Permeation-promoting and solubilizing meloxicam transdermal patch

Abstract

The invention discloses a permeation-promoting and solubilizing meloxicam transdermal patch, and belongs to the field of pharmaceutics. The patch consists of a backing layer, a drug-loading pressure-sensitive adhesive layer and an anti-sticking layer, wherein the drug-loading pressure-sensitive adhesive layer consists of a solvent type pressure-sensitive adhesive, meloxicam, a penetration enhancer and a solubilizer. According to the patch, transdermal delivery of meloxicam is achieved, various penetration enhancers and solubilizers are systematically screened, so that meloxicam in the patch is continuously administered at a proper transdermal permeation rate, effective blood concentration can be maintained in a relatively prolonged time, the administration frequency is reduced, and the problem that the in-vitro accumulated permeation amount of the meloxicam patch is low is solved. The meloxicam patch has the characteristics of high percutaneous penetration amount and continuous administration, and is effectively used for skin administration treatment of osteoarthritis and rheumatoid arthritis.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a meloxicam topical delivery system, namely a meloxicam transdermal patch, which can be used to treat osteoarthritis and rheumatoid arthritis. Background Technology

[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) play a crucial role in the treatment of inflammation-related diseases. They exert their anti-inflammatory, analgesic, and antipyretic effects by inhibiting the activity of cyclooxygenase (COX) and thus hindering prostaglandin synthesis. Meloxicam, an enolate NSAID, possesses potent anti-inflammatory and analgesic effects and is widely used in the treatment of osteoarthritis, rheumatoid arthritis, and other diseases. Clinical studies have shown that meloxicam can effectively relieve joint pain and swelling symptoms in patients with osteoarthritis, significantly improving their quality of life.

[0003] Transdermal drug delivery systems (TDDS) are third-generation drug formulations that use the skin as a drug delivery channel, ranking only after oral and injectable formulations. They are convenient and non-invasive, reducing the frequency of administration and improving patient compliance. TDDS can stabilize plasma drug concentrations, avoiding large fluctuations in blood drug concentrations, reducing the risk of side effects and overdose, and also avoid interference from the gastrointestinal environment and the liver's "first-pass effect" on drug efficacy. They effectively address the shortcomings of existing meloxicam formulations and have great development potential.

[0004] The simplest form of pressure-sensitive adhesive patch is the drug-loaded pressure-sensitive adhesive type, where the drug is directly dissolved or dispersed in a solvent-based pressure-sensitive adhesive matrix. Drug-loaded matrices offer multiple functions, including skin adhesion, drug storage, and control of the penetration rate of drug penetration enhancers. They also control the distribution of active ingredients in the stratum corneum, making them a simple and effective matrix type.

[0005] The stratum corneum is the biggest obstacle to meloxicam's transdermal penetration; without auxiliary methods, the drug has difficulty penetrating intact skin. Chemical penetration enhancers are an effective way to improve drug penetration through the skin, utilizing relatively inert chemicals to assist in transdermal absorption. Their mechanism of action primarily involves acting on the stratum corneum, reducing the resistance generated by intracellular keratin and intercellular lipid regions. Indirect effects include optimizing the drug's thermodynamic activity, influencing the partition coefficient, increasing the drug's solubility in carriers, and forming drug reservoirs in the skin.

[0006] In the treatment of chronic disease patients requiring long-term medication, such as those with dysphagia (e.g., the elderly), transdermal patches are convenient to use (one patch daily), avoiding the inconvenience of frequent oral medication and reducing the risk of missed doses. Therefore, this invention discloses a transdermal meloxicam formulation with good penetration, achieving continuous release of meloxicam through the skin, overcoming adverse reactions such as gastrointestinal ulcers and bleeding caused by oral administration, and better meeting the needs of clinical treatment.

[0007] A meloxicam-containing topical skin patch (CN1557320A) is a basic formulation of early meloxicam transdermal patches, focusing on dosage form design and material selection. CN106924223A aims to effectively improve the transdermal permeability of meloxicam through organic salts (such as diethylamine salts). Summary of the Invention

[0008] To address the problems existing in the prior art, the purpose of this invention is to provide a meloxicam topical drug delivery system, specifically a meloxicam transdermal patch; by systematically screening penetration enhancers and solubilizers, the drug release and transdermal permeability of the patch are further optimized, significantly improving the clinical application effect.

[0009] The technical solution adopted in this invention is: a meloxicam transdermal patch that promotes penetration and solubility, the patch comprising layers arranged in the following order: a backing layer, a drug-containing pressure-sensitive adhesive layer, and an anti-adhesive layer; the backing layer and the anti-adhesive layer are both PET films;

[0010] The medicated pressure-sensitive adhesive layer contains 70%-95% solvent-based pressure-sensitive adhesive by weight; 2-15% meloxicam by weight; 2%-10% penetration enhancer by weight; and 1%-5% solubilizer by weight.

[0011] Furthermore, the penetration enhancer is selected from one or more of oleic acid, myristic acid, lauric acid, peppermint oil, propylene glycol, and carbitol.

