BR112017003900B1 - PHARMACEUTICAL COMPOSITION COMPRISING A TESTOSTERONE ESTER AND USE THEREOF - Google Patents

Abstract

Pharmaceutical composition comprising a testosterone ester and use thereof. The present disclosure relates to an innovative pharmaceutical composition for administering testosterone or testosterone derivatives. The present disclosure also provides methods of treating diseases and disorders associated with fear and anxiety, a decrease in libido or hypogonadism.

Description

FUNDAMENTALS OF THE INVENTION

[001] This application claims the priority benefit of provisional patent application No. US62/043. 277, filed on August 28, 2014, the entirety of which is incorporated herein by way of reference.

1. FIELD OF THE INVENTION

[002] The present disclosure relates generically to the fields of medicine, pharmaceutical agents, hypogonadal disorders, and disorders associated with fear or anxiety. More particularly, it relates to testosterone compositions that can be used to treat disorders associated with fear and anxiety, erectile dysfunction, sexual dysfunction or decreased libido.

2. DESCRIPTION OF THE RELATED TECHNIQUE

[003] Testosterone administration is difficult as the hormone is not specifically amenable to oral administration. Typically, testosterone is administered intravenously, intramuscularly, or transdermally. All of these methods have drawbacks, including repeated syringe use, cross-contamination, or diminished amounts of the biologically active compound.

[004] Various nasal formulations for the administration of testosterone have been developed, including by Trimel Pharmaceuticals (PCT Publication WO 2006/113505, Patent No. US5.756.071, US Patent Publication 2013/059827, 2013/045958, 2013/0040923 and 2013/0040922). Intranasal administration of testosterone has been shown to increase testosterone concentrations dramatically and rapidly - increasing concentrations from baseline (mean 2.5 pmol/l) to maximum (mean 168.2 pmol/l) 1 to 2 minutes after dosing (Davison et al., 2005). Transdermal gel application, on the other hand, is a slower and considerably less efficient method of administration. Increasing concentrations to peak levels using transdermal gel are reported to take 10 days, and include daily gel applications (average 2.3 nmol/l on day 1 to a mean of 14.6 nmol/l on day 10 according to Rolf et al., 2002). Additionally, nasally administered testosterone has been shown to have a higher concentration in the brain than intravenously administered testosterone, with whole brain testosterone levels reported to be twice as high following intranasal administration compared to intravenous administration (Banks et al., 2009). These nasal formulations are developed using castor oil to disperse testosterone ester or active testosterone. Castor oil facilitates the absorption of compounds across the mucous membranes, but unfortunately it is not very selective in this absorption. An aqueous-based formulation can avoid much of the cross-contamination and irritation exhibited by castor oil-based formulations. Therefore, the development of new testosterone formulations is of therapeutic importance.

[005] At the most general level, anxiety disorders (which include post-traumatic stress disorder) are thought to be caused by an inability to properly regulate the brain's response to fear and danger in the environment (Beck, et al. , 2005). Testosterone has been shown to play a critical role in the body's response to fear and anxiety (van Honk, et al., 2005 and Hermans, 2008) and therefore, perhaps not surprisingly, low testosterone levels have been implicated as a factor. of risk for the development of post-traumatic stress disorder by Mason, et al. (1990), Karlovic, et al. (2012) and Reijnen, et al. (2014). Due to the fact that modulation of testosterone levels is believed to play an important role in the etiology of anxiety disorders (Giltay et al., 2012; Montgomery et al., 1987; van Honk et al., 2005), New and more effective methods of testosterone delivery are needed which will increase bioavailable testosterone.

SUMMARY OF THE INVENTION

[006] In some aspects, the present disclosure provides pharmaceutical compositions comprising the following components dissolved in an aqueous solution: (A) a compound of the formula: where: Ri is hydrogen, acyl (e<i2) or substituted acyl (e<i2); (B) a first additive substantially comprised of a compound of the formula: wherein: R2, R3 and R4 are each independently selected from alkyl (e<i2), alkenyl (e<i2), alkynyl (e<i2) or a substituted version of any of these groups; and (c) a second additive substantially comprised of a compound of the formula: wherein: x, y, z, a, b, and c are each independently a number selected from 0 to 40, provided that at least one of x, y, z, a, b, or c is not 0; and men are each independently selected from 0, i, or 2. In some embodiments, Ri is acyl (e<i2). In some embodiments, Ri is . In some embodiments, R2 is alkyl (e<i2) or substituted alkyl (e<i2). In some embodiments, R2 is alkyl (e6-i2). In some embodiments, R2 is octyl or decyl. In some embodiments, R3 is alkyl (e<i2) or substituted alkyl (e<i2). In some embodiments, R3 is alkyl (e6-i2). In some embodiments, R3 is octyl or decyl. In some embodiments, R4 is alkyl (e<i2) or substituted alkyl (e<i2). In some embodiments, R4 is alkyl (e6-i2). In some embodiments, R4 is octyl or decyl. In some embodiments, one of R2, R3 and R4 is decyle and the other two of R2, R3 and R4 are octyl. In some embodiments, m is 0. In other embodiments, m is i. In some embodiments, x, y, and z are 0. In other embodiments, a, b, and c are 0. In some embodiments, the compositions comprise between 0.1% to about 5% by weight of component (A). In some embodiments, the compositions comprise from about 1% to about 3% by weight of component (A). In some embodiments, the compositions comprise about 1.2% by weight of component (A). In other embodiments, the compositions comprise about 2.2% by weight of component (A). In some embodiments, the compositions comprise from about 1% to about 10% by weight of component (B). In some embodiments, the compositions comprise from about 3% to about 7% by weight of component (B). In some embodiments, the compositions comprise from about 4.5% to about 5.5% by weight of component (B). In some embodiments, the compositions comprise from about 10% to about 20% by weight of component (B). In some embodiments, the compositions comprise from about 12% to about 16% by weight of component (B). In some embodiments, the compositions comprise from about 14% to about 15% by weight of component (B). In some embodiments, the compositions comprise about 15% to about 40% by weight of component (e). In some embodiments, the compositions comprise about 15% to about 30% by weight of component (e). In some embodiments, the compositions comprise from about 22% to about 26% by weight of component (C). In some embodiments, the compositions comprise from about 50% to about 90% by weight of water. In some embodiments, the compositions comprise from about 60% to about 80% by weight of water. In some embodiments, the compositions comprise from about 68% to about 72% by weight of water. In other embodiments, the compositions comprise from about 50% to about 70% by weight of water. In some embodiments, the compositions comprise from about 55% to about 60% by weight of water. In some embodiments, the compositions are formulated for administration via the nasal route. In some embodiments, the compositions further comprise a preservative. In some embodiments, the composition comprises from about 0.01% by weight to about 5% by weight of the preservative. In some embodiments, the composition is sterilized. In some embodiments, the composition is filter sterilized. In some embodiments, the composition is filter sterilized with a Tuffryn® filter. In some embodiments, the Tuffryn® filter is a 0.22 micron Tuffryn® filter.

[007] In another aspect, the present disclosure provides pharmaceutical compositions comprising a testosterone ester (c<i2), water and a first additive. In some embodiments, the testosterone ester (c<i2) is testosterone propionate. In some embodiments, the water is distilled water. In some embodiments, the first additive is a reaction mixture from the reaction of castor oil with ethylene oxide. In some embodiments, the reaction comprises a molar ratio of ethylene oxide to castor oil of about 35:i. In some embodiments, the first additive is a cremophor® composition. In some embodiments, the first additive is cremophor® 35. In some embodiments, the compositions further comprise a second additive. In some embodiments, the second additive is a caprylic/capric triglyceride. In some embodiments, the second additive is a dicaprylic acid and monocapric triglyceride. In some embodiments, the second additive is a Neobee® medium chain triglyceride composition. In some embodiments, the second additive is Neobee® M-5. In some embodiments, the second additive comprises from about 1% to about 10% by weight of the composition. In some embodiments, the second additive comprises from about 4.5% to about 5.5% by weight of the composition. In some embodiments, the second additive comprises from about 10% to about 20% by weight of the composition. In some embodiments, the second additive comprises from about 14% to about 16% by weight of the composition. In some embodiments, the testosterone ester (e<i2) comprises from about 0.1% to about 5% by weight of the composition. In some embodiments, the testosterone ester (e<i2) is about 1.2% by weight of the composition. In other embodiments, the testosterone ester (e<i2) is about 2.2% by weight of the composition. In some embodiments, water comprises from about 65% to about 75% by weight of the composition. In some embodiments, the water is from about 68% to about 72% by weight of the composition. In other embodiments, water comprises from about 55% to about 65% by weight of the composition. In some embodiments, water comprises from about 57% to about 60% by weight of the composition. In some embodiments, the second additive comprises from about 15% to about 25% by weight of the composition. In some embodiments, the first additive is from about 22% to about 26% by weight of the composition. In some embodiments, the composition is formulated for administration via the nasal route. In some embodiments, the composition also comprises a preservative. In some embodiments, the compositions comprise from about 0.01% by weight to about 5% by weight of the preservative. In some embodiments, the compositions are sterilized. In some embodiments, the compositions are filter sterilized. In some embodiments, the compositions are filter sterilized with a Tuffryn® filter. In some embodiments, the Tuffryn® filter is a 0.22 micron Tuffryn® filter.

