A long-acting transdermal patch of levothyroxine sodium

Abstract

The application discloses a long-acting transdermal patch of levothyroxine sodium, and belongs to the field of pharmacy. The patch is composed of a backing layer, a drug-loaded pressure-sensitive adhesive layer and an anti-adhesion layer, and the drug-loaded pressure-sensitive adhesive layer is composed of a pressure-sensitive adhesive, levothyroxine sodium and a penetration enhancer. The patch realizes transdermal delivery of levothyroxine sodium, and levothyroxine sodium in the patch realizes long-time (2-4 days) continuous drug delivery at a suitable transdermal penetration rate, can maintain effective blood drug concentration in a relatively long time, and reduces the frequency of drug delivery. The patch has excellent stability, a high transdermal penetration amount and the characteristics of long-time continuous drug delivery, and can meet the requirement of once drug delivery per 3 days in clinic, and effectively treat hypothyroidism.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and to a transdermal drug delivery system for levothyroxine sodium salt, which is a synthetic sodium salt of tetraiodothyronine, specifically a levothyroxine sodium transdermal patch, which can be used to treat hypothyroidism. Background Technology

[0002] Hypothyroidism is a deficiency of thyroid hormones caused by insufficient secretion of thyroid hormones by thyroid follicular cells. Currently, the first-line treatment for hypothyroidism is oral levothyroxine sodium monotherapy. However, gastric pH, gastrointestinal diseases, and dietary factors such as soy have been reported to interfere with the absorption of levothyroxine sodium. The frequency and timing of L-T4 administration are more rigid and strict. Patients need to strictly control the frequency and timing of L-T4 administration, leading to poor patient adherence. These factors limit the oral route of levothyroxine. In this situation, patients urgently need a convenient and durable alternative.

[0003] Transdermal drug delivery systems (TDDS) are drug delivery systems that utilize the skin as a drug delivery route, representing the third generation of drug formulations after oral and injectable formulations. This route of administration is convenient, easy to use, and non-invasive. The use of long-acting formulations reduces the frequency of dosing, improving patient compliance. It also reduces fluctuations in blood drug concentrations, providing stable plasma levels and minimizing the possibility of overdose. Furthermore, it avoids interference from the gastrointestinal environment, such as pH, enzyme activity, drug-food interactions, and the liver's "first-pass effect," which can significantly impact drug efficacy. This dosage form precisely addresses the limitations of oral levothyroxine sodium formulations and represents a promising approach to levothyroxine sodium preparations.

[0004] In patch preparation, the type of base patch is crucial. Polyacrylate pressure-sensitive adhesive is one of the most important and widely used types of pressure-sensitive adhesives. It is widely used in patch preparation due to its excellent adhesive properties, mechanical properties, chemical stability, good drug miscibility, and advantages such as non-toxicity, harmlessness, and low cost. The simplest form of pressure-sensitive adhesive patch is the drug-eluting pressure-sensitive adhesive type, where the drug is directly dissolved or dispersed in the pressure-sensitive adhesive polymer. Drug-eluting pressure-sensitive adhesive bases provide multiple functions, including skin adhesion, drug storage, and control of drug penetration enhancer permeation rates. Furthermore, it controls the distribution of active ingredients in the stratum corneum, making it a simple and effective base type to prepare.

[0005] Due to its relatively large molecular weight, levothyroxine sodium is difficult to penetrate intact skin without any enhancement methods. Chemical penetration enhancers are an effective way to improve drug penetration through the skin, employing relatively inert chemicals to assist transdermal absorption. The mechanism of action of chemical penetration enhancers typically involves acting on the stratum corneum, thereby reducing the resistance provided by intracellular keratinocytes and intercellular lipid regions. Indirect effects include optimizing the thermodynamic activity of the drug, influencing the partition coefficient, increasing the solubility of the drug in carriers, and forming drug reservoirs in the skin.

[0006] In the treatment of hypothyroidism requiring long-term drug administration, transdermal formulations that can continuously deliver the drug to the body and reduce the frequency of administration are very useful. Therefore, this invention discloses a transdermal drug delivery formulation of levothyroxine sodium with good penetration, achieving long-term continuous release of levothyroxine sodium through the skin, overcoming the problem of variable bioavailability caused by oral administration, and better meeting the needs of clinical treatment.

