CN106924176B - Tamoxifen flexible nano liposome gel and preparation method thereof - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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Abstract
The invention discloses a tamoxifen flexible nano liposome gel and a preparation method thereof, wherein the gel is prepared from tamoxifen, cholesterol, a phospholipid material, a water-soluble gel matrix, a transdermal penetration enhancer, a surfactant, a preservative, a humectant, a pbs buffer solution, ammonia water, distilled water and ethanol which are used as raw materials according to a certain proportion. The preparation method comprises the following steps: 1) preparing tamoxifen flexible nanoliposome suspension; 2) preparing a blank gel matrix; 3) and uniformly mixing the blank gel matrix and the tamoxifen flexible nano liposome suspension to obtain the tamoxifen flexible nano liposome gel. The gel has high drug loading and encapsulation effects on tamoxifen, and has good stability and transdermal permeability. The preparation method is simple, convenient to operate and low in preparation cost.
Description
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to a tamoxifen flexible nano liposome gel and a preparation method thereof.
Background
Tamoxifen (TAM) is a Selective Estrogen Receptor Modulator (SERM) that interferes with certain activities of estrogen (estrogen), mimics the action of other estrogens, up-regulates the production of growth factor β, a factor that decreases in association with the development of malignancies, and also has a specific inhibitory effect on protein kinase C. These effects all have an inhibitory effect on tumor cells that depend on estrogen for their continued growth. Clinically, it is often used for the treatment of breast cancer in which estrogen (ER +) and progesterone receptor (PR +) progress before menopause.
Nearly hundreds of countries in the world use TAM to treat advanced recurrent breast cancer and ovarian cancer, mainly used for treating and preventing breast cancer, in recent years, the experimental and clinical research on TAM is fast developed, more than 40 patients in the world are prevented from dying due to TAM treatment every year, although new drugs for endocrine therapy of breast cancer are in endless, the situation cannot be shaken, however, oral TAM has many inevitable side effects, hot tide, endometrial thickening and the like, in clinical practice, the compliance of drug therapy is not high, if the adverse reaction can be improved on the premise of ensuring the local dose of breast, the compliance is undoubtedly a huge breakthrough, and a new window of chemical therapy is opened in a certain sense.
The preparation of TAM in clinical application is mostly tablet. TAM is widely distributed in vivo, can damage normal cells while killing tumor cells, can cause DNA damage, hypertriglyceridemia, bone marrow suppression, eye toxicity, psychosis attack, endocrine disorder, vascular embolic disease, ovarian lesion, endometriosis and the like in treatment, even induces endometrial cancer, increases systemic adverse reactions and influences clinical application. In order to enable the TAM to be more concentrated at the tumor site, the preparation research of the TAM becomes a hot spot, and modern research shows that the TAM is prepared into gel, and the TAM gel is found to have similar reduction degree of the Ki67 marking index in an oral administration scheme, and has smaller systemic effect. The drug storage is formed in mammary gland and tissues around the mammary gland after the tamoxifen citrate gel preparation is transdermally administered by cinnling and the like, so that the tamoxifen citrate gel preparation has a certain slow release characteristic and obviously prolongs the half-life period of tamoxifen in blood plasma. The TAM magnetic microspheres prepared by Liu et al improve the drug concentration at the tumor part and increase the drug effect, and the TAM microemulsion external preparation prepared by Zhang Yi et al has good transdermal promotion effect, so that the development of the TAM preparation becomes the first choice for researching and improving the side effect of tamoxifen and improving the drug effect.
Disclosure of Invention
Based on the prior art, the invention provides a tamoxifen flexible nano liposome gel and a preparation method thereof, and the gel has higher drug loading and encapsulation effects on tamoxifen, and has good stability and transdermal permeability.
The preparation method is simple, convenient to operate and low in preparation cost.
The technical scheme adopted for realizing the above purpose of the invention is as follows:
the tamoxifen flexible nano liposome gel is prepared from the following raw materials in percentage by mass:
the tamoxifen flexible nano liposome gel is prepared from the following raw materials in percentage by mass:
further, the phospholipid material is one of soybean lecithin, hydrogenated soybean lecithin and dipalmitoylphosphatidylcholine, or is a composite phospholipid of hydrogenated soybean lecithin and soybean lecithin, or is a composite phospholipid of hydrogenated soybean lecithin and dipalmitoylphosphatidylcholine.
Further, the water-soluble gel matrix is a cellulose derivative, and the cellulose derivative is methyl cellulose or sodium carboxymethyl cellulose.
