Celecoxib nanoemulsion, gel emplastrum and preparation method of celecoxib nanoemulsion and gel emplastrum

Abstract

The invention relates to the field of pharmacy, and discloses a celecoxib nanoemulsion, a gel emplastrum and a preparation method of the celecoxib nanoemulsion and the gel emplastrum. The celecoxib nano-emulsion is an oil-in-water nano-emulsion with the emulsion particle size of less than 50nm, and comprises the following raw materials: 0.2-5% of celecoxib, 1-35% of an oil-phase substance, 1-30% of an emulsifier, 1-25% of a co-emulsifier, 0.1-10% of a penetration enhancer and 30-75% of water, the preparation method comprises the following steps: firstly, preparing the celecoxib into an oil-in-water type nano-emulsion, then adding the oil-in-water type nano-emulsion into a hydrophilic gel matrix to prepare a paste body, and finally preparing the gel plaster. On one hand, the prepared celecoxib nanoemulsion has excellent stability; and on the other hand, the prepared celecoxib nanoemulsion has extremely small particle size (less than 50nm), is transparent, is beneficial to diffusion and permeation of celecoxib in skin, and is easier to absorb. The celecoxib nano-emulsion gel plaster is an external plaster dosage form, and compared with a conventional oral preparation, the celecoxib nano-emulsion gel plaster has the advantages of no first-pass effect, few side effects, high bioavailability and more comfortable and convenient use.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmacy, in particular to a celecoxib nanoemulsion, a gel patch and a preparation method thereof. BACKGROUND

[0002] Celecoxib is a selective COX-2 inhibitor non-steroidal anti-inflammatory drug (NSAIDs), mainly used for relieving osteoarthritis including joint swelling pain, limited activity, morning stiffness, etc.; pain and inflammation of adult rheumatoid arthritis, ankylosing spondylitis; also used for the treatment of adult acute pain such as post-extraction pain, postoperative recovery pain, primary dysmenorrhea and muscle joint soft tissue injury pain, etc. Compared with other non-steroidal anti-inflammatory analgesics, celecoxib has better efficacy and relatively fewer adverse reactions, so in recent years celecoxib has been widely used in the treatment of the above diseases.

[0003] But the team found that the approved celecoxib dosage forms at present are oral capsules and tablets, and oral preparations have a first-pass effect, that is, after oral administration, the drug enters the gastrointestinal tract, and before being absorbed into the blood circulation, a part of the drug is metabolized by the intestinal mucosa and the liver, resulting in a decrease in the amount of the original drug entering the blood circulation. The first-pass effect reduces the utilization rate of the drug and affects the therapeutic effect of the drug. In addition, celecoxib can stimulate the gastrointestinal tract and may cause abdominal pain, indigestion, nausea, diarrhea and other adverse reactions, and in severe cases, it may even cause gastrointestinal ulcers, bleeding or perforation, especially in patients with a history of gastrointestinal tract and long-term use.

[0004] The external patch drug is applied to the skin surface, and the drug is absorbed into the blood circulation through the capillary blood vessels to reach the affected area, without passing through the gastrointestinal tract, without first-pass effect, without stimulating the gastrointestinal tract, and the drug absorption is not affected by factors such as pH and food in the digestive tract; the drug is released slowly, which can maintain a stable blood drug concentration for a long time, reducing adverse reactions caused by too high blood drug concentration due to too fast drug absorption, thereby reducing the toxic and side effects of the drug; since the patch can act directly on the affected area, it is more suitable for patients with joint and spinal pain, muscle and soft tissue injury pain, etc. Therefore, if celecoxib is prepared as an external patch, more choices can be provided for patients, especially for patients with inflammatory pain such as arthritis and spondylitis for long-term use. SUMMARY

[0005] To solve the above technical problems, the application provides a celecoxib nanoemulsion, a gel patch and a preparation method thereof. The celecoxib is first prepared into an oil-in-water nanoemulsion, and then the nanoemulsion is added into a hydrophilic gel matrix to prepare a paste, and finally the gel patch is prepared. On the one hand, the prepared celecoxib nanoemulsion has excellent stability; on the other hand, the prepared celecoxib nanoemulsion has an extremely small particle size (< 50 nm), which is beneficial to the diffusion and penetration of celecoxib in the skin and is more easily absorbed. The celecoxib nanoemulsion gel patch of the application is an external patch preparation, compared with conventional oral preparations, has no first-pass effect, less side effects, high bioavailability, and the advantages of more comfortable and convenient use.

[0006] The specific technical scheme of the application is as follows: Firstly, the application provides a celecoxib nanoemulsion, which is an oil-in-water nanoemulsion with a particle size < 50 nm, and includes the following raw materials in mass percentage: celecoxib 0.2%-5%, oil phase substance 1%-35%, emulsifier 1%-30%, co-emulsifier 1%-25%, penetration enhancer 0.1%-10%, and water 30%-75%.