[008] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising about 1.2% by weight of testosterone propionate, about 71.6% by weight of distilled water, about 4.9% by weight of Neobee® M-5 and about 22.3% by weight Cremophor® EL. In some embodiments, the compositions are formulated for administration via the nasal route. In some embodiments, the compositions further comprise a preservative. In some embodiments, the compositions comprise from about 0.01% by weight to about 5% by weight of the preservative. In some embodiments, the compositions are sterilized. In some embodiments, the compositions are filter sterilized. In some embodiments, the compositions are filter sterilized with a Tuffryn® filter. In some embodiments, the Tuffryn® filter is a 0.22 micron Tuffryn® filter.

[009] In yet another aspect, the present disclosure provides pharmaceutical compositions comprising about 2.2% by weight of testosterone propionate, about 58.7% by weight of distilled water, about 14.3% by weight of Neobee® M-5 and about 24.8% by weight Cremophor® EL. In some embodiments, the compositions are formulated for administration via the nasal route. In some embodiments, the compositions further comprise a preservative. In some embodiments, the compositions comprise from about 0.01% by weight to about 5% by weight of the preservative. In some embodiments, the compositions are sterilized. In some embodiments, the compositions are filter sterilized. In some embodiments, the compositions are filter sterilized with a Tuffryn® filter. In some embodiments, the Tuffryn® filter is a 0.22 micron Tuffryn® filter.

[010] In another aspect, the present disclosure provides methods of treating a disease or disorder in a patient in need thereof comprising administering a therapeutically effective amount of testosterone to the patient by nasal route. In some embodiments, testosterone is formulated or comprised in a testosterone composition described herein. In some embodiments, the disease or disorder is a disease or disorder associated with fear and anxiety. In some embodiments, the disease or disorder is a disorder of the fear processing system. In some embodiments, the disease or disorder is an anxiety disorder, major depressive disorder, post-traumatic stress disorder, generalized anxiety disorder, panic disorder, social phobia, non-social phobia, social anxiety disorder, or obsessive-compulsive disorder. In some embodiments, the disease or disorder is a post-traumatic stress disorder. In other embodiments, the disease or disorder is major depressive disorder. In other embodiments, the disease or disorder is an anxiety disorder. In other embodiments, the disease or disorder is a generalized anxiety disorder. In other embodiments, the disease or disorder is a panic disorder. In other embodiments, the disease or disorder is a social phobia. In other embodiments, the disease or disorder is a non-social phobia. In other embodiments, the disease or disorder is a social anxiety disorder. In some embodiments, the disease or disorder is an obsessive-compulsive disorder. In some embodiments, the patient is female. In other embodiments, the patient is male. In some embodiments, the methods comprise administering a second therapeutic agent. In some embodiments, the second therapeutic agent is a second pharmaceutical agent, psychotherapy or cognitive behavioral therapy. In some embodiments, the second pharmaceutical agent is cortisol. In some embodiments, the second pharmaceutical agent is a compound that modulates the patient's cortisol levels. In some embodiments, the methods lead to the reduction of one or more symptoms of an anxiety or fear-related disease or disorder. In other embodiments, the disease or disorder is associated with a deficiency in testosterone. In some embodiments, testosterone deficiency leads to decreased libido. In some embodiments, decreased libido is self-reported. In some embodiments, decreased libido results in the patient having comparatively low libido or no libido. In some embodiments, the decreased libido is in a male or female patient. In some embodiments, the patient is female. In other embodiments, the patient is male. In some embodiments, the disease or disorder is associated with hypogonadism. In other modalities, the patient has erectile dysfunction. In some embodiments, the patient is a male. In some embodiments, the patient is a human. In some embodiments, the therapeutically effective amount is administered in a single dose per day. In other embodiments, the therapeutically effective amount is administered in two or more doses per day. In other embodiments, the therapeutically effective amount is administered as needed. In some embodiments, the patient is treated at least a second time. In some modalities, the patient is treated over a period of 1 week to 6 months. In other modalities, the patient is treated for a period of 6 months to 5 years.

[011] It is contemplated that any method or composition described herein may be implanted with respect to any other method or composition described herein.

[012] The terms “understand” (and any form of understanding, such as “comprehends” and “comprising”), “have” (and any form of having, such as “have” and “having”), “contain” ( and any form of contain, such as "contains" and "containing"), and "include" (and any form of include, such as "include" and "including") are open linking verbs. As a result, a method, composition, kit or system that "comprises", "has", "contains" or "includes" one or more recited steps or elements has these recited steps or elements, but is not limited to having only these elements or steps; it may have (ie cover) elements or steps that are not recited. Likewise, an element of a method, composition, kit or system that "comprises", "has", "contains" or "includes" one or more recited characteristics has these characteristics, but is not limited to having only the characteristics; it may have characteristics that are not recited.

[013] Any embodiment of any of the present methods, composition, kit and systems may consist of or consist essentially of, rather than comprising/included/containing/having the described steps and/or features. Thus, in any of the claims, the term "consisting of" or "consisting essentially of" may be replaced by any of the open linking verbs described above, in order to alter the scope of a given claim from what it would otherwise be using the open linking verb.

[014] The use of the term "or" in the claim is used to mean "and/or" unless explicitly stated otherwise to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition which refers to only alternatives and “and/or”.

[015] Throughout this descriptive report, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[016] Following longstanding patent law, the words "an" and "an", when used in conjunction with the word "comprising" in the claims or descriptive report, denote one or more, unless specifically indicated .

[017] As used herein, the term "substantially" is used to represent a composition comprising at least 90% of the desired compound. The term "more substantially" is used to represent a composition comprising at least 95% of the desired compound. The term "essentially" is used to represent a composition comprising at least 97% of the desired compound. In contrast, the term "substantially free of" or "substantially free" in terms of a specified component, is used herein to mean that none of the specified component was purposely formulated into a composition and/or is present only as a contaminant or amounts vestigial. The total amount of all containments, by-products and other materials is present in this composition in an amount of less than 5%. The term "more substantially free of" or "more substantially free" is used to represent that the composition contains less than 3% of the specific component. The term "essentially free of" or "essentially free" contains less than 2% of the specific component.

[018] Other objects, features and advantages of the present disclosure will be evident from the detailed description below. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments of the disclosure, are presented for illustrative purposes only, as various changes and modifications within the scope and scope of the disclosure will become apparent to those knowledgeable. in the technique from this detailed description.

BRIEF DESCRIPTION OF THE FIGURES

[019] The Figures below form part of this descriptive report and are included to further demonstrate certain aspects of this disclosure. The disclosure may be better understood by reference to one or more of these Figures in combination with the detailed description and examples provided herein.

[020] Figure 1 - shows the pharmacokinetic profile of the 2.2% aqueous testosterone spray described here. The pharmacokinetic profile shows that the maximum concentration of free testosterone is shown approximately 30 minutes after administration.

[021] Figure 2 - shows the correlation of PTSD symptoms displayed as a function of the average monthly number of traumatic war zone stressors based on the patient's cortisol levels. The trend lines in the graph show the mean number of PTSD symptoms for patients with high cortisol levels and low cortisol levels based on the mean number of traumatic war zone stressors.

[022] Figure 3 - shows the correlation of PTSD symptoms exhibited against the average monthly number of traumatic war zone stressors based on the patient's cortisol reactivity. The trend lines in the graph show the mean number of PTSD symptoms for patients with high elevated cortisol reactivity and low cortisol reactivity based on the mean number of traumatic war zone stressors.

[023] Figure 4 - shows the correlation of PTSD symptoms displayed as a function of the average monthly number of traumatic war zone stressors based on the patient's testosterone levels. The trend lines in the graph show the average number of PTSD symptoms for patients with high testosterone levels and low testosterone levels based on the average number of traumatic war zone stressors.

[024] Figure 5 - shows the correlation of PTSD symptoms exhibited as a function of the average monthly number of traumatic war zone stressors based on the patient's cortisol and testosterone levels. The trend lines in the graph show the average number of PTSD symptoms for patients with combinations of high and low cortisol levels and high and low testosterone levels based on the average number of traumatic war zone stressors.

[025] Figure 6 - shows cortisol concentration as a function of endogenous testosterone concentration. High testosterone levels showed lower cortisol levels whereas low testosterone concentration showed higher cortisol levels relative to high testosterone. The data presented in Figure 6 show that female participants with higher endogenous testosterone levels would be relatively immune to the stress-inducing effect of TSST, resulting in lower cortisol levels.

[026] Figure 7 - shows the self-reported experiences of patients treated with the nasal spray of aqueous testosterone described herein. The patient reported their experienced energy levels, libido, anxiety, irritability as well as general well-being before administration and 30, 60, 120, 180 and 240 minutes after administration. Patients reported increased energy and libido levels as well as increased general well-being from 30 to 120 minutes after administration, as well as decreased levels of anxiety and irritability for the same time period.

DESCRIPTION OF ILLUSTRATIVE MODALITIES

[027] The present disclosure provides novel compositions for administering testosterone to a patient. In some embodiments, the testosterone delivery composition is administered nasally. Without being bound by theory, administering testosterone through the nose allows testosterone to quickly reach the bloodstream, and increases the amount of testosterone reaching the brain. In some aspects, the present disclosure provides methods of treating testosterone diseases and disorders including hypogonadism including, without limitation, decreased libido, sexual dysfunction and erectile dysfunction, and fear and anxiety disorders, including, without limitation, post-traumatic stress disorder or social anxiety disorder.

