Methods and devices for drug delivery

Abstract

Provided herein are cannulas having one or more markers on their external surface (e.g., along a longitudinal axis of the cannulas). Such markers can help with identifying the location of one or more outlets and / or the distal end portion of a cannula under skin. In some embodiments, provided herein are methods for subcutaneously administering a pharmaceutical composition to a subject using a cannula having one or more markers provided herein. In some embodiments, the pharmaceutical composition is useful for inducing cell death of adipocytes in a subject and / or reducing subcutaneous fat in a subject.

Description

METHODS AND DEVICES FOR DRUG DELIVERY CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority from U. S. Provisional Application No. 63 / 716,638. filed on November 5, 2024, which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates to cannulas having one or more markers and their use in administering pharmaceutical compositions, for example, pharmaceutical compositions useful for inducing cell death of adipocytes in a subject and / or reducing subcutaneous fat in a subject.BACKGROUND

[0003] Surgical and non-surgical procedures for reducing fat and improving appearance are common as populations age and gain weight. For example, weight fluctuations and aging can lead to an altered distribution of subcutaneous fat that may be cosmetically undesirable and resistant to dieting and / or exercise. Liposuction is a common cosmetic surgical procedure involving the surgical removal of fat deposits using suction. However, surgical procedures are invasive, time consuming, can be complicated due to underlying anatomic structures. Furthermore, surgical procedures such as liposuction can have side effects such as bruising, fluid buildup, numbness, infection, internal puncture, fat embolisms, kidney and heart problems, and lidocaine toxicity. There is a need for alternative, non-surgical options for reducing fat and / or improving appearance.SUMMARY

[0004] Provided herein are cannulas having one or more markers. In some embodiments, the cannula includes a tubular body including a distal end portion and a proximal end portion, where the tubular body is sized and shaped to be inserted under a portion of skin of a subject. The cannula includes one or more markers on an external surface of the tubular body. Each of the one or markers is positioned along a corresponding location along a longitudinal axis of the tubular body. The cannulaincludes an outlet on the distal end portion of the tubular body and an inlet on the proximal end portion of the tubular body. The inlet is configured to receive, from an injection device in fluid connection with the tubular body, a fluid comprising the pharmaceutical composition to deliver a pharmaceutical composition subcutaneously through the outlet.

[0005] In some embodiments, the one or more markers include one or more recesses on the external surface of the tubular body. In some embodiments, the one or more markers include one or more protrusions on the external surface of the tubular body. In some embodiments, the one or more markers are printed on the external surface of the tubular body without forming a substantial recess or protrusion.

[0006] In some embodiments, at least a portion of the external surface of the tubular body is coated with a corrosion resistant coating material. In some embodiments, the corrosion resistant coating material includes chromium (Cr). In some embodiments, the corrosion resistant coating material includes chromium nitride (CrN).

[0007] In some embodiments, at least a portion of the external surface of the tubular body is matte. In some embodiments, at least a portion of the external surface of the tubular body is abraded.

[0008] In some embodiments, at least one of the one or more markers are colored to distinguish from another of the one or more markers.

[0009] In some embodiments, the cannula includes two or more markers on the external surface. In some embodiments, the two or more markers on the external surface are separated from each other by an equal distance.

[0010] In some embodiments, the tubular body has a length from a distal end of the tubular body to a proximal end of the tubular body of about 3 cm to about 30 cm.

[0011] In some embodiments, the tubular body has an inner diameter of about 0.2 mm to about 0.7 mm.

[0012] In some embodiments, the tubular body has an aspect ratio (length-to-width) of about 20: 1 to about 500: 1.

[0013] In some embodiments, the tubular body is made of a non-flexible material. In some embodiments, the tubular body includes a metal. In some embodiments, the tubular body includes a plastic.

[0014] In some embodiments, the outlet has a diameter of about 0.2 mm to about 0.6 mm.

[0015] In some embodiments, the outlet (e.g., an end hole, an ejection hole, an opening) is a first outlet (e.g., first end hole, ejection hole, opening ) to deliver the pharmaceutical composition at a first subcutaneous treatment site, the tubular body further including a second outlet to deliver the pharmaceutical composition at a second subcutaneous treatment site.

[0016] In some embodiments, the first outlet and the second outlet are sized and positioned to deliver the pharmaceutical composition at a same rate.

[0017] In some embodiments, the first outlet and second outlet are both at the distal end of the tubular body but circumferentially spaced about the distal end portion of the tubular body.

[0018] In some embodiments, the second outlet is positioned differently from the first outlet in the longitudinal axis.

[0019] In some embodiments, a diameter of the first outlet is larger than a diameter of the second outlet.

[0020] In some embodiments, the cannula includes a plurality of outlets on the tubular body.

[0021] In some embodiments, each of the outlets of the plurality of outlets is separated from each other by an equal distance.

[0022] Also provided herein are methods for administering a therapeutically effective amount of a pharmaceutical composition to a subcutaneous treatment area in a subject, the method comprising: puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subj ect; inserting any of the cannulas provided herein into the puncture hole in the skin to a subcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; and injecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality' of subcutaneous treatment sites.

[0023] Also provided herein are methods for inducing cell death of a plurality of adipocytes in a treatment area in a subject, the method comprising: puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subject; inserting any of the cannulas provided herein into the puncture hole in the skin to a subcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; andinjecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

[0024] In some embodiments, the cell death is due to apoptosis and / or necrosis. In some embodiments, the cell death is due to apoptosis.

[0025] Also provided herein are methods for inhibiting adipogenesis in a treatment area in a subject, the method comprising: puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subject; inserting any of the cannulas provided herein into the puncture hole in the skin to a subcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; and injecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

[0026] Also provided herein are methods of reducing subcutaneous fat in a treatment area in a subject, the method comprising: puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subject; inserting any of the cannulas provided herein into the puncture hole in the skin to a subcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; and injecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

[0027] In some embodiments, the method comprises inducing apoptosis of a plurality of adipocytes in the treatment area in the subject.

[0028] Also provided herein are methods of improving the appearance of convexity or fullness associated with fat tissue in a subject, the method comprising: puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subj ect; inserting any of the cannulas provided herein into the puncture hole in the skin to a subcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; and injecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

[0029] In some embodiments, the cannula is inserted such that one of the cannula markers is aligned with the puncture hole in the skin.

[0030] In some embodiments, an injection map contacts the skin over the subcutaneous treatment area and the injection map indicates a plurality of subcutaneous treatment sites.

[0031] In some embodiments, a method provided herein further comprises providing the injection map on the skin over the subcutaneous treatment area in the subject.

[0032] In some embodiments, a method provided herein further comprises generating the injection map prior to providing the injection map on the skin over the subcutaneous treatment area in the subject.

[0033] In some embodiments, the injection map on the skin comprises a grid having a plurality of cells, each cell of the plurality of cells corresponding to a distinct subcutaneous treatment site of the plurality of subcutaneous treatment sites. In some embodiments, each cell has a dimension of about 1 cm about 1 cm to about 3 cm x about 3 cm.

[0034] In some embodiments, providing the injection map on the skin of the subject comprises applying a temporary' tattoo onto the skin over the subcutaneous treatment area in the subject.

[0035] In some embodiments, a method provided herein further comprises one or more additional steps of injecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality' of subcutaneous treatment sites.

[0036] In some embodiments, a method provided herein comprises alternating each step of injecting the pharmaceutical composition with a step of retracting the cannula such that a subsequent cannula marker is aligned with the puncture hole in the skin.

[0037] In some embodiments, a method provided herein comprises alternating each step of injecting the pharmaceutical composition with a step of retracting the cannula such that the distal end portion of the cannula is located in a subsequent subcutaneous treatment site of the plurality' of subcutaneous treatment sites.

[0038] In some embodiments, determining the location of the distal end portion of the cannula comprises feeling the distal end portion of the cannula under the skin. In some embodiments, determining the location of the distal end portion of the cannulacomprises lining up a marker on the cannula with the puncture hole in the skin. In some embodiments, the spacing between each of the markers of the two or more markers on the cannula corresponds to the length of a cell of the injection map. In some embodiments, the spacing between each of the markers of a subset of the plurality of markers on the cannula corresponds to the length of a cell of the injection map.

[0039] In some embodiments, each injection uses a predetermined volume of the fluid. In some embodiments, the predetermined volume of the fluid is about 0.5 cc to about 3 cc. In some embodiments, the predetermined volume varies for each injection based on an amount of fat in each injection area. In some embodiments, the injection map further comprises information about an injection volume for each subcutaneous treatment site. In some embodiments, a method provided herein further comprises determining the injection volume for each subcutaneous treatment site.

[0040] In some embodiments, a method provided herein further comprises performing an ultrasound scan of the subcutaneous treatment area in the subject to determine which subcutaneous treatment site(s) contain more fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject. In some embodiments, the injection volume is increased for subcutaneous treatment site(s) containing more fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject.

[0041] In some embodiments, a method provided herein further comprises performing an ultrasound scan of the subcutaneous treatment area in the subject to determine which subcutaneous treatment site(s) contain less fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject. In some embodiments, the injection volume is decreased for subcutaneous treatment site(s) containing more fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject.

[0042] In some embodiments, the subcutaneous treatment area in the subject is in the abdomen, a flank, an inner thigh, an outer thigh, jowls, lower face, an arm, buttocks, chest, breast, back, or any other area of deposited subcutaneous fat of the subject. In some embodiments, the subcutaneous treatment area is in the back of the arm of the subject. In some embodiments, the subcutaneous treatment area is in the abdomen of the subject.

[0043] Also provided herein are kits comprising any of the cannulas provided herein; and a pharmaceutical composition. In some embodiments, a kit provided herein further comprises a syringe. In some embodiments, a kit provided herein further comprises an injection map. In some embodiments, the injection map is a temporary tattoo. In some embodiments, a kit provided herein further comprises a disinfectant to clean an injection site on a skin of a subject. In some embodiments, a kit provided herein further comprises comprising a gauze pad. In some embodiments, the pharmaceutical composition is contained within a vial or a syringe. In some embodiments, a kit provided herein further comprises instructions for performing any of the methods described herein.

[0044] Definitions

[0045] The term '‘pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary', and topical administration.

[0046] “APT’ refers to an active pharmaceutical ingredient.

[0047] The term “effective amount” as used herein, refers to a sufficient amount of a chemical entity7(e g., an API such as a compound exhibiting apoptotic activity' in an adipocyte) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system. For example, an “effective amount” can be the amount of an active pharmaceutical ingredient in a pharmaceutical composition required to provide a measurable reduction in fat and / or a visible improvement in appearance. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study or a study that assesses dose relative to subcutaneous fat quantity'. For example, the dose of an API may be increased for various quantities of subcutaneous fat until the dose that results in the highest fat reduction for each different quantity of subcutaneous fat is found. Such studies can be used to estimate the optimal dose(s) of an API for different quantities of subcutaneous fat. It will beappreciated that the optimal dose may be adjusted based on other factors, e.g., to minimize one or more side effects. For example, the optimal dose can be the dose at which the highest level of fast reduction is observed for a quantity of subcutaneous fat with minimal or no side effects. Quantities of fat can be determined using, e.g., the methods described herein.

[0048] As used herein, a "dose" refers to a measured quantity of an active pharmaceutical ingredient or pharmaceutical composition. A dose can refer to the measured quantity of an active pharmaceutical ingredient or pharmaceutical composition administered to a single treatment site. In some embodiments of any of the methods described herein, a single injection results in administration of one dose of an active pharmaceutical ingredient or pharmaceutical composition. For example, a cannula having a single outlet (e.g., at the distal end portion) can be used in the methods provided herein to administer a dose of an active pharmaceutical ingredient or pharmaceutical composition to a treatment site.

[0049] A dosage unit of a pharmaceutical composition provided herein can contain an amount of the active ingredient necessary to deliver an effective dose as described herein. In some embodiments, a pharmaceutical composition provided herein is administered as a single dose or as 2 or more doses (e.g., as 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 or more doses).

[0050] In some embodiments, a single injection can result in administration of two or more doses of an active pharmaceutical ingredient. For example, a cannula having two or more outlets (e.g., at the distal end portion) be used in the methods provided herein to administer two or more doses of an active pharmaceutical ingredient or pharmaceutical composition to two or more treatment sites.

[0051] As used herein, '‘subject,’’ “individual,” or “patient,” are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, goats, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or condition to be treated.

[0052] The term “subcutaneous” means situated or administered under the skin of a subject.

[0053] An ‘‘injection device'’ refers to a device that can be used to inject fluids into or withdraw fluids from a body of a subject. For example, an injection device can be a tube with a nozzle and piston or plunger such as a syringe. In some embodiments, an injection device can comprise a luer tip. Further non-limiting examples of an injection device include an infusion pump, a depot delivery7from a reservoir driven by a pump through tubing with a needle at the end of the tube, and a microneedling device. In some embodiments, an injection device can be manually driven. In some embodiments, an injection device can be mechanically driven.

[0054] As used herein, a “treatment area” or “subcutaneous treatment area” refers to a subcutaneous part or subcutaneous region of a subject’s body targeted for treatment with a pharmaceutical composition (e.g., any of the pharmaceutical compositions described herein). Non-limiting examples of treatment areas can include all or part of the abdomen, a flank, an inner thigh, an outer thigh, jowls, lower face, an arm, buttocks, chest, breast, or back. In some embodiments, a subcutaneous treatment area is an area of subcutaneous fat in a subject. For example, a treatment area can refer to a fat deposit in a subject’s body such as a fat deposit in the subject’s abdomen, flank, inner thigh, outer thigh, arm, back, buttocks, calf, ankle, jowls, preplatysmal submental area, breast, chest, lower face, or under an eye. In some embodiments, the treatment area or subcutaneous treatment area can include one treatment site or multiple treatment sites.

[0055] As used herein, a “treatment site” or “subcutaneous treatment site” refers to a site within a treatment area where a dose of the pharmaceutical composition is administered. In some embodiments, a treatment area contains a plurality7of treatment sites. For example, a treatment area can contain 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450. or 500 or more treatment sites. In some embodiments, a treatment area contains about 5 to about 550 treatment sites. For example, a treatment area can contain about 5 to about 15, about 5 to about 25, about 5 to about 50, about 5 to about 75, about 5 to about 100, about 5 to about 125, about 5 to about 150, about 5 to about 175, about 5 to about 200, about 5 to about 225, about 5 to about 250, about 5 to about 275, about 5 to about 300, about 5 to about 325, about 5 to about 350, about 5 to about 375, about 5 to about 400, about 5 to about 425, about 5 to about 450, about 5 to about 475, about 5 to about 500, about 15 to about 25, about 15 to about 50, about 15 to about 75, about 15 to about 100, about 15 to about 125, about 15 to about 150, about 15 to about 175, about 15 to about 200, about 15 to about 225. about15 to about 250, about 15 to about 275, about 15 to about 300, about 15 to about 325, about 15 to about 350, about 15 to about 375, about 15 to about 400, about 15 to about 425, about 15 to about 450, about 15 to about 475, about 15 to about 500, about 15 to about 550, about 25 to about 50, about 25 to about 75, about 25 to about 100, about 25 to about 125, about 25 to about 150, about 25 to about 175, about 25 to about 200, about 25 to about 225, about 25 to about 250, about 25 to about 275. about 25 to about 300, about 25 to about 325, about 25 to about 350, about 25 to about 375, about 25 to about 400, about 25 to about 425, about 25 to about 450, about 25 to about 475, about 25 to about 500, about 25 to about 550, about 50 to about 75, about 50 to about 100, about 50 to about 125, about 50 to about 150, about 50 to about 175, about 50 to about 200. about 50 to about 225, about 50 to about 250. about 50 to about 275. about 50 to about 300, about 50 to about 325, about 50 to about 350, about 50 to about 375, about 50 to about 400, about 50 to about 425, about 50 to about 450, about 50 to about 475, about 50 to about 500, about 50 to about 550, about 75 to about 100, about 75 to about 125, about 75 to about 150, about 75 to about 175, about 75 to about 200. about 75 to about 225, about 75 to about 250, about 75 to about 275, about 75 to about 300, about 75 to about 325, about 75 to about 350, about 75 to about 375, about 75 to about 400, about 75 to about 425, about 75 to about 450, about 75 to about 475, about 75 to about 500, about 75 to about 550, about 100 to about 125, about 100 to about 150, about 100 to about 175, about 100 to about 200. about 100 to about 225, about 100 to about 250, about 100 to about 275, about 100 to about 300, about 100 to about 325, about 100 to about 350, about 100 to about 375, about 100 to about 400, about 100 to about 425, about 100 to about 450, about 100 to about 475, about 100 to about 500, about 100 to about 550, about 125 to about 150, about 125 to about 175, about 125 to about 200, about 125 to about 225, about 125 to about 250, about 125 to about 275, about 125 to about 300, about 125 to about 325, about 125 to about 350, about 125 to about 375, about 125 to about 400, about 125 to about 425, about 125 to about 450, about 125 to about 475, about 125 to about 500, about 125 to about 550, about 150 to about 175, about 150 to about 200, about 150 to about 225, about 150 to about 250, about 150 to about 275, about 150 to about 300, about 150 to about 325, about 150 to about 350, about 150 to about 375, about 150 to about 400, about 150 to about 425, about 150 to about 450, about 150 to about 475, about 150 to about 500, about 150 to about 550, about 175 to about 200, about 175 to about 225. about 175 to about 250. about 175 to about 275,about 175 to about 300, about 175 to about 325, about 175 to about 350, about 175 to about 375, about 175 to about 400, about 175 to about 425. about 175 to about 450, about 175 to about 475, about 175 to about 500, about 175 to about 550, about 200 to about 225, about 200 to about 250, about 200 to about 275, about 200 to about 300, about 200 to about 325, about 200 to about 350, about 200 to about 375, about 200 to about 400, about 200 to about 425, about 200 to about 450. about 200 to about 475, about 200 to about 500, about 200 to about 550, about 225 to about 250, about 225 to about 275, about 225 to about 300, about 225 to about 325, about 225 to about 350, about 225 to about 375, about 225 to about 400, about 225 to about 425, about 225 to about 450, about 225 to about 475, about 225 to about 500, about 225 to about 550, about 250 to about 275, about 250 to about 300, about 250 to about 325, about 250 to about 350, about 250 to about 375, about 250 to about 400, about 250 to about 425, about 250 to about 450, about 250 to about 475, about 250 to about 500, about 250 to about 550, about 275 to about 300, about 275 to about 325, about 275 to about 350, about 275 to about 375, about 275 to about 400, about 275 to about 425, about 275 to about 450, about 275 to about 475, about 275 to about 500, about 275 to about 550, about 300 to about 325, about 300 to about 350, about 300 to about 375, about 300 to about 400, about 300 to about 425, about 300 to about 450, about 300 to about 475, about 300 to about 500, about 300 to about 550, about 325 to about 350, about 325 to about 375, about 325 to about 400. about 325 to about 425. about 325 to about 450, about 325 to about 475, about 325 to about 500, about 325 to about 550, about 350 to about 375, about 350 to about 400, about 350 to about 425, about 350 to about 450, about 350 to about 475, about 350 to about 500, about 350 to about 550, about 375 to about 400, about 375 to about 425, about 375 to about 450. about 375 to about 475, about 375 to about 500, about 375 to about 550, about 400 to about 425, about 400 to about 450, about 400 to about 475, about 400 to about 500, about 400 to about 550, about 425 to about 450, about 425 to about 475, about 425 to about 500, about 425 to about 550, about 450 to about 475, about 450 to about 500. about 450 to about 550, about 475 to about 500, about 475 to about 550, or about 500 to about 550 treatment sites.