Further, the transdermal penetration enhancer is amine, menthol, laurocapram, poloxamer, sodium lauryl sulfate, fatty acid or fatty acid ester.
Further, the amine is urea; the fatty acid is oleic acid or lauric acid; the fatty acid ester is lauryl lactate, isopropyl myristate, propylene glycol dinonyl acid ester or diethyl sebacate.
Further, the surfactant A is sodium cholate, sodium deoxycholate, fatty glyceride, sucrose fatty acid ester, polysorbate or polyoxyethylene fatty acid ester, and the surfactant B is sodium cholate, sodium deoxycholate or fatty glyceride.
Further, the preservative is benzoic acid, sodium benzoate, sorbic acid or parabens, and the parabens are methyl paraben, ethyl paraben, propyl paraben or butyl paraben.
Further, the humectant is glycerin, propylene glycol or sorbitol.
A preparation method of tamoxifen flexible nanoliposome gel comprises the following steps:
1) dissolving tamoxifen, cholesterol, a phospholipid material and a surfactant A in an organic solvent, wherein the organic solvent is chloroform, ethanol or diethyl ether, so as to obtain a solution A, concentrating the solution A to remove the organic solvent, adding a PBS (phosphate buffer solution), wherein the mass of the PBS buffer solution is 1-5% of that of a water-soluble gel matrix, and hydrating at normal temperature and pressure so as to obtain a tamoxifen flexible nano liposome suspension;
2) uniformly mixing a water-soluble gel matrix, a surfactant B and distilled water, wherein the mass of the added distilled water is 0.1-1% of that of the water-soluble gel matrix to obtain a solution B, dissolving a transdermal penetration enhancer, a preservative and a humectant in ethanol, wherein the mass of the added ethanol is 7-12% of that of the water-soluble gel matrix to obtain a solution C, adding the solution C into the solution B under stirring, adding ammonia water to adjust the solution C to be neutral after swelling, and adding the ammonia water to the solution C to obtain a blank gel matrix, wherein the mass of the added ammonia water is 1-5% of that of the water-soluble gel matrix;
3) and uniformly mixing the blank gel matrix and the tamoxifen flexible nano liposome suspension to obtain the tamoxifen flexible nano liposome gel.
Compared with the prior art, the invention has the beneficial effects and advantages that:
1. in the aspects of drug loading and encapsulation efficiency, the study of the invention finds that the sample loading amount of the tamoxifen flexible nano liposome gel is 0.5-1.2 mg/mL, and the encapsulation efficiency is 85.6-96.0%, which indicates that the flexible nano liposome gel has higher drug loading and encapsulation effects on tamoxifen.
2. In the aspect of stability, the research of the invention finds that the particle size of the tamoxifen flexible nanoliposome gel is 50.2 +/-0.12-100.8 +/-0.26 nm, the potential is-21.8 +/-0.15-37.7 +/-0.45 mv, the polydispersity coefficient is 0.1 +/-0.05-0.18 +/-0.01, the tamoxifen flexible nanoliposome gel is respectively placed at room temperature and 4 ℃, and the appearance, the particle size, the potential and the drug content are observed within 1, 5, 10 and 15 days, so that the tamoxifen flexible nanoliposome gel is found to have slightly increased particle size at room temperature, no obvious change in potential, slightly reduced tamoxifen content and no obvious change at 4 ℃, and therefore, the stability of the tamoxifen flexible nanoliposome gel is good at room temperature and 4 ℃.
3. In the aspect of in vitro transdermal permeability, the research of the invention finds that the transdermal steady state permeation rate and intradermal retention of the tamoxifen flexible nano liposome gel is about 3-7 times of those of the common tamoxifen gel, and the flexible nano liposome is a novel carrier capable of effectively promoting transdermal permeation.
In a word, the tamoxifen is used as a medicine, the flexible nano liposome gel is used as a carrier, and the defects of large side effect and drug compliance of the tamoxifen are overcome. In addition, the tamoxifen flexible nano liposome gel avoids the first pass effect of oral administration of the medicament through gastrointestinal tracts and liver, and improves the bioavailability. Therefore, the tamoxifen flexible nano liposome gel has the characteristics of high absorption rate, high transdermal capacity, stability and high efficiency, has obvious advantages in clinical application, and can effectively realize long-time continuous transdermal penetration of the drug, thereby achieving the targeting effect of local drug delivery.