[0012] Preferably, the penetration enhancer is either oleic acid or peppermint oil.

[0013] Preferably, the penetration enhancer uses oleic acid and peppermint oil in a mass ratio of 2:1.

[0014] Furthermore, the solubilizer is selected from propylene glycol, PEG4000, and triethyl citrate.

[0015] Preferably, the solubilizer is propylene glycol.

[0016] The transdermal patch maintains steady-state transdermal delivery for more than 24 hours; the patch has a thickness of 50 micrometers to 200 micrometers and an area of ​​20 cm². 2 ~200cm 2 .

[0017] This invention provides a meloxicam transdermal patch with enhanced penetration and solubility, which has the advantages of enabling continuous drug delivery at a suitable transdermal penetration rate. It maintains an effective blood drug concentration for a relatively prolonged period, reduces the frequency of administration, avoids the influence of other foods and medications on meloxicam absorption, and significantly improves patient compliance. Employing a single-layer DIA (Drug-in-Adhesive) transdermal patch structure, the drug is dissolved in a solvent-based pressure-sensitive adhesive. The preparation process is simple, quality is easy to control, and the cost is relatively low.

[0018] Without the use of chemical penetration enhancers, the in vitro penetration and release behavior of meloxicam patches is not ideal. Therefore, the technical feature of this invention is to improve the in vitro release and penetration effect of meloxicam patches from both the perspectives of penetration and release, so as to achieve the goal of effective percutaneous delivery of meloxicam in clinical practice.

[0019] Through the implementation of the above-mentioned series of methods, this invention has achieved significant technical results. A suitable compound penetration enhancer and solubilizer for the meloxicam transdermal drug delivery system was successfully screened and optimized. Experimental verification showed that, under this optimized formulation, the continuous cumulative penetration of meloxicam through the skin of nude mice over 24 hours reached approximately 93.29 μg / cm². Attached Figure Description

[0020] Figure 1 It is the penetration of meloxicam due to the different effects of compound penetration enhancers.

[0021] Figure 2 It is the release of meloxicam due to the effects of different compound penetration enhancers.

[0022] Figure 3 It is the penetration of meloxicam with different proportions of oleic acid and menthol oil.

[0023] Figure 4 It is the release of meloxicam from oleic acid and menthol oil in different proportions.

[0024] Figure 5 It is the permeation of meloxicam with different solubilizers.

[0025] Figure 6 This is a schematic diagram of the patch structure. Detailed Implementation

[0026] Unless otherwise specified, all percentages used in this invention are mass percentages.

[0027] A meloxicam transdermal patch with enhanced penetration and solubility comprises layers arranged in the following order: a backing layer, a drug-containing pressure-sensitive adhesive layer, and an anti-adhesive layer; wherein the backing layer and the anti-adhesive layer are both PET films; the drug-containing pressure-sensitive adhesive layer comprises 70%-95% solvent-based pressure-sensitive adhesive by weight; 2-15% meloxicam by weight; 2%-10% penetration enhancer by weight; and 1%-5% solubilizer by weight.

[0028] In some specific embodiments, the penetration enhancer is selected from one or more of oleic acid, tetradecanoic acid, lauric acid, peppermint oil, propylene glycol, and carbitol.

[0029] In some specific embodiments, the solubilizer is selected from propylene glycol, PEG4000, and triethyl citrate.

[0030] In some specific embodiments, the thickness of the patch is 50 micrometers to 200 micrometers, and the area is 20 cm². 2 ~200cm 2 .

[0031] Example 1

[0032] Prepare meloxicam transdermal patches according to the following formulation: Accurately weigh meloxicam and dissolve it in an appropriate amount of acetone. After the drug is completely dissolved, add the solubilizer and penetration enhancer in sequence, mix thoroughly, and then add a quantitative amount of solvent-based pressure-sensitive adhesive (acrylate matrix DURO-TAK 87-4098). Stir at room temperature for 2 hours, let stand for 0.5 hours to remove air bubbles, and apply the drug-containing adhesive to the backing layer using the direct coating method. Place in an oven at 50 ℃ for 20 minutes to dry and remove the solvent, cover with a protective layer, seal in aluminum foil packaging, store at room temperature, and use within one week.

[0033] Meloxicam transdermal patches were prepared using different types of penetration enhancers, and then in vitro release and in vitro permeation experiments were conducted. The results are shown in the table below.

[0034]

[0035] The following conclusions were drawn from Example 1:

[0036] The effects of three chemical penetration enhancers on the release and penetration of MLX in patches were evaluated. The effects of myristic acid, lauric acid, and oleic acid on the release and penetration enhancement of MLX in solvent-based pressure-sensitive adhesive matrices were compared. Compared with the control group (1-4), the addition of OA, myristic acid, and lauric acid increased the penetration by 8.73, 8.51, and 7.56 times, respectively, and increased the release rate by 3.91, 2.07, and 1.45 times, respectively.

