CN115919811A - Theophylline/beta-cyclodextrin composite aerosol inhalation preparation with targeting function and application thereof - Google Patents
Theophylline/beta-cyclodextrin composite aerosol inhalation preparation with targeting function and application thereof Download PDFInfo
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- CN115919811A CN115919811A CN202210792852.3A CN202210792852A CN115919811A CN 115919811 A CN115919811 A CN 115919811A CN 202210792852 A CN202210792852 A CN 202210792852A CN 115919811 A CN115919811 A CN 115919811A
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- theophylline
- beta
- cyclodextrin
- targeting function
- chitosan
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- 239000001116 FEMA 4028 Substances 0.000 title claims abstract description 69
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses a theophylline/beta-cyclodextrin composite aerosol inhalation preparation with a targeting function and application thereof. The atomization inhalation preparation disclosed by the invention directly acts on the airway of a patient through a dry powder inhalation device to quickly play the roles of resisting inflammation and relieving spasm, the theophylline blood-entering amount is small, the blood concentration is far lower than the highest value of a safety range, the adverse reaction of the traditional theophylline is avoided, and the safety and the applicability of a theophylline medicine are enhanced.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a theophylline/beta-cyclodextrin composite aerosol inhalation preparation with a targeting function and application thereof.
Background
The effective components of the theophylline medicines are theophylline and derivatives thereof, the existing theophylline medicine preparation is mainly administrated by intravenous drip or oral administration, the safety range of the effective blood concentration is narrow, toxic reaction can be caused if the blood concentration exceeds 20 mug/mL, and the blood concentration needs to be monitored regularly in clinical application to prevent poisoning caused by overhigh blood concentration of a patient. The oral administration mode has unstable absorption, a plurality of clearance influence factors in vivo and large individual difference, the blood concentration is difficult to control and is easy to generate poisoning, and excessive poisoning can be generated due to excessive dosage once, high intravenous injection speed or repeated medication effect accumulation. Moreover, sometimes the toxic symptoms are not easily found, even misdiagnosis is caused by the original disease itself, and thus the dosage of theophylline is further increased by mistake, resulting in serious poisoning. In addition, infection can affect theophylline metabolism and increase blood levels to toxic levels, and the clinical effects of bronchorelaxation are not definitive when patients are treated with theophylline. The clinical application of theophylline is greatly limited due to the above disadvantages. Therefore, the development of a theophylline pharmaceutical preparation which can target respiratory tract lesions, inhibit inflammation mediated by neutrophils and macrophages, and simultaneously can penetrate airway epithelia to smooth muscle cells to relieve airway spasm is urgently needed.
Chitosan (CS) is a natural polysaccharide with abundant resources, has the advantages of good biocompatibility, biodegradability and the like, and is widely applied to carriers of pharmaceutical preparations. The swelling property of the chitosan is just suitable for meeting the point, and the microspheres with proper size can avoid the scavenging action of macrophages after obtaining ideal lung deposition and generating enlarged volume under the action of lung liquid. In addition, chitosan also has the following advantages: (1) the surface is provided with positive charges, and the cell surface with negative charges is easy to generate electrostatic interaction and attach to the surface of the lung; (2) hydrogen bonds with the mucosal layer of the lung, and stronger mucosal adhesion is generated by combination of the hydrogen bonds and the mucosal layer; (3) enhancing the permeability of the membrane and the absorption of the mucosa layer to the drug; (4) enzyme inhibition. If the drug is loaded in the chitosan microspheres, the drug can be maximally deposited in the lung and the release of the drug in the lung can be prolonged. Cyclodextrin is cyclic and is connected by alpha-1, 4-glycosidic bond D-glucopyranose unit constituent oligomeric maltose, there are alpha-, beta-and gamma-cyclodextrin commonly, research shows that beta-cyclodextrin has larger cavity bore than alpha-cyclodextrin, compare gamma-cyclodextrin production cost lower, if adopt beta-cyclodextrin can carry more theophylline granule and carry on the mass production, have not seen in the prior art that chitosan wraps up beta-cyclodextrin and carry theophylline pharmaceutical preparation relevant report.
