CN105250244A - Pulmonary inhalation curcumin-phospholipid complex chitosan microspheres and preparation method thereof - Google Patents
Pulmonary inhalation curcumin-phospholipid complex chitosan microspheres and preparation method thereof Download PDFInfo
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- CN105250244A CN105250244A CN201410341770.2A CN201410341770A CN105250244A CN 105250244 A CN105250244 A CN 105250244A CN 201410341770 A CN201410341770 A CN 201410341770A CN 105250244 A CN105250244 A CN 105250244A
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Abstract
The present invention discloses pulmonary inhalation curcumin-phospholipid complex chitosan microspheres and a preparation method thereof, wherein the pulmonary inhalation curcumin-phospholipid complex chitosan microspheres comprise, by weight, 1 part of a curcumin compound, 2-4 parts of phospholipid, and 4-10 parts of chitosan, and are prepared by using a spray-drying method. According to the present invention, the microspheres have good dispersion property, do not have significant aggregation and other phenomena, have the particle size of 1-10 [mu]m, and are suitable for the dry powder inhalation agent so as to achieve the pulmonary administration purpose, wherein the effective site deposition rate determined by a two-stage glass impactor is 20-60%.
Description
Technical field
The present invention relates to the microball preparation that a kind of pulmonary sucks, specifically a kind of phospholipid complexes of curcumin chitosan microball and preparation method thereof.
The invention belongs to technical field of medicine.
Background technology
The application of pulmonary administration approach has thousands of years history.Medicine directly can be delivered to site of action by pulmonary administration, reduces the distribution of medicine in its hetero-organization; Pulmonary absorption area is large, blood flow enriches, drug absorption is rapid, and without liver first-pass effect, pulmonary administration is provided with and improves the bioavailability of medicine and the drug level of pulmonary, reduce drug dose, alleviate or avoid the advantages such as adverse effect, become effective route of administration of the pulmonary disease such as treatment pneumonia, bronchial asthma, pulmonary tuberculosis.
Current clinical conventional pulmonary sucks preparation mainly metered dose inhalation aerosol.There is following shortcoming in metered dose inhalation aerosol: the propellant dichlorodifluoromethan hydro carbons that (1) is commonly used can destroy atmospheric ozone layer, and accumulation has certain cardiac toxicity in vivo; (2) when using need the triggering of device and air-breathing to coordinate, patient is not easy to operate, and transport efficacy is low.Foradil Aerolizer formoterol fumarate is the another kind of form of Pulmonary inhalation, be by micronized medicine or/and carrier with the form such as capsule, vesicle, adopt special suction apparatus to be initiatively sucked into pulmonary by patient.Foradil Aerolizer formoterol fumarate, without the need to propellant and pressure vessel, avoids the coordination problem of breathing between atomization, simple to operation, now instead of the pressure-type metered dose inhalation aerosol kind of parts of traditional, has become a kind of new treatment means.
Foradil Aerolizer formoterol fumarate requires that preparation has good dust cloud, effective pulmonary deposition ratio, lower pulmonary's clearance rate and good vector safety etc.Chitosan microball meets these requirements, is applicable to pulmonary delivery system: the good biocompatibility of (1) chitosan and respiratory tract and alveolar epithelial cells, and has good biological degradability; (2) chitosan is positively charged, can interact with the negative charge of alveolar mucosa, improves adhesiveness, reduces clearance rate, extends pulmonary's holdup time; (3) have swellability, its microgranule gets final product water absorption and swelling after moistening pulmonary deposition, and volumetric diameter increases, and avoids engulfing of macrophage, reduces clearance rate; (4) controlled pharmacy rate of release; (5) chitosan can open cell connection, promotes drug absorption, and is reversible on the impact of mucosal function.
Phosphatide complexes be medicine and phospholipid with 1: 1 or 1: 2 a kind of lipid carrier of being connected to form by covalent bond of mol ratio, there is the dissolubility improving medicine, strengthen and absorb, improve the effects such as bioavailability.The 70-85% of alveolar surface composition is phospholipid substance, is that the carrier of main material has good biocompatibility in pulmonary administration with phospholipid, and the unique advantages such as absorption.
