CN117653641A - Pharmaceutical composition for treating acne, microemulsion-temperature-sensitive gel composition, and preparation method and application thereof - Google Patents
Pharmaceutical composition for treating acne, microemulsion-temperature-sensitive gel composition, and preparation method and application thereof Download PDFInfo
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- CN117653641A CN117653641A CN202311510704.9A CN202311510704A CN117653641A CN 117653641 A CN117653641 A CN 117653641A CN 202311510704 A CN202311510704 A CN 202311510704A CN 117653641 A CN117653641 A CN 117653641A
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- China
- Prior art keywords
- microemulsion
- quercetin
- temperature
- tanshinone iia
- oil phase
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- Pending
Links
- 208000002874 Acne Vulgaris Diseases 0.000 title claims abstract description 55
- 206010000496 acne Diseases 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 239000000203 mixture Substances 0.000 title claims description 20
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims abstract description 204
- 239000004530 micro-emulsion Substances 0.000 claims abstract description 103
- 229960001285 quercetin Drugs 0.000 claims abstract description 103
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 claims abstract description 102
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 claims abstract description 102
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims abstract description 102
- 235000005875 quercetin Nutrition 0.000 claims abstract description 102
- HYXITZLLTYIPOF-UHFFFAOYSA-N 1,6,6-trimethyl-8,9-dihydro-7H-naphtho[1,2-g]benzofuran-10,11-dione Chemical compound O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 claims abstract description 98
- AIGAZQPHXLWMOJ-UHFFFAOYSA-N tanshinone IIA Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 claims abstract description 79
- AZEZEAABTDXEHR-UHFFFAOYSA-M sodium;1,6,6-trimethyl-10,11-dioxo-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-2-sulfonate Chemical compound [Na+].C12=CC=C(C(CCC3)(C)C)C3=C2C(=O)C(=O)C2=C1OC(S([O-])(=O)=O)=C2C AZEZEAABTDXEHR-UHFFFAOYSA-M 0.000 claims abstract description 75
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a pharmaceutical composition for treating acne, a microemulsion-temperature-sensitive gel pharmaceutical composition for treating acne, a preparation method and application thereof, and tanshinone II loaded by the pharmaceutical composition A And quercetin, the microemulsion-temperature sensitive gel containing tanshinone IIA and quercetin prepared by the method is especially suitable for anti-inflammatory and repairing acne, and is prepared from tanshinone II A And adding the medicated microemulsion into the poloxamer system to form a microemulsion dispersion system composed of quercetin, oil phase, water phase, surfactant and cosurfactant. The microemulsion-temperature-sensitive gel of the traditional Chinese medicine tanshinone IIA and quercetin has good biocompatibility and biodegradability, and is suitable for application in the field of surgical and medical treatment.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to an external preparation, a preparation method and application, and in particular relates to a microemulsion-temperature-sensitive gel, a preparation method and application for treating chronic inflammatory skin diseases including acne, folliculitis and the like.
Background
Acne is a skin disease with loss beauty, affects more than 90% of teenagers and young people, and has a very high recurrence rate. Acne patients suffer from personal anxiety and psychological spelt caused by acne throughout the year, and seriously affect daily life and psychological health. Acne is often found in areas where sebum secretion is vigorous, such as the dermis layers of the forehead, face, chest and back, where pathological areas are often erythema, acne, pustules, papules or nodules, and where some moderate and severe inflammatory acne may cause melanin deposition and even severe scarring. It has been found that a number of causative factors are closely related to the occurrence and development of acne, and endocrine factors, particularly androgen metabolism levels, severely affect the development of acne. Androgens can promote sebum secretion, abnormal keratinization of sebaceous gland ducts and block the lumen, and the increase of propionibacterium acnes leads to acne onset, which is called androgenic acne. In addition, excessive keratinization of the pilo sebaceous glands, colonization by harmful microorganisms, etc. can affect the pathogenesis of acne. The pathological mechanism of acne may be hyper-hyperplasia of sebaceous glands after androgen stimulation, and synthesis and secretion of excess sebum; meanwhile, excessive keratinization of the pilosebaceous glands narrows sebum excretion channels, and sebum is accumulated in the hair follicles and sebaceous gland systems in a large quantity, so that excretion is not smooth. Anaerobic environment caused by pore blockage is beneficial to the growth of acne-related pathogenic bacteria such as staphylococcus aureus and propionibacterium acnes and accelerates the formation of acne.
Clinically, acne is usually treated with antibiotics, retinoic acid and hormonal drugs. Although these drugs for oral administration or external use can exert the therapeutic effects of resisting bacteria, diminishing inflammation and removing acnes at the same time, their use is limited by adverse reactions to different degrees. In addition, acne lesions often exhibit skin sensitivity and high resistance due to overuse or abuse of antibiotics, which greatly limit their use in acne treatment. Thus, more research is needed to find safe, effective and less adverse treatments.
Quercetin is a polyphenol flavonoid compound, can effectively inhibit the expression of androgen receptor genes as a plant estrogen, and can also convert aromatic testosterone into estradiol by increasing the activity of aromatic enzyme, thereby reducing the expression of androgens at the acne part and playing an antiandrogenic role. It is reported that it can remain in the human stratum corneum for a long time, and has strong and durable anti-inflammatory properties and antioxidant effects.
