CN100356906C - Method for preparing hollow minisphere for lung administration - Google Patents
Method for preparing hollow minisphere for lung administration Download PDFInfo
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- CN100356906C CN100356906C CNB2004100311007A CN200410031100A CN100356906C CN 100356906 C CN100356906 C CN 100356906C CN B2004100311007 A CNB2004100311007 A CN B2004100311007A CN 200410031100 A CN200410031100 A CN 200410031100A CN 100356906 C CN100356906 C CN 100356906C
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- chitosan
- polyvinylpyrrolidone
- pulmonary administration
- tiny balloon
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Abstract
The present invention relates to a method for preparing hollow microspheres used for lung administration. The method comprises the following steps: adding low boiling point solvent and surface acting agents into the aqueous solution of chitosan and/or polyvinylpyrrolidone, wherein the aqueous solution of chitosan and/or polyvinylpyrrolidone accounts for 0.8 to 3 wt% of the mixture, the low boiling point solvent accounts for 30 to 70 wt% of the mixture, and the surface acting agents are alkyl polyglycoside which acounts for 5 to 40 wt% of the chitosan and/or the polyvinylpyrrolidone; then carrying out spraying and drying to obtain the hollow microspheres of the present invention. The preparing method also comprises the steps of adding spherical silicon dioxide particles whose particle diameters are from 80 to 200 nm into the aqueous solution of the chitosan and/or the polyvinylpyrrolidone. The particle diameters of the hollow microspheres prepared by the present invention are smaller than 40 mu m, and can be adjusted. When used as carriers of medicines, the hollow microspheres can fly into alveolus and can not be phagocytized by macrophage because of large particle diameters. The hollow microspheres are especially suitable for powder inhalant to achieve the purpose of lung administration.
Description
Technical field
The present invention relates to a kind of preparation method that is used for the tiny balloon of pulmonary administration.
Background technology
It is found that in the research of pulmonary administration alveolar is the ideal zone that realizes that medicine contacts with blood system, and in order to make drug particles arrive alveolar, granule must have suitable kinetic diameter.For the solid administration particle of particle diameter at 2 μ m～30 μ m, owing to float and fly poor performance, under just can depositing on mouth, nose, the trachea and bronchus, and these zones do not have abundant blood capillary, thereby can't realize administration, and these zones all cover by one deck phlegmatic temperament, just can be pushed to the oral cavity by the cilium of ciliated epithelial cell in case particle falls into wherein, finally become sputum and get rid of external; For the administration particle of particle diameter less than 2 μ m, can enter alveolar, but when they enter the alveolar inner surface, the macrophage that their very fast meetings are spread all over the lung inner surface is engulfed and is eliminated very soon, also can't realize administration.In sum, because the immunologic mechanism of above-mentioned pulmonary, people are difficult to reach as pharmaceutical carrier with solid particle the effect of pulmonary administration.
Summary of the invention
The solid particle that the objective of the invention is to overcome prior art for preparing is difficult to reach the defective of pulmonary administration effect as pharmaceutical carrier, thereby provide a kind of can preparing to have less aerodynamic diameter, and have the preparation method of the tiny balloon that is used for pulmonary administration of greater particle size.
The objective of the invention is to realize by the following technical solutions:
The preparation method that is used for the tiny balloon of pulmonary administration provided by the invention comprises the steps:
Low boiling point solvent and surfactant will be added in the aqueous solution of the 4wt% acetic acid solution of chitosan or polyvinylpyrrolidone, the concentration of the 4wt% acetic acid solution of described chitosan or the aqueous solution of polyvinylpyrrolidone is 0.25～3wt%, accounts for 30.6wt%, 55.8wt%, 56.0wt% or the 70.3wt% of mixed system weight; Described low boiling point solvent accounts for 29.4wt%, 41.9wt%, 43.6wt% or the 68.7wt% of mixed system weight; 5～40wt% of described surfactant comprise chitosan or polyvinylpyrrolidone weight; Carry out spray drying then, its hot-wind inlet temperature 〉=140 ℃, nozzle operation pressure 6kgf/cm
2, obtain the tiny balloon that is used for pulmonary administration of the present invention.
Described chitosan is deacetylation 〉=60%.
Described polyvinylpyrrolidone is number-average molecular weight≤30000.
The preferred 1wt% of the concentration of the acetic acid solution of the 4wt% of described chitosan or polyvinylpyrrolidone aqueous solution.
Described low boiling point solvent comprises ethanol, acetone, oxolane, preferred 30～70wt% ethanol, more preferred 45wt% ethanol.
Described surfactant is an APG, and the carbon number of its alkyl is 8～14, and is preferred 12～14, its addition to account for chitosan or/and the 10wt% of polyvinylpyrrolidone weight serves as preferred.
