CN109833482A - A kind of Entogastric lingering, chitosan polymer pharmaceutic adjuvant of positioning release medicine and its preparation method and application - Google Patents
A kind of Entogastric lingering, chitosan polymer pharmaceutic adjuvant of positioning release medicine and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of Entogastric lingerings, the chitosan polymer pharmaceutic adjuvant of positioning release medicine and its preparation method and application, the chitosan polymer pharmaceutic adjuvant is with chitosan (CS) for hydrophilic skeleton, is made under the action of coupling agent by amide reaction covalent bond Carboxybenzeneboronic acid (CPBA).Chitosan polymer pharmaceutic adjuvant prepared by the present invention has the ability of Entogastric lingering and positioning release, can position release coccidiostat according to pH value specific in poultry gastrointestinal tract and concentration of glucose after loading coccidiostat by dialysis.Preparation process of the present invention is safely controllable, and organic solvent residual is few, can be used as the Novel Delivery material of slightly solubility coccidiostat Entogastric lingering and positioning release medicine.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to the chitosan polymer medicine of a kind of Entogastric lingering, positioning release medicine
With auxiliary material and its preparation method and application.
Background technique
Chitosan (CS) is one of nature alkaline polysaccharide, be dispersed on strand many free amine groups, hydroxyl and
N- acetylamino, these functional groups provide structure basis for the modification of chitosan.Chitosan and its derivative is also equipped with many
Unique physicochemical property and bioactivity, such as biodegradability, biocidal property, anti-tumor activity, mucosa adhesion, moisture retention
Deng.
Carboxybenzeneboronic acid (CPBA) is organic boric acid compounds, is a kind of Lewis that intensity is low acid, and toxicity is lower.It is by 3
Valence boron atom and 1 alkyl, 2 hydroxyls are constituted in the form of covalent bond.It is unionized be have in boron atom 1 unoccupied orbital perpendicular to
Other three substituent groups, heterocycle are sp2 plane trigonometry configuration；Borate hydridization is at tetrahedron sp3 configuration under free state.Boron
With cis-form dihydroxy class compound covalent reaction can occur for acid group sp3 hydridization, form the cyclic ester of five yuan or hexatomic ring.CPBA
Phenyl ring can be formed π-π stacking effect, have have non-specific adsorption to lyophobic dust, the dissolution of insoluble drug can be improved
Degree.
New type medicinal stuff patent mainly includes the following contents at this stage:
Patent CN104257628B discloses a kind of load salinomycin micella and its preparation method and application, with DSPE-
PEG2000-CRGDK copolymer contains Salinomycin Sodium as carrier.The carrier that this product uses is DSPE-PEG2000 and hypertonic
Permeability target polypeptide CRGDK is expensive, and practical application is not high, and without being detained the function with positioning release medicine.
Patent CN102399370A discloses a kind of preparation method of chitosan polymer, which uses natural chitosan
Realize that chemistry interlink and ionomer, gathers to obtain gelatinous chitosan with Geniposide and glycerol -2- disodium hydrogen phosphate respectively
Close object.The invention preparation flow is simple, and material therefor is from a wealth of sources, Nantural non-toxic.But the invention patent is not directed to function
Application of the fluidized polymer in art of pharmacy.
Patent CN102558391A disclose a kind of Vitamin E succinate-chitosan graft object and preparation method thereof and
Using.The amphiphilic copolymer copolymer of synthesis, there is surfactant, improves the solubility of drug, but it is not
With slow release and positioning releasability, its practical application is limited.
Patent CN105001425A discloses a kind of preparation method based on chitosan-polylactic acid grafted copolymer, the production
Product biocompatibility height, biodegradability, can be used as the slow-released carrier of newtype drug.But it carries medicine as pharmaceutic adjuvant
Low, and the ability without positioning release medicine is measured, its practical application is limited.
Summary of the invention
Goal of the invention: in view of the problems of the existing technology, it is poly- that the present invention provides a kind of Entogastric lingering, the shell of positioning release medicine
Glycopolymers pharmaceutic adjuvant, can overcome slightly solubility coccidiostat solubility is low, action time is short, positioning release difficulty etc. no
Foot, chitosan polymer pharmaceutic adjuvant of the invention be the Entogastric lingering that a kind of drugloading rate is big, slow release is strong, toxic side effect is low,
Position the chitosan polymer pharmaceutic adjuvant of release.Chitosan polymer pharmaceutic adjuvant prepared by the present invention have Entogastric lingering and
The ability for positioning release, accomplishes to release the drug on a small quantity under the conditions of low ph value, low glucose concentrations in stomach, in the intestine high ph-values, high Portugal
The a large amount of drug releases of positioning are realized under grape sugar concentration conditions；It can be according to specific in poultry enteron aisle after loading coccidiostat by dialysis
PH value and concentration of glucose position release coccidiostat.
