CN107595766B - Lidocaine microemulsion gel and preparation method thereof - Google Patents
Lidocaine microemulsion gel and preparation method thereof Download PDFInfo
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- CN107595766B CN107595766B CN201710735002.9A CN201710735002A CN107595766B CN 107595766 B CN107595766 B CN 107595766B CN 201710735002 A CN201710735002 A CN 201710735002A CN 107595766 B CN107595766 B CN 107595766B
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Abstract
A lidocaine microemulsion gel comprises the following components and is prepared by the following steps: dissolving lidocaine (2-6%), menthol (0-0.8%) in oil phase (3.75%) at 70 deg.C, adding surfactant (8.75%), and adding distilled water (82.1%) dropwise under stirring to obtain microemulsion. Adding antiseptic (0.1%), standing, cooling to room temperature, adding carbomer 980 (0.4%), swelling, stirring, degassing, and sterilizing. The invention is a non-invasive local anesthetic, can avoid the toxic and side effects of the whole body caused by injection, and can be used for skin surgery, beauty treatment, micro plastic and the like.
Description
Technical Field
The invention relates to a local anesthetic, in particular to a lidocaine microemulsion gel for noninvasive transdermal drug delivery and a preparation method thereof.
Background
Skin surgery, and various skin rejuvenation, wrinkle reduction, depilation, eyebrow washing and other cosmetic minimally invasive operations and tattooing and micro-plastic operations of various orders cause superficial traumatic and invasive pain in human skin to different degrees. The anesthesia and analgesia of the treatment part is generally carried out by a method of injecting anesthetic in clinic. However, many problems of injection include pain, difficulty in injection at some parts, inability of the beauty institution to use the injection for anesthesia legally, and more importantly, systemic toxicity and side effects caused by injection. Therefore, it is necessary to develop a non-injectable non-invasive preparation which can be directly applied to the skin surface and can achieve local anesthesia without pain. With the development of the beauty industry, the preparation has a wide application market.
The transdermal local anesthetic preparation which is clinically used at present is generally used at home and abroad, is enna cream, is actually lidocaine cream, is developed and produced by Sweden, and is produced and applied in European and American countries later. However, the time for anesthesia maintenance of the enna cream is averagely 50min, the depth of action is 5mm, the enna cream can only be generally applied to anesthesia of some small surgical operations, and the analgesic effect is difficult to achieve in relatively large operations such as facial plastic surgery. More particularly, the enna cream contains procaine with strong analgesic effect and toxic and side effects, has vasoconstriction effect, and can cause the toxic and side effects of vascular endothelial cell injury, skin whitening, increase of the content of the ferritin in blood and the like. In addition, there are also tetracaine cream, lidocaine gel, lidocaine pressure-sensitive adhesive patch, etc. used clinically, and they all have the same problem as enna cream, i.e. short acting time.
The microemulsion is a nano-dispersed transdermal drug delivery carrier with strong solubilization and excellent permeation promoting effect. The local anesthetic lidocaine with good anesthesia effect and small toxic and side effect is prepared into a microemulsion preparation to improve the anesthesia effect and reduce the toxic and side effect, and has many researches and applications at home and abroad. However, the conventional prepared microemulsion surfactant and cosurfactant have large dosage and relatively small drug-loading rate, and the safety and the effectiveness of the microemulsion surfactant and cosurfactant are still to be improved.
Disclosure of Invention
In order to avoid the systemic toxic and side effects caused by injection and infiltration administration, the invention particularly provides a non-invasive transdermal administration local anesthetic preparation, namely lidocaine microemulsion gel and a preparation method thereof.
The lidocaine microemulsion gel is prepared from the following substances in percentage by mass: 2-6% of lidocaine, 3.75% of oil phase, 8.75% of surfactant, 0-0.8% of penetration enhancer, 0.1% of preservative, 0.4% of carbomer 980, and the balance of water; the oil phase is the combination of two oil substances, wherein the two oil substances are any two of olive oil, isopropyl myristate, glyceryl monostearate and vitamin E succinate; the surfactant is prepared by mixing polyoxyethylene hydrogenated castor oil and span 80 in a mass ratio of 5: 1; the preservative is prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1.
