(12) Patent Application Publication (10) Pub. No.: US 2016/0346294 A1 SENGUPTA Et Al

Home , Astromicin, Ranbezolid

US 2016.0346294A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0346294 A1 SENGUPTA et al. (43) Pub. Date: Dec. 1, 2016

(54) TREATMENTS FOR RESISTANT ACNE Publication Classification (71) Applicant: VYOME BIOSCIENCES PVT. LTD., (51) Int. Cl. New Delhi (IN) A6II 3/55 (2006.01) A63L/92 (2006.01) (72) Inventors: Shiladitya SENGUPTA, Delhi (IN); A6II 47/08 (2006.01) Suresh Rameshlal CHAWRAI, Pune A6II 47/8 (2006.01) (IN); Shamik GHOSH, Delhi (IN); C07D 53/04 (2006.01) Sumana GHOSH, Delhi (IN); Nilu A6II 47/38 (2006.01) JAIN, New Delhi (IN); Suresh A6II 47/32 (2006.01) SADHASIVAM, Salem (IN); Richard A6II 47/36 (2006.01) BUCHTA, Melbourne (AU); Anamika A6II 47/02 (2006.01) BHATTACHARYYA, Delhi (IN) A6II 45/06 (2006.01) A6II 47/10 (2006.01) (73) Assignee: VYOME BIOSCIENCES PVT. LTD., (52) U.S. Cl. New Delhi (IN) CPC ...... A6 IK3I/55 (2013.01); A61K 45/06 (2013.01); A61K 31/192 (2013.01); A61 K (21) Appl. No.: 15/115,143 47/08 (2013.01); A61K 47/183 (2013.01); A61K 47/10 (2013.01); A61K 47/38 (2013.01); (22) PCT Fed: Jan. 29, 2015 A61K 47/32 (2013.01); A61K 47/36 (2013.01); PCT No.: PCT/N2O15/000057 A61K 47/02 (2013.01); C07D 513/04 (86) (2013.01) S 371 (c)(1), (2) Date: Jul. 28, 2016 (57) ABSTRACT (30) Foreign Application Priority Data The present disclosure relates generally to novel molecules, compositions, and formulations for treatment of bacterial Jan. 29, 2014 (IN) ...... 269/DELA2014 infections in general and more specifically to bacterial Nov. 10, 2014 (IN) ...... 3247/DELA2014 infections with antibiotic resistant pathogens Patent Application Publication Dec. 1, 2016 Sheet 1 of 14 US 2016/0346294 A1

50 Cephalothin O O Nadioxacin Roxythromycin Besifloxacin Pulifloxacin Clindamycin -- Cefoxitin --- Ulifloxacin

FIG. IA

5 Cephalothin Nadifloxacin OO Roxithromycin Besifloxacin Ulifloxacin Pulifloxacin Cindamycin Cefoxitin

FIG. IB Patent Application Publication Dec. 1, 2016 Sheet 2 of 14 US 2016/0346294 A1

DART molecules Dose response Curve Against P. acnes MTCC 1951

0.25

a 2 s SS

0.00 0.05 0.10 0.45 0.20 0.25 Antibiotic Concentration (u FIG. ID Patent Application Publication Dec. 1, 2016 Sheet 3 of 14 US 2016/0346294 A1

omp. 91 conc. (M) 0.25- 0.50 100 2.50 5.00

ane 1- Relaxed DNA (Negative Control) ane2- DNA+ Gyrase (Positive Control) ne3-7 Comp, 91 with increasing conc. ne8- Supercoiled DNA marker

o e an sh Gyrase t t t compound 91 0.25 0.50 1.00 2.50 5.00 Compound Conc. (M)

FIGS 2A and 2B Patent Application Publication Dec. 1, 2016 Sheet 4 of 14 US 2016/0346294 A1

Z Compound 113 S Compound 94 8 Compound 115 Compound 90 (III) Compound 116 EEEEEEEE Compound 91

1MCompound 2.5M Compound

FIG. 3A

Nadifloxacin Compound 91

Ø [IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

FIG. 3B Patent Application Publication Dec. 1, 2016 Sheet 5 of 14 US 2016/0346294 A1

P. acneS Compound 91 (25pg/ml) Dexamethasone (0.4 ug/ml) Vehicle

P. acnes Compound 91 (25pg/ml) Dexamethasone (0.4 g/ml) Vehicle

Data expressed as Meant SD, n=3

FIGS 4A and 4B Patent Application Publication Dec. 1, 2016 Sheet 6 of 14 US 2016/0346294 A1

O P. acnes Compound 91 (25pg/ml) Dexamethasone (0.4 g/ml) Vehicle

S o O. Ye c v s

P. acnes Compound 91 (25pg/ml) Dexamethasone (0.4 g/ml) Vehicle

Data expressed as Meant SD, n=3

FIGS 5A and 5B Patent Application Publication Dec. 1, 2016 Sheet 7 of 14 US 2016/0346294 A1

MICValue of the Formulations against P. acnes

0.5 O.3 - 0.25 0.13- 0.25

Besifloxacingel Besifloxacint-Adapatene Placebo ge gel

FIG. 6

Dose Respose Curve of Gels Against P, acnes

K Besifloxacingel O Besifloxacin-i-Adapalenegel A Placebo ge a log. (Besifloxacingel) Log. Besifloxacint-Adapalene gel) . . . . . Log. Placebogel)

a-as-as-as-as-as-as-a-A 0.25 O.5 O.75 1 Besifloxacin Concentration (ppm)

FIG. 7 Patent Application Publication Dec. 1, 2016 Sheet 8 of 14 US 2016/0346294 A1

Time Kill Kinetics of the Formulations against P. acnes

-----. Besigel (1ppm)

8. 5:::::: -- Besigel(10ppm)

"A" Besi-Adagel (1 ppm) 7

- A - Besi-Adagel (10ppm)

---O-- Placebo gel (1ppm)

-O- Placebo gel(10ppm)

Time (h)

------...-...------,-,-,------l

SSO

--Besifloxacin gel

-- Placebo get

------Fig. 9 Patent Application Publication Dec. 1, 2016 Sheet 9 of 14 US 2016/0346294 A1

Besifloxacinformulations Time Kill Against P. acnes MTCC 1951

O 5 1 O 15 2O 25 30

Time (Hrs.) -O- GL10201 ug?ml -O- GL102010 ugml -v- CR/0031 ug/ml -4- CR/00310 ug/mt -- CR/0291 ug/ml -- CR/029 10 ugm -0-- Broth Control

FIG. IO Patent Application Publication Dec. 1, 2016 Sheet 10 of 14 US 2016/0346294 A1

Besifloxacin Time Kill against S. aureus MTCC 6908

2 3 4 5

Time (Hrs.) -o- BTK-12.5ug/ml -o- BTK-2 2.5ugiml -v- BTK-32.5ug/ml -A- BTK-42.5ug/ml -- BTK-52.5ug/ml -- BTK-62.5ug/ml -- Broth Control

FIG II Patent Application Publication Dec. 1, 2016 Sheet 11 of 14 US 2016/0346294 A1

Besifloxacintime kill against P. acnes CCARM 9010

. 6

O 5 10 15 20 25 30

Time (hrs.) -0- Besifloxain 2.5ug/ml water -O- Besifloxacin 2.5ug/ml DMSO -v- Both Control

FIG. 12 Patent Application Publication Dec. 1, 2016 Sheet 12 of 14 US 2016/0346294 A1

7. S

5 O ------

O 8 12 6 2O A. Time Point (h) -WLN-F19/BSF/GL1068 --a-WLN-F21/BSF/G/OOA -WLN-F2OBSF/CRF004 Fig. 13 Patent Application Publication Dec. 1, 2016 Sheet 13 of 14 US 2016/0346294 A1

P. acneS Besifloxacin (10 pg/ml) Besifloxacin (30 pg/ml) Dexamethasone (0.4 pg/ml) Vehicle

1OOO - 500 O P. acneS Besifloxacin (10 g/ml) Besifloxacin (30 g/ml) DexamethaSone (0.4 g/ml) Vehicle Data expressed as Meant SD, n=3

FIGS. 14A and 14B Patent Application Publication Dec. 1, 2016 Sheet 14 of 14 US 2016/0346294 A1

P. acres Besifloxacin (10 g/ml) Adapalene (0.04 g/ml) Adapalene (0.4 g/ml) Dexamethasone (0.4 g/ml) Vehicle

2S S c O. ase o ad

Besifloxacin (10pg/ml) Adapalene (0.04 g/ml) Adapalene (0.4 ug/ml) Dexamethasone (0.4 g/ml) Vehicle Data expressed as Meant SD, n=3