The present invention also provides Entogastric lingering, the chitosan polymer pharmaceutic adjuvant of positioning release medicine preparation method and answer
With；Preparation process of the present invention is safely controllable, and organic solvent residual is few, can be used as slightly solubility coccidiostat Entogastric lingering and positioning
The Novel Delivery material of drug release；Entogastric lingering provided by the invention, positioning release chitosan polymer pharmaceutic adjuvant apply
Field of pharmaceutical preparations, especially coccidiostat.
Technical solution: to achieve the goals above, a kind of Entogastric lingering, the chitosan of positioning release medicine are poly- as described herein
Object pharmaceutic adjuvant is closed, is mainly hydrophilic back bone material by chitosan (CS), is reacted altogether under the action of coupling agent by amide
Valence combination Carboxybenzeneboronic acid (CPBA) is made.
Preferably, the molecular weight of chitosan is 4-10 ten thousand.
Preferably, the Carboxybenzeneboronic acid is in 2- Carboxybenzeneboronic acid, 3- Carboxybenzeneboronic acid, 4- Carboxybenzeneboronic acid
It is one or more of.
Preferably, the mass ratio of the chitosan and Carboxybenzeneboronic acid is 1:10-10:1.
Further, the coupling agent is 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne two that mass ratio is 1:2-2:1
Inferior amine salt hydrochlorate and n-hydroxysuccinimide；The mass ratio of coupling agent and chitosan is 1:5-5:1.
Entogastric lingering of the present invention, positioning release medicine chitosan polymer pharmaceutic adjuvant preparation method, feature
It is, includes the following steps:
(1) solution A is obtained after taking chitosan (CS) that acid solution stirring and dissolving is added；
(2) it takes Carboxybenzeneboronic acid (CPBA), organic solvent is added and stirs to 1- is added under condition of ice bath after completely dissolution
Ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) (EDC) and n-hydroxysuccinimide (NHS) activation obtain
Solution B；Solution B is added in solution A, solution C is reacted at room temperature to obtain under stirring；
(3) by solution C rotary evaporation to without dialysing after obvious bubble, drying obtains chitosan Carboxybenzeneboronic acid (CS-
CPBA) polymer powder.
Preferably, deacetylation >=80% of the chitosan (CS).
Wherein, step (1) acid solution is one or more of acetic acid, hydrochloric acid, sulfuric acid, citric acid, phosphoric acid.
Wherein, step (2) organic solvent is selected from methanol, ethyl alcohol, chloroform, dimethylformamide, dimethyl sulfoxide, four
One or more of hydrogen furans, carbon tetrachloride, ether, acetone, methyl tertiary butyl ether(MTBE).
Entogastric lingering of the present invention, positioning release medicine chitosan polymer pharmaceutic adjuvant to prepare coccidiostat slow
Application in controlled release and targeting dosage form.
Further, the Entogastric lingering, the chitosan polymer pharmaceutic adjuvant of positioning release medicine are specific in poultry in preparation
Gastrointestinal tract pH, concentration of glucose and stick can be with the anticoccidial dosage form of responsiveness positioning and slow release under environment；Specifically in poultry
Accomplish drug release and in the intestine high pH on a small quantity under the conditions of low ph value, low glucose concentrations in the specific stomach such as chicken, duck, pig, cat or dog
The anticoccidial dosage form largely to release the drug is positioned under the conditions of value, high glucose concentration.
Chitosan polymer pharmaceutic adjuvant prepared by the present invention has in stomach and intestine under low ph value and low glucose concentrations
Stablize, the property decomposed under high ph-values and high glucose concentration in stomach and intestine can root after loading coccidiostat by dialysis
Accomplish to discharge a large amount of coccidiostats in the enteron aisle positioning of coccidia parasitism according to poultry gastrointestinal tract environment.
Further, the chitosan polymer pharmaceutic adjuvant carry be added after medicine pharmaceutic adjuvant can be made into solution,
The coccidiostat of granula, capsule or dry suspensoid agent dosage form.The present invention is by chitosan (CS) and Carboxybenzeneboronic acid (CPBA)
It is made by amide reaction synthesis；The chitosan polymer pharmaceutic adjuvant of the Entogastric lingering of preparation, positioning release medicine, utilization are amphipathic
Polymer is carrier, improves dissolubility, the slow release, glucose responding of slightly solubility coccidiostat, and the present invention successfully solves
Slightly solubility coccidiostat solubility is low, action time is short, positioning release medicine is difficult, bioavilability is small, toxic side effect is big etc. lacks
It falls into.
