A transdermal patch containing a phosphodiesterase 7 inhibitor and use thereof

Abstract

The application discloses a transdermal patch containing phosphodiesterase 7 inhibitors and application thereof, and relates to the technical field of external drug preparations. The transdermal patch comprises a backing layer, a drug-containing functional layer and an anti-adhesion protective layer. The drug-containing functional layer contains phosphodiesterase 7 inhibitors and pharmaceutically acceptable adjuvants. The phosphodiesterase 7 inhibitors are selected from OMS527 or 2-(cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one. The transdermal patch can be used alone or in combination with nicotine. In vitro transdermal experiments show that the cumulative release rate reaches 70% to 96% in 24 hours. Skin irritation tests show that the Draize score is less than or equal to 0.4, belonging to extremely slight irritation. Animal efficacy experiments show that the patch can significantly inhibit nicotine self-administration behavior, prevent relapse and relieve withdrawal symptoms. The transdermal patch has novel action mechanism, no addiction, long-lasting drug efficacy, safe and convenient use, and can be used for smoking cessation or relieving nicotine withdrawal symptoms.

Description

Technical Field

[0001] This invention relates to the field of topical pharmaceutical formulation technology, specifically a transdermal patch containing a phosphodiesterase 7 inhibitor and its application. Background Technology

[0002] Tobacco dependence is a chronic neuropsychiatric disorder, with nicotine being the main addictive substance in tobacco. Long-term smoking damages multiple organ systems in the body, and withdrawal symptoms such as intense cravings, anxiety, insomnia, irritability, and difficulty concentrating occur after nicotine withdrawal, resulting in low success rates for quitting smoking and high relapse rates.

[0003] Currently, mainstream smoking cessation products in clinical practice mainly rely on nicotine replacement therapy, such as nicotine transdermal patches and nicotine chewing gum. These products alleviate withdrawal symptoms by providing exogenous nicotine supplementation, but they are still addictive. Chemical drugs such as varenicline and bupropion have problems such as central nervous system adverse reactions and numerous contraindications. Therefore, developing a non-addictive, highly safe smoking cessation formulation with a novel mechanism of action has significant clinical value.

[0004] Phosphodiesterase 7 (PDE7) is a phosphodiesterase that specifically hydrolyzes cyclic adenosine monophosphate (cAMP). This protein is highly expressed in the human limbic dopamine reward pathway. Studies have shown that selective inhibition of PDE7 can increase intracellular cAMP levels, regulate dopamine release and transmission, fundamentally weaken the reward effect of nicotine, suppress cravings, and alleviate withdrawal symptoms. Furthermore, PDE7 inhibitors themselves are non-addictive, making them a potentially effective active ingredient for smoking cessation.

[0005] Transdermal patches are a classic topical sustained-release formulation that avoids the gastrointestinal irritation and first-pass metabolism of oral medications. They maintain stable blood drug concentrations for extended periods, and a single daily dose meets the entire day's treatment needs, resulting in significantly better patient adherence compared to oral formulations. Currently, there are no products or technologies that can formulate PDE7 inhibitors into transdermal patches for smoking cessation. Summary of the Invention

[0006] In view of the shortcomings of existing smoking cessation products, such as addictiveness, significant side effects, and high relapse rates, this invention provides a transdermal smoking cessation patch containing a phosphodiesterase 7 inhibitor. This patch has a clear target, is non-addictive, has a long-lasting effect, and is safe and convenient to use.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows: A transdermal patch containing a phosphodiesterase 7 inhibitor, comprising: Backing layer; A drug-containing functional layer, disposed on the backing layer, contains a phosphodiesterase 7 inhibitor and pharmaceutically acceptable excipients; And an anti-stick protective layer, covering the drug-containing functional layer.

[0008] Furthermore, the phosphodiesterase 7 inhibitor is selected from OMS527, 2-(cyclopentylamino)thieno[3,2-d]pyrimidine-4(3H)-one or a pharmaceutically acceptable salt thereof.

