Transdermal delivery systems for certain factor Xa inhibitors and related methods of preparation and use thereof

Abstract

Transdermal delivery systems, such as patches, for certain direct factor Xa inhibitors ("FXa"), particularly in the treatment of thrombosis or other conditions where anticoagulants are desired, and for preventing stroke and embolism in people with atrial fibrillation (AF), and methods for making and using such transdermal patches.

Description

[Technical field]

[0001] The present invention relates to patches for the transdermal delivery of certain Factor Xa inhibitors ("FXa"), as well as methods for making and using such transdermal patches. [Background technology]

[0002] Transdermal patches are widely used as a means of administering active pharmaceutical ingredients (API) to patients in need of therapeutic treatment. Advantages of transdermal patches as a dosage form over other dosage forms include accurate and consistent delivery of API resulting in relatively consistent blood API concentrations, avoidance of the first-pass effect, and increased compliance compared to oral dosage forms since patients do not have to remember to take a tablet or capsule at a specific time. Transdermal patches also offer additional advantages over topical formulations, since topical formulations can be accidentally wiped off the skin or undesirably soil other locations on the skin or other individuals who come into contact with the topical formulation.

[0003] Generally, a transdermal patch comprises a backing layer that is impermeable to the API and a layer of an adhesive composition containing the API. The adhesive in such a composition comprises at least one adhesive polymer that allows the adhesive composition containing the API to adhere to the skin of a patient. The adhesives generally contained in these compositions are pressure sensitive adhesives (PSAs), which are (meth)acrylate-based, silicone-based, or polyisobutylene-based adhesives.

[0004] The development of transdermal patches can be complicated, for example, by issues arising from the inherent aqueous solubility of APIs, API-excipient and excipient-excipient incompatibilities, which may necessitate the further addition of other excipients in some formulations, which in turn may result in additional incompatibilities and / or undesirable increased costs. In addition, even if the aforementioned incompatibilities are overcome, certain APIs are difficult to formulate to provide acceptable levels of API concentration in the bloodstream for a desired period of time, and this inability to provide adequate API concentration is largely due to the barrier properties of human skin.

[0005] FXa, as a class, is known to be an effective anticoagulant and must often be administered as part of a regimen to treat chronic conditions such as thrombosis. A subclass of FXa, sometimes called direct factor Xa inhibitors (xabans), is an anticoagulant used to both treat and prevent blood clots in the vascular system (e.g., after knee and hip replacement surgery) and to prevent stroke and embolism in people with atrial fibrillation (AF). Direct factor Xa inhibitors block an enzyme called factor Xa, preventing the conversion of prothrombin to thrombin in the final common pathway for blood clot formation in the veins and heart. However, when administered orally (common), some FXa, such as direct FXa apixaban, can cause gastrointestinal bleeding in some patients. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US Patent Application Publication No. US20200338012A1 [Non-patent literature]

[0007] [Non-Patent Document 1] https: / / packageinserts.bms.com / pi / pi_eliquis.pdf Summary of the Invention [Problem to be solved by the invention]

[0008] Direct FXa, particularly the subclasses of direct FXa that include betrixaban, edoxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, elivaxaban, and apixaban, have been difficult to formulate into therapeutically effective and regulatory acceptable transdermal dosage forms. [Means for solving the problem]

[0009] The present invention was developed to provide transdermal delivery of one or more direct FXa's to patients in need thereof, because it is difficult to deliver therapeutically effective amounts of these direct FXas into a patient's bloodstream via the transdermal route.

[0010] In one aspect, the present invention provides a composition which can be provided as an ingredient in a patch, comprising Direct FXa comprising or consisting of one or more of betrixaban, edoxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, elivaxaban, and / or desirably apixaban, preferably apixaban alone, an API-containing adhesive layer comprising, consisting essentially of, or consisting of a C3-C6 fatty acid, a glycol ether, and an adhesive.

[0011] In a related embodiment, a patch can be provided by laminating the composition of the invention onto a backing layer, optionally covering the optionally exposed composition with a release layer, and removing the release layer prior to contacting the composition with the patient's skin.

[0012] It has been unexpectedly discovered that direct FXa including or consisting of one or more of betrixaban, edoxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, elivaxaban, and / or preferably apixaban alone, when combined with a C3-C6 fatty acid, a glycol ether, and an adhesive, preferably with certain fatty acids, glycol ethers, and adhesives, more preferably in certain amounts, results in an API-containing adhesive layer having desirable direct FXa drug release and / or flux values ​​that correlate with therapeutic concentrations of these direct FXas in the bloodstream.

[0013] In another aspect, the present invention also provides a method for preparing a transdermal patch, which comprises, consists essentially of, or consists only of the steps of: mixing Direct FXa, which includes or consists only of one or more of betrixaban, edoxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, erivaxaban, and / or preferably apixaban, with a C3-C6 fatty acid and a glycol ether to obtain a premix; adding an adhesive to the premix, followed by mixing, thereby obtaining a liquid; applying the liquid onto a release liner; drying the liquid to obtain a coating on the release liner; and laminating the coating onto a support layer.

[0014] In another aspect, the present invention provides a method for administering direct FXa to a patient in need thereof, comprising or consisting of one or more of betrixaban, edoxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, elivaxaban, and / or preferably apixaban alone, the method comprising applying a transdermal patch onto the skin of the patient, the patch comprising, consisting essentially of, or consisting of a backing layer and an API-containing adhesive layer, the API-containing adhesive layer comprising betrixaban, edoxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, elivaxaban, and / or preferably apixaban alone. The present invention provides a method for administering an API-containing adhesive to a patient comprising, consisting essentially of, or consisting of direct FXa including or consisting of one or more of doxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, elivaxaban, and / or desirably apixaban, preferably apixaban alone, a C3-C6 fatty acid, a glycol ether, and an adhesive, wherein the API-containing adhesive layer is in direct contact with the skin, and in a preferred embodiment further provides a desired direct FXa drug release and / or flux value and / or FXa concentration in the patient's bloodstream.

