CN109091465A - A kind of preparation method of bioadhesive microspheres preparation - Google Patents
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- 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
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- 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
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Abstract
The present invention relates to a kind of preparation methods of bioadhesive microspheres preparation, belong to biologic product technology field.Bioadhesive microspheres preparation prepared by the present invention is by chitin modified raising drug loading performance and makes its balling-up, recycles chitosan microball microcellular structure to achieve the effect that sustained release, then chitosan microball is adhered to cell surface with dopamine, reaches adhesiving effect；Good biocompatibility makes it have good adhesiveness while guaranteeing into spherical and release；Chitosan have the characteristics that it is nontoxic, can be fully absorbed by human body, while sustained release can also be played the role of；After chitosan alkylation processing, so that chitosan has hydrophilic backbone and hydrophobicity branch simultaneously, and chitosan is made to be gathered into the microballoon form of external hydrophilic and inner hydrophobic in water, bioadhesive microspheres are enabled to load some water-insoluble drugs, and be used in aqueous systems, substantially increase the drug carrying capacity of bioadhesive microspheres.
Description
Technical field
The present invention relates to a kind of preparation methods of bioadhesive microspheres preparation, belong to biologic product technology field.
Background technique
Bioadhesive drug delivery system is one kind by natural or synthetic polymer material, passes through itself and body tissue mucous membrane
Surface generates the close contact of long period, to extend drug in the residence time of mucous membrane, mucus part or be maintained close to
The position of absorption window, control drug are discharged in local positioning, are reached and are increased drug absorption, improve drug bioavailability, or mention
High local-pathological-changed tissues drug concentration, the drug delivery system for improving curative effect, reducing toxic side effect purpose.Bioadhesion administration system
Regional administrations, these positions such as direct oral cavity, nasal cavity, eye, alimentary canal, vagina, rectum are covered with mucous layer as unified.Mucous membrane
Epithelium layer secreting mucus, mucus exist generally in the form of the gel layer for being adhered to mucomembranous surface.
The advantage of bioadhesive drug delivery system is: (1) contained drug releases the drug in particular mucosal spots localization, extends drug
In the retention time of lesions position, the effect for the treatment of topical disorders is improved；(2) in oral administration system, preparation, which may adhere to, to disappear
Change road mucomembranous surface, by extending drug in the gastral residence time, extends the action time of drug；For molten in alimentary canal
Xie Du small or with specific absorption position drug can increase it and absorb total amount and absorption efficiency, improve the biological utilisation of drug
Degree；(3) administration frequency can also be reduced by delaying (control) release formulation with bioadhesion, reduced dosage, facilitated medication.
Adhesion material plays a key role in the adhesive attraction of bioadhesive drug delivery system.It is generally believed that for shape
At preferable adhesive attraction, polymer needs to have following characteristics: having a sufficient amount of oxygen key chemical group (OH and one
COOH)；Higher molecular weight；Strand flexibility is good；It can induce the suitable surface tension of mucous layer scattering and permeating.It grinds at present
Study carefully and is mainly polyacrylic, cellulose family, polysaccharide and their derivative using more bioadhesive material, these
Polymer material contains more carboxyl or hydroxyl or amino or sulfonic group, can generate interaction with mucous membrane mucus.In addition,
Hyaluronic acid, alginates, different gummy such as guar gum, xanthan gum and pectin also have been reported that as bioadhesive material.
Relative to conventional formulation, bioadhesive microspheres preparation has a requirement of more quality index, and because adhesion material addition,
Softwood viscosity is excessively high, and Traditional Industrialization production method is difficult to combine sustained release, adherency, the various requirements of balling-up.But it tests
The intra-liquid desiccation method that room research uses often requires to use a large amount of organic solvent (including volatile dispersed phase polar solvent again
And high boiling continuous phase nonpolar solvent), the various aspects such as more, process conditions complexity, difficult solvent recovery that there are influence factors
The problem of, it is difficult to adapt to the requirement of industrialized production.
Summary of the invention
The technical problems to be solved by the invention: it cannot be considered in terms of into for the bioadhesive microspheres production method that developed now
The problem of ball, release and adhesiveness, provides a kind of preparation method of bioadhesive microspheres preparation.