[0056] As used herein, an “injection map” refers to a representation of the locations of treatment sites that can be placed on the skin of a subject, and used, for example, to help place the cannula at a treatment site in the treatment area. For example, an injectionmap on the skin over a treatment area of a subject can be used to align one or more outlets in the cannula with one or more subcutaneous treatment sites.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0058] The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings, and from the claims.DESCRIPTION OF DRAWINGS

[0059] FIG. 1 is a diagram of an example of a cannula having markings.

[0060] FIG.2 is a diagram of an example of a distal end portion of a cannula.

[0061] FIG.3 is a diagram of an example of a cannula including multiple outlets.

[0062] FIGS. 4A-4C are diagrams illustrating a method provided herein. FIG. 4A shows a side view of skin over a subcutaneous treatment area of a subject in which a cannula has been inserted into the subcutaneous treatment area and a pharmaceutical composition administered to a first subcutaneous treatment area. FIG. 4B depicts retraction of the cannula to administer a pharmaceutical composition to a second subcutaneous treatment area. FIG. 4C depicts further retraction of the cannula to administer a pharmaceutical composition to a third subcutaneous treatment area.

[0063] FIG.5 is a diagram of a grid-type injection map.DETAILED DESCRIPTION

[0064] The present disclosure is based, at least in part, on a unique cannula having one or more markers on its external surface to indicate one or more locations along a longitudinal axis of the cannula. In various embodiments, a cannula provided herein can be used for subcutaneous administration of a pharmaceutical composition (e g., any of the pharmaceutical compositions provided herein). For example, the one or moremarkers on a cannula provided herein can be designed and positioned to provide precise information about the location of, e.g., the distal end portion or one or more outlets (e.g., ejection holes or openings) of the cannula under the skin of a subject. In some embodiments, a cannula provided herein is useful for accurately administrating a pharmaceutical composition (e.g., any of the pharmaceutical compositions provided herein) to a target subcutaneous treatment site.

[0065] Also provided in the present disclosure are methods of using a cannula provided herein to administer a therapeutically effective amount of a pharmaceutical composition (e.g., any of the pharmaceutical compositions provided herein) to a subcutaneous treatment area in a subject. In some embodiments, the methods provided herein include methods for inducing cell death of a plurality of adipocytes in a treatment area in a subject, and / or reducing fat in a treatment area in a subject, and / or improving the appearance of convexity or fullness associated with fat tissue in a subject. In some embodiments, such methods further include using an injection map on the skin over a treatment area of the subject. An injection map can be useful for, e.g., aligning one or more outlets (e.g., ejection holes or openings) of a cannula provided herein with one or more subcutaneous treatment sites.

[0066] A pharmaceutical composition can be administered to multiple subcutaneous treatment sites with one puncture in skin using a cannula provided herein. Accordingly, the methods described herein can advantageously reduce the number of punctures in skin needed to, e.g., administer pharmaceutical compositions useful for inducing cell death of adipocytes in a subject and / or reducing subcutaneous fat in a subject, compared to ty pical routes of administration such as those using a syringe and needle.

[0067] Cannulas having one or more markers are shown in FIGS. 1-3. A method of administering a pharmaceutical composition to a subcutaneous treatment site using a cannula provided herein is shown in FIGS.4A-4C. An injection map that can be applied to the skin of a subject is shown in FIG.5.Cannulas

[0068] In FIG. 1, an injection system 50 includes an injection device 90 and a cannula 100 having one or more markers 112. The cannula 100 includes a tubular body 102. The tubular body 102 is an elongate member extending along a longitudinal axis and extending between a distal end portion 104 and a proximal end portion 106 of thecannula 100. The cannula 100 includes an outlet 108 on the distal end portion 104 and an inlet 110 on the proximal end portion 106. The outlet 108 is, for example, an end hole or opening or ejection hole or opening from which a pharmaceutical composition is ejected. The tubular body 102 includes a passageway 114 extending from the distal end portion 104 to the proximal end portion 106 and fluidically coupling the inlet 110 to the outlet 108.

[0069] In some embodiments, the tubular body 102 can be sized and shaped to be inserted under a portion of skin of a subject. For example, the distal end portion 104 of the tubular body 102 can be sized and shaped to be inserted under the portion of the skin of the subject, thereby enabling a remainder of the tubular body 102 to be inserted under the portion of the skin. In some embodiments, the distal end portion 104 of the tubular body 102 can be tapered so that the distal end portion 104 can be more easily inserted into a puncture hole on skin of a subject. The inlet 110 is configured to receive a fluid including the pharmaceutical composition from an injection device 90 in fluid connection with the tubular body 102. For example, the injection device 90 can be fluidically connected to the inlet 110.

[0070] The inj ection device 90 is operable to deliver the fluid through the outlet 108 of the tubular body 102. In some embodiments, the injection device 90 contains the fluid including the pharmaceutical composition. The injection device 90, for example, includes a reservoir containing the fluid. In some embodiments, the injection device 90 is connected to an external reservoir containing the fluid. The injection device 90, when fluidically connected to the inlet 110, is configured to eject a pharmaceutical composition subcutaneously. Specifically, the injection device 90 is configured to eject the pharmaceutical composition (e.g., the fluid including the pharmaceutical composition) through the inlet 110, through the passageway 114, and then from the outlet 108 into a region under the portion of the skin. For example, in the example of FIG. 1, the injection device 90 is a syringe, although, as discussed in this specification, the injection device can vary in embodiments. The injection device 90 includes a drive mechanism 92 that applies force to the fluid to be ejected from the outlet 108. In the example depicted in FIG. 1, the drive mechanism 92 is a manually-operable drive mechanism including a plunger. The user applies a force to the plunger to eject the fluid through the outlet 108. In some embodiments, the drive mechanism 92 can include a powered actuator, e.g.. a pump, that generates the force applied to the fluid..

[0071] As illustrated in FIG. 1, the markers 112 are positioned on an external surface of the tubular body 102. While four individual markers are illustrated in FIG. 1, the number of markers is not limited to any number. For example, there can be only one marker or two, three, or more than four markers on the tubular body 102. The markers 112 can be distributed along the longitudinal axis of the tubular body 102. For example, each of the markers 112 is positioned at a corresponding location along the longitudinal axis of the tubular body 102 and thus at a corresponding distance from the distal end portion 104 of the cannula 100. The markers 112 indicate to a user of the cannula 100 (e.g., a medical professional operating the cannula) a position of the distal end portion 104, e.g., relative to a puncture hole on the skin through which the cannula 100 is inserted. For example, when any one of the markers 112 is aligned with the puncture hole in the skin, the marker aligned with the puncture hole in the skin can provide to the user precise information about a position of the distal end portion 104 under the skin relative to the puncture hole on the skin. The aligned marker can indicate to the user a length of the cannula 100 or the tubular body 102 that has been inserted under the portion of the skin of the subject.

[0072] The series of markers can enable subcutaneous injections at multiple subcutaneous treatment sites in which the cannula 100 is inserted through puncture holes at the treatment sites at vary ing distances as a function of the treatment site. For example, the cannula 100 can be inserted at a first distance corresponding to one of the markers 112 at a first treatment site and can be inserted at a second distance corresponding to another one of the markers 112 at a second treatment site. The same cannula 100 can be used at both treatment sites, with the markers 112 enabling the user to insert the cannula 100 at a corresponding desired distance, as indicated by the markers 112, at each treatment site. Moreover, the markers 112 enable the cannula 100, inserted through the same puncture hole, to deliver the pharmaceutical composition to multiple locations under the portion of the skin. For example, the cannula 100 can be inserted until the proximalmost marker of the markers 112 is aligned with the puncture hole, and then the user can operate the injection device 90 to deliver the fluid at a first location under the portion of the skin corresponding to the location of the outlet 108. The user can then retract the cannula 100 from the skin until the next marker of the markers 112 (distal to the proximalmost marker) is aligned with the puncture hole, and then the user can operate the injection device 90 to deliver the fluid at a second locationunder the portion of the skin corresponding to the location of the outlet 108. Thus, by moving the cannula 100 from one location indicated by one of the markers 112 to another location indicated by another of the markers 112, the user can deliver the fluid subcutaneously without requiring a separate puncture hole in the skin.

[0073] The markers 112 are visually distinguishable from the unmarked portion of the tubular body 102 and are configured to be aligned with the puncture hole formed in the skin as the cannula 100 is inserted through the puncture hole. The markers 112 can be formed on the external surface of the tubular body 102 by various methods. For example, they can be formed by engraving, printing, or its combination. In some embodiments, the markers 112 include one or more recesses or one or more protrusions on the external surface of the tubular body 102. In some embodiments, the one or more markers include one or more protrusions on the external surface of the tubular body. In some embodiments, the markers 112 are printed on the external surface of the tubular body 102. For example, ink jet printing, three dimensional (3D) printing, or other methods of printing can be used. In some embodiments, the markers 112 can be printed without forming a substantial recess or protrusion on a smooth surface, e.g., no recess or protrusion that varies the diameter of the tubular body 102 by more than 0.1%. In some embodiments, at least one of the markers 112 is colored to distinguish from another marker. In some embodiments, at least one of the markers 112 is engraved and colored. In some embodiments, to align with the puncture hole, the markers 112 extend in a direction perpendicular to the longitudinal axis of the tubular body 102. Each of the markers 112 includes, for example, one or more lines that are perpendicular to the longitudinal axis of the tubular body 102.

[0074] In some embodiments, the markers 112 are visually distinguishable from one another so that the user can easily determine which of the markers 112 is aligned with the puncture hole. For example, the markers 112 can be differently colored from one another. In some embodiments, each of the markers 112 includes one or more fiducials (e.g., a line, a circle, a shape, or other fiducial), and the quantities of fiducials for the markers 112 differ from one another. For example, the distalmost marker of the markers 112 can include one fiducial, the next marker can include two fiducials, etc.

[0075] Further, in some embodiments, at least a portion of the external surface of the tubular body 102 is matte. In some embodiments, the matte portion can be used as the markers 112. In some embodiments, at least a portion of the external surface of thetubular body 102 is abraded. In some embodiments, the abraded portion can be used as the markers 112.

[0076] In some embodiments, each of the markers 112 is positioned to assist multiple subcutaneous injections. In one or more embodiments, each marker is separated from each other by an equal distance.

[0077] Dimensions of the tubular body 102 are designed to be suitable for various medical treatments, e.g., subcutaneous retrograde injections. The dimensions of the tubular body 102 can be selected to provide sufficient structural strength to the tubular body 102 for insertion into a treatment area and / or treatment site while reducing a diameter of the tubular body 102 to reduce trauma to subcutaneous tissue of the subject during the insertion. The structural strength of the tubular body 102 can vary depending on a type of the subcutaneous tissue into which the tubular body 102 is inserted. For example, organ tissue and muscular tissue may resist insertion of the tubular body 102 more than fatty tissue and hence require higher structural strength for the tubular body 102 to prevent the tubular body 102 from buckling during insertion. The tubular body 102 can have a sufficient length to reach multiple treatment sites, e.g., in an abdomen, and a small diameter to be inserted through a puncture hole formed on the skin of the subject. In some embodiments, the treatment area is about 10 to 15 cm long, or less than 30 cm. Accordingly, in some embodiments, the length of the tubular body 102 can be about 3 cm to about 30 cm, about 3 cm to about 20 cm, about 3 cm to about 10 cm, about 3 cm to about 5 cm, about 5 cm to about 30 cm, about 10 cm to about 30 cm, or about 20 cm to about 30 cm. In one embodiment, the length of the tubular body 102 is about 5 cm to about 10 cm.

[0078] In some embodiments, the tubular body 102 has an inner diameter or the passageway 114 extending through the tubular body 102 has a diameter of about 0.2 mm to about 1.6 mm. For example, about 1.4 mm to about 1.6 mm, about 1.2 mm to about 1.6 mm, about 1 mm to about 1.6 mm, about 0.9 mm to about 1.6 mm, about 0.8 mm to about 1.6 mm, about 0.7 mm to about 1.6 mm, about 1.2 mm to about 1.4 mm. about 1 mm to about 1.4 mm, about 0.9 mm to about 1.4 mm, about 0.8 mm to about 1.4 mm, about 0.7 mm to about 1.4 mm, about 1 mm to about 1.2 mm, about 0.9 mm to about 1.2 mm, about 0.8 mm to about 1.2 mm, about 0.7 mm to about 1.2 mm, about 0.9 mm to about 1 mm. about 0.8 mm to about 1 mm, about 0.7 mm to about 1 mm, about 0.8 mm to about 0.9 mm, about 0.7 mm to about 0.9 mm, about 0.8 mm to about 0.9 mm,about 0.2 mm to about 0.7 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 0.3 mm, about 0.4 mm to about 0.7 mm. or about 0.6 mm to about 0.7 mm.

[0079] In some embodiments, the gauge of the tubular body 102 is about 12 to about 30 gauge. For example, the gauge of the tubular body 102 can be about 12 to about 14 gauge, about 12 to about 16 gauge, about 12 to about 18 gauge, about 12 to about 20 gauge, about 12 to about 22 gauge, about 12 to about 24 gauge, about 14 to about 16 gauge, about 14 to about 18 gauge, about 14 to about 20 gauge, about 14 to about 22 gauge, about 14 to about 24 gauge, about 16 to about 18 gauge, about 16 to about 20 gauge, about 16 to about 22 gauge, about 16 to about 24 gauge, about 18 to about 20 gauge, about 18 to about 22 gauge, about 18 to about 24 gauge, about 20 to about 22 gauge, about 20 to about 24 gauge, or about 22 to about 24 gauge. In some embodiments, the gauge of the tubular body 102 is about 18 to about 30 gauge, about 18 to about 28 gauge, about 18 to about 25 gauge, about 18 to about 23 gauge, about 20 to about 30 gauge, about 23 to about 30 gauge, or about 25 to about 30 gauge. In some embodiments, the gauge of the tubular body 102 is about 12 gauge, about 13 gauge, about 14 gauge, about 15 gauge, about 16 gauge, about 17 gauge, about 18 gauge, about 19 gauge, about 20 gauge, about 21 gauge, about 22 gauge, about 23 gauge, about 24 gauge, about 25 gauge, about 26 gauge, about 27 gauge, about 28 gauge, about 29 gauge, or about 30 gauge.

[0080] In some embodiments, the tubular body 102 has an aspect ratio (length-to-width) of about 20:1 to about 500:1, about 20:1 to about 300:1, about 20:1 to about 100:1, about 20:1 to about 50:1, about 50:1 to about 500:1, about 100:1 to about 500:1, or about 300:1 to about 500: 1.

[0081] The tubular body 102 can be made of one or more materials suitable for medical applications. For example, a material that is safe and cost effective for subcutaneous use in a subject can be used. Further, the tubular body 102 can be applicable for common sterilization conditions. Non-limiting examples of materials for a tubular body include a metal, a silicone, and a biocompatible plastic. In some embodiments, stainless steel, aluminum, a silicone, polytetrafluoroethylene (PTFE), a urethane, or a combination thereof can be used. In some embodiments, the material for the tubular body 102 is non-flexible when inserted subcutaneously. In some embodiments, the markers 112 can include a material different from the bulk of the tubular body 102.

[0082] Further, the tubular body 102 can also include a surface coating. The surface coating can provide the tubular body 102 with various features such as smoothness to reduce friction, corrosion resistance, and biocompatibility. In some embodiments, at least a portion of the external surface of the tubular body 102 is coated with a corrosion resistant coating material. In some embodiments, the corrosion resistant coating material includes chromium (Cr) such as chromium nitride (CrN). In some embodiments, the coating material includes silicone, polytetrafluoroethylene (PTFE), polyethylene glycol (PEG), polyethylene oxide (PEO), or other suitable polymeric materials.

[0083] The outlet 108 is shaped and positioned to deliver a pharmaceutical composition subcutaneously. The distal end portion 104 of the tubular body 102 can have any suitable shape, e.g., a beveled needle point, a blunt needle point, a conical needle, or other designs known for medical treatment applications. In some embodiments, the distal end portion 104 is beveled with an angle of about 15° to about 30°, about 15° to about 25°, about 15° to about 20°, about 20° to about 30°, or about 25° to about 30°. In some embodiments, the outlet 108 can be positioned at a lateral of the tip of the distal end portion 104.

[0084] FIG. 2 illustrates the distal end portion 104 of a cannula 100 having the outlet 108 in accordance with some embodiments. The cannula 100 of FIG. 2 can include features similar to those described with respect to the features of the cannula 100 of FIG. 1 except that the distal end portion of the cannula 100 of FIG. 2 can differ from the distal end portion fo the cannula 100 of FIG. 1. For example, as illustrated in FIG.2, the distal end portion 104 can include a blunt tip 200 designed to be used in aesthetic procedures. The outlet 108 can be positioned on a lateral portion 202 of the tubular body 102, e.g.. along a lateral surface of the tubular body 102. The position of the outlet 108 on the lateral surface 204 on the distal end portion 104 but not at the tip 200 can prevent clogging issues that may occur as a result of inserting the cannula 100 into subcutaneous fat.

[0085] In some embodiments, the tip 200 of the distal end portion 104 has a round shape with two or more openings, e.g., including the outlet 108. Specifically, the tip 200 can include multiple outlets through which the pharmaceutical composition can be ejected. For example, the outlet 108 can be a first outlet, and the cannula 100 can include a second outlet on the distal end portion 104. The first and second outlets can becircumferentially spaced from one another and can be located at the approximately the same positions along the longitudinal axis.

[0086] In some embodiments, the outlet 108 has a diameter of about 0.2 mm to about 0.6 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 0.4 mm, about 0.2 mm to about 0.3 mm, about 0.3 mm to about 0.6 mm, about 0.4 mm to about 0.6 mm, or about 0.5 mm to about 0.6 mm.