[0007] The application finds that celecoxib is insoluble in water and is difficult to be directly prepared into a gel patch for external use. Therefore, the application first prepares celecoxib into an oil-in-water nanoemulsion, and then adds the nanoemulsion into a hydrophilic gel matrix to prepare a paste, and finally prepares a gel patch.

[0008] On the one hand, the prepared celecoxib nanoemulsion has excellent stability, is transparent, and does not separate or precipitate after centrifugation. The oil phase substance can wrap the hydrophobic celecoxib, thereby significantly improving the solubility of celecoxib. On the other hand, the application finds that the particle size of the nanoemulsion is crucial to the absorption effect of celecoxib after external use. The prepared celecoxib nanoemulsion has an extremely small particle size (< 50 nm), which is beneficial to the diffusion and penetration of celecoxib in the skin, more easily penetrates the skin barrier, and is more easily absorbed, thereby significantly improving the bioavailability of the drug.

[0009] Preferably, the mass ratio of the emulsifier to the co-emulsifier is 1-8:1, and further preferably 1-3:1; and the mass ratio of the total mass of the emulsifier and the co-emulsifier to the mass of the oil phase substance is 2-8:1, and further preferably 3-5:1.

[0010] As mentioned above, the particle size of the celecoxib nanoemulsion has a crucial influence on its stability and transdermal absorption effect. Therefore, how to prepare a celecoxib nanoemulsion with a smaller particle size becomes a difficult problem. The present application finds that the mass ratio of emulsifier to co-emulsifier and the mass ratio of the total mass of emulsifier and co-emulsifier to the mass of oil phase substance have an important influence on the particle size of the celecoxib nanoemulsion. Finally, the present application finds that controlling the above two ratios in the above ranges respectively can be conducive to obtaining a celecoxib nanoemulsion with a particle size < 50 nm.

[0011] In addition, the present application finds that the content of celecoxib in the nanoemulsion also affects whether the nanoemulsion can be sequentially prepared. If the content of celecoxib is too high (more than 6%), the prepared emulsion is a white opaque emulsion liquid, which is a common emulsion. It can be seen that too much celecoxib cannot form a nanoemulsion but only large droplets.

[0012] Preferably, the oil phase substance is one or more of isopropyl myristate, glyceryl monolinoleate, oleyl polyoxyethylene glycerol ester, medium-chain triglyceride and capric and caprylic acid glycerol ester.

[0013] Preferably, the emulsifier is one or more of polysorbate 80, lauryl sorbitan and polyoxyethylene 20 oil ether; and the co-emulsifier is one or more of propylene glycol, glycerol, isopropyl alcohol and PEG400.

[0014] Preferably, the penetration enhancer is one or both of azone and menthol.

[0015] Secondly, the present application provides a preparation method of the above-mentioned celecoxib nanoemulsion, which comprises the following steps: weighing the emulsifier, co-emulsifier and oil phase substance, mixing them thoroughly, adding celecoxib and penetration enhancer, stirring to dissolve completely, then slowly adding water while stirring, and continuing to stir after the water is added, to obtain a colorless and transparent celecoxib nanoemulsion.

[0016] The present application further finds that the way of adding water in the preparation process of the emulsion determines the morphology of the emulsion. The formation of oil-in-water (O / W) nanoemulsion usually needs to go through a phase inversion process, i.e. from W / O to O / W. When water is slowly added to the oil phase containing surfactant and co-surfactant, the system is in a low water content state, at which time the interface film formed by the surfactant has a negative curvature, which tends to wrap water droplets to form a W / O type emulsion. With the continuous slow addition of the water phase, near the critical water content, the interface film curvature approaches zero from the negative value, forming a double continuous phase, with oil and water penetrating each other. When the water content exceeds the critical value, the interface film curvature changes to a positive value, which tends to wrap oil droplets. Under the action of stirring, the system spontaneously reorganizes to form an O / W type emulsion. However, when water is added at once, a large amount of water forms an oil / water macroscopic interface instantaneously, and under the action of stirring, the oil phase is torn into large-sized droplets, the phase inversion process is skipped, and an O / W type large droplet common emulsion is directly formed.

[0017] Further, the present application provides a celecoxib nanoemulsion gel patch, which comprises a backing layer, a paste layer and an anti-adhesion layer in sequence. The paste layer comprises the following raw materials in mass percentage: the above-mentioned celecoxib nanoemulsion 30%-60%, a hydrophilic gel framework 1%-15%, a filler 1%-15%, an adhesive 0.5%-10%, a cross-linking agent 0.1%-5%, a regulator 1%-15%, glycerol 10%-50% and water 1%-10%.

