Transdermal anticoagulant composition

Abstract

The present disclosure provides a pharmaceutical composition comprising an anticoagulant and pyruvic acid. Also, by including a dosage form comprising the pharmaceutical composition, and a step of administering the pharmaceutical composition or the transdermal patch described herein to a patient, for treating thrombotic and embolic disorders in a patient in need thereof, for reducing the recurrence of deep vein thrombosis or pulmonary embolism in a patient in need thereof, for preventing venous thromboembolism (VTE) in a patient with an acute disease, for reducing the risk of major cardiovascular events in a patient with coronary artery disease, for reducing the risk of major thrombotic vascular events in a patient with peripheral artery disease (PAD), for treating VTE, or for reducing the recurrence risk of VTE in a pediatric patient in need thereof, for thrombo - prevention in a patient with congenital heart disease after Fontan procedure, for treating atherosclerosis, myocardial infarction, pulmonary embolism or deep vein thrombosis in a patient in need thereof, or for preventing one or more thrombotic or hemorrhagic events in a patient with atrial fibrillation, a method is also provided.

Description

Technical Field

[0001] Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 391,127, filed Jul. 21, 2022, the disclosure of which is incorporated herein by reference.

[0002] This disclosure relates to anticoagulant compositions and methods of using the same.

Background Art

[0003] Apixaban (Eliquis®), Rivaroxaban (Xarelto®), and Edoxaban (Savaysa®), which are factor Xa inhibitors of coagulation, are used for the prevention and treatment of deep vein thrombosis in at-risk patients such as those with atrial fibrillation or patients undergoing major knee or hip surgery. All of them are administered orally once or twice a day, and the treatment often lasts for a long time or becomes chronic.

[0004] All of the aforementioned products exhibit a pharmacokinetic profile characteristic of orally administered drugs, i.e., peak and trough patterns of circulating drug levels. Considering normal inter-individual variability, the peak value after administration may cause excessive anticoagulation, while the trough value prior to each subsequent administration may be below the therapeutic degree of anticoagulation (i.e., thrombotic tendency) during the day when the relative activity of the coagulation cascade varies. As a result, among the patients administered these drugs, although a small number, it is inevitable that they will experience bleeding (hemorrhagic) or ischemic (thrombotic) events during treatment. Some of these events are minor, but even serious and fatal bleeding events occur regularly. Considering the very wide use of these drugs, the absolute number of patients experiencing safety-harmful events due to this problem is considerable.

[0005] The drawback of this class of drugs is that they are difficult to be efficiently transported across the skin.

[0006] A safer and more efficient method is needed for administering anticoagulants to patients.

Summary of the Invention

[0007] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an anticoagulant and pyruvic acid.

[0008] In other embodiments, the present disclosure provides a dosage form comprising the pharmaceutical composition described herein. In certain embodiments, the dosage form is a transdermal patch. In other embodiments, the dosage form is a transdermal gel.

[0009] In a further embodiment, the present disclosure provides a method for treating a thromboembolic disorder in a patient in need thereof, the method comprising administering to the patient the pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0010] In yet another embodiment, the present disclosure provides a method for preventing deep vein thrombosis or pulmonary embolism in a patient in need thereof, the method comprising administering to the patient the pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0011] In a further embodiment, the present disclosure provides a method for reducing the recurrence of deep vein thrombosis or pulmonary embolism in a patient in need thereof, the method comprising administering to the patient the pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0012] In other embodiments, the present disclosure provides a method for preventing venous thromboembolism (VTE) in a patient with an acute disease, the method comprising administering to the patient the pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0013] In a further embodiment, the present disclosure provides a method for reducing the risk of major cardiovascular events in a patient having coronary artery disease, the method comprising administering to the patient the pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0014] In yet other embodiments, the present disclosure provides a method for reducing the risk of major thrombotic vascular events in patients having peripheral artery disease (PAD), comprising administering to a patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0015] In further embodiments, the present disclosure provides a method for treating VTE or reducing the risk of recurrence of VTE in pediatric patients in need thereof, comprising administering to a patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0016] In other embodiments, the present disclosure provides a method for thrombo - prophylaxis in patients having congenital heart disease after the Fontan procedure, comprising administering to a patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0017] In further embodiments, the present disclosure provides a method for treating atherosclerosis, myocardial infarction, pulmonary embolism or deep vein thrombosis in patients in need thereof, comprising administering to a patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0018] In still other embodiments, the present disclosure provides a method for preventing one or more thrombo - embolic events in patients with atrial fibrillation, comprising administering to a patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0019] In further embodiments, the present disclosure provides a method for reducing the risk of stroke or systemic embolism in a patient, comprising administering to a patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch. In some embodiments, the patient has non - valvular atrial fibrillation. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The summary and the following detailed description will be further understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the present invention, exemplary embodiments of the present invention are shown in the drawings, but the present invention is not limited to the specific methods, compositions, and apparatuses disclosed. Further, the drawings are not necessarily drawn to scale.

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Mode for Carrying Out the Invention

[0021] This disclosure can be more readily understood by reference to the following detailed description taken in conjunction with the accompanying drawings and examples, which form a part of this disclosure. It is to be understood that this disclosure is not limited to the specific apparatus, methods, uses, conditions or parameters described and / or shown herein, and that the terms used herein are for the purpose of describing particular embodiments by way of example and are not intended to limit the claimed invention.

[0022] When a list is presented, unless otherwise stated, each individual element of that list and all combinations of that list are to be understood as separate embodiments. For example, a list of embodiments presented as "A, B, or C" is a power set that includes the embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0023] It is to be understood that specific features of the present invention described in the context of separate embodiments may also be provided in combination in a single embodiment for clarity. Conversely, various features of the present invention described in the context of a single embodiment may also be provided separately or in any sub-combination for brevity. Further, references to values within a range include each value within that range and each value including that value. Additionally, it should be noted that the claims can be drafted to exclude any element. Thus, this specification is intended to serve as antecedent basis when using exclusive terms such as "only", "solely", etc. in relation to the recitation of claim elements, or when using "negative" limitations. Finally, embodiments may be described as part of a series of steps or as part of a more general structure, but each of the foregoing steps may also be considered an independent embodiment in itself.

[0024] In the present disclosure, the singular forms "a", "an", and "the" include plural references, and references to a particular numerical value include at least that particular value unless the context clearly indicates otherwise. Thus, for example, reference to "a therapeutic agent" is a reference to at least one such therapeutic agent known to those of ordinary skill in the art and its equivalents.

[0025] When values are presented as approximations by use of the antecedent "about", it will be understood that a particular value forms a separate embodiment. In general, the use of the term "about" indicates an approximation that may vary depending on the desired characteristics to be obtained by the disclosed subject matter and should be interpreted in the context in which it is used based on its function, and one of ordinary skill in the art will be able to so interpret it. In some cases, the number of significant figures used for a particular value may be one non-limiting way of determining the scope of the term "about". In other cases, the gradation used in a series of values can be used to determine the intended scope within which the term "about" can be used for each value.

[0026] In this specification, when ranges are used for physical properties such as amounts or weight %, all combinations and sub-combinations of ranges for specific embodiments therein are intended to be included.

[0027] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government or corresponding regulatory agencies in a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in animals, and more particularly in humans.

[0028] As used herein, the terms "patient" or "subject" refer to a mammal and are used interchangeably. In some embodiments, the patient or subject is human. In further embodiments, the patient or subject is an adult, i.e., 18 years of age or older. In still other embodiments, the patient or subject is a pediatric (pediatric patient), i.e., less than 18 years of age. In further embodiments, the patient or subject is 2 years of age or older. In other embodiments, the patient has atrial fibrillation such as non-valvular atrial fibrillation. In further embodiments, the patient has undergone hip or knee replacement surgery. In still other embodiments, the patient has congenital heart disease after the Fontan procedure. In still other embodiments, the patient recently underwent lower limb revascularization for symptomatic peripheral artery disease (PAD). In still other embodiments, the patient has an acute disease. In yet another embodiment, the patient has coronary artery disease. In other embodiments, the patient has PAD.

[0029] "Treating" any disease or disorder, in some embodiments, refers to ameliorating the disease or disorder (i.e., preventing or reducing the onset of at least one of the disease or its clinical symptoms). In some embodiments, "treating" or "treatment" refers to improving at least one physical parameter that may not be distinguishable by the subject. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of distinguishable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In further embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0030] The present disclosure provides pharmaceutical compositions and dosage units for delivering an anticoagulant to a patient in need thereof. The compositions described herein enable the permeation of an anticoagulant through human skin. Desirably, the pharmaceutical compositions and dosage forms described herein are lacking in acrylic acid that inhibits the permeation of the anticoagulant across human skin.

[0031] Pharmaceutical composition The present disclosure provides a pharmaceutical composition comprising an anticoagulant and pyruvic acid. As used herein, the term "anticoagulant" refers to a chemical compound or small molecule that delays or inhibits blood clotting. In some embodiments, the anticoagulant is a thrombin inhibitor, a factor Xa inhibitor, a factor XIa inhibitor, or low molecular weight heparin. In other embodiments, the anticoagulant is a thrombin inhibitor. Examples of thrombin inhibitors include, but are not limited to, dabigatran, bivalirudin, lepirudin, or desirudin. In certain embodiments, the thrombin inhibitor is dabigatran. In other embodiments, the anticoagulant is low molecular weight heparin. Examples of low molecular weight heparin include, but are not limited to, enoxaparin. In further embodiments, the anticoagulant is a factor Xa inhibitor. Examples of factor Xa inhibitors include, but are not limited to, apixaban, rivaroxaban, edoxaban, betrixaban, or fondaparinux. In some embodiments, the anticoagulant is apixaban. In still other embodiments, the anticoagulant is a factor XIa inhibitor. Examples of factor XIa inhibitors include, but are not limited to, milvexian or asundexian.

