CN106267164B - Monodisperse insulin/chitosan gel rubber microballoon of size tunable and preparation method thereof - Google Patents
Monodisperse insulin/chitosan gel rubber microballoon of size tunable and preparation method thereof Download PDFInfo
- Publication number
- CN106267164B CN106267164B CN201610818252.4A CN201610818252A CN106267164B CN 106267164 B CN106267164 B CN 106267164B CN 201610818252 A CN201610818252 A CN 201610818252A CN 106267164 B CN106267164 B CN 106267164B
- Authority
- CN
- China
- Prior art keywords
- insulin
- preparation
- chitosan
- alcohol
- monodisperse
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses the monodisperse of a kind of size tunable insulin/chitosan gel rubber microballoons and preparation method thereof, its step are as follows: preparing dispersed phase solution and continuous phase solution, control the flow velocity and viscosity of dispersed phase solution and continuous phase solution, after converging dispersed phase solution and continuous phase solution in micro fluidic device, dispersed phase solution disperses in continuous phase solution, monodisperse insulin/chitosan emulsion droplet of size tunable is obtained, it is cured to obtain monodisperse insulin/chitosan gel rubber microballoon.Monodisperse insulin/chitosan gel rubber microsphere surface form prepared by the present invention is preferable, uniform particle sizes, 50~600 μm of particle size range, particle diameter distribution coefficient is less than 6%, carrying drug ratio 5%~30%, embedding rate 75%~85%, and there is insulin slow release performance, in the buffer solution that pH is 6.5~7.6 at 37 DEG C 14h cumulative release rate less than 60%.
Description
Technical field
The present invention relates to the preparation methods of mono-dispersion microballoon, and specifically monodisperse insulin/shell of size tunable is poly-
Sugared gel micro-ball and preparation method thereof.
Background technique
The choice drug insulin of insulin-dependent diabetes mellitus is treated, is clinically mainly administered in the form of injection, it is most
Patient needs frequent insulin injection (usually daily 1~4 time) all the life, with a variety of adverse reactions: such as hypoglycemic reaction, pancreas
Island element edema, lipoatrophy, hypertrophy lipodystrophia, injection site inflammation, scleroma and drug resistance etc., to patient with
Come inconvenience and great pain.
The report such as Mickel C, insulin active molecule can penetrate intestinal wall absorbed into serum, the absorptivity highest of small intestine, colon
Also there is higher absorptivity with rectum.Bendayan M confirms that insulin molecule is to be transported into intestines by intestinal epithelial cell
Interior environment, then infiltrate through capillary endothelial cell plasma membrane and enter blood circulation and play a role.
Carried medicine sustained-release microsphere is a kind of widely used novel medicine feeding system, is to carry with suitable high molecular material
Body, by drug dispersion or is formationed ball type carrier drug delivery system embedded therein, partial size be one arrive several hundred microns, can by take orally,
The modes such as injection, sucking enter internal.After carried medicine sustained-release microsphere, internal active drug can be maintained in a long time dense
Degree improves drug effect and reduces the adverse reaction of drug, validity, safety, the biddability of medication can be improved, has important
Clinical value.
Chitosan is the auxiliary material of a kind of good biocompatibility, low toxicity, is widely used in the various dosage forms of drug.Valerie
The researchs such as D have shown that chitosan can open the close connection between gastrointestinal epithelial cells, so that protein and peptide drugs be promoted to exist
Gastral absorption.Sustained-release micro-spheres are made in insulin and carry out enteric coating or loading capsulae enterosolubilis oral administration, can be overcome
Insulin is difficult to overcome acid catalyzed decomposition, proteasome degradation and mucous membrane penetrability poor as absorption of the protein in gastrointestinal tract
Equal barriers, the disadvantages of bioavilability is low, while patient can be overcome to need frequent insulin injection bring all the life not again
Just and generate a variety of adverse reactions.
Traditional microsphere preparation technology, which is typically necessary, first passes through mechanical stirring or emulsion droplet that sonic oscillation is dispersed.
