CN109589317A - It is a kind of to have both the preparation method for inhibiting the nano particle of histamine release and histamine receptor antagonism function - Google Patents
It is a kind of to have both the preparation method for inhibiting the nano particle of histamine release and histamine receptor antagonism function Download PDFInfo
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- CN109589317A CN109589317A CN201811503207.5A CN201811503207A CN109589317A CN 109589317 A CN109589317 A CN 109589317A CN 201811503207 A CN201811503207 A CN 201811503207A CN 109589317 A CN109589317 A CN 109589317A
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- Prior art keywords
- cetirizine
- hydroxyl butyl
- butyl chitosan
- histamine
- nano particle
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Abstract
The invention discloses a kind of preparation methods of nano particle for having both inhibition histamine release and histamine receptor antagonism function.Its preparation step are as follows: hydroxyl butyl chitosan (patent No. ZL201110214776.X) is synthesized by published method, the cetirizine scion grafting of desalination is obtained into cetirizine-hydroxyl butyl chitosan in hydroxyl butyl chitosan using Carbodiimide reaction；Cetirizine-hydroxyl butyl chitosan and Ketotifen are dissolved in dimethyl sulfoxide, is added dropwise in distilled water under stirring condition, obtains Ketotifen: cetirizine-hydroxyl butyl chitosan.This nano particle preparation process is simple, the period is short, at low cost, has both and inhibits histamine release and histamine H1Allergy classical symptom can be effectively relieved in receptor antagonism, have good development and application prospect in terms of the treatment of anaphylactia especially allergic rhinitis.
Description
Technical field
The invention belongs to a kind of have both of biomedical materials field to inhibit histamine release and histamine receptor antagonism function
The preparation method of nano particle.
Background technique
Chitosan (CS) is that a kind of macromolecule amino for being obtained by the chitin in dried small shrimp crab shell through deacetylation is more
Sugar has the characteristics that adhesion, antibiotic property and no biotoxicity, and can be degraded by enzymes certain in human body (such as: lysozyme).
Since a large amount of amino and hydroxyl being distributed in chitosan molecule chain, it is capable of forming intramolecular and intermolecular hydrogen bonding, makes it almost
Not soluble in water or alkaline solution limits its application in neutral environment in vivo.Hydroxyl butyl chitosan is that chitosan etherificate changes
Property product, hydroxyl butylation modification impart its good water solubility, effectively improve the office that chitosan can only be dissolved in acid solution
It is sex-limited.Hydroxyl butyl chitosan biological histocompatbility is good, and aqueous solution has temperature sensitivity and pH value of solution sensibility, can use
In minimally invasive injection, topical remedy's sustained release etc., have in terms of beautifying technique, medical engineering material and modernization industry huge
Potentiality.
Cetirizine is second generation nonsedating antihistamine, is hydroxyzine in the intracorporal carboxylation metabolite of people, has
High specific histamine H1Receptor antagonist performance, and have and be not easy across blood-brain barrier, the advantages such as tolerance is good, clinically often
For treating the diseases such as allergic rhinitis, allergic conjunctivitis, idiopathic urticaria.However, directly taking the plasma drug half
Declining, the phase is short, and dosage frequency is high and has the adverse reactions such as drowsiness, dizzy.Existing research at present reports chitosan scion grafting cetirizine
The feasibility of nano-micelle mucosa delivery is able to extend drug in the residence time of lesions position, slowly releases the drug, effectively make up
The defect of oral cetirizine.However, the use of acid preparation condition and crosslinking agent, so that the collection of nano particle and purifying become
Must be difficult, it limits its application to a certain extent.
