CN102580111A - Quercetin hydroxypropyl beta-cyclodextrin clathrate liposome, and preparation method thereof and application thereof - Google Patents
Quercetin hydroxypropyl beta-cyclodextrin clathrate liposome, and preparation method thereof and application thereof Download PDFInfo
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Abstract
The invention relates to a quercetin hydroxypropyl beta-cyclodextrin clathrate liposome, and a preparation method thereof and application thereof, and belongs to the field of medicinal preparations. According to the technical problem to be solved, a medicine capable of improving the bioavailability of quercetin and a method for preparing the medicine are provided. The medicine capable of improving the bioavailability of the quercetin is the quercetin hydroxypropyl beta-cyclodextrin clathrate liposome, wherein the quercetin hydroxypropyl beta-cyclodextrin clathrate liposome is prepared from the following components: 1 weight part of quercetin, 1 to 100 weight parts of hydroxypropyl beta-cyclodextrin, 5 to 50 weight parts of soyabean lecithin, 1 to 10 weight parts of cholesterol and 0.1 to 5 weight parts of polyethylene glycol-phosphatidyl ethanolamine distearate as well as a pharmaceutically-acceptable solvent.
Description
Technical field
The present invention relates to Quercetin hydroxypropyl bag and composite lipidosome, belong to field of pharmaceutical preparations.
Background technology
Pulmonary fibrosis (pulmonary fibrosis, PF) be one kind of multiple reasons cause disorderly with diffusivity alveolitis and alveolar structure, and finally to cause interstitial pulmonary fibrosis and respiratory failure be the disease of characteristic.The pneumonia that is caused by radioactivity and chemotherapeutics clinically is a common complication, and incidence rate is 36%-60%.Comprise antibacterial, dust, radioactive substance and chemotherapy and radiation treatment etc. by multiple reason.Its sickness rate is about 5,/10 ten thousand.Pulmonary fibrosis is made a definite diagnosis the average survival period in back and is about 2-4, and survival rate was about 50-70% in 5 years, also lacked specificity therapeutic method at present clinically.The treatment of past to pulmonary fibrosis only limits to non-specific antiinflammatory, immunosuppressant and glucocorticoid etc., curative effect and undesirable.And along with China's industrialization development, increasing environmental pollution, the sickness rate of the respiratory system disease that a variety of causes causes improves, and majority is converted into pulmonary fibrosis, thereby the national economy and social development of China has been caused very big influence.Thereby the new drug that exploitation is used to treat pulmonary fibrosis is extremely urgently with important.
(Bleomycin is one type of polypeptide series antineoplastic medicament BLM) to bleomycin, and is better to polytype oncotherapy effect in clinical use, but most humans can produce the dose dependent pulmonary fibrosis.Single can be set up BLM and the similar animal model of people's interstitial lung property disease biting tooth class animal intratracheal injection in scientific research, thereby is widely used in the foundation of pulmonary fibrosis animal model.The early stage injury of lung that BLM causes is no matter still all similar with human pulmonary fibrosis disease on the physiology on the histopathology.
Quercetin (Quercetin) is a kind of natural flavone compounds with multiple physiological action, extensively is present in vegetable, fruit and the multiple Chinese herbal medicine.Many forms with glycosides exist, and its basic structure is made up of three ring molecules that connect hydroxyl, and chemical structural formula is following:
Quercetin has wide material sources, biological activity and reaches pharmacological action advantage widely by force, and its pharmacological action comprises immune enhancing function, antibiotic, antiviral, analgesia, inhibition platelet aggregation, vasodilator, antioxidant activity, anticancer disease, anti-hepatitis virus, anti-hepatocarcinoma, anti-liver pulmonary fibrosis etc.Thereby Quercetin and derivant thereof are extremely paid attention in fields such as medicine, edible cosmetic products.But,, cause its bioavailability extremely low, and then limited its use clinically because Quercetin is water insoluble and be insoluble in other multiple medicinal solvents.Therefore, press at present and seek a kind of suitable method and improve the water solublity of Quercetin and improve its bioavailability in vivo, make it can be applied to clinical and can carry out industrialized great production as medicine.
Cyclodextrin bag and composite lipidosome are a kind of novel drug-supplying systems, are the earliest to be proposed cyclodextrin is applied to liposome in 1994 by McCormack and Gregoriadis.Such novel lipide is compared with conventional liposome has the stability raising, and the drug leakage rate descends, and drug loading improves, and improves the advantage that curative effect of medication reduces toxicity and untoward reaction.Simultaneously, such novel lipide can also change medicine behavior in vivo, has slow releasing function and targeting property.And beta-schardinger dextrin-is that the mass-produced cyclodextrin product of unique ability is gone up in industry at present because production technology is simple, and cost is lower, but because its C
2, C
3Form intramolecular hydrogen bond between the hydroxyl, cause its dissolubility in water lower (1.85g/100Ml, 20 ℃), limited the application of beta-schardinger dextrin-.Hydroxypropyl is that 2,3 or 6 hydroxyl hydrogen atoms of beta-schardinger dextrin-are by the substituted one type of amorphous multicomponent derivant of hydroxypropyl; Its water solublity improves (＞500g/L greatly than beta-schardinger dextrin-; 20 ℃), and have low, the safe advantage of hemolytic; Therefore can be used as the ejection preparation additive; And examine through U.S. food Drug Administration (FDA), the itraconazole oral liquid and the intravenous injection of Johnson Co.'s 40% hydroxypropyl increase-volume go on the market, so hydroxypropyl can be described as the most potential cyclodextrin material at present.
