Celecoxib cream and preparation method thereof

Abstract

The present invention provides a celecoxib cream and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations, the celecoxib cream comprises, by mass, 0.5%-2% of celecoxib, 1%-20% of an oily matrix, 1%-20% of an emulsifier, 0.1%-10% of a transdermal absorption enhancer, 1%-20% of a thickener, 2%-15% of a humectant, 0.1%-2% of a preservative, 0.1%-10% of a pH regulator, and the balance of deionized water. The prepared celecoxib cream is good in stability and high in bioavailability, and gastrointestinal reaction and oral first pass effect of a traditional oral dosage form are avoided. The celecoxib cream disclosed by the invention is also added with a transdermal absorption enhancer, so that medicine molecules can be helped to penetrate through a skin barrier and directly reach a focus part; the metabolism loss of the medicine on the skin surface can be reduced, more active ingredients enter blood circulation or deep tissues, the local treatment effect is enhanced, and the important clinical value is achieved.

Description

Technical Field

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

[0002] Celecoxib is a novel nonsteroidal anti-inflammatory drug (NSAID) with an affinity for cyclooxygenase-2 (COX-2) approximately 10-20 times higher than that for COX-1. It blocks the synthesis of prostaglandins (mainly PGE2) at the site of inflammation, thereby exerting anti-inflammatory, analgesic, and antipyretic effects. Clinically, it is primarily used for osteoarthritis and rheumatoid arthritis, and can also be used for peripheral and central analgesia. Compared to non-selective COX inhibitors, celecoxib has the same analgesic effect, but causes less damage to the gastrointestinal mucosa and has relatively manageable cardiovascular risks, making it a promising candidate for use in chronic inflammatory diseases.

[0003] Currently, oral formulations are predominantly used in clinical practice. However, celecoxib has significant physicochemical drawbacks: low molecular polarity and extremely poor water solubility (<10 μg / mL), classifying it as a poorly soluble drug. This results in large fluctuations in oral bioavailability and necessitates frequent dosing to maintain effective blood concentrations. Furthermore, although its gastrointestinal toxicity is relatively mild, long-term oral administration may still cause indigestion, ulcers, and even cardiovascular events. In addition, the significant first-pass effect and heavy hepatic metabolic burden limit its long-term safety and adherence. Therefore, developing new topical formulations of celecoxib to avoid gastrointestinal reactions and the first-pass effect of oral administration, while enhancing efficacy, has significant clinical value. Summary of the Invention

[0004] In view of the technical problems existing in the background art, this application provides a celecoxib cream and its preparation method, aiming to solve the technical problem that oral celecoxib may cause gastrointestinal reactions and first-pass effect.

[0005] In a first aspect, embodiments of this application provide a celecoxib cream, comprising, by mass fraction, 0.5% to 2% celecoxib, 1% to 20% oily matrix, 1% to 20% emulsifier, 0.1% to 10% transdermal absorption enhancer, 1% to 20% thickener, 2% to 15% moisturizer, 0.1% to 2% preservative, 0.1% to 10% pH adjuster, with the balance being deionized water.

[0006] Secondly, embodiments of this application provide a method for preparing celecoxib cream, comprising the following steps: S1. Mix the oily matrix, thickener, preservative and transdermal absorption enhancer at 50~90 ℃ to obtain the oil phase; mix the emulsifier, moisturizer, pH adjuster and deionized water at 40~80 ℃ to obtain the aqueous phase; S2. Celecoxib is added to the oil phase and then homogenized to obtain the celecoxib dispersed phase. S3. Under shear conditions, the celecoxib dispersion phase is added dropwise to the aqueous phase, followed by homogenization to obtain an ointment.

