Needle-assisted jet injection administration of testosterone composition

Abstract

To provide a method of obtaining steady state average blood concentration of testosterone.SOLUTION: A method of obtaining steady state average blood concentration of testosterone comprises the step of repeatedly administering a dose of testosterone over a prescribed time period such that a steady state blood plasma level of testosterone is obtained after three or more doses.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 61 / 941,875, entitled "Needle-Assisted Jet Injection Administration of Testosterone Compositions," filed February 19, 2014, the entire contents of which are incorporated herein by reference. [Background technology]

[0002]

[0002] Testosterone is a steroid hormone from the androgen group. In general, androgens promote protein biosynthesis and the growth of tissues that have androgen receptors. Testosterone is anabolic, which means that it increases bone and muscle mass. Testosterone has the following structural formula:

[0003] [ka]

[0004]

[0003] The original and primary use of testosterone is for the treatment of men with hypogonadism, who have too little or no natural endogenous testosterone production. However, over the years, testosterone has also been given for many other conditions, such as reducing infertility, correcting lack of libido or erectile dysfunction, correcting osteoporosis, encouraging penis enlargement, supporting height growth, supporting bone marrow stimulation, reversing the effects of anemia, and stimulating appetite.

[0005]

[0004] There are several application methods for testosterone, including subcutaneous injections and transdermal creams, gels and patches. However, subcutaneous injections tend to be painful and inconvenient, and increase the risk of erythrocytosis. Transdermal creams, gels and patches are often expensive, cause acne and skin irritation at the site of administration, have a lack of compliance with daily administration, and fail to provide sufficient testosterone levels for some patients.

[0006]

[0005] Thus, there is a pressing need for a method of administering testosterone that offers benefits and improvements over conventional methods of administering testosterone to patients, such as subcutaneous injections and transdermal creams, gels and patches. Summary of the Invention

[0007] This specification includes the disclosure of the following inventions. [1] A method for obtaining a steady-state average blood concentration of testosterone, comprising the step of repeatedly administering an amount of testosterone over a predetermined period of time such that a steady-state plasma level of testosterone is obtained after three or more doses. [2] The method according to [1], wherein the dose is selected from 50 mg, 75 mg, and 100 mg. [3] The method according to [2], wherein the concentration of the administered dose is 100 mg / ml, 150 mg / ml or 200 mg / ml. [4] The method according to [1], wherein the dose is 50 mg to 100 mg. [5] The method according to [1], wherein the specified period is one week of administration. [6] The method according to [1], wherein a steady state is reached after the fourth dose. [7] The method according to [1], wherein a steady state is reached after the fifth dose. [8] The method of [1], wherein the dose is continued after a steady state is reached. [9] The method of [8], wherein the dose administered after steady state is reached is the same as or different from the dose administered before steady state is reached.

[10] The method described in [5], wherein once steady state is reached, the mean plasma concentration obtained after administration of a subsequent dose or doses is less than + or -30% of the mean plasma concentration obtained during the immediately preceding week.

[11] The method according to [1], wherein the steady state therapeutic blood level maintained at steady state after multiple administrations is from about 800 ng / dl to about 1100 ng / dl.

[12] The method according to [1], wherein the steady state therapeutic blood level maintained at steady state after multiple administrations is from about 500 ng / dl to about 800 ng / dl.

[13] The method according to [1], wherein the steady state therapeutic blood level maintained at steady state after multiple administrations is from about 350 ng / dl to about 500 ng / dl.

[14] A method of titrating a patient to the lowest dose of testosterone that produces a desired plasma concentration, comprising administering multiple doses of testosterone subcutaneously and selecting from the two or more doses the lowest dose that produces the desired plasma concentration of testosterone compared to an intramuscular dose that provides the same desired plasma concentration of testosterone.

[0006] In one aspect, a method for obtaining a steady-state average blood concentration of testosterone is described, the method comprising the step of repeatedly administering a dose of testosterone over a period of time such that a steady-state plasma level of testosterone is obtained after three or more doses.

[0008]

[0007] In another aspect, a method of titrating a patient to the lowest testosterone dose that achieves a desired plasma concentration is described, the method comprising administering multiple doses of testosterone subcutaneously and selecting from two or more doses the lowest dose that provides the desired plasma concentration of testosterone compared to an intramuscular dose that provides the same desired plasma concentration of testosterone.

[0009]

[0008] These and other objects, features and advantages of the present disclosure will become apparent from consideration of the following non-limiting detailed description considered in conjunction with the drawings, in which: [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 is a side view of an injection device according to one embodiment of the present disclosure; [Diagram 2] FIG. 2 is a cross-sectional view of the injection device of FIG. 1 in a safe state taken along line AA; [Diagram 3]

[0011] FIG. 3 is an enlarged view of a portion of the cross-section shown in FIG. 2; [Figure 4]

[0012] 4A and 4B are perspective views of a safety element used in conjunction with the injection device of FIG. 1; [Diagram 5]

[0013] FIG. 5 is a partial cross-sectional perspective view of the device of FIG. 1 in a safe condition; [Figure 6A]

[0014] FIG. 6A is a cross-sectional view of the injection device of FIG. 1 in a ready state; [Figure 6B]

[0015] FIG. 6B is a cross-sectional view of the injection device of FIG. 1 at the start of the injection state; [Figure 6C]

[0016] FIG. 6C is a cross-sectional view of the injection device of FIG. 1 at the end of the injection state; [Figure 6D]

[0017] FIG. 6D is a cross-sectional view of the injection device of FIG. 1 in a locked state; [Figure 7]

[0018] FIG. 7 is an exploded view of a portion of the trigger mechanism associated with the injection device of FIG. 1; [Figure 8]

[0019] FIG. 8 is a perspective view of a needle guard of the injection device of FIG. 1; [Figure 9]

[0020] FIG. 9 is a cross-sectional view of the cap of the injection device of FIG. 1; [Figure 10]

[0021] FIG. 10 is a graph showing pressure in a fluid chamber as a function of time of one embodiment of an injection device according to the present disclosure; [Figure 11]

[0022] FIG. 11 is a cross-sectional view of a needleless jet injection nozzle; [Figure 12]

[0023] FIG. 12 is a graph illustrating one embodiment of the present disclosure, where serum testosterone peaks upon injection and then declines to therapeutically effective levels. [Figure 13]

[0024] FIG. 13 is a table illustrating the mean concentrations of testosterone in miniature pig serum; [Figure 14]

[0025] FIG. 14 is a graph illustrating serum concentrations of testosterone in minipigs of Group 1 of FIG. 13; [Figure 15]

[0026] FIG. 15 is a graph illustrating serum concentrations of testosterone in minipigs of Group 2 of FIG. 13; [Figure 16]

[0027] FIG. 16 is a graph illustrating testosterone serum concentrations for injection of 0.5 ml of 200 mg / ml testosterone enanthate in sesame oil with an autoinjector; [Figure 17]

[0028] FIG. 17 is a graph illustrating the serum concentrations of testosterone for injection of 200 mg / ml testosterone enanthate in sesame oil with a 0.5 ml needle and syringe; [Figure 18]

[0029] FIG. 18 is a graph illustrating testosterone serum concentrations for injection of 0.5 ml of 100 mg / ml testosterone enanthate in sesame oil with an autoinjector; [Figure 19]

[0030] FIG. 19 is a graph illustrating the serum concentrations of testosterone for injection of 100 mg / ml testosterone enanthate in sesame oil with a 0.5 ml needle and syringe; [Figure 20]

[0031] FIG. 20 is a graph illustrating testosterone serum concentrations for injections with a 0.5 ml autoinjector at 100 mg / ml and 200 mg / ml; [Figure 21]

[0032] FIG. 21 is a graph illustrating the serum concentrations of testosterone for injections with a 0.5 ml autoinjector at 100 mg / ml and 200 mg / ml compared to 200 mg of testosterone administered intramuscularly with a needle and syringe; [Figure 22]

[0033] FIG. 22 is a graph illustrating the steady state of testosterone levels achieved over a series of doses by injection with an automatic injection device; and [Figure 23]

[0034] FIG. 23 is a graph illustrating the averaged data for testosterone upon reaching steady state. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011]

[0035] Various aspects of the present invention are more fully described below with reference to the accompanying drawings. Some, but not all, aspects of the present invention are explicitly set forth. Indeed, various aspects of the present invention may be embodied in many different forms and should not be construed as limited to the aspects expressly described. Like numbers refer to like elements throughout. The singular forms "a," "an," and "the" include both singular and plural unless the context clearly dictates otherwise.

[0012]

[0036] A.Definition

[0037] "Leak back," as that term is used herein, refers to leakage from an injection site of a medication during and / or after injection of the medication.

[0013]

[0038] "Substantially no backflow" as used herein refers to an amount of backflow from an injection that is less than about 6% of the total volume of the pharmaceutical product (e.g., less than 0.05 ml) or less than about 6% by weight. In one embodiment, "substantially no backflow" is an amount of backflow that is at or below an amount that cannot be easily detected by swiping a finger across the site of injection immediately after the injection is completed. In one embodiment, "substantially no backflow" is an amount of backflow such that the therapeutic effect of testosterone administered by injection is not substantially altered. As a non-limiting example, the amount of backflow can be referenced in terms of the liquid volume of a fluid composition having a particular concentration of testosterone, or the amount of backflow can be referenced in terms of the amount of testosterone (e.g., mg testosterone) present in the total backflow volume.

[0014]

[0039] "Minimizing backflow," as that term is used herein, refers to impeding or preventing backflow associated with the injection of a medication.

[0040] "Preservative," as the term is used herein, refers to a compound known in the art to be used for the purpose of preserving pharmaceutical compositions, e.g., pharmaceuticals. As used herein, a preservative is intentionally used to aid in antimicrobial stability and thus to have antimicrobial activity. Substances that are not typically thought of as preservatives or that are not typically used to preserve other compositions are not included in this definition.

[0015]

[0041] "AUC" is the area under the curve that represents the concentration of a compound, e.g., testosterone, or a metabolite thereof, in the blood or plasma or serum of a patient as a function of time following administration of the compound to the patient. For example, following administration of testosterone as described herein, The AUC of testosterone can be determined by measuring the concentration of it or its metabolites in blood at various time intervals using methods such as liquid chromatography-tandem mass spectrometry (LC-MS / MS) and calculating the area under the blood, plasma or serum concentration versus time curve. The concentration versus time curve is sometimes called the pharmacokinetic profile. Suitable methods for calculating the AUC from a drug concentration versus time curve are well known in the art. Thus, the AUC for testosterone can be determined by measuring the concentration of testosterone in the patient's blood after administration of testosterone to the patient.

[0016]

[0042] "Bioavailability" refers to the amount of a compound, e.g., testosterone, that reaches a patient's systemic circulation following administration of the compound to the patient, and can be determined, for example, by assessing the blood or plasma levels of the compound.

[0017]

[0043] "Bioequivalence," as that term is used herein, refers to one or more of the following confidence intervals: (a) the maximum concentration ("Cmax") of a drug (e.g., testosterone) in a patient's plasma following administration of a dose of the drug to a patient via an injection device; (b) the time to reach the maximum concentration ("Tmax") of the drug in a patient's plasma following administration of a dose of the drug to a patient via an injection device; and (c) the area under the curve ("AUC") of the concentration of the drug in a patient's plasma following administration of a dose of the drug to a patient via an injection device, falls within about 80% to about 125% of the measured confidence interval for the same drug delivered by an alternative route.

[0018]

[0044] A "patient" and a "subject" both independently include mammals, such as, for example, humans.

[0045] "About" is understood to mean a range of + and -10% of the referenced value. However, the use of "about" in relation to a value does not exclude the referenced value alone. For example, "about 400" is understood to fully cover both "400" as well as "360 to 440".

[0019]

[0046] B. Compositions, Methods, and Embodiments of the Invention

[0047] The present disclosure encompasses aspects of injection devices as well as compositions and methods suitable for use alone or in combination with aspects of the injection devices.

[0020]

[0048] I. Injection device

[0049] A typical subcutaneous syringe utilizes a pushing force from one or more of the user's fingers to deliver the injection. In certain embodiments, the powered injection device of the present disclosure is designed to help subjects repeatedly, accurately, and quickly administer testosterone formulations to a preset depth without having to utilize such a pushing force with each injection.

[0021]

[0050] In certain embodiments, the powered injection device includes an automatic injection device, a needle-free jet injection device, or a needle-assisted jet injection device (collectively referred to as "injection devices").

[0022]

[0051] Known automatic injection device embodiments of powered injection devices use an energy source that generates a moderate to low pressure in the medicine chamber such that the medicine contained in the medicine chamber is expelled at a slow velocity, similar to the pressure and velocity from a finger-driven syringe. In contrast, the automatic injection device embodiments of the powered injection device of the present disclosure use an energy source that generates a moderate to high pressure in the medicine chamber such that the medicine contained in the medicine chamber is expelled at a high velocity and completely injected into the subject in less than about 10 seconds. Another embodiment of the powered injection device is a jet injection device, which can be a needle-assisted or needle-less injection device. An embodiment of a jet injection device uses an energy source that generates a medium to high pressure in the medicine chamber to expel the medicine with sufficient pressure, force and velocity to exit the injection device as a fluid jet. The jet injection device can be designed to have an energy source selected to generate high pressure at 1000 nm. As described in more detail below, medications injected into a subject via an autoinjector or subcutaneous syringe are delivered in a bolus near the tip of the needle so that backflow can occur, whereas medications delivered from jet injection devices are typically rapidly sprayed away from the tip of the needle into the tissue so that backflow can be minimized, and typically do not deposit a bolus of medication locally at the tip of the needle. Needle-free jet injection devices use sufficient pressure and injection speed so that the fluid jet breaks through the outer layer of the skin and deposits the medication underneath. Needle-assisted jet injection devices can use lower pressures than needle-free jet injection devices because they use a needle to break through the outer portion of the skin, but have a high enough pressure and speed so that the medication exits the tip of the needle as a fluid jet.

[0023]

[0052] Certain embodiments of the injection device disclosed herein are single-use or single-dose injection devices designed to deliver the entire amount of medication(s) contained in the chamber of the injection device or in a cartridge contained within the injection device in one shot. In other embodiments, the injection device is designed to inject only a portion of the contents of the injection device or a cartridge contained within the injection device, and may use a dose setting mechanism to allow selection of the volume of injection to be delivered in one shot, or other mechanisms to provide an adjustable dose. In each of the above embodiments, the injection device may be pre-filled or designed to receive a cartridge with a dose of pharmaceutical agent. Alternative embodiments are designed to be fillable as known in the art.

[0024]

[0053] The injection device provided by the present disclosure can be utilized by a patient to self-inject a testosterone formulation. Various aspects of the present disclosure relate to self-injection of a testosterone formulation by a subject without the assistance of a health care provider. In certain embodiments, the injection device uses a needle to inject the testosterone formulation into a target tissue of a subject, such as in the embodiments of an automatic injection device or a needle-assisted jet injection device, while other embodiments are needle-free injection devices and thus do not require a needle to inject the testosterone formulation into a target tissue of a subject. In certain embodiments, the injection device can utilize a pressure sufficient to completely and quickly deliver the testosterone formulation. In certain embodiments, the injection device can utilize a pressure high enough to completely and quickly deliver one or more testosterone formulations in a fluid jet.

