Compositions with penetration enhancers for drug delivery

Abstract

The present invention relates to compositions with penetration enhancers for drug delivery. Compositions and methods for delivering therapeutic agents across a barrier are provided. The composition comprises a therapeutic agent (e.g., an antimicrobial agent, an antibiotic or an anesthetic), a penetration enhancer that increases the flux of the therapeutic agent across the barrier, and a matrix former. The matrix former forms a gel at a suitable gelling temperature and has rheological properties for drug delivery, and in some cases, the gelling temperature and rheological properties are not significantly changed compared to the gelling temperature and rheological properties of the composition without the penetration enhancer. The invention also provides a matrix forming agent and a composition thereof. Such compositions are particularly useful in the treatment of infectious diseases (e.g., otitis media). Methods of treatment, methods of delivery, and kits for the compositions described herein are also provided.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of September 14, 2017, an application number of 201780069720.5, and an invention title of "Compositions with Penetration Enhancers for Drug Delivery".

[0002] Cross - reference to related applications

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 394,716, filed on September 14, 2016, which is hereby incorporated by reference in its entirety. Technical field

[0004] The present invention relates to compositions with penetration enhancers for drug delivery. Background art

[0005] In the United States, there are 12 to 16 million physician visits annually due to otitis media (OM), making it the most common disease specifically treated in children. [1] The prevalence of acute OM (AOM) is 90% within the first 5 years of life, [2] and 90% to 95% of all children in the United States have at least one documented episode of middle ear effusion by the age of 2. [3] 25% of all prescriptions written for children are for the treatment of acute otitis media. The recurrence of this disease is also significant, with one - third of all children in the United States having 6 or more episodes of AOM by the age of 7. [4] In addition, epidemiological studies have shown that the prevalence of recurrent OM is increasing in children, especially in infants and toddlers. [5] The incidence of OM in children in other industrialized countries is similar to that in the United States. In developing countries, OM remains a significant cause of child mortality due to the occurrence of chronic suppurative otitis media, which often leads to permanent hearing sequelae and is estimated to cause more than 25,000 deaths globally due to intracranial complications. [6]

[0006] Acute OM is the most common reason for prescribing antimicrobials to children in the United States and is thought to contribute in part to the continued increase in antibiotic resistance in pathogenic bacteria due to the high prevalence and frequent recurrence of the disease. Although the use of antimicrobials in children has been successfully reduced by approximately 25% over the past decade, the increase in antimicrobial resistance continues.

[0007] Current treatment of ear infections consists of systemic oral antibiotics, which require multiple doses over 5 to 10 days and systemic exposure to the antibiotics. The rise in antibiotic resistance, combined with the multifactorial etiology of OM, has created difficulties in the diagnosis and treatment of OM. In addition, current treatments have many drawbacks, including patient compliance issues due to gastrointestinal side effects, lack of effective concentrations of the drug at the site of infection, and the possibility of opportunistic infections. Even after the acute infection symptoms subside (usually within 72 hours), the underlying cause of the infection may persist and outlast the remainder of the treatment, even up to 2 months. Thus, it is important to comply with the physician's prescription to prevent recurrence of the infection.

[0008] Direct local sustained delivery of an active therapeutic agent to the middle ear to treat OM can allow drug concentrations in the middle ear to be much higher than those obtained by systemic administration, while minimizing systemic exposure and its side effects. However, the tympanic membrane (TM), although only 10 cell layers thick, provides a barrier that is largely impermeable to all but the smallest moderately hydrophobic molecules. Despite being the thinnest layer of skin, it remains a barrier to trans-tympanic diffusion. Thus, direct treatment of middle ear infections is problematic. The deficiencies in current treatments for ear diseases such as middle ear infections suggest a need for new non-invasive and direct-acting treatments. Summary of the Invention

[0009] Compositions and methods for non-invasive trans-tympanic treatment of otitis media (OM) aimed at having a sustained drug flux across the tympanic membrane (TM) are provided herein (see, for example Figure 1 ). Chemical permeation enhancers (CPEs), which are commonly used for transdermal delivery, can achieve such trans-tympanic flux. In certain embodiments, a single application of an optimized formulation can provide high antibiotic concentrations in the middle ear, thereby eradicating bacterial otitis media without the drawbacks of oral treatment. Such formulations can also be used to treat other ear diseases that require drug delivery across the tympanic membrane.

[0010] Typical OM treatment consists of a 10-day course of broad-spectrum oral antibiotics. The widespread use of systemic antibiotics for such a highly prevalent and recurrent disease is thought to contribute in part to the increasing and persistent antibiotic resistance seen in pathogenic bacteria in the nasopharynx. In most cases, antibiotic-resistant infections (such as pneumonia, skin, soft tissue, and gastrointestinal infections) require longer and / or more expensive treatment compared to infections that can be easily treated with antibiotics, prolong hospital stays, require additional doctor visits and healthcare services, and result in greater disability and death. In some parts of the world, compliance with multi-dose regimens can also be difficult. In the long-term prevention of recurrent OM, compliance and antibiotic resistance can also be more problematic. Effective and sustained topical treatment can address compliance issues, influence resistance and the development of chronic suppurative otitis media, and reduce the need for tympanostomy tube placement (devices implanted in the TM to enhance middle ear drainage in recurrent OM). [8]

[0011] The TM is a three-layer membrane whose outer layer is a stratified squamous keratinized epithelium that is continuous with the skin of the external auditory canal. The innermost layer is a single layer of cuboidal mucosal epithelium. Between these epithelia is a layer of fibroelastic connective tissue along with associated blood vessels and nerves. The human TM is only about 100 μm thick, but due to its keratin- and lipid-rich stratum corneum, the outer epithelium of 6 to 10 cell layers forms an impermeable barrier to all but the smallest lipophilic molecules.

[11]

[0012] Sustained local drug delivery directly to the target tissue has several advantages over systemic administration, including fewer adverse systemic effects, use of smaller amounts of drug, potentially better treatment outcomes, and cost reduction. The impermeability of the TM is a central challenge in the development of topical treatments.

[0013] Chemical penetration enhancers (CPEs) are used to safely increase the flux of small molecules in transdermal drug delivery. Several are FDA-approved for human use. These agents are generally surfactants that comprise a heterogeneous group of amphiphilic organic molecules with hydrophilic heads and hydrophobic tails. Several classes of surfactants have been studied. Surfactants reversibly alter lipid bilayers (such as in the stratum corneum) through adsorption at the interface and disruption of the bilayer structure. Cationic surfactants are known to increase permeate flux more than anionic surfactants, which in turn increase permeability more than nonionic surfactants. A wide range of non-surfactant chemical enhancers (such as terpenes) have also been used for some mechanisms of action, including protein denaturation within and between keratinocytes, and / or modification or disruption of the structural integrity of the lipid bilayer that results in increased lipid bilayer fluidity.

[0014] In the compositions provided herein, a therapeutic agent and a penetration enhancer are combined with a gelling agent to form a composition that forms a hydrogel under suitable conditions. Such conditions can include exposure to body heat during administration (e.g., in the ear canal), or after mixing two components of the composition or the gelling agent. A gelling agent is a compound or mixture of compounds that forms a gel after administration. The composition is typically liquid under ambient conditions; however, once administered to a subject, the gelling agent or combination of gelling agents causes a phase transition to a hydrogel. The temperature at which the storage modulus of the composition begins to increase and becomes greater than the loss modulus of the composition is referred to as the "sol-gel transition temperature." The terms "sol-gel transition temperature," "phase transition temperature," and "gelation temperature" are used interchangeably. The hydrogel has a highly porous structure that allows for the loading of drugs and other small molecules, and subsequent elution of the drug from the gel to produce a high local concentration in the surrounding tissue over an extended period of time. In certain embodiments, the drug is loaded in the liquid composition. The hydrogel can conform to the shape of the surface to which it is applied and adhere thereto, and is often biocompatible. In certain embodiments, the composition forms a gel at a sol-gel transition temperature of from about 0°C to about 39°C. In certain embodiments, the composition forms a gel at a sol-gel transition temperature of from about 0°C to about 37°C. In certain embodiments, the composition forms a gel at a sol-gel transition temperature of from about 0°C to about 35°C.

[0015] For the compositions provided herein, the combination of a permeation enhancer with a matrix former and a therapeutic agent provides a composition having increased flux of the therapeutic agent and improved or insignificantly impaired mechanical properties of the resulting hydrogel relative to a hydrogel formed from the composition in the absence of the permeation enhancer. For example, the sol-gel transition temperature of a composition having a permeation enhancer can be lower than that of a composition without a permeation enhancer, or, even if higher, can still fall within the useful range for forming a hydrogel after exposure to a biological surface (e.g., a sol-gel transition temperature of from about 0 °C to about 39 °C). As another example, the storage modulus and / or loss modulus of a composition having a permeation enhancer can be substantially the same as that of a composition without a permeation enhancer (e.g., within about 85%), or the storage modulus of a composition having a permeation enhancer can be higher than that of a composition without a permeation enhancer. As another example, the storage modulus and / or loss modulus of a composition having a permeation enhancer can be substantially the same as that of a composition without a permeation enhancer (e.g., within about 85% or 15 kPa, whichever is greater), or the storage modulus of a composition having a permeation enhancer can be higher than that of a composition without a permeation enhancer. For the compositions provided herein, the combination of a permeation enhancer with a matrix former and a therapeutic agent provides a composition having increased flux of the therapeutic agent and other improved properties (including but not limited to extended drug release, adhesion of the composition to the tympanic membrane over time, degradation (e.g., biodegradation), or combinations thereof), and improved or insignificantly impaired properties of the resulting hydrogel relative to a hydrogel formed from the composition in the absence of the permeation enhancer.

[0016] In one aspect, provided herein are compositions comprising:

[0017] (a) a therapeutic agent or combination of therapeutic agents;

[0018] (b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and

[0019] (c) a matrix former or combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0020] wherein:

[0021] the composition forms a gel at a temperature above the sol-gel transition temperature; and

[0022] the sol-gel transition temperature is below about 39 °C;

[0023] and satisfies at least one of the conditions (i), (ii), and (iii):

[0024] (i) The sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0025] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 13.5% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0026] (iii) At a temperature of about 37 °C, the loss modulus of the composition is about 12% to about 750% of the loss modulus of the reference composition;

[0027] wherein:

[0028] The reference composition is the composition that does not contain a penetration enhancer or a combination of penetration enhancers;

[0029] The penetration enhancer or the combination of penetration enhancers accounts for about 0.1% to 30% of the composition by weight per volume of the composition;

[0030] The polymer is a block copolymer comprising poloxamer;

[0031] Poloxamer accounts for about 19% to 45% of the composition by weight per volume of the composition.

[0032] In one aspect, the present invention provides a composition comprising:

[0033] (a) A therapeutic agent or a combination of therapeutic agents;

[0034] (b) A penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or the combination of penetration enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents through a barrier; and

[0035] (c) A matrix former or a combination of matrix formers, wherein the matrix former or the combination of matrix formers comprises a polymer;

[0036] wherein:

[0037] The composition forms a gel at a temperature above the sol-gel transition temperature; and

[0038] The sol-gel transition temperature is lower than about 39 °C;

[0039] And satisfies at least one of the conditions (i), (ii), and (iii):

[0040] (i) The sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0041] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition; and

[0042] (iii) At a temperature of about 37 °C, the loss modulus of the composition is from about 15% to about 750% of the loss modulus of the reference composition;

[0043] wherein the reference composition is the composition in the absence of (b) the permeation enhancer or combination of permeation enhancers;

[0044] The permeation enhancer or combination of permeation enhancers accounts for about 1% to 30% of the composition by weight per volume of the composition;

[0045] The polymer is a block copolymer comprising poloxamer;

[0046] Poloxamer accounts for about 19% to 45% of the composition by weight per volume of the composition.

[0047] In one aspect, there is provided a composition comprising:

[0048] (a) A therapeutic agent or combination of therapeutic agents;

[0049] (b) A permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and

[0050] (c) A matrix former or combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0051] wherein:

[0052] The composition forms a gel at a temperature above the sol-gel transition temperature; and

[0053] The sol-gel transition temperature is below about 39 °C;

[0054] And satisfies at least one of the conditions (i), (ii) and (iii):

[0055] (i) The sol-gel transition temperature of the composition is below the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0056] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0057] (iii) At a temperature of about 37 °C, the loss modulus of the composition is from about 12% to about 750% of the loss modulus of the reference composition;

[0058] wherein:

[0059] The reference composition is the composition in the absence of a penetration enhancer or a combination of penetration enhancers;

[0060] The penetration enhancer or combination of penetration enhancers includes sodium dodecyl sulfate and limonene, and

[0061] The penetration enhancer or combination of penetration enhancers accounts for about 3% to 6% of the composition by weight per volume of the composition;

[0062] The polymer is a block copolymer containing poloxamer P407; and

[0063] P407 accounts for about 22% to about 27% of the composition by weight per volume of the composition.

[0064] In one aspect, provided herein is a composition comprising:

[0065] (a) a therapeutic agent or a combination of therapeutic agents;

[0066] (b) a penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or combination of penetration enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and

[0067] (c) a matrix former or a combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0068] Wherein:

[0069] The composition forms a gel at a temperature above the sol-gel transition temperature; and

[0070] The sol-gel transition temperature is below about 39 °C;

[0071] And at least one of the conditions (i), (ii), and (iii) is satisfied:

[0072] (i) The sol-gel transition temperature of the composition is below the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0073] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0074] (iii) At a temperature of about 37 °C, the loss modulus of the composition is from about 15% to about 750% of the loss modulus of the reference composition;

[0075] Wherein:

[0076] The reference composition is the composition that does not contain a penetration enhancer or a combination of penetration enhancers;

[0077] The penetration enhancer or combination of penetration enhancers includes sodium dodecyl sulfate and limonene, and

[0078] The penetration enhancer or combination of penetration enhancers accounts for about 3% to 6% of the composition by weight per volume of the composition;

[0079] The polymer is a block copolymer containing poloxamer P407; and

[0080] P407 accounts for about 22% to about 27% of the composition by weight per volume of the composition.

[0081] In certain embodiments, condition (i) is met, i.e., the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater. In certain embodiments, condition (ii) is met, i.e., the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition. In certain embodiments, condition (ii) is met, i.e., the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller. In certain embodiments, condition (ii) is met, i.e., the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 1000 Pa, whichever is smaller. In certain embodiments, condition (iii) is met, i.e., the loss modulus of the composition is about 80% to about 120% of the loss modulus of the reference composition. In certain embodiments, condition (iii) is met, i.e., the loss modulus of the composition is about 12% to about 750% of the loss modulus of the reference composition. In certain embodiments, condition (iii) is met, i.e., the loss modulus of the composition is about 15% to about 750% of the loss modulus of the reference composition. In certain embodiments, both conditions (i) and (ii) are met. In certain embodiments, both conditions (ii) and (iii) are met. In certain embodiments, both conditions (i) and (iii) are met. In certain embodiments, each of conditions (i), (ii), and (iii) is met.

[0082] In certain embodiments, the polymer is biodegradable. In certain embodiments, the polymer is a copolymer. In certain embodiments, the copolymer is biodegradable or contains biodegradable monomers. In certain embodiments, the copolymer is a block copolymer. In certain embodiments, the copolymer contains at least one hydrophobic monomer block. In certain embodiments, the copolymer contains at least one hydrophobic monomer block and at least one non-hydrophobic monomer block.

[0083] In certain embodiments, the copolymer comprises a copolymer of poloxamer, poloxamer 407 (P407), poloxamer 331 (P331), poloxamer 188 (P188), or derivatives thereof, or combinations thereof. In certain embodiments, the copolymer comprises a poloxamer. In some embodiments, the copolymer comprises poloxamer 407. In some embodiments, the copolymer comprises poloxamer 331.

[0084] In certain embodiments, the composition is optically transparent.

[0085] In certain embodiments, the sol-gel transition temperature of the composition is the body temperature of the subject or lower than the body temperature of the subject. In certain embodiments, the sol-gel transition temperature of the composition is from about 10 °C to about 40 °C. In certain embodiments, the sol-gel transition temperature of the composition is from about 20 °C to about 40 °C. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the same composition without a permeation enhancer plus about 23 °C.

[0086] In certain embodiments, the composition can be used to treat a disease. In some embodiments, the composition is used to treat an infectious disease. In some embodiments, the composition can be used to treat an ear disease (e.g., the barrier is the tympanic membrane). In some embodiments, the composition can be used to treat otitis media.

[0087] In another aspect, provided herein is a composition for treating an infectious disease or an ear disease, comprising:

[0088] (a) a therapeutic agent or a combination of therapeutic agents;

[0089] (b) a permeation enhancer or a combination of permeation enhancers, wherein the permeation enhancer or the combination of permeation enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents across the barrier; and

[0090] (c) a matrix former or a combination of matrix formers, wherein the matrix former or the combination of matrix formers comprises a block copolymer containing poloxamer.

[0091] The therapeutic agent can be an antimicrobial agent, an antibiotic agent, an anesthetic agent, an anti-inflammatory agent, an analgesic agent, an anti-fibrotic agent, an anti-sclerosis agent, or an anticoagulant agent. In certain embodiments, the therapeutic agent is an antibiotic selected from the following: ciprofloxacin, cefuroxime, cephalexin, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefibutene, cefotaxime, ceftriaxone, cefepime, ceftobiprole, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, spectinomycin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, sulfamylon, sulfacetamide, sulfamethizole, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole. In some embodiments, the antibiotic is ciprofloxacin. In some embodiments, the antibiotic is amoxicillin, azithromycin, cefuroxime, ceftriaxone, or trimethoprim. In some embodiments, the antibiotic is gemifloxacin. In some embodiments, the antibiotic is levofloxacin. In certain embodiments, the therapeutic agent is an antiviral agent or an antifungal agent. In certain embodiments, the therapeutic agent is chlorhexidine. azole, trimethoprim, and trimethoprim-sulfamethoxazole. In some embodiments, the antibiotic is ciprofloxacin. In some embodiments, the antibiotic is amoxicillin, azithromycin, cefuroxime, ceftriaxone, or trimethoprim. In some embodiments, the antibiotic is gemifloxacin. In some embodiments, the antibiotic is levofloxacin. In certain embodiments, the therapeutic agent is an antiviral agent or an antifungal agent. In certain embodiments, the therapeutic agent is chlorhexidine.

[0092] The penetration enhancer can be a surfactant, a terpene, an amino amide, an amino ester, an azide-containing compound, an alcohol, or an anesthetic agent. The penetration enhancer can be a surfactant, a terpene, an amino amide, an amino ester, an azide-containing compound, an alcohol, a pyrrolidone, a sulfoxide, a fatty acid, or an anesthetic agent. The penetration enhancer can be a surfactant, a terpene, an amino amide, an amino ester, an azide-containing compound, an alcohol, a pyrrolidone, a sulfoxide, a fatty acid, a peptide, or an anesthetic agent. In some embodiments, the penetration enhancer is a surfactant (e.g., a cationic surfactant, anionic surfactant, nonionic surfactant). In some embodiments, the penetration enhancer is a terpene. In some embodiments, the composition comprises a surfactant penetration enhancer and a terpene penetration enhancer.

[0093] In certain embodiments, the penetration enhancer is sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyltrimethylammonium bromide, cetylpyridinium chloride Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl betaine (chembetaine oleyl), myristyl dimethyl ammonium propane sulfonate; benzylpyridinium chloride Dodecylpyridinium chloride Cetylpyridinium chloride Benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl myristyl ammonium chloride, benzyl dimethyl stearoyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. In certain embodiments, the penetration enhancer is sodium dodecyl sulfate, decyl methyl sulfoxide, nonoxynol-9, sodium pyrrolidone carboxylate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyl trimethyl ammonium bromide, cetylpyridinium chloride, benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl betaine, myristyl dimethyl ammonium propane sulfonate; benzylpyridinium chloride, dodecylpyridinium chloride, cetylpyridinium chloride, benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl myristyl ammonium chloride, benzyl dimethyl stearyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. In certain embodiments, the penetration enhancer is sodium octyl sulfate, sodium dodecyl sulfate, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20 or polysorbate 80. In some embodiments, the penetration enhancer is sodium dodecyl sulfate.

[0094] In certain embodiments, the penetration enhancer is sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000 molecular weight (MW)) or octyldodecanol. In certain embodiments, the penetration enhancer is methyl laurate, isopropyl myristate, sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000 molecular weight (MW)) or octyldodecanol.

[0095] In certain embodiments, the penetration enhancer is an azone-like compound. In certain embodiments, the penetration enhancer is a compound similar to azone (e.g., laurocapram) of the following formula: In certain embodiments, the penetration enhancer is a piperazine-containing compound. In certain embodiments, the penetration enhancer is 1-benzyl-4-(2-((1,1-biphenyl)-4-yloxy)ethyl)piperazine.

[0096] In certain embodiments, the penetration enhancer is a terpene (e.g., limonene). In certain embodiments, the penetration enhancer is limonene, cymene, pinene, camphor, menthol, camphene, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol, eugenyl acetate, safrole, benzyl benzoate, humulene, β-caryophyllene, eucalyptol, caproic acid, caprylic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl myristate, isopropyl palmitate, palmitoyl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, or ethyl piperazine carboxylate. In some embodiments, the penetration enhancer is limonene.

[0097] In certain embodiments, the penetration enhancer is bupivacaine, tetracaine, procaine, proxymetacaine, propoxycaine, dimethocaine, cyclomethycaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, carticaine, etidocaine, mepivacaine, piridocaine, or trimecaine. In some embodiments, the penetration enhancer is bupivacaine.

[0098] In some embodiments, the penetration enhancer is a combination of a surfactant and a terpene. In some embodiments, the penetration enhancer is a combination of a surfactant and an anesthetic. In some embodiments, the penetration enhancer is a combination of a terpene and an anesthetic. In some embodiments, the penetration enhancer is a combination of a surfactant, a terpene, and an anesthetic. In some embodiments, the penetration enhancer is a combination of a surfactant and a terpene selected from the following: sodium octyl sulfate, sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, and polysorbate 80. In some embodiments, the penetration enhancer is a combination of a surfactant and limonene selected from the following: sodium octyl sulfate, sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, and polysorbate 80. In some embodiments, the penetration enhancer is sodium dodecyl sulfate, limonene, or bupivacaine, or a combination thereof. In some embodiments, the penetration enhancer is a combination of sodium dodecyl sulfate and limonene. In some embodiments, the penetration enhancer is a combination of 2% sodium dodecyl sulfate and 2% limonene. In some embodiments, the penetration enhancer is a combination of sodium dodecyl sulfate, limonene, and bupivacaine.

[0099] The composition may further comprise additional therapeutic agents, including anti-inflammatory agents (such as dexamethasone), anesthetics (such as bupivacaine), or β-lactamase inhibitors. In some embodiments, the therapeutic agent or additional therapeutic agent also functions as a penetration enhancer. In some embodiments, an amino amide (such as bupivacaine) or an amino ester (such as tetracaine) local anesthetic functions as both a penetration enhancer and a therapeutic agent. In some embodiments, the composition comprises an amino amide (such as bupivacaine) or an amino ester (such as tetracaine) local anesthetic that functions as both a penetration enhancer and a therapeutic agent and does not comprise an additional therapeutic agent. In some embodiments, the composition comprises bupivacaine that functions as both a penetration enhancer and a therapeutic agent and does not comprise an additional therapeutic agent.

[0100] In certain embodiments, the therapeutic agent comprises from about 0.01% to about 30% of the composition. In certain embodiments, the therapeutic agent comprises from about 0.01% to about 25%, from about 0.01% to about 20%, from about 0.01% to about 15%, from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 5%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.25%, or from about 0.01% to about 0.1% of the composition. In certain embodiments, the therapeutic agent comprises from about 0.01% to about 10% of the composition. In certain embodiments, the weight percentage of the permeation enhancer in the composition is from about 0.1% to about 1%, from about 1% to about 3%, or from about 3% to about 10%. In certain embodiments, the weight percentage of the matrix former in the composition is from about 1% to about 10%, from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, or from about 40% to about 50%. Unless otherwise indicated, the percentage compositions herein refer to the weight of the components per volume of the composition.

[0101] In another aspect, the present disclosure provides a method for treating an infectious disease, the method comprising administering to a subject in need thereof a composition comprising a therapeutic agent, a permeation enhancer, and a matrix former as described herein.

[0102] In another aspect, the present disclosure provides a method for treating an ear disease, the method comprising administering to a subject in need thereof a composition comprising a therapeutic agent, a permeation enhancer, and a matrix former as described herein. In certain embodiments, the composition is administered into the ear canal or onto the tympanic membrane. In certain embodiments, the disease is otitis media. In certain embodiments, the disease is an ear infection. In certain embodiments, the disease is a bacterial infection (e.g., Haemophilus influenzae (H. influenza), Streptococcus pneumoniae (S. pneumoniae), or Moraxella catarrhalis (M. catarrhalis) infection).

[0103] In another aspect, the present disclosure provides a method for eradicating a biofilm, the method comprising administering to a subject in need thereof the composition described herein or contacting the biofilm with the composition described herein.

[0104] In another aspect, the present disclosure provides a method for inhibiting biofilm formation, the method comprising administering to a subject in need thereof the composition described herein or contacting a surface with the composition described herein.

[0105] In another aspect, the present disclosure provides a method for delivering the composition described herein, the method comprising administering the composition into the ear canal of a subject, wherein the composition contacts the surface of the tympanic membrane. The composition can be administered using an eyedropper, a syringe, a twin syringe, or a catheter (e.g., a vascular catheter).

[0106] In another aspect, the present disclosure provides a kit that includes a container, a composition as described herein, and instructions for administering the composition to a subject in need thereof. The kit may further include a device for administering the composition to the subject, such as a dropper, syringe, catheter, biphasic syringe, otoscope attachment, or a combination thereof.

[0107] The compositions, composition components (such as matrix formers, therapeutic agents, and penetration enhancers), methods, kits, and uses of the present disclosure may also incorporate any features described in the following: Khoo et al., Biomaterials. (2013) 34, 1281 - 8; U.S. Patent No. 8,822,410; U.S. Patent Application No. 12 / 993,358, filed May 19, 2009; U.S. Patent Application No. 11 / 734,537, filed Apr. 12, 2007; WIPO Patent Application No. PCT / US2009 / 003084, filed May 19, 2009; and WIPO Patent Application No. PCT / US2007 / 009121, filed Apr. 12, 2007, each of which is incorporated herein by reference. The compositions, composition components (such as matrix formers, therapeutic agents, and penetration enhancers), methods, kits, and uses of the present disclosure may also incorporate any features described in the following: Yang et al., Science Translational Medicine (2016) 8, 356ra120; and WIPO Patent Application No. PCT / US2016 / 45908, each of which is incorporated herein by reference.

[0108] As described below, details of certain embodiments of the present invention are set forth in the "Detailed Description of Certain Embodiments". Other features, objects, and advantages of the present invention will become apparent from the definitions, examples, drawings, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] The drawings, which are a part of this specification, illustrate several embodiments of the present invention and, together with the description, serve to explain the principles of the present invention.

[0110] Figure 1 : Protocol for trans - tympanic antibiotic delivery.

[0111] Figures 2A to 2D : Images of the tympanic membrane (TM): ( Figure 2A ) Normal untreated TM; ( Figure 2B ) TM with otitis media; ( Figure 2C ) TM with gel containing ciprofloxacin; ( Figure 2D ) TM with gel containing ciprofloxacin and a penetration enhancer. Scale bar = 20 μm.

[0112] Figure 3 Graph showing enhanced TM flux from gels containing permeation enhancers. (P407 is poloxamer 407, Cipro = ciprofloxacin, and 3CPE refers to 1% sodium dodecyl sulfate, 0.5% bupivacaine, 2% limonene).

