CN114425048A - Hydroxychloroquine lipidosome inhalant and preparation method thereof - Google Patents
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Abstract
The invention provides a hydroxychloroquine liposome inhalant, which comprises the following components in part by weight: hydroxychloroquine, phospholipids and cholesterol, said hydroxychloroquine liposome inhalant being administered in the form of an aerosol. The hydroxychloroquine is prepared into a liposome preparation, the medicine is wrapped in the liposome, so that the adverse taste stimulation can be reduced, the compliance of a patient is improved, the pulmonary administration mode of the hydroxychloroquine can enable the medicine to directly reach the lung to exert the medicine effect aiming at pneumonia, the curative effect of the medicine is improved, the adverse reaction is reduced, the final preparation is a freeze-dried product and is filled with nitrogen, the instability phenomenon of the liposome preparation in the storage and transportation processes can be avoided, the stability of the preparation is improved, the hydroxychloroquine is used as a new preparation form of the hydroxychloroquine, the blank of the preparation is filled, and the patient who uses the medicine aiming at different diseases can have better choice.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a hydroxychloroquine liposome inhalant and a preparation method thereof.
Background
The major problems of oral hydroxychloroquine therapy can be serious side effects and toxicity, which are mainly caused by inconsistent accumulation of the drug on alveolar target cells, depending on intestinal absorption, hepatic first-pass metabolism, etc. The medicine can be targeted to the lung of a patient by preparing the medicine into an inhalant, so that the purposes of reducing the dosage of the medicine, reducing systemic adverse reactions and improving the compliance of the patient are achieved.
Hydroxychloroquine is a crystalline powder, bitter in taste. The unpleasant smells such as the bitter taste of the medicine are important restriction factors for improving the medication compliance of patients, and a proper and effective taste masking method can improve the compliance of patients, increase the curative effect and improve the clinical value of the medicine. The existing taste masking methods comprise: 1. adding sweetener, correctant, etc. to confuse brain taste; 2. coating, microencapsulating, etc., to form a physical barrier to prevent the contact of the drug with taste buds; 3. granulating, solid dispersing, etc., changing the drug release behavior, delaying the drug release 4. bitter blocker, competing bitter receptor 5. forming compound, delaying release. Many drugs and excipients also cause throat irritation, particularly in the case of cough reflexes.
Liposome-encapsulated drugs can mask drug-induced adverse events, reduce local irritation, and increase therapeutic efficacy through sustained release. The components of the liposome are biocompatible and biodegradable, and the safety of the liposome to lung tissues has been widely studied in vitro and in vivo in animals and volunteers, so that the safety can be ensured. Early studies showed that inhalation of liposomes made from soy phospholipids did not cause pathological or histological changes in lung tissue and alveolar macrophages. The hydroxychloroquine liposome is delivered to lung tissues by adopting a pulmonary administration way, and is concentrated at the inflammation part of the lung, so that the local concentration of the drug is increased; the liposome can prolong the retention of hydroxychloroquine in the 'deep lung' and reduce the accumulation in other tissues, thereby increasing the treatment effect and reducing the side effect of the whole body. This demonstrates the fundamental applicability of pulmonary administration of hydrochloroquine to improve patient compliance.
The existing hydroxychloroquine preparation on the market only comprises oral preparations, including tablets, oral suspensions and oral liquids, which are all in a gastrointestinal administration mode. The administration mode not only has slow absorption and can not directly reach the focus, but also can lead the medicine to accumulate at the non-focus part along with the blood circulation, thereby causing the occurrence of adverse reaction.
Disclosure of Invention
The invention prepares a hydroxychloroquine liposome inhalant for pulmonary administration, the final administration form of the preparation is aerosol, the lyophilized liposome is redissolved by using a proper solvent (such as normal saline), and the inhalant is inhaled and administered through the mouth and the nose of an atomizer, and the medicine is concentrated in the lung along with the breath of a patient to play the local or systemic treatment effect. The liposome for pulmonary administration can improve the concentration of the drug at the focus part and reduce the occurrence of adverse reaction; meanwhile, the medicament is wrapped in liposome, so that bad taste stimulation and/or cough stimulation are effectively reduced.
