A ramelteon transdermal patch and a preparation method thereof

Abstract

The present application provides a ramelteon transdermal patch, comprising a backing layer, a drug-containing substrate layer and a release film anti-sticking layer, the drug-containing substrate layer comprises the following components by weight percentage: 0.1%-5% of ramelteon, 1%-50% of solvent, 0%-20% of transdermal enhancer, 20%-89% of carrier material, and 0%-5% of antioxidant. The present application creatively utilizes the dual role of diethylene glycol monoethyl ether, not only significantly improves the drug release efficiency, but also exhibits its unique advantages in safety and stability, and provides a new and efficient choice for the treatment of sleep maintenance disorder.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically a ramelteamide transdermal patch and its preparation method. Background Technology

[0002] Rametamide is an oral hypnotic drug developed by Takeda Pharmaceutical Company of Japan and approved by the US FDA in July 2005. It is the first melatonin receptor agonist used in clinical treatment of insomnia. It is mainly used to treat insomnia with difficulty falling asleep, and it also has a definite effect on chronic insomnia and short-term insomnia.

[0003] Ramelteline is a melatonin receptor agonist with high affinity for melatonin MT1 and MT2 receptors, exhibiting specific and complete agonistic effects on these receptors while refraining from interacting with MT3 receptors. Furthermore, it does not bind to neurotransmitter receptors such as the GABA receptor complex and, within certain limits, does not interfere with the activity of most enzymes. Therefore, it avoids the attention deficit, addiction, and dependence associated with GABA-containing drugs.

[0004] The main metabolite of ramelteinamide, M-II, is present in significantly higher quantities in vivo than the parent drug, approximately 20 to 100 times the concentration of the parent drug. Although M-II has relatively low biological activity, its binding affinity to MT1 and MT2 receptors is noteworthy, being about one-fifth and one-tenth that of the parent drug, respectively. This indicates that metabolite M-II plays a central role in the efficacy of ramelteinamide; while its affinity for receptors is somewhat reduced, its overall contribution to the drug's therapeutic effect is significant.

[0005] Ramelteline, an internationally recognized drug for treating insomnia, has been proven suitable for long-term use, but its primary indication is difficulty falling asleep, with limited effectiveness in patients with sleep maintenance disorders, possibly due to its short half-life. Developing a ramelteline formulation that is effective for patients with sleep maintenance disorders would provide a new treatment option for those with chronic insomnia. Therefore, developing a ramelteline formulation that can continuously release the drug throughout the entire sleep cycle while avoiding the first-pass effect of the liver has significant clinical value.

[0006] Currently, ramelteinamide is available in tablet form. Clinical data show that after oral administration, ramelteinamide is rapidly absorbed, with a median time to peak absorption of approximately 0.75 (0.5-1.5) h. At least 84% of the drug is absorbed after oral administration. However, due to the first-pass effect, its absolute bioavailability is only 1.4%. Furthermore, when taken with a high-fat meal, the AUC is 31% higher than that when administered on an empty stomach, the Cmax is 22% lower, and the median Tmax is delayed by 45 min.

[0007] Traditional ramelteamide formulations have a rapid-release characteristic, quickly inducing sleep. However, this formulation has a relatively short half-life (T1 / 2), approximately one hour, meaning its effects are limited in duration. Therefore, patients may wake up prematurely after the drug's effects wear off and find it difficult to fall back asleep, which not only reduces overall sleep quality but may also negatively impact daytime mental state. Given this, traditional ramelteamide formulations may not be the optimal choice for patients who need to maintain sleep throughout the night, especially those with sleep maintenance disorders.

[0008] Given that the main efficacy of ramelteinamide comes from its metabolite M-II, although M-II has relatively low biological activity, this could potentially affect the overall therapeutic effect of ramelteinamide. Therefore, developing a novel formulation is particularly important. This formulation should effectively bypass the first-pass effect, thereby improving the bioavailability of ramelteinamide. Optimizing the formulation can enhance the efficacy of ramelteinamide, allowing it to exert its primary effect in vivo. Simultaneously, the formulation should possess sustained-release properties to avoid the limitations imposed by the short half-life of ramelteinamide, ensuring continuous drug release throughout the night, reducing the time it takes for patients to fall asleep, and prolonging their sleep duration, thereby improving sleep quality. The development of such a formulation will provide patients with sleep disorders with a more effective and durable treatment option.