Summary of the invention
First technical problem to be solved by this invention provides a kind of medicine that can improve the Quercetin bioavailability.
Quercetin hydroxypropyl bag of the present invention and composite lipidosome add that following components in weight percentage pharmaceutically acceptable solvent is prepared from: 1 part of Quercetin; 1～100 part of hydroxypropyl; 5～50 parts of egg yolk lecithin or soybean phospholipids; 1～10 part in cholesterol, 0.1～5 part of the sour PHOSPHATIDYL ETHANOLAMINE of Polyethylene Glycol-distearyl.
Further; In order to make the Quercetin bioavailability higher; Quercetin hydroxypropyl bag of the present invention and composite lipidosome preferably add that following components in weight percentage pharmaceutically acceptable solvent is prepared from: 1 part of Quercetin, 10～60 parts of hydroxypropyls, 6～20 parts of egg yolk lecithin or soybean phospholipids; 2～6 parts in cholesterol, 0.2～2 part of the sour PHOSPHATIDYL ETHANOLAMINE of Polyethylene Glycol-distearyl.
Wherein, acting as of above-mentioned pharmaceutically acceptable solvent: hydroxypropyl and Quercetin are dissolved fully, and reach the purpose that the Quercetin enclose is got into the inner chamber of hydroxypropyl clathrate.Said solvent can be the dissolving hydroxypropyl used always and the solvent of Quercetin, as: at least a in dehydrated alcohol, ether, the n-butyl alcohol equal solvent.
Second technical problem to be solved by this invention provides the method for preparing Quercetin hydroxypropyl bag and composite lipidosome, and it comprises the steps:
A, by weight ratio 1～100 part of hydroxypropyl is added in the pharmaceutically acceptable solvent; Swelling; Processing mass volume ratio is the hydroxypropyl solution of 0.01%-99%, and 1 part of Quercetin or its solution are added in the hydroxypropyl solution mixing; Wherein, described pharmaceutically acceptable solvent is at least a in dehydrated alcohol, n-butyl alcohol, the ether; The mass volume ratio of Quercetin and pharmaceutically acceptable solvent is 0.001%-20%;
B, with 5～50 parts of egg yolk lecithin or soybean phospholipid, 1～10 part of cholesterol, 0.1～5 part of Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE or its solution add in a step gained solution, mixing; Wherein, the molecular weight of said Polyethylene Glycol is 2000-8000;
C, b step gained solution are heated to 30-80 ℃, and stirring and dripping mass volume ratio is the aqueous sucrose solution of 0.5-50%, stir 5-60min in 30-80 ℃ of constant temperature then; Wherein, above-mentioned aqueous sucrose solution is preheated to 30-80 ℃ earlier before dripping;
D, c step gained solution removal dehydrated alcohol promptly get Quercetin hydroxypropyl bag and composite lipidosome.
Wherein, the swelling time in the above-mentioned a step is preferably 1min～24h.
Wherein, can adopt conventional method to make Quercetin mixing (promptly dissolving) fully in solvent in the above-mentioned a step, as employing leave standstill, heat, methods such as stirring, ultrasonic or grinding are dissolved in the solvent Quercetin fully.
Wherein, the purpose that adds aqueous sucrose solution in the above-mentioned c step is for water etc. is oozed, and in the c step, the volume ratio of the pharmaceutically acceptable solvent described in aqueous sucrose solution and a step is preferably 1: 0.1-2.The excessive then organic solvent of volume ratio is very few, and fat-soluble Quercetin and liposome membrane material can not fully dissolve; The too small then organic solvent of volume ratio is too much, causes the later stage to remove the organic solvent time and prolongs greatly, and be unfavorable for the stable of liposome
Wherein, the too high meeting of the heating-up temperature of above-mentioned c step causes phospholipid oxidation, and temperature is crossed low then phospholipid and do not reached phase transition temperature and can not form liposome.
Wherein, can adopt conventional method to remove dehydrated alcohol in the above-mentioned d step, as adopting decompression rotary evaporation, decompression shunting, lyophilization or normal pressure volatilization etc.
The 3rd technical problem to be solved by this invention provides above-mentioned Quercetin hydroxypropyl bag and composite lipidosome and prevents and/or treats the purposes in the medicine of pulmonary fibrosis disease in preparation.
Wherein, above-mentioned pulmonary fibrosis disease mainly comprises the pulmonary fibrosis disease that causes by in chemotherapy and the radiation treatment, also comprises the pulmonary fibrosis disease that is caused by other reason.
The 4th technical problem to be solved by this invention provides a kind of Quercetin hydroxypropyl bag and composite lipidosome lyophilized injectable powder, and it adds that above-mentioned Quercetin hydroxypropyl bag and composite lipidosome pharmaceutically acceptable excipient is prepared from.
Wherein, above-mentioned excipient can be excipient pharmaceutically commonly used, as: sorbitol, mannitol, glucose, sucrose, trehalose or glycine.
