Melobalain transdermal delivery preparation

Abstract

The invention relates to a milobain transdermal delivery preparation which comprises the following components in percentage by weight: 8-12% of milobain or benzene sulfonate thereof (in terms of free alkali), 40-60% of an acrylic acid pressure-sensitive adhesive matrix, 8-12% of a polyvinylpyrrolidone crystal inhibitor, 9-22% of a solubilizer composition and 9-22% of a penetration enhancer composition, and the sum of the components is 100%. The preferable prescription of the transdermal drug delivery preparation has the following beneficial effects: (1) the crylic acid pressure-sensitive adhesive matrix is used as a drug carrying basis, and the crystal inhibitor is combined to effectively inhibit drug crystallization and separation, so that the long-term physical stability and uniformity of the preparation are ensured; (2) the solubilizing composition cooperates with the crystal inhibitor to maintain the supersaturated state of the medicine, so that the dissolving bottleneck of the miloabalin is overcome, and a foundation is laid for efficient transdermal release; (3) the penetration enhancer composition significantly improves the cumulative release rate, and shows excellent and stable penetration enhancing effect and long-acting release characteristic when being matched with different solubilizers; and (4) the adhesive force is moderate: the adhesive force of the preferable prescription is 9-14N, so that the adhesive strength and the comfort can be balanced, and the requirements of skin patches are met.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and specifically relates to a transdermal drug delivery formulation of melobalin. Background Technology

[0002] Mirogabalin Besilate was first approved for marketing in Japan by Daiichi Sankyo Co., Ltd. in January 2019, under the brand name Tarlige. ® It is used to treat diabetic peripheral neuropathy (DPNP), postherpetic neuralgia (PHN), and pain associated with peripheral nervous system disorders. It was approved by the China National Medical Products Administration (NMPA) in June 2024 under the brand name Delijing. ® It is currently only approved for use in adults with diabetic peripheral neuropathic pain.

[0003] Merobalin besylate is currently only available in oral tablet form, including regular film-coated tablets (2.5 mg, 5 mg, 10 mg, 15 mg) and orally disintegrating tablets (OD tablets). Current dosing regimens require gradual dose titration (starting at 5 mg twice daily, up to a maximum of 15 mg twice daily). However, neuropathic pain is characterized by a long course, often exceeding 3 months, and frequent administration of existing formulations leads to poor patient compliance. Common adverse reactions are central nervous system reactions, including drowsiness, dizziness, and peripheral edema, with the incidence of adverse reactions increasing significantly with increasing dosage.

[0004] As a transdermal drug delivery system, transdermal patches allow the active ingredients to be slowly absorbed into the systemic circulation through the skin, which can prolong the duration of drug action, reduce the frequency of administration, and avoid the peak-and-trough phenomenon of blood drug concentration common in oral administration, thus maintaining a more stable blood drug concentration and reducing the risk of dose-related adverse reactions.

[0005] Developing melobalin besylate oral tablets into a transdermal patch has the potential to improve patient compliance, reduce systemic adverse reactions, and facilitate dose adjustment; however, this transformation also faces key technical challenges such as matrix compatibility, solubility, and supersaturation stability. Summary of the Invention

[0006] The purpose of this invention is to provide a transdermal drug delivery formulation of milobalin with stable drug release properties, comprising:

[0007] (a) The active ingredient, wherein the active ingredient is milobalin or a pharmaceutically acceptable salt thereof;

[0008] (b) Acrylic pressure-sensitive adhesive matrix;

[0009] (c) A crystal inhibitor, wherein the crystal inhibitor is polyvinylpyrrolidone;

[0010] (d) Solubilizing composition;

[0011] (e) Penetration enhancer composition;

[0012] The sum of the components of the preparation is 100%.

[0013] In a preferred embodiment of the present invention, the pharmaceutically acceptable salt is selected from at least one of hydrochloride, hydrobromide, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, acetate, oxalate, malonate, valerate, glutamate, oleate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, hydroxyethylsulfonate, fumarate, maleate, malate, tartrate, benzoate, bis(hydroxynaphthyl)ate, salicylate, vanillate, mandelate, succinate, gluconate, and lactose, preferably benzenesulfonate.

[0014] In a preferred embodiment of the present invention, the active ingredient accounts for 1-15% (w / w) of the total weight of the formulation, preferably 5-15% (w / w), and more preferably 8-12% (w / w), based on free alkali.