[0009] Chinese patent CN112190555A discloses a rametamide sublingual tablet and its preparation technology. This sublingual tablet is cleverly designed to circumvent the first-pass effect, thereby improving the bioavailability and efficacy of rametamide to some extent. However, the formulation lacks sustained-release properties, resulting in an inability to maintain a stable drug concentration throughout the night. Although it can quickly induce sleep, patients are prone to waking up at night, affecting the continuity and quality of sleep.

[0010] Furthermore, Chinese patent CN113274365B discloses a dual-release formulation of ramelteamide, comprising both immediate and sustained release, and its preparation method. This formulation rapidly releases the immediate-release portion within 30 minutes to quickly induce sleep, followed by a gradual release of the sustained-release portion over 3 to 6 hours to prolong efficacy. Although this formulation achieves a certain balance in release kinetics, it still fails to effectively address the issue of insufficient bioavailability of ramelteamide. In this formulation, the metabolite M-II remains the main contributor to efficacy, but the overall therapeutic effect of ramelteamide is not significantly improved.

[0011] Furthermore, due to the long half-life of M-II, approximately 2 hours, its metabolism and clearance in the body are slower than that of ramelteamide itself. This means that during the 3 to 6 hours of drug absorption and metabolism, the concentration of M-II may accumulate to a high level during nighttime sleep (typically 6 to 8 hours). This not only fails to maintain the ideal drug concentration during sleep but may also lead to increased side effects the next day, potentially impacting the patient's daily life and health.

[0012] In summary, the main drawbacks of existing ramelteamide formulations are: the low bioavailability of ordinary tablets and sustained-release formulations limits the efficacy of ramelteamide; while sublingual or oral mucosal administration can have a rapid onset of action, it lacks sustained-release function.

[0013] Therefore, developing a novel formulation that can improve the bioavailability of ramelteamide, achieve sustained nighttime release, and control the concentration of its metabolite M-II is of great significance for improving patients' sleep quality and reducing side effects. Transdermal formulations are widely recognized for their ability to avoid the first-pass effect and provide sustained drug release. However, for the specific indication of sleep maintenance, new requirements are placed on transdermal formulations: the formulation needs to release the drug rapidly within a short period and maintain its efficacy for approximately 6 hours to avoid side effects such as drowsiness the following day. This presents a challenge to the design and development of transdermal formulations. Summary of the Invention

[0014] To address the aforementioned technical problems, the present invention aims to provide a rametamide transdermal patch that can rapidly induce sleep and maintain its efficacy throughout the night, thereby meeting clinical needs and improving patients' sleep quality.

[0015] To achieve the above-mentioned objectives of this invention, the present invention adopts the following technical solution:

[0016] A rameltein transdermal patch includes a backing layer, a drug-containing base layer, and a release film anti-adhesion layer. The drug-containing base layer comprises the following components in weight percentages: 0.1%–5% rameltein, 1%–50% solvent, 0%–20% transdermal facilitator, 20%–89% carrier material, and 0%–5% antioxidant.

[0017] Preferably, in the rameltein transdermal patch, the drug-containing base layer comprises the following components by weight percentage: 0.1%–5% rameltein, 10%–50% solvent, 0%–20% transdermal facilitator, 45%–89% carrier material, and 0%–5% antioxidant.

[0018] The rameltetinamide transdermal patch, wherein the solvent is one or more selected from diethylene glycol monoethyl ether, dimethyl sulfoxide, ethanol, polyethylene glycol, and dimethylformamide.

[0019] Preferably, in the rameltetinamide transdermal patch, the solvent is diethylene glycol monoethyl ether.

[0020] The transdermal patch containing ramelteamide contains one or more of the following: diethylene glycol monoethyl ether, polyglycerol oleate, oleoyl polyoxyethylene glycerol ester, caprylic / capric polyoxyethylene glycerol ester, propylene glycol monolaurate, and isopropyl myristate.

[0021] Preferably, in the ramelteamide transdermal patch, the transdermal facilitator is diethylene glycol monoethyl ether.