The mechanical external force introduced in this way be it is unstable, non-uniform (such as apart from mixing center or ultrasonic occurring source distance different parts by
Power is different), so as to cause obtained drop size, emulsion droplet inner material content and uneven concentration, the drug finally prepared is carried
Body size is inhomogenous, and structural difference is big, bad dispersibility.And the Particle dispersity and structure of pharmaceutical carrier are to determine vitro Drug
The most important factor of release behavior.Inhomogenous will lead to of the size of pharmaceutical carrier can not accurately investigate drug bearing microsphere amount and loading medicine
The relationship of object amount, diameter of carrier and drug release, and targeting is poor, it is difficult to it is used safely in the treatment of clinical disease.
Since mechanical stirring or concussion have very strong severity, often also results in the emulsion droplet collision of generation, is crushed, make it
In drug diffusion go out to cause damages, thus prepare carrier drug loading efficiency it is low, also will cause biologically active drug mistake
It is living.And traditional stirring prepares emulsion droplet process and takes a long time, and emulsion droplet can not promptly be treated as cured carrier, meeting in time
So that the drug in emulsion droplet is settled or is accumulated to emulsion droplet surface, causes carrier low to the encapsulation rate of drug, in subsequent drug release
In show as that phenomenon of burst release is obvious and drug release is too fast, or even the requirement of medicament slow release needed for clinical treatment is not achieved.Separately
Outside, traditional preparation process usually uses emulsifier, can also introduce more external uncontrollable factor, so that the drug of preparation carries
Weight is irregular, preparation method poor reproducibility.
Microfluidic droplet technology is manipulation very low volume fluids-drop on micro fluidic device, and droplet size is small, is easy to
Manipulation, accurately controls flow rate of liquid, it is ensured that the droplet size of preparation is uniform, composition is uniform, property is stablized.In micro-fluidic
The mild producing method of drop, the collision being reduced or avoided between drop is broken, and each drop is by incompatible another phase
It surrounds, drop does not contact each other, avoids the cross-infection of sample room.And in the stream of micro fluidic device up-regulation flow control body
Speed can regulate and control to generate the size of drop.Therefore it can regulate and control the list of size needed for preparing, uniform particle diameter using micro fluidic device
Dispersant liquid drop, resolidification at target sizes, uniform particle diameter monodispersed microballoon.
Summary of the invention
To solve the above-mentioned problems, it is poly- that the purpose of the present invention is to provide a kind of monodisperse of size tunable insulin/shells
The preparation method of sugared gel micro-ball.
Another object of the present invention is to provide a kind of monodisperse of size tunable insulin/chitosan gel rubber microballoons.
In order to achieve the object of the present invention, it is solidifying that the present invention provides a kind of monodisperse of size tunable insulin/chitosans
The preparation method of glue microballoon, its step are as follows: coagulation bath solution, dispersed phase solution and continuous phase solution is prepared, in micro-fluidic dress
The flow velocity and viscosity for setting middle control dispersed phase solution and continuous phase solution obtain after dispersed phase solution converges with continuous phase solution
Size uniformity insulin/chitosan solution drop, the drop pass through solidify acquisition size tunable monodisperse insulin/
Chitosan gel rubber microballoon.
More specifically, method includes the following steps:
(1) preparation of coagulation bath solution: amine or amino alcohol are added in alcohol are uniformly mixed in proportion, be configured to amine or amino
The coagulation bath solution that alcohol percent by volume is 20%~55%；
(2) preparation of dispersed phase solution and continuous phase solution: it is 0.5%~2% that chitosan, which is added containing weight percent,
Aqueous acetic acid in, add the insulin solutions that the weight percent that pH is 1.5~3.0 is 10%~30%, mixing is equal
It is even, as dispersed phase solution；Low polar compound is mixed with alcohol, prepare low polar compound and alcohol volume ratio be 100:(0~
250) continuous phase solution；
(3) adjust the flow velocity and viscosity of dispersed phase and continuous phase: adjustment dispersed phase flow velocity is 4~30 μ Lmin-1, continuously
Phase flow velocity is 50~300 μ Lmin-1, dispersed phase viscosity is 1~500mPas, and continuous phase viscosity is 50~2500mPas；
(4) insulin/chitosan drop formation: dispersed phase solution obtained by step (2) and continuous phase solution are micro-fluidic
After converging in device, monodisperse insulin/chitosan solution drop of size tunable can get；
(5) drop is solidified into microballoon: collection step (4) resulting drop is in the coagulation bath solution that step (1) prepares, liquid
Curable or semi-solid preparation is dripped, aldehydes is added, monodisperse insulin/shell that size tunable is further solidified into 25~60 DEG C is poly-
Sugared gel micro-ball.