[0025]

[0054] In some embodiments, the powered injection devices provided by the present disclosure do not require any priming or preparation steps to place them under conditions to deliver an injection, thereby reducing or eliminating exposure of the testosterone formulation to air and / or premature expulsion of the testosterone formulation from the needle of the injection device prior to firing of the delivery. Thus, the risk of contact with the testosterone formulation contained in the injection device by the subject or by non-users of the injection device is reduced or eliminated.

[0026]

[0055] Suitable injection devices for use with the present invention include the injection device shown in co-pending application Ser. No. 61 / 763,395, entitled "Needle-Assisted Jet Injection Device With Reduced Trigger Force," the contents of which are incorporated herein by reference in their entirety.

[0027]

[0056] With reference to Figures 1-5, one embodiment of an injection device according to one embodiment of the present disclosure is shown. The embodiment shown in these figures is a needle-type injection device, which can be designed as an automatic injection device or a needle-assisted jet injection device, depending on the spring used and the delivery tube containing the needle and injection outlet. The depicted injection device 12 has an external housing element 14 designed to allow the user to handle the injection device 12, which substantially houses most of the components shown in Figure 2. In one embodiment , the outer housing 14 is formed from two mating portions 14a, 14b, which can be designed to be attached to one another by a snap or press fit, or by adhesive, welding, etc. The housing 14 includes a fluid chamber 22 therein, which is designed to store and dispense one or more liquid pharmaceuticals, such as, for example, a testosterone formulation. In the embodiment shown in FIG. 2, the fluid chamber 22 is formed in a pre-filled syringe 18 that fits within the housing 14, although other types of fluid chambers can be used, including known types of cartridges that can be pre-filled with pharmaceutical(s), are refillable, etc. Additionally, the fluid chamber 22 can be integrally formed within the housing 14.

[0028]

[0057] In one embodiment, the stopper portion of the prefilled syringe, or other portions of the prefilled syringe designed to assist in the containment of the medicine contained in the prefilled syringe, are made of a material that is chemically resistant to one or more components contained in the prefilled syringe.In one embodiment, a suitable stopper has minimal or reduced elutable or extractable materials, and / or is resistant to one or more of acid, base, hydrocarbon, oil, lipid, carbohydrate, or oxygen.Non-limiting examples of suitable stoppers include physically modified rubber, chemically modified rubber, Teflon, and Teflon-coated materials.In one embodiment, the stopper is made of any material that enhances the stability and / or function of the stopper with respect to the containment of oil-based compositions, especially when compared with the function of standard rubber stoppers used to contain the same oil-based compositions.

[0029]

[0058] In the embodiment shown, the safety element 80 is located at the proximal end of the outer housing 14 and is removably attached thereto by a plurality of tabs that extend through matching openings formed in the outer housing 14 to form a press fit between the safety element 80 and the outer housing 14. The safety element 80 is designed to prevent or reduce the possibility of unintended firing of the injection device, for example, during shipping or handling of the injection device 12. The safety element 80 can be removed by a user of the injection device 12 to allow unrestricted use of the injection device 12. Alternative embodiments of the injection device can be constructed without the safety element 80.

[0030]

[0059] In further embodiments, a sleeve 16 is housed within and mounted to the housing 14 and serves as a syringe support element. In some embodiments, the sleeve 16 is designed to hold and position a prefilled syringe 18, such as a BD Hypak™ prefilled syringe (Becton, Dickinson and Company), capsule or other container of a type known in the art. One example of a suitable prefilled syringe for use in the depicted embodiment is a prefilled syringe, such as Becton Dickinson Hypak™, available in a variety of sizes and volumes and sold prefilled with a medicine. In some embodiments, the glass of the syringe body can be glued to the needle. The use of a prefilled syringe facilitates the handling of the medicine when the injection device is assembled, and there is extensive knowledge of how the medicine holds and behaves in a prefilled syringe. In some embodiments, the sleeve 16 is substantially fixed to the housing 12, such as by snapping, adhesive, welding, or another known attachment. The pre-filled syringe 18 can have a reservoir portion 20 defining an internal fluid chamber 22 that is pre-filled with an injectable medication, such as a testosterone formulation. In other embodiments, the medication reservoir and chamber are provided by other structures, such as a housing, needle hub 32, or chamber that can be integral with or retained within, for example, other injection outlet portions of an injection device. At the distal end of the pre-filled syringe 18, an injection 2. The needle 24 has an injection tip 26 designed as known in the art to penetrate the patient's tissue, which in one embodiment is the skin. A needle lumen extends through the needle 24 as known in the art. The needle lumen is in fluid communication with the medicinal product in the fluid chamber 22 and is open at the needle tip 26 for injecting the medicinal product.

[0031]

[0060] At the proximal end of the fluid chamber 22 opposite the needle 24 is a plunger 28 that seals the medication in the fluid chamber 22. In some embodiments, the wall of the syringe includes a tubular portion that, in some embodiments, is closed at a distal end and open at a proximal end to define the fluid chamber 22. The plunger 28 is slidably received in the tubular portion. The prefilled syringe 18 is designed such that when the plunger 28 is moved distally, the volume of the fluid chamber 22 decreases, forcing the medication out of the chamber 22 and through the lumen of the needle 24. At the distal end of the fluid chamber 22 is a needle hub portion 32 to which the needle is attached. A syringe flange 35 extends radially from the proximal end of the wall of the syringe. In embodiments of the injection device that use a cartridge, capsule, or other container that defines a chamber for containing a pharmaceutical agent, the needle may be fluidly connected to the chamber in different ways, for example, by connecting directly to the cartridge, capsule, or other container, or by connecting to another part of the injection device, for example its housing, through a separate needle hub.

[0032]

[0061] In the embodiment depicted in FIG. 2, the pre-filled syringe 18 has a syringe body 36, in which the flange 35, the syringe wall, and the hub portion 32 are of unitary construction. In one embodiment, the material comprising the syringe body 36 is glass, but other materials, such as plastic or metal, can be used in other embodiments. In order to radially position the distal end of the pre-filled syringe 18, in one embodiment, the sleeve 16 has a narrowed lumen portion 51, which can be designed to be adjacent to the outside of the syringe wall. This is particularly advantageous when the needle is inserted into the patient's skin. The narrowed lumen portion 51 can be made of a resilient material, such as an elastomer, or it can be made integral with the remaining portion of the sleeve 16, for example, by a series of radially aligned resilient flexible fingers. Additionally, the proximal end of the syringe 18 can be held in place by a shock absorbing device 33, which in some embodiments is located radially proximally of the syringe body 36 and absorbs shock from the impact of the sudden firing of a ram 60, for example in jet injection device embodiments that generate increased pressure in the fluid chamber 22 or container 20.

[0033]

[0062] A trigger mechanism may also be housed within the housing 14. In some embodiments, the trigger mechanism includes an inner housing 54, which may be attached to the outer housing 14, for example, by snaps, adhesives, welding, or other known attachments. A trigger projection 56 extends inwardly from the proximal end of the inner housing 54 and is resiliently biased outwardly. The trigger projection 56 is received in a blocking association with a recess 58 of the ram 60 to prevent distal movement of the ram 60 prior to firing of the device. The ram 60 is moved toward the distal end of the injection device 10 by an energy source, which in some embodiments is a compression spring 52, although in other embodiments other suitable energy sources may be used, such as an elastomeric or compressed gas spring, or a gas generator. One example of a compression spring 52 suitable for use with the injection device of the present disclosure is a coil spring. Alternate embodiments may use other suitable trigger mechanisms as known in the art.

[0034]

[0063] In one aspect, the present invention relates to a method for the treatment of a disease caused by a fungal infection, comprising administering to a subject matter disclosed in U.S. Pat. This includes a cam and ram assembly as described in U.S. Patent Application Serial No. 13,184,229.

[0035]

[0064] A latch housing 64 can be provided externally to the inner housing 54 to hold the trigger projection 56 in a blocking relationship in the recess 58 to hold the ram 60 in a proximal position until firing is actuated. The latch 64 can slide axially inwardly of the outer housing 14 in some embodiments relative to the inner housing 54, and in some embodiments the latch 64 surrounds the inner housing 54. In some embodiments the latch 64 is free to move relative to the outer housing 14 and is secured in place by pressure exerted on it by the trigger projection 56 only after removal of the safety element 80. In some aspects there is nothing, including a spring or the like, biasing the latch housing 54 away from the proximal end of the outer housing 14. Alternative embodiments can use a medication container that is moved forward when the device is actuated to pierce the skin with the needle, and some embodiments use a trigger mechanism actuated by a button on another portion of the injection device, for example on the proximal end of the housing or on the side as known in the art.

[0036]

[0065] The housing 14 can have a needle guard 66 that is movable relative to the outer housing 14. In the embodiment of the needle guard 66 shown in FIG. 2, the needle guard 66 is in a protective position where the needle 24 is disposed within the guard 66. A ridge 65 (FIG. 8) abuts the inner surface of the outer housing 14 to maintain the needle guard 66 within the housing 14 when the needle guard 66 is fully extended to the protective position. The needle guard 66 can, in some embodiments, be retracted proximally into the outer housing 14 to an injection position where the needle tip 26 and the distal portion of the needle 24 are exposed for insertion into a patient, as shown in FIGS. 6B and 6C. In some embodiments, proximal movement of the guard 66 is prevented in the injection position.

[0037]

[0066] The needle guard 66 can be associated with the latch 64 such that as the guard 66 moves proximally it slides the latch 64 proximally to release the trigger projection 56 from the recess 58. In some embodiments, the latch 64 has a latch portion 68 adjacent the inner housing 54 in a biased relationship that maintains the trigger projection 58 in a blocking relationship with the ram 60 prior to firing of the injection device 12. In some embodiments, when the latch 64 slides proximally by retracting the guard 66 to an injecting position, the latch portion 68 slides past the portion of the inner housing 54 it contacts, bending the trigger projection 56 away from the recess 58 of the ram 60 and allowing the trigger projection 56 to move radially outwardly from the recess 58 and thus from the blocking relationship. When this occurs, the spring 52 biases the ram 60 against the plunger 28, firing the injection device 12.

[0038]

[0067] In certain embodiments, a cap 110 can be attachable onto the distal end of the injection device 12 to cover the needle guard 66 and prevent it from accidentally moving during shipping or handling prior to injection. The cap 110 can be attached to the distal end of the outer housing 14 by press fit, screw fit, or the like. In certain embodiments, the cap 110 can include a pair of inwardly extending projections 112 (FIG. 9) that form a distally facing ridge 114. In such embodiments, the needle guard 66 can be formed by a pair of radially extending flanges 67 (FIG. 8) that are designed to abut the distal ridges 114 of the projections 112 to secure the cap 110 to the injection device 12. In certain embodiments, an upper edge 116 (FIG. 9) of the cap 110 can abut the distal end of the outer housing 14 such that the distal ridges 114 of the projections 112 are held against the flanges 67. This arrangement of the cap 110 prevents the needle guard 66 from being in contact with the housing since the cap 110 is juxtaposed between the guard 66 and the housing. This prevents proximal compression of 66 into the housing and secures needle guard 66 in a protective position to help prevent accidental firing of the injection mechanism.

[0039]

[0068] In certain embodiments, the cap 110 can be removed from the injection device 12 by twisting the cap 110 with respect to the housing 14 such that the projection 112 is moved out of alignment with the flange 67, which allows the cap 110 to be moved distally away from the needle guard 66. To prevent accidental removal of the cap 110 from the injection device 12 due to unintentional twisting of the cap 110, in certain embodiments, the cap 110 engages the housing 14 and / or the needle guard 66 in a manner that initially requires increased force, e.g., requiring the cap 110 to snap away from its closed position before completing the rotation to remove the cap 110. For example, the top edge 116 of the cap 110 can be angled as shown in FIG. 9. The angle can include a curved portion as shown, but generally the edge 116 can have one edge 118 that is higher than the other edge 120. In certain embodiments, the distal end of outer housing 14 can have a profile that matches the profile of top edge 118 of cap 110. This arrangement requires flexing of cap 110 to allow for its twisting and increases the force required to twist cap 110 relative to needle guard 66. In alternative embodiments, cap 110 can have a threaded or cam-type relationship with flange 67 or another arrangement therewith such that cap 110 is removed by rotation.

[0040]

[0069] The cap 110 can be attached to the injection device 12 during its assembly. This can be done by properly aligning the cap 110 with respect to the needle guard 66 and twisting it while applying a proximal force thereto so that the projections 112 move behind the fringes 67. Alternatively, the flanges 67 can be configured to be capable of inward deflection by placing them on corresponding tabs 69 formed on the needle guard 66. In such an embodiment, the cap 110 can be assembled onto the needle guard 66 prior to assembly of the springs 72 therein, since the springs 72 may interfere with the inward deflection of the flanges 67. Alternatively, the cap 110 can be elastically deformable to allow the cap 110 to be pressed onto the needle guard 66 so that the projections 112 pass over the flanges 67.

[0041]

[0070] In some embodiments, the needle guard 66 can be resiliently biased distally to a protective position by a compression coil spring 72. The needle guard 66 can also have an axial opening 74 to allow the needle 24 to pass therethrough, which can be sized depending on the type of injection device desired. In some embodiments, the configuration of the injection device 12 allows the user to press the distal end of the injection device against the patient's skin and drive the needle 24 into the skin at the insertion position at substantially the same rate that the injection device is driven into the skin. Once the needle 24 is fully inserted at the insertion point to the desired penetration depth, the trigger mechanism fires, causing the injection device 12 to inject the medicinal product into the injection site.

[0042]

[0071] In certain embodiments, for example, relating to subcutaneous injections using a needle assisted jet injection device, the needle guard 66 can be designed to permit insertion of the needle 24 to a penetration depth in the skin, which is up to about 5 mm below the skin surface. In certain embodiments, the penetration depth is about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5.0 mm, about 5.5 mm, about 6 mm, about 6.5 mm, or any range that can be determined from the foregoing depths (e.g., about 0.5 mm to about 2.0 mm, or about 3.5 mm to about 5.5 mm). In other embodiments, the needle tip 26 is inserted into the needle guard 66 or the distal end of the needle guard 66 that contacts the skin. In some embodiments, the distance that needle tip 26 extends past the distal surface of needle guard 66 that contacts the needle guard 66 or the skin is about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5.0 mm, about 5.5 mm, about 6 mm, or any range that can be determined from the depths described above (e.g., about 0.5 mm to about 2.0 mm, or about 3.5 mm to about 5.5 mm).

[0043]

[0072] In another embodiment, for example relating to intramuscular injection using a needle assisted jet injection device, the injection device 12 can be designed to allow the needle 24 to be inserted into the patient to a depth of penetration into the skin or a distance of up to about 20 mm past the distal surface of the needle guard 66. In certain embodiments, the injection device 12 can be designed to allow the needle 24 to be inserted into the patient to a depth of penetration into the skin or a distance of up to about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5.0 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7.0 mm, about 7.5 mm, about 8.0 mm, about 8.5 mm, about 9.0 mm, about 9.5 mm, about 10.0 mm, about 10.5 mm, about 11.0 mm, about 11.5 mm, about 12.0 mm , about 12.5 mm, about 13.0 mm, about 13.5 mm, about 14.0 mm, about 14.5 mm, about 15.0 mm, about 15.5 mm, about 16.0 mm, about 16.5 mm, about 17.0 mm, about 17.5 mm, about 18.0 mm, about 18.5 mm, about 19.0 mm, about 19.5 mm, about 20.0 mm, or any range that can be determined from the depths described above (e.g., about 0.5 mm to about 20.0 mm or about 3.5 mm to about 15.5 mm). Other lengths of exposed needle 24 can be selected for jet injection to different depths below the skin with a total penetration length of about 0.5 mm to about 20 mm. In these embodiments, the needle guard 66 can be designed to retract from a protective position (which in some embodiments covers the entire needle) to an injection position where a desired length of the tip 26 of the needle 24 is exposed.