[0015] In a preferred embodiment of the present invention, the acrylate pressure-sensitive adhesive is selected from copolymers containing 2-ethylhexyl acrylate; preferably one or more of DURO-TAK 2287, DURO-TAK 4098, DURO-TAK 2510, DURO-TAK 2516, DURO-TAK 2074, and DURO-TAK 2677; more preferably one or more of DURO-TAK 387-2287, DURO-TAK 87-4098, DURO-TAK 387-2516, DURO-TAK 87-2074, DURO-TAK 87-2677, DURO-TAK 387-2510, or DURO-TAK 87-2510.

[0016] In a preferred embodiment of the present invention, the acrylate pressure-sensitive adhesive accounts for 40-60% (w / w) of the total weight of the formulation, preferably 45-55% (w / w).

[0017] In a preferred embodiment of the present invention, the crystallization inhibitor is polyvinylpyrrolidone, and the polyvinylpyrrolidone is at least one of polyvinylpyrrolidone K90 and polyvinylpyrrolidone K30.

[0018] In a preferred embodiment of the present invention, the crystal inhibitor accounts for 5-15% (w / w) of the total weight of the formulation, preferably 8-12% (w / w).

[0019] In a preferred embodiment of the present invention, the solubilizing composition is selected from at least one of propylene glycol, polyethylene glycol glycerol caprylate, diethylene glycol monoethyl ether, or polyethylene glycol 400, preferably at least one of propylene glycol and polyethylene glycol glycerol caprylate.

[0020] In a preferred embodiment of the present invention, the solubilizing composition accounts for 5-25% (w / w) of the total weight of the formulation.

[0021] In a preferred embodiment of the present invention, the solubilizing composition comprises 9-22% (w / w) of the total weight of the formulation and is selected from one of the following:

[0022] (i) 5-15% (w / w) of propylene glycol;

[0023] (ii) 5-15% (w / w) of caprylic / capric glyceride polyethylene glycol ester;

[0024] (iii) A combination of 5-15% (w / w) propylene glycol and 5-15% caprylic / capric glyceride polyethylene glycol ester.

[0025] In a preferred embodiment of the present invention, the penetration enhancer composition is selected from at least one of oleyl alcohol, isopropyl myristate, lauryl ketone, propylene glycol monocaprylate, and diethylene glycol monoethyl ether, preferably at least one of lauryl ketone and propylene glycol monocaprylate.

[0026] In a preferred embodiment of the present invention, the penetration enhancer composition accounts for 5-25% (w / w) of the total weight of the formulation.

[0027] In a preferred embodiment of the present invention, the penetration enhancer composition accounts for 9-22% (w / w) of the total weight of the formulation and is selected from one of the following:

[0028] (i) 5-15% (w / w) lauryl azone;

[0029] (ii) 5-15% (w / w) propylene glycol monooctanoate;

[0030] (iii) A combination of 5-15% (w / w) laurocaptan and 5-15% propylene glycol monooctanoate.

[0031] In a preferred embodiment of the present invention, the transdermal drug delivery formulation further comprises a preservative selected from at least one of phenoxyethanol, methylparaben, methylisothiazolinone, methylparaben, methylparaben, ethylparaben, propylparaben, sodium benzoate, potassium sorbate, benzoic acid or its salt, sorbic acid or its salt, p-hydroxybenzoate, sodium metabisulfite, chlorhexidine, sodium citrate, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, ethylenediaminetetraacetic acid, propyl gallate, and quaternary ammonium compounds.

[0032] In a preferred embodiment of the present invention, the transdermal drug delivery formulation further contains an antioxidant selected from at least one of sodium bisulfite, tert-butyl-p-cresol, sodium metabisulfite, vitamin E, disodium EDTA, vitamin C, and glutathione.

[0033] In a preferred embodiment of the present invention, the transdermal drug delivery formulation does not contain ethanol solvent.

[0034] In a preferred embodiment of the present invention, the transdermal drug delivery formulation is a patch or a gel.

