CN109010262A - A kind of preparation method of virazole gel micro-ball - Google Patents
A kind of preparation method of virazole gel micro-ball Download PDFInfo
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- CN109010262A CN109010262A CN201810992273.7A CN201810992273A CN109010262A CN 109010262 A CN109010262 A CN 109010262A CN 201810992273 A CN201810992273 A CN 201810992273A CN 109010262 A CN109010262 A CN 109010262A
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- virazole
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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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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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
- A61K9/14—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
- A61K9/1611—Inorganic compounds
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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
- A61K9/14—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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Abstract
The invention discloses a kind of preparation methods of virazole gel micro-ball, prepare PBS buffer solution, calcium chloride solution, sodium alginate soln respectively, virazole injection distilled water is dissolved and diluted, and are configured to the stock solution that concentration is 0.5-4mg/ml；Configured virazole stock solution is added in configured good sodium alginate soln, is stirred to uniformly mixed；Virazole stock solution is instilled in calcium chloride solution using processed water dropper, stirs bottom liquid under magnetic stirring when instilling, be gelled 10-60min, is rinsed with PBS buffer solution, obtains virazole gel micro-ball.Product medicine controlled releasing effect of the invention is good, and embedding rate is high.
Description
Technical field
The invention belongs to medicament slow release technical fields, and in particular to a kind of preparation method of virazole gel micro-ball.
Background technique
Drug has an optimum concentration range, referred to as the curative effect window of drug after human body is taken.If being lower than this
Concentration range, drug will can not generate effective therapeutic effect because concentration is too small；But if having exceeded this concentration model
It encloses, drug will generate murder by poisoning to body and tissue.Common drug is after entering human body by modes such as oral, injections, drug
Concentration when reaching peak value, it is horizontal often beyond toxic concentration and generate toxic side effect；After a time again because of body
The metabolism of body and reduce rapidly the concentration of drug, drop to effective therapeutic concentration quickly hereinafter, can not continue to play a role, disease
People needs constantly medication to keep the effective concentration of drug in vivo.Drug is not only wasted in this way, but also toxic side effect is strong, treat
It is poor to imitate.Virazole is a kind of purine nucleoside analogs, and because the medicine is not likely to produce, drug resistance, activity are strong, clinical application is extensive, poison is secondary
Reacting less becomes current clinically widely used antiviral agent.Its ordinary tablet of virazole takes 3 ~ 4 times daily, blood concentration
It fluctuates larger.
And when using slow drug, control delivery systme administration, the concentration of active site drug can be at quite long one section
It is constant in time between curative effect window.During this period of time, the possible constant release of drug or period release, it is also possible to by outer
Boundary's environmental activity and cause to discharge.Have already appeared various sustained release preparations on the market at present, but still without effective
Virazole sustained release preparation.
Summary of the invention
To make up the deficiencies in the prior art, the present invention provides a kind of system of virazole gel micro-ball good using controlled-release effect
Preparation Method.
The present invention is achieved through the following technical solutions:
A kind of preparation method of virazole gel micro-ball, is characterized in that
The following steps are included:
(1) PBS buffer solution is prepared；
(2) compound concentration is the calcium chloride solution of 0.5-1.5%；
(3) compound concentration is the sodium alginate soln of 1-3%；
(4) virazole injection distilled water is dissolved and is diluted, be configured to the stock solution that concentration is 0.5-4mg/ml；
(5) configured virazole stock solution is added in configured good sodium alginate soln, is stirred to uniformly mixed；
(6) it is instilled in calcium chloride solution using the solution that processed water dropper obtains step (5), when instilling in magnetic agitation
Lower stirring bottom liquid, be gelled 10-60min, is rinsed with PBS buffer solution, obtains virazole gel micro-ball.
Preferably, in step (1) PBS buffer solution by potassium chloride, sodium chloride, sodium dihydrogen phosphate, biphosphate
Potassium is dissolved in distilled water and is formulated.
Further, in the PBS buffer solution potassium chloride, sodium chloride, sodium dihydrogen phosphate, potassium dihydrogen phosphate mass ratio
For 1:(35-50): (10-15): 1.
Further, the pH value of the PBS buffer solution is 2-4, and in the range, drug release is slow, sustainable 8h
More than, it is greater than the pH value, microspheres swell performance is poor.
Preferably, calcium chloride solution concentration is 1% in step (2), and drug releases in calcium ion concentration influence microballoon
Speed is put, with Ca2+The increase of concentration, the rate of release of drug slows down in microballoon, Ca2+Concentration must not be lower than 0.02 mol/L, no
The gelled pill hardness then prepared is small, and complete spherical shape, the mutual adhesion of bead are difficult to keep in preparation and flushing.
Preferably, sodium alginate soln concentration is 1% in step (3), and sodium alginate concentration is excessively high to will lead to solution
It crosses viscous, is unfavorable for the progress of dropping preparation method, and concentration is too low that will to will lead to droplet profile irregular.