The excipients and their formulation forms used in the present invention delay the rate of dissolution and release of the active drug, such that bitter taste receptor activation and laryngeal receptor levels do not exceed the perception threshold.
Hydroxychloroquine is distributed in tissues such as spleen, kidney, lung, heart, liver and the like, and melanin-containing tissues such as skin, eyes and the like have special affinity to the tissue, thereby causing adverse reaction of the medicine. The invention aims to reduce the accumulation of the medicament in other tissues and organs through pulmonary administration, thereby improving the adverse reaction of the medicament to the tissues and organs; also, liposome inhalation administration reduces unpleasant tastes such as bitter taste and minimizes the tendency to stimulate the cough reflex. The solution strategy consists in entrapping the liposomes or in using polymeric microspheres or nanospheres or the like capable of producing a sustained release effect, which other methods previously described are also capable of achieving this.
The hydroxychloroquine liposome inhalant comprises the following components: hydroxychloroquine, phospholipids and cholesterol, said hydroxychloroquine liposome inhalant being administered in the form of an aerosol.
Further, the mass ratio of the hydroxychloroquine to the phospholipid is 1:5-1: 15.
Further, the mass ratio of the phospholipid to the cholesterol is 1:1-6: 1.
Further, the phospholipid comprises natural phospholipid and synthetic phospholipid, wherein the natural phospholipid is selected from any one of lecithin, soybean phospholipid or egg yolk lecithin. The synthetic phospholipid is selected from any one of dipalmitoyl phosphatidylcholine, dipalmitoyl phosphatidylethanolamine and distearoyl phosphatidylcholine.
A method for preparing a hydroxychloroquine liposome inhalant, comprising the steps of:
(1) weighing a proper amount of phospholipid and cholesterol in a reactor, adding an organic solvent for dissolving, carrying out reduced pressure distillation, adding an ammonium sulfate solution into the reactor after the organic solvent is evaporated to dryness, dissolving and stirring, and filtering by using a 0.22 mu m filter membrane.
(2) Transferring the liquid obtained in step 1 into dialysis bag, adding into 1-10% glucose solution, and dialyzing at 37 + -0.5 deg.C in 100 rpm/min air bath oscillator.
(3) Pouring out the liquid in the dialysis bag after dialysis, adding appropriate amount of hydroxychloroquine, and incubating at 40-60 deg.C in water bath for 40-80 min to obtain hydroxychloroquine liposome liquid preparation.
(4) Subpackaging and sealing the hydroxychloroquine liposome liquid preparation prepared in the step 3, and freezing at-80 ℃ for 24 h. Before freeze-drying operation, uncovering a cover, sealing the cover with a preservative film and pricking holes; during freeze-drying operation, pre-freezing is firstly carried out according to the prompt of a machine, and after pre-freezing, the materials are uniformly placed on a partition plate or a drying disc for vacuum drying for 24-72 hours. And (3) after the freeze-drying is finished, adding protective gas nitrogen to obtain the hydroxychloroquine liposome inhalant.
Further, the organic solvent in the step (1) is: any one of ethanol, ethyl acetate and chloroform.
Further, the concentration of the ammonium sulfate solution in the step (1) is 100-300mmol/L.
The hydroxychloroquine liposome inhalant is applied to pneumonia caused by novel coronavirus.
The invention has the following beneficial effects:
the invention prepares the hydroxychloroquine into a liposome preparation, the medicament is wrapped in the liposome, the adverse taste stimulation can be reduced, the compliance of a patient is improved, and the pulmonary administration mode of the hydroxychloroquine can lead the medicament to directly reach the lung to exert the medicament effect aiming at the pneumonia, thereby improving the medicament curative effect and reducing the occurrence of adverse reaction.
The final preparation form of the invention is a freeze-dried product and is filled with nitrogen, so that the instability phenomenon of the liposome preparation in the processes of storage and transportation can be avoided, and the stability of the preparation is improved.