[0035] In a preferred embodiment of the present invention, the transdermal drug delivery formulation comprises:

[0036] (a) The active ingredient, which is milobalin or a pharmaceutically acceptable salt thereof, comprising 8-12% (w / w) of the total weight of the formulation as a free base;

[0037] (b) An acrylic pressure-sensitive adhesive matrix, wherein the acrylic pressure-sensitive adhesive matrix is ​​selected from copolymers containing 2-ethylhexyl acrylate, preferably DURO-TAK 87-2074; and comprises 40-60% (w / w) of the total weight of the formulation, preferably 45-55% (w / w);

[0038] (c) A crystallization inhibitor, wherein the crystallization inhibitor is polyvinylpyrrolidone, wherein the polyvinylpyrrolidone is at least one of povidone K90 and povidone K30, and accounts for 5-15% (w / w) of the total weight of the formulation, preferably 8-12%;

[0039] (d) A solubilizing composition comprising 9-22% (w / w) of the total weight of the formulation and selected from one of the following:

[0040] (i) 5-15% (w / w) of propylene glycol;

[0041] (ii) 5-15% (w / w) of caprylic / capric glyceride polyethylene glycol ester;

[0042] (iii) A combination of 5-15% (w / w) propylene glycol and 5-15% caprylic / capric glyceride polyethylene glycol ester;

[0043] (e) A penetration enhancer composition comprising 9-22% (w / w) of the total weight of the formulation and selected from one of the following:

[0044] (i) 5-15% (w / w) lauryl azone;

[0045] (ii) 5-15% (w / w) propylene glycol monooctanoate;

[0046] (iii) A combination of 5-15% (w / w) laurocaptan and 5-15% propylene glycol monooctanoate

[0047] The sum of the components of the preparation is 100%.

[0048] Compared with the prior art, the present invention has the following beneficial technical effects:

[0049] The preferred formulation of the transdermal drug delivery system provided by this invention significantly improves formulation performance through the following synergistic effects:

[0050] (1) Using acrylic pressure-sensitive adhesive matrix as the drug carrier, combined with the crystallization inhibitor polyvinylpyrrolidone, the drug crystallization is effectively inhibited, ensuring the long-term physical stability and uniformity of the formulation.

[0051] (2) The solubilizing composition enhances the solubility of the drug in a hydrophobic matrix, and works synergistically with the crystallization inhibitor polyvinylpyrrolidone to maintain the drug in a supersaturated state, thus overcoming the dissolution bottleneck of milobalin and laying the foundation for efficient transdermal release.

[0052] (3) The permeation enhancer composition significantly increases the cumulative permeation of the drug through the skin. When combined with different solubilizers, it exhibits excellent and stable permeation enhancement effects and long-lasting release characteristics. The permeation increase in 24 to 48 hours exceeds 11 μg / cm².

[0053] (4) Moderate adhesion: The preferred formulation of this invention has an adhesion force between 9-14N, which can balance adhesion strength and comfort and meet the requirements of skin patches. Detailed Implementation

[0054] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0055] Example 1: Solubility Experiment

[0056] Weigh out milobalin besylate and add it to 25-50 mL of the solvent shown in Table 1 at a constant temperature of 25℃±2℃. Shake vigorously for 30 seconds every 5 minutes. Observe continuously for 30 minutes. If the solution remains clear and transparent and there are no visible insoluble substances, it is considered to be completely dissolved.

[0057] Table 1

[0058]

[0059] As shown in Table 1, ethanol, propylene glycol, diethylene glycol monoethyl ether, and polyethylene glycol 400 exhibit the best solubility for milobalin p-benzenesulfonate (easily soluble), followed by PEG-3-caprylate (soluble), while ethyl acetate (almost insoluble), isopropyl myristate (almost insoluble), lauryl acetone (slightly soluble), and glycerol (slightly soluble) show poor solubility. Therefore, ethanol can be chosen as the solvent to dissolve the active pharmaceutical ingredient, and one or more of propylene glycol, PEG-3-caprylate, diethylene glycol monoethyl ether, or polyethylene glycol 400 can be chosen as the solubilizer.

[0060] Example 2: Investigation of different types of pressure-sensitive adhesives

[0061] The effect of different acrylic pressure-sensitive adhesive types on the stability of transdermal patches containing 5% milobalin was investigated.

[0062] Experimental Procedure: The active pharmaceutical ingredient (API) was dissolved in anhydrous ethanol and mixed thoroughly with different types of acrylate pressure-sensitive adhesive matrix as shown in Table 2. The mixture was then coated onto the surface of the backing material, dried to remove the anhydrous ethanol, thus obtaining the milobalin transdermal patch. Subsequently, the presence of drug crystal precipitation was observed using a polarizing microscope.