The 5th technical problem to be solved by this invention provides the method for preparing Quercetin hydroxypropyl bag and composite lipidosome lyophilized injectable powder; It adopts the above-mentioned method for preparing Quercetin hydroxypropyl bag and composite lipidosome to prepare Quercetin hydroxypropyl bag and composite lipidosome; Add excipient then; Freezing, dry, promptly get Quercetin hydroxypropyl bag and composite lipidosome injectable powder; Wherein, the mass volume ratio of excipient and Quercetin hydroxypropyl bag and composite lipidosome is 1%-50%: 1.Wherein, above-mentioned excipient can be excipient pharmaceutically commonly used, as: sorbitol, mannitol, glucose, sucrose, trehalose or glycine.
Quercetin hydroxypropyl bag of the present invention and composite lipidosome and injectable powder thereof can fully be dissolved in the solution that can be used for intravenous drip; Like 5% glucose or normal saline; Improve the bioavailability of Quercetin, prolonged its circulation time in vivo, and then enlarged its scope of application clinically; But Quercetin hydroxypropyl bag of the present invention and composite lipidosome and injectable powder thereof long preservation under 4 ℃ of-8 ℃ of conditions of low temperature is subsequent use, has good stable property.Quercetin hydroxypropyl bag of the present invention and composite lipidosome and injectable powder thereof are that the clinical use of Quercetin provides a kind of new approach, have broad application prospects.
Description of drawings
The therapeutic effect figure of the pulmonary fibrosis that Fig. 1 causes bleomycin for Quercetin hydroxypropyl bag of the present invention and composite lipidosome; A and F are model group among the figure; B and G are that empty liposome adds the bleomycin rent; C and H are Quercetin hydroxypropyl bag and composite lipidosome treatment group; D and I are simple Quercetin hydroxypropyl bag and composite lipidosome group; E and J are the normal saline group; A-E is H&E dyeing, and F-J is Masson dyeing (arrow dial gauge representation model group collagen extensively deposits among the figure, and collagen deposition partly significantly improves after treatment).
Fig. 2 is lung tissue section's row Sirius red colouring figure (ns group) as a result in the 3rd week.
Fig. 3 is lung tissue section's row Sirius red colouring figure (treatment group) as a result in the 3rd week.
Fig. 4 is lung tissue section's row Sirius red colouring figure (ns group) as a result in the 5th week.
Fig. 5 is lung tissue section's row Sirius red colouring figure (treatment group) as a result in the 5th week.
The specific embodiment
Quercetin hydroxypropyl bag of the present invention and composite lipidosome add that following components in weight percentage pharmaceutically acceptable solvent is prepared from: 1 part of Quercetin; 1～100 part of hydroxypropyl; 5～50 parts of egg yolk lecithin or soybean phospholipids; 1～10 part in cholesterol, 0.1～5 part of the sour PHOSPHATIDYL ETHANOLAMINE of Polyethylene Glycol-distearyl.
Further; In order to make the Quercetin bioavailability higher; Quercetin hydroxypropyl bag of the present invention and composite lipidosome preferably add that following components in weight percentage pharmaceutically acceptable solvent is prepared from: 1 part of Quercetin, 10～60 parts of hydroxypropyls, 6～20 parts of egg yolk lecithin or soybean phospholipids; 2～6 parts in cholesterol, 0.2～2 part of the sour PHOSPHATIDYL ETHANOLAMINE of Polyethylene Glycol-distearyl.
Wherein, acting as of above-mentioned pharmaceutically acceptable solvent: hydroxypropyl and Quercetin are dissolved fully, and reach the purpose that the Quercetin enclose is got into the inner chamber of hydroxypropyl clathrate.Said solvent can be the dissolving hydroxypropyl used always and the solvent of Quercetin, as: at least a in dehydrated alcohol, ether, the n-butyl alcohol equal solvent.
The present invention also provides the happy method for preparing Quercetin hydroxypropyl bag and composite lipidosome, and it comprises the steps:
A, by weight ratio 1～100 part of hydroxypropyl is added in the pharmaceutically acceptable solvent; Swelling; Processing mass volume ratio is the hydroxypropyl solution of 0.01%-99%, and 1 part of Quercetin or its solution are added in the hydroxypropyl solution mixing; Wherein, described pharmaceutically acceptable solvent is at least a in dehydrated alcohol, n-butyl alcohol, the ether; The mass volume ratio of Quercetin and pharmaceutically acceptable solvent is 0.001%-20%;
B, with 5～50 parts of egg yolk lecithin or soybean phospholipid, 1～10 part of cholesterol, 0.1～5 part of Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE or its solution add in a step gained solution, mixing; Wherein, the molecular weight of said Polyethylene Glycol is 2000-8000;
C, b step gained solution are heated to 30-80 ℃, and stirring and dripping mass volume ratio is the aqueous sucrose solution of 0.5-50%, stir 5-60min in 30-80 ℃ of constant temperature then; Wherein, above-mentioned aqueous sucrose solution is preheated to 30-80 ℃ earlier before dripping;
D, c step gained solution removal dehydrated alcohol promptly get Quercetin hydroxypropyl bag and composite lipidosome.
Wherein, the swelling time in the above-mentioned a step is preferably 1min～24h.
Wherein, can adopt conventional method to make Quercetin mixing (promptly dissolving) fully in solvent in the above-mentioned a step, as employing leave standstill, heat, methods such as stirring, ultrasonic or grinding are dissolved in the solvent Quercetin fully.