In order to solve the above technical problems, the technical solution adopted by the present invention is that:
(1) it takes chitosan, potassium hydroxide and isopropanol to be mixed and is warming up to 40~60 DEG C, microwave 0.5~2h of alkalization is obtained
Chitosan liquid；
(2) bromic ether is added dropwise into chitosan liquid and reacts 4~10h, obtain reaction solution A；
(3) it adds and methanol and is uniformly mixed into reaction solution, obtain reaction solution B, with 0.01mol/L hydrochloric acid solution by reaction solution B
PH value is adjusted to 7, reaction liquid C is obtained, then add acetone into reaction liquid C, obtains reaction solution D；
(4) reaction solution D is stood into 1~2h, precipitating is precipitated, filter residue is obtained after filtering, then repeatedly wash filter residue with acetone and ether,
Then drying obtains alkylated chitosan；
(5) it takes dopamine hydrochloride and deionized water to mix, obtains aqueous dopamine solution；
(6) it takes alkylated chitosan to be put into deionized water and obtains dispersion liquid after ultrasonic vibration 30min；
(7) aqueous dopamine solution and dispersion liquid are mixed, and maintain 20~40min of ultrasound, obtain bioadhesive microspheres dispersion liquid；
(8) bioadhesive microspheres dispersion liquid is filtered, bioadhesive microspheres preparation will be obtained after filter residue and drying.
The mass ratio of step (1) chitosan, potassium hydroxide and isopropanol is 1:2:20.
The mass ratio of step (3) methanol and acetone is 2:1.
The mass ratio of step (4) acetone and ether is 1:1, and washing times are 5~8 times.
Step (5) dopamine hydrochloride and the mass ratio of deionized water are 1:20.
Step (6) alkyl chitosan and the mass ratio of deionized water are 1:10.
The present invention is compared with other methods, and advantageous effects are:
(1) chitosan can be degraded to natural metabolin by the lysozyme of human body, with spy that is nontoxic, being fully absorbed by human body
Point, while sustained release can also be played the role of；After chitosan alkylation processing, so that chitosan has hydrophilic backbone simultaneously
With hydrophobicity branch, and chitosan is made to be gathered into the microballoon form of external hydrophilic and inner hydrophobic in water, so that adherency
Microballoon can load some water-insoluble drugs, and be used in aqueous systems, and the drug for substantially increasing bioadhesive microspheres is negative
Loading capability；
(2) ethylamino and catechol rich in functional group in dopamine, can be attached on microsphere surface, and be well
Microballoon provides extremely strong adhesiveness, can be attached on cell surface；
(3) the bioadhesive microspheres preparation prepared by the present invention by chitin modified raising drug loading performance and makes its balling-up,
It recycles chitosan microball microcellular structure to achieve the effect that sustained release, then chitosan microball is adhered to cell surface with dopamine,
Reach adhesiving effect；Good biocompatibility makes it have good adhesiveness while guaranteeing into spherical and release.
Specific embodiment
5~10g chitosan, 10~20g potassium hydroxide and 100~200g isopropanol is taken to be mixed and be warming up to 40~60
DEG C, microwave 0.5~2h of alkalization obtains chitosan liquid；2~4g bromic ether is added dropwise into chitosan liquid and reacts 4~10h, obtains
Reaction solution A；100~200g methanol is added into reaction solution and is uniformly mixed, and reaction solution B is obtained, it will be anti-with 0.01mol/L hydrochloric acid
It answers liquid B to adjust pH value to 7, obtains reaction liquid C, then add 50~100g acetone into reaction liquid C, obtain reaction solution D；It will reaction
Liquid D stands 1~2h, and precipitating is precipitated, filter residue is obtained after filtering, then washed filter residue 5~8 times with acetone and ether, then dried
To alkylated chitosan；It takes 1~2g dopamine hydrochloride and 20~40g deionized water to mix, obtains aqueous dopamine solution；Biology
Bioadhesive microspheres preparation take 2~4g alkylated chitosan be put into 20~40g deionized water maintain ultrasound 30min after dispersed
Liquid；Aqueous dopamine solution and dispersion liquid are mixed bioadhesive microspheres preparation, and maintain 20~40min of ultrasound, are glued
Attached microballoon dispersion liquid；Bioadhesive microspheres preparation filters bioadhesive microspheres dispersion liquid, micro- by bioadhesion is obtained after filter residue and drying
Ball preparation.