Drawings
Fig. 1 is a transdermal permeation curve of the tamoxifen flexible nanoliposome gel prepared in example 1 and a common tamoxifen gel.
Fig. 2 is a transdermal permeation curve of the tamoxifen flexible nanoliposome gel prepared in example 2 and a common tamoxifen gel.
Fig. 3 is a transdermal permeation curve of the tamoxifen flexible nanoliposome gel prepared in example 3 and a common tamoxifen gel.
Fig. 4 is a graph comparing the skin drug retention of the tamoxifen flexible nanoliposome gel prepared in example 1 and the common tamoxifen gel.
Fig. 5 is a graph comparing the skin drug retention of the tamoxifen flexible nanoliposome gel prepared in example 2 and the common tamoxifen gel.
Fig. 6 is a graph comparing the skin drug retention of the tamoxifen flexible nanoliposome gel prepared in example 3 and the common tamoxifen gel.
Detailed Description
The present invention will be described in detail with reference to the following embodiments.
Example 1
The tamoxifen flexible nano liposome gel is prepared from the following raw materials in percentage by mass:
the phospholipid material is a composite phospholipid of hydrogenated soybean phospholipid and soybean lecithin, and is marked as SPC/HSPC (the molar ratio of SPC to HSPC is 3: 1).
The preparation method of the tamoxifen flexible nano liposome gel comprises the following steps:
1) dissolving tamoxifen, cholesterol, SPC/HSPC and fatty glyceride in chloroform to obtain a solution A, performing rotary evaporation on the solution A at 37 ℃ under reduced pressure to remove chloroform, adding a PBS buffer solution (pH 7.4), and hydrating for 15min at normal temperature and normal pressure to obtain a tamoxifen flexible nano liposome suspension;
2) uniformly mixing sodium carboxymethylcellulose, sodium deoxycholate and distilled water to obtain a solution B, dissolving laurocapram, benzoic acid and propylene glycol in ethanol to obtain a solution C, gradually adding the solution C into the solution B, stirring at the rotating speed of 500rpm for 15min, uniformly mixing and swelling, adding ammonia water (25 wt%) to adjust the pH value to about 7.0, and obtaining a blank gel matrix;
3) mixing the blank gel matrix and the tamoxifen flexible nano liposome suspension, and stirring at the rotating speed of 500rpm for 15min to obtain the tamoxifen flexible nano liposome gel.
Experiment I, transdermal experiment of tamoxifen flexible nano liposome gel of the invention
The test method comprises the following steps:
1) the treated pigskin was fixed on a Frank diffusion cell, PBS buffer (PH 7.4) was added to the receiving cell, tamoxifen flexible nanoliposome gel (prepared in example 1) was added to the feeding chamber, and constant temperature water bath was performed at 37 ℃ for 300 r.min-1Stirring, taking receiving solution at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h and 48h, supplementing PBS with equal amount, diluting the receiving solution 10 times with mobile phase (acetonitrile: water: 60: 40), analyzing by high performance liquid chromatography, measuring the content of tamoxifen, and calculating the accumulated transdermal penetration; an ordinary tamoxifen gel (prepared by mixing and stirring blank gel prepared by the method in step 2 of the embodiment and tamoxifen in a laboratory) is used as a control, an experiment is carried out under the same condition, the content of tamoxifen is measured, and the accumulated transdermal penetration amount is calculated.
2) Taking down the pigskin after the skin permeation test in the step 1), removing the surface medicines of the pigskin, flushing stratum corneum and corium layer with PBS buffer solution, wiping surface water, precisely weighing, shearing the pigskin, placing the pigskin in a 10mL volumetric flask, performing ultrasonic extraction with methanol for 1h, diluting to constant volume to obtain skin extract, centrifuging the skin extract for 10min at 12000 r.min < -1 >, taking the supernatant, and performing ultrasonic extraction with a mobile phase (acetonitrile: 60 parts of water: 40) diluting by 10 times, analyzing by high performance liquid chromatography, determining the content of tamoxifen, and calculating the tamoxifen retention of unit mass of skin.