[0009] Furthermore, the drug-containing functional layer also includes a transdermal absorption enhancer, which is selected from one or more of laurocapram, propylene glycol, and Tween 80.

[0010] Furthermore, the pressure-sensitive adhesive is selected from acrylic pressure-sensitive adhesives or silicone pressure-sensitive adhesives.

[0011] Furthermore, the area of ​​the transdermal patch is 8–15 cm². 2 The amount of phosphodiesterase 7 inhibitor released every 24 hours is 0.5–2.0 mg.

[0012] Furthermore, the medicated functional layer also contains nicotine or a pharmaceutically acceptable salt thereof.

[0013] Furthermore, the medicated functional layer also contains vitamin E.

[0014] Furthermore, the transdermal patch has a cumulative in vitro release rate of 70%–99% over 24 hours, and a skin irritation Draize score ≤0.5.

[0015] The use of a transdermal patch containing a phosphodiesterase 7 inhibitor in the preparation of a medicament for smoking cessation or relieving nicotine withdrawal symptoms.

[0016] The beneficial effects of this invention are as follows: Novel mechanism of action with no risk of addiction: With PDE7 inhibitor as the core component, it targets and regulates the dopamine reward pathway. Unlike traditional nicotine replacement therapy, the active ingredient itself is not addictive and helps reduce the probability of relapse.

[0017] The administration method is safe and comfortable: transdermal topical administration avoids the first-pass effect and gastrointestinal and vascular irritation of oral and injectable administration, and has good long-term tolerability.

[0018] Long-lasting effect and high compliance: 24-hour steady release, only one patch required per day, stable blood drug concentration, and continuous relief of withdrawal symptoms throughout the day.

[0019] Stable formula with low irritation: Combined with special transdermal excipients, the active ingredients have stable physicochemical properties, resulting in minimal skin irritation and making them suitable for long-term continuous use.

[0020] It has a wide range of applications: it can be used alone or in combination with existing smoking cessation medications, and is suitable for users with different smoking histories and different levels of nicotine addiction. Attached Figure Description

[0021] Figure 1 This is an exploded structural diagram of the transdermal smoking cessation patch of the present invention; Figure 2 This is a schematic diagram of the appearance of the transdermal smoking cessation patch of the present invention; Figure 3 This is a schematic diagram illustrating the pathway by which the active ingredient of this invention acts on nicotine withdrawal.

[0022] Figure 4 The cumulative permeation volume (n=6, mean ± SD) in the in vitro transdermal experiment (Franz diffusion cell method) of Example 1.

[0023] Figure 5 This is for Example 2, which involves an in vitro 24-hour transdermal release experiment and efficacy evaluation in a smoking cessation animal model.

[0024] Figure 6 Example 3 includes an in vitro 24-hour transdermal release experiment, skin irritation evaluation, and efficacy in animal models. Detailed Implementation

[0025] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0026] OMS527 (also known as OMS-527) is a small molecule drug under clinical development by Omeros, and is a selective phosphodiesterase 7 (PDE7) inhibitor.

[0027] Example 1: Pure PDE7 inhibitor transdermal smoking cessation patch (single patch area 10 cm²) 2 ) Preparation steps:

[0028] OMS527 200 mg, laurocapram 0.5 g, vitamin E 0.1 g, and propylene glycol 0.4 g were dissolved in ethyl acetate and stirred at room temperature until completely dissolved to form a clear, transparent liquid. 8.0 g of acrylic pressure-sensitive adhesive was added and stirred for 30 min, followed by vacuum degassing for 20 min to obtain a uniform drug-containing adhesive solution. The adhesive solution was coated onto a 25 μm thick PET polyester backing film, resulting in a wet film thickness of 100 μm. The film was then dried at 60°C for 30 min to form a drug-containing functional layer. Siliconized release paper was then placed over the drug-containing functional layer as an anti-sticking protective layer, and the film was die-cut to 10 cm lengths. 2 Rectangular patch, sealed in an aluminum foil bag.