Preferred 160 ℃ of described spray-dired hot-wind inlet temperature.
The aqueous solution that the described preparation method that is used for the tiny balloon of pulmonary administration also is included in chitosan or polyvinylpyrrolidone adds the preparing spherical SiO 2 granule of particle diameter at 80～200nm, and its addition is a chitosan or/and 0～0.8 times of polyvinylpyrrolidone weight.
The tiny balloon particle diameter that is used for pulmonary administration that uses method preparation provided by the invention is less than 40 μ m, and adjustable grain, during as pharmaceutical carrier, both can float and fly into into alveolar, can be engulfed by macrophage more greatly and not because of particle diameter again.This granule is particularly useful for Foradil Aerolizer formoterol fumarate to reach the purpose of pulmonary administration.
The preparation method of the tiny balloon that is used for pulmonary administration provided by the invention is used to chitosan and polyvinylpyrrolidone to prepare carrier---the tiny balloon of pulmonary administration first.Chitosan is a kind of biopolymer that is obtained by the chitin deacetylase base.Chitin is the polysaccharide that is formed by connecting with β-1,4 glycosidic bond form by N-acetyl-2-amino-2-deoxy-D-glucose, the acetyl group on its strand is sloughed just obtained chitosan more than 50%.Shown in the molecule of chitosan is constructed as follows:
Owing to sloughed a large amount of acetyl group, the solubility property of chitosan increases greatly than chitin.Chitosan is a kind of nontoxic and degradable biological polysaccharide; Have good film property and become fibroid, can be used as the operation suture thread of degradable in vivo; In addition, it also has tangible bacteriostasis, also can be directly used in the inhibition tumor.It is to have utilized its good filming performance that the present invention is used for the pulmonary administration carrier with chitosan---and to form hollow microsphere, be again to have utilized its excellent biological compatibility, and certain antiinflammatory, antibacterial and suppress the effect of tumor.
The polyvinylpyrrolidone (PVP) that the present invention adopts, shown in its molecule is constructed as follows:
Polyvinylpyrrolidone is a kind of excipient substance of biological nontoxic commonly used, is widely used in solubilising, bonding, capsule shell, stably dispersing, film forming and the coating materials and the disintegrating agent etc. of medicine.Polyvinylpyrrolidone is as such as the coprecipitator of medicines such as Ah's morpholine, reserpine and beta-carotene, chloromycetin, dexamethasone, streptomycin and Testosterone the time, when it with dissolubility is little in water medicine co-precipitation after can improve the dissolubility and the dissolution velocity of medicine greatly, reach the result who reduces dosage and improve curative effect.Discover, when the molecular weight of polyvinylpyrrolidone less than 30000 the time, it just can be degraded in vivo smoothly, and its catabolite can not get rid of kidney and cause obstacle, has the biological safety of height.It promptly is to have utilized its biocompatibility as drug administration carrier that the present invention adopts polyvinylpyrrolidone, with and good film property and can disperse, the character of solubilising insoluble medicine.
The surfactant that adopts among the present invention is an APG, and this is a kind of All Pure Nature surfactant, and it is by starch or glucose and synthetic from the natural fatty alcohol of Oleum Cocois, nontoxic, non-stimulated to human body, the performance gentleness, can complete biodegradable, be safest surfactant.
In addition, the present invention also can add particle diameter at the preparing spherical SiO 2 granule of 80～200nm as additive.The ball wall of the microsphere of gained is more sticking when being equivalent to not add this composition, particle is reunited easily and is reduced flying quality, after adding silicon dioxide granule, help weakening intergranular bonding and reunion, hollow ball viscosity is descended, improve dispersibility, thereby help obtaining flying quality hollow bead preferably.
In sum, the preparation method that is used for the tiny balloon of pulmonary administration provided by the invention has the following advantages:
1) adopt spray drying, with short production cycle, and can control the particle diameter of thus obtained microsphere by regulating atomize, through experiment as can be known, dry and unlikely too high as long as temperature is enough to finish, the pattern that obtains microsphere is subjected to Temperature Influence little.
2) polysaccharide material of the excipient of employing high degree of biocompatibility and balling-up is as the wall material, and thus obtained microsphere has goodish biological safety.
3) chitosan that is adopted is by extracting in the chitin, its wide material sources, and price is lower, and has certain pharmaceutical characteristic.
Description of drawings
The chitosan tiny balloon that Fig. 1 makes for embodiment 1;
The tiny balloon that Fig. 2 makes for embodiment 1 is extruded the ball wall that the back of breaking forms;
Fig. 3 adds the tiny balloon that makes behind the nano-silicon dioxide particle for embodiment 3;
The spherical shell that breaks that shows after the tiny balloon extruding that Fig. 4 makes behind the nano-silicon dioxide particle for embodiment 3 adds;
The tiny balloon that Fig. 5 makes for embodiment 4.