[0007] Currently, there are no patents related to transdermal delivery of levothyroxine sodium, either domestically or internationally; almost all are oral formulations. An international article by Stewart SA et al. (doi:10.1016 / j.ijpharm.2021.121011.) developed a polycaprolactone-based subcutaneous implant for continuous delivery of levothyroxine. The implant was placed subcutaneously, and treatment duration could reach four weeks. Ghazi RF et al. (doi:10.5599 / admet.1317.) developed dissolving microneedles loaded with levothyroxine sodium for transdermal delivery. They established a highly efficient transdermal drug delivery system for L-T4 by using hyaluronic acid to dissolve the microneedles. The microneedles utilize a pointed needle to puncture the top layer of the skin in a minimally invasive manner to create a physical channel. However, both microneedles and subcutaneous implants rely on physical methods to enhance penetration, which can cause some damage to the skin and significantly reduce medication adherence. Summary of the Invention

[0008] The purpose of this invention is to provide a transdermal drug delivery system for levothyroxine sodium salt, which is a synthetically produced sodium salt of tetraiodothyronine, specifically a levothyroxine sodium transdermal patch.

[0009] The technical solution adopted in this invention is: a long-acting transdermal patch of levothyroxine sodium, which comprises layers arranged in the following order: a backing layer, a drug-containing pressure-sensitive adhesive layer, and an anti-adhesive layer;

[0010] Its features are:

[0011] Both the backing layer and the anti-stick layer are PET films;

[0012] The pressure-sensitive adhesive in the drug-containing pressure-sensitive adhesive layer is an acrylic pressure-sensitive adhesive; wherein the acrylic pressure-sensitive adhesive accounts for 73%-97% by weight; levothyroxine sodium accounts for 3%-12% by weight; and the penetration enhancer accounts for 0%-15% by weight.

[0013] The acrylic pressure-sensitive adhesive is selected from one of DURO-TAK 87-2287, DURO-TAK 87-2510, DURO-TAK 87-2852, DURO-TAK 87-4098, DURO-TAK 87-2051, and DURO-TAK 87-2052.

[0014] The drug-containing pressure-sensitive adhesive layer contains 1-15% by weight of a penetration enhancer, which is selected from one or a combination of isopropyl myristate, azone, oleic acid, propylene glycol, and polyglycerol fatty acid esters (IPM, NZ, OA, PG, POCC).

[0015] The in vitro permeation and release behavior of levothyroxine sodium patches are not ideal. Therefore, this invention improves the in vitro permeation effect of levothyroxine sodium patches from the perspectives of permeation and release.

[0016] The levothyroxine sodium patch prepared by this invention exhibits good stability in a pressure-sensitive adhesive matrix, with a drug loading of up to 9%, and no crystallization was observed in a one-month accelerated testing process. This achieves good solubility, release, and stability of levothyroxine sodium.

[0017] The patch of this invention has a thickness of 100 to 200 micrometers. After being applied to the skin, it can maintain good breathability and moisture permeability, thus effectively reducing skin irritation and other side effects.

[0018] This invention optimizes the patch formulation using in vitro permeation experiments to improve the transdermal penetration rate of the drug. Measurement method: An in vitro permeation experiment was conducted using a horizontal diffusion cell, with both the supply and receiving cells having a volume of 5 mL. Before the experiment, rat skin was naturally thawed at room temperature and fixed between the two chambers, with the stratum corneum facing the supply cell and the dermis facing the receiving cell. Then, a blank receiving solution was added to the receiving cell and incubated at 32±0.5℃ and 600 rpm for 30 min. Subsequently, a 40% PEG400-water-saturated solution of levothyroxine sodium was added to some of the supply cells as a control group, while the other supply cells were filled with a 40% PEG400-water-saturated solution of levothyroxine sodium containing isopropyl myristate, azone, oleic acid, propylene glycol, and polyglycerol fatty acid esters as penetration enhancers as the experimental group. Timing was started, and the in vitro transdermal permeation behavior of levothyroxine sodium was investigated. 200 μL of solution was taken from the receiving cell at 1, 3, 6, 9, 12, 24, 48 and 72 h, respectively, and an equal volume of isothermal blank receiving solution was added at the same time.