[0113] Figure 4 Graph showing the acoustic brainstem response (ABR) threshold shift following application of 18% poloxamer 407 (P407) containing a chemical permeation enhancer. The horizontal line indicates no change.

[0114] Figure 5 Isobologram showing the concentration of CPE B relative to the concentration of CPE A and indicating conditions of synergy and antagonism between CPEs.

[0115] Figure 6: Gelation of aqueous solutions of 18% [P407] without CPE and 3CPE-18% [P407] as a function of temperature. Note: 3CPE = 2% limonene, 1% SDS, and 0.5% bupivacaine. Data are mean ± SD, n = 4. For 18% [P407], the storage (G’) and loss (G”) moduli (measured by linear oscillatory shear rheology at 100 rad / s, 1% strain, 1 °C / min) were ~1 kPa at room temperature; it behaved as a viscous liquid. G’ and G” showed a sharp increase above a temperature of 27 °C and reached plateau values of ~6 and 4 kPa, respectively, exhibiting solid-like behavior. However, when 3CPE was added to the P407 solution at the desired concentration [which was previously used to enhance permeation across the TM (8)], the storage and loss moduli of the formulation were less than 2 kPa in the temperature range of 20 to 40 °C; in other words, the composition did not form a gel in the presence of 3CPE. Here, the inhibition of gelation can be attributed to the inhibitory effect of CPE on the micellization of P407 molecules. Above the critical micellization temperature, P407 molecules assemble into micelles that have a core containing the hydrophobic poly(propylene oxide) block and a shell of hydrated ethylene oxide blocks. As the temperature increases, the micelles form a liquid crystal gel with a body-centered cubic structure (see Mortensen et al., Phys. Rev. Lett. 68, 2340-2343 (1992)). Alternatively, as the temperature increases, the micelles form a liquid crystal gel with a face-centered cubic structure. Micelles with diameters of 100 to 150 nm were formed in a 1% P407 solution without CPE (1% [P407]) at room temperature as recorded by transmission electron microscopy (TEM). When CPE was added to P407 (3CPE-1% [P407]), no micelles were formed. The inhibition of micelle formation was attributed to the cooperative binding of small molecules (in this case CPE) on the block copolymer molecules, rendering the hydrophobic blocks hydrophilic (see 41). The shear rheology results were consistent with the observations by otoscopy in 2 / 2 chinchillas, i.e., Cip-3CPE-18% [P407] did not maintain structural integrity on the TM.

[0116] Figures 7A to 7C : Rheological data for 25% P407 compositions with various concentrations of CPE, including the effect of CPE concentration on the loss and storage moduli. Figure 7A : Rheological data for 25% P407 compositions with 1% SDS and 2% limonene (where limonene is designated as “LIM”). Figure 7B : Rheological data for 25% P407 compositions with 1% SDS and 4% limonene. Figure 7C : Rheological data for 25% P407 compositions with 2% SDS and 1% limonene. X-axis (temperature in °C); Y-axis (modulus in Pa).

[0117] Figure 8 : 25% P407 compositions with CPE at various concentrations, whose rheological data includes the effect of CPE concentration on loss modulus and storage modulus. Rheological data of 25% P407 compositions with 2% SDS and 2% / 4% limonene. Storage (G’) and loss (G”) moduli are shown. X-axis (temperature in °C); Y-axis (modulus in Pa).

[0118] Figure 9 : Rheological data of 50% P331 compositions (without CPE).

[0119] Figure 10 : Rheological data of 25% P407 compositions with variable amounts of CPE. Rheological data of 25% P407 compositions with the following components: without CPE; 1% SDS and 2% limonene; 1% SDS and 4% limonene; 2% SDS and 1% limonene; 2% SDS and 2% limonene; 2% SDS and 4% limonene; or 3CPE (1% SDS, 0.5% bupivacaine and 2% limonene).

[0120] Figure 11 A to 11B: Permeation of ciprofloxacin ( Figure 11 (A)) and dexamethasone ( Figure 11 (B)) through the TM over time. 4% Cip - 0.1% Dex = 4% ciprofloxacin and 0.1% dexamethasone aqueous solution; 4% Cip - 0.1% Dex - 3CPE = 4% ciprofloxacin, 0.1% dexamethasone, 1% SDS, 2% LIM, 0.5% BUP; 4% Cip - 0.1% Dex - 3CPE - 18% [P407] = 4% ciprofloxacin, 0.1% dexamethasone, 1% SDS, 2% LIM, 0.5% BUP, 18% P407.

[0121] Figure 12 : Concentration of ciprofloxacin in the middle ear fluid (MEF) of chinchillas infected with streptococcus pneumonia (SP). A formulation (referred to as "4% Cip - 25% [P407] - 2CPE") with 4% ciprofloxacin, 25% P407 and containing 2% SDS and 2% limonene is used to treat chinchillas with otitis media caused by streptococcus pneumonia (SP). SP is inoculated into the nasopharynx of chinchillas on day 5, and then into the auditory bulla of chinchillas on day 3. The 4% Cip - 25% [P407] - 2CPE hydrogel formulation is placed on the tympanic membrane of infected chinchillas using a soft catheter on day 0. Using HPLC( Figure 1) The concentration of ciprofloxacin (“Cip”) in the middle ear effusion (MEF) of infected chinchillas was measured at 0 and 6 hours after hydrogel application and on days 1, 2, 5, and 7. The minimum inhibitory concentration (MIC) of SP was 0.5 to 4 μg / ml. During the entire 7-day treatment period, the drug concentration in the MEF was several orders of magnitude higher than the MIC. A single application of the hydrogel formulation achieved sustained high concentrations of the drug ciprofloxacin.

[0122] Figure 13 : The infection rate of chinchillas with otitis media caused by SP. After 7 days of treatment with the 4% Cip-25%[P407]-2CPE formulation, approximately 60% of the chinchillas with otitis media caused by SP were cured. In contrast, the ear drops of 1% Cip-3CPE (1% ciprofloxacin and 1% SDS, 2% LIM, 0.5% BUP) used as a reference could not cure any chinchillas.

[0123] Figure 14 : The count of bacterial colony-forming units (CFU) in the middle ear effusion of chinchillas with otitis media caused by SP. Along with the treatment with the 4% Cip-25%[P407]-2CPE formulation, the average number of SP colony-forming units (CFU) in the MEF of infected chinchillas decreased significantly. In contrast, the average CFU in the MEF of chinchillas treated with the 1% Cip-3CPE ear drops increased over time, indicating the deterioration of otitis media in chinchillas.

[0124] Figure 15 A to 15B: ( Figure 15 A) Freshly prepared and ( Figure 15 B) HPLC spectra of the 4% Cip-25%[P407]-2CPE formulation stored at 4 °C for 5 months. Based on HPLC measurements of drug concentration, the 4% Cip-25%[P407]-2CPE formulation was also stable during storage. The 4% Cip-25%[P407]-2CPE formulation was stored at 4 °C for 5 months. The HPLC spectra of the freshly prepared 4% Cip-25%[P407]-2CPE formulation were compared with the HPLC spectra of the formulation stored at 4 °C for 5 months, and the two HPLC spectra of the fresh formulation and the formulation after 5 months of storage looked almost the same. After 5 months of storage, the concentration of ciprofloxacin remained at 4 ± 1% (w / v), indicating that there was almost no drug degradation during the storage of the formulation.

[0125] Figure 16 : Rheological data of the 25% P407 composition with 2% SDS and 2% limonene.

[0126] Figure 17: Rheological data of 25% P407 composition with the following: no CPE; 1% SDS and 2% limonene; 1% SDS and 4% limonene; 2% SDS and 1% limonene; 2% SDS and 2% limonene; 2% SDS and 4% limonene; or 3CPE (1% SDS, 0.5% bupivacaine, and 2% limonene). Detailed Description

[0127] Compositions and methods for delivering a therapeutic agent to a subject across a barrier are provided herein. In some embodiments, the composition is for delivering a therapeutic agent to the ear of a subject, and the barrier is the tympanic membrane. The composition and method allow for effective delivery of the agent to the middle ear and / or inner ear of the subject. In one aspect, the composition comprises a combination of a permeation enhancer, a therapeutic agent, and a matrix former. In one aspect, the composition comprises a combination of multiple permeation enhancers, a therapeutic agent, and a matrix former. The permeation enhancer increases the flux of the therapeutic agent across the barrier (e.g., the tympanic membrane) compared to the flux of a composition lacking the permeation enhancer. The multiple permeation enhancers increase the flux of the therapeutic agent across the barrier (e.g., the tympanic membrane) compared to the flux of a composition lacking the permeation enhancer. In multiple aspects, the composition is a single-application composition for local sustained delivery of a therapeutic agent across the tympanic membrane. In multiple aspects, the composition is a multiple-application composition for local sustained delivery of a therapeutic agent across the tympanic membrane. The compositions and methods of the present invention are particularly useful for treating otitis media by providing a sustained release and delivery of an antibiotic to the middle ear.

[0128] In one aspect, provided herein is a composition comprising:

[0129] (a) a therapeutic agent or combination of therapeutic agents;

[0130] (b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the barrier; and

[0131] (c) a matrix former or combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0132] wherein:

[0133] the composition forms a gel at a temperature above the sol-gel transition temperature; and

[0134] the sol-gel transition temperature is below about 39 °C;

[0135] and satisfies at least one of the conditions (i), (ii), and (iii):

[0136] (i) the sol-gel transition temperature of the composition is below the sol-gel transition temperature of a reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0137] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 13.5% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0138] (iii) At a temperature of about 37 °C, the loss modulus of the composition is from about 12% to about 750% of the loss modulus of the reference composition;

[0139] Wherein:

[0140] The reference composition is the composition that does not contain a permeation enhancer or a combination of permeation enhancers;

[0141] The permeation enhancer or combination of permeation enhancers accounts for about 0.1% to 30% of the composition by weight per volume of the composition;

[0142] The polymer is a block copolymer comprising poloxamer;

[0143] The poloxamer accounts for about 19% to 45% of the composition by weight per volume of the composition.

[0144] In one aspect, the present invention provides a composition comprising:

[0145] (a) A therapeutic agent or a combination of therapeutic agents;

[0146] (b) A permeation enhancer or a combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and

[0147] (c) A matrix former or a combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0148] Wherein:

[0149] The composition forms a gel at a temperature above the sol-gel transition temperature; and

[0150] The sol-gel transition temperature is lower than about 39 °C; and

[0151] And satisfies at least one of the conditions (i), (ii) and (iii):

[0152] (i) The sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0153] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition; and

[0154] (iii) At a temperature of about 37 °C, the loss modulus of the composition is about 15% to about 750% of the loss modulus of the reference composition;

[0155] wherein the reference composition is the composition without the penetration enhancer or combination of penetration enhancers;

[0156] The penetration enhancer or combination of penetration enhancers accounts for about 1% to 30% of the composition by weight per volume of the composition;

[0157] The polymer is a block copolymer comprising poloxamer;

[0158] Poloxamer accounts for about 19% to 45% of the composition by weight per volume of the composition.

[0159] In one aspect, provided herein is a composition comprising:

[0160] (a) A therapeutic agent or combination of therapeutic agents;

[0161] (b) A penetration enhancer or combination of penetration enhancers, wherein the penetration enhancer or combination of penetration enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and

[0162] (c) A matrix former or combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0163] wherein:

[0164] The composition forms a gel at a temperature above the sol-gel transition temperature; and

[0165] The sol-gel transition temperature is below about 39 °C;

[0166] And satisfies at least one of the conditions (i), (ii), and (iii):

[0167] (i) The sol-gel transition temperature of the composition is below the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0168] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0169] (iii) At a temperature of about 37 °C, the loss modulus of the composition is about 12% to about 750% of the loss modulus of the reference composition;

[0170] wherein:

[0171] The reference composition is the composition without the penetration enhancer or combination of penetration enhancers;

[0172] The penetration enhancer or combination of penetration enhancers comprises sodium dodecyl sulfate and limonene, and

[0173] the penetration enhancer or combination of penetration enhancers is present in the composition in an amount of about 3% to 6% by weight per volume of the composition;

[0174] the polymer is a block copolymer comprising poloxamer P407; and

[0175] P407 is present in the composition in an amount of about 22% to about 27% by weight per volume of the composition.

[0176] In one aspect, provided herein is a composition comprising:

[0177] (a) a therapeutic agent or combination of therapeutic agents;

[0178] (b) a penetration enhancer or combination of penetration enhancers, wherein the penetration enhancer or combination of penetration enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and

[0179] (c) a matrix former or combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0180] wherein:

[0181] the composition forms a gel at a temperature above the sol-gel transition temperature; and

[0182] the sol-gel transition temperature is less than about 39 °C;

[0183] and at least one of the conditions (i), (ii), and (iii) is satisfied:

[0184] (i) the sol-gel transition temperature of the composition is less than the sol-gel transition temperature of a reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0185] (ii) at a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0186] (iii) at a temperature of about 37 °C, the loss modulus of the composition is from about 15% to about 750% of the loss modulus of the reference composition;

[0187] wherein:

[0188] the reference composition is a composition that does not contain a penetration enhancer or combination of penetration enhancers;

[0189] the penetration enhancer or combination of penetration enhancers comprises sodium dodecyl sulfate and limonene, and

[0190] The penetration enhancer or combination of penetration enhancers is present in the composition in an amount of about 3% to 6% by weight per volume of the composition;

[0191] The polymer is a block copolymer comprising poloxamer P407; and

[0192] P407 is present in the composition in an amount of about 22% to about 27% by weight per volume of the composition.

[0193] In certain embodiments, condition (i) is met, i.e., the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater. In certain embodiments, condition (ii) is met, i.e., the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition. In certain embodiments, condition (ii) is met, i.e., the storage modulus of the composition is greater than about 15% or 500 Pa of the storage modulus of the reference composition, whichever is smaller. In certain embodiments, condition (ii) is met, i.e., the storage modulus of the composition is greater than about 15% or 1000 Pa of the storage modulus of the reference composition, whichever is smaller. In certain embodiments, in condition (iii), the loss modulus of the composition is about 80% to about 120% of the loss modulus of the reference composition. In certain embodiments, condition (iii) is met, i.e., the loss modulus of the composition is about 12% to about 750% of the loss modulus of the reference composition. In certain embodiments, condition (iii) is met, i.e., the loss modulus of the composition is about 15% to about 750% of the loss modulus of the reference composition. In certain embodiments, both conditions (i) and (ii) are met. In certain embodiments, both conditions (ii) and (iii) are met. In certain embodiments, both conditions (i) and (iii) are met. In certain embodiments, each of conditions (i), (ii), and (iii) is met.

[0194] In certain embodiments, the therapeutic agent is a single therapeutic agent. In certain embodiments, the therapeutic agent is a combination of two or more therapeutic agents (e.g., 2, 3, 4). In certain embodiments, the penetration enhancer is a single therapeutic agent. In certain embodiments, the therapeutic agent is a combination of two or more therapeutic agents (e.g., 2, 3, 4). In certain embodiments, the matrix former is a single matrix former. In certain embodiments, the matrix former is a combination of two or more matrix formers (e.g., 2, 3, 4). In certain embodiments, a therapeutic agent or penetration enhancer can be used simultaneously as a therapeutic agent and a penetration enhancer. In certain embodiments, a therapeutic agent can be used simultaneously as a therapeutic agent and a penetration enhancer. In certain embodiments, a penetration enhancer can be used simultaneously as a therapeutic agent and a penetration enhancer. In certain embodiments, a local anesthetic can be used simultaneously as a therapeutic agent and a penetration enhancer. In certain embodiments, an amide or ester local anesthetic can be used simultaneously as a therapeutic agent and a penetration enhancer. In certain embodiments, an amide or ester local anesthetic can be used simultaneously as a therapeutic agent and a penetration enhancer. In certain embodiments, an ester local anesthetic can be used simultaneously as a therapeutic agent and a penetration enhancer. In certain embodiments, bupivacaine can be used simultaneously as a therapeutic agent and a penetration enhancer. In certain embodiments, tetracaine can be used simultaneously as a therapeutic agent and a penetration enhancer.

[0195] In certain embodiments, the penetration enhancer or combination of penetration enhancers is present in an amount effective to increase the flux of the therapeutic agent across the barrier as compared to a reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, the penetration enhancer or combination of penetration enhancers is present in an amount effective to increase the flux of the therapeutic agent across the barrier by the following fold as compared to a reference composition (e.g., a composition without a penetration enhancer): at least about 1.05-fold, at least about 1.10-fold, at least about 1.2-fold, at least about, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, or at least about 1.9-fold. In certain embodiments, the penetration enhancer or combination of penetration enhancers is present in an amount effective to increase the flux of the therapeutic agent across the barrier by the following fold as compared to a reference composition: at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 25-fold, at least about 50-fold, at least about 100-fold, at least about 250-fold, at least about 500-fold, or at least about 1000-fold. In certain embodiments, the penetration enhancer or combination of penetration enhancers is present in an amount effective to increase the flux of the therapeutic agent across the barrier by about 1.5-fold to about 100-fold as compared to a reference composition.

[0196] In certain embodiments, the polymer is a copolymer. In some embodiments, the polymer is biodegradable. In certain embodiments, the copolymer is a block copolymer. In certain embodiments, the copolymer comprises at least one hydrophobic monomer block. In certain embodiments, the copolymer is biodegradable or comprises at least one biodegradable block.

[0197] As used herein, "hydrophobic" refers to a polymer that tends to have low solubility in water and / or is lipid-soluble. As used herein, "highly hydrophobic" refers to a polymer that has low water solubility and / or has high lipid solubility. In some embodiments, the hydrophobic polymer comprises hydrophobic side chains. In some embodiments, the highly hydrophobic polymer comprises hydrophobic side chains. Hydrophobic side chains include, but are not limited to, side chains containing hydrocarbon moieties such as alkyl (e.g., methyl), alkenyl, alkynyl, carbocyclic, and aryl groups. The hydrophobic moiety may also include groups selected from heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclic, and heteroaryl groups, where the heteroatom-containing groups are substantially similar to the hydrocarbon groups (e.g., only 1 or 2 carbons are replaced by heteroatoms). The hydrophobic side chains may contain groups that are the same as or are derivatives of the side chains of hydrophobic amino acids, including but not limited to glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, aminobutyric acid, alloisoleucine, tyrosine, and tryptophan. Non-hydrophobic or hydrophilic polymers are polymers that tend to be soluble in water.

[0198] In certain embodiments, the polymer or copolymer comprises a vinyl polymer (e.g., PE, PVC, PVDC, PS), a polyacrylate (e.g., polyacrylic acid polymethacrylic acid), a polyether (e.g., PEO, PPO, POM), a fluoropolymer (e.g., PTFE), a polysiloxane (e.g., PDMS), a polysaccharide (e.g., cellulose, dextran, hyaluronic acid, chitosan), a polyester (e.g., PET, polyhydroxyalkanoate (e.g., PHB)), a polyamide (e.g., poly(lactic acid), poly(glycolic acid)), a polyphosphate, a polyurethane or a polycarbonate, or a copolymer of combinations thereof. In certain embodiments, the copolymer comprises a natural polymer. In some embodiments, the copolymer comprises a polysaccharide, a proteoglycan, a glycosaminoglycan, collagen, fibrin, gelatin, or a derivative thereof, or a copolymer of combinations thereof. In certain embodiments, the polymer or copolymer comprises poly(ether-urethane) and poly(ether-carbonate) (Biomaterials, 24 (2003) 3707-3714), a peptide (Adv. Mater. 2007, 19, 3947-–3950), poly(ethylene glycol) and poly(trimethylene carbonate) (Macromolecules, 2007,  40(15), pp. 5519-5525), methylcellulose, chitosan, dextran, pNiPAAm (European Journal of Pharmaceutics and Biopharmaceutics, Vol. 68, No. 1, January 2008, pp. 34-45).

[0199] Exemplary polymer types suitable for the polymer or copolymer include, but are not limited to: poloxamers and their derivatives. In some embodiments, the copolymer comprises a poloxamer. In some embodiments, the copolymer comprises poloxamer 407, poloxamer 188, poloxalene, poloxamer 124, poloxamer 237, poloxamer 331 or poloxamer 338. In some embodiments, the copolymer comprises poloxamer 331. In some embodiments, the copolymer comprises poloxamer 407.

[0200] In certain embodiments, the copolymer is a block copolymer of the formula A-B-A, where B is a hydrophobic block and each A is a non-hydrophobic block. In certain embodiments, the copolymer is a block copolymer of the formula C-A-B-A-C, where each B or C is a hydrophobic block and A is a non-hydrophobic block. The polymers A-B-A and C-A-B-A-C may also include end groups attached to the terminal blocks A or C. In certain embodiments, B and C are different polymers. In certain embodiments, B and C are the same polymer. In certain embodiments, each block A is a polymer of 1 to 400 monomers. In certain embodiments, block A is a polymer of 20 to 200 monomers. In certain embodiments, each block B is a polymer of 1 to 400 monomers. In certain embodiments, block B is a polymer of 20 to 200 monomers. In certain embodiments, each block C is a polymer of 1 to 400 monomers. In certain embodiments, block C is a polymer of 20 to 200 monomers. In certain embodiments, each block A comprises a single type of monomer. In certain embodiments, each block A comprises more than one type of monomer. In certain embodiments, each block B comprises a single type of monomer. In certain embodiments, each block B comprises more than one type of monomer. In certain embodiments, each block C comprises a single type of monomer. In certain embodiments, each block C comprises more than one type of monomer.

[0201] In certain embodiments, polymer A is a hydrophilic polyether (e.g., polyethylene oxide). In certain embodiments, polymer A is a hydrophilic polyester (e.g., polyglycolic acid). In certain embodiments, polymer B is a hydrophobic polyether (e.g., polypropylene oxide). In certain embodiments, polymer B is a hydrophobic polyester (e.g., polylactic acid). In certain embodiments, polymer C is a polyphosphate.

[0202] Before being heated above the sol-gel transition temperature, the composition can be a liquid. In some embodiments, the sol-gel transition temperature is equal to or lower than the body temperature of the subject (e.g., about 37 °C). Thus, when administered to a subject, such as when the composition contacts a biological surface, the composition can form a gel. In some embodiments, the sol-gel transition temperature is from about 0 °C to about 37 °C, from about 10 °C to about 37 °C, from about 15 °C to about 37 °C, from about 20 °C to about 37 °C, from about 25 °C to about 30 °C to about 37 °C, from about 30 °C to about 35 °C, or from about 35 °C to about 40 °C. In some embodiments, the sol-gel transition temperature is from about 0 °C to about 37 °C, from about 10 °C to about 37 °C, from about 15 °C to about 37 °C, from about 20 °C to about 37 °C, from about 25 °C to about 37 °C, from about 30 °C to about 37 °C, from about 30 °C to about 35 °C, or from about 35 °C to about 40 °C. In some embodiments, the sol-gel transition temperature is from about 20 °C to about 37 °C. In some embodiments, the sol-gel transition temperature is from about 0 °C to about 60 °C, from about 10 °C to about 50 °C, from about 20 °C to about 40 °C, or from about 25 °C to about 35 °C. In some embodiments, the sol-gel transition temperature is from about 20 °C to about 37 °C. In some embodiments, the sol-gel transition temperature is from about 0 °C to about 60 °C, from about 10 °C to about 50 °C, from about 20 °C to about 40 °C, or from about 25 °C to about 35 °C. In some embodiments, the sol-gel transition temperature is from about 20 °C to 25 °C, from about 25 °C to about 30 °C, from about 30 °C to about 35 °C, or from about 35 °C to about 40 °C. In some embodiments, the sol-gel transition temperature is from about 25 °C to about 37 °C. In certain embodiments, the sol-gel transition temperature is from about 37 °C to about 39 °C. In some embodiments, the sol-gel transition temperature is from about 10 °C to about 50 °C. In some embodiments, the sol-gel transition temperature is from about 20 °C to about 40 °C. In some embodiments, the sol-gel transition temperature is from about 15 °C to about 40 °C. In some embodiments, the sol-gel transition temperature is higher than about 10 °C. In some embodiments, the sol-gel transition temperature is higher than about 20 °C. In some embodiments, the sol-gel transition temperature is higher than about 30 °C. In some embodiments, the sol-gel transition temperature is higher than about 35 °C. In some embodiments, the sol-gel transition temperature is lower than about 39 °C. In some embodiments, the sol-gel transition temperature is lower than about 38 °C. In some embodiments, the sol-gel transition temperature is lower than about 37 °C. In some embodiments, the sol-gel transition temperature is lower than about 36 °C. In some embodiments, the sol-gel transition temperature is lower than about 35 °C. In some embodiments, the sol-gel transition temperature is lower than about 34 °C. In some embodiments, the sol-gel transition temperature is lower than about 33 °C. In some embodiments, the sol-gel transition temperature is about 37 °C. In some embodiments, the sol-gel transition temperature is about 36 °C.In some embodiments, the sol-gel transition temperature is about 35°C. In some embodiments, the sol-gel transition temperature is about 33°C. In some embodiments, the sol-gel transition temperature is about 30°C. In certain embodiments, the composition forms a gel at a sol-gel transition temperature of from about 0°C to about 39°C. In certain embodiments, the composition forms a gel at a sol-gel transition temperature of from about 0°C to about 37°C. In certain embodiments, the composition forms a gel at a sol-gel transition temperature of from about 0°C to about 35°C.

[0203] For any composition comprising a matrix former, if an additive is added to the composition, the sol-gel transition temperature of the composition can be altered. The sol-gel transition temperature of the composition with the additive can be higher, lower, or the same as that of a reference composition without the additive, depending on the characteristics of the composition and the additive. As used herein, the term reference composition refers to a composition that contains the same components as the composition being compared, except for the specified component (e.g., a permeation enhancer). Unless otherwise stated, the difference in % weight / volume with or without a permeation enhancer consists of a change in the % weight / volume of the solvent (e.g., water). In certain embodiments, the reference composition comprises a therapeutic agent and a matrix former, but does not comprise a permeation enhancer. In certain embodiments, the reference composition comprises a matrix former, but does not comprise a therapeutic agent or a permeation enhancer. In certain embodiments, the reference composition comprises a permeation enhancer and a matrix former, but does not comprise a therapeutic agent.

[0204] In certain embodiments, the sol-gel transition temperature of the composition is higher than that of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition (e.g., a composition without a permeation enhancer) plus about 23 °C, or 39 °C, whichever is greater. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition (e.g., a composition without a permeation enhancer) plus about 23 °C. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition (e.g., a composition without a permeation enhancer) plus about 23 °C, about 22 °C, about 21 °C, about 20 °C, about 19 °C, about 18 °C, about 17 °C, about 16 °C, about 15 °C, about 14 °C, about 13 °C, about 12 °C, about 11 °C, about 10 °C, about 9 °C, about 8 °C, about 7 °C, about 6 °C, about 5 °C, about 4 °C, about 3 °C, about 2 °C, or about 1 °C; or 39 °C, whichever is greater. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition (e.g., a composition without a permeation enhancer) plus about 23 °C, about 22 °C, about 21 °C, about 20 °C, about 19 °C, about 18 °C, about 17 °C, about 16 °C, about 15 °C, about 14 °C, about 13 °C, about 12 °C, about 11 °C, about 10 °C, about 9 °C, about 8 °C, about 7 °C, about 6 °C, about 5 °C, about 4 °C, about 3 °C, about 2 °C, or about 1 °C. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition (e.g., a composition without a permeation enhancer) plus about 5 °C. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition (e.g., a composition without a permeation enhancer) plus about 37 °C. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition (e.g., a composition without a permeation enhancer) plus about 30 °C, about 20 °C, or about 10 °C. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition (e.g., a composition without a permeation enhancer).