Wherein, the purpose that adds aqueous sucrose solution in the above-mentioned c step is for water etc. is oozed, and in the c step, the volume ratio of the pharmaceutically acceptable solvent described in aqueous sucrose solution and a step is preferably 1: 0.1-2.The excessive then organic solvent of volume ratio is very few, and fat-soluble Quercetin and liposome membrane material can not fully dissolve; The too small then organic solvent of volume ratio is too much, causes the later stage to remove the organic solvent time and prolongs greatly, and be unfavorable for the stable of liposome.
Wherein, the too high meeting of the heating-up temperature of above-mentioned c step causes phospholipid oxidation, and temperature is crossed low then phospholipid and do not reached phase transition temperature and can not form liposome.
Wherein, can adopt conventional method to remove dehydrated alcohol in the above-mentioned d step, as adopting decompression rotary evaporation, decompression shunting, lyophilization or normal pressure volatilization etc.
The present invention also provides above-mentioned Quercetin hydroxypropyl bag and composite lipidosome to prevent and/or treat the purposes in the medicine of pulmonary fibrosis disease in preparation.
Wherein, above-mentioned pulmonary fibrosis disease mainly comprises the pulmonary fibrosis disease that causes by in chemotherapy and the radiation treatment, also comprises the pulmonary fibrosis disease that is caused by other reason.
The present invention also provides a kind of Quercetin hydroxypropyl bag and composite lipidosome lyophilized injectable powder, and it adds that above-mentioned Quercetin hydroxypropyl bag and composite lipidosome pharmaceutically acceptable excipient is prepared from.
Wherein, above-mentioned excipient can be excipient pharmaceutically commonly used, as: sorbitol, mannitol, glucose, sucrose, trehalose or glycine.
The present invention also provides the method for preparing Quercetin hydroxypropyl bag and composite lipidosome lyophilized injectable powder; It adopts the above-mentioned method for preparing Quercetin hydroxypropyl bag and composite lipidosome to prepare Quercetin hydroxypropyl bag and composite lipidosome; Add excipient then; Freezing, dry, promptly get Quercetin hydroxypropyl bag and composite lipidosome injectable powder; Wherein, the mass volume ratio of excipient and Quercetin hydroxypropyl bag and composite lipidosome is 1%-50%: 1.Wherein, above-mentioned excipient can be excipient pharmaceutically commonly used, as: sorbitol, mannitol, glucose, sucrose, trehalose or glycine.
Do further description below in conjunction with the embodiment specific embodiments of the invention, therefore do not limit the present invention among the described scope of embodiments.
The preparation of embodiment 1 Quercetin hydroxypropyl bag of the present invention and composite lipidosome and lyophilized injectable powder thereof
With hydroxypropyl 0.5g swelling 1h in dehydrated alcohol; Add Quercetin 10mg then; 25 ℃ are stirred down 0.5h Quercetin are dissolved fully, obtain hydroxypropyl Quercetin ethanol solution after, add soybean lecithin 100mg; Cholesterol 20mg, Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE 6mg.Wherein, the molecular weight of Polyethylene Glycol is 2000.Process mixed solution; Again above-mentioned mixed solution being added dropwise to the 20ml mass volume ratio in 60 ℃ is 2.5% sucrose solution; The volume ratio of dehydrated alcohol and sucrose solution is 1: 4, and behind the magnetic agitation 10min, it is that 10ml forms Quercetin hydroxypropyl bag and composite lipidosome that rotary evaporation is removed dehydrated alcohol to overall solution volume; Again it is positioned over and forms lyophilized powder in the freeze dryer, promptly get yellow green cotton-shaped Quercetin hydroxypropyl bag and composite lipidosome injectable powder.With its evacuation or charge into inert gas seal, be positioned over temperature and be preserve under 4 ℃ of-8 ℃ of conditions subsequent use.
The preparation of embodiment 2 Quercetin hydroxypropyl bags of the present invention and composite lipidosome and lyophilized injectable powder thereof
With hydroxypropyl 5g swelling 2h in dehydrated alcohol; Process solution, add Quercetin 0.2g then, 50 ℃ are stirred 0.5h down Quercetin are dissolved fully; After obtaining hydroxypropyl Quercetin ethanol solution; Add soybean lecithin 1g, cholesterol 0.2g, the Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE 30mg wherein molecular weight of Polyethylene Glycol is 2000; Process mixed solution, more above-mentioned mixed solution being added dropwise to the 0.2L mass volume ratio under 60 ℃ is 1.25% sucrose solution.The volume ratio of dehydrated alcohol and sucrose solution is 1: 4; Behind the magnetic agitation 20min; It is that 0.1L forms Quercetin hydroxypropyl bag and composite lipidosome that rotary evaporation is removed dehydrated alcohol to liquor capacity; The 0.25g sucrose dissolved in Quercetin hydroxypropyl bag and composite lipidosome, is positioned over it and forms lyophilized powder in the freeze dryer, be yellow green cotton-shaped Quercetin hydroxypropyl bag and composite lipidosome injectable powder.With its evacuation or charge into inert gas seal, be positioned over temperature and be preserve under 4 ℃ of-8 ℃ of conditions subsequent use.