[0044]

[0073] In one embodiment, the injection device can include a collar surrounding the needle and defining a collar cavity, the collar having a peripheral and anterior skin-contacting surface surrounding it being discontinuous and radially spaced from the needle and injection site by an area large enough to allow the patient's skin to move into the collar cavity to pierce the patient for intradermal delivery of the substance to the injection site, allowing diffusion of the injected substance under the skin, while being appropriately positioned to prevent or prevent back pressure in the skin from pushing the substance through the injection site. An example of such an embodiment can be found in U.S. Patent No. 8,162,886, which is incorporated herein by reference.

[0045]

[0074] The safety element 80 can be removably attached to the distal end of the outer housing 14 and can include a body portion 84 and a pair of resiliently flexible legs extending therefrom (FIGS. 4A and 4B). The legs 82 extend into corresponding holes or slots 15 formed in the proximal surface of the outer housing 14 and can be shaped to provide a press fit within the slots 15 to retain the safety element 80 on the housing 14. The legs 82 can be outwardly biased and can further include tabs 86 disposed on their exterior surface for capturing the interior of the outer housing 14 at the slots 15 to facilitate retention of the safety element 80 on the outer housing 14. In some embodiments, the legs 82 are shaped to allow a user to remove the safety element 80 from the outer housing 14 when an injection is desired. However, in some embodiments, the legs 82 prevent the safety element 80 from becoming accidentally or unintentionally removed from its attachment to the outer housing 14.

[0046]

[0075] The legs 82 act to inhibit proximal thrust of the latch site 64 which will fire the injection mechanism. 1 and 2. The legs 82 abut the proximal-most surface of the latch portion 64 when properly attached to the outer housing 14 to impede or prevent jostling or other movement (FIG. 3). In certain embodiments, the legs 82 are designed such that the force required to move the latch portion 64 out of the slot 15 in conjunction with the housing 14 and the trigger mechanism of the injection device 12 is sufficient to prevent the latch portion 64 from being dislodged out of position due to vibrations from shipping or acute shock during shipping or handling caused by dropping the injection device 12. Alternative safety elements can be used to prevent unintentional firing of the injection device 12.

[0047]

[0076] In one embodiment in which the injection device 12 is designed as a needle-assisted jet injection device, the spring 72 and the pre-filled syringe 18 can be designed to jet inject a pharmaceutical agent, such as a testosterone formulation. Thus, the spring 72 exerts a force on the plunger 28 that can be sufficient to increase the pressure in the fluid chamber 22 to a level high enough to expel the pharmaceutical agent from the needle 24 as a fluid jet. In some embodiments, a jet injection is an injection of a pharmaceutical agent from the needle tip 26 of the injection device 12 with sufficient speed and force to drive the pharmaceutical agent away from the needle tip 26.

[0048]

[0077] Some jet injection device embodiments, whether needle assisted or needleless, have an energy source selected to generate high pressure in the medication chamber 22 to expel the medication with sufficient force and velocity to then exit the injection device 12 as a fluid jet. Jet injection devices are believed to rapidly deliver medication under the subject's skin over a larger surface area by essentially "spraying" the medication subcutaneously into the subject, thereby rapidly exposing a larger surface area of ​​the subject's target tissue to the medication.

[0049]

[0078] When delivered by an automatic injection device, the pharmaceutical agent is typically localized away from the automatic injection device because it is not shot far from the injection outlet, and therefore is delivered in a bolus near the tip of the needle of the automatic injection device. This is because the automatic injection device requires additional injection time to deliver the injection into a resistant medium, such as tissue, as opposed to delivery into air. In contrast, the embodiments of the powered injection device disclosed herein, and particularly the embodiments of the jet injection device disclosed herein, do not show a difference in injection time when injecting into a resistant medium versus air. Because the pharmaceutical agent delivered by the jet injection device is essentially sprayed rapidly away from the tip of the needle into the tissue of the subject, the pharmaceutical agent does not leave the jet injection device as a single droplet or bolus, and therefore is not delivered to the subject as a bolus localized to the tip of the needle. Thus, by using the jet injection device disclosed herein, the pharmaceutical agent can be more efficiently dispersed in the tissue of the subject. In addition, because the jet injection device delivers the pharmaceutical agent with high pressure and velocity, the delivered pharmaceutical agent has a much lower tendency to leak back from the injection site around the needle or injection tract. Thus, leakage back from the depth at which the pharmaceutical agent was delivered back towards the injection site and / or back to the surface of the subject's skin can be significantly reduced by the use of the jet injection device. Thus, when used to deliver one or more pharmaceutical agents according to the present disclosure, such as testosterone formulations, in addition to ensuring the delivery of the entire dose to the desired depth, the jet injection device significantly reduces the risk of exposure to the pharmaceutical agent outside the injection site, thereby reducing the risk of exposure to the pharmaceutical agent to non-users and to the subject himself. Preventing or reducing leakage back is advantageous in improving compliance by ensuring that the pharmaceutical agent remains at the injection site at the desired depth. This not only improves the effectiveness of delivery, but also avoids migration of the pharmaceutical agent from the injection site to other tissues, layers of tissue, and / or outside the injection site. Preventing or reducing leakage back can also be advantageous in keeping the pharmaceutical agent contained in a single area, thereby preventing unintentional exposure to the subject and / or others in his vicinity from leakage back to the surface of the skin. Such exposure can be, for example, due to the fact that the subject This can include direct contact with the medicinal product on the elephant's skin or from sprayed medicinal product, which may reach the subject or nearby people through the air or through another medium. In addition, in many cases, patients using slow injection manual hypodermic syringes or automatic injection devices run the risk of prematurely removing the manual injection device from the injection site before the shot is complete, leading to exposure of the medicinal product outside the patient's tissue.

[0050]

[0079] In certain embodiments, the injection device 12 is designed and the injection is performed in a manner that prevents or significantly reduces the risk and incidence of leakage back and undue exposure of the medication to air or to the outer surface of the patient's skin.

[0051]

[0080] In some embodiments of the needle-assisted jet injection device, a short needle can be used to inject a pharmaceutical agent into different parts of the skin, in some embodiments subcutaneously, without any backflow. With a needle 24 extending about 2.5 mm past the distal surface of the needle guard 66, a 27 gauge needle 24, and a pressure in the fluid chamber 22 that peaks at about 300 psi and ends at approximately 100 psi, resulting in a flow rate of about 0.5 mL / sec, 1 mL of pharmaceutical agent can be successfully injected without significant backflow in about 100% of the test injections, such as those shown in Table 3, where negligible or still measurable little wetness at the injection site was observed. Thus, the needle-assisted jet injection device of the present disclosure allows one or more pharmaceutical agents to be reliably jet injected with a very short needle, regardless of the patient's skin thickness, age, weight, or other factors.

[0052]

[0081] In certain embodiments, the selection of the type of spring as the power source, the adjustment of the force delivered by the spring, and / or the manner in which the spring is packed into the assembled injection device can result in a significant reduction in the length of time required to deliver a complete injection into a subject, a significant reduction in the spring force required to deliver an injection, and a longer shelf life. For example, springs present in many known automatic injection devices are designed so that a typical injection in the volume range of about 0.8 to about 1.5 ml is fully delivered into a subject in 10 to 15 seconds. Embodiments of the injection device of the present disclosure can have their springs designed to deliver a complete injection of about 0.8 to about 1.0 ml volume in about 1 to about 5 seconds, in some embodiments in about 2 to about 4 seconds, in some embodiments in about 3 seconds. It is believed that this reduction in time will increase patient compliance when embodiments of the automatic injection device of the present invention are used, since less time is required to deliver a complete injection and therefore the patient will experience less pain.

[0053]

[0082] Additionally, in certain embodiments, the spring material can be selected to only allow a drop in spring force over the stroke length of the injection as shown. Many known automatic injection devices exhibit a drop in spring force over the course of an injection of less than approximately 20%. In contrast, embodiments of the injection devices of the present disclosure can be designed such that their spring force drops by at least about 25% over the course of an injection, in some embodiments from about 25% to about 50% over the course of an injection, in some embodiments from about 30% to about 50% over the course of an injection, and in some embodiments about 50% over the course of an injection.

[0054]

[0083] The spring material can also be selected and / or the spring can be set in the injection device so as not to place the spring in an overly compressed state during packaging and shipping of the spring to the end user or patient. This is advantageous because a spring that is overly compressed for an extended period of time will become overstressed and exhibit loss of force over time. For example, many known autoinjectors are packaged such that they spend most of their shelf life with their springs in a compressed state. When packaged in this manner, Such known automatic injection devices experience a loss in spring force over time as the automatic injection device sits on a shelf waiting to be used. In contrast, embodiments of the injection device of the present disclosure can have a spring that is made of a material that is sufficiently elastic so that it loses less force over time as it is compressed, and / or can have a spring designed such that in the fully assembled injection device it is not in a fully compressed state until the time of injection. In this manner, embodiments of the injection device of the present disclosure lose about 0% to about 15% of their spring force over a typical shelf life. In some embodiments, the injection devices of the present disclosure lose about 10% to about 12% of their spring force over a three-year shelf life.

[0055]

[0084] In certain embodiments of the single shot injection device, the injection device 12 includes a disabling mechanism, e.g., a locking element, which can be provided as a locking ring 70 associated with the injection mechanism. As shown in Figs. 6A-6D, the locking ring 70 can be disposed between the sleeve 16 and the needle guard 66 and can interact with the sleeve 16 and the needle guard 66 such that the locking ring 70 only allows the needle guard 66 to move relative to the outer housing 14 through one injection cycle. This includes movement from a protective position (Fig. 6A) under the force of a compression spring 72 to an injecting position (Figs. 6B, 6C) and then back to the protective position (Fig. 6D). When the needle guard 16 returns to the protective position at the end of the injection cycle, the locking ring is disposed relative to the sleeve 16 and the needle guard 66 such that further movement therebetween is restricted, thus disabling the injection device from performing further injections and safely retaining the needle 24 within the housing 14 of the injection device 12.

[0056]

[0085] As shown in Figures 6A-6D, movement of needle guard 66 through one locking cycle moves locking ring 70 from an injecting position to a locked position relative to sleeve 16. In the injecting position, locking ring 70 is positioned such that upper arm 71 of locking ring 70 captures a portion of the device associated with drug chamber 22, e.g., a proximal notch 92 formed in the exterior surface of sleeve 16. Engagement of upper arm 71 in proximal notch 92 releasably maintains locking ring 70 in the injecting position. As shown in Figure 7, locking ring 70 can be generally annular in shape to surround drug chamber 22, e.g., directly or indirectly (either) by surrounding sleeve 16. Locking ring 70 further includes a pair of lower arms 73, each having a tab 74 formed on an end thereof. When the locking ring 70 is in the injecting position, the tabs 74 are received in slots 95 formed in the needle guard 66 such that the needle guard 66 can slide a predetermined distance past the locking ring 70. As the needle guard 66 moves to the injecting position relative to the outer housing 14, the needle guard 66 slides past the locking ring 70 such that the tabs 74 reach the end of the slots 95 and are depressed inwardly, allowing the needle guard 66 to continue moving to the injecting position. Upon reaching the injecting position, the tabs 74 align with the holes 96 in the needle guard 66, allowing the lower arms 73 to return to their natural position where the upper surfaces of the tabs 74 capture the edges of the holes 96, thereby coupling the locking ring 70 to the needle guard 66.

[0057]

[0086] As the needle guard 66 returns to the protecting position, it pulls distally on the locking ring 70, causing the upper arm 71 to disengage from the proximal notch 92. In some embodiments, the upper arm 71 and proximal notch 92 are formed by mating sloped surfaces such that the sloped surface of the upper arm 71 captures another portion of the injection device 12 associated with the medication chamber 22, for example by extending into the proximal notch 92, but is pushed outward by distal movement therewith. This design allows the needle guard 66 to move the locking ring 70 with it out of the injecting position as the needle guard 66 moves distally toward the protecting position beyond the sleeve 16, which remains stationary.

[0058]

[0087] When the needle guard 66 reaches the protective position, the upper arm 71 moves over the distal notch 93 formed in the sleeve 16 such that the upper surface of the upper arm 71 captures the upper surface 94 of the distal notch 93. Furthermore, in such position, the flange 77 of the locking ring 70 abuts the surface 67 of the needle guard to impede distal movement of the needle guard 66 relative to the locking ring 70. This fit prevents the locking ring 70 from moving proximally relative to the sleeve 16. Because the locking ring 70 is coupled to the needle guard 66 in this design, and because the sleeve 16 is attached to the outer housing 14, the needle guard 66 is locked relative to the outer housing 14 and prevented from moving back to the injecting position. This prevents the needle 24 from accidentally becoming exposed after use of the injection device 12. Alternative embodiments may use other mechanisms to prevent reuse of the injection device or portions thereof. Some embodiments do not use such mechanisms so that the injection device can be reused. In some embodiments, after injection of a medicinal product, subsequent injections can be automatically prevented, and exposure to or contact with medicinal product residue that may remain on parts of the injection device after injection, such as on the tip of the needle or the jet injection nozzle, can also be prevented or avoided by the structure of the injection device 12.

[0059]

[0088] 11, the distal end of one embodiment of a needle-free jet injection device is shown. The depicted injection device can use the systems disclosed herein to fire an injection as described above with respect to the needle-based injection device embodiments, but instead of a needle, a jet nozzle 202 is used to inject the medicament into the subject. The nozzle 202 defines a jet outlet 204 having a diameter selected to cause the medicament 200 to exit the nozzle 202 as a fluid jet that is strong enough to penetrate the outer skin layer and continue to the desired injection depth.

[0060]

[0089] In some embodiments, the injection device can have one or more indicators that the injection of the medicine is complete. In one embodiment, the injection device can have one or more indicators that the injection of the medicine is in progress. In one embodiment, one or more indicators that independently and distinctly indicate that the injection is in progress and that the injection is complete. In one embodiment, the first indicator is different from the second indicator. The indicators can include, but are not limited to, an audible indicator, a tactile indicator (e.g., a click or vibration), a visual indicator, a physical indicator, an electronic indicator, or a chemical indicator.

[0061]

[0090] Table 1 shows the results of a study comparing the leakback of medication that reached the surface of a subject's skin after injection; data is shown for a needle-assisted jet injection device compared to a hand-actuated hypodermic syringe. The total number of injections for each group in the study was 126, all administered by trained healthcare professionals.

[0062] [Table 1]

[0063]

[0091] Jet injection devices deliver medicines rapidly, in some embodiments in less than about 2 seconds, so the length of time that patients must hold the injection device against their tissues is dramatically reduced compared to injections delivered by typical syringes or automatic injection devices.Therefore, it is believed that the use of jet injection devices according to the present disclosure will result in increased patient compliance and adherence to instructions, and thus will result in an increase in the injected dose that is correctly administered.In addition, the speed at which jet injection devices deliver medicines may further increase patient compliance with regular injections, as the amount of pain experienced by patients who self-inject medicines is believed to be minimal, and in many cases may be nonexistent.