FIGS, 15A and 15B US 2016/0346294 A1 Dec. 1, 2016

TREATMENTS FOR RESISTANT ACNE and nicotinamide; minerals such as zinc.; benzoyl peroxide; octopirox, triclosan; azelaic acid; phenoxyethanol; phenoxy RELATED APPLICATIONS propanol; and flavinoids, these agents tend to lack in poten 0001. This application claims benefit priority of Indian tial to mitigate the acne condition and may have negative Patent Application No. 269/DEL/2014, filed Jan. 29, 2014 side effects when devised in conventional topical formula and No. 3247/DEL/2014, filed Nov. 10, 2014, the content of tions. A key challenge that has limited the use of topical both applications is incorporated herein by reference in their formulations is the absence of formulations with the desired entirety. physicochemical properties and high drug loading, which maintains a concentration significantly higher than the MIC at the site of application by facilitating the right degree of FIELD OF THE INVENTION penetration over time but with minimal systemic exposure. 0002 The present disclosure relates generally to novel A formulation that addresses these unmet needs can be a molecules, compositions, and formulations for treatment of significant advance in the treatment of acne. bacterial infections in general and more specifically to 0007 Furthermore, as articulated in Taglietti et al. bacterial infections with antibiotic-tolerant pathogens. 2008, when it comes to the delivery of a drug to a specific site, topical formulations that are efficacious are probably BACKGROUND OF THE INVENTION among the most challenging products to develop. Once the 0003) Acne Vulgaris is a skin condition that affects over product is applied on the skin, a complex interaction occurs 85% of all people. Acne is a term for a medical condition of between the formulation, the active compounds, and the skin plugged pores typically occurring on the face, neck, and itself. The penetration of the active compound(s) into the upper torso. Following are four primary factors that are skin follows Fick's first law of diffusion, which describes the currently known to contribute to the formation of acne transfer rate of Solutes as a function of the concentration of Vulgaris; (1) increased sebum output resulting in oily, greasy the various ingredients, the size of the treatment Surface skin; (2) increased bacterial activity, normally due to an area, and the permeability of the skin. However, the skins overabundance of Propionibacterium acnes bacteria; (3) permeability can be influenced by many factors, such as the plugging (hypercornification) of the follicle or piloseba drying, moisturizing, or occluding effects of the excipients ceous duct; and (4) and inflammation. The plugged pores in the formulation, which, in combination, can modulate the result in blackheads, whiteheads, pimples or deeper lumps release of the product at the treatment site. In acne, the site such as cysts or nodules. Severe cases of acne can result in of action is inside the pilosebaceous unit and, therefore, an permanent scarring or disfiguring. efficacious anti-acne formulation should facilitate the pen 0004 Though acne Vulgaris is multifactoral, a commen etration of the active compound(s) into this extremely lipo sal skin bacteria (P. acnes) plays a major role in the philic environment. An effective topical formulation there formation of acne lesion. It is an infection of pilosebacious fore needs to provide a stable chemical environment in a glands, oil glands in the skin. In most cases Sudden break Suitable dispensing container in order to accommodate mul outs of acne can be correlated with Sudden increased pro tiple compounds that may have different, if not incompat duction of sebum in the affected individual. During adoles ible, physicochemical characteristics Tagleitti et al., 2008. cence androgen hormones play a crucial role. It leads to Once applied, a topical formulation must interact with the overproduction of sebum by the pilosebaceous gland. The skin environment, which can influence the rate of the release situation gets further accentuated by irregular shedding of of the compound(s) in order to achieve adequate skin dead skin from lining of hair follicles. As the dead skin cells absorption, and exert additional physical effects on the skin, clump together in the oily environment, they can form plugs Such as drying, occluding, or moisturizing Tagleitti et al. which block the pores of the hair follicles. A pore clogged 2008. For example, even if an active agent is very potent, by the shedding skin is referred to as a comedo. and is effective via a systemic route, in the case of topical 0005. This creates a very conducive anaerobic condition administration can behave completely differently, i.e. if the for P. acnes bacteria to grow. Hyperproliferation of P. acnes desired concentration is not reached in the pilosebaceous (or leads to destruction of follicular walls and it sends a danger skin) unit, it will not serve as an effective anti-acne therapy. signal to the host immune system. P. acnes may trigger an Similarly, a molecule or drug can behave entirely differently innate immune reaction both in very early (microcomedo if formulated with different compositions, which we dem genic) and in late (inflammatory) acne lesions via the onstrate later in an example. Similarly, two molecule or activation of Toll like receptors 2 (TLR2) on inante immune active agents may behave entirely differently in the same cells. TLR activation ultimately triggers the expression formulation or composition. Therefore, every new molecule various cytokines (like IL-6, IL-8, IL-12, IL-17 etc) and that needs to be formulated for topical skin application poses chemokines that stimulate recruitment of other host immune a novel and independent challenge as it is impossible to cells Jeremy et al., 2003; Thibout et al., 2014. Acne lesions predict which composition and ratio of active and excipients range in severity from blackheads, whiteheads and pimples will provide the desired efficacy benefit. to more serious lesions such as deeper lumps, cysts and 0008 Furthermore, an emerging condition is the evolu nodules. tion of strains of P. acnes, which do not respond to the 0006 Although various over-the-counter products are antibiotic agents such as clindamycin, tetracyclines and commercially available to counteract acne condition, Such as erythromycin currently approved for the treatment of acne. anti-acne agents for topical use, including salicylic acid; While the earlier dogma was that antibiotics failure arises Sulfur, lactic acid; glycolic acid; pyruvic acid; urea; resor due to selection of resistant strains, i.e. a mutation resulting cinol; N-acetylcysteine; retinoic acid; isotretinoin, tretinoin, in alteration of the target of the antibiotic rendering it adapalene; taZoretene; antibacterials such as clindamycin, ineffective, emerging evidence Suggests that antibiotic fail tetracyclines, and erythromycin; vitamins such as folic acid ure is more complex than this simple understanding. The US 2016/0346294 A1 Dec. 1, 2016 assumption was that if resistance develops, i.e. the target of had no effect against S. aureus, S. pneumonia, and E. coli. an antibiotic is altered, it is possible to treat the condition by Additionally, molecules of the same class can have different changing to an alternative antibiotic, the target of which is affinity for the same protein target but in different bacteria. still intact in the bacteria. However, recent knowledge has For example it has been found that both besifloxacin and rendered this assumption as false. For example, Regoes et al. moxifloxacin effectively bind to DNA gyrase than cipro 2004 demonstrates that even in the absence of any resis floxacin in S. aureus. In contrary ciprofloxacin binding tance, a Subset of bacteria can just exhibit tolerance to an towards DNA gyrase is more effective in E. coli than antibiotic, i.e. not undergo lysis. This could arise due to moxifloxacin or besifloxacin. Similarly, besifloxacin is physiological (metabolic) and morphological changes found to be best effective molecule against S. pneumonia observed in bacteria exposed to antibiotics. For example, in followed by moxifloxacin and ciprofloxacin. Cambau et al. a study published in Science, Miller et al., 2004 showed 2009. It is therefore not possible to predict the activity of a that a transient induction of SOS response by amplicillin can molecule against a bacteria or microbe based on its simi protect E. coli against the bactericidal effects of amplicillin. larity in structure another drug that shows activity against Regoes et al., 2004 Suggested that tolerance mechanisms the same microbe or a different microbe, even though they could cross over between some antibiotics, i.e. Antibiotic A might have similar mechanisms of action. Indeed, as shown might be rendered ineffective due to development of resis in FIG. 1, we observed that molecules that were verisimilar tance, but it is possible that Antibiotic B, which has an in structure had completely distinct activity against Pacnes, entirely different target/mechanism of action, and is shown i.e. where one was inactive the other was very potent against to be active in a different or sensitive bacterial strain, may both clindamycin-susceptible and -non-resistant P. acnes also be rendered ineffective in the resistant strain due to (FIGS. 1 A and 1B). In another example, which we discuss shared tolerance mechanisms. Indeed, massive changes in later, we observed a non-lincosamide molecule that was very gene expression leading to alteration in the syntheses of effective in a P. acnes strain resistant to clindamycin but not proteins of metabolic and stress response pathways and cell active in a clindamycin-sensitive P. acnes (FIGS. 1A and division during exposure of E. coli to amplicillin and ofloxa 1B). The identification of an effective drug that works cin have been observed, and a number of these alterations in against both sensitive as well as clindamycin-, minocycline-, the gene expression levels were shared between bacteria erythromycin-, or doxycycline-nonresponder P. acnes there exposed to amplicillin and ofloxacin, Suggesting a bacteria fore emerges through serendipity during systematic screen not responding to amplicillin may not respond to ofloxacin ing in P. acnes. although both agents have different targets. We saw a similar 0010 Furthermore, while an emerging problem is the observation in screening a library of antibiotics against development of resistant strains of microbes that are not different strains of P. acnes that are sensitive or non responding to antimicrobial compounds and compositions responsive to clindamycin (a lincosamide). As shown in well known in the art, there remains a need in the art for a FIG. 1A, the strain of P. acnes non-responsive to clindamy more effective antibiotic that not only works against resis cin also showed increased Survival capability in the presence tant microbes but also reduces the risk of development of ofroxithromycin (a macrollide), which targets a different site resistance by the microbes to this new antibiotic. Thus from clindamycin. Keren et al., 2004. Specialized persister molecules that are efficacious antibiotics and also prevent cells and the mechanism of multidrug tolerance in Escheri or reduce the development of resistance can be a major chia coli. J. Bacteriol. 186:8172-8180) suggested that ran advancement in the treatment of microbial diseases. dom fluctuations in gene expression are responsible for the 0011. The inflammatory character of acne has been cor formation of specialized persister cells. As argued by Regoes related with the host immune response targeting Propioni et al., 2004, phenotypic tolerance to antibiotic could actually bacterium acnes. In vitro studies demonstrate that P. acnes prevent clearance. As a result, while there remains a need in whole cells or cell fractions stimulate cytokine and matrix the art for compositions, formulations and methods for metalloproteinase release from immune cells, keratinocytes, treating acne that is not responding to the currently used and sebocytes Kim et al., 2002; Liu et al., 2005; Nagy et al., agents, especially clindamycin-, minocydine-, erythromy 2006; Lee et al., 2010 Though P. acnes are long been cin-, and/or doxycycline, the probability of tolerance makes present in the follicular area, they come in direct contact it improbable to predict a drug that may work against P with immune cells in dermis only after follicular rupture, CaS. The innate immune system recognizes P. acnes via TLR2 0009 Furthermore, it is increasingly becoming evident Kim et al., 2002, leading to the secretion of inflammatory that Subtle changes in chemical structure of a molecule can cytokines, including IL-6, IL-8, IL-12 etc. Follicular rupture dramatically change activity of the molecules against target happens very late in the disease process. But there are protein. For example erythromycin (a macrollide) and clin multiple evidences which suggest that the adaptive immune damycin bind to similar 50S ribosomal unit but crystal response also has a significant role in the inflammation structure Schulzen et al., 2001 showed different mode of observed even in early stages of acne, resulting from the binding between the agents and amino acid residues present recruitment of activated T helper 1 (Th1) lymphocytes to in 50S ribosomal sub-unit. There are known bacterial strains early acne lesions Mouser et al., 2003. A potential treat of P. acnes that are resistant to clindamycin but can be either ment of acne therefore needs to resolve inflammation, and non-responsive or Susceptible to erythromycin and vice should be able to target these inflammatory pathways. versa. Interestingly, tellithromycin, which is a semisynthetic 0012. An ideal treatment for acne therefore need mol derivative of erythromycin works well in a bacterial strain ecules that can work at two or more targets. Molecules that that is resistant to both erythromycin and clindamycin work against both antibiotic-sensitive as well as clindamy Beitru et al., 2003. Similarly, in another example, the cin-, minocycline-, erythromycin- and doxycycline-tolerant introduction of 8-chloro group dramatically enhanced the or non-responsive strains of P. acnes and can additionally potency of moxifloxacin but a similar change in gatifloxacin inhibit the P. acnes-activated inflammatory mediator/s, or US 2016/0346294 A1 Dec. 1, 2016