[0018] The gel framework used in the celecoxib nanoemulsion gel patch is a hydrophilic polymer material, the celecoxib nanoemulsion can be uniformly and stably distributed in the hydrophilic gel framework, and can slowly penetrate the skin and be absorbed into the body under the action of a penetration enhancer after being applied to the skin. The hydrophilic polymer material has good air permeability, is resistant to sweat, has no sensitization and no irritation, has strong affinity with the skin, does not pollute clothes, and is easy to wash off. Compared with conventional oral preparations, the celecoxib nanoemulsion gel patch has the advantages of no first-pass effect, less side effects (no irritation to the gastrointestinal tract), high bioavailability, and more comfortable and convenient use.

[0019] Preferably, the hydrophilic gel framework is one or more of partially neutralized sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl cellulose and xanthan gum. Preferably, the filler is one or more of silicon dioxide, kaolin, titanium dioxide and zinc oxide.

[0020] Preferably, the adhesive is one or more of sodium carboxymethylcellulose, hydroxypropyl methylcellulose, gelatin and povidone.

[0021] Preferably, the cross-linking agent is one or both of aluminum hydroxide and aluminum glycinate.

[0022] Preferably, the regulator is one or more of maleic acid, sodium tartrate, L-tartaric acid and citric acid.

[0023] Preferably, the backing layer is non-woven fabric or artificial cotton cloth, and the anti-adhesion layer is anti-adhesion paper or plastic film.

[0024] The backing layer is a carrier of the paste layer, and the paste layer is laid on the backing layer. Non-woven fabric, artificial cotton cloth and the like are commonly used. The anti-adhesion layer protects the paste layer, and anti-adhesion paper, plastic film and the like are commonly used.

[0025] Finally, the present application provides a preparation method of the celecoxib nanoemulsion gel patch, which comprises the following steps: 1) mixing the hydrophilic gel framework, the filler, the adhesive and the cross-linking agent with glycerol to obtain phase A; 2) dissolving the regulator in water to obtain phase B; 3) Mix B phase into celecoxib nanoemulsion to obtain C phase; 4) Mix C phase into A phase to obtain paste layer.

[0026] 5) Apply paste layer on backing layer and cover with anti-sticking layer.

[0027] The preparation method of the present application is simple, can be carried out at room temperature, has low cost and is suitable for large-scale industrial production.

[0028] Compared with the prior art, the present application has the following advantages: (1) In order to prepare celecoxib into gel patch for the first time, the present application innovatively prepares celecoxib into oil-in-water nanoemulsion first, then adds the nanoemulsion into hydrophilic gel matrix to prepare paste, and finally prepares gel patch. The celecoxib nanoemulsion gel patch of the present application is an external patch, which has the advantages of no first-pass effect, less side effects, high bioavailability and more comfortable and convenient use compared with conventional oral preparations.

[0029] (2) The celecoxib nanoemulsion prepared by the present application has excellent stability; in addition, the celecoxib nanoemulsion prepared by the present application has a very small particle size (<50 nm) and is transparent, which is beneficial to the diffusion and penetration of celecoxib in the skin and easier absorption.

[0030] (3) The present application combines nanoemulsion technology and gel patch technology to prepare nanoemulsion gel matrix, and celecoxib can be uniformly and stably distributed in the hydrophilic gel framework. The celecoxib nanoemulsion gel patch prepared by the prescription and process of the present application has stable drug release amount and drug transdermal amount, good air permeability, comfortable application and convenient use.

[0031] (4) The preparation method of the celecoxib nanoemulsion gel patch of the present application is simple, can be carried out at room temperature, has low cost and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 Appearance diagram of celecoxib nanoemulsion prepared in Example 1 of the present application; Figure 2 Appearance diagram of celecoxib nanoemulsion prepared in Comparative Example 1 of the present application; Figure 3 Appearance diagram of celecoxib submicron emulsion prepared in Comparative Example 2 of the present application; Figure 4 Appearance diagram of celecoxib ordinary emulsion prepared in Comparative Example 5 of the present application; Figure 5 Cumulative drug release amount curve of celecoxib nanoemulsion gel patch prepared in Examples 7-11 and Comparative Example 7 of the present application within 24 hours. Figure 6 Cumulative transdermal amount of celecoxib nanogel emulsion patch prepared for Examples 7-11 and Comparative Example 7 in vitro transdermal 24h drug release profile. DETAILED DESCRIPTION

[0033] The application will be further described in conjunction with the examples.

[0034] (I) Preparation of celecoxib nanogel emulsion Example 1 A celecoxib nanogel emulsion, comprising, by weight percentage: celecoxib 2%, isopropyl myristate 6%, polysorbate 80 18%, polyethylene glycol 400 9%, menthol 1%, pure water 64%.