Disclosure of Invention
In order to overcome the defects in the prior art, the first purpose of the invention is to provide theophylline/beta-cyclodextrin composite freeze-dried powder with targeting function.
The second purpose of the invention is to provide a theophylline/beta-cyclodextrin composite aerosol inhalation preparation with a targeting function, which comprises the theophylline/beta-cyclodextrin composite freeze-dried powder with the targeting function.
The third purpose of the invention is to provide the application of the theophylline/beta-cyclodextrin composite aerosol inhalation preparation with the targeting function as or in the preparation of medicines for treating chronic lung diseases.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides theophylline/beta-cyclodextrin composite freeze-dried powder with a targeting function, which is prepared by a preparation method comprising the following steps:
(1) Preparation of beta-cyclodextrin granules: preparing a sodium hydroxide solution with the concentration of 0.4g/mL, continuously stirring in a water bath at 40 ℃, slowly adding beta-cyclodextrin particles into the sodium hydroxide solution while stirring, obtaining a colorless transparent solution after 30min, filtering by using a 0.45 mu M filter, washing by using dilute HCl aqueous solution, absolute ethyl alcohol and deionized water sequentially for 3 times, washing by using acetone for 2 times to obtain a white solid, and air-drying at room temperature to obtain a white powdery solid, namely the beta-cyclodextrin particles;
(2) Preparation of theophylline/beta-cyclodextrin granules: dissolving anhydrous theophylline in anhydrous ethanol solution, adding the beta-cyclodextrin particles, stirring thoroughly to make the theoretical drug-loading rate reach 20.0% (w/w), standing to room temperature, refrigerating for 24h, taking out, filtering with 0.22 μ M filter, air drying in shade to obtain theophylline/beta-cyclodextrin particles;
(3) Preparing theophylline/beta-cyclodextrin composite freeze-dried powder with targeting function:
(3a) Dissolving chitosan in 1% (w/v) acetic acid solution to obtain chitosan solution, adjusting pH value to 6.0 with 10M sodium hydroxide, adding 20% (w/v) of theophylline/beta-cyclodextrin particles with the same volume, stirring uniformly, adding a Tripolyphosphate (TPP) aqueous solution with the same volume dropwise under mild magnetic stirring, spontaneously forming crosslinking and coacervation of chitosan, centrifuging at 8000rpm for 5min for purification, and dispersing in deionized water with the same volume to obtain theophylline/beta-cyclodextrin solvent wrapped by chitosan;
(3b) Gradient cooling of 3 μ M Aptammer 14DNA solution: cooling to room temperature at 95 ℃ for 5min,65 ℃ for 15min,37 ℃ for 25min, and diluting to 150nM with deionized water to obtain an aptamer Aptammer 14;
(3c) Adding polyethylene glycol (PEG) into 10mL of the chitosan-coated theophylline/beta-cyclodextrin solvent, simultaneously adding 20nM of the aptamer Aptammer 14, shaking at 37 ℃ for 1h, centrifuging at 8000rpm for 5min for purification, washing with deionized water for three times, freeze-spray drying (SFD) to obtain freeze-dried powder, and storing at 4 ℃ in a dark place.
Preferably, in step (1), the mass ratio of sodium hydroxide to β -cyclodextrin particles is 2.
Preferably, in step (3), the polyethylene glycol is polyethylene glycol 2000 having amino side groups.
Preferably, in step (3), the concentration of chitosan is 5mg/mL, the rotation speed of magnetic stirring is 500rpm, the concentration of the tripolyphosphate aqueous solution is 0.7mg/mL, and the concentration of polyethylene glycol is 0.1mg/mL.
Preferably, the single-stranded DNA sequence of Aptarmer 14 is 5-.
The invention also provides a theophylline/beta-cyclodextrin composite aerosol inhalation preparation with the targeting function, which is obtained by placing theophylline/beta-cyclodextrin composite frozen dry powder with the targeting function in a Dry Powder Inhalation System (DPIs).
The invention also provides application of the theophylline/beta-cyclodextrin composite aerosol inhalation preparation with the targeting function as or in preparation of a medicament for treating chronic lung diseases.