The preparation of embodiment 3 Quercetin hydroxypropyl bags of the present invention and composite lipidosome and lyophilized injectable powder thereof
With hydroxypropyl 0.5g swelling 1h in dehydrated alcohol, process solution, add Quercetin 20mg then; 25 ℃ dissolved Quercetin in ultrasonic 5 minutes down fully; After obtaining hydroxypropyl Quercetin ethanol solution, add soybean lecithin 100mg, cholesterol 20mg; Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE 2mg wherein the molecular weight of Polyethylene Glycol is 3000; Process mixed solution, more above-mentioned mixed solution is added dropwise to the sucrose solution (mass volume ratio) of 20ml 2.5% under 65 ℃, the volume ratio of dehydrated alcohol and sucrose solution is 1: 5; Behind the magnetic agitation 10min; It is that 10ml forms Quercetin hydroxypropyl bag and composite lipidosome that rotary evaporation is removed dehydrated alcohol to liquor capacity, it is positioned over forms lyophilized powder in the freeze dryer again, is yellow green cotton-shaped Quercetin hydroxypropyl bag and composite lipidosome injectable powder.With its evacuation or charge into inert gas seal, be positioned over temperature and be preserve under 4 ℃ of-8 ℃ of conditions subsequent use.
The preparation of embodiment 4 Quercetin hydroxypropyl bags of the present invention and composite lipidosome and lyophilized injectable powder thereof
With hydroxypropyl 1g swelling 2h in dehydrated alcohol, process solution, add Quercetin 40mg then; Grinding under 25 ℃ dissolved Quercetin in 10 minutes fully; After obtaining hydroxypropyl Quercetin ethanol solution, add soybean lecithin 200mg, cholesterol 50mg; Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE 5mg wherein the molecular weight of Polyethylene Glycol is 4000; Process mixed solution, more above-mentioned mixed solution is added dropwise to the sucrose solution (mass volume ratio) of 20ml 2.5% under 65 ℃, the volume ratio of dehydrated alcohol and sucrose solution is 1: 5; Behind the magnetic agitation 10min; It is that 10ml forms Quercetin hydroxypropyl bag and composite lipidosome that rotary evaporation is removed dehydrated alcohol to liquor capacity, it is positioned over forms lyophilized powder in the freeze dryer again, is yellow green cotton-shaped Quercetin hydroxypropyl bag and composite lipidosome injectable powder.With its evacuation or charge into inert gas seal, be positioned over temperature and be preserve under 4 ℃ of-8 ℃ of conditions subsequent use.
The preparation of embodiment 5 Quercetin hydroxypropyl bags of the present invention and composite lipidosome and lyophilized injectable powder thereof
With hydroxypropyl 0.4g swelling 20min in dehydrated alcohol, process solution, add the Quercetin ethanol solution 0.4ml of 5mg/ml then; Leave standstill under 25 ℃ the Quercetin ethanol solution is mixed with hydroxypropyl solution fully; After obtaining hydroxypropyl Quercetin ethanol solution, add soybean lecithin 200mg, cholesterol 50mg; Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE 12mg wherein the molecular weight of Polyethylene Glycol is 5000; Process mixed solution, more above-mentioned mixed solution is added dropwise to 5% sucrose solution (mass volume ratio) of 20ml under 55 ℃, the volume ratio of dehydrated alcohol and sucrose solution is 1: 3; Behind the magnetic agitation 10min; It is that 10ml forms Quercetin hydroxypropyl bag and composite lipidosome that rotary evaporation is removed dehydrated alcohol to liquor capacity, it is positioned over forms lyophilized powder in the freeze dryer again, is yellow green cotton-shaped Quercetin hydroxypropyl bag and composite lipidosome injectable powder.With its evacuation or charge into inert gas seal, be positioned over temperature and be preserve under 4 ℃ of-8 ℃ of conditions subsequent use.
The preparation of embodiment 6 Quercetin hydroxypropyl bags of the present invention and composite lipidosome and lyophilized injectable powder thereof
With hydroxypropyl 1g swelling 20min in dehydrated alcohol, process solution, add the Quercetin ethanol solution 1ml of 5mg/ml then; Leave standstill under 25 ℃ the Quercetin ethanol solution is mixed with hydroxypropyl solution fully; After obtaining hydroxypropyl Quercetin ethanol solution, add soybean lecithin 500mg, cholesterol 50mg; Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE 20mg wherein the molecular weight of Polyethylene Glycol is 6000; Process mixed solution, more above-mentioned mixed solution is added dropwise to 30ml 5% sucrose solution (mass volume ratio) under 65 ℃, the volume ratio of dehydrated alcohol and sucrose solution is 1: 3; Behind the magnetic agitation 10min; It is that 20ml forms Quercetin hydroxypropyl bag and composite lipidosome that rotary evaporation is removed dehydrated alcohol to liquor capacity, it is positioned over forms lyophilized powder in the freeze dryer again, is yellow green cotton-shaped Quercetin hydroxypropyl bag and composite lipidosome injectable powder.With its evacuation or charge into inert gas seal, be positioned over temperature and be preserve under 4 ℃ of-8 ℃ of conditions subsequent use.