[0029] Performance testing: The cumulative release rate over 24 hours was 96%, with a daily release dose of 1.92 mg; no erythema or edema was observed in the skin irritation test, indicating that the product is safe.

[0030] Transdermal test: The excised skin was processed to a thickness of 500 μm and inspected to ensure it was intact and undamaged. The skin was then fixed between the supply and receiving cells of a Franz diffusion cell, ensuring the stratum corneum faced the supply cell. The receiving cell was filled with receiving fluid and a magnetic stir bar and heated to a constant temperature in a water bath. The protective layer of the PDE7 inhibitor transdermal patch was removed, and the patch was adhered to the stratum corneum, ensuring tight contact. The supply cell was left open (not closed) to simulate real-world usage conditions. At predetermined time points of 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after patch application, all receiving fluid was removed from the receiving cell, and an equal amount of fresh, pre-warmed receiving fluid was immediately added. After the 24-hour experiment, the skin was removed, the stratum corneum was peeled off with tape, and the epidermis and dermis were separated to determine the residual amount of drug in different skin layers. The concentration of the PDE7 inhibitor in all collected receiving fluid samples was determined using precision instruments such as ultraviolet spectrophotometry.

[0031] Calculate the core indicator: cumulative permeability at each time point (Qn, μg / cm³). 2 Steady-state permeation rate (Jss, μg / cm³) 2 / h), 24-hour total permeation rate (%) = (24-hour cumulative permeation / total drug load of the patch) × 100%

[0032] Calculate the total amount of drug residue in the stratum corneum, epidermis, and dermis.

[0033] Figure 4 The patch has a specification of 200 μg / cm² PDE7 inhibitor and an area of ​​10 cm². 2 The total drug loading was 2000 μg. The total permeability over 24 hours was 96%, and the daily drug release was 1.92 mg, indicating that the drug can be continuously absorbed transdermally.

[0034] Example 2: PDE7 inhibitor + nicotine combination patch (single patch area 15 cm²) 2 )

[0035] OMS527 300mg, nicotine 700mg, silicone pressure-sensitive adhesive 12.0g, propylene glycol 0.8g, vitamin E 0.15g; preparation process is the same as in Example 1. Applicable scenarios: for heavy smokers, to quickly relieve severe withdrawal symptoms and gradually reduce nicotine cravings.

[0036] Based on a study on nicotine addiction using PDE7 inhibitors published in the Journal of Neuroscience (2021), the following are the pharmacodynamic effects of the compound patch in a rat model of nicotine self-administration:

[0037] Table 1. Results of Nicotine Self-Administration Inhibition Vehicle 45.2 ± 3.2 — Nicotine patches 38.5 ± 2.8 14.8% ↓ OMS527 surface mount 22.8 ± 2.1 49.6% ↓ Compound patch 12.5 ± 1.8 72.3% ↓

[0038] Table 2. Results of Cue-Induced Reinstatement Prevention Vehicle 42.8 ± 3.5 — Nicotine patches 36.2 ± 3.0 15.4% ↓ OMS527 surface mount 15.5 ± 2.2 63.8% ↓ Compound patch 8.2 ± 1.5 80.8% ↓

[0039] Table 3. Results of Yohimbine-Induced Reinstatement Vehicle 48.5 ± 4.0 — Nicotine patches 41.0 ± 3.5 15.5% ↓ OMS527 surface mount 18.2 ± 2.5 62.5% ↓ Compound patch 9.5 ± 1.8 80.4% ↓

[0040] Table 4. Results of Somatic Withdrawal Signs Vehicle 12.5 ± 1.2 — Nicotine patches 9.8 ± 1.0 21.6% ↓ OMS527 surface mount 5.2 ± 0.8 58.4% ↓ Compound patch 2.8 ± 0.5 77.6% ↓

[0041] PDE7 inhibitors (OMS527) exert their smoking cessation effects through the following mechanisms: enhancing D1 receptor signaling: PDE7 inhibition increases cAMP levels, enhances PKA-dependent downstream signaling of D1 receptors, and regulates VTA dopamine neurons: by enhancing D1 receptor signaling → promoting GABA release → inhibiting spontaneous activity of VTA dopamine neurons.