Novel auxiliary material prepared by the present invention has certain hemostasis and rush to the enteron aisle that poultry infects due to the presence of chitosan
Into the effect of wound healing, preparation can be improved in poultry Entogastric lingering, greatly strengthen the action time of coccidiostat,
Amino meeting deprotonation leads to the change of property in high ph-values environment, will lead to the destruction of its polymer stabilisation, it is easier to release
Put drug.Slightly solubility coccidiostat solubility not only can be improved in CPBA, moreover it is possible to contain neighbour two with glucose etc. after ionization
The substance of alcohol combined by reversible covalent bonds and forms more hydrophilic structure, imparts it with poultry gastrointestinal tract glucose sugar and pH
Responsiveness release function, the positioning for being able to achieve coccidiostat in coccidia enteral discharge.Pass through the characteristic using CPBA, synthesis tool
There is amphiphilic CS-CPBA polymer, the solubility for not only increasing slightly solubility coccidiostat is also able to achieve coccidiostat
It is discharged in the glucose and pH responsiveness of gastrointestinal tract site.
The chitosan polymer pharmaceutic adjuvant of Entogastric lingering, positioning release medicine that the present invention is prepared can be acid under one's belt
Under the conditions of keep certain stabilization, decomposed under high ph-values and high glucose concentration, and constituent of chitosan imparts it in auxiliary material
In the ability of Entogastric lingering.In addition, experiment shows chitosan polymer pharmaceutic adjuvant prepared by the present invention in the Portugal for being greater than 20mM
Volume can be gradually increased structure breaking in turn under conditions of grape sugar concentration and pH value are greater than 5.5, so as to cause the release of drug.This
The special responsiveness of kind, which realizes, carries medicine auxiliary material in time lag drug release (delay), 12 of poultry stomach (pH value 1.0-3.0) interior environment
Duodenum 12 largely releases the drug to the positioning in colon (pH value 5.0-8.0) range, achievees the purpose that intestinal-specific release treatment disease.
The utility model has the advantages that compared with prior art, the present invention has the advantage that
1. the chitosan polymer pharmaceutic adjuvant of a kind of Entogastric lingering that the present invention synthesizes, positioning release medicine, can be improved
The dissolubility of slightly solubility coccidiostat, slow release also have to enteron aisle positioning release medicine ability, the residual of drug have been alleviated or avoided
It stays and the generation of drug resistance.
2. preparation process of the present invention is simple, safely controllable, by using the lower organic reagent of toxicity, in conjunction with rotary evaporation
With dialysis technique, the residual of organic reagent in CS-CPBA auxiliary material is effectively reduced, improves the safety of preparation, meets doctor
Demand with auxiliary material to carrier material hypotoxicity can be used as the novel of slightly solubility coccidiostat Entogastric lingering and positioning release medicine
Delivery materials.
3. the chitosan polymer of Entogastric lingering prepared by the present invention, positioning release medicine is medicinal by being added after dialysis load medicine
Auxiliary material can be made into the coccidiostat of the dosage forms such as granule, tablet, suspension, dry suspensoid agent or solution, the coccidiostat
In the specific pH in digestive tract of poultry, concentration of glucose and sticks to position with responsiveness under environment and discharge, the anticoccidial drug agent
Type can not only in poultry chicken, duck, pig, cat or dog stomach low pH (pH < 3) and low glucose concentration (CGlucose sugar< 20mM) under the conditions of it is few
Amount drug release, moreover it is possible to which responsiveness positioning largely releases the drug at the high pH of enteron aisle (pH > 5.5) and concentration of glucose (C glucose sugar > 20mM)
Anticoccidial dosage form.
Detailed description of the invention
Fig. 1 be embodiment 4 nuclear magnetic resonance (1H NMR) map；
Fig. 2 is the transmission electron microscope photo of embodiment 8；
Fig. 3 is the particle size distribution figure of embodiment 8；
Fig. 4 is the In-vitro release curves schematic diagram under different pH value and concentration of glucose of embodiment 8.
Specific embodiment
The invention will be further described with attached drawing with reference to embodiments.
Embodiment 1
The preparation of CS-CPBA
It takes 40mg molecular weight 40000, the CS that deacetylation is 80%, 20mL is added and contains in the pure water of 40 μ L acetic acid, magnetic
Power stirring 10min makes it dissolve to obtain solution A.Take the 3-CPBA of 100mg, 20mL methanol be added and simultaneously stirs, after completely dissolution plus
Enter the NHS of the EDC and 20mg of 20mg, continues ice bath stirring 30min and obtain solution B.By solution B with the addition of 6 drops/minute speed
Into solution A, is reacted at room temperature after removal ice bath and obtain solution C for 24 hours.Solution C is transferred in Rotary Evaporators, 40 DEG C ,-
Product after rotary evaporation is put into the bag filter of 14000da thoroughly by 0.1MPa rotary evaporation about 10min to bubble is no longer generated
48h is analysed, changes a water every 4h.Then the product after dialysis is put into after 40 DEG C of baking ovens are sufficiently dried and obtains CS-CPBA powder.