The preparation of embodiment 7 Quercetin hydroxypropyl bags of the present invention and composite lipidosome and lyophilized injectable powder thereof
With hydroxypropyl 1g swelling 20min in dehydrated alcohol; Process solution, add Quercetin 50mg then, 25 ℃ grind down Quercetin was dissolved fully in 30 minutes to obtain hydroxypropyl Quercetin ethanol solution after; Add soybean lecithin 600mg; Cholesterol 100mg, the Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE 20mg wherein molecular weight of Polyethylene Glycol is 7000, processes mixed solution; Again above-mentioned mixed solution is added dropwise to 40ml 5% sucrose solution (mass volume ratio) under 65 ℃; The volume ratio of dehydrated alcohol and sucrose solution is 1: 5, and behind the magnetic agitation 10min, it is that 20ml forms Quercetin hydroxypropyl bag and composite lipidosome that rotary evaporation is removed dehydrated alcohol to liquor capacity; Again it is positioned over and forms lyophilized powder in the freeze dryer, be yellow green cotton-shaped Quercetin hydroxypropyl bag and composite lipidosome injectable powder.With its evacuation or charge into inert gas seal, be positioned over temperature and be preserve under 4 ℃ of-8 ℃ of conditions subsequent use.
The preparation of embodiment 8 Quercetin hydroxypropyl bags of the present invention and composite lipidosome and lyophilized injectable powder thereof
With hydroxypropyl 1g swelling 30min in dehydrated alcohol; Process solution, add Quercetin 50mg then, 55 ℃ stir down Quercetin was dissolved fully in 30 minutes to obtain hydroxypropyl Quercetin ethanol solution after; Add soybean lecithin 600mg; Cholesterol 100mg, the Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE 15mg wherein molecular weight of Polyethylene Glycol is 8000, processes mixed solution; Again above-mentioned mixed solution is added dropwise to 40ml 5% sucrose solution (mass volume ratio) under 65 ℃; The volume ratio of dehydrated alcohol and sucrose solution is 1: 5, and behind the magnetic agitation 10min, it is that 20ml forms Quercetin hydroxypropyl bag and composite lipidosome that rotary evaporation is removed dehydrated alcohol to liquor capacity; Again it is positioned over and forms lyophilized powder in the freeze dryer, be yellow green cotton-shaped Quercetin hydroxypropyl bag and composite lipidosome injectable powder.With its evacuation or charge into inert gas seal, be positioned over temperature and be preserve under 4 ℃ of-8 ℃ of conditions subsequent use.
Test Example 1 Quercetin hydroxypropyl bag of the present invention and composite lipidosome lyophilized injectable powder stability test
Embodiment 1～8 prepared Quercetin hydroxypropyl bag of the present invention and composite lipidosome lyophilized injectable powder preserved 0,1,6,12 month in 4 ℃-8 ℃; Observe its appearance character situation of change; And measure to place its content of different time, pH value respectively, seal Lu, the variation of particle diameter (nanometer) and distributing homogeneity (PDI), the result sees table 1.Liposome particle diameter and PDI are as shown in table 1.
Table 1 medicine stability test result of the present invention
The toxicology and pharmacology test of Test Example 2 medicines of the present invention
1, medicine of the present invention is to the acute toxicity test of mice
Get 20 of SD rats, 6-8 week, male and female half and half, fasting 12 hours is just becoming drinking-water, adopts the mode of tail intravenously administrable, and the content of Quercetin is 5mg/ml, and every dosage is 8ml.
Adopt embodiment 1～8 prepared medicine of the present invention to make an experiment as stated above respectively, tangible poisoning symptom and death condition all do not appear in rat after the medication, observe a week continuously; Animal all survives, activity freely, hair smoothing; Diet is normal; One week back dissection animal, naked eyes and microscopic examination internal organs tangible pharmacology all do not occur and change.
2, the pharmacokinetics of medicine of the present invention experiment
Get 100 of β ABL/c mices, in 6-8 week, male and female half and half are divided into matched group and experimental group at random, 50 every group.
Matched group: the Quercetin conventional liposome, wherein quercetin content is 5mg/ml, every mice dosage 0.2ml, the tail intravenously administrable is once.Before administration, get blank blood; 5 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, 180 minutes, 240 minutes eyeball veins are got blood after the administration; Centrifuging and taking blood plasma behind the adding anticoagulant heparin; Simultaneously its main viscera tissue (heart, liver, spleen, lung, kidney) is taken out respectively, after the extraction, Quercetin is in the concentration and the tissue distribution thereof of different time points in the HPLC mensuration blood plasma.
Experimental group (experimental group adopt be the medicine of embodiment 5 preparations): Quercetin hydroxypropyl bag and composite lipidosome, wherein quercetin content is 5mg/ml, every mice dosage 0.2ml, the tail intravenously administrable is once.Before administration, get blank blood; 5 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, 360 minutes, 480 minutes, 720 minutes, 1440 minutes eyeballs are got blood after the administration; Centrifuging and taking blood plasma behind the adding anticoagulant heparin; After the extraction, Quercetin is in the concentration of different time points in the HPLC mensuration blood plasma.
The result is as shown in table 2, can find out that from the blood drug level result half-life is 35.25 minutes after the administration of Quercetin conventional liposome group, and the half-life of Quercetin hydroxypropyl bag and composite lipidosome group is 144 minutes.The AUC of Quercetin hydroxypropyl bag and composite lipidosome group is 2.5 times of common Quercetin conventional liposome group.Therefore the obvious prolong drug circulation time in vivo of provable employing hydroxypropyl bag and composite lipidosome technology.