Tanshinone IIA is a liposoluble component of Saviae Miltiorrhizae radix, and has various pharmacological effects including antiinflammatory, antibacterial, and antiandrogen. Studies have shown that administration of tanshinone IIA in experimental animals can reduce the weight of androgen dependent organs (prostate and seminal vesicles). Based on these androgen-related indicators, studies predict that tanshinone IIA may exhibit anti-androgenic effects by inhibiting its binding to androgens by targeting AR. The tanshinone IIA has the effect of improving microcirculation, can promote cell metabolism and development, and effectively promote inflammatory wound healing. In addition, tanshinone IIA has broad-spectrum antibacterial effect, and can remarkably inhibit the activities of microorganisms such as propionibacterium acnes, staphylococcus aureus, staphylococcus epidermidis and the like.
The microemulsion is a nano dispersion system composed of an oil phase, a water phase, a surfactant and a cosurfactant, the appearance is transparent or semitransparent, the particle size of the microemulsion is generally between 10 and 100nm, the particle size is smaller, the distribution is uniform and the stability is high, the microemulsion has good solubility to lipophilic and hydrophilic drugs, and the bioavailability of the drugs can be improved.
The invention prepares the drug-loaded microemulsion of the encapsulated quercetin and tanshinone IIA by a microemulsion technology, thereby improving the solubility and bioavailability of the two drugs. The temperature-sensitive gel is prepared by changing the proportion of poloxamer P188 and P407, and the drug-loaded microemulsion is embedded into the in-situ gel to prepare a microemulsion-temperature-sensitive in-situ gel system, so that the microemulsion can be uniformly distributed in the three-dimensional network structure of the in-situ gel, and adhesion of the drug on the acne part is facilitated.
Disclosure of Invention
The invention aims at providing a pharmaceutical composition for treating acne, microemulsion-temperature-sensitive gel, a preparation method and application thereof, wherein the microemulsion-temperature-sensitive gel for treating acne uses tanshinone II as an active ingredient of a traditional Chinese medicine A And quercetin as therapeutic agent, and is prepared into loaded tanshinone II A And quercetin, and then adding the microemulsion into a poloxamer system to prepare tanshinone II A And a microemulsion-temperature sensitive gel of quercetin. Tanshinone II of the invention A And the microemulsion-temperature-sensitive gel of the quercetin has great application prospect in treating acute and chronic inflammatory dermatosis, including acne, folliculitis and other diseases.
To achieve the purpose of the invention, the invention provides a pharmaceutical composition for treating acne, which comprises quercetin and tanshinone IIA.
Wherein, the weight ratio of the quercetin to the tanshinone IIA is 1: (1-2), preferably 1:1.
the invention also provides a preparation method of the microemulsion-temperature-sensitive gel pharmaceutical composition for treating acne, which comprises the following steps:
1) Preparation of microemulsion loaded with quercetin and tanshinone IIA
1A) Mixing the oil phase and the compound surfactant through first stirring to prepare a blank oil phase, wherein the compound surfactant consists of the surfactant and the cosurfactant;
1B) Adding the mixture of quercetin and tanshinone IIA into the blank oil phase, stirring and mixing for the second time, and dissolving to obtain mixed oil phase;
1C) Adding deionized water into the mixed oil phase under stirring, and stirring to obtain quercetin-tanshinone IIA microemulsion;
2) Adding poloxamer P470 and poloxamer P188 into quercetin-tanshinone IIA microemulsion, stirring, dissolving, and making into quercetin-tanshinone IIA temperature-sensitive gel stock solution;
3) The temperature of the quercetin-tanshinone IIA temperature-sensitive gel stock solution reaches 30.44 ℃, and the gel stock solution is converted from a liquid state to a gel state, so that the microemulsion-temperature-sensitive gel pharmaceutical composition for treating acne is formed.
Wherein, in the blank oil phase in the step 1A), the mass ratio of the oil phase to the composite surfactant is (8-10): (38-40), preferably 8:38.
In particular, the oil phase is one or more of ethyl Oleate (OE), isopropyl myristate (IPP), isopropyl Palmitate (IPM), preferably ethyl Oleate (OE); the surfactant is one or more of Tween 80 (Tween 80), tween 20 (Tween 20) and polyoxyethylene castor oil (CREL), preferably polyoxyethylene castor oil; the cosurfactant is one or more of Span 80 (Span 80), 1, 2-propylene glycol (1, 2-PG) and polyethylene glycol 400 (PFG 400), preferably 1, 2-propylene glycol.
In particular, the weight part ratio of the surfactant to the cosurfactant in step 1A) is (1-3): 1, preferably 1:1.
In particular, the temperature of the first, second and third stirring and mixing in steps 1A), 1B) and 1C) is 30-50 ℃, preferably 40 ℃; the stirring rate is 300-600rpm, preferably 450rpm.
In particular, the weight part ratio of the quercetin to the tanshinone IIA in the step 1B) is 1: (1-2), preferably 1:1.
In particular, 5-30mg, preferably 20mg, of the pharmaceutical composition (i.e. the mixture of quercetin, tanshinone IIA) is added per 2g of blank oil phase in step 1B).
In particular, the weight part ratio of the quercetin to the tanshinone IIA in the pharmaceutical composition is 1: (1-2), preferably 1:1.
In particular, the mass ratio of the deionized water or distilled water in the step 1C) to the oil phase and the compound surfactant in the step 1A) is (50-54): (8-10): (38-40), preferably 54:8:38.
preparing microemulsion of tanshinone IIA and quercetin by phase inversion method, mixing oil phase, surfactant and cosurfactant (i.e. compound surfactant) at 40deg.C, adding tanshinone IIA and quercetin, stirring, adding distilled water, and mixing to obtain microemulsion loaded with tanshinone IIA and quercetin
In particular, the mass percentage concentration of the oil phase in the quercetin-tanshinone IIA microemulsion prepared in the step 1) is (8-10)%, preferably 8%; the mass percentage concentration of the composite surfactant is (38-40)%, preferably 38%.
