Application of titanium dioxide fatty acid complex oil phase in improving the stability of gel patch

Abstract

The invention discloses the application of a titanium dioxide fatty acid complex oil phase in improving the stability of a gel patch, and relates to the technical field of gel patch preparation. The preparation method of the titanium dioxide fatty acid complex oil phase is as follows: adding water to nano-sized titanium dioxide for dispersion and wetting, and then dehydrating through a molecular sieve, and then slowly adding it to an oil phase containing fatty acids in an anhydrous environment, stirring; then heating to 45-75°C, continuing to stir for 2h-6h, and dispersing until uniform, to obtain a complex oil phase; wherein the molar ratio of nano-sized titanium dioxide to fatty acids is 1:1-3:1, and the mass ratio of the total mass of titanium dioxide and fatty acids to the oil phase is 1:4-1:6. The invention creatively modifies titanium dioxide to obtain an amphiphilic titanium dioxide fatty acid complex, and then prepares a gel patch, stably encapsulates poorly soluble drugs in the oil phase, improves the stability of the preparation under light, prevents oil seepage of the gel patch, and improves the stability of the gel patch.

Description

Technical Field

[0001] The invention relates to the technical field of gel patch preparation, and more specifically to the application of a titanium dioxide fatty acid complex oil phase in improving the stability of a gel patch. Background Art

[0002] Gel patches have complex ingredients, and adjusting various performance indicators of the preparations, such as viscosity, formability, uniformity, and stability, has always been a major challenge in the research and production process. In order to increase drug loading and regulate drug release, emulsion technology is widely used in gel and gel patch preparations, but the preparation of conventional emulsions usually requires the addition of highly toxic organic substances such as surfactants and initiators, which brings potential human and environmental toxicity. On the other hand, the problem of oil seepage in the patch often occurs in existing prescription research, resulting in the inability to detect and use the preparations normally, so finding a non-toxic and harmless stabilizer that can stabilize the emulsion interface system is also a major challenge faced by practitioners.

[0003] An emulsion is a dispersion system formed by two immiscible liquids, and usually requires the addition of a certain amount of surfactant to stabilize the dispersion. An emulsion stabilized by colloidal particles instead of surfactants is called a Pickering emulsion.

[0004] Although various types of surfactants have been widely used in emulsions, Pickering emulsions also show unique application advantages. Specifically: 1. Pickering emulsions have higher safety and can avoid the toxicity to humans and the environment caused by the use of surfactants; 2. Pickering emulsions have better compatibility and are suitable for most commonly used oil phases, and the volume fraction of the internal phase, the pH and salt concentration of the aqueous phase can vary in a wide range; 3. Pickering emulsions have higher stability and can meet the requirements of long-term drug stability; 4. The unique and controllable rheological properties can provide the texture and viscosity required by the product, so that the product has a better sensory experience.

[0005] Therefore, how to provide a composite material that can maintain the stability of a gel patch, prepare it into a Pickering emulsion, and apply it to a gel patch is an urgent problem to be solved by those skilled in the art. Summary of the invention

[0006] In view of this, the present invention provides the use of a titanium dioxide fatty acid complex oil phase in improving the stability of a gel patch.

[0007] In order to achieve the above object, the present invention adopts the following technical solution:

[0008] The invention discloses an application of a titanium dioxide fatty acid complex oil phase in improving the stability of a gel patch. The preparation method of the titanium dioxide fatty acid complex oil phase is as follows: adding water to nano-sized titanium dioxide for dispersion and wetting and then dehydrating through a molecular sieve, wherein the weight ratio of titanium dioxide to water is 1:5; then slowly adding the mixture to an oil phase containing fatty acids in an anhydrous environment and stirring; then heating to 45-75°C, continuing stirring for 2h-6h, and dispersing the mixture until uniform, thereby obtaining a complex oil phase; wherein the molar ratio of nano-sized titanium dioxide to fatty acids is 1:1-3:1, and the mass ratio of the total mass of titanium dioxide and fatty acids to the oil phase is 1:4-1:6.

[0009] In the above technical solution, the fatty acid includes lauric acid, myristic acid, stearic acid or oleic acid.