Ketotifen, benzocyclohepta thiophene derivant have potent inhibition histamine release and histamine H1Receptor antagonist function,
Good effect and it is not likely to produce drug resistance, in diseases such as nettle rash, allergic dermatitis, allergic conjunctivitis, allergic rhinitis and asthma
Disease treatment aspect is significant in efficacy.Existing research reports the chitosan microball for loading Ketotifen as abdominal cavity delivering antihistamine drug
Carrier, prepared microballoon encapsulation rate with higher and drugloading rate.However, excessive partial size (1.0-1.3 μm) limits
The feasibility of its mucosa delivery.The present invention introduces west by Carbodiimide reaction on the basis of hydroxyl butyl chitosan for benefit
Piperazine, cetirizine-hydroxyl butyl chitosan of formation can be self-assembly of nano particle under fluid environment, while by hydrophobicity
Drug Ketotifen is effectively contained into its hydrophobic microcell, and the nano particle diameter is uniform and smaller, meets mucosa delivery nanometer load
Body Particle size requirements can extend drug in the residence time of medicine-feeding part by being released and being sustained, and it has both and histamine is inhibited to release
Put with histamine receptor antagonism function, in terms of the treatment of anaphylactia have good development and application prospect.
Summary of the invention
The object of the present invention is to provide a kind of have both to inhibit histamine release and the nano particle of histamine receptor antagonism function
Preparation method, to make up the defect of existing treatment method.
The present invention specifically comprises the steps of
(1) firstly, by hydroxyl butyl chitosan (molecular weight ranges of chitosan be 600-1700 kDa, according to the patent No.:
ZL201110214776. X method synthesizes) it is dissolved in distilled water, methanol dilution is used afterwards, and the ratio of methanol and water is 3-4:1.
(2) Cetirizine Hydrochloride is dissolved in dimethyl sulfoxide (DMSO), triethylamine, Cetirizine Hydrochloride and three is added
The molar ratio of ethamine is 1:1-3, after being protected from light desalination, EDC, NHS(Cetirizine Hydrochloride is added, the molar ratio of EDC, NHS are 1:
1.5-5:1.5-5), 1-5 h is stirred at room temperature, activates the γ-COOH in cetirizine.
(3) (hydroxyl butyl chitosan, west is added dropwise in hydroxyl butyl chitosan solution in the cetirizine mixed solution of activation
Mass ratio for sharp piperazine is 1:0.25-4), reaction temperature is 0-8 DEG C, and after 24-48 h, reaction solution is transferred to methanol and water
Mixed solution in dialyse, the ratio of methanol and water is 3-4:1, after dialysed with distilled water.Reaction solution is frozen after dialysis
It does to get cetirizine-hydroxyl butyl chitosan.
(4) cetirizine-hydroxyl butyl chitosan and Ketotifen are dissolved in dimethyl sulfoxide (cetirizine-hydroxyl butyl
The mass ratio of chitosan and Ketotifen is 1:0.4-2), mixed liquor is added dropwise in distilled water, dimethyl sulfoxide and distilled water
Volume ratio be 1:1-7, reaction temperature be 0-8 DEG C, can be prepared by Ketotifen: cetirizine-hydroxyl butyl chitosan nano
Grain.
Specific embodiment
Target product, i.e. cetirizine-is made using hydroxyl butyl chitosan as raw material, by Carbodiimide reaction in the present invention
Hydroxyl butyl chitosan.By the way that target product and Ketotifen are codissolved in dimethyl sulfoxide and instilled in distilled water, ketone can be prepared by
For sweet smell: cetirizine-hydroxyl butyl chitosan nano particle.
Embodiment 1
40 mg hydroxyl butyl chitosans are weighed, molecular weight is 600 KDa, is dissolved in 1 mL distilled water, and it is dilute that 4 mL methanol are added
It releases；40 mg Cetirizine Hydrochlorides are weighed, are dissolved in 16 mL dimethyl sulfoxides, 36 mL triethylamines are added, it is anti-under the conditions of being protected from light
Answer 120 min；74.7 mg EDC, 45.0 mg NHS are added into reaction solution and persistently stir 5 h under room temperature, activate
γ-COOH in cetirizine；γ-COOH the cetirizine solutions activated are added dropwise in hydroxyl butyl chitosan solution, 4
It after reacting 48 h under the conditions of DEG C, is transferred in bag filter, is dialysed after 24 h in the solution that methanol and water ratio are 4:1, be transferred to steaming
Continue 24 h that dialyse in distilled water；Solution is lyophilized after dialysing, and cetirizine-hydroxyl butyl chitosan can be obtained；20 west mg are replaced
Sharp piperazine-hydroxyl butyl chitosan and 40 mg Ketotifens are codissolved in 10 mL dimethyl sulfoxides, after completely dissolution, are added dropwise 70
In mL distilled water, 10 min are persistently stirred under the conditions of 4 DEG C, 24 h that dialyse is transferred in bag filter, is freeze-dried to obtain
Ketotifen: cetirizine-hydroxyl butyl chitosan nano particle.