[0205] In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of a reference composition (e.g., a composition without a permeation enhancer) plus about 25°C, about 23°C, about 20°C, about 15°C, about 10°C, about 5°C, plus about 2°C or plus about 1°C, and higher than the sol-gel transition temperature of a reference composition (e.g., a composition without a permeation enhancer) plus about 23°C or about 30°C. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition by 39°C, whichever is greater. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of a reference composition (e.g., a composition without a permeation enhancer) plus about 23°C. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of a reference composition (e.g., a composition without a permeation enhancer) plus about 23°C and higher than about 20°C. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of a reference composition (e.g., a composition without a permeation enhancer) plus about 5°C and higher than about 20°C.

[0206] As a non-limiting example, consider the following compositions. The sol-gel transition temperature of composition "A" containing the following is about 33°C: (i) 1% ciprofloxacin and (ii) 18% poloxamer 407 copolymer. For the corresponding composition "B" containing the components of "A" and (iii) 1% sodium dodecyl sulfate, the sol-gel transition temperature is reduced to about 31°C. For the corresponding composition "C" containing the components of "A" and (iii) 0.5% bupivacaine, the sol-gel transition temperature remains about 33°C. Both compositions "B" and "C" meet the following criteria: the phase transition temperature of the composition with a permeation enhancer is lower than or slightly higher than (e.g., <5°C) the sol-gel transition temperature of the composition without a permeation enhancer.

[0207] In certain embodiments, the composition is a gel at a temperature above the sol-gel transition temperature and below about 60 °C, below about 50 °C, or below about 40 °C. In certain embodiments, the composition is a gel at a temperature above the sol-gel transition temperature and below about 50 °C. In certain embodiments, the composition is a gel at a temperature of from about 0 °C to about 60 °C, from about 10 °C to about 50 °C, from about 20 °C to about 40 °C, or from about 25 °C to about 35 °C. In some embodiments, the composition is a gel at a temperature of from about 20 °C to 25 °C, from about 25 °C to about 30 °C, from about 30 °C to about 35 °C, or from about 35 °C to about 40 °C. In some embodiments, the composition is a gel at a temperature of from about 10 °C to about 50 °C. In some embodiments, the composition is a gel at a temperature of from about 20 °C to about 40 °C. In some embodiments, the composition is a gel at a temperature of from about 15 °C to about 40 °C.

[0208] For any composition comprising a matrix former, if an additive is added to the composition, the storage modulus and loss modulus of the composition can change. The storage modulus of the composition with the additive can be higher, lower, or the same relative to the same composition without the additive, depending on the characteristics of the composition and the additive. The loss modulus of the composition with the additive can be higher, lower, or the same relative to a reference composition without the additive, depending on the characteristics of the composition and the additive. In certain embodiments, the reference composition comprises a therapeutic agent and a matrix former, but does not comprise a permeation enhancer. In certain embodiments, the reference composition comprises a matrix former, but does not comprise a therapeutic agent or a permeation enhancer. In certain embodiments, the reference composition comprises a permeation enhancer and a matrix former, but does not comprise a therapeutic agent.

[0209] In certain embodiments, condition (ii) is met, i.e., the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition, or greater than about 500 Pa, whichever is smaller. In certain embodiments, condition (ii) is met, i.e., the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition, or greater than about 1000 Pa, whichever is smaller. In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 15%, greater than about 30%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 100% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 13.5%, greater than about 30%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 80%, greater than about 90%, or greater than about 100% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 13.5% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 30% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 50% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 60% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 70% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 80% or about 90% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 100% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer). In certain embodiments, at a given temperature, the storage modulus of the composition is greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, greater than about 150%, greater than about 175%, or greater than about 200% of the storage modulus of the reference composition (e.g., a composition without a penetration enhancer).In certain embodiments, at a given temperature, the storage modulus of the composition is less than about 200%, less than about 500%, or less than about 1000% of the storage modulus of a reference composition (e.g., a composition without a permeability enhancer). In certain embodiments, the given temperature is about 37°C. In certain embodiments, the given temperature is a temperature from the sol-gel transition temperature to about 37°C.

[0210] In certain embodiments, at a given temperature, the loss modulus of the composition is less than about 200%, less than about 150%, less than about 125%, less than about 110%, or less than about 100% of the storage modulus of a reference composition (e.g., a composition without a permeability enhancer). In certain embodiments, at a given temperature, the loss modulus of the composition is greater than about 50%, less than about 75%, or greater than about 90% of the loss modulus of a reference composition (e.g., a composition without a permeability enhancer). In certain embodiments, at a given temperature, the loss modulus of the composition is from about 50% to about 150%, from about 70% to about 130%, from about 80% to about 120%, or from about 90% to about 110% of the loss modulus of a reference composition (e.g., a composition without a permeability enhancer). In certain embodiments, at a given temperature, the loss modulus of the composition is from about 80% to about 120% of the loss modulus of a reference composition (e.g., a composition without a permeability enhancer). In certain embodiments, condition (iii): at a temperature of about 37°C, the loss modulus of the composition is from about 12% to about 750% of the loss modulus of a reference composition. In certain embodiments, condition (iii): at a temperature of about 37°C, the loss modulus of the composition is from about 15% to about 750% of the loss modulus of a reference composition. In certain embodiments, condition (iii): at a temperature of about 37°C, the loss modulus of the composition is from about 15% to about 500% of the loss modulus of a reference composition. In certain embodiments, condition (iii): at a temperature of about 37°C, the loss modulus of the composition is from about 15% to about 300% of the loss modulus of a reference composition. In certain embodiments, condition (iii): at a temperature of about 37°C, the loss modulus of the composition is from about 15% to about 200% of the loss modulus of a reference composition. In certain embodiments, condition (iii): at a temperature of about 37°C, the loss modulus of the composition is from about 80% to about 150% of the loss modulus of a reference composition. In certain embodiments, condition (iii): at a temperature of about 37°C, the loss modulus of the composition is from about 15% to about 150% of the loss modulus of a reference composition. In certain embodiments, the given temperature is about 37°C. In certain embodiments, the given temperature is a temperature from the sol-gel transition temperature to about 37°C.

[0211] In certain embodiments, the composition comprises at least about 0.1% of a penetration enhancer. In certain embodiments, the composition comprises at least about 0.5% of a penetration enhancer. In certain embodiments, the composition comprises at least about 1% of a penetration enhancer. In certain embodiments, the composition comprises at least about 2% of a penetration enhancer. In certain embodiments, the composition comprises at least about 3% of a penetration enhancer. In certain embodiments, the composition comprises at least about 4% of a penetration enhancer. In certain embodiments, the composition comprises at least about 5% of a penetration enhancer. In certain embodiments, the composition comprises at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, or at least about 30% of a penetration enhancer. In certain embodiments, the composition comprises at least about 0.5% weight / volume of the composition (weight / volume) of a penetration enhancer. In certain embodiments, the composition comprises at least about 1% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 2% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 3% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 4% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 5% of a penetration enhancer. In certain embodiments, the composition comprises at least about 6% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 7% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 8% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 10% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 15% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 20% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 25% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises at least about 30% weight / volume of a penetration enhancer. In certain embodiments, the composition comprises, by weight / volume of the composition of the penetration enhancer, about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 10%, 15%, 20%, 25% or 30% of a penetration enhancer. In certain embodiments, the composition comprises about 0.1% to about 1% of a penetration enhancer. In certain embodiments, the composition comprises about 0.5% to about 3% of a penetration enhancer. In certain embodiments, the composition comprises about 0.5% to about 10% of a penetration enhancer. In certain embodiments, the composition comprises about 2% to about 10% of a penetration enhancer. In certain embodiments, the composition comprises about 1% to about 30% of a penetration enhancer.In certain embodiments, the composition comprises from about 1% to about 20% of a penetration enhancer. In certain embodiments, the composition comprises from about 1% to about 25% of a penetration enhancer. In certain embodiments, the composition comprises from about 1% to about 20% of a penetration enhancer. In certain embodiments, the composition comprises from about 1% to about 15% of a penetration enhancer.

[0212] In certain embodiments, the composition is applied to a surface at a temperature equal to or higher than the sol-gel transition temperature. In some embodiments, the surface is a biological surface. In certain embodiments, the surface is the skin. In certain embodiments, the surface is the surface in the ear canal of an object. In certain embodiments, the object is the tympanic membrane. In certain embodiments, the surface is the surface in the respiratory tract of an object (e.g., in the nasal cavity or buccal cavity). In certain embodiments, the surface is the surface in the mouth of an object (e.g., the surface of teeth or gums). The composition may be administered to an in vivo surface, for example, by intradermal or interfollicular delivery or during a surgical procedure. In certain embodiments, the surface is an intradermal surface. In certain embodiments, the surface is the surface of an organ (e.g., the heart, lung, spleen, pancreas, kidney, liver, stomach, intestine, bladder). In certain embodiments, the surface is connective tissue. In certain embodiments, the surface is muscle tissue (e.g., smooth muscle, skeletal muscle, cardiac muscle). In certain embodiments, the surface is a mucosal surface (e.g., middle ear mucosa, lung mucosa, vaginal mucosa). In certain embodiments, the surface is nerve tissue (e.g., the brain, spinal cord). In certain embodiments, the surface is epithelial tissue. In certain embodiments, the surface is the surface of the digestive tract (e.g., the colon, rectum). In certain embodiments, the surface is epithelial tissue. In certain embodiments, the surface is the surface of the reproductive tract (e.g., the vagina, cervix). In certain embodiments, the surface is bone. In certain embodiments, the surface is vascular tissue. In certain embodiments, the surface is a wound bed. In certain embodiments, the surface is a biofilm. In certain embodiments, the surface is hair or fur. In certain embodiments, the surface is the surface of a medical implant.

[0213] Generally, for the addition of a penetration enhancer, it is preferred that the change in the sol-gel transition temperature, storage modulus, or loss modulus is small or no change. A small change is considered to be a change in the sol-gel transition temperature of less than 5 °C, or a change in the modulus of less than 10%. For the change in the sol-gel transition temperature, a lower sol-gel transition temperature is preferred for the composition having the penetration enhancer. For the change in the storage modulus (e.g., values between 500 and about 10 kPa), a higher storage modulus is preferred for the composition having the penetration enhancer. For the change in the storage modulus at values above 10 pKa, a higher storage modulus is not preferred for the composition having the penetration enhancer. The shift to a lower sol-gel transition temperature can be referred to as a "left shift" or "L-shift", rather than a "right shift" or "R-shift". For the change in the storage modulus, a higher storage modulus is preferred for the composition having the penetration enhancer. For the change in the loss modulus, a lower loss modulus is preferred for the composition having the penetration enhancer. For the change in the loss modulus, a lower loss modulus is preferred with respect to the storage modulus of the composition having the penetration enhancer.

[0214] In certain embodiments, the sol-gel transition temperature of the composition is within about 5 °C, within about 3 °C, or within about 1 °C of the sol-gel transition temperature of a reference composition, wherein the composition comprises a penetration enhancer P1 and the reference composition does not comprise the penetration enhancer P1. In certain embodiments, the storage modulus of the composition is within about 10%, within about 5%, or within about 2% of the storage modulus of a reference composition, wherein the composition comprises a penetration enhancer P1 and the reference composition does not comprise the penetration enhancer P1. In certain embodiments, the loss modulus of the composition is within about 10%, within about 5%, or within about 2% of the loss modulus of a reference composition, wherein the composition comprises a penetration enhancer P1 and the reference composition does not comprise the penetration enhancer P1. In certain embodiments, the sol-gel transition temperature of the composition is within about 5 °C, within about 3 °C, or within about 1 °C of the sol-gel transition temperature of a reference composition, and the storage modulus of the composition is within about 10%, within about 5%, or within about 2% of the storage modulus of the reference composition, wherein the composition comprises a penetration enhancer P1 and the reference composition does not comprise the penetration enhancer P1.

[0215] In certain embodiments, the penetration enhancer P1 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, amino amide, amino ester, azide-containing compound, or alcohol. In certain embodiments, the penetration enhancer P1 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, amino amide, amino ester, azide-containing compound, pyrrolidone, sulfoxide, fatty acid, or alcohol. In certain embodiments, the penetration enhancer P1 is a surfactant (e.g., sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyltrimethylammonium bromide, cetylpyridinium chloride benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl betaine (chembetaine oleyl), myristyl dimethyl ammonium propane sulfonate; benzylpyridinium chloride dodecylpyridinium chloride cetylpyridinium chloride Benzyl dimethyldodecyl ammonium chloride, benzyl dimethyldodecyl ammonium chloride, benzyl dimethyldecyl ammonium chloride, benzyl dimethylstearyl ammonium chloride, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80). In certain embodiments, the penetration enhancer P1 is a terpene (e.g., limonene, cymene, pinene, camphor, menthol, camphene, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol, eugenyl acetate, safrole, benzyl benzoate, humulene, β-caryophyllene, eucalyptol, caproic acid, caprylic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl myristate, isopropyl palmitate, palmitic acid palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, ethyl piperazine carboxylate). In certain embodiments, the penetration enhancer P1 is decyl methyl sulfoxide, nonoxynol-9 or sodium pyrrolidone carboxylate. In certain embodiments, the penetration enhancer P1 is a terpene. In certain embodiments, the composition comprises 0.5% to 6.0% by weight of a terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight of a terpene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight of a terpene. In certain embodiments, the composition comprises 2.0% by weight of a terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight of limonene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight of limonene. In certain embodiments, the composition comprises 2.0% by weight of limonene. In certain embodiments, the penetration enhancer P1 is an anesthetic (e.g., bupivacaine, tetracaine, procaine, prilocaine, propoxycaine, dimethocaine, cyclomethycaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, carticaine, etidocaine, mepivacaine, piridocaine, trimecaine). In some embodiments, the penetration enhancer P1 is bupivacaine. In some embodiments, the penetration enhancer P1 is sodium dodecyl sulfate. In some embodiments, the penetration enhancer P1 is 2.0% by weight of sodium dodecyl sulfate. In some embodiments, the penetration enhancer P1 is methyl laurate. In some embodiments, the penetration enhancer P1 is limonene. In some embodiments, the penetration enhancer P1 is a combination of at least two of a surfactant, a terpene, and an anesthetic. In some embodiments, the penetration enhancer P1 is a combination of bupivacaine, sodium dodecyl sulfate, and limonene. In some embodiments, the penetration enhancer P1 is a combination of sodium dodecyl sulfate and limonene.In certain embodiments, the penetration enhancer P1 is sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000 MW), or octyldodecanol. In certain embodiments, the penetration enhancer P1 is methyl laurate, isopropyl myristate, sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000 MW), or octyldodecanol.

[0216] In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of a reference composition, where the composition comprises a penetration enhancer P2 and the reference composition does not comprise the penetration enhancer P2. In certain embodiments, the storage modulus of the composition is within about 10%, within about 5%, or within about 2% of the storage modulus of the reference composition, where the composition comprises a penetration enhancer P2 and the reference composition does not comprise the penetration enhancer P2. In certain embodiments, the storage modulus of the composition is within about 100%, within about 10%, within about 5%, or within about 2% of the storage modulus of the reference composition, where the composition comprises a penetration enhancer P2 and the reference composition does not comprise the penetration enhancer P2. In certain embodiments, the loss modulus of the composition is within about 10%, within about 5%, or within about 2% of the loss modulus of the reference composition, where the composition comprises a penetration enhancer P2 and the reference composition does not comprise the penetration enhancer P2. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition, and the storage modulus of the composition is within about 10%, within about 5%, or within about 2% of the storage modulus of the reference composition, where the composition comprises a penetration enhancer P2 and the reference composition does not comprise the penetration enhancer P2.

[0217] In certain embodiments, the penetration enhancer P2 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, amino amide, amino ester, azide-containing compound, or alcohol. In certain embodiments, the penetration enhancer P2 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, amino amide, amino ester, azide-containing compound, pyrrolidone, sulfoxide, fatty acid, or alcohol. In certain embodiments, the penetration enhancer P2 is a surfactant (e.g., sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyltrimethylammonium bromide, cetylpyridinium chloride benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate, dimethyl sulfoxide, sodium tridecyl phosphate; decyldimethylammonium propane sulfonate, oleyl betaine, myristyldimethylammonium propane sulfonate; benzyl chloride

[0218] Pyridine Dodecylpyridinium chloride Cetylpyridinium chloride Benzyl dimethyldodecyl ammonium chloride, benzyl dimethyldodecyl ammonium chloride, benzyl dimethyldecanoyl ammonium chloride, benzyl dimethylstearoyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80). In certain embodiments, the penetration enhancer P2 is decyl methyl sulfoxide, nonoxynol-9 or sodium pyrrolidone carboxylate. In certain embodiments, the penetration enhancer P2 is terpene (e.g., limonene, cymene, pinene, camphor, menthol, camphene, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol, eugenyl acetate, safrole, benzyl benzoate, humulene, β-caryophyllene, eucalyptol, caproic acid, caprylic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl myristate, isopropyl palmitate, palmitoyl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, ethyl piperazine carboxylate). In certain embodiments, the penetration enhancer P2 is terpene. In certain embodiments, the composition comprises 0.5% to 6.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight of terpene. In certain embodiments, the composition comprises 2.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight of limonene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight of limonene. In certain embodiments, the composition comprises 2.0% by weight of limonene. In certain embodiments, the penetration enhancer P2 is anesthetic (e.g., bupivacaine, tetracaine, procaine, proxymetacaine, propoxycaine, dimethocaine, cyclomethycaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, carticaine, etidocaine, mepivacaine, piridocaine, trimecaine). In some embodiments, the penetration enhancer P2 is bupivacaine. In some embodiments, the penetration enhancer P2 is sodium dodecyl sulfate. In some embodiments, the penetration enhancer P2 is 2.0% by weight of sodium dodecyl sulfate. In some embodiments, the penetration enhancer P2 is limonene. In some embodiments, the penetration enhancer P2 is a combination of at least two of surfactant, terpene and anesthetic. In some embodiments, the penetration enhancer P2 is a combination of bupivacaine, sodium dodecyl sulfate and limonene. In some embodiments, the penetration enhancer P1 is a combination of sodium dodecyl sulfate and limonene. In certain embodiments, the penetration enhancer P2 is sodium lauroyl sarcosine, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000MW) or octyldodecanol.In certain embodiments, the penetration enhancer P2 is methyl laurate, isopropyl myristate, sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000 MW), or octyldodecanol.

[0219] In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of a reference composition, wherein the composition comprises penetration enhancer P3 and the reference composition does not comprise penetration enhancer P3. In certain embodiments, the storage modulus of the composition is greater than the storage modulus of the reference composition, wherein the composition comprises penetration enhancer P3 and the reference composition does not comprise penetration enhancer P3. In certain embodiments, the loss modulus of the composition is greater than the loss modulus of the reference composition, wherein the composition comprises penetration enhancer P3 and the reference composition does not comprise penetration enhancer P3. In certain embodiments, the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition, and the storage modulus of the composition is greater than the storage modulus of the reference composition, wherein the composition comprises penetration enhancer P3 and the reference composition does not comprise penetration enhancer P3.

[0220] In certain embodiments, the penetration enhancer P3 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, amino amide, amino ester, azide-containing compound, or alcohol. In certain embodiments, the penetration enhancer P3 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, amino amide, amino ester, azide-containing compound, pyrrolidone, sulfoxide, fatty acid, or alcohol. In certain embodiments, the penetration enhancer P3 is a surfactant (e.g., sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyltrimethylammonium bromide, cetylpyridinium chloride benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate, dimethyl sulfoxide, sodium tridecyl phosphate; decyldimethylammonium propane sulfonate, oleyl betaine, myristyldimethylammonium propane sulfonate; benzylpyridinium chloride dodecylpyridinium chloride cetylpyridinium chloride Benzyl dimethyldodecyl ammonium chloride, benzyl dimethyldodecyl ammonium chloride, benzyl dimethylmyristyl ammonium chloride, benzyl dimethylstearyl ammonium chloride, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80). In certain embodiments, the penetration enhancer P3 is decyl methyl sulfoxide, nonoxynol-9 or sodium pyrrolidone carboxylate. In certain embodiments, the penetration enhancer P3 is a terpene (e.g., limonene, cymene, pinene, camphor, menthol, camphene, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol, eugenyl acetate, safrole, benzyl benzoate, humulene, β-caryophyllene, eucalyptol, caproic acid, caprylic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl myristate, isopropyl palmitate, palmitoyl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, ethyl piperazine carboxylate). In certain embodiments, the penetration enhancer P3 is a terpene. In certain embodiments, the composition comprises 0.5% to 6.0% by weight of a terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight of a terpene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight of a terpene. In certain embodiments, the composition comprises 2.0% by weight of a terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight of limonene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight of limonene. In certain embodiments, the composition comprises 2.0% by weight of limonene. In certain embodiments, the penetration enhancer P3 is an anesthetic (e.g., bupivacaine, tetracaine, procaine, prilocaine, propoxycaine, dimethocaine, cyclomethycaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, carticaine, etidocaine, mepivacaine, piridocaine, trimecaine). In some embodiments, the penetration enhancer P3 is bupivacaine. In some embodiments, the penetration enhancer P3 is sodium dodecyl sulfate. In some embodiments, the penetration enhancer P3 is 2.0% by weight of sodium dodecyl sulfate. In some embodiments, the penetration enhancer P3 is limonene. In some embodiments, the penetration enhancer P3 is a combination of at least two of a surfactant, a terpene, and an anesthetic. In some embodiments, the penetration enhancer P3 is a combination of bupivacaine, sodium dodecyl sulfate, and limonene. In some embodiments, the penetration enhancer P3 is a combination of sodium dodecyl sulfate and limonene. In certain embodiments, the penetration enhancer P3 is sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000 MW), or octyldodecanol.In certain embodiments, the penetration enhancer P3 is methyl laurate, isopropyl myristate, sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000 MW), or octyldodecanol.

[0221] In certain embodiments, the composition can be used to treat a disease. In some embodiments, the composition can be used to treat an infectious disease. In some embodiments, the composition can be used to treat an ear disease (e.g., the barrier is the tympanic membrane). In some embodiments, the composition can be used to treat otitis media.

[0222] As described, the gelling temperature (sol-gel transition temperature) of the composition is a factor in determining whether the composition is suitable (e.g., allows sustained delivery to the tympanic membrane). The temperature at which the storage modulus exceeds the loss modulus is considered the gelling temperature. The gelling temperature of the compositions herein can be below or above 39 °C, but is preferably below 39 °C to accelerate gelling after the composition, particularly the matrix former, is exposed to body heat following administration.

[0223] The timing of the sol-gel transition will affect the convenience of administration. Generally, a faster in situ transition is useful for administration to a subject (e.g., a recalcitrant child). In certain embodiments, the composition forms a gel within about 5 seconds, about 10 seconds, about 20 seconds, about 30 seconds, about 1 minute, about 5 minutes, or about 10 minutes of administration (e.g., administration to the ear canal). In some embodiments, the composition forms a gel within about 1 second to about 20 seconds after administration.

[0224] In certain embodiments, the composition is cold stored (e.g., refrigerated at about 5 °C) before administration. Cold storage can be useful for compositions with a gelling temperature below room temperature to prevent gelling before administration or during handling.

[0225] In one aspect, the present disclosure provides a composition comprising:

[0226] (a) a therapeutic agent or combination of therapeutic agents;

[0227] (b) a penetration enhancer or combination of penetration enhancers, wherein the penetration enhancer or combination of penetration enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and

[0228] (c) a matrix former or combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0229] wherein:

[0230] the composition forms a gel at a temperature above the sol-gel transition temperature; and

[0231] The sol-gel transition temperature is below about 39 °C;

[0232] and meets at least one of the conditions (i), (ii), and (iii):

[0233] (i) The sol-gel transition temperature of the composition is below the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0234] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 13.5% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0235] (iii) At a temperature of about 37 °C, the loss modulus of the composition is from about 12% to about 750% of the loss modulus of the reference composition;

[0236] wherein:

[0237] The reference composition is a composition that does not contain a penetration enhancer or a combination of penetration enhancers;

[0238] The composition contains about 0.1% to 30% of a penetration enhancer or a combination of penetration enhancers by weight / volume of the composition;

[0239] The polymer is a block copolymer containing poloxamer;

[0240] The composition contains about 19% to 45% of poloxamer by weight per volume of the composition.

[0241] In one aspect, the present disclosure provides a composition comprising:

[0242] (a) A therapeutic agent or a combination of therapeutic agents;

[0243] (b) A penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or the combination of penetration enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents across a barrier; and

[0244] (c) A matrix former or a combination of matrix formers, wherein the matrix former or the combination of matrix formers contains a polymer;

[0245] wherein:

[0246] The composition forms a gel at a temperature above the sol-gel transition temperature; and

[0247] The sol-gel transition temperature is below about 39 °C;

[0248] and meets at least one of the conditions (i), (ii), and (iii):

[0249] (i) The sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0250] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0251] (iii) At a temperature of about 37 °C, the loss modulus of the composition is from about 15% to about 750% of the loss modulus of the reference composition;

[0252] wherein the reference composition is a composition that does not contain a penetration enhancer or a combination of penetration enhancers;

[0253] The composition contains about 1% to 30% of a penetration enhancer or a combination of penetration enhancers by weight / volume of the composition;

[0254] The polymer is a block copolymer containing poloxamer;

[0255] The composition contains about 19% to 45% of poloxamer by weight / volume of the composition.

[0256] In another aspect, the present disclosure provides a composition for treating an infectious disease, comprising: (a) a therapeutic agent or a combination of therapeutic agents;

[0257] (b) a penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or the combination of penetration enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents across a barrier; and

[0258] (c) a matrix former or a combination of matrix formers, wherein the matrix former or the combination of matrix formers contains a polymer;

[0259] wherein:

[0260] The composition forms a gel at a temperature above the sol-gel transition temperature; and

[0261] The sol-gel transition temperature is lower than about 39 °C;

[0262] And at least one of the conditions (i), (ii), and (iii) is satisfied:

[0263] (i) The sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0264] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 13.5% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0265] (iii) At a temperature of about 37 °C, the loss modulus of the composition is about 12% to about 750% of the loss modulus of the reference composition;

[0266] Wherein:

[0267] The reference composition is a composition that does not contain a penetration enhancer or a combination of penetration enhancers;

[0268] The composition contains about 0.1% to 30% by weight / volume of the composition of a penetration enhancer or a combination of penetration enhancers;

[0269] The polymer is a block copolymer containing poloxamer;

[0270] The composition contains about 19% to 45% by weight / volume of the composition of poloxamer.

[0271] In another aspect, the present invention provides a composition for treating infectious diseases, which comprises: (a) a therapeutic agent or a combination of therapeutic agents;

[0272] (b) a penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or the combination of penetration enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents through the barrier; and

[0273] (c) a matrix former or a combination of matrix formers, wherein the matrix former or the combination of matrix formers contains a polymer;

[0274] The composition contains about 1% to 30% by weight / volume of the composition of a penetration enhancer or a combination of penetration enhancers;

[0275] The polymer is a block copolymer containing poloxamer;

[0276] The composition contains about 19% to 45% by weight / volume of the composition of poloxamer.

