CN107233313B - Psoralen nano cubic liquid crystal transdermal preparation and preparation method and application thereof - Google Patents
Psoralen nano cubic liquid crystal transdermal preparation and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a psoralen nano-cubic liquid crystal transdermal preparation as well as a preparation method and application thereof. The transdermal preparation comprises the following components: psoralen, a lipid material, a stabilizer, an organic solvent, water and a transdermal penetration enhancer, wherein the weight ratio of the psoralen to the lipid material to the stabilizer to the organic solvent to the water is 1: 6.67: 0.33 to 1.33: 55.67-59.00: 666.67-4000.00, and the dosage of the transdermal penetration enhancer is 1-5% of the total weight of other components. The transdermal preparation is prepared by quickly injecting the precursor solution into the aqueous solution and carrying out ultrasonic oscillation, can reduce the unit area accumulated permeation amount of the preparation and enhance the retention capacity of psoralen in epidermis and dermis, thereby increasing the interaction time of the medicament and skin lesions, has the advantages of good solubility, strong targeting capacity, remarkable medicinal effect and the like, and can be used for preparing medicaments for treating skin diseases such as leucoderma, alopecia areata, psoriasis, neoplastic dermatosis and the like.
Description
Technical Field
The invention relates to a psoralen nano-cubic liquid crystal transdermal preparation as well as a preparation method and application thereof, belonging to the technical field of medicines.
Background
Psoralen (Psoralen, PS) is a planar heterocyclic compound extracted from Psoralea corylifolia of Leguminosae, is a combination of furan ring and pyrone ring, and has poor water solubility. Psoralen has strong photosensitization effect and biological activity, such as tranquilizing, spasmolytic, hemostatic, and photosensitizing effects; is an effective medicine for treating vitiligo, and also has therapeutic effect on alopecia areata, psoriasis and dermatosis with tumor. At present, the clinical treatment is mainly achieved by fructus psoraleae tablets, injections and tinctures. The fructus psoraleae tablet can generate obvious toxic and side effects in the using process, nausea, headache and epigastric discomfort can be caused, the systemic side effects such as mental depression, insomnia, solar dermatitis, acute keratitis and the like can be caused after a small part of people take the fructus psoraleae tablet, the first pass effect of the liver is strong, the individual difference is large, and therefore the dosage of the fructus psoraleae tablet needs to be strictly controlled. After the psoralea fruit injection is used, severe adverse reactions such as local red swelling, blister, occasional dizziness, blood pressure rise and even anaphylactic shock can be caused. Compared with the former two dosage forms, the fructus psoraleae tincture obviously reduces systemic toxic and side effects in the using process of transdermal administration, but the preparation is a common externally-applied tincture, the medicine is easy to flow, the retention time of the medicine on the skin is short, the absorption and the effect of the medicine are influenced, and meanwhile, the medicine penetrates through a fat-soluble skin stratum corneum barrier and the skin targeting effect is poor, so that the fructus psoraleae tablet, the injection and the tincture have certain limitations in application.
Transdermal Drug Delivery Systems (TDDS) are a type of preparation that is applied by transdermal application, and the drug is absorbed from the skin and enters the systemic blood circulation to reach an effective blood concentration, thereby realizing the treatment or prevention of diseases. The transdermal drug delivery system has the advantages of avoiding the first pass effect of the liver, maintaining constant effective blood concentration, reducing toxic and side effects, reducing drug delivery times, improving treatment efficiency, being convenient to use and the like, and is accepted by most patients.
The nano cubic liquid crystal (cubsomes) is composed of a bicontinuous lipid phase and a water phase, a surfactant is inserted into a lipid bilayer, and unit cells are arranged in an infinite circulation mode in a three-dimensional direction to form a compact honeycomb-like structure with extremely small curvature. The system is an isotropic, thermodynamically stable, clear-looking dispersion system. Cubic liquid crystals have many advantages in TDDS, such as: the liquid crystal has a chemical structure similar to a biological membrane, can improve the skin barrier penetrating capacity of the medicine, has a skin targeting effect, and improves the bioavailability. Meanwhile, the method is widely used for simulating the aspects of matrixes of biological membranes and protein crystals, materials science, drug delivery carriers and the like, and also has the advantages of capability of adopting the traditional method for sterilization, simple preparation process, cheap and easily obtained auxiliary materials, suitability for industrial production and the like. Therefore, the system has attracted great interest in the field of medicine as one kind of medicine carrier.