[0007] The advantages of this application, which differ from existing technical solutions, include: Celecoxib is a poorly soluble drug, difficult to completely dissolve in the aqueous matrix of gels. This invention, however, effectively dissolves celecoxib in the oily matrix of creams to improve its bioavailability. This invention also includes a transdermal absorption enhancer, such as lauryl acetonide, which can temporarily increase intercellular permeability by interfering with the lipid arrangement of the stratum corneum, helping drug molecules penetrate the skin barrier and reach the lesion site directly. It can also reduce metabolic loss of the drug on the skin surface, allowing more active ingredients to enter the bloodstream or deeper tissues, enhancing the local therapeutic effect.

[0008] The celecoxib cream provided by this invention exhibits good stability. This formulation improves transdermal absorption efficiency and has high bioavailability, making it suitable for the local treatment of osteoarthritis and rheumatoid arthritis. This cream, administered topically, avoids the significant gastrointestinal reactions and first-pass effects of existing oral formulations, as well as the potential for toxic side effects from systemic exposure. Both safety and patient compliance are significantly improved. Furthermore, the dosage ratio allows for considerable adjustment, which is more conducive to industrial production.

[0009] The above description is only an overview of the technical solution of this application. In order to better understand the technical means of this application and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of this application more obvious and understandable, the following are specific embodiments of this application. Attached Figure Description

[0010] To more clearly illustrate the technical solutions of this application, the accompanying drawings used in this application will be briefly described below. Obviously, the drawings described below are merely some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without any creative effort.

[0011] Figure 1 This is a graph showing the cumulative in vitro drug release of the celecoxib cream prepared in Examples 1-2 of the present invention.

[0012] Figure 2 This is a transdermal penetration diagram of the celecoxib cream prepared in Examples 1-2 of the present invention.

[0013] Figure 3 The flow curve of the celecoxib cream prepared in Example 2 of this invention is shown.

[0014] Figure 4 The scan frequency diagram is for the celecoxib cream prepared in Example 2 of the present invention. Detailed Implementation

[0015] The embodiments of the technical solution of this application will now be described in detail with reference to the accompanying drawings. These embodiments are only used to more clearly illustrate the technical solution of this application and are therefore merely examples, and should not be used to limit the scope of protection of this application.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains; the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the application; the terms “comprising” and “having”, and any variations thereof, in the specification, claims, and foregoing description of the drawings are intended to cover non-exclusive inclusion.

[0017] To address the technical issues of potential gastrointestinal reactions and first-pass effects associated with oral celecoxib, this application provides a celecoxib cream and its preparation method. In this invention, celecoxib is well dissolved in the oily matrix of the cream to improve its bioavailability.

[0018] In a first aspect, embodiments of this application provide a celecoxib cream, comprising, by mass fraction, 0.5% to 2% celecoxib, 1% to 20% oily matrix, 1% to 20% emulsifier, 0.1% to 10% transdermal absorption enhancer, 1% to 20% thickener, 2% to 15% moisturizer, 0.1% to 2% preservative, 0.1% to 10% pH adjuster, with the balance being deionized water.

[0019] Furthermore, in some embodiments, the oily matrix includes one or more of lanolin, beeswax, peanut oil, olive oil, petrolatum, paraffin wax, liquid paraffin, lanolin alcohol, cholesterol, glyceryl stearate, and isopropyl palmitate. Preferably, the oily matrix is ​​white petrolatum and light liquid paraffin, preferably in a mass ratio of 1:1.

[0020] Furthermore, in some embodiments, the emulsifier includes one or more of sodium / potassium stearate, Tween, sodium lauryl sulfate, phospholipids, methylcellulose, sodium carboxymethylcellulose, glyceryl monostearate, carbomer, and cholesterol. Preferably, the emulsifier is carbomer and sodium lauryl sulfate.

[0021] Furthermore, in some embodiments, the transdermal absorption enhancer includes one or more of lauryl benzoate, oleic acid, sodium lauryl sulfate, ethanol, urea, menthol, and eucalyptus oil. Preferably, the transdermal absorption enhancer is lauryl benzoate.

[0022] Furthermore, in some embodiments, the thickener includes one or more of cetearyl alcohol, xanthan gum, and hydroxypropyl methylcellulose. Preferably, the thickener is cetearyl alcohol.