Example 1
It takes 5g chitosan, 10g potassium hydroxide and 100g isopropanol to be mixed and is warming up to 40 DEG C, microwave alkalization 0.5h is obtained
Chitosan liquid；2g bromic ether is added dropwise into chitosan liquid and reacts 4h, obtains reaction solution A；100g methanol is added into reaction solution
And be uniformly mixed, reaction solution B is obtained, reaction solution B is adjusted into pH value to 7 with 0.01mol/L hydrochloric acid, obtains reaction liquid C, then toward instead
Addition 50g acetone in liquid C is answered, reaction solution D is obtained；Reaction solution D is stood into 1h, precipitating is precipitated, obtains filter residue after filtering, then with third
Ketone and ether wash filter residue 5 times, and then drying obtains alkylated chitosan；Take 1g dopamine hydrochloride and 20g deionized water mixed
It closes, obtains aqueous dopamine solution；Bioadhesive microspheres preparation takes 2g alkylated chitosan to be put into 20g deionized water and maintains ultrasound
Dispersion liquid is obtained after 30min；Aqueous dopamine solution and dispersion liquid are mixed bioadhesive microspheres preparation, and maintain ultrasound
20min obtains bioadhesive microspheres dispersion liquid；Bioadhesive microspheres preparation filters bioadhesive microspheres dispersion liquid, will obtain after filter residue and drying
To bioadhesive microspheres preparation.
Example 2
It takes 8g chitosan, 15g potassium hydroxide and 150g isopropanol to be mixed and is warming up to 50 DEG C, microwave alkalization 1.5h is obtained
Chitosan liquid；3g bromic ether is added dropwise into chitosan liquid and reacts 7h, obtains reaction solution A；150g methanol is added into reaction solution
And be uniformly mixed, reaction solution B is obtained, reaction solution B is adjusted into pH value to 7 with 0.01mol/L hydrochloric acid, obtains reaction liquid C, then toward instead
Addition 80g acetone in liquid C is answered, reaction solution D is obtained；Reaction solution D is stood into 1h, precipitating is precipitated, obtains filter residue after filtering, then with third
Ketone and ether wash filter residue 6 times, and then drying obtains alkylated chitosan；Take 1g dopamine hydrochloride and 30g deionized water mixed
It closes, obtains aqueous dopamine solution；Bioadhesive microspheres preparation takes 3g alkylated chitosan to be put into 30g deionized water and maintains ultrasound
Dispersion liquid is obtained after 30min；Aqueous dopamine solution and dispersion liquid are mixed bioadhesive microspheres preparation, and maintain ultrasound
30min obtains bioadhesive microspheres dispersion liquid；Bioadhesive microspheres preparation filters bioadhesive microspheres dispersion liquid, will obtain after filter residue and drying
To bioadhesive microspheres preparation.
Example 3
It takes 10g chitosan, 20g potassium hydroxide and 200g isopropanol to be mixed and is warming up to 60 DEG C, microwave alkalization 2h obtains shell
Glycan liquid；4g bromic ether is added dropwise into chitosan liquid and reacts 10h, obtains reaction solution A；200g methanol is added simultaneously into reaction solution
It is uniformly mixed, obtains reaction solution B, reaction solution B is adjusted into pH value to 7 with 0.01mol/L hydrochloric acid, obtains reaction liquid C, then past reaction
100g acetone is added in liquid C, obtains reaction solution D；Reaction solution D is stood into 2h, precipitating is precipitated, obtains filter residue after filtering, then with third
Ketone and ether wash filter residue 8 times, and then drying obtains alkylated chitosan；Take 2g dopamine hydrochloride and 40g deionized water mixed
It closes, obtains aqueous dopamine solution；Bioadhesive microspheres preparation takes 4g alkylated chitosan to be put into 40g deionized water and maintains ultrasound
Dispersion liquid is obtained after 30min；Aqueous dopamine solution and dispersion liquid are mixed bioadhesive microspheres preparation, and maintain ultrasound
40min obtains bioadhesive microspheres dispersion liquid；Bioadhesive microspheres preparation filters bioadhesive microspheres dispersion liquid, will obtain after filter residue and drying
To bioadhesive microspheres preparation.
Reference examples: the bioadhesive microspheres preparation of Jiangxi Pharmaceuticals Ltd production.
The bioadhesive microspheres preparation of example and reference examples is detected, specific detection is as follows:
Vitro release measurement: it is released according to two annex XC dissolution method the first method Rotating shakers of China's coastal port and XD
The first method of degree of putting measuring method carries out.Dissolution medium is pH3.6 phosphate buffer 900mL；Temperature is 37 ± 0.5 DEG C, revolving speed
50rpm.It takes bioadhesive microspheres appropriate (about 60mg), release liquid 2mL is taken out respectively in the regulation moment, with 0.45um miillpore filter
Filtering, takes subsequent filtrate to be measured, while supplementing dissolution medium 2mL.Separately take bioadhesive microspheres appropriate, it is finely ground, weigh it is a certain amount of (about
16.7mg), 250mL volumetric flask is transferred to appropriate dissolution medium, water bath sonicator 2h lets cool, is settled to scale, micro- with 0.45um
Hole membrane filtration, takes subsequent filtrate.The above sample is respectively at measuring its UV absorption angle value under 252nm.