At present, no report of a psoralen nano cubic crystal transdermal preparation is published, the psoralen is encapsulated in the nano cubic crystal transdermal preparation and is administered through skin, so that the psoralen can be directly targeted to a skin lesion part for administration, systemic toxic and side effects are reduced, the drug loading capacity can be obviously improved, the skin retention capacity of the psoralen is obviously enhanced, the action time is effectively prolonged, the curative effect is further improved, the administration times are reduced, the requirements of patients are met, and a wider prospect is provided for reasonable development and utilization of the psoralen. It brings the hope of treating patients suffering from vitiligo, alopecia areata, psoriasis and neoplastic dermatosis, and improves the quality of life of the patients.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a psoralen nano cubic liquid crystal transdermal preparation which has the advantages of good solubility, high drug stability, high skin retention, lasting action time, capability of obviously improving the curative effect of the drug, reducing the administration times, convenient administration and the like, a preparation method thereof and application thereof in preparing drugs for treating leucoderma, alopecia areata, psoriasis and tumor-like dermatosis.
In order to achieve the purpose, the invention provides a psoralen nano cubic liquid crystal, which comprises the following components: psoralen, a lipid material, a stabilizer, an organic solvent, deionized water and a transdermal penetration enhancer, wherein the weight ratio of psoralen, the lipid material, the stabilizer, the organic solvent and the deionized water is 1: 6.67: 0.33 to 1.33: 55.67-59.00: 666.67-4000.00, more preferably 1: 6.67: 0.67: 58.33: 666.67.
preferably, the lipid material is Glycerol Monooleate (GMO).
Preferably, the stabilizer is poloxamer 407 (F127).
Preferably, the organic solvent is at least one of methanol, absolute ethyl alcohol, propylene glycol and n-butanol; more preferably anhydrous ethanol.
Preferably, the transdermal penetration enhancer is at least one of azone, menthol, glycerol and propylene glycol; more preferably azone.
Preferably, the content of the transdermal penetration enhancer is 1 to 5 percent of the total weight of other components; more preferably 3%.
The invention also provides a preparation method of the psoralen nano cubic liquid crystal transdermal preparation, which comprises the following steps:
1) weighing psoralen, a lipid material, a stabilizer, an organic solvent and deionized water according to the weight ratio of the invention;
2) adding psoralen, lipid material and stabilizer into organic solvent, and mixing;
3) ultrasonically heating the solution obtained in the step 2) until the solution is completely dissolved to obtain a uniform precursor solution;
4) quickly injecting the solution obtained in the step 3) into deionized water, and quickly oscillating;
5) adding a certain amount of transdermal penetration enhancer into the solution obtained in the step 4), and performing vortex to obtain a uniform cubic liquid crystal solution of the opalescent bluish cream, namely the psoralen nano cubic liquid crystal transdermal preparation.
Preferably, the temperature of the ultrasonic heating in the step 3) is 20-60 ℃; more preferably 30 deg.c.
Preferably, the ultrasonic heating time in the step 3) is 10-30 min; more preferably 15 min.
Preferably, the dosage of the transdermal penetration enhancer in the step 5) is 1 to 5 percent of the total weight of other components; more preferably 3%.
Preferably, the vortex time in the step 5) is 3-15 min; more preferably 3 min.
The invention provides application of the psoralen cubic liquid crystal transdermal preparation, which can be used for preparing medicines for treating leucoderma, alopecia areata, psoriasis and neoplastic dermatosis.
Preferably, the medicament is administered by external application.
The invention also provides a medicine smearing external preparation for treating leucoderma, alopecia areata, psoriasis and tumor-like dermatosis, which contains the psoralen cubic liquid crystal transdermal preparation.