A. CHEMICAL DEFINITIONS

[028] When used in the context of a chemical group: “hydrogen” means -H; "hydroxy" means -OH; “oxo” means =O; "carbonyl" means -C (=O)-; "carboxy" means -C (=O)OH (also written as -COOH or -CO2H); "halo" independently means -F, -Cl, -Br, or -I; "amino" means -NH2; "hydroxyamino" means -NHOH; "nitro" means -NO2; means imino = NH; "cyan" means -CN; "isocyanate" means -N = C = O; "azido" means -N3; in a monovalent context, "phosphate" means -OP(O)(OH)2 or a deprotonated form thereof; in a divalent context, "phosphate" means -OP(O)(OH)O- or a deprotonated form thereof; “mercapto” means -SH; and "uncle" means =S; "sulfate" means -S(O)2OH-; "sulfonyl" means -S(O) 2 -; and "sulfinyl" means -S(O)-.

[029] In the context of chemical formulas, the symbol, “-” means a single bond, “=“ means a double bond and “≡” means a triple bond. The symbol It is represents an optional bond, which when present is single or double. The symbol represents a single bond or a double bond. So, for example, the formula includes . And it is understood that no ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol “-”, when linking one or two stereogenic atoms, does not indicate any preferred stereochemistry. Rather, it covers all stereoisomers as well as mixtures thereof. The symbol , when drawn perpendicular to a bond (e.g., for methyl) indicates a point of attachment of the group. Note that the connection point is normally only identified this way for larger groups, in order to assist the reader in unambiguously identifying a connection point. The symbol Means a simple link in which the group attached to the thick end of the slice is” off the page. "The symbol means a single bond where the group bonded to the thick end of the slice is “inside the page”. The symbol means a single bond, where the geometry around a double bond (eg, either E or Z) is undefined. Both options as well as combinations thereof are therefore intended. Any undefined valence on an atom of a structure presented in this application implicitly represents a hydrogen atom bonded to this atom. A bold dot on a carbon atom indicates that the hydrogen bonded to the carbon is oriented out of the plane of the paper.

[030] When an “R” group is described as a “floating group” in a ring system, for example, in the formula: then, R can replace any hydrogen atom bonded to any of the ring atoms, including a represented, implicitly, or explicitly defined hydrogen atom, provided that a stable structure is formed. When an "R" group is described as a "floating group" in a fused ring system, for example in the formula: then, R may replace any hydrogen atom bonded to any of the ring atoms of any of the fused rings, unless otherwise specified. Replaceable hydrogen atoms include depicted hydrogens (e.g., the hydrogen atom bonded to the nitrogen atom in the above formula), implied hydrogens (e.g., a hydrogen atom of the above formula, which is not shown but is understood to be present), expressly defined hydrogen atoms, and optional hydrogen atoms whose presence depends on the identity of a ring atom (for example, a hydrogen atom bonded to the group X, when X equals -CH-), while a stable structure is formed. In the illustrated example, R can reside in either the 5-membered ring or the 6-membered ring of the fused ring system. In the formula above, the letter subscript “y” immediately following the group “R” in parentheses, represents a numerical variable. Unless otherwise specified, this variable can be 0, 1, 2, or any integer greater than 2, limited only by the maximum number of replaceable hydrogen atoms in the ring or ring system.

[031] For the groups and classes below, the following indices in parentheses further define the group/class as follows: “(Cn)” defines the exact number (n) of carbon atoms in the group/class. “C<n” “defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number being the smallest possible for the group in question, for example, it is understood that the minimum number of carbon atoms in the group “alkenyl (C<8)” or the class “alkene (C<8)” is two. For example, "alkoxy (C<10)" designates those alkoxy groups having from 1 to 10 carbon atoms. (Cn-n') defines both the minimum (n) and maximum number (n') of carbon atoms in the group. Similarly, "(2-10C) alkyl" designates alkyl groups having from 2 to 10 carbon atoms.

[032] The term "saturated" as used herein means that the compound or group so modified has no carbon-carbon double bond and carbon-carbon triple bond, except as provided below. In the case of substituted versions of saturated groups, one or more carbon-oxygen double bonds or a carbon-nitrogen double bond may be present. And, when this bond is present, then carbon-carbon double bonds that can occur as part of keto-enol tautomerism or imine/enamine tautomerism are not excluded.

[033] The term "aliphatic", when used without the modifier "substituted" means that the compound/group so modified is an acyclic or cyclic group or compound, but of non-aromatic hydrocarbon. In aliphatic compounds/groups, the carbon atoms can be joined together in straight chains, branched chains or non-aromatic (alicyclic) rings. Aliphatic compounds/groups can be saturated, that is, united by single bonds (alkanes/alkyl) or unsaturated, with one or more double bonds (alkenes/alkenyl) or with one or more triple bonds (alkynes/alkynyl).

[034] The term "alkyl", when used without the modifier "substituted" refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon atoms. carbon and hydrogen. The groups -CH3 (Me), -CH2CH3 (Et), -CH2CH2CH3 (n-Pr or propyl), -CH(CH3)2 (i-Pr, iPr or isopropyl), -CH2CH2CH2CH3 (n-Bu), -CH (CH3)CH2CH3 (sec-butyl), -CH2CH(CH3)2 (isobutyl), -C(CH3)3 (tert-butyl, t-butyl, t-Bu or tBu) and -CH2C(CH3)3 (neo -pentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" when used without the modifier "substituted" refers to a divalent saturated aliphatic group, with one or two saturated carbon atoms as points of attachment, a straight or branched acyclic structure, no double or triple bonds of carbon- carbon and no atoms other than carbon and hydrogen atoms. The groups -CH2- (methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non-limiting examples of alkanediyl groups. An "alkane" refers to the compound H-R, where R is alkyl as this term is defined above. When any of these terms are used with the modifier “substituted”, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3 , -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -OC(O)CH3, or -S( O)2NH2. The following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2Cl, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O) ) CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2Cl.

[035] The term "alkenyl" when used without the modifier "substituted", refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon-carbon double bond non-aromatic carbon, no carbon triple bonds, and no atoms other than carbon and hydrogen atoms. Non-limiting examples include: -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. The term "alkenediyl" when used without the modifier "substituted" refers to a divalent unsaturated aliphatic group having two carbon atoms as points of attachment, a straight or branched acyclic structure, straight or branched chain, at least one double bond non-aromatic carbon-carbon bonds, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen atoms. The groups -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2- and -CH2CH=CHCH2- are non-limiting examples of alkenediyl groups. Note that although the alkenediyl group is aliphatic, once attached at both ends this group is not precluded from being part of an aromatic structure. The terms "alkene" or "olefin" are synonymous and refer to a compound having the formula H-R, where R is alkenyl as this term has been defined above. A "terminal alkene" refers to an alkene that has only one carbon-carbon double bond, where this bond forms a vinyl group at one end of the molecule. When any of these terms are used with the modifier “substituted,” one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3 , -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -OC(O)CH3, or -S( O)2NH2. The groups -CH = CHF, -CH = CHCl and -CH = CHBr are non-limiting examples of substituted alkenyl groups.

[036] The term "alkynyl" when used without the modifier "substituted", refers to a monovalent unsaturated aliphatic group with a carbon atom as a point of attachment, a linear or branched acyclic structure, at least a carbon triple bond and without atoms other than carbon and hydrogen atoms. As used herein, the term alkynyl does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C=CH, -C=CCH3, and -CH2C=CCH3 are non-limiting examples of alkynyl groups. An "alkyne" refers to the compound H-R, where R is alkynyl. When any of these terms are used with the modifier “substituted”, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3 , -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -OC(O)CH3, or -S( O)2NH2.

[037] The term "aryl", when used without the modifier "substituted", refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as a point of attachment, said carbon atom forming part of one or more of a six-membered aromatic ring structure, in which the ring atoms are all carbon, and in which the group consists of no atoms other than carbon and hydrogen atoms. If more than one ring is present, the rings can be fused or unfused. As used herein, the term does not exclude the presence of one or more alkyl or aralkyl (carbon number limitation allowed) groups attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl. The term "arenodiyl", when used without the modifier "substituted", refers to a divalent aromatic group having two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more aromatic ring structures of six members, in which the ring atoms are all carbon and in which the monovalent group consists of none other than carbon and hydrogen. As used herein, the term does not exclude the presence of one or more alkyl, aryl or aralkyl (carbon number limitation allowed) groups attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings can be fused or unfused. Unfused rings may be linked via one or more of the following: a covalent bond, alkanediyl or alkenediyl groups (carbon number limitation allowed). Non-limiting examples of arenodiyl groups include:

[038] An "arene" refers to the compound H-R, where R is aryl as the term is defined above. Benzene and toluene are non-limiting examples of arenes. When any of these terms are used with the modifier “substituted”, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3 , -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -OC(O)CH3, or -S( O)2NH2.

[039] The term "aralkyl", when used without the modifier "substituted", refers to the monovalent -alkanediyl-aryl group, where the terms alkanediyl and aryl are each used in a manner consistent with the definitions given above . Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the modifier “substituted”, one or more hydrogen atoms of the alkanediyl and/or aryl group have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2 , -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -OC(O) ) CH3 or -S(O)2NH2. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-eth-1-yl.

[040] The term "heteroaryl", when used without the modifier "substituted", refers to a monovalent aromatic group with an aromatic carbon atom or a nitrogen atom as a point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, in which at least one of the ring atoms is nitrogen, oxygen or sulfur, and in which the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings can be fused or unfused. As used herein, the term does not exclude the presence of one or more alkyl, aryl and/or aralkyl (carbon number limitation allowed) groups attached to the aromatic ring or aromatic ring system. Examples of non-limiting heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl and triazolyl. The term "N-heteroaryl" refers to a heteroaryl group with a nitrogen atom as the point of attachment. A "heteroarene" refers to the compound H-R, where R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. When these terms are used with the modifier “substituted”, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, - CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -OC(O)CH3, or -S(O) 2NH2.