[0022] The ramelteamide transdermal patch described above uses one or more of the following as carrier materials: acrylate pressure-sensitive adhesive, polyvinyl ketone, polyisobutylene, and silicone pressure-sensitive adhesive.

[0023] The ramelteamide transdermal patch mentioned above, wherein the antioxidant is one or more selected from butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, vitamin E, and sodium metabisulfite.

[0024] The preparation method of the rameltetinamide transdermal patch includes the following steps:

[0025] (1) Weighing: Accurately weigh the batch prescription sample;

[0026] (2) Preparation of drug solution: Dissolve rameltein in an appropriate amount of solvent;

[0027] (3) Solution preparation: Dissolve the remaining excipients and add them to the drug solution and mix well;

[0028] (4) Coating and drying: Coating is carried out using a vacuum heating doctor blade and bar split coating tester.

[0029] In this invention, we innovatively reveal the multiple roles of diethylene glycol monoethyl ether in ramelteinamide transdermal patches, a discovery that unexpectedly demonstrated its unique potential during solvent screening. Diethylene glycol monoethyl ether not only efficiently dissolves ramelteinamide as a solvent, ensuring the uniformity and stability of the drug within the patch, but it also exhibits a significant transdermal enhancement effect on ramelteinamide, unprecedented in the prior art. More importantly, the use of diethylene glycol monoethyl ether achieves rapid release and efficient permeation of ramelteinamide, enabling a release rate of over 80% within 6 hours, far exceeding the efficiency of other existing enhancers or solvents. Compared to other components, diethylene glycol monoethyl ether demonstrates a significant advantage in promoting the release and permeation of ramelteinamide, an advantage so significant that it is unmatched by other components in the prior art. This enhancing effect of diethylene glycol monoethyl ether not only provides new insights for the development of ramelteinamide transdermal patches but also represents a new breakthrough in the field of transdermal drug delivery.

[0030] In this invention, we provide an innovative transdermal drug delivery system based on diethylene glycol monoethyl ether, discovered through screening, as a key component. This component acts not only as a solvent but also as a transdermal transdermal enhancer, achieving a breakthrough in drug release. Samples prepared using this technology exhibit superior drug release characteristics within 6 hours, with a cumulative release rate significantly exceeding 80%, an achievement unprecedented with other excipients (solvents or transdermal transdermal enhancers). This rapid and stable release rate not only meets the urgent needs of patients with sleep maintenance disorders for rapid onset and sustained therapeutic effects but also significantly reduces the risk of next-day side effects by optimizing drug bioavailability.

[0031] The beneficial effects of this invention are as follows:

[0032] 1) This invention is the first to develop ramelteamide into a transdermal patch. The patch effectively avoids the first-pass effect of the liver caused by oral administration and has higher bioavailability and efficacy compared to the original tablet.

[0033] 2) This invention creatively utilizes the dual effects of diethylene glycol monoethyl ether to significantly improve drug release efficiency, providing a new and efficient option for the treatment of sleep maintenance disorders.

[0034] 3) Through specially selected excipients and precise formulation, the patch of the present invention achieves excellent physical properties and sustained-release effect, while ensuring the stability of the drug.

[0035] 4) This product is a sustained-release patch that can quickly induce sleep while maintaining the effect for about 6 hours, meeting the needs of patients with sleep maintenance disorders and is more suitable for patients with sleep disorders.

[0036] 5) This invention provides a more stable blood drug concentration, which helps to improve efficacy and reduce side effects.

[0037] 6) Oral ramelteamide may cause gastrointestinal adverse reactions, while the sustained-release patch delivers the medication through the skin, avoiding direct contact with the gastrointestinal tract and reducing the incidence of adverse reactions.