[0015] As used herein, "treatment" or "therapeutic benefit" includes relief or reduction of symptoms as well as prevention of symptoms, while a "therapeutically effective" amount refers to the amount of direct FXa in the API-containing adhesive layer that provides a therapeutic benefit to a patient in need thereof. Examples of conditions that may be treated using the direct FXa transdermal patch of the present invention are the same as those for which the corresponding oral FXa formulations are approved, such as for the prevention or reduction of risk of blood clots (thromboembolism, e.g., deep vein thrombosis, pulmonary embolism) in the vascular system, particularly in treatments such as after (and also in some cases before) knee and hip replacement surgery, and as an anticoagulant in treatments for the prevention or reduction of risk of stroke and embolism in people with atrial fibrillation (AF).

[0016] Thus, aspects of the invention include the use of an API-containing adhesive layer, or a transdermal patch comprising said layer, in the treatment of patients suffering from thromboembolism, patients suffering from atrial fibrillation and at risk of stroke and / or embolism, and / or patients undergoing (e.g., within the past week) or who have undergone (e.g., within the past week) a knee or hip replacement. In a further aspect, the invention is provided comprising a pharmaceutical composition for the treatment of patients suffering from thromboembolism, patients suffering from atrial fibrillation and at risk of stroke and / or embolism, and / or patients undergoing (e.g., within the past week) or who have undergone (e.g., within the past week) a knee or hip replacement. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] APIs useful in the various aspects of the present invention are well known and include, consist essentially of, or consist solely of one or more of betrixaban, edoxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, elivaxaban, and desirably apixaban, preferably apixaban alone. These APIs are poorly water soluble: betrixaban (about 2.5-2.7 mg / mL), edoxaban (about 0.093 mg / mL), fondaparinux (about 7.91 mg / mL), rivaroxaban (about 0.01 mg / mL), darexaban (about 0.0048 mg / mL), otamixaban (about 0.0088 mg / mL), retaxaban (about 0.217 mg / mL), erivaxaban (about 0.00717 mg / mL), and apixaban (about 0.11 mg / mL). Apixaban is currently commercially available in the United States only in tablet form for oral administration and is the preferred API in the embodiments of the invention described herein.

[0018] Desirably, these APIs are substantially non-crystalline, i.e., at least about 50%, 60%, 70%, 80%, 90%, or 95% non-crystalline, in the API-containing adhesive layer after being coated and dried, because these crystalline APIs are less soluble in the other adhesive layer formulation components, thereby resulting in a relatively low flux. One way to reduce the crystallinity of these APIs in the coated and dried API-containing adhesive layer is to include a crystallization inhibitor therein, such as, for example, crospovidone. When included, the inhibitor may be present in the API-containing adhesive layer in an amount ranging from about 5 wt.% to about 35 wt.%, desirably from about 7 wt.% to about 25 wt.%, more desirably from about 10 wt.% to about 20 wt.%, and even more desirably from about 12 wt.% to about 18 wt.%.

[0019] The amount of the direct FXa API described above in the embodiments of the present invention may vary, but generally may be included in the API-containing adhesive layer in an amount sufficient to provide a concentration of FXa in the bloodstream that is approximately the same as that provided by daily dosing of the same oral formulation of FXa. For example, in patients with AF, administration of apixaban (based on data from the ELIQUIS® ARISTOTLE study): (i) twice daily (2.5 mg each dose) resulted in steady-state plasma concentrations of apixaban (reached 3 days after administration) ranging from about 90 to about 320 ng / mL (peak) and about 40 to about 230 ng / mL (trough); and (ii) twice daily (5 mg each dose) resulted in steady-state plasma concentrations of apixaban (reached 3 days after administration) ranging from about 70 to about 220 ng / mL (peak) and about 30 to about 160 ng / mL (trough). As a further example, administration of apixaban for the treatment of venous thromboembolism (based on data from the ELIQUIS® AMPLIFY trial): (i) twice daily (2.5 mg dose), steady state plasma concentrations of apixaban (reached 3 days after administration) ranged from about 30 to about 160 ng / mL (peak) and about 10 to about 100 ng / mL (trough); (ii) twice daily (5 mg dose), steady state plasma concentrations of apixaban (reached 3 days after administration) ranged from about 60 to about 100 ng / mL (peak) and about 20 to about 80 ng / mL (trough); and (iii) twice daily (10 mg dose), steady state plasma concentrations of apixaban (reached 3 days after administration) ranged from about 100 to about 575 ng / mL (peak) and about 40 to about 340 ng / mL (trough). All concentration ranges are given as + / - 2SD. See also the ELIQUIS® Package Insert (Revised: September 2021), accessed at the following URL: https: / / packageinserts.bms.com / pi / pi_eliquis.pdf.

[0020] Generally, on a weight percent basis, the amount of direct FXa included in various embodiments may range from about 2 wt% to about 20 wt%, more preferably from about 3 wt% to about 15 wt%, even more preferably from about 4 wt% to about 12 wt%, more preferably from about 5 wt% to about 10 wt%, even more preferably from about 6 wt% to about 8 wt%. In absolute amounts, the direct FXa API may be included in a wide range of amounts, as the amount depends on the final (after drying) mass and thickness of the API-containing adhesive layer, the area of ​​that layer in contact with the skin (also referred to as patch size), and the desired dosing regimen. For example, the transdermal patch of the present invention may be provided in a variety of doses, and it is contemplated that the variation in dosage will be proportional to the size of the API-containing adhesive layer in contact with the skin. Thus, due to different patch sizes and associated dosage variations, the absolute amount of direct FXa API in the API-containing adhesive layer of a particular patch may range from about 0.1 mg to about 400 mg, from about 0.5 mg to about 300 mg, or from about 1 to about 200 mg.