[0064]

[0092] In one embodiment, devices and methods for administering a viscous pharmaceutical formulation to a subject are included herein. In one embodiment, a method for administering a viscous pharmaceutical formulation to a subject includes formulating the pharmaceutical formulation in the form of a solution or suspension having a viscosity of about 25-2500 cps, providing the formulation in an injection device that includes a needle having a length of less than about 10 mm or is needle-free; and administering the formulation from the injection device into the subject by jet injection through an opening having a diameter of at least about 0.2 mm. In certain embodiments, the viscosity referred to herein can be a dynamic viscosity that can be measured by a Brookfield viscometer. In other embodiments, the viscosity referred to herein can be a kinematic viscosity determined by using a capillary viscometer, where a fixed amount of fluid passes through a small opening under the influence of gravity at a controlled temperature. In certain embodiments, the viscosity is measured at 20° C. In other embodiments, the viscosity is measured at 25° C.

[0065]

[0093] In other embodiments, the injectable carrier containing an amount of testosterone suspended or dissolved therein has a viscosity at room temperature (e.g., 20-25° C.) of 25-300 cps. In certain embodiments, the viscosity is 90-120 cps, and in other embodiments, the viscosity is about 110 cps. In other embodiments, the viscosity is greater than or equal to about 70 cps.

[0066]

[0094] In certain embodiments, the carrier is coconut oil, soybean oil, sesame oil, castor oil. Other oils include the following oils: arachis (peanut) oil, castor oil, cottonseed oil, ethyl oleate, polyoxyethylated castor oil (HCO-60, polyoxyl 60 hydrogenated castor oil, Cremophor® EL), safflower oil, and soybean oil.

[0067]

[0095] In one embodiment, the formulation comprises a pharma- ceutical suitable oil and is administered from an injection device at a pressure greater than about 50 psi, hi one embodiment, the oil is sesame oil.

[0096] In one embodiment, the injection device has an injection needle with a caliber of about 0.3 mm or about 0.5 mm.

[0068]

[0097] With reference to the graph shown in FIG. 10, numeral 132 represents the time when one embodiment of the injection device 12 is fired, and numeral 134 represents the time when the injection is completed. In one embodiment, the injection is completed when the plunger 28 hits the distal wall of the medication container 20. Numeral 136 represents the initial and peak pressure during the injection, and numeral 130 represents the final pressure during the injection. In one embodiment, the spring 72 has a linear spring constant, and the needle 24, which assists the injection, is used to pierce the skin before starting the injection. Thus, the pressure of the injection drops substantially linearly from the start of the injection 132 to the completion of the injection 134. The final pressure 130 at the end of the injection 134 is sufficiently elevated such that even at the end of the firing stroke of the ram 60, the medication is still being jet-injected, and only a very small amount of medication is bolused around the needle tip 26, or no medication is bolused at all.

[0069]

[0098] In certain embodiments of the needle assisted jet injection device, the peak pressure 136 during injection is less than about 1,000 psi, in some embodiments less than 950 psi, in some embodiments less than 900 psi, in some embodiments less than 850 psi, in some embodiments less than 800 psi, in some embodiments less than 750 psi, in some embodiments less than 700 psi, in some embodiments less than 650 psi, in some embodiments less than 600 psi, in some embodiments less than 550 psi, in some embodiments less than 500 psi, in some embodiments less than 450 psi, in some embodiments less than 400 psi, and in some embodiments less than about 350 psi. In some embodiments, the pressure 130 exerted on the pharmaceutical agent in the fluid chamber 22 at the end of injection 1080 can be at least about 80 psi, in some embodiments at least about 90 psi, in some embodiments at least about 100 psi, in some embodiments at least about 150 psi, in some embodiments at least about 200 psi, in some embodiments at least about 250 psi, in some embodiments at least about 300 psi, in some embodiments at least about 350 psi, in some embodiments at least about 400 psi, in some embodiments at least about 450 psi, and in some embodiments at least about 500 psi. In some embodiments, the initial pressure 136 can be about 330 psi and the final pressure 130 is about 180 psi. In some embodiments, the initial pressure 136 is about 300 psi and drops to approximately 60 psi at the end of injection 134. Other injection rates are used with respect to other embodiments discussed herein. For example, needleless jet injection devices can exert injection pressures in the range of about 4,000 psi or greater. Other embodiments of jet injection devices utilize lower injection pressures, such as at least about 80 psi or at least about 60 psi. In contrast, known automatic injection devices typically use pressures below 60 psi.

[0070]

[0099] The needles used in some embodiments of both the autoinjector and needle-assisted jet injection devices are 26-28 gauge, and in some embodiments, approximately 27 gauge. Other needle gauges can also be used if other components, including, for example, mini-needles, are cooperatively designed to provide the desired injection. In some embodiments, the components of the injection device 12 can be designed to jet inject one or more pharmaceutical agents into a subcutaneous injection site.

[0071]

[0100] At about room temperature, the needle-assisted jet injection device embodiments described herein In devices having a gauge needle as described in, the injection rate is less than about 0.75 mL / sec, in some embodiments less than about 0.6 mL / sec, in some embodiments at least about 0.2 mL / sec, in some embodiments at least about 0.3 mL / sec, and in some embodiments at least about 0.4 mL / sec. In some embodiments, the injection rate is selected from less than about 0.75 mL / sec, less than about 0.7 mL / sec, less than about 0.65 mL / sec, less than about 0.6 mL / sec, less than about 0.55 mL / sec, less than about 0.5 mL / sec, less than about 0.45 mL / sec, less than about 0.4 mL / sec, less than about 0.35 mL / sec, less than about 0.3 mL / sec, and less than about 0.25 mL / sec. In certain embodiments, the injection rate is about 0.05 mL / sec, about 0.1 mL / sec, about 0.15 mL / sec, about 0.20 mL / sec, about 0.25 mL / sec, about 0.30 mL / sec, about 0.35 mL / sec, about 0.40 mL / sec, about 0.45 mL / sec, about 0.50 mL / sec, about 0.55 mL / sec, about 0.60 mL / sec, about 0.65 mL / sec, about 0.70 mL / sec, about 0.75 mL / sec, about 0.80 mL / sec, about 0.85 mL / sec, about 0.90 mL / sec, or any range that can be determined from the above injection rates (e.g., about 0.05 mL / sec to about 1.5 mL / sec or about 0.70 mL / sec to about .75 mL / sec). In embodiments of the needle-assisted jet injection device, the injection rate is at least about 0.2 mL / sec, at least about 0.25 mL / sec, at least about 0.3 mL / sec, at least about 0.35 mL / sec, mL / sec, at least about 0.4 mL / sec, at least about 0.45 mL / sec, at least about 0.5 mL / sec, at least about 0.55 mL / sec, at least about 0.6 mL / sec, at least about 0.65 mL / sec, and at least about 0.7 mL / sec.

[0072]

[0101] In some embodiments, the injection of the entire amount of the pharmaceutical agent is in less than about 15 seconds. In some embodiments, the reaction is completed in less than about 12 seconds, in some embodiments less than about 11.5 seconds, in some embodiments less than about 11.0 seconds, in some embodiments less than about 10.5 seconds, in some embodiments less than about 10.0 seconds, in some embodiments less than about 9.5 seconds, in some embodiments less than about 9.0 seconds, in some embodiments less than about 8.5 seconds, in some embodiments less than about 8.0 seconds, in some embodiments less than about 7.5 seconds, in some embodiments less than about 7.0 seconds, in some embodiments less than about 6.5 seconds, in some embodiments less than about 6.0 seconds, in some embodiments less than about 5.5 seconds, in some embodiments less than about 5.0 seconds, in some embodiments less than about 4.5 seconds, in some embodiments less than about 4 seconds, in some embodiments less than about 3.5 seconds, in some embodiments less than about 3 seconds, in some embodiments less than about 2.5 seconds, in some embodiments less than about 2 seconds, and in some embodiments less than about 1.5 seconds. In certain embodiments, the injection of the pharmaceutical agent takes a time of at least about 1.0 seconds, about 1.5 seconds, about 2.0 seconds, about 2.5 seconds, about 3.0 seconds, about 3.5 seconds, about 4.0 seconds, about 4.5 seconds, about 5.0 seconds, about 5.5 seconds, about 6.0 seconds, about 6.5 seconds, about 7.0 seconds, about 7.5 seconds, about 8.0 seconds, about 8.5 seconds, about 9.0 seconds, about 9.5 seconds, about 10.0 seconds, about 10.5 seconds, about 11.0 seconds, about 11.5 seconds, about 12.0 seconds, or any range determinable from the foregoing times (e.g., from about 3.0 seconds to about 8 seconds or from about 10 seconds to about 12 seconds).

[0073]

[0102] In some embodiments, the injection of the pharmaceutical agent is performed at about 0.1 mL / sec, and the injection rate is about 1 mL. The injection is completed in about 10 seconds, however, other injection rates are possible with alternative embodiments of the injection device 12 disclosed herein. For example, in some embodiments, the injection device 12 can be designed to deliver a flow rate typical for a needleless jet injection, which can be about 1.5 mL / sec, and in some embodiments, the injection device 12 can be designed to deliver a flow rate typical for an automatic injection device, which can be about 0.5 mL in 0.3 seconds.

[0074]

[0103] The injection rate may vary depending on factors such as the gauge of the needle used to inject the drug, the dosage of the drug, The viscosity of the tissue itself may be affected by the sliding force of the plunger 28 in the barrel of the syringe, the temperature of the pharmaceutical agent to be injected, and the temperature of the room in which the injection is administered (as temperature can have a direct effect on viscosity). In various embodiments, tissue resistance does not affect the rate of injection that the embodiments of the injection device of the present disclosure can achieve. In various aspects, these parameters can be selected and optimized to deliver a certain amount of injection in a desired manner. Such selection and optimization can be readily performed by one of ordinary skill in the art without undue experimentation.

[0075]

[0104] In one embodiment, the injection device comprises a testosterone composition contained therein. The object can have the ability to heat and thereby reduce the viscosity, thereby shortening the injection time of the composition contained therein. In one embodiment, the heating device is an integral part of the injection device. In one embodiment, the heating device is external to the injection device. In one embodiment, the heating device has a control device that senses the optimal temperature. In one embodiment, the injection device has one heating device. In one embodiment, the injection device has more than one heating device. Non-limiting examples of heating methods and / or devices include electrical, chemical, and exothermic sources.

[0076]

[0105] In one embodiment, the heating mechanism heats the pharmaceutical agent contained within the injection device to room temperature. In one embodiment, the heating device heats the pharmaceutical agent contained within the injection device to a temperature of about 5° C. above room temperature, or about 10 to about 15° C. above room temperature (e.g., 20 to 25° C.). 5, about 20, about 25, about 30, about 35, about 40, about 45, or about 50° C. In one embodiment, the heating mechanism is an electrical, chemical, or mechanical heating mechanism. In another embodiment, the mechanism or method of use includes placing the device proximal to a heat source (e.g., under a person's arm).

[0077]

[0106] In one embodiment, the heating device or mechanism further comprises: In one embodiment, the heating device includes at least one indicia that the device is in an activated state, is in an inactivated state, and / or is at a desired temperature. In one embodiment, the heating device has one or more indicia that indicate to a user that the device has reached a temperature suitable for dispensing medication from the device. In one embodiment, the indicator is a visual indicator. In one embodiment, the indicator is an audible or tactile indicator.

[0078]

[0107] In some embodiments, the administration of viscous liquid that would otherwise require longer injection times is A pharmaceutical agent of a high viscosity can still be injected into a subject at the rates described above by changing the gauge of the needle. For example, in some embodiments, a 26 gauge needle can be utilized with the needle-assisted injection device of the present disclosure to inject various substances, in some embodiments, a 27 gauge needle can be utilized with the needle-assisted injection device of the present disclosure to inject various substances, and in some embodiments, a 28 gauge needle can be utilized with the needle-assisted injection device of the present disclosure to inject various substances. In each of the above embodiments, the rate of injection is the same as the rate disclosed above. Thus, the rate of injection can be maintained by changing the gauge of the needle according to the viscosity of the pharmaceutical agent to be injected. In some embodiments, a 27 gauge needle can be utilized with one or more embodiments of the injection device of the present disclosure to deliver 1.0 ml of aqueous solution into air in a period of about 1.0 to about 2.0 seconds, in some embodiments, in a period of about 1.5 to about 2.0 seconds, and in some embodiments, in about 1.7 seconds. In some embodiments, a 27 gauge needle can be utilized with one or more embodiments of the injection device of the present disclosure to deliver 1.0 ml of an aqueous solution into tissue over a period of about 1.0 to about 2.0 seconds, in some embodiments, about 1.3 to about 2.0 seconds, in some embodiments, about 1.5 seconds, and in some embodiments, about 1.3 seconds. In some embodiments, a 27 gauge needle can be utilized with one or more embodiments of the injection device of the present disclosure to deliver 1.0 ml of a viscous solution having a viscosity equivalent to 10% w / w polyethylene glycol 20,000 in water into air over a period of about 1.0 to about 5.0 seconds, in some embodiments, about 2.5 to about 5.0 seconds, in some embodiments, about 4.3 seconds, and in some embodiments, about 4.0 seconds. In some embodiments, a 27 gauge needle can be utilized with one or more embodiments of the injection device of the present disclosure to deliver 1.0 ml of a viscous solution having a viscosity equivalent to 20% w / w polyethylene glycol 20,000 in water into air over a period of about 10 to about 15 seconds, in some embodiments from about 12 to about 15 seconds, and in some embodiments, about 14 seconds.

[0079]

[0108] The cgs physical unit for mechanical viscosity is the poise (P), which is It is generally expressed as centipoise (cP) in ASTM standards. Typically, an aqueous solution at 20°C has a viscosity of approximately 1 cP. In some embodiments, the injection device of the present disclosure can be designed to provide a flow rate or injection rate through a 27-gauge needle of 0.5 ml / sec for an aqueous solution having a cP of 1.0 or close to it. In some embodiments, the injection device of the present disclosure can be designed to provide a flow rate or injection rate through a 27-gauge needle into the skin of 0.5 ml / sec for an aqueous solution having a cP of 1.0 or close to it.

[0080]

[0109] U.S. Patent No. 6,391,003 describes a method for scanning glass with 26 and 27 gauge needles. Table 2 discloses experimental results of the pressure that can be successfully applied to the medicine in the cartridge using a needle-assisted jet injection device (specifically a glass pre-filled syringe). FIG. 1 illustrates a typical injection with different peak pressures that can be used with the injection:

[0081] [Table 2]

[0082]

[0110] Alternative embodiments may use higher or lower injection pressures. For example, a needle-free injection device may use higher pressure to penetrate the skin without a needle, while an automatic injection device will typically use lower pressure to mimic a manual syringe injection.