[0023] Furthermore, in some embodiments, the moisturizer includes one or more of glycerin, hyaluronic acid, propylene glycol, and sorbitol. Preferably, the moisturizer is propylene glycol.

[0024] Furthermore, in some embodiments, the preservative is selected from one or more of methylparaben, ethylparaben, benzalkonium chloride, benzoic acid, tea tree oil, and thymol. Preferably, the preservative is methylparaben.

[0025] Furthermore, in some embodiments, the pH adjuster includes triethanolamine or sodium hydroxide. Preferably, the pH adjuster is triethanolamine.

[0026] Secondly, embodiments of this application provide a method for preparing celecoxib cream, comprising the following steps: S1. Mix the oily matrix, thickener, preservative and transdermal absorption enhancer at 50~90 ℃ to obtain the oil phase; mix the emulsifier, moisturizer, pH adjuster and deionized water at 40~80 ℃ to obtain the aqueous phase; S2. Celecoxib is added to the oil phase and then homogenized to obtain the celecoxib dispersed phase. S3. Under shear conditions, the celecoxib dispersion phase is added dropwise to the aqueous phase, followed by homogenization to obtain an ointment.

[0027] Furthermore, in some embodiments, the homogenization pressure is 6~15 MPa, the homogenization time is 15~30 min, and the homogenization speed is 500~2000 rpm.

[0028] The following are some specific embodiments. It should be noted that the embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0029] I. Preparation Method Example 1 A celecoxib cream is composed of the following components: celecoxib 2.00 g, carbomer 1.20 g, sodium lauryl sulfate 16.00 g, white petrolatum 10.00 g, cetearyl alcohol 20.00 g, light liquid paraffin 10.00 g, propylene glycol 12.00 g, lauryl benzoate 2.00 g, methylparaben 1.00 g, triethanolamine 2.80 g, and deionized water 123.00 g.

[0030] The preparation method of the above-mentioned celecoxib cream includes the following steps: (1) Preparation of oil phase: Weigh the prescribed amount of white petrolatum, light liquid paraffin, cetearyl alcohol, methylparaben and lauryl acetone into a beaker, and then put the beaker into a 75 ℃ constant temperature water bath for heating.

[0031] (2) Preparation of aqueous phase: Weigh the prescribed amounts of sodium dodecyl sulfate, carbomer, propylene glycol, triethanolamine and deionized water into a beaker, and then place the beaker in a 75 ℃ constant temperature water bath for heating.

[0032] (3) Cream preparation: After the oil and aqueous phases have stabilized at their temperatures, the prescribed amount of celecoxib is added to the oil phase. The homogenizer is stirred at 2000 rpm for 5-10 min. After the active pharmaceutical ingredient is evenly dispersed, the mixture is stirred continuously for 15 min. The oil phase is then added dropwise to the aqueous phase. The homogenizer speed is then reduced to 1000 rpm, and the mixture is stirred for 5 min. Finally, the homogenizer speed is further reduced to 500 rpm, and the mixture is stirred for 5 min. The beaker is removed, and the temperature is allowed to drop to room temperature to obtain the celecoxib cream. The prepared celecoxib cream has a white, viscous, milky, semi-solid appearance.

[0033] Example 2 A celecoxib cream was prepared under the same conditions as in Example 1, except that the amount of cetearyl alcohol was reduced to 18.00 g and the amount of laurocapram was increased to 4.00 g. The celecoxib cream was white, viscous, milky, and semi-solid.

[0034] The celecoxib cream prepared in Examples 1 and 2 has a pH of 6-7.

[0035] Comparative Example 1 A celecoxib cream, with all other conditions the same as in Example 1, except that laurocapram is not added.

[0036] II. Analysis of Test Results for Each Embodiment and Comparative Example The celecoxib creams prepared in Examples 1 and 2 were subjected to in vitro release experiments. High-performance liquid chromatography (HPLC) was used to detect the drug concentration, and the release rate of the active ingredient celecoxib over 24 hours was calculated. The results are as follows: Figure 1 As shown, the creams prepared in Examples 1 and 2 can both achieve sustained drug release and have a sustained-release effect, with Example 2 having a faster release rate.