Embodiment 2
The preparation of CS-CPBA
It takes 80mg molecular weight 40000, the CS that deacetylation is 80%, 20mL is added and contains in the pure water of 20 μ L acetic acid, magnetic
Power stirring 10min makes it dissolve to obtain solution A, takes the 3-CPBA of 100mg, and 20mL acetone is added and stirs, exists after completely dissolution
The NHS of the EDC and 20mg of 40mg are added under ice bath stirring, continues ice bath stirring 30min and obtains solution B.By solution B with 6 drop/point
The speed of clock is added in solution A, and removal ice bath reacts at room temperature obtains solution C for 24 hours.Solution C is moved on Rotary Evaporators,
50 DEG C, -0.1MPa rotary evaporation about 15min to no longer generation bubble.Product after rotary evaporation is put into the dialysis of 13000da
Dialyse 48h in bag, changes a water every 6h.Then the product after dialysis is put into after 50 DEG C of baking ovens are sufficiently dried and obtains CS-CPBA
Powder.
Embodiment 3
The preparation of CS-CPBA
It takes 50mg molecular weight 50000, the CS that deacetylation is 80%, 25mL is added and contains in the pure water of 40 μ L sulfuric acid, magnetic
Power stirring 15min makes it dissolve to obtain solution A, takes the 4-CPBA of 50mg, and 25mL methanol is added and stirs, after completely dissolution in ice
Bath is added with stirring the NHS of the EDC and 40mg of 40mg, continues ice bath stirring 30min and obtains solution B.By solution B with 6 drops/minute
Speed be added in solution A, removal ice bath react at room temperature for 24 hours solution C.Solution C is transferred in Rotary Evaporators,
50 DEG C, -0.1MPa rotary evaporation about 10min to no longer generation bubble.Product after rotary evaporation is put into the dialysis of 15000da
Dialyse 48h in bag, changes a water every 8h.Then the product after dialysis is freeze-dried to obtain CS-CPBA powder.
Embodiment 4
The preparation of CS-CPBA
It takes 50mg molecular weight 50000, the CS that deacetylation is 90%, 20mL is added and contains in the pure water of 40 μ L hydrochloric acid, magnetic
Power stirring 10min makes it dissolve to obtain solution A, takes the 3-CPBA of 100mg, and 25mL ethyl alcohol is added and simultaneously stirs, after completely dissolution plus
Enter the NHS of the EDC and 50mg of 70mg, continues ice bath stirring 30min and obtain solution B.By solution B with the addition of 7 drops/minute speed
Into solution A, is reacted at room temperature after removal ice bath and obtain solution C for 24 hours, solution C is transferred in Rotary Evaporators, 50 DEG C ,-
0.1MPa rotary evaporation about 10min to no longer generate bubble.Product after rotary evaporation is put into the bag filter of 15000da thoroughly
48h is analysed, a water is changed every 8h, the product spray drying after dialysis is then obtained into CS-CPBA powder.
Embodiment 5
It takes 6mg molecular weight 40000, the CS that deacetylation is 80%, 20mL is added and contains in the pure water of 40 μ L citric acids, magnetic
Power stirring 10min makes it dissolve to obtain solution A.The 3-CPBA of 60mg is taken, 20mL chloroform is added and is stirred, is added after completely dissolution
The NHS of the EDC and 10mg of 20mg continue ice bath stirring 30min and obtain solution B.Solution B is added to 6 drops/minute speed
In solution A, is reacted at room temperature after removal ice bath and obtain solution C for 24 hours.Solution C is transferred in Rotary Evaporators, 40 DEG C ,-
Product after rotary evaporation is put into the bag filter of 14000da thoroughly by 0.1MPa rotary evaporation about 10min to bubble is no longer generated
48h is analysed, changes a water every 4h.Then the product after dialysis is put into after 40 DEG C of baking ovens are sufficiently dried and obtains CS-CPBA powder.
Embodiment 6
It takes 60mg molecular weight 100000, the CS that deacetylation is 80%, 20mL is added and contains in the pure water of 40 μ L phosphoric acid, magnetic
Power stirring 10min makes it dissolve to obtain solution A.The 3-CPBA of 6mg is taken, 20mL dimethyl sulfoxide is added and is stirred, is sufficiently dissolved
The NHS of the EDC and 8mg of 4mg are added afterwards, continues ice bath stirring 30min and obtains solution B.Solution B is added with 6 drops/minute speed
Enter into solution A, is reacted at room temperature after removal ice bath and obtain solution C for 24 hours.Solution C is transferred in Rotary Evaporators, 40 DEG C ,-
Product after rotary evaporation is put into the bag filter of 14000da thoroughly by 0.1MPa rotary evaporation about 10min to bubble is no longer generated
48h is analysed, changes a water every 4h.Then the product after dialysis is put into after 40 DEG C of baking ovens are sufficiently dried and obtains CS-CPBA powder.