[0083]

[0111] II. Other injection devices

[0112] In one or more alternative embodiments, the present disclosure provides a pharmaceutical product comprising testosterone (e.g. The present invention relates to an automatic injection device for dispensing a predetermined dose of a pharmaceutical composition (e.g., preservative-free), which includes a housing that is preferably oval or elliptical in shape so that it is more ergonomic. In these alternative embodiments, U.S. Patent Nos. 7,449,012 and 7,794,432 are incorporated herein by reference in their entirety. The oval shape prevents the automatic injection device from rolling off a desk or flat surface while providing a larger surface area for printing instructions to the user. A cartridge receptacle is disposed within the housing. A cartridge is received within the cartridge receptacle. The cartridge has at least one opening therein and contains a pharmaceutical composition. The pharmaceutical composition is trapped rearwardly by a plunger. The cartridge includes a needle assembly for dispensing the pharmaceutical composition therethrough. The cartridge is advanced from a stored position within the cartridge receptacle to an actuated position where a needle extends from the cartridge receptacle so that a dose of the pharmaceutical composition can be administered. A power assembly or power pack provides a stored energy source that can be released to drive a plunger in the cartridge to dispense medicinal drug through the needle assembly and into the user, making the needle accessible upon activation.

[0084]

[0113] Another aspect of the automatic injection device of the alternative embodiment is a needle cover received within the housing. The needle cover provides sharps protection by protecting the user from unintentional exposure to the needle after use of the automatic injection device. In theory, activation of the needle cover is a safety device since the cover will not deploy until after the needle pierces the user. During activation, the needle of the cartridge extends through an opening in the needle cover to allow for the dispensing of a dose of medication. After use of the automatic injection device, the needle cover is held in a locked position to prevent the cover from retracting and exposing the needle. According to another aspect of the alternative embodiment, the needle cover has a locked retracted position prior to activation of the automatic injection device, thus maintaining the compact shape of the device prior to use. According to another aspect of the alternative embodiment, the operating forces associated with the automatic injection device are not transmitted to the needle cover.

[0085]

[0114] According to another aspect of the alternative embodiment, the automatic injection device includes a needle cover in a first locked position. The cartridge receptacle has a first locking assembly that holds the needle cover in place. The first locking assembly can be disposed on the cartridge receptacle. The first locking assembly can include at least one locking tooth pivotally connected to the cartridge receptacle or the needle cover. Each locking tooth releasably captures the needle cover and includes a locking surface configured and arranged to contact a surface on the needle cover or the cartridge receptacle. Each locking tooth can be formed as a separate component connected to the receptacle or cover. It is contemplated that the locking tooth can be formed as an integral part of the needle cover or cartridge. A spring force of the locking tooth biases the locking surface into contact with the needle cover. The spring force can be provided by a spring portion of the locking tooth. The spring force can also be provided by a separate spring assembly that biases the locking surface into contact with the needle cover. Each locking tooth is preferably pivotally connected to the cartridge receptacle. Each locking tooth pivots in response to movement of the cartridge within the cartridge receptacle. It is also contemplated that the locking teeth may pivot in response to movement of the collet or power pack. Typically, the locking surfaces pivot out of contact with the needle cover as the locking teeth pivot in response to movement of the cartridge. The spring force on the cartridge and the forces exerted by the locking teeth are controlled such that they negligibly or minimally impede movement of the cartridge during an injection operation to avoid any premature rupture of the septum within the cartridge and premature administration of medication.

[0086]

[0115] In one aspect of the alternative embodiment, the needle cover includes a first locking assembly. The needle cover is spring biased to bias outwardly from the housing to cover the exposed needle after the needle cover is released. According to another aspect of the alternative embodiment, the automatic injection device has a second locking assembly that holds the needle cover in the second locked position. The second locking assembly can be disposed on the cartridge receptacle, the outer body, or the cover element. The second locking assembly can include at least one locking arm or wing, preferably connected to the cartridge receptacle. Each locking arm is spaced apart from the cartridge receptacle such that the locking arm can be temporarily compressed against the cartridge receptacle as the needle cover moves from the first locked position to the second locked position. Each locking arm has a locking surface for capturing the needle cover when the needle cover is in the locked, extended position. Each locking arm has a thick strut portion and a thin strut portion, where the thick strut portion is bent outward and the thin strut portion is bent inward. This structure maintains the locking arms in a normal, uncompressed state to reduce stress on the cartridge receptacle. This also allows for smooth deployment of the cover element. Furthermore, this arrangement ensures that the thick strut portion will flex into a stable state. This creates a stronger lock to prevent the cover element from moving backwards into the retracted position. The inwardly curved nature of the thin strut portion allows the thick portion to flex into a stable state in a controlled manner. Additionally, the outwardly curved shape of the thick strut portion provides a fail-safe lock in the extended position of the cover element. In the event that the thin strut breaks, the thick strut portion will still capture the cover element and maintain it in the extended, locked position.

[0087]

[0116] The cartridge container of the alternative embodiment further includes a small The housing may include at least one protrusion. Each protrusion is constructed and arranged to capture an edge of an opening in the needle cover when the needle cover is in the extended position to limit movement of the needle cover relative to the cartridge receptacle. When the protrusions on the cartridge receptacle capture an edge of the opening, outward movement of the needle cover is limited. The second locking assembly limits inward movement of the needle cover. The needle cover and cartridge receptacle include openings formed therein. When the openings are aligned prior to activation of the automatic injection device, a user can view the contents of the cartridge through the housing and the openings. The housing is transparent. Or it can be opaque. If opaque, the housing can include an opening that can align with the opening in the needle cover and cartridge container so that the color of the medication can be checked to determine if the medication is suitable for injection. If the medication has changed color, the user will know that the medication should not be administered. If the opening does not align after activation of the automatic injection device, the user will no longer be able to see the contents of the cartridge through the opening, which provides a visual indication to the user that the automatic injection device is being used.

[0088]

[0117] Another aspect of the alternative embodiment is the structure and operation of the operating assembly or power pack. and an arrangement that is mounted within the housing adjacent the open end. A release pin or safety pin is removably attached to the operating assembly to prevent unintentional actuation of the automatic injection device when the release pin is in place. A pin or stem on the release pin is received within an opening in the operating assembly to prevent actuation of the automatic injection device. This opening in the power pack is spaced from the open end of the housing such that the opening is unlikely to be visible to a user prior to administration of a medication. This arrangement is provided to prevent a user from pointing the wrong end of the automatic injection device towards the user's injection surface. The power pack is recessed or spaced from the end of the housing, which provides an indication to the user that pressing the power pack will not activate the automatic injection device. The recessed nature of the power pack serves to hide the hole of the release pin in the power pack when the user is looking at the instructions on the outer body such that the user does not mistake the hole of the release pin for the opening through which the needle passes to administer the medication. The release pin includes at least one tab extending therefrom. The tabs compressively fit into complementary recesses formed in the operating assembly to prevent inadvertent removal of the release pin. The tabs also prevent the release pin from rotating so that a user will easily recognize that the release pin must be pulled to be removed.

[0089]

[0118] The operating assembly of the alternative embodiment includes an outer body that captures the release pin. The cartridge is designed to be inserted into the housing. The outer body is configured to connect to the housing. The inner body is operatively coupled to the outer body. At least one retention tab on the inner body secures the inner body to the outer body. The inner body is capable of limited movement relative to the outer body. The collet is operatively coupled to the inner body. An energy source is operatively connected to the inner body and the collet. Unlike conventional collets, the collet in the present invention is molded as a single piece. No spacers or other components are provided between the collet and the plunger in the cartridge. This arrangement simplifies the construction of alternative embodiments. Different sized collets can be manufactured and installed in the operating assembly so that only the collet needs to be changed when a different sized cartridge is used or a different sized dose of pharmaceutical drug is to be administered.

[0090]

[0119] III. Pharmaceutical Compositions

[0120] In certain embodiments, the pharmaceutical agent of the present invention is any drug that contains testosterone. The drug may be a substance that can be useful alone or in combination with other embodiments and / or devices encompassed herein. In one embodiment, the drug is testosterone.

[0091]

[0121] In one embodiment, the testosterone formulations encompassed herein comprise at least At least one type of preservative, particularly a pharma- ceutical acceptable preservative, more particularly a preservative suitable for one or more of intramuscular, subdermal, and subcutaneous administration. Suitable preservatives include, but are not limited to, antimicrobial agents, halogenated alcohols, parabens, and phenylmercuric salts. Non-limiting examples of preservatives include phenol, meta-cresol, benzyl alcohol, methyl These include propylparaben, propylparaben, butylparaben, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric borate, and phenylmercuric nitrate.

[0092]

[0122] In one embodiment, the testosterone formulations encompassed herein contain no preservatives. It is free or preservative-free, particularly free of the preservatives mentioned above. In one embodiment, the preservative-free testosterone formulation encompassed herein comprises testosterone enanthate. In one embodiment, the preservative-free testosterone formulation is a unit dose of testosterone or a pharma- ceutically acceptable ester or salt thereof in a pharma-ceutically acceptable carrier. In one embodiment, the preservative-free testosterone formulation is at least a multiple of two unit doses of testosterone or a pharma-ceutically acceptable ester or salt thereof in a pharma-ceutically acceptable carrier. In yet another embodiment, the composition is free or substantially free of precipitates (e.g., precipitates of testosterone enanthate or testosterone cypionate).

[0093]

[0123] In one embodiment, the testosterone formulation (e.g., preservative-free) comprises at least In yet another embodiment, the testosterone formulation (e.g., preservative-free) comprises testosterone in oil. In one embodiment, the testosterone formulation (e.g., preservative-free) comprises testosterone in sesame oil.

[0094]

[0124] In one embodiment, the testosterone in the compositions encompassed herein is present in an amount selected from: about 5 mg, about 10 mg, about 15, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 99 mg, less than 99 mg, about 100 mg, less than 100 mg, about 105 mg , about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 1 65mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220m g, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, About 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 33 5 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg of the pharmaceutical agent, or any range that can be determined from the above dosage amounts (e.g., about 75 mg to about 150 mg or about 100 mg to about 200 mg). In another embodiment, the testosterone is present in an amount greater than about 5 mg.

[0095]

[0125] As will be appreciated by those of skill in the art, the testosterone-containing The amount of testosterone can be contained in an appropriate volume of fluid (e.g., a suitable carrier or oil) based, among other things, on the method of administration and / or device used for administration, the desired testosterone concentration, etc. In one embodiment, the amount of pharmaceutical agent contained in fluid chamber 22 and injected therefrom can be from about 0.02 mL to about 4 mL, and in some embodiments, less than about 3 mL. In other embodiments, the amount of pharmaceutical agent contained in the fluid chamber 22 and injected therefrom is about 0.02 mL, about 0.04 mL, about 0.06 mL, about 0.08 mL, about 0.5 mL, about 1.00 mL, about 1.02 mL, about 1.04 mL, about 1.06 mL, about 1.08 mL, about 2.00 mL, about 2.02 mL, about 2.04 mL, about 2.06 mL, about 2.08 mL, about 3.00 mL, about 3.02 mL, about 3.04 mL, about 3.06 mL, about 3.08 mL, about 4.00 mL, about 4.02 mL, about 4.04 mL, about 4.0 The volume can be about 6 mL, about 4.08 mL, about 5.00 mL, or any range that can be determined from the above volumes (e.g., about 0.04 mL to about 5.00 mL or about 1.04 mL to about 3.02 mL). Larger volumes can also be selected depending on the particular drug(s) utilized and the dosage required. In some embodiments, for example, see FIG. 6A, a prefilled syringe 18 containing a desired amount of drug is assembled into the remainder of the injection device 12. In some embodiments, the prefilled syringe 18 contains about 0.02 mL to about 4.00 mL of a fluid containing a drug. In some embodiments, the prefilled syringe 18 contains one or more pharmaceuticals of about 0.02 mL, about 0.04 mL, about 0.06 mL, about 0.08 mL, about 1.00 mL, about 1.02 mL, about 1.04 mL, about 1.06 mL, about 1.08 mL, about 2.00 mL, about 2.02 mL, about 2.04 mL, about 2.06 mL, about 2.08 mL, about 3.00 mL, about 3.02 mL, about 3.04 mL, about 3.06 mL, about 3.08 mL, about 4.00 mL, about 4.02 mL, about 4.04 mL, about 4.06 mL, about 4.08 mL, about 5.00 mL, or any range that can be determined from the volumes described above (e.g., about 0.04 mL to about 5.00 mL or about 1.04 mL to about 3.02 mL).

[0096]

[0126] In some embodiments, the carrier device (e.g., an ampoule or a prefilled The concentration of testosterone (in the ludo syringe) can be about 50 mg / ml, about 75 mg / ml, about 100 mg / ml, about 125 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, about 225 mg / ml, about 250 mg / ml, or any range that can be determined from the above concentrations (e.g., about 50 mg / ml to about 100 mg / ml or about 75 mg / ml to about 225 mg / ml).

[0097]

[0127] In one embodiment, an ester form of testosterone is used. In this regard, the testosterone formulations encompassed herein include testosterone enanthate and / or testosterone cypionate, which are collectively referred to herein as "testosterone." It is understood that alternative compounds that contain a testosterone moiety are within the scope of the term "testosterone," including active metabolites of testosterone.

[0098]

[0128] In one embodiment, the testosterone formulation encompassed herein is one in which it is A fine gauge needle, such as can be administered through the methods and devices for administration contained herein and / or described in detail elsewhere herein. A non-limiting example of a fine gauge needle is a 27 gauge needle. However, other examples of fine gauge needles are described in detail elsewhere herein. In one embodiment, the testosterone formulations contained herein, when administered in combination with the devices contained herein, can be administered with sufficient force to smoothly overcome resistance and flow through the body or needle of the syringe. Methods for determining and optimizing the flow rate of injection of pharmaceuticals are also described in detail elsewhere herein.

[0099]

[0129] IV. Method of Treatment

[0130] The present disclosure relates, in part, to a method for treating hypogonadism, reduced infertility, lack of libido or erectile dysfunction. The present invention provides methods, devices, and compositions for treating osteoporosis, osteoporosis, and anemia, methods for supporting penis enlargement and height growth, and methods for stimulating bone marrow and appetite.

[0100]

[0131] The concentration of testosterone in the bloodstream of a subject is determined by the amount of testosterone in the composition administered to the subject. The amount of tosterone administered will depend on the route of administration and the particular formulation used.

[0132] In one embodiment, the subject is treated with a single dose of the compositions encompassed herein. In one embodiment, the subject is treated with two or more doses of the compositions encompassed herein. In one embodiment, the subject is treated with multiple doses of the compositions encompassed herein. In one embodiment, the subject treated with multiple doses is treated for at least one day. In one embodiment, the subject treated with multiple doses is treated for at least one week. In one embodiment, the subject treated with multiple doses is treated for at least one month. In some embodiments, the patient is injected with one or more doses of testosterone every week or every other week. The patient is preferably injected in the abdomen or thigh, but not limited thereto.

[0101]

[0133] V. Pharmacokinetics

[0134] In one embodiment, the testosterone administered to the subject encompassed herein is A composition comprising testosterone (e.g., a preservative-free testosterone composition) provides pharmacokinetics, including systemic bioavailability, that are substantially the same (or similar) as when the same dose of testosterone is administered intramuscularly or subcutaneously to said subject using a needle and syringe. In another embodiment, a method of treating hypogonadism encompassed herein comprises introducing a composition comprising testosterone (e.g., preservative-free) in a dose range of about 5 mg to about 400 mg from a needle-assisted jet injection device into a subcutaneous, intradermal, or intramuscular tissue of a subject, wherein the pharmacokinetic profile of said testosterone administered by said needle-assisted jet injection device is substantially the same as the pharmacokinetic profile of the same dose of testosterone administered intramuscularly or subcutaneously to said subject using a needle and syringe.