molecules that target two or more cellular targets in these 0017. In some embodiments, the DART has at least two microbes while additionally exerting an inhibitory effect on distinct anti-bacterial mechanisms of action, for example the P. acnes-activated inflammatory mediator/s, and is for inhibits DNA gyrase or topoisomerase IV and transpepti mulated in an optimal formulation that enables the desired dase-mediated cross-linking of peptidoglycans; inhibits iso concentration of the active agent on the skin or piloseba prenyl pyrophosphate and transpeptidase-mediated cross ceous region following topical application can emerge as a linking of peptidoglycans; inhibits isoprenyl pyrophosphate powerful strategy for the treatment of acne. and DNA gyrase of topoisomerase IV: inhibits folate syn thesis and DNA gyrase of topoisomerase IV: inhibits folate SUMMARY synthesis and transpeptidase-mediated cross-linking of pep tidoglycans; inhibits DNA gyrase or topoisomerase IV and Dart the 30S ribosomal sub-unit in bacteria; inhibits DNA gyrase 0013. A series of novel DART (Dual Action Rational or topoisomerase IV and the 50S sub-unit in bacteria: Therapeutics) molecules were designed and synthesized for inhibits transpeptidase-mediated cross-linking of peptido treatment of bacterial infections caused by both susceptible glycans and the 30S or the 50S ribosomal sub-unit in and resistant gram positive and gram negative bacteria and bacteria; inhibits folate synthesis and the 30S or the 50S specially for curing acne and different skin and skin structure Sub-unit in bacteria; or inhibits isoprenyl pyrophosphate and infections and additionally prevent the development of resis the 30S or the 50S sub-unit in bacteria, or causes DNA tance. DART molecules can mount its activity through two modification, such as inducing DNA nicks while inhibiting distinct mechanisms of action in a microbe (such as a the induction of negative supercoils in DNA; or altering the bacteria), and create less chance in mutation development at fluidity of the cell membrane while exerting an activity on both target sites in the bacteria. Additionally, it can also act the DNA; or altering the levels of metal ions in a cell while at the host level by modulating the immune response, Such inducing DNA changes. In some embodiments, the first as altering the levels of inflammatory cytokines. mechanism of action is an anti-bacterial action and the 0014. The design of DART comprises of two active second mechanism of action is anti-inflammatory or immu domains. The two active domains can be selected from nomodulatory. different families, for example, B-lactam, B-lactam deriva 0018. In some embodiments, the DART molecule has at tives, 2- and 4-quinolones, quinolones having halogenated least two distinct treating acne mechanisms of action and atom specially fluorine atom attached at C-6 or C-7 position modulates at least two different targets. In some embodi of the central ring system, fluoroquinolone with halogenated ments, the first mechanism is an antibacterial action and the atom specially chlorine atom attached at C-8 position of the second mechanism of action is inhibition of keratinocyte central ring system, tetracycline, oxazolidinone, hydroxy proliferation and differentiation. In some embodiments, the pyridones, derivatives of hydroxypyridones, pleuromutilin, DART molecule has two distinct acne treating mechanisms azoles, nitroimidazoles, monoxycarbolic acid class, fusidic of action and wherein the first mechanism is an antibacterial acid, Sulfonamide, Sulfonamide derivatives, retinoids, dif action and the second mechanism of action is anti-inflam ferent fatty acids (saturated, unsaturated), propylene glycol matory. In some embodiments, the DART molecule is effec and glycerol derivatives of different fatty acids and a stra tive against forms of Propionbacterium acnes that respond tegic combination from each of the families. The design was poorly to clindamycin-, or doxycycline-, or erythromycin-, made strategically by arranging the two active domains in or minocycline-containing anti-acne products. In some the right steric arrangement for both the active domains to embodiments, they are effective against one or more of maintain their function against bacteria or fungus. Overall clindamycin-, minocycline-, erythromycin-, and/or doxycy these molecules possess faster bacterial killing with reduc cline-tolerant or resistant strains of Propionbacterium acnes. tion in inflammation and activity against resistant pathogens. In some embodiments, it prevents the development of resis These molecules also show a lower risk of development of tance in P. acnes. resistance. 0019. In some embodiments, the DART molecule has at 0.015. In some embodiments, the DART molecule has at least two distinct anti-bacterial mechanisms of action and least two chemical domains. Each of said chemical domains modulates at least two different targets against a pathogen. binds to a distinct or different active site in a target cell. In Non limiting examples of Such pathogens are: Bartonella a preferred embodiment, a third chemical domain may be hemselae, Borrelia burgdorferi, Campylobacter jejuni, present. In a further preferred embodiment, said two chemi Campylobacterfetus, Chlamydia trachomatis, Chlamydia cal domains may be bound together through a said third pneumoniae, Chylamydia psittaci, Simkania negevensis, domain. In some embodiments, the DART molecule has at Escherichia coli (e.g., O157:H7 and K88), Ehrlichia cha least two distinct or different anti-bacterial mechanisms of feensis, Clostridium botulinum, Clostridium perfringens, action. In some embodiments, the DART molecule has at Clostridium tetani, Enterococcus faecalis, Haemophilius least two distinct or different anti-acne mechanisms of influenzae, Haemophilius ducreyi, Coccidioides immitis, action. Without limitations, the DARTs can act on the same Bordetella pertussis, Coxiella burnetii, Ureaplasma ure target or on different targets, for example, the bacteria and alyticum, Mycoplasma genitalium, Trichomatis vaginalis, the host. In some embodiments, the DART acts on at least Helicobacter pylori, Helicobacter hepaticus, Legionella two different targets. In some embodiments, at least one of pneumophila, Mycobacterium tuberculosis, Mycobacterium the targets is different than that affected by conventional bovis, Mycobacterium africanum, Mycobacterium leprae, antibiotics. Mycobacterium asiaticum, Mycobacterium avium, Myco 0016. In some embodiments, the DART molecule has a bacterium cellatum. Mycobacterium celonae, Mycobacte B-lactam ring and a quinolone nucleus, or a quinolone rium fortuitum, Mycobacterium genavense, Mycobacterium nucleus and a nitro-heterocycle, or a B-lactam ring and a haemophilum, Mycobacterium intracellulare, Mycobacte nitroheterocycle. rium kansasii, Mycobacterium malmoense, Mycobacterium US 2016/0346294 A1 Dec. 1, 2016 marinum, Mycobacterium scrofiliaceum, Mycobacterium gels, emulgel, oils, serums, powders, sprays, ointments, simiae, Mycobacterium Szulgai, Mycobacterium ulcerans, Solutions, Suspensions, dispersions, pastes, foams, peels, Mycobacterium xenopi, Corynebacterium diptheriae, Rho films, masks, patches, Sticks, rollers, cleansing liquid dococcus equi, Rickettsia aeschlimannii, Rickettsia africae, washes, cleansing Solid bars, pastes, foams, powders, shav Rickettsia Conorii, Arcanobacterium haemolyticum, Bacillus ing creams, impregnated fabric), and the like. In some anthracis, Bacillus cereus, Lysteria monocytogenes, Yers embodiments, the formulation is in a form selected from the inia pestis, Yersinia enterocolitica, Shigella dysenteriae, group consisting of gel, cream, spary, face wash, Soap bar, Neisseria meningitides, Neisseria gonorrhoeae, Streptococ body wash, lotion, Suspended drug loaded gel, Suspended cus bovis, Streptococcus hemolyticus, Streptococcus mutans, drug loaded cream, and any combinations thereof. Streptococcus pyogenes, Streptococcus pneumoniae, 0027. In some embodiments, the API or the formulation Staphylococcus aureus, Staphylococcus epidermidis, can be used to treat acne not responding to antibiotics. Staphylococcus pneumoniae, Staphylococcus saprophyticus, Specifically, it exerts greater efficacy against forms of Pro Vibrio cholerae, Vibrio parahaemolyticus, Salmonella typhi, pionbacterium acnes that respond poorly to clindamycin-, or Salmonella paratyphi, Salmonella enteritidis, Treponema doxycycline-, or erythromycin-, or minocycline-containing pallidum, Candida, CryptcoOccus, Cryptosporidium, Giar anti-acne products. dia lamblia, Microsporidia, Plasmodium vivax, Pneumocys 0028. In some embodiments, the API or the formulation tis carinii, Toxoplasma gondii, Trichophyton mentagro can be used to treat acne by exerting an anti-inflammatory phytes, Enterocytozoon bieneusi, Cyclospora Cayetanensis, effect. Encephalitozoon hellem, Encephalitozoon cuniculi, among 0029. In some embodiments, the API or the formulation other bacteria, archaea, protozoa, and fungi. can be used to treat acne by killing strains of Propionbac 0020. In some embodiments, the first and second terium acne that are sensitive to one or more of clindamy domains independently have antibacterial activity against a cin-, minocycline-, erythromycin-, and/or doxycycline and Staphylococcus species. Examples of Staphylococcus spe additionally exerting a greater efficacy by inhibiting P cies include, but are not limited to, S. aureus group (e.g., S. acnes-mediated inflammatory pathways (i.e. dual mecha aureus, S. Simiae), S. auricularis group (e.g., S. auricularis), nisms of action). S. carnosus group (e.g., S. carnosus, S. condimenti, S. massiliensis, S. piscifermentans, S. simulans), S. epidermidis Combinations group (e.g., S. capitis, S. Caprae, S. epidermidis, S. Saccha 0030 The disclosure also provides formulations compris rolyticus), S. haemolyticus group (e.g., S. deVriesei, S. hae ing a combination of two or more antibiotic agents. For molyticus, S. hominis). S. hyicus-intermedius group (e.g., S. example, an 8-chloro fluoroquinolone in combination with chromogenes, S. felis, S. delphini, S. hyicus, S. intermedius, another anti-acne agent. In some embodiments, the formu S. lutrae, S. microti, S. muscae, S. pseudintermedius, S. lation comprises two or more different 8-chloro fluoroqui rostri, S. Schleiferi), S. lugdunensis group (e.g., S. lugdunen nolones. In some embodiments, the formulation comprises sis), S. saprophyticus group (e.g., S. arlettae, S. cohnii, S. besifloxacin and a retinoid, such as adapalene. equorum, S. gallinarum, S. kloosii, S. leei, S. nepalensis, S. 0031. In some embodiments, the formulation comprises Saprophyticus, S. Succinus, S. xylosus). S. Sciuri group (e.g., an anti-acne agent and an anti-inflammatory agent. For S. fleurettii, S. lentus, S. Sciuri, S. Stepanovicii, S. vitulinus), example, the formulation can comprise an 8-chloro fluoro S. simulans group (e.g., S. Simulans), and S. warneri group quinolone and an anti-inflammatory agent. (e.g., S. pasteuri, S. warneri). 0032. In some embodiments, the two or more antibiotic 0021. Without limitations, the DARTS can be in the form agents can be a DART molecule or two or more different of particles, powders, Suspensions, dispersions, emulsions, DART molecules. In some embodiments, one of the two or liposomes, micelles, globules, Solutions, vesicles, aggre more antibiotic agent is a DART and the other is not a DART gates, creams, gels, and the like. molecule. 0022. The disclosure also provides formulations compris 0033. As described herein, the disclosure provides for ing DARTs as the active pharmaceutical ingredient (API). mulations comprising DART and/or non-DART antibiotic Antibiotics agent as the API. As such, exemplary APIs for the formu lations include DARTs, anti-bacterial, anti-fungal and anti 0023 The disclosure also provides formulations compris acne agents. In some embodiments, the API can be in the ing antibiotic agents, which are not DARTs, as the API. In form of a drug carrier, i.e., the API can be nanotized, coated, Some embodiments, the antibiotic agent is a 8-chloro fluo made into vesicles, liposome, emulsions, and the like for the roquinolone. Exemplary 8-chloro fluoroquinolones include, formulation. Without limitations the formulation or the but are not limited to, besifloxacin, clinafloxacin and sita composition can be formulated for administration by any floxacin. In some embodiments, the formulation comprises appropriate route known in the art including, but not limited besifloxacin as the API. to, topical (including buccal and Sublingual) and oral or 0024. In various embodiments, the API can be micron parenteral routes, including intravenous, intramuscular, Sub ized, Suspended, or Solubilized. In some embodiments, the cutaneous, transdermal, airway (aerosol), pulmonary, and API can be in the form of particles, powders, Suspensions, nasal administration. dispersions, emulsions, liposomes, micelles, globules, Solu 0034. The DARTs and formulations disclosed herein can tions, vesicles, aggregates, and the like. In some embodi be used for treating bacterial infections due to Gram-positive ments, the API can in the form of a drug carrier. or Gram-negative bacteria. Additionally, the DARTs are 0025. In some embodiments, the API can be coated. In effective against resistant forms of pathogens. Furthermore, some other embodiments, the API can be uncoated. the DARTs are effective in preventing the development of 0026. Without limitations, the formulation can be in a resistant forms of pathogens. Thus, the DARTs and formu form selected from the group consisting of lotions, creams, lations disclosed herein can be used for treating antibiotic US 2016/0346294 A1 Dec. 1, 2016

