Pioglitazone nanoemulsion, preparation method and application thereof

Abstract

The present application relates to the technical field of pharmaceutical preparation, in particular to a pioglitazone nanoemulsion and a preparation method and application thereof.In the present application, propylene glycol laurate is used as an oil phase, and propylene glycol laurate is used as a medium-chain fatty acid;on the basis of not affecting the solubility of pioglitazone, the stable nanoemulsion is formed by embedding the surfactant and penetrating the interface film.The present application uses a complex mode of a main surfactant and a cosurfactant to prepare the nanoemulsion, so that the surfactant can form a better hydrophilic-lipophilic balance, the flexibility of the surfactant layer is enhanced, and the surfactant can be distributed to the oil-water interface to a higher degree, so that the stable pioglitazone nanoemulsion can be obtained more easily.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a pioglitazone nanoemulsion, its preparation method, and its application. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Inflammatory skin diseases are a group of conditions caused by immune system dysfunction leading to skin tissue damage. These include eczema, atopic dermatitis, psoriasis, chronic urticaria, vitiligo, and pemphigus. Interleukin (IL)-1α, IL-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) are key mediators of skin inflammation; reducing the excessive production of pro-inflammatory cytokines is an effective treatment for skin inflammation.

[0004] Pioglitazone, a thiazolidinedione oral antidiabetic drug, is a highly selective agonist of peroxidase proliferator-activated receptor gamma (PPARγ). Pioglitazone controls blood glucose levels by increasing insulin sensitivity in the peripheral nervous system and liver. Currently, it is marketed in oral tablet form, primarily for the treatment of type 2 diabetes. PPARγ is a ligand-activated nuclear transcription factor whose functions include regulating cell differentiation, proliferation, immune / inflammatory responses, lipid metabolism, glycolysis, and insulin resistance. Pioglitazone has a regulatory effect on inflammatory markers such as IL-6, IL-17, and TNF-α, and can inhibit the production of pro-inflammatory factors IL-1β, IL-6, and TNF-α, indicating that pioglitazone is an effective candidate drug for controlling inflammatory diseases. However, pioglitazone is poorly soluble in water, resulting in low bioavailability and limiting its application. In addition, thiazolidinediones, including pioglitazone, have the potential risk of causing or aggravating congestive heart failure when taken orally. When using pioglitazone or increasing the dosage, patients should be closely monitored for signs and symptoms of heart failure (including abnormally rapid weight gain, dyspnea, and / or edema). Summary of the Invention

[0005] To overcome the above problems, the present invention provides a pioglitazone nanoemulsion, its preparation method and application.

[0006] To achieve the above technical objectives, the present invention adopts the following technical solution:

[0007] A first aspect of the present invention provides a pioglitazone nanoemulsion comprising, by weight percentage:

[0008] Pioglitazone 1%–5%; oil phase 16%–32%; main surfactant 30%–36%; co-surfactant 9%–12%; balance water;

[0009] The oil phase is propylene glycol lauryl ester.

[0010] A second aspect of the present invention provides a method for preparing the pioglitazone nanoemulsion described in the first aspect, comprising:

[0011] (1) Pioglitazone and the oil phase are mixed to obtain a first mixture;

[0012] (2) Add the main surfactant and the co-surfactant to the first mixture in sequence, and mix to obtain the second mixture;

[0013] (3) Add water to the second mixture to obtain pioglitazone nanoemulsion.

[0014] A third aspect of the present invention provides the use of the pioglitazone nanoemulsion described in the first aspect and / or the pioglitazone nanoemulsion prepared by the preparation method described in the second aspect in the preparation of a medicament for treating inflammatory skin diseases.

[0015] A fourth aspect of the present invention provides a medicament or pharmaceutical composition for treating inflammatory skin diseases, comprising the pioglitazone nanoemulsion described in the first aspect and / or the pioglitazone nanoemulsion prepared by the preparation method described in the second aspect.

[0016] The beneficial effects of this invention are as follows:

[0017] (1) Pioglitazone nanoemulsion formulations can overcome the disadvantages of poor water solubility and poor transdermal absorption of pioglitazone, and improve the skin bioavailability of pioglitazone.

[0018] (2) Compared with the current oral administration of pioglitazone, the preparation of pioglitazone nano-emulsion allows for topical administration, with the active molecules being directly applied to the skin without entering the bloodstream, thereby reducing exposure to other organs and tissues throughout the body and thus reducing systemic side effects.