Preferably, the pharmaceutical dosage form is an aerosol inhalation preparation, and the administration mode is inhalation administration through oral cavity or nasal cavity airways.
Preferably, the chronic lung disease includes, but is not limited to, chronic obstructive pulmonary disease, bronchial asthma, chronic bronchitis, and emphysema with bronchospasm.
In the preferable technical scheme, hydrophilic and biocompatible hydroxypropyl HP-beta-cyclodextrin is adopted, but the HP-beta-cyclodextrin carries anions on the surface, so that the HP-beta-cyclodextrin cannot be taken by cells and cannot pass through the mucus layer of the airway, and CS/PEG is used for wrapping the material to better pass through the mucus layer of the airway. In addition, the action target of theophylline is airway smooth muscle cells, which are the middle layer of the airway, and below airway epithelium, the theophylline is reported to cause adverse reactions of the airway, and in order to reduce the adverse reactions and increase the number and concentration of theophylline reaching the airway smooth muscle, an RNA Aptamer Aptamer 14 is further used, which mediates the uptake of nanoparticles by the smooth muscle cells, but is hardly taken up by the airway epithelium and vascular endothelial cells. The theophylline/beta-cyclodextrin composite atomization inhalation preparation is prepared by carrying theophylline particles by HP-beta-cyclodextrin, coating the theophylline particles by CS/PEG and then modifying RNA aptamers, thereby ensuring that the preparation is more effective in airway smooth muscle cells, and playing the roles of resisting inflammation and relieving spasm.
Compared with the prior art, the invention has the beneficial effects that:
(1) The theophylline/beta-cyclodextrin compound atomization inhalation preparation directly acts on an air passage through a dry powder inhalation device, so that the theophylline quickly and directly reaches the action part of the air passage in a targeted manner to quickly play the roles of resisting inflammation and relieving spasm, and the theophylline/beta-cyclodextrin compound atomization inhalation preparation is suitable for treating chronic obstructive pulmonary disease, bronchial asthma and the like, relaxing bronchus, inhibiting the inflammatory reaction of the air passage to relieve the asthmatic symptoms and is also suitable for treating chronic bronchitis and the bronchospasm symptoms accompanied by emphysema.
(2) The aerosol inhalation preparation can be directly acted on respiratory tract focuses to play a role through oral or nasal airway inhalation type administration, the theophylline blood-entering amount is small, the blood concentration is far lower than the highest value of a safety range, adverse reactions of the traditional theophylline are avoided, the safety and the applicability of theophylline medicines are enhanced, and the safety and the efficacy problems caused by the narrow safety range of effective blood concentration or long time of reaching the focuses of the existing theophylline medicine preparation in an intravenous drip or oral mode are solved.
Drawings
FIG. 1 is a flow chart of the preparation process of theophylline/beta-cyclodextrin composite frozen dry powder with targeting function in the example.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention are clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.
Example 1
In this embodiment, a theophylline/β -cyclodextrin composite lyophilized powder with a targeting function is prepared according to a process flow diagram shown in fig. 1, and the specific steps are as follows:
(1) Preparation of beta-cyclodextrin granules: weighing 4.00g of sodium hydroxide, placing the sodium hydroxide in a beaker, adding 10mL of deionized water, fully and uniformly mixing, and standing to room temperature. Continuously stirring a sodium hydroxide solution in a water bath at 40 ℃, weighing 6.00g of beta-cyclodextrin particles, slowly adding the beta-cyclodextrin particles into the sodium hydroxide solution while stirring, and obtaining a colorless transparent solution after about 30 min; filtering the solution with a 0.45 mu M filter, washing with dilute HCl aqueous solution, absolute ethyl alcohol and deionized water for 3 times, washing with acetone for 2 times to obtain a white solid, and air-drying at room temperature to obtain a white powdery solid, namely the beta-cyclodextrin particles.
(2) Preparation of theophylline/beta-cyclodextrin granules: the anhydrous theophylline is fully dissolved in an anhydrous ethanol solution, then a certain amount of beta-cyclodextrin particles are added, the mixture is fully stirred and uniformly mixed for 24 hours, the theoretical drug-loading rate reaches 20.0 percent (w/w), the mixture is placed in a refrigerating chamber for 24 hours after standing to room temperature, then the mixture is taken out and filtered by a 0.22 mu M filter, and the mixture is placed in the shade and dried to obtain the theophylline/beta-cyclodextrin particles.
