7. the preparation method according to claim 3 or 4, it is characterised in that the consumption of the pure water accounts for the compound Ah Moses 3% ratio of woods solid dispersion gross weight.
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Citations (5)

* Cited by examiner, † Cited by third party
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Application publication date: 20170531