[0019] (3) This invention prepares pioglitazone nanoemulsions via emulsification. The difficulty in preparing nanoemulsions lies in the selection and ratio of the oil phase and surfactant. In this invention, a single-factor method is used to screen propylene glycol laurate as the oil phase and propylene glycol laurate as a medium-chain fatty acid. Without affecting the solubility of pioglitazone, the surfactant is embedded and penetrates the interfacial film to form a stable nanoemulsion.

[0020] (4) The pioglitazone nanoemulsion provided by this invention is prepared by a combination of a main surfactant and a co-surfactant, which allows the surfactant to form a better hydrophilic-lipophilic balance, enhances the flexibility of the surfactant layer, and can be distributed to the oil-water interface to a greater extent, making it easier to obtain a stable pioglitazone nanoemulsion. The surfactant combination obtained by this invention is: polyethylene glycol-12-hydroxystearate as the main surfactant, and diethylene glycol monoethyl ether and propylene glycol as co-surfactants. Furthermore, the addition of propylene glycol in the co-surfactant can affect the particle size of the nanoemulsion, and thus affect the stability of the nanoemulsion. As the amount of propylene glycol added increases, the particle size of the nanoemulsion decreases, and then remains unchanged, and the stability increases; this is because the short carbon chain of propylene glycol is more likely to insert into the interfacial film of the emulsifier, reduce the interfacial tension, increase the solubility of the emulsifier, and make the emulsion form smaller droplets. Attached Figure Description

[0021] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0022] Figure 1 This is a particle size distribution diagram of the pioglitazone nanoemulsion prepared in Example 1;

[0023] Figure 2 This is a particle size distribution diagram of the pioglitazone nanoemulsion prepared in Example 2;

[0024] Figure 3 This is a particle size distribution diagram of the pioglitazone nanoemulsion prepared in Example 5;

[0025] Figure 4 Microscopic image of the pioglitazone nanoemulsion (0.5 wt%) prepared in Example 7. Detailed Implementation

[0026] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0027] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0028] A first typical embodiment of the present invention provides a pioglitazone nanoemulsion, comprising, by weight percentage:

[0029] Pioglitazone 1%–5%; oil phase 16%–32%; main surfactant 30%–36%; co-surfactant 9%–12%; balance water;

[0030] The oil phase is propylene glycol lauryl ester.

[0031] In one or more embodiments, the main surfactant comprises polyethylene glycol-12-hydroxystearate.

[0032] In one or more embodiments, the co-surfactant is a compound surfactant, which is composed of diethylene glycol monoethyl ether and propylene glycol;

[0033] Preferably, the mass ratio of diethylene glycol monoethyl ether to propylene glycol is (1-3):1, more preferably 2:1.

[0034] In one or more embodiments, the particle size distribution of the pioglitazone nanoemulsion ranges from 80 to 150 nm.

[0035] In one or more embodiments, the pioglitazone nanoemulsion comprises, by weight percentage:

[0036] Pioglitazone 1.5%; propylene glycol laurate 22% (oil phase); polyethylene glycol-12-hydroxystearate 35% (main surfactant); co-surfactant 9%; balance: water.

[0037] The co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:1.

[0038] In one or more embodiments, the pioglitazone nanoemulsion comprises, by weight percentage:

[0039] Pioglitazone 1%; propylene glycol laurate 16% (oil phase); polyethylene glycol-12-hydroxystearate 30% (main surfactant); co-surfactant 12%; balance: water.

[0040] The co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:1.

[0041] In one or more embodiments, the pioglitazone nanoemulsion comprises, by weight percentage:

[0042] Pioglitazone 2%; propylene glycol laurate 22% (oil phase); polyethylene glycol-12-hydroxystearate 35% (main surfactant); co-surfactant 9%; balance: water.

[0043] The co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:1.

[0044] In one or more embodiments, the pioglitazone nanoemulsion comprises, by weight percentage:

[0045] Pioglitazone 2%; propylene glycol laurate 22% (oil phase); polyethylene glycol-12-hydroxystearate 35% (main surfactant); co-surfactant 9%; balance: water.

[0046] The co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 1:1.

[0047] In one or more embodiments, the pioglitazone nanoemulsion comprises, by weight percentage:

[0048] Pioglitazone 2%; propylene glycol laurate 22% (oil phase); polyethylene glycol-12-hydroxystearate 35% (main surfactant); co-surfactant 9%; balance: water.