The invention is used as a new formulation of hydroxychloroquine, fills the gap in the preparation, and provides better choices for patients taking medicines for different diseases.
Drawings
FIG. 1 is the in vitro release profile of the hydroxychloroquine liposomes of example 1.
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1: hydroxychloroquine lipidosome inhalant and preparation method thereof
(1) Weighing a proper amount of phospholipid and cholesterol according to the mass ratio of 4:1, putting the phospholipid and the cholesterol into an eggplant-shaped bottle, adding 10mL of ethanol, and performing ultrasonic treatment to completely dissolve the phospholipid and the cholesterol. The eggplant-shaped bottle was set on a rotary evaporator and the organic solvent was evaporated at 40 ℃. When ethanol is completely volatilized, 5mL ammonium sulfate solution (200 mmol/L) is added into the eggplant-shaped bottle, the mixture is hydrated for 40min at 40 ℃, ultrasonic treatment is carried out for 5 min after sufficient hydration, and the mixture is filtered by using a 0.22 mu m filter membrane.
(2) And (3) transferring the liquid in the step (1) into a dialysis bag, putting the dialysis bag into 250 mL of 1% glucose solution, dialyzing the solution in an air bath oscillator at 37 ℃ and 100 rpm/min, and replacing the dialysis medium every 1 h, wherein the dialysis medium needs to be replaced for 6 times in the whole dialysis process.
(3) And (3) pouring out the liquid in the dialysis bag after the dialysis is finished, adding a proper amount of hydroxychloroquine into the liquid, and incubating for 40min under the condition of water bath at 40 ℃ to obtain the hydroxychloroquine liposome liquid preparation.
(4) Subpackaging and sealing the hydroxychloroquine liposome liquid preparation prepared in the step 3, and freezing at-80 ℃ for 24 h. Before freeze-drying operation, uncovering a cover, sealing the cover with a preservative film and pricking holes; during freeze-drying operation, pre-freezing is performed according to the prompt of a machine, and after pre-freezing, the materials are uniformly placed on a partition plate or a drying disc for vacuum drying, wherein the drying time is 48 hours. And (3) after the freeze-drying is finished, adding protective gas nitrogen to obtain the hydroxychloroquine liposome inhalant.
Example 2 preparation of Hydroxychloroquine Liposome lyophilized powder
(1) Weighing a proper amount of phospholipid and cholesterol according to the mass ratio of 4:1, putting the phospholipid and the cholesterol into a eggplant-shaped bottle, adding 10mL of ethanol, and performing ultrasonic treatment to completely dissolve the phospholipid and the cholesterol. The eggplant-shaped bottle was set on a rotary evaporator and the organic solvent was evaporated at 40 ℃. When ethanol is completely volatilized, 5mL ammonium sulfate solution (300 mmol/L) is added into the eggplant-shaped bottle, the mixture is hydrated for 40min at 40 ℃, ultrasonic treatment is carried out for 5 min after sufficient hydration, and the mixture is filtered by using a 0.22 mu m filter membrane.
(2) And (3) transferring the liquid in the step (1) into a dialysis bag, putting the dialysis bag into 250 mL of 1% glucose solution, dialyzing the solution in an air bath oscillator at 37 ℃ and 100 rpm/min, and replacing the dialysis medium every 1 h, wherein the dialysis medium needs to be replaced for 6 times in the whole dialysis process.
(3) And (3) pouring out the liquid in the dialysis bag after the dialysis is finished, adding 8mg of hydroxychloroquine into the liquid, and incubating for 40min under the condition of water bath at 40 ℃ to obtain the hydroxychloroquine liposome liquid preparation.
(4) Subpackaging and sealing the hydroxychloroquine liposome liquid preparation prepared in the step 3, and freezing at-80 ℃ for 24 h. Before freeze-drying operation, uncovering a cover, sealing the cover with a preservative film and pricking holes; during freeze-drying operation, pre-freezing is performed according to the prompt of a machine, and after pre-freezing, the materials are uniformly placed on a partition plate or a drying disc for vacuum drying, wherein the drying time is 48 hours. And (3) after the freeze-drying is finished, adding protective gas nitrogen to obtain the hydroxychloroquine liposome inhalant.