[0102]

[0135] As used herein, the results obtained with respect to measured testosterone The values ​​or calculated values ​​can be for total testosterone, free testosterone, bioavailable testosterone, or serum testosterone.

[0103]

[0136] In one embodiment, the testosterone administered according to the disclosure contained herein is Testosterone is C-reductase inhibitor, which is a 500mg / kg / day dose of testosterone, compared to when the same dose is delivered intramuscularly, intradermally, or subcutaneously via needle and syringe for the same period of time. max and T max In one embodiment, testosterone administered according to the disclosures contained herein has a C for the same period of time as compared to when the same dose of testosterone is delivered intramuscularly, intradermally, or subcutaneously via needle and syringe. max and T max The present invention achieves a pharmacokinetic profile which is superior to the pharmacokinetic profile obtained by producing

[0104]

[0137] In one embodiment, the test administered to a subject according to the methods disclosed herein is A composition comprising testosterone (e.g., a preservative-free composition) provides pharmacokinetics including enhanced systemic bioavailability of testosterone when the same dose of testosterone is administered intramuscularly, intradermally, or subcutaneously to the subject using one of a transdermal cream, gel, or patch, or needle and syringe. In one embodiment, a method of administering testosterone according to the disclosures contained herein comprises introducing a composition comprising testosterone (e.g., preservative-free) in a dose range of about 5 mg to about 400 mg into a subcutaneous, intradermal, or intramuscular tissue of a subject from an injection device as contained herein and described elsewhere herein, wherein the pharmacokinetic profile of the testosterone delivered by the injection device is enhanced compared to the pharmacokinetic profile of the same dose of testosterone when administered intramuscularly, intradermally, or subcutaneously to the subject using one of a transdermal cream, gel, or patch, or needle and syringe. In one embodiment, a method of administering testosterone in accordance with the disclosure encompassed by the present invention comprises introducing into a subcutaneous, intradermal, or intramuscular tissue of a subject a composition (e.g., preservative-free) comprising a dose of testosterone ranging from about 5 mg to about 400 mg from a needle-assisted jet injection device as encompassed by and described elsewhere herein, wherein the pharmacokinetic profile of the testosterone delivered by the needle-assisted jet injection device is consistent with the pharmacokinetic profile of the needle and syringe. In another embodiment, the bioequivalent pharmacokinetic profile of testosterone delivered by needle-assisted jet injection device is enhanced compared to the reference-listed drug when administered intramuscularly, intradermally, or subcutaneously by needle and syringe.

[0105]

[0138] In the 5 mg to 400 mg dose embodiment of the present disclosure, the pharmacokinetic profile is In one embodiment, the pharmacokinetic profile provides a linear increase in testosterone exposure with an increase in the dose of testosterone administered. max In another embodiment, the pharmacokinetic profile provides a dose-proportional increase in AUC(ng * When the AUC(ng h / ml) values ​​were plotted against the corresponding dose values ​​in a Cartesian plane, the AUC(ng * In another embodiment, the pharmacokinetic profile provides a linear or non-linear relationship between the C max The C value of testosterone when plotted against the corresponding dose value in a Cartesian plane max and the dose of testosterone. Pharmacokinetic information regarding testosterone and needle-assisted jet injection devices can also be found in co-pending provisional application Ser. No. 61 / 621,298, the contents of which are incorporated herein by reference in their entirety.

[0106]

[0139] Thus, one aspect of the present invention is a method for treating hypogonadism in a subject in need thereof. The present invention provides a method of treating a patient in need of testosterone comprising introducing a composition (e.g., preservative-free) comprising a dose ranging from about 5 mg to about 400 mg of testosterone from a needle-assisted jet injection device into a subcutaneous or intramuscular tissue of a patient in need of testosterone, whereby the method provides a pharmacokinetic profile in which testosterone exposure increases linearly in proportion to an increase in dose strength (or level) of testosterone. In one embodiment, the pharmacokinetic profile provides an AUC that increases linearly in proportion to an increase in dose strength (or level) of testosterone administered. In another embodiment, the pharmacokinetic profile provides a C that increases linearly in proportion to an increase in dose level of testosterone administered. max to provide.

[0107]

[0140] For comparison purposes, Androgel 1% (NDA No. 021015) Commercially available testosterones from Androgel 1.62% (NDA No. 022309), Testim (NDA No. 021454) and Axiron (NDA No. 022504) and associated medication guides and package insert labels may be used, each of which is incorporated herein by reference in its entirety.

[0108]

[0141] A. Effective plasma levels of testosterone

[0142] In one embodiment, the method of administering testosterone comprises administering a unit dose of testosterone. The method includes subcutaneously administering to a mammal a composition (e.g., preservative-free) comprising testosterone or a pharma- ceutical acceptable ester or salt thereof in a pharma- ceutical acceptable carrier, wherein after administration, the plasma level of testosterone is maintained at a therapeutically effective level for a period of time. In one embodiment, the Z1 period is the period of time during which the plasma level of testosterone is maintained at a therapeutically effective level.

[0109]

[0143] In another aspect, the compositions encompassed herein are When administered according to the methods and devices, the compositions encompassed herein maintain plasma levels of testosterone at therapeutically effective levels, beginning at about 1 minute after administration and ending at about 1 month after administration. In such embodiments, the compositions encompassed herein maintain plasma levels of testosterone at therapeutically effective levels, when administered according to the methods and devices encompassed herein. and maintaining the dose at about 2 minutes after administration, or about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours after administration, up to about 1 month after administration. In one embodiment, the compositions encompassed herein, when administered according to the methods and devices encompassed herein, maintain plasma levels of testosterone at therapeutically effective levels starting at about 1 minute after administration and ending at about 25 days after administration, about 20 days after administration, about 15 days after administration, about 14 days after administration, about 13 days after administration, about 12 days after administration, about 11 days after administration, about 10 days after administration, about 9 days after administration, about 8 days after administration, about 7 days after administration, about 6 days after administration, about 5 days after administration, about 4 days after administration, about 3 days after administration, about 2 days after administration, about 1 day after administration, or about 0.5 days after administration.

[0110]

[0144] In one embodiment, the first dose has a first profile and subsequent doses (the first Each dose (which may be the same or different from the previous dose) will provide a different profile. Depending on the patient's response, dose, dose volume and timing of subsequent administrations, the patient's pharmacokinetic profile can be customized to meet the needs of an individual patient with the use of the present invention, as shown by the single dose profile shown in Figure 20. In some embodiments, the present invention can be used to maintain therapeutic levels of testosterone during and / or over a prescribed dosing cycle (e.g., weekly dosing for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 5 months, 1 year, or longer).

[0111]

[0145] In one embodiment, the method of administering testosterone comprises administering a unit dose of testosterone. The method includes subcutaneously administering to a mammal a composition (e.g., preservative-free) comprising testosterone or a pharma- ceutical acceptable ester or salt thereof in a pharma- ceutical acceptable carrier, wherein after administration, the plasma level of testosterone is maintained at about 300 ng / ml to about 1100 ng / ml for a period of time "Z1."

[0112]

[0146] In one aspect, the compositions encompassed herein are When administered according to the methods and devices, the compositions encompassed herein maintain plasma levels of testosterone at, for example, about 300 ng / ml to about 1100 ng / ml, beginning at about 1 minute and ending at about 1 month after administration. In yet another embodiment, the compositions encompassed herein maintain plasma levels of testosterone at, for example, about 300 ng / ml to about 1100 ng / ml, beginning at about 2 minutes, or about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or beginning at about 12 hours and up to about 1 month after administration. In certain embodiments, the compositions encompassed herein, when administered according to the methods and devices encompassed herein, maintain plasma levels of testosterone at, for example, about 300 ng / ml to about 1100 ng / ml starting at about 1 minute after administration and ending at about 25 days after administration, about 20 days after administration, about 15 days after administration, about 14 days after administration, about 13 days after administration, about 12 days after administration, about 11 days after administration, about 10 days after administration, about 9 days after administration, about 8 days after administration, about 7 days after administration, about 6 days after administration, about 5 days after administration, about 4 days after administration, about 3 days after administration, about 2 days after administration, about 1 day after administration, or ending at about 0.5 days after administration.

[0113]

[0147] In one embodiment, the plasma level of testosterone is from about 300 ng / ml to about 1100ng / ml, about 350ng / ml to about 1050ng / ml, about 400ng / ml to about 1000ng / ml, about 450ng / ml to about 950ng / ml, about 500ng / ml to about 900ng / ml, about 550ng / ml to about 850ng / ml, about 600ng / ml to about 800ng / ml, about 650ng / ml to about 750ng / ml, and about 675ng / ml In one embodiment, the plasma level of testosterone is maintained at a value selected from the group consisting of about 300 ng / ml, about 350 ng / ml, about 400 ng / ml, about 450 ng / ml, about 500 ng / ml, about 550 ng / ml, about 600 ng / ml, about 650 ng / ml, about 700 ng / ml, about 750 ng / ml, about 800 ng / ml, about 850 ng / ml, about 900 ng / ml, about 950 ng / ml, about 1000 ng / ml, about 1050 ng / ml, and about 1100 ng / ml. In one embodiment, the plasma level of testosterone is maintained at a value selected from the group consisting of at least about 300 ng / ml, at least about 350 ng / ml, at least about 400 ng / ml, at least about 450 ng / ml, at least about 500 ng / ml, at least about 550 ng / ml, at least about 600 ng / ml, at least about 650 ng / ml, at least about 700 ng / ml, at least about 750 ng / ml, at least about 800 ng / ml, at least about 850 ng / ml, at least about 900 ng / ml, at least about 950 ng / ml, at least about 1000 ng / ml, at least about 1050 ng / ml, and at least about 1100 ng / ml. In one embodiment, the plasma level of testosterone is maintained at a value selected from the group consisting of about 300 ng / ml or less, about 350 ng / ml or less, about 400 ng / ml or less, about 450 ng / ml or less, about 500 ng / ml or less, about 550 ng / ml or less, about 600 ng / ml or less, about 650 ng / ml or less, about 700 ng / ml or less, about 750 ng / ml or less, about 800 ng / ml or less, about 850 ng / ml or less, about 900 ng / ml or less, about 950 ng / ml or less, about 1000 ng / ml or less, about 1050 ng / ml or less, and about 1100 ng / ml or less.

[0114]

[0148] In some embodiments, testosterone levels are measured using a method similar to that illustrated in FIG. In some embodiments, the levels of testosterone are maintained in the mammal as illustrated in Figure 12. In some embodiments, the levels of testosterone are maintained in the serum of the mammal as illustrated in Figure 12. In some embodiments, the mammal is a human.

[0115]

[0149] B. At elevated or within effective levels of plasma testosterone Maintaining

[0150] In another embodiment, the present invention relates to a method for the treatment of elevated testosterone levels in a mammal in need thereof. Provided herein is a method for maintaining plasma levels of testosterone. In certain embodiments, this involves maintaining plasma levels from a subcutaneous dose at or above therapeutic levels (e.g., about 400ng / ml, about 500ng / ml, about 600ng / ml, about 700ng / ml, about 800ng / ml, about 900ng / ml) for an extended period of time. In some embodiments, the levels are maintained for a longer period of time than an intramuscular dose of the same volume and concentration. In one embodiment, the method comprises subcutaneously administering to a mammal a composition (e.g., preservative-free) comprising a unit dose of testosterone or a pharma- ceutical acceptable ester or salt thereof in a pharma-ceutical acceptable carrier, where after administration, the plasma level of testosterone is maintained at an elevated level of up to about 1800ng / ml for a period of time. In one embodiment, the period during which the plasma level of testosterone is maintained at an elevated level is referred to as the "Z2 period."

[0116]

[0151] In some embodiments, the plasma level of testosterone is about 300 ng / ml to About 1800ng / ml, about 400ng / ml to about 1800ng / ml, about 500ng / ml to about 1800ng / ml, about 600ng / ml to about 1800ng / ml, about 700ng / ml to about 1800ng / ml, about 800ng / ml to about 1800ng / ml, about 900 ng / ml~about 1800ng / ml, about 1000ng / ml~about 1800ng / ml, about 300ng / ml~about 1100ng / ml, about 400ng / ml~about 1100ng / ml, about 500ng / ml~about 1100ng / ml, about 600ng / ml~about 1100ng / ml ml, about 700ng / ml to about 1100ng / ml, about 800ng / ml to about 1100ng / ml, about 300ng / ml to about 1800ng / ml, about 300ng / ml to about 1700ng / ml, about 300ng / m l ~ approx. 1600ng / ml, approx. 300ng / ml ~ approx. 1500ng / ml, approx. 300ng / ml ~ approx. 1400ng / ml, approx. 300ng / ml ~ approx. 1300ng / ml, approx. 300ng / ml ~ approx. 1200ng / m l, about 300ng / ml to about 1100ng / ml, about 300ng / ml to about 1000ng / ml, about 300ng / ml to about 900ng / ml, about 300ng / ml to about 800ng / ml, about 300ng / ml to about 700ng / ml, about 300ng / ml to about 600ng / ml, about 300ng / ml to about 500ng / ml, or about 300ng / ml to about 400ng / ml.

[0117]

[0152] In certain embodiments, plasma levels of testosterone are monitored over the course of a treatment regimen. , typically maintained between 400-1100 ng / ml, and more typically between 400-900 ng / ml. In certain embodiments, plasma levels at values ​​of about 400 to about 1000 ng / ml are considered "therapeutically effective," particularly with respect to maintaining steady-state testosterone levels during the treatment regimen.

[0118]

[0153] In one aspect, the compositions encompassed herein are and when administered according to the device, maintains plasma levels of testosterone at elevated levels beginning at about 1 minute after administration and ending at about 1 month after administration. In one embodiment, the compositions encompassed herein, when administered according to the methods and devices encompassed herein, maintain plasma levels of testosterone at elevated levels beginning at about 2 minutes after administration, or about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours after administration, up to about 1 month after administration. In one embodiment, the compositions encompassed herein, when administered according to the methods and devices encompassed herein, maintain plasma levels of testosterone at elevated levels beginning at about 1 minute after administration and ending at about 25 days after administration, about 20 days after administration, about 15 days after administration, about 14 days after administration, about 13 days after administration, about 12 days after administration, about 11 days after administration, about 10 days after administration, about 9 days after administration, about 8 days after administration, about 7 days after administration, about 6 days after administration, about 5 days after administration, about 4 days after administration, about 3 days after administration, about 2 days after administration, about 1 day after administration, or about 0.5 days after administration.

[0119]

[0154] C. Peak plasma concentration

[0155] In another embodiment, the present invention provides a method for the treatment of a peak in testosterone in a mammal in need thereof. Provided herein are methods for obtaining peak plasma concentrations of testosterone using compositions and devices encompassed herein, where the plasma concentration of testosterone then declines to a therapeutically effective level for a period of time. In another embodiment, provided herein are methods for obtaining peak plasma concentrations of testosterone using compositions and devices encompassed herein, where the plasma concentration of testosterone then declines to an elevated level for a period of time.