Wherein, alcohol described in step (1) is isoamyl alcohol, isooctanol or hexanol；Amine is triethylamine or trioctylamine；Amino alcohol is
Triethanolamine or diethanol amine.
Low polar compound described in step (2) is silicone oil, soybean oil or salad oil；The alcohol is isoamyl alcohol, different
One or both of octanol or hexanol.
Aldehydes described in step (5) is low toxicity or nontoxic glutaraldehyde or vanillic aldehyde, preferably nontoxic vanillic aldehyde, because making
The vanillic aldehyde that the insulin made from vanillic aldehyde/chitosan gel rubber microballoon is degraded out be it is nontoxic, it is harmless.
The preparation method further includes the post-processing of step (6) insulin/aquagel microballoon: by step (5) institute
Insulin/chitosan gel rubber the microballoon obtained is after filtering or decantation, remaining organic solution organic solvent washing, filters off molten
Agent is dried in vacuo 6~9h to get monodispersity insulin/chitosan gel rubber microballoon；The organic solvent is hydrocarbon, halogenated hydrocarbons, alcohol
And the one or more of ketone；The hydrocarbon is pentane, hexane, petroleum ether；Halogenated hydrocarbons is methylene chloride, chloroform, four chlorinations
Carbon；Alcohol is methanol, ethyl alcohol, isopropanol；Ketone is acetone or butanone.
Invention further provides monodisperse insulin/chitosan gel rubbers of the size tunable of above-mentioned preparation method preparation
Microballoon, the particle size range of the monodisperse insulin/chitosan gel rubber microballoon are 50~600 μm, and coefficient of dispersion CV is less than 6%；
Carrying drug ratio 5%~30%, embedding rate 75%~85%, and there is insulin slow release performance, the buffering for being 6.5~7.6 in pH is molten
In liquid at 37 DEG C 14h cumulative release rate less than 60%.
The present invention using Microfluidic droplet technology preparation monodisperse insulin/chitosan gel rubber microsphere surface form compared with
Good, particle size range is 50~600 μm, and the vanillic aldehyde degraded out especially with microballoon made from vanillic aldehyde is harmless；It is logical
Cross adjustment capillary diameter and dispersed phase solution and continuous phase solution flow velocity and viscosity, can be convenient to prepared pancreas islet
Element/chitosan gel rubber microballoon size is regulated and controled.
Detailed description of the invention
Fig. 1 is monodisperse insulin/chitosan microball elution profiles figure prepared by embodiment 1.
Fig. 2 is monodisperse insulin/chitosan microball elution profiles figure prepared by embodiment 2.
Fig. 3 is monodisperse insulin/chitosan microball elution profiles figure prepared by embodiment 3.
Fig. 4 is monodisperse insulin/chitosan microball elution profiles figure prepared by embodiment 4.
Fig. 5 is the schematic diagram for the micro fluidic device that the present invention uses.
Fig. 6 is the portion the A enlarged drawing of Fig. 5.
The label of each component is as follows in figure: 1-1, dispersed phase syringe pump；1-2, continuous phase syringe pump；2-1, dispersed phase injection
Device；2-2, continuous phase syringe；3, capillary.
Specific embodiment
Related content that present invention will be further explained below with reference to specific examples.It should be pointed out that these embodiments are only
For illustrating the present invention rather than limiting the scope of the invention, moreover, after reading the contents of the present invention, this field phase
Various changes or modification can be made to the present invention by closing technical staff, and such equivalent forms equally fall into right appended by the application and want
Seek book limited range.
Embodiment 1
Monodisperse insulin/chitosan gel rubber microballoon preparation method of size tunable, specifically:
5mL triethanolamine is added in 16mL isooctanol, magnetic agitation mixes, and is configured to coagulation bath solution.
Chitosan is added in the aqueous acetic acid for being 1% containing weight percent, the shell that weight percent is 2.5% is made into
Glycan solution；It is molten by weight being that the 20% insulin hydrochloric acid of weight percent that pH is 2.0 is added into chitosan solution by 5:1 again
Liquid is uniformly mixed, as dispersed phase solution；By isooctanol, 1:1 is uniformly mixed by volume with silicone oil, obtains continuous phase solution.