In order to improve the micro-emulsion area and further improve the solubilization capacity of the micro-emulsion on the lidocaine, the invention adopts a method of compounding two oil substances and mutually solubilizing the two oil substances; in order to make the finally prepared microemulsion gel easy to absorb and coat, one of the oils must be in a liquid phase at normal temperature, and isopropyl myristate which has strong skin permeability is the best.
In order to promote the skin permeation of lidocaine, menthol which is a traditional Chinese medicine permeation promoter and has an anesthetic effect is added into the lidocaine-containing skin-permeation enhancer, and the concentration of the menthol is preferably 0.4%.
In order to utilize the drug storage effect of the lipid bilayer of the stratum corneum of the skin, lidocaine was selected from its alkaline form according to the dissociation constant of the drug.
A lidocaine microemulsion gel and a preparation method thereof comprise the following steps:
(1) dissolving two oil substances mutually at 70 deg.C, adding lidocaine and penetration enhancer, and adding surfactant to obtain oil soluble solution;
(2) dropwise titrating the oil-soluble solution in the step (1) by using distilled water under the stirring condition of 70 ℃ to prepare lidocaine microemulsion;
(3) adding a preservative into the microemulsion of the step (2);
(4) and (3) standing the microemulsion obtained in the step (3), cooling to room temperature, then spreading carbomer 980, fully swelling, stirring, degassing and sterilizing to obtain the microemulsion.
The invention improves the content of the oil phase in the microemulsion and the solubilization capacity of the microemulsion on lidocaine by compounding the oil phase. The moistening property and the transdermal permeability of the oil phase substances have important influence on the continuous acting time of the lidocaine microemulsion gel, and the acting time can be prolonged to more than 340min by screening and compounding and using a penetration enhancer.
Drawings
FIG. 1 shows the evaluation of local anesthetic effect of a lidocaine transdermal preparation.
FIG. 2, evaluation of local anesthetic effect of lidocaine microemulsion gel.
FIG. 3, effect of oil on local anesthetic effect of lidocaine microemulsion gel.
Figure 4, effect of menthol on local anesthetic effect of lidocaine microemulsion gel.
Detailed Description
Example 1 to a mixed oil of 3.75g of olive oil and vitamin E succinate (6: 1 by mass) at 70 ℃, 2g of lidocaine was dissolved, 8.75g of a surfactant (polyoxyethylene hydrogenated castor oil mixed with span 80 at 5:1 by mass) was added, and then a desired amount of distilled water was added dropwise under stirring to form a microemulsion. Adding 0.1g of preservative (prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1), standing, cooling to room temperature, then spreading 0.4g of carbomer 980, fully swelling, stirring, degassing, and sterilizing to obtain 100g of lidocaine microemulsion gel with a concentration of 2%.
Example 2 4g of lidocaine was dissolved in 3.75g of a mixed oil of olive oil and vitamin E succinate (6: 1 by mass) at 70 c, 8.75g of a surfactant (polyoxyethylene hydrogenated castor oil mixed with span 80 at 5:1 by mass) was added, and then a desired amount of distilled water was added dropwise under stirring to form a microemulsion. Adding 0.1g of preservative (prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1), standing, cooling to room temperature, then spreading 0.4g of carbomer 980, fully swelling, stirring, degassing, and sterilizing to obtain 100g of 4% lidocaine microemulsion gel.
Example 3 to a mixed oil of 3.75g of olive oil and vitamin E succinate (6: 1 by mass) at 70 c, 5g of lidocaine was dissolved, 8.75g of a surfactant (polyoxyethylene hydrogenated castor oil mixed with span 80 at 5:1 by mass) was added, and then a desired amount of distilled water was added dropwise under stirring to form a microemulsion. Adding 0.1g of preservative (prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1), standing, cooling to room temperature, then spreading 0.4g of carbomer 980, fully swelling, stirring, degassing, and sterilizing to obtain 100g of 5% lidocaine microemulsion gel.