Example 3 preparation of Hydroxychloroquine Liposome lyophilized powder
(1) Weighing a proper amount of phospholipid and cholesterol according to the mass ratio of 5:1, putting the phospholipid and the cholesterol into a eggplant-shaped bottle, adding 10mL of ethanol, and performing ultrasonic treatment to completely dissolve the phospholipid and the cholesterol. The eggplant-shaped bottle was set on a rotary evaporator and the organic solvent was evaporated at 40 ℃. When ethanol is completely volatilized, 5mL ammonium sulfate solution (400 mmol/L) is added into the eggplant-shaped bottle, the mixture is hydrated for 40min at 40 ℃, ultrasonic treatment is carried out for 5 min after sufficient hydration, and the mixture is filtered by using a 0.22 mu m filter membrane.
(2) And (3) transferring the liquid in the step (1) into a dialysis bag, putting the dialysis bag into 250 mL of 1% glucose solution, dialyzing the solution in an air bath oscillator at 37 ℃ and 100 rpm/min, and replacing the dialysis medium every 1 h, wherein the dialysis medium needs to be replaced for 6 times in the whole dialysis process.
(3) And (3) pouring out the liquid in the dialysis bag after the dialysis is finished, adding 6.67mg of hydroxychloroquine into the liquid, and incubating for 40min under the condition of water bath at 40 ℃ to obtain the hydroxychloroquine liposome liquid preparation.
(4) Subpackaging and sealing the hydroxychloroquine liposome liquid preparation prepared in the step 3, and freezing at-80 ℃ for 24 h. Before freeze-drying operation, uncovering a cover, sealing the cover with a preservative film and pricking holes; during freeze-drying operation, pre-freezing is performed according to the prompt of a machine, and after pre-freezing, the materials are uniformly placed on a partition plate or a drying disc for vacuum drying, wherein the drying time is 48 hours. And (3) after the freeze-drying is finished, adding protective gas nitrogen to obtain the hydroxychloroquine liposome inhalant.
Example 4 preparation of Hydroxychloroquine Liposome lyophilized powder
(1) Weighing a proper amount of phospholipid and cholesterol according to the mass ratio of 4:1, putting the phospholipid and the cholesterol into a eggplant-shaped bottle, adding 10mL of ethanol, and performing ultrasonic treatment to completely dissolve the phospholipid and the cholesterol. The eggplant-shaped bottle was set on a rotary evaporator and the organic solvent was evaporated at 40 ℃. When ethanol is completely volatilized, 5mL ammonium sulfate solution (200 mmol/L) is added into the eggplant-shaped bottle, the mixture is hydrated for 40min at 40 ℃, ultrasonic treatment is carried out for 5 min after sufficient hydration, and the mixture is filtered by using a 0.22 mu m filter membrane.
(2) And (3) transferring the liquid in the step (1) into a dialysis bag, putting the dialysis bag into 250 mL of 1% glucose solution, dialyzing the solution in an air bath oscillator at 37 ℃ and 100 rpm/min, and replacing the dialysis medium every 1 h, wherein the dialysis medium needs to be replaced for 6 times in the whole dialysis process.
(3) And (3) pouring out the liquid in the dialysis bag after the dialysis is finished, adding 10.67mg of hydroxychloroquine into the liquid, and incubating for 40min under the condition of water bath at 40 ℃ to obtain the hydroxychloroquine liposome liquid preparation.
(4) Subpackaging and sealing the hydroxychloroquine liposome liquid preparation prepared in the step 3, and freezing at-80 ℃ for 24 h. Before freeze-drying operation, uncovering a cover, sealing the cover with a preservative film and pricking holes; during freeze-drying operation, pre-freezing is performed according to the prompt of a machine, and after pre-freezing, the materials are uniformly placed on a partition plate or a drying disc for vacuum drying, wherein the drying time is 48 hours. And (3) after the freeze-drying is finished, adding protective gas nitrogen to obtain the hydroxychloroquine liposome inhalant.