[0037] The celecoxib creams prepared in Examples 1 and 2 and Comparative Example 1 were subjected to in vitro transdermal diffusion experiments on a fully automated transdermal diffusion system. The results of the celecoxib transdermal penetration were as follows: Figure 2 It can be seen that after adding the transdermal absorption enhancer lauryl ketone, the creams prepared in Examples 1 and 2 both showed good transdermal effects.

[0038] The celecoxib cream prepared under the conditions of Example 2 was subjected to rheological testing, and the obtained rheological curves are shown below. Figure 3 As shown, this indicates that the cream conforms to the rheological characteristics of a pseudoplastic fluid; the obtained frequency scan curve is shown in Figure 1. Figure 4 As shown, this indicates that the cream is easy to apply and has good storage stability.

[0039] It should be noted that this application is not limited to the above-described embodiments. The above embodiments are merely examples, and any embodiments with the same structure and effect as the technical concept within the scope of this application are included in the technical scope of this application. Furthermore, various modifications that can be conceived by those skilled in the art to the embodiments, and other ways of constructing by combining some of the constituent elements of the embodiments, without departing from the spirit of this application, are also included in the scope of this application.

Claims

1. A celiac cream characterized by, The cream includes celecoxib 0.5% to 2% by mass fraction, an oily base 1% to 20%, an emulsifier 1% to 20%, a transdermal absorption enhancer 0.1% to 10%, a thickening agent 1% to 20%, a humectant 2% to 15%, a preservative 0.1% to 2%, a pH adjuster 0.1% to 10%, and the balance being deionized water.

2. The celecoxib cream according to claim 1, wherein The oily base includes one or more of lanolin, beeswax, peanut oil, olive oil, vaseline, paraffin, liquid paraffin, lanolin alcohol, cholesterol, glyceryl stearate, and isopropyl palmitate.

3. The celecoxib cream according to claim 1, wherein The emulsifier includes one or more of sodium / potassium stearate, Tween, sodium lauryl sulfate, phospholipids, methyl cellulose, sodium carboxymethyl cellulose, glyceryl monostearate, carbomer, and cholesterol.

4. The celecoxib cream according to claim 1, wherein The transdermal absorption enhancer includes one or more of laurazidone, oleic acid, sodium lauryl sulfate, ethanol, urea, menthol, and eucalyptus oil.

5. The celecoxib cream according to claim 1, wherein The thickening agent includes one or more of cetearyl alcohol, xanthan gum, and hydroxypropyl methyl cellulose.

6. The celecoxib cream according to claim 1, wherein The humectant includes one or more of glycerol, hyaluronic acid, propylene glycol, and sorbitol.

7. The celecoxib cream according to claim 1, wherein The preservative is selected from one or more of methyl paraben, ethyl paraben, benzalkonium chloride, benzoic acid, tea tree oil, and thymol.

8. The celecoxib cream according to claim 1, wherein The pH adjuster includes triethanolamine or sodium hydroxide.

9. A process for preparing the celecoxib cream according to any one of claims 1 to 8, characterized by, The method includes the following steps: S1, mixing the oily base, the thickening agent, the preservative, and the transdermal absorption enhancer at 50 to 90 ℃ to obtain an oil phase; mixing the emulsifier, the humectant, the pH adjuster, and deionized water at 40 to 80 ℃ to obtain an aqueous phase; S2, adding the celecoxib to the oil phase, and then homogenizing to obtain a celecoxib dispersion phase; S3, dropwise adding the celecoxib dispersion phase to the aqueous phase under shearing, and then homogenizing to obtain the cream.

10. The method of preparing the celecoxib cream according to claim 9, characterized in that, The homogenization pressure is 6 to 15 Mpa, the homogenization time is 15 to 30 min, and the homogenization speed is 500 to 2000 rpm.

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