[0010] In the above technical solution, the oil phase includes crotamiton or caprylic / capric glyceride.

[0011] In the above technical solution, the stability of the gel patch is: no oil leakage under light conditions, strong adhesive force, and stable release behavior.

[0012] As an inventive concept identical to the above technical solution, the present invention also seeks to protect a Pickering emulsion for maintaining the stability of a gel patch, wherein the Pickering emulsion comprises a titanium dioxide fatty acid complex oil phase and purified water in a volume ratio of 1:2.

[0013] As an inventive concept identical to the above technical solution, the present invention also claims a method for preparing a drug-loaded Pickering emulsion for maintaining the stability of a gel patch, the preparation process comprising:

[0014] 1) Weigh 10 parts of the prescribed amount of the raw material drug and add them to 50 parts of the prescribed amount of the complex oil phase, stir at 300 rpm for more than 10 minutes, and disperse until uniform, to obtain system 1; wherein the weight ratio of the raw material drug to the complex oil phase is 1:5;

[0015] 2) Then, the system 1 was slowly added into 120 parts of purified water, while stirring at 60 rpm, and after the addition was completed, stirring was continued at 200 rpm for more than 30 minutes to obtain the drug-loaded Pickering emulsion.

[0016] As an inventive concept identical to the above-mentioned technical scheme, the present invention also requests protection for a gel patch comprising 180 parts of a titanium dioxide fatty acid complex oil phase, 30 parts of polyacrylic acid, 40 parts of sodium carboxymethyl cellulose, 50 parts of talc, 60 parts of a tartaric acid aqueous solution, 5 parts of aluminum glycolate, 2 parts of sodium edetate, 5 parts of menthol, 400 parts of a gelatin aqueous solution and 280 parts of glycerol.

[0017] In the above technical solution, the tartaric acid aqueous solution is prepared by dissolving 10 parts of tartaric acid in 50 parts of purified water; the gelatin aqueous solution is prepared by dissolving 100 parts of gelatin in 300 parts of purified water.

[0018] As an inventive concept identical to the above technical solution, the present invention also seeks protection for a method for preparing a gel patch, the process comprising:

[0019] 1) Add the prescribed amount of polyacrylic acid, sodium carboxymethyl cellulose and talc into 90 parts of glycerol, stir and disperse, then add 190 parts of glycerol and stir until it becomes a paste to obtain system 1;

[0020] 2) While the system 1 is being stirred, a prescribed amount of tartaric acid aqueous solution is added, and the drug-loaded Pickering emulsion prepared above is slowly added, and stirring is continued for more than 15 minutes after the addition is completed;

[0021] 3) adding aluminum glycolate, sodium edetate, gelatin aqueous solution and menthol, and stirring for 10 minutes to obtain a paste;

[0022] 4) The paste is quickly transferred to a coating machine for coating, and then cut according to the required preparation area, sealed in a sealed bag for storage, and placed at room temperature for cross-linking to obtain a drug-containing gel patch.

[0023] The applicant found in the process of research and experiment that titanium dioxide, which is usually used as a whitening agent and filler in gel patches, has the conditions of colloidal particles in Pickering emulsions, and has certain chemical activity, so it can be modified in a targeted manner. Further research found that the titanium dioxide fatty acid complex obtained by modification can well encapsulate poorly soluble drugs (including but not limited to non-steroidal anti-inflammatory drugs such as flurbiprofen, ibuprofen, and celecoxib) without using surfactants, and can remain stable for a long time and under a wide range of storage conditions.