Compared with the prior art, the invention has the beneficial effects that:
the psoralen, a transdermal drug delivery system and cubic liquid crystal are combined to be applied to prepare the medicine for resisting leucoderma, alopecia areata, psoriasis and neoplastic dermatosis, and the medicine has small toxic and side effect, good stability and high curative effect. At present, no cubic liquid crystal transdermal psoralen preparation is disclosed and reported, the cubic liquid crystal transdermal psoralen preparation can obviously improve the drug loading capacity, obviously enhance the capability of psoralen for penetrating through a skin barrier, increase the unit area retention of epidermal dermis, effectively prolong the action time, further improve the curative effect, reduce the administration times and facilitate the administration.
The skin barrier effect of the stratum corneum in a transdermal drug delivery system limits the drug to penetrate through the skin, and in order to achieve better curative effect, the inventor conducts long-term research, selects cubic liquid crystal as a carrier, has good stability and small particle size, is easy to penetrate through structures such as skin hair follicle holes and micro-slits, can increase the compatibility of the drug which is difficult to penetrate with the skin due to self structural factors, changes the structure of lipid bilayers, increases the transdermal penetration of the drug, targets the dermis of the epidermis of the skin, and determines the weight ratio of each component.
Drawings
Fig. 1 is a graph showing the cumulative permeation rate of the transdermal preparation of the present invention in the presence of different permeation enhancers (n-3,
blank;
propanedione;
menthol;
(ii) azone;
glycerin);
fig. 2 is a graph showing the cumulative permeation rate of the transdermal preparation of the present invention when containing various amounts of azone (n-3,
5% azone;
3% azone;
2% azone;
1% azone;
blank);
fig. 3 is a bar graph of percent encapsulation for each example of the invention (n-3);
fig. 4 is a graph of the cumulative permeation rate of the transdermal formulation of the present invention and commercially available tinctures (n-3,
cubic liquid crystal;
commercially available tincture);
fig. 5 shows the cumulative retention of the transdermal preparations of the invention and commercially available tinctures (n-3, ■ commercially available tinctures; □ cubic liquid crystal).
Detailed description of the invention
Firstly, the invention takes the encapsulation efficiency as an index, examines the influence of each organic solvent on the cubic liquid crystal encapsulation efficiency, and the measurement result is shown in table 1:
TABLE 1 encapsulation efficiency of cubic liquid crystals in different organic solvents
As can be seen from Table 1, the most preferred organic solvent for highest encapsulation efficiency is absolute ethanol.
Subsequently, the invention investigates the influence of various transdermal penetration enhancers (azone, propylene glycol, menthol and glycerol) on the in-vitro transdermal penetration of the PS through in-vitro transdermal penetration experiments, and takes the accumulated penetration amount as an index, and the result is shown in fig. 1, which shows that the preferred transdermal penetration enhancer is azone. Meanwhile, the influence of different contents of azone on the in-vitro percutaneous permeation of PS is considered, and the result is shown in figure 2, and the preferable content of azone is 3 percent (the azone accounts for the percentage of the total amount of other components).
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Example 1
The preparation method comprises the following steps:
1) weighing psoralen, a lipid material, a stabilizer, an organic solvent and deionized water according to the prescription amount;
2) adding psoralen, lipid material and stabilizer into organic solvent, and mixing;
3) ultrasonically heating the solution obtained in the step 2) until the solution is completely dissolved to obtain a uniform precursor solution, wherein the ultrasonic temperature is 30 ℃, and the ultrasonic time is 15 min;
4) quickly injecting the solution obtained in the step 3) into deionized water, and quickly oscillating;
5) adding a transdermal penetration enhancer into the solution obtained in the step 4), and vortexing for 3min to obtain a uniform cubic liquid crystal solution of the opalescent bluish cream, namely the transdermal preparation of the invention.
Example 2
The preparation method comprises the following steps: the same as in example 1.
Example 3
The preparation method comprises the following steps: the same as in example 1.
Example 4
The preparation method comprises the following steps: the same as in example 1.
Example 5
The preparation method comprises the following steps: the same as in example 1.
Example 6
The preparation method comprises the following steps: the same as in example 1.