[041] The term "acyl", when used without the modifier "substituted", refers to the group -C (O)R, where R is a hydrogen, alkyl, cycloalkyl, alkenyl, aryl, aralkyl or heteroaryl, such as these terms are defined above. The groups, -CHO, -C(O)CH3 (acetyl, Ac), -C(O)CH2CH3, -C(O)CH2CH2CH3, -C(O)CH(CH3)2, -C(O)CH( CH2)2, -C(O)C6H5, -C(O)C6H4CH3, -C(O)CH2C6H5, -C(O)(imidazolyl) are non-limiting examples of acyl groups. A “thioacyl” is defined analogously, except that the oxygen atom of the -C(O)R group has been replaced by a sulfur atom, -C(S)R. The term “aldehyde” corresponds to an alkane, such as defined above, wherein at least one of the hydrogen atoms has been replaced with a -CHO group. When any of these terms are used with the modifier “substituted”, one or more hydrogen atoms (including a hydrogen atom bonded directly to the carbon atom of the carbonyl or thiocarbonyl group, if any) have been replaced independently by -OH, -F , -Cl, -Br, -I, -NH2, -SH, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -OC(O)CH3, or -S(O)2NH2. The groups, -C(O)CH2CF3, -CO2H (carboxy), -CO2CH3 (methylcarboxyl), -CO2CH2CH3, -C(O)NH2 (carbamoyl), and -CON(CH3)2, are non-limiting examples of acyl groups replaced.

[042] The composition “Neobee® M-5” is a medium chain triglyceride with registration number 73398-61-5. The composition “Cremophor EL®” or “Kolliphor EL” is a polyethoxylated castor oil with registration number CAS61791-12-6. The “Tuffryn®” syringe filter is a hydrophilic polysulfone membrane filter.

[043] The term "effective", as this term is used in the specification and/or claims, means adequate to achieve a desired, expected or intended result. "Effective amount", "therapeutically effective amount" or "pharmaceutically effective amount", when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to a subject or patient for the treatment of a disease, it is sufficient to carry out this treatment for the disease.

[044] As used herein, the term "patient" or "individual" refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig India or species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human beings are adults, juveniles, infants and fetuses.

[045] As used herein, "PEG" is polyethylene glycol with a repeating unit of -(OCH2CH2)nOH, where n is the number of repeats. A molecule that has been "PEGylated" or contains "one or more PEG groups" is a molecule that has been covalently attached to a polyethylene glycol group such as the group is described above.

[046] As generally used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with tissues, organs and/or body fluids of humans and animals without excessive toxicity, irritation, allergic reaction, or other problems or complications commensurate with a reasonable risk/benefit ratio.

[047] “Prevention” or “preventing” includes: (1) inhibiting the onset of a disease in an individual or patient who may be at risk and/or predisposed to the disease, but who does not yet suffer or present any or all of the disease pathology or symptomatology, and/or (2) delay the onset of the disease pathology or symptomatology in an individual or patient who may be at risk and/or predisposed to the disease but who is not yet suffering from or exhibiting any or the totality of the pathology or symptomatology of the disease.

[048] "Prodrug" means a compound that is convertible in vivo metabolically into a biologically active compound according to the present disclosure. The prodrug itself may or may not also have activity towards a given target protein. For example, a compound comprising a hydroxyl group can be administered as an ester, which is converted by hydrolysis in vivo to the hydroxyl compound. Suitable esters which can be converted in vivo to hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bis-β-hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, amino acid esters and the like. Similarly, a compound comprising an amine group can be administered as an amide which is converted by hydrolysis in vivo to the amine compound.

[049] A "testosterone ester", as used in the context of this patent application, is a testosterone derivative comprising at least one substitution on the hydroxyl group on the cyclopentyl ring of the steroid nucleus with an acyl functional group or an acyl functional group substituted as these functional groups are defined above. When a carbon boundary is assigned to a testosterone ester, the carbon boundary is relative only to the carbon atoms in the acyl substitution. The terms "testosterone", "testosterone ester" or "testosterone derivative" are used interchangeably unless specifically noted otherwise.

[050] “Treatment” or “treating” includes (1) inhibiting a disease in an individual or patient experiencing or exhibiting the pathology or symptomatology of the disease (e.g., preventing further development of the pathology and/or symptomatology), (2) ameliorating a disease in an individual or patient suffering from or exhibiting the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology) and/or (3) effecting any measurable decrease in a disease in an individual or patient experiencing or displays the pathology or symptomatology of the disease.

[051] The definitions below supersede any conflict of definition in any reference that is incorporated herein by reference. The fact that some terms are defined, however, should not be taken as implying that any term that is not defined is undefined. Rather, it is believed that all terms used to describe the disclosure are in terms such that a person of ordinary skill would appreciate the scope and practice of the present disclosure.

B. DISEASES AND DISORDERS RELATED TO FEAR AND ANXIETY

[052] Diseases and disorders related to fear and anxiety are associated with dysregulation of fear processing centers in the brain. In particular, testosterone or derivatives thereof or the formulations of the present disclosure can be used to treat a fear or anxiety related disease or disorder. Without being bound by theory, treatment of these diseases and disorders with an agent that modulates the brain's fear response is effective in treating these diseases and disorders. In general, phobias, such as social phobia and non-social phobia, are centered around the fear of a particular thing. In a non-limiting example, non-social phobias include arachnophobia, hemophobia or chemophobia and related to a fear of specific objects such as spiders, blood and chemicals, respectively. Social phobia, on the other hand, is a generalized or specific fear of any social situation. In some non-limiting examples, social phobias can be associated with such generalized social situations as attending an event with a crowd, talking to strangers, or meeting new people at a club. On the other hand, specific social phobias can include a fear of public speaking, a fear of talking to a particular group such as the opposite sex, or a fear of interacting with a specific group of people such as dentists or doctors in a few examples not limiting.

[053] In addition, diseases or disorders related to fear or anxiety include panic disorders that are associated with a fear of a particular situation or stimulus that is present during an initial attack. Panic disorders are notable for the rapid and repeated onset of fear, in some cases debilitating fear, which can affect an individual's ability to work and can last from minutes to hours. Additionally, the patient tends to be afraid of having an attack. Treatment of these diseases or disorders with compounds that can modulate fear are potentially and therapeutically important treatment options. Additionally, generalized anxiety disorder is when a patient exhibits anxiety in the sense of a routine worry that cannot be resolved even when the patient no longer has a rational reason to be concerned.

[054] Additionally, people can become so fixated on patterns and routines that they become an obsession. When the individual feels compelled to perform these activities as a means of reducing anxiety - even though the activities interfere with the individual's daily life - the individual may be diagnosed with obsessive-compulsive disorder. Such anxiety-triggered compulsions in an individual can be modulated by altering the individual's fear response.

[055] Finally, post-traumatic stress disorder (PTSD) results when the body's fight-or-flight systems become dysregulated from exposure to real or imagined painful stimuli. In individuals with PTSD, the individual continues to react as if painful stimuli are present even after the stimuli are removed. Traditionally, the disorder is more associated with war veterans, but it can occur after the individual has suffered any traumatic event or someone close to the individual has suffered a traumatic event. Often these events are associated with a threat of bodily harm.

C. HYPOGONADISM AND DECREASE SEXUAL DRIVE

[056] In some aspects of the present disclosure, testosterone can be used to treat males with clinically low testosterone levels - hypogonadism - or decreased libido in both males and females. Although both males and females can show symptoms of hypogonadism, hypogonadism is usually diagnosed only in males. In males, hypogonadism is a physiological condition in which the body does not produce enough testosterone. Hypogonadism can be acquired or congenital, and testosterone administration can be effective in treating both forms. In some modalities, hypogonadism can be treated with testosterone replacement therapy. Male hypogonadism is associated with a number of different complications, including, without limitation, decreased sexual appetite, fatigue, muscle wasting or weakness, erectile dysfunction, osteoporosis, or infertility. Furthermore, low testosterone levels have been implicated in decreased life expectancy in males. Although testosterone levels decline with age, in some embodiments, suboptimal testosterone levels can be treated with nasal administration of testosterone. In some embodiments, nasal testosterone treatment is in conjunction with another method of administering testosterone on a long-term basis, such as via a transdermal patch, injections, or topical administration.

[057] Additionally, in some embodiments, testosterone can be used to treat women with decreased sexual desire or appetite. Administration of a single dose of testosterone has been shown to increase subjective sexual desire, genital responsiveness, and genital arousal in women when testosterone has been administered sublingually. In some embodiments, the women being treated have a clinically diagnosed low level of sexual desire compared to the population average. In some embodiments, administration of testosterone increases sexual desire. In some embodiments, testosterone is administered to women who are postmenopausal or who use hormonal contraceptives. Additionally, in some embodiments, testosterone is administered to women who have low energy levels or to combat a decrease in bone density or muscle mass.

D. NASAL PHARMACEUTICAL FORMULATIONS AND ADMINISTRATION ROUTES

[058] In some aspects of the present disclosure, testosterone is formulated for administration via the nasal route. Nasal formulations comprise the pharmaceutically active compound and at least one excipient that allows aerosolization of the compound. Ideally, the compound in combination with the excipient will produce an aerosol without leading to dulling or precipitation of the pharmaceutically active compound. In some embodiments, the composition of the present disclosure further comprises a preserving agent. In some embodiments, the preservative comprises from about 0.01% to about 5% of the solution by weight. Preservative agents are well known to those skilled in the art and include, without limitation, benzalkonium salts, thimerosal, sodium or potassium phosphate, phenylcarbinol, benzyl alcohol, sodium EDTA, providone, iodine, and sodium silicoaluminate. In some embodiments, the nasal formulation of an active pharmaceutical compound such as testosterone must not be irritating to the nasal mucosa or mucous membranes. In some embodiments, aqueous formulations for nasal administration are more effective, more easily absorbed, or faster drying than other compositions. Additionally, it is anticipated that testosterone and these testosterone compositions described herein may also be administered in other ways, such as sublingually if the method is tolerated by the patient.

