Transdermal anticoagulant composition

Abstract

The present disclosure provides a pharmaceutical composition comprising an anticoagulant and pyruvic acid. Also provided are dosage forms comprising the pharmaceutical composition and methods for treating a thromboembolic condition in a patient in need thereof, methods for reducing recurrence of deep vein thrombosis or pulmonary embolism in a patient in need thereof, methods for preventing venous thromboembolism (VTE) in an acute patient, methods for treating a thromboembolic condition in a patient in need thereof, and methods for treating a thromboembolic condition in a patient in need thereof. Methods for reducing the risk of a major cardiovascular event in a patient suffering from coronary artery disease, methods for reducing the risk of a major thrombovascular event in a patient suffering from peripheral artery disease (PAD), methods for treating VTE or reducing the risk of recurrence of VTE in a pediatric patient in need thereof, methods for reducing the risk of a major cardiovascular event in a patient suffering from coronary artery disease, methods for reducing the risk of a major thrombovascular event in a patient suffering from peripheral artery disease (PAD), and methods for treating or reducing the risk of recurrence of VTE in a patient in need thereof. The present invention relates to a method for preventing thrombus after Fontan surgery in a patient suffering from a congenital heart disease, a method for treating atherosclerosis, myocardial infarction, pulmonary embolism or deep vein thrombosis in a patient in need thereof, or a method for preventing one or more thromboembolic events or bleeding events in a patient suffering from atrial fibrillation, the methods comprise administering to the patient a pharmaceutical composition or transdermal patch described herein.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 391,127, filed Jul. 21, 2022, the disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION

[0003] The present disclosure relates to anticoagulant compositions and methods of using the same. BACKGROUND OF THE INVENTION

[0004] Drug products delivering the factor Xa inhibitors apixaban ( ), rivaroxaban ( ), and edoxaban ( ) are used to prevent or treat deep vein thrombosis in high-risk patients such as those suffering from atrial fibrillation or undergoing major knee or hip surgery. All of these drugs are administered orally once or twice daily, and the therapy is typically long-term or chronic.

[0005] All of the above products exhibit the pharmacokinetic profile characteristics of orally administered drugs, i.e., the peak and trough pattern of circulating drug levels. Given normal inter-individual variability, the peak levels after dosing may induce excessive anticoagulation, while the trough levels prior to each subsequent dose may be associated with a sub-therapeutic degree of anticoagulation (i.e., thrombogenicity), where the relative activity of the coagulation cascade varies daily. Thus, a small but inevitable percentage of patients administered these agents will experience bleeding (hemorrhagic) or ischemic (thrombotic) events during the course of therapy. While some of these events have minor consequences, severe and even fatal bleeding events occur frequently. Given the widespread use of these drugs, the absolute number of patients experiencing adverse safety events due to this problem is substantial.

[0006] One challenge with such drugs is that they do not readily cross the skin efficiently.

[0007] There is a need for safer and more efficient methods of administering anticoagulants to patients. SUMMARY OF THE INVENTION

[0008] In some aspects, the present disclosure provides a pharmaceutical composition comprising an anticoagulant and pyruvic acid.

[0009] In other aspects, 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.

[0010] In another aspect, the present disclosure provides a method for treating a thromboembolic disorder in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0011] In yet other aspects, 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 a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0012] In still another aspect, 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 a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0013] In other embodiments, the present disclosure provides a method for preventing venous thromboembolism (VTE) in an acutely ill patient, the method comprising administering to the patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0014] In another embodiment, the present disclosure provides a method for reducing the risk of major cardiovascular events in a patient with coronary artery disease, the method comprising administering to the patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0015] In still other embodiments, the present disclosure provides a method for reducing the risk of major thrombotic vascular events in a patient with peripheral artery disease (PAD), the method comprising administering to the patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0016] In yet another embodiment, the present disclosure provides a method for treating VTE in a pediatric patient in need thereof or reducing the risk of VTE recurrence, the method comprising administering to the patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0017] In other embodiments, the present disclosure provides a method for thromboembolism prophylaxis after Fontan surgery in a patient with congenital heart disease, the method comprising administering to the patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0018] In another embodiment, the present disclosure provides 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 or dosage form described herein, such as a transdermal patch.

[0019] In still other embodiments, the present disclosure provides a method of preventing one or more thromboembolic events in a patient with atrial fibrillation, the method comprising administering to the patient a pharmaceutical composition or dosage form described herein, such as a transdermal patch.

[0020] In still further embodiments, the present disclosure provides a method for reducing the risk of stroke or systemic embolism in a patient, the method comprising administering to the 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

[0021] The invention will be further understood from the following detailed description when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, exemplary embodiments of the invention are shown in the drawings; however, the invention is not limited to the specific methods, compositions, and devices disclosed. Additionally, the drawings are not necessarily to scale. In the drawings:

[0022] FIG. 1 is a graph showing the cumulative human skin permeability (μg / cm 2 ) of apixaban using a formulation containing pyruvic acid. Figure 1B is a graph showing the permeation rate (μg / cm² / hour) of apixaban using a formulation containing pyruvic acid.

[0023] FIG. 2 is a graph showing the cumulative human skin permeability (μg / cm 2 ) of apixaban using a formulation containing pyruvic acid and the nonionic surfactant BRIJ O20. Figure 2B is a graph showing the permeation rate (μg / cm² / hour) of apixaban using a formulation containing pyruvic acid and the nonionic surfactant BRIJ O20.

[0024] Figure 3 is a schematic diagram of a transdermal reservoir patch for delivering apixaban.

[0025] Figure 4 is a graph showing the cumulative human skin permeability (mg / cm 2 ) of apixaban using reservoir patches containing increasing concentrations of pyruvic acid.

[0026] Figure 5 is a graph comparing the cumulative human skin permeability (mg / cm 2 ) of apixaban using reservoir patches or adhesive matrix patches.

[0027] Figure 6 is a drawing of a matrix-type transdermal patch.

[0028] Figure 7It is a diagram comparing the adhesive matrix type patches of Example 5. Detailed Description

[0029] The present disclosure can be more readily understood by reference to the following detailed description of the drawings and embodiments that form a part hereof. It should be understood that the present disclosure is not limited to the specific devices, methods, applications, situations, or parameters described and / or illustrated herein, and the terms used herein are for the purpose of describing particular embodiments by way of example only and are not intended to limit the claimed invention.

[0030] When a list is presented, unless otherwise stated, each individual element of the list and each combination of the list should be construed as a separate embodiment. For example, a list of embodiments presented as "A, B, or C" will be construed to include the embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0031] It should be understood that, for clarity, certain features of the invention described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, the various features of the invention described in the context of a single embodiment may also be provided separately or in any sub-combination. Additionally, references to values stated in a range include each value within that range. It should also be noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended as a prerequisite for the use of exclusive terms such as "alone", "only", etc. in relation to the recitation or "negative" limitation of claim elements. Finally, although an embodiment may be described as part of a series of steps or a more general structure, each of the steps itself may also be considered an independent embodiment.

[0032] In the present disclosure, the singular forms "a / an" and "the" include plural referents, and references to a particular numerical value include at least that particular value unless the context clearly dictates otherwise. Thus, for example, a reference to "a therapeutic agent" is a reference to at least one therapeutic agent and its equivalents known to those skilled in the art, and so forth.

[0033] Similarly, when values are expressed as approximations by use of the antecedent "about", it should be understood that the particular value forms another embodiment. In general, use of the term "about" indicates an approximation that may vary depending on the desired property being sought in the subject matter disclosed and should be interpreted based on its function in the particular context in which it is used, and one of ordinary skill in the art will be able to so interpret such approximation. In some cases, the number of significant digits used for a particular value can be a non-limiting method for determining the extent of the word "about". In other cases, the gradations used in a series of values can be used to determine the established range of the term "about" that can be used for each value.

[0034] When ranges are used herein for physical properties, such as amounts or weight %, all combinations and sub-combinations of ranges of the specific embodiments therein are intended to be included.

[0035] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a State government or the corresponding agency in a country other than the United States, or listed in the U.S. Pharmacopeia (U.S.P.) or other generally recognized pharmacopeias for use in animals and more particularly in humans.

[0036] As used herein, the terms "patient" or "subject" refer to a mammal and are used interchangeably. In some embodiments, the patient or subject is a human. In additional embodiments, the patient or subject is an adult, i.e., ≥ 18 years old. In still other embodiments, the patient or subject is a child (pediatric patient), i.e., < 18 years old. In yet additional embodiments, the patient or subject is ≥ 2 years old. In other embodiments, the patient has atrial fibrillation, such as non-valvular atrial fibrillation. In additional embodiments, the patient has undergone hip or knee replacement surgery. In still other embodiments, the patient has congenital heart disease and has undergone the Fontan procedure. In yet additional embodiments, the patient has recently undergone lower extremity revascularization for symptomatic peripheral artery disease (PAD). In still other embodiments, the patient has an acute illness. In yet additional embodiments, the patient has coronary artery disease. In other embodiments, the patient has PAD.

[0037] In some embodiments, "treating" any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of its clinical symptoms). In some embodiments, "treating / treatment" refers to ameliorating at least one physical parameter that may not be discernible by a subject. In other embodiments, "treating / treatment" refers to modulating the disease or disorder physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In additional embodiments, "treating / treatment" refers to delaying the onset of the disease or disorder.

[0038] The present disclosure provides pharmaceutical compositions and dosage units for delivering an anticoagulant to a patient in need thereof. The compositions described herein permit the permeation of the anticoagulant through human skin. Desirably, the pharmaceutical compositions and dosage forms described herein are free of acrylic acid, which inhibits the permeation of the anticoagulant across human skin.

[0039] Pharmaceutical composition

[0040] 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 retards or inhibits blood clotting. In some embodiments, the anticoagulant is a thrombin inhibitor, a factor Xa inhibitor, a factor XIa inhibitor, or a 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 aspects, the thrombin inhibitor is dabigatran. In other embodiments, the anticoagulant is a low molecular weight heparin. Examples of low molecular weight heparins include, but are not limited to, enoxaparin. In additional 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 aspects, the anticoagulant is apixaban. In yet other embodiments, the anticoagulant is a factor XIa inhibitor. Examples of factor XIa inhibitors include, but are not limited to, milvexian or asundexian.