[0087] A cannula provided herein can include two or more outlets. A cannula with multiple outlets can improve the efficiency of administering a pharmaceutical composition. For example, the presence of multiple outlets can enable the simultaneous delivery (e.g., administration of a pharmaceutical composition described herein) to multiple subcutaneous treatment sites by using a single puncture hole. Most parts of a cannula having two or more outlets can be identical to those described above referring to FIG. 1, and thus will not be repeated.

[0088] FIG. 3 is a schematic diagram of another example of a cannula 300 having two outlets. The cannula 300 can include features similar to the features of the cannula 100 of FIG. 1. In FIG. 3, the cannula 300 has a second outlet 302 in addition to the outlet 108 (also referred to as the first outlet 108 in the context of FIG. 3). The cannula 300 can simultaneously deliver the pharmaceutical composition to two different subcutaneous treatment sites after being inserted into a single puncture hole.

[0089] In some embodiments, the first outlet 108 and the second outlet 302 are sized and positioned to deliver the pharmaceutical composition at the same rate. Accordingly, the size of each outlet can be designed based on each of their locations and the target flow rate. In embodiments in which multiple outlets are present, each outlet of the multiple outlets can be larger than all outlets proximal to that outlet. For example, a diameter of the first outlet 108 can be larger than a diameter of the second outlet 302. In some embodiments, as illustrated in FIG. 3, the first outlet 108 is on the distal end portion 104, and the second outlet 302 is positioned at about 20% to about 40% of the total length of the tubular body 102 away from the distal end portion 104. In other embodiments, the relative distance of the second outlet 302 from the distal end portion 104 can be about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 50%, about 30% to about 50%, or about 40% to about 50% of the total length of the tubular body 102.

[0090] In some embodiments, the cannula 300 can include more than two outlets on the tubular body 102. For example, the cannula 300 can include 2, 3, 4, 5, 6, 7, 8. 9, 10, or more outlets. In some embodiments, each outlet is sized and positioned to deliver a pharmaceutical composition at the same rate at each outlet. In some embodiments, the diameters of the outlets gradually increase along the longitudinal axis of the cannula toward the distal end portion. In some embodiments, the diameter of each outlet is such that when the cannula contains a fluid (e.g., a fluid comprising a pharmaceutical composition) the surface tension at each outlet can maintain the fluid inside the cannula.

[0091] In some embodiments, the outlets are evenly spaced apart along the longitudinal axis of the cannula 300.

[0092] In some embodiments, the tubular body 102 has inner partitions that guide the flow of the fluid containing the pharmaceutical composition. For example, the inner partitions may be located in the passageway 114 of the tubular body 102 to divert flow of the fluid through the passageway 114. The tubular body 102 can, in some embodiments, include a partition for each corresponding outlet. The partition can be positioned to direct the fluid to the outlet. Moreover, in some embodiments, the partitions can modulate a flow rate of the fluid through the passageway 114. The partitions can be designed and positioned in the passageway 114 of the tubular body 102 to enable or assist the uniform delivery of the fluid to the multiple outlets.Methods

[0093] A cannula provided herein can be used to deliver a pharmaceutical composition to one or more subcutaneous treatment sites. For example, a cannula provided herein can be used to deliver a pharmaceutical composition (e.g., any of the pharmaceutical compositions described herein) to a particular treatment site so as to provide local administration of the active ingredient(s) to the site in need of treatment. In some embodiments, relatively low systemic exposure of the pharmaceutical compositions described herein occurs during said local administration.

[0094] Provided herein are methods for administenng a therapeutically effective amount of a pharmaceutical composition to a subcutaneous treatment area (e.g., any of the subcutaneous treatment areas described herein) in a subject, the method comprising: puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subject; inserting a cannula provided herein into the puncture hole in the skin to asubcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; and injecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

[0095] In some embodiments, a method provided herein includes inducing cell death of a plurality of adipocytes in a treatment area in a subject and / or inhibiting adipogenesis of a plurality of adipocytes in a treatment area in a subj ect. In some embodiments, the cell death is due to apoptosis and / or necrosis. In some embodiments, the cell death is due to apoptosis. Cell death through apoptosis rather than necrosis can help minimize side effects. Compositions that reduce fat locally through necrosis can lead to necrosis of surrounding cells, inflammation, and pain. In some embodiments, a method provided herein includes inhibiting adipogenesis in a treatment area in a subject.

[0096] In some embodiments, a method provided herein includes reducing subcutaneous fat in a treatment area in a subject. In some embodiments, a method provided herein includes improving the appearance of convexity or fullness associated with fat tissue in a subject. For example, reducing subcutaneous fat in a treatment area and / or improving the appearance of convexity or fullness associated with fat tissue in a subject can include inducing apoptosis of a plurality of adipocytes in the treatment area in the subject.

[0097] In some embodiments, the cannula is inserted such that one of the cannula markers is aligned with the puncture hole in the skin.

[0098] The methods provided herein can further include one or more additional steps of injecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site. In some embodiments, the methods provided herein include alternating each step of injecting the pharmaceutical composition with a step of retracting the cannula such that a subsequent cannula marker is aligned with the puncture hole in the skin of a subject.

[0099] FIGS. 4A-4C are schematics showing side views of a treatment area 400 during this method at different stages. In FIG. 4A, a syringe 402, or a similar injection device, containing a pharmaceutical composition (e.g., any of the pharmaceutical compositions described herein) can be attached to the inlet of a cannula 100 having one or more markers (e.g., akin to the markers 112 of FIG. 1). The skin 406 can be puncturedto form a puncture hole 404 in or near the treatment region 400. For example, the puncture hole 404 can be formed proximal to subcutaneous treatment sites 408, 410. and 412, e.g., using a puncture device or needle separate from the syringe 402. In some embodiments, the cannula 100 is the puncture device. In such embodiments, the cannula 100 can be inserted (as described next) as the puncture hole is formed by the cannula 100. In embodiments in which the puncture hole 404 is formed using a puncture device separate from the cannula 100, the puncture device can be used to form a pilot hole into which the cannula 100 is inserted. A diameter of the tubular body of the cannula 100 can be larger than a diameter of the puncture device such that the tubular body of the cannula 100 stretches the pilot hole formed by the puncture device as the tubular body of the cannula 100 is inserted into the pilot hole. The gauge of the tubular body of the cannula 100 can be one to two lower than the gauge of the puncture device. In FIG. 4A, the quantity and locations of subcutaneous treatment sites are exemplary, and treatment sites, in embodiments, are not limited to those illustrated in FIGS. 4A-C.

[0100] After the puncture hole 404 is formed, the cannula 100 can be inserted into the puncture hole 404 in the skin 406. The cannula 100 can be inserted through the puncture hole and under the skin until, e.g., the distal end portion of the cannula 100 reaches one of the subcutaneous treatment sites (e.g., site 408 in FIG.4A). The markers of the cannula 100 can be used to indicate to a user of the cannula 100 a location of the distal end portion of the cannula 100 (e.g.. the distal end portion 104 of the cannula 100 of FIG. 1), e.g., relative to the puncture hole 404 through which the cannula 100 is inserted or relative to the subcutaneous treatment site where the puncture hole 404 is located. One of the markers of the cannula 100 can be used to identify the location of the distal end portion of the cannula. For example, the cannula 100 can be inserted through the puncture hole 404 and under the skin until one of the markers (e.g., a first marker) is aligned with the puncture hole 404. In some embodiments, after the marker is aligned with the puncture hole 404, the user can determine the location of the distal end portion of the cannula based on the number of markers that have not been inserted into the skin and that are visible to the user (e.g., 0 visible markers, 1 visible markers, 2 visible markers, etc.). The number of visible markers is, for example, inversely proportional to the distance between the distal end portion of the cannula and the puncture hole 404.

[0101] After the the market is aligned with the puncture hole 404, a predetermined amount of the pharmaceutical composition can be injected from the syringe 402 to at least one subcutaneous treatment site (e.g., a first treatment site, e.g., site 408 in FIG.4A). As described in this specification, in some embodiments, the pharmaceutical composition can be delivered to multiple outlets along the tubular body of the cannula 100, while in other embodiments, the pharmaceutical composition can be delivered to a single outlet of the tubular body of the cannula 100.

[0102] After completing an injection, the cannula 100 can be retracted fully or partly. In some embodiments, the cannula 100 can be partially retracted without being removed from the puncture hole 404 to allow the pharmaceutical composition to be delivered to another treatment site. For example, the cannula can be retracted until the distal end portion is located at a subsequent subcutaneous treatment site (e.g., a second treatment site, e.g., site 410 in FIG. 4B). In some embodiments, the cannula 100 is retracted until a subsequent cannula marker (e.g., a second cannula marker) is aligned with the puncture hole 404. In some embodiments, determining the location of the distal end portion of the cannula 100 comprises feeling the distal end portion of the cannula under the skin. For example, a user of the cannula 100 can manually (e g., using a finger or hand) feel the cannula 100 under the skin of the subject to determine the location of the distal end portion.

[0103] Alternating steps of injecting a pharmaceutical composition with retracting the cannula can be repeated one or more times such that the pharmaceutical composition is administered to multiple subcutaneous treatment sites through a single puncture hole. In some embodiments, a pharmaceutical composition described herein is administered to two or more sites in the treatment area. For example, a pharmaceutical composition described herein can be administered to 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, or 40 or more sites in the treatment area.

[0104] In some embodiments, the steps can be repeated until the cannula 100 is entirely pulled out of the skin 406. For example, FIG. 4C illustrates the step of the third injection at the third treatment site 412. In some embodiments, subsequent injections can be further performed through a different puncture hole. For example, subsequent injections can be further performed.

[0105] In some embodiments, a pharmaceutical composition described herein is administered to the subcutaneous treatment area in a subject via at least 2 injections(e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, or 40 or more injections to the subcutaneous treatment area in the subject). A plurality of subcutaneous treatment sites can be spaced throughout the subcutaneous treatment area. For example, a pharmaceutical composition described herein can be administered to a plurality of subcutaneous treatment sites that are spaced about 0.1 cm to about 5 cm apart (e.g., about 0.1 cm to about 1 cm, about 0.1 cm to about 2 cm, about 0.5 cm to about 1.5 cm. about 0.5 cm to about 2.5 cm, or about 1 cm to about 2 cm apart). In some embodiments, a pharmaceutical composition described herein can be administered to a plurality of subcutaneous treatment sites that are spaced about 0.1 cm, about 0.5 cm, about 1 cm, about 1.5 cm, about 2 cm, about 3 cm, about 4 cm, or about 5 cm apart. In some embodiments, the subcutaneous treatment sites are evenly spaced throughout the subcutaneous treatment area. In some embodiments, the spacing between subcutaneous treatment sites can vary throughout the subcutaneous treatment area.

[0106] In some embodiments, the one or more injections are guided by imaging. For example, imaging can be used to help localize the placement of the cannula. In some embodiments, the one or more injections are guided by ultrasound imaging, computerized tomography (CT) scans, or magnetic resonance imaging (MRI).

[0107] The methods provided herein can further include using an injection map.FIG. 5 illustrates an example of an injection map 500. For example, the steps of puncturing and injecting can be aided with an injection map (FIG. 5) that contacts the skin over the subcutaneous treatment area. Such injection maps can indicate locations for puncture holes and / or locations of subcutaneous treatment sites. For example, the injection map 500 includes multiple cells 502 (one of which is marked in FIG. 5) that indicate the locations for puncture holes to be formed and / or indicate the locations of subcutaneous treatment sites. In some embodiments, a method provided herein further includes providing an injection map (e.g., the injection map 500) on the skin of the subject over the subcutaneous treatment area in the subject. For example, the injection map can be transferred from a substrate (e.g.. for a temporary tattoo corresponding to the injection map) where the injection map is initially generated onto the skin of the subject. In other examples, the injection map can be directly generated on the skin of the subject, e.g., using a physical stencil or a light-based stencil.

[0108] An injection map can include a plurality of cells. For example, an injection map can include 5. 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70. 80. 90. 100, 150. 200, 250,300, 350, 400, 450, or 500 or more cells. In some embodiments, an injection map includes about 5 to about 550 cells. For example, an injection map can include about 5 to about 15, about 5 to about 25, about 5 to about 50, about 5 to about 75, about 5 to about 100, about 5 to about 125, about 5 to about 150, about 5 to about 175, about 5 to about 200, about 5 to about 225, about 5 to about 250, about 5 to about 275, about 5 to about 300, about 5 to about 325, about 5 to about 350, about 5 to about 375, about 5 to about 400, about 5 to about 425, about 5 to about 450, about 5 to about 475, about 5 to about 500, about 15 to about 25, about 15 to about 50, about 15 to about 75, about 15 to about 100, about 15 to about 125, about 15 to about 150, about 15 to about 175, about 15 to about 200, about 15 to about 225, about 15 to about 250, about 15 to about 275, about 15 to about 300, about 15 to about 325, about 15 to about 350, about 15 to about 375, about 15 to about 400, about 15 to about 425, about 15 to about 450, about 15 to about 475, about 15 to about 500, about 15 to about 550, about 25 to about 50, about 25 to about 75, about 25 to about 100, about 25 to about 125, about 25 to about 150, about 25 to about 175, about 25 to about 200, about 25 to about 225. about 25 to about 250, about 25 to about 275, about 25 to about 300, about 25 to about 325, about 25 to about 350, about 25 to about 375, about 25 to about 400, about 25 to about 425, about 25 to about 450, about 25 to about 475, about 25 to about 500, about 25 to about 550, about 50 to about 75, about 50 to about 100, about 50 to about 125, about 50 to about 150, about 50 to about 175, about 50 to about 200, about 50 to about 225, about 50 to about 250, about 50 to about 275, about 50 to about 300, about 50 to about 325, about 50 to about 350, about 50 to about 375, about 50 to about 400, about 50 to about 425, about 50 to about 450, about 50 to about 475, about 50 to about 500, about 50 to about 550, about 75 to about 100, about 75 to about 125, about 75 to about 150, about 75 to about 175, about 75 to about 200, about 75 to about 225, about 75 to about 250, about 75 to about 275, about 75 to about 300, about 75 to about 325, about 75 to about 350, about 75 to about 375, about 75 to about 400, about 75 to about 425, about 75 to about 450, about 75 to about 475, about 75 to about 500, about 75 to about 550, about 100 to about 125, about 100 to about 150, about 100 to about 175, about 100 to about 200, about 100 to about 225, about 100 to about 250, about 100 to about 275, about 100 to about 300, about 100 to about 325, about 100 to about 350, about 100 to about 375, about 100 to about 400, about 100 to about 425, about 100 to about 450, about 100 to about 475, about 100 to about 500, about 100 to about 550, about 125 to about 150, about 125 toabout 175, about 125 to about 200, about 125 to about 225, about 125 to about 250, about 125 to about 275, about 125 to about 300, about 125 to about 325, about 125 to about 350, about 125 to about 375, about 125 to about 400, about 125 to about 425, about 125 to about 450, about 125 to about 475, about 125 to about 500, about 125 to about 550, about 150 to about 175, about 150 to about 200, about 150 to about 225, about 150 to about 250, about 150 to about 275, about 150 to about 300, about 150 to about 325, about 150 to about 350, about 150 to about 375, about 150 to about 400, about 150 to about 425, about 150 to about 450, about 150 to about 475, about 150 to about 500, about 150 to about 550, about 175 to about 200, about 175 to about 225, about 175 to about 250, about 175 to about 275, about 175 to about 300, about 175 to about 325, about 175 to about 350. about 175 to about 375. about 175 to about 400, about 175 to about 425, about 175 to about 450, about 175 to about 475, about 175 to about 500, about 175 to about 550, about 200 to about 225, about 200 to about 250, about 200 to about 275, about 200 to about 300, about 200 to about 325, about 200 to about 350, about 200 to about 375, about 200 to about 400. about 200 to about 425, about 200 to about 450, about 200 to about 475, about 200 to about 500, about 200 to about 550, about 225 to about 250, about 225 to about 275, about 225 to about 300, about 225 to about 325, about 225 to about 350, about 225 to about 375, about 225 to about 400, about 225 to about 425, about 225 to about 450. about 225 to about 475, about 225 to about 500, about 225 to about 550, about 250 to about 275, about 250 to about 300, about 250 to about 325, about 250 to about 350, about 250 to about 375, about 250 to about 400, about 250 to about 425, about 250 to about 450, about 250 to about 475, about 250 to about 500, about 250 to about 550, about 275 to about 300, about 275 to about 325, about 275 to about 350, about 275 to about 375, about 275 to about 400, about 275 to about 425, about 275 to about 450, about 275 to about 475, about 275 to about 500, about 275 to about 550, about 300 to about 325, about 300 to about 350, about 300 to about 375, about 300 to about 400, about 300 to about 425, about 300 to about 450, about 300 to about 475, about 300 to about 500, about 300 to about 550, about 325 to about 350, about 325 to about 375, about 325 to about 400, about 325 to about 425, about 325 to about 450, about 325 to about 475, about 325 to about 500, about 325 to about 550, about 350 to about 375, about 350 to about 400, about 350 to about 425, about 350 to about 450, about 350 to about 475, about 350 to about 500, about 350 to about 550. about 375 to about 400. about 375 to about 425,about 375 to about 450, about 375 to about 475, about 375 to about 500, about 375 to about 550, about 400 to about 425, about 400 to about 450. about 400 to about 475, about 400 to about 500, about 400 to about 550, about 425 to about 450, about 425 to about 475, about 425 to about 500, about 425 to about 550, about 450 to about 475, about 450 to about 500, about 450 to about 550, about 475 to about 500, about 475 to about 550, or about 500 to about 550 cells. In some embodiments, an injection map includes a grid having a plurality of cells. In some embodiments, an injection map includes a radial pattern having a plurality of cells.

[0109] A cell of an injection map can correspond to a distinct subcutaneous treatment site in the subcutaneous treatment area of a subject. In some embodiments, each cell of an injection map corresponds to a distinct subcutaneous treatment site. For example, each cell of a plurality of cells of an injection map can correspond to a distinct subcutaneous treatment site in a plurality of subcutaneous treatment sites.