The specific embodiment
Embodiment 1,
Low viscosity pharmaceutical grade chitosan 1g (deacetylation 60%) is dissolved in the acetic acid solution of 50ml 4%, add 27ml ethanol (accounting for the 30wt% of mixed system weight), and adding 0.2g APG APG-1214 (is provided by Nanjing petrochemical industry academy of Co., Ltd of SINOPEC, product grade is APG-1214, alkyl length is 12～14, solid content 50%) solution carries out spray drying, nozzle exit pressure 6kgf/cm behind the mixed solution mixing
2, fluid flow 20ml/min, 160 ℃ of hot blast inlet temperatures, spraying after finishing the 1.05g mean diameter is 18 microns a powder, promptly be used for the tiny balloon of pulmonary administration, its electron scanning micrograph such as Fig. 1 and Fig. 2.
As shown in Figure 1, the tiny balloon sphericity of gained is fine.This product process is rolled the back pattern that can observe as Fig. 2 under scanning electron microscope, this figure can be clear that through roll break after unfolded chitosan thin film, this thin film has certain elasticity, this figure further proves: the microsphere among Fig. 1 is a tiny balloon, and its wall material is a rubber-like chitosan thin film.
With polyvinylpyrrolidone (trade mark PVP K17, viscosity-average molecular weight is 10000, weight average molecular weight is 9500, number-average molecular weight is 2500) 2.7g is dissolved in the 50ml deionized water, add 50ml acetone, and adding 2.16g APG APG-0810 (is provided by Nanjing petrochemical industry academy of Co., Ltd of SINOPEC, carbon chain lengths 8～10, solid content 50%) solution, carry out spray drying behind the mixed solution mixing, the spray drying condition is with embodiment 1, the 4.5g mean diameter is 20 microns a powder, promptly be used for the tiny balloon of pulmonary administration.(wherein polyvinylpyrrolidone accounts for the 3wt% of mixed system weight, surfactant comprise polyvinylpyrrolidone 40%)
Embodiment 3,
Low viscosity pharmaceutical grade chitosan 1.33g (deacetylation 70%) is dissolved in 50ml 4% acetic acid solution, add 146ml ethanol (accounting for the 70wt% of mixed system weight), and the preparing spherical SiO 2 particles 1g of adding particle diameter 200nm, the solution that adds 0.133g APG APG-1214 (as described in example 1 above) again, carry out spray drying behind the mixed solution mixing, spray condition is with embodiment 1, the 1.75g mean diameter is 40 microns a powder, the tiny balloon that promptly is used for pulmonary administration, its scanning electron micrograph such as Fig. 3 and Fig. 4.(wherein dosage of surfactant is the 5wt% of chitosan, SiO
2Consumption is 0.8 times of chitosan)
Fold on the microsphere and hole increase as shown in Figure 3, and this all helps floating of particle and flies performance.Fig. 4 is for rolling this product the particle morphology that the back is seen under scanning electron microscope, can be clear that by Fig. 4 particle still is tiny balloon, but the fragility of its ball wall obviously increases than the microsphere among the embodiment shown in Figure 21, presents the pattern of non-plastic fracture after rolling.
Embodiment 4,
2.16g is dissolved in 150ml 4% acetic acid solution with low viscosity pharmaceutical grade chitosan (deacetylation 80%), add 150ml ethanol, and the preparing spherical SiO 2 particles 0.8g of adding particle diameter 80nm, the solution that adds 0.43g APG APG-0810 (as described in example 2 above) again, carry out spray drying behind the mixed solution mixing, spray condition is with embodiment 1, the 3.2g mean diameter is 23 microns a powder, the tiny balloon that promptly is used for pulmonary administration, its scanning electron micrograph such as Fig. 5.(chitosan content 0.8wt%)
Can find out obviously that from Fig. 5 granule is a hollow ball, and its wall material is more crisp, has and significantly breaks and fold, this all is the result who adds nanometer grade silica.
Claims (10)
1, a kind of preparation method that is used for the tiny balloon of pulmonary administration comprises the steps:
Low boiling point solvent and surfactant will be added in the aqueous solution of the 4wt% acetic acid solution of chitosan or polyvinylpyrrolidone, the concentration of the 4wt% acetic acid solution of described chitosan or the aqueous solution of polyvinylpyrrolidone is 0.25～3wt%, accounts for 30.6wt%, 55.8wt%, 56.0wt% or the 70.3wt% of mixed system weight; Described low boiling point solvent accounts for 29.4wt%, 41.9wt%, 43.6wt% or the 68.7wt% of mixed system weight; 5～40wt% of described surfactant comprise chitosan or polyvinylpyrrolidone weight; Carry out spray drying then, its hot-wind inlet temperature 〉=140 ℃, nozzle operation pressure 6kgf/cm
2, obtain being used for the tiny balloon of pulmonary administration.