[0021] The length of administration, combined with the dose, may also vary depending on the treatment. For reducing the risk of stroke and embolism in patients with atrial fibrillation, a dose equivalent to 5 mg orally twice daily, or 2.5 mg orally twice daily, should be administered in patients with at least two of the following characteristics: age 80 years or older; weight less than 60 kg; serum creatinine greater than or equal to 1.5 mg / dL. For prevention of thrombosis (e.g., deep vein thrombosis) after hip or knee replacement surgery, a dose equivalent to 2.5 mg orally twice daily should be administered for 35 days in patients undergoing hip replacement surgery and 12 days in patients undergoing knee replacement surgery, with the initial dose administered 12-24 hours after surgery. For treatment of deep vein thrombosis and pulmonary embolism, a dose equivalent to 10 mg orally twice daily should be administered for the first 7 days, followed by a dose equivalent to 5 mg orally. For reduction of the risk of recurrent deep vein thrombosis or pulmonary embolism, a dose equivalent to 2.5 mg taken orally twice daily should be administered at least 6 months after treatment for deep vein thrombosis or pulmonary embolism.

[0022] Furthermore, to the extent that it may be desirable to ensure that the concentration of the direct FXa API is maintained within the therapeutic range over an extended period of time, administration of the direct FXa API according to the present invention may be supplemented with oral administration of the direct FXa API. For example, it may be supplemented for one day (one or two doses) or optionally two days, starting on the first day that the API-containing adhesive layer is used on the patient, or on any day that the exhausted API-containing adhesive layer is removed from the patient's skin (i.e., after the patient has worn the adhesive layer for an appropriate number of days) and replaced with a new API-containing adhesive layer. The API-containing adhesive layer may be co-administered with an oral direct FXa API formulation, where the oral formulation is administered at a relatively low dose such that the combined administration of the direct FXa API by the oral formulation and the API-containing adhesive layer is sufficient to provide the direct FXa API at the desired therapeutic level, while also providing a reduction in undesirable side effects incurred at relatively high oral doses. The supplemental administration or co-administration may be provided to the patient in the form of a kit comprising one or more individual oral formulations together with the API-containing adhesive layer.

[0023] In addition to one or more direct FXa APIs, the API-containing adhesive layer in various embodiments of the present invention further comprises a C3-C6 fatty acid, preferably lactic acid. The fatty acid may be present in the following amounts: from about 5 wt% to about 35 wt%, desirably from about 10 wt% to about 30 wt%, more desirably from about 15 wt% to about 25 wt%, and more desirably from about 18 wt% to about 22 wt%.

[0024] It has further been unexpectedly discovered that the inclusion of a relatively significant amount of a glycol (or phenol) ether, preferably 2-phenoxyethanol, in the API-containing adhesive layer contributes, at least in part, to the relatively high flux of FXa. This component may be present in the API-containing adhesive layer in various embodiments of the present invention at about 5 wt% to about 35 wt%, desirably about 10 wt% to about 30 wt%, more desirably about 15 wt% to about 25 wt%, and even more desirably about 18 wt% to about 22 wt%.

[0025] These components are also preferably present in a weight ratio (C3-C6 fatty acid:glycol ether) ranging from about 1:0.5 to about 1:2, more preferably from about 1:0.7 to about 1:1.5, even more preferably from about 1:0.8 to about 1:1.2, and most preferably in a ratio of about 1:1.

[0026] The API-containing adhesive layer is preferably 14 ~C 22 Fatty acids, preferably C 16 ~C 20 The adhesive layer further comprises a fatty acid, preferably unsaturated, most preferably linoleic acid, which, when present, is present in an amount of about 1 wt% to about 20 wt%, desirably about 3 wt% to about 15 wt%, more desirably about 4 wt% to about 12 wt%, and even more desirably about 5 wt% to about 10 wt%.

[0027] These components are also preferably in a weight ratio (C3-C6 fatty acids:C6 fatty acids) ranging from about 0.5:1 to about 6:1, more preferably from about 0.7:1 to about 5:1, and even more preferably from about 0.8:1 to about 4:1. 14 ~C 22 fatty acids), most preferably present in a weight ratio of about 3:1.

[0028] The adhesive layer is C 14 ~C 22 It has been unexpectedly found that when fatty acids, C3-C6 fatty acids, and glycol ethers are included, not only are the components in the adhesive layer compatible, but the flux of FXa is relatively high even when relatively low levels of FXa crystallization inhibitors are included.

[0029] The API-containing adhesive layer also preferably comprises an adhesive, preferably a plurality of adhesives. More preferably, the plurality of adhesives comprises (meth)acrylic and silicone adhesives. For purposes of the present invention, (meth)acrylic refers to both methacrylic and acrylic adhesives.

[0030] Suitable acrylate-based adhesives include polyacrylate-based pressure sensitive adhesives (PSA). These adhesives are well known and include, by way of example and not limitation, adhesives sold under the trade name DURO-TAK, 87 and 387 series, such as, for example, Duro-Tak 87-202A; Duro-Tak 87-208A; Duro-Tak 87-502A; Duro-Tak 87-503A; Duro-Tak 87-2051; Duro-Tak 87-2054; Duro-Tak 87-2287; Duro-Tak 87-2353; Duro-Tak 87-2510; Duro-Tak 87-2516; Duro-Tak 87-4098; Duro-Tak 87-4287; Duro-Tak 87-9088; and Duro-Tak 87-9301; and Duro-Tak 87-2516, adhesives sold under the trade name GELVA®, such as Gelva GMS 9083, Gelva GMS 9073, Gelva GMS 3083, Gelva GMS 788, Gelva GMS 3253, Gelva GMS 737, Gelva GMS 3087, Gelva GMS 3235, and the like, all available from Henkel Corporation. Duro-Tak 87-4098 is preferred because it provides the desired hardness and / or aids in obtaining the desired viscosity in the adhesive layer.