[0063] Table 2

[0064]

[0065] Pressure-sensitive adhesive model 87-2074 showed the best performance in inhibiting crystallization, with only a very small amount of crystallization, indicating optimal compatibility with the API and effective maintenance of drug stability. Models 87-4098 and 87-2054 both exhibited a small amount of crystallization and can be considered as alternatives, but require the use of a crystallization inhibitor. Model 87-2287 exhibited a large amount of crystallization, indicating poor compatibility and making it unsuitable for this API patch system.

[0066] Example 3: Investigation of different crystal inhibitors

[0067] Experimental Procedure: The active pharmaceutical ingredient (API) was dissolved in anhydrous ethanol, and then acrylate pressure-sensitive adhesive was added and mixed thoroughly. Subsequently, different types of crystal inhibitors (as shown in Table 3) were added and stirred until dissolved (or uniformly dispersed). The uniformly mixed drug adhesive was coated onto the surface of the backing material, and after drying to remove the anhydrous ethanol, milobalin transdermal patches were obtained. The drug crystal precipitation in each patch was observed using a polarizing microscope.

[0068] Table 3

[0069]

[0070] Both povidone K90 and K30 completely inhibited crystallization, demonstrating their high compatibility with the 87-2074 pressure-sensitive adhesive system. While EPO was compatible with the system, it failed to effectively inhibit crystallization (crystallization occurred after one month of accelerated crystallization). EPO L100 was incompatible with the system, indicating it was fundamentally unsuitable as a crystallization inhibitor in this system. Povidone-based crystallization inhibitors (K90 and K30) performed excellently in the 87-2074 pressure-sensitive adhesive system, while EPO-based inhibitors (especially L100) were unsuitable.

[0071] Example 4: Screening of penetration enhancers

[0072] Skin permeability test method

[0073] Experimental Methods: Transdermal tests were conducted using a Franz diffusion cell with Bama miniature pig skin and a water bath temperature of 32℃. The stirring speed was 600 rpm, the transdermal area was 1.76 cm², the receiving cell volume was 7 ml, and the receiving solution was physiological saline. Patches of formulations 15-20 were adhered to the stratum corneum of the skin, ensuring close contact between the dermis and the receiving medium, and fixed to the receiving cell. 5 mL samples were taken periodically, and blank receiving solution at 32℃ was added. The sampled receiving solutions were analyzed for drug concentration using high-performance liquid chromatography (HPLC).

[0074] Table 4

[0075]

[0076] The results showed that without the penetration enhancer (Formula 15), the in vitro permeation volume was less than 8.5 μg / cm² in 24 hours, while the addition of an effective penetration enhancer could increase the permeation volume by 2.5 to 7.5 times. Among them, laurocaptan (Formula 18) performed best, with an in vitro permeation rate of 61.595 μg / cm² in 24 hours, significantly improving the transdermal efficiency of the drug; propylene glycol monocaprylate (Formula 19) was the second best choice, with an in vitro permeation rate of 48.578 μg / cm² in 24 hours; oleyl alcohol (Formula 16) had an in vitro permeation rate of 38.294 μg / cm² in 24 hours, which was effective but weaker than laurocaptan; isopropyl myristate (Formula 17) had an in vitro permeation rate of 20.947 μg / cm² in 24 hours, with limited effect (only 153% higher than without a permeation enhancer); while diethylene glycol monoethyl ether (Formula 20) also had a permeation rate of less than 8.5 μg / cm², indicating that diethylene glycol monoethyl ether had no permeation-enhancing effect.

[0077] Example 5: Preparation of Miloebarine transdermal patches with different formulations

[0078] The preparation process is as follows:

[0079] The active pharmaceutical ingredient (API) is dissolved in anhydrous ethanol, and then a solubilizer (propylene glycol and / or polyethylene glycol glycerol caprylate), a penetration enhancer (laurocaptanone and / or propylene glycol monocaprylate), and an acrylate pressure-sensitive adhesive are added sequentially and mixed thoroughly. Subsequently, a crystallization inhibitor (PVPK90) is added and stirred until completely dissolved or uniformly dispersed. The resulting mixed adhesive is then coated onto the surface of a backing material. After drying to remove the solvent, the milobalin transdermal patch is obtained.

[0080] Table 5

[0081]

[0082] Example 6

[0083] The in vitro release of milobalin transdermal patches with different formulations in Example 5 was investigated.