In particular, the weight ratio of poloxamer P188 to P407 in step 2) is (8-9): 1, preferably 9:1.
In particular, the volume-mass ratio of quercetin-tanshinone IIA microemulsion to poloxamer P470 is 1: (150-200), preferably 1:180, namely, the mass of poloxamer P470 added into each 1ml of quercetin-tanshinone IIA microemulsion is 150-200mg, preferably 180mg; the volume-mass ratio of the quercetin-tanshinone IIA microemulsion to poloxamer P188 is 1: (10-30), preferably 1:20, namely, the mass of poloxamer P188 added into each 1mL of quercetin-tanshinone IIA microemulsion is 10-30mg, preferably 20mg.
Dissolving the polymer material, standing and swelling for at least 18 hr to stretch the polymer chain segment to obtain Ginseng radix II A And a microemulsion-temperature sensitive gel of quercetin.
In a further aspect, the invention provides a microemulsion-temperature-sensitive gel for treating acne, which is prepared by the method.
In yet another aspect, the present invention provides a loaded tanshinone II A And application of the microemulsion-temperature-sensitive gel of quercetin in preparing medicines for treating acne.
Wherein the tanshinone II is loaded A And the microemulsion-temperature-sensitive gel of quercetin are prepared according to the method.
In particular, the loaded tanshinone II A And the weight part ratio of quercetin to tanshinone IIA in the microemulsion-temperature sensitive gel of quercetin is 1: (1-2), preferably 1:1.
another aspect of the invention provides a tanshinone II for treating acne A And a method for preparing the quercetin microemulsion, comprising the following steps:
1) Screening an oil phase reagent, a surfactant and a cosurfactant for preparing the microemulsion;
2) Screening the optimal proportion of the surfactant and the cosurfactant through a pseudo ternary phase diagram;
3) The phase inversion method is used for preparing the microemulsion of tanshinone IIA and quercetin, the oil phase, the surfactant and the cosurfactant are mixed uniformly at 40 ℃, then the tanshinone IIA and the quercetin are added, stirred uniformly, and then distilled water is added to mix uniformly, thus obtaining the microemulsion loaded with tanshinone IIA and quercetin.
The invention provides a microemulsion-temperature-sensitive gel of tanshinone IIA and quercetin, which is applied to treating chronic inflammatory skin diseases.
The invention also provides an application of the microemulsion-temperature-sensitive gel of tanshinone IIA and quercetin in medicines for repairing chronic inflammatory skin diseases; use in the preparation of a dressing for acne, for a drug delivery vehicle.
Wherein the chronic inflammatory skin diseases comprise acne, folliculitis, etc.
Compared with the prior art, the invention has the following obvious advantages:
the traditional transdermal administration dosage forms such as cream, ointment, patch and the like have a plurality of defects of poor transdermal property, limited curative effect, immunosuppression and the like. The microemulsion technology in the invention can improve the curative effect of the medicine, promote the transdermal effect of the medicine, and can be combined with a temperature-sensitive gel system to enhance the adhesion practice of the medicine at the acne part, so that the microemulsion-temperature-sensitive gel of tanshinone IIA and quercetin has wide prospect in transdermal preparations. In addition, the side effects of common antibiotics, retinoic acid and hormone medicines can be reduced by using the active ingredients of the traditional Chinese medicine as the therapeutic medicine, and the safety and the patient compliance are high.
Drawings
FIG. 1 shows tanshinone IIA (TanII A Abbreviated as TA) and Quercetin (QU) in different media, wherein A, B, C is tanshinone iia and quercetin respectivelySolubility of the element in the oil phase, surfactant, cosurfactant;
fig. 2 is a pseudo-ternary phase diagram of a microemulsion system at different surfactant/co-surfactant (Smix) ratios, where a: smix=1:1; smix=2:1; smix=3:1; smix=3:2;
FIG. 3 is a representation of a quercetin-tanshinone IIA microemulsion system, wherein A is quercetin-tanshinone II A A transmission electron microscope photograph of the microemulsion; b is the potential diagram of quercetin-tanshinone IIA microemulsion;
FIG. 4 is an in vitro drug release profile of quercetin-tanshinone IIA microemulsion, wherein TA is tanshinone II A QU is quercetin;
FIG. 5 is an in vitro bacteriostasis effect evaluation chart of quercetin-tanshinone IIA microemulsion, wherein A is an in vitro bacteriostasis circle photo; b is an in-vitro bacteriostasis circle diameter quantitative analysis chart; KB-ME is a blank microemulsion treatment group, QT-ME is a quercetin-tanshinone IIA microemulsion treatment group, and Vancomycin is a positive control Vancomycin treatment group;
FIG. 6 is a graph of quercetin-tanshinone IIA microemulsion-temperature sensitive gel storage modulus (G ') and loss modulus (G') as a function of temperature;
FIG. 7 is a graph showing the evaluation result of treatment of quercetin-tanshinone IIA microemulsion-thermosensitive gel acne, wherein A is an observation chart of the appearance of ear skin of a acne mouse; b is skin injury score; c is a HE staining result graph of the acne part of the ear tissue of the acne mouse; d is the content of inflammatory factor IL-1 beta in the serum of the mice.
Detailed Description
The invention will be further illustrated with reference to specific examples. These examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods of the specific experimental conditions are not noted in the following examples, and are generally performed under conventional conditions or under conditions recommended by the manufacturer.