[0041] Based on the weight of the pharmaceutical composition, the pharmaceutical composition of the present disclosure may contain from about 5 wt% to about 25 wt% of an anticoagulant. In some embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt% or about 25 wt% of an anticoagulant. In other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 5 wt% to about 24 wt%, from about 5 wt% to about 23 wt%, from about 5 wt% to about 22 wt%, from about 5 wt% to about 21 wt%, from about 5 wt% to about 20 wt%, 5 wt% to about 19 wt%, from about 5 wt% to about 18 wt%, from about 5 wt% to about 17 wt%, from about 5 wt% to about 16 wt%, from about 5 wt% to about 15 wt%, from about 5 wt% to about 14 wt%, from about 5 wt% to about 13 wt%, from about 5 wt% to about 12 wt%, from about 5 wt% to about 11 wt%, from about 5 wt% to about 10 wt%, from about 5 wt% to about 9 wt%, from about 5 wt% to about 8 wt%, from about 5 wt% to about 7 wt%, from about 5 wt% to about 6 wt%, from about 6 wt% to about 25 wt%, from about 6 wt% to about 24 wt%, from about 6 wt% to about 23 wt%, from about 6 wt% to about 22 wt%, from about 6 wt% to about 21 wt%, from about 6 wt% to about 20 wt%, from about 6 wt% to about 19 wt%, from about 6 wt% to about 18 wt%, from about 6 wt% to about 17 wt%, from about 6 wt% to about 16 wt%, from about 6 wt% to about 15 wt%, from about 6 wt% to about 14 wt%, from about 6 wt% to about 13 wt%, from about 6 wt% to about 12 wt%, from about 6 wt% to about 11 wt%, from about 6 wt% to about 10 wt%, from about 6 wt% to about 9 wt%, from about 6 wt% to about 8 wt%, from about 6 wt% to about 7 wt%, from about 7 wt% to about 25 wt%, from about 7 wt% to about 24 wt%, from about 7 wt% to about 23 wt%, from about 7 wt% to about 22 wt%, from about 7 wt% to about 21 wt%, from about 7 wt% to about 20 wt%, from about 7 wt% to about 19 wt%, from about 7 wt% to about 18 wt%, from about 7 wt% to about 17 wt%, from about 7 wt% to about 16 wt%, from about 7 wt% to about 15 wt%, from about 7 wt% to about 14 wt%, from about 7 wt% to about 13 wt%, from about 7 wt% to about 12 wt%, from about 7 wt% to about 11 wt%, from about 7 wt% to about 10 wt%, from about 7 wt% to about 9 wt%, from about 7 wt% to about 8 wt%, from about 8 wt% to about 25 wt%, from about 8 wt% to about 24 wt%, from about 8 wt% to about 23 wt%,From about 8 wt% to about 22 wt%, from about 8 wt% to about 21 wt%, from about 8 wt% to about 20 wt%, from about 8 wt% to about 19 wt%, from about 8 wt% to about 18 wt%, from about 8 wt% to about 17 wt%, from about 8 wt% to about 16 wt%, from about 8 wt% to about 15 wt%, from about 8 wt% to about 14 wt%, from about 8 wt% to about 13 wt%, from about 8 wt% to about 12 wt%, from about 8 wt% to about 11 wt%, from about 8 wt% to about 10 wt%, from about 8 wt% to about 9 wt%, from about 9 wt% to about 25 wt%, from about 9 wt% to about 24 wt%, from about 9 wt% to about 23 wt%, from about 9 wt% to about 22 wt%, from about 9 wt% to about 21 wt%, from about 9 wt% to about 20 wt%, from about 9 wt% to about 19 wt%, from about 9 wt% to about 18 wt%, from about 9 wt% to about 17 wt%, from about 9 wt% to about 16 wt%, from about 9 wt% to about 15 wt%, from about 9 wt% to about 14 wt%, from about 9 wt% to about 13 wt%, from about 9 wt% to about 12 wt%, from about 9 wt% to about 11 wt%, from about 9 wt% to about 10 wt%, from about 10 wt% to about 25 wt%, from about 10 wt% to about 24 wt%, from about 10 wt% to about 23 wt%, from about 10 wt% to about 22 wt%, from about 10 wt% to about 21 wt%, from about 10 wt% to about 20 wt%, from about 10 wt% to about 19 wt%, from about 10 wt% to about 18 wt%, from about 10 wt% to about 17 wt%, from about 10 wt% to about 16 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 14 wt%, from about 10 wt% to about 13 wt%, from about 10 wt% to about 12 wt%, from about 10 wt% to about 11 wt%, from about 11 wt% to about 25 wt%, from about 11 wt% to about 24 wt%, from about 11 wt% to about 23 wt%, from about 11 wt% to about 22 wt%, from about 11 wt% to about 21 wt%, from about 11 wt% to about 20 wt%, from about 11 wt% to about 19 wt%, from about 11 wt% to about 18 wt%, from about 11 wt% to about 17 wt%, from about 11 wt% to about 16 wt%, from about 11 wt% to about 15 wt%, from about 11 wt% to about 14 wt%, from about 11 wt% to about 13 wt%, from about 11 wt% to about 12 wt%, from about 12 wt% to about 25 wt%, from about 12 wt% to about 24 wt%, from about 12 wt% to about 23 wt%, from about 12 wt% to about 22 wt%, from about 12 wt% to about 21 wt%, from about 12 wt% to about 20 wt%, from about 12 wt% to about 19 wt%, from about 12 wt% to about 18 wt%, from about 12 wt% to about 17 wt%, from about 12 wt% to about 16 wt%, from about 12 wt% to about 15 wt%, from about 12 wt% to about 14 wt%, from about 12 wt% to about 13 wt%, from about 13 wt% to about 25 wt%from about 13 wt% to about 24 wt%, from about 13 wt% to about 23 wt%, from about 13 wt% to about 22 wt%, from about 13 wt% to about 21 wt%, from about 13 wt% to about 20 wt%, from about 13 wt% to about 19 wt%, from about 13 wt% to about 18 wt%, from about 13 wt% to about 17 wt%, from about 13 wt% to about 16 wt%, from about 13 wt% to about 15 wt%, from about 13 wt% to about 14 wt%, from about 14 wt% to about 25 wt%, from about 14 wt% to about 24 wt%, from about 14 wt% to about 23 wt%, from about 14 wt% to about 22 wt%, from about 14 wt% to about 21 wt%, from about 14 wt% to about 20 wt%, from about 14 wt% to about 19 wt%, from about 14 wt% to about 18 wt%, from about 14 wt% to about 17 wt%, from about 14 wt% to about 16 wt%, from about 15 wt% to about 25 wt%, from about 15 wt% to about 24 wt%, from about 15 wt% to about 23 wt%, from about 15 wt% to about 22 wt%, from about 15 wt% to about 21 wt%, from about 15 wt% to about 20 wt%, from about 15 wt% to about 19 wt%, from about 15 wt% to about 18 wt%, from about 15 wt% to about 17 wt%, from about 15 wt% to about 16 wt%, from about 16 wt% to about 25 wt%, from about 16 wt% to about 24 wt%, from about 16 wt% to about 23 wt%, from about 16 wt% to about 22 wt%, from about 16 wt% to about 21 wt%, from about 16 wt% to about 20 wt%, from about 16 wt% to about 19 wt%, from about 16 wt% to about 18 wt%, from about 16 wt% to about 17 wt%, from about 17 wt% to about 25 wt%, from about 17 wt% to about 24 wt%, from about 17 wt% to about 23 wt%, from about 17 wt% to about 22 wt%, from about 17 wt% to about 21 wt%, from about 17 wt% to about 20 wt%, from about 17 wt% to about 19 wt%, from about 17 wt% to about 18 wt%, from about 18 wt% to about 25 wt%, from about 18 wt% to about 24 wt%, from about 18 wt% to about 23 wt%, from about 18 wt% to about 22 wt%, from about 18 wt% to about 21 wt%, from about 18 wt% to about 20 wt%, from about 18 wt% to about 19 wt%, from about 19 wt% to about 25 wt%, from about 19 wt% to about 24 wt%, from about 19 wt% to about 23 wt%, from about 19 wt% to about 22 wt%, from about 19 wt% to about 21 wt%, from about 19 wt% to about 20 wt%, from about 20 wt% to about 25 wt%, from about 20 wt% to about 24 wt%, from about 20 wt% to about 23 wt%, from about 20 wt% to about 22 wt%, from about 20 wt% to about 21 wt%, from about 21 wt% to about 25 wt%, from about 21 wt% to about 24 wt%, from about 21 wt% to about 23 wt%, from about 21 wt% to about 22 wt%,An anticoagulant of about 22% to about 25% by weight, about 22% to about 24% by weight, about 22% to about 23% by weight, about 23% to about 25% by weight, about 23% to about 24% by weight or about 24% to about 25% by weight. In additional embodiments, the pharmaceutical composition contains about 7% to about 12% by weight of an anticoagulant, based on the weight of the pharmaceutical composition. In still other embodiments, the pharmaceutical composition contains about 9% by weight of an anticoagulant, based on the weight of the pharmaceutical composition. In yet additional embodiments, the pharmaceutical composition contains about 10% by weight of an anticoagulant, based on the weight of the pharmaceutical composition. In other embodiments, the pharmaceutical composition contains about 11% by weight of an anticoagulant.,

[0042] According to the present disclosure, the pharmaceutical composition further contains pyruvic acid. Based on the weight of the pharmaceutical composition, the pharmaceutical composition may contain from about 20% to about 90% by weight of pyruvic acid. In some embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, 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. In other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, 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 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 30% to about 35%, 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% by weight, from about 40% to about 50% by weight, from about 40% to about 45% by weight, from about 45% to about 90% by weight, from about 45% to about 85% by weight, from about 45% to about 80% by weight, from about 45% to about 75% by weight, from about 45% to about 70% by weight, from about 45% to about 65% by weight, from about 45% to about 60% by weight, from about 45% to about 55% by weight, from about 45% to about 50% by weight, from about 50% to about 90% by weight, from about 50% to about 85% by weight, from about 50% to about 80% by weight, from about 50% to about 75% by weight, from about 50% to about 70% by weight, from about 50% to about 65% by weight, from about 50% to about 60% by weight, from about 50% to about 55% by weight, from about 55% to about 90% by weight, from about 55% to about 85% by weight, from about 55% to about 80% by weight, from about 55% to about 75% by weight, from about 55% to about 70% by weight, from about 55% to about 65% by weight, from about 55% to about 60% by weight, from about 60% to about 90% by weight, from about 60% to about 85% by weight, from about 60% to about 80% by weight, from about 60% to about 75% by weight, from about 60% to about 70% by weight, from about 60% to about 65% by weight, from about 65% to about 90% by weight, from about 65% to about 85% by weight, from about 65% to about 80% by weight, from about 65% to about 75% by weight, from about 65% to about 70% by weight, from about 70% to about 90% by weight, from about 70% to about 85% by weight, from about 70% to about 80% by weight, from about 70% to about 75% by weight, from about 75% to about 90% by weight, from about 75% to about 85% by weight, from about 75% to about 80% by weight, from about 80% to about 90% by weight, from about 80% to about 85% by weight or from about 85% to about 90% by weight of pyruvic acid. In additional embodiments, the pharmaceutical composition contains from about 25% to about 45% by weight of pyruvic acid, based on the weight of the pharmaceutical composition. In still other embodiments, the pharmaceutical composition contains from about 30% to about 45% by weight of pyruvic acid, based on the weight of the pharmaceutical composition.

[0043] The pharmaceutical compositions described herein may also contain surfactants, permeation enhancers, or combinations thereof. In some embodiments, the pharmaceutical composition contains a surfactant. In other embodiments, the pharmaceutical composition contains a permeation enhancer. In additional embodiments, the pharmaceutical composition contains a surfactant and a permeation enhancer. Examples of surfactants or permeation 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).

[0044] In some aspects, the surfactant or permeation enhancer is dimethyl sulfoxide (DMSO). Based on the weight of the pharmaceutical composition, the pharmaceutical composition can contain from about 5% to about 20% by weight of DMSO. In some embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, 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. In other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, 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 wt% to about 14 wt%, from about 9 wt% to about 13 wt%, from about 9 wt% to about 12 wt%, from about 9 wt% to about 11 wt%, from about 9 wt% to about 10 wt%, from about 10 wt% to about 20 wt%, from about 10 wt% to about 19 wt%, from about 10 wt% to about 18 wt%, from about 10 wt% to about 17 wt%, from about 10 wt% to about 16 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 14 wt%, from about 10 wt% to about 13 wt%, from about 10 wt% to about 12 wt%, from about 10 wt% to about 11 wt%, from about 11 wt% to about 20 wt%, from about 11 wt% to about 19 wt%, from about 11 wt% to about 18 wt%, from about 11 wt% to about 17 wt%, from about 11 wt% to about 16 wt%, from about 11 wt% to about 15 wt%, from about 11 wt% to about 14 wt%, from about 11 wt% to about 13 wt%, from about 11 wt% to about 12 wt%, from about 12 wt% to about 20 wt%, from about 12 wt% to about 19 wt%, from about 12 wt% to about 18 wt%, from about 12 wt% to about 17 wt%, from about 12 wt% to about 16 wt%, from about 12 wt% to about 15 wt%, from about 12 wt% to about 14 wt%, from about 12 wt% to about 13 wt%, from about 13 wt% to about 20 wt%, from about 13 wt% to about 19 wt%, from about 13 wt% to about 18 wt%, from about 13 wt% to about 17 wt%, from about 13 wt% to about 16 wt%, from about 13 wt% to about 15 wt%, from about 13 wt% to about 14 wt%, from about 14 wt% to about 20 wt%, from about 14 wt% to about 19 wt%, from about 14 wt% to about 18 wt%, from about 14 wt% to about 17 wt%, from about 14 wt% to about 16 wt%, from about 14 wt% to about 15 wt%, from about 15 wt% to about 20 wt%, from about 15 wt% to about 19 wt%, from about 15 wt% to about 18 wt%, from about 15 wt% to about 17 wt%, from about 15 wt% to about 16 wt%, from about 16 wt% to about 20 wt%, from about 16 wt% to about 19 wt%, from about 16 wt% to about 18 wt%, from about 16 wt% to about 17 wt%, from about 17 wt% to about 20 wt%, from about 17 wt% to about 19 wt%, from about 17 wt% to about 18 wt%, from about 18 wt% to about 20 wt%, from about 18 wt% to about 19 wt%, or from about 19 wt% to about 20 wt% DMSO. In a further embodiment, the pharmaceutical composition contains from about 8 wt% to about 15 wt% DMSO, based on the weight of the pharmaceutical composition.

[0045] In other aspects, the surfactant or penetration enhancer is lactic acid. Based on the weight of the pharmaceutical composition, the pharmaceutical composition can contain from about 20% to about 45% by weight of lactic acid. In some embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, 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% by weight of lactic acid. In other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, 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 45%, from about 25% to about 40%, from about 25% to about 35%, from about 25% to about 30%, from about 30% to about 45%, from about 30% to about 40%, from about 30% to about 35%, from about 35% to about 45%, from about 30% to about 40% or from about 40% to about 45% by weight of lactic acid. In additional embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 25% to about 35% by weight of lactic acid.

[0046] In another aspect, the surfactant or penetration enhancer is oleic acid. Based on the weight of the pharmaceutical composition, the pharmaceutical composition can contain from about 1 wt% to about 10 wt% of oleic acid. In some embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt% of lactic acid. In other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 1 wt% to about 9 wt%, from about 1 wt% to about 8 wt%, from about 1 wt% to about 7 wt%, from about 1 wt% to about 6 wt%, from about 1 wt% to about 5 wt%, from about 1 wt% to about 4 wt%, from about 1 wt% to about 3 wt%, from about 1 wt% to about 2 wt%, from about 2 wt% to about 10 wt%, from about 2 wt% to about 9 wt%, from about 2 wt% to about 8 wt%, from about 2 wt% to about 7 wt%, from about 2 wt% to about 6 wt%, from about 2 wt% to about 5 wt%, from about 2 wt% to about 4 wt%, from about 2 wt% to about 3 wt%, from about 3 wt% to about 10 wt%, from about 3 wt% to about 9 wt%, from about 3 wt% to about 8 wt%, from about 3 wt% to about 7 wt%, from about 3 wt% to about 6 wt%, from about 3 wt% to about 5 wt%, from about 3 wt% to about 4 wt%, from about 4 wt% to about 10 wt%, from about 4 wt% to about 9 wt%, from about 4 wt% to about 8 wt%, from about 4 wt% to about 7 wt%, from about 4 wt% to about 6 wt%, from about 4 wt% to about 5 wt%, from about 5 wt% to about 10 wt%, from about 5 wt% to about 9 wt%, from about 5 wt% to about 8 wt%, from about 5 wt% to about 7 wt%, from about 5 wt% to about 6 wt%, from about 6 wt% to about 10 wt%, from about 6 wt% to about 9 wt%, from about 6 wt% to about 8 wt%, from about 6 wt% to about 7 wt%, from about 7 wt% to about 10 wt%, from about 7 wt% to about 9 wt%, from about 7 wt% to about 8 wt%, from about 8 wt% to about 10 wt%, from about 8 wt% to about 9 wt% or from about 9 wt% to about 10 wt% of lactic acid. In another embodiment, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 3 wt% to about 7 wt% of lactic acid. In yet other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 1 wt% to about 5 wt% of lactic acid.