[0031] Suitable silicone-based PSAs are also well known and include, but are not limited to, adhesives sold by DuPont under the trade name Liveo™ Bio-PSA, such as BIO-PSA 7-4101, BIO-PSA 7-4103, BIO-PSA 7-4201, BIO-PSA 7-4203, BIO-PSA 7-4301, BIO-PSA 7-4303, BIO-PSA 7-4102, BIO-PSA 7-4202, BIO-PSA 7-4302, BIO-PSA 7-4401, BIO-PSA 7-4403, BIO-PSA 7-4501, BIO-PSA 7-4503, BIO-PSA 7-4601, BIO-PSA 7-4603, BIO-PSA Examples of suitable polymers include BIO-PSA 7-4402, BIO-PSA 7-4502, BIO-PSA 7-4602, BIO-PSA 7-4560, BIO-PSA 7-4402, BIO-PSA 7-4408 Cosmetic Fluid, 7-4405 Cosmetic Fluid, 7-4408 Cosmetic Fluid, 7-4411 Cosmetic Fluid, 7-4412 Cosmetic Fluid, and 7-4413 Cosmetic Fluid. Uncapped polymers, such as BIO-PSA 7-4402 (polydimethylsiloxane polymer), are preferred because they contribute to providing the desired hardness, skin adhesion, and / or drug permeability to the adhesive layer. Skin adhesion can vary depending on the number of silanol functional groups available for hydrogen bonding. A higher number of functional groups is generally expected to correlate with increased adhesion. Silicone adhesives are known to those skilled in the art to provide high drug permeation rates relative to those provided by other classes of adhesives, such as acrylate adhesives, and thus the drug diffusion rate of the drug-containing composition can be adjusted, in part, by varying the mass ratio of silicone adhesive to non-silicone adhesive.

[0032] The amount of adhesive to be included in the API-containing adhesive layer may generally range from about 15 wt% to about 90 wt%, desirably from about 25 wt% to about 65 wt%, more desirably from about 35 wt% to about 55 wt%, and even more desirably from about 40 wt% to about 50 wt%. When both an acrylate-based adhesive and a silicone-based adhesive are included, they may be present preferably in a mass ratio (acrylate:silicone) of about 1:0.7; more desirably from about 1:0.9, and even more desirably from about 1:1.

[0033] The API-containing adhesive layer may further optionally comprise at least one of an antioxidant, a chelating agent, or both. Without wishing to be bound by any particular theory, the antioxidant can help stabilize the API-containing adhesive layer by helping to reduce, preferably eliminate, any color change (e.g., yellowing) and / or oxidation and associated degradation of the permeation enhancer during the shelf life of the product, while the chelating agent can bind to or complex with any trace metals that may be present in the components present in the API-containing adhesive layer, thereby reducing, and desirably eliminating, any ability of these metals to catalyze oxidation reactions.

[0034] Antioxidants that may be used in the present invention include, but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium pyrosulfite, and sodium sulfite, with butylated hydroxytoluene being preferred.Chelating agents that may be used in the present invention include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates.

[0035] If included, the antioxidants and chelating agents may each be present (alone or together) in an amount ranging from about 0.1 wt % to about 2 wt %, more desirably from about 0.2 wt % to about 1 wt %, and even more desirably from about 0.4 wt % to about 0.6 wt %.

[0036] The weight percentage of the components in the API-containing adhesive layer described herein should be understood to be relative to the total weight of the API-containing adhesive layer after drying, where drying is performed to remove all volatile components from the API-containing adhesive layer. For example, the adhesives described herein are provided by the manufacturer as solids in a volatile liquid vehicle. The weight percentage of the adhesive in the API-containing adhesive layer, as described herein, refers to the weight of adhesive solids (i.e., excluding the volatile liquid vehicle) remaining in the API-containing adhesive layer after drying.

[0037] Table A shows a series of exemplary API-containing adhesive layer formulations according to the present invention.

[0038] [Table 1]

[0039] The aforementioned API-containing adhesive layer formulations can provide transdermal products exhibiting desirable drug release rates as well as desirable flux values. The drug release rate of the API-containing adhesive layer, preferably in embodiments where apixaban is the API, can range from at least about 30, 35, or 40% to about 45, 50, 55, or 60% of the drug from the adhesive layer in 1 day, and / or at least about 70, 75, 80, 85, or 90% and up to about 92, 95, 97, or 99% in 7 days, as determined by the methodology described in paragraphs

[0047] to

[0048] herein. In an embodiment of the API-containing adhesive layer, preferably where apixaban is the API, the API-containing adhesive layer has a flux value of at least about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or 6.5 μg / cm for 1, 2, 3, 4, 5, 6, or 7 days, as determined by the methodology described in paragraphs

[0058] to

[0060] herein. 2 / hour and about 7, 7.5, 8, 9, or 10 μg / cm 2 / hour or less.

[0040] An embodiment of the invention provides a transdermal patch that can be worn for extended periods of time, such as 3, 4, 5, 6, 7, 8, or 9 days, while transdermally delivering a therapeutically effective amount of the direct FXa API to a patient. The patch may also be used in place of oral FXa if a patient taking FXa orally experiences undesirable side effects, or 1, 2, or 3 days after administration of an oral dosage form (e.g., to reduce any anticipated side effects associated with oral administration).