Above-mentioned dispersed phase solution and continuous phase solution are respectively charged into syringe 2-1,2-2 of 10mL and 60mL, are placed in
It on two syringe pumps 1-1,1-2, is connected in Fig. 5 and micro fluidic device shown in fig. 6, setting dispersed phase flow velocity is 10 μ L
min-1, viscosity 200mPas, continuous phase flow velocity is 100 μ Lmin-1, viscosity 560mPas, capillary 3 in micro fluidic device
Outer diameter/internal diameter be 165/98 μm, open micro fluidic device, prepare monodisperse insulin/chitosan solution liquid of size tunable
Drop；Insulin/chitosan solution the drop generated is collected in the culture dish equipped with above-mentioned coagulation bath solution, slowly stirs room temperature
After lower formation gel, be added 0.2mL glutaraldehyde (25%) curing reaction 3.0h at 37 DEG C, drop can be solidified into insulin/
Chitosan gel rubber microballoon.After simply decanting, remaining organic solution petroleum ether, chloroform are respectively washed 2 times, then use ethyl alcohol
After washing 2 times, ethyl alcohol is filtered off, is dried in vacuo to get monodisperse insulin/chitosan gel rubber microballoon.
Insulin manufactured in the present embodiment/chitosan gel rubber microballoon is in nearly spheroidal, and there is slight gauffer on surface, and partial size is equal
One, there is monodispersity, partial size is 85 μm, carrying drug ratio 11%, embedding rate 76%, and microballoon is slow in the mixed phosphate that pH is 6.86
Rush in solution that sustained release performance is shown in Fig. 1 at 37 DEG C.As seen from Figure 1, microballoon burst release degree is small, has slow release characteristic, 14h is tired at 37 DEG C
Product medicine realeasing rate is less than 50%.
Embodiment 2
18mL triethylamine is added in 20mL isooctanol, magnetic agitation mixes, and is configured to coagulation bath solution.
Chitosan is added in the aqueous acetic acid for being 1% containing weight percent, the shell that weight percent is 2.5% is made into
Glycan solution；It is molten by weight being that the 20% insulin hydrochloric acid of weight percent that pH is 2.0 is added into chitosan solution by 5:1 again
Liquid is uniformly mixed, as dispersed phase solution；By isooctanol, 1:1 is uniformly mixed by volume with silicone oil, obtains continuous phase solution.
Above-mentioned dispersed phase solution and continuous phase solution are respectively charged into syringe 2-1,2-2 of 10mL and 60mL, are placed in
It on two syringe pumps 1-1,1-2, is connected in Fig. 5 and micro fluidic device shown in fig. 6, setting dispersed phase solution flow velocity is 5 μ
L·min-1, viscosity 200mPas, continuous phase solution flow velocity is 70 μ Lmin-1, viscosity 560mPas, in micro fluidic device
Outer diameter/internal diameter of capillary 3 is 165/98 μm, opens micro fluidic device, prepares monodisperse insulin/chitosan solution drop；
The drop generated is collected in the culture dish equipped with above-mentioned coagulation bath solution, slowly stirs after forming gel at room temperature, is added
0.01g vanillic aldehyde curing reaction 1.5h at 60 DEG C, drop can be solidified into insulin/chitosan gel rubber microballoon.By simple
Decantation after, remaining organic solution petroleum ether, chloroform respectively wash 2 times, then with after ethanol washing 2 times, filter off ethyl alcohol, vacuum
Drying is to get monodisperse insulin/chitosan gel rubber microballoon.
Monodisperse insulin/chitosan gel rubber sustained-release micro-spheres manufactured in the present embodiment are in nearly spheroidal, and there is certain journey on surface
Gauffer is spent, uniform particle diameter has monodispersity, and partial size is 55 μm, carrying drug ratio 10%, embedding rate 75%, and microballoon is 7.2 in pH
Sustained release performance is shown in Fig. 2 at 37 DEG C in mixed phosphate salt buffer solution.From Figure 2 it can be seen that microballoon phenomenon of burst release is unobvious, there is sustained release
Characteristic, 14h cumulative release rate is less than 60% at 37 DEG C.
Embodiment 3
15mL triethylamine is added in 20mL isooctanol, magnetic agitation mixes, and is configured to coagulation bath solution.