[0047] In still other aspects, the surfactant or permeation enhancer is levulinic acid. Based on the weight of the pharmaceutical composition, the pharmaceutical composition can contain from about 1 wt% to about 20 wt% of levulinic acid. In some embodiments, the pharmaceutical composition contains 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, based on the weight of the pharmaceutical composition, from about 1 wt% to about 18 wt%, from about 1 wt% to about 16 wt%, from about 1 wt% to about 14 wt%, from about 1 wt% to about 12 wt%, from about 1 wt% to about 10 wt%, from about 1 wt% to about 8 wt%, from about 1 wt% to about 6 wt%, from about 1 wt% to about 4 wt%, from about 1 wt% to about 3 wt%, from about 3 wt% to about 20 wt%, from about 3 wt% to about 18 wt%, from about 3 wt% to about 16 wt%, from about 3 wt% to about 14 wt%, from about 3 wt% to about 12 wt%, from about 3 wt% to about 10 wt%, from about 3 wt% to about 8 wt%, from about 3 wt% to about 6 wt%, from about 3 wt% to about 5 wt%, from about 5 wt% to about 19 wt%, from about 5 wt% to about 18 wt%, from about 5 wt% to about 17 wt%, from about 5 wt% to about 16 wt%, from about 5 wt% to about 15 wt%, from about 5 wt% to about 14 wt%, from about 5 wt% to about 13 wt%, from about 5 wt% to about 12 wt%, from about 5 wt% to about 11 wt%, from about 5 wt% to about 10 wt%, from about 5 wt% to about 9 wt%, from about 5 wt% to about 8 wt%, from about 5 wt% to about 7 wt%, from about 5 wt% to about 6 wt%, from about 6 wt% to about 20 wt%, from about 6 wt% to about 19 wt%, from about 6 wt% to about 18 wt%, from about 6 wt% to about 17 wt%, from about 6 wt% to about 16 wt%, from about 6 wt% to about 15 wt%, from about 6 wt% to about 14 wt%, from about 6 wt% to about 13 wt%, from about 6 wt% to about 12 wt%, from about 6 wt% to about 11 wt%, from about 6 wt% to about 10 wt%, from about 6 wt% to about 9 wt%, from about 6 wt% to about 8 wt%, from about 6 wt% to about 7 wt%, from about 7 wt% to about 20 wt%, from about 7 wt% to about 19 wt%, from about 7 wt% to about 18 wt%, from about 7 wt% to about 17 wt%, from about 7 wt% to about 16 wt%, from about 7 wt% to about 15 wt%, from about 7 wt% to about 14 wt%, from about 7 wt% to about 13 wt%, from about 7 wt% to about 12 wt%, from about 7 wt% to about 11 wt%, from about 7 wt% to about 10 wt%, from about 7 wt% to about 9 wt%, from about 7 wt% to about 8 wt%, from about 8 wt% to about 20 wt%, from about 8 wt% to about 19 wt%, from about 8 wt% to about 18 wt%, from about 8 wt% to about 17 wt%, from about 8 wt% to about 16 wt%,from about 8 wt% to about 15 wt%, from about 8 wt% to about 14 wt%, from about 8 wt% to about 13 wt%, from about 8 wt% to about 12 wt%, from about 8 wt% to about 11 wt%, from about 8 wt% to about 10 wt%, from about 8 wt% to about 9 wt%, from about 9 wt% to about 20 wt%, from about 9 wt% to about 19 wt%, from about 9 wt% to about 18 wt%, from about 9 wt% to about 17 wt%, from about 9 wt% to about 16 wt%, from about 9 wt% to about 15 wt%, from about 9 wt% to about 14 wt%, from about 9 wt% to about 13 wt%, from about 9 wt% to about 12 wt%, from about 9 wt% to about 11 wt%, from about 9 wt% to about 10 wt%, from about 10 wt% to about 20 wt%, from about 10 wt% to about 19 wt%, from about 10 wt% to about 18 wt%, from about 10 wt% to about 17 wt%, from about 10 wt% to about 16 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 14 wt%, from about 10 wt% to about 13 wt%, from about 10 wt% to about 12 wt%, from about 10 wt% to about 11 wt%, from about 11 wt% to about 20 wt%, from about 11 wt% to about 19 wt%, from about 11 wt% to about 18 wt%, from about 11 wt% to about 17 wt%, from about 11 wt% to about 16 wt%, from about 11 wt% to about 15 wt%, from about 11 wt% to about 14 wt%, from about 11 wt% to about 13 wt%, from about 11 wt% to about 12 wt%, from about 12 wt% to about 20 wt%, from about 12 wt% to about 19 wt%, from about 12 wt% to about 18 wt%, from about 12 wt% to about 17 wt%, from about 12 wt% to about 16 wt%, from about 12 wt% to about 15 wt%, from about 12 wt% to about 14 wt%, from about 12 wt% to about 13 wt%, from about 13 wt% to about 20 wt%, from about 13 wt% to about 19 wt%, from about 13 wt% to about 18 wt%, from about 13 wt% to about 17 wt%, from about 13 wt% to about 16 wt%, from about 13 wt% to about 15 wt%, from about 13 wt% to about 14 wt%, from about 14 wt% to about 20 wt%, from about 14 wt% to about 19 wt%, from about 14 wt% to about 18 wt%, from about 14 wt% to about 17 wt%, from about 14 wt% to about 16 wt%, from about 14 wt% to about 15 wt%, from about 15 wt% to about 20 wt%, from about 15 wt% to about 19 wt%, from about 15 wt% to about 18 wt%, from about 15 wt% to about 17 wt%, from about 15 wt% to about 16 wt%, from about 16 wt% to about 20 wt%, from about 16 wt% to about 19 wt%, from about 16 wt% to about 18 wt%, from about 16 wt% to about 17 wt%, from about 17 wt% to about 20 wt%, from about 17 wt% to about 19 wt%, from about 17 wt% to about 18 wt%, from about 18 wt% to about 20 wt%From about 18% to about 19% by weight or from about 19% to about 20% by weight of levulinic acid. In additional embodiments, the pharmaceutical composition contains from about 3% to about 10% by weight of levulinic acid, based on the weight of the pharmaceutical composition.

[0048] In still another aspect, the surfactant or penetration enhancer is 3-hydroxypropionic acid. In some embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, 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% of 3-hydroxypropionic acid. In other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, about 20 wt% to about 85 wt%, about 20 wt% to about 80 wt%, about 20 wt% to about 75 wt%, about 20 wt% to about 70 wt%, about 20 wt% to about 60 wt%, about 20 wt% to about 55 wt%, about 20 wt% to about 50 wt%, about 20 wt% to about 45 wt%, about 20 wt% to about 40 wt%, about 20 wt% to about 35 wt%, about 20 wt% to about 30 wt%, about 20 wt% to about 25 wt%, about 25 wt% to about 90 wt%, about 25 wt% to about 85 wt%, about 25 wt% to about 80 wt%, about 25 wt% to about 75 wt%, about 25 wt% to about 70 wt%, about 25 wt% to about 65 wt%, about 25 wt% to about 60 wt%, about 25 wt% to about 55 wt%, about 25 wt% to about 50 wt%, about 25 wt% to about 45 wt%, about 25 wt% to about 40 wt%, about 25 wt% to about 35 wt%, about 25 wt% to about 30 wt%, about 30 wt% to about 90 wt%, about 30 wt% to about 85 wt%, about 30 wt% to about 80 wt%, about 30 wt% to about 75 wt%, about 30 wt% to about 70 wt%, about 30 wt% to about 65 wt%, about 30 wt% to about 60 wt%, about 30 wt% to about 55 wt%, about 30 wt% to about 50 wt%, about 30 wt% to about 45 wt%, about 30 wt% to about 40 wt%, about 30 wt% to about 35 wt%, about 35 wt% to about 90 wt%, about 35 wt% to about 85 wt%, about 35 wt% to about 80 wt%, about 35 wt% to about 75 wt%, about 35 wt% to about 70 wt%, about 35 wt% to about 65 wt%, about 35 wt% to about 60 wt%, about 35 wt% to about 55 wt%, about 35 wt% to about 50 wt%, about 35 wt% to about 45 wt%, about 30 wt% to about 40 wt%, about 40 wt% to about 90 wt%, about 40 wt% to about 85 wt%, about 40 wt% to about 80 wt%, about 40 wt% to about 75 wt%, about 40 wt% to about 70 wt%, about 40 wt% to about 65 wt%, about 40 wt% to about 60 wt%, about 40 wt% to about 55 wt%, about 40 wt% to about 50 wt%,From about 40 wt% to about 45 wt%, from about 45 wt% to about 90 wt%, from about 45 wt% to about 85 wt%, from about 45 wt% to about 80 wt%, from about 45 wt% to about 75 wt%, from about 45 wt% to about 70 wt%, from about 45 wt% to about 65 wt%, from about 45 wt% to about 60 wt%, from about 45 wt% to about 55 wt%, from about 45 wt% to about 50 wt%, from about 50 wt% to about 90 wt%, from about 50 wt% to about 85 wt%, from about 50 wt% to about 80 wt%, from about 50 wt% to about 75 wt%, from about 50 wt% to about 70 wt%, from about 50 wt% to about 65 wt%, from about 50 wt% to about 60 wt%, from about 50 wt% to about 55 wt%, from about 55 wt% to about 90 wt%, from about 55 wt% to about 85 wt%, from about 55 wt% to about 80 wt%, from about 55 wt% to about 75 wt%, from about 55 wt% to about 70 wt%, from about 55 wt% to about 65 wt%, from about 55 wt% to about 60 wt%, from about 60 wt% to about 90 wt%, from about 60 wt% to about 85 wt%, from about 60 wt% to about 80 wt%, from about 60 wt% to about 75 wt%, from about 60 wt% to about 70 wt%, from about 60 wt% to about 65 wt%, from about 65 wt% to about 90 wt%, from about 65 wt% to about 85 wt%, from about 65 wt% to about 80 wt%, from about 65 wt% to about 75 wt%, from about 65 wt% to about 70 wt%, from about 70 wt% to about 90 wt%, from about 70 wt% to about 85 wt%, from about 70 wt% to about 80 wt%, from about 70 wt% to about 75 wt%, from about 75 wt% to about 90 wt%, from about 75 wt% to about 85 wt%, from about 75 wt% to about 80 wt%, from about 80 wt% to about 90 wt%, from about 80 wt% to about 85 wt%, or from about 85 wt% to about 90 wt% of 3-hydroxypropionic acid. In additional embodiments, the pharmaceutical composition contains from about 25 wt% to about 45 wt% of 3-hydroxypropionic acid, based on the weight of the pharmaceutical composition. In still other embodiments, the pharmaceutical composition contains from about 30 wt% to about 45 wt% of 3-hydroxypropionic acid, based on the weight of the pharmaceutical composition.