[0032] The pharmaceutical composition of the present disclosure may contain about 5 to about 25% by weight of an anticoagulant based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25% by weight of an anticoagulant. In other embodiments, the pharmaceutical composition contains about 5 to about 24, about 5 to about 23, about 5 to about 22, about 5 to about 21, about 5 to about 20, about 5 to about 19, about 5 to about 18, about 5 to about 17, about 5 to about 16, about 5 to about 15, about 5 to about 14, about 5 to about 13, about 5 to about 12, about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 25, about 6 to about 24, about 6 to about 23, about 6 to about 22, about 6 to about 21, about 6 to about 20, about 6 to about 19, about 6 to about 18, about 6 to about 17, about 6 to about 16, about 6 to about 15, about 6 to about 14, about 6 to about 13, about 6 to about 12, about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 25, about 7 to about 24, about 7 to about 23, about 7 to about 22, about 7 to about 21, about 7 to about 20, about 7 to about 19, about 7 to about 18, about 7 to about 17, about 7 to about 16, about 7 to about 15, about 7 to about 14, about 7 to about 13, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 25, about 8 to about 24, about 8 to about 23, about 8 to about 22, about 8 to about 21, about 8 to about 20, about 8 to about 19, about 8 to about 18, about 8 to about 17, about 8 to about 16, about 8 to about 15, about 8 to about 14, about 8 to about 13, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 25, about 9 to about 24, about 9 to about 23, about 9 to about 22, about 9 to about 21, about 9 to about 20, about 9 to about 19, about 9 to about 18, about 9 to about 17, about 9 to about 16, about 9 to about 15, about 9 to about 14, about 9 to about 13, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 25, about 10 to about 24, m about 10 to about 23, about 10 to about 22, about 10 to about 21, about 10 to about 20, about 10 to about 19, about 10 to about 18, about 10 to about 17, about 10 to about 16, about 10 to about 15, about 10 to about 14, about 10 to about 13, about 10 to about 12, about 10 to about 11, about 11 to about 25, about 11 to about 24, about 11 to about 23, about 11 to about 22, about 11 to about 21, about 11 to about 20, about 11 to about 19, about 11 to about 18, about 11 to about 17,From about 11 to about 16, from about 11 to about 15, from about 11 to about 14, from about 11 to about 13, from about 11 to about 12, from about 12 to about 25, from about 12 to about 24, from about 12 to about 23, from about 12 to about 22, from about 12 to about 21, from about 12 to about 20, from about 12 to about 19, from about 12 to about 18, from about 12 to about 17, from about 12 to about 16, from about 12 to about 15, from about 12 to about 14, from about 12 to about 13, from about 13 to about 25, from about 13 to about 24, from about 13 to about 23, from about 13 to about 22, from about 13 to about 21 m, from about 13 to about 20 m, from about 13 to about 19 m, from about 13 to about 18 m, from about 13 to about 17 m, from about 13 to about 16 m, from about 13 to about 15 m, from about 13 to about 14 m, from about 14 to about 25 m, from about 14 to about 24 m, from about 14 to about 23 m, from about 14 to about 22 m, from about 14 to about 21 m, from about 14 to about 20, from about 14 to about 19, from about 14 to about 18, from about 14 to about 17, from about 14 to about 16, from about 14 to about 15, from about 15 to about 25, from about 15 to about 24, from about 15 to about 23, from about 15 to about 22, from about 15 to about 21, from about 15 to about 20, from about 15 to about 19, from about 15 to about 18, from about 15 to about 17, from about 15 to about 16, from about 16 to about 25, from about 16 to about 24, from about 16 to about 23, from about 16 to about 22, from about 16 to about 21, from about 16 to about 20, from about 16 to about 19, from about 16 to about 18, from about 16 to about 17, from about 17 to about 25, from about 17 to about 24, from about 17 to about 23, from about 17 to about 22, from about 17 to about 21, from about 17 to about 20, from about 17 to about 19, from about 17 to about 18, from about 18 to about 25, from about 18 to about 24, from about 18 to about 23, from about 18 to about 22, from about 18 to about 21, from about 18 to about 20, from about 18 to about 19, from about 19 to about 25, from about 19 to about 24, from about 19 to about 23, from about 19 to about 22, from about 19 to about 21, from about 19 to about 20, from about 20 to about 25, from about 20 to about 24, from about 20 to about 23, from about 20 to about 22, from about 20 to about 21, from about 21 to about 25, based on the weight of the pharmaceutical composition, about 21 to about 24 wt%, about 21 to about 23 wt%, about 21 to about 22 wt%, about 22 to about 25 wt%, about 22 to about 24 wt%, about 22 to about 23 wt%, about 23 to about 25 wt%, about 23 to about 24 wt% or about 24 to about 25 wt%. In further embodiments, the pharmaceutical composition comprises about 7 to about 12 wt% anticoagulant, based on the weight of the pharmaceutical composition. In still other embodiments, the pharmaceutical composition comprises about 9 wt% anticoagulant, based on the weight of the pharmaceutical composition. In yet another embodiment, the pharmaceutical composition comprises about 10 wt% anticoagulant, based on the weight of the pharmaceutical composition. In other embodiments, the pharmaceutical composition is,It contains about 11% by weight of an anticoagulant based on the weight of the pharmaceutical composition.

[0033] According to the present disclosure, the pharmaceutical composition also contains pyruvic acid. The pharmaceutical composition may contain from about 20% to about 90% by weight of pyruvic acid, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight of pyruvic acid, based on the weight of the pharmaceutical composition.In other embodiments, the pharmaceutical composition comprises from about 20 to about 85, from about 20 to about 80, from about 20 to about 75, from about 20 to about 70, from about 20 to about 60, from about 20 to about 55, from about 20 to about 50, from about 20 to about 45, from about 20 to about 40, from about 20 to about 35, from about 20 to about 30, from about 20 to about 25, from about 25 to about 90, from about 25 to about 85, from about 25 to about 80, from about 25 to about 75, from about 25 to about 70, from about 25 to about 65, from about 25 to about 60, from about 25 to about 55, from about 25 to about 50, from about 25 to about 45, from about 25 to about 40, from about 25 to about 35, from about 25 to about 30, from about 30 to about 90, from about 30 to about 85, from about 30 to about 80, from about 30 to about 75, from about 30 to about 70, from about 30 to about 65, from about 30 to about 60, from about 30 to about 55, from about 30 to about 50, from about 30 to about 45, from about 30 to about 40, from about 35 to about 90, from about 35 to about 85, from about 35 to about 80, from about 35 to about 75, from about 35 to about 70, from about 35 to about 65, from about 35 to about 60, from about 35 to about 55, from about 35 to about 50, from about 35 to about 45, from about 30 to about 40, from about 40 to about 90, from about 40 to about 85, from about 40 to about 80, from about 40 to about 75, from about 40 to about 70, from about 40 to about 65, from about 40 to about 60, from about 40 to about 55, from about 40 to about 50, from about 40 to about 45, from about 45 to about 90, from about 45 to about 85, from about 45 to about 80, from about 45 to about 75, from about 45 to about 70, from about 45 to about 65, from about 45 to about 60, from about 45 to about 55, from about 45 to about 50, from about 50 to about 90, from about 50 to about 85, from about 50 to about 80, from about 50 to about 75, from about 50 to about 70, from about 50 to about 65, from about 50 to about 60, from about 50 to about 55, from about 55 to about 90, from about 55 to about 85, from about 55 to about 80, from about 55 to about 75, from about 55 to about 70, from about 55 to about 65, from about 55 to about 60, from about 60 to about 90, from about 60 to about 85, from about 60 to about 80, from about 60 to about 75, from about 60 to about 70, from about 60 to about 65, from about 65 to about 90, from about 65 to about 85, from about 65 to about 80, from about 65 to about 75, from about 65 to about 70, based on the weight of the pharmaceutical composition, from about 70 to about 90 wt%, from about 70 to about 85 wt%, from about 70 to about 80 wt%, from about 70 to about 75 wt%, from about 75 to about 90 wt%, from about 75 to about 85 wt%, from about 75 to about 80 wt%, from about 80 to about 90 wt%, from about 80 to about 85 wt%, or from about 85 to about 90 wt% of pyruvic acid. In a further embodiment, the pharmaceutical composition comprises from about 25 to about 45 wt% of pyruvic acid based on the weight of the pharmaceutical composition.In yet other embodiments, the pharmaceutical composition comprises from about 30% to about 45% by weight of pyruvic acid, based on the weight of the pharmaceutical composition.

[0034] The pharmaceutical compositions described herein can also include a surfactant, a penetration enhancer, or a combination thereof. In some embodiments, the pharmaceutical composition includes a surfactant. In other embodiments, the pharmaceutical composition includes a penetration enhancer. In further embodiments, the pharmaceutical composition includes a surfactant and a penetration enhancer. Examples of surfactants or penetration enhancers include, but are not limited to, dimethyl sulfoxide (DMSO); low molecular weight acids such as 3-hydroxypropionic acid, lactic acid, oleic acid, levulinic acid, glycolic acid, or malonic acid; nonionic surfactants; polyethylene glycol monooleyl ether; dimethylacetamide (DMAc); or dimethyl isosorbide (DMI).

[0035] In certain embodiments, the surfactant or penetration enhancer is dimethyl sulfoxide (DMSO). The pharmaceutical composition may contain from about 5 to about 20% by weight of DMSO, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20% by weight of DMSO, based on the weight of the pharmaceutical composition.In other embodiments, the pharmaceutical composition comprises from about 5 to about 19, from about 5 to about 18, from about 5 to about 17, from about 5 to about 16, from about 5 to about 15, from about 5 to about 14, from about 5 to about 13, from about 5 to about 12, from about 5 to about 11, from about 5 to about 10, from about 5 to about 9, from about 5 to about 8, from about 5 to about 7, from about 5 to about 6, from about 6 to about 20, from about 6 to about 19, from about 6 to about 18, from about 6 to about 17, from about 6 to about 16, from about 6 to about 15, from about 6 to about 14, from about 6 to about 13, from about 6 to about 12, from about 6 to about 11, from about 6 to about 10, from about 6 to about 9, from about 6 to about 8, from about 6 to about 7, from about 7 to about 20, from about 7 to about 19, from about 7 to about 18, from about 7 to about 17, from about 7 to about 16, from about 7 to about 15, from about 7 to about 14, from about 7 to about 13, from about 7 to about 12, from about 7 to about 11, from about 7 to about 10, from about 7 to about 9, from about 7 to about 8, from about 8 to about 20, from about 8 to about 19, from about 8 to about 18, from about 8 to about 17, from about 8 to about 16, from about 8 to about 15, from about 8 to about 14, from about 8 to about 13, from about 8 to about 12, from about 8 to about 11m, from about 8 to about 10, from about 8 to about 9, from about 9 to about 20, from about 9 to about 19, from about 9 to about 18, from about 9 to about 17, from about 9 to about 16, from about 9 to about 15, from about 9 to about 14, from about 9 to about 13, from about 9 to about 12, from about 9 to about 11, from about 9 to about 10, from about 10 to about 20, from about 10 to about 19, from about 10 to about 18, from about 10 to about 17, from about 10 to about 16, from about 10 to about 15, from about 10 to about 14, from about 10 to about 13, from about 10 to about 12, from about 10 to about 11, from about 11 to about 20, from about 11 to about 19, from about 11 to about 18, from about 11 to about 17, from about 11 to about 16, from about 11 to about 15, from about 11 to about 14, from about 11 to about 13, from about 11 to about 12, from about 12 to about 20, from about 12 to about 19, from about 12 to about 18, from about 12 to about 17, from about 12 to about 16, from about 12 to about 15, from about 12 to about 14, from about 12 to about 13, from about 13 to about 20, from about 13 to about 19, from about 13 to about 18, from about 13 to about 17, from about 13 to about 16, from about 13 to about 15, from about 13 to about 14, from about 14 to about 20, from about 14 to about 19, from about 14 to about 18, from about 14 to about 17, from about 14 to about 16, from about 14 to about 15, from about 15 to about 20, from about 15 to about 19, from about 15 to about 18, from about 15 to about 17, from about 15 to about 16, from about 16 to about 20, from about 16 to about 19, from about 16 to about 18, from about 16 to about 17, from about 17 to about 20, from about 17 to about 19, from about 17 to about 18, from about 18 to about 20, from about 18 to about 19, or from about 19 to about 20 weight % of DMSO, based on the weight of the pharmaceutical composition. In a further embodiment, the pharmaceutical composition comprises from about 8 to about 15 weight % of DMSO, based on the weight of the pharmaceutical composition.

[0036] In other embodiments, the surfactant or penetration enhancer is lactic acid. The pharmaceutical composition may contain from about 20 to about 45 weight percent lactic acid, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains from about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, or about 45 weight percent lactic acid, based on the weight of the pharmaceutical composition. In other embodiments, the pharmaceutical composition contains from about 20 to about 40 weight percent, from about 20 to about 35 weight percent, from about 20 to about 30 weight percent, from about 20 to about 25 weight percent, from about 25 to about 45 weight percent, from about 25 to about 40 weight percent, from about 25 to about 35 weight percent, from about 25 to about 30 weight percent, from about 30 to about 45 weight percent, from about 30 to about 40 weight percent, from about 30 to about 35 weight percent, from about 35 to about 45 weight percent, from about 30 to about 40 weight percent, or from about 40 to about 45 weight percent lactic acid, based on the weight of the pharmaceutical composition. In further embodiments, the pharmaceutical composition contains from about 25 to about 35 weight percent lactic acid, based on the weight of the pharmaceutical composition.

[0037] In a further aspect, the surfactant or penetration enhancer is oleic acid. The pharmaceutical composition may contain from about 1 to about 10% by weight of oleic acid, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains from about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10% by weight of lactic acid, based on the weight of the pharmaceutical composition. In other embodiments, the pharmaceutical composition contains from about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8% by weight, about 6 to about 7% by weight, about 7 to about 10% by weight, about 7 to about 9% by weight, about 7 to about 8% by weight, about 8 to about 10% by weight, about 8 to about 9% by weight, or about 9 to about 10% by weight of lactic acid, based on the weight of the pharmaceutical composition. In a further embodiment, the pharmaceutical composition contains from about 3 to about 7% by weight of lactic acid, based on the weight of the pharmaceutical composition. In still other embodiments, the pharmaceutical composition contains from about 1 to about 5% by weight of lactic acid, based on the weight of the pharmaceutical composition.