[0041] The API-containing adhesive layer may be laminated onto a backing layer that is impermeable to the permeation of the ingredients in the adhesive layer after coating and drying, and the exposed adhesive layer may be covered with a release layer that is removed before use. The backing layer may be of a size larger than the area of ​​the API-containing adhesive layer, and the area not covered by the adhesive layer may have an adhesive coated thereon that can help hold the API-containing adhesive layer on the skin. These backing layers are well known and include, by way of example only, polyester films. The adhesive layers described herein are designed to directly contact the skin, so no membrane is required to cover the coated and dried adhesive layer. EXAMPLES

[0042] Exemplary transdermal apixaban formulations as described in Tables 1 and 2 were prepared and tested to assess their crystallinity, dissolution, and flux.

[0043] [Table 2A]

[0044] [Table 2B]

[0045] [Table 3A]

[0046] [Table 3B]

[0047] The formulations in Tables 1 and 2 were prepared as follows: Apixaban was introduced into a 100 ml bottle. Lactic acid, linoleic acid, 2-phenoxyethanol, and / or 1-methyl-2-pyrrolidinone were then added thereto. The resulting suspension was vortexed and the bottle was placed on a vial rocker until apixaban was completely dissolved. If crospovidone was included, it was then added to the solution and mixed for 2 minutes (@2000 rpm). Silicone-based pressure sensitive adhesive (SiPSA) and / or acrylic-based PSA was then added and the resulting mixture was mixed for 4 minutes (@2000 rpm). The resulting formulation was an opaque, white, viscous liquid.

[0048] The liquid formulation was then coated onto a 3 mil Scotchpak™ 9709 fluorosilicone release liner (fluorosilicone coated polyester film) using a manual knife-by-roll lab coater with a gap of 0.017 inches. The coated formulation was then dried at room temperature for 10 minutes and then at 70°C for 10 minutes. After drying, the formulation was laminated onto a 2 mil polyester support film to obtain the transdermal dosage form. The actual mass of the dried coating layer was 6 mg / cm2 as listed in the table. 2 ~30mg / cm 2 The range was between .

[0049] The dissolution / drug release values ​​reported in this example were obtained as follows: receiver volume 8 mL and receiver chamber opening area 1.00 cm 2 A jacketed Franz cell with a 100% elution buffer was used. The receiver medium was 1% sodium dodecyl sulfate (SDS) in Dulbecco's phosphate buffered saline (DPBS) without CaCl2 and MgCl2 at 32.5° C.

[0050] The laminated transdermal product sample was placed on a 1.6 cm 2 The release liner on the sample was then removed and the sample product was cut into 1.0 cm pieces. 2The donor chamber was then placed on the Franz receiver cell, completely covering the open area of ​​the donor chamber. The donor chamber was then attached onto the receiver cell, thereby completing the assembly of the test unit. 8.0 ml (pre-heated to 32.5° C.) of receiver medium was introduced into the receiver chamber and the timer was started. Sampling of the receiver medium was performed at the following time points: 6, 24, 48, 78, 143, and 168 hours (unless otherwise indicated in the table). After sampling at each time interval, the sampled receiver medium from the Franz cell was transferred to individual HPLC vials and assayed for FXa concentration using the HPLC method. After the completion of each sampling, the remaining contents in the receiver chamber were removed and a new 8.0 ml (pre-heated to 32.5° C.) of receiver medium was introduced into the receiver chamber. Drug release was then calculated for each sample.

[0051] References to "Crystals (Y / N)" in Tables 1 and 2 refer to visual observation of the adhesive layer after casting. A "Y" indicates that FXa crystals (in this case, apixaban crystals) were observed under a compound microscope (up to 400x magnification) or with the naked eye, e.g., as needle-like or fan-like objects, the presence of which is undesirable. An "N" indicates that such crystals were not observed with the naked eye or at 400x. These Y / N values ​​reflect observations of the adhesive layer made through three months after casting.

[0052] The data in Table 2 show that there was no crystal formation in the formulations containing crospovidone, where these formulations contained a 1:1 weight ratio of 7-4402 silicone adhesive:87-4098 acrylic adhesive. Complete (i.e., 100%) dissolution / drug release was achieved only in the formulations that contained crospovidone. Furthermore, the inclusion of 1-methyl-2-pyrrolidinone, a solvent for apixaban, apparently helped to provide the formulation with adequate drug release, but did not help to provide the formulation with the desired flux of apixaban. EXAMPLES

[0053] Exemplary transdermal apixaban formulations were prepared as described in Table 3 and tested as described in Example 1 to obtain their apixaban drug release profiles.

[0054] [Table 4]

[0055] This formulation was tested in triplicate and the average drug release values ​​of the three runs are shown in FIG.

[0056] [ka]

[0057] The examples demonstrate that approximately 100% of the drug is released within 7 days (168 hours). EXAMPLES

[0058] Exemplary transdermal apixaban formulations were prepared as described in Table 4 and tested over a 3-day or 7-day period to obtain their skin flux values, which were also compared against known transdermal apixaban formulations.

[0059] The formulations of Examples 2, 3, and 4 were prepared as described in Example 1. Example 22 from the known apixaban formulation, US Patent Application Publication No. US20200338012A1, was prepared as follows: 1.71 g of apixaban was weighed into a 100 ml glass jar, and then 9.40 g of acrylic acid, 9.40 g of lactic acid, 6.41 g of octanoic acid, 1.71 g of eugenol, and 4.28 g of methyl lactate were weighed into the jar. The contents of the jar were then vortexed until apixaban was completely dissolved. 42.21 g of Duro-Tak 87-2510 (40.5% solids) was then added to the apixaban solution and mixed at 2,000 rpm for 4 minutes. Each liquid formulation was then coated onto a 3 mil Scotchpak™ 9709 fluorosilicone release liner using a manual knife-on-roll lab coater with a 0.017 inch gap. The coated formulations were then dried at room temperature for 10 minutes and then at 70°C for 10 minutes. After drying, the formulations were laminated onto a 2 mil polyester backing film to obtain the transdermal dosage form. The actual mass of the dried coating layer was 6 mg / cm. 2 It was.

