Orforglipron transdermal patch

Abstract

The invention relates to a patch for the treatment of type 2 diabetes and obesity, comprising an outer protective and adhesive layer made of polyester, which keeps the patch in contact with the skin; a reservoir consisting of an EVA polymer matrix containing between 84 mg and 252 mg of orforglipron dispersed in molecular form; a release membrane, which is a semi-permeable polyurethane laminar filter that releases a dose of between 12 mg / day and 36 mg / day of orforglipron, and which is positioned below the reservoir: a hypoallergenic, medical-grade silicone adhesive layer, which is a permeable layer and is positioned below the release membrane and remains in contact with the skin; and a removable protective layer which is a polyester protective film that covers the adhesive layer and is removed before the patch is applied.

Description

[0001] DESCRIPTION

[0002] ORFORGLIPRON TRANSDERMAL PATCH

[0003] Object of the invention

[0004] The present invention relates to a new type of transdermal patch comprising an Orforglipron reservoir and intended for use in the treatment of type 2 diabetes and obesity.

[0005] The invention falls within the field of the medicinal and pharmaceutical industry, more specifically with the development of medicinal preparations characterized by a particular aspect being, in the case of the present invention, a transdermal patch.

[0006] Background of the invention

[0007] It is widely known that a transdermal patch is a means by which a medicinal substance can be released in a controlled manner into the bloodstream through the skin.

[0008] In this regard, it is known that the skin acts as a protective barrier, but it is permeable to some substances, including certain medicinal substances or drugs. When absorbed through the skin, drugs do not pass through the gastrointestinal system, thus avoiding various adverse reactions. This is the main advantage of using transdermal patches. In other words, the development of transdermal systems as an alternative drug delivery strategy to injectables or oral tablets has gained significant acceptance due to its advantages in improving treatment adherence, reducing side effects, and optimizing drug pharmacokinetics.

[0009] The mechanism of action of a transdermal patch is based on the fact that, when placed on the skin, the patch creates a concentration gradient between the high concentration of the drug in the patch and the low concentration of the drug in the skin. The drug passively diffuses from the patch through the outermost layer of the skin to reach the capillaries of the epidermis, releasing its action and acting on the disease or condition being treated. Furthermore, it is now known that glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized the treatment of type 2 diabetes and obesity by providing sustained glycemic control and facilitating weight loss. The usual approach to treating these conditions has been through subcutaneous injections and oral tablets.

[0010] The use of medications for this same purpose is well-known, such as Ozempic®, Trulicity®, and Victoza®, which are administered via subcutaneous injections. These types of medications, which are based on GLP-1 receptor agonists and mimic the effects of the endogenous GLP-1 hormone, are known to increase insulin secretion, decrease glucagon release, and slow gastric emptying, thus contributing to greater satiety and weight loss. However, these treatments require weekly or daily subcutaneous injections, which can affect adherence in some patients and increase the complexity of administration.

[0011] The use of oral coated tablets is also known; these tablets work by reducing glucose production in the liver and improving the body's sensitivity to insulin, allowing the body to use insulin more effectively. Specifically, recent studies have shown that orforglipron is effective in managing type 2 diabetes in oral tablet form. The findings published in “Efficacy and Safety of Oral Orforglipron in Patients with Type 2 Diabetes: A Multicentre, Randomised, Dose-Response, Phase 2 Study” (Lancet, 2024) and “Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron” (Diabetes Therapy, 2024) are known. It has also been shown to be effective against obesity when used in oral tablet form, as reported in “Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity” (New England Journal of Medicine, 2024).However, as with other oral treatments, its use is associated with some gastrointestinal side effects and the need for daily dosing, which can affect tolerance and adherence in certain patients.

[0012] In this context, the present invention proposes a new type of transdermal patch that gradually releases Orforglipron for the management of obesity and type 2 diabetes. This patch overcomes the limitations and problems of oral injectable forms, such as pronounced plasma peaks and gastrointestinal adverse effects, and also facilitates rapid systemic absorption.

[0013] The applicant for the present invention is unaware of any type of transdermal patch that is either similar or as advantageous as the one described and claimed below.

[0014] Explanation of the invention

[0015] The invention is an Orforglipron transdermal patch for use in the treatment of type 2 diabetes and obesity that, in its different embodiments, resolves the problems and limitations present in the prior art previously raised.