[0024] Moreover, the titanium dioxide commonly used in the current gel patch is usually used as a whitening agent and filler (there are hydroxyl groups, strong hydrophilicity, small three-phase contact angle, and the strong polarity and fine particles of ultrafine titanium dioxide itself make it difficult to disperse in organic media). The present invention utilizes its characteristics to produce new effects through surface modification (organic modification changes the surface characteristics, can inhibit its photochemical activity to a certain extent, and improve lipophilicity) to obtain an amphiphilic titanium dioxide fatty acid complex (without affecting its original whitening, filling and other functions, it has functions similar to O / W surfactants, encapsulates oil phase and oil-soluble drugs, and is evenly dispersed. The oil phase includes but is not limited to fatty acid esters, glycerides, fatty alcohols, mineral oil, crotamiton, etc.) to make a Pickering emulsion, and then prepare a gel patch, stably encapsulate the poorly soluble drugs in the oil phase, improve the stability of the preparation under light, prevent and control the oil seepage of the gel patch, avoid the potential toxicity caused by the surfactant, and the texture and viscosity of the preparation during the preparation process have a wider adjustment range. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0026] Figure 1 The accompanying drawings are photographs of the mixtures left at room temperature for 1 day; from left to right: Example 1, adding an equal volume of water and mixing, Example 2, adding an equal volume of water and mixing, a mixture of the same components of Example 1, adding an equal volume of water and mixing, a mixture of excess titanium dioxide + oleic acid + water, a mixture of titanium dioxide + crotamiton + water, and a comparative example 1, adding an equal volume of water and mixing the oil phase components;

[0027] Figure 2 The accompanying drawings are photos of the mixtures left at room temperature for 10 days, from left to right: Example 1, adding an equal volume of water and mixing, Example 2, adding an equal volume of water and mixing, a mixture of the same components of Example 1, adding an equal volume of water and mixing, a mixture of excess titanium dioxide + oleic acid + water, a mixture of titanium dioxide + crotamiton + water, and a comparative example 1, adding an equal volume of water and mixing the oil phase components;

[0028] Figure 3 The accompanying figure is a state diagram of the gel patch placed under light conditions for 5 days; wherein the left side is the preparation F-1 prepared using the emulsion of Example 1, and the right side is the preparation comparative example 1 prepared by adding a surfactant;

[0029] Figure 4The accompanying figure is a state diagram of the gel patch placed under light conditions for 10 days; wherein the left side is the preparation F-1 prepared using the emulsion of Example 1, and the right side is the preparation comparative example 1 prepared by adding a surfactant;

[0030] Figure 5 The attached figure is titanium dioxide ( Figure 5 A), a mixture of titanium dioxide and lauric acid in a weight ratio of 1:2 ( Figure 5 B), Example 1 composite oil phase ( Figure 5 C) infrared spectrum;

[0031] Figure 6 The attached drawings are the release curves of F1-F3 and Comparative Example 1-Comparative Example 2 under light conditions. DETAILED DESCRIPTION

[0032] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] Weigh the raw materials according to the components and proportions described in Table 1 to prepare the amphiphilic titanium dioxide fatty acid complex oil phase:

[0034] Table 1

[0035]

[0036] Example 1 Preparation of amphiphilic titanium dioxide fatty acid complex oil phase

[0037] Take 5g of nano-scale titanium dioxide, add a certain amount of water to disperse and wet, and then pass through molecular sieves for dehydration. The weight ratio of titanium dioxide to water is 1:5. Then slowly add it to 60g of oil phase containing 10g of fatty acid in an anhydrous environment, and stir vigorously at the same time. Then heat it to 45°C, continue to stir vigorously for 6h, and disperse it evenly to obtain the composite oil phase.

[0038] Example 2

[0039] Refer to the preparation method of Example 1 and follow the component ratios listed in Table 1.

[0040] Example 1 was mixed with an equal volume of water, Example 2 was mixed with an equal volume of water, a mixture of the same components as Example 1 was mixed with an equal volume of water, a mixture of excess titanium dioxide + oleic acid + water, a mixture of titanium dioxide + crotamiton + water, and an oil phase component of Comparative Example 1 was mixed with an equal volume of water and placed at room temperature for 1 day and 10 days to observe the state; the results are shown in Figure 1 and Figure 2 It is shown that the composite oil phase of Example 1 and Example 2 can form a stable emulsion by mixing equal volumes of water, and remain stable at room temperature for 1 day and 10 days without changing its properties; the other mixtures have a certain degree of stratification and sedimentation after 1 day, and the phenomenon is obvious after 10 days, which proves that simple mixtures cannot form stable emulsions.