[0049] In other aspects, the penetration enhancer is malonic acid. In some embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, 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% of malonic acid. In other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, about 20 wt% to about 85 wt%, about 20 wt% to about 80 wt%, about 20 wt% to about 75 wt%, about 20 wt% to about 70 wt%, about 20 wt% to about 60 wt%, about 20 wt% to about 55 wt%, about 20 wt% to about 50 wt%, about 20 wt% to about 45 wt%, about 20 wt% to about 40 wt%, about 20 wt% to about 35 wt%, about 20 wt% to about 30 wt%, about 20 wt% to about 25 wt%, about 25 wt% to about 90 wt%, about 25 wt% to about 85 wt%, about 25 wt% to about 80 wt%, about 25 wt% to about 75 wt%, about 25 wt% to about 70 wt%, about 25 wt% to about 65 wt%, about 25 wt% to about 60 wt%, about 25 wt% to about 55 wt%, about 25 wt% to about 50 wt%, about 25 wt% to about 45 wt%, about 25 wt% to about 40 wt%, about 25 wt% to about 35 wt%, about 25 wt% to about 30 wt%, about 30 wt% to about 90 wt%, about 30 wt% to about 85 wt%, about 30 wt% to about 80 wt%, about 30 wt% to about 75 wt%, about 30 wt% to about 70 wt%, about 30 wt% to about 65 wt%, about 30 wt% to about 60 wt%, about 30 wt% to about 55 wt%, about 30 wt% to about 50 wt%, about 30 wt% to about 45 wt%, about 30 wt% to about 40 wt%, about 35 wt% to about 90 wt%, about 35 wt% to about 85 wt%, about 35 wt% to about 80 wt%, about 35 wt% to about 75 wt%, about 35 wt% to about 70 wt%, about 35 wt% to about 65 wt%, about 35 wt% to about 60 wt%, about 35 wt% to about 55 wt%, about 35 wt% to about 50 wt%, about 35 wt% to about 45 wt%, about 30 wt% to about 40 wt%, about 40 wt% to about 90 wt%, about 40 wt% to about 85 wt%, about 40 wt% to about 80 wt%, about 40 wt% to about 75 wt%, about 40 wt% to about 70 wt%, about 40 wt% to about 65 wt%, about 40 wt% to about 60 wt%, about 40 wt% to about 55 wt%, about 40 wt% to about 50 wt%, about 40 wt% to about 45 wt%,From about 45% to about 90% by weight, from about 45% to about 85% by weight, from about 45% to about 80% by weight, from about 45% to about 75% by weight, from about 45% to about 70% by weight, from about 45% to about 65% by weight, from about 45% to about 60% by weight, from about 45% to about 55% by weight, from about 45% to about 50% by weight, from about 50% to about 90% by weight, from about 50% to about 85% by weight, from about 50% to about 80% by weight, from about 50% to about 75% by weight, from about 50% to about 70% by weight, from about 50% to about 65% by weight, from about 50% to about 60% by weight, from about 50% to about 55% by weight, from about 55% to about 90% by weight, from about 55% to about 85% by weight, from about 55% to about 80% by weight, from about 55% to about 75% by weight, from about 55% to about 70% by weight, from about 55% to about 65% by weight, from about 55% to about 60% by weight, from about 60% to about 90% by weight, from about 60% to about 85% by weight, from about 60% to about 80% by weight, from about 60% to about 75% by weight, from about 60% to about 70% by weight, from about 60% to about 65% by weight, from about 65% to about 90% by weight, from about 65% to about 85% by weight, from about 65% to about 80% by weight, from about 65% to about 75% by weight, from about 65% to about 70% by weight, from about 70% to about 90% by weight, from about 70% to about 85% by weight, from about 70% to about 80% by weight, from about 70% to about 75% by weight, from about 75% to about 90% by weight, from about 75% to about 85% by weight, from about 75% to about 80% by weight, from about 80% to about 90% by weight, from about 80% to about 85% by weight, or from about 85% to about 90% by weight of malonic acid. In additional embodiments, the pharmaceutical composition contains from about 25% to about 45% by weight of malonic acid, based on the weight of the pharmaceutical composition. In yet other embodiments, the pharmaceutical composition contains from about 30% to about 45% by weight of malonic acid, based on the weight of the pharmaceutical composition.

[0050] In another aspect, the surfactant or permeation enhancer is a nonionic surfactant. Examples of nonionic enhancers include, but are not limited to, polysorbates such as polysorbate 80, for example Based on the weight of the pharmaceutical composition, the pharmaceutical composition may contain from about 5 wt% to about 15 wt% of a nonionic enhancer. In some embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt% or about 15 wt% of a nonionic enhancer. In other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 5 wt% to about 14 wt%, from about 5 wt% to about 13 wt%, from about 5 wt% to about 12 wt%, from about 5 wt% to about 11 wt%, from about 5 wt% to about 10 wt%, from about 5 wt% to about 9 wt%, from about 5 wt% to about 8 wt%, from about 5 wt% to about 7 wt%, from about 5 wt% to about 6 wt%, from about 6 wt% to about 15 wt%, from about 6 wt% to about 14 wt%, from about 6 wt% to about 13 wt%, from about 6 wt% to about 12 wt%, from about 6 wt% to about 11 wt%, from about 6 wt% to about 10 wt%, from about 6 wt% to about 9 wt%, from about 6 wt% to about 8 wt%, from about 6 wt% to about 7 wt%, from about 7 wt% to about 15 wt%, from about 7 wt% to about 14 wt%, from about 7 wt% to about 13 wt%, from about 7 wt% to about 12 wt%, from about 7 wt% to about 11 wt%, from about 7 wt% to about 10 wt%, from about 7 wt% to about 9 wt%, from about 7 wt% to about 8 wt%, from about 8 wt% to about 14 wt%, from about 8 wt% to about 13 wt%, from about 8 wt% to about 12 wt%, from about 8 wt% to about 11 wt%, from about 8 wt% to about 10 wt%, from about 8 wt% to about 9 wt%, from about 9 wt% to about 14 wt%, from about 9 wt% to about 13 wt%, from about 9 wt% to about 12 wt%, from about 9 wt% to about 11 wt%, from about 9 wt% to about 10 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 14 wt%, from about 10 wt% to about 13 wt%, from about 10 wt% to about 12 wt%, from about 10 wt% to about 11 wt%, from about 11 wt% to about 15 wt%, from about 11 wt% to about 14 wt%, from about 11 wt% to about 13 wt%, from about 11 wt% to about 12 wt%, from about 12 wt% to about 15 wt%, from about 12 wt% to about 14 wt%, from about 12 wt% to about 13 wt%, from about 13 wt% to about 15 wt%, from about 13 wt% to about 14 wt% or from about 14 wt% to about 15 wt% of a nonionic enhancer. In additional embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 7 wt% to about 12 wt% of a nonionic enhancer. In still other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 0.5 wt% to about 2 wt% of a nonionic enhancer.

[0051] In still other aspects, the surfactant or penetration enhancer is polyethylene glycol monooleate. Examples of polyethylene glycol monooleate include polyoxyethylene (20) oleyl ether, such as O20. Based on the weight of the pharmaceutical composition, the pharmaceutical composition may contain from about 0.01% to about 5% by weight of polyethylene glycol monooleate. In some embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, 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 monooleate. In other embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 0.5% to about 4.5%, from about 0.5% to about 4%, from about 0.5% to about 3.5%, from about 0.5% to about 3%, from about 0.5% to about 2.5%, from about 0.5% to about 2%, from about 0.5% to about 1.5%, from about 0.5% to about 1%, from about 1% to about 5%, from about 1% to about 4.5%, from about 1% to about 4%, from about 1% to about 3.5%, from about 1% to about 3%, from about 1% to about 2.5%, from about 1% to about 2%, from about 1% to about 1.5%, from about 1.5% to about 5%, from about 1.5% to about 4.5%, from about 1.5% to about 4%, from about 1.5% to about 3.5%, from about 1.5% to about 3%, from about 1.5% to about 2.5%, from about 1.5% to about 2%, from about 2% to about 5%, from about 2% to about 4.5%, from about 2% to about 4%, from about 2% to about 3.5%, from about 2% to about 3%, from about 2% to about 2.5%, from about 2.5% to about 5%, from about 2.5% to about 4.5%, from about 2.5% to about 4%, from about 2.5% to about 3.5%, from about 2.5% to about 3%, from about 3% to about 5%, from about 3% to about 4.5%, from about 3% to about 4%, from about 3% to about 3.5%, from about 3.5% to about 5%, from about 3.5% to about 4.5%, from about 3.5% to about 4%, from about 4% to about 5%, from about 4% to about 4.5% or from about 4.5% to about 5% by weight of polyethylene glycol monooleate. In additional embodiments, the pharmaceutical composition contains, based on the weight of the pharmaceutical composition, from about 0.5% to about 2% by weight of polyethylene glycol monooleate.

[0052] The pharmaceutical compositions 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 compositions of the present disclosure may further include excipients. Examples of suitable excipients include, but are not limited to, those further comprising one or more of fillers, binders, disintegrants, emulsifiers, antistatic agents, or solvates.

[0053] Dosage form

[0054] The present disclosure also contemplates dosage forms comprising the pharmaceutical compositions described herein. Thus, the pharmaceutical compositions can be formulated into gels, transdermal patches, lotions, creams, sprays, aerosols, emulsions, or dispersions. Suitable excipients for formulating gels, transdermal patches, lotions, creams, sprays, or aerosols will be apparent to those skilled in the art and include, but are not limited to, stabilizers, emulsifiers, thickeners, antimicrobial agents, wetting agents, propellants, spreading agents, polymers, and adhesives such as pressure-sensitive adhesives. Specifically, excipients that can be used to form a transdermal gel include, but are not limited to, alcohols, glycols, glycerol, 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 other embodiments, the dosage form is a cream. In yet other embodiments, the dosage form is a spray. In other embodiments, the dosage form is an aerosol. In further embodiments, the dosage form is an emulsion. In still other embodiments, the dosage form is a dispersion.

[0055] The dosage form can be designed to deliver the pharmaceutical composition over a period of time (depending on the patient). In some embodiments, the dosage form is designed to deliver the anticoagulant over a period of one day (i.e., 24 hours). In other embodiments, the dosage form is designed to deliver the anticoagulant over a period of two days (e.g., 48 hours). In further embodiments, the dosage form is designed to deliver the anticoagulant over a period of three days. In still further embodiments, the dosage form is designed to deliver the anticoagulant over a period of 3.5 days. In yet other embodiments, the dosage form is designed to deliver the anticoagulant over a period of four days. In still further embodiments, the dosage form is designed to deliver the anticoagulant over a period of five days. In other embodiments, the dosage form is designed to deliver the anticoagulant over a period of six days. In further embodiments, the dosage form is designed to deliver the anticoagulant over a period of seven days (e.g., one week).

[0056] The specific 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-in-adhesive patch, a multi-layer drug-in-adhesive patch, a reservoir patch, a matrix patch, or a vapor patch. In other embodiments, the dosage form is a single-layer drug-in-adhesive patch. In further embodiments, the dosage form is a multi-layer drug-in-adhesive patch. In still further embodiments, the dosage form is a reservoir patch. In yet other embodiments, the dosage form is a matrix patch. In other embodiments, the dosage form is a vapor patch.

[0057] The amount of anticoagulant present in the dosage form depends on the daily dose of the anticoagulant to be administered and the particular anticoagulant selected. Thus, if the dosage form is intended to release the anticoagulant for more than 1 day, the amount of anticoagulant is adjusted accordingly. In some embodiments, the dosage form administers the anticoagulant over a 2-day period and the amount of anticoagulant is 2 times the daily dose. In some embodiments, the dosage form administers the anticoagulant over a 3-day period and the amount of anticoagulant is 3 times the daily dose. In some embodiments, the dosage form administers the anticoagulant over a 4-day period and the amount of anticoagulant is 4 times the daily dose. In some embodiments, the dosage form administers the anticoagulant over a 5-day period and the amount of anticoagulant is 5 times the daily dose. In some embodiments, the dosage form administers the anticoagulant over a 6-day period and the amount of anticoagulant is 6 times the daily dose. In some embodiments, the dosage form administers the anticoagulant over a 7-day (i.e., 1 week) period and the amount of anticoagulant is 7 times the daily dose.

[0058] In some embodiments, the dosage form contains an excess amount of anticoagulant to ensure a concentration gradient that favors transdermal flux from the patch throughout the application period. As used herein, the term "excess" refers to an amount that is about 2 to about 5 times greater than the weight of the anticoagulant in the dosage form. In some embodiments, the excess is about 2-fold excess, i.e., about 2 times the weight of the anticoagulant in the dosage form. In other embodiments, the excess is about 3-fold excess, i.e., about 3 times the weight of the anticoagulant in the dosage form. In further embodiments, the excess is about 4-fold excess, i.e., about 4 times the weight of the anticoagulant in the dosage form. In still other embodiments, the excess is about 5-fold excess, i.e., about 5 times the weight of the anticoagulant in the dosage form. By way of example, the following formula can be used to calculate the amount of anticoagulant in the dosage form:

[0059] Amount of anticoagulant in dosage form (mg) = (Daily dose of anticoagulant (mg)) × (Number of days of patch application) × (Excess multiple of anticoagulant in dosage form)

[0060] For example, if the daily dose of an anticoagulant is about 100 mg and the dosage unit is designed to release the anticoagulant over a seven-day period, the dosage form contains from about 1400 mg (100 mg x 2-fold excess x 7 days) to about 3500 mg (100 mg x 5-fold excess x 7 days).

[0061] In some embodiments, the dosage form contains an amount of apixaban that delivers from about 2.5 mg / day to about 20 mg / day of apixaban to a patient. In certain aspects, the dosage form contains an amount of apixaban that delivers about 2.5 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 11 mg / day, about 12 mg / day, about 13 mg / day, about 14 mg / day, about 15 mg / day, about 16 mg / day, about 17 mg / day, about 18 mg / day, about 19 mg / day, or about 20 mg / day of apixaban to a patient. In other aspects, the dosage form contains an amount of apixaban that delivers from about 2.5 mg / day to about 17.5 mg / day, from about 2.5 mg / day to about 15 mg / day, from about 2.5 mg / day to about 12.5 mg / day, from about 2.5 mg / day to about 10 mg / day, from about 2.5 mg / day to about 7.5 mg / day, from about 7.5 mg / day to about 5 mg / day, from about 5 mg / day to about 20 mg / day, from about 5 mg / day to about 17.5 mg / day, from about 5 mg / day to about 15 mg / day, from about 5 mg / day to about 12.5 mg / day, from about 5 mg / day to about 10 mg / day, from about 5 mg / day to about 7.5 mg / day, from about 7.5 mg / day to about 20 mg / day, from about 7.5 mg / day to about 17.5 mg / day, from about 7.5 mg / day to about 15 mg / day, from about 7.5 mg / day to about 12.5 mg / day, from about 7.5 mg / day to about 10 mg / day, from about 10 mg / day to about 20 mg / day, from about 10 mg / day to about 17.5 mg / day, from about 10 mg / day to about 15 mg / day, from about 10 mg / day to about 12.5 mg / day, from about 12.5 mg / day to about 20 mg / day, from about 12.5 mg / day to about 17.5 mg / day, from about 12.5 mg / day to about 15 mg / day, from about 15 mg / day to about 20 mg / day, from about 15 mg / day to about 17.5 mg / day, or from about 17.5 mg / day to about 20 mg / day of apixaban to a patient.