And (3) test results:
1. tamoxifen flexibility prepared in example 1The transdermal permeation curves of the nano liposome gel and the common tamoxifen gel are shown in fig. 1, the fitting equation of the transdermal permeation curve of the tamoxifen flexible nano liposome gel is Q-8.196 t-15.935 (r-0.994), and the fitting equation of the common tamoxifen gel is Q-2.1717 t-4.03 (r-0.991). Releasing the drug for 48h at constant speed, wherein the cumulative penetration of the tamoxifen flexible nanoliposome gel prepared in example 1 is 378.26 mug cm-1The percutaneous steady-state permeation rate J is 8.196ug cm-2·h-1。
2. The skin drug retention of the tamoxifen flexible nanoliposome gel prepared in example 1 and the common tamoxifen gel are shown in fig. 4, and as can be seen from fig. 4, the skin drug retention of the tamoxifen flexible nanoliposome gel prepared in example 1 is 15.96 mug g-1The skin drug retention of the common tamoxifen gel is 5.63 mug.g-1。
Therefore, the tamoxifen flexible nano liposome gel provided by the invention has good drug release control effect, and can be used for remarkably improving the skin retention of a drug, so that the action time of the drug is prolonged, the toxic and side effects of the drug are reduced, and local treatment is realized.
Example 2
The tamoxifen flexible nano liposome gel is prepared from the following raw materials in percentage by mass:
the phospholipid material is a compound phospholipid of dipalmitoyl phosphatidylcholine and soybean lecithin, and is marked as DPPC/HSPC (the molar ratio of DPPC to HSPC is 1: 3).
The preparation method of the tamoxifen flexible nano liposome gel comprises the following steps:
1) dissolving tamoxifen, cholesterol, DPPC/HSPC and sodium cholate in chloroform to obtain a solution A, performing rotary evaporation on the solution A at 37 ℃ under reduced pressure to remove the chloroform, adding a PBS buffer solution (pH 7.4), and hydrating for 15min at normal temperature and normal pressure to obtain a tamoxifen flexible nano liposome suspension;
2) uniformly mixing sodium carboxymethylcellulose, sodium deoxycholate and distilled water to obtain a solution B, dissolving laurocapram, benzoic acid and propylene glycol in ethanol to obtain a solution C, gradually adding the solution C into the solution B, stirring at the rotating speed of 500rpm for 15min, uniformly mixing and swelling, and adding ammonia water to adjust the pH value to about 7.0 to obtain a blank gel matrix;
3) mixing the blank gel matrix and the tamoxifen flexible nano liposome suspension, and stirring at the rotating speed of 500rpm for 15min to obtain the tamoxifen flexible nano liposome gel.
Experiment II, transdermal experiment of tamoxifen flexible nano liposome gel of the invention
The test method comprises the following steps:
1) the treated pigskin was fixed on a Frank diffusion cell, PBS buffer (PH 7.4) was added to the receiving cell, tamoxifen flexible nanoliposome gel (prepared in example 2) was added to the feeding chamber, and constant temperature water bath was performed at 37 ℃ for 300 r.min-1Stirring, taking receiving solution at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h and 48h, supplementing PBS with equal amount, diluting the receiving solution 10 times with mobile phase (acetonitrile: water: 60: 40), analyzing by high performance liquid chromatography, measuring the content of tamoxifen, and calculating the accumulated transdermal penetration; an ordinary tamoxifen gel (prepared by mixing and stirring blank gel prepared by the method in step 2 of the embodiment and tamoxifen in a laboratory) is used as a control, an experiment is carried out under the same condition, the content of tamoxifen is measured, and the accumulated transdermal penetration amount is calculated.
2) Taking down the pigskin after the skin permeation test in the step 1), removing the surface medicines of the pigskin, flushing stratum corneum and corium layer with PBS buffer solution, wiping surface water, precisely weighing, shearing the pigskin, placing the pigskin in a 10mL volumetric flask, performing ultrasonic extraction with methanol for 1h, diluting to constant volume to obtain skin extract, centrifuging the skin extract for 10min at 12000 r.min < -1 >, taking the supernatant, and performing ultrasonic extraction with a mobile phase (acetonitrile: 60 parts of water: 40) diluting by 10 times, analyzing by high performance liquid chromatography, determining the content of tamoxifen, and calculating the tamoxifen retention of unit mass of skin.
And (3) test results:
1. the transdermal permeation curves of the tamoxifen flexible nano-liposome gel prepared in example 2 and the common tamoxifen gel are shown in figure 2, the uniform-speed drug release is carried out for 48h, and the cumulative permeation amount of the tamoxifen flexible nano-liposome gel prepared in example 2 is 523.87 mug cm-1The percutaneous steady-state permeation rate J is 11.383ug cm-2·h-1。
2. The skin drug retention of the tamoxifen flexible nanoliposome gel prepared in example 2 and the common tamoxifen gel are shown in fig. 5, and as can be seen from fig. 5, the skin drug retention of the tamoxifen flexible nanoliposome gel prepared in example 2 is 11.47 mug g-1The skin drug retention of the common tamoxifen gel is 5.43 mu g-1。
Therefore, the tamoxifen flexible nano liposome gel provided by the invention has good drug release control effect, and can be used for remarkably improving the skin retention of a drug, so that the action time of the drug is prolonged, the toxic and side effects of the drug are reduced, and local treatment is realized.