The tanshinone II of the present invention is further illustrated by the following test examples A And the therapeutic effect of the microemulsion-temperature-sensitive gel of quercetin on acne, these test examples include tanshinone II of the present invention A And structural characterization, biosafety of microemulsion-temperature-sensitive gel of quercetinSexual experiment, in vivo degradation experiment and tanshinone II of the invention A And a drug release experiment and an in vivo pharmacodynamics experiment using a microemulsion-temperature sensitive gel of quercetin as a drug carrier.
Test example 1 screening of oil phase, surfactant, cosurfactant types required for preparing tanshinone IIA and Quercetin microemulsion
1. Oil phase test
Mixing the medicines (TA, QU) with different oil phase media (ethyl Oleate (OE), isopropyl myristate (IPP), isopropyl Palmitate (IPM)) to form supersaturated solutions, and mixing for 2h by using an ultrasonic mixer; these mixtures were then stirred at 37℃for 24h; taking out the sample, centrifuging at 5000rpm for 15min, filtering the obtained supernatant with 0.45 μm filter membrane, and analyzing the drug concentration in different solvents by HPLC to obtain the solubility of the drug in different oil phases, wherein the measurement result is shown in figure 1A;
2. drug solubility test of surfactants
The solubility of the drug in the different surfactants was measured as shown in fig. 1B, except that the drug was mixed with the different surfactants (tween 80, tween 20, polyoxyethylated castor oil (CREL)) to form a supersaturated solution, respectively, in the same manner as the treatment of the oil phase medium;
3. cosurfactant drug solubility test
The solubility of the drug in the different cosurfactants was measured as shown in fig. 1C, except that the drug was mixed with the different cosurfactants (span 80, 1, 2-propanediol (1, 2-PG), polyethylene glycol 400 (PFG 400)) to form a supersaturated solution, respectively, the other steps were the same as the treatment method of the oil phase medium;
from the experimental results of fig. 1, it can be seen that: the solubility of the two drugs in ethyl Oleate (OE) in fig. 1A was the highest, so the oil phase was chosen to be ethyl Oleate (OE). From the solubility profile in FIGS. 1B and 1C, as well as the stability and light transmittance of the formed microemulsions (Table 2), the surfactant was selected to be polyoxyethylated castor oil (CREL) and the cosurfactant was 1, 2-propanediol (1, 2-PG).
4. Transmittance test
After a certain amount of ethyl oleate was mixed with an equal amount of surfactant (tween 80, tween 20, CREL) or cosurfactant (span 80, 1,2-PG, PFG 400) and an equal amount of distilled water, the microemulsion grade was evaluated according to the microemulsion scoring rule (emulsification time, microemulsion appearance) of table 1 according to the formation of the microemulsion. And (3) measuring the absorbance (A) of the selected oil phase ethyl oleate after being mixed with different surfactants and cosurfactants respectively by using an ultraviolet spectrophotometer, and calculating the light transmittance (T) according to a formula (1). The measurement results are shown in Table 2.
T＝10 -A (1)
TABLE 1 microemulsion emulsification fractionation
Table 2 OE and the formation of microemulsion of each surfactant, cosurfactant and light transmittance
Test example 2 screening of the ratio of surfactant and cosurfactant for preparing tanshinone IIA and Quercetin microemulsion System
Surfactant polyoxyethylated castor oil (CREL) screened according to test example 1, cosurfactant 1, 2-propanediol (1, 2-PG), surfactant and cosurfactant at a surfactant/cosurfactant (Smix) mass ratio of 1:1, 2:1, 3:1, 3:2 (total mass of surfactant and cosurfactant of 1 g), then taking the composite surfactant and oil phase (OE) of different Smix as (1-9): (1-9) ratio (e.g., 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9) ratio (total mass of the three (oil phase, surfactant, co-surfactant) was 2 g), titrated with a graduated syringe containing distilled water on a magnetic stirrer (rotation speed 300rpm, temperature 37 ℃) to make it transparent, blue opalescent and exhibit the tyndall effect, and the amount of water added as the system was cleared-cloudy-cleared was recorded. The pseudo ternary phase diagram takes a certain mass of Smix, an oil phase and a water phase as three vertexes respectively, the mass fractions of the oil phase, the Smix and the water phase are input into Origin software for analysis, and the pseudo ternary phase diagram is manufactured, as shown in figure 2, the most suitable surfactant and the compound surfactant (Smix) consisting of cosurfactants are selected according to the area of a curve closed area of the pseudo ternary phase diagram.
The experimental results are shown in fig. 2: when the Smix ratio is 1:1, the area of the formed micro emulsion is the largest. The Smix ratio is generally (1-3): 1) The area of the formed microemulsion region is also large, and therefore, the Smix ratio is (1-3): 1) It is also suitable.
Test example 3 screening and optimization of formula of microemulsion System
According to the mass percentages of the three components of the oil phase, the water phase and the Smix of the shadow area center point in the pseudo-ternary phase diagram drawn when the weight ratio of the Smix polyoxyethylene castor oil to the 1, 2-propylene glycol is 1:1, the level of an orthogonal table is designed, the optimization experiment of the orthogonal design prescription is shown in table 3, and the microemulsion prescription is evaluated by taking the particle size, PDI and Zeta-potential of the formed microemulsion as indexes, and the test result is shown in table 4. The experiment is to explore the optimal prescription for preparing blank microemulsion, so no drug is added in the examination of orthogonal experiment.