Example 4 to a mixed oil of 3.75g of olive oil and vitamin E succinate (6: 1 by mass) at 70 ℃, 6g of lidocaine was dissolved, 8.75g of a surfactant (polyoxyethylene hydrogenated castor oil mixed with span 80 at 5:1 by mass) was added, and then a desired amount of distilled water was added dropwise under stirring to form a microemulsion. Adding 0.1g of preservative (prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1), standing, cooling to room temperature, then spreading 0.4g of carbomer 980, fully swelling, stirring, degassing, and sterilizing to obtain 100g of 6% lidocaine microemulsion gel.
Example 5g of lidocaine was dissolved in 3.75g of a mixed oil of olive oil and isopropyl myristate (1: 1 by mass) at 70 c, 8.75g of a surfactant (a mixture of polyoxyethylene hydrogenated castor oil and span 80 in a 5:1 by mass ratio) was added, and then a desired amount of distilled water was added dropwise under stirring to form a microemulsion. Adding 0.1g of preservative (prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1), standing, cooling to room temperature, then spreading 0.4g of carbomer 980, fully swelling, stirring, degassing, and sterilizing to obtain 100g of 5% lidocaine microemulsion gel.
Example 6 to a mixed oil of 3.75g of glyceryl monostearate and isopropyl myristate (1: 1 by mass) at 70 ℃, 5g of lidocaine was dissolved, 8.75g of a surfactant (a mixture of polyoxyethylene hydrogenated castor oil and span 80 in a 5:1 by mass ratio) was added, and then a desired amount of distilled water was added dropwise under stirring to form a microemulsion. Adding 0.1g of preservative (prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1), standing, cooling to room temperature, then spreading 0.4g of carbomer 980, fully swelling, stirring, degassing, and sterilizing to obtain 100g of 5% lidocaine microemulsion gel.
Example 75g of lidocaine was dissolved in 3.75g of a mixed oil of olive oil and isopropyl myristate (1: 1 by mass) at 70 c, 0.4g of menthol was added, 8.75g of a surfactant (polyoxyethylene hydrogenated castor oil mixed with span 80 at 5:1 by mass) was further added, and a desired amount of distilled water was added dropwise under stirring to form a microemulsion. Adding 0.1g of preservative (prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1), standing, cooling to room temperature, then spreading 0.4g of carbomer 980, fully swelling, stirring, degassing, and sterilizing to obtain 100g of 5% lidocaine microemulsion gel.
Example 8 5g of lidocaine was dissolved in 3.75g of a mixed oil of olive oil and isopropyl myristate (1: 1 by mass) at 70 c, 0.8g of menthol was added, 8.75g of a surfactant (polyoxyethylene hydrogenated castor oil mixed with span 80 at 5:1 by mass) was further added, and a desired amount of distilled water was added dropwise under stirring to form a microemulsion. Adding 0.1g of preservative (prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1), standing, cooling to room temperature, then spreading 0.4g of carbomer 980, fully swelling, stirring, degassing, and sterilizing to obtain 100g of 5% lidocaine microemulsion gel.
Test part:
the local anesthetic effect of the lidocaine microemulsion gel prepared by the invention is evaluated by a needle punching method.
The experimental method comprises the following steps: the guinea pig with the weight of 250 g-350 g is put on the back and is covered by the skin of the middle partSkin is slightly larger than 2cm2The hair in the area is cut off completely, so that the skin area is exposed. Each group had 6 guinea pigs. At room temperature, a cotton swab is used to locate 2cm in the center of the exposed area2The skin of (1) was coated and the pain response was tested by needle-punching a band-like zone approximately 6mm wide around the skin of the applied part. When the pain sensation exists, the skin area at the stimulation part has a contraction phenomenon, which is called positive response; no shrinkage phenomenon, called negative reaction. Each guinea pig was stimulated a total of 10 times at different points in the zona, each time at 5s intervals, and the number of negative responses to stimulation was recorded for each guinea pig. The test is carried out within 60min after the application of the medicine, every 10min, every 15min after 60min, every 30min after 120min, and every 1h after 210 min. The time is used as the abscissa, and the average value of the negative reaction times of 6 guinea pigs is used as the ordinate to plot, so as to evaluate whether the onset speed, onset time and release speed of the medicine are stable, the strength of the anesthetic action and the like.