[0038] 7) Sustained-release patches are simple and convenient to use, making them especially suitable for the elderly, children, or patients who do not wish to take oral medications. Furthermore, their non-invasive and continuous-release characteristics give them unique advantages in home care. Detailed Implementation

[0039] Example 1

[0040] The prescription is shown in the table below. Based on ramelteinamide at a strength of 2mg, with each tablet weighing 20mg and a batch size of 1000 tablets, the dosage (unit: g) and weight percentage of each component are as follows:

[0041] Rametamide 2 2 2 2 dimethylformamide 10 / / / ethanol / 10 / / polyethylene glycol / / 10 / Dimethyl sulfoxide / / / 10 Acrylic pressure-sensitive adhesive 88 88 88 88 total 100 100 100 100

[0042] Process:

[0043] Weighing: Accurately weigh the batch prescription sample;

[0044] Drug solution preparation: Dissolve rameltein in an appropriate amount of solvent (dimethylformamide, ethanol, polyethylene glycol, dimethyl sulfoxide).

[0045] Solution preparation: Place the remaining excipients in an appropriate amount of ethyl acetate and sonicate for 10 minutes to mix thoroughly;

[0046] Coating and drying: Coating is carried out using a vacuum-heated doctor blade / bar split coating tester. The heating temperature is tentatively set at 60℃ and the coating speed is 5-15mm / s. The parameters are adjusted according to the coating effect.

[0047] In vitro transdermal experiments were conducted using the skin of male 1-month-old Panamanian miniature pigs as the transdermal material. The receiving solution was a physiological saline solution, and the bath temperature was 32℃±0.5℃. Six replicates were performed, and samples were taken at 1h, 2h, 4h, 5h, and 6h to serve as the test solution. Blank receiving solution was also added simultaneously.

[0048] By permeating the above prescription, the following results can be obtained:

[0049]

[0050] Example 2

[0051] The prescription is shown in the table below. The dosage (unit: g) and weight percentage of each component are as follows:

[0052]

[0053]

[0054] Process:

[0055] Weighing: Accurately weigh the batch prescription sample;

[0056] Drug solution preparation: Dissolve ramelteamide in an appropriate amount of dimethyl sulfoxide.

[0057] Solution preparation: Place the remaining excipients in an appropriate amount of ethyl acetate and sonicate for 10 minutes to mix thoroughly;

[0058] Coating and drying: Coating is carried out using a vacuum-heated doctor blade / bar split coating tester. The heating temperature is tentatively set at 60℃ and the coating speed is 5-15mm / s. The parameters are adjusted according to the coating effect.

[0059] In vitro transdermal experiments were conducted using the skin of male 1-month-old Panamanian miniature pigs as the transdermal material. The receiving solution was a physiological saline solution, and the bath temperature was 32℃±0.5℃. Six replicates were performed, and samples were taken at 1h, 2h, 4h, 5h, and 6h to serve as the test solution. Blank receiving solution was also added simultaneously.

[0060] By permeating the above prescription, the following results can be obtained:

[0061]

[0062] Experimental results show that diethylene glycol monoethyl ether has a significant advantage in promoting the skin penetration of ramelteinamide. Compared with traditional transdermal penetration enhancers, diethylene glycol monoethyl ether can significantly improve the release efficiency of ramelteinamide, achieving a cumulative release of over 80% within 6 hours, a performance indicator that is extremely rare in the current technology.

[0063] Example 3

[0064] The prescription is shown in the table below. The dosage (unit: g) and weight percentage of each component are as follows:

[0065] Rametamide 0.1 1 2 5 Diethylene glycol monoethyl ether 10 20 30 50 Acrylic pressure-sensitive adhesive 89.9 79 68 45 total 100 100 100 100

[0066] Process:

[0067] Weighing: Accurately weigh the batch prescription sample;

[0068] Drug solution preparation: Dissolve ramelteamide in an appropriate amount of diethylene glycol monoethyl ether.

[0069] Solution preparation: Place the remaining excipients in an appropriate amount of ethyl acetate and sonicate for 10 minutes to mix thoroughly;

[0070] Coating and drying: Coating is carried out using a vacuum-heated doctor blade / bar split coating tester. The heating temperature is tentatively set at 60℃ and the coating speed is 5-15mm / s. The parameters are adjusted according to the coating effect.

[0071] In vitro transdermal experiments were conducted using the skin of male 1-month-old Panamanian miniature pigs as the transdermal material. The receiving solution was a physiological saline solution, and the bath temperature was 32℃±0.5℃. Six replicates were performed, and samples were taken at 1h, 2h, 4h, 5h, and 6h to serve as the test solution. Blank receiving solution was also added simultaneously.