Experimental example 1 description of examples and analysis of encapsulation efficiency test results
The invention inspects the influence of two different precursor solution formulas and three different proportions of GMO and deionized water on the cubic liquid crystal encapsulation efficiency through embodiments.
As can be seen from the test results shown in fig. 3, the encapsulation efficiency was the highest for example 1, followed by example 2. The results show that the preferred formulation of the precursor solution is PS: GMO: f127: ethanol ═ 0.015: 0.1: 0.01: 0.875; the preferred amount of deionized water is GMO: deionized water 0.1: 10.
in combination with the previously discussed preferred embodiments of transdermal penetration enhancers, the most preferred formulation of the present invention is a PS: GMO: f127: ethanol: deionized water: azone ═ 0.015: 0.1: 0.01: 0.875: 10: 0.33.
experimental example 2 in vitro percutaneous permeation experiment
The psoralen nano cubic liquid crystal transdermal preparation (by weight, PS: GMO: F127: ethanol: deionized water: azone ═ 0.015: 0.1: 0.01: 0.875: 10: 0.33) is prepared, and the externally accumulated permeation quantity comparison experiment is carried out with the commercially available psoralen tincture (China general hospital of the liberation force).
(1) Laboratory apparatus
TP-3A intelligent transdermal tester, KQ3200E medical ultrasonic cleaner, Waters 2695 model high performance liquid chromatograph.
(2) Selection of receiving medium
Because psoralen is a water-insoluble drug, the present invention considers the dissolving capacity of various receiving mediums to PS at 37 ℃, and the measurement results of the saturation solubility are shown in Table 2:
TABLE 2 solubility of psoralen in different media at 37 deg.C
The results show that the highest saturation solubility of PS in 10% Tween-80-normal saline, 611.7. mu.g/mL, is sufficient to achieve sink conditions, so 10% Tween-80-normal saline can be used as the receiving medium.
(3) Skin treatment method
SD rats (body weight 180-220 g) were sacrificed after anaesthesia with chloral hydrate and the back skin was peeled off after carefully removing the hair on the back skin with eye scissors. Carefully removing subcutaneous fat and adhesion on the inner side of skin with a blade, washing with physiological saline, placing in physiological saline solution, magnetically stirring for 2h, carefully checking skin integrity, sealing in a sealed bag, and storing in a refrigerator at-80 deg.C. Before the experiment, the rat skin is taken out and placed in the normal saline solution to be stirred and washed, and the rat skin is carefully checked not to have any visible damage.
(4) Experimental methods
A TP-3A intelligent transdermal tester is adopted for carrying out experiments, the back skin of a selected rat is fixed between a receiving pool and a dosing pool, and the horny layer is upward. The release area is 1.31cm2The receiving tank had a volume of 20 mL. Psoralen nano cubic liquid crystal 2mL and commercially available ointment 2mL were uniformly applied to the skin on the supply reservoir side. Adding the receiving medium into a receiving pool, stirring at constant speed in a constant-temperature water bath at 37 +/-1 ℃, taking 1mL of the receiving medium in 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours respectively, and simultaneously adding an equal amount of blank receiving medium at the same temperature into the receiving pool.
(5) Cumulative amount measurement
Filtering the sample solution at each time point with 0.45 μm filter membrane, discarding the primary filtrate, collecting the subsequent filtrate, and measuring the content of the drug in the receiving medium by high performance liquid chromatography. Chromatographic conditions are as follows: topsil C18(200 mm. times.4.6 mm, 5 μm) column, mobile phase: methanol-water (55: 45), wavelength: 246nm, flow rate: 1.0mL/min, sample size: 10 μ L, column temperature: 37 ℃ is carried out. The concentration in each time was calculated as the peak area ratio of the sample solution to the control solution, and was substituted into the formula to calculate the cumulative permeation amount (Q).
The cumulative permeation quantity formula is as follows: the concentration of the drug measured by HPLC was corrected by the formula (1-1), and the cumulative permeation amount (Q, μ g/cm) of the drug was calculated by substituting the formula (1-2)2)。
In the formula:
Ci-the measured concentration of the drug t times ago;
Cn-measured concentration of drug at time t;
v is the sampling volume;
V0-the volume of solution in the receiving reservoir;
Qn-t time unit area cumulative permeation;
a-effective diffusion area of the skin.