Embodiment 7
It takes 60mg molecular weight 40000, the CS that deacetylation is 80%, 20mL is added and contains in the pure water of 40 μ L acetic acid, magnetic
Power stirring 10min makes it dissolve to obtain solution A.The 3-CPBA of 120mg is taken, 20mL tetrahydrofuran is added and is stirred, is sufficiently dissolved
The NHS of the EDC and 40mg of 20mg are added afterwards, continues ice bath stirring 30min and obtains solution B.By solution B with 6 drops/minute speed
It is added in solution A, is reacted at room temperature after removal ice bath and obtain solution C for 24 hours.Solution C is transferred in Rotary Evaporators, 40
DEG C, -0.1MPa rotary evaporation about 10min to no longer generate bubble, the product after rotary evaporation is put into the bag filter of 14000da
Middle dialysis 48h changes a water every 4h.Then the product after dialysis is put into after 40 DEG C of baking ovens are sufficiently dried and obtains CS-CPBA powder
End.
Embodiment 8
The preparation of CS-CPBA load solution of diclazuril agent
Prescription:
Preparation:
20mg CS-CPBA powder prepared by Example 4 is added 3mL ultrapure water stirring 5min and makes it dissolve to obtain blank
Carrier solution.3mg diclazuril is taken to be dissolved in 300 μ L DMF, with 6 drops/minute under the magnetic agitation effect of 400r/min
Speed be added drop-wise in empty vectors solution, then under ice bath and high speed disperser 10000rpm under the conditions of shears 5min.It will
It shears obtained transferred product to dialyse into the bag filter of 12000da 12h, during which change water 3 times.The product obtained after dialysis is led to
It is molten to get diclazuril is carried to the chitosan polymer pharmaceutic adjuvant of Entogastric lingering, positioning release medicine to cross 0.8 μm of filtering with microporous membrane
Liquor.
Embodiment 9
The preparation of CS-CPBA load solution of diclazuril agent
Prescription:
Preparation:
50mg CS-CPBA powder prepared by Example 4 is added 4mL ultrapure water stirring 5min and makes it dissolve to obtain blank
Carrier solution.3mg diclazuril is taken to be dissolved in 700 μ L DMF.With 7 drops/minute under the magnetic agitation effect of 500r/min
Speed be added drop-wise in empty vectors solution, then under ice bath and 100w ultrasonic disperser act on 15min.After dispersion
Transferred product is dialysed 12h into the bag filter of 12000da, is during which changed water 3 times.The product obtained after dialysis is micro- by 0.8 μm
Hole membrane filtration carries solution of diclazuril agent to get to the chitosan polymer pharmaceutic adjuvant of Entogastric lingering, positioning release medicine.
Embodiment 10
The preparation of CS-CPBA load Maduramicin ammonium solution
Prescription:
Preparation:
20mg CS-CPBA powder prepared by Example 4 is added stirring 15min in 4mL ultrapure water and makes it dissolve to obtain sky
White carrier solution takes 5mg Maduramicin ammonium to be dissolved in 500 μ L ethyl alcohol, with 5 under the magnetic agitation effect of 500r/min
The speed of second/drop is added drop-wise in empty vectors solution, then the ice-bath ultrasonic 15min in the ultrasonic disperser of 100w.It will divide
Transferred product after dissipating is dialysed 12h into the bag filter of 14000da, is during which changed water 4 times.The product obtained after dialysis is passed through
0.8 μm of filtering with microporous membrane carries Maduramicin ammonium solution to get to intestinal-specific chitosan polymer pharmaceutic adjuvant.
Embodiment 11
The preparation of CS-CPBA load toltrazuril solution agent
Prescription:
Preparation:
30mg CS-CPBA powder prepared by Example 4 is added 4mL ultrapure water stirring 5min and makes it dissolve to obtain blank
Carrier solution takes 3mg toltrazuril pearl benefit to be dissolved in 500 μ L DMF.500r/min magnetic agitation effect under with 10 drop/
The speed of minute is added drop-wise in empty vectors solution, then high under conditions of 12000r/min, ice bath using high speed disperser
During which speed shearing 5min changes the 12h that dialyses in the bag filter of the transferred product after shearing to 14000da water 4 times.After dialysing
Obtained product carries toltrazuril by 0.8 μm of filtering with microporous membrane to get to intestinal-specific chitosan polymer pharmaceutic adjuvant
Solution.
Embodiment 12
The nuclear magnetic resonance of CS-CPBA characterizes
CS-CPBA prepared by Example 4 is dissolved in the D2O of 0.5ml, is made into certain density solution, is placed in nuclear-magnetism
Guan Zhong carries out table to the structure of compound CS and CS-CPBA respectively with 1H-NMR (AMX 600MHz, BRUKER) Nuclear Magnetic Resonance
Sign.As a result as shown in Figure 1, the 1 of synthetic product CS-CPBA1H NMR spectra existsThe absorption having at place
Peak is the characteristic absorption peak of hydrogen on phenyl ring in CPBA molecular structure, phenyl ring characteristic peak occurs in CS-CPBA group and then shows
CPBA functional group has successfully synthesized CS-CPBA polymer.