[0277] In another aspect, the present invention provides a composition for treating ear diseases, which comprises:

[0278] (a) a therapeutic agent or a combination of therapeutic agents;

[0279] (b) a penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or the combination of penetration enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents through the barrier; and

[0280] (c) a matrix former or a combination of matrix formers, wherein the matrix former or the combination of matrix formers contains a polymer;

[0281] Wherein:

[0282] The composition forms a gel at a temperature above the sol-gel transition temperature; and

[0283] The sol-gel transition temperature is below about 39 °C;

[0284] And at least one of the conditions (i), (ii) and (iii) is satisfied:

[0285] (i) The sol-gel transition temperature of the composition is below the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0286] (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0287] (iii) At a temperature of about 37 °C, the loss modulus of the composition is from about 12% to about 750% of the loss modulus of the reference composition;

[0288] Wherein:

[0289] The reference composition is a composition that does not contain a penetration enhancer or a combination of penetration enhancers;

[0290] The penetration enhancer or combination of penetration enhancers comprises sodium dodecyl sulfate and limonene, and the composition comprises about 3% to 6% by weight / volume of the composition of the penetration enhancer or combination of penetration enhancers;

[0291] The polymer is a block copolymer comprising poloxamer P407; and

[0292] The composition comprises about 22% to about 27% by weight / volume of P407.

[0293] In another aspect, the present invention provides a composition for treating ear diseases, which comprises:

[0294] (a) A therapeutic agent or a combination of therapeutic agents;

[0295] (b) A penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or combination of penetration enhancers increases the flux of the therapeutic agent or combination of therapeutic agents through the barrier; and

[0296] (c) A matrix former or a combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0297] Wherein:

[0298] The composition forms a gel at a temperature above the sol-gel transition temperature; and

[0299] The sol-gel transition temperature is below about 39 °C;

[0300] and satisfies at least one of the conditions (i), (ii), and (iii):

[0301] (i) the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of the reference composition plus about 23 °C, or 39 °C, whichever is greater;

[0302] (ii) at a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller; and

[0303] (iii) at a temperature of about 37 °C, the loss modulus of the composition is from about 15% to about 750% of the loss modulus of the reference composition;

[0304] wherein:

[0305] the reference composition is a composition that does not contain a penetration enhancer or a combination of penetration enhancers;

[0306] the penetration enhancer or the combination of penetration enhancers comprises sodium dodecyl sulfate and limonene, and the composition comprises about 3% to 6% by weight / volume of the penetration enhancer or the combination of penetration enhancers;

[0307] the polymer is a block copolymer comprising poloxamer P407; and

[0308] the composition comprises about 22% to about 27% by weight / volume of P407.

[0309] In another aspect, the present invention provides a composition for treating ear diseases, comprising:

[0310] (a) a therapeutic agent or a combination of therapeutic agents;

[0311] (b) a penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or the combination of penetration enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents through the tympanic membrane; and

[0312] (c) a matrix former or a combination of matrix formers, wherein the matrix former or the combination of matrix formers comprises a polymer;

[0313] the composition comprises about 1% to 30% by weight / volume of the penetration enhancer or the combination of penetration enhancers;

[0314] the polymer is a block copolymer comprising poloxamer;

[0315] the composition comprises about 19% to 45% by weight / volume of poloxamer.

[0316] In another aspect, the compositions provided herein comprise:

[0317] (a) a diagnostic agent or combination of diagnostic agents;

[0318] (b) a penetration enhancer or combination of penetration enhancers, wherein the penetration enhancer or combination of penetration enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the tympanic membrane; and

[0319] (c) a matrix former or combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer;

[0320] The composition comprises about 1% to 30% by weight / volume of the composition of a penetration enhancer or combination of penetration enhancers;

[0321] The polymer is a block copolymer comprising poloxamer;

[0322] The composition comprises about 19% to 45% by weight / volume of the composition of poloxamer.

[0323] The compositions provided herein generally include penetration enhancers (e.g., surfactants, terpenes), therapeutic agents (e.g., antimicrobials, antibiotics or anesthetics), and matrix formers (e.g., poloxamer derivatives). Penetration enhancers are agents that alter the stratum corneum of the tympanic membrane to increase the flux of therapeutic agents across the tympanic membrane. Penetration enhancers assist in delivering the therapeutic agent to the middle ear and / or inner ear. Therapeutic agents include agents that have a therapeutic benefit in the ear. In certain embodiments, the matrix former is a liquid under ambient conditions that forms a gel (e.g., becomes more viscous) once administered to a subject. In certain embodiments, the matrix former forms a gel after mixing with two components of the composition. In some embodiments, each component comprises a matrix former. In some embodiments, one component comprises a matrix former and the second component comprises an activator or catalyst that causes gelling when mixed with the matrix former. In certain embodiments, the matrix former forms a gel after mixing with two components of the composition. In some embodiments, each component comprises a matrix former. In some embodiments, one component comprises a matrix former and the second component comprises an activator and / or catalyst and / or crosslinking agent that causes gelling when mixed with the matrix former. In certain embodiments, the pharmaceutical composition substantially does not interfere with the subject's hearing.

[0324] Matrix former

[0325] A matrix former is a compound or mixture of compounds that forms a gel after administration. In certain embodiments, the matrix former forms a gel after being administered into the ear canal of a subject. The gel composition serves as a reservoir containing a therapeutic agent and a permeation enhancer, thereby allowing for sustained release of the therapeutic agent across a barrier (e.g., the tympanic membrane). In certain embodiments, the gel maintains contact with the tympanic membrane. In some embodiments, the gel maintains contact for 0.5 to 1 hour, 1 to 4 hours, 1 to 8 hours, 1 to 16 hours, or 1 to 24 hours. In some embodiments, the gel maintains contact for 1 day to 3 days, 1 to 7 days, or 1 to 14 days. In some embodiments, the gel allows for a flux of the therapeutic agent across the tympanic membrane to continue for 0.5 to 1 hour, 1 to 4 hours, 1 to 8 hours, 1 to 16 hours, or 1 to 24 hours. In some embodiments, the gel allows for a flux of the therapeutic agent across the tympanic membrane to continue for 0.5 to 1 hour, 1 to 4 hours, 1 to 8 hours, 1 to 16 hours, or 1 to 24 hours, or 1 to 48 hours, or 1 to 72 hours, or 1 to 96 hours, or 1 to 120 hours, or 1 to 144 hours, or 1 to 168 hours. In some embodiments, the gel maintains contact for 1 day to 3 days, 1 to 7 days, or 1 to 14 days. Such a reservoir maintains contact with the tympanic membrane, thereby increasing the time for the therapeutic agent to cross the tympanic membrane and be delivered to the middle ear or inner ear. Such a reservoir maximizes the exposure of the tympanic membrane to the permeation enhancer and the therapeutic agent and facilitates a sustained flux of the therapeutic agent into the middle ear and inner ear.

[0326] In various embodiments, the composition is a sustained release formulation. In various aspects, the sustained release of the permeation enhancer and / or the therapeutic agent can be at a constant rate to deliver an effective amount of the permeation enhancer or the therapeutic agent to the surface of the tympanic membrane, middle ear, or inner ear. In various embodiments, the sustained release provides a sufficient flux of the therapeutic agent within about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In various embodiments, the sustained release provides a sufficient flux of the therapeutic agent within about 7 to about 10 days. In various embodiments, the sustained release can be at a constant rate within about 7 days to about 14 days. In various embodiments, the sustained release provides a sufficient flux of the therapeutic agent within about 14 to about 21 days. In various embodiments, the sustained release provides a sufficient flux of the therapeutic agent within about 21 to about 30 days. As used herein, a sufficient flux is the flux required for the therapeutic agent to be present in the middle ear in a therapeutically effective amount or a prophylactically effective amount. In some embodiments, the sufficient flux is sufficient to provide an antimicrobial agent or an antibiotic agent at a concentration equal to or greater than the minimum inhibitory concentration of the infectious microorganism. In some embodiments, the infectious microorganism is Haemophilus influenzae (H. influenza), Streptococcus pneumoniae (S. pneumoniae), or Moraxella catarrhalis (M. catarrhalis).

[0327] In multiple aspects, a sustained release profile is obtained by adding a matrix former to the composition. In multiple embodiments, the composition may further comprise a matrix former. In multiple embodiments, based on phase change, change in solubility, evaporation of a solvent, or mixing components comprising the matrix former, the matrix former may undergo an in situ viscosity change. Such a matrix former forms a gel in situ after being applied to the ear canal of a patient to form a reservoir containing a therapeutic agent and a permeation enhancer, thereby allowing for the sustained release of the therapeutic agent. Such a reservoir maintains contact with the tympanic membrane, thereby increasing the time for the therapeutic agent to permeate the tympanic membrane and being delivered to the middle ear or inner ear. Such a reservoir maximizes the exposure of the tympanic membrane to the permeation enhancer and the therapeutic agent.

[0328] In certain embodiments, the matrix former is a hydrogel or forms a hydrogel upon application. The matrix former may include, but is not limited to: thermoresponsive gelling agents, prepolymers, alginates, uncrosslinked polymers, and monomers, thermoresponsive gelling agents (such as poloxamer copolymers) and polymers having crosslinkable functional groups. The matrix former may include, but is not limited to: thermoresponsive gelling agents, prepolymers, alginates, uncrosslinked polymers, crosslinking agents, catalysts, and monomers, thermoresponsive gelling agents (such as poloxamer copolymers) and polymers having crosslinkable functional groups. In certain embodiments, the matrix former is separated into first and second components that form a matrix or gel after mixing. In some embodiments, the first matrix former component is a first polymer comprising a first type of crosslinkable functional group, and the second matrix former component is a second polymer comprising a second type of crosslinkable functional group, wherein after mixing the first and second components, crosslinks are formed between the two types of crosslinkable functional groups between the two polymers. In some embodiments, the first matrix former component comprises a polymer having crosslinkable functional groups, and the second matrix former component comprises an activator, wherein after mixing the first and second components, crosslinks are formed between the polymers. In some embodiments, the activator is an acid, a base, or a catalyst. In some embodiments, the activator is an acid, a base, a salt, or a catalyst.

[0329] The matrix former may further comprise a biocompatible reagent. The matrix former may further comprise a biodegradable reagent. In certain embodiments, the matrix former degrades and is excreted from the patient's body within 3 days of application, within 7 days of application, within 10 days of application, or within 14 days of application. In multiple embodiments, when applied to the ear canal of an object, the matrix former has little or no effect on the hearing threshold. In multiple aspects, the matrix former may account for about 0% to about 40% of the composition. In multiple embodiments, the matrix former may account for about 0% to about 10% of the composition, about 10% to about 20% of the composition, about 20% to about 30% of the composition, about 30% to about 40% of the composition, or about 40% to about 50% of the composition.

[0330] The polymer can be a block copolymer. Exemplary polymer types suitable for block copolymers include, but are not limited to: poloxamers, poloxamer 331, poloxamer 407, poloxamer 188, and poloxamer. In some embodiments, the matrix former comprises a poloxamer. In some embodiments, the matrix former comprises poloxamer 407, poloxamer 188, poloxamer, poloxamer 124, poloxamer 237, poloxamer 331, or poloxamer 338.

[0331] Exemplary poloxamers include, but are not limited to: poloxamer 407, poloxamer 188, poloxaline, poloxamer 124, poloxamer 237, poloxamer 331, or poloxamer 338. 10R5 17R2 17R4 25R2 25R4 31R1 F108 Cast Solid Surfactant F 108NF F108Pastille F 108NF Prill poloxamer 338 F 127NF F 127NF 500BHT Prill F 127NF Prill poloxamer 407 F 38 F 38Pastille F 68 F 68LF Pastille F 68NF F 68NF Prill poloxamer 188 F 68Pastille F77 F 77Micropastille F 87 F 87NF F87NF Prill poloxamer 237 F 88 F 88Pastille FT L61 L 10 L101 L 121 L 31, L 35, L 43, L 61, L 62, L62LF, L 62D, L 64, L 81, L 92, L44 NF INH surfactant Poloxamer 124, N 3, P 103, P104, P 105, P 123 surfactant, P 65, P 84, P 85, PE / F 108, PE / P105, PE / P84, PE / L31, PE / L61, PE / L101, PE / L121, PE / L42, PE / L62, PE / L92, PE / L44, PE / L64, PE / P84, PE / P75, PE / P103, PE / F87, PE / F127, PE / F38, PE / F68,

[0332] P 188, P 407, P 188micro, P407micro, P237, P 338, EL, HS15, PS 80, PS 60, RH 40, TPG S, CS L, CS A, CS S, CS B, CS20 and CS12. In some embodiments, the matrix former comprises any one of the foregoing poloxamers, their derivatives, or their block copolymers.

[0333] When CPE is added to a solution of the matrix former at a lower concentration, the composition does not form a gel, as shown by the low storage modulus and loss modulus of the formulation within a temperature range of 20 to 40 °C. For example, as Figure 6 shown, when CPE (2% w / v limonene, 1% w / v SDS, and 0.5% w / v bupivacaine) is added to a solution of the matrix former at a lower concentration (e.g., 18% P407), the composition does not form a gel, as shown by the storage and loss moduli of the formulation being much lower than 2 kPa within a temperature range of 20 to 40 °C (see Figure 6 ). However, unexpectedly, by adding a combination of multiple CPEs to the matrix former solution at a series of matrix former concentrations, rheological data of the storage and loss moduli indicate that for formulations with a solution of the matrix former at a higher concentration, the composition does form a gel. For example, as Figures 7A to 7C , Figure 8 and Figure 10 shown, unexpectedly, by adding a combination of multiple CPEs to a P407 solution at a series of P407 concentrations, rheological data of the storage and loss moduli indicate that for formulations with a solution of the matrix former at a higher concentration (e.g., more than 18% of the matrix former), the composition does form a gel (see Figures 7A to 7C , Figure 8 and Figure 10 ).

[0334] In certain embodiments, the percentage by weight of the matrix former in the composition is from about 1% to about 10%, from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, from about 40% to about 50%, or from about 50% to about 90%. In some embodiments, the percentage by weight of the matrix former in the composition is from 1% to about 10%. In some embodiments, the percentage by weight of the matrix former in the composition is from about 10% to about 20%. In some embodiments, the percentage by weight of the matrix former in the composition is from 20% to about 30%. In some embodiments, the percentage by weight of the matrix former in the composition is from 19% to about 45%. In some embodiments, the percentage by weight of the matrix former in the composition is from 19% to about 40%. In some embodiments, the percentage by weight of the matrix former in the composition is from 19% to about 35%. In some embodiments, the percentage by weight of the matrix former in the composition is from 19% to about 30%. In some embodiments, the percentage by weight of the matrix former in the composition is from 19% to about 25%. In some embodiments, the percentage by weight of the matrix former in the composition is from 22% to about 35%. In some embodiments, the percentage by weight of the matrix former in the composition is from 22% to about 27%. In some embodiments, the percentage by weight of the matrix former in the composition is from 22% to about 25%. In some embodiments, the percentage by weight of the matrix former in the composition is from 24% to about 25%. In some embodiments, the percentage by weight of the matrix former in the composition is about 25%.

[0335] In some embodiments, the percentage by weight of poloxamer in the composition is from 19% to about 45%. In some embodiments, the percentage by weight of poloxamer in the composition is from 19% to about 40%. In some embodiments, the percentage by weight of poloxamer in the composition is from 19% to about 35%. In some embodiments, the percentage by weight of poloxamer in the composition is from 19% to about 30%. In some embodiments, the percentage by weight of poloxamer in the composition is from 19% to about 25%. In some embodiments, the percentage by weight of poloxamer in the composition is from 22% to about 35%. In some embodiments, the percentage by weight of poloxamer in the composition is from 22% to about 27%. In some embodiments, the percentage by weight of poloxamer in the composition is from 22% to about 25%. In some embodiments, the percentage by weight of poloxamer in the composition is from 24% to about 25%. In some embodiments, the percentage by weight of poloxamer in the composition is about 25%. In some embodiments, the percentage by weight of P407 in the composition is about 25%.

[0336] In some embodiments, the composition has a high degree of hydrophobicity. In some embodiments, the block copolymer has a high degree of hydrophobicity. In some embodiments, the composition is light-transmissive.

[0337] The matrix former can also include systems that provide reverse thermal gelation, including but not limited to: organic base gels, ionic liquids, supramolecular transition metal assemblies, and Diels-Alder polymer networks.

[0338] Penetration enhancer

[0339] A penetration enhancer is any agent that increases the flux of a therapeutic agent across a barrier (e.g., a membrane, a cell layer). In some embodiments, the barrier is the skin. In some embodiments, the barrier is the tympanic membrane. Penetration enhancers can include but are not limited to: surfactants (anionic, cationic, nonionic, zwitterionic), terpenes, aminoamides, aminoesters, azide-containing compounds, and alcohols. Penetration enhancers can include but are not limited to: surfactants (anionic, cationic, nonionic, zwitterionic), terpenes, aminoamides, aminoesters, azide-containing compounds, pyrrolidones, sulfoxides, fatty acids, and alcohols. In certain embodiments, the penetration enhancer is an anionic surfactant. In certain embodiments, the penetration enhancer is a cationic surfactant. In certain embodiments, the penetration enhancer is a nonionic surfactant. In certain embodiments, the penetration enhancer is a zwitterionic surfactant. In certain embodiments, the penetration enhancer is a terpene. In certain embodiments, the penetration enhancer is an aminoamide. In certain embodiments, the penetration enhancer is an aminoester. In certain embodiments, the penetration enhancer is an azide-containing compound. In certain embodiments, the penetration enhancer is a pyrrolidone. In certain embodiments, the penetration enhancer is a sulfoxide. In certain embodiments, the penetration enhancer is a fatty acid. In certain embodiments, the penetration enhancer is an alcohol. In certain embodiments, the penetration enhancer is sodium lauroyl sarcosine. In certain embodiments, the penetration enhancer is sorbitan monooleate. In certain embodiments, the penetration enhancer is octoxynol-9. In certain embodiments, the penetration enhancer is diethyl sebacate. In certain embodiments, the penetration enhancer is sodium polyacrylate (molecular weight (MW) 2,500,000). In certain embodiments, the penetration enhancer is octyldodecanol. In certain embodiments, the penetration enhancer has a solid form. In certain embodiments, the penetration enhancer is a solid form of bupivacaine. In certain embodiments, the penetration enhancer does not have a solid form. In certain embodiments, the penetration enhancer is in liquid form.

[0340] Surfactant penetration enhancers can include but are not limited to: sodium dodecyl sulfate, ammonium lauryl sulfate, sodium laureth sulfate, cetyltrimethylammonium bromide, cetylpyridinium chloride Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl betaine, myristyl dimethyl ammonium propane sulfonate; benzylpyridinium chloride Dodecylpyridinium chloride Cetylpyridinium chloride Benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl myristyl ammonium chloride, benzyl dimethyl stearyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and benzalkonium chloride. In some embodiments, the penetration enhancer is sodium dodecyl sulfate, sodium lauryl sulfate, or sodium octyl sulfate. In some embodiments, the penetration enhancer is sodium dodecyl sulfate. In some embodiments, the penetration enhancer is octyl-trimethyl-ammonium bromide or dodecyl-trimethyl-ammonium bromide. In some embodiments, the penetration enhancer is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. In some embodiments, the penetration enhancer is benzalkonium chloride.

[0341] In certain embodiments, the penetration enhancer is sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (molecular weight (MW) 2500000), or octyldodecanol. In certain embodiments, the penetration enhancer is methyl laurate, isopropyl myristate, sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol 9, diethyl sebacate, sodium polyacrylate (2500000 MW), or octyldodecanol. In certain embodiments, the penetration enhancer is sodium lauroyl sarcosinate. In certain embodiments, the penetration enhancer is sorbitan monooleate. In certain embodiments, the penetration enhancer is octoxynol-9. In certain embodiments, the penetration enhancer is diethyl sebacate. In certain embodiments, the penetration enhancer is sodium polyacrylate (molecular weight (MW) 2500000). In certain embodiments, the penetration enhancer is octyldodecanol. In certain embodiments, the penetration enhancer is decyl methyl sulfoxide, nonoxynol-9, or sodium pyrrolidone carboxylate.

[0342] In various embodiments, the penetration enhancer is an azone-like compound. In certain embodiments, the penetration enhancer is a compound similar to azone of the formula (such as laurocapram):

[0343] In certain embodiments, the penetration enhancer is 1-benzyl-4-(2-((1,1-biphenyl)-4-yloxy)ethyl)piperazine.

[0344] In various embodiments, the penetration enhancer is a lipid. In certain embodiments, the lipid used in the composition is selected from phosphoglycerides; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleoyl phosphatidylethanolamine (DOPE); dioleoyloxypropyltriethylammonium (DOTMA); dioleoyl phosphatidylcholine; cholesterol; cholesterol esters; diacylglycerol; succinoyl diglyceride; dipalmitoyl phosphatidylglycerol (DPPG); hexadecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surface-active fatty acids such as palmitic acid or oleic acid; fatty acids; fatty acid amides; sorbitan trioleate (Span 85); glycocholate; surfactin; poloxamer; sorbitan fatty acid esters such as sorbitan trioleate; lecithin; lysophosphatidylcholine; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetyl phosphate; dipalmitoyl phosphatidylglycerol; stearamide; dodecylamine; hexadecylamine; acetyl palmitate; glycerol ricinoleate; cetyl stearate; isopropyl myristate; tyloxapol; poly(ethylene glycol)5000-phosphatidylethanolamine; and phospholipids. In certain embodiments, the lipid used in the composition is selected from phosphoglycerides; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleoyl phosphatidylcholine; dioleoyloxypropyltriethylammonium (DOTMA); dioleoyl phosphatidylcholine; cholesterol; cholesterol esters; diacylglycerol; succinoyl diglyceride; dipalmitoyl phosphatidylglycerol (DPPG); hexadecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surface-active fatty acids such as palmitic acid or oleic acid; fatty acids; fatty acid amides; sorbitan trioleate (Span 85); glycocholate; surfactin; poloxamer; fatty acid esters (such as stearyl methacrylate); sorbitan fatty acid esters such as sorbitan trioleate; lecithin; lysophosphatidylcholine; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetyl phosphate; dipalmitoyl phosphatidylglycerol; stearamide; dodecylamine; hexadecylamine; acetyl palmitate; glycerol ricinoleate; cetyl stearate; isopropyl myristate; tyloxapol; poly(ethylene glycol)5000-phosphatidylethanolamine; and phospholipids. In certain embodiments, the penetration enhancer is a fatty acid ester. In certain embodiments, the penetration enhancer is stearyl methacrylate. The lipid can be positively charged, negatively charged or neutral. In certain embodiments, the lipid is a combination of lipids.Phospholipids useful in the compositions of the present invention include negatively charged phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, diphosphatidylglycerol, poly(ethylene glycol)-phosphatidylethanolamine, dimyristoyl phosphatidylglycerol, dioleoyl phosphatidylglycerol, dilauroyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, distearoyl phosphatidylglycerol, dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, dimyristoyl phosphatidylserine, dipalmitoyl phosphatidylserine, phosphatidylserine, and mixtures thereof. Useful zwitterionic phospholipids include phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, lecithin, lysophosphatidylcholine, lysophosphatidylethanolamine, cerebroside, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, di[trans-9-octadecenoyl]phosphatidylcholine, dioleoyl phosphatidylcholine, dilauroyl phosphatidylcholine, 1-myristoyl-2-palmitoyl phosphatidylcholine, 1-palmitoyl-2-myristoyl phosphatidylcholine, 1-palmitoyl-phosphatidylcholine, 1-stearoyl-2-palmitoyl phosphatidylcholine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, sphingomyelin, dipalmitoyl sphingomyelin, distearoyl sphingomyelin, and mixtures thereof. Zwitterionic phospholipids comprise any phospholipid having ionizable groups wherein the net charge is zero. In certain embodiments, the lipid is phosphatidylcholine.

[0345] Exemplary surfactants include, but are not limited to: sodium dioctyl sulfosuccinate, sodium lauryl sulfate, cocamidopropyl betaine, and sodium laureth sulfate, alkyl and alkyl ether sulfates (e.g., sodium cocoalkyl triethylene glycol ether sulfate; lithium tallow alkyl triethylene glycol ether sulfate; sodium tallow alkyl hexaoxyethylene sulfate), succinamates, sulfosuccinamates (e.g., disodium N-octadecyl sulfosuccinamate, tetrasodium N-(1,2-dicarboxyethyl)-N-octadecyl sulfosuccinamate, dipentyl sulfosuccinate sodium salt, dihexyl sulfosuccinate sodium salt, dioctyl sulfosuccinate sodium salt), olefin sulfonates, hydroxyalkane sulfonates, β-alkoxyalkane sulfonates (e.g., potassium β-methoxydecane sulfonate, sodium 2-methoxytridecane sulfonate, potassium 2-ethoxytetradecane sulfonate, sodium 2-isopropoxyhexadecane sulfonate, lithium 2-tert-butoxytetradecane sulfonate, sodium β-methoxyoctadecane sulfonate, ammonium β-n-propoxydodecane sulfonate), dioctyl sulfosuccinate sodium salt, ethoxylated alkyl sulfates, alkyl sulfates, aliphatic secondary and quaternary amines (e.g., sodium 3-dodecylaminopropionate, N-alkyl taurine, stearamidopropyl dimethylamine, diethylaminoethyl stearamide, dimethyl stearamine, dimethyl soyamine, soyamine, myristylamine, tridecylamine, ethyl stearamine, N-tallow propanediamine, ethoxylated (5 moles E.O) Stearamine, dihydroxyethyl stearamine, and arachidyl behenylamine; alkyl ampho glycinate (e.g., coco ampho glycinate, lauryl ampho carboxyglycinate, coco ampho carboxyglycinate); alkyl ampho propionate (e.g., isostearoyl ampho propionate, coco ampho carboxypropionate); ethoxylated alkyl sulfate; alkyl sulfate; aliphatic quaternary ammonium compound (e.g., tallow propanediammonium dichloride, dialkyldimethylammonium chloride, ditallow dimethylammonium chloride, ditallow dimethylammonium methyl sulfate, distearyldimethylammonium chloride, di(hydrogenated tallow)dimethylammonium chloride, distearyldimethylammonium chloride, dilauryldimethylammonium chloride, didocosyldimethylammonium chloride, di(hydrogenated tallow)dimethylammonium acetate, distearyldimethylammonium chloride, distearyldimethylammonium acetate, ditallow dipropylammonium phosphate, ditallow dimethylammonium nitrate, and di(coconut alkylbenzylammonium chloride)); aliphatic phosphine compound, aliphatic sulfonium compound, alkyl amidosulfonate / ester, alkyl betaine (e.g., coco dimethyl carboxymethyl betaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethyl α-carboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, lauryl bis-(2-hydroxyethyl) carboxymethyl betaine, stearyl bis-(2-hydroxypropyl) carboxymethyl betaine, oleyl dimethyl γ-carboxypropyl betaine, lauryl bis-(2-hydroxypropyl) α-carboxyethyl betaine), sulfobetaine (e.g., coco dimethyl sulfopropyl betaine, stearyl dimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, lauryl bis(2-hydroxyethyl) sulfopropyl betaine), alkylamide betaine, 4-[N,N-bis(2-hydroxyethyl)-N-octadecylammonium]-butane-1-carboxylate; 5-[S-3-hydroxypropyl-S-hexadecylsulfonium]-3-hydroxy-pentane-sulfate; 3-[P,P-diethyl-P-3,6,9-trioxatetradecyloxyphosphine. -2-hydroxy-propane-1-phosphate; 3-[N,N-dipropyl-N-3-dodecyloxy-2-hydroxypropylammonium]-propane-1-phosphate; 3-(N,N-dimethyl-N-hexadecylammonium)propane-1-sulfonate; 3-(N,N-dimethyl-N-hexadecylammonium)-2-hydroxy-propane-1-sulfonate; 4-[N,N-bis-(2-hydroxy-ethyl)-N-(2-hydroxydodecyl)ammonium]butane-1-carboxylate; 3-[S-ethyl-S-(3-dodecyloxy-2-hydroxypropyl)sulfonium]-propane-1-phosphate; 3-[P,P-dimethyl-P-dodecylphosphine -Propane-1-phosphonate; and 5-[N,N-bis(3-hydroxypropyl)-N-hexadecylammonium]-2-hydroxypentane-1-sulfate, sodium 3-dodecylaminopropanesulfonate; alkyl amphoteric sulfonates / esters; alkyl amphoteric sulfosuccinates / esters; oleoyl amphopropionate / ester and cocoyl amphopropionate / ester; polyethylene oxide condensates; long-chain tertiary phosphine oxides; long-chain dialkyl sulfoxides; silicone copolyols (e.g., polydimethylsiloxane copolyol), stearamide diethanolamide (DEA), cocoamide monoethanolamide (MEA), glyceryl monooleate, sucrose stearate / ester, Cetheth-2, poloxamer 181, hydrogenated tallowamide DEA, polyoxyethylene 4 sorbitan beeswax derivative (ATLAS 6-1702), polyoxyethylene 2 cetyl ether (BRIJ 52), polyoxyethylene 2 stearyl ether (BRIJ 72), polyoxyethylene 2 oleyl ether (BRIJ 92), polyoxyethylene 2 oleyl ether (BRIJ 93), sorbitan monopalmitate (SPAN 40), sorbitan monostearate (SPAN 60), sorbitan tristearate (SPAN 65), sorbitan monooleate, NF (SPAN 80) sorbitan trioleate (SPAN85), fluorinated alkyl quaternary ammonium iodides; mixed mono- and bis-perfluoroalkyl ammonium phosphates; mixed mono- and bis-perfluoroalkyl ammonium phosphates complexed with aliphatic quaternary methyl sulfates; perfluoroalkyl ammonium sulfonates; mixed telomer diethanolamine phosphates; perfluoroalkyl sulfonamides; perfluoroalkyl ammonium sulfonates; perfluoroalkyl potassium sulfonates; fluorinated alkyl potassium carboxylates; perfluoroalkyl ammonium sulfonates; and perfluoroalkyl carboxylates; sodium dioctyl sulfosuccinate; magnesium dioctyl sulfosuccinate; ammonium dioctyl sulfosuccinate; magnesium dodecyl sulfate; ammonium dodecyl sulfate; cocoamidopropyl betaine sodium dinonyl sulfosuccinate; sodium alpha-olefin sulfonate; sodium laureth sulfate; magnesium laureth sulfate; ammonium laureth sulfate; cocoamidopropyl betaine; polyethoxylated diol ether of isostearic acid glyceride; polyethoxylated diol ether of glyceryl monooleate; PEG-30 isostearic acid glyceride; polyoxyethylene glyceryl monooleate; polyethylene glycol; PPG-18; PPG-10; 18 polydimethylsiloxane; 1 dimethicone; cetyl polyethylene glycol; glycerol monostearate; laureth-23; and PEG 75 lanolin. In certain embodiments, the surfactant is a silicon-containing compound. Exemplary silicon-based detergents, emulsifiers, or surfactants useful in cosmetic compositions include polydimethylsiloxane, cyclopentasiloxane, cyclohexasiloxane, PEG / polydimethylsiloxane copolymer, PPG / polydimethylsiloxane copolymer, phenyl trimethylsiloxane, alkyl silicone, aminopropyl end-capped polydimethylsiloxane (amodimethicone), silicone quaternary ammonium salt-18, and polydimethylsiloxanol.