tolerant or resistant bacterial infections. Exemplary bacterial 115 and 116 in both clindamycin-susceptible (MTCC 1951) infections include, but are not limited to, infection by (FIG. 1C) and clindamycin-nonresponsive (CCARM 9010) Bartonella hemselae, Borrelia burgdorferi, Campylobacter (FIG. 1D) Pacnes strains. The molecules have different and jejuni, Campylobacterfetus, Chlamydia trachomatis, Chla unpredictable activity against MTCC 1951 and mydia pneumoniae, Chylamydia psittaci, Simkania negeven CCARM9010 strains of P. acnes. Compound 91 showed sis, Escherichia coli (e.g., O157:H7 and K88), Ehrlichia highly efficacious bacterial killing profile for both bacterial chafeensis, Clostridium botulinum, Clostridium perfiringens, strains. Compound 90 shows activity in P. acnes that do not Clostridium tetani, Enterococcus faecalis. Haemophilius respond to clindamycin but is ineffective in the P. acnes influenzae, Haemophilius ducreyi, Coccidioides immitis, strain that responds to clindamycin. Bordetella pertussis, Coxiella burnetii, Ureaplasma ure 0038 FIGS. 2A and 2B show concentration-dependent alyticum, Mycoplasma genitalium, Trichomatis vaginalis, inhibition of DNA gyrase activity (super-coiling) by com Helicobacter pylori, Helicobacter hepaticus, Legionella pound 91. FIG. 2A—Agarose gel electrophoresis showing pneumophila, Mycobacterium tuberculosis, Mycobacterium effect of compound 91 on Super-coiling of E. coli plasmid bovis, Mycobacterium africanum, Mycobacterium leprae, DNA by DNA Gyrase. FIG. 2B Percentage of DNA super Mycobacterium asiaticum, Mycobacterium avium, Myco coiling by DNA gyrase in presence increasing concentra bacterium cellatum, Mycobacterium celonae, Mycobacte tions of compound 91. rium fortuitum, Mycobacterium genavense, Mycobacterium 0039 FIG. 3A is a bar graph showing percentage of DNA haemophilum, Mycobacterium intracellulare, Mycobacte Super-coiling by DNA gyrase in presence of compounds 90. rium kansasii, Mycobacterium malmoense, Mycobacterium 91, 94, 113, 115 and 116 with relaxed E. coli plasmid DNA. marinum, Mycobacterium scrofiliaceum, Mycobacterium Compound 91 and compound 116 seemed to have the best simiae, Mycobacterium Szulgai, Mycobacterium ulcerans, gyrase inhibiting activity among all the comparators. Mycobacterium xenopi, Corynebacterium diptheriae, Rho Though this observation is mostly correlated with MIC data dococcus equi, Rickettsia aeschlimannii, Rickettsia africae, against P. acnes, yet there is some species-specific advan Rickettsia Conorii, Arcanobacterium haemolyticum, Bacillus tages is observed with compound 91. anthracis, Bacillus cereus. Lysteria monocytogenes, Yers 0040 FIG. 3B is a bar graph showing percentage of DNA inia pestis, Yersinia enterocolitica, Shigella dysenteriae, Super-coiling by DNA gyrase in presence of compound 91 Neisseria meningitides, Neisseria gonorrhoeae, Streptococ and nadifloxacin with relaxed E. coli plasmid DNA. Com cus bovis, Streptococcus hemolyticus, Streptococcus mutans, pound 91 shows greater efficacy than Nadifloxacin. Streptococcus pyogenes, Streptococcus pneumoniae, 0041 FIGS. 4A and 4B are bar graphs showing the effect Staphylococcus aureus, Staphylococcus epidermidis, of compound 91 on P. acnes-induced cytokine IL-6 (FIG. Staphylococcus pneumoniae, Staphylococcus saprophyticus, 4A), IL-8 (FIG. 4B) release in THP-1 cells. Compound 91 Vibrio cholerae, Vibrio parahaemolyticus, Salmonella typhi, exerts an anti-inflammatory activity against P. acnes-in Salmonella paratyphi, Salmonella enteritidis, Treponema duced cytokine production. Statistical analysis was per pallidum, Candida, CryptcoOccus, Cryptosporidium, Giar formed using Student's t-test (p=0.05; **p=0.005). dia lamblia, Microsporidia, Plasmodium vivax, Pneumocys 0042 FIGS.5A and 5B are bar graphs showing the effect tis carinii, Toxoplasma gondii, Trichophyton mentagro of compound 91 on P. acnes-induced cytokine IL-1C. (FIG. phytes, Enterocytozoon bieneusi, Cyclospora Cayetanensis, 5A), IL-1 B (FIG. 5B) release in THP-1 cells. Encephalitozoon hellem, Encephalitozoon cuniculi, among 0043 FIG. 6. is a bar graph showing the minimum other bacteria, archaea, protozoa, and fungi. In some inhibition value for Some exemplary topical gel formulations embodiments, infection is with a Staphylococcus species. against P. acnes. 0035. In some embodiments, the DARTS and formula 0044 FIG. 7 is a line graph showing the dose response tions disclosed herein can be used for treating acne. In some curve of Zone of Inhibition (ZOI) of some exemplary gel embodiments, the DARTS and formulations disclosed formulations against P. acnes. herein are effective against forms of Propionbacterium 0045 FIG. 8 is a line graph showing the time kill kinetics acnes that respond poorly to clindamycin-, or doxycycline-, of Some exemplary gel formulations against P acnes. or erythromycin-, or minocycline-containing anti-acne prod 0046 FIG. 9 Graph shows the efficacy of a topical ucts. In some embodiments, the DARTs and formulations formulation of besifloxacin in P. acnes in an in vivo skin disclosed herein are effective against one or more of clin infection model. Besifloxacin gel formulation has the ability damycin-, minocycline-, erythromycin-, and/or doxycy to clear almost 1.5 log CFU (~95%) of inoculum of clin cline-tolerant or resistant strains of Propionbacterium acnes. damycin resistant P. acnes within first 24 hours. For treating infections, the DART or the formulation dis 0047 FIG. 10 is a line graph showing time kill kinetics closed herein can be administered once or daily to the of Some exemplary besifloxacin formulations against P Subject as a single dose or a plurality of doses. acnes MTCC 1951, showing that the composition of the formulation can change the efficacy of an antibiotic. BRIEF DESCRIPTION OF THE DRAWINGS 0048 FIG. 11 is a line graph showing time kill kinetics of 0036 FIGS. 1A and 1B shows dose response curves of Some exemplary besifloxacin formulations and besifloxacin different antibiotics against both MTCC1951 and CCARM APIs against S. aureus. 9010 strains of P. acnes. While MTCC1951 is killed by 0049 FIG. 12 is a line graph showing time kill kinetics clindamycin, the drug has no effect on CCARM9010. Dif of besifloxacin against P. acnes (CCARM 9010). ferent antibiotics behave differently and unpredictably on 0050 FIG. 13 Graph shows that topical formulations the different strains belong to a different family from Clin with different excipient compositions for the same antibiotic damycin. can result in different profiles in the skin and in Systemic 0037 FIGS. 1C and 1D are line graphs showing concen circulation of SD rats. Fully suspended 1% Besifloxacingel tration efficacy curve of DART compounds 90,91, 94, 113, (VLN-F19/BSF/GL/068), fully soluble 1% Besifloxacingel US 2016/0346294 A1 Dec. 1, 2016

(VLN-F21/BSF/GL/001A) and fully suspended 1% Besi nodeficiency virus (HIV) or AIDS or other immune disor floxacin gel (VLN-F20/BSF/CR/004) were used for com ders, or hepatitis, and who is undergoing chemotherapy or parison purpose. To be efficacious, a formulation should not treatment with other drugs that Suppress the immune system. only be physicochemically compatible with the antibiotic 0056 Common skin bacterial infections include celluli but also enable a Sustained concentration of the antibiotic at tis, erysipelas, impetigo, folliculitis, and furuncles and car a concentration greater than MIC level. buncles. Cellulitis is a painful, erythematous infection of the 0051 FIGS. 14A and 14B are bar graphs showing the dermis and Subcutaneous tissue characterized by warmth, concentration-dependent inhibitory effect of Besifloxacin on edema, and advancing borders and is usually caused by P. acnes-induced cytokines IL-6 (FIG. 14A) but not IL-8 Streptococcus or Staphylococcus species. Erysipelas is a (FIG. 14B) release in THP-1 cells. Statistical analysis was superficial form of cellulitis with sharply demarcated bor performed using Student's t-test (p=0.005; **p=0.0005). ders and is caused almost exclusively by Streptococcus. 0052 FIGS. 15A and 15B are bar graph showing the Impetigo is also caused by Streptococcus or Staphylococcus combination of Besifloxacin and Adapalene increases the and can lead to lifting of the Stratum corneum resulting in efficacy of inhibiting P acnes-induced cytokines IL-6 (FIG. the commonly seen bullous effect. Folliculitis is an inflam 15A) but has no effect on IL-8 (FIG. 15B) release in THP-1 mation of the hair follicles, and it is most commonly caused cells. Statistical analysis was performed using Students by Staphylococcus. If the infection of the follicle is deeper t-test (p=0.005; **p=0.001). and involves more follicles, it moves into the furuncle and carbuncle stages and usually requires incision and drainage. DETAILED DESCRIPTION OF THE Two different kinds of skin diseases occurred due to the INVENTION toxins produced by the bacteria include, Staphylococcal 0053 Acne Vulgaris is a skin condition that affects over Scaled Skin Syndrome (SSSS) which usually affects chil 85% of all people. Acne is a term for a medical condition of dren less than 5 years old, adults with kidney failure and the plugged pores typically occurring on the face, neck, and other one is Toxic Shock Syndrome. There is more chance upper torso. Following are four primary factors that are of colonization of S. aureus is found with patients suffering currently known to contribute to the formation of acne from eczema and atopic dermatitis, a type of inflammatory, Vulgaris; (1) increased sebum output resulting in oily, greasy relapsing, non-contagious, itchy skin disorder. Thus Staphy skin; (2) increased bacterial activity, normally due to an lococcus aureus infection plays an important role in atopic overabundance of Propionibacterium acnes bacteria; (3) dermatitis (AD) or atopic eczema (AE). Unfortunately, some plugging (hypercornification) of the follicle or piloseba strains of Staphylococcus have become resistant to methi ceous duct; and (4) and inflammation. The plugged pores cillin and other similar antibiotics which are known as result in blackheads, whiteheads, pimples or deeper lumps MRSA. Recently it has been found that more than one-half Such as cysts or nodules. Severe cases of acne can result in of all cases of skin bacterial infections caused by MRSA permanent scarring or disfiguring. species. The infections associated with MRSA species can 0054 As articulated in http://thescienceofacne.com/anti not be cured with traditional penicillin-related drugs. biotic-susceptibility-of-ropionibacterium-acnes/results from Instead, MRSA must be treated with alternate antibiotics. studies over last four decades clearly demonstrate that over 0057. However as articulated in http://thescienceofacne. time P. acnes bacteria has become increasingly resistant to com/antibiotic-susceptibility-of-propionibacterium-acnes/ certain classes of antibiotics. Particularly important are “Not all antibiotics are created equal”. The same is true for observations that a significant percentage of the bacteria bacteria. Some types of antibiotics are highly effective isolated from acne patients are now resistant to the most against certain types of bacteria, while essentially worthless common antibiotics used in acne treatment: Clindamycin, against others. Moreover, antibiotic Susceptibility and resis Erythromycin, Tetracycline, Doxycycline and Minocycline. tance is a dynamic process that is constantly changing. Over Additionally, such resistant or antibiotic-tolerant strains can time, certain types of bacteria may gain or lose resistance to cause relapse of acne, and also cause other disease states. particular antibiotics. The primary problem with standard, There is a need for antibiotics that can kill P. acnes while laboratory-based antibiotic resistance testing is that the minimizing the probability of development of mutant or susceptibility of a bacteria to an antibiotic is often different tolerant strains that can Survive the antibiotic exposure, and when it is growing on a petri dish versus when it is growing those that can work against Strains that are not responding to on your body. This is because bacteria are not static organ the current drugs. Additionally, if these novel molecules can isms, they adapt to their environment. A P. acnes bacteria target additional steps in acne formation, Such as inflamma growing in a follicle and feeding on sebum has a different tion, then the clinical outcome in acne can be greater than metabolic profile than one growing on a petri dish and existing therapies. feeding on a bacterial nutrition Supplement. Furthermore, 0055 Skin is a major organ of the body, and performs bacteria modulate expression of Surface proteins, cell wall many essential functions besides acting as a barrier, Such as structures and genes depending on their environment, and maintaining homeostasis. Besides acne, there are many other these changes can have a profound effect on their suscepti skin diseases that are caused by bacterial colonization of the bility to a particular antibiotic. As a result, in the case of skin. The most common bacteria for mild to moderate skin topical antibiotics for treatment of skin bacterial conditions, infection are Staphylococcus and Streptococcus e.g., Acute a priori knowledge does not exist, i.e. there is no mechanism Bacterial Skin and Skin Structure Infection (ABSSSI). Such to predict that an antibiotic will be effective against Pacnes bacteria can infect the skin of both pediatric and adult or any other skin bacterial condition until it has been tested patients; mainly develop during hospitalization or living in on the bacterial strain. For example, as shown in http:// a nursing home, while gardening, or while Swimming. Some thescienceofacne.com/antibiotic-susceptibility-of-propioni people are at particular risk of developing skin infections, bacterium-acnes?, P. acnes was reported to be highly resis for example, people Suffering with diabetes, human immu tant to a nitroimidazole (metronidazole) or a tetracycline US 2016/0346294 A1 Dec. 1, 2016