[0110] In some embodiments, an inj ection map indicates a plurality of subcutaneous treatment sites. For example, an injection map can indicate 5, 10, 15, 20, 25, 30, 35, 40, 45. 50. 60, 70, 80. 90. 100. 150, 200, 250, 300, 350, 400. 450. or 500 or more subcutaneous treatment sites. In some embodiments, an injection map indicates about 5 to about 550 subcutaneous treatment sites. For example, an injection map can indicate about 5 to about 15, about 5 to about 25, about 5 to about 50, about 5 to about 75. about 5 to about 100. about 5 to about 125, about 5 to about 150, about 5 to about 175. about 5 to about 200, about 5 to about 225, about 5 to about 250, about 5 to about 275, about 5 to about 300, about 5 to about 325, about 5 to about 350, about 5 to about 375, about 5 to about 400, about 5 to about 425, about 5 to about 450, about 5 to about 475, about 5 to about 500. about 15 to about 25, about 15 to about 50, about 15 to about 75. about 15 to about 100, about 15 to about 125, about 15 to about 150, about 15 to about 175, about 15 to about 200, about 15 to about 225, about 15 to about 250, about 15 to about 275, about 15 to about 300, about 15 to about 325, about 15 to about 350, about 15 to about 375, about 15 to about 400, about 15 to about 425, about 15 to about 450, about 15 to about 475, about 15 to about 500, about 15 to about 550, about 25 to about 50, about 25 to about 75, about 25 to about 100, about 25 to about 125, about 25 to about 150, about 25 to about 175, about 25 to about 200, about 25 to about 225, about 25 to about 250, about 25 to about 275, about 25 to about 300, about 25 to about 325, about 25 to about 350, about 25 to about 375. about 25 to about 400. about 25 to about 425,about 25 to about 450, about 25 to about 475, about 25 to about 500, about 25 to about 550, about 50 to about 75, about 50 to about 100, about 50 to about 125, about 50 to about 150, about 50 to about 175, about 50 to about 200, about 50 to about 225, about 50 to about 250, about 50 to about 275, about 50 to about 300, about 50 to about 325, about 50 to about 350, about 50 to about 375, about 50 to about 400, about 50 to about 425, about 50 to about 450, about 50 to about 475, about 50 to about 500. about 50 to about 550, about 75 to about 100, about 75 to about 125, about 75 to about 150, about 75 to about 175, about 75 to about 200, about 75 to about 225, about 75 to about 250, about 75 to about 275, about 75 to about 300, about 75 to about 325, about 75 to about 350, about 75 to about 375, about 75 to about 400, about 75 to about 425, about 75 to about 450, about 75 to about 475, about 75 to about 500. about 75 to about 550. about 100 to about 125, about 100 to about 150, about 100 to about 175, about 100 to about 200, about 100 to about 225, about 100 to about 250, about 100 to about 275, about 100 to about 300, about 100 to about 325, about 100 to about 350, about 100 to about 375, about 100 to about 400, about 100 to about 425, about 100 to about 450, about 100 to about 475, about 100 to about 500, about 100 to about 550, about 125 to about 150, about 125 to about 175, about 125 to about 200, about 125 to about 225, about 125 to about 250, about 125 to about 275, about 125 to about 300, about 125 to about 325, about 125 to about 350, about 125 to about 375, about 125 to about 400, about 125 to about 425, about 125 to about 450, about 125 to about 475, about 125 to about 500, about 125 to about 550, about 150 to about 175, about 150 to about 200, about 150 to about 225, about 150 to about 250, about 150 to about 275, about 150 to about 300, about 150 to about 325, about 150 to about 350, about 150 to about 375, about 150 to about 400, about 150 to about 425, about 150 to about 450. about 150 to about 475, about 150 to about 500, about 150 to about 550, about 175 to about 200, about 175 to about 225, about 175 to about 250, about 175 to about 275, about 175 to about 300, about 175 to about 325, about 175 to about 350, about 175 to about 375, about 175 to about 400, about 175 to about 425, about 175 to about 450. about 175 to about 475, about 175 to about 500, about 175 to about 550, about 200 to about 225, about 200 to about 250, about 200 to about 275, about 200 to about 300, about 200 to about 325, about 200 to about 350, about 200 to about 375, about 200 to about 400, about 200 to about 425, about 200 to about 450, about 200 to about 475, about 200 to about 500, about 200 to about 550, about 225 to about 250, about 225 to about 275, about 225 toabout 300, about 225 to about 325, about 225 to about 350, about 225 to about 375, about 225 to about 400, about 225 to about 425, about 225 to about 450, about 225 to about 475, about 225 to about 500, about 225 to about 550, about 250 to about 275, about 250 to about 300, about 250 to about 325, about 250 to about 350, about 250 to about 375, about 250 to about 400, about 250 to about 425, about 250 to about 450, about 250 to about 475, about 250 to about 500, about 250 to about 550, about 275 to about 300, about 275 to about 325, about 275 to about 350, about 275 to about 375, about 275 to about 400, about 275 to about 425, about 275 to about 450, about 275 to about 475, about 275 to about 500, about 275 to about 550, about 300 to about 325, about 300 to about 350, about 300 to about 375, about 300 to about 400, about 300 to about 425, about 300 to about 450, about 300 to about 475, about 300 to about 500, about 300 to about 550, about 325 to about 350, about 325 to about 375, about 325 to about 400, about 325 to about 425, about 325 to about 450, about 325 to about 475, about 325 to about 500, about 325 to about 550, about 350 to about 375, about 350 to about 400, about 350 to about 425, about 350 to about 450. about 350 to about 475, about 350 to about 500, about 350 to about 550, about 375 to about 400, about 375 to about 425, about 375 to about 450, about 375 to about 475, about 375 to about 500, about 375 to about 550, about 400 to about 425, about 400 to about 450, about 400 to about 475, about 400 to about 500, about 400 to about 550. about 425 to about 450, about 425 to about 475, about 425 to about 500, about 425 to about 550, about 450 to about 475, about 450 to about 500, about 450 to about 550, about 475 to about 500, about 475 to about 550, or about 500 to about 550 subcutaneous treatment sites.

[0111] In some embodiments, a cell of an injection map has a length of about 0.5 cm to about 3 cm. For example, a cell of an injection map can have a length of about 0.5 cm to about 2.75 cm, about 0.5 cm to about 2.5 cm, about 0.5 cm to about 2.25 cm, about 0.5 cm to about 2 cm, about 0.5 cm to about 1.75 cm, about 0.5 cm to about 1.5 cm, about 0.5 cm to about 1.25 cm, about 0.5 cm to about 1 cm, about 0.5 cm to about 0.75 cm. about 0.75 cm to about 3 cm, about 0.75 cm to about 2.75 cm, about 0.75 cm to about 2.5 cm, about 0.75 cm to about 2.25 cm. about 0.75 cm to about 2 cm, about 0.75 cm to about 1.75 cm, about 0.75 cm to about 1.5 cm, about 0.75 cm to about 1.25 cm, about 0.75 cm to about 1 cm, about 1 cm to about 3 cm, about 1 cm to about 2.75 cm, about 1 cm to about 2.5 cm, about 1 cm to about 2.25 cm, about 1 cm to about 2 cm, about 1 cm to about 1.75 cm, about 1 cm to about 1.5 cm. about 1 cm to about 1.25 cm,about 1.25 cm to about 3 cm, about 1.25 cm to about 2.75 cm, about 1.25 cm to about 2.5 cm. about 1.25 cm to about 2.25 cm. about 1.25 cm to about 2 cm, about 1.25 cm to about 1.75 cm, about 1.25 cm to about 1.5 cm, about 1.5 cm to about 3 cm, about 1.5 cm to about 2.75 cm, about 1.5 cm to about 2.5 cm, about 1.5 cm to about 2.25 cm, about 1.5 cm to about 2 cm, about 1.5 cm to about 1.75 cm, about 1.75 cm to about 3 cm, about 1.75 cm to about 2.75 cm, about 1.75 cm to about 2.5 cm, about 1.75 cm to about 2.25 cm, about 1.75 cm to about 2 cm, about 2 cm to about 3 cm, about 2 cm to about 2.75 cm, about 2 cm to about 2.5 cm, about 2 cm to about 2.25 cm, about 2.25 cm to about 3 cm, about 2.25 cm to about 2.75 cm, about 2.25 cm to about 2.5 cm, about 2.5 cm to about 3 cm, about 2.5 cm to about 2.75 cm, or about 2.75 cm to about 3 cm. In some embodiments, a cell has a length of about 0.5 cm, about 0.75 cm, about 1 cm, about 1.25 cm, about 1.5 cm, about 1.75 cm, about 2 cm, about 2.25 cm, about 2.5 cm, about 2.75 cm, or about 3 cm.

[0112] In some embodiments, a cell of an injection map has a width of about 0.5 cm to about 3 cm. For example, a cell of an injection map can have a width of about 0.5 cm to about 2.75 cm, about 0.5 cm to about 2.5 cm, about 0.5 cm to about 2.25 cm, about 0.5 cm to about 2 cm, about 0.5 cm to about 1.75 cm, about 0.5 cm to about 1.5 cm, about 0.5 cm to about 1.25 cm, about 0.5 cm to about 1 cm, about 0.5 cm to about 0.75 cm. about 0.75 cm to about 3 cm, about 0.75 cm to about 2.75 cm, about 0.75 cm to about 2.5 cm, about 0.75 cm to about 2.25 cm. about 0.75 cm to about 2 cm, about 0.75 cm to about 1.75 cm, about 0.75 cm to about 1.5 cm, about 0.75 cm to about 1.25 cm, about 0.75 cm to about 1 cm, about 1 cm to about 3 cm, about 1 cm to about 2.75 cm, about 1 cm to about 2.5 cm, about 1 cm to about 2.25 cm, about 1 cm to about 2 cm, about 1 cm to about 1.75 cm, about 1 cm to about 1.5 cm, about 1 cm to about 1.25 cm, about 1.25 cm to about 3 cm, about 1.25 cm to about 2.75 cm, about 1.25 cm to about 2.5 cm, about 1.25 cm to about 2.25 cm, about 1.25 cm to about 2 cm, about 1.25 cm to about 1.75 cm, about 1.25 cm to about 1.5 cm, about 1.5 cm to about 3 cm, about 1.5 cm to about 2.75 cm, about 1.5 cm to about 2.5 cm, about 1.5 cm to about 2.25 cm. about 1.5 cm to about 2 cm. about 1.5 cm to about 1.75 cm. about 1.75 cm to about 3 cm. about 1.75 cm to about 2.75 cm, about 1.75 cm to about 2.5 cm, about 1.75 cm to about 2.25 cm, about 1.75 cm to about 2 cm, about 2 cm to about 3 cm, about 2 cm to about 2.75 cm, about 2 cm to about 2.5 cm, about 2 cm to about 2.25 cm. about 2.25 cm to about 3 cm. about 2.25 cm to about 2.75 cm, about 2.25 cm to about 2.5 cm, about 2.5 cm toabout 3 cm, about 2.5 cm to about 2.75 cm, or about 2.75 cm to about 3 cm. In some embodiments, a cell has a width of about 0.5 cm, about 0.75 cm, about 1 cm, about 1.25 cm, about 1.5 cm, about 1.75 cm, about 2 cm, about 2.25 cm, about 2.5 cm, about 2.75 cm, or about 3 cm.

[0113] In some embodiments, the width and length of a cell are the same. For example, the cell can have a dimension of about 0.5 cm x about 0.5 cm to about 3 cm x about 3 cm. In some embodiments, the width and length of a cell are different. For example, the cell can have a dimension of about 0.5 cm x about 3 cm, about 1 cm x about 3 cm, about 2 cm x about 3 cm, about 0.5 cm x about 2 cm, about 1 cm x about 2 cm, or about 0.5 cm x about 1 cm.

[0114] In some embodiments, the spacing between markers on the cannula corresponds to the length and / or width of a cell of the injection map. For example, the spacing between each marker on the cannula can correspond to the length and / or width of a cell of the injection map. In some embodiments, the spacing between a subset of markers on the cannula corresponds to the length and / or width of a cell of the injection map.

[0115] The methods provided herein can further include generating an inj ection map (e.g., any of the injection maps described herein). For example, an injection map can be generated prior to providing the injection map on the skin over the subcutaneous treatment area in a subject. In some embodiments, the injection map is generated after the amount of adipose tissue in the treatment area of the subject is assessed (e.g., assess using any of the methods for assessing a quantity of adipose tissue described herein).

[0116] An injection map can be composed of any suitable material for marking the skin of a subject. For example, an injection map can be composed of an ink and / or dye. In some embodiments, an injection map is a temporary tattoo.

[0117] The methods provided herein can further include applying a predetermined pressure to the injection device to inject a pharmaceutical composition (e.g., a fluid containing a pharmaceutical composition). In some embodiments, the predetermined pressure is related to the surface tension of the pharmaceutical composition at the one or more outlets. In some embodiments, the amount of pressure must exceed the force from the surface tension at the outlet. There is an inverse relationship between the size of the outlet and the pressure needed to inject a pharmaceutical composition. Forexample, as an outlet gets smaller, the surface tension increases resulting in an increase in the predetermined injection pressure.

[0118] In some embodiments, wherein a specific pressure is applied to the injection device to inject a pharmaceutical composition, the cannula has two or more outlets, and the diameters of the outlets gradually increase along the longitudinal axis of the cannula toward the distal end portion. In some embodiments, the predetermined pressure is applied to the injection device when one of the two or more cannula markers is aligned with the puncture hole in the skin. In some embodiments, a predetermined amount of a fluid comprising a pharmaceutical composition is delivered at each of the two or more outlets. In some embodiments, approximately equal amounts of the fluid comprising a pharmaceutical composition are delivered at each of the two or more outlets of the cannula.

[0119] The methods provided herein can further include priming the inj ection device and / or cannula with a fluid comprising a pharmaceutical composition. In some embodiments, priming the cannula includes infusing a fluid comprising a pharmaceutical composition into the cannula until small drops exit each outlet in the cannula. In some embodiments, the cannula is primed while cannula is parallel to the floor and the outlets are facing upward. Priming the cannula can allow the fluid comprising a pharmaceutical composition to be immediately and uniformly delivered from each of the outlets after the cannula is inserted into the puncture hole and the injection device is activated (e g., the plunger of a syringe is pushed).

[0120] In some embodiments, wherein the cannula is primed, the diameter of each outlet of the cannula is such that when the cannula contains the fluid the surface tension at each outlet can maintain the fluid inside the cannula. In some embodiments, a cannula provided herein can be primed prior to inserting the cannula into the puncture hole in the skin. In some embodiments, a cannula provided herein can be primed after inserting the cannula into the puncture hole in the skin.

[0121] In some embodiments, where the cannula has two or more outlets, a sheath is placed over the tubular body of the cannula pnor to inserting the cannula into the puncture hole in the skin. In some embodiments, the sheath covers the tubular body of the cannula such that the tw o or more outlets of the cannula are covered. A sheath over tubular body of the cannula can be used to maintain the fluid comprising a pharmaceutical composition in the cannula while a predetermined pressure is applied tocannula. Once the cannula and sheath are inserted into the puncture hole to one or more subcutaneous treatment sites, the sheath can be removed and the contents of fluid containing the pharmaceutical composition can be uniformly dispensed from each of the outlets to the one or more subcutaneous treatment sites.

[0122] In some embodiments, a dosage unit of a pharmaceutical composition described herein is administered daily. In some embodiments, a dosage unit of a pharmaceutical composition provided herein is administered on a non-daily basis. For example, a dosage unit of a pharmaceutical composition provided herein can be administered every other day, every' two days, every three days, once per week, twice per week, once every two weeks, once a month, twice a month, or once every two months. In some embodiments a pharmaceutical composition described herein is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 3 months, about 6 months, about 9 months, about 1 year, or beyond. For example, a dosage unit can be administered weekly for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, or about 3 months or more.

[0123] The pharmaceutical compositions provided herein can be administered at the same subcutaneous treatment sites, adjacent subcutaneous treatment sites, or nearby subcutaneous treatment sites and at various frequencies and dosages as described herein. In some embodiments, each injection uses a predetermined volume of the fluid. In some embodiments, each injection uses about 0.1 cc to about 3 cc. For example, each injection can independently use about 0.1 cc to about 2.75 cc, about 0.1 cc to about 2.5 cc, about 0.1 cc to about 2.25 cc, about 0.1 cc to about 2 cc, about 0.1 cc to about 1.75 cc, about 0.1 cc to about 1.5 cc, about 0.1 cc to about 1.25 cc, about 0.1 cc to about 1 cc. about 0.1 cc to about 0.75 cc, about 0.5 cc to about 2.75 cc, about 0.5 cc to about 2.5 cc, about 0.5 cc to about 2.25 cc, about 0.5 cc to about 2 cc, about 0.5 cc to about 1.75 cc, about 0.5 cc to about 1.5 cc, about 0.5 cc to about 1.25 cc, about 0.5 cc to about 1 cc, about 0.5 cc to about 0.75 cc, about 0.75 cc to about 3 cc, about 0.75 cc to about 2.75 cc. about 0.75 cc to about 2.5 cc, about 0.75 cc to about 2.25 cc, about 0.75 cc to about 2 cc, about 0.75 cc to about 1.75 cc, about 0.75 cc to about 1.5 cc, about 0.75 cc to about 1.25 cc, about 0.75 cc to about 1 cc, about 1 cc to about 3 cc, about 1 cc to about 2.75 cc, about 1 cc to about 2.5 cc, about 1 cc to about 2.25 cc, about 1 cc to about 2 cc, about 1 cc to about 1.75 cc, about 1 cc to about 1.5 cc, about 1 cc to about 1.25 cc, about 1.25 cc toabout 3 cc, about 1.25 cc to about 2.75 cc, about 1.25 cc to about 2.5 cc, about 1.25 cc to about 2.25 cc, about 1.25 cc to about 2 cc, about 1.25 cc to about 1.75 cc, about 1.25 cc to about 1.5 cc, about 1.5 cc to about 3 cc, about 1.5 cc to about 2.75 cc, about 1.5 cc to about 2.5 cc, about 1.5 cc to about 2.25 cc, about 1.5 cc to about 2 cc, about 1.5 cc to about 1.75 cc, about 1.75 cc to about 3 cc, about 1.75 cc to about 2.75 cc, about 1.75 cc to about 2.5 cc, about 1.75 cc to about 2.25 cc, about 1.75 cc to about 2 cc, about 2 cc to about 3 cc, about 2 cc to about 2.75 cc, about 2 cc to about 2.5 cc, about 2 cc to about 2.25 cc, about 2.25 cc to about 3 cc, about 2.25 cc to about 2.75 cc, about 2.25 cc to about 2.5 cc, about 2.5 cc to about 3 cc, about 2.5 cc to about 2.75 cc, or about 2.75 cc to about 3 cc. In some embodiments, each injection can independently use about 0.5 cc, about 0.75 cc, about 1 cc, about 1.25 cc, about 1.5 cc, about 1.75 cc. about 2 cc. about 2.25 cc, about 2.5 cc, about 2.75 cc, or about 3 cc.