External adhesiveness measurement: taking Kunming mouse (25~30g, male and female are regardless of), and after fasting is supplied water for 24 hours, the neck that breaks is put to death,
Stomach is taken out, is cut off along lesser curvature, smooth Xiang Jiao Dian Shang is fixed in tiling after physiological saline rinsing removes content, viscous in stomach
The equal sentence of film surface sprinkles bioadhesive slow release microballoon 100, is subsequently placed at containing saturation KNO3In the closed container of solution
(RH93%) it after moisturizing 30min, takes out, is fixed on 45 ° of inclined-planes, with pH1.3 hydrochloric acid-sodium chloride solution with the punching of 22mL/min flow velocity
Gastric lavage mucous membrane surface 5min.The particle of surface detention is counted, microballoon is calculated and is detained percentage.
The experiment proved that: the yield of scale-up batches microballoon is 88.4%, microballoon drugloading rate 17.6%, encapsulation rate 70.4%.It is related
Content of material meets States Pharmacopoeia specifications standard less than 0.7%；
Scale-up batches bioadhesive microspheres have a preferable adhesiveness in isolated mouse gastric mucosa surface, and batch in it is poor without conspicuousness
Different (P > 0.05).
Claims (6)
1. a kind of preparation method of bioadhesive microspheres preparation, which is characterized in that specific production step are as follows:
(1) it takes chitosan, potassium hydroxide and isopropanol to be mixed and is warming up to 40~60 DEG C, microwave 0.5~2h of alkalization is obtained
Chitosan liquid；
(2) bromic ether is added dropwise into chitosan liquid and reacts 4~10h, obtain reaction solution A；
(3) it adds and methanol and is uniformly mixed into reaction solution, obtain reaction solution B, with 0.01mol/L hydrochloric acid solution by reaction solution B
PH value is adjusted to 7, reaction liquid C is obtained, then add acetone into reaction liquid C, obtains reaction solution D；
(4) reaction solution D is stood into 1~2h, precipitating is precipitated, filter residue is obtained after filtering, then repeatedly wash filter residue with acetone and ether,
Then drying obtains alkylated chitosan；
(5) it takes dopamine hydrochloride and deionized water to mix, obtains aqueous dopamine solution；
(6) it takes alkylated chitosan to be put into deionized water and obtains dispersion liquid after ultrasonic vibration 30min；
(7) aqueous dopamine solution and dispersion liquid are mixed, and maintain 20~40min of ultrasound, obtain bioadhesive microspheres dispersion liquid；
(8) bioadhesive microspheres dispersion liquid is filtered, bioadhesive microspheres preparation will be obtained after filter residue and drying.
2. a kind of preparation method of bioadhesive microspheres preparation as described in claim 1, which is characterized in that step (1) is described
The mass ratio of chitosan, potassium hydroxide and isopropanol is 1:2:20.
3. a kind of preparation method of bioadhesive microspheres preparation as described in claim 1, which is characterized in that step (3) is described
The mass ratio of methanol and acetone is 2:1.
4. a kind of preparation method of bioadhesive microspheres preparation as described in claim 1, which is characterized in that step (4) is described
The mass ratio of acetone and ether is 1:1, and washing times are 5~8 times.
5. a kind of preparation method of bioadhesive microspheres preparation as described in claim 1, which is characterized in that step (5) is described
Dopamine hydrochloride and the mass ratio of deionized water are 1:20.
6. a kind of preparation method of bioadhesive microspheres preparation as described in claim 1, which is characterized in that step (6) is described
Alkyl chitosan and the mass ratio of deionized water are 1:10.
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|---|---|---|---|---|
| CN113577296A (en) * | 2021-07-30 | 2021-11-02 | 复旦大学 | Preparation method of adhesive drug microcarrier |
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| CN107582527A (en) * | 2017-10-10 | 2018-01-16 | 雷笑天 | A kind of enteral administration bioadhesive microspheres preparation and preparation method thereof |
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| CN107582527A (en) * | 2017-10-10 | 2018-01-16 | 雷笑天 | A kind of enteral administration bioadhesive microspheres preparation and preparation method thereof |
Non-Patent Citations (3)
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| ELVIRA DE GIGLIO等: "Dopamine-loaded chitosan nanoparticles: formulation and analytical characterization", 《ANAL BIOANAL CHEM》 * |
| 代昭等: "壳聚糖烷基化改性及其纳米微球负载扑热息痛的研究", 《现代化工》 * |
| 陶彩虹等: "基于聚多巴胺的表面改性方法研究现状", 《化学通报》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113577296A (en) * | 2021-07-30 | 2021-11-02 | 复旦大学 | Preparation method of adhesive drug microcarrier |
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