Embodiment 2
40 mg hydroxyl butyl chitosans are weighed, molecular weight is 700 KDa, is dissolved in 2 mL distilled water, and it is dilute that 6 mL methanol are added
It releases；40 mg Cetirizine Hydrochlorides are weighed, are dissolved in 4 mL dimethyl sulfoxides, 12 mL triethylamines are added, it is anti-under the conditions of being protected from light
Answer 20 min；24.9 mg EDC, 15.0 mg NHS are added into reaction solution and persistently stir 1.5 h under room temperature, activate
γ-COOH in cetirizine；γ-COOH the cetirizine solutions activated are added dropwise in hydroxyl butyl chitosan solution, 0
It after reacting 24 h under the conditions of DEG C, is transferred in bag filter, is dialysed after 24 h in the solution that methanol and water ratio are 4:1, be transferred to steaming
Continue 24 h that dialyse in distilled water；Solution is lyophilized after dialysing, and cetirizine-hydroxyl butyl chitosan can be obtained；By the west 20 mg
It is codissolved in 5 mL dimethyl sulfoxides for sharp piperazine-hydroxyl butyl chitosan and 8 mg Ketotifens, after completely dissolution, is added dropwise 15
In mL distilled water, 30 min are persistently stirred under the conditions of 0 DEG C, 24 h that dialyse is transferred in bag filter, is freeze-dried to obtain
Ketotifen: cetirizine-hydroxyl butyl chitosan nano particle.
Embodiment 3
40 mg hydroxyl butyl chitosans are weighed, molecular weight is 1700 KDa, is dissolved in 4 mL distilled water, and 16 mL methanol are added
Dilution；160 mg Cetirizine Hydrochlorides are weighed, are dissolved in 4 mL dimethyl sulfoxides, 12 mL triethylamines are added, under the conditions of being protected from light
React 60 min；124.5 mg EDC, 75.0 mg NHS are added into reaction solution and persistently stir 1 h under room temperature, swash
γ-COOH in cetirizine living；γ-COOH the cetirizine solutions activated are added dropwise in hydroxyl butyl chitosan solution,
It after reacting 24 h under the conditions of 8 DEG C, is transferred in bag filter, dialyses after 24 h, turn in the solution that methanol and water ratio are 3:1
Enter and continues 24 h that dialyse in distilled water；Solution is lyophilized after dialysing, and cetirizine-hydroxyl butyl chitosan can be obtained；By 20 mg
Cetirizine-hydroxyl butyl chitosan and 20 mg Ketotifens are codissolved in 20 mL dimethyl sulfoxides, after completely dissolution, dropwise plus
Enter in 20 mL distilled water, persistently stirs 120 min under the conditions of 8 DEG C, be transferred in bag filter 24 h that dialyse, freeze-drying is
Ketotifen can be obtained: cetirizine-hydroxyl butyl chitosan nano particle.
Claims (4)
1. a kind of have both the preparation method for inhibiting the nano particle of histamine release and histamine receptor antagonism function, specific steps
Are as follows:
Step 1: Cetirizine Hydrochloride is dissolved in dimethyl sulfoxide, and appropriate triethylamine is added and carries out desalting processing, rear to be added
A certain amount of EDC, NHS, activate the γ-COOH of cetirizine at lasting stirring a period of time
Step 2: preparing hydroxyl butyl chitosan according to patent (patent No. ZL201110214776.X), and hydroxyl butyl chitosan is molten
A certain proportion of methanol is added in distilled water in solution, and mixing is added dropwise in the cetirizine solutions of γ-COOH obtained by step 1
In solution, freeze-drying can be prepared by cetirizine-hydroxyl butyl chitosan after dialysis
Step 3: cetirizine-hydroxyl butyl chitosan and Ketotifen are dissolved in dimethyl sulfoxide, after being completely dissolved, dropwise
Be added distilled water in, be freeze-dried to obtain after dialysis have both inhibit histamine release and histamine receptor antagonism function ketone replace
It is fragrant: cetirizine-hydroxyl butyl chitosan nano particle.