[0346] Terpene penetration enhancers can include, but are not limited to, limonene, cymene, pinene, camphor, menthol, camphene, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol, eugenyl acetate, safrole, benzyl benzoate, humulene, β-caryophyllene, eucalyptol, caproic acid, caprylic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl myristate, isopropyl palmitate, palmitic acid palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, and ethyl piperazine carboxylate. Any terpene or terpene compound can be used as a penetration enhancer in the compositions of the present invention. In certain embodiments, the penetration enhancer is limonene.

[0347] Alcohol penetration enhancers can include, but are not limited to, methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, and tert-amyl alcohol. In certain embodiments, the penetration enhancer is a compound having more than one hydroxyl group (such as glycerol). For example, the penetration enhancer can contain two, three, four, five or more hydroxyl groups. In certain embodiments, the penetration enhancer is a hydroxyl-containing polymer.

[0348] In certain embodiments, the amino amide or amino ester penetration enhancer is an anesthetic. Amino amide and amino ester penetration enhancers can include, but are not limited to, bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dimethocaine, cyclomethycaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, carticaine, etidocaine, mepivacaine, piridocaine, and trimecaine. In certain embodiments, the penetration enhancer is bupivacaine.

[0349] In certain embodiments, the composition comprises a combination of penetration enhancers. In certain embodiments, the combination comprises penetration enhancers of the same type (such as both being surfactants, both being terpenes). In certain embodiments, the combination comprises penetration enhancers of different types (such as a surfactant and a terpene). In certain embodiments, the combination comprises a surfactant and a terpene. In certain embodiments, the combination comprises a cationic surfactant and a terpene. In certain embodiments, the combination comprises anionic surfactant and a terpene. In certain embodiments, the combination comprises a nonionic or zwitterionic surfactant and a terpene. In certain embodiments, the combination comprises sodium dodecyl sulfate and limonene. [[ID=II]]

[0350] In certain embodiments, the combination comprises a surfactant and an amino amide or amino ester. In certain embodiments, the combination comprises a cationic surfactant and an amino amide or amino ester. In certain embodiments, the combination comprises an anionic surfactant and an amino amide or amino ester. In certain embodiments, the combination comprises a nonionic or zwitterionic surfactant and an amino amide or amino ester. In certain embodiments, the combination comprises a terpene and an amino amide or amino ester. In some embodiments, the amino amide or amino ester is an anesthetic. In some embodiments, the anesthetic is bupivacaine.

[0351] In some embodiments, the penetration enhancer is a combination of compounds selected from two or three of groups (i) to (iii):

[0352] (i) Surfactants selected from: sodium lauryl sulfate, ammonium lauryl sulfate, sodium laureth sulfate, cetyltrimethylammonium bromide, cetylpyridinium chloride benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethylammonium propane sulfonate, oleyl betaine, myristyl dimethylammonium propane sulfonate; benzylpyridinium chloride dodecylpyridinium chloride cetylpyridinium chloride benzyl dimethyldodecylammonium chloride, benzyl dimethyldodecylammonium chloride, benzyl dimethylmyristylammonium chloride, benzyl dimethylstearylammonium chloride, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, polysorbate 40, polysorbate 6, polysorbate 80, and benzalkonium chloride;

[0353] (ii) Terpenes selected from: limonene, cymene, pinene, camphor, menthol, camphene, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol, eugenyl acetate, safrole, benzyl benzoate, humulene, β-caryophyllene, eucalyptol, caproic acid, caprylic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl myristate, isopropyl palmitate, palmitoyl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, or ethyl piperazine carboxylate;

[0354] (iii) and anesthetic agents selected from: bupivacaine, tetracaine, procaine, proxymetacaine, propoxycaine, dimethocaine, cyclomethycaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, carticaine, etidocaine, mepivacaine, piridocaine, and trimecaine.

[0355] In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes sodium octyl sulfate, sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, or polysorbate 80 as surfactants. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes sodium dodecyl sulfate as a surfactant. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes limonene as a surfactant. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, or polysorbate 80 as surfactants, and limonene as a terpene. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes sodium dodecyl sulfate and limonene as a terpene. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, or polysorbate 80 as surfactants, and bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes sodium dodecyl sulfate and bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes limonene as a terpene and bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, or polysorbate 80 as surfactants, limonene as a terpene, and bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds from at least two of groups (i) to (iii) listed above and includes sodium dodecyl sulfate, limonene as a terpene, and bupivacaine as an anesthetic. In certain embodiments, the penetration enhancer includes decyl methyl sulfoxide, nonoxynol-9, or sodium pyrrolidone carboxylate.

[0356] In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 0.1% to about 1%, from about 1% to about 3%, from about 3% to about 10%, or from about 1% to about 30%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 0.1% to about 1%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 1% to about 3%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 1% to about 30%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 1% to about 25%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 1% to about 20%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 1% to about 15%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 1% to about 10%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 1% to about 8%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 1% to about 5%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 0.1% to about 10%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is 0.1% to about 1%, from about 1% to about 2%, from about 2% to about 3%, from about 3% to about 4%, from about 4% to about 5%, from about 5% to about 6%, from about 6% to about 7%, from about 7% to about 8%, from about 8% to about 9%, from about 9% to about 10%, from about 10% to about 11%, from about 11% to about 12%, from about 12% to about 13%, from about 13% to about 14%, from about 14% to about 15%, from about 15% to about 16%, from about 16% to about 17%, from about 17% to about 18%, from about 18% to about 19%, from about 19% to about 20%, from about 20% to about 21%, from about 21% to about 22%, from about 22% to about 23%, from about 23% to about 24%, from about 24% to about 25%, from about 25% to about 26%, from about 26% to about 27%, from about 27% to about 28%, from about 28% to about 29%, or from about 29% to about 30%.

[0357] In some embodiments, the weight percentage of sodium lauryl sulfate in the composition is from about 0.1% to about 3% or from about 1% to about 30%. In some embodiments, the weight percentage of sodium lauryl sulfate in the composition is from about 0.1% to about 4%. In some embodiments, the weight percentage of sodium lauryl sulfate in the composition is about 1%. In some embodiments, the weight percentage of sodium lauryl sulfate in the composition is about 2%. In some embodiments, the weight percentage of sodium lauryl sulfate in the composition is about 3%. In some embodiments, the weight percentage of sodium lauryl sulfate in the composition is about 4%. In some embodiments, the weight percentage of bupivacaine in the composition is from about 0.1 to about 3% or from about 1% to about 30%. In some embodiments, the weight percentage of bupivacaine in the composition is from about 0.1% to about 4%. In some embodiments, the weight percentage of bupivacaine in the composition is about 0.5%. In some embodiments, the weight percentage of limonene in the composition is from about 0.1% to about 3% or from about 1% to 30%. In some embodiments, the weight percentage of limonene in the composition is about 0.5%. In some embodiments, the weight percentage of limonene in the composition is about 1%. In some embodiments, the weight percentage of limonene in the composition is about 2%. In some embodiments, the weight percentage of limonene in the composition is about 3%. In some embodiments, the weight percentage of limonene in the composition is about 4%.

[0358] In certain embodiments, the composition comprises an anesthetic penetration enhancer, and a surfactant and a terpene penetration enhancer, wherein the anesthetic penetration enhancer promotes an enhanced flux (e.g., drug flux) of a therapeutic agent across a barrier (e.g., a membrane, a cell layer) via the surfactant and the terpene penetration enhancer. In certain embodiments, the composition comprises the anesthetic penetration enhancer bupivacaine, the surfactant penetration enhancer sodium lauryl sulfate, and the terpene penetration enhancer limonene. In certain embodiments, the composition comprises the anesthetic penetration enhancer bupivacaine, the surfactant penetration enhancer sodium lauryl sulfate, and the terpene penetration enhancer limonene, wherein bupivacaine promotes an enhanced drug flux across the barrier via sodium lauryl sulfate and limonene.

[0359] Therapeutic agent

[0360] A therapeutic agent can be any agent for treating any ear disease or symptom of an ear disease. The therapeutic agent can include an antimicrobial agent. The therapeutic agent can include, but is not limited to, antimicrobial agents, antibiotics, anesthetics, anti-inflammatory agents, analgesics, antifibrotic agents, anti-sclerosis agents, and anticoagulants. The therapeutic agent can include, but is not limited to, antibiotics, anesthetics, anti-inflammatory agents, analgesics, antifibrotic agents, anti-sclerosis agents, and anticoagulants. In certain embodiments, the therapeutic agent is an antimicrobial agent. In certain embodiments, the therapeutic agent is an antibiotic agent. In certain embodiments, the therapeutic agent is an anesthetic. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the therapeutic agent is an analgesic. In certain embodiments, the therapeutic agent is an antifibrotic agent. In certain embodiments, the therapeutic agent is an anti-sclerosis agent. In certain embodiments, the therapeutic agent is an anticoagulant.

[0361] In various aspects, the therapeutic agent can be from about 0.01% to about 30% of the composition. In various aspects, the therapeutic agent can be from about 0.01% to about 10% of the composition. In various embodiments, the therapeutic agent can be from about 0.01% to about 1% of the composition, from about 1% to about 2% of the composition, from about 2% to about 3% of the composition, from about 3% to about 4% of the composition, from about 4% to about 5% of the composition, from about 5% to about 6% of the composition, from about 6% to about 7% of the composition, from about 7% to about 8% of the composition, from about 8% to about 9% of the composition, from about 9% to about 10% of the composition, from about 10% to about 20% of the composition, or from about 20% to about 30% of the composition. In various aspects, the therapeutic agent can be about 4% of the composition. In various aspects, ciprofloxacin can be about 4% of the composition.

[0362] Depending on the species, age, and general condition of the subject, the particular compound, its mode of administration, its mode of activity, the disorder being treated, etc., the exact amount required will vary from subject to subject. The compositions described herein are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. However, it is to be understood that the total daily usage of the compounds and compositions will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disease and the severity of the disease being treated; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, the route of administration, and the rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed; and like factors well known in the medical arts.

[0363] In certain embodiments, the therapeutic agent is an agent for treating a microbial infection (e.g., an antimicrobial agent). In certain embodiments, the antimicrobial agent is an antiviral agent. In certain embodiments, the antimicrobial agent is an antifungal agent. In certain embodiments, the antimicrobial agent is chlorhexidine. In certain embodiments, the therapeutic agent is an antibiotic. Any antibiotic can be used in the system of the present invention. In certain embodiments, the antibiotic is approved for use in humans or other animals. In certain embodiments, the antibiotic is approved for use by the U.S. Food and Drug Administration. In certain embodiments, the antibiotic can be selected from: cephalosporins, quinolones, polypeptides, macrolides, penicillins, and sulfonamides. Exemplary antibiotics can include, but are not limited to, ciprofloxacin, cefuroxime, cephalexin, cefazolin, cefalotin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefibutene, cefotaxime, ceftriaxone, cefepime, ceftobiprole, chlorhexidine, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, spectinomycin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, sulfamylon, sulfacetamide, sulfamethizole, sulfasalazine, sulfisoxazole azole, trimethoprim, and trimethoprim-sulfameth azole.

[0364] In certain embodiments, the antibiotic is a quinolone. In certain embodiments, the antibiotic is a carbapenem. In certain embodiments, the antibiotic is. In certain embodiments, the antibiotic is amoxicillin, azithromycin, cefuroxime, ceftriaxone, trimethoprim, levofloxacin, moxifloxacin, meropenem, or ciprofloxacin. In some embodiments, the antibiotic is ciprofloxacin. In some embodiments, the antibiotic is ciprofloxacin and its pharmaceutically acceptable salts. In some embodiments, the antibiotic is ciprofloxacin hydrochloride. In some embodiments, the antibiotic is levofloxacin. In some embodiments, the antibiotic is chlorhexidine.

[0365] Exemplary antibiotics include, but are not limited to: abamectin, actinomycin (e.g., actinomycin A, actinomycin C, actinomycin D, aurantin), alatrofloxacin mesylate, amikacin sulfate, aminosalicylic acid, anthracyclines (e.g., aclarubicin, doxorubicin, doxorubicin hydrochloride, epirubicin, idarubicin), antimycin (e.g., antimycin A), avermectin, BAL30072, bacitracin, bleomycin, cephalosporins (e.g., 7-aminocephalosporanic acid, 7-amino-deacetoxycephalosporanic acid, cefaclor, cefadroxil, cefamandole, cefazolin, cefepime, cefixime, cefmenoxime, cefmetazole, cefoperazone, cefotaxime, cefotetan, cefotiam, cefoxitin, cefpirome, cefpodoxime proxetil, cefsulodin, cefsulodin sodium, ceftazidime, cefizoxime, ceftriaxone, cefuroxime, cephalexin, cephaloridine, cephalosporin C, cephalothin, cephalothin sodium, cephapirin, cefradine), ciprofloxacin, enrofloxacin, clarithromycin, clavulanic acid, clindamycin, colicin, cyclosporine (e.g., cyclosporine A), dalfopristin / quinupristin, daunorubicin, doxorubicin, epirubicin, GSK 1322322, geneticin, gentamicin, gentamicin sulfate, gramicidin (e.g., gramicidin A), grepafloxacin hydrochloride, ivermectin, kanamycin (e.g., kanamycin A), lasalocid, leucomycin, levofloxacin, linezolid, lomefloxacin, lovastatin, MK 7655, meropenem, mevastatin, mithramycin, mitomycin, monomycin, natamycin, neocarzinostatin, neomycin (e.g., neomycin sulfate), nystatin, oligomycin, olivomycin, pefloxacin, penicillins (e.g., 6-aminopenicillanic acid, amoxicillin, amoxicillin-clavulanic acid, ampicillin, ampicillin sodium, azlocillin, carbenicillin, cefoxitin, cephaloridine, cloxacillin, dicloxacillin, mecillinam, methicillin, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin G potassium, procaine penicillin G, penicillin G sodium, penicillin V, piperacillin, piperacillin-tazobactam, sulbactam, tazobactam, ticarcillin), phleomycin, polymyxins (e.g., colistin, polymyxin B), pyocyanin (e.g., pyocyanin R), RPX 7009, rapamycin, ristocetin, salinomycin, sparfloxacin, spectinomycin, spiramycin, streptogramins, streptovaricin, tedizolid phosphate, teicoplanin, telithromycin, tetracyclines (e.g., tetracycline phosphate complex, demeclocycline, multicycline, doxycycline monohydrate, minocycline, oxytetracycline, oxytetracycline hydrochloride, tetracycline, tetracycline hydrochloride), trichostatin A, trovafloxacin, tunicamycin, tyrocidine, valinomycin, (-)-florfenicol, acetylsulfisoxazole Oxazoles, actinomycin, amikacin sulfate, benzethonium chloride, cetrimide, chelerythrine, chlorhexidine (e.g., chlorhexidine gluconate), chlorhexidine acetate, chlorhexidine gluconate, chlorothalonil, compound sulfamethoxazole Oxazoles, dichlorophen, didodecyldimethylammonium chloride, dihydrostreptomycin, enoxacin, ethambutol, fleroxacin, furazolidone, methylisothiazolinone, glycerol monolaurate, Nalidixic acid, povidone iodine, spirocheticides (e.g., arsphenamine, neoarsphenamine), sulfachinoxaline, thiamphenicol, tinidazole, triclosan, trovafloxacin, tuberculosis inhibitors (e.g., 4-aminosalicylic acid, AZD 5847, aminosalicylic acid, ethionamide), vidarabine, zinc pyrithione, and zirconium phosphate.

[0366] In certain embodiments, the therapeutic agent is a Food and Drug Administration (FDA)-approved drug for treating an infection or infectious disease. Exemplary FDA-approved agents include, but are not limited to: Avycaz (ceftazidime-avibactam), Cresemba (isavuconazole sulfate), Evotaz (atazanavir and cobicistat), Prezcobix (delavirdine and cobicistat), Dalvance (dalbavancin), Harvoni (ledipasvir and sofosbuvir), Impavido (miltefosine), Jublia (eflucanazole), Kerydin (tavaborole), metronidazole, Orbactiv (oritavancin), Rapivab (peramivir injection), Sivextro (tedizolid phosphate), Triumeq (abacavir, dolutegravir, and lamivudine), Viekira Pak (ombitasvir, paritaprevir, ritonavir, and dasabuvir), Xtoro (nemonoxacin), Zerbaxa (ceftolozane + tazobactam), Luzu (luliconazole), Olysio (simeprevir), Sitavig (acyclovir), Sovaldi (sofosbuvir), Abthrax (raxibacumab), Afinitor (everolimus), Cystaran (cysteamine hydrochloride), Dymista (azelastine hydrochloride and fluticasone propionate), Fulyzaq (crofelemer), Jetrea (ocriplasmin), Linzess (linaclotide), Qnasl (beclomethasone dipropionate) nasal aerosol, Sirturo (bedaquiline), Sklice (ivermectin), Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate), Tudorza Pressair (aclidinium bromide inhalation powder), Complera (emtricitabine / rilpivirine / tenofovir disoproxil fumarate), Dificid (fidaxomicin), Edurant (rilpivirine), Eylea (aflibercept), Firazyr (icatibant), Gralise (gabapentin), Incivek (telaprevir), Victrelis (boceprevir), Egrifta (tesamorelin), Teflaro (ceftobiprole medocaril), Zymaxid (gatifloxacin), Bepreve (bepotastine besilate), Vibativ (telavancin), Aptivus (tipranavir), Astepro (azelastine hydrochloride nasal spray), Intelence (etravirine), Patanase (olopatadine hydrochloride), Viread (tenofovir disoproxil fumarate), Isentress (raltegravir), Selzentry (maraviroc), Veramyst (fluticasone furoate), Xyzal (levocetirizine hydrochloride),Eraxis (anidulafungin), Noxafil (posaconazole), Prezista (darunavir), Tyzeka (telbivudine), Veregen (catechin extract), Baraclude (entecavir), Fuzeon (enfuvirtide), Lexiva (fosamprenavir calcium), Reyataz (atazanavir sulfate), desloratadine (Clarinex), Hepsera (adefovir dipivoxil), Pegasys (peginterferon alfa-2a), efavirenz (Sustiva), Vfend (voriconazole), Zelnorm (tegaserod maleate), Avelox (moxifloxacin hydrochloride), Cancidas (caspofungin acetate), Invanz (ertapenem), Peg-Intron (peginterferon alfa-2b), Ribavirin (Rebetol), Spectracef, Tavist (clemastine fumarate), Twinrix, Valcyte (valganciclovir hydrochloride), Xigris (drotrecogin alfa), ABREVA (docosanol), cefazolin, Kaletra, Lamisil (terbinafine hydrochloride), Lotrisone (clotrimazole / betamethasone dipropionate), Lotronex (alosetron hydrochloride), Trizivir (abacavir sulfate, lamivudine, zidovudine AZT), Synercid, Synagis, Viroptic, Aldara (imiquimod), Bactroban, Ceftin (cefuroxime axetil), Combivir, Condylox (podofilox), Famvir (famciclovir), Floxin, Fortovase, INFERGEN (interferon alfacon-1), Intron A (interferon alfa-2b, recombinant), Mentax (butenafine hydrochloride), Norvir (ritonavir), Omnicef, Rescriptor (delavirdine mesylate), paclitaxel, ticarcillin / clavulanate, Trovan, VIRACEPT (nelfinavir mesylate), Zerit (stavudine), AK-Con-A (naphazoline ophthalmic solution), Allegra (fexofenadine hydrochloride), Astelin nasal spray, Atrovent (ipratropium bromide), Augmentin (amoxicillin / clavulanate), Crixivan (indinavir sulfate), Elmiron (pentosan polysulfate sodium), Havrix, Leukine (sargramostim), Merrem (meropenem), Nasacort AQ (triamcinolone acetonide), Tavist (clemastine fumarate), Vancenase AQ, Videx (didanosine), Viramune (nevirapine),Zithromax (azithromycin), Cedax (cefotetan), Biaxin (clarithromycin), Epivir (lamivudine), Invirase (saquinavir), Valtrex (valacyclovir hydrochloride), Zyrtec (cetirizine hydrochloride), acyclovir, penicillin (penicillin g potassium), Cubicin (daptomycin), Factive (gemifloxacin), Albenza (albendazole), Alinia (nitazoxanide), Altabax (retapamulin), AzaSite (azithromycin), Besivance (besifloxacin ophthalmic suspension), Biaxin XL (extended-release clarithromycin), Cayston (aztreonam), Cleocin (clindamycin phosphate), Doribax (doripenem), Dynabac, FlagylER, Ketek (telithromycin), Moxatag (amoxicillin), Rapamune (sirolimus), Restasis (cyclosporine), Tindamax (tinidazole), Tygacil (tigecycline), and Xifaxan (rifaximin).

[0367] In certain embodiments, the therapeutic agent is an anesthetic. Any anesthetic can be used in the system of the present invention. In certain embodiments, the anesthetic is approved for use in humans or other animals. In certain embodiments, the anesthetic is approved for use by the US Food and Drug Administration. Exemplary anesthetics can include, but are not limited to, bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dimethocaine, cyclomethycaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, carticaine, etidocaine, mepivacaine, piridocaine, and trimecaine. In certain embodiments, the anesthetic is bupivacaine.

[0368] In certain embodiments, the antimicrobial agent is an antiviral agent. Exemplary antiviral agents include, but are not limited to: (-)-oseltamivir, β-D-ribofuranose, 1-acetate 2,3,5-tribenzoate, 1-docosanol, 2-amino-6-chloropurine, 5-iodo-2'-deoxyuridine, 6-chloropurine, abacavir sulfate, abacavir-epzicom mixture, acyclovir, acyclovir sodium, adefovir dipivoxil, amantadine (such as amantadine hydrochloride), amantadine hydrochloride, anti-HIV drugs (such as abacavir, amprenavir, atazanavir, azidothymidine, bryostatin (e.g., bryostatin 1, bryostatin 10, bryostatin 11, bryostatin 12, bryostatin 13, bryostatin 14, bryostatin 15, bryostatin 16, bryostatin 17, bryostatin 18, bryostatin 19, bryostatin 2, bryostatin 20, bryostatin 3, bryostatin 4, bryostatin 5, bryostatin 6, bryostatin 7, bryostatin 8, bryostatin 9), didanosine, dideoxycytidine, efavirenz, indinavir, lamivudine, lopinavir, nevirapine, ritonavir, saquinavir, stavudine, tenofovir), azacitidine, ombivir, deoxynojirimycin, docosanol, fomivirsen sodium, foscarnet, ganciclovir, integrase inhibitors (e.g., 5CITEP, Chloropeptin I, complement-binding inhibitor, dolutegravir, elvitegravir, L 708906, L731988, MK 2048, raltegravir, raltegravir potassium), MK 5172, MK 8742, palivizumab, pegylated interferon α-2b, phosphonoacetic acid, ribavirin, simeprevir, sofosbuvir, tuberactinomycin, vidarabine, and virus entry inhibitors (e.g., vicriviroc, maraviroc).

[0369] In certain embodiments, the antimicrobial agent is an antifungal agent. Exemplary antifungal agents include, but are not limited to: (-)-fumagillin, (-)-metalaxyl, 1,2,5-fluorocytosine, acridinium zine, anilazine, antifouling agent, azoxystrobin, benomyl, Bordeaux mixture, captan, carbendazim, caspofungin acetate, chlorothalonil, clotrimazole, dichlofluanid, eruconazole, dodine, cyprodinil, fenpropimorph, ferbam, fluconazole, fosetyl-aluminum, griseofulvin, guanidines (such as agmatine, amiloride hydrochloride, biguanides (such as imidodicarbonimidamide, N,N-dimethyl-, hydrochloride (1:1) (e.g., metformin hydrochloride), metformin), cimetidine, guanethidine, guanfacine, guanidine, guanidine salts, methylguanidine, sulfaguanidine), isoprothiolane, iprodione, isoprothiolane, itraconazole, ketoconazole, mancozeb, metalaxyl, metiram, miconazole, natamycin, nystatin, oxycarboxine, quintozene, prochloraz, procymidone, propiconazole, pyrazophos, reductiotoxin A3, salicylanilide, tebuconazole, terbinafine, phagocytin, thiophanate, thiophanate-methyl, triadimefon, vinclozolin, and voriconazole.