[0035] Preparation method: polysorbate 80, polyethylene glycol 400, isopropyl myristate were weighed and mixed thoroughly, celecoxib and menthol were added and stirred until completely dissolved, then pure water was slowly added dropwise while stirring (each drop of pure water was stirred until the solution was clear and no longer changed significantly before the next drop was added), and stirring was continued for 20 minutes after the addition of pure water, to obtain a colorless and transparent celecoxib nanogel emulsion.

[0036] Example 2 A celecoxib nanogel emulsion, comprising, by weight percentage: celecoxib 2%, isopropyl myristate 6%, polysorbate 80 18%, propylene glycol 9%, azone 1%, pure water 64%.

[0037] Preparation method: polysorbate 80, propylene glycol, isopropyl myristate were weighed and mixed thoroughly, celecoxib and azone were added and stirred until completely dissolved, then pure water was slowly added dropwise while stirring (each drop of pure water was stirred until the solution was clear and no longer changed significantly before the next drop was added), and stirring was continued for 20 minutes after the addition of pure water, to obtain a colorless and transparent celecoxib nanogel emulsion.

[0038] Example 3 A celecoxib nanogel emulsion, comprising, by weight percentage: celecoxib 2%, glyceryl monolinoleate 8%, polyoxyethylene 20 oil ether 14%, isopropyl alcohol 8%, azone 4%, pure water 64%.

[0039] Preparation method: polyoxyethylene 20 oil ether, isopropyl alcohol, glyceryl monolinoleate were weighed and mixed thoroughly, celecoxib and azone were added and stirred until completely dissolved, then pure water was slowly added dropwise while stirring (each drop of pure water was stirred until the solution was clear and no longer changed significantly before the next drop was added), and stirring was continued for 20 minutes after the addition of pure water, to obtain a colorless and transparent celecoxib nanogel emulsion.

[0040] Example 4 A celecoxib nanoemulsion, comprising, in percentage by weight: celecoxib 2%, monolinolein 8%, polyoxyethylene 20 oil ether 14%, propylene glycol 8%, menthol 1%, pure water 64%.

[0041] Preparation method: weigh polyoxyethylene 20 oil ether, propylene glycol, monolinolein, mix thoroughly, add celecoxib, menthol, stir to dissolve completely, then slowly add pure water while stirring (each drop of pure water needs to be stirred until the solution is clear and no longer changes obviously before continuing to add), continue to stir for 20 minutes after adding pure water, to obtain colorless and transparent celecoxib nanoemulsion.

[0042] Example 5 A celecoxib nanoemulsion, comprising, in percentage by weight: celecoxib 2%, medium-chain triglyceride 10%, polysorbate 80 13%, isopropyl alcohol 7%, azone 4%, pure water 64%.

[0043] Preparation method: weigh polysorbate 80, isopropyl alcohol, medium-chain triglyceride, mix thoroughly, add celecoxib, azone, stir to dissolve completely, then slowly add pure water while stirring (each drop of pure water needs to be stirred until the solution is clear and no longer changes obviously before continuing to add), continue to stir for 20 minutes after adding pure water, to obtain colorless and transparent celecoxib nanoemulsion.

[0044] Example 6 A celecoxib nanoemulsion, comprising, in percentage by weight: celecoxib 2%, oleoyl polyoxyethylene glycerol 9%, lauryl sorbitan 16%, polyethylene glycol 400 8%, menthol 1%, pure water 64%.

[0045] Preparation method: weigh lauryl sorbitan, polyethylene glycol 400, oleoyl polyoxyethylene glycerol, mix thoroughly, add celecoxib, menthol, stir to dissolve completely, then slowly add pure water while stirring (each drop of pure water needs to be stirred until the solution is clear and no longer changes obviously before continuing to add), continue to stir for 20 minutes after adding pure water, to obtain colorless and transparent celecoxib nanoemulsion.

[0046] Comparative example 1 A celecoxib nanoemulsion, different from example 1 in that the ratio of emulsifier to co-emulsifier is different (1:1).

[0047] Comprising, in percentage by weight: celecoxib 2%, isopropyl myristate 6%, polysorbate 80 13.5%, polyethylene glycol 400 13.5%, menthol 1%, pure water 64%.

[0048] Preparation method: take polysorbate 80, polyethylene glycol 400, isopropyl myristate, mix well, add celecoxib, menthol, stir to dissolve completely, then slowly add pure water while stirring (each drop of pure water needs to be stirred until the solution is clear and no longer obvious change before continuing to drop), after adding pure water continue to stir for 20 minutes, get light blue translucent liquid.

[0049] Comparative example 2 A kind of celecoxib microemulsion, and the difference of example 1 is that the ratio of emulsifier and coemulsifier is different (1:2).