2. a kind of system of nano particle for having both inhibition histamine release and histamine receptor antagonism function according to claim 1
Preparation Method, it is characterized in that the molecular weight ranges of the chitosan are 600-1700 kDa.
3. a kind of system of nano particle for having both inhibition histamine release and histamine receptor antagonism function according to claim 1
Preparation Method, it is characterized in that the feed ratio of hydroxyl butyl chitosan and cetirizine is 1:0.25-4, reaction temperature is 0-8 DEG C.
4. a kind of system of nano particle for having both inhibition histamine release and histamine receptor antagonism function according to claim 1
Preparation Method, it is characterized in that the feed ratio of cetirizine-hydroxyl butyl chitosan and Ketotifen is 1:0.4-2, dimethyl sulfoxide and water
Volume ratio be 1:1-7.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811503207.5A CN109589317A (en) | 2018-12-10 | 2018-12-10 | It is a kind of to have both the preparation method for inhibiting the nano particle of histamine release and histamine receptor antagonism function |
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| CN201811503207.5A CN109589317A (en) | 2018-12-10 | 2018-12-10 | It is a kind of to have both the preparation method for inhibiting the nano particle of histamine release and histamine receptor antagonism function |
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| CN109589317A true CN109589317A (en) | 2019-04-09 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20090028045A (en) * | 2007-09-13 | 2009-03-18 | 재단법인서울대학교산학협력재단 | Microsphere for nasal spray comprising drug for treating allergic rhinitis and preparation method thereof |
| CN101524353A (en) * | 2008-03-03 | 2009-09-09 | 重庆华邦制药股份有限公司 | Oral anti-allergy compound pharmaceutical composition |
| CN102276756A (en) * | 2011-07-29 | 2011-12-14 | 中国海洋大学 | Preparation method of chitosan hydroxybutyl derivative |
| CN106214639A (en) * | 2016-08-27 | 2016-12-14 | 中国海洋大学 | A kind of preparation method of chitosan scion grafting cetirizine nano-micelle |
| CN107915787A (en) * | 2016-10-11 | 2018-04-17 | 中国海洋大学 | A kind of preparation method of pH temperature dual-sensitivity chitosan nano particle |
-
2018
- 2018-12-10 CN CN201811503207.5A patent/CN109589317A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20090028045A (en) * | 2007-09-13 | 2009-03-18 | 재단법인서울대학교산학협력재단 | Microsphere for nasal spray comprising drug for treating allergic rhinitis and preparation method thereof |
| CN101524353A (en) * | 2008-03-03 | 2009-09-09 | 重庆华邦制药股份有限公司 | Oral anti-allergy compound pharmaceutical composition |
| CN102276756A (en) * | 2011-07-29 | 2011-12-14 | 中国海洋大学 | Preparation method of chitosan hydroxybutyl derivative |
| CN106214639A (en) * | 2016-08-27 | 2016-12-14 | 中国海洋大学 | A kind of preparation method of chitosan scion grafting cetirizine nano-micelle |
| CN107915787A (en) * | 2016-10-11 | 2018-04-17 | 中国海洋大学 | A kind of preparation method of pH temperature dual-sensitivity chitosan nano particle |
Non-Patent Citations (4)
| Title |
|---|
| GUERRERO ET AL.: "Characterization and in vivo evaluation of ketotifen-loaded chitosan microspheres", 《CARBOHYDRATE POLYMERS》 * |
| WANG ET AL.: "Influence of the graft density of hydrophobic groups onthermo-responsive nanoparticles for anti-cancer drugs delivery", 《COLLOIDS AND SURFACES B: BIOINTERFACES》 * |
| YANG ET AL.: "Preparation and characterization of a novel thermosensitive nanoparticle for drug delivery in combined hyperthermia and chemotherapy", 《JOURNAL OF MATERIALS CHEMISTRY B》 * |
| 薛巍等主编: "《生物医用水凝胶》", 31 December 2012, 暨南大学出版社 * |
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Application publication date: 20190409 |