[0084] In vitro release rates were determined using a Franz diffusion cell apparatus, and the experimental parameters are as follows:

[0085] Artificial membrane material: Polyethersulfone membrane (PES, pore size 0.45 μm)

[0086] Water bath temperature: 32℃

[0087] Mixing speed: 600 rpm

[0088] Effective release area: 1.76 cm²

[0089] Receiver volume: 7 mL

[0090] Receiving medium: physiological saline solution

[0091] Sample patches (numbered S-250501 to S-250506) were fixed onto the surface of a polyethersulfone membrane and assembled into a receiving cell system. At preset time points, 5 mL of the receiving liquid was collected, and an equal volume of pre-warmed blank receiving medium at 32°C was added simultaneously. The samples were analyzed for drug content using high-performance liquid chromatography (HPLC), and the results are shown in Table 6.

[0092] Liquid phase detection methods

[0093]

[0094] Table 6

[0095]

[0096] S-250501 exhibited the best release performance, but had the lowest pressure-sensitive adhesive content (40%). In formulations with 50% pressure-sensitive adhesive content, the 48-hour release rates of S-250502, S-250505, S-250504, and S-250506 ranged from 55% to 59.5%, with S-250502 slightly higher (59.5%), followed by S-250505 (58.8%), then S-250504 (57.6%) and S-250506 (55.0%). S-250503 (60% pressure-sensitive adhesive) had the lowest release rate, indicating that excessively high pressure-sensitive adhesive content can hinder drug release.

[0097] The content of pressure-sensitive adhesive (PSA) is a key factor affecting drug release. Reducing the PSA content can improve the release rate, but the adhesive properties of the patch must be balanced. In formulations with 50% PSA content, different combinations of solubilizers and penetration enhancers lead to differences in release rates, but the differences are relatively small (55%-59.5%). Among them, S-250502 (without PEG-3-ethylhexyl caprylate, but containing propylene glycol and dual penetration enhancers) and S-250505 (with dual solubilizers but without laurocapram) performed best.

[0098] Example 7

[0099] This embodiment examines the adhesion of milobalin transdermal patches with different formulations in Example 5, and the results are shown in Table 7.

[0100] Testing instrument: Material testing machine (equipped with a clean stainless steel substrate)

[0101] Patch size: 25 mm wide

[0102] Pre-treatment: Ensure the adhesive adheres fully to the stainless steel substrate, removing air bubbles (light pressure with your fingers is permissible).

[0103] Environmental equilibration: 5 minutes (constant room temperature and humidity)

[0104] Peeling conditions: Peeling angle: 90° (vertical peeling); Peeling speed: 300 mm / min

[0105] Output parameter: Maximum force (N) during the peeling process.

[0106] Table 7

[0107]

[0108] Experimental data showed significant differences in the adhesive strength of milobalin transdermal patches with different formulations (7.34~15.81 N). S-250503 showed the highest adhesive strength (15.81 N), but its excessive peeling force may increase the risk of skin irritation. S-250501 showed the lowest adhesive strength (7.34 N), posing a potential risk of detachment during clinical application. Considering all factors, batches S-250502 (12.60 N), S-250504 (9.03 N), S-250505 (11.32 N), and S-250506 (13.53 N) demonstrated both stability and safety. Further optimization of the pressure-sensitive adhesive and excipient ratio based on drug release data is needed to achieve a balance between adhesive performance and drug delivery efficiency.

[0109] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0110] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and controls without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A transdermal drug delivery formulation, characterized in that, The transdermal drug delivery formulation comprises: (a) An active ingredient, wherein the active ingredient is milobalin or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from at least one of hydrochloride, hydrobromide, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, acetate, oxalate, malonate, valerate, glutamate, oleate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, hydroxyethylsulfonate, fumarate, maleate, malate, tartrate, benzoate, bis(hydroxynaphthyl)ate, salicylate, vanillate, mandelate, succinate, gluconate, and lactobionate, preferably benzenesulfonate; (b) Acrylic pressure-sensitive adhesive matrix; (c) A crystal inhibitor, wherein the crystal inhibitor is polyvinylpyrrolidone; (d) A solubilizing composition selected from at least one of propylene glycol, polyethylene glycol glycerol caprylate, diethylene glycol monoethyl ether or polyethylene glycol 400, preferably propylene glycol, polyethylene glycol glycerol caprylate or combinations thereof, wherein the solubilizing composition accounts for 5-25% (w / w) of the total weight of the formulation. (e) A penetration enhancer composition selected from at least one of oleyl alcohol, isopropyl myristate, lauryl ketone, propylene glycol monocaprylate, and diethylene glycol monoethyl ether, preferably lauryl ketone, propylene glycol monocaprylate, and combinations thereof, wherein the penetration enhancer composition accounts for 5-25% (w / w) of the total weight of the formulation. The sum of the components of the preparation is 100%.