Obtaining an optimal blank microemulsion prescription according to an orthogonal experiment, adding the medicine into the oil phase of the blank microemulsion according to the optimal prescription proportion, respectively adding 2.5mg,5mg,10mg and 15mg (shown in Table 5) of quercetin and tanshinone IIA into 2g of microemulsion, uniformly mixing, adding distilled water with the prescription quality at 37 ℃, and uniformly mixing to obtain the medicine-carrying microemulsion. And determining the drug addition amount by taking the particle size, drug loading, encapsulation efficiency and 24-hour internal and external properties of the drug-loaded microemulsion as indexes. The test results are shown in Table 5.
TABLE 3 orthogonal experimental Table for optimization of microemulsion formulations
TABLE 4 optimization of experimental design and results for microemulsion formulations
As shown in the experimental results of Table 4, the formula 2 microemulsion has smaller particle size and PDI, the potential is-11+ -2.23 mV, and the stability of the obtained microemulsion formula is good, so that the formula 2 is selected as the optimal formula of the microemulsion system. Second, prescriptions 1, 5, 6, 7, 9 are also suitable for this system.
TABLE 5 screening of the dosage of microemulsion formulations
Experimental results show that the drug-loaded microemulsion has uniform particle size, strong stability and higher drug-loading rate and encapsulation efficiency when the dosage of the two drugs is 10 mg; the dosage of both medicaments is 2.5-15mg, which is suitable for the invention.
Test example 4 Transmission Electron microscopy and Zeta potential test of tanshinone IIA and quercetin microemulsion
The microemulsion electron microscope photograph and the surface Zeta potential prepared in test example 3 with the dosage of 20mg (quercetin and tanshinone IIA 10:10 (mg)) were measured by using a transmission electron microscope and a nano-particle sizer.
The transmission electron micrographs of the loaded TA and QU microemulsions are shown in FIG. 3A, and the potential detection results of the loaded TA and QU microemulsions are shown in FIG. 3B. The particle size of the drug-loaded microemulsion is about 60nm, and the Zeta potential is about-8.12 mV.
From the experimental results of test examples 1-4, the oil phase of the microemulsion of the invention is selected from ethyl oleate, the compound surfactant is selected from polyoxyethylene castor oil and 1, 2-propanediol compounds, and the mass ratio of the two is (1-3): 1, preferably 1:1; the mass ratio of the oil phase to the composite surfactant is (8-10): (38-40), preferably 8:38; the medicine is a composition of quercetin and tanshinone IIA, and the mass ratio of the quercetin to the tanshinone IIA is 1: (1-2), preferably 1:1.
EXAMPLE 1 preparation of tanshinone IIA and quercetin-loaded microemulsion
A low energy phase inversion method is adopted to prepare the microemulsion containing TanIIa and QU. Firstly, mixing ethyl oleate (8%), polyoxyethylene castor oil and 1, 2-propylene glycol (38%), then adding 10mg of quercetin and 10mg of tanshinone IIA, and finally, slowly dripping deionized water (54%) into the mixed oil phase to obtain the microemulsion carrying tanshinone IIA and quercetin. The reaction temperature was 40℃and the stirring speed was 450rpm.
1-1, uniformly mixing an oil phase (ethyl oleate) and a compound surfactant (polyoxyethylene castor oil and a compound of 1, 2-propylene glycol) under a stirring state to prepare a blank oil phase, wherein the mass ratio of the ethyl oleate to the compound surfactant (polyoxyethylene castor oil and 1, 2-propylene glycol) in the blank oil phase is 8:38 (usually (8-10): 38-40)); the mass ratio of the polyoxyethylene castor oil and the 1, 2-propylene glycol in the composite surfactant is 1:1 (generally (1-3): 1); the stirring rate is 450rpm (typically 400-500 rpm); the stirring temperature is 40 ℃ (typically 30-50 ℃);
the mass ratio of the ethyl oleate to the compound surfactant (polyoxyethylene castor oil and 1, 2-propylene glycol) in the blank oil phase is (8-10): 38-40, which are all suitable for the invention.
1-2, adding a quercetin and tanshinone IIA composition into a blank oil phase under stirring to prepare a mixed oil phase, wherein 20mg of the quercetin and tanshinone IIA composition is added into every 2g of the blank oil phase, and the mass ratio of the quercetin to the tanshinone IIA in the quercetin and tanshinone IIA composition is 1:1 (usually 1 (1-2)); the stirring rate is 450rpm (typically 400-500 rpm);
in the invention, the addition amount of the quercetin and tanshinone IIA composition is 5-30mg of the quercetin and tanshinone IIA composition added into every 2g of the blank oil phase;
1-3, slowly dropwise adding deionized water into the mixed oil phase in a stirring state to obtain quercetin-tanshinone IIA microemulsion, namely TA-QU microemulsion, wherein the mass ratio of the added deionized water to the mixed oil phase is 54:46 (usually (50-60): 40-50)); the stirring rate is 450rpm (typically 400-500 rpm); the mass ratio of deionized water to oil phase and composite surfactant is 54:8:38 (generally (50-54): 8-10): 38-40).