[0124] In some embodiments, the volume varies for each injection based on an amount of fat in the subcutaneous treatment site. The methods provided here can further include determining the injection volume for each subcutaneous treatment site.

[0125] In some embodiments, an injection map (e.g., any of the injection maps described herein) further comprises information about the injection volume for each subcutaneous treatment site. The injection map can include numerical indicators of the injection volume for each subcutaneous treatment site. One or more of the cells of the injection map can include a corresponding numerical indicator of the injection volume.

[0126] The injection volume can be determined using an ultrasound scan. For example, a method provided herein can further include performing an ultrasound scan of the subcutaneous treatment area in the subject to determine which subcutaneous treatment site(s) contain more fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject. The injection volume can be increased for subcutaneous treatment site(s) containing more fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject.

[0127] A method provided herein can further include performing an ultrasound scan of the subcutaneous treatment area in the subject to determine which subcutaneous treatment site(s) contain less fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject. The injection volume can be decreased for subcutaneous treatment site(s) containing less fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject.

[0128] An ultrasound scan can also be used to calculate the amount of fat in a subcutaneous treatment area (e.g., any of the subcutaneous treatment areas described herein). In some embodiments, a method described herein further includes administering an ultrasound of a subcutaneous treatment area. In some embodiments, the amount of fat per cm2is calculated from the ultrasound scan. In some embodiments, the calculated amount of fat is used to generate an injection map (e.g., any of the injection maps described herein). In some embodiments, the injection map includes a grid with a 1 cm x 1 cm cells corresponding to the targeted subcutaneous treatment sites in the subcutaneous treatment area. In some embodiments, the injection map includes the amount of the pharmaceutical composition to be administered to each subcutaneous treatment site.

[0129] The injection map can be provided on the skin of the subject in a number of different ways. In some embodiments, the injection map is printed. The printer can use skin-safe ink and printed the ink onto a material that allows transfer of the ink to skin. In some embodiments, the printer contains multiple colors of skin-safe inks. Nonlimiting examples of skin-safe inks include temporary tattoo inks and semi-permanent tattoo inks. In some embodiments, each cell of the injection map is color-coded to indicate the amount of a pharmaceutical composition to be administered to the corresponding subcutaneous treatment site. In some embodiments, the printed injection map is placed on the skin over the subcutaneous treatment area of the subject. In some embodiments, the ink is transferred to the skin over the subcutaneous treatment area of the subject.

[0130] In some embodiments, upon administration, the local concentration of a pharmaceutical composition described herein in a subcutaneous treatment site or in the treatment area is higher (e.g., about 2 to about 1,000, about 2 to about 900, about 2 to about 800, about 2 to about 700, about 2 to about 500, about 2 to about 400, about 2 to about 300, about 2 to about 200, about 2 to about 100, about 2 to about 50, about 5 to about 1,000, about 5 to about 900. about 5 to about 800, about 2 to about 700, about 5 to about 500, about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 50, about 5 to about 25, or about 5 to about 15 times higher) than the concentration of the pharmaceutical composition in a site or an area outside the treatment site or the treatment area.

[0131] In some embodiments each subcutaneous treatment site receives a dose of a pharmaceutical composition provided herein. In some embodiments, each dose is administered as a single injection. In some embodiments, two or more doses are administered with a single injection.

[0132] A treatment area can include a fat deposit in a subject’s body such as a fat deposit in the subject's abdomen, flank, inner thigh, outer thigh, arm, back, buttocks, calf, ankle, jowls, preplatysmal submental area, breast, chest, or lower face. In some embodiments, the treatment area is in preplatysmal submental area of the subject. In some embodiments, the subject can have moderate to severe submental convexity.

[0133] Fat reduction in a treatment area in a subject can be evaluated using methods known in the art. For example, reduction in submental fat can be assessed using the Clinician-Rated SMF Rating Scale (CR-SMFRS) or the Subject Self-Rating Scale (SSRS). See, e.g., Jalian et al. J Cosmet Dermatol. 21(6): 2437-2444 (2022). Fat reduction in a treatment area can also be evaluated using an imaging method such as magnetic resonance imaging (MRI), ultrasound, and computed tomography (CT).Pharmaceutical Compositions

[0134] Pharmaceutical compositions that can be used in any of the methods described herein include dermal fillers and compositions that induce adipocyte cell death. Non-limiting examples of dermal fillers include a poly-L-lactic acid (PLLA-SCA) injectable (e.g., SCULPTRA®) and a hyaluronic acid (HA) injectable. In some embodiments, a poly-L-lactic acid injectable contains microparticles of poly-L-lactic acid (PLLA), sodium carboxymethylcellulose, non-pyrogenic mannitol and sterile water for injection. Non-limiting examples of HAinjectables include HA manufactured from streptococcal cultures cross-linked with a binding agent 1,4-butanediol diglycidyl ether (BDDE) in two consecutively executed reactions and reconstituted in a physiologic buffer at pH 7 and concentration of 22.5 mg / mL (e.g., BELOTERO® BALANCE); crosslinked HA produced by Streptococcus species of bacteria, formulated to a concentration of 24 mg / mL and suspended in a physiologic buffer with lidocaine (JUVEDERM® ULTRA PLUS) or without lidocaine (e.g., JUVEDERM® ULTRA XC); a gel of HA generated by Streptococcus species of bacteria, chemically crosslinked with BDDE, stabilized and suspended in phosphate buffered saline at pH=7 and concentration of 20 mg / mL with 0.3% lidocaine (e.g., RESTYLANE® SILK,RESTYLANE® LYFT with lidocaine) or without lidocaine (e.g., RESTYLANE®); and 20 mg HA gel with 3 mg lidocaine (lignocaine) hydrochloride monohydrate in phosphate buffer pH 7.2 q.s. 1 mL (e.g., VOLUMA®).

[0135] Pharmaceutical compositions that can induce adipocyte cell death include compositions comprising a curcuminoid. In some embodiments, a pharmaceutical composition provided herein includes a particle containing a curcuminoid. Curcuminoids are natural phenol compounds and can be isolated from turmeric. Nonlimiting examples of a curcuminoid include curcumin, demethoxy curcumin, and bisdemethoxycurcumin. In some embodiments of any of the pharmaceutical compositions described herein, the curcuminoid is curcumin.

[0136] In some embodiments, a particle of a pharmaceutical composition used in any of the methods described herein contains a flavonoid, resveratrol, or a mixture thereof. In some embodiments, a particle of a pharmaceutical composition used in any of the methods described herein contains cinnamaldehyde, a cinnamaldehyde derivative, resveratrol, or a mixture thereof. The particles of the pharmaceutical compositions provided herein can be used to deliver the curcuminoid, flavonoid, resveratrol, or combination thereof to a local site in a subject.

[0137] In some embodiments, a pharmaceutical composition provided herein includes (i) a particle containing a curcuminoid; (ii) a particle containing a flavonoid (e.g., any of the flavonoids described herein); (iii) a particle containing resveratrol; (iv) a particle containing a flavonoid and resveratrol; (v) a particle containing a curcuminoid and a flavonoid, resveratrol, or a mixture thereof; or (vi) any mixture of particles thereof. For example, a pharmaceutical composition provided herein can include (vii) a particle containing a curcuminoid and a particle containing a flavonoid and / or resveratrol; (viii) a particle containing a flavonoid and a particle containing resveratrol; (ix) a particle containing a curcuminoid, a particle containing a flavonoid, and a particle containing resveratrol; (x) or a mixture thereof. In some embodiments, a pharmaceutical composition provided herein includes a plurality of particles.

[0138] In some embodiments, a particle of a pharmaceutical composition provided herein contains a flavonoid. Non-limiting examples of flavonoids include flavanols, flavanones, flavones, and isoflavones. Cinnamaldehyde is a naturally occurring flavonoid. Non-limiting examples of a cinnamaldehyde derivative include 4-hydroxy-3-methoxy cinnamaldehyde and 2-hydroxy cinnamaldehyde. In some embodiments, aparticle of a pharmaceutical composition provided herein contains cinnamaldehyde, a cinnamaldehyde derivative, or a mixture thereof.

[0139] In some embodiments, wherein a pharmaceutical composition provided herein includes a curcuminoid and cinnamaldehyde and / or a derivative thereof, the weight ratio of the cinnamaldehyde and / or derivative thereof to the curcuminoid (e.g., any of the curcuminoids described herein) is about 1:30 to about 9:1. For example, the weight ratio of the cinnamaldehyde and / or derivative thereof to the curcuminoid can be about 1:25 to about 9:1, 1:20 to about 9:1, about 1:15 to about 9:1, about 1:10 to about 9:1, 1:5 to about 9:1, 1:1 to about 9:1, about 1:30 to about 8:1, about 1:30 to about 7:1, about 1:30 to about 6:1, about 1:30 to about 5:1, about 1:30 to about 4:1, about 1:30 to about 3:1, about 1:30 to about 2: 1, or about 1:30 to about 1:1. In some embodiments, the weight ratio of the cinnamaldehyde and / or derivative thereof to the curcuminoid is about 1:5, about 1:6, about 1:7, about 1:8, or about 1:9.

[0140] In some embodiments, wherein a pharmaceutical composition used in any of the methods described herein includes cinnamaldehyde and / or a derivative thereof, the weight ratio of the cinnamaldehyde and / or derivative thereof to the curcuminoid (e.g., any of the curcuminoids described herein) is about 99: 1 to about 65:45. For example, the weight ratio of the cinnamaldehyde and / or derivative thereof to the curcuminoid can be about 75:1 to about 65:45, about 50:1 to about 65:45, about 99:3 to about 65:45, about 25: 1 to about 65:45, about 50:3 to about 65:45, about 75:5 to about 65:45, about 25:3 to about 65:45, about 85: 15 to about 65:45, about 25:6 to about 65:45, about 2: 1 to about 65:45, about 60:40 to about 65:45, about 99: 1 to about 60:40, about 75: 1 to about 60:40, about 50:1 to about 60:40, about 99:3 to about 60:40, about 25:1 to about 60:40, about 50:3 to about 60:40, about 75:5 to about 60:40, about 25:3 to about 60:40, about 85:15 to about 60:40, about 25:6 to about 60:40, about 2: 1 to about 60:40, about 99: 1 to about 2:1, about 75:1 to about 2:1, about 50:1 to about 2:1, about 99:3 to about 2:1, about 25:1 to about 2:1, about 50:3 to about 2:1, about 75:5 to about 2:1, about 25:3 to about 2:1, about 85:15 to about 2:1, about 25:6 to about 2:1, about 99:1 to about 25:6, about 75:1 to about 25:6, about 50:1 to about 25:6, about 99:3 to about 25:6, about 25:1 to about 25:6, about 50:3 to about 25:6, about 75:5 to about 25:6, about 25:3 to about 25:6, about 85:15 to about 25:6, about 99:1 to about 85:15, about 75:1 to about 85:15, about 50:1 to about 85:15, about 99:3 to about 85:15, about 25:1 to about 85:15, about 50:3 to about 85:15, about 75:5 to about 85:15, about 25:3 to about 85:15, about 99:1 to about 25:3,about 75:1 to about 25:3, about 50:1 to about 25:3, about 99:3 to about 25:3, about 25:1 to about 25:3, about 50:3 to about 25:3. about 75:5 to about 25:3, about 99:1 to about 75:5, about 75: 1 to about 75:5, about 50: 1 to about 75:5, about 99:3 to about 75:5, about 25:1 to about 75:5, about 50:3 to about 75:5, about 99:1 to about 50:3, about 75:1 to about 50:3, about 50:1 to about 50:3, about 99:3 to about 50:3, about 25:1 to about 50:3, about 99: 1 to about 25: 1. about 75: 1 to about 25: 1, about 50: 1 to about 25:1, about 99:3 to about 25:1, about 99:1 to about 99:3, about 75:1 to about 99:3, about 50:1 to about 99:3, about 99:1 to about 50:1, about 75:1 to about 50:1, or about 99:1 to about 50:1. In some embodiments, the weight ratio of the cinnamaldehyde and / or derivative thereof to the curcuminoid is about 85:15 to about 60:40.

[0141] In some embodiments, wherein a pharmaceutical composition used in any of the methods described herein includes a curcuminoid and resveratrol, the weight ratio of resveratrol to the curcuminoid (e.g., any of the curcuminoids described herein) is about 1:30 to about 9:1. For example, the weight ratio of resveratrol to curcumin can be about 1:25 to about 9:1, 1:20 to about 9:1. about 1:15 to about 9:1, about 1:10 to about 9:1, 1:5 to about 9:1, 1:1 to about 9:1, about 1:30 to about 8:1, about 1:30 to about 7:1, about 1:30 to about 6:1, about 1:30 to about 5:1, about 1:30 to about 4:1, about 1:30 to about 3:1, about 1:30 to about 2:1, or about 1:30 to about 1:1.

[0142] The particles of a pharmaceutical composition used in any of the methods described herein can encapsulate the curcuminoid. For example, a particle of a pharmaceutical composition provided herein can partially or fully encapsulate the curcuminoid. In some embodiments, the particle of a pharmaceutical composition used in any of the methods described herein encapsulates (e.g., partially or fully) the curcuminoid and the cinnamaldehyde, cinnamaldehyde derivative, resveratrol, or mixture thereof. Encapsulation can be determined using any method known in the art. For example, the amount of a non-encapsulated active ingredient (e.g., a curcuminoid and / or cinnamaldehyde and / or a derivative thereol) can be determined and compared to the total amount of the active ingredient. See, e.g., J. Pharm. Biomed. Anal. 236: 115751 (2023).

[0143] The curcuminoid and cinnamaldehyde, cinnamaldehyde derivative, resveratrol, or mixture thereof can be co-encapsulated in a single particle of a pharmaceutical composition provided herein. Co-encapsulation of two or more active ingredients (e.g., a curcuminoid and cinnamaldehyde, cinnamaldehyde derivative,resveratrol, or mixture thereof) can decrease the difficulty of manufacturing pharmaceutical compositions comprising the active ingredients and / or improve accuracy in delivering the active ingredients. Co-encapsulation of two or more active ingredients can also enhance therapeutic efficacy. For example, co-encapsulation of two or more active ingredients can increase the additive or synergistic effect exhibited by the combination of the active ingredients compared to the effect of the active ingredients when administered alone as a single agent or when administered in a single composition where the active ingredients are not co-encapsulated in particles. In some embodiments, co-encapsulated active ingredients are delivered to the target (e.g., a cell such as an adipocyte) simultaneously.

[0144] In some embodiments, a pharmaceutical composition used in any of the methods described herein contains about 41 pM to about 4.1 mM of encapsulated curcuminoid. For example, a pharmaceutical composition used in any of the methods described herein can contain about 41 pM to about 100 pM, about 41 pM to about 250 pM, about 41 pM to about 500 pM, about 41 pM to about 750 pM, about 41 pM to about 1 mM, about 41 pM to about 1.25 mM, about 41 pM to about 1.5 mM, about 41 pM to about 1.75 mM, about 41 pM to about 2 mM, about 41 pM to about 2.25 mM, about 41 pM to about 2.5 mM, about 41 pM to about 2.75 mM, about 41 pM to about 3 mM, about 41 pM to about 3.25 mM, about 41 pM to about 3.5 mM, about 41 pM to about 3.75 mM, about 41 pM to about 4 mM, about 100 pM to about 250 pM. about 100 pM to about 500 pM, about 100 pM to about 750 pM, about 100 pM to about 1 mM, about 100 pM to about 1.25 mM, about 100 pM to about 1.5 mM, about 100 pM to about 1.75 mM, about 100 pM to about 2 mM, about 100 pM to about 2.25 mM, about 100 pM to about 2.5 mM, about 100 pM to about 2.75 mM, about 100 pM to about 3 mM, about 100 pM to about 3.25 mM, about 100 pM to about 3.5 mM, about 100 pM to about 3.75 mM, about 100 pM to about 4 mM, about 250 pM to about 500 pM, about 250 pM to about 750 pM, about 250 pM to about 1 mM, about 250 pM to about 1.25 mM, about 250 pM to about 1.5 mM, about 250 pM to about 1.75 mM. about 250 pM to about 2 mM, about 250 pM to about 2.25 mM, about 250 pM to about 2.5 mM, about 250 pM to about 2.75 mM, about 250 pM to about 3 mM, about 250 pM to about 3.25 mM, about 250 pM to about 3.5 mM, about 250 pM to about 3.75 mM, about 250 pM to about 4 mM, about 500 pM to about 750 pM, about 500 pM to about 1 mM, about 500 pM to about 1.25 mM. about 500 pM to about 1.5 mM, about 500 pM toabout 1.75 mM, about 500 iM to about 2 mM, about 500 iM to about 2.25 mM, about 500 gM to about 2.5 mM, about 500 |iM to about 2.75 mM, about 500 |iM to about 3 mM, about 500 gM to about 3.25 mM, about 500 |_iM to about 3.5 mM, about 500 |iM to about 3.75 mM, about 500 |iM to about 4 mM, about 750 |iM to about 1 mM, about 750 iM to about 1.25 mM, about 750 |1M to about 1.5 mM, about 750 iM to about 1.75 mM, about 750 |_iM to about 2 mM, about 750 pM to about 2.25 mM, about 750 |_iM to about 2.5 mM, about 750 |iM to about 2.75 mM, about 750 |iM to about 3 mM, about 750 pM to about 3.25 mM, about 750 |iM to about 3.5 mM, about 750 pM to about 3.75 mM, about 750 iM to about 4 mM, about 1 mM to about 1.25 mM, about 1 mM to about 1.5 mM, about 1 mM to about 1.75 mM, about 1 mM to about 2 mM, about 1 mM to about 2.25 mM, about 1 mM to about 2.5 mM, about 1 mM to about 2.75 mM. about 1 mM to about 3 mM, about 1 mM to about 3.25 mM, about 1 mM to about 3.5 mM, about 1 mM to about 3.75 mM, about 1 mM to about 4 mM, about 1.25 mM to about 1.5 mM, about 1.25 mM to about 1.75 mM, about 1.25 mM to about 2 mM, about 1.25 mM to about 2.25 mM, about 1.25 mM to about 2.5 mM, about 1.25 mM to about 2.75 mM, about 1.25 mM to about 3 mM, about 1.25 mM to about 3.25 mM, about 1.25 mM to about 3.5 mM, about 1.25 mM to about 3.75 mM, about 1.25 mM to about 4 mM, about 1.5 mM to about 1.75 mM, about 1.5 mM to about 2 mM, about 1.5 mM to about 2.25 mM, about 1.5 mM to about 2.5 mM, about 1.5 mM to about 2.75 mM, about 1.5 mM to about 3 mM. about 1.5 mM to about 3.25 mM, about 1.5 mM to about 3.5 mM. about 1.5 mM to about 3.75 mM, about 1.5 mM to about 4 mM, about 1.75 mM to about 2 mM, about 1.75 mM to about 2.25 mM, about 1.75 mM to about 2.5 mM, about 1.75 mM to about 2.75 mM, about 1.75 mM to about 3 mM, about 1.75 mM to about 3.25 mM, about 1.75 mM to about 3.5 mM, about 1.75 mM to about 3.75 mM, about 1.75 mM to about 4 mM, about 2 mM to about 2.25 mM, about 2 mM to about 2.5 mM, about 2 mM to about 2.75 mM, about 2 mM to about 3 mM, about 2 mM to about 3.25 mM, about 2 mM to about 3.5 mM, about 2 mM to about 3.75 mM, about 2 mM to about 4 mM, about 2.25 mM to about 2.5 mM, about 2.25 mM to about 2.75 mM, about 2.25 mM to about 3 mM, about 2.25 mM to about 3.25 mM, about 2.25 mM to about 3.5 mM, about 2.25 mM to about 3.75 mM, about 2.25 mM to about 4 mM, about 2.5 mM to about 2.75 mM, about 2.5 mM to about 3 mM, about 2.5 mM to about 3.25 mM, about 2.5 mM to about 3.5 mM, about 2.5 mM to about 3.75 mM, about 2.5 mM to about 4 mM, about 2.75 mM to about 3 mM. about 2.75 mM to about 3.25 mM. about 2.75 mMto about 3.5 mM, about 2.75 mM to about 3.75 mM. about 2.75 mM to about 4 mM, about 3 mM to about 3.25 mM, about 3 mM to about 3.5 mM, about 3 mM to about 3.75 mM, about 3 mM to about 4 mM, about 3.25 mM to about 3.5 mM, about 3.25 mM to about 3.75 mM, about 3.25 mM to about 4 mM, about 3.5 mM to about 3.75 mM, about 3.5 mM to about 4 mM, or about 3.75 mM to about 4 mM of encapsulated curcuminoid.