[0060] The in vitro cadaver skin permeation profiles (flux values) reported in this example were obtained using the following methodology: 8 mL receiver volume and 1.00 cm 2 A jacketed Franz cell was used with a receiver chamber opening area of ​​100 μm. The receiver medium was 1% sodium dodecyl sulfate (SDS) in Dulbecco's phosphate buffered saline (DPBS) without CaCl2 and MgCl2 at 32.5° C.

[0061] Frozen donor cadaver skin from the posterior torso was received and utilized in this study. The cadaver skin was quickly thawed in DPBS at 37.5°C for 20 minutes. 2Circular skin specimens were punched from the thawed cadaver skin and immediately placed, stratum corneum side up, on the receiver chamber of each vertical Franz cell. Approximately 6 ml of receiver medium at 32.5°C was transferred into each jacketed Franz cell, and the cadaver skin was allowed to equilibrate at 32.5°C for 1 hour with magnetic stirring.

[0062] Then, 0.785 cm from each dermal sample to be tested 2 The test was started by punching out a sample of 1.0 cm. The release liner on the sample was then removed and the sample was placed over the center of the Franz receiver cell containing the cadaver skin. The PET film was punched out (3.89 cm. 2 A donor chamber was then attached onto the receiver cell, thereby completing the assembly of the test unit. 8.0 ml (pre-heated to 32.5° C.) of receiver medium was introduced into the receiver chamber and a timer was started. Sampling of the receiver medium was performed at the following time points: 6, 24, 48, 78, 143, and 168 hours (except for Example 22 from US20200338012A1, where sampling ended at 72 hours). After sampling at each time interval, the sampled receiver medium from the Franz cell was transferred to individual HPLC vials and assayed for apixaban concentration using an HPLC method. After completion of each sampling, the remaining contents in the receiver chamber were removed and a new 8.0 ml of pre-heated (to 32.5° C.) receiver medium was introduced into the receiver chamber. The following was then calculated for each sample: Cumulative Delivery: μg / cm 2 / 7 days;Percentage of apixaban delivered after 7 days (%);Flux 0~168時間 :μg / cm 2 / hour; and t lag Values ​​obtained at various time points for the formulation described in Example 22 from U.S. Patent Application Publication No. US20200338012A1 were also calculated.

[0063] Each formulation was tested in triplicate and the average of the three runs is reported in Table 4.

[0064] [Table 5]

[0065] Certain results are reported graphically in the figures below.

[0066] FIG. 2 shows the mean cumulative apixaban delivery profile (of three runs) for each formulation in Table 4.

[0067] [ka]

[0068] FIG. 3 shows the apixaban flux profiles (from three runs) at various time intervals for each formulation in Table 4.

[0069] [ka]

[0070] The data show that formulation examples 2, 3, and 4 provide significantly higher drug delivery and flux profiles relative to Example 22 of U.S. Patent Application Publication No. US20200338012A1.

[0071] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0072] References to weight percent herein should be understood to describe the amount of a component or ingredient relative to the total weight of the adhesive layer formulation (the "dry composition"), unless otherwise contradicted by clear language or context, without any volatiles being removed upon drying.

[0073] The use of the terms "a," "an," "the," and "at least one," and similar referents in the context of describing the present invention (especially in the context of the claims that follow) shall be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term "at least one" before a list of one or more items (e.g., "at least one of A and B") shall be construed to mean one item selected from the listed items (A or B) or a combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" shall be construed as open-ended terms (i.e., "including, but not limited to"), unless otherwise indicated. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually set forth herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "exemplary," "etc.") provided herein is intended only to further clarify the invention, and does not pose a limitation on the scope of the invention unless otherwise asserted. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0074] Although preferred embodiments of the present invention are described herein, variations of these preferred embodiments may be apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that such variations will be employed by those skilled in the art as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Furthermore, any combination of the above-described elements in all possible variations thereof is encompassed by the present invention unless otherwise indicated herein or clearly contradicted by context.

Claims

1. A composition suitable for direct transdermal delivery of FXa to a patient in need thereof, comprising or consisting of one or more of betrixaban, edoxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, erivaxaban, or preferably apixaban, and a combination of FXa and C. ３ ~C ６ A composition comprising, consisting essentially of, or consisting of a fatty acid, a glycol ether, and a tackifier.

2. 10. The composition of claim 1, wherein the glycol ether is present in an amount ranging from about 5 to about 30 wt %, desirably from about 10 to about 25 wt %, and more desirably from about 15 to about 20 wt %, based on the total weight of the dry composition.

3. 3. The composition of claim 1, wherein the glycol ether is 2-phenoxyethanol.

4. C ３ ~C ６ 4. The composition of any one of claims 1 to 3, wherein the fatty acid is present in an amount ranging from about 5 to about 35 wt %, preferably from about 10 to about 30 wt %, and more preferably from about 15 to about 25 wt %, based on the total weight of the dry composition.

5. The composition according to claim 1 , wherein the adhesive comprises a silicone adhesive and an acrylic adhesive.

6. C ３ ~C ６ 6. The composition of any one of claims 1 to 5, wherein the weight ratio of fatty acid to glycol ether ranges from about 1:0.5 to about 1:2, more preferably from about 1:0.7 to about 1:1.5, even more preferably from about 1:0.8 to about 1:1.2, and most preferably about 1:

1.

7. About 5 to about 35 wt %, preferably about 10 to about 30 wt %, more preferably about 15 to about 25 wt %, C based on the total weight of the dry composition. １４ ~C ２２ 7. The composition of claim 1 further comprising a fatty acid.