Example 5: morphological observation
Dripping 1 drop of the prepared hydroxychloroquine liposome solution on a copper mesh (covered with a support film), fixing for 2-3 min, sucking off redundant liquid at the edge of the copper mesh, dyeing with 1% phosphotungstic acid solution, sucking off redundant dyeing liquid after 2-3 min, naturally drying, and observing the appearance of the hydroxychloroquine liposome under a transmission electron microscope. As a result, the particle size of the hydroxychloroquine liposome inhalant prepared in example 1 was 130. + -.15 nm, and the prepared hydroxychloroquine liposome had a spherical or spheroidal appearance.
Example 6: particle size and particle size distribution
The prepared hydroxychloroquine liposome solution is diluted by using a proper amount of distilled water, and the particle size distribution of the hydroxychloroquine liposome inhalant prepared in example 1 is less than 200nm, the particle size distribution is uniform, and the stability of nanoparticles is good by adopting a Malvern laser particle size analyzer to measure the hydroxychloroquine liposome inhalant.
Example 7: determination of the Encapsulation Efficiency (EE)
Separating free drug and liposome by ultrafiltration centrifugation, and measuring and calculating EE and DL of drug in hydroxychloroquine liposome. The specific operation is as follows: precisely sucking appropriate amount of hydroxychloroquine liposome, placing in an ultrafiltration tube, centrifuging at 4 deg.C and 14000r/min for 30min, diluting the centrifuged solution, filtering with 0.45 μm filter membrane, and collecting the filtratePerforming liquid phase analysis, measuring and calculating the content (W) of free drugFree form) (ii) a HPLC is used for measuring the concentration of the original diluted sample, and the total content (W) of the medicine in the sample is calculatedGeneral assembly）；WMedicineIs the amount of hydroxychloroquine entrapped in the hydroxychloroquine liposomes; substituting the result into the calculation of equation (1)EE(ii) a Calculation by substituting equation (2)DL。
EE（%）=（WGeneral assembly - WFree form）/ WGeneral assembly × 100% （1）
As a result: the entrapment rate of the hydroxychloroquine liposome prepared in example 1 is above 93.12 + -0.67%.
Example 8: in vitro release assay
And (3) selecting a dynamic dialysis method for determination, selecting a PBS (phosphate buffer solution) solution with pH of 5.5 as a release medium, and inspecting the in-vitro release characteristics of the hydroxychloroquine liposome. Sucking a certain amount of hydroxychloroquine liposome, placing in a dialysis bag, sealing, placing in a release medium, and performing in vitro release experiment in an oscillator at 37 + -5 deg.C and 100 r/min.
As a result: as shown in fig. 1, it can be seen that, compared with the hydroxychloroquine solution reaching the release plateau after 4 hours, the hydroxychloroquine liposome is released steadily within 48 hours, and reaches the release plateau after 48 hours, and the cumulative release degree is 92.41%. The hydroxychloroquine liposome preparation can produce certain slow release effect.
In conclusion, the hydroxychloroquine is prepared into the liposome preparation, the medicament is wrapped in the liposome, so that the adverse taste stimulation can be reduced, the compliance of a patient is improved, and the pulmonary administration mode of the hydroxychloroquine can ensure that the medicament directly reaches the lung to exert the medicament effect aiming at the pneumonia, so that the curative effect of the medicament is improved, and the occurrence of adverse reactions is reduced.
The final preparation form of the invention is a freeze-dried product and is filled with nitrogen, so that the instability phenomenon of the liposome preparation in the processes of storage and transportation can be avoided, and the stability of the preparation is improved.
The invention is used as a new formulation of hydroxychloroquine, fills the gap in the preparation, and provides better choices for patients taking medicines for different diseases.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (8)
1. A hydroxychloroquine liposome inhalant, wherein said hydroxychloroquine liposome inhalant comprises: hydroxychloroquine, phospholipids and cholesterol, said hydroxychloroquine liposome inhalant being administered in the form of an aerosol.