[0072] By permeating the above prescription, the following results can be obtained:

[0073]

[0074]

[0075] Example 4

[0076] The prescription is shown in the table below. The dosage (unit: g) and weight percentage of each component are as follows:

[0077] Rametamide 2 2 Diethylene glycol monoethyl ether 20 20 Polyglycerol oleate 5 5 BHA 0.1 / BHT 0.1 / Vitamin E / 5 Acrylic pressure-sensitive adhesive 72.8 68 total 100 100

[0078] Process:

[0079] Weighing: Accurately weigh the batch prescription sample;

[0080] Drug solution preparation: Dissolve ramelteamide in an appropriate amount of diethylene glycol monoethyl ether.

[0081] Solution preparation: Place the remaining excipients in an appropriate amount of ethyl acetate and sonicate for 10 minutes to mix thoroughly;

[0082] Coating and drying: Coating is carried out using a vacuum-heated doctor blade / bar split coating tester. The heating temperature is tentatively set at 60℃ and the coating speed is 5-15mm / s. The parameters are adjusted according to the coating effect.

[0083] In vitro transdermal experiments were conducted using the skin of male 1-month-old Panamanian miniature pigs as the transdermal material. The receiving solution was a physiological saline solution, and the bath temperature was 32℃±0.5℃. Six replicates were performed, and samples were taken at 1h, 2h, 4h, 5h, and 6h to serve as the test solution. Blank receiving solution was also added simultaneously.

[0084] By permeating the above prescription, the following results can be obtained:

[0085]

[0086] The above prescription was stored at 25°C and 65% relative humidity for 3 months. The changes in related substances in the drug samples are detailed in the table below (%).

[0087] Prescription 3-3 99.4 99.2 99.2 99.1 Prescription 4-1 99.5 99.4 99.4 99.4 Prescription 4-2 97.2 97.0 96.5 96.3

[0088] This invention also conducted an in-depth study on the chemical stability of the sample. The stability study results showed that after storage at room temperature for 3 months, the active ingredients and related substances in the sample did not undergo significant changes, thus confirming its excellent chemical stability under normal storage conditions. This finding not only ensures the long-term effectiveness of the product but also provides patients with a safer and more reliable treatment option.

[0089] In summary, this invention creatively utilizes the dual effects of diethylene glycol monoethyl ether, achieving a significant improvement in drug release efficiency and demonstrating unique advantages in safety and stability, thus providing a novel and efficient option for the treatment of sleep maintenance disorders.

[0090] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention are included within the protection scope of the present invention.

Claims

1. A rameltein transdermal patch, comprising a backing layer, a drug-containing base layer, and a release film anti-adhesion layer, characterized in that... The drug-containing base layer is composed of the following components by weight percentage: 0.1%-5% ramelteamide, 20%-30% diethylene glycol monoethyl ether, 20%-89% carrier material, and 0%-5% antioxidant, with the sum of the contents of each component being 100%.

2. The rameltetinamide transdermal patch as described in claim 1, characterized in that... The drug-containing base layer is composed of the following components in weight percentage: 0.1%-5% ramelteamide, 20%-30% diethylene glycol monoethyl ether, 45%-89% carrier material, and 0%-5% antioxidant.

3. A rameltein transdermal patch as described in any one of claims 1 or 2, characterized in that... The carrier material is one or more of acrylate pressure-sensitive adhesive, polyvinyl ketone, polyisobutylene, and silicone pressure-sensitive adhesive.

4. A rameltein transdermal patch as described in any one of claims 1 or 2, characterized in that... The antioxidant is one or more of butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, vitamin E, and sodium metabisulfite.

5. A method for preparing a rameltein transdermal patch according to any one of claims 1 to 4, characterized in that... The steps include the following: (1) Weighing: Accurately weigh the batch prescription sample; (2) Preparation of drug solution: Dissolve rameltein in diethylene glycol monoethyl ether; (3) Solution preparation: Dissolve the remaining excipients and add them to the drug solution and mix well; (4) Coating and drying: Coating is carried out using a vacuum heating doctor blade and bar split coating tester.

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