[0049] The co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 3:1.

[0050] In one or more embodiments, the pioglitazone nanoemulsion comprises, by weight percentage:

[0051] Pioglitazone 3%; propylene glycol laurate 30% (oil phase); polyethylene glycol-12-hydroxystearate 32% (main surfactant); co-surfactant 9%; balance: water.

[0052] The co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:1.

[0053] In one or more embodiments, the pioglitazone nanoemulsion comprises, by weight percentage:

[0054] Pioglitazone 5%; propylene glycol laurate 32% (oil phase); polyethylene glycol-12-hydroxystearate 36% (main surfactant); co-surfactant 9%; balance: water.

[0055] The co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:1.

[0056] A second typical embodiment of the present invention provides a method for preparing the pioglitazone nanoemulsion described in the first aspect, comprising:

[0057] (1) Pioglitazone and the oil phase are mixed to obtain a first mixture;

[0058] (2) Add the main surfactant and the co-surfactant to the first mixture in sequence, and mix to obtain the second mixture;

[0059] (3) Add water to the second mixture to obtain pioglitazone nanoemulsion.

[0060] In one or more embodiments, in step (1), the mixing time of pioglitazone and the oil phase is 25 to 40 minutes, preferably 30 minutes.

[0061] In one or more embodiments, in step (3), water is added drop by drop to the second mixture while stirring until the system becomes thin and transparent or translucent, and then water is added drop by drop to the required total amount.

[0062] A third aspect of the present invention provides the use of the pioglitazone nanoemulsion described in the first aspect and / or the pioglitazone nanoemulsion prepared by the preparation method described in the second aspect in the preparation of a medicament for treating inflammatory skin diseases.

[0063] A fourth aspect of the present invention provides a medicament or pharmaceutical composition for treating inflammatory skin diseases, comprising the pioglitazone nanoemulsion described in the first aspect and / or the pioglitazone nanoemulsion prepared by the preparation method described in the second aspect.

[0064] In one or more embodiments, the pharmaceutical composition for treating inflammatory skin diseases includes pioglitazone nanoemulsion, wherein the pioglitazone nanoemulsion is prepared by adding pioglitazone nanoemulsion as the active ingredient to an cream matrix.

[0065] The route of administration for pioglitazone nanoemulsion is topical application.

[0066] Preferably, the cream base is composed of white petrolatum, liquid paraffin, cetyl alcohol, polyethylene glycol-7-stearate, glycerin, ethylparaben, and water.

[0067] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0068] Example 1

[0069] Preparation of pioglitazone nanoemulsion:

[0070] The pioglitazone nanoemulsion, by mass percentage, comprises 1.5% pioglitazone, 22% oil phase, 35% main surfactant, 9% co-surfactant, and the balance being water. The specific formulation is shown in Table 1.

[0071] Table 1 Prescription Composition

[0072] Pioglitazone 1.5 1.5 Propylene glycol lauryl ester 22 22 Polyethylene glycol-12-hydroxystearate 35 35 Diethylene glycol monoethyl ether 6 6 Propylene glycol 3 3 water 32.5 32.5

[0073] Preparation method: Pioglitazone was added to propylene glycol laurate according to the proportions in Table 1 and stirred for 30 min to obtain the first mixture; polyethylene glycol-12-hydroxystearate, a compounded diethylene glycol monoethyl ether and propylene glycol mixture were added to the first mixture in sequence and stirred evenly to obtain the second mixture; purified water was added dropwise to the second mixture while stirring, and the system became thin and transparent or translucent. Water was then added dropwise to the required total amount to obtain pioglitazone nanoemulsion.

[0074] Figure 1 This is a particle size distribution diagram of the pioglitazone nanoemulsion prepared in this embodiment. Figure 1 As can be seen from the data, the pioglitazone nanoemulsion prepared in this embodiment has a particle size of 96 nm and a PDI of 0.168.

[0075] Example 2

[0076] Preparation of pioglitazone nanoemulsion:

[0077] The pioglitazone nanoemulsion, by mass percentage, comprises 1% pioglitazone, 16% oil phase, 30% surfactant, 12% co-surfactant, and the balance being water. The specific formulation is shown in Table 2.