Determination of plasma concentration result in the table 2 BABL/c mice body
3, the pharmacological experiment of medicine of the present invention and result
3.1 Quercetin hydroxypropyl bag and composite lipidosome are to the therapeutic effect of the inductive pulmonary fibrosis of bleomycin
3.1.1 experiment group technology and modelling
The SD rat, in age, female in 6-8 week, the about 200g of body weight is available from Sichuan University's West China Experimental Animal Center.Raise at Animal House earlier, animal freely advances diet, and daytime at night alternately.After conforming, animal begins experiment.Be divided into 5 groups at random, 5 every group are carried out index and detect.Its grouping is respectively 1: bleomycin model injection groups; The 2:BBLM model adds the empty liposome group; 3: Quercetin liposome therapeutic group (10mg/kg); 4: free Quercetin treatment group (dosage 4mg/kg); 5: the normal saline group.
More than each group (remove normal saline group) after setting up model, carried out administration in 6 hours, every day drug administration by injection once, continue 14 days altogether.Handle the 14th day capable bronchoalveolar lavage in back at bleomycin; Through detecting number of inflammatory cells and the inflammatory factor tumor necrosis factor (TNF-α) in the BAL fluid (BALF); Il-1 β (IL-1 β) and interleukin-6 (IL-6) level are observed Quercetin hydroxypropyl bag and composite lipidosome to the acutely inflamed influence of lung due to the bleomycin; Handle the back at bleomycin and put to death rat on the 28th day, measure its lung tissue hydroxyproline content, quantitatively understand the pulmonary fibrosis situation; Preparation lung tissue paraffin section, the lung tissue morphological change is observed in row HE and Masson dyeing
Adopt in the air flue and splash into the bleomycin method, set up the Pulmonary Fibrosis in Rats model.Every rat makes rat get dorsal position after anesthesia comes into force and is fixed on the Mus plate, exposes its cervical region all with 10% chloral hydrate (3ml/kg) lumbar injection; The local iodophor disinfection of using is done laterally big otch in the cervical region center position, and passivity is separated subcutaneous tissue and musculi colli; Expose trachea, raise head Mus plate then and make rat be head height foot low level, the rat cephalocaudal axis becomes miter angle approximately with ground level; About 3mm place is a point of puncture with the cricoid cartilage below, and the right hand is held the 1ml glass syringe that connects No. 7 syringe needles, makes needle forward lower direction and trachea be miter angle; The row direct-view is trachea puncture down; After the sense of breakthrough was arranged, the pumpback non-resistance also saw constantly have air flow to go in the needle tubing, shows to get into the trachea intracavity.Bleomycin group this moment implantation concentration (bleomycin 5mg/kg is dissolved in the 100ul normal saline) in trachea; The normal saline group is then injected normal saline 100 μ l and is done contrast; Subsequently that rat is upright, and about rocked gently 1～2 minute, make medicinal liquid be uniformly distributed in two lungs as far as possible.At last, the sterilization otch, interrupted suture, sterilize once every day, takes out stitches after five days.All the other groups are injected the equivalent physiological saline solution.
3.2 the therapeutic effect of the pulmonary fibrosis that Quercetin hydroxypropyl bag and composite lipidosome cause radiotherapy
3.2.1 the foundation of laboratory animal tumor model: model adopts the female C57BL/6 mice about 6～8 ages in week, 18g, and the radiation pneumonia model is set up in the disposable irradiation 14Gy of linear accelerator in the fixing back of anesthesia.
3.2.2 Quercetin hydroxypropyl bag and composite lipidosome liposome (4mg/kg) radiotherapy property pneumonia: the radiation pneumonia mouse model is divided into 4 groups with mice after setting up at random, and 10 every group, begin treatment is specially:
1) Quercetin hydroxypropyl bag and composite lipidosome: every mouse tail vein injection 200 μ l, begin treatment after the radiation pneumonia modelling, once a day, totally 7 times;
2) DM group (Dexamethasone group): every mouse tail vein injection dexamethasone 200 μ l (5mg), begin treatment after the radiation pneumonia modelling, once a day, totally 7 times;
3) n.s group (normal saline group): every mouse tail vein injection normal saline 200 μ l, begin treatment after the radiation pneumonia modelling, once a day, totally 7 times.
The effect of Quercetin hydroxypropyl bag and composite lipidosome hepatic fibrosis, liver section are carried out Sirius red colouring labelling collagen protein and are generated, and the red position of dying shows collagen protein.With the 3rd week, the 5th the week lung tissue section's row Sirius red colouring (like Fig. 2,3,4, shown in 5; Fig. 2,4 is the ns group; Fig. 3,5 is the treatment group); Except the collagen staining redness around the trachea, organized whole presents redness in the mouse lung tissue that visible n.s organizes among the figure, and alveolar septum also has collagen to form; To the 5th week visible significantly collagen form the zone, in the same time through then obviously minimizing of collagen staining in the mouse lung tissue slice of Quercetin hydroxypropyl bag and composite lipidosome treatment.The green pigmented section prompting of histological quantitative analysis light control group mice lung tissue collagen protein is generated as 8.13%, and Quercetin hydroxypropyl bag is 1.75% (comparing P＜0.001 with matched group) with the composite lipidosome collagen protein.
Claims (11)
1. Quercetin hydroxypropyl bag and composite lipidosome; It is characterized in that adding that following components in weight percentage pharmaceutically acceptable solvent is prepared from: 1 part of Quercetin; 1～100 part of hydroxypropyl; 5～50 parts of egg yolk lecithin or soybean phospholipids, 1～10 part in cholesterol, 0.1～5 part of the sour PHOSPHATIDYL ETHANOLAMINE of Polyethylene Glycol-distearyl.