Curcumin chemical compounds is the effective constituents extracted from the rhizome of zingiberaceous plant Rhizoma Curcumae Longae, mainly comprises curcumin, demethoxycurcumin, Bisdemethoxycurcumin etc.Curcumin chemical compounds shows good therapeutic value and application prospect in the pulmonary disease such as prevention and therapy pulmonary fibrosis, pulmonary carcinoma.But curcumin chemical compounds water solublity extreme difference, oral administration biaavailability is extremely low, and pulmonary drug concentrations is lower, limits its clinical practice.
Summary of the invention
The object of this invention is to provide a kind of phospholipid complexes of curcumin chitosan microball and preparation method thereof that can be used for pulmonary and suck, treat pulmonary fibrosis, pulmonary carcinoma for Foradil Aerolizer formoterol fumarate through pulmonary administration.
Technical scheme of the present invention is:
The phospholipid complexes of curcumin chitosan microball that pulmonary sucks, is made up of the component of following weight portion:
Curcumin chemical compounds: 1 part
Phospholipid: 2-4 part
Chitosan: 4-10 part
Sodium tripolyphosphate: 2-20 part
Described curcumin chemical compounds is made up of one or more in curcumin, demethoxycurcumin, Bisdemethoxycurcumin.
Described deacetylating degree of chitosan >=90%, viscosity is between 70-300mpas.
The preparation method of described microsphere, step is as follows:
(1) curcumin chemical compounds and phospholipid are dissolved in dehydrated alcohol, stirring in water bath 3-12h, are re-introduced in purified water, obtained phospholipid complexes of curcumin aqueous dispersions;
(2) chitosan is dissolved in the glacial acetic acid of 0.5-2wt%, is mixed with certain density chitosan solution, then in the aqueous dispersions of impouring above-mentioned steps (1), mix homogeneously, drips sodium tripolyphosphate solution under Keep agitation condition;
(3) solution spray of above-mentioned steps (2) is dry, obtained powder microsphere:
The preparation method of described microsphere, is characterized in that: described bath temperature is 40-60 DEG C, and the volume ratio of dehydrated alcohol and purified water is 1: 40-1: 100.
The preparation method of described microsphere, is characterized in that: described chitosan solution concentration is 1-3% (w/v), and tripolyphosphate na concn is 0.1-3% (w/v), and the consumption of sodium tripolyphosphate is 0.5-2 times of chitosan mass.
The preparation method of described microsphere, is characterized in that: the rotating speed of stirring is 1000-2500rpm.
The preparation method of described microsphere, is characterized in that: described spray drying condition is: inlet temperature: 120-160 DEG C, sample introduction speed: 1-10mlmin
-1, atomisation pressure: 0.1-0.3Mpa.
Obtained microsphere powder is the spherical of rounding, smooth surface, particle diameter at 1-10 μm, preferred 1-5 μm, even particle size distribution.
The invention has the advantages that: this phospholipid complexes of curcumin chitosan microball has good dispersibility, without phenomenons such as obvious gatherings, pulmonary deposition ratio is at 20-60%, and not easily by alveolar clearance, the carrier organism compatibility is good; Be applicable to Foradil Aerolizer formoterol fumarate through Pulmonary inhalation, without liver first-pass effect, pulmonary drug concentrations is high, applies simple and convenient.
Detailed description of the invention
Below in conjunction with case study on implementation, the invention will be further described.Preferred case study on implementation described herein, only for instruction and explanation of the present invention, is not intended to limit the present invention.
Embodiment 1: the curcumin phosphatide complexes chitosan microball that a kind of pulmonary sucks, is made up of the component of following weight portion:
Curcumin: 0.5g
Phospholipid: 1g
Chitosan (deacetylation is 92.7%, and viscosity is 298mpas): 2g
Sodium tripolyphosphate: 4g
The preparation method of above-mentioned curcumin phosphatide complexes chitosan microball is: curcumin and phospholipid are dissolved in 50ml dehydrated alcohol, is injected into 2000ml purified water after 40 DEG C of stirring in water bath (2000rpm) 12h; Chitosan is dissolved in the glacial acetic acid of 0.5%, is mixed with the solution that concentration is 1%, in the above-mentioned phospholipid complexes of curcumin aqueous dispersions of impouring, and mix homogeneously, (1500rpm) drips the sodium tripolyphosphate solution 2000ml of 0.2% under agitation; Gained liquid spray is dry, and collect microsphere, spray drying condition is: inlet temperature: 120 DEG C, sample introduction speed: 10mlmin
-1, atomisation pressure: 0.1Mpa.