Embodiment 13
Morphology is investigated
Experimental method: using H-7000 electron microscope (Hitachi, Tokyo, Japan) under the acceleration voltage of 100kV
Solution of diclazuril agent is carried to 8 gained CS-CPBA of embodiment and carries out morphology investigation.The negative staining of sample carries out as follows: by one
Drop sample solution is placed on the copper grid for being coated with carbon, then applies 1% phosphotungstic acid so that nanoparticle deposition is on grid.Sample
It is dry under infrared lamp.By focusing make that clearly image is presented on screen.
Experimental result is as shown in Fig. 2, made CS-CPBA load solution of diclazuril agent monnolithic case rounding is spherical in shape.
Embodiment 14
Size distribution is investigated
Experimental method: solution of diclazuril agent grain is carried to 8 gained CS-CPBA of embodiment with Brookhaven nanometer particle size instrument
Diameter measurement, is measured in parallel three times, carries software processing experimental result with system.Experimental result CS-CPBA as shown in Figure 3 carries ground gram
The average grain diameter of pearl benefit solution is in 120nm or so.
Embodiment 15
Enteron aisle positions release experiment and investigates
Experimental method: 8 gained CS-CPBA of embodiment load solution of diclazuril agent is sealed in bag filter (MWCO:12000-
14000) it in, is placed in PBS (Tween-80 containing 0.5%) dissolution medium of the 0.01M pH 2.0,5.5,6.8 of 100ml, point
Not She Zhi pH 2.0,5.5 20mM glucose of pH 5.5, pH, 5.5 50mM glucose of pH, 6.8 Portugal 20mM pH 6.8, pH
Grape sugar, 6.8 50mM glucose of pH amount to 7 control groups, Yu Hengwen (37 ± 0.5) DEG C, under revolving speed 100r/min, 0.5h,
1h, 2h, 3h, 6h, 12h, for 24 hours, 36h, 48h, 72h respectively sample 1ml, while the fresh medium of supplement equivalent equality of temperature rapidly, with height
Effect liquid phase chromatogram instrument measures the content of drug, draws drug release patterns.
As a result as shown in figure 4, it can be observed that the release behavior of CS-CPBA micella is typical two-phase release profiles, packet
Quick release and slow release phase are included.It is quick release phase first, drug largely discharges in a short time, and drug concentration is rapid
Increase, facilitate after vivo medicine-feeding to reach the treatment concentration for inhibiting coccidia and play therapeutic effect, and subsequent slowly persistently releases
A long-acting anticoccidial effect will be provided by putting.In addition, drug tires out it can be seen from Fig. 4-A in the presence of no glucose
Product burst size increases with the increase of dissolution medium pH value.When pH is 2 (chicken stomach pH value), the cumulative release amount of drug reaches
In the cumulative release of pH 5.5 (46.6%) and pH 6.8 (55.7%) after 44.2%, substantially less than 72h.This may be because low
Under the conditions of pH, since the protonation of amino of chitosan stablizes micellar structure, after pH value raising, change after amino deprotonation
Ionic interaction between polymer chain, which results in DIC/CS-CPBA in high pH, and stability is destroyed, it is easier to be discharged
Drug.The release profiles result of the pH responsiveness of DIC/CS-CPBA confirms that drug is easier to discharge in chicken caecum pH 6.8, because
This can play certain pH targeted therapy effect.In order to further confirm that the release of drug in DIC/CS-CPBA has glucose
Responsiveness, different glucose dissolution medium (as shown in Fig. 4-B and Fig. 4-C) simulate the height in enteron aisle under fed conditions
Blood sugar concentration.Wherein, whether 20mM or under the concentration of glucose of 50mM, the cumulative release of DIC all dramatically increases, and
Reach maximum value (85.0%) when concentration of glucose is 50mM and pH 6.8.This release characteristics are because of Carboxybenzeneboronic acid
PKa value is about 8.6, therefore the about high borate that is more conducive to of the pH in solution ionizes, and the phenyl boric acid after ionization has can be with 1,2-
Glycol combines and forms the ability of stable soluble phenylboronate.About 7.9/10000ths borate as pH=5.5
It is ionized, about 1.6% phenyl boric acid is ionized in the environment of pH 6.8, so drug release of the Glu concentration to micella
Influence it is obvious, dissociate after borate in conjunction with glucose, cause polymeric inner hydrophobicity to be destroyed, drug therewith by
It releases.The mediation of phenyl boric acid polymer release characteristic by Glu concentration and pH value double influence, due to animal intestinal tract
High pH and Glu concentration can make carrier micelle be oriented to enteron aisle release, can more efficiently treat enteron aisle globidiosis.