Example 3
The tamoxifen flexible nano liposome gel is prepared from the following raw materials in percentage by mass:
the preparation method of the tamoxifen flexible nano liposome gel comprises the following steps:
1) dissolving tamoxifen, cholesterol, HSPC and polysorbate in chloroform to obtain a solution A, performing rotary evaporation on the solution A at 37 ℃ under reduced pressure to remove chloroform, adding a PBS buffer solution (pH 7.4), and hydrating at normal temperature and normal pressure for 15min to obtain a tamoxifen flexible nano liposome suspension;
2) uniformly mixing sodium carboxymethylcellulose, fatty glyceride and distilled water to obtain a solution B, dissolving laurocapram, benzoic acid and propylene glycol in ethanol to obtain a solution C, gradually adding the solution C into the solution B, stirring at the rotating speed of 500rpm for 15min, uniformly mixing and swelling, and adding ammonia water to adjust the pH value to about 7.0 to obtain a blank gel matrix;
3) mixing the blank gel matrix and the tamoxifen flexible nano liposome suspension, and stirring at the rotating speed of 500rpm for 15min to obtain the tamoxifen flexible nano liposome gel.
Experiment III, transdermal experiment of tamoxifen flexible nano liposome gel of the invention
The test method comprises the following steps:
1) the treated pigskin was fixed on a Frank diffusion cell, PBS buffer (PH 7.4) was added to the receiving cell, tamoxifen flexible nanoliposome gel (prepared in example 3) was added to the feeding chamber, and constant temperature water bath was performed at 37 ℃ for 300 r.min-1Stirring, taking receiving solution at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h and 48h, supplementing PBS with equal amount, diluting the receiving solution 10 times with mobile phase (acetonitrile: water: 60: 40), analyzing by high performance liquid chromatography, measuring the content of tamoxifen, and calculating the accumulated transdermal penetration; an ordinary tamoxifen gel (prepared by mixing and stirring blank gel prepared by the method in step 2 of the embodiment and tamoxifen in a laboratory) is used as a control, an experiment is carried out under the same condition, the content of tamoxifen is measured, and the accumulated transdermal penetration amount is calculated.
2) Taking down the pigskin after the skin permeation test in the step 1), removing the surface medicines of the pigskin, flushing stratum corneum and corium layer with PBS buffer solution, wiping surface water, precisely weighing, shearing the pigskin, placing the pigskin in a 10mL volumetric flask, performing ultrasonic extraction with methanol for 1h, diluting to constant volume to obtain skin extract, centrifuging the skin extract for 10min at 12000 r.min < -1 >, taking the supernatant, and performing ultrasonic extraction with a mobile phase (acetonitrile: 60 parts of water: 40) diluting by 10 times, analyzing by high performance liquid chromatography, determining the content of tamoxifen, and calculating the tamoxifen retention of unit mass of skin.
And (3) test results:
1. the transdermal permeation curves of the tamoxifen flexible nano-liposome gel prepared in example 3 and the common tamoxifen gel are shown in fig. 3, the uniform-speed drug release is carried out for 48h, and the cumulative permeation amount of the tamoxifen flexible nano-liposome gel prepared in example 3 is 1289.32 mug cm-1The percutaneous steady-state permeation rate J is 27.367ug cm-2·h-1。
2. The skin drug retention of the tamoxifen flexible nanoliposome gel prepared in example 3 and the common tamoxifen gel are shown in fig. 6, and as can be seen from fig. 6, the skin drug retention of the tamoxifen flexible nanoliposome gel prepared in example 3 is 8.27 mug g-1The skin drug retention of the common tamoxifen gel is 5.13 mu g-1。
Therefore, the tamoxifen flexible nano liposome gel provided by the invention has good drug release control effect, and can be used for remarkably improving the skin retention of a drug, so that the action time of the drug is prolonged, the toxic and side effects of the drug are reduced, and local treatment is realized.