[0019] This invention optimizes the patch formulation using in vitro release experiments to improve the in vitro drug release rate. The assay method involves using a vertical diffusion cell with a receiving cell volume of 10 mL. The patch backing layer is attached to a transparent adhesive tape serving as a support, and then assembled onto the diffusion cell. The temperature is set at 32°C, and stirring is provided by a magnetic rod at 600 rpm. Sampling times are 200 μL per hour at 1 h, 3 h, 6 h, 9 h, 12 h, 24 h, and 27 h, with an equal volume and temperature of blank receiving solution (40% PEG400-aqueous solution) added.

[0020] By employing the methods described above, this invention has achieved good technical results. Using DURO-TAK 87-2852 pressure-sensitive adhesive, the cumulative penetration of levothyroxine sodium into the skin of hairless rats exceeded 22.976 μg / cm³ over 72 hours. 2 Levothyroxine sodium is stable in the patch.

[0021] This invention employs a synergistic permeation-enhancing method, increasing the cumulative permeation volume over 72 hours by 5.048 times compared to the method without a permeation enhancer. The levothyroxine sodium matrix-type transdermal patch provided by this invention has the advantages of enabling prolonged (2-4 days) continuous administration of levothyroxine sodium at an appropriate transdermal permeation rate. This maintains an effective blood drug concentration over a relatively extended period, reduces the frequency of administration, avoids the influence of other foods and medications on the absorption of levothyroxine sodium, and significantly improves patient compliance.

[0022] An acrylic pressure-sensitive adhesive matrix suitable for a levothyroxine sodium transdermal drug delivery system was screened and optimized. The matrix should have the following characteristics: levothyroxine sodium has a solubility of greater than 9% wt in the matrix, capable of carrying the dose of levothyroxine sodium required for 2-4 days of effective transdermal treatment; levothyroxine sodium can be stably present in the matrix for a long period of time; and levothyroxine sodium can be continuously released from the matrix at an appropriate transdermal rate to maintain an effective therapeutic dose for 2-4 days.

[0023] It adopts a single-layer skeleton transdermal patch structure, which is simple to prepare, easy to control in terms of quality, and relatively low in cost. Attached Figure Description

[0024] Figure 1 Release of levothyroxine sodium under the action of different permeation enhancers.

[0025] Figure 2 Release of levothyroxine sodium under different oleic acid contents.

[0026] Figure 3 Permeation of levothyroxine sodium under the action of different permeation enhancers.

[0027] Figure 4The effects of different azone concentrations on the osmotic pressure of levothyroxine sodium.

[0028] Figure 5 The effects of different oleic acid contents on the osmosis of levothyroxine sodium.

[0029] Figure 6 The permeation of levothyroxine sodium by the combined action of permeation enhancers.

[0030] Figure 7 This is a schematic diagram of the patch structure. Detailed Implementation

[0031] Example 1

[0032] Prepare levothyroxine sodium transdermal patches according to the following formulation: Accurately weigh the finely ground levothyroxine sodium and dissolve it in a small amount of ethyl acetate. Add this solution to the polyacrylate pressure-sensitive adhesive, followed by a penetration enhancer. Stir at room temperature for 2 hours to ensure homogeneity, allow to stand for 1 hour to remove air bubbles, and then apply the medicated adhesive solution onto the backing layer using a transfer coating method. Dry at 60-70℃ for 10 minutes to remove the solvent, press on a protective layer, punch and cut into patches of appropriate size, package in aluminum foil, store at room temperature, and use within one week. Conduct in vitro release experiments.

[0033]

[0034]

[0035] Example 2

[0036] Pramipexole transdermal patches were prepared using pressure-sensitive adhesives containing different functional groups. The drug crystallization was observed under a microscope in a high-temperature, high-humidity, and high-light environment to investigate the stability of pramipexole in the pressure-sensitive adhesive.

[0037]

[0038] Example 3

[0039] Levothyroxine sodium transdermal patches were prepared using pressure-sensitive adhesives containing different functional groups. The patches were placed in an accelerated testing chamber (40℃, 75%RH) and the crystallization of the drug was observed under a microscope to investigate the solubility of levothyroxine sodium in the pressure-sensitive adhesive.

[0040]

[0041]

[0042] The results from Examples 1-3 combined show that:

[0043] 1. In in vitro drug release experiments, the release rates were generally low due to the use of diffusion cells, but the release effect of DURO-TAK 2852 pressure-sensitive adhesive matrix was relatively better.