And (4) drawing by taking the accumulated permeation amount of the unit area as a vertical coordinate and the time as a horizontal coordinate, and drawing an accumulated permeation curve. The results are shown in FIG. 4.
(6) Measurement of Retention amount
After the termination of the experiment, the skin was removed, the residual drug on the skin surface was washed with physiological saline and dried with a cotton swab, and the retention of the drug in the stratum corneum and the epidermis and dermis layers was measured.
Horny layer: sticking 3M adhesive tape on the skin of the hair side, discarding the adhesive tape used for the first time, repeatedly sticking for fifteen times, cutting the adhesive tape into pieces, placing the pieces in a 10mL centrifuge tube, adding 5mL methanol, ultrasonically extracting for 10min by a cell disrupter, fixing the volume by methanol, carrying out vortex oscillation for 3min, centrifuging for 10min at 15000r/min, taking supernatant, filtering by a 0.45-micron filter membrane, and determining the drug content.
Epidermis layer and dermis layer: cutting the rest skin, placing into 10mL centrifuge tube, adding 5mL methanol, homogenizing with tissue homogenizer for 10min, adding methanol to constant volume, vortex oscillating for 3min, centrifuging at 15000r/min for 10min, collecting supernatant, filtering with 0.45 μm filter membrane, and determining drug content.
The skin retention per unit area is plotted as the ordinate on a histogram of the cumulative skin retention. The plotted results are shown in fig. 5 (P <0.05 compared to the control component).
(7) Determination of drug-loading content of psoralen cubic liquid crystal and commercially available tincture
The results of the drug loading measurements are shown in Table 3.
TABLE 3 drug content of psoralen cubic liquid crystal and commercially available tincture (unit:%)
The content of psoralen in the tincture sold in the market is 0.15%, and the content of psoralen in the psoralen nano cubic crystal transdermal preparation is 0.13%.
(8) Analysis of results
As shown in fig. 4, the cumulative permeation amount results of the psoralen nano cubic crystal transdermal preparation and the commercially available tincture transdermal preparation which can continuously release the medicament within 24 hours are as follows: transdermal penetration rate of commercial psoralea tincture (181.83 + -8.19 μ g/cm)2) Compared with the psoralen nano cubic crystal transdermal preparation (108.25 +/-3.23 mu g/cm)2) High. The transdermal penetration amount of the psoralea corylifolia tincture for 24 hours is 1.68 times that of the cubic crystal. As shown in fig. 5, the epidermis layer concentration of the psoralen nanocube transdermal preparation group of the invention is 1.9 times of the epidermis layer concentration of the psoralen nanocube transdermal preparation group of the invention, and the dermis and cuticle drug concentration of the psoralen nanocube transdermal preparation group of the invention is 1.69 times of the commercially available tincture group. Therefore, compared with the commercially available psoralea fruit tincture, the psoralen nano cubic crystal transdermal preparation has larger retention in dermis and cuticle.
It can be seen that the content, the accumulated permeation amount and the permeation rate of the psoralen nano cubic crystal transdermal preparation are lower than those of the commercially available tinctures, but most of the active ingredients of the commercially available tinctures only stay in the epidermis layer, and the active ingredients of the psoralen nano cubic crystal transdermal preparation of the invention are deep into the dermis layer and the cuticle layer, and the content of the active ingredients is 1.69 times of that of the commercially available preparation group. The psoralen nano cubic crystal transdermal preparation has higher capability of penetrating through cuticle and targeting skin than commercially available tinctures, can obviously improve the bioavailability of psoralen, can provide a slow release effect for psoralen, prolongs the action time of a medicament, enables the medicament to be retained in the skin, achieves the aim of targeting treatment, and has good clinical application prospect.