EXAMPLE 2 preparation of tanshinone IIA and Quercetin microemulsion-temperature sensitive gel
2-1, 1mL of the TA-QU microemulsion prepared in example 1 was taken and placed in a penicillin bottle (2.7 cm. Times.4.7 cm);
2-2, adding poloxamer P407 and poloxamer P188 into the penicillin bottle, and stirring until the poloxamer is dissolved, so as to prepare Cheng Wenmin pregelatinized solution; wherein the mass ratio of P407 to P188 is 9:1 (typically (8-9): 1); the mass of poloxamer P188 added into each 1ml of TA-QU microemulsion is 20mg (usually 10-30 mg), namely the ratio of the TA-QU microemulsion to the poloxamer P188 is 1:20 (usually 1 (10-30)); the mass of poloxamer P407 added into 1ml of TA-QU microemulsion is 180mg (usually 150-200 mg), namely the ratio of the TA-QU microemulsion to poloxamer P188 is 1:180 (usually 1 (150-200));
2-3, standing the temperature-sensitive pregelatinized solution for 24 hours (usually 18-24 hours), fully stretching a macromolecular material molecular chain segment to form a stable colloid solution, wherein the colloid solution is a temperature-sensitive gel stock solution, namely the tanshinone IIA and the quercetin microemulsion-temperature-sensitive gel stock solution are prepared;
when the temperature of tanshinone IIA and quercetin microemulsion-temperature-sensitive gel stock solution reaches 30.44 ℃, the gel stock solution is converted from a liquid state to a gel state, so that tanshinone IIA-quercetin microemulsion-temperature-sensitive gel is formed.
Test example 5 drug-loading amount measurement of tanshinone IIA and quercetin microemulsion
1. Freeze-drying the tanshinone IIA and quercetin loaded microemulsion prepared according to the method of example 1;
2. then accurately weighing 25mg (m) 1 ) Freeze-dried tanshinone IIA and quercetin microemulsion, mixing the freeze-dried microemulsion with methanol, and dispersing with ultrasonic waves to thoroughly destroy the microemulsion so as to release the medicine;
3. centrifuging the mixture solution after drug release at 10000rpm for 10min, and determining the concentration of the drug in the supernatant by HPLC, wherein the HPLC determination chromatographic conditions are as follows:
quercetin chromatographic conditions: the organic phase in the mobile phase is methanol, the aqueous phase is 0.2% phosphoric acid solution, the mobile phase composition is (organic phase: aqueous phase=65:35), the detection wavelength is 370nm, the flow rate is 1mL/min, the sample injection amount is 10 mu L, and the column temperature is 30 ℃.
Tanshinone IIA chromatographic conditions: the organic phase in the mobile phase is methanol, the aqueous phase is ultrapure water, the composition ratio of the mobile phase is (organic phase: aqueous phase=85:15), the detection wavelength is 270nm, the flow rate is 1mL/min, the sample injection amount is 10 mu L, and the column temperature is 30 ℃.
Quality of microemulsion traditional Chinese medicine (m) by HPLC 2 ) The drug loading was calculated according to the following formula (2):
drug loading = mass of drug loaded by HPLC measured microemulsion (m 2 ) Mass of lyophilized microemulsion (m 1 )(2)
Experimental results: the drug-loading rate of quercetin in the microemulsion is (7.45+/-0.21) mg/g, and the drug-loading rate of tanshinone IIA is (4.55+/-0.38) mg/g;
test example 6 in vitro drug Release study of tanshinone IIA and Quercetin microemulsion-temperature sensitive gel
And (3) researching in-vitro release behaviors of the tanshinone IIA and quercetin microemulsion-temperature sensitive gel by adopting a dialysis bag method.
(1) Taking 1mL of tanshinone IIA and quercetin microemulsion-temperature sensitive gel stock solution prepared in example 1, rapidly adding into a fastened dialysis bag, sealing, placing in a 37 ℃ environment, and placing into isothermal 40mL of release medium (PBS with pH of 6.8 of 1% Tween 80) after complete gelation.
(2) Drug release was performed in a thermostatted shaker with shaking temperature set at 37℃and rotational speed 200 rpm. 1mL of the release medium was taken out 8 times at 0.25, 0.5, 1,2, 4, 8, 12 and 24 hours from the beginning of release, stored at 4℃and then the same amount of fresh release medium was added. The medium solution was filtered through a microporous membrane with a pore size of 0.45. Mu.m, and the contents of TA and QU were measured by HPLC. Calculating the in vitro cumulative release percentage of the drug according to formulas (3) and (4);
Q n ＝C 1 ×V 1 +C 2 × V2 +C 3 ×V 3 +…C n ×V n (3)
wherein: q (Q) n Is the accumulated release amount of the drug at the nth sampling; c (C) n Is the concentration of drug in the release medium at the nth sampling; vn is the volume of released solution taken n times; n is an integer, n=1, 2, 3..8; q (Q) Total (S) Is the content of the medicine in the gel.
The release results are shown in fig. 4: wherein: the in vitro release behaviors of the quercetin and the tanshinone IIA both show the characteristic of slow release. At 24h, the in vitro cumulative release rate of both is 88.69% of quercetin and 17.61% of tanshinone IIA. The drug release characteristics can effectively ensure that the drug plays a therapeutic role on the skin surface, and the drug is released on the skin surface rapidly and simultaneously has long-acting release behavior.
Test example 7 evaluation of tanshinone IIA and quercetin microemulsion by paper sheet method in vitro bacteriostasis
(1) Preparation of blank microemulsion (KB-ME):
and preparing blank microemulsion by adopting a low-energy phase inversion method. Firstly, uniformly mixing ethyl oleate (8%), polyoxyethylene castor oil (19%) and 1, 2-propylene glycol (19%) to prepare a blank mixed oil phase. Deionized water (54%) was then slowly added dropwise to the mixed oil phase to give a blank microemulsion. The reaction temperature was 40℃and the stirring speed was 450rpm.