Preferably, microballoon is rinsed 3-5 times with PBS buffer solution in step (6).
Preferably, the drug release concentration of the virazole gel micro-ball of preparation is surveyed using ultraviolet spectrophotometry
It is fixed.
Further, virazole assay wavelength is 213nm in virazole gel micro-ball.
The beneficial effects of the present invention are: the present invention can form the property of slightly solubility gel using alginic acid with divalent calcium ions
The virazole gel micro-ball of preparation, drug release slowly up to 8 hours or more, swelling behavior it is good, embedding rate up to 65% or more,
It can make full use of curative effect of medication.
Specific embodiment
The present invention will be further described in detail with reference to the specific embodiments, to help those skilled in the art
There is more complete, accurate and deep understanding to inventive concept of the invention, technical solution, protection scope of the present invention includes but not
It is limited to following embodiment, the details of any pair of technical solution of the present invention under the premise of without departing from spirit and scope
It is fallen within the protection scope of the present invention with the modification that form is made.
Embodiment 1
A kind of preparation method of virazole gel micro-ball, comprising the following steps:
(1) potassium chloride 0.2g, sodium chloride 8.0g, sodium dihydrogen phosphate 2.84g, potassium dihydrogen phosphate 0.2g are accurately weighed and is dissolved in steaming
In distilled water, PBS buffer solution is configured in 1000ml volumetric flask, it is spare；
(2) calcium chloride solution that compound concentration is 1%；
(3) sodium alginate soln that compound concentration is 1%；
(4) virazole injection one is taken, content 0.1g/2ml is placed in 100ml measuring bottle, is dissolved with distilled water and is diluted to quarter
Degree, shakes up, the stock solution of 1mg/ml is made；
(5) configured virazole stock solution is added in configured good sodium alginate soln, is stirred to uniformly mixed；
(6) it is instilled in calcium chloride solution using the solution that processed water dropper obtains step (5), when instilling in magnetic agitation
Lower stirring bottom liquid avoids generating adhesion between microballoon with this, and be gelled 30min, is rinsed 3-5 times with PBS buffer solution, and it is solidifying to obtain virazole
Glue microballoon.
Embodiment 2
A kind of preparation method of virazole gel micro-ball, comprising the following steps:
(1) potassium chloride 0.2g, sodium chloride 9.0g, sodium dihydrogen phosphate 3g, potassium dihydrogen phosphate 0.2g are accurately weighed and is dissolved in distilled water
In, PBS buffer solution is configured in 1000ml volumetric flask, it is spare；
(2) calcium chloride solution that compound concentration is 0.5%；
(3) sodium alginate soln that compound concentration is 2%；
(4) virazole injection one is taken, content 0.1g/2ml is placed in 100ml measuring bottle, is dissolved with distilled water and is diluted to quarter
Degree, shakes up, the stock solution of 0.5mg/ml is made；
(5) configured virazole stock solution is added in configured good sodium alginate soln, is stirred to uniformly mixed；
(6) it is instilled in calcium chloride solution using the solution that processed water dropper obtains step (5), when instilling in magnetic agitation
Lower stirring bottom liquid avoids generating adhesion between microballoon with this, and be gelled 20min, is rinsed 3-5 times with PBS buffer solution, and it is solidifying to obtain virazole
Glue microballoon.
Embodiment 3
A kind of preparation method of virazole gel micro-ball, comprising the following steps:
(1) potassium chloride 0.2g, sodium chloride 8.0g, sodium dihydrogen phosphate 2.84g, potassium dihydrogen phosphate 0.2g are accurately weighed and is dissolved in steaming
In distilled water, PBS buffer solution is configured in 1000ml volumetric flask, it is spare；
(2) calcium chloride solution that compound concentration is 1.5%；
(3) sodium alginate soln that compound concentration is 3%；
(4) virazole injection one is taken, content 0.1g/2ml is placed in 100ml measuring bottle, is dissolved with distilled water and is diluted to quarter
Degree, shakes up, the stock solution of 4mg/ml is made；
(5) configured virazole stock solution is added in configured good sodium alginate soln, is stirred to uniformly mixed；
(6) it is instilled in calcium chloride solution using the solution that processed water dropper obtains step (5), when instilling in magnetic agitation
Lower stirring bottom liquid avoids generating adhesion between microballoon with this, and be gelled 60min, is rinsed 3-5 times with PBS buffer solution, and it is solidifying to obtain virazole
Glue microballoon.
Drug release test
Virazole gel micro-ball prepared by embodiment 1-3 carries out drug release determination, using determined by ultraviolet spectrophotometry virus
The drug concentration of azoles.
The drafting of working curve
The present embodiment takes virazole reference substance appropriate, using distilled water as solvent, is diluted to the solution of debita spissitudo, prepares phase with method
The auxiliary material solution for answering concentration, carries out UV scanning in 150nm-600nm wave-length coverage.Ultraviolet scanning atlas shows, virazole
Have maximal ultraviolet absorption at 213nm wavelength, and auxiliary material at the wavelength without absorption, therefore determine that 213nm contains as virazole
Measure fixed wavelength.