[0145] In some embodiments, a pharmaceutical composition used in any of the methods described herein contains about 41 pM, 200 pM, 300 pM, 350 pM, 360 pM, 370 pM, 380 pM, 390 pM, 400 pM, 410 pM, 420 pM, 430 pM, 440 pM, 450 pM, 500 pM, 750 pM, 1 mM, 1.5 mM, 2 mM, 2.5 mM, 3 mM, 3.5 mM, or about 4.1 mM of encapsulated curcuminoid.

[0146] In some embodiments, a particle of a pharmaceutical composition used in any of the methods described herein has a size of about 20 nm to about 1000 pm. For example, a particle of a a pharmaceutical composition used in any of the methods described herein can have a size of about 20 nm to about 60 nm, about 20 nm to about 80 nm, about 20 nm to about 100 nm, about 20 nm to about 200 nm, about 20 nm to about 400 nm, about 20 nm to about 600 nm, about 20 nm to about 800 nm, about 20 nm to about 1 pm, about 20 nm to about 200 pm, about 20 nm to about 400 pm, about 20 nm to about 600 pm, about 20 nm to about 800 pm, about 200 nm to about 400 nm, about 200 nm to about 600 nm, about 200 nm to about 800 nm, about 200 nm to about 1 pm, about 200 nm to about 200 pm. about 200 nm to about 400 pm, about 200 nm to about 600 pm, about 200 nm to about 800 pm, about 200 nm to about 1000 pm, about 400 nm to about 600 nm, about 400 nm to about 800 nm, about 400 nm to about 1 pm, about 400 nm to about 200 pm, about 400 nm to about 400 pm, about 400 nm to about 600 pm, about 400 nm to about 800 pm, about 400 nm to about 1000 pm, about 600 nm to about 800 nm, about 600 nm to about 1 pm, about 600 nm to about 200 pm, about 600 nm to about 400 pm, about 600 nm to about 600 pm, about 600 nm to about 800 pm, about 600 nm to about 1000 pm, about 800 nm to about 1 pm, about 800 nm to about 200 pm, about 800 nm to about 400 pm, about 800 nm to about 600 pm, about 800 nm to about 800 pm, about 800 nm to about 1000 pm, about 1 pm to about 200 pm, about 1 pm to about 400 pm, about 1 pm to about 600 pm, about 1 pm to about 800 pm, about 1 pm to about 1000 pm, about 200 pm to about 400 pm, about 200 pm to about 600 pm, about 200 pm to about 800 pm, about 200 pm to about 1000 pm, about 400 pm to about 600 pm. about 400 pm to about 800 pm, about 400 pm to about 1000 pm,about 600 pm to about 800 pun, about 600 pun to about 1000 pm, or about 800 un to about 1000 pun. In some embodiments, a particle of a pharmaceutical composition provided herein has a size of about 20 nm, about 30 nm, about 40 nm, about 50 nm, about 60 nm, about 70 nm, about 80 nm, about 90 nm, about 100 nm, about 200 nm, about 400 nm, about 600 nm, about 800 nm, about 1 pm, about 200 pm, about 400 pm, about 600 pm, about 800 pm, or about 1000 pm.

[0147] In some embodiments, a particle of a pharmaceutical composition used in any of the methods described herein is a nanoparticle (e.g., has a size of less than about 1 pm). In some embodiments, the nanoparticle has a size of about 20 nm to about 200 nm. In some embodiments, the nanoparticle has a size of about 50 nm to about 100 nm. In some embodiments, a particle of a pharmaceutical composition used in any of the methods described herein is a microparticle (e.g., has a size of about 1 pm to about 1000 pm).

[0148] In some embodiments, a pharmaceutical composition used in any of the methods described herein includes a plurality of particles (e.g., a plurality of any of the particles described herein).

[0149] The Polydispersity Index (PDI Index) is a parameter that indicates the particle size distribution. In some embodiments, the plurality' of particles in a pharmaceutical composition used in any of the methods described herein has a Poly dispersity Index (PDI) of about 0.25 or less. For example, the plurality of particles can have a PDI of about 0.22 or less, about 0.2 or less, about 0.18 or less, about 0.16 or less, about 0.14 or less, or about 0.12 or less, about 0.01 or less, about 0.09 or less, about 0.08 or less, about 0.07 or less, about 0.06 or less, about 0.05 or less, about 0.04 or less, about 0.03 or less, or about 0.02 or less. In some embodiments, the plurality of particles in a pharmaceutical composition provided herein has a PDI of about 0.001 to about 0.25. For example, the plurality of particles in a pharmaceutical composition provided herein can have a PDI of about 0.001 to about 0.005, about 0.001 to about 0.01, about 0.001 to about 0.05, about 0.001 to about 0.1, about 0.001 to about 0.15, about 0.001 to about 0.2, about 0.005 to about 0.01, about 0.005 to about 0.05, about 0.005 to about 0.1, about 0.005 to about 0.15, about 0.005 to about 0.2, about 0.005 to about 0.25, about 0.01 to about 0.05, about 0.01 to about 0.1, about 0.01 to about 0.15, about 0.01 to about 0.2, about 0.01 to about 0.25, about 0.05 to about 0.1, about 0.05 to about 0.15, about 0.05 to about 0.2, about 0.05 to about 0.25, about 0.1 to about 0.15. about 0.1 to about 0.2,about 0.1 to about 0.25, about 0.15 to about 0.2, about 0.15 to about 0.25, or about 0.2 to about 0.25.

[0150] In some embodiments, a particle of a pharmaceutical composition used in any of the methods described herein includes a lipid, a surfactant, or a mixture thereof. For example, the particle can be a lipid particle or a micelle. Non-limiting examples of a lipid particle include a liposome, a nanoemulsion, a solid lipid nanoparticle (SLN), a nanostructured lipid carrier, and a lipid polymer hybrid nanoparticle. In some embodiments, a pharmaceutical composition used in any of the methods described herein includes a curcuminoid; and a lipid, a surfactant, or a mixture thereof. In some embodiments, the particle is a lipid particle. Non-limiting examples of a lipid particle include a liposome, a nanoemulsion, a solid lipid nanoparticle (SLN), a nanostructured lipid carrier, and a lipid polymer hybrid nanoparticle. The particles of a pharmaceutical composition used in any of the methods described herein can include any combination of lipids. Non-limiting examples of lipids that can be used in a lipid particle include sterols, fatty acids, phospholipids, glycerides, sphingolipids, and prenols. Non-limiting examples of glycendes include monoglycendes, diglycendes, and triglycerides (e.g., triolein (glyceryl trioleate) and tricaprylin). Non-limiting examples of sphingolipids include sphingomyelin. In some embodiments, the sphingomyelin is egg sphingomyelin.

[0151] In some embodiments, a pharmaceutical composition used in any of the methods described herein includes a liposome containing a curcuminoid (e.g.. any of the curcuminoids described herein). In some embodiments, a pharmaceutical composition used in any of the methods described herein includes a liposome containing a curcuminoid (e.g., any of the curcuminoids described herein) and cinnamaldehyde, a cinnamaldehyde derivative, resveratrol, or a mixture thereof. The curcuminoid and cinnamaldehyde, cinnamaldehyde derivative, resveratrol, or mixture thereof can be coencapsulated in a liposome or the curcuminoid can be encapsulated in one liposome and the cinnamaldehyde, cinnamaldehyde derivative, resveratrol, or mixture thereof can be encapsulated in another liposome.

[0152] In some embodiments, the weight ratio of the curcuminoid (e.g., any of the curcuminoids described herein) to the lipid (e.g., the lipid(s) of any of the particles described herein) is about 1:20 to about 10:1. For example, the weight ratio of the curcuminoid to the lipid can be about 1:20 to about 8:1, about 1:20 to about 6:1, about 1:20 to about 4:1, about 1:20 to about 2:1. about 1:20 to about 1:1, about 1:15 to about10:1, about 1:15 to about 8:1, about 1:15 to about 6:1, about 1:15 to about 4:1, about 1:15 to about 2:1, about 1:15 to about 1:1, about 1:10 to about 10:1. about 1: 10 to about 8:1, about 1:10 to about 6:1, about 1:10 to about 4:1, about 1:10 to about 2:1, about 1:10 to about 1:1, about 1:5 to about 10:1, about 1:5 to about 8:1, about 1:5 to about 6:1, about 1: 5 to about 4:1, about 1: 5 to about 2:1, about 1: 5 to about 1:1, about 1: 1 to about 10:1, about 1:1 to about 8: 1, about 1:1 to about 6:1, about 1:1 to about 4: 1, or about 1:1 to about 2:1. In some embodiments, the weight ratio of the cinnamaldehyde and / or derivative thereof to the curcuminoid is about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, or about 1:15.

[0153] In some embodiments, the molar ratio of the curcuminoid (e.g., any of the curcuminoids described herein) to the lipid (e.g., the lipid(s) of any of the particles described herein) is about 1:20 to about 10:1. For example, the molar ratio of the curcuminoid to the lipid can be about 1:20 to about 8:1, about 1:20 to about 6:1, about 1:20 to about 4:1, about 1:20 to about 2:1, about 1:20 to about 1:1, about 1:15 to about 10:1, about 1:15 to about 8:1, about 1:15 to about 6:1, about 1:15 to about 4:1, about 1:15 to about 2:1, about 1:15 to about 1:1, about 1:10 to about 10: 1, about 1:10 to about 8:1, about l:10to about 6:1, about l:10 to about4:l, about l:10 to about 2:1, about 1:10 to about 1:1, about 1:5 to about 10:1, about 1:5 to about 8:1, about 1:5 to about 6:1, about 1: 5 to about 4:1, about 1: 5 to about 2:1, about 1: 5 to about 1:1, about 1: 1 to about 10:1, about 1:1 to about 8: 1, about 1:1 to about 6:1, about 1:1 to about 4: 1, or about 1:1 to about 2: 1. In some embodiments, the molar ratio of the curcuminoid to the lipid is about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, or about 1:15. In some embodiments, the molar ratio of the curcuminoid to the lipid is about 1:12.

[0154] In some embodiments, the weight ratio of the curcuminoid (e.g., any of the curcuminoids described herein) to the lipid (e.g., the lipid(s) of any of the particles described herein) is about 5:1 to about 15:1. For example, the weight ratio of the curcuminoid to the lipid can be about 6:1 to about 15:1, about 7:1 to about 15:1, about 8:1 to about 15:1, about 9:1 to about 15:1, about 10:1 to about 15:1, about 11:1 to about 15:1, about 12:1 to about 15:1, about 13:1 to about 15:1, about 14:1 to about 15:1, about 5:1 to about 14:1, about 6:1 to about 14:1, about 7:1 to about 14:1, about 8:1 to about 14:1, about 9:1 to about 14:1, about 10:1 to about 14:1, about 11:1 to about 15:1, about 12: 1 to about 14:1. about 13: 1 to about 14:1. about 5: 1 to about 13:1, about 6: 1 to about13:1, about 7:1 to about 13:1, about 8:1 to about 13:1, about 9:1 to about 13:1, about 10:1 to about 13:1, about 11:1 to about 13:1, about 12:1 to about 13:1, about 5:1 to about 12:1, about 6:1 to about 12:1, about 7:1 to about 12:1, about 8:1 to about 12:1, about 9:1 to about 12:1, about 10:1 to about 12:1, about 11:1 to about 12:1, about 5:1 to about 11:1, about 6:1 to about 11:1, about 7:1 to about 11:1, about 8:1 to about 11:1, about 9:1 to about 11:1, about 10:1 to about 11:1, about 5:1 to about 10:1, about 6:1 to about 10:1, about 7: 1 to about 10:1, about 8:1 to about 10:1, about 9:1 to about 10:1, about 5:1 to about 9:1, about 6: 1 to about 9:1, about 7:1 to about 9:1, about 8:1 to about 9:1, about 5:1 to about 8:1, about 6:1 to about 8:1, about 7:1 to about 8:1, about 5:1 to about 7:1, about 6: 1 to about 7: 1, or about 5: 1 to about 6:1.

[0155] In some embodiments, the curcuminoid comprises curcumin. In some embodiments, the curcumin comprises at least about 80% by weight of the total curcuminoids present in the pharmaceutical composition. For example, the curcumin can comprise about 80% to about 100%, about 82% to about 100%, about 84% to about 100%, about 86% to about 100%, about 88% to about 100%, about 90% to about 100%, about 92% to about 100%, about 94% to about 100%, about 96% to about 100%, about 98% to about 100%, about 99% to about 100%, about 80% to about 98%, about 82% to about 98%, about 84% to about 98%, about 86% to about 98%, about 88% to about 98%, about 90% to about 98%. about 92% to about 98%, about 94% to about 98%, about 96% to about 98%, about 80% to about 96%, about 82% to about 96%, about 84% to about 96%, about 86% to about 96%, about 88% to about 96%, about 90% to about 96%, about 92% to about 96%, about 94% to about 96%, about 80% to about 94%, about 82% to about 94%, about 84% to about 94%, about 86% to about 94%, about 88% to about 94%, about 90% to about 94%. about 92% to about 94%, about 80% to about 92%, about 82% to about 92%, about 84% to about 92%, about 86% to about 92%, about 88% to about 92%, about 90% to about 92%, about 80% to about 90%, about 82% to about 90%, about 84% to about 90%, about 86% to about 90%, about 88% to about 90%, about 80% to about 88%, about 82% to about 88%. about 84% to about 88%, about 86% to about 88%, about 80% to about 86%, about 82% to about 86%, about 84% to about 86%, about 80% to about 84%, about 82% to about 84%, about 80% to about 82%, at least about 82%, at least about 84%, at least about 86%, at least about 88%, at least about 90%, at least about 92%, at least about 94%, at least about 96%, at least about 97%, at least about 98%, at least about 99% by weight of the total curcuminoids present in the pharmaceuticalcomposition. In some embodiments, the curcumin comprises at least about 99%, 99.1 %, 99.2%, 99.3%. 99.4% or 99.5% by weight of the total curcuminoids present in the pharmaceutical composition.

[0156] In some embodiments, a liposome of a pharmaceutical composition used in any of the methods described herein includes a phospholipid (e.g., any of the phospholipids described herein) and a sterol (e.g., any of the sterols described herein). Non-limiting examples of phospholipids include phosphatidylcholines (e.g., distearoylphosphatidylcholine (DSPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and l-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC)), phosphatidylglycerols (e.g., a l,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG) salt, a l,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) salt, and a l,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) salt), phosphatidylethanolamines (e.g., l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), hydrogenated soy phosphatidylcholine (HSPC), l,2-dierucoyl-sn-glycero-3-phosphocholine (DEPC), and l,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)), and phosphatidylinositols. Non-limiting examples of sterols include cholesterol, 0-sitosterol, ergosterol, and stigmasterol.

[0157] In some embodiments, a phospholipid in a liposome of a pharmaceutical composition provided herein is present in an amount of about 35% to about 99% w / w of the total lipid content of the liposome (e.g., about 45% to about 90%, about 50% to about 80% w / w, or about 60% to about 70% of the total lipid content of the liposome). In some embodiments, a phospholipid in a liposome of a pharmaceutical composition provided herein is present in an amount of about 70% to about 99% w / w of the total lipid content of the liposome. For example, a phospholipid in a liposome of a pharmaceutical composition provided herein can be present in an amount of about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 55%, about 35% to about 60%, about 40% to about 45%. about 40% to about 50%. about 40% to about 55%, about 40% to about 60%, about 40% to about 65%, about 45% to about 50%, about 45% to about 55%, about 45% to about 60%, about 45% to about 65%, about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 55% to about 60%, about 55% to about 65%, or about 60% to about 65%, about 45% to about 90%, about 50% to about 80% w / w, or about 60% to about 70%, about 70% to about75%, about 70% to about 80%, about 70% to about 85%, about 70% to about 90%, about 70% to about 95%, 70% to about 99%, about 75% to about 80%, about 75% to about 85%, about 75% to about 90%, about 75% to about 95%, about 75% to about 99%, about 75% to about 100%, about 80% to about 85%, about 80% to about 90%, about 80% to about 95%, about 80% to about 99%, about 80% to about 100%, about 85% to about 90%, about 85% to about 95%, about 85% to about 99%, about 85% to about 100%, about 90% to about 95%, about 90% to about 99%, about 90% to about 100%, about 95% to about 99%, about 95% to about 100%, or about 99% to about 100% w / w of the total lipid content of the liposome. In some embodiments, a phospholipid in a liposome of a pharmaceutical composition provided herein is present in an amount of about 92% to about 98% w / w of the total lipid content of the liposome.