[0062] In some embodiments, the transdermal dosage forms described herein deliver the same amount of apixaban as an oral dosage form comprising apixaban within about 24 hours. For example, in some aspects, the transdermal dosage form will exhibit the same or a 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 forms described herein produce a C max that is not the same or not similar to the C max . In some aspects, the transdermal dosage form will exhibit a C max that is lower (e.g., about 10%, about 15%, about 20%, about 25%, or about 30% lower) than the C max exhibited when an oral dosage form comprising apixaban is administered. In additional embodiments, the trough levels produced by the transdermal dosage forms described herein are higher than the trough levels achieved using an oral apixaban dosage form. 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 compared to oral dosage forms comprising apixaban, the described transdermal dosage forms will have comparable or improved safety.

[0063] In other embodiments, the dosage form contains an amount of rivaroxaban that delivers from about 2.5 mg / day to about 30 mg / day of rivaroxaban to a patient. In certain aspects, the dosage form contains an amount of rivaroxaban that delivers about 2.5 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 11 mg / day, about 12 mg / day, about 13 mg / day, about 14 mg / day, about 15 mg / day, about 16 mg / day, about 17 mg / day, about 18 mg / day, about 19 mg / day, about 20 mg / day, about 21 mg / day, about 22 mg / day, about 23 mg / day, about 24 mg / day, about 25 mg / day, about 26 mg / day, about 27 mg / day, about 28 mg / day, about 29 mg / day, or about 30 mg / day of rivaroxaban to a patient. In other aspects, the dosage form contains an amount of rivaroxaban that delivers from about 2.5 mg / day to about 30 mg / day, from about 2.5 mg / day to about 27.5 mg / day, from about 2.5 mg / day to about 25 mg / day, from about 2.5 mg / day to about 22.5 mg / day, from about 2.5 mg / day to about 20 mg / day, from about 2.5 mg / day to about 17.5 mg / day, from about 2.5 mg / day to about 15 mg / day, from about 2.5 mg / day to about 12.5 mg / day, from about 2.5 mg / day to about 10 mg / day, from about 2.5 mg / day to about 7.5 mg / day, from about 2.5 mg / day to about 5 mg / day, from about 5 mg / day to about 30 mg / day, from about 5 mg / day to about 27.5 mg / day, from about 5 mg / day to about 25 mg / day, from about 5 mg / day to about 22.5 mg / day, from about 5 mg / day to about 20 mg / day, from about 5 mg / day to about 17.5 mg / day, from about 5 mg / day to about 15 mg / day, from about 5 mg / day to about 12.5 mg / day, from about 5 mg / day to about 10 mg / day, from about 5 mg / day to about 7.5 mg / day, from about 7.5 mg / day to about 30 mg / day, from about 7.5 mg / day to about 27.5 mg / day, from about 7.5 mg / day to about 25 mg / day, from about 7.5 mg / day to about 22.5 mg / day, from about 7.5 mg / day to about 20 mg / day, from about 7.5 mg / day to about 17.5 mg / day, from about 7.5 mg / day to about 15 mg / day, from about 7.5 mg / day to about 12.5 mg / day, from about 7.5 mg / day to about 10 mg / day, from about 10 mg / day to about 30 mg / day, from about 10 mg / day to about 27.5 mg / day, from about 10 mg / day to about 25 mg / day, from about 10 mg / day to about 22.5 mg / day, from about 10 mg / day to about 20 mg / day, from about 10 mg / day to about 17.5 mg / day, from about 10 mg / day to about 15 mg / day, from about 10 mg / day to about 12.5 mg / day, about 12.Rivaroxaban is delivered to the patient at a dose of 5 mg / day to about 30 mg / day, about 12.5 mg / day to about 27.5 mg / day, about 12.5 mg / day to about 25 mg / day, about 12.5 mg / day to about 22.5 mg / day, about 12.5 mg / day to about 20 mg / day, about 12.5 mg / day to about 17.5 mg / day, about 12.5 mg / day to about 15 mg / day, about 15 mg / day to about 30 mg / day, about 15 mg / day to about 27.5 mg / day, about 15 mg / day to about 25 mg / day, about 15 mg / day to about 22.5 mg / day, about 15 mg / day to about 20 mg / day, about 15 mg / day to about 17.5 mg / day, about 17.5 mg / day to about 30 mg / day, about 17.5 mg / day to about 27.5 mg / day, about 17.5 mg / day to about 25 mg / day, about 17.5 mg / day to about 22.5 mg / day, about 17.5 mg / day to about 20 mg / day, about 20 mg / day to about 30 mg / day, about 20 mg / day to about 27.5 mg / day, about 20 mg / day to about 25 mg / day, about 20 mg / day to about 22.5 mg / day, about 22.5 mg / day to about 30 mg / day, about 22.5 mg / day to about 27.5 mg / day, about 22.5 mg / day to about 25 mg / day, about 25 mg / day to about 30 mg / day, about 25 mg / day to about 27.5 mg / day or about 27.5 mg / day to about 30 mg / day.

[0064] In another embodiment, the dosage form contains an amount of edoxaban that delivers from about 15 mg / day to about 60 mg / day of edoxaban to a patient. In certain aspects, the dosage form contains an amount of edoxaban that delivers about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, or about 60 mg / day of edoxaban to a patient. In other aspects, the dosage form contains an amount of edoxaban that delivers from about 15 mg / day to about 55 mg / day, from about 15 mg / day to about 50 mg / day, from about 15 mg / day to about 45 mg / day, from about 15 mg / day to about 40 mg / day, from about 15 mg / day to about 35 mg / day, from about 15 mg / day to about 30 mg / day, from about 15 mg / day to about 25 mg / day, from about 15 mg / day to about 20 mg / day, from about 20 mg / day to about 60 mg / day, from about 20 mg / day to about 55 mg / day, from about 20 mg / day to about 50 mg / day, from about 20 mg / day to about 45 mg / day, from about 20 mg / day to about 40 mg / day, from about 20 mg / day to about 35 mg / day, from about 20 mg / day to about 30 mg / day, from about 25 mg / day to about 60 mg / day, from about 25 mg / day to about 55 mg / day, from about 25 mg / day to about 50 mg / day, from about 25 mg / day to about 45 mg / day, from about 25 mg / day to about 40 mg / day, from about 25 mg / day to about 35 mg / day, from about 25 mg / day to about 30 mg / day, from about 30 mg / day to about 60 mg / day, from about 30 mg / day to about 55 mg / day, from about 30 mg / day to about 50 mg / day, from about 30 mg / day to about 45 mg / day, from about 30 mg / day to about 40 mg / day, from about 30 mg / day to about 35 mg / day, from about 35 mg / day to about 60 mg / day, from about 35 mg / day to about 55 mg / day, from about 35 mg / day to about 50 mg / day, from about 35 mg / day to about 45 mg / day, from about 35 mg / day to about 40 mg / day, from about 40 mg / day to about 60 mg / day, from about 40 mg / day to about 55 mg / day, from about 40 mg / day to about 50 mg / day, from about 40 mg / day to about 45 mg / day, from about 45 mg / day to about 60 mg / day, from about 45 mg / day to about 55 mg / day, from about 45 mg / day to about 50 mg / day, from about 50 mg / day to about 60 mg / day, from about 50 mg / day to about 55 mg / day, or from about 55 mg / day to about 60 mg / day of edoxaban to a patient. In yet other aspects, the dosage form contains an amount of edoxaban that delivers from about 15 mg / day to about 30 mg / day of edoxaban to a patient.

[0065] In still other embodiments, the dosage form contains an amount of betrixaban that delivers from about 40 mg / day to about 160 mg / day of betrixaban to a patient. In certain aspects, the dosage form contains an amount of betrixaban that delivers about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, or about 160 mg / day of betrixaban to a patient. In additional aspects, the dosage form contains an amount of betrixaban that delivers from about 40 mg / day to about 140 mg / day, from about 40 mg / day to about 120 mg / day, from about 40 mg / day to about 100 mg / day, from about 40 mg / day to about 80 mg / day, from about 40 mg / day to about 60 mg / day, from about 60 mg / day to about 160 mg / day, from about 60 mg / day to about 140 mg / day, from about 60 mg / day to about 120 mg / day, from about 60 mg / day to about 100 mg / day, from about 60 mg / day to about 80 mg / day, from about 80 mg / day to about 160 mg / day, from about 80 mg / day to about 140 mg / day, from about 80 mg / day to about 120 mg / day, from about 80 mg / day to about 100 mg / day, from about 100 mg / day to about 160 mg / day, from about 100 mg / day to about 140 mg / day, from about 100 mg / day to about 120 mg / day, from about 120 mg / day to about 160 mg / day, from about 120 mg / day to about 140 mg / day, or from about 140 mg / day to about 160 mg / day of betrixaban to a patient. In other embodiments, the dosage form contains an amount of betrixaban that delivers from about 80 mg / day to about 160 mg / day of betrixaban to a patient.

[0066] In yet still other embodiments, the dosage form contains an amount of fondaparinux that delivers from about 2.5 mg / day to about 10 mg / day of fondaparinux to a patient. In certain aspects, the dosage form contains an amount of fondaparinux that delivers about 2.5 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, or about 10 mg / day of fondaparinux to a patient. In other aspects, the dosage form contains an amount of fondaparinux that delivers from about 2.5 mg / day to about 10 mg / day, from about 2.5 mg / day to about 7.5 mg / day, from about 7.5 mg / day to about 5 mg / day, from about 5 mg / day to about 10 mg / day, from about 5 mg / day to about 7.5 mg / day, or from about 7.5 mg / day to about 10 mg / day of fondaparinux to a patient.

[0067] In other embodiments, the dosage form contains an amount of dabigatran that delivers from about 75 mg to about 220 mg of dabigatran to a patient. In certain aspects, the dosage form contains an amount of dabigatran that delivers about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, or about 220 mg of dabigatran to a patient. In other aspects, the dosage form contains an amount of dabigatran that delivers from about 75 mg / day to about 200 mg / day, from about 75 mg / day to about 175 mg / day, from about 75 mg / day to about 150 mg / day, from about 75 mg / day to about 125 mg / day, from about 75 mg / day to about 100 mg / day, from about 100 mg / day to about 220 mg / day, from about 100 mg / day to about 200 mg / day, from about 100 mg / day to about 175 mg / day, from about 100 mg / day to about 150 mg / day, from about 100 mg / day to about 125 mg / day, from about 125 mg / day to about 220 mg / day, from about 125 mg / day to about 200 mg / day, from about 125 mg / day to about 175 mg / day, from about 125 mg / day to about 150 mg / day, from about 150 mg / day to about 220 mg / day, from about 150 mg / day to about 200 mg / day, from about 150 mg / day to about 175 mg / day, from about 175 mg / day to about 220 mg / day, from about 175 mg / day to about 200 mg / day, or from about 200 mg / day to about 220 mg / day of dabigatran to a patient. In additional aspects, the dosage form contains an amount of dabigatran that delivers from about 75 mg / day to about 150 mg / day of dabigatran to a patient.

[0068] In another embodiment, the dosage form contains an amount of enoxaparin that delivers from about 30 mg / day to about 60 mg / day of enoxaparin to a patient. In certain aspects, the dosage form contains an amount of enoxaparin that delivers about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, or about 60 mg / day of enoxaparin to a patient. In other aspects, the dosage form contains an amount of enoxaparin that delivers from about 30 mg / day to about 60 mg / day, from about 30 mg / day to about 55 mg / day, from about 30 mg / day to about 50 mg / day, from about 30 mg / day to about 45 mg / day, from about 30 mg / day to about 40 mg / day, from about 30 mg / day to about 35 mg / day, from about 35 mg / day to about 60 mg / day, from about 35 mg / day to about 55 mg / day, from about 35 mg / day to about 50 mg / day, from about 35 mg / day to about 45 mg / day, from about 35 mg / day to about 40 mg / day, from about 40 mg / day to about 60 mg / day, from about 40 mg / day to about 55 mg / day, from about 40 mg / day to about 50 mg / day, from about 40 mg / day to about 45 mg / day, from about 45 mg / day to about 60 mg / day, from about 45 mg / day to about 55 mg / day, from about 45 mg / day to about 50 mg / day, from about 50 mg / day to about 60 mg / day, from about 50 mg / day to about 55 mg / day, or from about 55 mg / day to about 60 mg / day of enoxaparin to a patient. In other aspects, the dosage form contains an amount of enoxaparin that delivers about 40 mg / day of enoxaparin to a patient.