2. The hydroxychloroquine liposome inhaler of claim 1, wherein the mass ratio of hydroxychloroquine to phospholipid is from 1:5 to 1: 15.
3. The hydroxychloroquine liposome inhaler of claim 2, wherein the mass ratio of said phospholipid to cholesterol is from 1:1 to 6: 1.
4. The hydroxychloroquine liposome inhaler of claim 3, wherein said phospholipid comprises natural phospholipid and synthetic phospholipid, said natural phospholipid is selected from any one of lecithin, soybean phospholipid or egg yolk lecithin; the synthetic phospholipid is selected from any one of dipalmitoyl phosphatidylcholine, dipalmitoyl phosphatidylethanolamine and distearoyl phosphatidylcholine.
5. A process for the preparation of a hydroxychloroquine liposomal inhalation of claim 1, comprising the steps of:
(1) weighing a proper amount of phospholipid and cholesterol in a reactor, adding an organic solvent for dissolving, carrying out reduced pressure distillation, adding an ammonium sulfate solution into the reactor after the organic solvent is evaporated to dryness, dissolving and stirring, and filtering by using a 0.22 mu m filter membrane;
(2) transferring the liquid in the step 1 into a dialysis bag, placing the dialysis bag into 1-10% glucose solution, and dialyzing in an air bath oscillator with the temperature of 37 +/-0.5 ℃ and the rpm/min of 100;
(3) pouring out the liquid in the dialysis bag after dialysis, adding appropriate amount of hydroxychloroquine, and incubating at 40-60 deg.C in water bath for 40-80 min to obtain hydroxychloroquine liposome liquid preparation;
(4) subpackaging and sealing the hydroxychloroquine liposome liquid preparation prepared in the step 3, and freezing at-80 ℃ for 24 h;
before freeze-drying operation, uncovering a cover, sealing the cover with a preservative film and pricking holes; during freeze-drying operation, pre-freezing according to the prompt of a machine, uniformly placing the materials on a partition plate or a drying disc for vacuum drying after pre-freezing, wherein the drying time is 24-72 hours;
and (3) after the freeze-drying is finished, adding protective gas nitrogen to obtain the hydroxychloroquine liposome inhalant.
6. The method for preparing hydroxychloroquine liposome inhalant of claim 5, wherein said organic solvent in step (1) is: any one of ethanol, ethyl acetate and chloroform.
7. The method for preparing hydroxychloroquine liposome inhalant of claim 6, wherein the concentration of ammonium sulfate solution in said step (1) is 100-300mmol/L.
8. The use of the hydroxychloroquine liposomal inhalation of claim 1 for pneumonia caused by a novel coronavirus.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080138397A1 (en) * | 2006-10-24 | 2008-06-12 | Aradigm Corporation | Processes for taste-masking of inhaled formulations |
| CN103585109A (en) * | 2013-11-20 | 2014-02-19 | 河南牧翔动物药业有限公司 | Cefquinome liposome and preparation method thereof |
| CN109562060A (en) * | 2016-06-21 | 2019-04-02 | 泰克年研究发展基金会公司 | Mix mucoadhesive delivery system and its purposes |
| CN111297838A (en) * | 2020-04-08 | 2020-06-19 | 宁波合康生物医药科技有限公司 | Inhalation spray of antiviral drug |
-
2020
- 2020-10-29 CN CN202011171589.3A patent/CN114425048A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080138397A1 (en) * | 2006-10-24 | 2008-06-12 | Aradigm Corporation | Processes for taste-masking of inhaled formulations |
| CN103585109A (en) * | 2013-11-20 | 2014-02-19 | 河南牧翔动物药业有限公司 | Cefquinome liposome and preparation method thereof |
| CN109562060A (en) * | 2016-06-21 | 2019-04-02 | 泰克年研究发展基金会公司 | Mix mucoadhesive delivery system and its purposes |
| CN111297838A (en) * | 2020-04-08 | 2020-06-19 | 宁波合康生物医药科技有限公司 | Inhalation spray of antiviral drug |
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