Result: it is 5.89 μm that this pulmonary sucks microsphere average grain diameter, and carry out pulmonary deposition ratio investigation according to the People's Republic of China's 2010 editions States Pharmacopoeia specifications methods, the pulmonary deposition ratio of preparation reaches 26.59%.
Embodiment 2: the curcumin phosphatide complexes chitosan microball that a kind of pulmonary sucks, forming to be divided into and form by following weight portion:
Curcumin: 0.5g
Phospholipid: 1g
Chitosan (deacetylation is 91.3%, and viscosity is 196mpas): 3g
Sodium tripolyphosphate: 3g
The preparation method of above-mentioned curcumin phosphatide complexes chitosan microball is: by curcumin and phospholipid, be dissolved in 50ml dehydrated alcohol, is injected into 3000ml purified water after 50 DEG C of stirring in water bath (1500rpm) 5h; Chitosan is dissolved in the glacial acetic acid of 1%, is mixed with the solution that concentration is 2%, in the above-mentioned phospholipid complexes of curcumin aqueous dispersions of impouring, and mix homogeneously, (2000rpm) drips the sodium tripolyphosphate solution 300ml of 1% under agitation; Gained liquid spray is dry, and collect microsphere, spray drying condition is: inlet temperature: 140 DEG C, sample introduction speed: 5mlmin
-1, atomisation pressure: 0.2Mpa.
Result: it is 3.89 μm that this pulmonary sucks microsphere average grain diameter, and carry out pulmonary deposition ratio investigation according to the People's Republic of China's 2010 editions States Pharmacopoeia specifications methods, the pulmonary deposition ratio of preparation reaches 59.36%.
Embodiment 3: the curcumin phosphatide complexes chitosan microball that a kind of pulmonary sucks, forming to be divided into and form by following weight portion:
Curcumin: 0.5g
Phospholipid: 2g
Chitosan (deacetylation is 93.20%, and viscosity is 112mpas): 8g
Sodium tripolyphosphate: 4g
The preparation method of above-mentioned curcumin phosphatide complexes chitosan microball is: curcumin and phospholipid are dissolved in 50ml dehydrated alcohol, 5000ml purified water is injected into after 60 DEG C of stirring in water bath (1000rpm) 3h, chitosan is dissolved in the glacial acetic acid of 2%, be mixed with the solution that concentration is 3%, in the above-mentioned phospholipid complexes of curcumin aqueous dispersions of impouring, mix homogeneously, (2500rpm) drips the sodium tripolyphosphate solution 133ml of 3% under agitation; Gained liquid spray is dry, and collect microsphere, spray drying condition is: inlet temperature: 160 DEG C, sample introduction speed: 3mlmin
-1, atomisation pressure: 0.2Mpa.
Result: it is 4.48 μm that this pulmonary sucks microsphere average grain diameter, and carry out pulmonary deposition ratio investigation according to the People's Republic of China's 2010 editions States Pharmacopoeia specifications methods, the pulmonary deposition ratio of preparation reaches 39.77%.
Embodiment 4: the curcumin phosphatide complexes chitosan microball that a kind of pulmonary sucks, forming to be divided into and form by following weight portion:
Curcumin: 0.5g
Phospholipid: 2g
Chitosan (deacetylation is 91.50%, and viscosity is 70mpas): 6g
Sodium tripolyphosphate: 3g
The preparation method of above-mentioned curcumin phosphatide complexes chitosan microball is: curcumin and phospholipid are dissolved in 50ml dehydrated alcohol, is injected into 3000ml purified water after 60 DEG C of stirring in water bath (1000rpm) 3h; Chitosan is dissolved in the glacial acetic acid of 2%, is mixed with the solution that concentration is 2%, in the above-mentioned phospholipid complexes of curcumin aqueous dispersions of impouring, and mix homogeneously, (2000rpm) drips the sodium tripolyphosphate solution 600ml of 0.5% under agitation; Gained liquid spray is dry, and collect microsphere, spray drying condition is: inlet temperature: 140 DEG C, sample introduction speed: 3mlmin
-1, atomisation pressure: 0.3Mpa.