Claims (13)
1. A psoralen nano cubic liquid crystal transdermal preparation is characterized by comprising the following components: psoralen, a lipid material, a stabilizer, an organic solvent, deionized water and a transdermal penetration enhancer, wherein:
the weight ratio of psoralen, lipid material, stabilizer, organic solvent and deionized water is 1: 6.67: 0.33 to 1.33: 55.67-59.00: 666.67-4000.00;
the lipid material is glycerol monooleate;
the stabilizer is poloxamer 407;
the organic solvent is at least one of methanol, absolute ethyl alcohol, propylene glycol and n-butyl alcohol;
the transdermal penetration enhancer is at least one of azone, menthol, glycerol and propylene glycol;
the content of the transdermal penetration enhancer is 1 to 5 percent of the total weight of other components.
2. The psoralen nanocube liquid crystal transdermal formulation of claim 1, wherein: the weight ratio of psoralen, lipid material, stabilizer, organic solvent and deionized water is 1: 6.67: 0.67: 58.33: 666.67.
3. the psoralen nanocube liquid crystal transdermal formulation of claim 1, wherein: the organic solvent is absolute ethyl alcohol.
4. The psoralen nanocube liquid crystal transdermal formulation of claim 1, wherein: the transdermal penetration enhancer is azone.
5. The psoralen nanocube liquid crystal transdermal formulation of claim 1, wherein: the content of the transdermal penetration enhancer is 3 percent of the total weight of other components.
6. The method for preparing psoralen nanocube liquid crystal transdermal preparation of claim 1, which comprises the following steps:
1) weighing psoralen, lipid material, stabilizer, organic solvent and deionized water according to the weight ratio of claim 1;
2) adding psoralen, lipid material and stabilizer into organic solvent, and mixing;
3) ultrasonically heating the solution obtained in the step 2) until the solution is completely dissolved to obtain a uniform precursor solution;
4) quickly injecting the solution obtained in the step 3) into deionized water, and quickly oscillating;
5) adding a certain amount of transdermal penetration enhancer into the solution obtained in the step 4), and performing vortex to obtain a uniform cubic liquid crystal solution of the opalescent bluish cream, namely the psoralen nano cubic liquid crystal transdermal preparation.
7. The method of claim 6, wherein: the temperature of the ultrasonic heating in the step 3) is 20-60 ℃; the ultrasonic heating time is 10-30 min.
8. The method of claim 6, wherein: the temperature of the ultrasonic heating in the step 3) is 30 ℃; the ultrasonic heating time is 15 min.
9. The method of claim 6, wherein: the dosage of the transdermal penetration enhancer in the step 5) is 3 percent of the total weight of other components.
10. The method of claim 6, wherein: and 5) the vortex time in the step 5) is 3-15 min.
11. The method of claim 6, wherein: the time for the vortexing in step 5) was 3 min.
12. Use of a psoralen cubic liquid crystal transdermal formulation according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of vitiligo, alopecia areata, psoriasis and neoplasia-like skin disorders.
13. A medicinal external application liquid preparation for treating vitiligo, alopecia areata, psoriasis and neoplastic dermatosis is characterized in that: a transdermal psoralen nanocube liquid crystal formulation comprising the psoralen of any of claims 1-5.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1350862A (en) * | 2000-11-01 | 2002-05-29 | 张若飞 | Composition for treating leukoderma |
| CN104013600A (en) * | 2014-06-05 | 2014-09-03 | 暨南大学 | Psoralen-enveloped nanostructure lipid carrier preparation and preparation method thereof |
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2017
- 2017-04-26 CN CN201710282468.8A patent/CN107233313B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1350862A (en) * | 2000-11-01 | 2002-05-29 | 张若飞 | Composition for treating leukoderma |
| CN104013600A (en) * | 2014-06-05 | 2014-09-03 | 暨南大学 | Psoralen-enveloped nanostructure lipid carrier preparation and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| Characterization of cubosomes as a targeted and sustained transdermal delivery system for capsaicin;Xinsheng Peng等;《Drug Design, Development and Therapy》;20150803;第9卷;第453页左栏 * |
| 脂质立方液晶纳米粒作为药物载体的研究进展;吴红兵等;《药学学报》;20081231;第43卷(第5期);摘要 * |
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| CN107233313A (en) | 2017-10-10 |
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