(2) Sheet handling
Each sterile paper sheet (diameter 1 cm) is soaked in 500.00 mug/mL blank microemulsion (KB-ME), tanshinone IIA and quercetin microemulsion (QT-ME) prepared in example 1 and Vancomycin (Vancomycin) as positive control for 0.5h respectively, and then taken out from a sterile operation table to be naturally air-dried, so that paper tablets loaded with different medicines are prepared for standby.
(3) Bacterial liquid coating
Under the aseptic condition, 100 mu L of staphylococcus aureus bacterial suspension (0.6 MCF) is taken and evenly coated on a nutrient agar medium under the baking of an alcohol lamp, and after the bacterial liquid is micro-dried, paper tablets loaded with medicines are respectively stuck on the nutrient agar medium. Experiments were performed 3 times in parallel.
(4) Culturing
After the adhesion, the nutrient agar culture medium is placed in a 37 ℃ incubator for inversion culture for 24 hours, the nutrient agar culture medium is taken out, the diameter of a bacteriostasis zone of each sample is measured by using a vernier caliper and recorded, and the measurement result is shown in figure 5.
Compared with the blank microemulsion group, the diameters of the inhibition zones of the tanshinone IIA and the quercetin microemulsion group and the Vancomycin group are obviously higher than those of the blank microemulsion group (p < 0.01), which indicates that the tanshinone IIA and the quercetin microemulsion have stronger inhibition effect.
Test example 8 results of the rheological experiments of tanshinone IIA and quercetin microemulsion-temperature sensitive gel prescription
Tanshinone IIA and quercetin microemulsion-temperature sensitive gel samples prepared according to the method of example 2 were placed in an ice box to be in a flowing state, and rheological property measurement was performed using a rotary rheometer Modular Compact Rheometer (MCR 302).
The rotary rheometer is opened, a PP10 type (SN 42093) rotor is used for testing, an oscillation mode and temperature scanning are adopted, a fixed frequency of 1Hz is set, the strain amplitude is 0.01%, the temperature range is 15-40 ℃, the heating rate is 1 ℃/min, and 30 fixed discs of the test point and a rotor gap of 1mm are set. After the temperature of the sample table reaches the test temperature, 200 mu L of gel sample is instilled in the center of the sample table, the rotor is lowered to a fixed position, the sample is ensured to completely wrap the rotor, redundant samples around the rotor are erased, and the test is started. The relationship between the elastic modulus (G ') and the loss modulus (G') and the temperature was examined. The measurement results are shown in FIG. 6.
As can be seen from fig. 6: the storage modulus and the loss modulus of the gel all show increasing trend along with the rise of the temperature, and when the temperature is lower than 30.44 ℃, the loss modulus is obviously higher than the storage modulus, and the gel is in a liquid state; when the temperature reaches 30.44 ℃, the storage modulus is equal to the loss modulus, and the liquid gel starts to be converted into a gel state; and then rapidly increases, during which the storage modulus increases at a rate significantly higher than the loss modulus, resulting in the final formation of a semi-solid gel state. The rheologically measured gel temperature is close to the gel temperature determined by the recipe optimization, so the temperature at which the phase transition occurs is considered to correspond to the skin surface application temperature.
Test example 9 evaluation of treatment of acne with tanshinone IIA and quercetin microemulsion-thermosensitive gel
(1) Preparation of quercetin microemulsion-temperature sensitive gel:
and preparing blank microemulsion by adopting a low-energy phase inversion method. Firstly, uniformly mixing ethyl oleate (8%), polyoxyethylene castor oil and 1, 2-propylene glycol mixed solution (the mass ratio is 1:1, and 38%) to prepare a blank oil phase; then adding 10mg of quercetin and uniformly mixing to obtain an oil phase containing quercetin; then, deionized water (54%) was slowly added dropwise to the quercetin-containing oil phase to obtain a quercetin microemulsion. The reaction temperature was 40℃and the stirring speed was 450rpm.
Taking 1mL of quercetin microemulsion, placing the quercetin microemulsion in a penicillin bottle (2.7 cm multiplied by 4.7 cm), then adding poloxamer P407 (P407, 180 mg) and poloxamer P188 (P188, 20 mg), stirring, standing the mixed solution for 24 hours after the poloxamer is dissolved, and fully stretching a polymer material molecular chain segment to form the quercetin microemulsion-temperature sensitive gel stock solution.
(2) Preparation of tanshinone IIA microemulsion-temperature-sensitive gel:
except that 10mg tanshinone IIA is added into the blank oil phase to prepare tanshinone IIA microemulsion, the preparation process of the tanshinone IIA microemulsion-temperature sensitive gel stock solution is the same as that of the quercetin microemulsion-temperature sensitive gel.
(3) Moulding
Randomly dividing 70 mice into 2 parts, a first part of 60 mice and a second part of 10 mice, wherein 100% oleic acid is smeared in ears (0.1 mL/mouse) of the first part of mice, 0.05% testosterone solution (0.1 mL/mouse) is smeared every other day, and continuously molding for 14 days to establish ear composite acne model mice; the second portion of mice was smeared with an equal amount of physiological saline once daily for 14 consecutive days.