2. The transdermal drug delivery formulation as described in claim 1, characterized in that, The active ingredient, calculated as free alkali, accounts for 1-15% (w / w) of the total weight of the formulation, preferably 5-15% (w / w), and more preferably 8-12% (w / w).

3. The transdermal drug delivery formulation as described in claim 1 or 2, characterized in that, The acrylic pressure-sensitive adhesive matrix is ​​selected from copolymers containing 2-ethylhexyl acrylate; preferably at least one of DURO-TAK 87-4098, DURO-TAK 87-2074, DURO-TAK 87-2054, and DURO-TAK 87-2287; more preferably DURO-TAK 87-2074; accounting for 40-60% (w / w) of the total weight of the formulation, preferably 45-55% (w / w).

4. The transdermal drug delivery formulation according to any one of claims 1-3, characterized in that, The polyvinylpyrrolidone is at least one of povidone K90 and povidone K30, accounting for 5-15% (w / w) of the total weight of the formulation, preferably 8-12% (w / w).

5. The transdermal drug delivery formulation according to any one of claims 1-4, characterized in that, The solubilizing composition comprises 9-22% (w / w) of the total weight of the formulation and is selected from one of the following: (i) 5-15% (w / w) of propylene glycol; (ii) 5-15% (w / w) of caprylic / capric glyceride polyethylene glycol ester; (iii) A combination of 5-15% (w / w) propylene glycol and 5-15% (w / w) octyl decanoic acid polyethylene glycol glycerol ester.

6. The transdermal drug delivery formulation according to any one of claims 1-5, characterized in that, The penetration enhancer composition comprises 9-22% (w / w) of the total weight of the formulation and is selected from one of the following: (i) 5-15% (w / w) lauryl azone; (ii) 5-15% (w / w) propylene glycol monooctanoate; (iii) A combination of 5-15% (w / w) laurocaptan and 5-15% (w / w) propylene glycol monooctanoate.

7. The transdermal drug delivery formulation according to any one of claims 1-6, characterized in that, The formulation does not contain ethanol solvent.

8. The transdermal drug delivery formulation according to any one of claims 1-7, characterized in that, The formulation is a patch or gel.

9. The transdermal drug delivery formulation according to any one of claims 1-8, characterized in that, The formulation also contains 0.01-5% (w / w) of a preservative selected from phenoxyethanol, parabens, benzoates, or sorbates.

10. The transdermal drug delivery formulation according to any one of claims 1-9, characterized in that, The formulation also contains 0.01-3% (w / w) of an antioxidant selected from tert-butyl-p-cresol, vitamin E, or disodium ethylenediaminetetraacetate.

11. A transdermal drug delivery formulation, characterized in that, The transdermal drug delivery formulation comprises: (a) The active ingredient, which is milobalin or a pharmaceutically acceptable salt thereof, comprising 8-12% (w / w) of the total weight of the formulation as a free base; (b) An acrylic pressure-sensitive adhesive matrix, wherein the acrylic pressure-sensitive adhesive matrix is ​​selected from copolymers containing 2-ethylhexyl acrylate, preferably DURO-TAK 87-2074; and comprises 40-60% (w / w) of the total weight of the formulation, preferably 45-55% (w / w); (c) A crystal inhibitor, wherein the crystal inhibitor is polyvinylpyrrolidone, wherein the polyvinylpyrrolidone is at least one of povidone K90 and povidone K30, and accounts for 5-15% (w / w) of the total weight of the formulation, preferably 8-12% (w / w). (d) A solubilizing composition comprising 9-22% (w / w) of the total weight of the formulation and selected from one of the following: (i) 5-15% (w / w) of propylene glycol; (ii) 5-15% (w / w) of caprylic / capric glyceride polyethylene glycol ester; (iii) A combination of 5-15% (w / w) propylene glycol and 5-15% caprylic / capric glyceride polyethylene glycol ester; (e) A penetration enhancer composition comprising 9-22% (w / w) of the total weight of the formulation and selected from one of the following: (i) 5-15% (w / w) lauryl azone; (ii) 5-15% (w / w) propylene glycol monooctanoate; (iii) A combination of 5-15% (w / w) laurocaptan and 5-15% propylene glycol monooctanoate The sum of the components of the preparation is 100%.

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