[059] The nasal formulation is an aqueous formulation containing at least 10% water. In some embodiments, the formulation comprises at least 25% water. In some embodiments, the formulation comprises at least 50% water. In some embodiments, the formulation comprises at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%. In some aspects, formulations and compositions provided herein comprise one or more hydrophobic additives. Hydrophobic additives can be composed of triglycerides. In some embodiments, the triglyceride compounds have medium-length fatty acid chains having a carbon length of 6 to 14 carbon atoms. Other hydrophobic additives that can be used include triglyceride derivatives that contain one or more PEGylated portions of the molecule. In some embodiments, the triglyceride contains one or more polyethylene glycol groups on the fatty acid. In other embodiments, the polyethylene glycol group is incorporated between the glyceride and the fatty acid. Some non-limiting examples of such compounds include compounds of the Formula: wherein: x, y, z, a, b, and c are each independently a number selected from 0 to 40, provided that at least one of x, y, z, a, b, or c is not 0; and and m are each independently selected from 0, 1, or 2. In some embodiments, x, y, and z are each 0. In other embodiments, a, b, and c are each 0. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, Cremophor® 35 is an example of a PEGylated triglyceride. In some embodiments, the composition or formulation consists essentially of testosterone, water and one or more hydrophobic additives. In some embodiments, the composition or formulation consists essentially of testosterone, water and two hydrophobic additives.

[060] In some aspects, the compositions of the present disclosure can act faster than compositions described in the prior art. The pharmacokinetic aspects of the present compositions can be used to achieve a high serum concentration of free testosterone within a short period of time after administration. In some embodiments, the high serum testosterone concentration can also be reduced within a relatively short window of time. The high testosterone concentration can be a total serum testosterone concentration greater than 8 ng/ml within 45 minutes after administration. In some embodiments, the serum total testosterone concentration is greater than 10 ng/ml within 45 minutes of administration. In some embodiments, high serum testosterone concentration is achieved within 30 minutes of administration. The high testosterone concentration can be achieved within 15, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, or 45 minutes, or any range derivable therefrom, of administration. On the other hand, the serum testosterone concentration may also be reduced rapidly after administration. In some embodiments, the serum total testosterone concentration is reduced by more than 15% within 90 minutes of administration. Serum total testosterone concentration can be reduced by more than 25% within 90 minutes after administration. In some embodiments, total serum testosterone concentration is reduced by more than 15% within 60 minutes of administration. The serum total testosterone concentration can be reduced by more than 25% within 60, 65, 70, 75, 80, 85 or 90 minutes, or any range derivable therefrom, of administration. Without wishing to be bound by any theory, it is believed that administering testosterone in such a way that it achieves high serum concentrations within about 45 minutes of administration, but the serum concentration is rapidly reduced within 1, 2, 4 or 6 hours after administration is beneficial for numerous applications and reduce side effects. Studies suggest that long-term testosterone therapy in hypogonadal men is linked to increased risk of death from cardiovascular disease (Vigen, et al., 2013). Furthermore, the use of testosterone in gel formations has been linked to secondary contamination (de Ronde, 2009).

[061] For administration to a mammal in need of such treatment, the compositions of the present disclosure further comprise one or more excipients appropriate for the indicated route of administration. In some embodiments, the formulation further comprises an excipient such as an agent that increases the solubility of the pharmaceutically active compound or a carrier that allows the pharmaceutically active compound to cross the blood-brain barrier. Excipients that can be used are well and widely known in the pharmaceutical art.

[062] In some embodiments, pharmaceutical compositions useful in the present disclosure are subject to conventional pharmaceutical operations such as sterilization and/or further comprise conventional pharmaceutical carriers and excipients such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. In some embodiments, the composition also comprises a preservative. Preservatives that can be used in combination with the pharmaceutical composition of the present invention are known to those skilled in the art. Some preservatives that may be used in the present composition include, without limitation, an antibiotic, an antiviral agent, antioxidants such as vitamin A, vitamin E, vitamin C, retinol palmitate, and selenium, amino acids such as methionine and cysteine, citrus, sodium citrate, or preservatives such as synthetic parabens including methylparaben and propylparaben. In some embodiments, the composition of the present disclosure is sterilized. In some embodiments, the composition is filter sterilized. Some filters that may be used for sterilization, such as, without limitation, Tuffryn® and Durapore® filter discs. The filter should have a pore size of about 20 microns to remove microorganisms such as bacteria. Additionally, a nanofilter is used with a pore size of about 20 to 50 nanometers which will also remove viruses.

[063] The composition described in the present disclosure is administered in a therapeutically effective dosage sufficient to treat a condition in a patient. For example, the effectiveness of the compound of the present disclosure can be evaluated in an animal model system that can be predictive of effectiveness in treating disease in humans, such as the model systems shown in the examples and Figures.

[064] The actual dosage amount of the composition of the present disclosure administered to an individual can be determined by physical and physiological factors such as age, sex, body weight, severity of the condition, type of disease being treated, previous or ongoing therapeutic interventions simultaneous, idiopathic of the subject and route of administration. These factors can be determined by one skilled in the art. The administering physician will normally determine the concentration of active ingredient(s) in an appropriate dose(s) and composition for the individual subject. The dosage can be adjusted by the individual physician in the event of any complications.

[065] An effective amount will typically range from about 0.001 mg/kg to about 50 mg/kg, in one or more daily dose administrations, over one or several days (depending on the course on the factors discussed above). In some particular embodiments, the amount is less than 5000 mg per day, with a range from 0.01 mg to 4500 mg per day.

[066] The effective amount may be less than 10 mg/kg/day, less than 50 mg/kg/day, less than 100 mg/kg/day, less than 250 mg/kg/day. It may alternatively be in the range of 0.01 mg/kg/day to 250 mg/kg/day.

[067] In other non-limiting examples, a dose may also comprise between about 0.001 mg/kg/body weight, about 0.01 mg/kg/body weight, about 0.1 mg/kg/body weight, about of 5 mg/kg/body weight, or more per administration, and any derivable range therefrom. In non-limiting examples of a range derivable from the numbers listed herein, a range from about 1 mg/kg/body weight to about 50 mg/kg/body weight, about 5 g/kg/body weight to about 10 g/kg/body weight, etc., can be given, based on the numbers described above.

[068] In certain embodiments, a pharmaceutical composition of the present invention may comprise, for example, at least about 0.01% of a testosterone of the present disclosure. In other embodiments, the compound of the present invention can comprise from about 0.1% to about 75% by weight of the unit, or from about 0.25% to about 60%, or from about 0.25 % to about 10%, for example, and any derivable variation therein.

[069] Single or multiple doses of the composition of the present disclosure are contemplated. Desired time intervals for administration of multiple doses can be determined by one skilled in the art employing no more than routine experimentation. As an example, subjects may be dosed twice daily at approximately 12 hour intervals. In some embodiments, the agent is administered once daily. In other embodiments, the agent is administered more than once a day. In other embodiments, the agent is administered as needed to lessen the effects of a disease or disorder. In some embodiments, the agent is administered to a patient to treat an acute condition. In other embodiments, the agent is administered to a patient for the treatment of a chronic condition.

[070] The compounds can be administered on a routine schedule. As used herein, a routine schedule refers to a predetermined designated period of time. The routine schedule can encompass periods of time that are identical or that differ in duration, provided the schedule is predetermined. For example, the routine schedule might involve dosing twice a day, every day, every other day, every third day, every four days, every five days, every six days, weekly, monthly, or every other day. any given number of days or weeks between them. Alternatively, the predetermined routine schedule may involve administration on a twice-daily basis for the first week, then daily for several months, etc. Thus, for example, the agent can be taken every morning and/or every night, regardless of when the subject has eaten or is about to eat.

E. COMBINATION THERAPY

[071] In addition to being used as a monotherapy, the composition may also find utility in combination therapies. Effective combination therapy can be achieved with a single drug composition or formulation that includes both agents, or with two distinct compositions or formulations administered at the same time, where one composition includes one compound and the other includes the second(s). s) agent(s). The other therapeutic modality can be administered before, concurrently with, or after administration of the composition of the present disclosure. Therapy using the composition of the present disclosure can precede or follow administration of the other agent (or agents) by intervals ranging from minutes to weeks. In embodiments where the other agent and the composition of the present disclosure are administered separately, one can generally ensure that a significant period of time has not elapsed between the time of each delivery, such that each agent would still be able to exert a advantageously combined effect. In such cases, it is contemplated that one would typically administer the composition of the present disclosure and another therapeutic agent within about 12 to 24 hours of each other, and more preferably, within about 6 to 12 hours of each other, with a time delay of only about 12 hours being more preferred. In some situations it may be desirable to extend the time period for treatment significantly, however when several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4) , 5, 6, 7 or 8) between the respective administrations.