(4) Grouping and administration of experimental animals:
after the modeling was completed, 50 ear compound acne model mice were randomly selected and randomly divided into 5 groups of 10 mice each: model group (Model, physiological saline, administration dose 0.1 mL/ear), metronidazole gel group (Metronidazole gel, metronidazole gel, 1.4X10 drug dose) -5 g/kg administration), quercetin microemulsion-temperature sensitive in situ gel group (QU nanoemulgel)The drug was administered at 80 mg/kg), tanshinone microemulsion-temperature-sensitive in situ gel group (tanII Ananoemulgel, drug was administered at 80 mg/kg), quercetin-tanshinone microemulsion-temperature-sensitive in situ gel group (TQ nanoemulgel, drug was administered at 80 mg/kg), and the treatment was given for 7 days. The second mice were fed normally (Control (blank Control), smeared with normal saline, and dosed at 0.1 mL/ear). Observation of the appearance of ear skin of each group of mice a photograph of the appearance of ear skin of the mice was taken as shown in fig. 7A, and skin scoring was performed according to the criteria of table 6, and the result is shown in fig. 7B.
After the treatment, the anesthetized mice were removed from the skin tissue with acne lesions on the ears, and the serum of the mice was collected. Mouse ear tissues were HE stained and the staining results are shown in fig. 7C. The serum was assayed for the amount of inflammatory factor IL-1. Beta. And the results are shown in FIG. 7D.
TABLE 6 mice ear epidermis lesion condition observation index and scoring criteria
As shown in fig. 7A: as can be seen from the skin appearance photographs, none of the skin surfaces of the Metronidazole gel, QU, tanIIA, TQ nanoemulgel mice showed significant skin keratinization, no skin surface redness, red spots, nodules, and other skin damage symptoms, and only the Model mice had ears with a partially rough, red and swollen appearance. The administration treatment can effectively relieve the skin damage condition of the ear of the acne mouse. As shown in fig. 7B: the skin damage score of the TQ nanoemulgel group was significantly reduced compared to the Model group, and the score of the TQ nanoemulgel group was the lowest among all Model animals, indicating that TQ nanoemulgel was the most significant in acne treatment, and the combination of quercetin and tanshinone IIA synergistically enhanced and improved the effect on acne treatment.
As can be seen from the HE staining results of FIG. 7C, the Model group still showed auricle epidermopapilla, with a small number of cells showing interstitial edema, inflammatory cell infiltration; metronidazole gel the epidermis thickness is reduced, inflammatory cells in dermis are greatly reduced, tissue edema is weakened, and sebaceous gland diameter is reduced after treatment; the QU nanoemulgel group, the tanii Ananoemulgel group and the TQ nanoemulgel group have reduced auricle thickness, reduced hair follicle and tissue edema, reduced inflammatory cells and reduced infiltration area, and no significant proliferation of sebaceous gland hyperplasia. As shown in FIG. 7D, the amount of serum inflammatory factor IL-1. Beta. Was significantly reduced after TQ nanoemulgel treatment compared to the Model group, indicating that TQ nanoemulgel was significantly effective in treating acne.
In conclusion, the tanshinone IIA and quercetin microemulsion-temperature-sensitive gel prepared by the method is simple to operate. The hydrogel can also be used as a drug carrier to effectively slow down the drug release process, and has good biocompatibility. The tanshinone IIA and the quercetin microemulsion-temperature sensitive gel can promote the repair of acne, and have wide prospects in clinical surgical application.
Claims (10)
1. A pharmaceutical composition for treating acne is characterized by comprising quercetin and tanshinone IIA.
2. The pharmaceutical composition as claimed in claim 1, wherein the ratio of the quercetin to the tanshinone IIA in parts by weight is 1: (1-2), preferably 1:1.
3. the preparation method of the microemulsion-temperature-sensitive gel pharmaceutical composition for treating acne is characterized by comprising the following steps of:
1) Preparation of microemulsion loaded with quercetin and tanshinone IIA
1A) Mixing an oil phase and a compound surfactant to prepare a blank oil phase, wherein the compound surfactant consists of the surfactant and a cosurfactant;
1B) Adding the mixture of quercetin and tanshinone IIA into the blank oil phase, stirring for dissolving, and making into mixed oil phase;
1C) Adding deionized water into the mixed oil phase under stirring, and mixing to obtain quercetin-tanshinone IIA microemulsion;
2) Adding poloxamer P470 and poloxamer P188 into quercetin-tanshinone IIA microemulsion, stirring, dissolving, and making into quercetin-tanshinone IIA temperature-sensitive gel stock solution;
3) The temperature of the quercetin-tanshinone IIA temperature-sensitive gel stock solution reaches 30.44 ℃, and the gel stock solution is converted from a liquid state to a gel state, so that the microemulsion-temperature-sensitive gel pharmaceutical composition for treating acne is formed.
4. A method according to claim 3, wherein the ratio of the mass of oil phase to the mass of the complex surfactant in the blank oil phase in step 1A) is (8-10): (38-40), preferably 8:38.
5. A process according to claim 3, wherein the ratio of parts by weight of surfactant to cosurfactant in step 1A) is (1-3): 1, preferably 1:1.
6. The preparation method as claimed in claim 3, wherein the ratio of the quercetin to the tanshinone IIA in the step 1B) is 1: (1-2), preferably 1:1.
7. The method according to claim 3, wherein the mass ratio of the deionized water in step 1C) to the oil phase and the complex surfactant in step 1A) is (50-54): (8-10): (38-40), preferably 54:8:38.
8. the method of claim 3, wherein the ratio of parts by weight of poloxamer P188 to P407 in step 2) is (8-9): 1.
9. A microemulsion-temperature-sensitive gel composition for treating acne, characterized in that it is prepared according to the method of any one of claims 3 to 8.
10. Loaded tanshinone II A And quercetin microUse of milk-temperature sensitive gel composition in preparing medicine for treating acne is provided.
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