Chitosan is added in the aqueous acetic acid for being 1% containing weight percent, the shell that weight percent is 2.5% is made into
Glycan solution；It is molten by weight the 30% insulin hydrochloric acid of weight percent that pH=2.0 is added into chitosan solution for 5:1 again
Liquid is uniformly mixed, as dispersed phase solution；By isooctanol, 2:1 is uniformly mixed by volume with silicone oil, obtains continuous phase solution.
Above-mentioned dispersed phase solution and continuous phase solution are respectively charged into syringe 2-1,2-2 of 10mL and 60mL, are placed in
It on two syringe pumps 1-1,1-2, is connected in Fig. 5 and micro fluidic device shown in fig. 6, setting dispersed phase flow velocity is 12 μ L
min-1, viscosity 270mPas, continuous phase flow velocity is 100 μ Lmin-1, viscosity 420mPas, capillary 3 in micro fluidic device
Outer diameter/internal diameter be 360/225 μm, open micro fluidic device, prepare monodisperse insulin/chitosan solution drop；Collect life
At drop in equipped with above-mentioned coagulation bath solution culture dish in, slowly stir at room temperature formed gel after, be added 0.01g vanilla
Aldehyde curing reaction 2.0h at 50 DEG C, drop can be solidified into insulin/aquagel microballon.By simply decanting
Afterwards, remaining organic solution petroleum ether, chloroform respectively wash 2 times, then with after ethanol washing 2 times, filtering off ethyl alcohol, vacuum drying,
Up to monodisperse insulin/chitosan gel rubber sustained-release micro-spheres.
Monodisperse insulin/chitosan gel rubber sustained-release micro-spheres manufactured in the present embodiment are in elliposoidal, and partial size is 250 μm, table
There is gauffer to a certain degree in face, and uniform particle diameter has monodispersity.Microballoon carrying drug ratio 16%, embedding rate 82%, microballoon are in pH
Sustained release performance is shown in Fig. 3 at 37 DEG C in 6.5 mixed phosphate salt buffer solution.As seen from Figure 3, microballoon is released lesser extent, has
Slow release characteristic, 14h cumulative release rate is less than 50% at 37 DEG C.
Embodiment 4
15mL triethylamine, 20mL dehydrated alcohol are added in 20mL isooctanol, magnetic agitation mixes, and is configured to coagulation bath
Solution.
Chitosan is added in the aqueous acetic acid for being 1% containing weight percent, the shell that weight percent is 2.5% is made into
Glycan solution；It is molten by weight the 20% insulin hydrochloric acid of weight percent that pH=2.0 is added into chitosan solution for 5:1 again
Liquid is uniformly mixed, as dispersed phase solution；By isooctanol, 1:1 is uniformly mixed by volume with silicone oil, obtains continuous phase solution.
Above-mentioned dispersed phase solution and continuous phase solution are respectively charged into syringe 2-1,2-2 of 10mL and 60mL, are placed in
It on two syringe pumps 1-1,1-2, is connected in Fig. 5 and micro fluidic device shown in fig. 6, setting dispersed phase flow velocity is 10 μ L
min-1, viscosity 250mPas, continuous phase flow velocity is 100 μ Lmin-1, viscosity 560mPas, capillary 3 in micro fluidic device
245/98 μm of outer diameter/internal diameter, open micro fluidic device, prepare monodisperse insulin/chitosan solution drop；Collect generation
Drop in equipped with above-mentioned coagulation bath solution culture dish in, slowly stir at room temperature formed gel after, be added 0.01g vanillic aldehyde in
Curing reaction 1.5h at 60 DEG C, drop can be solidified into insulin/aquagel microballon.It is residual after simply decanting
The organic solution stayed petroleum ether, chloroform respectively wash 2 times, then with after ethanol washing 2 times, filter off ethyl alcohol, are dried in vacuo to get list
Dispersed islet cells element/chitosan gel rubber sustained-release micro-spheres.
Monodisperse insulin/chitosan gel rubber sustained-release micro-spheres manufactured in the present embodiment are in elliposoidal, and partial size is 95 μm, surface
There is gauffer to a certain degree, uniform particle diameter has monodispersity.Microballoon carrying drug ratio 11%, embedding rate 78%, microballoon are 7.6 in pH
Mixed phosphate salt buffer solution at 37 DEG C sustained release performance see Fig. 4.From fig. 4, it can be seen that microballoon phenomenon of burst release is unobvious, have slow
Characteristic is released, 14h cumulative release rate is less than 45% at 37 DEG C.