8. 8. The composition of any one of claims 1 to 7, further comprising about 5 to about 35 wt%, about 7 to about 25 wt%, or more desirably about 10 to about 20 wt% of crospovidone, based on the total weight of the dry composition.

9. C ３ ~C ６ 9. The composition of any one of claims 1 to 8, wherein the weight ratio of fatty acid to glycol ether ranges from about 1:0.5 to about 1:2, more preferably from about 1:0.7 to about 1:1.5, even more preferably from about 1:0.8 to about 1:1.2, and most preferably about 1:

1.

10. 10. The composition of any one of claims 1 to 9, wherein FXa is present in the composition in an amount ranging from about 2 to about 20 wt%, preferably from about 3 wt% to about 15 wt%, even more preferably from about 4 wt% to about 12 wt%, even more preferably from about 5 wt% to about 10 wt%, and even more preferably from about 6 wt% to about 8 wt%, based on the weight of the dry composition.

11. 11. The composition of any one of claims 1 to 10, wherein FXa is apixaban.

12. A composition suitable for direct transdermal delivery of FXa to a patient in need thereof, comprising about 4 wt % to about 12 wt % apixaban and about 15 wt % to about 25 wt % C, based on the total weight of the dry composition. ３ ~C ６ 1. A composition comprising, consisting essentially of, or consisting of a fatty acid, about 15 wt % to about 25 wt % of a glycol ether, about 15 wt % to about 30 wt % of a silicone-based adhesive, about 15 wt % to about 30 wt % of an acrylic-based adhesive, and about 10 wt % to about 20 wt % of crospovidone.

13. About 4 wt % to about 12 wt % C based on the total weight of the dry composition １６ ~C ２０ The composition of claim 12 further comprising a fatty acid.

14. A composition suitable for direct transdermal delivery of FXa to a patient in need thereof, comprising about 5 wt % to about 8 wt % apixaban and about 18 wt % to about 25 wt % C, based on the total weight of the dry composition. ３ ~C ６ 1. A composition comprising, consisting essentially of, or consisting of a fatty acid, about 18 wt % to about 22 wt % of a glycol ether, about 20 wt % to about 25 wt % of a silicone-based adhesive, about 20 wt % to about 25 wt % of an acrylic-based adhesive, and about 10 wt % to about 20 wt % of crospovidone.

15. About 5 wt % to about 10 wt % C based on the total weight of the dry composition １６ ~C ２０ The composition of claim 12 further comprising a fatty acid.

16. 16. The composition of claim 1 further comprising an antioxidant.

17. 17. The composition of claim 1, further comprising a chelating agent.

18. 18. The composition of any one of claims 1 to 17, wherein the drug release rate of the API-containing adhesive layer is in the range of at least about 30, 35, or 40% to about 45, 50, 55, or 60% of the drug from the adhesive layer in 1 day, and / or at least about 70, 75, 80, 85, or 90% and not more than about 92, 95, 97, or 99% in 7 days, as determined by the methodology described in paragraphs [0047] to [0048] herein.

19. The transdermal flux of the API-containing adhesive layer is at least about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or 6.5 μg / cm for 1, 2, 3, 4, 5, 6, or 7 days. ２ / hour and about 7, 7.5, 8, 9, or 10 μg / cm ２ 18. The composition of claim 1, wherein the flux is in the range of 0.1 to 1.5 times the flux per hour, and the flux is determined by the cadaver skin methodology described in paragraphs [0058] to [0060] herein.

20. 18. The composition of any one of claims 1 to 17, wherein FXa is apixaban and the amount of apixaban in the composition is sufficient to provide a steady state plasma concentration in the range of about 70 to about 320 ng / mL (peak) and about 30 to about 230 ng / mL (trough) for 3, 4, 5, 6, 7, 8, 9, or 10 days in an AF patient.

21. 18. The composition of any one of claims 1 to 17, wherein FXa is apixaban and the amount of apixaban in the composition is sufficient to provide a steady state plasma concentration in the range of about 30 to about 575 ng / mL (peak) and about 10 to about 340 ng / mL (trough) for 3, 4, 5, 6, 7, 8, 9, or 10 days in a patient suffering from venous thromboembolism.

22. 18. The composition of any one of claims 1 to 17, which provides a therapeutically effective amount of FXa to a patient in need thereof for 3, 4, 5, 6, 7, 8, 9, or 10 days.

23. A method for preparing a transdermal patch suitable for direct transdermal delivery of FXa to a patient in need thereof, comprising: ３ ~C ６ 1. A method comprising, consisting essentially of, or consisting of the steps of: mixing a fatty acid with a glycol ether to obtain a premix and adding an adhesive to the premix to obtain a liquid; applying the liquid onto a release liner; drying the liquid to obtain a coating on the release liner; and laminating the coating onto a support layer.

24. 24. The method of claim 23, wherein the glycol ether is present in an amount ranging from about 5 to about 30 wt %, desirably from about 10 to about 25 wt %, and more desirably from about 15 to about 20 wt %, based on the total weight of the dry composition.

25. The method of claim 23 or 24, wherein the glycol ether is 2-phenoxyethanol.

26. C ３ ~C ６ 26. The method of any one of claims 23 to 25, wherein the fatty acid is present in an amount ranging from about 5 to about 35 wt%, preferably from about 10 to about 30 wt%, more preferably from about 15 to about 25 wt%, based on the total weight of the dry composition.

27. 27. The method of any one of claims 23 to 26, wherein the adhesive comprises a silicone adhesive and an acrylic adhesive.

28. C ３ ~C ６ 28. The method of any one of claims 23 to 27, wherein the weight ratio of fatty acid to glycol ether ranges from about 1:0.5 to about 1:2, more preferably from about 1:0.7 to about 1:1.5, even more preferably from about 1:0.8 to about 1:1.2, and most preferably about 1:

1.