2, the preparation method that is used for the tiny balloon of pulmonary administration as claimed in claim 1 is characterized in that, described chitosan is deacetylation 〉=60%.
3, the preparation method that is used for the tiny balloon of pulmonary administration as claimed in claim 1 is characterized in that, described polyvinylpyrrolidone is a number-average molecular weight 530000.
4, the preparation method that is used for the tiny balloon of pulmonary administration as claimed in claim 1 is characterized in that, the concentration of the acetic acid solution of the 4wt% of described chitosan or polyvinylpyrrolidone aqueous solution is 1wt%.
5, the preparation method that is used for the tiny balloon of pulmonary administration as claimed in claim 1 is characterized in that, described low boiling point solvent comprises ethanol, acetone, oxolane.
6, the preparation method that is used for the tiny balloon of pulmonary administration as claimed in claim 5 is characterized in that, described ethanol is 30～70wt% ethanol.
7, the preparation method that is used for the tiny balloon of pulmonary administration as claimed in claim 1 is characterized in that, described surfactant is an APG.
8, the preparation method that is used for the tiny balloon of pulmonary administration as claimed in claim 7 is characterized in that, the carbon number of the alkyl of described APG is 8～14.
9, the preparation method that is used for the tiny balloon of pulmonary administration as claimed in claim 7 is characterized in that, the carbon number of the alkyl of described APG is 12～14, and its addition accounts for the 10wt% of chitosan or polyvinylpyrrolidone weight.
10, the preparation method that is used for the tiny balloon of pulmonary administration as claimed in claim 1 is characterized in that, described spray-dired hot-wind inlet temperature is 160 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100311007A CN100356906C (en) | 2004-04-23 | 2004-04-23 | Method for preparing hollow minisphere for lung administration |
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| CNB2004100311007A CN100356906C (en) | 2004-04-23 | 2004-04-23 | Method for preparing hollow minisphere for lung administration |
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| CN100356906C true CN100356906C (en) | 2007-12-26 |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101433521B (en) * | 2007-11-14 | 2012-08-08 | 中国医学科学院药用植物研究所 | Medicinal inhalable particles, pulmonary inhalation using the same and preparation method thereof |
| CN101705068B (en) * | 2009-09-17 | 2012-11-21 | 广东海洋大学 | Method for preparing microcapsule adhesive used for novel heat-preserving and sound-insulating building coating |
| CN102728079A (en) * | 2012-06-21 | 2012-10-17 | 厦门蓝湾科技有限公司 | Drying method of water-soluble low molecular weight chitosan |
| CN105343007B (en) * | 2015-12-11 | 2018-05-25 | 中国人民解放军63975部队 | A kind of drug-additive pattern composite micro-powder preparation method |
| CN105456203B (en) * | 2015-12-11 | 2018-05-15 | 中国人民解放军63975部队 | A kind of drug-carrier pattern composite micro-powder preparation method |
| CN106045875A (en) * | 2016-06-25 | 2016-10-26 | 仇颖超 | Preparation method of occrycetin |
| CN112030206A (en) * | 2020-09-08 | 2020-12-04 | 重庆市真诚电镀有限公司 | Electroplating process for spectacle frame |
Citations (4)
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| WO2002009674A2 (en) * | 2000-07-28 | 2002-02-07 | Inhale Therapeutic Systems, Inc. | Methods and compositions to upregulate, redirect or limit immune responses to bioactive compounds |
| CN1371748A (en) * | 2002-03-18 | 2002-10-02 | 浙江大学 | Zhonghua soft-shelled turtle aeromonad oral slow-releasing microsphere vaccinum and preparation process thereof |
| CN1425457A (en) * | 2003-01-02 | 2003-06-25 | 濮桂宝 | Granular preparation for dysmenorrhea |
| CN1449748A (en) * | 2003-04-24 | 2003-10-22 | 王立强 | Dry powder microsphere inhalant for lung and preparation process thereof |
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- 2004-04-23 CN CNB2004100311007A patent/CN100356906C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002009674A2 (en) * | 2000-07-28 | 2002-02-07 | Inhale Therapeutic Systems, Inc. | Methods and compositions to upregulate, redirect or limit immune responses to bioactive compounds |
| CN1371748A (en) * | 2002-03-18 | 2002-10-02 | 浙江大学 | Zhonghua soft-shelled turtle aeromonad oral slow-releasing microsphere vaccinum and preparation process thereof |
| CN1425457A (en) * | 2003-01-02 | 2003-06-25 | 濮桂宝 | Granular preparation for dysmenorrhea |
| CN1449748A (en) * | 2003-04-24 | 2003-10-22 | 王立强 | Dry powder microsphere inhalant for lung and preparation process thereof |
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