[0044] 2. The results of the influencing factor experiment show that high light conditions have little effect on the patch, while high temperature has a greater effect. Microscopic observation under the three conditions shows that only DURO-TAK 2852 did not show crystallization, while other pressure-sensitive adhesive patches showed varying degrees of crystallization within 10 days.

[0045] 3. Stability tests showed that DURO-TAK 2510, DURO-TAK 4098, DURO-TAK 2051, and DURO-TAK 2052 pressure-sensitive adhesives exhibited a small amount of crystallization on the fifth day and a larger amount of crystallization on the tenth day. Therefore, their drug loading was less than 3%. No crystallization was observed in DURO-TAK 2287 and DURO-TAK 2852, therefore, DURO-TAK 2287 and DURO-TAK 2852 meet the stability requirements.

[0046] In summary, since levothyroxine sodium is stable and has good release effect in the DURO-TAK 2852 matrix, DURO-TAK 2852 was chosen as the pressure-sensitive adhesive matrix for the patch.

[0047] Example 4

[0048] Levothyroxine sodium transdermal patches were prepared according to the specific implementation method and the following prescription, and then in vitro release and in vitro permeation experiments were conducted. The results are shown in the table below.

[0049]

[0050] The results of Example 4 show that the drug release and penetration effects are better with increasing drug loading. Higher drug loading is preferred.

[0051] Example 5

[0052] Levothyroxine sodium transdermal patches with different drug loading were prepared and placed in an accelerated testing chamber (40℃, 75%RH). The drug crystallization was observed under a microscope to investigate the drug loading of levothyroxine sodium in pressure-sensitive adhesive.

[0053]

[0054] In Example 5, only 12% of the drug loading crystallized after 30 days, indicating that the drug solubility in DURO-TAK 2852 is between 9% and 12%. The drug loading should not exceed 9%.

[0055] Drug loading was screened using Examples 4 and 5. Drug release and penetration in the patch increased with increasing drug loading. Considering crystallization, 9% wt was chosen as the drug loading, ensuring that the drug would not crystallize and precipitate in the pressure-sensitive adhesive while maintaining optimal penetration. Example 6 prepared a levothyroxine sodium transdermal patch according to the specific implementation method and the following formulation, and then conducted an in vitro release experiment. The resulting release curve is shown in the attached figure. Figure 1-2 As shown.

[0056] Patch number Types of pressure-sensitive adhesives Drug loading Types of penetration enhancers Penetration enhancer content 1-1 DURO-TAK 87-2852 3％ OA 5％ 1-2 DURO-TAK 87-2852 3％ PG 5％ 1-3 DURO-TAK 87-2852 3％ NZ 5％ 1-4 DURO-TAK 87-2852 3％ POCC 5％ 1-5 DURO-TAK 87-2852 3％ IPM 5％ 1-6 DURO-TAK 87-2852 3％ None 0 2-1 DURO-TAK 87-2852 3％ OA 3％ 2-2 DURO-TAK 87-2852 3％ OA 6％ 2-3 DURO-TAK 87-2852 3％ OA 9％ 2-4 DURO-TAK 87-2852 3％ OA 12％

[0057] Example 7

[0058] A 40% PEG400 saturated solution of levothyroxine sodium was prepared, and a permeation enhancer of the same proportion and type as in Example 6 was added. An in vitro permeation experiment was then performed, and the resulting transdermal curve is shown in the attached figure. Figure 3 As shown.

[0059] Example 8

[0060] Levothyroxine sodium transdermal patch was prepared according to the following prescription, and then an in vitro permeation experiment was performed. The resulting transdermal curve is shown in the attached figure. Figure 4-6 As shown.