The first test example: the results of 6 experiments were performed according to the above-described needling test method, and are shown in FIG. 1. The medicines applied to each curve are respectively as follows: curve 1 is a negative control without lidocaine; curve 2 is 0.3ml of lidocaine hydrochloride injection with an injection concentration of 2%; curve 3 is 0.3g of compound lidocaine cream positive control substance used by the dermatology department of the second people hospital in the Taiyuan city; curve 4 is the application of 0.3g of the 2% lidocaine microemulsion gel of example 1; curve 5 is 0.3g of a 4% lidocaine microemulsion gel as applied in example 2; curve 6 is a 6% lidocaine microemulsion gel 0.3g applied from example 4.
As shown in fig. 1, the negative control containing no lidocaine almost agreed with the average of the number of negative reactions in 6 guinea pigs over the test period, and the number of negative reactions was significantly increased in the remaining 5 lines. In contrast, the lidocaine hydrochloride injection can quickly take effect after being injected for 2-3 min, the local anesthesia effect reaches the peak value after 10min, and then the local anesthesia effect is rapidly reduced; in the experimental process, the guinea pig is unconscious until death within 5min when 4.5ml, namely 90mg of lidocaine is injected; when 0.3ml, that is, 6mg, is injected, guinea pigs are out of order and have no state of being out of order by percutaneous administration until the dose reaches 90 mg. Therefore, the injection administration is easy to enter blood and difficult to control local effect. 2-6% of the microemulsion gel prepared by the method has higher effect taking speed than that of a positive control, but has short effect taking time and unstable drug release rate; the anesthetic effect of each concentration has no concentration dependence, and the anesthetic effect is optimal at medium concentration.
Test example two: 7 sets of experiments were performed according to the above-described needling test method, and the results are shown in FIG. 2. The medicines applied to each curve are respectively as follows: curve 1 is a negative control without lidocaine; curve 2 is a positive control, namely 0.9g of compound lidocaine cream used by the dermatology department of the second people hospital in Taiyuan city is smeared; curve 3 is the low dose group, i.e. 0.3g of a 5% lidocaine microemulsion gel applied from example 3; curve 4 is the medium dose group, i.e. 0.9g of a 5% lidocaine microemulsion gel applied in example 3; curve 5 is the high dose group, i.e. applying 1.8g of the 5% lidocaine microemulsion gel of example 3; curve 6 is 0.9g of self-made 5% lidocaine suspension by smearing; curve 7 is the application of 0.9g of the homemade lidocaine cream.
Compared with curve 1 negative control, the negative reaction times of the lidocaine preparation are obviously improved. The self-made emulsion has the worst action strength and response speed, and the suspension is inferior; compared with a positive control, the microemulsion gel prepared by the invention has strong anesthetic effect, high onset speed and short onset time in medium dosage; compared with a positive control, the low-dose microemulsion gel has the advantages of high onset speed, short onset time and no obvious difference in anesthesia effect. Compared with a positive control, the high-dose microemulsion gel has the advantages of high onset speed, long onset time, large drug release speed fluctuation and lower anesthesia effect than a medium-low dose group.
Test example three: the results of the test example I and the test example II show that the microemulsion gel prepared by the invention has high onset speed, but has short onset time, inconstant drug release rate and no correlation between the anesthesia effect and the concentration and the dosage. Suggesting that the stratum corneum does not act as a drug reservoir and that the drug only reaches the superficial penetration of the skin. For this purpose, isopropyl myristate with high skin permeability is used as one of the oils in the oil phase to promote deep skin penetration of the drug. The results of 4 sets of experiments performed according to the above-described needling test method are shown in FIG. 3. The medicines applied to each curve are respectively as follows: curve 1 shows that the oil phase of example 5 is a 5% lidocaine microemulsion gel 0.9g mixed by isopropyl myristate and olive oil (mass ratio 1: 1); curve 2. oil phase for coating example 6 was 0.9g of 5% lidocaine microemulsion gel mixed with isopropyl myristate and glyceryl monostearate (1: 1 by mass); curve 3 is a positive control; curve 4 is a 5% lidocaine microemulsion gel 0.9g applied from example 3.