29. About 5 to about 35 wt %, preferably about 10 to about 30 wt %, more preferably about 15 to about 25 wt %, C based on the total weight of the dry composition. １４ ~C ２２ 29. The method of any one of claims 23 to 28, further comprising a fatty acid.

30. 30. The method of any one of claims 23 to 29, further comprising about 5 to about 35 wt%, about 7 to about 25 wt%, or more desirably about 10 to about 20 wt% of crospovidone, based on the total weight of the dry composition.

31. C ３ ~C ６ 31. The method of any one of claims 23 to 30, wherein the weight ratio of fatty acid to glycol ether ranges from about 1:0.5 to about 1:2, more preferably from about 1:0.7 to about 1:1.5, even more preferably from about 1:0.8 to about 1:1.2, and most preferably about 1:

1.

32. 32. The method of any one of claims 23 to 31, wherein FXa is present in the composition in an amount ranging from about 2 to about 20 wt%, preferably from about 3 wt% to about 15 wt%, even more preferably from about 4 wt% to about 12 wt%, even more preferably from about 5 wt% to about 10 wt%, and even more preferably from about 6 wt% to about 8 wt%, based on the weight of the dry composition.

33. 33. The method of any one of claims 23 to 32, wherein FXa is apixaban.

34. A method for transdermal administration of direct FXa to a patient in need thereof, comprising the step of applying a transdermal patch onto the skin of a patient in need thereof, the patch comprising, consisting essentially of, or consisting of a backing layer and an API-containing adhesive layer, the API-containing adhesive layer comprising or consisting of one or more of betrixaban, edoxaban, fondaparinux, rivaroxaban, darexaban, otamixaban, retaxaban, elivaxaban, or preferably apixaban, FXa, C ３ ~C ６ The method comprises, consists essentially of, or consists of a fatty acid, a glycol ether, and an adhesive, wherein the API-containing adhesive layer is in direct contact with the skin.

35. 35. The method of claim 34, wherein the glycol ether is present in an amount ranging from about 5 to about 30 wt %, desirably from about 10 to about 25 wt %, and more desirably from about 15 to about 20 wt %, based on the total weight of the dry composition.

36. The method of claim 34 or 35, wherein the glycol ether is 2-phenoxyethanol.

37. C ３ ~C ６ 37. The method of any one of claims 34 to 36, wherein the fatty acid is present in an amount ranging from about 5 to about 35 wt%, preferably from about 10 to about 30 wt%, more preferably from about 15 to about 25 wt%, based on the total weight of the dry composition.

38. 38. The method of any one of claims 34 to 37, wherein the adhesive comprises a silicone adhesive and an acrylic adhesive.

39. C ３ ~C ６ 39. The method of any one of claims 34 to 38, wherein the weight ratio of fatty acid to glycol ether ranges from about 1:0.5 to about 1:2, more preferably from about 1:0.7 to about 1:1.5, even more preferably from about 1:0.8 to about 1:1.2, and most preferably about 1:

1.

40. About 5 to about 35 wt %, preferably about 10 to about 30 wt %, more preferably about 15 to about 25 wt %, C based on the total weight of the dry composition. １４ ~C ２２ 40. The method of any one of claims 34 to 39, further comprising a fatty acid.

41. 41. The method of any one of claims 34 to 40, further comprising about 5 to about 35 wt%, about 7 to about 25 wt%, or more desirably about 10 to about 20 wt% of crospovidone, based on the total weight of the dry composition.

42. C ３ ~C ６ 42. The method of any one of claims 34 to 41, wherein the weight ratio of fatty acid to glycol ether ranges from about 1:0.5 to about 1:2, more preferably from about 1:0.7 to about 1:1.5, even more preferably from about 1:0.8 to about 1:1.2, and most preferably about 1:

1.

43. 43. The method of any one of claims 34 to 42, wherein FXa is present in the composition in an amount ranging from about 2 to about 20 wt%, preferably from about 3 wt% to about 15 wt%, even more preferably from about 4 wt% to about 12 wt%, even more preferably from about 5 wt% to about 10 wt%, and even more preferably from about 6 wt% to about 8 wt%, based on the weight of the dry composition.

44. 44. The method of any one of claims 34 to 43, wherein FXa is apixaban.

45. 45. The method of any one of claims 34 to 44, wherein a patient in need thereof is in need of treatment for a thromboembolic disorder.

46. 45. The method of any one of claims 34 to 44, wherein a patient in need thereof is undergoing or has undergone within the last week a knee or hip replacement.

47. 45. The method of any one of claims 34 to 44, wherein a patient in need thereof suffers from atrial fibrillation and is at risk of stroke and / or embolism.

48. 20. Use of a composition according to any one of claims 1 to 19 in the treatment of a patient suffering from a thromboembolic disorder.

49. 20. Use of a composition according to any one of claims 1 to 19 in the treatment of patients suffering from atrial fibrillation and at risk of stroke and / or embolism.

50. 20. Use of a composition according to any one of claims 1 to 19 in the treatment of a patient undergoing or who has undergone a total knee or hip replacement.

51. 20. Use of a composition according to any one of claims 1 to 19 in the treatment of a patient who has previously suffered from deep vein thrombosis or pulmonary embolism to reduce the risk of recurrence of deep vein thrombosis or pulmonary embolism.

52. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of a patient suffering from a thromboembolic disorder.

53. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of patients suffering from atrial fibrillation and at risk of stroke and / or embolism.

54. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of patients who are undergoing or have undergone within the last week a knee or hip replacement.

55. 20. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment of a patient previously affected by deep vein thrombosis or pulmonary embolism to reduce the risk of recurrence of deep vein thrombosis or pulmonary embolism.

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