[0041] Example 3

[0042] Referring to the preparation method of Example 1, according to the component ratio listed in Table 1, the heating temperature is 75°C, and the vigorous stirring time after heating is 4 hours.

[0043] Example 4

[0044] Referring to the preparation method of Example 1, according to the component ratios listed in Table 1, the corresponding heating temperature was 55° C., and the vigorous stirring time after heating was 2 h.

[0045] Example 5

[0046] Referring to the preparation method of Example 1, according to the component ratios listed in Table 1, the heating temperature was 60° C., and the vigorous stirring time after heating was 4 h.

[0047] Example 6

[0048] Referring to the preparation method of Example 1, according to the component ratio listed in Table 1, the heating temperature is 65° C., and the vigorous stirring time after heating is 6 h.

[0049] Example 7 Preparation of Pickering Emulsion and Gel Patch

[0050] Weigh 10 parts of the prescribed amount of the raw material drug and add them to 50 parts of the prescribed amount of the complex oil phase, stir for more than 10 min, and disperse evenly to obtain system 1. Then slowly add system 1 to 120 parts of purified water, stirring at a low speed while adding, and stir at a high speed for more than 30 minutes after the addition is completed, to obtain system 2 (drug-containing Pickering emulsion).

[0051] Preparation of gel patch:

[0052] 1) Add the prescribed amount of polyacrylic acid, sodium carboxymethyl cellulose and talc into 90 parts of glycerol, stir and disperse, then add 190 parts of glycerol and stir until it becomes a paste to obtain system 3.

[0053] 2) While the system 3 is being stirred, a prescribed amount of tartaric acid aqueous solution (50 parts of purified water) is added, and then slowly added to the system 2, and stirring is continued for more than 15 minutes after the addition is completed.

[0054] 3) Add aluminum glycolate, sodium edetate, gelatin aqueous solution (300 parts of purified water, dissolved at 35-40° C.), and menthol, and stir for 10 minutes to obtain a paste.

[0055] 4) The paste is quickly transferred to a coating machine for coating, and then cut according to the required preparation area, sealed in a sealed bag for storage, and placed at room temperature for cross-linking to obtain a drug-containing gel patch.

[0056] Prepare the gel patch according to the ingredients and proportions in Table 2 and the method of Example 7:

[0057] Table 2

[0058]

[0059]

[0060] Comparative Example 1

[0061] Referring to the preparation method of Example 7, the oil phase of the composite was replaced with a mixture of titanium dioxide, polysorbate 80 and crotamiton, and Comparative Example 1 was prepared according to the corresponding composition listed in Table 2.

[0062] Comparative Example 2

[0063] Referring to the preparation method of Example 7, the oil phase of the composite was replaced with a mixture of titanium dioxide and crotamiton, and Comparative Example 2 was prepared according to the corresponding composition listed in Table 2.

[0064] The gel patch obtained in Example 7 was used for the experiment.

[0065] Adhesion test:

[0066] According to the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 0952, Adhesion Test Method, the F-1 and Comparative Examples 1 and 2 preparations were tested for adhesion and peel strength. The results are shown in Table 3;

[0067] Table 3

[0068] result Holding force h Peel strength (steel plate) N / 30mm F-1 Example 1 11.2 4.01 F-2 Example 2 10.5 3.54 Comparative Example 1 9.4 3.33 Comparative Example 2 4.2 1.31 Comparative Example 1 (10 days of illumination) / / F-1 Example 1 (10 days of illumination) 10.7 3.89

[0069] Note: Comparative Example 1 (10 days of light exposure) had serious oil seepage and could not be tested for normal adhesion.

[0070] Stability test

[0071] The gel patches obtained from F-1 to F-6 in Example 7 and Comparative Examples 1 to 2 were placed at 40°C for stability study and the patches were observed regularly (5 days and 10 days). Figure 3 and Figure 4 F-1 to F-6 have good properties, while the most intuitive manifestation of Comparative Examples 1 to 2 is discoloration and oil seepage, which leads to poor properties. The photos are similar, so Figure 3 and Figure 4The photos provided are only a typical comparison between F-1 and Comparative Example 1. The results show that the conventional preparations with added surfactants will change color under light conditions (intuitively reflected) and have oil leakage (difficult to reflect in the photos). This group of figures shows that the preparations prepared in Example 1 are stable under light conditions, solving the problems that may exist in daily storage.