[0016] The patch that is the subject of the present invention consists of a transdermal patch that gradually releases Orforglipron, a non-peptide oral agonist of the GLP-1 receptor, developed for the management of obesity and type 2 diabetes. In this regard, the patch comprises:

[0017] an outer protective and adhesive layer, which is a waterproof sheet that protects the entire patch from external factors such as moisture, water, sweat or mechanical friction, and that keeps the patch in contact with the skin ensuring the effectiveness of transdermal release without irritating the skin, and where this layer is made of polyester;

[0018] an Orforglipron reservoir consisting of an ethylene-vinyl acetate (EVA) polymer matrix containing Orforglipron homogeneously dispersed in molecular form, wherein this matrix controls the release of the drug at a constant rate emulating the release profile of injectable GLP-1 agonists; wherein the drug release rate is controlled by a balance between permeability and diffusive resistance;

[0019] a release membrane, which is a semi-permeable polyurethane laminar filter, with a thickness of between 5 and 25 m, which allows the constant and sustained release of Orforglipron throughout the patch's lifespan, and acts as a diffusion barrier that limits the amount of orforglipron released per unit of time and acts as a zero-order release system, allowing constant release regardless of external conditions, with the concentration gradient being controlled to maintain a predictable and constant diffusion rate;

[0020] an adhesive layer, made of hypoallergenic medical-grade silicone, which remains in contact with the skin, and which is a permeable layer that allows adhesion of the patch without causing irritation or discomfort to the skin and allows absorption of the drug into the bloodstream through the skin; and a removable protective layer, which is a protective polyester film that covers the adhesive surface and protects the drug in the reservoir until the patient is ready for use, where this layer is removed just before application, ensuring that the adhesive is fresh and that the drug dose is in optimal condition; and where the thickness is between 40 and 60 µm.

[0021] The present invention is designed for the release of orforglipron over a 7-day period, providing continuous 24-hour release. This avoids the plasma peaks observed with daily oral administration of orforglipron (12-45 mg), which have been associated with an increased risk of gastrointestinal side effects such as nausea, vomiting, and diarrhea. Unlike oral formulations, which undergo first-pass hepatic metabolism, the transdermal system ensures direct absorption into the bloodstream, resulting in more predictable and efficient pharmacokinetics and reduced interindividual variability.

[0022] In this regard, trials have been conducted comparing the use of this transdermal patch in patients with type 2 diabetes and obesity, with daily doses of orforglipron of 3 mg / day, 12 mg / day, 25 mg / day, 36 mg / day, 45 mg / day, a placebo, and an injectable dulaglutide-based treatment with a dose of 1.5 mg / day. These trials are shown in Table 1.

[0023] PBO P1 P2 P3 P4 P5 ID N 55 51 56 47 61 63 50 HbA1c

[0024] M 8.06 8.03 8.23 ​​8.07 8.04 8.11 8.00 C26 -0.13 -1.19 -1.91 -1.99 -2.01 -2.03 -1.10 r OV3

[0025] M 172 164.4 172.6 169.7 157.9 166.4 167.2 C26 -11.1 -32.6 -53.2 -53.8 -53.9 -54.9 -33.2 BW

[0026] M 101.9 98.6 99.9 98.4 99.1 104.8 98.8 C26 -2.2 -3.7 -6.5 -9.4 -9.5 -10.1 -3.9

[0027]

[0028] Table 1

[0029] N represents the number of patients undergoing testing;

[0030] PBO is the placebo test;

[0031] P1 is the patch test with a dose of 3 mg / day; P2 is the patch test with a dose of 12 mg / day;

[0032] P3 is the patch test with a dose of 25 mg / day;

[0033] P4 is the patch test with a dose of 36 mg / day;

[0034] P5 is the patch test with a dose of 45 mg / day;

[0035] ID is the test for an injectable dulaglutide with a dose of 1.5 mg / day;

[0036] HbA1c is the % value of glycated hemoglobin;

[0037] FBG is the value in mg / dL of fasting blood glucose;

[0038] BW is the weight value in kg;

[0039] where for HbA1c, FBG and BW, M is the mean value at the start of treatment; and 026 is the change value after 26 weeks of treatment.

[0040] It can be observed that the patch of the present invention yields better results in relation to the values ​​that end type 2 diabetes and in the fight against obesity than a placebo or an injectable; and specifically, it is considered that, among the patches tested, the optimal result is for P3, since it allows for results similar to those of higher doses (36-45 mg / day), which are known to cause problems in oral tablets; and it gives much better results than for lower doses (3-12 mg / day). Specifically, for a dose of 25 mg / day and after 26 weeks of treatment in 47 patients with type 2 diabetes and overweight, it has been observed that for type 2 diabetes, there is an average reduction of 1.99% in glycated hemoglobin compared to the start of treatment and an average reduction of 53.7 mg / dL in fasting blood glucose; And as for the fight against overweight, an average weight loss of 9.7 kg has been achieved.

[0041] Therefore, based on these results, the daily dose of Orforglipron ranges from 12 mg / day to 36 mg / day for one week, allowing plasma concentrations to be maintained within the optimal therapeutic range, with the initial dose adjustable according to clinical requirements. In a preferred embodiment of the invention, the patch is designed to release 25 mg / day for one week. In conditions such as obesity and type 2 diabetes, where treatment adherence is crucial, a transdermal patch reduces the daily administration burden compared to other oral solutions, including oral solutions containing Orforglipron.

[0042] Regarding the release membrane, as mentioned, the release of Orforglipron is controlled by a release gradient based on a balance between permeability and diffusive resistance.