Claims (4)
1. The tamoxifen flexible nanoliposome gel is characterized by comprising the following raw materials in percentage by mass:
the water-soluble gel matrix is cellulose derivative, and the cellulose derivative is methylcellulose or sodium carboxymethylcellulose.
The transdermal penetration enhancer is laurocapram;
the surfactant A is sodium cholate, sodium deoxycholate, fatty glyceride, sucrose fatty acid ester, polysorbate or polyoxyethylene fatty acid ester, and the surfactant B is sodium cholate, sodium deoxycholate or fatty glyceride;
the humectant is glycerin, propylene glycol or sorbitol.
2. The tamoxifen flexible nanoliposome gel according to claim 1, wherein: the phospholipid material is one of soybean lecithin, hydrogenated soybean lecithin and dipalmitoyl phosphatidylcholine, or composite phospholipid of hydrogenated soybean lecithin and soybean lecithin, or composite phospholipid of hydrogenated soybean lecithin and dipalmitoyl phosphatidylcholine.
3. The tamoxifen flexible nanoliposome gel according to claim 1, wherein: the preservative is benzoic acid, sodium benzoate, sorbic acid or parabens, and the parabens are methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate or butyl p-hydroxybenzoate.
4. A method of preparing a tamoxifen flexible nanoliposome gel according to any one of claims 1 to 3 comprising the steps of:
1) dissolving tamoxifen, cholesterol, a phospholipid material and a surfactant A in an organic solvent, wherein the organic solvent is chloroform, ethanol or diethyl ether, so as to obtain a solution A, concentrating the solution A to remove the organic solvent, adding pbs buffer solution, wherein the mass of the pbs buffer solution is 1-5% of that of a water-soluble gel matrix, and hydrating at normal temperature and normal pressure, so as to obtain tamoxifen flexible nano liposome suspension;
2) uniformly mixing a water-soluble gel matrix, a surfactant B and distilled water, wherein the mass of the added distilled water is 0.1-1% of that of the water-soluble gel matrix to obtain a solution B, dissolving a transdermal penetration enhancer, a preservative and a humectant in ethanol, wherein the mass of the added ethanol is 7-12% of that of the water-soluble gel matrix to obtain a solution C, adding the solution C into the solution B under stirring, adding ammonia water to adjust the solution C to be neutral after swelling, and adding the ammonia water to the solution C to obtain a blank gel matrix, wherein the mass of the added ammonia water is 1-5% of that of the water-soluble gel matrix;
3) and uniformly mixing the blank gel matrix and the tamoxifen flexible nano liposome suspension to obtain the tamoxifen flexible nano liposome gel.
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| CN107998070A (en) * | 2017-12-12 | 2018-05-08 | 南京中医药大学 | A kind of composite phospholipid carrier and its application in percutaneous drug administration preparation is prepared |
| CN110037987B (en) * | 2018-01-15 | 2021-07-13 | 北京斯利安药业有限公司 | Tamoxifen citrate liposome and preparation method thereof |
| CN115429745A (en) * | 2021-06-04 | 2022-12-06 | 武汉科福新药有限责任公司 | Atenolol flexible nano liposome gel and preparation method thereof |
| CN115501181A (en) * | 2021-06-07 | 2022-12-23 | 武汉科福新药有限责任公司 | Nadolol flexible nano gel emulsion and preparation method thereof |
| CN113350288A (en) * | 2021-06-09 | 2021-09-07 | 山东良福制药有限公司 | All-trans-retinoic acid/betamethasone co-loaded flexible nano-liposome and preparation method of gel thereof |
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| CN1234232A (en) * | 1999-04-15 | 1999-11-10 | 上海医科大学附属儿科医院 | External-use medicine composition for treating angioma and preparation method thereof |
| CN1634033A (en) * | 2004-11-10 | 2005-07-06 | 广州市瑞迅生物科技有限公司 | Triptolide nano lipsome gelling agent of external use and its preparation method |
| CN1857242A (en) * | 2006-03-16 | 2006-11-08 | 张怡 | Externally applied tamoxifen citrate microemulsion preparation and its preparing process |
| CN102397242A (en) * | 2011-09-02 | 2012-04-04 | 河南康倍得药业有限公司北京技术开发中心 | Hydrogel containing coenzyme Q10, and cataplasm prepared by hydrogel |
| CN102600079A (en) * | 2012-03-19 | 2012-07-25 | 吉林大学 | Nystatin flexible liposome as well as gel and preparation method of nystatin flexible liposome |
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