2. Quercetin hydroxypropyl bag according to claim 1 and composite lipidosome; It is characterized in that adding that following components in weight percentage pharmaceutically acceptable solvent is prepared from: 1 part of Quercetin; 10～60 parts of hydroxypropyls; 6～20 parts of egg yolk lecithin or soybean phospholipids, 2～6 parts in cholesterol, 0.2～2 part of the sour PHOSPHATIDYL ETHANOLAMINE of Polyethylene Glycol-distearyl.
3. Quercetin hydroxypropyl bag according to claim 1 and 2 and composite lipidosome is characterized in that: described pharmaceutically acceptable solvent is at least a in dehydrated alcohol, n-butyl alcohol, the ether.
4. the method for preparing Quercetin hydroxypropyl bag and composite lipidosome is characterized in that comprising the steps:
A, by weight ratio 1～100 part of hydroxypropyl is added in the pharmaceutically acceptable solvent; Swelling; Processing mass volume ratio is the hydroxypropyl solution of 0.01%-99%, and 1 part of Quercetin or its solution are added in the hydroxypropyl solution mixing; Wherein, described pharmaceutically acceptable solvent is at least a in dehydrated alcohol, n-butyl alcohol, the ether; The mass volume ratio of Quercetin and pharmaceutically acceptable solvent is 0.001%-20%;
B, with 5～50 parts of egg yolk lecithin or soybean phospholipid, 1～10 part of cholesterol, 0.1～5 part of Polyethylene Glycol-distearyl acid PHOSPHATIDYL ETHANOLAMINE or its solution add in a step gained solution, mixing; Wherein, the molecular weight of said Polyethylene Glycol is 2000-8000;
C, b step gained solution are heated to 30-80 ℃, and stirring and dripping mass volume ratio is the aqueous sucrose solution of 0.5-50%, stir 5-60min in 30-80 ℃ of constant temperature then; Wherein, above-mentioned aqueous sucrose solution is preheated to 30-80 ℃ earlier before dripping;
D, c step gained solution removal dehydrated alcohol promptly get Quercetin hydroxypropyl bag and composite lipidosome.
5. the method for preparing Quercetin hydroxypropyl bag and composite lipidosome according to claim 4 is characterized in that: the swelling time in a step is 1min～24h.
6. according to claim 4 or the 5 described methods that prepare Quercetin hydroxypropyl bag and composite lipidosome, it is characterized in that: in the c step, the volume ratio of the pharmaceutically acceptable solvent described in aqueous sucrose solution and a step is 1: 0.1-2.
7. each described Quercetin hydroxypropyl bag of claim 1～3 and composite lipidosome prevent and/or treat the purposes in the medicine of pulmonary fibrosis disease in preparation.
8. Quercetin hydroxypropyl bag and composite lipidosome lyophilized injectable powder is characterized in that: add that each described Quercetin hydroxypropyl bag of claim 1～3 and composite lipidosome pharmaceutically acceptable excipient is prepared from.
9. Quercetin hydroxypropyl bag according to claim 8 and composite lipidosome lyophilized injectable powder is characterized in that: described excipient is sorbitol, mannitol, glucose, sucrose, trehalose or glycine.
10. the method for preparing Quercetin hydroxypropyl bag and composite lipidosome lyophilized injectable powder; It is characterized in that: adopt each described method for preparing Quercetin hydroxypropyl bag and composite lipidosome of claim 4～6 to prepare Quercetin hydroxypropyl bag and composite lipidosome; Add excipient then; Freezing, dry, promptly get Quercetin hydroxypropyl bag and composite lipidosome injectable powder; Wherein, the mass volume ratio of excipient and Quercetin hydroxypropyl bag and composite lipidosome is 1%-50%: 1.
11. the method for preparing Quercetin hydroxypropyl bag and composite lipidosome lyophilized injectable powder according to claim 10 is characterized in that: described excipient is sorbitol, mannitol, glucose, sucrose, trehalose or glycine.
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| CN113908294A (en) * | 2021-11-02 | 2022-01-11 | 成都格纯生物医药有限公司 | Preparation method and application of double inclusion compound containing refined cauliflower extract |
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| CN103070826B (en) * | 2012-12-31 | 2015-09-02 | 清华大学深圳研究生院 | A kind of Quercetin Dermatological Liposomes and lyophilized powder and its production and use thereof |
| CN105086002B (en) * | 2015-08-11 | 2017-11-07 | 华南理工大学 | A kind of conveyor screw dextrin Quercetin inclusion compound and preparation method thereof |
| CN105568552A (en) * | 2016-01-14 | 2016-05-11 | 武汉轻工大学 | Quercetin inclusion compound electrospining nanofilm and preparation method and application thereof |
| PL3411047T3 (en) * | 2016-02-04 | 2021-11-15 | Czap Research And Development, Llc | Controlled-release and stratified cyclodextrin inclusion complex vehicles |
| IT201700059875A1 (en) * | 2017-05-31 | 2018-12-01 | Univ Degli Studi Cagliari | COMPOSITIONS BASED ON PHOSPHOLIPIDS, HYDRO-SOLUBLE FIBERS AND ACTIVE PRINCIPLES ANTIOXIDANTS OF NATURAL ORIGIN, THEIR PREPARATION AND USE IN ORAL FORMULATIONS |
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