[0120]

[0156] In some embodiments, the peak testosterone level is about 400 ng / ml. ~2400ng / ml, 500ng / ml~2400ng / ml, 600ng / ml~2400ng / ml, 700ng / ml~2400ng / ml, 800ng / ml~2400ng / ml, 900ng / ml~2400ng / ml, 1000ng / ml~2400 ng / ml, 1100ng / ml~2400ng / ml, 1200ng / ml~2400ng / ml, 1300ng / ml~2400ng / ml, 1400ng / ml~2400ng / ml, 1500ng / ml~2400ng / ml, 1600ng / ml~2400 ng / ml, 1700ng / ml to 2400ng / ml, 1800ng / ml to 2400ng / ml, 1900ng / ml to 2400ng / ml, 2000ng / ml to 2400ng / ml, 2100ng / ml to 2400ng / ml, 2200ng / ml to 2400ng / ml, or about 2300ng / ml to 2400ng / ml.

[0121]

[0157] In another embodiment, the compositions and devices encompassed herein are used to In some embodiments, the plasma concentration of testosterone is increased to a peak level, after which the plasma concentration of testosterone declines to a level lower than the peak for a period of time, the lower level being from about 300 ng / ml to about 1800 ng / ml, from about 400 ng / ml to about 1800 ng / ml, from about 500 ng / ml to about 1800 ng / ml, from about 600 ng / ml to about 1800 ng / ml, from about 700 ng / ml to about 1800 ng / ml, Approximately 800ng / ml to approximately 1800ng / ml, approximately 900ng / ml to approximately 1800ng / ml, approximately 1000ng / ml to approximately 1800ng / ml, approximately 300ng / ml to approximately 1100ng / ml, approximately 4 00ng / ml ~ approx. 1100ng / ml, approx. 500ng / ml ~ approx. 1100ng / ml, approx. 600ng / ml ~ approx. 1100ng / ml, approx. 700ng / ml ~ approx. 1100ng / ml, approx. 800ng / ml ~ approx. 1100ng / ml, approx. 300ng / ml ~ approx. 1800ng / ml, approx. 300ng / ml ~ approx. 1700ng / ml, approx. 300ng / ml ~ approx. 1600ng / ml, approx. 300ng / ml ~1500ng / ml, 300ng / ml~1400ng / ml, 300ng / ml~1300ng / ml, 300ng / ml~1200ng / ml, 300ng / ml~11 Provided herein are methods in which the concentration of the IgG4 antibody is selected from about 300 ng / ml, about 300 ng / ml to about 1000 ng / ml, about 300 ng / ml to about 900 ng / ml, about 300 ng / ml to about 800 ng / ml, about 300 ng / ml to about 700 ng / ml, about 300 ng / ml to about 600 ng / ml, about 300 ng / ml to about 500 ng / ml, or about 300 ng / ml to about 400 ng / ml.

[0122]

[0158] In one embodiment, the compositions and devices encompassed herein are used to perform tests. Provided herein is a method for obtaining peak plasma concentration of testosterone, wherein peak plasma concentration of testosterone is achieved in about 48 hours, about 36 hours, about 24 hours, about 18 hours, about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, or about 0.5 hours.In one embodiment, peak plasma concentration of testosterone is achieved in less than 48 hours, less than 36 hours, less than 24 hours, less than 18 hours, less than 12 hours, less than 11 hours, less than 10 hours, less than 9 hours, less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, or less than 0.5 hours.

[0123]

[0159] D. Effective levels of testosterone after relatively low dose reduction below effective levels maintain

[0160] In one embodiment, surprisingly, the testosterone compounds encompassed herein Administration of the composition provides plasma levels of testosterone that are maintained at therapeutically effective levels for a longer period of time than a comparable dose of testosterone administered intramuscularly, intradermally, or subcutaneously to the same subject by one of a transdermal cream, gel, or patch, or needle and syringe. In one embodiment, at the time point following injection, the testosterone compositions encompassed herein (e.g., preservative-free) maintain a higher plasma concentration of testosterone than would be maintained by a comparable testosterone administered to the same subject by intramuscular injection by transdermal cream, gel, or patch, or needle and syringe over the same period of time.

[0124]

[0161] Referring to the Figures, and in particular to Figure 12, in one embodiment, a method for administering testosterone is The method includes subcutaneously administering to a mammal a composition comprising a unit dose of testosterone in a pharma- ceutical acceptable carrier, wherein after administration, the plasma level of testosterone is maintained at about 700 ng / ml to about 1800 ng / ml for a period of time "Z2," wherein the testosterone The plasma levels of terone are also maintained at about 300 ng / ml to about 1100 ng / ml during period "Z3", which is the time after which the plasma levels of an equivalent intramuscularly administered dose fall below the plasma levels of a subcutaneously administered dose at the same time point after administration.

[0125]

[0162] In one embodiment, the plasma levels of an equivalent intramuscularly administered dose are approximately 1 day after administration. to below the plasma level of the subcutaneously administered dose at about day 2, at about day 3, at about day 4, at about day 5, at about day 6, at about day 7, at about day 8, at about day 9, at about day 10, at about day 11, at about day 12, at about day 13, or at about day 14.

[0126]

[0163] In one embodiment, referring to FIG. 12, after administration, plasma levels of testosterone The level is maintained at or between a level selected from about 700ng / ml to about 1800ng / ml, about 750ng / ml to about 1750ng / ml, about 800ng / ml to about 1700ng / ml, about 850ng / ml to about 1650ng / ml, about 900ng / ml to about 1600ng / ml, about 950ng / ml to about 1550ng / ml, about 1000ng / ml to about 1500ng / ml, about 1050ng / ml to about 1450ng / ml, about 1100ng / ml to about 1400ng / ml, about 1150ng / ml to about 1350ng / ml, and about 1200ng / ml to about 1300ng / ml during the Z2 period.

[0127]

[0164] In one embodiment, after administration, the plasma level of testosterone is , about 700ng / ml, about 750ng / ml, about 800ng / ml, about 850ng / ml, about 900ng / ml, about 950ng / ml, about 1000ng / ml, about 1050ng / ml, about 1100ng / ml, about 1150ng / ml, about 1200ng / ml, about 1250ng / ml, about 1300ng / ml, about 1350ng / ml, about 1400ng / ml, about 1450ng / ml, about 1500ng / ml, about 1550ng / ml, about 1600ng / ml, about 1650ng / ml, about 1700ng / ml, about 1750ng / ml, and about 1800ng / ml.

[0128]

[0165] In one embodiment, the Z2 period is at least 1 hour, at least 2 hours, at least at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 36 hours, at least 48 hours, or at least 72 hours.

[0129]

[0166] In one embodiment, plasma levels of testosterone are comparable at the same time points. The plasma levels of testosterone are maintained above the plasma levels associated with the testosterone administered by the intramuscularly administered dose for the Z3 period. In another embodiment, the plasma levels of testosterone are maintained above the therapeutic levels of testosterone for the Z3 period.

[0130]

[0167] In yet another embodiment, and with reference to FIG. 12, after administration, testosterone The plasma level of ron is maintained at a value selected from the group consisting of about 300 ng / ml to about 1100 ng / ml, about 350 ng / ml to about 1050 ng / ml, about 400 ng / ml to about 1000 ng / ml, about 450 ng / ml to about 950 ng / ml, about 500 ng / ml to about 900 ng / ml, about 550 ng / ml to about 850 ng / ml, about 600 ng / ml to about 800 ng / ml, about 650 ng / ml to about 750 ng / ml, about 675 ng / ml to about 725 ng / ml, and a concentration above about 300 ng / ml for a Z3 period after the plasma level of a comparable intramuscularly administered dose has fallen below the plasma level at the same time point after administration of a subcutaneously administered dose.

[0131]

[0168] In one embodiment, after administration, plasma levels of testosterone are comparable to those of intramuscular administration. After the plasma level of a given dose falls below the plasma level at the same time point after administration of the subcutaneously administered dose, it is maintained at a value selected from the group consisting of about 300 ng / ml, about 350 ng / ml, about 400 ng / ml, about 450 ng / ml, about 500 ng / ml, about 550 ng / ml, about 600 ng / ml, about 650 ng / ml, about 700 ng / ml, about 750 ng / ml, about 800 ng / ml, about 850 ng / ml, about 900 ng / ml, about 950 ng / ml, about 1000 ng / ml, about 1050 ng / ml, and about 1100 ng / ml during the Z3 period.

[0132]

[0169] In some embodiments, the Z3 period is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 36 hours, at least 48 hours, or at least 72 hours.

[0133]

[0170] E. Maintaining Effective Levels Over Multiple Treatments

[0171] Multiple treatments may be used in combination with the compositions, devices, and methods encompassed herein. The method may include administering two or more doses of testosterone (e.g., preservative-free) according to the combination. In one embodiment, the plasma level of testosterone during the Z3 period is maintained at a therapeutically effective level (e.g., steady state at or above 300ng / ml, or at or above about 400ng / ml, or other possible values ​​described herein above). In one embodiment, the plasma level of testosterone during the Z3 period is maintained at or above a therapeutically effective level while the second dose is administered. In one embodiment, the plasma level of testosterone during the Z3 period is maintained above a therapeutically effective level until the second dose is administered. In one embodiment, the plasma level of testosterone during the Z3 period is maintained at an elevated level. In one embodiment, the plasma levels of testosterone during the Z3 period are maintained at levels between 300ng / ml and 700ng / ml, between 300ng / ml and 1100ng / ml, between 300ng / ml and 1800ng / ml, between 700ng / ml and 1100ng / ml, between 700ng / ml and 1800ng / ml, or between 1100ng / ml and 1800ng / ml, and / or above about 300ng / ml until the second dose is administered, after which the blood levels of testosterone will likely increase again according to well-understood pharmacokinetics.

[0134]

[0172] In one embodiment, continued treatment according to the methods described herein results in , resulting in a sustainable steady-state or plateau-type profile in which little variation in the plasma concentration of testosterone is caused by a given subsequent administration. More specifically, the average blood concentration observed over a given time interval (e.g., one week) does not increase or decrease substantially compared to the blood concentration measured during the preceding time interval after an earlier dose (e.g., one week between weekly administrations). More specifically, by following the administration methods described herein, upon reaching a steady state, the plasma concentration of testosterone can be maintained within the narrow ranges described herein without the need to increase the concentration of the dose, decrease the concentration of the dose, or stop treatment. In some embodiments, once a steady state is reached, the peak plasma concentration obtained after administration of a subsequent dose(s) is less than 5%, 10%, 20%, or 30% higher than the peak plasma concentration observed during the immediately preceding dose (e.g., the previous week between weekly administrations). In some embodiments, the peak plasma concentration of testosterone can be lower than the peak plasma concentration observed during the immediately preceding administration period. In certain embodiments, once steady state is reached, the average plasma concentration obtained after administration of a subsequent dose(s) is + or - about 5%, about 10%, about 20%, or about 30% less than the average plasma concentration observed during the immediately preceding dose (e.g., the previous week between weekly doses), as shown in Figures 21 and 23. Furthermore, total testosterone levels over time are also under reduced fluctuation, as illustrated in Figure 22.

[0135]

[0173] In some such embodiments, steady state occurs at a dose of 3 weeks or In some such embodiments, the steady state can be reached at or after 4 weeks of weekly administration. In some such embodiments, the steady state can be reached at or after 5 weeks. In some such embodiments, the steady state can be reached at or after 6 weeks. In other embodiments, the steady state can be reached after a given number of doses. In some embodiments, the steady state can be reached at or after 3 doses. In some embodiments, the steady state can be reached after 4 doses. In some embodiments, the steady state can be reached at or after 5 doses. In some embodiments, the steady state can be reached at or after 6 doses. Typically, the doses are continued at regular intervals after the steady state is reached. In some embodiments, the dose administered to the subject after the steady state is reached is the same dose or a different dose than the dose(s) administered before the steady state is reached.

[0136]

[0174] Steady state is maintained after multiple doses (e.g., after 4-6 weeks of weekly dosing). Steady state therapeutic blood levels can be about 800 ng / dl to about 1100 ng / dl, about 500 ng / dl to about 800 ng / dl, or about 350 ng / dl to about 500 ng / dl. In other embodiments, plasma levels can be maintained at or within a range according to any of the levels described herein, as shown in FIG.

[0137]

[0175] The methods of the present invention allow for accurate and repeatable administration of a drug (e.g., testosterone). In some embodiments, the present invention allows for a method of titrating a patient that would not be achievable by conventional IM treatment. In particular, given the substantially reduced variability of observed plasma concentrations from a given subcutaneous dose, with respect to the present invention, a greater number of administration concentrations are available to provide a desired plasma concentration of testosterone. Thus, in accordance with the methods described herein, a patient can be titrated to either one, two, or three or more subcutaneous doses that are lower in concentration than an intramuscular dose that provides a similar or the same desired plasma concentration of testosterone. Additionally, with respect to the present invention, including the subcutaneous methods and compositions described herein, a reduced peak-to-trough fluctuation is provided compared to the peak-to-trough fluctuation seen with higher doses of testosterone administered (e.g., intramuscularly) on a once-to-twice-per-month schedule, as illustrated in FIG. 21.

[0138]

[0176] In one embodiment, the administration of the testosterone compositions encompassed herein is by injection. Immediately after injection, the testosterone plasma level is above the plasma therapeutic level of testosterone for a period of time, but not so high that it is toxic to the subject. In one embodiment, the stimulating level of plasma testosterone can be detected by measuring the plasma level of testosterone. In another embodiment, the stimulating level of testosterone can be detected by measuring a surrogate for plasma testosterone level, such as (but not limited to) one or more endocrinology profiles of the subject to which testosterone is administered. In one embodiment, the endocrinology markers include, but are not limited to, erythrocyte proliferation and / or other markers indicative of hormone function.

[0139]

[0177] F. Stimulant effect

[0178] In another embodiment, administration of the testosterone compositions encompassed herein comprises: Immediately after injection, the plasma levels of testosterone provide a stimulating effect such that for a period of time the plasma levels of testosterone are above therapeutic levels of testosterone, but not so high as to be toxic to the subject. After the plasma level of testosterone has fallen from the stimulating level, the plasma level of testosterone is within the therapeutically effective level discussed herein. In one embodiment, administration of the testosterone composition encompassed herein provides a minimal stimulating effect immediately after injection such that the plasma level of testosterone is above the plasma therapeutic level of testosterone for a period of time, but not so high as to be toxic to the subject, and thereafter the plasma level of testosterone is within the therapeutically effective level discussed herein. In one embodiment, administration of the testosterone composition encompassed herein does not provide a stimulating effect immediately after injection, and the plasma level of testosterone is maintained at the therapeutically effective level discussed herein.

[0140]

[0179] In one embodiment, the testosterone administered to a subject according to the methods of the present invention is , pharmacokinetics, including systemic bioavailability, that have reduced systemic bioavailability of testosterone when the same dose of testosterone is administered intramuscularly or subcutaneously to the subject using a needle and syringe.

[0141]

[0180] EXAMPLES

[0142]

[0181] Example 1: Injection of a viscous fluid composition.

[0182] Peanut oil and 10% benzyl alcohol and testosterone base A formulation was prepared containing 0.5 ml of active pharmaceutical ingredient. The formulation had a viscosity of 1000 cps. An MJ-7 needleless injection device manufactured by Antares Pharma was used to administer 0.5 ml of the formulation. The study used the following device power and needleless syringe aperture settings to achieve needleless injection of peanut oil-10% benzyl alcohol solution:

[0143]

[0183] To achieve intramuscular injection, the injection device has a spring force of 100 lbs. The syringe was spring powered and had a needleless syringe with a 0.36 mm (0.014") diameter orifice.