[0050] According to the percentage by weight, including: celecoxib 2%, isopropyl myristate 6%, polysorbate 80 9%, polyethylene glycol 400 18%, menthol 1%, pure water 64%.

[0051] Preparation method: take polysorbate 80, polyethylene glycol 400, isopropyl myristate, mix well, add celecoxib, menthol, stir to dissolve completely, then slowly add pure water while stirring (each drop of pure water needs to be stirred until the solution is clear and no longer obvious change before continuing to drop), after adding pure water continue to stir for 20 minutes, get light blue translucent liquid.

[0052] Comparative example 3 A kind of celecoxib microemulsion, and the difference of example 1 is that the ratio of emulsifier and coemulsifier is different (1:2).

[0053] According to the percentage by weight, including: celecoxib 2%, isopropyl myristate 16.5%, polysorbate 80 11%, polyethylene glycol 400 5.5%, menthol 1%, pure water 64%.

[0054] Preparation method: take polysorbate 80, polyethylene glycol 400, isopropyl myristate, mix well, add celecoxib, menthol, stir to dissolve completely, then slowly add pure water while stirring (each drop of pure water needs to be stirred until the solution is clear and no longer obvious change before continuing to drop), after adding pure water continue to stir for 20 minutes, get light blue translucent liquid.

[0055] Comparative example 4 A kind of celecoxib microemulsion, and the difference of example 1 is that the ratio of emulsifier and coemulsifier is different (1:2).

[0056] According to the percentage by weight, including: celecoxib 2%, isopropyl myristate 3%, polysorbate 80 20%, polyethylene glycol 400 10%, menthol 1%, pure water 64%.

[0057] Preparation method: take polysorbate 80, polyethylene glycol 400, isopropyl myristate, mix well, add celecoxib, menthol, stir to dissolve completely, then slowly drop pure water while stirring (each drop of pure water needs to be stirred until the solution is clear and no obvious change is observed before continuing to drop), continue to stir for 20 minutes after adding pure water, get light blue and white emulsion liquid.

[0058] Comparative example 5 A common celecoxib emulsion, and the difference between example 1 is that the amount of celecoxib is different, which is 3 times of the amount of example.

[0059] According to the weight percentage, it includes: celecoxib 6%, isopropyl myristate 6%, polysorbate 80 18%, polyethylene glycol 400 9%, menthol 1%, pure water 60%.

[0060] Preparation method: take polysorbate 80, polyethylene glycol 400, isopropyl myristate, mix well, add celecoxib, menthol, stir to dissolve completely, then slowly drop pure water while stirring (each drop of pure water needs to be stirred until the solution is clear and no obvious change is observed before continuing to drop), continue to stir for 20 minutes after adding pure water, get white opaque emulsion liquid.

[0061] Comparative example 6 A common celecoxib emulsion, and the difference between example 1 is that the preparation process is different, and the pure water is added at one time.

[0062] According to the weight percentage, it includes: celecoxib 2%, isopropyl myristate 6%, polysorbate 80 18%, polyethylene glycol 400 9%, menthol 1%, pure water 64%.

[0063] Preparation method: take polysorbate 80, polyethylene glycol 400, isopropyl myristate, mix well, add celecoxib, menthol, stir to dissolve completely, add all the pure water at one time, continue to stir for 20 minutes, get white opaque emulsion liquid.

[0064] (1) Particle size test Emulsion is composed of water phase, oil phase and emulsifier, according to the size of emulsion droplet, it is divided into common emulsion, submicroemulsion and nanometer emulsion, when the size of emulsion droplet is less than 100nm, it is nanometer emulsion. Among them, the droplet of common emulsion is greater than 1000nm, and the emulsion is milky white opaque liquid; The droplet of submicroemulsion is 100nm-1000nm, and the emulsion is blue and white emulsion; When the droplet of nanometer emulsion is 50nm-100nm, the emulsion is gray and semi-transparent liquid; When the droplet of nanometer emulsion is less than 50nm, the emulsion is transparent liquid.

[0065] The appearance of the emulsion prepared in examples 1-6 of the application is colorless and transparent, like Figure 1As shown, the nanoemulsion with small particle size prepared in Example 1 (emulsifier: co-emulsifier 2:1) is an example; the emulsion prepared in Comparative Example 1 (emulsifier: co-emulsifier 1:1) is a light blue semi-transparent liquid. Figure 2 As shown, this is a nanoemulsion with a relatively large particle size. It is evident that different ratios of emulsifier to co-emulsifier affect the particle size of the nanoemulsion. When the emulsifier:co-emulsifier ratio is 1:2, a submicroemulsion is formed (Comparative Example 2). Figure 3 As shown; the emulsions prepared in Comparative Examples 3 and 4 of this invention are pale blue-white milky liquids, also submicron emulsions. This demonstrates that the ratio of the total amount of emulsifier and co-emulsifier to the oil phase affects the particle size of the emulsion, even to the point of being submicron emulsions; the emulsion prepared in Comparative Example 5 of this invention is a white, opaque milky liquid, as shown... Figure 4 As shown, this is a regular emulsion. It can be seen that if the amount of raw material is too large, it cannot form a nano-emulsion, but can only form large droplets, thus becoming a regular emulsion.