Embodiment 16
The preparation of CS-CPBA load medicine dry suspensoid agent
Prescription:
Preparation:
The CS-CPBA powder for taking 18mg embodiment 1 to prepare is added 2mL ultrapure water stirring 5min and makes it dissolve to obtain blank load
Liquid solution takes 3mg diclazuril to be dissolved in 300 μ L DMF.With 6 drops/minute under the magnetic agitation effect of 400r/min
Speed is added drop-wise in empty vectors solution, then shears 5min under ice bath and under the conditions of high speed disperser 10000r/min.It will
Transferred product after shearing is dialysed 12h into the bag filter of 12000da, is during which changed water 3 times.Micella after dialysis is passed through into 0.8 μ
Freeze-drying obtains CS-CPBA powder after m filtering with microporous membrane, by obtained powder and hydroxypropyl methylcellulose and carboxymethyl cellulose
Plain sodium crushes sieve with 100 mesh sieve respectively, is uniformly mixed the mannitol of product and recipe quantity after sieving with equivalent gradually-increased, then plus
The talcum powder, magnesium stearate, corrigent for entering recipe quantity are sufficiently mixed uniformly, and packing obtains 1000 bags.
Embodiment 17
The preparation of CS-CPBA drug loaded emulsion
Prescription:
Preparation:
The CS-CPBA powder for taking 20mg embodiment 1 to prepare is added 3mL ultrapure water stirring 5min and makes it dissolve to obtain blank load
Liquid solution takes 3mg diclazuril to be dissolved in 300 μ L DMF.With 6 drops/minute under the magnetic agitation effect of 400r/min
Speed is added drop-wise in empty vectors solution, then shears 5min under ice bath and under the conditions of high speed disperser 10000r.It will shearing
Transferred product afterwards is dialysed 12h into the bag filter of 12000da, is during which changed water 3 times.Micella after dialysis is micro- by 0.8 μm
Drying to obtain CS-CPBA carries diclazuril powder after the membrane filtration of hole.CS-CPBA load diclazuril powder is dissolved in MCT,
It is slowly added into the pure water for being dissolved in Tween 80 under the effect of 15000rpm high speed shear, obtained colostrum is in 800bar pressure
Under the conditions of recycled homogeneous 5 times by high pressure homogenizer or Microfluidizer, 0.8 μm of membrane filtration is filling up to emulsion.
Embodiment 18
The preparation of CS-CPBA load medicine soft capsule
Prescription:
Preparation:
The CS-CPBA powder for taking 20mg embodiment 3 to prepare is added 2mL ultrapure water stirring 5min and makes it dissolve to obtain blank load
Liquid solution takes 3mg diclazuril to be dissolved in 300 μ L DMF.With 6 drops/minute under the magnetic agitation effect of 400r/min
Speed is added drop-wise in empty vectors solution, then shears 5min under ice bath and under the conditions of high speed disperser 10000r.It will shearing
Transferred product afterwards is dialysed 12h into the bag filter of 12000da, is during which changed water 3 times.Micella after dialysis is micro- by 0.8 μm
It is dried after the membrane filtration of hole and carries diclazuril powder to get to SA-CS-CPBA.By powder and gelatin, glycerol, sorbierite and pure
Water prepare gelatin solution, set sprawl it is spare in case.It is made under conditions of 25 ± 2 DEG C of room temperature, relative humidity 40% of dropping preparation method
Soft capsule, cold air drying is for 24 hours under conditions of 25 ± 2 DEG C, relative humidity 40% to obtain the final product.
Embodiment 19
The preparation of CS-CPBA load tablet
Prescription:
Preparation:
The CS-CPBA powder for taking 20mg embodiment 2 to prepare is added 2mL ultrapure water stirring 5min and makes it dissolve to obtain blank load
Liquid solution takes 3mg diclazuril to be dissolved in 300 μ L DMF.With 6 drops/minute under the magnetic agitation effect of 400r/min
Speed is added drop-wise in empty vectors solution, then shears 5min under ice bath and under the conditions of high speed disperser 10000r.It will shearing
Transferred product afterwards is dialysed 12h into the bag filter of 12000da, is during which changed water 3 times.Micella after dialysis is micro- by 0.8 μm
It is dried after the membrane filtration of hole and carries diclazuril powder to get to CS-CPBA.The crystallite that obtained powder is added to recipe quantity is fine
It with 95% ethyl alcohol is wetting agent wet granulation after mixing in dimension element, lactose and sodium carboxymethyl starch, addition recipe quantity after drying
Magnesium stearate, tabletting obtain 1000.