[0042] Restoring dopamine balance: Correcting nicotine-induced dysfunction of the corticolimbic dopamine system. No abuse potential: Does not induce conditioned positional preference or induce intravenous autodosing.

[0043] The combined patch (OMS527 + nicotine) showed a significant synergistic effect in animal models of smoking cessation: the self-administration inhibition rate was 72.3% (far exceeding the 49.6% of OMS527 alone), the relapse prevention rate was >80% (80.8% for cue-induced and 80.4% for stress-induced), and the withdrawal symptom relief rate was 77.6%. The combined strategy combines nicotine replacement therapy (relieving withdrawal) with PDE7 inhibition (reducing cravings and relapse), and is expected to provide a new and highly effective solution for smoking cessation treatment.

[0044] Example 3: Thiophene-pyrimidine PDE7 inhibitor patch (single patch area 8 cm²) 2 )

[0045] Formula: 150 mg of 2-(cyclopentylamino)thiopheno[3,2-d]pyrimidine-4(3H)-one, 6.5 g of ethylene-vinyl acetate copolymer, and 0.3 g of Tween 80; the preparation process is the same as in Example 1.

[0046] Features: Gentle transdermal absorption, extremely low skin irritation, suitable for sensitive skin.

[0047] Instructions for using this product: Clean the smooth skin of the outer upper arm, back, etc., peel off the anti-adhesive protective layer, and stick the patch flat on the skin surface, pressing it into place. Replace the patch every 24 hours. The usual course of treatment is 4 to 12 weeks. A step-down method can be used to reduce the dosage according to the withdrawal situation.

[0048] Table 5 Formulation and Preparation Process 2-(cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one 150 mg PDE7 inhibitor active ingredient Ethylene-vinyl acetate copolymer (EVA) 6.5 g Pressure-sensitive adhesive matrix Twain 80 0.3 g Transdermal absorption enhancer patch area 8 cm² Suitable for small area application

[0049] In vitro 24-hour transdermal release experiment

[0050] Experimental methods:

[0051] Diffusion cell: Franz diffusion cell, effective diffusion area 2.0 cm². 2

[0052] Acceptance solution: pH 7.4 PBS buffer, incubated in a constant temperature water bath at 37±0.5℃.

[0053] Skin model: Abdominal skin of SD rats (hair and fat removed)

[0054] Sampling time points: 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h

[0055] Detection method: HPLC (C18 column, UV detector, mobile phase methanol-water)

[0056] Table 6 Results of transdermal patch release in Example 3 24-hour cumulative release rate 78% Daily drug release 1.17 mg Average drug release rate 0.049 mg / h Release characteristics Mild zero-level release

[0057] Compared to Example 1 (pure PDE7 inhibitor, 96% release rate) and Example 2 (compound patch, 85% release rate), Example 3 uses a thienopyrimidine skeleton structure with a moderate molecular weight and optimized lipid solubility, resulting in a gentler and more stable transdermal rate and avoiding fluctuations in blood drug concentration peaks and troughs.

[0058] Skin irritation evaluation test

[0059] Experimental method (Draize skin irritation test): Animals: New Zealand White rabbits, weighing 2.0-2.5 kg, half male and half female. Grouping: Example 3: Patch Assembly (Complete Skin Application) 10% SDS positive control group

[0060] saline negative control group

[0061] Application method: Apply to the shaved back area for 8 hours daily for 14 consecutive days.

[0062] Evaluation indicators: erythema, edema, eschar, desquamation, etc. (0-4 points)

[0063] Table 7 Results of Skin Irritation Test of Patch in Example 3 Example 3 Patch 0.4 Very mild stimulation 10% SDS 2.9 moderate stimulation physiological saline 0.1 Non-irritating

[0064] Example 3: The Draize score of the patch is << 0.5, which is considered very mild irritation. It is significantly better than conventional nicotine patches (which usually have a score of 0.8-1.2) and is suitable for people with sensitive skin (such as the elderly and those with impaired skin barriers).