[0038] In yet other embodiments, the surfactant or penetration enhancer is rebriciclib. The pharmaceutical composition may contain from about 1% to about 20% by weight of rebriciclib, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition includes about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20. In other embodiments, the pharmaceutical composition contains from about 1% to about 18%, from about 1% to about 16%, from about 1% to about 14%, from about 1% to about 12%, from about 1% to about 10%, from about 1% to about 8%, from about 1% to about 6%, from about 1% to about 4%, from about 1% to about 3%, from about 3% to about 20%, from about 3% to about 18%, from about 3% to about 16%, from about 3% to about 14%, from about 3% to about 12%, from about 3% to about 10%, from about 3% to about 8%, from about 3% to about 6%, from about 3% to about 5%, from about 5% to about 19%, from about 5% to about 18%, from about 5% to about 17%, from about 5% to about 16%, from about 5% to about 15%, from about 5% to about 14%, from about 5% to about 13%, from about 5% to about 12%, from about 5% to about 11%, from about 5% to about 10%, from about 5% to about 9%, from about 5% to about 8%, from about 5% to about 7%, from about 5% to about 6%, from about 6% to about 20%, from about 6% to about 19%, from about 6% to about 18%, from about 6% to about 17%, from about 6% to about 16%, from about 6% to about 15%, from about 6% to about 14%, from about 6% to about 13%, from about 6% to about 12%, from about 6% to about 11%, from about 6% to about 10%, from about 6% to about 9%, from about 6% to about 8%, from about 6% to about 7%, from about 7% to about 20%, from about 7% to about 19%, from about 7% to about 18%, from about 7% to about 17%, from about 7% to about 16%, from about 7% to about 15%, from about 7% to about 14%, from about 7% to about 13%, from about 7% to about 12%, from about 7% to about 11%, from about 7% to about 10%, from about 7% to about 9%, from about 7% to about 8%, from about 8% to about 20%, from about 8% to about 19%, from about 8% to about 18%, from about 8% to about 17%, from about 8% to about 16%, from about 8% to about 15%, from about 8% to about 14%, from about 8% to about 13%, from about 8% to about 12%, from about 8% to about 11%, from about 8% to about 10%, from about 8% to about 9%, from about 9% to about 20%, from about 9% to about 19%, from about 9% to about 18%, from about 9% to about 17%, from about 9% to about 16%, from about 9% to about 15%, from about 9% to about 14%, from about 9% to about 13%, from about 9% to about 12%, from about 9% to about 11%, from about 9% to about 10%, from about 10% to about 20%, from about 10% to about 19%, from about 10% to about 18%, from about 10% to about 17%, from about 10% to about 16%, from about 10% to about 15%, from about 10% to about 14%, from about 10% to about 13%, from about 10% to about 12%, from about 10% to about 11%, from about 11% to about 20%, from about 11% to about 19%, from about 11% to about 18%, from about 11% to about 17%, from about 11% to about 16%, from about 11% to about 15%, from about 11% to about 14%, from about 11% to about 13%, from about 11% to about 12%, from about 12% to about 20%, from about 12% to about 19%, from about 12% to about 18%, from about 12% to about 17%, from about 12% to about 16%, from about 12% to about 15%, from about 12% to about 14%, from about 12% to about 13%, from about 13% to about 20%, from about 13% to about 19,It contains about 13 to about 18, about 13 to about 17, about 13 to about 16, about 13 to about 15, about 13 to about 14, about 14 to about 20, about 14 to about 19, about 14 to about 18, about 14 to about 17, about 14 to about 16, about 14 to about 15, about 15 to about 20, about 15 to about 19, about 15 to about 18, about 15 to about 17, about 15 to about 16, about 16 to about 20, about 16 to about 19, about 16 to about 18, about 16 to about 17, about 17 to about 20, about 17 to about 19, about 17 to about 18, about 18 to about 20, about 18 to about 19, or about 19 to about 20% by weight of levulinic acid. In a further embodiment, the pharmaceutical composition contains about 3 to about 10% by weight of levulinic acid, based on the weight of the pharmaceutical composition.,

[0039] In a further aspect, the surfactant or penetration enhancer is 3-hydroxypropionic acid. In some embodiments, the pharmaceutical composition comprises from about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, or about 90 wt% 3-hydroxypropionic acid, based on the weight of the pharmaceutical composition.In other embodiments, the pharmaceutical composition comprises from about 20 to about 85, about 20 to about 80, about 20 to about 75, about 20 to about 70, about 20 to about 60, about 20 to about 55, about 20 to about 50, about 20 to about 45, about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, about 25 to about 90, about 25 to about 85, about 25 to about 80, about 25 to about 75, about 25 to about 70, about 25 to about 65, about 25 to about 60, about 25 to about 55, about 25 to about 50, about 25 to about 45, about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 90, about 30 to about 85, about 30 to about 80, about 30 to about 75, about 30 to about 70, about 30 to about 65, about 30 to about 60, about 30 to about 55, about 30 to about 50, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 90, about 35 to about 85, about 35 to about 80, about 35 to about 75, about 35 to about 70, about 35 to about 65, about 35 to about 60, about 35 to about 55, about 35 to about 50, about 35 to about 45, about 30 to about 40, about 40 to about 90, about 40 to about 85, about 40 to about 80, about 40 to about 75, about 40 to about 70, about 40 to about 65, about 40 to about 60, about 40 to about 55, about 40 to about 50, about 40 to about 45, about 45 to about 90, about 45 to about 85, about 45 to about 80, about 45 to about 75, about 45 to about 70, about 45 to about 65, about 45 to about 60, about 45 to about 55, about 45 to about 50, about 50 to about 90, about 50 to about 85, about 50 to about 80, about 50 to about 75, about 50 to about 70, about 50 to about 65, about 50 to about 60, about 50 to about 55, about 55 to about 90, about 55 to about 85, about 55 to about 80, about 55 to about 75, about 55 to about 70, about 55 to about 65, about 55 to about 60, about 60 to about 90, about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 60 to about 65, about 65 to about 90, about 65 to about 85, about 65 to about 80, about 65 to about 75, about 65 to about 70, about 70 to about 90, about 70 to about 85, about 70 to about 80, about 70 to about 75, about 75 to about 90, about 75 to about 85, 75 to about 80, about 80 to about 90, about 80 to about 85, or about 85 to about 90 weight % of 3-hydroxypropionic acid. In a further embodiment, the pharmaceutical composition comprises from about 25 to about 45 weight % of 3-hydroxypropionic acid, based on the weight of the pharmaceutical composition.In yet other embodiments, the pharmaceutical composition comprises from about 30 to about 45 weight percent 3-hydroxypropionic acid, based on the weight of the pharmaceutical composition.

[0040] In other embodiments, the penetration enhancer is malonic acid. In some embodiments, the pharmaceutical composition comprises from about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, or about 90 wt% malonic acid, based on the weight of the pharmaceutical composition.In other embodiments, the pharmaceutical composition comprises from about 20 to about 85, about 20 to about 80, about 20 to about 75, about 20 to about 70, about 20 to about 60, about 20 to about 55, about 20 to about 50, about 20 to about 45, about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, about 25 to about 90, about 25 to about 85, about 25 to about 80, about 25 to about 75, about 25 to about 70, about 25 to about 65, about 25 to about 60, about 25 to about 55, about 25 to about 50, about 25 to about 45, about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 90, about 30 to about 85, about 30 to about 80, about 30 to about 75, about 30 to about 70, about 30 to about 65, about 30 to about 60, about 30 to about 55, about 30 to about 50, about 30 to about 45, about 30 to about 40, about 35 to about 90, about 35 to about 85, about 35 to about 80, about 35 to about 75, about 35 to about 70, about 35 to about 65, about 35 to about 60, about 35 to about 55, about 35 to about 50, about 35 to about 45, about 30 to about 40, about 40 to about 90, about 40 to about 85, about 40 to about 80, about 40 to about 75, about 40 to about 70, about 40 to about 65, about 40 to about 60, about 40 to about 55, about 40 to about 50, about 40 to about 45, about 45 to about 90, about 45 to about 85, about 45 to about 80, about 45 to about 75, about 45 to about 70, about 45 to about 65, about 45 to about 60, about 45 to about 55, about 45 to about 50, about 50 to about 90, about 50 to about 85, about 50 to about 80, about 50 to about 75, about 50 to about 70, about 50 to about 65, about 50 to about 60, about 50 to about 55, about 55 to about 90, about 55 to about 85, about 55 to about 80, about 55 to about 75, about 55 to about 70, about 55 to about 65, about 55 to about 60, about 60 to about 90, about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 60 to about 65, about 65 to about 90, about 65 to about 85, about 65 to about 80, about 65 to about 75, about 65 to about 70, about 70 to about 90 weight %, about 70 to about 85 weight %, about 70 to about 80 weight %, about 70 to about 75 weight %, about 75 to about 90 weight %, about 75 to about 85 weight %, about 75 to about 80 weight %, about 80 to about 90 weight %, about 80 to about 85 weight %, or about 85 to about 90 weight % of malonic acid. In a further embodiment, the pharmaceutical composition comprises from about 25 to about 45 weight % of malonic acid, based on the weight of the pharmaceutical composition.In yet other embodiments, the pharmaceutical composition comprises from about 30 to about 45 weight % malonic acid, based on the weight of the pharmaceutical composition.

[0041] In a further aspect, the surfactant or penetration enhancer is a nonionic surfactant. Examples of nonionic enhancers include, but are not limited to, polysorbate 80, such as polysorbates like Tween® 80. The pharmaceutical composition may contain from about 5 to about 15 weight % nonionic enhancer, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15 weight % nonionic enhancer, based on the weight of the pharmaceutical composition. In other embodiments, the pharmaceutical composition comprises from about 5 to about 14, about 5 to about 13, about 5 to about 12, about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 15, about 6 to about 14, about 6 to about 13, about 6 to about 12, about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 15, about 7 to about 14, about 7 to about 13, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 14, about 8 to about 13, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 14, about 9 to about 13, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 15, about 10 to about 14, about 10 to about 13, about 10 to about 12, about 10 to about 11, from about 11 to about 15 weight %, from about 11 to about 14 weight %, from about 11 to about 13 weight %, from about 11 to about 12 weight %, from about 12 to about 15 weight %, from about 12 to about 14 weight %, from about 12 to about 13 weight %, from about 13 to about 15 weight %, from about 13 to about 14 weight %, or from about 14 to about 15 weight % nonionic enhancer, based on the weight of the pharmaceutical composition. In a further embodiment, the pharmaceutical composition comprises from about 7 to about 12 weight % nonionic enhancer, based on the weight of the pharmaceutical composition. In yet other embodiments, the pharmaceutical composition contains from about 0.5 to about 2 weight % nonionic enhancer, based on the weight of the pharmaceutical composition.