[0078] Table 2 Prescription Composition

[0079] Pioglitazone 1 1 Propylene glycol lauryl ester 16 16 Polyethylene glycol-12-hydroxystearate 30 30 Diethylene glycol monoethyl ether 8 8 Propylene glycol 4 4 water 41 41

[0080] Preparation method: Same as in Example 1.

[0081] Figure 2 This is a particle size distribution diagram of the pioglitazone nanoemulsion prepared in this embodiment. Figure 2 As can be seen from the data, the pioglitazone nanoemulsion prepared in this embodiment has a particle size of 77 nm and a PDI of 0.143.

[0082] Example 3

[0083] Preparation of pioglitazone nanoemulsion:

[0084] The pioglitazone nanoemulsion, by mass percentage, comprises 2% pioglitazone, 22% oil phase, 35% surfactant, 9% co-surfactant, and the balance being water. The specific formulation is shown in Table 3.

[0085] Table 3 Prescription Composition

[0086] Pioglitazone 2 2 Propylene glycol lauryl ester 22 22 Polyethylene glycol-12-hydroxystearate 35 35 Diethylene glycol monoethyl ether 6 6 Propylene glycol 3 3 water 32 32

[0087] Preparation method: Same as in Example 1.

[0088] Example 4

[0089] Preparation of pioglitazone nanoemulsion:

[0090] The pioglitazone nanoemulsion, by mass percentage, comprises 2% pioglitazone, 22% oil phase, 35% surfactant, 9% co-surfactant, and the balance being water. The specific formulation is shown in Table 3.

[0091] Table 4 Prescription Composition

[0092] Pioglitazone 1.5 1.5 Propylene glycol lauryl ester 22 22 Polyethylene glycol-12-hydroxystearate 35 35 Diethylene glycol monoethyl ether 4.5 4.5 Propylene glycol 4.5 4.5 water 32.5 32.5

[0093] Preparation method: Same as in Example 1.

[0094] Example 5

[0095] Preparation of pioglitazone nanoemulsion:

[0096] The pioglitazone nanoemulsion, by mass percentage, comprises 2% pioglitazone, 22% oil phase, 35% surfactant, 9% co-surfactant, and the balance being water. The specific formulation is shown in Table 5.

[0097] Table 5 Prescription Composition

[0098] Pioglitazone 1.5 1.5 Propylene glycol lauryl ester 22 22 Polyethylene glycol-12-hydroxystearate 35 35 Diethylene glycol monoethyl ether 6.8 6.8 Propylene glycol 2.2 2.2 water 32.5 32.5

[0099] Preparation method: Same as in Example 1.

[0100] Example 6

[0101] Preparation of pioglitazone nanoemulsion:

[0102] The pioglitazone nanoemulsion, by mass percentage, comprises 3% pioglitazone, 30% oil phase, 32% surfactant, 9% co-surfactant, and the balance being water. The specific formulation is shown in Table 6.

[0103] Table 6 Prescription Composition

[0104] Pioglitazone 3 3 Propylene glycol lauryl ester 30 30 Polyethylene glycol-12-hydroxystearate 32 32 Diethylene glycol monoethyl ether 6 6 Propylene glycol 3 3 water 26 26

[0105] Preparation method: Same as in Example 1.

[0106] Example 7

[0107] Preparation of pioglitazone nanoemulsion:

[0108] The pioglitazone nanoemulsion, by mass percentage, comprises 5% pioglitazone, 32% oil phase, 36% surfactant, 9% co-surfactant, and the balance being water. The specific formulation is shown in Table 7.

[0109] Table 7 Prescription Composition

[0110] Pioglitazone 5 5 Propylene glycol lauryl ester 32 32 Polyethylene glycol-12-hydroxystearate 36 36 Diethylene glycol monoethyl ether 6 6 Propylene glycol 3 3 water 18 18

[0111] Preparation method: Same as in Example 1.

[0112] Figure 3 This is a particle size distribution diagram of the pioglitazone nanoemulsion prepared in this embodiment. Figure 3 As can be seen from the data, the pioglitazone nanoemulsion prepared in this embodiment has a particle size of 141 nm and a PDI of 0.044.

[0113] Example 8

[0114] Cream base preparation:

[0115] Weigh out 76g of white petrolatum, 152g of liquid paraffin, 152g of cetyl alcohol, and 32g of polyethylene glycol-7-stearate, and melt and mix them evenly at 80℃ to form phase I; mix 55g of glycerin, 1g of ethylparaben, and 532g of water evenly, and heat to 60℃ to form phase II; add phase II to phase I at 80℃, stir and mix at 1500rpm for 20min, and cool to 50℃ for later use.