Virazole injection one is taken, content 0.1g/2ml is placed in 100ml measuring bottle, is dissolved and be diluted to distilled water
Scale shakes up, and the stock solution of 1mg/ml is made.Virazole solution is diluted with two times of methods, obtains the virazole of various concentration
Solution is followed successively by 31.25,15.63,7.81,3.91,1.95,0.98,0.49,0.24 μ g/ml, shakes up, using distilled water as blank,
Absorbance is measured at 213nm wavelength.Linear regression is carried out to concentration C (μ g/ml) with absorbance A, obtains regression equation are as follows: Y=
0.0530X+0.0600(R2=0.999).
Drug release determination
The virazole calcium alginate gel bead of Example 1-3 is put in configured good PBS buffer solution.Revolving speed is 50r/
Min, 37 DEG C of temperature, PBS buffer solution (pH6.8) 250ml is dissolution medium.It is taken respectively in the 0.5th, 1,2,3,4,5,6,8,10h
Sample, each 5ml, while dissolution medium 5ml is supplemented, absorbance is measured at 213nm, the result is as follows:
。
Claims (9)
1. a kind of preparation method of virazole gel micro-ball, it is characterised in that: the following steps are included:
(1) PBS buffer solution is prepared；
(2) compound concentration is the calcium chloride solution of 0.5-1.5%；
(3) compound concentration is the sodium alginate soln of 1-3%；
(4) virazole injection distilled water is dissolved and is diluted, be configured to the stock solution that concentration is 0.5-4mg/ml；
(5) configured virazole stock solution is added in configured good sodium alginate soln, is stirred to uniformly mixed；
(6) it is instilled in calcium chloride solution using the solution that processed water dropper obtains step (5), when instilling in magnetic agitation
Lower stirring bottom liquid, be gelled 10-60min, is rinsed with PBS buffer solution, obtains virazole gel micro-ball.
2. a kind of preparation method of virazole gel micro-ball according to claim 1, it is characterised in that: PBS in step (1)
Buffer solution is dissolved in distilled water and is formulated by potassium chloride, sodium chloride, sodium dihydrogen phosphate, potassium dihydrogen phosphate.
3. a kind of preparation method of virazole gel micro-ball according to claim 2, it is characterised in that: the PBS buffering
Chlorine in Solution potassium, sodium chloride, sodium dihydrogen phosphate, potassium dihydrogen phosphate mass ratio be 1:(35-50): (10-15): 1.
4. a kind of preparation method of virazole gel micro-ball according to claim 2 or 3, it is characterised in that: the PBS is slow
The pH value for rushing solution is 2-4.
5. a kind of preparation method of virazole gel micro-ball according to claim 1, it is characterised in that: chlorine in step (2)
Changing calcium solution concentration is 1%.
6. a kind of preparation method of virazole gel micro-ball according to claim 1, it is characterised in that: extra large in step (3)
Solution of sodium alginate concentration is 1%.
7. a kind of preparation method of virazole gel micro-ball according to claim 1, it is characterised in that: micro- in step (6)
Ball is rinsed 3-5 times with PBS buffer solution.
8. a kind of preparation method of virazole gel micro-ball according to claim 1, it is characterised in that: the virazole of preparation
The drug release concentration of gel micro-ball uses determined by ultraviolet spectrophotometry.
9. a kind of preparation method of virazole gel micro-ball according to claim 8, it is characterised in that: virazole gel is micro-
Virazole assay wavelength is 213nm in ball.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810992273.7A CN109010262A (en) | 2018-08-29 | 2018-08-29 | A kind of preparation method of virazole gel micro-ball |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810992273.7A CN109010262A (en) | 2018-08-29 | 2018-08-29 | A kind of preparation method of virazole gel micro-ball |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111387214A (en) * | 2020-04-07 | 2020-07-10 | 青岛农业大学 | Insect virus preparation with ultraviolet resistance and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244036A (en) * | 2008-03-28 | 2008-08-20 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | High dispersion does type containing cholesterol group phosphoryl nucleoside analogue |
| CN107802602A (en) * | 2017-12-09 | 2018-03-16 | 任冉 | The preparation method of gossypol acetate calcium alginate gel bead |
-
2018
- 2018-08-29 CN CN201810992273.7A patent/CN109010262A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244036A (en) * | 2008-03-28 | 2008-08-20 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | High dispersion does type containing cholesterol group phosphoryl nucleoside analogue |
| CN107802602A (en) * | 2017-12-09 | 2018-03-16 | 任冉 | The preparation method of gossypol acetate calcium alginate gel bead |
Non-Patent Citations (1)
| Title |
|---|
| 刘文: "《药用高分子材料学》", 31 July 2017, 中国中医药出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111387214A (en) * | 2020-04-07 | 2020-07-10 | 青岛农业大学 | Insect virus preparation with ultraviolet resistance and preparation method thereof |
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Application publication date: 20181218 |