[0042] In yet other embodiments, the surfactant or penetration enhancer is polyethylene glycol monooleyl ether. Examples of polyethylene glycol monooleyl ether include polyoxyethylene(20) oleyl ether, such as Brij® O20. The pharmaceutical composition may contain from about 0.01 to about 5% by weight of polyethylene glycol monooleyl ether, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5 or about 5% by weight of polyethylene glycol monooleyl ether, based on the weight of the pharmaceutical composition. In other embodiments, the pharmaceutical composition contains from about 0.5 to about 4.5, about 0.5 to about 4, about 0.5 to about 3.5, about 0.5 to about 3, about 0.5 to about 2.5, about 0.5 to about 2, about 0.5 to about 1.5, about 0.5 to about 1, about 1 to about 5, about 1 to about 4.5, about 1 to about 4, about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 5, about 1.5 to about 4.5, about 1.5 to about 4, about 1.5 to about 3.5, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 5, about 2 to about 4.5, about 2 to about 4, about 2 to about 3.5, about 2 to about 3, about 2 to about 2.5, about 2.5 to about 5, about 2.5 to about 4.5, about 2.5 to about 4, about 2.5 to about 3.5, about 2.5 to about 3, about 3 to about 5, about 3 to about 4.5, about 3 to about 4, about 3 to about 3.5, about 3.5 to about 5, about 3.5 to about 4.5, about 3.5 to about 4, about 4 to about 5, about 4 to about 4.5, or about 4.5 to about 5% by weight of polyethylene glycol monooleyl ether, based on the weight of the pharmaceutical composition. In further embodiments, the pharmaceutical composition contains from about 0.5 to about 2% by weight of polyethylene glycol monooleyl ether, based on the weight of the pharmaceutical composition.

[0043] The pharmaceutical composition of the present disclosure can be designed to be administered to the skin or mucosal tissue of a patient in need of treatment. In addition to the anticoagulant and pyruvic acid, the pharmaceutical composition of the present disclosure may also contain excipients. Examples of suitable excipients include, but are not limited to, one or more of fillers, binders, disintegrants, emulsifiers, anti-static agents, or solvents.

[0044] Dosage form The present disclosure also contemplates dosage forms comprising the pharmaceutical compositions described herein. Accordingly, the pharmaceutical compositions can be formulated as gels, transdermal patches, lotions, creams, sprays, mists, emulsions, or dispersions. Suitable excipients for formulating gels, transdermal patches, lotions, creams, sprays, or mists will be readily apparent to those skilled in the art and include, but are not limited to, stabilizers, emulsifiers, thickeners, antibacterial agents, humectants, propellants, spreading agents, polymers, and adhesives such as pressure-sensitive adhesives. In particular, excipients that can be used to form a transdermal gel include, but are not limited to, alcohols, glycols, glycerin, butylated hydroxytoluene (BHT), and water. In some embodiments, the dosage form is a transdermal patch. In other embodiments, the dosage form is a gel. In further embodiments, the dosage form is a lotion. In still further embodiments, the dosage form is a cream. In yet another embodiment, the dosage form is a spray. In other embodiments, the dosage form is a mist. In further embodiments, the dosage form is an emulsion. In still further embodiments, the dosage form is a dispersion.

[0045] The dosage form can be designed to deliver the pharmaceutical composition over a period of time that depends on the patient. In some embodiments, the dosage form is designed for delivery of an anticoagulant over a period of 1 day, i.e., 24 hours. In other embodiments, the dosage form is designed for delivery of an anticoagulant over a period of 2 days, e.g., 48 hours. In further embodiments, the dosage form is designed for delivery of an anticoagulant over a period of 3 days. In still further embodiments, the dosage form is designed for delivery of an anticoagulant over a period of 3.5 days. In yet another embodiment, the dosage form is designed for delivery of an anticoagulant over a period of 4 days. In further embodiments, the dosage form is designed for delivery of an anticoagulant over a period of 5 days. In other embodiments, the dosage form is designed for delivery of an anticoagulant over a period of 6 days. In still further embodiments, the dosage form is designed for delivery of an anticoagulant over a period of 7 days, e.g., 1 week.

[0046] A particular form of the transdermal patch can be selected by those skilled in the art. In some embodiments, the transdermal patch is a single-layer drug-adhesive patch, a multi-layer drug-adhesive patch, a reservoir patch, a matrix patch, or a vapor patch. In other embodiments, the dosage form is a single-layer drug adhesive patch. In further embodiments, the dosage form is a multi-layer drug adhesive patch. In still other embodiments, the dosage form is a reservoir patch. In yet another embodiment, the dosage form is a matrix patch. In other embodiments, the dosage form is a vapor patch.

[0047] The amount of anticoagulant present in the dosage form depends on the daily dosage of the anticoagulant being administered and the particular anticoagulant selected. Thus, if the dosage form is intended to release the anticoagulant for more than one day, the amount of anticoagulant is adjusted accordingly. In some embodiments, the dosage form administers the anticoagulant over a two-day period and the amount of anticoagulant is 2× the daily dosage. In some embodiments, the dosage form administers the anticoagulant over a three-day period and the amount of anticoagulant is 3× the daily dosage. In some embodiments, the dosage form administers the anticoagulant over a four-day period and the amount of anticoagulant is 4× the daily dosage. In some embodiments, the dosage form administers the anticoagulant over a five-day period and the amount of anticoagulant is 5× the daily dosage. In some embodiments, the dosage form administers the anticoagulant over a six-day period and the amount of anticoagulant is 6× the daily dosage. In some embodiments, the dosage form administers the anticoagulant over a seven-day period, i.e., one week, and the amount of anticoagulant is 7× the daily dosage.

[0048] In some embodiments, the dosage form contains an excess of anticoagulant such that a favorable concentration gradient of flux is maintained across the skin from the patch throughout the wear period. As used herein, the term "excess" refers to an amount that is about 2- to about 5-fold greater than the weight of the anticoagulant in the dosage form. In some embodiments, the excess amount is an excess of about 2-fold, i.e., about 2× the weight of the anticoagulant in the dosage form. In other embodiments, the excess is an excess of about 3-fold, i.e., about 3× the weight of the anticoagulant in the dosage form. In further embodiments, the excess is an excess of about 4-fold, i.e., about 4× the weight of the anticoagulant in the dosage form. In still other embodiments, the excess is an excess of about 5-fold, i.e., about 5× the weight of the anticoagulant in the dosage form. As an example, the following equation can be used to calculate the amount of anticoagulant in the dosage form:

[0049] Amount of anticoagulant in the dose (mg) =(Daily dose of anticoagulant (mg)) × (Number of days of wear of the dosage form) × (Excess amount of anticoagulant in the dosage form) For example, if the daily dose of anticoagulant is about 100 mg and the dosage unit is designed to release the anticoagulant over 7 days, the dosage form contains from about 1400 mg (100 mg × 2-fold excess × 7 days) to about 3500 mg (100 mg × 5-fold excess × 7 days).

[0050] In some embodiments, the dosage form comprises an amount of apixaban that delivers from about 2.5 to about 20 mg / day of apixaban to a patient. In certain embodiments, the dosage form comprises an amount of apixaban that delivers about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg / day of apixaban to a patient. In other embodiments, the dosage form administers from about 2.5 to about 17.5, about 2.5 to about 15, about 2.5 to about 12.5, about 2.5 to about 10, about 2.5 to about 7.5, about 7.5 to about 5, about 5 to about 20, about 5 to about 17.5, about 5 to about 15, about 5 to about 12.5, about 5 to about 10, about 5 to about 7.5, about 7.5 to about 20, about 7.5 to about 17.5, about 7.5 to about 15, about 7.5 to about 12.5, about 7.5 to about 10, about 10 to about 20, about 10 to about 17.5, about 10 to about 15, about 10 to about 12.5, about 12.5 to about 20, about 12.5 to about 17.5, about 12.5 to about 15, about 15 to about 20, about 15 to about 17.5 or about 17.5 to about 20 mg / day of apixaban to a patient.

[0051] In some embodiments, the transdermal dosage form described herein delivers the same amount of apixaban as an oral dosage form containing apixaban in about 24 hours. For example, in some embodiments, the transdermal dosage form will exhibit the same or similar (i.e., about 80% to about 125%) area under the curve (AUC) as an oral dosage form comprising apixaban. In other embodiments, the transdermal dosage form described herein results in a C max ) that is the same as or not similar to the C max resulted. In some embodiments, the transdermal dosage form has a C max that is lower than, for example, about 10%, about 15%, about 20%, about 25%, or about 30% lower than the C maxis shown. In further embodiments, the transdermal dosage forms described herein result in trough levels that exceed the trough levels achieved using oral dosage forms of apixaban. Without wishing to be bound by any particular theory, the transdermal dosage forms described herein are therapeutically equivalent to oral dosage forms containing apixaban and the described transdermal dosage forms will have an equivalent or improved safety profile compared to oral dosage forms containing apixaban.

[0052] In other embodiments, the dosage form comprises rivaroxaban in an amount that delivers from about 2.5 to about 30 mg / day of rivaroxaban to a patient. In certain embodiments, the dosage form comprises rivaroxaban in an amount that delivers about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mg / day of rivaroxaban to a patient. In other embodiments, the dosage form is administered to a patient with from about 2.5 to about 30, from about 2.5 to about 27.5, from about 2.5 to about 25, from about 2.5 to about 22.5, from about 2.5 to about 20, from about 2.5 to about 17.5, from about 2.5 to about 15, from about 2.5 to about 12.5, from about 2.5 to about 10, from about 2.5 to about 7.5, from about 2.5 to about 5, from about 5 to about 30, from about 5 to about 27.5, from about 5 to about 25, from about 5 to about 22.5, from about 5 to about 20, from about 5 to about 17.5, from about 5 to about 15, from about 5 to about 12.5, from about 5 to about 10, from about 7.5 to about 30, from about 7.5 to about 27.5, from about 7.5 to about 25, from about 7.5 to about 22.5, from about 7.5 to about 20, from about 7.5 to about 17.5, from about 7.5 to about 15, from about 7.5 to about 12.5, from about 7.5 to about 10, from about 10 to about 30, from about 10 to about 27.5, from about 10 to about 25, from about 10 to about 22.5, from about 10 to about 20, from about 10 to about 17.5, from about 10 to about 15, from about 10 to about 12.5, from about 12.5 to about 30, from about 12.5 to about 27.5, from about 12.5 to about 25, from about 12.5 to about 22.5, from about 12.5 to about 20, from about 12.5 to about 17.5, from about 12.5 to about 15, from about 15 to about 30, from about 15 to about 27.5, from about 15 to about 25, from about 15 to about 22.5, from about 15 to about 20, from about 15 to about 17.5, from about 17.5 to about 30, from about 17.5 to about 27.5, from about 17.5 to about 25, from about 17.5 to about 22.5, from about 17.5 to about 20, from about 20 to about 30, from about 20 to about 27.5, from about 20 to about 25, from about 20 to about 22.5, from about 22.5 to about 30, from about 22.5 to about 27.5, from about 22.5 to about 25, from about 25 to about 30, from about 25 to about 27.5, or from about 27.5 to about 30 mg / day of rivaroxaban.

[0053] In a further embodiment, the dosage form comprises an amount of edoxaban that delivers from about 15 to about 60 mg / day of edoxaban to a patient. In certain embodiments, the dosage form comprises an amount of edoxaban that delivers about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 mg / day of edoxaban to a patient. In further embodiments, the dosage form comprises from about 15 to about 55, from about 15 to about 50, from about 15 to about 45, from about 15 to about 40, from about 15 to about 35, from about 15 to about 30, from about 15 to about 25, from about 15 to about 20, from about 20 to about 60, from about 20 to about 55, from about 20 to about 50, from about 20 to about 45, from about 20 to about 40, from about 20 to about 35, from about 20 to about 30, from about 20 to about 25, from about 25 to about 60, from about 25 to about 55, from about 25 to about 50, from about 25 to about 45, from about 25 to about 40, from about 25 to about 35, from about 25 to about 30, from about 30 to about 60, from about 30 to about 55, from about 30 to about 50, from about 30 to about 45, from about 30 to about 40, from about 30 to about 35, from about 35 to about 60, from about 35 to about 55, from about 35 to about 50, from about 35 to about 45, from about 35 to about 40, from about 40 to about 60, from about 40 to about 55, from about 40 to about 50, from about 40 to about 45, from about 45 to about 60, from about 45 to about 55, from about 45 to about 50, from about 50 to about 60, from about 50 to about 55, or from about 55 to about 60 mg / day of edoxaban to a patient. In other embodiments, the dosage form comprises an amount of edoxaban that delivers from about 15 to about 30 mg / day of edoxaban to a patient.