[0370] In certain embodiments, the therapeutic agent is an anti-inflammatory agent. The anti-inflammatory agent can be a non-steroidal anti-inflammatory agent or a steroidal anti-inflammatory agent. In certain embodiments, the therapeutic agent is a steroidal anti-inflammatory agent. In certain embodiments, the therapeutic agent is a steroid. Exemplary anti-inflammatory agents can include, but are not limited to acetylsalicylic acid, amoxiprin, paracetamol / benorylate, choline magnesium salicylate, diflunisal, etodolac, faislamine, methyl salicylate, magnesium salicylate, salicyl salicylate, salicylamide, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indomethacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, ibuprofen, alminoprofen, benoprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, aminopyrine, azapropazone, clofezone, ketophenylbutazone, metamizole, morfebutazone, oxyphenbutazone, phenazone, phenylbutazone, sulfinpyrazone, piroxicam, tenoxicam, lornoxicam, meloxicam, tinoridine, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, desoxycorticosterone acetate, and aldosterone.

[0371] In multiple embodiments, it has been observed that combinations of various penetration enhancers and therapeutic agents have synergistic and enhanced efficacy. In multiple embodiments, it has been observed that combinations of various penetration enhancers have synergistic and enhanced efficacy. In multiple embodiments, it has been observed that combinations of various therapeutic agents have synergistic and enhanced efficacy. In multiple aspects, such combinations can include, but are not limited to, ciprofloxacin and limonene. In multiple aspects, such combinations can include, but are not limited to, ciprofloxacin and sodium dodecyl sulfate. In multiple aspects, such combinations can include, but are not limited to, sodium dodecyl sulfate, limonene, bupivacaine, and ciprofloxacin. In multiple aspects, such combinations can include, but are not limited to, sodium dodecyl sulfate, limonene, and ciprofloxacin.

[0372] In another aspect, provided herein is a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable derivative thereof as described herein. In certain embodiments, the pharmaceutical composition comprises a combination of therapeutic agents. In certain embodiments, the composition comprises an antibiotic and an additional therapeutic agent. In certain embodiments, the composition comprises an antibiotic agent and an anti-inflammatory agent. In other embodiments, the composition comprises an antibiotic agent and an anesthetic. In certain embodiments, the composition comprises more than one antibiotic agent. In certain embodiments, the composition comprises a β-lactamase inhibitor antibiotic agent and an additional antibiotic agent. In certain embodiments, the composition comprises a clavulanate and an additional antibiotic agent. In certain embodiments, the composition comprises tazobactam and an additional antibiotic agent. In certain embodiments, the composition comprises an anti-inflammatory agent and an antibiotic agent. In certain embodiments, the composition comprises dexamethasone and an antibiotic agent.

[0373] In certain embodiments, the additional therapeutic agent is an anti-inflammatory agent (such as a steroid). In certain embodiments, the first therapeutic agent is an antibiotic and the additional therapeutic agent is an anti-inflammatory agent. In certain embodiments, the first therapeutic agent is an antibiotic and the additional therapeutic agent is a steroid. Steroids include, but are not limited to, cortisol, hydrocortisone acetate, cortisone acetate, thiohydrocortisone pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinonide acetate, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, flucortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasol-17-butyrate, clobetasol-17-propionate, flucortolone hexanoate, flucortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-acetate, hydrocortisone-17-butyrate propionate, ciclesonide, and prednicarbate. In some embodiments, the additional anti-inflammatory agent is dexamethasone.

[0374] In certain embodiments, the additional therapeutic agent is a β-lactamase inhibitor. In certain embodiments, the first therapeutic agent is an antibiotic (e.g., a β-lactam), and the additional therapeutic agent is a β-lactamase inhibitor. β-lactamase inhibitors include, but are not limited to, avibactam, clavulanic acid, tazobactam, and sulbactam. β-lactamase inhibitors can be particularly useful in compositions comprising β-lactam antibiotics. β-lactamase inhibitors can enhance the efficacy of β-lactam antibiotics or allow β-lactam antibiotics to be present in the composition at a lower concentration than in compositions without a β-lactamase inhibitor.

[0375] In addition, after formulation with a suitable pharmaceutically acceptable carrier in the desired dose, the pharmaceutical composition can be administered to humans and other animals.

[0376] Dosage forms include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the composition may also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, as well as flavoring agents. In certain embodiments, the composition contains solubilizing agents, such as Cremophor, alcohols, oils, modified oils, diols, polysorbates, cyclodextrins, polymers, and combinations thereof.

[0377] It will also be appreciated that the compositions described herein can be used in combination therapy, i.e., the compounds and pharmaceutical compositions can be administered simultaneously, before, or after one or more other desired therapeutic agents or medical procedures. The particular combination of therapies (therapeutic agents or procedures) used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It will also be understood that the therapies employed can achieve the desired effect for the same disease (e.g., the compounds of the present invention can be administered simultaneously with another anti-cancer agent), or they can achieve different effects (e.g., control any adverse effects).

[0378] In certain embodiments, the composition contains a diagnostic agent. In some examples, the diagnostic agent is an X-ray contrast agent. In some embodiments, the diagnostic agent contains a radioisotope. In some embodiments, the diagnostic agent is a dye.

[0379] Other additives

[0380] In certain embodiments, the composition comprises one or more additional additives. For example, the additional additives can be diluents, binders, preservatives, buffers, lubricants, flavorants, antimicrobial agents, or oils.

[0381] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dried starch, corn starch, powdered sugar, and mixtures thereof.

[0382] Exemplary binders include starches (such as corn starch and starch paste), gelatin, sugars (such as sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (such as gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate and larch arabinogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohols, and / or mixtures thereof.

[0383] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In some other embodiments, the preservative is a chelating agent. In certain embodiments, the preservative is benzalkonium chloride.

[0384] Exemplary antioxidants include α-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0385] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0386] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate esters, and phenylethyl alcohol.

[0387] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, β-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0388] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium bisulfite, potassium metabisulfite, Plus, methyl paraben, 115, II, and

[0389] Exemplary buffers include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconolactate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, calcium hydrogen phosphate, phosphoric acid, calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, and mixtures thereof.

[0390] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0391] Exemplary natural oils include almond, apricot, avocado, babassu, bergamot, black currant seed, borage, juniper, chamomile, canola, coriander, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, macadamia, lavender, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, cardamom, olive, orange, tilapia, Oils of palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, camellia, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0392] In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0393] The composition may comprise water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0394] Formulations suitable for administration (e.g., to the ear canal) include, but are not limited to, liquid and / or semi-liquid preparations, such as liniments, lotions, oil-in-water and / or water-in-oil emulsions (e.g., creams, ointments, and / or pastes), and / or solutions and / or suspensions. Although topical formulations may, for example, contain from about 1% to about 10% (weight / weight) of the therapeutic agent, the concentration of the therapeutic agent may be as high as the solubility limit of the active ingredient in the solvent.

[0395] Matrix forming agents (and compositions thereof)

[0396] In one aspect, provided herein is a matrix former as described herein. In certain embodiments, the matrix former comprises a polymer. In certain embodiments, the matrix former comprises a polymer that forms a gel through electrostatic interactions. In certain embodiments, the matrix former comprises a polymer that exhibits shear thinning. In certain embodiments, the matrix former comprises a rheological blend of polymers. In certain embodiments, the rheological polymer blend comprises two different polymers, wherein the viscoelasticity of the rheological polymer blend is more gel-like than the viscoelasticity of the constituent polymers measured separately. The polymer can be a block copolymer. In certain embodiments, the polymer is not a block copolymer.

[0397] In some embodiments, the matrix former comprises a poloxamer. Exemplary poloxamers include, but are not limited to: poloxamer 407, poloxamer 188, poloxaline, poloxamer 124, poloxamer 237, or poloxamer 338. 10R5, 17R2, 17R4, 25R2, 25R4, 31R1, F 108 cast solid surfactant, F 108NF, F 108Pastille, F 108NF Prill poloxamer 338, F127NF, F 127NF 500BHT Prill, F 127NF Prill poloxamer 407, F 38, F 38Pastille, F 68, F 68LFPastille, F 68NF, F 68NF Prill poloxamer 188, F68Pastille, F 77, F 77Micropastille, F 87, F 87NF, F 87NF Prill poloxamer 237, F 88, F 88Pastille, FT L 61, L 10, L101, L 121, L 31, L 35, L 43, L61, L 62, L 62LF, L 62D, L 64, L 81, L 92, L44 NF INH surfactant Poloxamer 124, N 3, P 103, P104, P 105, P123 surfactant, P 65, P 84, P 85, PE / F 108, PE / P105, PE / P84, PE / L31, PE / L61, PE / L101, PE / L121, PE / L42, PE / L62, PE / L92, PE / L44, PE / L64, PE / P84, PE / P75, PE / P103, PE / F87, PE / F127, PE / F38, PE / F68, P 188, P 407, P 188micro, P407micro, P237, P338, EL, HS15, PS 80, PS 60, RH 40, TPG S, CS L, CS A, CS S, CS B, CS20 and CS12. In some embodiments, the matrix former comprises any one of the foregoing poloxamers, derivatives thereof, or block copolymers thereof.

[0398] In certain embodiments, the matrix former comprises poloxamer 407, poloxamer 188, poloxaline, poloxamer 124, poloxamer 237, or poloxamer 338. In certain embodiments, the block copolymer comprises poloxamer 407.

[0399] Methods of treatment and uses

[0400] Methods of various embodiments using the compositions described herein generally involve methods of treating infectious diseases or ear diseases. In certain embodiments, the compositions described herein are used in methods of treating diseases. In certain embodiments, the compositions described herein are used in methods of treating infectious diseases. In certain embodiments, the compositions described herein are used in methods of treating ear diseases. In certain embodiments, the compositions described herein are used in methods of treating infections. In certain embodiments, the compositions described herein are used in methods of treating diseases. In certain embodiments, the disease is a bacterial infection. In certain embodiments, the bacterial infection is caused by Haemophilus influenzae. In certain embodiments, the bacterial infection is caused by Streptococcus pneumoniae. In certain embodiments, the bacterial infection is caused by Moraxella catarrhalis. In certain embodiments, the matrix former described herein is used in methods of treating infectious diseases. In certain embodiments, the compositions described herein are used in methods of treating ear diseases. In certain embodiments, the compositions described herein are used in methods of treating infectious ear diseases. In certain embodiments, the compositions described herein are used in methods of treating a microbial infection in a subject, comprising administering an effective amount of the compositions described herein. In certain embodiments, the microbial infection is a fungal infection, i.e., a fungal infection. In certain embodiments, the microbial infection is a viral infection, i.e., a viral infection. In certain embodiments, the microbial infection is a bacterial infection, i.e., a bacterial infection. A variety of microbial infections include, but are not limited to: skin infections, GI infections, urinary tract infections, urogenital infections, sepsis, blood infections, and systemic infections. Methods of various embodiments using the compositions described herein generally involve methods of treating infectious diseases. In several aspects, the compositions can be used to deliver a therapeutic or diagnostic agent across the tympanic membrane. Accordingly, the compositions are particularly suitable for treating middle ear and / or inner ear diseases. In certain embodiments, the compositions described herein are used in methods of treating middle ear diseases. In certain embodiments, the compositions described herein are used in methods of treating inner ear diseases.

[0401] In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.

[0402] In multiple aspects, the compositions described herein can be used to treat ear diseases, including but not limited to ear infections, the development of fibromas in the middle ear, or otosclerosis. In certain embodiments, the matrix formers described herein can be used to treat ear diseases, including but not limited to ear infections, the development of fibromas in the middle ear, or otosclerosis. In multiple other aspects, the compositions described herein can be used to treat vertigo, Meniere’s disease, mastoiditis, cholesteatoma, labyrinthitis, perilymph fistula, superior canal dehiscence syndrome, otorrhea, earache, tinnitus, barotrauma, ear cancer, autoimmune inner ear disease, acoustic neuroma, benign paroxysmal positional vertigo, Ramsay Hunt syndrome, suppurative labyrinthitis, vestibular neuronitis, tympanic membrane perforation, or myringitis. In multiple other aspects, the compositions described herein can be used to treat vertigo, Meniere’s disease, mastoiditis, cholesteatoma, labyrinthitis, perilymph fistula, superior canal dehiscence syndrome, otorrhea, earache, tinnitus, barotrauma, ear cancer, autoimmune inner ear disease, acoustic neuroma, benign paroxysmal positional vertigo, Ramsay Hunt syndrome, suppurative labyrinthitis, vestibular neuronitis, tympanic membrane perforation, or myringitis. In certain embodiments, the matrix formers described herein can be used to treat vertigo, Meniere’s disease, mastoiditis, cholesteatoma, labyrinthitis, perilymph fistula, superior canal dehiscence syndrome, otorrhea, earache, tinnitus, barotrauma, ear cancer, autoimmune inner ear disease, acoustic neuroma, benign paroxysmal positional vertigo, Ramsay Hunt syndrome, suppurative labyrinthitis, vestibular neuronitis, tympanic membrane perforation, or myringitis. In some embodiments, the methods disclosed herein are for treating otitis media (OM). The different forms of OM treatable by the methods disclosed herein can be differentiated by the presence of fluid (exudate) and / or the duration or persistence of inflammation. In certain embodiments, the infectious disease is acute otitis media, chronic otitis media, or otitis media with effusion. If present, the exudate can be of any consistency from watery (serous) to viscous mucous (mucoid) to pus-like (purulent); the duration is classified as acute, subacute, or chronic. Otitis media with effusion (OME) indicates inflammation with middle ear fluid (MEF), but without any signs of acute infection. Acute otitis media (AOM), with or without effusion, is characterized by the rapid onset of signs and symptoms associated with an acute infection in the middle ear (e.g., earache, fever). In some embodiments, the methods are for treating otitis media associated with infection by any of a number of pathogenic bacteria, including, for example, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.

[0403] An infectious disease can be a bacterial infection. In certain embodiments, the bacterial infection is a Streptococcus, Haemophilus, or Moraxella infection. In certain embodiments, the bacterial infection is a Staphylococcus, Escherichia, or Bacillus infection. In certain embodiments, the bacterial infection is a Haemophilus influenzae infection. In certain embodiments, the bacterial infection is a Streptococcus pneumoniae infection. In certain embodiments, the bacterial infection is a Moraxella catarrhalis infection. In certain embodiments, the infectious disease is an ear infection. In certain embodiments, the infectious disease is otitis media.

[0404] The infectious disease can be a microbial infection. In certain embodiments, the microbial infection is a viral infection. In certain embodiments, the microbial infection is a fungal infection.

[0405] In multiple embodiments, the administration of the compositions of the present invention consists of applying the composition into the ear canal of an object. In certain embodiments, applying the composition into the ear canal of an object includes spraying the composition into the ear canal of the object. In certain embodiments, the administration of the compositions of the present invention consists of applying the composition into the inner ear of an object. In certain embodiments, the administration of the compositions of the present invention consists of applying the composition into the middle ear of an object. In certain embodiments, the administration of the compositions of the present invention consists of applying the composition into the inner ear, sinuses, eyes, vagina or skin of an object. In certain embodiments, the administration of the compositions of the present invention consists of applying the composition into the sinuses of an object. In certain embodiments, the administration of the compositions of the present invention consists of applying the composition into the eyes of an object. In certain embodiments, the administration of the compositions of the present invention consists of applying the composition into the vagina of an object. In certain embodiments, the administration of the compositions of the present invention consists of applying the composition to the skin of an object. The subject to be treated can be any mammal in need of treatment. In multiple aspects, the composition is in direct contact with the tympanic membrane for about 1 day to about 30 days. In multiple aspects, the composition is in contact with the tympanic membrane for about 1 day to about 3 days, about 3 days to about 7 days, about 7 days to about 14 days, about 14 days to about 21 days, or about 21 days to about 30 days. In multiple embodiments, the composition forms a sustained release depot in contact with the tympanic membrane. In multiple aspects, the composition is applied as a liquid into the ear canal, and the composition forms a gel in situ on the surface of the tympanic membrane. When in contact with the tympanic membrane, the therapeutic agent penetrates the tympanic membrane and is delivered to the middle ear. In multiple embodiments, the delivery through the tympanic membrane is a sustained release of the therapeutic agent for several days. The number of days the composition can be in contact with the tympanic membrane can be, but is not limited to, 5 days, 7 days, 10 days, 14 days, 21 days or 30 days. During the treatment, the composition can be administered singly or repeatedly. In multiple aspects, the composition can be administered periodically from about every 1 day to about every 7 days, from about every 1 day to about every 14 days, or from about every 1 day to about every 30 days. In multiple embodiments, the composition is naturally expelled from the object at the end of the treatment by a natural process similar to the excretion of ear wax. In certain embodiments, the composition can decompose naturally, and its degradation products can be eliminated by the object. In multiple embodiments, the administration of the compositions of the present invention includes adding a matrix former, a penetration enhancer and a therapeutic agent to the ear canal; then adding a second therapeutic agent to the ear canal; and mixing the matrix former, the penetration enhancer and the therapeutic agent on the ear canal. In certain embodiments, the second therapeutic agent is an anesthetic. In certain embodiments, the second therapeutic agent is a local anesthetic.

[0406] In multiple embodiments, the administration of the compositions of the invention includes adding a matrix former to the ear canal; adding a penetration enhancer to the ear canal; adding a therapeutic agent to the ear canal; and mixing the matrix former, penetration enhancer, and therapeutic agent on the ear canal. In multiple embodiments, the administration of the compositions of the invention includes adding a matrix former to the ear canal; adding a penetration enhancer to the ear canal; adding a therapeutic agent to the ear canal; adding an additional therapeutic agent to the ear canal; and mixing the matrix former, penetration enhancer, and therapeutic agent on the ear canal. In certain embodiments, adding the therapeutic agent and adding the penetration enhancer to the ear canal includes spraying the therapeutic agent and spraying the penetration enhancer into the ear canal.

[0407] In multiple embodiments, the administration of the compositions of the invention includes adding a therapeutic agent to the ear canal; adding a penetration enhancer to the ear canal; adding a matrix former to the ear canal; and mixing the matrix former, penetration enhancer, and therapeutic agent on the ear canal. In multiple embodiments, the administration of the compositions of the invention includes adding a therapeutic agent to the ear canal; adding an additional therapeutic agent to the ear canal; adding a penetration enhancer to the ear canal; adding a matrix former to the ear canal; and mixing the matrix former, penetration enhancer, and therapeutic agent on the ear canal. In certain embodiments, adding the therapeutic agent and adding the penetration enhancer to the ear canal includes spraying the therapeutic agent and spraying the penetration enhancer into the ear canal. In certain embodiments, the therapeutic agent is an antibiotic or an anesthetic. In certain embodiments, the therapeutic agent is an antibiotic. In certain embodiments, the therapeutic agent is an anesthetic. In certain embodiments, the penetration enhancer is bupivacaine.

[0408] In multiple embodiments, the administration of the compositions of the present invention includes adding a composition comprising one or more therapeutic agents, one or more penetration enhancers, and one or more matrix formers to the ear canal; and subsequently adding a composition that does not contain a therapeutic agent or contains one or more therapeutic agents, does not contain a penetration enhancer or contains one or more penetration enhancers, and does not contain a matrix former or contains one or more matrix formers to the ear canal. In certain embodiments, subsequently adding one or more therapeutic agents includes the same therapeutic agent as the one or more therapeutic agents added the first time. In certain embodiments, subsequently adding one or more therapeutic agents includes a different therapeutic agent than the one or more therapeutic agents added the first time. In certain embodiments, subsequently adding a penetration enhancer includes the same penetration enhancer as the penetration enhancer added the first time. In certain embodiments, subsequently adding a penetration enhancer includes a different penetration enhancer than the penetration enhancer added the first time. In certain embodiments, subsequently adding a matrix former includes the same matrix former as the matrix former added the first time. In certain embodiments, subsequently adding a matrix former includes a different matrix former than the matrix former added the first time. In certain embodiments, the time interval between adding the first composition and the second composition is about 1 minute. In certain embodiments, the time interval between adding the first composition and the second composition is less than 1 minute. In certain embodiments, the time interval between adding the first composition and the second composition is greater than 1 minute.

[0409] The dose is determined based on the minimum inhibitory concentration required at the site of infection. Without being bound by a particular theory, in many aspects, for ciprofloxacin, the minimum inhibitory concentration for middle ear infections by Haemophilus influenzae or Streptococcus pneumoniae is about 4 μg / mL. In many aspects, based on an average middle ear volume of 3 mL, a typical dose will require about 12 μg of ciprofloxacin. In many embodiments, the composition will contain a sufficient dose to deliver 12 μg of ciprofloxacin to the middle ear. In many aspects, the administration of the composition comprises a single application. In other aspects, the administration of the composition comprises multiple applications. For example, the composition can be administered two, three, four or more times. In certain embodiments, the composition is repeatedly administered until a desired clinical outcome is achieved. For example, the infection is resolved. In certain embodiments, the administration of the composition comprises a first administration of the composition, followed by a second administration of the composition after a period of time. In certain embodiments, the period of time between the first administration and the second administration of the composition is one week. In certain embodiments, the period of time between the first administration and the second administration of the composition is greater than one week. In certain embodiments, the period of time between the first administration and the second administration of the composition is one month. In certain embodiments, the period of time between the first administration and the second administration of the composition is greater than one month. In many embodiments, the administration of the composition of the present invention comprises a first administration of the composition without a local anesthetic to the ear canal; followed by a second administration of the composition without a local anesthetic to the ear canal. In certain embodiments, the administration of the composition of the present invention comprises a first administration of the composition with a local anesthetic to the ear canal; followed by a second administration of the composition without a local anesthetic to the ear canal.

[0410] In many embodiments, the administration of the composition of the present invention comprises a first administration of the composition without a local anesthetic to the ear canal; followed by a second administration of the composition without a permeation enhancer other than a local anesthetic to the ear canal. In certain embodiments, the administration of the composition of the present invention comprises a first administration of the composition with a local anesthetic to the ear canal; followed by a second administration of the composition without a permeation enhancer other than a local anesthetic to the ear canal. In certain embodiments, the composition administered for the first time and the composition administered for the second time are the same. In certain embodiments, the composition administered for the first time and the composition administered for the second time are different.

[0411] Methods for delivering the compositions of the present disclosure to the surface of the tympanic membrane of a subject are provided herein. In certain embodiments, the subject has an ear disorder. In some embodiments, the subject has otitis media. In some embodiments, the subject is a human. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep or goat.

[0412] In certain embodiments, the delivery method includes administering the composition into the ear canal through an applicator. In certain embodiments, the delivery method includes placing drops of the composition into the ear canal. In some embodiments, the drops are delivered from a dropper (e.g., a pipette, an eye dropper). In some embodiments, the drops are delivered by a syringe. The syringe can be connected to a needle, a rigid catheter, or a flexible catheter.

[0413] In certain embodiments, the delivery method includes using a catheter to place a dose of the composition into the ear canal. In some embodiments, the catheter is connected to a syringe. In some embodiments, the catheter is rigid. In some embodiments, the catheter is flexible. In certain embodiments, the delivery method includes using a needle to place a dose of the composition into the ear canal. In some embodiments, the needle is connected to a syringe. In some embodiments, the needle has a blunt tip.

[0414] In certain embodiments, the delivery method includes using a dual syringe to place a dose of the composition into the ear canal. The dual syringe can be used to hold two components of the composition until mixing of the two components occurs during administration (e.g., in situ). In some embodiments, the dual syringe is connected to a single catheter or needle. In some embodiments, each barrel of the dual syringe is connected to a separate needle or catheter.

[0415] In certain embodiments, a method of treating an infectious disease or an ear disorder includes instructing a subject to administer the composition to the subject or providing the subject with instructions for self-administering the composition.

[0416] On the other hand, provided herein is a method of eradicating a biofilm in a subject, which includes administering to a subject in need thereof the composition described herein. On the other hand, provided herein is a method of eradicating a biofilm, which includes contacting the biofilm with the composition described herein.

[0417] On the other hand, provided herein is a method of inhibiting biofilm formation in a subject, which includes administering to a subject in need thereof the composition described herein. On the other hand, provided herein is a method of inhibiting biofilm formation, which includes contacting a surface with the composition described herein.

[0418] Kit

[0419] The present disclosure provides a kit comprising any of the compositions described herein, which may additionally comprise a sterile-packaged composition. The present disclosure provides a kit comprising any of the compositions or matrix formers described herein, which may additionally comprise a sterile-packaged composition or matrix former. The kit may comprise two containers for a two-part matrix former. The therapeutic agent may be included in one or both containers of the matrix former, or the therapeutic agent may be separately packaged. The permeation enhancer may be included in one or both containers of the matrix former, or the permeation enhancer may be separately packaged. In various aspects, the kit may comprise a vial, and a dropper or syringe for each vial.

[0420] In certain embodiments, the kit comprises one or more droppers (e.g., pipettes, eye droppers). In certain embodiments, the kit comprises one or more syringes. In some embodiments, the syringe is pre-loaded with the composition or one or more components of the composition. In certain embodiments, the kit comprises one or more needles (e.g., blunt needles). In certain embodiments, the kit comprises one or more catheters (e.g., flexible catheters). In certain embodiments, the kit comprises one or more otoscope attachments.

[0421] In certain embodiments, the kit comprises a dual-barrel syringe. In some embodiments, the dual-barrel syringe is pre-loaded with two components of the composition. In some embodiments, the dual-barrel syringe is connected to a single catheter or needle. In some embodiments, each barrel of the dual-barrel syringe is connected to a separate needle or catheter.

[0422] In certain embodiments, the kit described herein further comprises instructions for using the kit, such as instructions for using the kit in the methods of the present disclosure (e.g., instructions for administering a compound or pharmaceutical composition described herein to a subject). The kit described herein may further comprise information required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).

[0423] Definitions

[0424] Chemical Definitions

[0425] The definitions of specific functional groups and chemical terms are described in more detail below. According to the Periodic Table of the Elements, CAS version, inside front cover of the 75th edition of the Handbook of Chemistry and Physics th(Ed., inside cover) Identify chemical elements, and specific functional groups are generally defined as such. In addition, the general principles of organic chemistry and descriptions of specific functional moieties and reactivity are in the following: Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0426] The compounds described herein may contain one or more asymmetric centers and thus can exist in various stereoisomeric forms (such as enantiomers and / or diastereomers). For example, the compounds described herein can be in the form of individual enantiomers, diastereomers, or geometric isomers, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, page 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention also includes compounds as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0427] Unless otherwise indicated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium, replacing 18 F with 19 F, or replacing 13 C or 14 C with 12 C, compounds having the structures of the present invention are also within the scope of the present invention. Such compounds can be used, for example, as analytical tools or probes in biological assays.

[0428] When a range of values is listed, it is intended to include every value and sub-range within that range. For example, "C 1-6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl group.

[0429] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0430] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon-based group having 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl has 2 to 6 carbon atoms ("C 2-6 alkyl"). Examples of C 1-6 alkyl include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, amyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each instance of alkyl is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl"). In certain embodiments, the alkyl is unsubstituted C 1-10 alkyl (e.g., unsubstituted C 1-6Alkyl, such as -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, such as unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, such as unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl is a substituted C 1-10 alkyl (such as a substituted C 1-6 alkyl, such as -CF3, Bn).

[0431] The term "haloalkyl" is a substituted alkyl in which one or more hydrogen atoms are independently replaced by a halogen such as fluorine, bromine, chlorine, or iodine. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 haloalkyl"). Examples of haloalkyls include –-CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, etc.