[072] More than one administration of a composition of the present disclosure is also conceivable, or the other agent will be desired. In this regard, various combinations can be employed. By way of illustration, when the compounds of the present disclosure are "A" and the other agent is "B", the following permutations based on 3 and 4 total administrations are exemplary: A/B/A B/A/B B/B/A A /A/B B/A/A A/B/B B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A /B/A B/A/A/B B/B/B/A A/A/A/B B/A/A/A A/B/A/A A/A/B/A A/B/B/B B/A/B /B B/B/A/B

[073] Other combinations are also contemplated. Non-limiting examples of pharmacological agents that can be used in the present disclosure include other forms of testosterone, another hormone or hormone derivative such as a testosterone derivative, another sex hormone, or cortisol modulating compounds. In some embodiments, the composition of the present disclosure is administered with another form of testosterone such as intravenous or transdermal testosterone dosing. In some embodiments, the composition of the present disclosure is administered with an agent that modulates cortisol levels or the patient's cortisol reactivity. In some embodiments, the composition of the present disclosure is administered in combination with cortisol.

F. EXAMPLES

[074] The following examples are included to demonstrate preferred embodiments of disclosure. It should be appreciated by those skilled in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to work well in the practice of the disclosure and, thus, may be considered to constitute preferred modes for its practice. However, those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still achieve the same or similar result without departing from the essence and scope of the disclosure.

EXAMPLE 1: FORMULATION OF AN AQUEOUS NASAL TESTOSTERONE FORMULATION

[075] A testosterone ester formulation was prepared using a combination of water and other additives that help solubilize testosterone in the aqueous environment. The formulation was prepared by combining testosterone with the first and second additives, Cremophor EL® and Neobee M5®, respectively, with stirring until all components dissolved. Distilled water, which has been heated to a temperature of about 65°C to about 80°C, is added to the mixture of testosterone, Cremophor EL® and Neobee M5®. The mixture was then brought to the phase inversion temperature followed by cooling until the mixture became transparent. The mixture was cooled either to room temperature or using an ice bath to achieve clarity. The resulting emulsion was passed through a 0.22 micron Tuffryn® filter and collected in the administration container. Passage through the filter both sterilized the emulsion and imparted greater consistency to the droplet size within the emulsion. Without being bound by theory, emulsion filtration and increased consistency may result in more consistent drug absorption kinetics. The emulsion was then added to a nasal actuator for administration. The resulting emulsion was a nasally administered testosterone formula containing 1.2% e, wt/wt Testosterone Propionate with 24 wt/wt Cremophor EL®, 5 wt/wt Neobee M5® and 69.8% w/w distilled water. Additionally, a 2.2% w/w testosterone propionate formulation was prepared with 24.8% w/w Cremophor EL®, 14.3% Neobee M5® and 58.7% w/w. weight of distilled water.

[076] If the mixture was not brought to the phase inversion temperature, the resulting mixture did not reach the proper particle size for administration, but formed a translucent emulsion. A variety of different combinations of additives, including many different types of oils, have not achieved the results obtained in terms of clarity, lack of irritation or manageability when using the above additives. For example, ethyl oleate and ethoxydiglycol were used, but the resulting mixture was too viscous to produce an aerosol. Additional oils that produced aerosol formulations included sesame oil, olive oil, isopropyl myristate and ethyl oleate. These oils failed for a variety of reasons including, without limitation, producing a coarse emulsion rather than a nanoemulsion, testosterone precipitation, sensory intolerability, and stickiness. Without being bound by any theory, it is believed that the concentration of oils, such as Cremophor®, is important for maintaining a nanoemulsion capable of being aerosolized, as well as solubilizing testosterone. Additionally, when higher concentrations of testosterone and other hydrophobic additives are used, the formulation can form a pro-nano emulsion. Without wishing to be bound by any theory, it is believed that when the composition is administered to the nostrils, the composition mixes with nasal fluids and forms a nanoemulsion. Additionally, modifying the concentration of additional hydrophobic additives, such as Neobee® M-5 or other triglycerides, can affect the viscosity of solutions and thus can be used to reduce the ability of the compositions to flow.

[077] The pharmacokinetic profile of the 2.2% wt/wt testosterone spray is shown in Figure 1. The pharmacokinetic profile showed that the peak concentration of testosterone for “free”, or bioavailable testosterone (the fraction that is considered bioactive and can readily enter cells), (Figure 1) after approximately 30 minutes. After the peak concentration (476.6%) was reached at about 30 minutes after administration, the concentration began to decrease such that the concentration was reduced by about 33% from the peak concentration at about 60 minutes. Serum testosterone concentrations were determined by enzyme-linked immunosorbent assay (ELISA), based on the principle of competitive binding, using antibody kits manufactured by DRG International, Inc.

EXAMPLE 2: ADMINISTRATION OF TESTOSTERONE TO TREAT ANXIETY AND FEAR DISORDERS

[078] Studies illustrated in Figures 2 through 5 have shown that testosterone levels are a greater predictive risk factor for symptoms of post-traumatic stress disorder (PTSD) than cortisol or cortisol reactivity. The pathogenic nature of the cortisol reactivity was completely neutralized when coupled with elevated testosterone levels (see Figure 5). Statistical analysis of these results showed that low preimplantation testosterone levels were pathogenic and strong predictors of increased PTSD symptoms (Tables 1 to 4). All hormonal predictors were either modeled alongside monthly within-person deviations from their own average traumatic stressor (PTEWP) or time-varying traumatic stressor score (PTETV). When modeled in conjunction with PTEWP, the effect of mean exposure to stressors was interpreted as the total among-soldier effect of having a higher mean level of stressor exposure (PTEBP), and when modeled with time-varying stressors (PTETV), the The effect among soldiers becomes a contextual or compositional effect, reflecting the effect of having a certain level of overall average stressor exposure while equaling soldiers on month-to-month fluctuations in stressor exposure (PTEComp). This method of explicitly modeling the between-soldier, within-soldier, and compounding components of stressors avoided imposing the problematic assumption that their effects are equal (Hedeker & Gibbons, 2006; Hoffman & Stawski, 2009). Compounding effects that look at differences between soldiers, while equalizing soldiers in the effects of month-to-month stressor fluctuation and the moderating effects of hormones on the effects of month-to-month stressor fluctuation were used for the analysis. TABLE 1: STATISTICAL ANALYSIS OF PTSD SYMPTOMS OF CORTISOL LEVELS AND POTENTIAL TRAUMATIC WAR ZONE STRESSORS TABLE 2: STATISTICAL ANALYSIS OF PTSD SYMPTOMS OF CORTISOL REACTIVITY AND POTENTIAL TRAUMATIC WAR ZONE STRESSORS TABLE 3: STATISTICAL ANALYSIS OF PTSD SYMPTOMS OF TESTOSTERONE LEVELS AND POTENTIAL TRAUMATIC WAR ZONE STRESSORS TABLE 4: STATISTICAL ANALYSIS OF PTSD SYMPTOMS OF TESTOSTERONE LEVELS AND POTENTIAL TRAUMATIC WAR ZONE STRESSORS

[079] In addition, testosterone has been found to have strong fear-reducing effects. Given the relationship between testosterone and PTSD and depressive symptoms depicted in Figures 2 to 5, testosterone administration has been shown to lead to reduced symptoms of PTSD and depression. Testosterone levels predicted a fear-based disorder when fear-inducing stimuli are in abundance, such as a high number of stressors.

EXAMPLE 3: INFLUENCE OF ENDOGENOUS TESTOSTERONE ON WOMEN'S STRESS RESPONSE TO A PERFORMANCE STRESSOR.

[080] Given the debilitating nature of anxiety disorders, a greater understanding of their etiology and the development of appropriate early interventions are critical. Without being bound by any theory, due to the fact that testosterone has been implicated in reducing fear and anxiety, it is believed that women with elevated levels of endogenous testosterone would experience less stress (as measured by cortisol production ) when exposed to an intense acute performance stressor.

A. PROCEDURES

[081] 52 female participants were recruited from the SONA participant pool of the Department of Psychology at the University of Texas at Austin. All participants were scheduled to participate during the estimated luteal phase of their menstrual cycles (between the 17th and 28th day after the onset of menses) in order to minimize the possible effects of cycling sex hormones on the HPA axis. To assess cycle phase, female participants were asked to recall the first day of their most recent menstruation during telephone screening. Participants currently taking hormonal contraceptives were excluded.

[082] During the study, participants were administered the Trier Social Stress Test and a total of 7 saliva samples were collected to be analyzed for testosterone and cortisol concentrations.

[083] A Trier Social Stress Test (TSST; Kirschbaum, Pirke, & Hellhammer, 1993) was used to trigger activation of the HPA axis. Participants were informed that they will be assessed on their verbal and non-verbal skills (eg, posture, facial expression, etc.) in an improvised mock interview by a panel of behavioral experts. In addition, they were also instructed that their speeches must span five minutes and that their performances will be videotaped for later in-depth analysis. Participants were given 10 minutes to prepare their presentations. When the five minutes allotted for their speeches ended, participants were asked to count from 1022 to 0, in decrements of 13, where they must start from 1022 again if they produced an incorrect response at any point in the speech. sequence.

[084] After the 30 minutes after arrival, the participants were taken to another room to prepare for the TSST. Once seated in the preparation room, participants were asked to drool 2 ml of saliva into a 10 ml cryovial. Immediately after this, participants were taken to the TSST room where public speaking instructions were provided via a pre-recorded message. Participants were then brought back into the preparation room and told to prepare for their speech describing why they would be an ideal candidate for a vacancy. After 10 minutes of anticipation, participants provided another saliva sample and were then administered TSST. After the TSST, participants provided a third saliva sample until 4 additional samples were collected. In total, 7 saliva samples were collected.