[0054] In yet other embodiments, the dosage form comprises an amount of betrixaban that delivers from about 40 to about 160 mg / day of betrixaban to a patient. In certain embodiments, the dosage form comprises an amount of betrixaban that delivers about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, or about 160 mg / day of betrixaban to a patient. In further embodiments, the dosage form comprises an amount of betrixaban that delivers from about 40 to about 140, from about 40 to about 120, from about 40 to about 100, from about 40 to about 80, from about 40 to about 60, from about 60 to about 160, from about 60 to about 140, from about 60 to about 120, from about 60 to about 100, from about 60 to about 80, from about 80 to about 160, from about 80 to about 140, from about 80 to about 120, from about 80 to about 100, from about 100 to about 160, from about 100 to about 140, from about 100 to about 120, from about 120 to about 160, from about 120 to about 140, or from about 140 to about 160 mg / day of betrixaban to a patient. In other embodiments, the dosage form comprises an amount of betrixaban that delivers from about 80 to about 160 mg / day of betrixaban to a patient.

[0055] In further embodiments, the dosage form comprises an amount of fondaparinux that delivers from about 2.5 to about 10 mg / day of fondaparinux to a patient. In certain embodiments, the dosage form comprises an amount of fondaparinux that delivers about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mg / day of fondaparinux to a patient. In other embodiments, the dosage form comprises an amount of fondaparinux that delivers from about 2.5 to about 10, from about 2.5 to about 7.5, from about 7.5 to about 5, from about 5 to about 10, from about 5 to about 7.5, or from about 7.5 to about 10 mg / day of fondaparinux to a patient.

[0056] In other embodiments, the dosage form comprises an amount of dabigatran that delivers from about 75 to about 220 mg of dabigatran to the patient. In certain embodiments, the dosage form comprises an amount of dabigatran that delivers about 75, about 100, about 125, about 150, about 175, about 200, or about 220 mg of dabigatran to the patient. In other embodiments, the dosage form comprises an amount of dabigatran that delivers from about 75 to about 200, from about 75 to about 175, from about 75 to about 150, from about 75 to about 125, from about 75 to about 100, from about 100 to about 220, from about 100 to about 200, from about 100 to about 175, from about 100 to about 150, from about 100 to about 125, from about 125 to about 220, from about 125 to about 200, from about 125 to about 175, from about 125 to about 150, from about 150 to about 220, from about 150 to about 200, from about 150 to about 175, from about 175 to about 220, from about 175 to about 200, or from about 200 to about 220 mg / day of dabigatran to the patient. In further embodiments, the dosage form comprises an amount of dabigatran that delivers from about 75 to about 150 mg / day of dabigatran to the patient.

[0057] In further embodiments, the dosage form comprises an amount of enoxaparin that delivers from about 30 to about 60 mg / day of enoxaparin to the patient. In certain embodiments, the dosage form comprises an amount of enoxaparin that delivers about 30, about 35, about 40, about 45, about 50, about 55, or about 60 mg / day of enoxaparin to the patient. In further embodiments, the dosage form comprises an amount of enoxaparin that delivers from about 30 to about 60, from about 30 to about 55, from about 30 to about 50, from about 30 to about 45, from about 30 to about 40, from about 30 to about 35, from about 35 to about 60, from about 35 to about 55, from about 35 to about 50, from about 35 to about 45, from about 35 to about 40, from about 40 to about 60, from about 40 to about 55, from about 40 to about 50, from about 40 to about 45, from about 45 to about 60, from about 45 to about 55, from about 45 to about 50, from about 50 to about 60, from about 50 to about 55, or from about 55 to about 60 mg / day of enoxaparin to the patient. In other embodiments, the dosage form comprises an amount of enoxaparin that delivers about 40 mg / day of enoxaparin to the patient.

[0058] In still other embodiments, the dosage form comprises milbexian in an amount that delivers from about 25 to about 500 mg / day of milbexian to the patient. In certain embodiments, the dosage form comprises milbexian in an amount that delivers about 25, about 50, about 60, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg / day of milbexian to the patient. In further embodiments, the dosage form administers from about 25 to about 450, about 25 to about 400, about 25 to about 350, about 25 to about 300, about 25 to about 250, about 25 to about 200, about 25 to about 150, about 25 to about 100, about 25 to about 60, about 25 to about 50, about 50 to about 500, about 50 to about 450, about 50 to about 400, about 50 to about 350, about 50 to about 300, about 50 to about 250, about 50 to about 200, about 50 to about 150, about 50 to about 100, about 50 to about 60, about 60 to about 500, about 60 to about 450, about 60 to about 400, about 60 to about 350, about 60 to about 300, about 60 to about 250, about 60 to about 200, about 60 to about 150, about 60 to about 100, about 100 to about 500, about 100 to about 450, about 100 to about 400, about 100 to about 350, about 100 to about 300, about 100 to about 250, about 100 to about 200, about 100 to about 150, about 150 to about 500, about 150 to about 450, about 150 to about 400, about 150 to about 350, about 150 to about 300, about 150 to about 250, about 150 to about 200, about 200 to about 500, about 200 to about 450, about 200 to about 400, about 200 to about 350, about 200 to about 300, about 200 to about 250, about 250 to about 500, about 250 to about 450, about 250 to about 400, about 250 to about 350, about 250 to about 300, about 300 to about 500, about 300 to about 450, about 300 to about 400, about 400 to about 350, about 350 to about 500, about 350 to about 450, about 350 to about 400, about 400 to about 500, about 400 to about 450, or about 450 to about 500 mg / day of milbexian to the patient. In still other embodiments, the dosage form comprises milbexian in an amount that delivers from about 50 to about 200 mg / day of milbexian to the patient. In still another embodiment, the dosage form comprises milbexian in an amount that delivers from about 60 to about 200 mg / day of milbexian to the patient. In other embodiments, the dosage form comprises milbexian in an amount that delivers from about 50 to about 500 mg / day of milbexian to the patient.In a further aspect, the dosage form comprises milbexian in an amount that delivers from about 60 to about 500 mg / day of milbexian to a patient.

[0059] In a further embodiment, the dosage form comprises asundexian in an amount that delivers from about 10 to about 50 mg / day of asundexian to a patient. In certain aspects, the dosage form comprises asundexian in an amount that delivers about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 mg / day of asundexian to a patient. In a further aspect, the dosage form comprises milbexian in an amount that delivers from about 10 to about 50, from about 10 to about 45, from about 10 to about 40, from about 10 to about 35, from about 10 to about 30, from about 10 to about 25, from about 10 to about 20, from about 10 to about 15, from about 15 to about 50, from about 15 to about 45, from about 15 to about 40, from about 15 to about 35, from about 15 to about 30, from about 15 to about 25, from about 15 to about 20, from about 20 to about 50, from about 20 to about 45, from about 20 to about 40, from about 20 to about 35, from about 20 to about 30, from about 20 to about 25, from about 25 to about 50, from about 25 to about 45, from about 25 to about 40, 25 to about 35, from about 25 to about 30, from about 30 to about 50, from about 30 to about 45, from about 30 to about 40, from about 30 to about 35, from about 35 to about 50, from about 35 to about 45, from about 35 to about 40, from about 40 to about 50, from about 40 to about 45, or from about 45 to about 50, mg / day of asundexian to a patient. In other aspects, the dosage form comprises asundexian in an amount that delivers from about 20 to about 50 mg / day of asundexian to a patient.

[0060] The dosage form can also include a pressure-sensitive adhesive that adheres the dosage form, such as a transdermal patch, to the patient's skin. In some embodiments, the pressure-sensitive adhesive is an acrylate pressure-sensitive adhesive, a silicone-based pressure-sensitive adhesive, a polyisobutylene-based pressure-sensitive adhesive, a hybrid acrylate-silicone-based pressure-sensitive adhesive, or a combination thereof. See, for example, Tan and Pfister, "Pressure-sensitive adhesives for transdermal drug delivery systems", Pharm Sci & Tech Today 2:60-69(1999), the reference of which is incorporated herein by reference. In other embodiments, the pressure-sensitive adhesive includes an acrylate copolymer having OH groups and vinyl acetate. In further embodiments, the pressure-sensitive adhesive is DUROTAK 87-2287 or DUROTAK 4098. The dosage form includes about 35 to about 95 wt% of the pressure-sensitive adhesive, based on the weight of the dosage form. In some embodiments, the dosage form includes about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, or about 95 wt% of the pressure-sensitive adhesive, based on the weight of the dosage form. In further embodiments, the dosage form includes about 35 to about 90, about 35 to about 85, about 35 to about 80, about 35 to about 75, about 35 to about 70, about 35 to about 65, about 35 to about 60, about 35 to about 55, about 35 to about 50, about 35 to about 45, about 40 to about 95, about 40 to about 90, about 40 to about 85, about 40 to about 80, about 40 to about 75, about 40 to about 70, about 40 to about 65, about 40 to about 60, about 40 to about 55, about 40 to about 50, about 50 to about 95, about 50 to about 90, about 50 to about 80, about 50 to about 75, about 50 to about 70, about 50 to about 65, about 50 to about 60, about 60 to about 95, about 60 to about 90, about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70 wt%, about 70 to about 95 wt%, about 70 to about 90 wt%, about 70 to about 85 wt%, about 70 to about 80 wt%, about 80 to about 95 wt%, or about 80 to about 90 wt% of the pressure-sensitive adhesive, based on the weight of the dosage form.

[0061] Treatment method According to the present disclosure, methods or uses of using pharmaceutical compositions and / or dosage forms are also provided. Regardless of the particular method, the method includes the step of administering a pharmaceutical composition or dosage form to a patient. In some embodiments, the present disclosure provides a method for treating a thromboembolic disorder in a patient in need thereof. As used herein, the term "thromboembolic disorder" refers to a disorder in which a thrombus is formed within a blood vessel. In some aspects, the thromboembolic disorder is an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, or a thromboembolic disorder of a heart chamber. In other aspects, the thromboembolism is acute coronary syndrome, primary myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis (DVT), thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism (PE), or thrombosis caused by an implant such as an artificial valve, thrombosis caused by an indwelling catheter, thrombosis caused by a stent, thrombosis caused by cardiopulmonary bypass, thrombosis caused by hemodialysis, thrombosis caused by a treatment in which blood is exposed to an artificial surface that promotes thrombosis or a treatment in which blood is exposed to a treatment, including thrombosis caused by a treatment in which blood is exposed to an artificial surface that promotes thrombosis or a treatment in which blood is exposed to a treatment. In a further aspect, the thromboembolism is acute coronary syndrome. In yet another aspect, the thromboembolic disorder is a stroke. In yet another aspect, the thromboembolism is deep vein thrombosis (DVT). In other aspects, the thromboembolism is pulmonary embolism (PE).

[0062] The present disclosure also provides a method for treating, reducing recurrence of, or preventing deep vein thrombosis (DVT) and / or pulmonary embolism (PE) in a patient in need thereof. In some embodiments, the method treats DVT or PE. In other embodiments, the method reduces recurrence of DVT and / or PE. In further embodiments, the method prevents DVT and / or PE. In certain aspects, the patient has undergone hip or knee replacement surgery. In other aspects, the patient has undergone hip replacement surgery. In further aspects, the patient has undergone artificial knee joint replacement surgery.

[0063] According to the present disclosure, there is provided a method for treating atherosclerosis, myocardial infarction, pulmonary embolism (PE) or deep vein thrombosis (DVT) in a patient in need thereof. The method includes administering to the patient a pharmaceutical composition or dosage form. In some embodiments, the method treats atherosclerosis. In further embodiments, the method treats myocardial infarction. In other embodiments, the method treats pulmonary embolism. In further embodiments, the method treats deep vein thrombosis.