(lymecycline) but partially responsive to doxycycline (an cefditoren, ceftazidime, ceftizoxime, ceftaroline fosamil, other tetracycline), and showing no resistance to ciprofloxa ceftaroline, cefiobiprole, aztreonam, ertapenem, doripenem cin but resistant to another fluoroquinolone, Levofloxacin. It and cilastatin: penicillin combinations such as amoxicillin/ is therefore impossible to predict which antibiotic will work clavulanate, amplicillin/Sulbactam, piperacillin/taZobactam based on a priori activity in other bacterial strains. There is and ticarcillin/clavulanate; quinolones Such as nalidixic a need for a systematic development of novel antibiotics that acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, show activity against acne. ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lom 0058. In this regard DART molecules can act as an ideal efloxacin, fleroxacin, grepafloxacin, sparfloxacin, trova drug candidate to acne caused by P. acnes, and additionally floxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxa for the treatment of other skin and skin structure infections cin, ganefloxacin, gemifloxacin, paZufloxacin, besifloxacin, caused by other bacteria such as MRSA. DARTs were ulifloxacin, prulifloxacin, cinoxacin, piromidic acid, pipemi designed to contain two distinct chemical domains, selected dic acid, roSoxacin, rufloxacin, balofloxacin, toSufloxacin, from different families as mentioned earlier, for example a delafloxacin, nemonoxacin; antibacterial Sulfonamides and B-lactam ring and a quinolone nucleus, or a quinolone antibacterial Sulphanilamides, including para-aminobenzoic nuclues and nitro-heterocycle, or a B-lactam ring and a acid, Sulfadiazine, silver Sulfadiazine, Sulfisoxazole, Sul nitroheterocycle, which confers two distinct mechanisms of famethoxazole, Sulfadimethoxine, Sulfadoxine, Sulfame action. This creates less chance in mutation development at thizole and Sulfathalidine, mafenide, Sulfacetamide, Sulfiso both target sites of bacteria resulting in less resistance midine, sulfanilimide, Sulfasalazine and development against these antibiotics. Some of the mol Sulfonamidochrysoidine; aminoglycosides Such as strepto ecules can exert additional anti-inflammatory mechanisms mycin, neomycin, kanamycin, paromycin, gentamicin, to reduce host inflammatory response, further enhancing the tobramycin, amikacin, netilmicin, spectinomycin, Sisomicin, anti-acne efficacy. dibekalin, isepamicin, dihydrostreptomycin, framycetin, 0059. The embodiments of the various aspects disclosed ribostamycin, arbekacin, bekanamycin, dibekacin, hygro herein are based on the molecules designed by the inventors, mycin b, verdamicin and, astromicin; tetracyclines tetracy which can act on at least two different or distinct targets. cline, chlortetracycline, demeclocycline, minocycline, Generally, the molecule includes at least two different or oxytetracycline, methacycline, doxycycline, clomocycline, distinct chemical domains. Each of said chemical domains lymecycline, meclocycline, penimepicycline, and rollitetra binds to a distinct or different active site in a target cell. The cycline; rifamycins such as rifampicin (also called rifam said chemical domains can be bound together through a third pin), rifapentine, rifabutin, beZoxazin, orifamycin and rifaxi domain. As used herein, the term “chemical domain” means min; lincosamides Such as lincomycin and clindamycin; a part of a molecule that is involved in a desired property. lipopeptide like daptomycin; glycopeptides such as Vanco For example, a chemical domain can be part of the molecule mycin, telavancin and teicoplanin; Streptogramins such as involved in binding of the molecule with a target or involved quinupristin and daflopristin; ansamycins such as geldan in modulating an activity of the target. amycin, herbimycin, rifaximin, oxazolidinones Such as lin eZolid, eperezolid, posiZolid, radeZolid, ranbeZolid, Sut 0060. In some embodiments, the first and second chemi eZolid and tedizolid; pleuromutilins such as retapamulin, cal domains independently have anti-bacterial or bacteri tiamulin, valnemulin; steroid antibacterials such as fusidic cidal activity. In some embodiments, the first and second acid; amphenicols such as chloramphenicol, azidamfenicol, domain can independently comprise an antibacterial agent. thiamphenicol, florfenicol; nitrofurans Such as furazolidone, As used herein, the term “antibacterial agent” or “antibiotic nitrofurantoin: Streptogramins such as pristinamycin, quinu agent' is defined as a compound having either a bactericidal pristin?dalfopristin Virginiamycin; other antibacterials such or bacteriostatic effect upon bacteria contacted by the com as arsphenamine, fosfomycin, mupirocin, platensimycin, pound. As used herein, the term “bactericidal' is defined to mean having a destructive killing action upon bacteria. As tigecycline, trimethoprim, polymyxin, bacitracin, colistin, used herein, the term “bacteriostatic' is defined to mean colymycin, metronidazole, cotrimoxazole and phosphono having an inhibiting action upon the growth of bacteria. mycin; and anti-mycobacterial drugs such as clofazimine, Examples of antibacterial agents include, but are not limited dapsone, capreomycin, cycloserine, ethambutol, ethiona to, macrollides or ketolides such as erythromycin, azithro mide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifa mycin, clarithromycin, dirithromycin, troleandomycin, Spi pentine, Streptomycin. in Some embodiments, the antibacte ramycin, tellithromycin, carbomycina, josamycin, kitasamy rial agent can be selected from the group consisting of cin, midecamycin acetate, oleandomycin, Solithromycin, azithromycin, roXithromycin, ceftaroline, cefotaxime, spiramycin, troleandomycin, cethromycin, Solithromycin, cefoxitin, ceftriaxone, cephalothin, minocycline, nadifloxa spiramycin, ansamycin, oleandomycin, carbomycin and cin, moxifloxacin, besifloxacin, ulifloxacin, prulifloxacin, tylosin; beta-lactams including penicillin, cephalosporin and retapamulin, metronidazole, ornidazole and any combina carbapenems such as carbapenem, imipenem and mero tions thereof. In some embodiments, antibacterial agent can penem; monolactams such as penicillin g, penicillin V, be hyaluronic acid or a derivative thereof. methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, 0061. In some embodiments of the DART molecule, the ampicillin, azlocillin, amoxicillin, carbenicillin, ticarcillin, first and second domains independently have anti-acne meZlocillin, piperacillin, azlocillin, temocillin, flucloxacil activity. In some embodiments, the first and second chemical lin, cepalothin, cephapirin, cephradine, cephaloridine, cefa domains are independently an anti-acne agent. As used Zolin, cefamandole, cefuroxime, cephalexin, cefprozil, cefa herein, the term “anti-acne agent” refers to any chemical that clor, loracarbef, cefoxitin, cefimetazole, cefotaxime, is effective in the treatment of acne and/or the symptoms ceftizoxime, cefiriaxone, cefoperaZone, ceftazidime, associated therewith. Anti-acne agents are well known in the cefixime, cefpodoxime, ceftibuten, cefdinir, ce?pirome, art such as U.S. Pat. App. Pub. No. 2006/0008538 and U.S. cefepime, cefadroxil, cefalothin, cefalexin, cefuroxime, Pat. No. 5,607,980, content of both of which is incorporated US 2016/0346294 A1 Dec. 1, 2016 herein by reference. Examples of useful anti-acne agents toxic peroxidation or direct lysis of bacterial cells. Their include, but are not limited to keratolytics, such as Salicylic broad spectrum of non-specific activity makes them as a acid, derivatives of Salicylic acid, and resorcinol; retinoids, promising antimicrobial candidate for treatment and preven Such as retinoic acid, tretinoin, adapalene, tazarotene; Sulfur tion of antimicrobial infections caused by number of gram containing D- and L-amino acids and their derivatives and positive and gram-negative bacteria that generates various salts; lipoic acid; antibiotics and antimicrobials, such as skin and skin structure infections. In some embodiments, the benzoyl peroxide, triclosan, chlorhexidine gluconate, FA and derivatives alone or in combination with any anti octopiroX, tetracycline, 2,4,4-trichloro-2'-hydroxy diphenyl biotics or covalent conjugates with any antibiotics (e.g. ether, 3,4,4-trichlorobanilide, nicotinamide, tea tree oil, DARTs) are effective against antibiotic prone Propionbac rofecoxib, aZelaic acid and its derivatives, phenoxyethanol, terium acnesas well as P. acnes that respond poorly to phenoxypropanol, phenoxisopropanol, ethyl acetate, clin clindamycin-, or doxycycline-, or erythromycin-, or mino damycin, erythromycin, and meclocycline; sebostats, such cycline-containing anti-acne products. In some embodi as flavonoids; and bile salts, such as Scymnol sulfate and its ments, they are effective against one or more of clindamy derivatives, deoxycholate, and cholate; and combinations cin-, minocycline-, erythromycin-, and/or doxycycline thereof. These agents are well known and commonly used in tolerant or resistant strains of Propionbacterium acnes. In the field of personal care. Some embodiments, it prevents the development of resistant 0062. In some embodiments, the anti-acne agent can be forms of pathogens an antimicrobial peptide having activity against P. acnes. 0064. In some embodiments, the first and second anti Antimicrobial peptides are ubiquitous in nature and play an acne agents in the DART or formulations disclosed herein important role in the innate immune system of many species are selected independently from the group consisting of Zasloff et al., 2002; and Epand et al., 1999. The antimi acetretin, adapalene, alitretinoin, azelaic acid, Azithromy crobial peptide can be a naturally occurring peptide or an cin, benzoyl peroxide, Besifloxacin, bexarotene, Cefo analog thereof, or it can be a synthetic peptide. As used taxime, Cefoxitin, Ceftaroline, Ceftobiprole, Ceftriaxone, herein an “analog refers to a naturally-occurring antimi Cephalothin, clindamycin, erythromycin, etretinate, crobial peptide that has been chemically modified to Garenoxacin, glycolic acid, isotretinoin, lactic acid, Mino improve its effectiveness and/or reduce its toxic side effects. cycline, Moxifloxacin, N-acetylcystein, Nadifloxacin, The antimicrobial peptide can be a peptide known to be octopirox, phenoxyethanol, phenoxypropanol, Prulifloxacin, effective against Gram positive bacteria. Non-limiting pyruvic acid, Radezolid (RX-1741), resorcinol, Retapamu examples include lantibiotics, such as nisin, Subtilin, epi lin, retinoic acid, Roxithromycin, salicylic acid, Sitafloxa dermin and gallidermin; defensins; attacins, such as sarco cin, sodium Sulfacetamide, spirinolactone, Sulfacetamide, toxin; cecropins, such as cecropin A, bactericidin, and Sulfur, tazarotene, tretinoin, triclosan, ulifloxacin, metron lepidopteran; magainins; melittins; histatins; brevinins; and idazole, ornidazole, urea, and any combinations thereof. combinations thereof. Additionally, antimicrobial peptides having activity against P. acnes have been reported, for 0065. In some embodiments, the first and second chemi example, in U.S. Pat. App. Pub. No. 2005/0282755; No. cal domains are independently an antifungal agent. As used 2005/02455452; and No. 2005/0209157, and U.S. Pat. No. herein, the term “antifungal agent' is intended to mean a 6.255.279, content of all of which is incorporated herein by Substance capable of inhibiting or preventing the growth, reference. Suitable examples of antimicrobial peptides hav viability and/or reproduction of a fungal cell. Preferable ing reported activity against P. acnes include, but are not antifungal agents are those capable of preventing or treating limited to, novispirins (Hogenhaug, Supra), and those a fungal infection in an animal or plant. A preferable described in U.S. Pat. App. Pub. No. 2007/0265431, content antifungal agent is a broad spectrum antifungal agent. How of which is incorporated herein by reference. In some ever, an antifungal agent can also be specific to one or more embodiments, the antimicrobial peptide can be cathilicidine particular species of fungus. and its derivatives. 0.066 Examples of antifungal agents include, but are not 0063. In some embodiments, the anti-bacterial agent can limited to, azoles (e.g., Fluconazole, Isavuconazole, Itracon befree fatty acid (FFA) or fatty acid derivatives or fatty acid azole, Ketoconazole, Miconazole, Clortrimazole, Voricon esters of propylene glycol (PG) or glycerol (G) derivatives azole, Posaconazole, Ravucoriazole, Ciclopirox, etc.), and any combinations thereof. For example, lauric acid, polyenes (e.g., natamycin, lucensomycin, nystatin, ampho Stearic acid, myristic acid, oleic acid, linoleic acid, myris tericin B, etc.), echinocandins (e.g., Cancidas), pradimicins toleic acid, palmitooleic acid, linoleic acid, linolenic acid, (e.g., beanomicins, nikkomycins, Sordarins, allylamines, sapienic acid, different polyunsaturated FAs (PUFA), pro etc.), Triclosan, Piroctone and its olamine salt, fenpropi pylene glycol monolaurate, glycerol mono and/or dilaurate, morph, terbinafine, and derivatives and analogs thereof. propylene glycol monoloeate, glycerol mono and/or di Additional antifungal agents include those described, for oleate and other derivatives known in art. Fatty acids are example, in Int. Pat. Pub. No. WO2001/066551, No. well known antimicrobial agent Kabara et al., 1972 and WO2002/090354, No. WO2000/043390, No. WO2010/ their activity varies with chain length, degree of unsaturation 032652, No. WO2003/008391, No. WO2004/018485, No. and number of fatty acid ester present in propylene glycol or WO2005/006860, No. WO2003/086271, No. WO2002/ glycerol backbones. The prime target of FAS and derivatives 067880; in U.S. Pat. App. Pub. No. 2008/0194661, No. is bacterial cell membrane, which is nonspecific in nature. 2008/0287.440, No. 2005/0130940, No. 2010/0063285, No. Disruption of bacterial membrane causes disruption in cel 2008/0032994, No. 2006/0047135, No. 2008/0182885; and lular electron transport activity or oxidative phosphorylation in U.S. Pat. No. 6,812,238; U.S. Pat. No. 4,588,525; U.S. or inhibition to a particular enzyme activity or diminishing Pat. No. 6,235,728; U.S. Pat. No. 6,265,584; U.S. Pat. No. cellular energy production or impairment of nutrient uptake 4.942,162; and U.S. Pat. No. 6,362,172, content of all of or auto-oxidation of degradation products or generation of which is incorporated herein by reference. US 2016/0346294 A1 Dec. 1, 2016