[0116] Example 9

[0117] Preparation of pioglitazone nanoemulsion (0.5 wt%):

[0118] The mass ratio of cream base to nanoemulsion is 2:1. Weigh 20g of cream base, heat to 60℃, add 10g of pioglitazone nanoemulsion from Example 1 to the cream base, keep at 60℃ and stir until homogeneous, cool to obtain 0.5wt% pioglitazone nanoemulsion.

[0119] Figure 4 This is a microscopic image of the pioglitazone nanoemulsion (0.5 wt%) prepared in this embodiment. From... Figure 4 It can be seen that the nano-emulsion droplets are spherical and evenly distributed.

[0120] Example 10

[0121] Preparation of pioglitazone nanoemulsion (1.0 wt%):

[0122] The mass ratio of cream base to nanoemulsion is 1:1. Weigh 10g of cream base, heat to 60℃, add 10g of pioglitazone nanoemulsion from Example 3 to the cream base, maintain 60℃ and stir until homogeneous, cool to obtain 1.0wt% pioglitazone nanoemulsion.

[0123] Example 11

[0124] Preparation of pioglitazone nanoemulsion (1.5 wt%):

[0125] The mass ratio of cream base to nanoemulsion is 1:1. Weigh 10g of cream base, heat to 60℃, add 10g of pioglitazone nanoemulsion from Example 6 to the cream base, keep at 60℃ and stir until homogeneous, cool to obtain 1.5wt% pioglitazone nanoemulsion.

[0126] Example 12

[0127] Preparation of pioglitazone nanoemulsion (2.5 wt%):

[0128] The mass ratio of cream base to nanoemulsion is 1:1. Weigh 10g of cream base, heat to 60℃, add 10g of pioglitazone nanoemulsion from Example 7 to the cream base, keep at 60℃ and stir until homogeneous, cool to obtain 2.5wt% pioglitazone nanoemulsion.

[0129] Comparative Example 1

[0130] Preparation of pioglitazone cream:

[0131] Weigh 49.5g of cream base, heat to 60℃, and add 0.5g of pioglitazone (particle size d) to the cream base. 0.9 (Value less than 30 μm), stir at 60℃ for 30 min, then cool to obtain 1.0 wt% pioglitazone cream.

[0132] Example 13

[0133] Stability test of pioglitazone nanoemulsion:

[0134] (1) Centrifugal stability: 5 mL of the nanoemulsion sample prepared in the example was added to a 10 mL centrifuge tube and placed in a high-speed centrifuge. The tube was centrifuged at 5000 rpm for 15 min. The sample was observed to see if it separated into layers and if there was any sediment at the bottom.

[0135] (2) Stability under thermal cycling: 5 mL of the nanoemulsion sample prepared in the example was added to a 10 mL transparent sample tube and placed in a thermal environment for testing. First, it was placed in a constant temperature incubator (40℃) for 30 min, and then taken out and placed in a refrigerator (4℃) for 30 min. This was one cycle, and a total of 8 cycles were performed. The presence of precipitate at the bottom of the sample tube or stratification of the sample in the sample tube was observed.

[0136] The results are shown in Table 8.

[0137] Table 8. Stability test results of pioglitazone nanoemulsions

[0138]

[0139] Example 14

[0140] Stability study of pioglitazone nano-emulsion:

[0141] The nanoemulsions obtained in Example 1 and the nanoemulsion samples obtained in Examples 9, 10 and 11 were subjected to stability tests as shown in Table 9. The results are shown in Table 9.

[0142] Table 9. Results of stability study of pioglitazone nanoemulsion

[0143]

[0144] As can be seen from Table 9, the nanoemulsions obtained in Examples 9, 10 and 11 have higher stability than the nanoemulsion prepared in Example 1.

[0145] Example 15

[0146] Anti-inflammatory efficacy determination of pioglitazone nano-emulsion:

[0147] Mouse ear swelling method: A self-controlled method was used (inflammation induced in the right ear, left ear as self-control). Xylene was applied to both the anterior and posterior surfaces of the right ear of mice to induce inflammation. After 15 minutes, the drug was evenly applied to each group, with an application rate of approximately 0.5 g / cm³. 2 The mice were euthanized 1.5 hours later. Circular ear pieces of the same diameter were punched into the same location on both ears using a puncher, and their weight was measured. The degree of swelling was calculated (right ear weight minus left ear weight). The results of the anti-inflammatory efficacy assay are shown in Table 10.