[0432] The term "heteroalkyl" refers to an alkyl that further contains at least one heteroatom selected from oxygen, nitrogen, or sulfur (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain and / or at one or more terminal positions. In certain embodiments, heteroalkyl refers to a saturated group having 1 to 10 carbon atoms and one or more heteroatoms within the parent chain ("hetero C 1-10 alkyl"). In some embodiments, heteroalkyl is a saturated group having 1 to 9 carbon atoms and one or more heteroatoms within the parent chain ("hetero C 1-9 alkyl"). In some embodiments, heteroalkyl is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms within the parent chain ("hetero C 1-8 alkyl"). In some embodiments, heteroalkyl is a saturated group having 1 to 7 carbon atoms and one or more heteroatoms within the parent chain ("hetero C 1-7 alkyl"). In some embodiments, heteroalkyl is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms within the parent chain ("hetero C1-6 alkyl”). In some embodiments, a heteroalkyl is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-5 alkyl”). In some embodiments, a heteroalkyl is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”). In some embodiments, a heteroalkyl is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”). In some embodiments, a heteroalkyl refers to a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”). In certain embodiments, a heteroalkyl is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, a heteroalkyl is a substituted heteroC 1-10 alkyl.

[0433] The term “alkenyl” refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl has 2 to 9 carbon atoms (“C 2-9 alkenyl”). In some embodiments, an alkenyl has 2 to 8 carbon atoms (“C 2-8 alkenyl”). In some embodiments, an alkenyl has 2 to 7 carbon atoms (“C 2-7 alkenyl”). In some embodiments, an alkenyl has 2 to 6 carbon atoms (“C 2-6 alkenyl”). In some embodiments, an alkenyl has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In some embodiments, an alkenyl has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some embodiments, an alkenyl has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In some embodiments, an alkenyl has 2 carbon atoms (“C2 alkenyl”). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2-4Examples of alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. C 2-6 Examples of alkenyl include the above C 2-4 alkenyl and pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Unless otherwise specified, each example of alkenyl is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, the alkenyl is unsubstituted C 2-10 alkenyl. In certain embodiments, the alkenyl is substituted C 2-10 alkenyl. In the alkenyl, a C═C double bond for which the stereochemistry is not specified (e.g., -CH═CHCH3 or ) can be an (E)- or (Z)-double bond.

[0434] The term "heteroalkenyl" refers to an alkenyl that also contains at least one heteroatom selected from oxygen, nitrogen, or sulfur (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal positions. In certain embodiments, heteroalkenyl refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-10 alkenyl"). In some embodiments, heteroalkenyl has 2 to 9 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-9 alkenyl"). In some embodiments, heteroalkenyl has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-8 alkenyl"). In some embodiments, heteroalkenyl has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-7 alkenyl"). In some embodiments, heteroalkenyl has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-6 alkenyl"). In some embodiments, heteroalkenyl has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("hetero C 2-5 alkenyl"). In some embodiments, heteroalkenyl has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("hetero C 2-4 alkenyl"). In some embodiments, heteroalkenyl has 2 to 3 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("hetero C 2-3"Alkenyl"). In some embodiments, the heteroalkenyl has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("hetero C 2-6 alkenyl"). Unless otherwise specified, each instance of the heteroalkenyl is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In certain embodiments, the heteroalkenyl is unsubstituted hetero C 2-10 alkenyl. In certain embodiments, the heteroalkenyl is substituted hetero C 2-10 alkenyl.

[0435] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbyl group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2-10 alkynyl"). In some embodiments, the alkynyl has 2 to 9 carbon atoms ("C 2-9 alkynyl"). In some embodiments, the alkynyl has 2 to 8 carbon atoms ("C 2-8 alkynyl"). In some embodiments, the alkynyl has 2 to 7 carbon atoms ("C 2-7 alkynyl"). In some embodiments, the alkynyl has 2 to 6 carbon atoms ("C 2-6 alkynyl"). In some embodiments, the alkynyl has 2 to 5 carbon atoms ("C 2-5 alkynyl"). In some embodiments, the alkynyl has 2 to 4 carbon atoms ("C 2-4 alkynyl"). In some embodiments, the alkynyl has 2 to 3 carbon atoms ("C 2-3 alkynyl"). In some embodiments, the alkynyl has 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (e.g., in 2-butyne) or terminal (e.g., in 1-butyne). C 2-4 alkynyl examples include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butyne (C4), 2-butyne (C4), etc. C 2-6 alkenyl examples include the above C 2-4 alkynyl and pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each instance of the alkynyl is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, the alkynyl is unsubstituted C 2-10 alkynyl. In certain embodiments, the alkynyl is substituted C 2-10 alkynyl.

[0436] The term "heteroalkynyl" refers to an alkynyl group that also contains at least one heteroatom selected from oxygen, nitrogen, or sulfur (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal positions. In certain embodiments, heteroalkynyl refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-10 alkynyl"). In some embodiments, heteroalkynyl has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-9 alkynyl"). In some embodiments, heteroalkynyl has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-8 alkynyl"). In some embodiments, heteroalkynyl has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-7 alkynyl"). In some embodiments, heteroalkynyl has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("hetero C 2-6 alkynyl"). In some embodiments, heteroalkynyl has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("hetero C 2-5 alkynyl"). In some embodiments, heteroalkynyl has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("hetero C 2-4 alkynyl"). In some embodiments, heteroalkynyl has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("hetero C 2-3 alkynyl"). In some embodiments, heteroalkynyl has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("hetero C 2-6 alkynyl"). Unless otherwise specified, each instance of heteroalkynyl is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl"). In certain embodiments, heteroalkynyl is an unsubstituted hetero C 2-10 alkynyl. In certain embodiments, heteroalkynyl is a substituted hetero C 2-10 alkynyl.

[0437] The term "carbocyclic group" or "carbocycle" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms ("C 3-14 carbocyclic group") and zero heteroatoms in a non-aromatic ring system. In some embodiments, the carbocyclic group has 3 to 10 ring carbon atoms ("C 3-10 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 7 ring carbon atoms ("C3-7 carbocyclic group”). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclic group”). In some embodiments, the carbocyclic group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclic group”). In some embodiments, the carbocyclic group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclic group”). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclic group”). Exemplary C 3-6 carbocyclic groups include but are not limited to cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3-8 carbocyclic groups include but are not limited to the above C 3-6 carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C 3-10 carbocyclic groups include but are not limited to the above C 3-8 carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decyl (C 10 ), etc. As shown in the foregoing examples, in certain embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic group”) or polycyclic (e.g., containing a fused ring, bridged ring or spiro ring system such as a bicyclic system (“bicyclic carbocyclic group”) or a tricyclic system (“tricyclic carbocyclic group”)) and can be saturated or can contain one or more carbon-carbon double bonds or triple bonds. “Carbocyclic group” also includes a ring system in which a carbocyclic group ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclic group ring, and in such cases, the number of carbons continues to indicate the number of carbons in the carbocyclic group ring system. Unless otherwise specified, each instance of the carbocyclic group is independently unsubstituted (“unsubstituted carbocyclic group”) or substituted with one or more substituents (“substituted carbocyclic group”). In certain embodiments, the carbocyclic group is an unsubstituted C 3-14 carbocyclic group. In certain embodiments, the carbocyclic group is a substituted C 3-14 carbocyclic group.

[0438] In some embodiments, “carbocyclic group” is a monocyclic saturated carbocyclic group having 3 to 14 ring carbon atoms (“C 3-14cycloalkyl”). In some embodiments, the cycloalkyl has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In some embodiments, the cycloalkyl has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In some embodiments, the cycloalkyl has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”). In some embodiments, the cycloalkyl has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In some embodiments, the cycloalkyl has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, the cycloalkyl has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). C 5-6 Examples of cycloalkyl include cyclopentyl (C5) and cyclohexyl (C5). C 3-6 Examples of cycloalkyl include the foregoing C 5-6 cycloalkyl and cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl include the foregoing C 3-6 cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In certain embodiments, the cycloalkyl is unsubstituted C 3-14 cycloalkyl. In certain embodiments, the cycloalkyl is substituted C 3-14 cycloalkyl.

[0439] The term “heterocyclic group” or “heterocycle” refers to a 3- to 14-membered non-aromatic ring system group having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“C 3-14"heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as permitted by the valence. The heterocyclic group can be monocyclic ("monocyclic heterocyclic group") or polycyclic (e.g., fused, bridged or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclic group") or tricyclic systems ("tricyclic heterocyclic group")), and can be saturated or can contain one or more carbon-carbon double or triple bonds. The heterocyclic polycyclic system can contain one or more heteroatoms in one or two rings. "Heterocyclic group" also includes a ring system in which a heterocyclic group ring as defined above is fused to one or more carbocyclic group moieties, where the point of attachment is on the carbocyclic or heterocyclic group ring, or a ring system in which a heterocyclic group ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclic group ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic group ring system. Unless otherwise specified, each instance of the heterocyclic group is independently unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In certain embodiments, the heterocyclic group is an unsubstituted 3- to 14-membered heterocyclic group. In certain embodiments, the heterocyclic group is a substituted 3- to 14-membered heterocyclic group.

[0440] In some embodiments, the heterocyclic group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heterocyclic group"). In some embodiments, the heterocyclic group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclic group"). In some embodiments, the heterocyclic group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclic group"). In some embodiments, the 5- to 6-membered heterocyclic group has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclic group has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclic group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0441] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, diazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and di alkyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary bicyclic heterocyclic groups include, but are not limited to, dihydroindolyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, dihydroindolyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepin groups such as base, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, etc.

[0442] The term "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) group having 6-14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 aryl"). In some embodiments, aryl has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, aryl has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, aryl has 14 ring carbon atoms ("C 14 aryl"; e.g., anthryl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, where the linking group or point is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of aryl is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, aryl is unsubstituted C 6-14 aryl. In certain embodiments, aryl is substituted C 6-14 aryl.

[0443] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl moiety.

[0444] The term "heteroaryl" refers to a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) group that has ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In a heteroaryl containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. The heteroaryl polycyclic ring system can contain one or more heteroatoms in one or two rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, where the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, where the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. The point of attachment of a polycyclic heteroaryl in which one ring is heteroatom-free (e.g., indolyl, quinolinyl, carbazolyl, etc.) can be on either ring, i.e., the ring with heteroatoms (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl).

[0445] In some embodiments, the heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of the heteroaryl is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5- to 14-membered heteroaryl.

[0446] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, Azolyl, iso Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, but are not limited to, triazolyl, Examples of exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, but are not limited to, tetrazolyl. Examples of exemplary 6-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyridinyl. Examples of exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of exemplary 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, aza Azepinyl, oxa Oxepinyl and thia Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzo Azolyl, benzyl Azolyl, benzo Examples of the present invention include oxadiazole, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenanthrid ... oxazinyl and phenazinyl.

[0447] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0448] Adding the suffix “-ene” to a group indicates that the group is a divalent moiety. For example, alkylene is the divalent moiety of an alkyl group, alkenylene is the divalent moiety of an alkenyl group, alkynylene is the divalent moiety of an alkynyl group, heteroalkylene is the divalent moiety of a heteroalkyl group, heteroalkenylene is the divalent moiety of a heteroalkenyl group, heteroalkynylene is the divalent moiety of a heteroalkynyl group, carbocyclylene is the divalent moiety of a carbocyclic group, heterocyclylene is the divalent moiety of a heterocyclic group, arylene is the divalent moiety of an aryl group, and heteroarylene is the divalent group moiety of a heteroaryl group.

[0449] Unless expressly provided otherwise, a group is optionally substituted. The term “optionally substituted” means substituted or unsubstituted. In certain embodiments, an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is optionally substituted. “Optionally substituted” means a group that may be substituted or unsubstituted (e.g., a “substituted” or “unsubstituted” alkyl, a “substituted” or “unsubstituted” alkenyl, a “substituted” or “unsubstituted” alkynyl, a “substituted” or “unsubstituted” heteroalkyl, a “substituted” or “unsubstituted” heteroalkenyl, a “substituted” or “unsubstituted” heteroalkynyl, a “substituted” or “unsubstituted” carbocyclic, a “substituted” or “unsubstituted” heterocyclic, a “substituted” or “unsubstituted” aryl, or a “substituted” or “unsubstituted” heteroaryl). Generally, the term “substituted” means that at least one hydrogen present on the group is replaced by an allowed substituent, e.g., a substituent that results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents at each position are the same or different. It is contemplated that the term “substituted” includes substitution with all allowed substituents of an organic compound and includes any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all such combinations to obtain a stable compound. For the purposes of the present invention, a heteroatom (such as nitrogen) may have a hydrogen substituent and / or any suitable substituent as described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety. The present invention is not intended to be limited in any way by the exemplary substituents described herein.

[0450] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa)3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(OR cc )2、-P(R cc )3 + X - 、-P(OR cc )3 + X - 、-P(R cc )4、-P(OR cc )4、-OP(R cc )2、-OP(R cc )3 + X - 、-OP(OR cc )2、-OP(OR cc )3 + X - 、-OP(R cc )4、-OP(OR cc )4、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc )、C 1-10 烷基、C 1-10 全卤代烷基、C 2-10 烯基、C 2-10 炔基、杂C1-10 alkyl, hetero-C 2-10 alkenyl, hetero-C 2-10 alkynyl, C 3-10 carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 aryl and 5- to 14-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; wherein X - is a counterion;

[0451] or two geminal hydrogens on a carbon atom are replaced by the groups ═O, ═S, ═NN(R bb )2, ═NNR bb C(═O)R aa ═NNR bb C(═O)OR aa ═NNR bb S(═O)2R aa ═NR bb or ═NOR cc substitute.

[0452] R aa each instance of which is independently selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 alkyl, hetero-C 2-10 alkenyl, hetero-C 2-10 alkynyl, C 3-10 carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R aa groups are joined to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0453] R bb each instance of which is independently selected from hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(═O)R aa , -C(═O)N(R cc )2, -CO2R aa , -SO2R aa , -C(═NR cc )OR aa, -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 alkyl, hetero-C 2-10 alkenyl, hetero-C 2-10 alkynyl, C 3-10 carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R bb groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; wherein X - is a counterion;

[0454] Each instance of R cc is independently selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 alkyl, hetero-C 2-10 alkenyl, hetero-C 2-10 alkynyl, C 3-10 carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R cc groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0455] Each instance of R ddEach instance is independently selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2、-C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)(ORee ) 2, -P(=O)(R ee ) 2, -OP(=O)(R ee ) 2, -OP(=O)(OR ee ) 2, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 carbocyclic group, 3 - 10 - membered heterocyclic group, C 6-10 aryl, 5 - 10 - membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl are each independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups, or two paired R dd substituents may be joined to form =O or =S; wherein X - is a counterion;

[0456] R ee Each instance of is independently selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 carbocyclic group, C 6-10 aryl, 3 - 10 - membered heterocyclic group and 3 - 10 - membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl are each independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;

[0457] R ff Each instance of is independently selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 carbocyclic group, 3 - 10 - membered heterocyclic group, C 6-10 aryl and 5 - 10 - membered heteroaryl, or two R ffThe groups are linked to form a 3- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl are each independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups; and

[0458] Each instance of R gg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 alkyl, -SO2OC 1-6 alkyl, -OSO2C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3

[0459] -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 alkyl)2, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 alkyl, hetero-C 2-6 alkenyl, hetero-C 2-6 alkynyl, C 3-10 carbocyclic group, C 6-10 aryl, 3- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl; or two paired R gg substituents may be joined to form =O or =S; wherein X - is a counterion.

[0460] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0461] The term "hydroxyl" or "hydroxy group" refers to the group -OH. The related term "substituted hydroxyl" or "substituted hydroxy group" refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule is substituted by a group other than hydrogen, and includes groups selected from: -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -OC(=NR bb [[ID=2))N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2 and -OP(=O)(N(R bb ))2, where X - , R aa , R bb and R cc are as defined herein.

[0462] The term "amino" refers to the group -NH2. The related term "substituted amino" refers to a mono-substituted amino, di-substituted amino or tri-substituted amino. In certain embodiments, "substituted amino" is a mono-substituted amino or di-substituted amino group.

[0463] The term "mono-substituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted by one hydrogen and one group other than hydrogen, and includes groups selected from: -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb)2, -NHSO2R aa , -NHP(=O)(OR cc )2 and -NHP(=O)(N(R bb )2)2, where R aa , R bb and R cc are as defined herein, and where the R bb of the group -NH(R bb ) is not hydrogen.

[0464] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted by two groups other than hydrogen, and includes groups selected from: -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2 and -NR bb P(=O)(N(R bb )2)2, where R aa , R bb and R cc are as defined herein, provided that the nitrogen atom directly attached to the parent molecule is not substituted by hydrogen.

[0465] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted by three groups, and includes groups selected from -N(R bb )3 and -N(R bb )3 + X - , where R bb and X - are as defined herein.

[0466] The term "acyl" refers to having the general formulas -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-O-C(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(RX1 ) 2, and -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 )OR X1 , -C(=NR X1 )SR X1 and -C(=NR X1 )N(R X1 )2 groups, where R X1 is hydrogen; halogen; substituted or unsubstituted hydroxy; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic thioxy, heteroaliphatic thioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphatic amino, mono- or di-heteroaliphatic amino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino or mono- or di-heteroarylamino; or two R X1 groups together form a 5- to 6-membered heterocycle. Exemplary acyl groups include aldehyde (-CHO), carboxylic acid (-CO2H), ketone, acyl halide, ester, amide, imine, carbonate, carbamate and urea. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocycle, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxy, thiol, halogen, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic thioxy, heteroaliphatic thioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may be further substituted or unsubstituted).

[0467] The term "carbonyl" refers to a group in which the carbon directly attached to the parent molecule is sp 2 hybridized and is substituted by an oxygen, nitrogen or sulfur atom, such as a group selected from: ketone (-–C(=O)R aa ), carboxylic acid (-–CO2H), aldehyde (-CHO), ester (–CO2Raa 、 –C(=O)SR aa 、 –C(=S)SR aa )、 amide (–C(=O)N(R bb )2, –-C(=O)NR bb SO2R aa 、 -C(=S)N(R bb )2) and imine (-–C(=NR bb )R aa 、 -–C(=NR bb )OR aa )、 –-C(=NR bb )N(R bb )2), where R aa and R bb are as defined herein.

[0468] The term "oxo" refers to the group =O, and the term "thio" refers to the group =S.

[0469] The nitrogen atom can be substituted or unsubstituted as valence permits, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa 、 -N(R cc )2, -CN, -C(=O)R aa 、 -C(=O)N(R cc )2, -CO2R aa 、 -SO2R aa 、 -C(=NR bb )R aa 、 -C(=NR cc )OR aa 、 -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc 、 -SO2OR cc 、 -SOR aa 、 -C(=S)N(R cc )2, -C(=O)SR cc 、 -C(=S)SR cc 、 -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 alkyl, hetero C2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R groups connected to the N atom cc The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are each independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted and wherein R aa 、R bb 、R cc and R dd As defined above.

[0470] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxy protecting group"). Oxygen protecting groups include, but are not limited to, -R aa 、-N(R bb )2, -C(=O)SR aa 、-C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-S(=O)R aa 、-SO2R aa 、-Si(R aa )3、-P(R cc )2、-P(R cc )3 + X - 、-P(OR cc )2、-P(OR cc )3 + X - 、-P(=O)(R aa )2、-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where X - 、R aa 、R bb and R ccAs defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0471] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a “hydroxy protecting group”). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where X - , R aa , R bb and R cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0472] "Counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electrical neutrality. An anionic counterion can be monovalent (i.e., containing one formal negative charge). An anionic counterion can also be polyvalent (i.e., containing more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F -– , Cl -– , Br –- , I –- ), NO3 –- , ClO4 –- , OH –- , H2PO4 –- , HCO3 - , HSO4 -– , sulfonate ions (e.g., mesylate, triflate, tosylate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 -– , PF6 -– , AsF6 -– , SbF6 – , B[3,5-(CF3)2C6H3]4] – , B(C6F5)4 - , BPh4 – , Al(OC(CF3)3)4 – and carborane anions (e.g., CB 11 H 12 -– or (HCB 11 Me5Br6) – ). Exemplary counterions that can be polyvalent include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.) and carboranes.

[0473] As used herein, the use of the phrase "at least one instance" refers to 1, 2, 3, 4 or more instances, but also encompasses ranges such as 1 to 4, 1 to 3, 1 to 2, 2 to 4, 2 to 3, or 3 to 4 instances, including the end values.

[0474] "Non-hydrogen group" refers to any group defined for a particular variable that is not hydrogen.

[0475] The term "polysaccharide" refers to a polymer composed of long chains of carbohydrates or monosaccharide units, or derivatives thereof (e.g., monosaccharides modified to include crosslinkable functional groups). Exemplary polysaccharides include, but are not limited to, glycan, dextran, starch, glycogen, arabinoxylan, cellulose, hemicellulose, chitin, pectin, dextran, pullulan, chrysolaminarin, curdlan, laminarin, lentinan, lichenin, pleuran, zymosan, glycosaminoglycan, dextran, hyaluronic acid, chitosan, and chondroitin. The monosaccharide monomers of polysaccharides are typically linked by glycosidic linkages. Polysaccharides can be hydrolyzed to form oligosaccharides, disaccharides, and / or monosaccharides. The term "carbohydrate" or "sugar" refers to an aldehyde or ketone derivative of a polyol. Monosaccharides are the simplest carbohydrates because they cannot be hydrolyzed into smaller carbohydrates. Most monosaccharides can be represented by the general formula C y H 2y O y (e.g., C6H 12 O6 (hexose, e.g., glucose)), where y is an integer equal to or greater than 3. Certain polyols not represented by the above general formula are also considered monosaccharides. For example, deoxyribose has the formula C5H 10O4 and is a monosaccharide. Monosaccharides usually consist of five or six carbon atoms and are called pentoses and hexoses, respectively. If a monosaccharide contains an aldehyde, it is called an aldose; if it contains a ketone, it is called a ketose. Monosaccharides can also consist of three, four, or seven carbon atoms in the form of aldoses or ketoses, called trioses, tetroses, and heptoses, respectively. Glyceraldehyde and dihydroxyacetone are considered an aldotriose and a ketotriose, respectively. Examples of aldotetroses include erythrose and threose; ketotetroses include erythrulose. Aldopentoses include ribose, arabinose, xylose, and lyxose; ketopentoses include ribulose, arabinulose, xylulose, and lyxulose. Examples of aldohexoses include glucose (e.g., dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; ketohexoses include fructose, psicose, sorbose, and tagatose. Heptuloses include sedoheptulose. Except for the first and last carbons, each carbon atom of a monosaccharide bearing a hydroxyl group (-OH) is asymmetric, making the carbon atom a stereocenter with two possible configurations (R or S). Due to this asymmetry, any given monosaccharide formula can exist in many isomeric forms. For example, the aldohexose D-glucose has the formula C6H 12 O6, and all but two of its six carbon atoms are stereogenic, making D-glucose one of 16 (i.e., 2 4 to the fourth power) possible stereoisomers. Assignment of D or L is based on the orientation of the asymmetric carbon atom farthest from the carbonyl group: in the standard Fischer projection, if the hydroxyl group is on the right, the molecule is a D-sugar; otherwise, it is an L-sugar. The aldehyde or ketone group of a linear monosaccharide reacts reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, thereby forming a heterocycle with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and there is an equilibrium with the linear form. During the conversion from the linear form to the cyclic form, the carbon atom bearing the carbonyl oxygen (called the anomeric carbon) becomes a stereocenter with two possible configurations: the oxygen atom can be above or below the plane of the ring. The resulting pair of possible stereoisomers is called anomers. In the α-anomer, the -OH substituent on the anomeric carbon is on the side of the ring opposite the -CH2OH side branch (trans). The other form, in which the -CH2OH substituent and the anomeric hydroxyl are on the same side of the plane of the ring (cis), is called the β-anomer. The term carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.

[0476] The term "polymer" refers to a compound that contains linked repeating units. In certain embodiments, the polymer is naturally occurring. In certain embodiments, the polymer is synthetic (i.e., not naturally occurring). Examples of polymers include, but are not limited to, poloxamers, poly(ether-urethane), and poly(ether-carbonate) (Biomaterials, 24 (2003) 3707-3714), peptides (Adv. Mater. 2007, 19, 3947-3950), poly(ethylene glycol), and poly(trimethylene carbonate) (Macromolecules, 2007, 40 (15), pp. 5519-5525), methylcellulose, chitosan, dextran, and pNiPAAm (European Journal of Pharmaceutics and Biopharmaceutics, Vol. 68, No. 1, January 2008, pp. 34-45).

[0477] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above list of exemplary substituents.

[0478] Other Definitions

[0479] Animal: As used herein, the term "animal" refers to humans as well as non-human animals, including, for example, mammals, birds, reptiles, amphibians, and fish. Preferably, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, primate, or pig). The non-human animal can be a transgenic animal.

[0480] About or approximately: As used herein, the term "about" or "approximately" with respect to a number is generally considered to include numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number, unless otherwise specified or otherwise apparent from the context (unless such a number would be less than 0% or exceed 100% of the possible value).

[0481] Biocompatible: As used herein, the term "biocompatible" refers to a substance that is non-toxic to cells. In some embodiments, a substance is considered "biocompatible" if adding the substance to a cell body does not induce inflammation and / or other side effects in vivo. In some embodiments, a substance is considered "biocompatible" if adding the substance to cells in vitro or in vivo results in less than or equal to about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, or less than about 5% cell death.

[0482] Biodegradable: As used herein, the term "biodegradable" refers to a substance that degrades under physiological conditions. In some embodiments, a biodegradable substance is a substance that is broken down by cellular machinery. In some embodiments, a biodegradable substance is a substance that is broken down by a chemical process.

[0483] Translucency: As used herein, the term "translucency" refers to a substance through which light passes and little or no light is absorbed or reflected. In some embodiments, translucency refers to a substance through which light passes and no light is absorbed or reflected. In some embodiments, translucency refers to a substance through which light passes and little light is absorbed or reflected. In some embodiments, a translucent substance is substantially clear. In some embodiments, a translucent substance is clear.

[0484] Effective amount: Generally, an "effective amount" of an active agent is an amount sufficient to elicit a desired biological response. As will be understood by one of ordinary skill in the art, the effective amount of a compound of the invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient. The effective amount of a compound for treating an infection is the amount required to kill the organism causing the infection or to prevent the growth of the organism causing the infection.

[0485] In vitro: As used herein, the term "in vitro" refers to an event that occurs in an artificial environment such as in a test tube or reaction vessel, in cell culture, etc., and not within an organism (e.g., an animal, a plant, and / or a microorganism).

[0486] In vivo: As used herein, the term "in vivo" refers to an event that occurs within an organism (e.g., an animal, a plant, and / or a microorganism).

[0487] Affected with: An individual "affected with" a "disease, disorder, and / or condition" has been diagnosed as having or exhibiting one or more symptoms of the disease, disorder, and / or condition.

[0488] Treatment: As used herein, the term "treatment" refers to partially or completely alleviating, ameliorating, relieving, delaying the onset, inhibiting the progression, reducing the severity, and / or reducing the morbidity of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. For example, "treating" a microbial infection can refer to inhibiting the survival, growth, and / or spread of the microbe. Treatment can be administered to a subject who does not exhibit the signs of a disease, disorder, and / or condition and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition to reduce the risk of developing the pathology associated with the disease, disorder, and / or condition. In some embodiments, treatment includes delivering a vaccine nanocarrier of the invention to a subject.

[0489] Therapeutic agent: Also referred to as a "drug", is an agent administered to a subject herein for treating a disease, disorder or other clinically recognized condition harmful to the subject, or for prophylactic purposes, and having a clinically significant effect on the body to treat or prevent a disease, disorder or condition. Therapeutic agents include, but are not limited to, agents listed in the following: United States Pharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition., McGraw Hill, 2001; Katzung, B. (ed.) Basic and Clinical Pharmacology, McGraw-Hill / Appleton & Lange; 8th Edition (September 21, 2000); Physician's Desk Reference (Thomson Publishing), and / or The Merck Manual of Diagnosis and Therapy, 17th Edition. (1999), or its 18th Edition. (2006) after publication, Mark H. Beers and Robert Berkow (editors), Merck Publishing Group, or in the case of animals, The Merck Veterinary Manual, 9th Edition., Kahn, C. A. (ed.), Merck Publishing Group, 2005.