[0144]

[0184] To achieve subcutaneous injection, the injection device has a spring force of 85 lbs. It was spring powered and equipped with a needleless syringe with an orifice of 0.28 mm (0.011") in diameter.

[0145]

[0185] The results were as follows:

[0186]

[0146] [Table 3]

[0147] [Table 4]

[0148]

[0187] In one embodiment, a mini-needle device is used instead of a needle-free injection device. It will be understood that if present, the lumen of the needle will be in the same order as the opening of the needleless device.

[0149]

[0188] Example 2: Cavg for various testosterone formulations and delivery methods and Cmax comparison

[0189]

[0150] [Table 5]

[0151]

[0190]

[0152] [Table 6]

[0153]

[0191] Example 3: Pharmacokinetics of testosterone by injection in castrated minipigs research

[0192] The purpose of this study was to determine the 1-day efficacy and safety of cyclosporine when administered by injection to castrated minipigs. The objective of this study was to evaluate the pharmacokinetics of testosterone (Antares QS autoinjector device with an injection depth of 10 mm) at 1 h and 15 days.

[0154]

[0193] The test system included Yucatan strain minipigs. Castrated males Minipigs were obtained from Sinclair Research Center, Inc., Windham, Maine. Minipigs were 15-20 weeks old and had a target weight of 20-25 kg at the start of dosing. The Yucatan minipigs were chosen as the animal model for this study because it is the preferred non-rodent species for preclinical toxicity testing by regulatory agencies. Housing and care were as specified in the USDA Animal Welfare Act (9 CFR, parts 1, 2, and 3) and as described in the Guide for the Care and Use of Laboratory Animals from the National Research Council. Animals were housed individually in pig pens / cages.

[0155]

[0194] The experiment was designed as follows:

[0156] [Table 7]

[0157]

[0195] The test articles used for injection of the animals included the following: Test article 1, 100 mg / ml testosterone enanthate in a prefilled syringe; test article 2, 200 mg / ml testosterone enanthate in a prefilled syringe; test article 3, 100 mg / ml testosterone enanthate in a vial; and test article 4, 200 mg / ml testosterone enanthate in a vial.

[0158]

[0196] On day 1, the dose was administered into a preloaded Antares QS autoinjector. The injection was delivered by a device (see, for example, co-pending application Ser. No. 61 / 763,395, incorporated by reference). On Day 15, the dose was delivered by needle and syringe. Test Articles 1 and 2 were administered to appropriate animals on Day 1 at Test Site 1, in the scapular region, by injection with a mini-needle autoinjector. Prior to the first dose, the dorsal area of ​​the animals was clipped free of hair with small animal clippers to allow clear visualization of the test site, and then clipped as frequently as necessary. Care was taken to avoid abrasion of the skin during the clipping procedure. The injection site (approximately 2 cm x 2 cm) was outlined with an indelible marker and then remarked as necessary. Test Articles 3 and 4 were administered to appropriate animals on Day 15 at Test Site 2, in the proximal portion of the hind paw, to a depth of approximately 3 / 4 inch, by intramuscular injection with a 1 mL syringe with a 27 gauge x 1 inch needle. Prior to the first dose, the proximal hind limbs of the animals were clipped free of hair with small animal clippers to allow clear visualization of the test site, and then clipped as frequently as needed. Care was taken to avoid abrasion of the skin during the clipping procedure. The injection site (approximately 2 cm x 2 cm) was outlined with an indelible marker and then re-marked as needed. After all 22 days of study observations and bioanalysis sampling, the animals (including a replacement male pig) were assigned to the exploratory testing phase of the study. Prior to the first dose, the dorsal area of ​​the animals was clipped free of hair with small animal clippers to allow clear visualization of the test site, and then clipped as frequently as needed. A 0.5 mL dose of dye was delivered by injection into the untreated scapular region using a QS autoinjector device. A 0.5 mL dose of dye was injected into the untreated proximal portion of the hind limb by intramuscular injection using a 27 gauge x 1 inch needle and syringe. Injection sites (approximately 2 cm x 2 cm) were outlined with an indelible marker. After dose administration, animals (including replacement animals) were euthanized and the experiment was performed. The day of the first dose was designated as study day 1.

[0159]

[0197] The injectable route of exposure was chosen as this is the intended route of human exposure. An injection depth of 10 mm was examined as part of this study. Dose levels of 100 mg and 200 mg were determined to provide a comparison of the intramuscular route of administration via an autoinjector and needle and syringe for toxicokinetic purposes. The intramuscular route was selected for further investigation because this route resulted in less loss of material after injection than subcutaneous administration based on macroscopic observations. Doses less than 100 mg may not have provided the necessary circulating concentrations, while doses greater than 200 mg were not required. Dose levels and weekly dosing schedules were based on the following supplied reference: “Daily Testosterone and Gonadotropin Levels Are Similar in Azoospermic and Nonazoospermic Normal Men Administered Weekly Testosterone: Implications for Male contraceptive Development” Journal of Andrology Vol. 22, No. 6 November / December 2001.

[0160]

[0198] The injection site of each animal was examined on the day of randomization and on days 1 through 22. Patients were observed daily (approximately 1 and 4 hours after dosing on dosing days, and once daily on non-dosing days) at 0.5° C. Injection sites were noted for erythema, edema, and any other additional adverse findings.

[0161]

[0199] Blood was collected by venipuncture of the vena cava. Samples were collected according to the following table: :

[0162] [Table 8]

[0163]

[0200] Blood was collected by venipuncture of the vena cava. Samples were collected according to the following table: : Samples were allowed to clot for at least 30 minutes at room temperature and then centrifuged.

[0201] The samples were centrifuged at 1800×g at ambient temperature. Serum was divided into three aliquots of approximately 0.5 mL each for analysis. One aliquot was designated for testosterone and DHT analysis, one aliquot was designated for sex hormone binding globulin (SHBG) analysis, and one aliquot was designated for total serum albumin determination. Serum samples were transferred into uniquely labeled polypropylene tubes and stored frozen in a freezer set to maintain -70°C. Samples to be analyzed were shipped overnight on dry ice to the bioanalytical laboratory for analysis.

[0164]

[0202] One set of serum samples was analyzed for total testosterone concentration using a validated analytical procedure. The serum levels of testosterone were analyzed for serotonin, serotonin, and serotonin levels. Samples taken for sex hormone binding globulin (SHBG) and serum albumin will not be analyzed at this time. DHT was not analyzed for this study. Testosterone analysis was performed by LCMS using a method validated under Charles River Study 20027106. Data collection was performed using Analyst from MDS Sciex. Statistical analyses including regression analysis, and descriptive statistics including arithmetic mean and standard deviation, accuracy and precision were performed using the Watson Laboratory Information Management System (LIMS) and Microsoft Excel.

[0165]

[0203] Toxicokinetic parameters were analyzed using the Watson Laboratory Information Management System (LIMS) ) and Microsoft Excel. A noncompartmental approach consistent with the subcutaneous and intramuscular routes of administration was used for parameter estimation. Individual and mean PK parameters were reported, including Cmax, Tmax, and AUC0-last. When data permitted, the slope of the terminal elimination phase of each concentration versus time curve was determined by log-linear regression, and the following additional parameters were also estimated: AUC0-inf, terminal elimination half-life. All parameters were generated from serum testosterone (total) concentrations from days 1 and 15, unless otherwise stated. Parameters were estimated using sample collection times relative to the start of administration of the respective doses.

[0166]

[0204] 13-19 are, in part, schematic diagrams of an automatic injection device or a traditional needle and syringe. 1 illustrates the results of the study described in Example 3 for various testosterone enanthate concentrations delivered by either method.

[0167]

[0205] No animals died during the course of the study. There were no clinical signs. Sporadic occurrences of scabs, red areas, or mechanical damage were noted during the study. These were thought to be background findings related to the animals rubbing against the cage or areas that were irritated during the dosing procedure when the animal was in the sling. One animal was noted struggling during dosing on day 15; however, this did not appear to affect dose administration.

[0168]

[0206] Once the device or needle is removed, a small amount of The injected material leaked from the injection site. The amount of leakage was comparable across sites and animals. In addition, redness was noted at the injection site following injection across the test sites. No additional skin changes were noted during the study period.

[0169] No test article-related effects on body weight occurred during the study. All animals showed an increase in body weight from their starting weight during the study. Results of the study using injections of dye in sesame oil resulted in validation of subcutaneous delivery in all animals that received a dose from the QS autoinjector device. Conventional administration by needle and syringe administration resulted in intramuscular delivery of dye, except for one animal that had subcutaneous delivery with a dark area in the muscle.

[0170]

[0207] Example 4

[0208] 20 adults (aged 31-69 years) (300 participants at two screening visits) Patients (< 2.5 ng / dL testosterone, with documented clinical symptoms) were given 50 mg (n=10) or 100 mg (n=10) of JT administered by a health care professional weekly in the clinic for 6 weeks. Mean baseline testosterone was 301 ng / dL for patients in the 50 mg group and 214 ng / dL for patients in the 100 mg group. At week 1, both doses produced normal mean total testosterone 24 hours after administration. Testosterone concentrations (433 ng / dL [range 197-821 ng / dL] in the 50 mg group and 545 ng / dL [range 388-833 ng / dL] in the 100 mg group) increased with successive doses and reached a plateau at week 5. At week 6, mean testosterone 24 hours after dosing was 421 ng / dL (range 263-640) in the 50 mg group and 1042 ng / dL (range 526-1420) in the 100 mg group. In the 50 mg group, testosterone Cmin generally did not change. In the 100 mg group, testosterone Cmin increased throughout week 5. Steady-state Cavg[0-168h] testosterone levels at week 6 were higher in the 100 mg group versus the 50 mg group (927 vs. 420 ng / dL; 2.21-fold higher). In the 50 mg group, at week 6, Cmax was 624 ng / dL (range 388-825 ng / dL), Tmax was 46.2 h; Cmin was 286 ng / dL (range 211-372 ng / dL). At the 100 mg dose, at week 6, Cmax was 1427 ng / dL (range 662-2120 ng / dL), testosterone maximum was 33.9 h; Cmin was 584 ng / dL (range 236-860 ng / dL). The mean AUC(0-168h) at week 6 was 704.96 and 1556.94ng*h / ml for the 50 and 100mg doses, respectively. Serum estradiol and dihydrotestosterone increased proportionately with testosterone levels. The needle-assisted jet injection took 3-4 seconds per patient, delivered a consistent and accurate dose, and rapidly restored and maintained steady-state physiological Cavg[0-168h] levels of testosterone with attenuated peak-trough fluctuations compared to those seen with higher doses of testosterone administered on a once-to-twice-per-month schedule. This may be clinically important in avoiding the treatment-related mood swings observed with IM testosterone.These PK data suggest that JT may represent an alternative to daily topical testosterone with reduced risks associated with secondary exposure during weekly delivery of testosterone replacement with the option of self-administration.

[0171]

[0209] Each and every reference herein is incorporated by reference in its entirety. The entire disclosures of U.S. Patent Nos. 8,021,335, 7,776,015, and 6,391,003 and PCT Publication WO 2010 / 108116 are also incorporated herein by reference as if fully set forth herein.

[0172]

[0210] Changes may be made to the exemplary embodiments described above without departing from the broad inventive concept thereof. It will be understood by those skilled in the art that various modifications may be made to the disclosed embodiments. Accordingly, it is understood that the present invention is not limited to the exemplary embodiments described, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims. For example, certain features of the exemplary embodiments may or may not be part of the claimed invention, and features of the disclosed embodiments may be combined.

[0173]

[0211] At least some of the drawings and descriptions of the present invention are relevant for a clear understanding of the present invention. It should be understood that the description has been simplified to focus on relevant elements while, for purposes of clarity, excluding other elements that one of ordinary skill in the art would understand may also comprise a part of the invention, but because such elements are well known in the art and because they do not necessarily facilitate a better understanding of the invention, descriptions of such elements are not provided herein.

[0174]

[0212] Further, to the extent that the method does not rely on a particular order of steps set forth herein, The particular order of steps should not be construed as limitations to the claims. Any claims directed to the methods of the invention are limited to the performance of those steps in the order recited. It should not be construed as limiting the scope of the present invention, and one of ordinary skill in the art can readily appreciate that the process can be modified and still remain within the spirit and scope of the present invention. [Explanation of symbols]

[0175] 12 Injection device 14 External housing elements 14a Fitting part 14b Fitting part 15 Holes or Slots 16 Sleeve 18 Pre-filled Syringes 20 Container part 22 Fluid chamber 22 24 needles 26 Tip 28 Plunger 32 needle hub 33 Shock Absorption Device 35 Syringe flange 36 Syringe body 51 Luminal part 52 Compression spring 54 Inner housing 56 Trigger protrusion 58 Depression 60 Ram 64 Latch housing 65 Prominence 66 Needle Guard 67 A pair of radially extending flanges 68 Latch part 70 Lock Ring 71 Upper Arm 72 Spring 73 Lower Arm 74 Shaft opening 77 Flange 80 Safety Elements 82 legs 84 Main body part 86 Tabs 92 Proximal Notch 93 Distal notch 94 Upper surface 95 Slots 96 holes 110 Cap 112 Pair of protrusions 114 Distally Facing Ridge 116 Upper edge 118 En 130 Final pressure during injection 132 When one embodiment of the injection device 12 is fired 134 At the completion of injection 136 Initial and peak pressure during injection 200 Medicines 202 Jet Nozzle 204 Jet Exit

Claims

1. 1. A method for obtaining a steady state average blood concentration of testosterone, comprising the step of repeatedly administering an amount of testosterone over a predetermined period of time such that a steady state plasma level of testosterone is obtained after three or more doses.

2. 2. The method of claim 1, wherein the dose is selected from 50 mg, 75 mg, and 100 mg.

3. 3. The method of claim 2, wherein the concentration of the administered dose is 100 mg / ml, 150 mg / ml or 200 mg / ml.

4. 2. The method of claim 1, wherein the dose is between 50 mg and 100 mg.

5. 2. The method of claim 1, wherein the predetermined period is one week of administration.

6. 13. The method of claim 1, wherein a steady state is reached after the fourth dose.

7. 13. The method of claim 1, wherein a steady state is reached after the fifth dose.

8. 10. The method of claim 1, wherein the dose is continued after a steady state is reached.

9. 9. The method of claim 8, wherein the dose administered after steady state is reached is the same or different from the dose administered before steady state is reached.

10. 6. The method of claim 5, wherein once steady state is reached, the average plasma concentration obtained after administration of a subsequent dose or doses is less than + or -30% of the average plasma concentration obtained during the immediately preceding week.

11. 10. The method of claim 1, wherein the steady state therapeutic blood level maintained at steady state after multiple administrations is from about 800 ng / dl to about 1100 ng / dl.

12. 10. The method of claim 1, wherein the steady state therapeutic blood level maintained at steady state after multiple administrations is from about 500 ng / dl to about 800 ng / dl.

13. 10. The method of claim 1, wherein the steady state therapeutic blood level maintained at steady state after multiple administrations is from about 350 ng / dl to about 500 ng / dl.

14. 1. A method of titrating a patient to the lowest dose of testosterone that will achieve a desired plasma concentration, comprising administering multiple doses of testosterone subcutaneously and selecting from the two or more doses the lowest dose that provides the desired plasma concentration of testosterone compared to an intramuscular dose that provides the same desired plasma concentration of testosterone.

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