[0037] Example 2

[0038] Meloxicam transdermal patches were prepared by compounding different types of penetration enhancers (the patches consist of meloxicam, penetration enhancers, and pressure-sensitive adhesive; the drug loading and the amount of penetration enhancers are shown in the table below, with the remainder being pressure-sensitive adhesive). In vitro release and in vitro permeation experiments were then conducted, and the permeation curves are shown in Figure 1 and the release curves are shown in Figure 2.

[0039]

[0040] Example 3

[0041] Meloxicam transdermal patches were prepared according to different ratios of oleic acid and menthol oil (the patches consisted of meloxicam, a penetration enhancer, and a pressure-sensitive adhesive; the drug loading and the amount of penetration enhancer are shown in the table below, with the remainder being the pressure-sensitive adhesive). In vitro release and in vitro permeation experiments were then conducted, and the resulting permeation curves are shown in the attached figure. Figure 3 As shown in Figure 4, the release curve is as follows.

[0042]

[0043] The following conclusions were drawn from Examples 2-3:

[0044] Compared with the control group (2-4), the combination of oleic acid and carbitol actually reduced the cumulative permeation over 24 hours, while the combination of oleic acid and peppermint oil, and oleic acid and propylene glycol increased the cumulative permeation over 24 hours. There was no significant difference between the two combinations. Figure 1 However, the release rates of the oleic acid and propylene glycol combination were lower than those of the control group (2-4). Figure 2 Then, the effect of the ratio of oleic acid to peppermint oil on MLX release and penetration was further screened, and the results are as follows: Figure 3 , 4 As shown, the ratio of oleic acid to peppermint oil is 2:1, resulting in the best penetration effect, with a cumulative penetration amount of 93.29 μg / cm³ over 24 hours. 2 It increases by 1.83 times compared to using oleic acid alone. Figure 3 Furthermore, using oleic acid:peppermint oil = 2:1 as a composite penetration enhancer can achieve a cumulative release rate of 37% over 8 hours. Figure 4 ).

[0045] Example 4

[0046] Meloxicam transdermal patches were prepared using different solubilizers (the patches consist of meloxicam, penetration enhancers, solubilizers, and pressure-sensitive adhesives; the drug loading and solubilizer amounts are shown in the table below; the composite penetration enhancers used were oleic acid and menthol oil, with contents of 5% and 2.5%, respectively; the remainder was pressure-sensitive adhesives), and then in vitro permeation experiments were conducted. The resulting permeation curves are shown in Figure 5.

[0047]

[0048] By analyzing Example 4, the following conclusions can be drawn:

[0049] Propylene glycol, PEG4000, and triethyl citrate were screened in equal proportions. Only propylene glycol had a slightly higher 24-hour cumulative permeation than the control group (4-4), while PEG4000 and triethyl citrate had lower permeation than the control group (4-4).

[0050] This invention optimizes the patch formulation through in vitro release and permeation experiments, thereby improving the in vitro drug release and permeation rates. The in vitro release experiment used a vertical diffusion cell with a 10 mL receiving chamber. The patch backing layer, supported by adhesive tape, was placed on the diffusion cell. The temperature was 32°C, and the stirring speed was 600 rpm. 200 μL samples were collected at multiple time points (0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h), and blank receiving solution (medium: PBS 8.0) was added. The in vitro permeation experiment also used a vertical diffusion cell with a 10 mL receiving chamber. The patch backing layer was attached to nude mouse skin and then placed on the diffusion cell. The conditions were the same as the release experiment. 200 μL samples were collected at multiple time points (2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h), and blank receiving solution (medium: 20% ethanol-PBS 8.0) was added.

[0051] The above embodiments are only used to illustrate the present invention. Any equivalent transformations and improvements made on the basis of the technical solutions of the present invention should not be excluded from the protection scope of the present invention.

Claims

1. A meloxicam transdermal patch that promotes penetration and solubility, characterized in that, The patch comprises layers arranged in the following order: a backing layer, a medicated pressure-sensitive adhesive layer, and a release layer; both the backing layer and the release layer are PET films. The drug-containing pressure-sensitive adhesive layer comprises 70%-95% solvent-based pressure-sensitive adhesive by weight; 2-15% meloxicam by weight; 2%-10% penetration enhancer by weight; and 1%-5% solubilizer by weight.

2. The transdermal patch according to claim 1, characterized in that: The penetration enhancer is selected from one or more of oleic acid, tetradecanoic acid, lauric acid, peppermint oil, propylene glycol, and carbitol.

3. The transdermal patch according to claim 2, characterized in that: The penetration enhancer is either oleic acid or peppermint oil.

4. The transdermal patch according to claim 3, characterized in that: The penetration enhancer uses oleic acid and peppermint oil in a mass ratio of 2:

1.

5. The transdermal patch according to claim 4, characterized in that: The solubilizer is selected from propylene glycol, PEG4000, and triethyl citrate.

6. The transdermal patch according to claim 5, characterized in that: The solubilizer is propylene glycol.

7. The transdermal patch according to any one of claims 1-6, characterized in that: The transdermal patch maintains steady-state transdermal delivery for more than 24 hours; the patch has a thickness of 50 micrometers to 200 micrometers and an area of ​​20 cm². 2 ~200cm 2 .

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