Embodiment 20
The preparation of CS-CPBA load medicine granule
Prescription:
Preparation:
The CS-CPBA powder for taking 20mg embodiment 4 to prepare is added 2mL ultrapure water stirring 5min and makes it dissolve to obtain blank load
Liquid solution takes 3mg diclazuril to be dissolved in 300 μ L DMF.With 6 drops/minute under the magnetic agitation effect of 400r/min
Speed is added drop-wise in empty vectors solution, then shears 5min under ice bath and under the conditions of high speed disperser 10000r.It will shearing
Transferred product afterwards is dialysed 12h into the bag filter of 12000da, is during which changed water 3 times.Micella after dialysis is micro- by 0.8 μm
It is dried after the membrane filtration of hole and carries diclazuril powder to get to CS-CPBA.The crystallite that obtained powder is added to recipe quantity is fine
It ties up element, sucrose, in essence and crosslinked carboxymethyl fecula sodium, with 30% ethyl alcohol is wetting agent wet granulation after mixing, 40 mesh of mistake
Sieve, dispenses after drying, obtains 1000 bags.
Claims (10)
1. the chitosan polymer pharmaceutic adjuvant of a kind of Entogastric lingering, positioning release medicine, which is characterized in that be mainly parent by chitosan
Aqueous framework material reacts covalent bond Carboxybenzeneboronic acid by amide under the action of coupling agent and is made.
2. the chitosan polymer pharmaceutic adjuvant of Entogastric lingering according to claim 1, positioning release medicine, which is characterized in that
The molecular weight of chitosan is in 4-10 ten thousand.
3. the chitosan polymer pharmaceutic adjuvant of Entogastric lingering according to claim 1, positioning release medicine, which is characterized in that
The Carboxybenzeneboronic acid is selected from one or more of 2- Carboxybenzeneboronic acid, 3- Carboxybenzeneboronic acid, 4- Carboxybenzeneboronic acid.
4. the chitosan polymer pharmaceutic adjuvant of Entogastric lingering according to claim 1, positioning release medicine, which is characterized in that
The reaction mass of the chitosan and Carboxybenzeneboronic acid is than being preferably 1:10-10:1.
5. the chitosan polymer pharmaceutic adjuvant of Entogastric lingering according to claim 1, positioning release medicine, which is characterized in that
The coupling agent is 1- ethyl-(3- dimethylaminopropyl) the phosphinylidyne diimmonium salt hydrochlorate and N- hydroxyl that mass ratio is 1:2-2:1
Base succinimide；The mass ratio of coupling agent and chitosan is 1:5-5:1.
6. a kind of preparation method of the chitosan polymer pharmaceutic adjuvant of Entogastric lingering described in claim 1, positioning release medicine,
It is characterized in that, includes the following steps:
(1) solution A is obtained after taking chitosan that acid solution stirring and dissolving is added；
(2) Carboxybenzeneboronic acid is taken, organic solvent is added and stirs to the addition 1- ethyl-(3- bis- under condition of ice bath after completely dissolution
Dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) and n-hydroxysuccinimide activate to obtain solution B；Solution B is added to molten
In liquid A, solution C is reacted at room temperature to obtain under stirring；
(3) by solution C rotary evaporation to without dialysing after obvious bubble, drying obtains chitosan Carboxybenzeneboronic acid polymer powder.
7. preparation method according to claim 6, which is characterized in that step (1) acid solution be acetic acid, hydrochloric acid,
One or more of sulfuric acid, citric acid, phosphoric acid.
8. preparation method according to claim 6, which is characterized in that step (2) organic solvent is selected from methanol, second
Alcohol, chloroform, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, carbon tetrachloride, ether, acetone, in methyl tertiary butyl ether(MTBE)
It is one or more of.
9. the chitosan polymer pharmaceutic adjuvant of a kind of Entogastric lingering described in claim 1, positioning release medicine is preparing anti-ball
Application in worm medicine sustained and controlled release and targeting dosage form.
10. application according to claim 9, which is characterized in that the chitosan polymer of the Entogastric lingering, positioning release medicine
Pharmaceutic adjuvant is being prepared in the specific gastrointestinal tract pH of poultry, concentration of glucose and stick can be with responsiveness positioning and slow release under environment
Anticoccidial dosage form.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112206325A (en) * | 2020-09-21 | 2021-01-12 | 温州医科大学附属眼视光医院 | Long-ocular-surface retention artificial tear and preparation method thereof |
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| CN107674210A (en) * | 2017-09-21 | 2018-02-09 | 浙江大学 | Triphenylphosphine chitosan stearic acid grafting carrier micelle and preparation and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107674210A (en) * | 2017-09-21 | 2018-02-09 | 浙江大学 | Triphenylphosphine chitosan stearic acid grafting carrier micelle and preparation and application |
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| ZHANG XIN ET AL: "Dual-sensitive chitosan derivative micelles for site-specific drug release in the treatment of chicken coccidiosis", 《RSC ADVANCES》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112206325A (en) * | 2020-09-21 | 2021-01-12 | 温州医科大学附属眼视光医院 | Long-ocular-surface retention artificial tear and preparation method thereof |
| CN112206325B (en) * | 2020-09-21 | 2022-11-18 | 温州医科大学附属眼视光医院 | Long ocular surface retention artificial tear and preparation method thereof |
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Application publication date: 20190604 |