Result: it is 4.37 μm that this pulmonary sucks microsphere average grain diameter, and carry out pulmonary deposition ratio investigation according to the People's Republic of China's 2010 editions States Pharmacopoeia specifications methods, the pulmonary deposition ratio of preparation reaches 46.21%.
Claims (9)
1. a phospholipid complexes of curcumin chitosan microball for pulmonary's suction, is characterized in that, be made up of the component of following weight portion:
Curcumin chemical compounds: 1 part
Phospholipid: 2-4 part
Chitosan: 4-10 part
Sodium tripolyphosphate: 2-20 part.
2. microsphere according to claim 1, is characterized in that: described curcumin chemical compounds is made up of one or more in curcumin, demethoxycurcumin, Bisdemethoxycurcumin.
3. microsphere according to claim 1, is characterized in that: described deacetylating degree of chitosan >=90%, viscosity is between 70-300mpas.
4. microsphere according to claim 1, is characterized in that: the particle diameter of microsphere powder between 1-10 μm, preferred 1-5 μm.
5. the preparation method of the microsphere according to any one of claim 1-4, it said method comprising the steps of:
(1) curcumin chemical compounds and phospholipid are dissolved in dehydrated alcohol, stirring in water bath 3-12h, are re-introduced in purified water, obtained phospholipid complexes of curcumin aqueous dispersions;
(2) chitosan is dissolved in the glacial acetic acid of 0.5-2wt%, is mixed with certain density chitosan solution, then in the aqueous dispersions of impouring above-mentioned steps (1), be uniformly mixed, under Keep agitation condition, drip sodium tripolyphosphate solution;
(3) solution spray of above-mentioned steps (2) is dry, obtained powder microsphere.
6. the preparation method of microsphere according to claim 5, is characterized in that: described bath temperature is 40-60 DEG C, and the volume ratio of dehydrated alcohol and purified water is 1: 40-1: 100.
7. the preparation method of microsphere according to claim 5, it is characterized in that: described chitosan solution concentration is 1-3% (w/v), tripolyphosphate na concn is 0.1-3% (w/v), and the consumption of sodium tripolyphosphate is 0.5-2 times of chitosan mass.
8. the preparation method of microsphere according to claim 5, is characterized in that: the rotating speed stirred in step (1), (2) is 1000-2500rpm.
9. the preparation method of microsphere according to claim 5, is characterized in that: described spray drying condition is: inlet temperature: 120-160 DEG C, sample introduction speed: 1-10mlmin
-1, atomisation pressure: 0.1-0.3Mpa.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017186065A1 (en) * | 2016-04-26 | 2017-11-02 | 北京五和博澳药业有限公司 | Phospholipid/chitosan drug delivery system, preparation method and uses thereof |
| CN111714471A (en) * | 2020-06-15 | 2020-09-29 | 广东省医疗器械研究所 | Polymer microsphere for pulmonary drug delivery and preparation method and application thereof |
| WO2022162565A1 (en) * | 2021-01-27 | 2022-08-04 | Rashidinejad Ali | Flavonoid-enriched spray-dried powder |
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2014
- 2014-07-18 CN CN201410341770.2A patent/CN105250244A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017186065A1 (en) * | 2016-04-26 | 2017-11-02 | 北京五和博澳药业有限公司 | Phospholipid/chitosan drug delivery system, preparation method and uses thereof |
| CN107308132A (en) * | 2016-04-26 | 2017-11-03 | 北京五和博澳药业有限公司 | A kind of phosphatide chitosan drug delivery system and its production and use |
| CN113768901A (en) * | 2016-04-26 | 2021-12-10 | 北京五和博澳药业股份有限公司 | Phospholipid chitosan drug delivery system and preparation method and application thereof |
| CN113768901B (en) * | 2016-04-26 | 2023-09-22 | 北京五和博澳药业股份有限公司 | Phospholipid chitosan drug delivery system and preparation method and application thereof |
| CN111714471A (en) * | 2020-06-15 | 2020-09-29 | 广东省医疗器械研究所 | Polymer microsphere for pulmonary drug delivery and preparation method and application thereof |
| WO2022162565A1 (en) * | 2021-01-27 | 2022-08-04 | Rashidinejad Ali | Flavonoid-enriched spray-dried powder |
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