[0148] Table 10 Results of Anti-inflammatory Efficacy Determination

[0149]

[0150] The results showed that the auricular swelling in the pioglitazone nanoemulsion and mupirocin ointment groups was significantly lower than that in the control group (untreated) and the blank ointment matrix group, but the anti-inflammatory efficacy of pioglitazone nanoemulsion was slightly lower than that of mupirocin ointment.

[0151] Example 16

[0152] In vitro transdermal assay of pioglitazone nanoemulsion:

[0153] In vitro transdermal tests were conducted using 1-month-old Bama miniature pig skin to compare the transdermal absorption of the pioglitazone nano-emulsion of Example 10 and the pioglitazone cream of Comparative Example 1. The tests were performed on an Andisso 12-position transdermal diffusion apparatus. The in vitro receiving solution was diethylene glycol monoethyl ether:water (60:40, v / v), the temperature was 32 ± 0.5 °C, and the pig skin area was approximately 1.77 cm². 2 The amount of sample applied was 300 mg. The amount of pioglitazone in the receiving solution was detected by HPLC. The results are shown in Table 11.

[0154] Table 11 Results of in vitro transdermal assays of pioglitazone nanoemulsion

[0155]

[0156] The results showed that the skin permeability of pioglitazone nanoemulsion was significantly higher than that of the control pioglitazone cream.

[0157] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises pioglitazone nanoemulsion and cream matrix; The pioglitazone nanoemulsion comprises, by mass percentage: Pioglitazone 1%~5%; oil phase 16%~32%; main surfactant 30%~36%; co-surfactant 9%~12%; balance water; The oil phase is propylene glycol lauryl ester; the main surfactant is polyethylene glycol-12-hydroxystearate; the co-surfactant is a compound surfactant, which is diethylene glycol monoethyl ether and propylene glycol; The particle size distribution range of the pioglitazone nanoemulsion is 80~150 nm; The cream base is composed of white petrolatum, liquid paraffin, cetyl alcohol, polyethylene glycol-7-stearate, glycerin, ethylparaben, and water.

2. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of diethylene glycol monoethyl ether to propylene glycol is (1~3):

1.

3. The pharmaceutical composition according to claim 1, characterized in that, The pioglitazone nanoemulsion comprises, by mass percentage: Pioglitazone 1.5%; propylene glycol lauryl ester 22%; polyethylene glycol-12-hydroxystearate 35%; co-surfactant 9%, balance being water; wherein the co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:1; Alternatively, pioglitazone 1%; propylene glycol lauryl 16%; polyethylene glycol-12-hydroxystearate 30%; co-surfactant 12%, with the remainder being water; wherein the co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:

1. Alternatively, pioglitazone 2%; propylene glycol lauryl ester 22%; polyethylene glycol-12-hydroxystearate 35%; co-surfactant 9%, balance being water; wherein the co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:

1. Alternatively, pioglitazone 3%; propylene glycol lauryl 30%; polyethylene glycol-12-hydroxystearate 32%; co-surfactant 9%, the balance being water; wherein the co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:

1. Alternatively, pioglitazone 5%; propylene glycol lauryl ester 32%; polyethylene glycol-12-hydroxystearate 36%; co-surfactant 9%, with the remainder being water; wherein the co-surfactant is a compound surfactant composed of diethylene glycol monoethyl ether and propylene glycol, with a mass ratio of diethylene glycol monoethyl ether to propylene glycol of 2:

1.

4. The pharmaceutical composition according to claim 1, characterized in that, The preparation method of the pioglitazone nanoemulsion includes the following steps: (1) Pioglitazone and the oil phase are mixed to obtain a first mixture; (2) Add the main surfactant and co-surfactant to the first mixture in sequence, and mix to obtain the second mixture. (3) Add water to the second mixture to obtain pioglitazone nanoemulsion.

5. The pharmaceutical composition according to claim 4, characterized in that, In step (1), the mixing time between pioglitazone and the oil phase is 25-40 min; In step (3), water is added drop by drop to the second mixture while stirring until the system becomes thin and transparent or translucent, and then water is added drop by drop to the required total amount.

6. The use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a medicament for treating inflammatory skin diseases; The inflammatory skin disease mentioned is atopic dermatitis or psoriasis.

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