[0069] In yet other embodiments, the dosage form contains an amount of Mylvicene that delivers from about 25 mg / day to about 500 mg / day of Mylvicene to a patient. In certain aspects, the dosage form contains an amount of Mylvicene that delivers about 25 mg / day, about 50 mg / day, about 60 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 450 mg / day or about 500 mg / day of Mylvicene to a patient. In additional aspects, the dosage form contains an amount of Mylvicene that delivers from about 25 mg / day to about 450 mg / day, from about 25 mg / day to about 400 mg / day, from about 25 mg / day to about 350 mg / day, from about 25 mg / day to about 300 mg / day, from about 25 mg / day to about 250 mg / day, from about 25 mg / day to about 200 mg / day, from about 25 mg / day to about 150 mg / day, from about 25 mg / day to about 100 mg / day, from about 25 mg / day to about 60 mg / day, from about 25 mg / day to about 50 mg / day, from about 50 mg / day to about 500 mg / day, from about 50 mg / day to about 450 mg / day, from about 50 mg / day to about 400 mg / day, from about 50 mg / day to about 350 mg / day, from about 50 mg / day to about 300 mg / day, from about 50 mg / day to about 250 mg / day, from about 50 mg / day to about 200 mg / day, from about 50 mg / day to about 150 mg / day, from about 50 mg / day to about 100 mg / day, from about 50 mg / day to about 60 mg / day, from about 60 mg / day to about 500 mg / day, from about 60 mg / day to about 450 mg / day, from about 60 mg / day to about 400 mg / day, from about 60 mg / day to about 350 mg / day, from about 60 mg / day to about 300 mg / day, from about 60 mg / day to about 250 mg / day, from about 60 mg / day to about 200 mg / day, from about 60 mg / day to about 150 mg / day, from about 60 mg / day to about 100 mg / day, from about 100 mg / day to about 500 mg / day, from about 100 mg / day to about 450 mg / day, from about 100 mg / day to about 400 mg / day, from about 100 mg / day to about 350 mg / day, from about 100 mg / day to about 300 mg / day, from about 100 mg / day to about 250 mg / day, from about 100 mg / day to about 200 mg / day, from about 100 mg / day to about 150 mg / day, from about 150 mg / day to about 500 mg / day, from about 150 mg / day to about 450 mg / day, from about 150 mg / day to about 400 mg / day, from about 150 mg / day to about 350 mg / day, from about 150 mg / day to about 300 mg / day, from about 150 mg / day to about 250 mg / day, from about 150 mg / day to about 200 mg / day, from about 200 mg / day to about 500 mg / day,Mirvetuximab is delivered to a patient at about 200 mg / day to about 450 mg / day, about 200 mg / day to about 400 mg / day, about 200 mg / day to about 350 mg / day, about 200 mg / day to about 300 mg / day, about 200 mg / day to about 250 mg / day, about 250 mg / day to about 500 mg / day, about 250 mg / day to about 450 mg / day, about 250 mg / day to about 400 mg / day, about 250 mg / day to about 350 mg / day, about 250 mg / day to about 300 mg / day, about 300 mg / day to about 500 mg / day, about 300 mg / day to about 450 mg / day, about 300 mg / day to about 400 mg / day, about 400 mg / day to about 350 mg / day, about 350 mg / day to about 500 mg / day, about 350 mg / day to about 450 mg / day, about 350 mg / day to about 400 mg / day, about 400 mg / day to about 500 mg / day, about 400 mg / day to about 450 mg / day or about 450 mg / day to about 500 mg / day. In still other aspects, the dosage form contains an amount of mirvetuximab that delivers about 50 mg / day to about 200 mg / day of mirvetuximab to the patient. In yet other aspects, the dosage form contains an amount of mirvetuximab that delivers about 60 mg / day to about 200 mg / day of mirvetuximab to the patient. In other aspects, the dosage form contains an amount of mirvetuximab that delivers about 50 mg / day to about 500 mg / day of mirvetuximab to the patient. In additional aspects, the dosage form contains an amount of mirvetuximab that delivers about 60 mg / day to about 500 mg / day of mirvetuximab to the patient.

[0070] In still further embodiments, the dosage form contains an amount of asundexian that delivers from about 10 mg / day to about 50 mg / day of asundexian to a patient. In certain aspects, the dosage form contains an amount of asundexian that delivers about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, or about 50 mg / day of asundexian to a patient. In additional aspects, the dosage form contains an amount of asundexian that delivers from about 10 mg / day to about 50 mg / day, from about 10 mg / day to about 45 mg / day, from about 10 mg / day to about 40 mg / day, from about 10 mg / day to about 35 mg / day, from about 10 mg / day to about 30 mg / day, from about 10 mg / day to about 25 mg / day, from about 10 mg / day to about 20 mg / day, from about 10 mg / day to about 15 mg / day, from about 15 mg / day to about 50 mg / day, from about 15 mg / day to about 45 mg / day, from about 15 mg / day to about 40 mg / day, from about 15 mg / day to about 35 mg / day, from about 15 mg / day to about 30 mg / day, from about 15 mg / day to about 25 mg / day, from about 15 mg / day to about 20 mg / day, from about 20 mg / day to about 50 mg / day, from about 20 mg / day to about 45 mg / day, from about 20 mg / day to about 40 mg / day, from about 20 mg / day to about 35 mg / day, from about 20 mg / day to about 30 mg / day, from about 20 mg / day to about 25 mg / day, from about 25 mg / day to about 50 mg / day, from about 25 mg / day to about 45 mg / day, from about 25 mg / day to about 40 mg / day, from about 25 mg / day to about 35 mg / day, from about 25 mg / day to about 30 mg / day, from about 30 mg / day to about 50 mg / day, from about 30 mg / day to about 45 mg / day, from about 30 mg / day to about 40 mg / day, from about 30 mg / day to about 35 mg / day, from about 35 mg / day to about 50 mg / day, from about 35 mg / day to about 45 mg / day, from about 35 mg / day to about 40 mg / day, from about 40 mg / day to about 50 mg / day, from about 40 mg / day to about 45 mg / day, or from about 45 mg / day to about 50 mg / day of asundexian to a patient. In other aspects, the dosage form contains an amount of asundexian that delivers from about 20 mg / day to about 50 mg / day of asundexian to a patient.

[0071] The dosage form may also contain a pressure-sensitive adhesive that adheres the dosage form (e.g., 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, e.g., Tan and Pfister, "Pressure-sensitive adhesives for transdermal drug delivery systems", Pharm Sci & Tech Today 2:60-69 (1999), which is incorporated by reference. In other embodiments, the pressure-sensitive adhesive contains 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 contains about 35 wt% to about 95 wt% of the pressure-sensitive adhesive, based on the weight of the dosage form. In some embodiments, the dosage form contains 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% of the pressure-sensitive adhesive, based on the weight of the dosage form.In additional embodiments, the dosage form contains a pressure-sensitive adhesive in an amount of about 35 wt% to about 90 wt%, about 35 wt% to about 85 wt%, about 35 wt% to about 80 wt%, about 35 wt% to about 75 wt%, about 35 wt% to about 70 wt%, about 35 wt% to about 65 wt%, about 35 wt% to about 60 wt%, about 35 wt% to about 55 wt%, about 35 wt% to about 50 wt%, about 35 wt% to about 45 wt%, about 40 wt% to about 95 wt%, about 40 wt% to about 90 wt%, about 40 wt% to about 85 wt%, about 40 wt% to about 80 wt%, about 40 wt% to about 75 wt%, about 40 wt% to about 70 wt%, about 40 wt% to about 65 wt%, about 40 wt% to about 60 wt%, about 40 wt% to about 55 wt%, about 40 wt% to about 50 wt%, about 50 wt% to about 95 wt%, about 50 wt% to about 90 wt%, about 50 wt% to about 80 wt%, about 50 wt% to about 75 wt%, about 50 wt% to about 70 wt%, about 50 wt% to about 65 wt%, about 50 wt% to about 60 wt%, about 60 wt% to about 95 wt%, about 60 wt% to about 90 wt%, about 60 wt% to about 85 wt%, about 60 wt% to about 80 wt%, about 60 wt% to about 75 wt%, about 60 wt% to about 70 wt%, about 70 wt% to about 95 wt%, about 70 wt% to about 90 wt%, about 70 wt% to about 85 wt%, about 70 wt% to about 80 wt%, about 80 wt% to about 95 wt% or about 80 wt% to about 90 wt% based on the weight of the dosage form.

[0072] Treatment method

[0073] According to the present disclosure, there is also provided a method or use of a pharmaceutical composition and / or dosage form. Regardless of the specific method, the method includes 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 blood clot forms in a blood vessel. In some aspects, the thromboembolic disorder is an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, or a thromboembolic disorder in a cardiac chamber. In other aspects, the thromboembolic disorder is acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis (DVT), thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism (PE), or thrombosis caused by a surgery in which blood is exposed to an artificial surface that promotes thrombus formation, such as thrombosis caused by an implant such as a prosthetic 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 surgery in which blood is exposed to an artificial surface that promotes thrombus formation. In additional aspects, the thromboembolic disorder is acute coronary syndrome. In still other aspects, the thromboembolic disorder is stroke. In yet additional aspects, the thromboembolic disorder is deep DVT. In other aspects, the thromboembolic disorder is pulmonary embolism (PE).

[0074] The present disclosure also provides a method for treating or preventing deep vein thrombosis (DVT) and / or pulmonary embolism (PE) in a patient in need thereof and reducing its recurrence. In some embodiments, the method treats DVT or PE. In other embodiments, the method reduces the recurrence of DVT and / or PE. In additional 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 additional aspects, the patient has undergone knee replacement surgery.

[0075] 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 a pharmaceutical composition or dosage form to the patient. In some embodiments, the method treats atherosclerosis. In additional embodiments, the method treats myocardial infarction. In other embodiments, the method treats pulmonary embolism. In yet additional embodiments, the method treats deep vein thrombosis.

[0076] According to the present disclosure, there are provided methods for treating or preventing venous thromboembolism (VTE) and reducing the risk of its recurrence, and which comprise administering to a patient a pharmaceutical composition or dosage form described herein. In some embodiments, the present disclosure provides methods for preventing VTE. In other embodiments, the present disclosure provides methods for treating VTE. In a further aspect, the present disclosure provides methods for reducing the risk of VTE recurrence. In certain aspects, the patient has an acute disease. In other aspects, the patient is a pediatric patient.

[0077] The present disclosure also provides methods for reducing the risk of major cardiovascular events in a patient. These methods comprise administering to the patient a pharmaceutical composition or dosage form. In certain aspects, the patient has coronary artery disease. In some aspects, the patient has acute myocardial infarction, i.e., a heart attack. In other aspects, the patient has a pulmonary embolism. In a further aspect, the patient has heart failure. In still other aspects, the patient has a stroke.

[0078] According to the present disclosure, there are provided methods for reducing the risk of major thrombotic vascular events in a patient. These methods comprise administering to the patient a pharmaceutical composition or dosage form. In certain aspects, the patient has peripheral artery disease (PAD). In other aspects, the patient has recently undergone lower extremity vascular reconstruction due to symptomatic PAD. In a further aspect, the patient has deep vein thrombosis. In still other aspects, the patient has a systemic embolism. In yet a further aspect, the patient has thrombophlebitis. In other aspects, the patient has a pulmonary embolism.

[0079] The present disclosure also provides methods for thrombo - prevention in a patient. The methods comprise administering to the patient a pharmaceutical composition or dosage form. In some aspects, the patient has congenital heart disease and has undergone a Fontan procedure. In other aspects, the patient is 2 years of age or older.

[0080] 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 condition that results in a hypercoagulable state of the blood or a tendency to produce clots. In some embodiments, a thromboembolic disorder may lead to a thromboembolic event. As used herein, the term "thromboembolic event" refers to a condition in which a blood clot (thrombus) is formed and optionally transported to another region of the body. The methods comprise administering to the patient a pharmaceutical composition or dosage form. In some embodiments, the patient has atrial fibrillation.

[0081] The present disclosure also provides methods for reducing the risk of stroke or systemic embolism in a patient. The methods comprise administering to the patient a pharmaceutical composition or dosage form. In some aspects, the patient has non - valvular atrial fibrillation.

[0082] For all methods of the present disclosure, the pharmaceutical composition or dosage form may be administered transdermally.

[0083] The method further comprises administering more than one anticoagulant described herein. The attending physician may select an additional anticoagulant or a second anticoagulant. In some embodiments, the second anticoagulant is aspirin. In further embodiments, the second anticoagulant is clopidogrel.

[0084] Aspect

[0085] Aspect 1: A pharmaceutical composition comprising an anticoagulant and pyruvic acid.

[0086] Aspect 2: The pharmaceutical composition according to aspect 1, wherein the anticoagulant is a thrombin inhibitor, a factor Xa inhibitor, a factor Xia inhibitor or a low molecular weight heparin.

[0087] Aspect 3: The pharmaceutical composition according to aspect 1, wherein the thrombin inhibitor is dabigatran, bivalirudin, lepirudin or desirudin, or like dabigatran.

[0088] Aspect 4: The pharmaceutical composition according to aspect 1, wherein the low molecular weight heparin is enoxaparin.

[0089] Aspect 5: The pharmaceutical composition according to aspect 1, wherein the factor Xa inhibitor is apixaban, rivaroxaban, edoxaban, betrixaban or fondaparinux or a combination thereof, or like apixaban.

[0090] Aspect 6: The pharmaceutical composition according to aspect 1, wherein the factor XIa inhibitor is milvexian or asundexian.

[0091] Aspect 7: The pharmaceutical composition according to any one of the preceding aspects, further comprising a surfactant, a permeation enhancer or a combination thereof.

[0092] Aspect 8: The pharmaceutical composition according to aspect 7, wherein the surfactant or the permeation enhancer is dimethyl sulfoxide, lactic acid, oleic acid, levulinic acid, 3-hydroxypropionic acid, malonic acid, or a nonionic surfactant such as polysorbate, such as Tween 80, or polyethylene glycol monooleate, such as Brij O20.

[0093] Aspect 9: The pharmaceutical composition according to any one of the preceding aspects, further comprising lactic acid.

[0094] Aspect 10: The pharmaceutical composition according to aspect 8 or 9, comprising about 20 wt% to about 45 wt% or about 25 wt% to about 35 wt% of lactic acid based on the weight of the pharmaceutical composition.

[0095] Aspect 11: The pharmaceutical composition according to any one of the foregoing aspects, further comprising dimethyl sulfoxide.