[0043] Specifically, it must be taken into account that the permeability coefficient (P m) that measures the membrane's capacity to allow the passage of Orforglipron through its structure is:

[0044] P m = 1.2 x 10 -5 cm / s

[0045] where this low value of P m It ensures controlled release and avoids concentration peaks in the plasma, this value being adjusted by the thickness and properties of the polyurethane.

[0046] On the other hand, the diffusion constant (D) describes the rate at which Orforglipron molecules move across the membrane down their concentration gradient, being:

[0047] D= 2.8 x 10' 6 cm 2 / s

[0048] where the constant D depends on the solubility of Orforglipron in the membrane and the interaction with the polyurethane, and where, in this case, this value D indicates that diffusion is slow, which is ideal to ensure a uniform and uninterrupted release of Orforglipron.

[0049] Based on these values, the release flow, according to Pick's law and taking into account the flow of 25 mg / day indicated previously, yields a reservoir result with an initial concentration of 175 mg of Orforglipron, adjusted to maintain stable plasma levels.

[0050] Based on these results and the tests carried out beforehand, the reservoir is designed to hold a total concentration of between 84 mg and 252 mg of Orforglipron. In a preferred embodiment, the reservoir has a capacity or total concentration of 175 mg of Orforglipron.

[0051] With the present invention, as previously mentioned, gastrointestinal side effects are reduced, since in studies with oral Orforglipron, the most common side effects are nausea and vomiting, especially at high doses (36-45 mg / day). Transdermal patches minimize this impact by avoiding direct exposure of the drug to the digestive system, an advantage also demonstrated in other types of patches.

[0052] Furthermore, as demonstrated in tests conducted for different daily dosages, a transdermal patch reduces the daily administration burden required to achieve good results in the treatment of type 2 diabetes and in the fight against overweight compared to the doses required for both oral tablets and subcutaneous injectable solutions. It should be noted that, throughout the description and claims, the term "comprises" and its variants are not intended to exclude other technical features or additional elements.

[0053] Brief description of the figures

[0054] In order to complete the description and to aid in a better understanding of the characteristics of the invention, a figure is presented which, for illustrative and non-limiting purposes, represents the following:

[0055] Figure 1: shows a schematic representation of the patch that is the subject of the present invention with its different layers.

[0056] Figure 2: shows a schematic representation of the positioning of the patch at the time of application and absorption of a dose of Orforglipron through the skin.

[0057] Detailed explanation of a mode of implementation of the invention

[0058] A preferred embodiment of the invention consists of a transdermal patch comprising

[0059] an outer protective and adhesive layer (1), which is made of polyester and keeps the patch in contact with the skin (P);

[0060] a reservoir (2) consisting of an ethylene-vinyl acetate (EVA) polymer matrix containing 175 mg Orforglipron homogeneously dispersed in molecular form;

[0061] a release membrane (3), which is arranged below the reservoir, and which is a semipermeable polyurethane laminar filter, with a thickness of between 15 pm, which allows the release of a dose (O) of 25 mg / day of Orforglipron for 7 days;

[0062] an adhesive layer (4) of hypoallergenic medical-grade silicone, which is disposed under the release membrane and remains in contact with the skin; which is a permeable layer that allows, on the one hand, adhesion of the patch without causing irritation or discomfort to the skin and, on the other hand, allows absorption of the Orforglipron dose through the skin (P);

[0063] a removable protective layer (5), which is a 50 µm thick polyester protective film that covers the lower surface of the adhesive layer and is removed just before application.This patch contains Orforglipron, an active ingredient that, at a dose of 25 mg / day, binds to GLP-1 receptors, stimulating glucose-dependent insulin release, reducing glucagon release, and slowing gastric emptying. This contributes to blood glucose control and a feeling of satiety. Compared to injectable or oral solutions, it has been shown to reduce fasting blood glucose, postprandial glycemia, and facilitate weight loss. Specifically, at a dose of 25 mg / day, after 26 weeks of treatment in 47 overweight patients with type 2 diabetes, the patch resulted in an average reduction of 1.99% in glycated hemoglobin compared to baseline and an average reduction of 53.7 mg / dL in fasting blood glucose. Regarding weight loss, an average weight loss of 9.7 kg was observed.Furthermore, being a non-peptide molecule, it is more stable, which makes it ideal for inclusion in a transdermal system.

[0064] Additionally, it has the advantage of being convenient and improving adherence, since by eliminating the need for daily injections and applications, the weekly patch with this dose improves adherence, especially in patients who find injectable therapies inconvenient; it allows for stable glycemic control, since the continuous release of Orforglipron at a dose of 25 mg / day for one week ensures stable blood glucose levels, avoiding the peaks and drops that can occur with other treatments; and it reduces side effects, specifically reducing the risk of hypoglycemia and other side effects associated with concentration fluctuations or administration of high doses, for example, above 36 mg / day.

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