(3) Preparing targeted chitosan/polyethylene glycol-theophylline/beta-cyclodextrin particles:
a.50mg of chitosan was dissolved in 10mL of 1% (w/v) acetic acid solution, after sufficient dissolution, the pH value was adjusted to 6.0 with 10M sodium hydroxide, then 20% (w/v) of theophylline/beta-cyclodextrin particles of the same volume were added, and the mixture was sufficiently stirred and mixed. Dropwise adding under mild magnetic stirring (500 rpm), adding an equal volume of tripolyphosphate aqueous solution (0.7 mg/mL), allowing chitosan to spontaneously form cross-linking and coacervation, centrifuging at 8,000rpm for 5min for purification, and dispersing in 10mL of deionized water to obtain chitosan-theophylline/beta-cyclodextrin solvent;
b. synthesis of aptamer 14: the single-stranded DNA sequence of Aptarmer 14 is 5' TCGGGCGAGTCGTCTTGGGGAGGTCAGAACGAAAGGCCCGCATCGTCCCCC-. After synthesis, a 3 μ M solution of DNA was subjected to gradient cooling: 95 ℃ for 5min,65 ℃ for 15min,37 ℃ for 25min. Then cooling to room temperature, and then diluting to 150nM with diluted deionized water;
c. adding 1mg of polyethylene glycol 2000 with amino side groups into 10mL of chitosan-theophylline/beta-cyclodextrin solvent, simultaneously adding 20nM aptamer Aptammer 14, shaking at 37 ℃ for 1h, then purifying by centrifuging at 8,000rpm for 5min, then washing with deionized water for three times, and carrying out freeze spray drying on the nano material and storing in the dark at 4 ℃ to obtain the chitosan/theophylline/beta-cyclodextrin nanoparticle.
Example 2
The theophylline/beta-cyclodextrin composite freeze dry powder with the targeting function prepared in the example 1 is used for treating chronic lung diseases of patients, and is administered by oral or nasal airway inhalation, and the specific steps are as follows:
(1) Placing the atomized inhalation preparation in dry powder inhalation Devices (DPIs) and uncovering;
(2) The patient adjusts breathing, slowly exhales the air (the air can not be exhaled facing to the suction nozzle of the device, the hand holding the device does not need to block the two air inlet holes below the bottle body), the suction nozzle part of the device is placed between the upper and lower teeth, the suction nozzle is completely wrapped by the two lips, the patient inhales the air forcefully and deeply, after the inhalation is completed, the suction nozzle is moved away and holds the breath for 5-10 seconds, and then the breathing is recovered.
(3) After the inhalation action of a patient, the atomized inhalation preparation enters the respiratory tract and reaches smooth muscle cells through the leakage effect of airway epithelium, so that the atomized inhalation preparation can inhibit inflammation mediated by neutrophile and macrophage on one hand, can penetrate the airway epithelium and leak to the smooth muscle cells on the other hand, and slowly release theophylline, thereby playing the roles of resisting inflammation and relieving airway spasm.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. The theophylline/beta-cyclodextrin composite frozen dry powder with the targeting function is characterized by being prepared by a preparation method comprising the following steps:
(1) Preparation of beta-cyclodextrin granules: preparing a sodium hydroxide solution with the concentration of 0.4g/mL, continuously stirring in a water bath at 40 ℃, slowly adding beta-cyclodextrin particles into the sodium hydroxide solution while stirring, obtaining a colorless transparent solution after 30min, filtering by using a 0.45 mu M filter, washing by using dilute HCl aqueous solution, absolute ethyl alcohol and deionized water sequentially for 3 times, washing by using acetone for 2 times to obtain a white solid, and air-drying at room temperature to obtain a white powdery solid, namely the beta-cyclodextrin particles;