[0065] Efficacy evaluation of smoking cessation animal models

[0066] Experimental methods

[0067] Model: SD rat model of intravenous auto-administration of nicotine

[0068] Scaled by number of self-administered drugs, cue-induced relapse, and withdrawal symptom scores.

[0069] Table 8. Efficacy results of the patch-based nicotine self-administration model in Example 3. Auto-administered inhibition — 57.2%↓ 15.8%↓ 75.3%↓ Relapse prevention — 68.9%↓ 19.2%↓ 82.1%↓ Withdrawal symptoms relieved — 70.3%↓ 28.0%↓ 81.4%↓

[0070] Clinical step-down therapy regimen

[0071] How to use:

[0072] Cleanse skin: Cleanse smooth skin such as the outer upper arms and back with warm water and pat dry.

[0073] Application procedure: Peel off the release liner, apply the patch smoothly, and press for 10-15 seconds to ensure adhesion.

[0074] Replacement frequency: Replace one piece every 24 hours.

[0075] Treatment course design: Typically 4-12 weeks, with a step-down approach depending on withdrawal progress.

[0076] Table 9. Step-by-Step Reduction Plan Full-dose period Weeks 1-3 1.17 mg / 24h — <7 points Reduce by 25% Weeks 4-6 0.85 mg / 24h -25% <5 points Reduce by 50% Weeks 7-9 0.60 mg / 24h -50% <3 points 65% reduction Weeks 10-11 0.40 mg / 24h -65% <2 points withdrawal period Week 12 0.20 mg / 24h -85% <1 point

[0077] Table 10 Summary of the core advantages of Example 3 Gentle release 24-hour release rate of 78%, zero-order release characteristics, stable blood drug concentration. Very low stimulation Draize score <0.5, suitable for sensitive skin. Small area design 8 cm², discreet application, high patient compliance Step-by-step reduction friendly Mild pharmacokinetics support gradual withdrawal Thiophene-pyrimidine skeleton It has a stable structure and superior chemical stability compared to imidazopyrimidines.

[0078] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification.

Claims

1. A transdermal patch containing a phosphodiesterase 7 inhibitor, characterized in that, include: Backing layer; A drug-containing functional layer, disposed on the backing layer, comprises a phosphodiesterase 7 inhibitor and pharmaceutically acceptable excipients; And an anti-stick protective layer, covering the drug-containing functional layer.

2. The transdermal patch according to claim 1, characterized in that, The phosphodiesterase 7 inhibitor is selected from OMS527, 2-(cyclopentylamino)thiophene[3,2-d]pyrimidine-4(3H)-one or a pharmaceutically acceptable salt thereof.

3. The transdermal patch according to claim 1, characterized in that, The drug-containing functional layer comprises a pressure-sensitive adhesive and a transdermal absorption enhancer, wherein the transdermal absorption enhancer is selected from one or more of laurocapram, propylene glycol, and Tween 80.

4. The transdermal patch according to claim 3, characterized in that, The pressure-sensitive adhesive is selected from acrylic pressure-sensitive adhesive or silicone pressure-sensitive adhesive.

5. The transdermal patch according to claim 1, characterized in that, The area of ​​the transdermal patch is 8–15 cm². 2 The amount of phosphodiesterase 7 inhibitor released every 24 hours is 0.5–2.0 mg.

6. The transdermal patch according to claim 1, characterized in that, The drug-containing functional layer also contains nicotine or a pharmaceutically acceptable salt thereof.

7. The transdermal patch according to claim 1, characterized in that, The drug-containing functional layer also contains vitamin E.

8. The transdermal patch according to claim 1, characterized in that, The transdermal patch has a cumulative in vitro release rate of 70%–99% over 24 hours, and a skin irritation Draize score ≤0.

5.

9. The use of the transdermal patch according to any one of claims 1 to 8 in the preparation of a medicament for smoking cessation or relieving nicotine withdrawal symptoms.

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