0067. In some embodiments, the antifungal agent is a the second chemical domain comprises a functional group pyrithione salt. Examples of useful pyrithione salts include, selected from the group consisting of an amino group, a but are not limited to, Zinc pyrithione, Sodium pyrithione, N-Substituted amino group, a carboxyl group, a carbonyl potassium pyrithione, lithium pyrithione, ammonium pyri group, an acid anhydride group, an aldehyde group, a thione, copper pyrithione, calcium pyrithione, magnesium hydroxyl group, an epoxy group, a thiol, a disulfide group, pyrithione, strontium pyrithione, silver pyrithione, gold an alkenyl group, a hydrazine group, a hydrazide group, a pyrithione, manganese pyrithione, and combinations semicarbazide group, a thiosemicarbazide group, an amide thereof. Non-metal pyrithione salts such as the ethanolamine group, an aryl group, an ester group, an ether group, a salt, chitosan salt, and the disulfide salt of pyrithione (which glycidyl group, a halo group, a hydride group, an isocyanate is commercially available as OMADINE MDS or OMDS), group, a urea group, a urethane group, and any combinations can also be used. The pyrithione salt can be used in any thereof for binding with the first chemical domain. In some particulate form, including, but not limited to, crystalline embodiments, the first and second chemical domains are form such as platelets, rods, needles, blocks, round and bound to each other via same functional group. In some amorphous, regularly or irregularly shaped particles. embodiments, the first and second chemical domains are 0068. In some embodiments, the pyrithione salt is zinc bound to each other via different functional groups. pyrithione. Zinc pyrithione is best known for its use in 0072. In some embodiments, the third domain can treating dandruff and seborrhoeic dermatitis. It also has enhance or increase an activity of at least one of the antibacterial properties and is effective against many patho chemical domains. For example, the activity of at least one gens from the Streptococcus and Staphylococcus genera. Its of the chemical domains is increased or enhanced relative to other medical applications include treatments of psoriasis, when the third domain is absent. In some embodiments, the eczema, ringworm, fungus, athlete's foot, dry skin, atopic third domain can increase or enhance antibacterial activity dermatitis, tinea, and vitiligo. of at least one of the chemical domains in the DART. In 0069. In some embodiments, the antifungal agent is an Some embodiments, the third domain can increase or antifungal peptide. Antifungal peptides are well known in enhance anti-acne activity of at least one of the chemical the art (see for example, De Lucca et al., 2000. The domains in the DART. In some embodiments, the third antifungal peptide can be a naturally occurring peptide or an domain can increase or enhance anti-inflammatory activity analog thereof, or it can be a synthetic peptide. As used of at least one of the chemical domains in the DART. herein, the term “analog refers to a naturally occurring 0073. In some embodiments, the third domain itself has antifungal peptide that has been chemically modified to biological activity. For example, the third domain can be an improve its effectiveness and/or reduce its toxic/side effects. active agent. In some embodiments, the third domain can Exemplary antifungal peptides can include, but are not have anti-bacterial or anti-fungal activity. In some embodi limited to, Syringomycins, syringostatins, Syringotoxins, ments, the third domain can have anti-inflammatory activity. nikkomycins, echinocandins, pneumocadins, aculeacins, 0074 The third domain of the DARTs can be a direct mulundocadins, cecropins, alpha-defensins, beta-defensins, bond or an atom such as oxygen or Sulfur, a unit Such as novispirins, and combinations thereof. Other antifungal pep NR', C(O), C(O)O, C(O)NH, SS, SO, SO, SONH or a tides include those described, for example, in U.S. Pat. No. chain of atoms, such as Substituted or unsubstituted alkyl, 6.255.279 and U.S. Pat. App. Pub. No. 2005/0239709; No. substituted or unsubstituted alkenyl, substituted or unsub 2005/0187.151; No. 2005/0282755, and No. 2005/0245452, stituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, het content all of which is incorporated herein by reference. eroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, hetero 0070. In some embodiments, the first chemical domain is cyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, an anti-bacterial agent and the second chemical domain is heteroaryl, heterocyclyl cycloalkyl, cycloalkenyl, alkylary anti-acne agent or an antifungal agent. lalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, 0071. Without limitations, the first and the second chemi alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, cal domains in the DART can be bound to each other alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylal covalently. One of skill in the art is well aware of different kyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenyl functional groups in chemical domains that can be used for heteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroary covalently binding a first chemical domain with a second lalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, chemical domain. For example, the first chemical domain alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylhet can comprise a functional group selected from the group erocyclylalkenyl, alkylhererocyclylalkynyl, alkenylhetero consisting of an amino group, a N-Substituted amino group, cyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocy a carboxyl group, a carbonyl group, an acid anhydride clylalkynyl, alkynylheterocyclylalkyl, group, an aldehyde group, a hydroxyl group, an epoxy alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, group, a thiol, a disulfide group, an alkenyl group, a hydra alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenyl Zine group, a hydrazide group, a semicarbazide group, a heteroaryl, alkynylhereroaryl, where one or more methyl thiosemicarbazide group, an amide group, an aryl group, an enes can be interrupted or terminated by O, S, S(O), SO ester group, an ether group, a glycidyl group, a halo group. N(R'), C(O), C(O)O, cleavable linking group, substituted a hydride group, an isocyanate group, a urea group, a or unsubstituted aryl, substituted or unsubstituted heteroaryl, urethane group, and any combinations thereof for binding substituted or unsubstituted heterocyclic; where R' is hydro with the second chemical domain. In some embodiments, gen, acyl, aliphatic or Substituted aliphatic. US 2016/0346294 A1 Dec. 1, 2016