[0066] The preparation process of Comparative Example 6 differed from other cases; pure water was added all at once, resulting in the formation of only a conventional emulsion. This indicates that the method of water addition in Comparative Example 6 determined the emulsion morphology. The formation of oil-in-water (O / W) nanoemulsions typically requires a phase inversion process, i.e., a change from W / O to O / W. When water is slowly added to the oil phase containing surfactants and co-surfactants, the system is in a low-water-content state. At this point, the interfacial film formed by the surfactants has a negative curvature, tending to encapsulate water droplets, forming a W / O type emulsion. As the water phase is continuously and slowly added, near the critical water content, the interfacial film curvature approaches zero from a negative value, forming a bicontinuous phase where oil and water interpenetrate. When the water content exceeds the critical value, the interfacial film curvature becomes positive, tending to encapsulate oil droplets. Under stirring, the system spontaneously reorganizes, forming an O / W type emulsion. However, when water is added all at once, a large amount of water instantly forms an oil / water macroscopic interface. Under stirring, the oil phase is torn into large droplets, the phase inversion process is skipped, and a conventional O / W type large-droplet emulsion is formed directly.

[0067] The particle size of celecoxib emulsion was measured using a particle size analyzer, and the results are as follows.

[0068] Table 1: Particle Size Test (2) Centrifugal stability test Centrifugal stability tests were conducted on the celecoxib emulsions prepared in Examples 1-6 and Comparative Examples 1-6. The prepared celecoxib emulsions were placed in a high-speed centrifuge and centrifuged at 12000 r / min for 10 min, and the presence or absence of stratification or precipitation was observed. The results are shown in Table 2.

[0069] Table 2: Centrifugal Stability Test As can be seen from the table above, the nanoemulsions with a particle size <50nm obtained in Examples 1-6 have good stability, are colorless and transparent in appearance, do not separate into layers or precipitate after centrifugation; the emulsion obtained in Comparative Example 1 has a particle size <100nm, is light blue and semi-transparent in appearance, does not separate into layers or precipitate after centrifugation, and also has good stability; the submicron emulsions with a particle size >100nm obtained in Comparative Examples 2-4 and the ordinary emulsions with a particle size >1000nm obtained in Comparative Examples 5-6 have poor stability and are prone to precipitation after centrifugation.

[0070] (II) Preparation of Celecoxib Nanoemulsion Gel Patch Celecoxib nanoemulsion prepared in Example 1 was used as the drug-containing ingredient to prepare celecoxib nanoemulsion gel patches (Examples 7-11).

[0071] Example 7 A celecoxib nanoemulsion gel patch, the technical solution of which is as follows: Preparation method: (1) Mix the gel skeleton, filler, binder and crosslinking agent with glycerol to obtain phase A; (2) Dissolve the regulator in water to obtain phase B; (3) Add phase B to celecoxib nanoemulsion and mix well to obtain phase C; (4) Add phase C to phase A and stir to obtain a paste layer.

[0072] (5) Apply the paste layer onto the backing layer and cover it with the non-stick layer.

[0073] Example 8 A celecoxib nanoemulsion gel patch, the technical solution of which is as follows: The preparation method is the same as in Example 7.

[0074] Example 9 A celecoxib nanoemulsion gel patch, the technical solution of which is as follows: The preparation method is the same as in Example 7.

[0075] Example 10 A celecoxib nanoemulsion gel patch, the technical solution of which is as follows: The preparation method is the same as in Example 7.

[0076] Example 11 A celecoxib nanoemulsion gel patch, the technical solution of which is as follows: The preparation method is the same as in Example 7.

[0077] Comparative Example 7 A celecoxib nanoemulsion gel patch, differing from Example 10 in that it uses the celecoxib nanoemulsion prepared in Comparative Example 1 as the drug-containing ingredient, is prepared as follows: The preparation method is the same as in Example 7.

[0078] Comparative Example 8 The difference between this comparative example and Example 10 is the amount of aluminum hydroxide used, which is 10 times that of Example 10.

[0079] Preparation process: (1) Mix the hydrophilic gel skeleton, filler, binder and crosslinking agent with glycerol to obtain phase A; (2) Dissolve the regulator in water to obtain phase B; (3) Add phase B to celecoxib nanoemulsion and mix well to obtain phase C; (4) Add phase C to phase A and stir to obtain a paste layer.