[0061] Patch number Types of pressure-sensitive adhesives Drug loading Types of penetration enhancers Penetration enhancer content 3-1 DURO-TAK 87-2852 9％ NZ 1％ 3-2 DURO-TAK 87-2852 9％ NZ 2％ 3-3 DURO-TAK 87-2852 9％ NZ 3％ 3-4 DURO-TAK 87-2852 9％ None 0 4-1 DURO-TAK 87-2852 9％ OA 3％ 4-2 DURO-TAK 87-2852 9％ OA 6％ 4-3 DURO-TAK 87-2852 9％ OA 9％ 4-4 DURO-TAK 87-2852 9％ OA 12％ 5-1 DURO-TAK 87-2852 9％ OA+NZ 9％+1％

[0062] Based on a comprehensive analysis of Examples 6-8, the following conclusions can be drawn:

[0063] 1. The effects of five chemical penetration enhancers with different mechanisms on the release of L-T4 in the patch were evaluated. The effects of equal mass fractions (5%) of OA, PG, NZ, POCC, and IPM on the release enhancement of levothyroxine sodium from the pressure-sensitive adhesive matrix were investigated. Results are shown below. Figure 1 As shown, compared with the blank group (1-6), all five penetration enhancers can enhance the release effect. Among them, oleic acid has a stronger promoting effect on L-T4-PSA, OA can increase the release of L-T4 in the matrix by 1.646 times, while PG, NZ, POCC and IPM can only increase the L-T4 content by 0.960, 1.214, 1.276 and 1.15 times, respectively.

[0064] 2. Studies on the permeation enhancement effect of saturated drug solutions typically provide a better picture and eliminate interference from the patch matrix. The permeation enhancement effects of five chemical permeation enhancers with different mechanisms on L-T4 saturated solutions are shown below. Figure 3 As shown. Compared with the blank group (1-6), NZ can significantly increase the cumulative L-T4 permeation by 5.137 times, while the L-T4 permeation of the OA, PG, POCC and IPM groups increased by 1.467, 1.98, 2.615 and 0.972 times, respectively.

[0065] 3. In summary, while oleic acid has a strong release-promoting effect, its penetration-promoting effect is not good; and while azone has an excellent penetration-promoting effect, it does not improve drug release in the matrix. For the complementary processes of release and penetration, the combined use of these two compounds may greatly promote drug penetration through the skin. Therefore, we combined azone and oleic acid and conducted formulation screening, with the following results: Figure 2 , 4 5. The higher the OA content, the better the drug release effect. Figure 2 Reaching 9% seems to have hit a plateau; increasing it to 12% didn't significantly increase the release effect. As the OA content increases, the penetration effect shows a trend consistent with the release effect. Figure 5 As the NZ content increases, the penetration effect of the L-T4 patch decreases. Figure 4 Azone has a certain ability to promote drug dissolution, which may be due to the increased solubility of L-T4 in the patch matrix caused by the increased NZ content, which is not conducive to its release from the patch. Considering efficacy and skin irritation, 9% wt OA and 1% wt azone were ultimately selected for patch preparation.

[0066] 4. Results of drug penetration, such as Figure 6 As shown, the cumulative permeability of the OA+NZ group over 72 hours was 22.976 ± 3.312 μg / cm³. 2 The OA group had a concentration of 8.858 ± 0.877 μg / cm³. 2 The NZ group had a concentration of 16.107 ± 2.076 μg / cm³. 2 Compared with the use of NZ alone, the use of oleic acid alone, and the blank group, the combination of OA and NZ can significantly improve the penetration effect of L-T4 in the patch.

Claims

1. A long-acting transdermal patch for levothyroxine sodium, comprising layers arranged in the following order: a backing layer, a drug-containing pressure-sensitive adhesive layer, and an anti-adhesive layer; characterized in that: Both the backing layer and the anti-stick layer are PET films; The pressure-sensitive adhesive in the drug-containing pressure-sensitive adhesive layer is an acrylic pressure-sensitive adhesive; the acrylic pressure-sensitive adhesive accounts for 73%-97% by weight in the drug-containing pressure-sensitive adhesive layer; levothyroxine sodium accounts for 3%-12% by weight; the penetration enhancer is azone and oleic acid, wherein azone accounts for 1% by weight and oleic acid accounts for 9% by weight; The acrylic pressure-sensitive adhesive is DURO-TAK 87-2852.

2. The long-acting transdermal patch of levothyroxine sodium according to claim 1, characterized in that: The levothyroxine sodium transdermal patch can maintain an effective transdermal therapeutic dose for 2-4 days; the thickness of the patch is 100-200 micrometers.

3. The long-acting transdermal patch of levothyroxine sodium according to claim 1, characterized in that: A skeleton-type patch was prepared using a solvent method.

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