0075. In some embodiments, the first and second chemi P(O)(H)-O-, - O P(S)(H)-O-, -S P(O)(H) cal domains are covalently bound to each other via a third O— —S P(S) (H)—O— —S P(O)(H)—S , and domain comprising at least one cleavable group. A cleavable —O—P(S)(H)—S , wherein R is optionally substituted group is one which is sufficiently stable under a first set of linear or branched C-C alkyl); acid cleavable groups (e.g., conditions and can be cleaved to release the two parts the hydrazones, esters, and esters of amino acids, -C=NN cleavable group is holding together. In a preferred embodi and —OC(O)—); ester-based cleavable groups (e.g., ment, the cleavable group is cleaved at least 10 times or —C(O)O—); peptide-based cleavable groups, (e.g., groups more, preferably at least 100 times faster under a first that are cleaved by enzymes such as peptidases and pro reference condition (which can, e.g., be selected to mimic or teases, e.g., -NHCHRC(O)NHCHRC(O) , where R' represent intracellular conditions) than under a second ref and Rare the R groups of the two adjacent amino acids). erence condition (which can, e.g., be selected to mimic or A peptide based cleavable group comprises two or more represent conditions found in the blood or serum). amino acids. In some embodiments, the peptide-based cleav 0076 Cleavable groups are susceptible to cleavage able group comprises the amino acid sequence that is the agents, e.g., pH, redox potential or the presence of degra Substrate for a peptidase or a protease found in/secreted by dative molecules. Generally, cleavage agents are more P. acnes. prevalent or found at higher levels or activities at the desired 0078. In some embodiments, the cleavable group is an site of action of the molecule comprising the cleavable acid labile group. Generally, an acid cleavable group is cleavable in an acidic environment with a pH of about 6.5 group. Examples of Such degradative agents include: redox or lower (e.g., about 6.5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, or agents which are selected for particular substrates or which lower), or by agents such as enzymes that can act as a have no substrate specificity, including, e.g., oxidative or general acid. reductive enzymes or reductive agents such as mercaptains, 0079. In some embodiments, the first and second chemi present in cells, that can degrade a redox cleavable linking cal domains are covalently bound together by a third domain group by reduction; esterases; amidases; endoSomes or selected from the group consisting of 11-hydroxyundecenic agents that can create an acidic environment, e.g., those that acid; 1,10-decanediol; 1,3-propanediol; 1.5-pentanedil; result in a pH of five or lower; enzymes that can hydrolyze 10-hydroxydecenic acid; Succinic; lactic acid; 3-hydroxy or degrade an acid cleavable linking group by acting as a propionic acid; and any combinations thereof. general acid, peptidases (which can be substrate specific) 0080. In some embodiments, the third domain can be linker, e.g., a cleavable or non-cleavable linker. and proteases, and phosphatases. 0081. The first chemical domain can be bound to the 0077 Exemplary cleavable groups include, but are not second chemical domain or the domain connecting the first limited to, redox cleavable groups (e.g., -S-S- and and second chemical domains via a direct bond or an atom —C(R) S S , wherein R is H or C-C alkyl and at such as oxygen or sulfur, a unit such as NH, C(O), C(O)O. least one R is C-C alkyl such as CH or CHCH): C(O)NH, SS, SO, SO, or SONH. phosphate-based cleavable linking groups (e.g., -O-P(O) I0082 Similarly, the second chemical domain can be bound to the first chemical domain or the domain connecting the first and second chemical domains via a direct bond or an atom such as oxygen or Sulfur, a unit Such as NH, C(O), C(O)O, C(O)NH, SS, SO, SO, or SONH. I0083. The DARTs can be synthesized using methods known in the art. Exemplary methods for synthesizing the DARTs are described in the Examples section herein. See Examples 2 to 10. 0084. In some embodiments, the DART can be selected from those shown in Tables 1 A & 1B. TABLE 1A

Exemplary DARTs Set-1

US 2016/0346294 A1 Dec. 1, 2016 11

TABLE 1 A-continued Exemplary DARTs Set-1

US 2016/0346294 A1 Dec. 1, 2016 12

TABLE 1 A-continued

Exemplary DARTs Set-1

O F 1-1N1-1N1-1'

S \ / N N Hill I N O OH

HN O - O O V NR / >N

O O 6 F

N N CN HN F\

(2N-CH, 7 | N le US 2016/0346294 A1 Dec. 1, 2016 13

TABLE 1 A-continued

Exemplary DARTs Set-1

O O SN1 N O

C %. N / O ~. |No. O

O N 4Ns F

NH2

p O O W 1N1 S-1N h F O S N

21 S Y y O o S- p-(

NH2

US 2016/0346294 A1 Dec. 1, 2016 14

TABLE 1 A-continued Exemplary DARTs Set-1

US 2016/0346294 A1 Dec. 1, 2016 15

TABLE 1 A-continued Exemplary DARTs Set-1

/ 15

19 US 2016/0346294 A1 Dec. 1, 2016 16

TABLE 1 A-continued

Exemplary DARTs Set-1

21 US 2016/0346294 A1 Dec. 1, 2016 17

TABLE 1 A-continued

Exemplary DARTs Set-1

23 US 2016/0346294 A1 Dec. 1, 2016 18

TABLE 1 A-continued

Exemplary DARTs Set-1

O S N HN2. h F ls --- O Y Sull- N 7 NN M es

25 X O O O

1N1 So F US 2016/0346294 A1 Dec. 1, 2016 19

TABLE 1 A-continued

Exemplary DARTs Set-1

V NS O (es X 27 O O O

F Nulln

st Ns O /es

O O O O

O 1N1N1S O F ( Null

s NS O US 2016/0346294 A1 Dec. 1, 2016 20

TABLE 1 A-continued

Exemplary DARTs Set-1

() N-CH3 29

(2) N-CH 30 US 2016/0346294 A1 Dec. 1, 2016 21

TABLE 1 A-continued

Exemplary DARTs Set-1

O aH

32 US 2016/0346294 A1 Dec. 1, 2016 22

TABLE 1 A-continued

Exemplary DARTs Set-1

(2) N-CH3 33 | N le

NH2

(2) N- 34 | N le

US 2016/0346294 A1 Dec. 1, 2016 23

TABLE 1 A-continued Exemplary DARTs Set-1

35 SE

O O O O N N O O S /

F 1N1 So O

38 US 2016/0346294 A1 Dec. 1, 2016 24

TABLE 1 A-continued

Exemplary DARTs Set-1

42 US 2016/0346294 A1 Dec. 1, 2016 25

TABLE 1 A-continued Exemplary DARTs Set-1

() N- 43 |

45 US 2016/0346294 A1 Dec. 1, 2016 26

TABLE 1 A-continued

Exemplary DARTs Set-1

HO US 2016/0346294 A1 Dec. 1, 2016 27

TABLE 1 A-continued

Exemplary DARTs Set-1

(2) N- 48 |

50 US 2016/0346294 A1 Dec. 1, 2016 28

TABLE 1 A-continued

Exemplary DARTs Set-1

53 US 2016/0346294 A1 Dec. 1, 2016 29

TABLE 1 A-continued

Exemplary DARTs Set-1

55 US 2016/0346294 A1 Dec. 1, 2016 30

TABLE 1 A-continued

Exemplary DARTs Set-1

NH2 56

OH US 2016/0346294 A1 Dec. 1, 2016 31

TABLE 1 A-continued

Exemplary DARTs Set-1

S NM Sir N KO-N O s----.

- N

O O O HN F OH H. O S N O O N 21 O s O O US 2016/0346294 A1 Dec. 1, 2016 32

TABLE 1 A-continued

Exemplary DARTs Set-1

N N / -O O HN O H. N S O Z O N b/{ N \ OH

US 2016/0346294 A1 Dec. 1, 2016 33

TABLE 1 A-continued

Exemplary DARTs Set-1

64 US 2016/0346294 A1 Dec. 1, 2016 34

TABLE 1 A-continued

Exemplary DARTs Set-1

67 US 2016/0346294 A1 Dec. 1, 2016 35

TABLE 1 A-continued

Exemplary DARTs Set-1

HO N / O

( O)-( )-O- F

e 70

O O NH O O N 'it H. O O \ S

N C O O HO F US 2016/0346294 A1 Dec. 1, 2016 36

TABLE 1 A-continued

Exemplary DARTs Set-1

73 US 2016/0346294 A1 Dec. 1, 2016 37

TABLE 1 A-continued

Exemplary DARTs Set-1

76 US 2016/0346294 A1 Dec. 1, 2016 38

TABLE 1 A-continued

Exemplary DARTs Set-1

79 US 2016/0346294 A1 Dec. 1, 2016 39

TABLE 1 A-continued

Exemplary DARTs Set-1

82 US 2016/0346294 A1 Dec. 1, 2016 40

TABLE 1 A-continued

Exemplary DARTs Set-1

)—o OH

85 US 2016/0346294 A1 Dec. 1, 2016 41

TABLE 1 A-continued

Exemplary DARTs Set-1

88 US 2016/0346294 A1 Dec. 1, 2016 42

TABLE 1 A-continued

Exemplary DARTs Set-1

NH2 89 p-( / O

O O

O C

TABLE 2A

Exemplary DARTs Set-2

N Yo G Y- S HO /N N O US 2016/0346294 A1 Dec. 1, 2016 43

TABLE 2A-continued

Exemplary DARTs Set-2

95 US 2016/0346294 A1 Dec. 1, 2016 44

TABLE 2A-continued Exemplary DARTs Set-2

99 US 2016/0346294 A1 Dec. 1, 2016 45

TABLE 2A-continued

Exemplary DARTs Set-2

100

101

102

103 US 2016/0346294 A1 Dec. 1, 2016 46

TABLE 2A-continued

Exemplary DARTs Set-2

H H 104

105

S O

106

S O

107

S O

O 108

OH US 2016/0346294 A1 Dec. 1, 2016 47

TABLE 2A-continued

Exemplary DARTs Set-2

109

SCX OH

110 Sky X-OH N

111

S. HO '? US 2016/0346294 A1 Dec. 1, 2016 48

TABLE 2A-continued

Exemplary DARTs Set-2 uly 112 N NO \e y Z \ HO O S. y OX ( S O H O -N, \ N -(

HOOC N Yu.O N1 S O

N 113 - N AsV l O Y O /N N O

O \U/ \ OH

() F O

114

O O

O O US 2016/0346294 A1 Dec. 1, 2016 49

TABLE 2A-continued

Exemplary DARTs Set-2

115

116

117

C O V N/ \N OH

118 N S. Ny ON N N OH \ / O O -( 119

OH US 2016/0346294 A1 Dec. 1, 2016 50

TABLE 2A-continued

Exemplary DARTs Set-2

120

O S

F 121

122

n-n-n-n-n- \U/ OH

123

10 124 US 2016/0346294 A1 Dec. 1, 2016 51

TABLE 2A-continued

Exemplary DARTs Set-2

125

126

127

128 US 2016/0346294 A1 Dec. 1, 2016 52

TABLE 2A-continued Exemplary DARTs Set-2 129

N O 21 N N

O \U/ OH

F O

130 rs O N-1N r S N N lo F

O OH s 131 2 O-N-1NN ~ ). O N-N-N- S a F

O OH

O 132

HN C N O N \ OH

F O R = Lauric acid, oleic acid, palmitoletic acid, Myristoleic acid, linoleic acid, linolenic acid

133 R-1\ H HNo. C N O N \ OH

F O R= FA-ester of propylene glycol and glycerol and their derivatives US 2016/0346294 A1 Dec. 1, 2016

0085. The present invention also provides formulations -continued comprising DART as the API. Various features of the O O formulations are described in more detail vide infra. F OH Antibiotics (Non-DART) N N I0086. The present invention also envisages compounds which are not DARTs. Accordingly, the invention also C l provides formulations comprising an antibiotic agent which HN w" is not a DART, i.e., a formulation comprising a non-DART antibiotic agent as the API. For example, the present inven Sitafloxacin tion describes the use of 8-chloro fluoroquinolones for the treatment of acne conditions, especially those caused by I0087. Without wishing to be bound by a theory, microni resistant forms of P acnes. It is a Sub class of fluoroquino Zation of an antibiotic agent, such as besifloxacin, can have lones where C8 position is substituted with chlorine. Thus, an impact on its bioactivity. For example, micronization can in Some embodiments, the disclosure provides a formulation enhance antibiotic agent's bioactivity or its retention at a desired site. Further, micronization can also affect the anti comprising 8-chlorofluoroquinolone as the API. Exemplary biotic agent's stability and amounts in a formulation. More 8-chloro fluoroquinolones include, but are not limited to, over, micronization can also allow optimizing properties of besifloxacin, Sitafloxacin, and clinafloxacin. In some formulations comprising micronized besifloxacin. Accord embodiments, the formulation comprises besifloxacin. ingly, without limitations, the API in the formulation, (e.g., the antibiotic agent) can be in the form of particles, powders, Suspensions, dispersions, emulsions, liposomes, micelles, globules, Solutions, vesicles, aggregates, and the like. I0088. In some embodiments, the API, for example, but not limited to, besifloxacin or DART, can be micronized, i.e., OH formed as a particle. I0089 Generally, the micronized API has a size in the N N range from about 0.2 Lum to about 15 Lum. In some embodi R ments, the micronized API has a size in the range from about C 1 um to about 10 Jum. In some embodiments, the micronized HN API has a size in the range from about 1.5 um to about 9 um. R In some embodiments, the micronized API has a size in the 8-Chlorofluoroquinolones range from about 2 um to about 8 um. 0090. In some embodiments, the API is in the form of a R = H, F particle and comprises a surface modifier on the Surface R2 = H, Cyclopropyl thereof. Generally a surface modifier is a molecule that can Examples - change the Surface of the particle (such as by coating) in question and help in adhering the whole particle, hence, to O O the specific Surface(s). Generally, the Surface modification F does not involve chemical bonding alterations or creation of OH any chemical bond. The Surface modifier just physically