[0096] Aspect 12: The pharmaceutical composition according to aspect 11, comprising about 5% to about 20% by weight or about 8% to about 15% by weight of dimethyl sulfoxide based on the weight of the pharmaceutical composition.

[0097] Aspect 13: The pharmaceutical composition according to any one of the foregoing aspects, further comprising levulinic acid.

[0098] Aspect 14: The pharmaceutical composition according to aspect 13, comprising about 1% to about 20% by weight or about 3% to about 10% by weight of levulinic acid based on the weight of the pharmaceutical composition.

[0099] Aspect 15: The pharmaceutical composition according to any one of the foregoing aspects, further comprising oleic acid.

[0100] Aspect 16: The pharmaceutical composition according to aspect 15, comprising about 1% to about 10% by weight or about 3% to about 7% by weight of oleic acid based on the weight of the pharmaceutical composition.

[0101] Aspect 17: The pharmaceutical composition according to any one of the foregoing aspects, further comprising polysorbate, such as polysorbate 80.

[0102] Aspect 18: The pharmaceutical composition according to aspect 17, comprising about 5% to about 15% by weight or about 7% to about 12% by weight of the polysorbate based on the weight of the pharmaceutical composition.

[0103] Aspect 19: The pharmaceutical composition according to any one of the foregoing aspects, further comprising polyethylene glycol monooleate.

[0104] Aspect 20: The pharmaceutical composition according to aspect 19, comprising about 0.01% to about 5% by weight or about 0.5% to about 2% by weight of the polyethylene glycol monooleate based on the weight of the pharmaceutical composition.

[0105] Aspect 21: The pharmaceutical composition according to any one of the foregoing aspects, comprising about 5% to about 25% by weight or about 7% to about 12% by weight, such as about 9%, about 10% or about 11% by weight of an anticoagulant based on the weight of the pharmaceutical composition.

[0106] Aspect 22: The pharmaceutical composition according to any one of the preceding aspects, which comprises, based on the weight of the pharmaceutical composition, about 20% to about 90% by weight, or about 25% to about 45% by weight, or about 30% to about 45% by weight of pyruvic acid.

[0107] Aspect 23: The pharmaceutical composition according to any one of the preceding aspects, which comprises about 0.1 mg / day 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 an anticoagulant.

[0108] Aspect 24: The pharmaceutical composition according to any one of the preceding aspects, which does not contain acrylic acid.

[0109] Aspect 25: A dosage form, which comprises the pharmaceutical composition according to any one of the preceding aspects.

[0110] Aspect 26: The dosage form according to aspect 25, which is a transdermal patch.

[0111] Aspect 27: The dosage form according to aspect 26, wherein 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 or like a reservoir patch.

[0112] Aspect 28: A method for treating a thromboembolic disorder 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.

[0113] 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 cardiac chamber.

[0114] Aspect 30: The method according to aspect 28, wherein the thromboembolic disorder is acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism or thrombosis caused by surgery where blood is exposed to an artificial surface that promotes thrombosis, such as thrombosis caused by implants such as prosthetic valves, thrombosis caused by indwelling catheters, thrombosis caused by stents, thrombosis caused by cardiopulmonary bypass, thrombosis caused by hemodialysis, thrombosis caused by surgery where blood is exposed to an artificial surface that promotes thrombosis.

[0115] Aspect 31: The method according to aspect 28, wherein the thromboembolic disorder is acute coronary syndrome.

[0116] Aspect 32: The method according to aspect 28, wherein the thromboembolic disorder is stroke.

[0117] Aspect 33: The method according to aspect 28, wherein the thromboembolic disorder is deep vein thrombosis.

[0118] Aspect 34: The method according to aspect 28, wherein the thromboembolic disorder is pulmonary embolism.

[0119] 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 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.

[0120] 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 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.

[0121] Aspect 37: The method according to aspect 35 or 36, wherein the patient has undergone hip or knee replacement surgery.

[0122] Aspect 38: A method for preventing venous thromboembolism (VTE) in an acutely ill patient, the method comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 24 or a dosage form according to any one of aspects 25 to 27.

[0123] Aspect 39: A method for reducing the risk of major cardiovascular events in a patient suffering from coronary artery disease, 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.

[0124] Aspect 40: A method for reducing the risk of major thrombotic vascular events in a patient suffering from peripheral artery 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.

[0125] Aspect 41: The method according to aspect 40, wherein the patient has recently undergone lower limb revascularization due to symptomatic PAD.

[0126] Aspect 42: A method for treating VTE or reducing the risk of VTE recurrence 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.

[0127] Aspect 43: A method for thromboembolism prophylaxis after Fontan surgery in a patient with congenital heart disease, 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.

[0128] Aspect 44: The method according to aspect 42, wherein the patient is 2 years of age or older.

[0129] 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.

[0130] Aspect 46: The method according to any one of aspects 28 to 45, wherein the pharmaceutical composition is administered transdermally.

[0131] Aspect 47: The method according to any one of aspects 28 to 46, further comprising administering a second anticoagulant.

[0132] Aspect 48: The method according to aspect 47, wherein the second anticoagulant is aspirin.

[0133] Aspect 49: The method according to any one of aspects 35 to 41 or 43 to 48, wherein the patient is an adult.

[0134] Aspect 50: The method according to any one of aspects 35 to 49, wherein the patient is a child.

[0135] Aspect 51: A method for preventing one or more thromboembolic events in a patient with atrial fibrillation, 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.

[0136] The following examples, while illustrative of separate embodiments, are not intended to limit the scope of the described invention, and the reader should not interpret these examples in this manner.

[0137] Examples

[0138] Example 1: Effects of pyruvic acid and BRIJ O20 on skin permeability

[0139] Apixaban formulations in Table 1 were prepared to study the effects of enhancers, solvates, and emulsifiers on the permeability of apixaban through human cadaver skin. The formulations were mixed under vortex conditions until all of the apixaban was dissolved. The mixing time depends on the size of the container, but is typically about 15 minutes. Formulation F6 is based on the formulation described in U.S. Patent Publication No. 2020 / 0338012.

[0140]

[0141] During the duration of the experiment, skin permeability studies of the formulations were carried out using Franz diffusion cells maintained at 37 °C. 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 2 . 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 with the continuously mixed receptor medium. Samples of the receptor phase were obtained on Day 1, Day 2, Day 3, Day 4, Day 5, and Day 7, and the apixaban concentration was determined using an HPLC method [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 three formulations were determined and are shown in Figure 1A and 1B .

[0142] Figure 1 shows that the formulation (F7) containing pyruvic acid and the nonionic surfactant BRIJ O20 gave the highest flux through human skin. The formulation (F6) without pyruvic acid gave the lowest skin permeability, even though it contained a high level of the nonionic surfactant TWEEN 80. The formulation (F8) containing pyruvic acid and TWEEN 80 gave a skin flux slightly higher than that of formulation F6, but still significantly lower than that of formulation F7. Several conclusions can be drawn from this experiment: a) Pyruvic acid increased skin permeability, b) Pyruvic acid together with the surfactant BRIJ O20 provided a synergistic effect on skin permeability, c) Surfactants seem to be important for the delivery of apixaban, even though many other aspects of the surfactant are also important, such as the hydrophilic-lipophilic balance (HLB) and melting point (MP).

[0143] Example 2: Effects of pyruvic acid and BRIJ O20 on the skin permeability of AXB at a constant amount of DMSO

[0144] To verify the importance of pyruvic acid and BRIJ O20 on the skin permeability of apixaban, three formulations were prepared as shown in Table 2.

[0145]

[0146] As described in Example 1, all three formulations were tested in a Franz diffusion cell, and the skin permeability was plotted as a function of time, as Figure 2A and 2B shown. Figure 2A and 2B show the skin permeability of formulation F7 from Example 2 (labeled '1 / 28 data'). The F7 curve shows a similar skin flux, which is well within the expected error of the skin flux experiment, thus demonstrating the reproducibility of the results of the experiment.

[0147] The skin permeability data confirmed the conclusion drawn in Example 2 that pyruvic acid and BRIJ O20 are enhancers of the skin permeability of apixaban and that they are not affected by other excipients.

[0148] In formulation F10, the concentration of levulinic acid was increased by proportionally decreasing the concentration of pyruvic acid, and as a result, the skin flux of apixaban decreased significantly. This indicates that the utility of the oleic acid / levulinic acid combination has limited value in enhancing the transdermal delivery of apixaban, and pyruvic acid is the main cause of the increased flux found in these experiments.

[0149] Example 3: Preparation and testing of a reservoir-type transdermal patch

[0150] A reservoir-type transdermal patch was prepared that contains formulation F7 as a saturated solution within the patch. As shown in Examples 2 and 3, formulation F7 gave the best skin permeability among any of the apixaban formulations tested. Considering that pyruvic acid is shown herein to be a good enhancer of apixaban, formulations F12 and F14 containing higher amounts of pyruvic acid were prepared. Table 3 gives the compositions of the three formulations.

[0151]

[0152] Figure 3A schematic diagram of the prepared reservoir-type transdermal patch is shown. The patch consists of four components: an impermeable backing, a drug reservoir containing the drug (i.e., the active gel) dissolved in a vehicle, 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) contains the backing layer. A pressure-sensitive adhesive (i.e., DUROTAK 4098) was cast onto a release liner (SCOTCHPAK 9747, 3M) and dried. The CELGARD layer was placed on top of the pressure-sensitive adhesive. The backing film was placed on top of the membrane, and the edges of a 1.77 cm 2 circle were heat-sealed using a die compressed at 70 °C for 10 seconds to form an empty pouch-shaped reservoir between the CELGARD and the backing layer. The patch reservoir was loaded with the active gel formulation by inserting a subcutaneous syringe into the hole leading to the reservoir chamber, filling it with 0.4 mL of apixaban gel solution, and then sealing the hole.

[0153] The three prepared reservoir-type patches were placed on human cadaver skin and then mounted in Franz cells (area 1.77 cm 2 ) as used above for skin flux studies. The skin permeability study was conducted as described in Example 2. As Figure 4 shown, the amount of apixaban permeated (in mg / cm 2 ) was determined and plotted against time (a 7-day period). The results showed that the higher the amount of pyruvic acid in the patch, the better the skin permeability.

[0154] Example 4:

[0155] Two formulations were prepared: a gel formulation (Formulation F15) suitable for use as a reservoir-type patch and an adhesive matrix-type patch formulation (Comparative Formulation #1) using DUROTAK 87-2287. Table 4 provides the final composition of the two formulations.

[0156]

[0157] Skin permeability experiments were conducted in parallel using the protocol of Example 2 but using synthetic skin PERMEAPAD instead of human cadaver skin. In the Franz cell, a large excess of F15 gel was applied in the donor chamber layered on top of the skin membrane. Thus, the results of the gel formulation were comparable to those obtained using the reservoir-type patch. The purpose here was to compare the relative permeability of the transdermal formulations of the reservoir-type patch and the drug adhesive matrix-type patch. See Table 4 and Figure 5 .

[0158]

[0159] Figure 5 It is shown that due to the "dilution" effect of the adhesive component being the formulation composition, the skin permeability of the apixaban in the drug-in-adhesive (DIA) formulation is not as good as that of the reservoir patch formulation. Nevertheless, the DIA formulation provides sufficient permeability.

[0160] Example 5:

[0161] A. Patch Preparation

[0162] Two "drug-in-adhesive dispersion matrix type" patch formulations were prepared. See Table 6.

[0163]

[0164] Prepare Figure 6 the matrix type transdermal patch shown. In Figure 6 it, the backing film (1) is fixed on top of the adhesive drug matrix (2), and the adhesive drug matrix is supported by a large-sized release liner film (3).

[0165] The matrix type transdermal patch was prepared as follows by adding ethyl acetate to a 200-mL glass vial, and then adding apixaban. The additional components noted in Table 6 were added, and the blend was mixed to dissolve apixaban. During mixing, DUROTAK 87-2287 acrylic adhesive was added. The batch was mixed for 60 minutes or until it was homogeneous. The resulting wet solution was cast onto a release liner film (3M) using a 20-mil casting coater. The cast piece was dried in a forced-air oven at 80 °C for 10 minutes. After drying, the dried cast piece was laminated onto a SCOTCHPAK 9723 (3M drug delivery system) patch backing film. The patch was die-cut into 10 cm 2 50 cm 2 or 100 cm 2 shapes to provide different dosing requirements. The patches were bagged in multi-layer laminated aluminum bags.

[0166] The resulting transdermal patch has an adhesive matrix thickness of 6 mils and contains 6.5% of apixaban. HPLC analysis confirmed that the patch contains approximately 6.5% of apixaban. The patch has good skin adhesiveness and adheres closely to the skin. The patch was die-cut to be fixed on a Franz cell for skin permeability studies.

[0167] B. Skin Permeability Studies

[0168] Skin permeability experiments were conducted in parallel using the protocol described in Example 2. The results are shown in Table 7 and are reported as the amount of apixaban permeated per day (mg / cm 2 ).

[0169]

[0170]

[0171] C. Stability Study

[0172] The stability of formulation F20 was evaluated. Specifically, the bagged patches of formulation F20 were stored in environmental chambers at 25°C / 60% RH and 40°C / 75% RH and were monitored regularly for HPLC determination and color testing. See Table 8.

[0173]

[0174] The results showed that the purity of apixaban after storage was approximately 99% to approximately 100% as measured by HPLC. The apixaban transdermal patch was considered stable when stored under the following conditions: (i) at 25°C / 60% RH for up to 6 months, and (ii) at 40°C / 75% RH for up to 1 month.