Claims (7)
1. a kind of monodisperse insulin/chitosan gel rubber microballoon preparation method of size tunable, which is characterized in that including following
Step:
(1) preparation of coagulation bath solution: amine or amino alcohol are added in alcohol are uniformly mixed in proportion, be configured to amine or amino alcohol
The coagulation bath solution that product percentage is 20%~55%；
(2) chitosan the preparation of dispersed phase solution and continuous phase solution: is added to the vinegar for being 0.5%~2% containing weight percent
In aqueous acid, the insulin solutions that the weight percent that pH is 1.5~3.0 is 10%~30% are added, are uniformly mixed, are made
For dispersed phase solution；Low polar compound is mixed with alcohol, low polar compound is prepared and alcohol volume ratio is 100:(0~250)
Continuous phase solution；
(3) adjust the flow velocity and viscosity of dispersed phase and continuous phase: adjustment dispersed phase flow velocity is 4~30 μ Lmin-1, continuous phase stream
Speed is 50~300 μ Lmin-1, dispersed phase viscosity is 1~500mPas, and continuous phase viscosity is 50~2500mPas；
(4) insulin/chitosan drop formation: dispersed phase solution obtained by step (2) and continuous phase solution are in micro fluidic device
In converge after, can get size tunable monodisperse insulin/chitosan solution drop；
(5) drop is solidified into microballoon: for collection step (4) resulting drop in the coagulation bath solution that step (1) prepares, drop can
Solidification or semi-solid preparation, add vanillic aldehyde, monodisperse insulin/chitosan of size tunable are further solidified into 25~60 DEG C
Gel micro-ball.
2. preparation method as described in claim 1, which is characterized in that alcohol described in step (1) be isoamyl alcohol, isooctanol or oneself
Alcohol；Amine is triethylamine or trioctylamine；Amino alcohol is triethanolamine or diethanol amine.
3. preparation method as described in claim 1, which is characterized in that low polar compound described in step (2) be silicone oil,
Soybean oil or salad oil；The alcohol is one or both of isoamyl alcohol, isooctanol or hexanol.
4. preparation method as described in claim 1, which is characterized in that the preparation method further includes step (6) insulin/shell
The post-processing of polysaccharide gel sustained-release micro-spheres: by the resulting insulin of step (5)/chitosan gel rubber microballoon by filtering or decantation
Afterwards, remaining organic solution organic solvent washing filters off organic solvent, is dried in vacuo 6~9h to get monodispersity pancreas islet
Element/chitosan gel rubber microballoon.
5. preparation method as claimed in claim 4, which is characterized in that the organic solvent is the one of hydrocarbon, halogenated hydrocarbons, alcohol and ketone
Kind is several.
6. preparation method as claimed in claim 5, which is characterized in that the hydrocarbon is pentane, hexane, petroleum ether；Halogenated hydrocarbons
For methylene chloride, chloroform, carbon tetrachloride；Alcohol is methanol, ethyl alcohol, isopropanol；Ketone is acetone or butanone.
7. monodisperse insulin/chitosan of the size tunable of the preparation of preparation method described in claim 1~6 any one is solidifying
Glue microballoon.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610818252.4A CN106267164B (en) | 2016-09-12 | 2016-09-12 | Monodisperse insulin/chitosan gel rubber microballoon of size tunable and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610818252.4A CN106267164B (en) | 2016-09-12 | 2016-09-12 | Monodisperse insulin/chitosan gel rubber microballoon of size tunable and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106267164A CN106267164A (en) | 2017-01-04 |
| CN106267164B true CN106267164B (en) | 2019-11-26 |
Family
ID=57710655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610818252.4A Expired - Fee Related CN106267164B (en) | 2016-09-12 | 2016-09-12 | Monodisperse insulin/chitosan gel rubber microballoon of size tunable and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106267164B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110280192B (en) * | 2019-07-10 | 2022-05-20 | 南京理工大学 | Preparation method of carbon nano tube-polyvinyl alcohol gel microspheres |
| CN113617237A (en) * | 2021-08-10 | 2021-11-09 | 吉林大学 | Preparation method of oil-water emulsion with uniform and controllable particle size and stable system |