[0158] In some embodiments, the phospholipid (e.g., any of the phospholipids described herein) is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 35%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% w / w of the total lipid content of the liposome. In some embodiments, the phospholipid is present in a pharmaceutical composition used in any of the methods described herein in an amount of about 55% w / w of the total lipid content of the liposome. In some embodiments, the phospholipid is a DSPC. In some embodiments, the phospholipid is present in a liposome of a pharmaceutical composition provided herein in an amount of about 95% w / w of the total lipid content of the liposome.

[0159] In some embodiments, the phospholipid includes DMPC. In some embodiments, the phospholipid includes DMPC and a DMPG salt.

[0160] In some embodiments, the phospholipid is DSPC. In some embodiments, the phospholipid is DMPC.

[0161] The phospholipid can include a neutral phospholipid. In some embodiments, a neutral lipid is a lipid that is either uncharged or has a neutral zwitterionic form at a selected pH (e.g., at physiological pH). Non-limiting examples of neutral lipids include distearoylphosphatidylcholine (DSPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and l-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), hydrogenated soy phosphatidylcholine (HSPC). 1,2-dierucoyl-sn-glycero-3-phosphocholine (DEPC), and l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). In some embodiments, the neutral phospholipid includes DSPC, DOPC, DMPC, DPPC, POPC, DOPE, HSPC, DEPC, or a mixture thereof. In some embodiments, the phospholipid is a neutral phosphatidylcholine.

[0162] A neutral phospholipid can be present in a liposome of a pharmaceutical composition provided herein in an amount of about 70% to about 99% w / w of the total lipid content of the liposome. For example, a neutral phospholipid can be present in a liposome of a pharmaceutical composition provided herein in an amount of about 70% to about 75%, about 70% to about 80%. about 70% to about 85%, about 70% to about 90%, about 70% to about 95%, about 75% to about 80%, about 75% to about 85%, about 75% to about 90%, about 75% to about 95%, about 75% to about 99%, about 80% to about 85%, about 80% to about 90%, about 80% to about 95%, about 80% to about 99%, about 85% to about 90%. about 85% to about 95%, about 85% to about 99%, about 90% to about 95%, about 90% to about 99%, or about 95% to about 99% w / w of the total lipid content of the liposome. In some embodiments, the neutral phospholipid in a liposome of a pharmaceutical composition provided herein is present in an amount of about 82% to about 88% w / w of the total lipid content of the liposome.

[0163] In some embodiments, a neutral phospholipid in a liposome of a pharmaceutical composition provided herein is present in an amount of about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 95%, or about 99% w / w of the total lipid content of the liposome.

[0164] In some embodiments, a sterol in a liposome of a pharmaceutical composition provided herein is present in an amount of about 0.1% to about 60% w / w of the total lipid content of the liposome (e.g., about 0.1% to about 25%, about 1% to about 40%. or about 10% to about 50% w / w of the total lipid content of the liposome).

[0165] In some embodiments, a sterol in a liposome of a pharmaceutical composition provided herein is present in an amount of about 0.1% to about 20% w / w of the total lipid content of the liposome. For example, the sterol can be present in a liposome of a pharmaceutical composition provided herein in an amount of about 0.1% to about 1%, about 0.1% to about 2%, about 0.1% to about 4%, about 0.1% to about 6%,about 0.1% to about 8%, about 0.1% to about 10%, about 0.1% to about 12%, about 0.1% to about 14%, about 0.1% to about 16%. about 0.1% to about 18%, about 0.1% to about 20%, about 1% to about 2%, about 1% to about 4%, about 1% to about 6%, about 1% to about 8%, about 1% to about 10%, about 1% to about 12%, about 1% to about 14%, about 1% to about 16%, about 1% to about 18%, about 1% to about 20%, about 2% to about 4%, about 2% to about 6%, about 2% to about 8%, about 2% to about 10%, about 2% to about 12%, about 2% to about 14%, about 2% to about 16%, about 2% to about 18%, about 2% to about 20%, about 4% to about 6%, about 4% to about 8%, about 4% to about 10%, about 4% to about 12%, about 4% to about 14%, about 4% to about 16%, about 4% to about 18%, about 4% to about 20%. about 6% to about 8%, about 6% to about 10%, about 6% to about 12%. about 6% to about 14%, about 6% to about 16%, about 6% to about 18%, about 6% to about 20%, about 8% to about 10%, about 8% to about 12%, about 8% to about 14%, about 8% to about 16%, about 8% to about 18%, about 8% to about 20%, about 10% to about 12%, about 10% to about 14%, about 10% to about 16%, about 10% to about 18%. about 10% to about 20%, about 12% to about 14%, about 12% to about 16%, about 12% to about 18%, about 12% to about 20%. about 14% to about 16%, about 14% to about 18%, about 14% to about 20%, about 16% to about 18%, about 16% to about 20%, or about 18% to about 20% w / w of the total lipid content of the liposome.

[0166] In some embodiments, the sterol is present in a liposome of a pharmaceutical composition provided herein in an amount of about 1% to about 15% w / w of the total lipid content of the liposome. In some embodiments, the sterol is present in a liposome of a pharmaceutical composition provided herein in an amount of about 12% to about 18% w / w of the total lipid content of the liposome. In some embodiments, the sterol is present in a liposome of a pharmaceutical composition provided herein in an amount of about 1% to about 10% w / w of the total lipid content of the liposome. In some embodiments, the sterol is present in a liposome of a pharmaceutical composition provided herein in an amount of about 2% to about 8% w / w of the total lipid content of the liposome.

[0167] In some embodiments, a sterol in a liposome of a pharmaceutical composition used in any of the methods described herein is present in an amount of about 20% to about 60% w / w of the total lipid content of the liposome. For example, the sterol can be present in a liposome of a pharmaceutical composition used in any ofthe methods described herein in an amount of about 20% to about 25%, about 20% to about 30%. about 20% to about 35%. about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 20% to about 55%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 55%, about 25% to about 60%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%. about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 55%, about 35% to about 60%, about 40% to about 45%, about 40% to about 50%, about 40% to about 55%, about 40% to about 60%, about 45% to about 50%, about 45% to about 55%, about 45% to about 60%. about 50% to about 55%, about 50% to about 60%. or about 55% to about 60% w / w of the total lipid content of the liposome.

[0168] In some embodiments, the sterol is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 30% to about 50% w / w of the total lipid content of the liposome. In some embodiments, the sterol is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 35% to about 45% w / w of the total lipid content of the liposome.

[0169] In some embodiments, the sterol (e.g., any of the sterols described herein) is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 0.1 %, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 14%, about 16%, about 18%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%. about 50%, about 55%, or about 60% w / w of the total lipid content of the liposome. In some embodiments, the sterol is present in a liposome of a pharmaceutical composition provided herein in an amount of about 5% w / w of the total lipid content of the liposome. In some embodiments, the sterol is present in a particle of a pharmaceutical composition provided herein in an amount of about 15% w / w of the total lipid content of the particle. In some embodiments, the sterol is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 40% w / w of the total lipid content of the liposome. In some embodiments, the sterol is cholesterol.

[0170] In some embodiments, a liposome of a pharmaceutical composition used in any of the methods described herein can include a cationic lipid and / or an anionic lipid. A cationic lipid can have a positive or partial positive charge at physiological pH. Nonlimiting examples of cationic lipids include a N-[1-(2,3-dioleoyloxy)propyl]-N, N, N-trimethylammonium (DOTAP) salt (e.g., DOTAP-Cl) and a N-[1-(2,3-dioleyloxy)propyl]-N, N, N-trimethylammonium (DOTMA) salt (e.g., DOTMA-Cl). In some embodiments, an anionic lipid has a negative or partial negative charge at physiological pH. Non-limiting examples of anionic lipids include a 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol sodium salt (DPPG-Na), 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol sodium salt (DMPG-Na), 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol ammonium salt (DMPG-NH4). and l,2-distearoyl-sn-glycero-3-phosphoglycerol sodium salt (DSPG-Na). In some embodiments, a liposome of a pharmaceutical composition used in any of the methods described herein can include a PEGylated lipid. A PEGylated lipid refers to a lipid modified with polyethylene glycol (PEG).

[0171] In some embodiments, a liposome of a pharmaceutical composition used in any of the methods described herein can include a neutral phospholipid (e.g., any of the neutral phospholipids described herein), a sterol (e.g., any of the sterols described herein), and one or more of an anionic lipid (e.g., any of the anionic lipids described herein), a cationic lipid (e.g., any of the cationic lipids described herein), and a PEGylated lipid (e.g., any of the PEGylated lipids described herein). For example, a liposome of a pharmaceutical composition used in any of the methods described herein can formed by a neutral phospholipid (e.g., any of the neutral phospholipids described herein), a sterol (e.g.. any of the sterols described herein), and one or more of an anionic lipid (e.g., any of the anionic lipids described herein), a cationic lipid (e.g., any of the cationic lipids described herein), and a PEGylated lipid (e.g., any of the PEGylated lipids described herein).

[0172] In some embodiments, a liposome of a pharmaceutical composition used in any of the methods described herein includes a neutral phospholipid (e.g., any of the neutral phospholipids described herein), a sterol (e g., any of the sterols described herein), and an anionic lipid (e.g., any of the anionic lipids described herein). In some embodiments, a liposome of a pharmaceutical composition used in any of the methods described herein includes a neutral phospholipid (e.g., any of the neutral phospholipidsdescribed herein), a sterol (e.g., any of the sterols described herein), and a cationic lipid (e.g., any of the cationic lipids described herein). In some embodiments, a liposome of a pharmaceutical composition used in any of the methods described herein includes a neutral phospholipid (e.g., any of the neutral phospholipids described herein), a sterol (e.g., any of the sterols described herein), and a PEGylated lipid (e.g., any of the PEGylated lipids described herein).

[0173] In some embodiments, an anionic lipid, a cationic lipid, or a mixture thereof in a liposome of a pharmaceutical composition used in any of the methods described herein is present in an amount of about 0.1% to about 15% w / w of the total lipid content of the liposome. For example, the sterol can be present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 0.1% to about 1%, about 0.1% to about 2%, about 0.1% to about 4%, about 0.1% to about 6%, about 0.1% to about 8%, about 0.1% to about 10%, about 0.1% to about 12%, about 0.1% to about 14%, about 1% to about 2%, about 1% to about 4%, about 1% to about 6%, about 1% to about 8%, about 1% to about 10%, about 1% to about 12%. about 1% to about 14%, about 1% to about 15%, about 2% to about 4%, about 2% to about 6%, about 2% to about 8%, about 2% to about 10%, about 2% to about 12%, about 2% to about 14%, about 2% to about 15%, about 4% to about 6%, about 4% to about 8%, about 4% to about 10%, about 4% to about 12%, about 4% to about 14%, about 4% to about 15%. about 6% to about 8%, about 6% to about 10%, about 6% to about 12%. about 6% to about 14%, about 6% to about 15%, about 8% to about 10%, about 8% to about 12%, about 8% to about 14%, about 8% to about 15%, about 10% to about 12%, about 10% to about 14%, about 10% to about 15%, about 12% to about 14%, about 12% to about 15%, or about 14% to about 15% w / w of the total lipid content of the liposome. In some embodiments, an anionic lipid, a cationic lipid, or a mixture thereof is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 4% to about 6% w / w of the total lipid content of the liposome.

[0174] In some embodiments, an anionic lipid (e.g., any of the anionic lipids described herein), a cationic lipid (e.g., any of the cationic lipids described herein), or a mixture thereof is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 0.1 %, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%. about 13%, about 14%, or about 15% w / w of the total lipid content ofthe liposome. In some embodiments, an anionic lipid, a cationic lipid, or a mixture thereof is present in a liposome of a pharmaceutical composition provided herein in an amount of about 10% w / w of the total lipid content of the liposome. In some embodiments, an anionic lipid, a cationic lipid, or a mixture thereof is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 5% w / w of the total lipid content of the liposome.

[0175] In some embodiments, a pharmaceutical composition used in any of the methods described herein includes an anionic lipid (e.g., any of the anionic lipids described herein). In some embodiments, the anionic lipid is DSPG-Na. In some embodiments, the anionic lipid comprises DMPG-Na, DMPG-NH4. or a combination thereof. In some embodiments, the anionic lipid is DMPG-Na. In some embodiments, the anionic lipid is DMPG-NH4.

[0176] In some embodiments, a liposome of a pharmaceutical composition used in any of the methods described herein includes a cationic lipid (e.g., any of the cationic lipids described herein). In some embodiments, the anionic lipid is DOTAP-C1.

[0177] In some embodiments, a PEGylated lipid in a liposome of a pharmaceutical composition used in any of the methods described herein is present in an amount of about 0.1% to about 15% w / w of the total lipid content of the liposome. For example, the PEGylated lipid can be present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 0.1% to about 1%. about 0.1% to about 2%, about 0.1% to about 4%, about 0.1% to about 6%, about 0.1% to about 8%, about 0.1% to about 10%, about 0.1% to about 12%, about 0.1% to about 14%, about 1% to about 2%, about 1% to about 4%, about 1% to about 6%, about 1% to about 8%, about 1% to about 10%, about 1% to about 12%, about 1% to about 14%, about 1% to about 15%, about 2% to about 4%, about 2% to about 6%, about 2% to about 8%, about 2% to about 10%, about 2% to about 12%, about 2% to about 14%, about 2% to about 15%, about 4% to about 6%, about 4% to about 8%, about 4% to about 10%. about 4% to about 12%, about 4% to about 14%, about 4% to about 15%, about 6% to about 8%, about 6% to about 10%, about 6% to about 12%, about 6% to about 14%, about 6% to about 15%, about 8% to about 10%, about 8% to about 12%, about 8% to about 14%, about 8% to about 15%, about 10% to about 12%, about 10% to about 14%, about 10% to about 15%, about 12% to about 14%, about 12% to about 15%, or about 14% to about 15% w / w of the total lipid content of the liposome. In someembodiments, a PEGylated lipid is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 4% to about 6% w / w of the total lipid content of the liposome. In some embodiments, a PEGylated lipid is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 0.1%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% w / w of the total lipid content of the liposome. In some embodiments, a PEGylated lipid is present in a liposome of a pharmaceutical composition used in any of the methods described herein in an amount of about 5% w / w of the total lipid content of the liposome. In some embodiments, the PEGylated lipid is a PEGylated phospholipid. For example, the PEGylated lipid can be a PEGylated phosphatidylethanolamine (e.g., any of the phosphatidylethanolamines described herein). In some embodiments, the PEGylated lipid is DSPE- PEG2000.

[0178] In some embodiments, a liposome used in any of the methods described herein includes a neutral phospholipid present in an amount of about 75% to about 95% w / w of the total lipid content of the liposome and an anionic lipid (e.g., any of the anionic lipids described herein), a cationic lipid (e.g., any of the cationic lipids described herein), a PEGylated lipid (e.g., any of the PEGylated lipids described herein) or a mixture thereof present in an amount of about 1% to about 15% w / w of the total lipid content of the liposome.

[0179] In some embodiments, the liposome includes a neutral phospholipid present in an amount of about 78% to about 82% w / w of the total lipid content of the liposome. In some embodiments, the liposome includes a neutral phospholipid present in an amount of about 82% to about 88% w / w of the total lipid content of the liposome. In some embodiments, the liposome includes a neutral phospholipid present in an amount of about 88% to about 92% w / w of the total lipid content of the liposome.

[0180] In some embodiments, the liposome includes an anionic lipid (e.g., any of the anionic lipids described herein), a cationic lipid (e.g., any of the cationic lipids described herein), a PEGylated lipid (e.g., any of the PEGylated lipids described herein) or a mixture thereof present in an amount of about 2% to about 8% w / w of the total lipid content of the liposome. In some embodiments, the liposome includes an anionic lipid (e.g., any of the anionic lipids described herein), a cationic lipid (e.g., any of the cationic lipids described herein), a PEGylated lipid (e.g., any of the PEGylated lipids describedherein) or a mixture thereof present in an amount of about 12% to about 18% w / w of the total lipid content of the liposome.

[0181] In some embodiments, the liposome further includes a sterol present in an amount of about 1 % to about 20% w / w of the total lipid content of the liposome. In some embodiments, the liposome further includes a sterol present in an amount of about 12% to about 18% w / w of the total lipid content of the liposome. In some embodiments, the liposome further includes a sterol present in an amount of about 2% to about 8% w / w of the total lipid content of the liposome. In some embodiments, the neutral phospholipid includes DSPC. In some embodiments, the neutral phospholipid includes DMPC. In some embodiments, the sterol is cholesterol. In some embodiments, the cationic lipid includes DOTAP-C1. In some embodiments, the anionic lipid includes DMPG-Na and DMPG-NH4. In some embodiments, the anionic lipid is DMPG-Na. In some embodiments, the anionic lipid is DMPG-NH4. In some embodiments, the anionic lipid includes DSPG-Na. In some embodiments, the PEGylated lipid includes DSPE-PEG2000.

[0182] In some embodiments, a pharmaceutical composition used in any of the methods described herein includes a liposome containing: a curcuminoid (e.g., any of the curcuminoids described herein); cinnamaldehyde and / or a derivative thereof (e.g., any of the cinnamaldehyde derivatives described herein); DMPC present in an amount of about 75% to about 95% w / w of the total lipid content of the liposome; and an anionic lipid (e g., any of the anionic lipids described herein), a cationic lipid (e g., any of the cationic lipids described herein), a PEGylated lipid (e.g., any of the PEGylated lipids described herein) or a mixture thereof present in an amount of about 1% to about 15% w / w of the total lipid content of the liposome.

[0183] In some embodiments, the liposome includes DMPC present in an amount of about 78% to about 82% w / w of the total lipid content of the liposome and a cationic lipid (e.g., any of the cationic lipids described herein) present in an amount of about 2% to about 8% w / w of the total lipid content of the liposome. In some embodiments, the cationic lipid is DOTAP-C1. In some embodiments, the liposome further includes a cholesterol present in an amount of about 1 % to about 20% w / w of the total lipid content of the liposome. In some embodiments, the liposome further includes a sterol present in an amount of about 12% to about 18% w / w of the total lipid content of the liposome.

[0184] In some embodiments, the liposome includes DMPC present in an amount of about 82% to about 88% w / w of the total lipid content of the liposome and an anionic lipid (e.g., any of the anionic lipids described herein) present in an amount of about 8% to about 12% w / w of the total lipid content of the liposome. In some embodiments, the anionic lipid includes DMPG-Na, DMPG-NH4, or a combination thereof. In some embodiments, the anionic lipid is DMPG-Na. In some embodiments, the anionic lipid is DMPG-NH4. In some embodiments, the liposome further includes a cholesterol present in an amount of about 1% to about 20% w / w of the total lipid content of the liposome. In some embodiments, the liposome further includes a sterol present in an amount of about 12% to about 18% w / w of the total lipid content of the liposome. In some embodiments, the liposome further includes a sterol present in an amount of about 2% to about 8% w / w of the total lipid content of the liposome.