[0175] Example 6: Comparative Study

[0176] This example was conducted using rivaroxaban (XARELTO), which is a direct oral anticoagulant of the factor Xa inhibitor class.

[0177] A reservoir-type patch containing rivaroxaban was prepared. Table 9 includes the components of each formulation.

[0178]

[0179] As described in Example 1, skin permeability studies were conducted using formulations 1A and 1B. See Table 10 for the drug with average permeation.

[0180]

[0181] The results showed that the transdermal delivery of apixaban was more effective than that of rivaroxaban, as the rivaroxaban formulation produced very little transdermal rivaroxaban permeation.

[0182] Example 7: Summary

[0183] Examples 1 - 6 demonstrated that the transdermal delivery of apixaban is feasible in both therapeutic doses and stable near-zero order kinetic profiles with appropriate selection of excipients and skin penetration enhancers.

[0184] The lower MW acids appear to improve the skin permeability of apixaban.

[0185] Example 8:

[0186] This study will evaluate the pharmacokinetics of the apixaban formulation as described herein and ELIQUIS (apixaban tablets for oral use) in healthy adult subjects 18 years of age or older.

[0187] Transdermal delivery (as opposed to oral) of apixaban as described herein will achieve near zero-order kinetics over the duration of patch application. Generally, the cumulative in vitro drug permeation rate (μg / cm 2 ) across human cadaver skin at any given time point can be predicted to represent the in vivo dose delivered to the circulation, since drug across the skin via a 1 cm2 patch is typically 100% bioavailable to the systemic circulation (i.e., no hepatic first-pass metabolism). Data from the first few days when the daily absorption rate is as close to linear as possible (i.e., the cumulative absorption rate curve is close to a straight line) are analyzed, and the cumulative drug permeation rate is used at the end of those days. Data at multiple time points on Day 1 are also analyzed to determine whether delivery on that day is at least close to linear (zero-order kinetics). Thus, one of ordinary skill in the art can determine the amount of apixaban delivered in vivo based on the surface area of the transdermal patch.

[0188] A. Detailed Description

[0189] Each subject will be randomly assigned to one of two groups according to a randomization table. In one group, the subjects will receive ELIQUIS. In the other group, the subjects will receive the apixaban formulation as described herein.

[0190] B. Eligibility Criteria

[0191] The inclusion and exclusion criteria will be as follows:

[0192] Inclusion Criteria:

[0193] 1. The signing of the informed consent form will be completed before the test, and the subjects will be fully informed about the test content, process, and possible adverse reactions;

[0194] 2. The subjects will be able to complete the study according to the requirements of the test plan;

[0195] 3. After signing the informed consent form, the subjects (including male subjects) will agree to have no pregnancy plan and voluntarily take effective contraceptive measures for 3 months after the end of the study;

[0196] 4. Both male and female subjects will be 18 years of age or older;

[0197] 5. The weight of male subjects will be at least 50 kg. The weight of female subjects will be at least 45 kg. Body mass index = weight (kg) / height2 (m 2 ) and will be between 18.0 kg / m 2 and 26.0 kg / m2 within the range (including the critical values).

[0198] Exclusion criteria:

[0199] 1. Subjects with a history of neuropsychiatric diseases, respiratory diseases, cardiovascular diseases, digestive system diseases, hematolymphatic system diseases, liver or kidney insufficiency diseases, endocrine diseases, skeletal-muscular system diseases or other diseases, and the investigator determines that this past medical history may affect drug metabolism or safety;

[0200] 2. Persons who smoked more than 5 cigarettes per day on average during the 3 months prior to screening;

[0201] 3. Persons with a specific history of allergies (such as asthma, urticaria, eczema, etc.), allergic populations (e.g., allergic to two or more drugs, foods), known to be allergic to the components of this drug or (including but not limited to) rivaroxaban;

[0202] 4. Lactose-intolerant individuals (e.g., individuals who experience diarrhea after drinking milk);

[0203] 5. A history of alcohol abuse in the past year (weekly alcohol consumption ≥ 14 units: 1 unit = 285 ml of beer, or 25 ml of spirits over 40 degrees, or 100 ml of wine);

[0204] 6. Donated blood or lost ≥ 400 ml of blood within 3 months before the trial, or intend to donate blood or blood components during or within 3 months after the trial;

[0205] 7. A history of dysphagia or any gastrointestinal disorder that interferes with drug absorption;

[0206] 8. Use of any recombinant cytochrome P450 3A4 (CYP3A4) or permeability glycoprotein (P-gp) inhibitors (e.g., ketoconazole, itraconazole, voriconazole, and posaconazole, ritonavir, diltiazem, naproxen, amiodarone, verapamil, quinidine, famotidine, macrolides, nitroimidazole, sedative hypnotics, fluoroquinolones, antihistamines), CYP3A4 and P-gp inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, or St. John's wort, omeprazole, glucocorticoids);

[0207] 9. Use of any anticoagulants, platelet aggregation inhibitors, selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors or non-steroidal anti-inflammatory drugs, and drugs that may cause severe bleeding, such as unfractionated heparin and heparin derivatives (including low molecular weight heparin), oligosaccharides that inhibit factor Xa (e.g., sulforaphane sodium), direct thrombin II inhibitors, thrombolytics, thienopyridines (e.g., clopidogrel), dipyridamole, dextran, sulpiride, vitamin K antagonists, and other oral anticoagulants within 30 days before the trial;

[0208] 10. Taking any prescription drugs, over-the-counter drugs, herbal or nutritional drugs within 14 days before the administration of the investigational drug;

[0209] 11. Having taken a special diet (caffeine, alcohol, or foods and beverages rich in xanthine, including pitaya, mango, grapefruit, chocolate, or tea), or smoked, or had a significant change in exercise habits, or other factors affecting drug absorption, distribution, metabolism, or excretion within 48 hours before the administration of the investigational drug;

[0210] 12. Subjects with a positive alcohol screening test;

[0211] 13. Subjects who participated in another drug clinical trial and took the test drug within 3 months before taking the investigational drug;

[0212] 14. Abnormalities of clinical significance as judged by a clinician, including physical examination, vital sign examination, electrocardiogram examination, or clinical laboratory examination (including blood routine examination, urine routine examination, blood biochemical examination, coagulation function examination);

[0213] 15. Subjects with creatinine clearance rate ≤ 50 ml / min;

[0214] 16. Subjects with coagulation disorders, or subjects with a bleeding tendency (e.g., frequent recurrent gingival bleeding), or subjects with an increased risk of bleeding events in the past 6 months, with a history of intracranial hemorrhage, gastrointestinal hemorrhage, purpura, or subjects who have undergone major surgery in the past 30 days, or subjects with active pathological bleeding;

[0215] 17. Positive for hepatitis B surface antigen, positive for hepatitis C antibody, positive for HIV antibody, or positive for early syphilis screening;

[0216] 18. Subjects with a positive drug abuse screening or a history of drug abuse in the past five years;

[0217] 19. Subjects with a history of blood faint or needle faint, difficult blood collection, or intolerance to intravenous puncture blood collection;

[0218] 20. Subjects who are unable or unwilling to comply with the ward management regulations;

[0219] 21. Subjects who have suffered from a major illness or undergone major surgery within 4 weeks before the administration of the study drug;

[0220] 22. Subjects who are unable to complete the trial due to personal reasons;

[0221] 23. Subjects who are judged by the researcher to be unfit to participate in this trial study;

[0222] 24. Female subjects who are lactating or have a positive pregnancy test result during the screening period or during the trial process;

[0223] 25. Female subjects who use oral contraceptives 30 days before taking the study drug and during the trial;

[0224] 26. Female subjects who use long-acting estrogen or progesterone injections or implant tablets within 6 months before the administration of the study drug and during the trial;

[0225] 27. Female subjects who have had unprotected sex two weeks before screening.

[0226] C. Primary outcome measures

[0227] The following outcome measures will be determined and compared with the results obtained for ELIQUIS:

[0228] ● Peak plasma concentration (C max )

[0229] ● Area under the plasma concentration-versus-time curve (AUC 0-t )

[0230] ● Area under the plasma concentration-versus-time curve (AUC 0-∞ )

[0231] ● Safety and tolerability as determined by adverse event reports, clinical laboratory results, vital signs, physical examinations, and ECGs.

[0232] The disclosure of each patent, patent application, and publication cited or described in this document is hereby incorporated by reference in its entirety.

[0233] Those skilled in the art will understand that many changes and modifications can be made to the preferred embodiments of the invention, and such changes and modifications can be made without departing from the spirit of the invention. Accordingly, the appended claims are intended to cover all such equivalent variations that fall within the true spirit and scope of the invention.

Claims

1. A pharmaceutical composition comprising apixaban and pyruvic acid.

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

3. The pharmaceutical composition according to claim 2, wherein the surfactant or the permeation enhancer is dimethyl sulfoxide, lactic acid, oleic acid, levulinic acid, 3-hydroxypropionic acid, malonic acid, or a nonionic surfactant such as polysorbate, such as TWEEN80, or polyethylene glycol monooleate, such as BRIJ O20.

4. The pharmaceutical composition according to any one of the preceding claims, further comprising lactic acid.

5. The pharmaceutical composition according to claim 3 or 4, comprising about 20% to about 45% by weight or about 25% to about 35% by weight of lactic acid based on the weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of the preceding claims, further comprising dimethyl sulfoxide.

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

8. The pharmaceutical composition according to any one of the preceding claims, further comprising levulinic acid.

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

10. The pharmaceutical composition according to any one of the preceding claims, further comprising oleic acid.

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

12. The pharmaceutical composition according to any one of the preceding claims, further comprising polysorbate, or such as polysorbate 80.

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

14. The pharmaceutical composition according to any one of the preceding claims, further comprising polyethylene glycol monooleate.

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

16. The pharmaceutical composition according to any one of the preceding claims, comprising about 5% to about 25% by weight or about 7% to about 12% by weight, such as about 9%, about 10%, or about 11% by weight of an anticoagulant based on the weight of the pharmaceutical composition.

17. The pharmaceutical composition according to any one of the preceding claims, comprising about 20% to about 90% by weight or about 25% to about 45% by weight, or about 30% to about 45% by weight of pyruvic acid based on the weight of the pharmaceutical composition.

18. The pharmaceutical composition according to any one of the preceding claims, which comprises apixaban in an amount of from about 0.1 mg / day 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.

19. The pharmaceutical composition according to any one of the preceding claims, which does not contain acrylic acid.

20. A dosage form, which comprises the pharmaceutical composition according to any one of the preceding claims.

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

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

23. The dosage form according to any one of claims 20 to 22, which further comprises a pressure-sensitive adhesive.

24. A method for treating a thromboembolic disorder in a patient in need thereof, the method comprising administering to the patient the pharmaceutical composition according to any one of claims 1 to 19 or the dosage form according to any one of claims 20 to 22.

25. The method according to claim 24, wherein the thromboembolic disorder is an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder or a thromboembolic disorder in a cardiac chamber.

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

27. The method according to claim 24, wherein the thromboembolic disorder is acute coronary syndrome.

28. The method according to claim 24, wherein the thromboembolic disorder is stroke.

29. The method according to claim 24, wherein the thromboembolic disorder is deep vein thrombosis.

30. The method according to claim 24, wherein the thromboembolic disorder is pulmonary embolism.

31. 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 claims 1 to 19 or the dosage form according to any one of claims 20 to 23.

32. 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 a pharmaceutical composition according to any one of claims 1 to 19 or a dosage form according to any one of claims 20 to 23.

33. The method according to claim 31 or 32, wherein the patient has undergone hip or knee replacement surgery.

34. A method for preventing venous thromboembolism (VTE) in an acutely ill patient, the method comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 19 or a dosage form according to any one of claims 20 to 23.

35. A method for reducing the risk of major cardiovascular events in a patient with coronary artery disease, the method comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 19 or a dosage form according to any one of claims 20 to 23.

36. A method for reducing the risk of major thrombotic vascular events in a patient with peripheral artery disease (PAD), the method comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 19 or a dosage form according to any one of claims 20 to 23.

37. The method according to claim 36, wherein the patient has recently undergone lower limb vascular reconstruction due to symptomatic PAD.

38. A method for treating VTE in a pediatric patient in need thereof or reducing the risk of VTE recurrence, the method comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 19 or a dosage form according to any one of claims 20 to 23.

39. A method for thrombo - prevention after Fontan surgery in a patient with congenital heart disease, the method comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 19 or a dosage form according to any one of claims 20 to 23.

40. The method according to claim 38, wherein the patient is 2 years of age or older.

41. 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 claims 1 to 19 or a dosage form according to any one of claims 20 to 23.

42. The method according to any one of claims 24 to 41, wherein the pharmaceutical composition is administered transdermally.

43. The method according to any one of claims 24 to 42, further comprising administering a second anticoagulant.

44. The method according to claim 43, wherein the second anticoagulant is aspirin.

45. The method according to any one of claims 31 to 37 or 39 to 44, wherein the patient is an adult.

46. The method according to any one of claims 31 to 45, wherein the patient is a child.

47. A method for preventing one or more thromboembolic events or bleeding events in a patient suffering from atrial fibrillation, the method comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 19 or a dosage form according to any one of claims 20 to 23.

48. A method for reducing the risk of stroke or systemic embolism in a patient, the method comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 19 or a dosage form according to any one of claims 20 to 23.

49. The method according to claim 48, wherein the patient has non-valvular atrial fibrillation.

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