(2) Preparation of theophylline/beta-cyclodextrin granules: dissolving anhydrous theophylline in anhydrous ethanol solution, adding the beta-cyclodextrin particles, stirring thoroughly to make the theoretical drug-loading rate reach 20.0% (w/w), standing to room temperature, refrigerating for 24h, taking out, filtering with 0.22 μ M filter, air drying in shade to obtain theophylline/beta-cyclodextrin particles;
(3) Preparing theophylline/beta-cyclodextrin composite freeze-dried powder with a targeting function:
(3a) Dissolving chitosan in 1% (w/v) acetic acid solution to obtain chitosan solution, adjusting pH value to 6.0 with 10M sodium hydroxide, adding 20% (w/v) of theophylline/beta-cyclodextrin particles with the same volume, stirring uniformly, adding a Tripolyphosphate (TPP) aqueous solution with the same volume dropwise under mild magnetic stirring, spontaneously forming crosslinking and coacervation of chitosan, centrifuging at 8000rpm for 5min for purification, and dispersing in deionized water with the same volume to obtain theophylline/beta-cyclodextrin solvent wrapped by chitosan;
(3b) Gradient cooling of 3 μ M Aptammer 14DNA solution: cooling to room temperature at 95 ℃ for 5min,65 ℃ for 15min,37 ℃ for 25min, and diluting to 150nM with deionized water to obtain aptamer Aptammer 14;
(3c) Adding polyethylene glycol (PEG) into 10mL of the theophylline/beta-cyclodextrin solvent coated by chitosan, adding 20nM of the aptamer Aptammer 14, shaking at 37 ℃ for 1h, centrifuging at 8000rpm for 5min for purification, washing with deionized water for three times, freeze-spray drying to obtain freeze-dried powder, and storing at 4 ℃ in a dark place.
2. The theophylline/beta-cyclodextrin composite freeze-dried powder with the targeting function according to claim 1, wherein in the step (1), the mass ratio of sodium hydroxide to beta-cyclodextrin particles is 2.
3. The theophylline/beta-cyclodextrin composite lyophilized powder with a targeting function according to claim 1, wherein the beta-cyclodextrin particles are hydroxypropyl-beta-cyclodextrin particles.
4. The theophylline/beta-cyclodextrin composite lyophilized powder having a targeting function according to claim 1, wherein in the step (3), the polyethylene glycol is polyethylene glycol 2000 having an amino side group.
5. The theophylline/beta-cyclodextrin composite frozen dry powder with the targeting function according to claim 1, wherein in the step (3), the concentration of chitosan is 5mg/mL, the rotation speed of magnetic stirring is 500rpm, the concentration of the tripolyphosphate aqueous solution is 0.7mg/mL, and the concentration of polyethylene glycol is 0.1mg/mL.
6. The theophylline/beta-cyclodextrin composite frozen dry powder with targeting function according to claim 1, wherein the single-stranded DNA sequence of Aptarmer 14 is 5.
7. A theophylline/β -cyclodextrin composite aerosol inhalation formulation with a targeting function, comprising the theophylline/β -cyclodextrin composite lyophilized powder with a targeting function according to any one of claims 1 to 6.
8. Use of the theophylline/β -cyclodextrin composite aerosol inhalation formulation with targeting function according to claim 7 as or in the manufacture of a medicament for the treatment of chronic lung disease.
9. The use according to claim 8, wherein the pharmaceutical dosage form is an inhaled aerosol formulation and is administered by inhalation through the oral or nasal airways.
10. The use of claim 8, wherein said chronic lung disease includes, but is not limited to, chronic obstructive pulmonary disease, bronchial asthma, chronic bronchitis, and emphysema with bronchospasm.
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| CN102090395A (en) * | 2011-01-05 | 2011-06-15 | 贵州省烟草科学研究所 | Abscisic acid-embedded chitosan nanoparticles and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| 刘长辉: "DNA介导的功能化介孔二氧化硅的药物控释与生物传感研究", 中国博士学位论文全文数据库 工程科技Ⅰ辑, no. 2, pages 50 * |
| 杨黎燕等: "茶碱β-环糊精聚合物微球的制备与缓释性能", 中国实验方剂学杂志, vol. 17, no. 16, pages 1 - 2 * |
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