[0185] In some embodiments, the liposome includes DMPC present in an amount of about 88% to about 92% w / w of the total lipid content of the liposome and an anionic lipid (e g., any of the anionic lipids described herein) present in an amount of about 8% to about 12% w / w of the total lipid content of the liposome. In some embodiments, the anionic lipid includes DMPG-Na, DMPG-NH4, or a combination thereof. In some embodiments, the anionic lipid is DMPG-Na. In some embodiments, the anionic lipid is DMPG-NH4.

[0186] In some embodiments, a liposome provided herein includes: any of the active pharmaceutical ingredients described herein (e g., a curcuminoid, a cinnamaldehyde, a cinnamaldehyde derivative, resveratrol, or any mixture thereof); DMPC present in an amount of about 88% to about 92% w / w of the total lipid content of the liposome; and an anionic lipid present in an amount of about 8% to about 12% w / w of the total lipid content of the liposome, wherein the anionic lipid comprises DMPG-Na, DMPG-NH4, or a combination thereof. In some embodiments, the active pharmaceutical ingredient includes curcumin. In some embodiments, the active pharmaceutical ingredient includes curcumin and cinnamaldehyde. In some embodiments, wherein the active pharmaceutical ingredient includes curcumin and cinnamaldehyde, the curcumin and cinnamaldehyde are present at a weight ratio of about 5:1 curcumin: cinnamaldehyde.

[0187] In some embodiments, a liposome provided herein includes: curcumin; a neutral phospholipid (e.g., any of the neutral phospholipids described herein); and an anionic lipid (e.g.. any of the anionic lipids described herein), wherein the neutralphospholipid and anionic lipid are present at a molar ratio of about 90:5 to about 90:15 neutral phospholipid: anionic lipid; and wherein the curcumin is present at a molar ratio of about 1:10 to about 1:14 curcumin:lipid. In some embodiments, the curcumin is present at a molar ratio of about 1:12 curcumin: lipid. In some embodiments, the neutral phospholipid and anionic lipid are present at a molar ratio of about 90:10 neutral phospholipid: anionic lipid. In some embodiments, the neutral phospholipid is DMPC. In some embodiments, the anionic lipid is DMPG-Na, DMPG-NH4, or a combination thereof.

[0188] In some embodiments, the particle of a pharmaceutical composition used in any of the methods described herein is a micelle. In some embodiments, a pharmaceutical composition used in any of the methods described herein includes a micelle containing a curcuminoid (e.g., any of the curcuminoids described herein). In some embodiments, a pharmaceutical composition provided herein includes a micelle containing a curcuminoid (e.g., any of the curcuminoids described herein) and resveratrol.

[0189] In some embodiments, a micelle of a pharmaceutical composition used in any of the methods described herein includes a surfactant. Non-limiting examples of surfactants include Triton X-100 (e.g., polyethylene glycol tert-octylphcnyl ether), Brij 35 (e.g., polyoxyethylene lauryl ether), Brij 30 (e.g., polyoxyethelene 4 lauryl ether), a Tween (e.g., polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80), decaethylene glycol monododecyl ether, cetylpyridinium chloride (CPC), sodium dodecyl sulfate (SDS), sodium lauroyl sarcosinate (SLS), cetyltrimethylammonium bromide (CTAB), tetradecyltrimethylammonium bromide (TTAB), dodecyltrimethylammonium bromide (DTAB), dioctyl sodium sulfosuccinate (AOT), polyethylene-polypropylene glycol, polyoxyethylene-monostearate, and poly oxy ethylene-poly oxypropylene copolymer.

[0190] In some embodiments, the weight ratio of the curcuminoid (e.g., any of the curcuminoids described herein) to the surfactant (e.g., any of the surfactants described herein) is about 1:8 to about 1:500. For example, the weight ratio of the curcuminoid to the surfactant can be about 1:8 to about 1:500, 1:10 to about 1:500, 1:50 to about 1:500, 1:75 to about 1:500, 1:100 to about 1:500, 1:125 to about 1:500, 1:150 to about 1:500, 1:175 to about 1:500, 1:200 to about 1:500, 1:225 to about 1:500, 1:250 to about 1:500, 1:275 to about 1:500, 1:300 to about 1:500, 1:325 to about 1:500. 1:350 to about 1:500,1:375 to about 1:500, 1:400 to about 1:500, 1:425 to about 1:500, 1:450 to about 1:500, or 1:475 to about 1:500.

[0191] A surfactant can be a non-ionic surfactant. Non-limiting examples of a nonionic surfactant include an alkyl ether, an alkyl ester, an alkyl amide, and an ester of a fatty acid. For example, the non-ionic surfactant can be polyethylene glycol tertoctylphenyl ether, polyoxyethylene lauryl ether, polyoxyethelene 4 lauryl ether, a polyoxyethylene cetyl ether, a polyoxyethylene stearyl ether (e.g., Brij 72 and Brij 76), polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl 15 hydroxy stearate, a castor oil derivative, or a mixture thereof. Non-limiting examples of a castor oil derivative include a polyoxyethylene castor oil derivative, polysorbate 80, polyoxyl 15 hydroxy stearate, polyoxyl-35 castor oil, PEG-40 hydrogenated castor oil, and 2-hydroxy ethyl 12-hydroxy octadecanoate. In some embodiments, the hydrophilic-lipophilic balance value (HLB value) of the castor oil derivative is greater than 10.

[0192] In some embodiments, the surfactant includes a castor oil derivative. In some embodiments, the curcuminoid (e.g., any of the curcuminoid described herein) and castor oil derivative (e.g., any of the castor oil derivatives described herein) are present at a weight ratio of about 1:20 to about 1:15 curcuminoid: castor oil derivative. For example, the curcuminoid and castor oil derivative are present at a weight ratio of about 1:19 to about 1:15, about 1:18 to about 1:15, about 1:17 to about 1:15, or about 1:16 to about 1:15 curcuminoid: castor oil derivative.

[0193] In some embodiments, a micelle of a pharmaceutical composition used in any of the methods described herein is formed by a castor oil derivative comprising a polyoxyethylene castor oil derivative, polysorbate 80, polyoxyl 15 hydroxy stearate, polyoxyl-35 castor oil, PEG-40 hydrogenated castor oil, 2-hydroxyethyl 12-hydroxyoctadecanoate, or a mixture thereof. In some embodiments, the curcuminoid (e.g., any of the curcuminoids described herein) and castor oil derivative are present at a weight ratio of about 1:8 to about 1:500 curcuminoid: castor oil derivative.

[0194] In some embodiments, a micelle of a pharmaceutical composition used in any of the methods described herein fully encapsulates the curcuminoid (e.g., any of the curcuminoids described herein). In some embodiments, the micelle partially encapsulates the curcuminoid (e.g., any of the curcuminoids described herein). In some embodiments, wherein the pharmaceutical composition includes resveratrol, the liposome fully encapsulates the resveratrol. In some embodiments, wherein thepharmaceutical composition includes resveratrol, the liposome partially encapsulates the resveratrol.

[0195] Other pharmaceutical compositions that can be used in the methods described herein include those described in International Application No. PCT / 2025 / 027591; U. S. Patent Nos. 10,226,503; 10,716,824; and 10,537,548; U. S. Publication Nos. 2023 / 0372378; 2016 / 0129068; and 2016 / 0374911.Kits

[0196] Also provided herein are kits useful, for example, in administering a therapeutically effective amount of a pharmaceutical composition (e.g., any of the pharmaceutical compositions described herein) to a subcutaneous treatment area (e.g., any of the subcutaneous treatment areas described herein) in a subject, which include any of the cannulas provided herein; and a pharmaceutical composition (e.g., any of the pharmaceutical compositions described herein). In some embodiments, the cannula is a disposable cannula. For example, the tubular body of the cannula can be plastic. Such kits can further include, if desired, an injection device (e.g., any of the injection devices described herein) and / or an injection map (e.g., any of the injection maps described herein). In some embodiments, a kit provided herein further includes one or more of a disinfectant to clean an injection site on a skin of a subject, a gauze pad, a disposable towel, a surgical marker, and an introducer needle.

[0197] In some embodiments, a kit provided herein contains a cannula (e.g., any of the cannulas described herein) and one or more of an injection device (e.g., any of the injection devices described herein), an injection map (e.g., any of the injection maps described herein), a disinfectant, a gauze pad, a disposable towel, a surgical marker, and an introducer needle.

[0198] In some embodiments, a kit provided herein contains a pharmaceutical composition (e.g., any of the pharmaceutical compositions described herein) and one or more of an injection device (e.g., any of the injection devices described herein), an injection map (e.g., any of the injection maps described herein), a disinfectant to clean an injection site on a skin of a subject, a gauze pad, a disposable towel, a surgical marker, and an introducer needle.

[0199] A kit provided herein can further include one or more of various conventional pharmaceutical kit components, such as vials or syringes with one or morepharmaceutically acceptable carriers, additional vials, additional syringes, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.OTHER EMBODIMENTS

[0200] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A cannula comprising:a tubular body comprising a distal end portion and a proximal end portion, the tubular body sized and shaped to be inserted under a portion of skin of a subject;one or more markers on an external surface of the tubular body, wherein each of the one or markers is positioned along a corresponding location along a longitudinal axis of the tubular body;an outlet on the distal end portion of the tubular body; andan inlet on the proximal end portion of the tubular body configured to receive, from an injection device in fluid connection with the tubular body, a fluid comprising a pharmaceutical composition to deliver the pharmaceutical composition subcutaneously through the outlet.

2. The cannula of claim 1, wherein the one or more markers comprise one or more recesses on the external surface of the tubular body.

3. The cannula of claim 1 or 2, wherein the one or more markers comprise one or more protrusions on the external surface of the tubular body.

4. The cannula of claim 1, wherein the one or more markers are printed on the external surface of the tubular body without forming a substantial recess or protrusion.

5. The cannula of any one of claims 1-4, wherein at least a portion of the external surface of the tubular body is coated with a corrosion resistant material and / or a material to reduce friction.

6. The cannula of claim 5, wherein the corrosion resistant material comprises chromium (Cr).

7. The cannula of claim 5, wherein the corrosion resistant material comprises chromium nitride (CrN).

8. The cannula of any one of claims 1-7, wherein at least a portion of the external surface of the tubular body is matte.

9. The cannula of any one of claims 1-8, wherein at least a portion of the external surface of the tubular body is abraded.

10. The cannula of any one of claims 1-9, wherein at least one of the one or more markers is colored to distinguish from another of the one or more markers.

11. The cannula of any one of claims 1-10, wherein the cannula comprises two or more markers on the external surface.

12. The cannula of claim 11, wherein each of the two or more markers on the external surface is separated from each other by an equal distance.

13. The cannula of any one of claims 1-12, wherein the tubular body has a length from a distal end of the tubular body to a proximal end of the tubular body of about 3 cm to about 30 cm.

14. The cannula of any one of claims 1-13, wherein the tubular body has an inner diameter of about 0.2 mm to about 0.7 mm.

15. The cannula of any one of claims 1-13, wherein the gauge of the tubular body is about 12 to about 24 gauge.

16. The cannula of any one of claims 1-13, wherein the gauge of the tubular body is about 14 to about 18 gauge.

17. The cannula of any one of claims 1-16, wherein the tubular body has an aspect ratio (length-to-width) of about 20:1 to about 500:1.

18. The cannula of any one of claims 1-17, wherein the tubular body is made of a non-flexible material.

19. The cannula of any one of claims 1-18, wherein the tubular body comprises a metal.

20. The cannula of any one of claims 1-19, wherein the tubular body comprises a plastic.

21. The cannula of any one of claims 1-20, wherein the outlet has a diameter of about 0.2 mm to about 0.6 mm.

22. The cannula of any one of claims 1-21, wherein the outlet is a first outlet to deliver the pharmaceutical composition at a first subcutaneous treatment site, the tubular body further comprising a second outlet to deliver the pharmaceutical composition at a second subcutaneous treatment site.

23. The cannula of claim 22, wherein the first outlet and the second outlet are sized and positioned to deliver the pharmaceutical composition at the same rate.

24. The cannula of claim 22 or 23, wherein the first outlet and the second outlet are positioned at the distal end portion of the tubular body and are circumferentially spaced about the distal end portion of the tubular body.

25. The cannula of claim 22 or 23, wherein the second outlet is positioned differently from the first outlet in the longitudinal axis.

26. The cannula of any one of claims 22-25, wherein the diameter of the first outlet is larger than the diameter of the second outlet.

27. The cannula of any one of claims 1-26, further comprising a plurality of outlets on the tubular body.

28. The cannula of claim 27, wherein each of the outlets of the plurality of outlets is separated from each other by an equal distance.

29. A method for administering a therapeutically effective amount of a pharmaceutical composition to a subcutaneous treatment area in a subject, the method comprising:puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subject;inserting the cannula of any one of claims 1-28 into the puncture hole in the skin to a subcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; andinjecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

30. A method for inducing cell death of a plurality of adipocytes in a treatment area in a subject, the method comprising:puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subject;inserting the cannula of any one of claims 1-28 into the puncture hole in the skin to a subcutaneous treatment site wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; andinjecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

31. The method of claim 30, wherein the cell death is due to apoptosis and / or necrosis.

32. The method of claim 30 or 31, wherein the cell death is due to apoptosis.

33. A method for inhibiting adipogenesis in a treatment area in a subject, the method comprising:puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subject;inserting the cannula of any one of claims 1-28 into the puncture hole in the skin to a subcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; andinjecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

34. A method of reducing subcutaneous fat in a treatment area in a subject, the method comprising:puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subject;inserting the cannula of any one of claims 1-28 into the puncture hole in the skin to a subcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; andinjecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

35. The method of claim 34, wherein the method comprises inducing apoptosis of a plurality of adipocytes in the treatment area in the subject.

36. A method of improving the appearance of convexity or fullness associated with fat tissue in a subject, the method comprising:puncturing a hole in the skin proximate to the skin over the subcutaneous treatment area in the subject;inserting the cannula of any one of claims 1-28 into the puncture hole in the skin to a subcutaneous treatment site, wherein the cannula body is fluidly connected to an injection device containing a fluid comprising the pharmaceutical composition; andinjecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

37. The method of any one of claims 30-36, wherein an injection map contacts the skin over the subcutaneous treatment area and the injection map indicates a plurality of subcutaneous treatment sites.

38. The method of claim 37, further comprising providing the injection map on the skin over the subcutaneous treatment area in the subject.

39. The method of claim 38, further comprising generating the injection map prior to providing the injection map onto the skin over the subcutaneous treatment area in the subject.

40. The method of any one of claims 29-39, wherein the injection map on the skin comprises a grid having a plurality of cells, each cell of the plurality of cells corresponding to a distinct subcutaneous treatment site of the plurality of subcutaneous treatment sites.

41. The method of claim 40, wherein each cell has a dimension of about 1 cm x about 1 cm to about 3 cm x about 3 cm.

42. The method of any one of claims 38-41, wherein providing the injection map onto the skin of the subject comprises applying a temporary tattoo onto the skin over the subcutaneous treatment area in the subj ect.

43. The method of any one of claims 29-42, further comprising one or more additional steps of injecting the pharmaceutical composition from the injection device through the cannula body to at least one subcutaneous treatment site of the plurality of subcutaneous treatment sites.

44. The method of claim 43, comprising alternating each step of injecting the pharmaceutical composition with a step of retracting the cannula such that a subsequent cannula marker is aligned with the puncture hole in the skin.

45. The method of claim 43, comprising alternating each step of injecting the pharmaceutical composition with a step of retracting the cannula such that the distal end portion of the cannula is located in a subsequent subcutaneous treatment site of the plurality of subcutaneous treatment sites.

46. The method of any one of claims 29-45, wherein determining the location of the distal end portion of the cannula comprises feeling the distal end portion of the cannula under the skin.

47. The method of any one of claims 29-46, wherein determining the location of the distal end portion of the cannula comprises lining up a marker on the cannula with the puncture hole in the skin.

48. The method of any one of claims 29-47, wherein the spacing between each of the markers of the two or more markers on the cannula corresponds to the length of a cell of the injection map.

49. The method of any one of claims 29-48, wherein the spacing between each of the markers of a subset of the plurality of markers on the cannula corresponds to the length of a cell of the injection map.

50. The method of any one of claims 29-49, wherein each injection uses a predetermined volume of the fluid.

51. The method of claim 50, wherein the predetermined volume of the fluid is about 0.5 cc to about 3 cc.

52. The method of claim 50 or 51, wherein the predetermined volume varies for each injection based on an amount of fat in each injection area.

53. The method of any one of claims 29-52, wherein the injection map further comprises information about an injection volume for each subcutaneous treatment site.

54. The method of any one of claims 29-53, further comprising determining the injection volume for each subcutaneous treatment site.

55. The method of any one of claims 29-54, further comprising performing an ultrasound scan of the subcutaneous treatment area in the subject to determine which subcutaneous treatment site(s) contain more fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject.

56. The method of claim 55, wherein the injection volume is increased for subcutaneous treatment site(s) containing more fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject.

57. The method of any one of claims 29-56, further comprising performing an ultrasound scan of the subcutaneous treatment area in the subject to determine which subcutaneous treatment site(s) contain less fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject.

58. The method of claim 57, wherein the injection volume is decreased for subcutaneous treatment site(s) containing more fat compared to other subcutaneous treatment site(s) in the subcutaneous treatment area of the subject.

59. The method of any one of claims 29-58, wherein the subcutaneous treatment area in the subject is in the abdomen, a flank, an inner thigh, an outer thigh,jowls, lower face, an arm. buttocks, chest, breast, back, or any other area of deposited subcutaneous fat of the subject.

60. The method of claim 59, wherein the subcutaneous treatment area is in the back of the arm of the subject.

61. The method of claim 59, wherein the subcutaneous treatment area is in the abdomen of the subject.

62. The method of any one of claims 29-61, wherein the cannula is inserted such that one of the cannula markers is aligned with the puncture hole in the skin.

63. A kit comprising:the cannula of any one of claims 1-28; anda pharmaceutical composition.

64. The kit of claim 63, further comprising a syringe.

65. The kit of claim 63 or claim 64, further comprising an injection map.

66. The kit of claim 65, wherein the injection map is a temporary tattoo.

67. The kit of any one of claims 63-66, further comprising a disinfectant to clean an injection site on a skin of a subject.

68. The kit of any one of claims 63-67, further comprising a gauze pad.

69. The kit of any one of claims 63-68, wherein the pharmaceutical composition is contained within a vial.

70. The kit of any one of claims 63-69, further comprising instructions for performing the method of any one of claims 29-62.

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