[0080] (5) The paste layer was applied to the backing layer. It was found that the paste layer cured quickly and the coating was uneven. Therefore, this method was abandoned and subsequent tests were conducted.

[0081] Comparative Example 9 The difference between this comparative example and Example 10 is the amount of tartaric acid used; the amount used is one-sixth of that used in Example 10.

[0082] Preparation process: (1) Mix the hydrophilic gel skeleton, filler, binder and crosslinking agent with glycerol to obtain phase A; (2) Dissolve the regulator in water to obtain phase B; (3) Add phase B to celecoxib nanoemulsion and mix well to obtain phase C; (4) Add phase C to phase A and stir to obtain a paste layer.

[0083] (5) The paste layer was applied to the backing layer and covered with an anti-stick layer. It was found that it had not cured after 2 days, so this method was abandoned and subsequent tests were conducted.

[0084] Comparative Example 10 The difference from Example 10 is the preparation process. In this comparative example, the modifier tartaric acid, hydrophilic gel skeleton, filler, binder, and crosslinking agent were mixed together with glycerin, and then celecoxib nanoemulsion was added and stirred. As a result, the paste was found to be in the form of many granular clumps and unevenly coated. Therefore, this method was abandoned for subsequent testing.

[0085] Analysis of the reasons for the failure of Comparative Examples 8-10: Partially neutralized sodium polyacrylate (SPA) exists as linear molecular chains. Trivalent aluminum ions can establish connections between these chains, ultimately crosslinking individual linear macromolecules into a large three-dimensional network structure capable of holding a large amount of water. This network structure is the gel, possessing a stable shape, strong cohesion, and viscoelasticity. Therefore, the trivalent aluminum crosslinking agent is crucial. Too little crosslinking results in insufficient crosslinking, while too much leads to rapid crosslinking, causing quick curing and difficulty in coating. Aluminum hydroxyl is poorly soluble in water, releasing trivalent aluminum very slowly. Adding tartaric acid can regulate the release rate; too little tartaric acid results in slow release of trivalent aluminum, leading to a prolonged curing time. In Comparative Example 10, tartaric acid and other matrices were mixed with glycerol to form a suspension. After adding the aqueous nanoemulsion, because the suspension is a non-uniform dispersion system, the local concentration of tartaric acid was uneven, resulting in uneven concentration of released trivalent aluminum. This caused the paste to form granular clumps, making it difficult to coat.

[0086] (1) Sensory evaluation The samples from Examples 7-11 and Comparative Example 7 were applied to the forearm for sensory evaluation of appearance, viscoelasticity, skin residue, irritation, allergy, peel pain, and comfort. The results are shown in the table below: Table 3: Sensory Evaluation As can be seen from the above tests, the celecoxib nanoemulsion gel patch prepared by the present invention has a uniform and delicate texture; a smooth surface; no skin residue; no irritation; low allergenicity; no pain when peeling off the skin; and a cool and comfortable feeling when applied to the skin.

[0087] (2) Adhesion test The gel patches prepared in Examples 7-11 and Comparative Example 7 were subjected to adhesion tests. The initial adhesion of the patches was determined by the first method (determination of initial adhesion) in "0952 Adhesion Determination Method" of Part IV of the 2020 Chinese Pharmacopoeia using the rolling ball ramp stopping method. The experimental results are shown in Table 4.

[0088] Table 4: Adhesion Test The adhesion test shows that the celecoxib nanoemulsion gel patch prepared by the present invention has good overall adhesion. Example 10 has the best adhesion and is the least likely to fall off. Comparative Example 7 is not significantly different from the examples. It can be seen that the size of the nanoemulsion particles has no significant effect on the adhesion of the prepared gel patch.

[0089] (3) In vitro release test Using a vertical diffusion cell, an artificial membrane was fixed between the administration and receiving cells. A sample (circular area 1.767 cm²) was taken, the anti-adhesive layer was removed, and the sample was attached to the artificial membrane. Phosphate buffer (pH 6.8) containing 35% methanol was injected into the receiving cell. Air bubbles were removed, and the membrane was continuously stirred at 32°C (600 rpm). 5 mL of the receiving solution was collected at 1, 2, 4, 8, 12, and 24 hours after administration, and the same volume of receiving solution was added simultaneously. A 24-hour cumulative drug release curve was plotted as the cumulative drug release per unit area (Q) against time (t). Figure 5 As shown in the figure, the in vitro release of the example was faster, with almost complete release within 12 hours, while that of Comparative Example 7 was slightly slower. This indicates that the particle size of the nanoemulsion affects the in vitro release rate; larger particle sizes result in a slower release rate.