[085] Salimetric testosterone and cortisol concentrations were analyzed at home with commercially available Salimetrics enzyme immunoassay kits (Salimetrics, State College PA). Frozen saliva samples were thawed completely and centrifuged for 10 minutes at 3000 rpm immediately before assay. All samples were run in duplicate. Hypotheses were tested using correlations, factorial ANOVAs and independent sample t-tests. All analyzes were performed using SPSS Statistics 21.0 for Mac OS X (SPSS, Inc., Chicago IL). An alpha cut-off level of 0.05 was used to determine statistical significance.

B. RESULTS

[086] Without being bound by any theory, it is believed that female participants with higher levels of endogenous testosterone would be relatively immune to the stress-inducing effect of TSST, resulting in lower cortisol levels. This belief was tested using linear regression in which a total increase in testosterone over the course of the experiment (area under the curve - increase, or AUCi) was used to predict the total increase in cortisol. As seen in Figure 6, the belief was confirmed. Total testosterone was linearly associated with TSST-evoked cortisol accumulation (p<.001), a finding that is consistent with the view that testosterone is protective against stress-inducing environmental threats and trauma.

PROPHETIC EXAMPLE 4: EFFECTS OF FAST-ACTING TESTOSTERONE NASAL SPRAY ON THE EMOTIONAL AND BEHAVIORAL ANXIETY RESPONSE OF YOUNG MALE

[087] The effects of a nasal spray of fast-acting testosterone on the fear reactions of young men will be tested. Two distinct anxiety challenges (social and non-social) will be used in a double-blind randomized experimental design. The study will determine whether men administered a testosterone nasal spray have lower levels of anxiety (anticipatory and situational) and higher levels of approach behavior in response to two distinct anxiety challenges (social and non-social) relative to men. administered with a placebo spray. The study will also determine whether the type of anxiety challenge (social vs. non-social) moderates the effect of testosterone administration on a subject's response to challenge. Finally, the study will determine whether rejection sensitivity (high sensitivity to evaluative threat) moderates the effects of drug conditions in response to two anxiety challenge tests.

C. PROCEDURES

[088] The target population for this study will be approximately eighty men, ages 18 to 25, with no current medical conditions that preclude testosterone use and no current use of testosterone-boosting products.

[089] Data collection will be completed in a single visit to the laboratory, which will last between 2 and 3 hours. Each individual will be equipped with a chest strap for recording heart rate and a wristband for recording the electrodermal response. Testosterone salivary samples will be collected at two different times: after signing the consent form and after completing the pre-challenge battery (30 minutes after nasal spraying). Testosterone and cortisol salivary concentrations will be analyzed at home with commercially available Salimetrics Enzyme Immunoassay kits (Salimetrics, State College PA). Frozen saliva samples will be completely thawed and centrifuged for 10 minutes at 3,000 rpm immediately before assay. All samples will be tested in duplicate.

[090] Participants will participate in two separate anxiety challenges - one designed to elicit social anxiety and one designed to elicit non-social anxiety. Each challenge will consist of two phases – an anticipatory phase and a performance phase. Prior to administration of testosterone/placebo, subjects will complete a computerized Premedication Assessment Battery.

[091] The testosterone spray will consist of 7 mg of testosterone in a solution with 125 mg of 0.5% chlorobutanol in 50 ml saline solution with a pH of approximately 5. The placebo spray will be identical to the testosterone spray without the testosterone. Both solutions will be sterilized using a 0.22 micron filter and inserted into a sterile disposable nasal applicator, which will be condition-coded so that the experimenter and participant are blinded to the drug condition.

1. SOCIAL ANXIETY CHALLENGE

[092] The participant will be in front of a table, two examiners and a video camera. Examiners will remain expressionless throughout the encounter and maintain eye contact with the participant at all times. The experimenter will turn on the recorded message and the instructions for the social anxiety challenge will be played back. After the instructions are heard, the experimenter will take the participant to the preparation room, where they will immediately complete the post-instructional assessment battery. After completing the post-instruction assessment battery, the researcher will remind the subject that he or she has five minutes to prepare for the speech. The experimenter will leave the room and return after five minutes to escort the participant to the door of the filming room. The experimenter will direct the participant inside the room and close the door from the outside. The participant will be instructed to begin speaking until one of the following conditions is met: (a) 5 minutes have elapsed; or (b) the participant chooses to stop the speech before the 5 minute limit. If the participant finishes their speech in less than five minutes, the examiner will be quiet for 20 seconds, ask if the participant is finished speaking, and if so, then tell the participant that they are about to do a five-minute arithmetic task. minutes.

[093] In the arithmetic task, the participant will be informed that they are about to do a five-minute arithmetic task in which their non-verbal behavior and their arithmetic accuracy will be assessed. The subject will be asked to serially subtract the number 13 from 1022 as quickly and accurately as possible. Every time subjects make a mistake, they are instructed to stop, informing them that they were wrong and that they need to start over from the beginning and subtract 13 from 1022. The arithmetic task will end when a) five minutes have elapsed or b) the participant stops the task. The total speech time will be recorded and will serve as the main index of the behavioral approach. During the course of your speech, the participant will be recorded on video.

[094] Upon completion of the social anxiety challenge, the participant will be escorted back to the testing room and will be administered a “Questionnaire Assignment” along with the “Post-Anxiety Challenge Assessment Battery”. Once completed, the participant will be instructed to relax for 5 minutes prior to the Claustrophobia Anxiety Challenge.

2. CLAUSTROPHOBIA ANXIETY CHALLENGE

[095] Attendees will watch a video clip with instructions. Immediately following the video clip, participants will complete the Post-Assessment Assessment Battery. They will then be escorted to the “claustrophobia room” and given 5 minutes alone to prepare. After the 5 minutes have passed, the participant will be assisted into the chamber and positioned on their back, at which point the chamber door will be closed and locked. The task will continue until one of the following conditions is met: (a) 5 minutes have elapsed; or (b) the entrant chooses to stop the challenge by signaling that they wish to exit before the 5-minute time limit.

[096] Upon completion of the Claustrophobia Anxiety Challenge, the participant will be escorted back to the testing room and administered the “Post Anxiety Challenge Assessment Battery”. After completing the two anxiety challenges, the participant will be administered the interrogation battery.

J. MEASUREMENTS 1. PRE-MEDICATION EVALUATION BATTERY

[097] The computerized Premedication Assessment Battery consisting of the following empirically supported psychometric self-report scales.

[098] Acceptance and Action Questionnaire This 9-item version of the Acceptance and Action Questionnaire (AAQ; Hayes et al., 2004) is widely used to assess the psychological construct of experiential avoidance. This scale will be used to test experiential avoidance as a putative moderator of testosterone's effects on anxiety scores.

[099] Trait Anxiety Scale (STAI-T; Spielberger et al,. 1983) is a widely used and psychometrically sound 20-item self-report questionnaire designed to assess trait anxiety. This scale will be used to test whether trait anxiety moderates the effects of testosterone on participants' fear response to the two anxiety challenges.

[0100] Anxiety Sensitivity Index -3 (ASI-3; Taylor et al.,2007) is a widely used and psychometrically sound 18-item self-report questionnaire designed to assess the physical, cognitive, and social concerns associated with fear of anxiety . This scale will be used to test whether the same level of anxiety moderates the effects of testosterone on participants' fear response to the two anxiety challenges.

[0101] Social Interaction Anxiety Scale (SIAS; Mattick & Clarke, 1998) is a widely used 20-item scale describing people's reactions to situations involving social interactions. This scale will be used to test whether the participants' level of social anxiety moderates the effects of testosterone on the participants' fear response to the claustrophobia challenge.

[0102] Claustrophobia Concerns Questionnaire (CCQ. Valentiner et al, 1996) was developed to assess the level of entrapment and suffocation concerns that are common factors in the psychopathogenesis of claustrophobia. This scale will be used to test whether fear of anxiety moderates the effects of testosterone on participants' fear response to the claustrophobia challenge.

[0103] Mood State Profile - Short Form (POMS-SF; Shachman, 1983) is a widely used and psychometrically sound 37-item self-report scale for assessing mood disturbance with individual scores for six different mood states - fatigue, vigor, anxiety, depression, anger and confusion. This scale will be used for mood index changes between different phases of the experimental session.

2. POST-INSTRUCTION EVALUATION BATTERY

[0104] The computerized Post-Instructional Assessment Battery consisting of the following scales. POMS-SF - See above.

[0105] Anticipated Fear (0 to 100). Global anticipated (expected) fear scores will be collected immediately prior to each of the two anxiety challenges to index the effects of testosterone/placebo on participants' perception of their reactivity to anticipated fear of challenge.

[0106] Perceived Coping Self-efficacy (0 to 100). Global scores of perceived coping efficacy will be collected immediately before each of the two anxiety challenges to index the effects of testosterone/placebo on participants' perceptions of coping self-efficacy.

3. POST-CHALLENGE EVALUATION BATTERY

[0107] Participants will complete a computerized assessment battery to index their maximum fear, perceived performance and mood state. Note that this battery will be administered twice (ie, once after each of the two anxiety challenges). Specific measures include the following. POMS-SF - See above.

[0108] Maximum Fear Rating (0 to 100) - Participants will be asked to rate the highest level of fear they experienced at any point during the anxiety challenge.

[0109] Global Performance Rating (0 to 100) - Participants will be asked to rate their actual performance during the challenge on a scale ranging from 0 (extremely poor performance) to 100 (extremely strong performance).

[0110] Behavioral Approach Score (0 to 300) - The experimenter will record the total duration in seconds that the participant performed the challenge. Note that participants are not aware of the 300-second performance limit.