| CN115590200A (en) * | 2022-11-02 | 2023-01-13 | 北京逯博士行为医学科技研究院有限公司（Cn） | Effective component embedding method based on meal replacement powder |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1698900A (en) * | 2005-06-02 | 2005-11-23 | 中国科学院过程工程研究所 | Chitosan drug carrying microsphere with uniform size, high embedding rate and high drug activity maintaining rate and its preparation process |
| CN1843600A (en) * | 2006-03-28 | 2006-10-11 | 上海一鸣过滤技术有限公司 | Intensified microporous membrane of polyethersulfone and method for preparing the same |
| CN102068409A (en) * | 2011-01-13 | 2011-05-25 | 清华大学 | Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology |
-
2016
- 2016-09-12 CN CN201610818252.4A patent/CN106267164B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1698900A (en) * | 2005-06-02 | 2005-11-23 | 中国科学院过程工程研究所 | Chitosan drug carrying microsphere with uniform size, high embedding rate and high drug activity maintaining rate and its preparation process |
| CN1843600A (en) * | 2006-03-28 | 2006-10-11 | 上海一鸣过滤技术有限公司 | Intensified microporous membrane of polyethersulfone and method for preparing the same |
| CN102068409A (en) * | 2011-01-13 | 2011-05-25 | 清华大学 | Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology |
Non-Patent Citations (1)
| Title |
|---|
| 采用离子交联法制备壳聚糖胰岛素纳米粒的研究进展;欧歌等;《中南药学》;20130228;第11卷(第2期);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106267164A (en) | 2017-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Luo et al. | Microfluidic devices in fabricating nano or micromaterials for biomedical applications | |
| Liu et al. | Preparation of monodisperse calcium alginate microcapsules via internal gelation in microfluidic-generated double emulsions | |
| Tu et al. | Controlling the stability and size of double-emulsion-templated poly (lactic-co-glycolic) acid microcapsules | |
| CN107376008B (en) | A kind of preparation method of inorganic nanoparticles-gelatin composite material of core-shell structure particle | |
| Kashani et al. | Microfluidics for core–shell drug carrier particles–a review | |
| CN106267164B (en) | Monodisperse insulin/chitosan gel rubber microballoon of size tunable and preparation method thereof | |
| CN101690879A (en) | Method for preparing polymer micro balls with uniform grain diameter and controllable size | |
| Gao et al. | Recent advances in microfluidic-aided chitosan-based multifunctional materials for biomedical applications | |
| CN102068409A (en) | Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology | |
| JP2002538194A (en) | Cell-protecting biocompatible encapsulation system for bioactive substances and method for producing the same | |
| Ngwuluka et al. | Natural polymers in micro-and nanoencapsulation for therapeutic and diagnostic applications: part I: lipids and fabrication techniques | |
| Xue et al. | Microfluidic synthesis of monodisperse PEGDA microbeads for sustained release of 5-fluorouracil | |
| Ge et al. | Electrospun self-emulsifying core-shell nanofibers for effective delivery of paclitaxel | |
| Ma et al. | Advances in uniform polymer microspheres and microcapsules: preparation and biomedical applications | |
| CN111569798A (en) | Degradable core-shell calcium alginate oxide gel microspheres and preparation method and application thereof | |
| Morelli et al. | Microparticles for cell encapsulation and colonic delivery produced by membrane emulsification | |
| CN113975250A (en) | Preparation and application of double-water-phase porous islet microcapsules with core-shell structure | |
| CN102219938A (en) | Preparation method of hydrophobically modified sodium alginate | |
| CN107715169A (en) | The sodium alginate of the nanoparticle containing PLGA carries the preparation method and product of the compound embolism microball of medicine | |
| CN107714674A (en) | A kind of preparation method of PLGA microballoons | |
| Qu et al. | Aqueous two-phase droplet-templated colloidosomes composed of self-formed particles via spatial confined biomineralization | |
| CN104225614A (en) | Chitosan grafted polylactic acid composite microsphere simultaneously carried with hydrophilic and hydrophobic biological molecules and preparation method of chitosan grafted polylactic acid composite microsphere | |
| CN112641755A (en) | Method for preparing colon-targeted microcapsules by applying microfluidics technology | |
| Luo et al. | Well-designed microcapsules fabricated using droplet-based microfluidic technique for controlled drug release | |
| Cesur et al. | Controlled release of metformin loaded polyvinyl alcohol (PVA) microbubble/nanoparticles using microfluidic device for the treatment of type 2 diabetes mellitus |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20191126 Termination date: 20200912 |