Comparing the curves 1 and 2 in fig. 3 with the curves 3 and 4, when isopropyl myristate with strong skin permeability is used as one of the oils in the microemulsion gel, the onset speed is reduced compared with that of example 3, and is lower than that of the positive control, the release speed is not stable, but the onset time is significantly prolonged, especially example 5.
Test example four: menthol, a traditional Chinese medicine penetration enhancer, was added in example 5 in order to further improve the skin penetration effect of lidocaine. The results of 4 sets of experiments performed according to the above-described needling test method are shown in FIG. 4. The medicines applied to each curve are respectively as follows: curve 1 is a positive control of 0.9 g; curve 2 is the application of 0.9g of a microemulsion gel without menthol, example 5; curve 3 is the application of 0.9g of a microemulsion containing 0.4% menthol, example 7. Curve 4 is 0.9g of a microemulsion containing 0.8% menthol applied, example 8.
As can be seen from fig. 4, in curve 3, after adding 0.4% menthol, the number of negative reactions of the microemulsion gel prepared by the present invention can be maintained at a high level after 340min of spreading, which is significantly higher than the positive control represented by curve 1; compared with curve 2, curve 3 is much more stable and the number of negative reactions is significantly increased, indicating that menthol promotes the deep penetration of lidocaine. However, as shown in curve 4, when the menthol concentration is 0.8%, the drug release is not smooth and the onset time is even lower than that of curve 2 without menthol, probably due to the cooling effect of menthol, which slows the diffusion rate of lidocaine.
Claims (3)
1. The lidocaine microemulsion gel is characterized by comprising the following substances in percentage by mass: 2-6% of lidocaine, 3.75% of oil phase, 8.75% of surfactant, 0-0.8% of penetration enhancer, 0.1% of preservative, 0.4% of carbomer 980, and the balance of water; the oil phase is a combination of two oil substances, wherein the two oil substances are any two of olive oil, isopropyl myristate, glyceryl monostearate and vitamin E succinate which are mixed according to a mass ratio of 1: 1-6: 1; the surfactant is prepared by mixing polyoxyethylene hydrogenated castor oil and span 80 in a mass ratio of 5: 1; the preservative is prepared by mixing methyl paraben sodium and propyl paraben sodium in a mass ratio of 1: 1; one of the two oils adopted in the oil phase is liquid at normal temperature.
2. A lidocaine microemulsion gel according to claim 1, wherein the penetration enhancer is menthol with anesthetic effect, and the concentration is 0.4%.
3. A method for preparing a lidocaine microemulsion gel, which is used for preparing the lidocaine microemulsion gel of claim 1, and is characterized by comprising the following steps:
(1) dissolving two oil substances mutually at 70 deg.C, adding lidocaine and penetration enhancer, and adding surfactant to obtain oil soluble solution;
(2) dropwise titrating the oil-soluble solution in the step (1) by using distilled water under the stirring condition of 70 ℃ to prepare lidocaine microemulsion;
(3) adding a preservative into the microemulsion of the step (2);
(4) and (3) standing the microemulsion obtained in the step (3), cooling to room temperature, then spreading carbomer 980, fully swelling, stirring, degassing, and sterilizing to obtain the product.
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| CN112220779A (en) * | 2020-11-12 | 2021-01-15 | 浙江鼎泰药业股份有限公司 | Novel transdermal preparation for local analgesia and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03146600A (en) * | 1989-09-02 | 1991-06-21 | Procter & Gamble Co:The | Granular detergent composition containing compound incorporated in microemulsion base gel |
| CN1583175A (en) * | 2004-06-11 | 2005-02-23 | 华中科技大学 | Skin targeting medicinal composition and its preparation and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03146600A (en) * | 1989-09-02 | 1991-06-21 | Procter & Gamble Co:The | Granular detergent composition containing compound incorporated in microemulsion base gel |
| CN1583175A (en) * | 2004-06-11 | 2005-02-23 | 华中科技大学 | Skin targeting medicinal composition and its preparation and use |
Non-Patent Citations (1)
| Title |
|---|
| 利多卡因微乳凝胶剂的制备及体外透皮特性;葛敏等;《中国临床药学杂志》;20151231;第24卷(第6期);第339-342页 * |
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