[0072] Take the oil phase of the composite of Example 1 ( Figure 5 C), titanium dioxide ( Figure 5 A), a mixture of titanium dioxide and lauric acid in a weight ratio of 1:2 ( Figure 5 B) After being fully rinsed with ethanol, the mixture was freeze-dried for 24 hours to obtain a white to off-white powder as a sample.

[0073] Infrared detection:

[0074] The sample structure was tested using Fourier transform infrared spectrometer, ATR test mode, wavelength range 4000 ~ 400cm -1 The results are shown in Figure 5 .

[0075] Release test:

[0076] According to the dissolution and release test method "Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Fourth Method", the dissolution and release behavior of F1-3, Comparative Examples 1-2 and Comparative Example 1 placed under light for 10 days were investigated using a dissolution instrument in a pH 7.4 phosphate buffer medium. The specific method is as follows:

[0077] Dissolution method: paddle-disc method; instrument: Tianjin Tianda Tianfa RC806D; dissolution medium: pH 7.4 phosphate buffer (containing 3% NaCl to prevent excessive swelling of the patch); dissolution volume: 900 ml; rotor speed: 50 rpm; sampling time: 1 h, 2 h, 4 h, 6 h, 8 h, 12 h; sampling volume: 5 ml; after sampling, the sample solution was centrifuged through a 0.45 μm filter membrane, and the filtrate was determined by HPLC.

[0078] The results are shown in Table 4;

[0079] Table 4

[0080]

[0081] Taking Comparative Example 1, i.e., the prescription preparation with the addition of conventional surfactants, as a reference, the release behaviors of preparations F1 to F3 are similar to those of the preparations; Comparative Example 2, i.e., the prescription preparation without the addition of surfactants, shows a faster release behavior, which to a certain extent indicates that its drug encapsulation is unstable, and on the other hand, too fast drug release is not conducive to stable and continuous drug administration; the faster release behavior of Comparative Example 1 (10 days of light exposure) proves that the drug loading structure in the preparation has been destroyed, and the plateau release rate does not reach about 100%, which may be due to the drug loss caused by oil seepage; in contrast, the release behavior of F-1 (10 days of light exposure) has not changed, proving that it has good stability under light conditions. Figure 6 .

[0082] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0083] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A gel patch, It is characterized in that The invention comprises 180 parts of a titanium dioxide fatty acid complex oil phase, 30 parts of polyacrylic acid, 40 parts of sodium carboxymethylcellulose, 50 parts of talcum powder, 60 parts of a tartaric acid aqueous solution, 5 parts of aluminum glycolate, 2 parts of sodium edetate, 5 parts of menthol, 400 parts of a gelatin aqueous solution and 280 parts of glycerol. The preparation method of the titanium dioxide fatty acid complex oil phase comprises the following steps: adding water to nano-sized titanium dioxide for dispersion and wetting, and then dehydrating the nano-sized titanium dioxide through a molecular sieve, and then slowly adding the nano-sized titanium dioxide to an oil phase containing fatty acids under an anhydrous environment, and stirring the nano-sized titanium dioxide; then heating the nano-sized titanium dioxide to 45-75° C., stirring the nano-sized titanium dioxide for 2-6 hours, and dispersing the nano-sized titanium dioxide to obtain a uniform oil phase; wherein the molar ratio of the nano-sized titanium dioxide to the fatty acid is 1:1-3:1, and the mass ratio of the total mass of the titanium dioxide and the fatty acid to the oil phase is 1:4-1:6; the fatty acid comprises lauric acid, myristic acid, stearic acid or oleic acid; and the oil phase comprises crotamiton or caprylic capric glyceride.

2. A gel patch according to claim 1, It is characterized in that The tartaric acid aqueous solution is prepared by dissolving 10 parts of tartaric acid in 50 parts of purified water; the gelatin aqueous solution is prepared by dissolving 100 parts of gelatin in 300 parts of purified water.

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