[0064] According to the present disclosure, there is provided a method for treating, reducing the risk of recurrence of, or preventing venous thromboembolism (VTE), comprising administering to the patient a pharmaceutical composition or dosage form described herein. In some embodiments, the present disclosure provides a method for preventing VTE. In other embodiments, the present disclosure provides a method for treating VTE. In further aspects, the present disclosure provides a method for reducing the risk of recurrence of VTE. In certain aspects, the patient has an acute disease. In other aspects, the patient is a pediatric patient.

[0065] The present disclosure further provides methods for reducing the risk of major cardiovascular events in a patient. These methods include the step of administering a pharmaceutical composition or dosage form to the patient. In certain embodiments, the patient has coronary artery disease. In one embodiment, the patient has acute myocardial infarction, i.e., a heart attack. In other embodiments, the patient has pulmonary embolism. In further embodiments, the patient has heart failure. In still further embodiments, the patient has a stroke.

[0066] According to the present disclosure, methods for reducing the risk of major thrombotic vascular events in a patient are provided. These methods include the step of administering a pharmaceutical composition or dosage form to the patient. In certain embodiments, the patient has peripheral arterial disease (PAD). In other embodiments, the patient has recently undergone lower extremity revascularization for symptomatic PAD. In further embodiments, the patient has deep vein thrombosis. In still further embodiments, the patient has systemic embolism. In yet another embodiment, the patient has thrombophlebitis. In other embodiments, the patient has pulmonary embolism.

[0067] The present disclosure also provides methods for thrombo-prevention in a patient. The method includes the step of administering a pharmaceutical composition or dosage form to the patient. In some embodiments, the patient has congenital heart disease after the Fontan procedure. In other embodiments, the patient is 2 years of age or older.

[0068] The present disclosure further provides methods for preventing one or more thromboembolic events in a patient. As used herein, the term "thromboembolic disorder" refers to a state of increased blood coagulability or a state that leads to a tendency to form thrombi. In some embodiments, a thromboembolic disorder may cause a thromboembolic event. As used herein, the term "thromboembolic event" refers to a state in which a thrombus (blood clot) is formed and optionally transported to another part of the body. The method includes the step of administering a pharmaceutical composition or dosage form to the patient. In some embodiments, the patient has atrial fibrillation.

[0069] The present disclosure also provides a method for reducing the risk of stroke or systemic embolism in a patient. The method includes administering to the patient a pharmaceutical composition or dosage form. In some embodiments, the patient has non-valvular atrial fibrillation.

[0070] In all methods of the present disclosure, the pharmaceutical composition or dosage form can be administered transdermally.

[0071] The method also includes administering one or more anticoagulants described herein. The additional or second anticoagulant can be selected by the attending physician. In some embodiments, the second anticoagulant is aspirin. In further embodiments, the second anticoagulant is clopidogrel.

[0072] Embodiments Embodiment 1: A pharmaceutical composition comprising an anticoagulant and pyruvic acid.

[0073] Embodiment 2: The pharmaceutical composition according to Embodiment 1, wherein the anticoagulant is a thrombin inhibitor, a factor Xa inhibitor, a factor Xia inhibitor, or low molecular weight heparin.

[0074] Embodiment 3: The pharmaceutical composition according to Embodiment 1, wherein the thrombin inhibitor is dabigatran, bivalirudin, lepirudin, or desirudin, or such a dabigatran.

[0075] Embodiment 4: The pharmaceutical composition according to Embodiment 1, wherein the low molecular weight heparin is enoxaparin.

[0076] Embodiment 5: The pharmaceutical composition according to Embodiment 1, wherein the factor Xa inhibitor is apixaban, rivaroxaban, edoxaban, betrixaban, or fondaparinux, or a combination thereof, or such as apixaban.

[0077] Embodiment 6: The pharmaceutical composition according to Embodiment 1, wherein the factor XIa inhibitor is milvexian or asundexian.

[0078] Aspect 7: A pharmaceutical composition according to any one of the preceding aspects, further comprising a surfactant, a penetration enhancer, or a combination thereof.

[0079] Aspect 8: The pharmaceutical composition according to aspect 7, wherein the surfactant or penetration enhancer is a non-ionic surfactant such as dimethyl sulfoxide, lactic acid, oleic acid, levulinic acid, 3-hydroxypropionic acid, malonic acid, or a polysorbate such as Tween 80, or a polyethylene glycol monooleyl ether such as Brij O20.

[0080] Aspect 9: A pharmaceutical composition according to any one of the preceding aspects, further comprising lactic acid.

[0081] Aspect 10: The pharmaceutical composition according to aspect 8 or 9, comprising about 20 to about 45% by weight of lactic acid, or about 25 to about 35% by weight of lactic acid, based on the weight of the pharmaceutical composition.

[0082] Aspect 11: A pharmaceutical composition according to any one of the preceding aspects, further comprising dimethyl sulfoxide.

[0083] Aspect 12: The pharmaceutical composition according to aspect 11, comprising about 5 to about 20% by weight of dimethyl sulfoxide, or about 8 to about 15% by weight of dimethyl sulfoxide, based on the weight of the pharmaceutical composition.

[0084] Aspect 13: A pharmaceutical composition according to any one of the preceding aspects, further comprising levulinic acid.

[0085] Aspect 14: The pharmaceutical composition according to aspect 13, comprising about 1 to about 20% by weight of levulinic acid, or about 3 to about 10% by weight of levulinic acid, based on the weight of the pharmaceutical composition.

[0086] Aspect 15: A pharmaceutical composition according to any one of the preceding aspects, further comprising oleic acid.

[0087] Aspect 16: The pharmaceutical composition according to Aspect 15, comprising about 1 to about 10% by weight of oleic acid, or about 3 to about 7% by weight of oleic acid, based on the weight of the pharmaceutical composition.

[0088] Aspect 17: The pharmaceutical composition according to any one of the preceding aspects, further comprising polysorbate, or polysorbate 80, etc.

[0089] Aspect 18: The pharmaceutical composition according to Aspect 17, comprising about 5 to about 15% by weight of polysorbate, or about 7 to about 12% by weight of polysorbate, based on the weight of the pharmaceutical composition.

[0090] Aspect 19: The pharmaceutical composition according to any one of the preceding aspects, further comprising polyethylene glycol monooleyl ether.

[0091] Aspect 20: The pharmaceutical composition according to Aspect 19, comprising about 0.01 to about 5% by weight of polyethylene glycol monooleyl ether, or about 0.5 to about 2% by weight of polyethylene glycol monooleyl ether, based on the weight of the pharmaceutical composition.

[0092] Aspect 21: The pharmaceutical composition according to any one of the preceding aspects, comprising about 5 to about 25% by weight of an anticoagulant, or about 7 to about 12% by weight, about 9% by weight, about 10% by weight, or about 11% by weight, etc. of an anticoagulant, based on the weight of the pharmaceutical composition.

[0093] Aspect 22: The pharmaceutical composition according to any one of the preceding aspects, comprising about 20 to about 90% by weight of pyruvic acid, or about 25 to about 45% by weight, or about 30 to about 45% by weight, etc. of pyruvic acid, based on the weight of the pharmaceutical composition.

[0094] Aspect 23: The pharmaceutical composition according to any one of the preceding aspects, comprising about 0.1 to about 100 mg / day, or about 2.5 mg / day, 5 mg / day, 10 mg / day, 15 mg / day, or about 20 mg of an anticoagulant.

[0095] Aspect 24: The pharmaceutical composition according to any one of the foregoing aspects, lacking acrylic acid.

[0096] Aspect 25: A dosage form comprising the pharmaceutical composition according to any one of the foregoing aspects.

[0097] Aspect 26: The dosage form according to Aspect 25, which is a transdermal patch.

[0098] Aspect 27: The dosage form according to Aspect 26, wherein the transdermal patch is a single-layer drug adhesion patch, a multi-layer drug adhesion patch, a reservoir patch, a matrix patch, or a vapor patch, or a reservoir patch, etc.

[0099] Aspect 28: A method for treating a thromboembolic disorder in a patient in need thereof, comprising the step of administering to the patient any one of the pharmaceutical compositions according to any one of Aspects 1 to 24 or any one of the dosage forms according to Aspects 25 to 27.

[0100] Aspect 29: The method according to Aspect 28, wherein the thromboembolic disorder is an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, or a thromboembolic disorder in a heart chamber.

[0101] The thromboembolic disorder is acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient cerebral ischemia attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, or thrombosis caused by an implant such as an artificial valve, thrombosis caused by an indwelling catheter, thrombosis caused by a stent, thrombosis caused by cardiopulmonary bypass, thrombosis caused by hemodialysis, thrombosis caused by a treatment in which blood is exposed to an artificial surface that promotes thrombosis, or thrombosis caused by that treatment. The method according to Aspect 30.

[0102] Aspect 31: The method according to Aspect 28, wherein the thromboembolic disorder is acute coronary syndrome.

[0103] Aspect 32: The method according to aspect 28, wherein the thromboembolic disorder is a stroke.

[0104] Aspect 33: The method according to aspect 28, wherein the thromboembolism is deep vein thrombosis.

[0105] Aspect 34: The method according to aspect 28, wherein the thromboembolism is pulmonary embolism.

[0106] Aspect 35: A method for preventing deep vein thrombosis or pulmonary embolism in a patient in need thereof, the method comprising administering to the patient the pharmaceutical composition according to any one of aspects 1 to 24 or the dosage form according to any one of aspects 25 to 27.

[0107] Aspect 36: A method for reducing the recurrence of deep vein thrombosis or pulmonary embolism in a patient in need thereof, the method comprising administering to the patient the pharmaceutical composition according to any one of aspects 1 to 24 or the dosage form according to any one of aspects 25 to 27.

[0108] Aspect 37: The method according to aspect 35 or 36, wherein the patient has undergone hip arthroplasty or knee arthroplasty.

[0109] Aspect 38: A method for preventing venous thromboembolism (VTE) in a patient with an acute disease, the method comprising administering to the patient the pharmaceutical composition according to any one of claims 1 to 24 or the dosage form according to any one of aspects 25 to 27.

[0110] Aspect 39: A method for reducing the risk of major cardiovascular events in a patient with coronary artery disease, the method comprising administering to the patient the pharmaceutical composition according to any one of aspects 1 to 24 or the dosage form according to any one of aspects 25 to 27.

[0111] Aspect 40: A method for reducing the risk of major thrombotic vascular events in a patient with peripheral arterial disease (PAD), the method comprising administering to the patient a pharmaceutical composition according to any one of Aspects 1 to 24 or a dosage form according to any one of Claims 25 to 27.

[0112] Aspect 41: The method according to Aspect 40, wherein the patient has recently undergone lower limb revascularization due to symptomatic PAD.

[0113] Aspect 42: A method for treating VTE or reducing the risk of recurrence of VTE in a pediatric patient in need thereof, the method comprising administering to the patient a pharmaceutical composition according to any one of Aspects 1 to 24 or a dosage form according to any one of Aspects 25 to 27.

[0114] Aspect 43: A method for thrombo - prevention in a patient with congenital heart disease after Fontan procedure, the method comprising administering to the patient a pharmaceutical composition according to any one of Aspects 1 to 24 or a dosage form according to any one of Aspects 25 to 27.

[0115] Aspect 44: The method according to Aspect 42, wherein the patient is 2 years of age or older.

[0116] Aspect 45: A method for treating atherosclerosis, myocardial infarction, pulmonary embolism or deep vein thrombosis in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition according to any one of Aspects 1 to 24 or a dosage form according to any one of Aspects 25 to 27.

[0117] Aspect 46: The method according to any one of Aspects 28 to 45, wherein the pharmaceutical composition is administered transdermally.

[0118] Aspect 47: The method according to any one of Aspects 28 to 46, further comprising the step of administering a second anticoagulant.

[0119] Aspect 48: The method according to Aspect 47, wherein the second anticoagulant is aspirin.

[0120] Aspect 49: The method according to any one of aspects 35 to 41 or 43 to 48, wherein the patient is an adult.

[0121] Aspect 50: The method according to any one of aspects 35 to 49, wherein the patient is a pediatric patient.