[0090] (4) In vitro transdermal test Experimental setup: Bama miniature pig skin was fixed between the supply and receiving chambers of a Franz diffusion apparatus. A circular sample (1.767 cm²) was taken, the anti-adhesive layer removed, and applied to the epidermal layer of the Bama miniature pig skin, with the backing layer facing the supply chamber. A pH 7.4-1.0% polyoxyethylene 20 oil ether solution was added to the receiving chamber, ensuring the dermal side was in contact with the receiving solution. The mixture was kept at a constant temperature of (32±0.5) ℃ and stirred at 600 r / min. Samples were taken at 1, 2, 4, 6, 8, 12, 18, and 24 hours after drug administration, filtered, and the filtrate was used for analysis. A 24-hour cumulative transdermal drug delivery curve was plotted based on the cumulative drug release per unit area versus time. Figure 6 As can be seen from the figure, the in vitro transdermal transmission in the embodiment is slow and stable, while the comparative embodiment is significantly slower than the embodiment. This shows that the particle size of the nanoemulsion affects the rate of in vitro transdermal transmission; larger particle sizes result in a slower rate of penetration through the skin.

Claims

1. A celecoxib nanoemulsion, characterized in that: The emulsion is an oil-in-water nanoemulsion with a particle size of <50nm, comprising the following raw materials by mass percentage: celecoxib 0.2%-5%, oil phase substance 1%-35%, emulsifier 1%-30%, co-emulsifier 1%-25%, penetration enhancer 0.1%-10%, and water 30%-75%; The mass ratio of the emulsifier to the co-emulsifier is 1-8:1; The total mass ratio of the emulsifier and co-emulsifier to the oil phase substance is 2-8:

1.

2. The celecoxib nanoemulsion as described in claim 1, characterized in that: The mass ratio of the emulsifier to the co-emulsifier is 1-3:1; The total mass ratio of the emulsifier and co-emulsifier to the oil phase substance is 3-5:

1.

3. The celecoxib nanoemulsion as described in claim 1 or 2, characterized in that: The oil phase substance is one or more of the following: isopropyl myristate, monolinoleic glycerol, oleoyl polyoxyethylene glycerol, medium-chain triglycerides, and mono- and dicaprylic glycerol.

4. The celecoxib nanoemulsion as described in claim 1 or 2, characterized in that: The emulsifier is one or more of polysorbate 80, lauryl sorbitan and polyoxyethylene 20 oleyl ether; The co-emulsifier is one or more of propylene glycol, glycerin, isopropanol, and PEG400.

5. The celecoxib nanoemulsion as described in claim 1, characterized in that: The penetration enhancer is one or both of azone and menthol.

6. The method for preparing celecoxib nanoemulsion as described in any one of claims 1-5, characterized in that: The process includes the following steps: weigh out the emulsifier, co-emulsifier, and oil phase substance, mix them well, add celecoxib and penetration enhancer and stir until completely dissolved, then add water dropwise while stirring, and continue stirring after adding all the water to obtain celecoxib nanoemulsion.

7. A celecoxib nanoemulsion gel patch, characterized in that: It includes a backing layer, a paste layer, and an anti-stick layer that are bonded together in sequence; The ointment layer comprises the following raw materials in weight percentages: 30%-60% celecoxib nanoemulsion as described in any one of claims 1-4, 1%-15% hydrophilic gel skeleton, 1%-15% filler, 0.5%-10% binder, 0.1%-5% crosslinking agent, 1%-15% regulator, 10%-50% glycerin, and 1%-10% water.

8. The celecoxib nanoemulsion gel patch as described in claim 7, characterized in that: The hydrophilic gel framework is one or more of the following: partially neutralized sodium polyacrylate, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and xanthan gum; The filler is one or more of silicon dioxide, kaolin, titanium dioxide, and zinc oxide; The adhesive is one or more of sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, gelatin, and povidone; The crosslinking agent is one or both of aluminum hydroxide and aluminum hydroxyl; The regulator is one or more of maleic acid, sodium tartrate, L-tartaric acid, and citric acid.

9. The celecoxib nanoemulsion gel patch as described in claim 7, characterized in that: The backing layer is non-woven fabric or rayon fabric. The anti-stick layer is anti-stick paper or plastic film.

10. The method for preparing the celecoxib nanoemulsion gel patch according to any one of claims 7-9, characterized in that: The steps include the following: 1) Mix the hydrophilic gel skeleton, filler, binder, and crosslinking agent with glycerol to obtain phase A; 2) Dissolve the regulator in water to obtain phase B; 3) Add phase B to the celecoxib nanoemulsion and mix well to obtain phase C; 4) Add phase C to phase A and stir to combine, obtaining a paste layer; 5) Apply the paste layer onto the backing layer and cover it with the non-stick layer.

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