[0111] Body Alertness Questionnaire - 15-item body sensation subscales (Schmidt et al. 1997) - The Body Alertness Scale (BVS) is a measure developed to assess conscious participation to internal stimuli. The 15-item body sensation subscale of the body surveillance questionnaire will be used after each anxiety challenge as a measure of participants' anxiety sensitivity. The body sensation subscale involves separate assessments for attention to 15 alertness and anxiety 15 body sensations (for example, heart palpitations) that include all DSM-IV physical symptoms described for panic attacks, according to the Diagnostic and Statistician of Mental Disorders (DSM IV; American Psychiatric Association, 1994).

[0112] Attribution of Performance - Social Anxiety Challenge Questionnaire - Social Challenge Performance Attribution will measure with the Attribution of Performance - Social Anxiety Challenge Questionnaire that was created for this study. The questionnaire consists of 5 items that participants respond on a 7-point Likert scale with 3 of the items assessing how well participants believe they did compared to others on the social anxiety challenge and two of the items assessing who they are blame for their performance.

4. BATTERY OF INTERROGATORY

[0113] At the conclusion of the experiment, participants will complete measures to assess their rumination, their perceived medication attribution, and perceived medication effects.

[0114] 14-item negative thoughts subscale of the Thoughts Questionnaire (Edwards et al., 2003). - State rumination on the social anxiety challenge will be assessed using the 14-item negative thoughts subscale of the Thoughts Questionnaire. Participants will indicate how often they had specific thoughts about social anxiety challenges using a 5-point scale, ranging from “never” (0) to “often” (4). Items will be added together for a total state rumination score.

[0115] Perceived Medication Assignment Survey -This two-item survey will assess participants' beliefs about their medication assignment. The first survey item will ask the individual to indicate which medication (testosterone or placebo) was administered. The second index will index your degree of confidence in your medication assignment using a scale of 0 to 100 points.

[0116] Medication Effects Form -This 30-item survey assesses possible physical effects of medication over a brief (30 minute) time interval. Participants are presented with 30 possible symptoms and asked to rate their presence on a 4-point scale, ranging from 0-Not present to 3-severe.

EXAMPLE 5: PERCEIVED EFFECTS OF FAST-ACTING TESTOSTERONE NASAL SPRAY ON SEXUAL AND EMOTIONAL RESPONSES OF YOUNG MALE

[0117] Patients administered the aqueous nasal testosterone spray described here reported their perceptions of emotional and sexual state (Figure 7). Testosterone-treated patients (N = 4) showed increased energy, libido and general well-being relative to the placebo group (N = 3) from 30 minutes after administration to 120 minutes after administration. Likewise, the testosterone nasal spray-treated group reported experiencing decreased anxiety and irritability relative to the placebo group over the same time period. Data were collected using an online data collection program (Survey Monkey Inc., Palo Alto). Scale values were anchored at 1 and 7, with 1 = not at all and 7 = extremely high.

[0118] All compositions and methods disclosed and claimed herein can be made and performed without undue experimentation in light of the present disclosure. While the compositions and methods of the present disclosure have been described in terms of certain embodiments, it will be apparent to those skilled in the art that variations can be applied to the compositions and methods and to the steps or sequence of steps of the methods described herein without departing from the concept, essence and scope of disclosure. More specifically, it will be apparent that certain agents that are chemically and physiologically related can be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and apparent modifications to those skilled in the art are considered to be within the essence, scope and concept of the disclosure as defined by the appended claims. REFERENCES The following references, to the extent that they provide exemplary, procedural or other details supplementing those set forth, are specifically incorporated herein by reference. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV 4th ed. Washington (DC): American Psychiatric Association; 1994, p. 866 Banks, et al., Delivery of testosterone to the brain by intranasal administration:comparison to intravenous testosterone, Journal of Drug Targeting, 17(2):91 to 97, 2009. Beck, et al., Anxiety disorders and phobias :A cognitive perspective. Basic Books, 2005. Davison, et al., Pharmacokinetics and acute safety of inhaled testosterone in postmenopausal women, The Journal of Clinical Pharmacology, 45(2):177 to 184, 2005. De Ronde, Hyperandrogenism after transfer of topical testosterone gel: case report and review of published and unpublished studies, Human Reproduction, 24(2), 425 a 428, 2009. Edwards et al., Post-event rumination and recall bias for a social performance event in high and low socially anxious individuals, Cognitive Therapy and Research, 27:603 to 617, 2003. Giltay, et al., Salivary testosterone: Associations with depression, anxiety disorders, and antidepressant use in a large cohort study, Journal of psychosomatic research, 72(3):205 to 213 , 2012. Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002). Hayes et al., Measuring experiential avoidance: A preliminary test of a working model, The Psychological Record, 54:553 to 578, 2004. Hedeker & Gibbons, Longitudinal data analysis, (Vol. 451), John Wiley & Sons, 2006. Hoffman & Stawski, Persons as contexts: Evaluating between-person and within-person effects in longitudinal analysis, Research in Human Development, 6(2-3):97 to 120, 2009. Mattick & Clarke, Development and validation of measures of social phobia scrutiny fear and social interaction anxiety, Behav. Res. ,36(4):455 to 470, 1998. Montgomery, et al., Effect of estrogen and testosterone implants on psychological disorders in the climacteric, The Lancet, 329(8528):297 to 299, 1987. Reijnen, et al. , The Effect of Deployment to a Combat-zone on Testosterone Levels and the Association with the Development of Posttraumatic Stress Symptoms; a Longitudinal Prospective Dutch Military Cohort Study, Psychoneuroendocrinology, 2014. Rolf, C., et al., Pharmacokinetics of a new transdermal testosterone gel in gonadotrophin-suppressed normal men, European Journal of Endocrinology, 146(5):673 to 679, 2002 Shacham, A shortened version of the Profile of Mood States, Journal of Personality Assessment, 47:305-306, 1983. Spielberger et al., Manual for the State-Trait Anxiety Inventory, Palo Alto, CA: Consulting Psychologists Press, 1983 Taylor et al., Robust Dimensions of Anxiety Sensitivity: Development and Initial Validation of the Anxiety Sensitivity Index-3, Psychological Assessment, 19:176 to 188, 2007. Tuiten, et al., Time Course of Effects of Testosterone Administration on Sexual Arousal in Women, Arch. Gen. Psychiatry, 57:149 to 153, 2000. Valentiner et al., Cognitive mechanisms in claustrophobia: An examination of Reiss and McNally's expectancy model and Bandura's self-efficacy theory, Cognitive Therapy and Research, 20:593 to 612, 1996. Vigen, et al., Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels, J. Am. Med. Assc. ,310(17), 1829 to 1836, 2013.

Claims (14)

1. Pharmaceutical composition, CHARACTERIZED by the fact that it comprises a testosterone ester (C<12), water, and a first additive, and a second additive; wherein water comprises from about 50% to about 90% by weight of the composition, the first additive is a reaction mixture from the reaction of castor oil with ethylene oxide, the second additive is a caprylic/capric triglyceride, and the pharmaceutical composition is formulated for nasal administration. 2. Composition according to claim 1, CHARACTERIZED by the fact that the testosterone ester (C<12) is testosterone propionate. 3. Composition according to claim 1, CHARACTERIZED by the fact that the reaction comprises a molar ratio of ethylene oxide to castor oil of approximately 35:1. 4. Composition, according to claim 1, CHARACTERIZED by the fact that the first additive is a polyethoxylated castor oil with CAS registration number 61791-12-6. 5. Composition, according to any one of claims 1 to 4, CHARACTERIZED by the fact that the second additive is a dicaprylic acid and monocapric triglyceride. 6. Composition according to any one of claims 1 to 5, characterized by the fact that the second additive comprises from about 1% to about 10% or from about 10% to about 20% by weight of the composition. 7. Composition according to any one of claims 1 to 6, characterized by the fact that the testosterone ester (C<12) comprises from about 0.1% to about 5% by weight of the composition. 8. Composition according to any one of claims 1 to 7, characterized by the fact that water comprises from about 65% to about 75% by weight of the composition, or from about 55% to about 65% in composition weight. 9. Composition according to any one of claims 1 to 8, characterized by the fact that the first additive comprises from about 15% to about 26% by weight of the composition. 10. Pharmaceutical composition CHARACTERIZED by the fact that it comprises about 1.2% by weight of testosterone propionate, about 69.8% by weight of distilled water, about 5.0% by weight of a medium-chain triglyceride with CAS Registry Number 73398-61-5, and about 24% by weight of a polyethoxylated castor oil with CAS Registry Number 61791-12-6, or about 2.2% by weight of Testosterone Propionate, about 58.7% by weight of distilled water, about 14.3% by weight of a medium chain triglyceride with CAS registration number 73398-61-5, and about 24.8% by weight of a polyethoxylated castor oil with CAS registration number 61791-12-6. 11. Composition, according to any one of claims 1 to 10, characterized by the fact that the composition further comprises a preservative or the composition is sterilized. 12. Use of a composition, as defined in any one of claims 1 to 11, CHARACTERIZED by the fact that it is in the manufacture of a medicine for the treatment of a disease or disorder in a patient in need thereof. 13. Use, according to claim 12, CHARACTERIZED by the fact that the disease or disorder is an anxiety disorder, major depressive disorder, post-traumatic stress disorder, generalized anxiety disorder, panic disorder, social phobia, phobia non-social disorder, social anxiety disorder, or obsessive compulsive disorder. 14. Use, according to claim 12 or 13, CHARACTERIZED by the fact that the disease or disorder is associated with a testosterone deficiency that leads to decreased libido associated with hypogonadism, or the patient has erectile dysfunction.