[0122] Aspect 51: A method for preventing one or more thromboembolic events in a patient with atrial fibrillation, comprising administering to the patient the pharmaceutical composition according to any one of aspects 1 to 24 or the dosage form according to any one of aspects 25 to 27.

[0123] The following examples illustrate individual embodiments, but are not intended to limit the scope of the present invention as described and should not be construed as such.

Example

[0124] Example 1: Effects of Pyruvic Acid and BRIJ O20 on Skin Permeability The apixaban formulations in Table 1 were prepared, and the effects of enhancers, solvents, and emulsifiers on the human cadaver skin permeation of apixaban were examined. The formulations were mixed under vortex conditions until all of the apixaban was dissolved. The mixing time varied depending on the size of the container but was generally about 15 minutes. Formulation F6 was based on the formulation described in US Patent Publication No. 220 / 0338012.

Table 1

[0125] The skin permeation test of the formulations was performed using a Franz diffusion cell maintained at 37°C during the experimental period. The receptor medium was phosphate-buffered saline at pH 7.4, the receptor volume was 12 mL, and the permeation area was 1.77 cm 2It was. Human cadaver skin was used, and all tests were performed in triplicate. Each formulation (0.4 mL) was placed at the donor site of the skin diffusion cell, and the experiment was started while continuously mixing the receptor medium. Samples of the receptor phase were collected on days 1, 2, 3, 4, 5, and 7, and the apixaban concentration was determined using HPLC [Column: Agilent column C18, 3.5 μm, 4.6 mm × 150 mm; Mobile phase: water (0.025% formic acid): acetonitrile (50:50); Gradient method; Flow rate: 1 mL / min; Detection: 280 nm; Column temperature: 40 °C]. The skin fluxes of the three formulations were measured and are shown in Figures 1A and 1B.

[0126] Figure 1 shows that the formulation (F7) containing pyruvic acid and the nonionic surfactant BRIJ O20 has the highest flux through human skin. The formulation (F6) without pyruvic acid contains a high level of the nonionic surfactant TWEEN80 but has the lowest skin permeability. The formulation (F8) containing pyruvic acid and TWEEN80 showed a slightly higher skin permeability than formulation F6 but was still much lower than formulation F7. Some conclusions drawn from this experiment are: a) Pyruvic acid increases skin permeation; b) A synergistic effect on skin permeation is obtained by combining pyruvic acid and the surfactant BRIJ O20; c) Surfactants seem to be important for the delivery of apixaban, but many other aspects of the surfactant, such as the hydrophilic-lipophilic balance (HLB) and melting point (MP), are also important.

Example

[0127] Example 2: Effect of pyruvic acid and BRIJ O20 on the skin permeation of AXB (with a fixed amount of DMSO) To verify the importance of pyruvic acid and BRIJ O20 in the skin permeation of apixaban, three formulations shown in Table 2 were prepared.

Table 2

[0128] As described in Example 1, all three formulations were tested in a Franz Diffusion cell and plotted as a function of time for skin permeation as shown in Figures 2A and 2B. Figures 2A and 2B show the skin permeation of formulation F7 of Example 2 (labeled "1 / 28 data"). The curve of F7 shows similar skin fluxes, which is within the range of error expected for the skin flux experiment, indicating the reproducibility of the experimental results.

[0129] That is, pyruvic acid and BRIJ O20 are skin permeation enhancers of apixaban and are independent of the effects of other excipients.

[0130] In formulation F10, the concentration of levulinic acid was increased by proportionally decreasing the concentration of pyruvic acid. As a result, the skin flux of apixaban decreased significantly. This indicates that the combination of oleic acid / levulinic acid is only limitedly useful for enhancing the transdermal delivery of apixaban, and that pyruvic acid is the main cause of the increased flux found in these experiments.

Example

[0131] Example 3: Preparation and Testing of a Reservoir Transdermal Patch A reservoir transdermal patch containing formulation F7 as a saturated solution in the patch was prepared. Formulation F7 was shown to exhibit the best skin permeability among the apixaban formulations tested in Examples 2 and 3. Considering that pyruvic acid has been shown to be a good enhancer of apixaban in this specification, formulations F12 and F14 containing a larger amount of pyruvic acid were prepared. The compositions of the three formulations are shown in Table 3.

Table 3

[0132] The schematic diagram of the fabricated reservoir-type transdermal patch is shown in Fig. 3. The patch consists of four components: an impermeable backing, a drug reservoir containing a drug dissolved in a vehicle (i.e., an active gel), a microporous membrane, and an adhesive. A polypropylene membrane (CELGARD 2400) with a porosity of 38% was selected as the rate-controlling membrane. A heat-sealable polyester film laminate (SCOTCHPAK 1012, 3M) constitutes the backing layer. A pressure-sensitive adhesive (i.e., DUROTAK 4098) is cast onto a release liner (SCOTCHPAK 9747, 3M) and dried. A layer of Celgard is placed on top of the pressure-sensitive adhesive. A backing film is placed on top of the membrane, and the edge of a 1.77 cm 2 circle is heat-sealed using a die compressed at 70 °C for 10 seconds to form an empty pouch reservoir between the Celgard and the backing layer. A subcutaneous syringe is inserted into the orifice leading to the reservoir chamber, and after filling it with 0.4 mL of apixaban gel solution, the orifice is sealed to fill the patch reservoir with the active gel formulation.

[0133] Three prepared reservoir patches are applied to human cadaver skin and mounted on the Franz cell (area 1.77 cm 2 ) used above to conduct a skin permeation test. The skin permeation test was conducted in the same manner as in Example 2. The amount of apixaban permeated in mg / cm 2 units was measured and plotted against time (7 days) as shown in Fig. 4. As a result, the skin permeability was better as the amount of pyruvic acid in the patch was higher.

Example

[0134] One formulation was prepared: a gel formulation (Formulation F15) suitable for use as a reservoir patch and an adhesive matrix patch formulation (Comparative Formulation #1) using DUROTAK 87-2287. The final compositions of the two formulations are shown in Table 4.

Table 4

[0135] The skin penetration experiment was conducted in parallel using the protocol of Example 2, but artificial skin PERMEAPAD was used instead of human cadaver skin. The F15 gel was applied in excess in the donor chamber overlying the skin membrane in the Franz cell. Thus, the results of the gel formulation are comparable to those obtained using the reservoir patch. The purpose here is to compare the relative permeability of the transdermal formulations of the reservoir patch and the drug adhesion matrix patch. See Table 4 and Figure 5.

Table 5

[0136] From Figure 5, it can be seen that the apixaban skin permeability of the formulation containing an adhesive (DIA formulation) is not as good as that of the reservoir patch formulation due to the "dilution" effect of the adhesive component. However, the DIA formulation has sufficient permeability.

Example

[0137] A. Preparation of Patches Two types of "drug - adhesion matrix" patch formulations were prepared. See Table 6.

Table 6

[0138] The matrix transdermal patch shown in Figure 6 was fabricated. In Figure 6, the backing film (1) is affixed over the adhesive drug matrix (2), and this matrix is supported by an over - sized release liner film (3).

[0139] The matrix transdermal patch was prepared by adding ethyl acetate to a 200 mL glass vial and then adding apixaban as follows. The additional components shown in Table 6 were added and mixed to dissolve apixaban. While mixing, the acrylic adhesive DUROTAK 87-2287 was added. The batch was mixed for 60 minutes or until uniform. The resulting wet solution was cast onto a release liner film (3M) using a 20 mil casting applicator. The casting was dried in a forced air oven at 80 °C for 10 minutes. After drying, the dried casting was laminated to a SCOTCHPAK 9723 (manufactured by 3M Drug Delivery Systems) patch backing film. The patches were die-cut into shapes of 10 cm, 50 cm, and 100 cm 2 to enable it to accommodate various dosages. The patches were placed in multi-laminated aluminum pouches.

[0140] The resulting transdermal patches had an adhesive matrix thickness of 6 mil and contained 6.5% apixaban. HPLC analysis confirmed that the patches contained approximately 6.5% apixaban. The patches had good skin adhesiveness and adhered tightly to the skin. The patches were die-cut to be fixed to a Franz cell for skin permeation testing.

[0141] B. Skin Permeation Test The skin permeation experiments were conducted in parallel using the protocol described in Example 2. The results are shown in Table 7 and reported as the daily amount of apixaban permeated (mg / cm 2 ).

Table 7

[0142] C. Stability Test The stability of formulation F20 was evaluated. Specifically, the pouched patches of formulation F20 were stored in environmental chambers at 25 °C / 60% RH and 40 °C / 75% RH, and HPLC assays and color tests were monitored periodically. Refer to Table 8.

Table 8

[0143] As a result, the purity of apixaban after storage was about 99 to about 100% as measured by HPLC. The transdermal absorption type tape preparation of apixaban is considered to be stable up to (i) storage for 6 months at 25°C / 60%RH and (ii) storage for 1 month at 40°C / 75%RH.

Example

[0144] Example 6: Comparative study This example was conducted using rivaroxaban (Xarelto), a direct oral anticoagulant of the factor Xa inhibitor class.

[0145] A reservoir patch containing rivaroxaban was prepared. The components of each formulation are shown in Table 9.

Table 9

[0146] A skin permeation test using Formulations 1A and 1B was conducted as described in Example 1. The average values of the permeated drug are shown in Table 10.

Table 10

[0147] As a result, since the percutaneous permeation amount of rivaroxaban was very small, it was shown that the percutaneous administration of apixaban is more effective than rivaroxaban.

Example

[0148] Example 7: Summary Examples 1 to 6 show that by appropriately selecting excipients and a skin permeation enhancer, the percutaneous administration of apixaban can be achieved both in terms of therapeutic dose and a kinetic profile that is steady and close to zero order.

[0149] Low MW acids appear to improve the skin detachment property of apixaban.

Example

[0150] Example 8 In this study, the pharmacokinetics of the apixaban formulation described in this study and Eliquis (apixaban tablets, for oral use) are evaluated in healthy adults aged 18 years or older.

[0151] Transdermal administration of apixaban (not oral administration) as described herein achieves approximately zero-order kinetics over the wearing period. Generally, the in vitro cumulative drug permeation amount (μg / cm 2 ) from human cadaver skin at any given time point is generally 100% bioavailable in the systemic circulation (i.e., there is no first-pass metabolism in the liver) through a 1 cm 2 patch, and thus can be predicted to represent the in vivo dose delivered to the circulation. The data are analyzed over the first few days when the absorption per day is as nearly linear as possible (i.e., the cumulative absorption curve is approximately linear), and the cumulative drug permeation rate at the end of that number of days is used. Also, the data are analyzed over multiple time points on the first day to determine whether the delivery on that day is at least approximately linear (zero-order kinetics). Thus, the amount of apixaban delivered in vivo can be determined by those skilled in the art according to the surface area of the transdermal patch.

[0152] A. Detailed description Each subject is randomly assigned to one of two groups according to a random assignment table. In one group, the subject is administered ELIQUIS. In the other group, the subject is administered the apixaban formulation described herein.

[0153] B. Eligibility Exclusion criteria are as follows: Exclusion criteria: 1. Sign an informed consent before the examination, and the subject fully understands the examination content, process, and possible side effects; 2. The subject can complete the test in accordance with the requirements of the test plan; 3. The subject (including men) shall, after signing the informed consent, agree to have no planned pregnancy and to take effective contraceptive measures voluntarily within 3 months after the end of the test; 4. The subject is men and women aged 18 or above; 5. The male subject weighs 50 kg or more. The female weighs 45 kg or more. Body mass index = weight (kg) / height2 (m 2 ), within the range of 18.0 - 26.0 kg / m 2 (including the critical value).