[0490] Diagnostic agent: As used herein, the term "diagnostic agent" refers to an agent administered to a subject to assist in diagnosing a disease, disorder or condition. In some embodiments, the diagnostic agent is used to define and / or characterize the location of a pathological process. Diagnostic agents include X-ray contrast agents, radioisotopes and dyes.

[0491] Microbial infection: As used herein, the term "microbial infection" refers to an infection by a microorganism, such as a fungus, bacterium or virus. In certain embodiments, the microbial infection is a fungal infection, i.e., mycosis. In certain embodiments, the microbial infection is a viral infection, i.e., virosis. In certain embodiments, the microbial infection is a bacterial infection, i.e., bacteriosis. Multiple microbial infections include, but are not limited to, skin infections, GI infections, urinary tract infections, urogenital infections, sepsis, blood infections and systemic infections.

[0492] Sol-gel transition temperature: As used herein, the term "sol-gel transition temperature" refers to the temperature at which the storage modulus of a composition begins to increase and becomes greater than the loss modulus of the composition. The terms "sol-gel transition temperature", "phase transition temperature", and "gelation temperature" are used interchangeably.

[0493] Surfactant: As used herein, the term "surfactant" refers to any agent that preferentially adsorbs at the interface between two immiscible phases (e.g., the interface between water and an organic solvent, the water / air interface, or the organic solvent / air interface). Surfactants typically have a hydrophilic portion and a hydrophobic portion. Surfactants can also enhance the flux of a therapeutic or diagnostic agent across a biological membrane (e.g., the tympanic membrane).

[0494] Terpene: As used herein, the term "terpene" refers to any agent derived from, for example, biosynthesis or thought to be derived from isoprene units (five-carbon units). For example, the isoprene units of a terpene can be linked together to form a straight chain, or they can be arranged in a ring. Typically, the terpenes disclosed herein enhance the flux of a therapeutic or diagnostic agent across a biological membrane (e.g., the tympanic membrane). Terpenes can be of natural origin or synthetically prepared.

[0495] The terms "composition" and "formulation" are used interchangeably.

[0496] Examples

[0497] In order to more fully understand the invention described herein, the following examples are given. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0498] Materials and Methods

[0499] Methods and Design: The experiments compared the effects of the introduction of a polymer matrix and CPE on TM permeability and OM cure rate. For in vitro experiments, the sample size for each formulation was chosen to be 4, which provides 80% power to detect a 50% flux difference using non-parametric Friedman's test (version 7.0, nQuery Advisor, Statistical Solutions, Saugus, MA) based on a power analysis. A sample size of 8 to 10 was used for in vivo experiments, which was supported by a previous publication (Pelton et al., Antimicrob. Agents Chemother. 44, 654 - 657 (2000)). The comparison between positive and negative efficacy results was evaluated using Fisher's exact test. Statistical analysis was performed using SAS software (version 9.2, SAS Institute, Cary, NC). To control for type I error, a two-tailed p < 0.05 with appropriate Bonferroni-Sidak adjustment for multiple comparisons was considered statistically significant. During in vitro experiments, data collection was stopped after 48 hours due to microbial growth on the harvested TM; while during in vivo experiments, data collection was stopped after 7 days as the OM would either be cleared or cause the animals to develop a severe disease requiring euthanasia. The in vivo experiments were blinded. All experiments were randomized.

[0500] Materials: 2-Chloro-2-oxo-1,3,2-dioxaphospholane (COP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), n-butanol, diethyl ether, acetic acid, anhydrous dichloromethane, anhydrous tetrahydrofuran were used, which were obtained from Sigma-Aldrich Company (St. Louis, MO). P 407 microprilled (Poloxamer 407) was obtained from BASF (Florham Park, NJ).

[0501] Animal Maintenance: Healthy adult male chinchillas weighing 500 to 650 g were purchased from Ryerson Chinchilla Ranch (Plymouth, OH) and cared for according to institutional and nationally approved protocols. Experiments were performed in accordance with the Boston Children's Hospital, Boston University Medical Center, and Massachusetts Eye and Ear Infirmary Animal Use Guidelines and approved by each institution's Animal Care and Use Committee.

[0502] Gel time: The hydrogel formulation in a scintillation vial was immersed in a water bath maintained at 37° C. under constant stirring (200 rpm). The time at which the stirring bar stopped rotating after immersion was recorded as the gel time.

[0503] Gelation temperature: measured using linear oscillatory shear rheology (100 rads -1 ,1% strain,1℃min -1 ) to quantify the gelation temperature. The gelation temperature is taken as the temperature at which the storage modulus (G') becomes greater than the loss modulus (G"). Changes in G' and G" are recorded over the temperature range from 0°C to above body temperature to reflect changes in mechanical properties.

[0504] In vitro release studies: The release of ciprofloxacin from each formulation was measured using a diffusion system. Membrane inserts (0.4 μm pore size, 1.1 cm2 area; Costar, Cambridge, MA) and 24-well culture plates served as donor and receiver chambers, respectively. 200 μL of each formulation was pipetted directly onto the preheated filter insert to obtain a solid hydrogel. The filter insert with the formed gel (donor chamber) was suspended in a well (receiver chamber) filled with preheated phosphate-buffered saline (PBS), and the plate was then incubated in a 37°C oven. At each time point (0.5, 1, 2, 6, 12, 24, 48 hours), a 1 mL aliquot of PBS receiving medium was taken, and the insert was sequentially transferred to a new well with fresh PBS. The aliquots were suspended in 70:30 acetonitrile / PBS to ensure total drug dissolution. The sample aliquots were chromatographed by HPLC to determine the ciprofloxacin concentration (λ = 275 nm). More detailed information on ciprofloxacin measurement and HPLC conditions can be found in reference (8). The experiments were performed in quadruplicate.

[0505] Ex vivo permeation experiment: The trans-TM permeation rate of ciprofloxacin was determined using auditory bullae harvested from healthy chinchillas. All formulations were applied to the bullae maintained at 37 °C and deposited on the TM. The applied volume was 200 μL, which was equivalent to 2 mg of ciprofloxacin. The permeation of ciprofloxacin across the TM into the receiving chamber was quantified using HPLC. Details regarding TM harvest, TM resistance measurement, and the configuration of the ex vivo permeation experiment can be found in reference (8).

[0506] Cytotoxicity analysis: The mitochondrial metabolic activity was determined using the tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and the electron coupling agent (phenazine ethosulfate; PES) in the CellTiter Aqueous One Solution Cell Proliferation Assay (Promega Corp.) to evaluate cell viability. On days 1 and 3 of culture, human dermal fibroblasts (hFB), PC12, and normal adult primary epidermal keratinocytes (ATCC) were incubated with CellTiter Aqueous One Solution at 37 °C for 120 minutes. The absorbance of the culture medium at 490 nm was immediately recorded using a 96-well plate reader. The amount of formazan product (converted from tetrazolium) measured by the absorbance at 490 nm is proportional to the cell metabolic activity in the culture. Flat cultures on 24-well plates were used as controls. For each group, n = 4. The Viability / Cytotoxicity Kit (Molecular Probes, Invitrogen) was used to confirm cell viability. Cells were incubated with 1 μM calcein-AM and 2 μM ethidium homodimer-1 (EthD-1) at 37 °C for 30 minutes to label live and dead cells, respectively. Cell viability was calculated as live / (live + dead) × 100.

[0507] Histopathology: The formulation was applied to the ear canals of live healthy / OM chinchillas. After seven days, they were euthanized as described elsewhere (8). After euthanasia, the TM was excised by the Pathology Department of Boston Children's Hospital using standard techniques and immediately fixed in 10% neutral buffered formalin overnight, then decalcified, paraffin-embedded, sectioned (5 μm thick), and stained with hematoxylin and eosin (paid service). All stained specimens were evaluated under optical microscopy (Olympus FSX-100).

[0508] Auditory brainstem response (ABR) measurement: The ABR experiment was conducted using a custom-designed stimulus generation and measurement system built around National Instruments (Austin, TX) software (Lab View) and hardware. Detailed information on ABR can be found in reference (8).

[0509] NTHi OM model and pharmacokinetics: At the Boston University School of Medicine, all procedures and operations were performed under sedation and analgesia with a mixture of intramuscularly administered ketamine and xylazine according to an approved IACUC protocol. Baseline plasma samples were obtained by sinus puncture 24 hours before bacterial inoculation. NTHi isolates grown to mid-log phase were diluted in HBSS, and approximately 25 to 75 cfu in 100 μL were introduced directly into each middle ear bulla under sterile conditions. Tympanometry and otomicroscopy were performed daily to determine the presence of fluid in the middle ear bulla and signs of infection, including tympanic membrane bulging. Erythema and photographs were taken. Once an abnormality was identified, the middle ear cavity was accessed 48 to 72 hours later as previously described (see Sabharwal et al., Infect. Immun. 77, 1121 - 1127 (2009)). Direct cultures of the middle ear were obtained with calcium alginate swabs and streaked immediately on blood agar plates. Middle ear fluid was obtained with a 22-gauge angiocatheter attached to an empty tuberculin syringe, and 10 to 20 μL of middle ear fluid was diluted 1:10 in HBSS to prepare three consecutive 10-fold dilutions. 100 μL of each dilution was plated on blood agar. The lower limit of detection of viable organisms in middle ear fluid using this dilution series was 100 cfu mL -1 . Direct and indirect ear examinations were performed every 1 to 2 days until the middle ear cultures were sterile. Serial plasma samples were obtained during the experiment to determine systemic drug levels.

[0510] Statistical analysis: Data with a normal distribution were described by the mean and standard deviation and compared using unpaired Student's t-tests. Alternatively, data were expressed as the median ± interquartile range. All data analyses were performed using Origin 8 software.

[0511] Methods and Results

[0512] Isolation of intact chinchilla TM

[0513] The size of the tympanic membrane (TM), middle ear structure, and auditory range of chinchillas are very close to those of humans. A reproducible ex vivo method has been established for studying the flux across the TM. The TM is removed without damage, still attached to the tympanic annulus of the bone. In a setup where the TM is placed horizontally in a 12-well plate (donor solution above, receiving solution below), its integrity is evaluated by measuring its resistance (indicated by RA≥18 kOhm*cm 2 ). The same setup is used to measure the drug flux, which replaces the conventional diffusion cell that can deform or rupture the TM. Skin samples with poorer reproducibility than the TM are only used as screening tools to minimize the use of animals.

[0514] Trans-tympanic delivery of antibiotics

[0515] For the trans-tympanic delivery of the antibiotic ciprofloxacin, the synthetic fluoroquinolone antibiotic was chosen because of its known activity against non-typable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (SP), low molecular weight, and moderate lipophilicity.

[0516] CPE enhances drug flux across intact TM

[0517] Sodium dodecyl sulfate (SDS; anionic surfactant) and limonene (a monocyclic terpene) were chosen as chemical permeation enhancers (CPEs) based on their use in transdermal drug delivery and their favorable enhancement / irritation ratio.

[28] Bupivacaine, an amide local anesthetic, was introduced into some formulations due to its potential clinical benefits for OM-related ear pain and due to aminoester anesthetics (such as tetracaine) being used as CPEs.

[15] In the absence of CPE, ciprofloxacin permeation across the chinchilla TM was undetectable at 37 °C up to 12 hours. At 24 hours, 109 μg (out of 2 mg total ciprofloxacin) or 5.5% of the starting drug load had permeated the TM; at 48 hours, 364 μg (18%) had permeated. The addition of limonene promoted drug permeation; ciprofloxacin was detected in the receiving buffer as early as 1 to 2 hours. A concentration-dependent increase of 2- to 3-fold in ciprofloxacin transfer at 48 hours was also achieved. The permeation of ciprofloxacin was further enhanced by using all three CPEs together (1% SDS, 0.5% bupivacaine, and 2% limonene; designated as 3CPE).

[0518] Hydrogel at the TM

[0519] During the experiment, the hydrogel component poloxamer 407 (P407) was used to hold the drug-CPE combination in place at the TM. When deposited on the chinchilla TM at 37 °C, the formulation of 18% P407 loaded with drug formed a soft, clear gel. The hydrogel matrix slowed the transtympanic transfer of ciprofloxacin ( Figure 3 ). The addition of 3CPE increased the flux (but still did not reach the level o...

Claims

1. A composition comprising: (a) a therapeutic agent or combination of therapeutic agents; (b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and (c) a matrix former or combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer; wherein: the composition forms a gel at a temperature above the sol-gel transition temperature; and the sol-gel transition temperature is below about 39 °C; and at least one of conditions (i), (ii), and (iii) is satisfied: (i) the sol-gel transition temperature of the composition is below the sol-gel transition temperature of a reference composition plus about 23 °C, or 39 °C, whichever is greater; (ii) at a temperature of about 37 °C, the storage modulus of the composition is greater than about 13.5% of the storage modulus of the reference composition, or greater than about 500 Pa, whichever is smaller; and (iii) at a temperature of about 37 °C, the loss modulus of the composition is from about 12% to about 750% of the loss modulus of the reference composition; wherein: the reference composition is a composition that does not contain the permeation enhancer or combination of permeation enhancers; the permeation enhancer or combination of permeation enhancers comprises from about 0.1% to 30% by weight of the composition per volume of the composition; the polymer is a block copolymer comprising poloxamer; the poloxamer comprises from about 19% to 45% by weight of the composition per volume of the composition.

2. The composition according to claim 1, comprising: (a) a therapeutic agent or combination of therapeutic agents; (b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and (c) a matrix former or combination of matrix formers, wherein the matrix former or combination of matrix formers comprises a polymer; wherein: the composition forms a gel at a temperature above the sol-gel transition temperature; and the sol-gel transition temperature is below about 39 °C; and at least one of conditions (i), (ii), and (iii) is satisfied: (i) the sol-gel transition temperature of the composition is below the sol-gel transition temperature of a reference composition plus about 23 °C, or 39 °C, whichever is greater; (ii) at a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition, or greater than about 500 Pa, whichever is smaller; and (iii) at a temperature of about 37 °C, the loss modulus of the composition is from about 15% to about 750% of the loss modulus of the reference composition; wherein: the reference composition is a composition that does not contain the permeation enhancer or combination of permeation enhancers; the permeation enhancer or combination of permeation enhancers comprises from about 1% to 30% by weight of the composition per volume of the composition; the polymer is a block copolymer comprising poloxamer; the poloxamer comprises from about 19% to 45% by weight of the composition per volume of the composition.

3. The composition according to claim 1, wherein condition (i) is satisfied.

4. The composition according to claim 1, wherein condition (ii) is satisfied.

5. The composition according to claim 1, wherein condition (iii) is satisfied.

6. The composition according to claim 1, wherein condition (i) and (ii); (i) and (iii); or (ii) and (iii) are satisfied.

7. The composition according to claim 1, wherein each of condition (i), (ii), and (iii) is satisfied.

8. The composition according to any one of claims 1 to 7, wherein at a temperature of about 37 °C, the storage modulus is greater than about 13.5%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% of the storage modulus of the reference composition.

9. The composition according to any one of claims 1 to 8, wherein the sol-gel transition temperature is lower than the sol-gel transition temperature of the reference composition.

10. The composition according to any one of claims 1 to 8, wherein the sol-gel transition temperature is higher than about 10 °C.

11. The composition according to any one of claims 1 to 8, wherein the sol-gel transition temperature is higher than about 20 °C.

12. The composition according to any one of claims 1 to 8, wherein the sol-gel transition temperature is higher than about 30 °C.

13. The composition according to any one of claims 1 to 8, wherein the sol-gel transition temperature is higher than about 35 °C.

14. The composition according to any one of claims 1 to 8, wherein the sol-gel transition temperature is higher than about 37 °C or higher than about 39 °C.

15. The composition according to any one of claims 1 to 14, wherein the composition comprises about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 10%, 15%, 20%, 25%, or 30% of a penetration enhancer by weight per volume of the composition.

16. The composition according to claim 15, wherein the composition comprises about 4% of a penetration enhancer by weight per volume of the composition.

17. The composition according to claim 1, wherein the composition comprises about 22% to about 35% of poloxamer by weight per volume of the composition.

18. The composition according to claim 17, wherein the composition comprises about 22% to about 27% of poloxamer by weight per volume of the composition.

19. The composition according to claim 17, wherein the composition comprises about 25% of poloxamer by weight per volume of the composition.

20. The composition according to claim 1, wherein the poloxamer is P407.

21. The composition according to claim 1, wherein the poloxamer is P331.

22. The composition according to any one of claims 1 to 21, wherein the permeation enhancer is a surfactant, terpene, amino amide, amino ester, azide-containing compound, alcohol, pyrrolidone, sulfoxide, fatty acid, peptide or anesthetic.

23. The composition according to any one of claims 1 to 21, wherein the penetration enhancer is sodium dodecyl sulfate, decyl methyl sulfoxide, nonoxynol-9, sodium pyrrolidone carboxylate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyltrimethylammonium bromide, cetylpyridinium chloride benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate, dimethyl sulfoxide, sodium tridecyl phosphate; decyldimethylammonium propane sulfonate, oleyl betaine, myristyldimethylammonium propane sulfonate; benzylpyridinium chloride dodecylpyridinium chloride cetylpyridinium chloride benzyldimethyldodecylammonium chloride, benzyldimethyldodecylammonium chloride, benzyldimethylmyristylammonium chloride, benzyldimethylstearylammonium chloride, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.

24. The composition according to any one of claims 1 to 21, wherein the permeation enhancer is limonene, cymene, pinene, camphor, menthol, camphene, phellandrene, sabinene, terpinene, borneol, cineole, geraniol, linalool, piperitone, terpineol, eugenol, eugenyl acetate, safrole, benzyl benzoate, humulene, β-caryophyllene, eucalyptol, caproic acid, caprylic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl myristate, isopropyl palmitate, palmitoyl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, or ethyl piperazine carboxylate.

25. The composition according to any one of claims 1 to 21, wherein the permeation enhancer comprises: an anesthetic permeation enhancer; and a surfactant and terpene permeation enhancer, wherein the anesthetic permeation enhancer enhances the enhancement of the flux of the therapeutic agent through the barrier obtained by the surfactant and terpene permeation enhancer.

26. The composition according to claim 25, wherein: the anesthetic permeation enhancer is bupivacaine; the surfactant permeation enhancer is sodium dodecyl sulfate; and the terpene permeation enhancer is limonene; wherein bupivacaine enhances the enhancement of the flux of the therapeutic agent through the barrier obtained by sodium dodecyl sulfate and limonene.

27. The composition according to any one of claims 1 to 21 or 24, wherein the permeation enhancer is methyl laurate, isopropyl myristate, sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000 MW) or octyldodecanol.

28. The composition according to any one of claims 1 to 21, wherein the permeation enhancer is pyrrolidone; dimethyl sulfoxide; long-chain dialkyl sulfoxide; fatty acid; or azone-like compound.

29. The composition according to claim 28, wherein the azone-like compound is 1-benzyl-4-(2-((1,1-biphenyl)-4-yloxy)ethyl)piperazine.

30. The composition according to any one of claims 1 to 29, wherein the permeation enhancer is sodium dodecyl sulfate, limonene or a combination thereof.

31. The composition according to claim 30, wherein the permeation enhancer is a combination of sodium dodecyl sulfate and limonene.

32. The composition according to claim 31, wherein the composition comprises about 2% sodium dodecyl sulfate and 2% limonene by weight of the permeation enhancer per volume of the composition.

33. The composition according to any one of claims 1 to 32, wherein the therapeutic agent is an antimicrobial agent, antibiotic agent, anesthetic, anti-inflammatory agent, analgesic, antifibrotic agent, anti-sclerosis agent, anticoagulant or diagnostic agent.

34. The composition according to any one of claims 1 to 32, wherein the therapeutic agent is an antibiotic agent selected from ciprofloxacin, amoxicillin, azithromycin, cefuroxime, ceftriaxone, trimethoprim, and levofloxacin.

35. The composition according to any one of claims 1 to 33, wherein the therapeutic agent is an anesthetic agent selected from: bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dimethocaine, cyclomethycaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, carticaine, etidocaine, mepivacaine, piridocaine, and trimecaine.

36. The composition according to any one of claims 1 to 33, wherein the therapeutic agent is an anti-inflammatory agent selected from the following: acetylsalicylic acid, amoxiprine, benorylate, choline magnesium salicylate, diflunisal, etodolac, faislamine, methyl salicylate, magnesium salicylate, salicyl salicylate, salicylamide, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indomethacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, ibuprofen, alminoprofen, ibuprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, aminopyrine, azapropazone, clofezone, ketophenylbutazone, metamizole, morfebutazone, oxyphenbutazone, phenazone, phenylbutazone, sulfinpyrazone, piroxicam, tenoxicam, lornoxicam, meloxicam, tenoxicam, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, desoxycorticosterone acetate, and aldosterone.

37. The composition according to any one of claims 1 to 33, wherein the therapeutic agent is an antiviral agent or an antifungal agent.

38. The composition according to any one of claims 1 to 37, further comprising an additional therapeutic agent.

39. The composition according to claim 38, wherein the additional therapeutic agent is a steroid, an anesthetic agent, an anti-inflammatory agent, or a β-lactamase inhibitor.

40. The composition according to claim 39, wherein the additional therapeutic agent is bupivacaine or dexamethasone.

41. The composition according to any one of claims 1 to 40, wherein the composition forms a gel at a sol-gel transition temperature of from about 0 °C to about 39 °C.

42. A composition comprising: (a) a therapeutic agent or a combination of therapeutic agents; (b) a permeation enhancer or a combination of permeation enhancers, wherein the permeation enhancer or the combination of permeation enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents across a barrier; and (c) a matrix former or a combination of matrix formers, wherein the matrix former or the combination of matrix formers comprises a polymer; wherein: the composition forms a gel at a temperature above the sol-gel transition temperature; and the sol-gel transition temperature is below about 39 °C; and at least one of the conditions (i), (ii), and (iii) is satisfied: (i) the sol-gel transition temperature of the composition is lower than the sol-gel transition temperature of a reference composition plus about 23 °C, or 39 °C, whichever is greater; (ii) at a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition, or greater than about 500 Pa, whichever is smaller; and (iii) at a temperature of about 37 °C, the loss modulus of the composition is from about 12% to about 750% of the loss modulus of the reference composition; wherein: the reference composition is a composition that does not contain the permeation enhancer or the combination of permeation enhancers; the permeation enhancer or the combination of permeation enhancers comprises sodium dodecyl sulfate and limonene, and the permeation enhancer or the combination of permeation enhancers accounts for about 3% to 6% by weight per volume of the composition; the polymer is a block copolymer comprising poloxamer P407; and the P407 accounts for about 22% to about 27% by weight per volume of the composition.

43. The composition according to claim 42, comprising: (a) a therapeutic agent or a combination of therapeutic agents; (b) A penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or the combination of penetration enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents through a barrier; and (c) A matrix former or a combination of matrix formers, wherein the matrix former or the combination of matrix formers comprises a polymer; Wherein: The composition forms a gel at a temperature above the sol-gel transition temperature; and The sol-gel transition temperature is below about 39 °C; And at least one of the conditions (i), (ii) and (iii) is satisfied: (i) The sol-gel transition temperature of the composition is below the sol-gel transition temperature of a reference composition plus about 23 °C, or 39 °C, whichever is greater; (ii) At a temperature of about 37 °C, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition, or greater than about 500 Pa, whichever is smaller; And (iii) At a temperature of about 37 °C, the loss modulus of the composition is from about 15% to about 750% of the loss modulus of the reference composition; Wherein: The reference composition is a composition that does not contain the penetration enhancer or the combination of penetration enhancers; The penetration enhancer or the combination of penetration enhancers comprises sodium dodecyl sulfate and limonene, and The penetration enhancer or the combination of penetration enhancers accounts for about 3% to 6% of the composition by weight per volume of the composition; The polymer is a block copolymer comprising poloxamer P407; and The P407 accounts for about 22% to about 27% of the composition by weight per volume of the composition.

44. A method of treating a disease, which comprises administering to a subject in need thereof a composition according to any one of claims 1 to 43.

45. A method of treating an ear disease, which comprises administering to a subject in need thereof a composition according to any one of claims 1 to 43.

46. The method according to any one of claims 44 or 45, wherein the disease is an infection.

47. The method according to any one of claims 44 or 45, wherein the disease is an infectious disease.

48. The method according to any one of claims 44 or 45, wherein the disease is a bacterial infection.

49. The method according to claim 48, wherein the bacterial infection is caused by Haemophilus influenzae (H. influenzae), Streptococcus pneumoniae (S. pneumoniae) or Moraxella catarrhalis (M. catarrhalis).

50. The method according to claim 47, wherein the infectious disease is otitis media.

51. A method of eradicating a biofilm, which comprises administering to a subject in need thereof a composition according to any one of claims 1 to 43.

52. A method of delivering a composition according to any one of claims 1 to 43, the method comprising administering the composition to the ear canal of a subject, wherein the composition contacts the surface of the tympanic membrane.

53. A method of delivering a composition according to any one of claims 1 to 43, the method comprising administering the composition to the ear canal of a subject.

54. The method according to claim 52, wherein the administration comprises placing a dose of the composition into the ear canal using a catheter or placing several drops of the composition into the ear canal.

55. The method according to claim 52, wherein the administration comprises placing the composition into the ear canal using a dispenser.

56. The method according to claim 52, wherein the administration comprises: adding to the ear canal a composition comprising one or more therapeutic agents, one or more permeation enhancers, and one or more matrix formers; and subsequently adding to the ear canal a composition that does not contain a therapeutic agent or contains one or more therapeutic agents, does not contain a permeation enhancer or contains one or more permeation enhancers, and does not contain a matrix former or contains one or more matrix formers.

57. The method according to claim 56, wherein the therapeutic agent, permeation enhancer, and matrix former in the composition added for the first time are the same as those in the composition added for the second time.

58. The method according to claim 56, wherein the therapeutic agent, permeation enhancer, and matrix former in the composition added for the first time are different from those in the composition added for the second time.

59. The method according to claim 52, wherein the administration comprises: administering the composition having a local anesthetic to the ear canal; and administering the composition without a local anesthetic to the ear canal.

60. The method according to claim 52, wherein the administration comprises: adding the matrix former to the ear canal; adding the permeation enhancer to the ear canal; adding the therapeutic agent to the ear canal; and mixing the matrix former, the permeation enhancer, and the therapeutic agent in the ear canal.

61. The method according to claim 52, wherein the administration comprises: adding the matrix former to the ear canal; adding the permeation enhancer to the ear canal; adding the therapeutic agent to the ear canal; adding an additional therapeutic agent to the ear canal; and mixing the matrix former, the permeation enhancer, and the therapeutic agent in the ear canal.

62. The method according to claim 61, wherein adding the therapeutic agent and the permeation enhancer to the ear canal comprises spraying the therapeutic agent and the permeation enhancer into the ear canal.

63. The method according to claim 53, wherein the administration comprises placing the composition into the ear canal using a binocular syringe.

64. A kit for treating an infectious disease, comprising a container, the composition according to any one of claims 1 to 43, and instructions for administering the composition to a subject in need thereof.

65. The kit according to claim 64, wherein the infectious disease is an ear disease.

66. The kit according to any one of claims 64 or 65, further comprising a dropper, a syringe, a catheter, or an otoscope attachment.

67. The kit according to claim 64, further comprising a binocular syringe.

Images