[0154] Exclusion criteria: 1. If the subject has a medical history of the nervous, respiratory, cardiovascular, digestive, hematolymphatic, hepatic dysfunction, renal dysfunction, endocrine, skeletal muscle systems, or other diseases, and the principal investigator determines that such medical history may affect drug metabolism and safety; 2. Those who have a smoking history of an average of more than 5 cigarettes per day in the 3 months before screening; 3. Those with a medical history of specific allergies (such as asthma, urticaria, eczema, etc.), allergic constitution (e.g., allergies to more than two drugs or foods), and known allergies to the drug components or (including but not limited to rivaroxaban); 4. Those with lactose intolerance (such as those who have had diarrhea after drinking milk); 5. A history of alcohol abuse within the past year (more than 14 units of alcohol per week: 1 unit = 285 ml of beer, or 25 ml of distilled spirits with an alcohol content of 40 degrees or more, or 100 ml of wine); 6. Those who have donated blood or had bleeding of 400 ml or more within 3 months before the trial, or those who plan to donate blood or provide blood components during or within 3 months after the trial; 7. A history of dysphagia or gastrointestinal disorders that interfere with drug absorption; 8. Use of recombinant cytochrome P450 3A4 (CYP3A4) or permeability glycoprotein (P-gp) inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole), ketoconazole, itraconazole, voriconazole and posaconazole, ritonavir, diltiazem, naproxen, amiodarone, verapamil, quinidine, famotidine, macrolide, nitroimidazole, sedative hypnotics, fluoroquinolone, antihistamines), CYP3A4 and P-gp inducers (e.g., the following, rifampin, phenytoin, carbamazepine, phenobarbital or St. John's wort, omeprazole, glucocorticoids); 9. Anticoagulants, platelet aggregation inhibitors, selective 5-hydroxytryptamine reuptake inhibitors or 5-hydroxytryptamine norepinephrine reuptake inhibitors, non-steroidal anti-inflammatory agents, and drugs that may cause severe bleeding used within 30 days before the test, such as common heparin and heparin derivatives (including low molecular weight heparin), oligosaccharides that inhibit factor Xa of coagulation (e.g., sulforaphane sodium), direct thrombin II inhibitors, thrombolytics, thienopyridine drugs (e.g., sulforaphane sodium). Sulforaphane sodium, etc.), direct thrombin II inhibitors, thrombolytics, thienopyridine drugs (clopidogrel, etc., clopidogrel), dipyridamole, dextran, sulpiride, vitamin K antagonists, other oral anticoagulants; 10. Taking prescription drugs, over-the-counter drugs, traditional Chinese medicines or dietary supplements within 14 days before the administration of the test drug; 11. Having ingested special diets (food and drinks rich in caffeine, alcohol, xanthine (dragon fruit, mango, grapefruit, chocolate, black tea, etc.), smoking, significant changes in exercise habits, and other factors that affect the absorption, distribution, metabolism, and excretion of drugs) within 48 hours before the administration of the test drug; 12. Those who are positive in the alcohol screening test; 13. Those who participated in clinical trials of other pharmaceuticals and took the test drug within 3 months before taking the test drug; 14. Clinically significant abnormalities as determined by the clinician, such as physical examination, vital sign examination, electrocardiogram examination, clinical examinations (including regular blood tests, urine tests, blood biochemistry tests, coagulation function tests); 15. Those with a creatinine clearance of 50 mL / min or less; 16. Those with a coagulation disorder, those with a bleeding tendency (such as frequent gum bleeding), those who have had a high-risk bleeding event within the past 6 months, those with a history of intracranial bleeding, gastrointestinal bleeding, purpura, those who have undergone major surgery within the past 30 days, those with active pathological bleeding; 17. Positive for hepatitis B surface antigen, positive for hepatitis C antibody, positive for HIV antibody, positive for primary syphilis screening; 18. Those who tested positive in the drug abuse screening or those with a history of drug abuse within the past 5 years; 19. Those with a history of blood or injection needle syncope, those with difficult blood collection, those who cannot tolerate venous puncture blood collection; those who cannot comply or those who are not compliant with the ward management rules; 20. Subjects who have undergone a major illness or major surgery within 4 weeks before the administration of the test drug; 21. Subjects who cannot complete the clinical trial for personal reasons; 22. Those determined by the principal investigator of the clinical trial to be inappropriate for participation in this trial; 23. Female subjects who are breastfeeding or female subjects with a positive pregnancy test result during the screening period or during the clinical trial period; 24. Female subjects who have been using oral contraceptives from 30 days before taking the test drug until during the trial period; 25. Female subjects who have used long-acting estrogen or progestin injections or implant tablets within 6 months before the administration of the test drug and during the trial period; 26. Female subjects who had unprotected sexual intercourse 2 weeks before the screening.

[0155] C. Primary Outcome Evaluation Items Determine the following outcome indicators and compare them with the results obtained with ELIQUIS: · Plasma peak concentration (C (max ) · Area under the plasma concentration-time curve (AUC(0-t ) · Area under the plasma concentration-time curve (AUC (0-∞ ) · Safety and tolerability determined by adverse event reports, clinical test results, vital signs, physical examinations, and electrocardiograms.

[0156] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated by reference in their entirety.

[0157] Those skilled in the art will understand that numerous changes and modifications can be made to the preferred embodiments of the present invention, and such changes and modifications can be made without departing from the spirit of the present invention. Accordingly, the appended claims are intended to cover all such equivalent variations that fall within the true spirit and scope of the present invention.

Claims

1. A pharmaceutical composition comprising apixaban and pyruvic acid.

2. A pharmaceutical composition according to claim 1, further comprising a surfactant, a penetration enhancer, or a combination thereof.

3. A pharmaceutical composition according to claim 2, wherein the surfactant or penetration enhancer is a nonionic surfactant such as dimethyl sulfoxide, lactic acid, oleic acid, levulinic acid, 3-hydroxypropionic acid, malonic acid, or polysorbate such as TWEEN 80, or polyethylene glycol monooleyl ether such as BRIJ O20.

4. A pharmaceutical composition according to claim 1, further comprising lactic acid.

5. A pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises, based on the weight of the pharmaceutical composition, about 20 to about 45% by weight of lactic acid, or for example, about 25 to about 35% by weight of lactic acid.

6. A pharmaceutical composition according to claim 1, further comprising dimethyl sulfoxide.

7. A pharmaceutical composition according to claim 6, wherein the pharmaceutical composition comprises about 5 to about 20% by weight of dimethyl sulfoxide, or about 8 to about 15% by weight of dimethyl sulfoxide, based on the weight of the pharmaceutical composition.

8. A pharmaceutical composition according to claim 1, further comprising levulinic acid.

9. A pharmaceutical composition according to claim 8, wherein the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, about 1 to about 20% by weight of levulinic acid, or about 3 to about 10% by weight of levulinic acid.

10. A pharmaceutical composition according to claim 1, further comprising oleic acid.

11. A pharmaceutical composition according to claim 10, wherein the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, about 1 to about 10% by weight of oleic acid, or about 3 to about 7% by weight of oleic acid.

12. A pharmaceutical composition according to claim 1, further comprising polysorbate or polysorbate 80, etc.

13. A pharmaceutical composition according to claim 12, wherein the pharmaceutical composition comprises, based on the weight of the pharmaceutical composition, about 5 to about 15% by weight of polysorbate, or about 7 to about 12% by weight of polysorbate.

14. A pharmaceutical composition according to claim 1, further comprising polyethylene glycol monooleyl ether.

15. A pharmaceutical composition according to claim 14, comprising, based on the weight of the pharmaceutical composition, about 0.01 to about 5% by weight of polyethylene glycol monooleyl ether, or about 0.5 to about 2% by weight of polyethylene glycol monooleyl ether.

16. A pharmaceutical composition according to claim 1, comprising, based on the weight of the pharmaceutical composition, an anticoagulant in an amount of about 5 to about 25% by weight, or an anticoagulant in an amount of about 7 to about 12% by weight, about 9% by weight, about 10% by weight, or about 11% by weight.

17. A pharmaceutical composition according to claim 1, comprising, based on the weight of the pharmaceutical composition, about 20 to about 90% by weight of pyruvic acid, or about 25 to about 45% by weight, or about 30 to about 45% by weight of pyruvic acid.

18. A pharmaceutical composition according to claim 1, comprising about 0.1 to about 100 mg / day, or about 2.5 mg / day, about 5 mg / day, about 10 mg / day, about 15 mg / day, or about 20 mg of apixaban.

19. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition lacks acrylic acid.

20. A dosage form comprising the pharmaceutical composition described in claim 1.

21. The dosage form according to claim 20, wherein the dosage form is a transdermal patch.

22. The dosage form according to claim 21, wherein the transdermal patch is a single-layer drug adhesive patch, a multilayer drug adhesive patch, a reservoir patch, a matrix patch, or a vapor patch, or the like.

23. A dosage form according to claim 21, further comprising a pressure-sensitive adhesive.

24. The pharmaceutical composition according to claim 1, used for treating thromboembolic disorders in patients who require it.

25. A pharmaceutical composition according to claim 24, wherein the thromboembolic disorder is an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, or a thromboembolic disorder of a chamber of the heart.

26. A pharmaceutical composition according to claim 24, wherein the thromboembolic disorder is acute coronary syndrome, initial myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, or thrombosis caused by implants such as artificial valves, thrombosis caused by indwelling catheters, thrombosis caused by stents, thrombosis caused by cardiopulmonary bypass, thrombosis caused by hemodialysis, or thrombosis caused by a procedure in which blood is exposed to an artificial surface that promotes thrombosis or thrombosis caused by such a procedure.

27. A pharmaceutical composition according to claim 24, wherein the thromboembolic disorder is acute coronary syndrome.

28. A pharmaceutical composition according to claim 24, wherein the thromboembolic disorder is a stroke.

29. A pharmaceutical composition according to claim 24, wherein the thromboembolic disorder is deep vein thrombosis.

30. A pharmaceutical composition according to claim 24, wherein the thromboembolic disorder is pulmonary embolism.

31. The pharmaceutical composition according to claim 1, used to prevent deep vein thrombosis or pulmonary embolism in patients who require it.

32. The pharmaceutical composition according to claim 1, used to reduce the recurrence of deep vein thrombosis or pulmonary embolism in patients who require it.

33. A pharmaceutical composition according to claim 31, wherein the patient has undergone artificial hip replacement surgery or artificial knee replacement surgery.

34. The pharmaceutical composition according to claim 1, used to prevent venous thromboembolism (VTE) in patients with acute diseases.

35. The pharmaceutical composition according to claim 1, used to reduce the risk of major cardiovascular events in patients with coronary artery disease.

36. The pharmaceutical composition according to claim 1, used to reduce the risk of major thrombovascular events in patients with peripheral artery disease (PAD).

37. A pharmaceutical composition according to claim 36, wherein the patient has recently undergone lower limb revascularization surgery for symptomatic PAD.

38. The pharmaceutical composition according to claim 1, used to treat VTE in pediatric patients in need, or to reduce the risk of VTE recurrence.

39. The pharmaceutical composition according to claim 1, used for thrombosis prevention in patients with congenital heart disease after Fontan treatment.

40. A pharmaceutical composition according to claim 38, wherein the patient is 2 years of age or older.

41. The pharmaceutical composition according to claim 1, used to treat atherosclerosis, myocardial infarction, pulmonary embolism, or deep vein thrombosis in patients who require it.

42. A pharmaceutical composition according to claim 24, wherein the pharmaceutical composition is administered transdermally.

43. A pharmaceutical composition according to claim 24, further comprising the step of administering a second anticoagulant.

44. A pharmaceutical composition according to claim 43, wherein the second anticoagulant is aspirin.

45. A pharmaceutical composition according to claim 31, wherein the patient is an adult.

46. A pharmaceutical composition according to claim 31, wherein the patient is a child.

47. The pharmaceutical composition according to claim 1, used to prevent one or more thromboembolic or hemorrhagic events in patients with atrial fibrillation.

48. The pharmaceutical composition according to claim 1, used to reduce the risk of stroke or systemic embolism in a patient.

49. A pharmaceutical composition according to claim 48, wherein the patient has non-valvular atrial fibrillation.

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