associates with the particle. 0091. The surface modifier can be selected from the N N group consisting of lipids, oils, polymers, peptides, proteins, carbohydrates, glycolipids, phospholipids, lipoproteins, cat ionic molecules, and any combinations thereof. The Surface A modifier can form a coating layer on the particle Surface. H Without limitations, the particle can be partially or fully coated with the surface modifier. Besifloxacin 0092. Some non-limiting exemplary formulations com O O prising a micronized antibiotic agent, e.g., besifloxacin, are F described in Examples 18-20 and shown in Table 18. OH 0093. In some embodiments, the formulation can be a spray formulation. Exemplary non-limiting spray formula tions are described in Example 23 and Table 19. In some N N embodiments, the formulation can be in the form of a face wash. Exemplary non-limiting face wash formulations are C l described in Example 24, and Table 20. In some embodi HN ments, the formulation can be in the form of a Soap bar. Exemplary non-limiting soap bar formulations are described Clinafloxacin in Example 25 and Table 21. In some embodiments, the formulation can be in the form of a body wash. Exemplary US 2016/0346294 A1 Dec. 1, 2016 54 non-limiting body wash formulations are described in like-polymers to avoid any incompatibility issues during the Example 26, and Table 22. In some embodiments, the product shelf life. Accordingly, in some embodiments, the formulation can be in the form of a lotion. Exemplary formulation is essentially free of viscosity modifiers. Exem non-limiting lotion formulations are described in Example plary formulations that are essentially free of a viscosity 27, and Table 23. modifier are described in Example 32 and Table 28. 0094 Surfactants are known to solubilize hydrophobic 0098. In some embodiments, the API can be coated with Substances by reducing the interfacial tension. Accordingly, a molecule selected from the group consisting of lipids, oils, in some embodiments, the antibiotic agent can be solubi polymers, peptides, proteins, carbohydrates, glycolipids, lized with a surfactant before forming the formulation. phospholipids, lipoproteins, cationic molecules, and any In-addition to Surfactants, co-solvents or co-surfactants can combinations thereof. Without limitations, the API can be also help in solubilization of the poorly water-soluble com partially or fully coated with the coating molecule. Exem pounds by increasing the wetting property or reducing the plary formulations comprising coated or non-coated API are interfacial tension of the hydrophobic molecule. Some described in Example 46 and Tables 52 and 53. exemplary Surfactants and co-surfactants can include, but are not limited to, sodium laurylsulfate, tween 80, tween 20, 0099. It is noted that various formulations features dis span 20, and any combinations thereof. Exemplary co cussed in more detail vide infra are applicable to the Solvents for Solubilizing the antibiotic agent, such as besi formulation comprising antibiotic agent, e.g., besifloxacin, floxacin, can include propylene glycol monocaprylate and described herein. diethylene glycol monoethyl ether. Additional Surfactants, co-Surfactants and co-solvents that are amenable for Solu Combination bilizing the antibiotic agent are described elsewhere in the 0100. In some embodiments, the formulation comprises disclosure. Without wishing to be bound by a theory, solu two or more antibiotic agents. For example, the formulation bilizing the antibiotic agent, e.g., besifloxacin, can provide can comprise two or more different anti-acne agents. In formulations that are within FDA prescription guidelines Some embodiments, the formulation comprises an 8-chloro and limits of inactive excipients or ingredients. Non-limiting fluoroquinolones alone or in combination with another anti exemplary formulations comprising a solubilized API, e.g., acne agent. Exemplary 8-chloro fluoroquinolones include, antibiotic agent such as besifloxacin, are described in but are not limited to, besifloxacin, sitafloxacin, and clina Examples 28, 31 and 33, and shown in Tables 24, 27 and floxacin. In some embodiments, the formulation comprises 30-32. besifloxacin. In some embodiments, the formulation com 0095 Preparation of drug-loaded (suspended form) gel prises besifloxacin and adapalene. via conventional methods usually leads to exposure of the drug to a wide range of pH conditions, which can lead to, in 0101. Without limitations, the two or more antibiotic Some instances, solubilization of the drug, and then repre agents can be in the same form or different forms. For cipitation. This solubilization-reprecipitation phenomenon example, the first and second anti-biotic agents can be in most cases leads to change in original particle size, independently micronized, suspended, or solubilized for the impurity profile or crystal pattern, or others. In order to API. Accordingly, in some embodiments, both the first circumvent this issue, the inventors have used an inventive anti-biotic agent and the second anti-biotic agent are micron approach to prepare different Suspended drug-loaded formu ized. In some embodiments, the first anti-biotic agent is lations. Thus, in some embodiments, the formulation is in micronized and the second anti-biotic agent is solubilized. In form of a Suspended gel with negligible or minimal drug Some embodiments, the first anti-biotic agent is micronized solubilization-reprecipitation. In the Suspended drug formu and the second anti-biotic agent is suspended in the formu lations, the API particles are dispersed in a carrier media, lation. In some embodiments, the first anti-biotic agent is Such as, but not limited to, glycerol, and processed to the solubilized and the second anti-biotic agent is micronized. In desired formulation. Exemplary Suspended gel formulations Some embodiments, both the first anti-biotic agent the sec are described in Example 24, 26, 28, 29, 30, 31 and 32 and ond anti-biotic agent are solubilized. In some embodiments, shown in Tables 25, 27, 29, 33, 34, 37 and 38. Exemplary the first anti-biotic agent is solubilized and the second Suspended drug loaded cream formulations are described in anti-biotic agent is suspended. In some embodiments, the Examples 30 and 32 and Tables 26 and 28. first anti-biotic agent is suspended and the second anti-biotic 0096. In addition to the various components, the formu agent is micronized. In some embodiments, the first anti lation can also comprise one or more viscosity modifiers. In biotic agent is suspended and the second anti-biotic agent is Some embodiments, the Viscosity modifier is a polymer. solubilized. In some embodiments, both the first anti-biotic Exemplary polymeric viscosity modifiers include, but are agent and the second antibiotic agent are Suspended. not limited to, carbopol, hydroxypropyl cellulose, hydroxy 0102. In some embodiments, the formulation comprises propyl methyl cellulose, hydroxyethyl cellulose, and sodium besifloxacin and adapalene, wherein besifloxacin is solubi hyaluronate. In some other embodiments, the Viscosity lized and adapalene is suspended. In some other embodi modifier is a non-polymeric viscosity modifier or gelling ments, the formulation comprises besifloxacin and ada agent. Additional exemplary viscosity modifiers are palene, wherein both the besifloxacin and adapalene are described elsewhere in the disclosure. Exemplary formula solubilized. Exemplary formulation comprising both besi tions comprising various viscosity modifiers are described in floxacin and adapalene are described in Examples 18, 23-27 Example 33 and Tables 29-32. and 31 and Tables 18-23 and 27. 0097. According to published literature there may be (0103. It is noted that various formulations features dis Some kind of physical and/or chemical interaction between cussed in more detail vide infra are applicable to the carbopol and fluoroquinolones. For which, there may be a formulation comprising two or more antibiotic agents need to prepare formulations without carbopol or carbopol described herein. US 2016/0346294 A1 Dec. 1, 2016

Features Applicable to DART. Non-DART and 0109. The surface modifier can be selected from the Combination APIs group consisting of lipids, oils, polymers, peptides, proteins, 0104 Furthermore, as articulated in http://thescienceo carbohydrates, glycolipids, phospholipids, lipoproteins, cat facne.com/antibiotic-susceptibility-of-propionibacterium ionic molecules, and any combinations thereof. The Surface acnes?) The second major limitation of treatment of acne is modifier can form a coating layer on the particle Surface. that antibiotics are not evenly dispersed throughout the Without limitations, the particle can be partially or fully different tissues in the body. Many antibiotics do not effec coated with the surface modifier. tively accumulate in the follicle and/or sebaceous glands, 0110. In some embodiments, the drug carriers and for and therefore do not effectively reach the bacteria respon mulations disclosed herein can further comprise an active sible for acne. Even if a bacteria is highly susceptible to a agent, i.e., an active agent in addition to the DART and/or particular antibiotic in lab-based testing, if that antibiotic anti-bacterial agent. As used herein, the term “active agent' does not make it to the site of infection at a sufficient means a compound or composition that has a particular concentration, it is not going to be an effective treatment. As desired activity. For example, an active agent can be a a result there can be major differences in the effectiveness of therapeutic compound. Without limitations the active agent oral antibiotics and topical antibiotics used in acne treat can be selected from the group consisting of Small organic ments. This extends to all bacterial diseases of the skin. or inorganic molecules, saccharines, oligosaccharides, poly There is a need to develop unique optimal topical formula saccharides, peptides; proteins, peptide analogs and deriva tions and is described later. tives, peptidomimetics, nucleic acids, nucleic acid analogs 0105 Skin, e.g., micro-cracks, Sweat or secretion pores, and derivatives, antibodies, antigen binding fragments of and hair follicles can act as reservoirs for drug carriers of antibodies, lipids, extracts made from biological materials, particular sizes. Efficacy of active agents, e.g., antifungal naturally occurring or synthetic compositions, and any com and antibacterial formulations can be enhanced using infun binations thereof. dibular delivery. A drug carrier can enhance the delivery of 0111. In some embodiments, the active agent can be active agent on sebum filled hair follicles and also exhibit selected from the group consisting of antifungal agents, fusogenecity of Such drug carriers to lipophilic microbial antibacterial agents, antimicrobial agents, anti-acne agents, cell wall/cell membrane. This allows retention of the drug antioxidant agents, cooling agents, soothing agents, wound carrier on the skin, followed by slow and continuous release healing agents, anti-inflammatory-agents, penetration of the DART or antibacterial agent from the drug carrier. enhancers, permeation enhancers, anti-oxidants, anti-aging Exemplary drug carriers include, but are not limited to agents, anti-Wrinkle agents, skin whitening or bleaching microparticles, nanoparticles, vesicles, liposomes, emul agents, ultraviolet (UV) light absorbing or scattering agents, sions, globules, and Solutions. skin depigmentation agents, regenerative agents, scar heal 0106. In addition to the API (e.g., DART and/or other ing agents, dyes or coloring agents, deodorizing agents, anti-bacterial agent), the drug carrier can further comprise fragrances, keratolytic agent, and any combinations thereof. one or more additional components. For example, the drug In some embodiments, the active agent can be a keratolytic carrier can further comprise a compound selected from the agent. group consisting of lipids, oils, polymers, peptides, proteins, 0112 In some embodiments, the active agent is an anti carbohydrates, glycolipids, phospholipids, lipoproteins, cat inflammatory agent. As used herein the term “anti-inflam ionic molecules, and any combinations thereof. The API, matory agent” refers to a compound (including its analogs, e.g., DART or other anti-bacterial agent, can be present in derivatives, prodrugs and pharmaceutically salts) which can the core of the drug carrier and the additional component can be used to treat inflammation or inflammation related dis form a coating layer over the core. Without limitation, the ease or disorder. Exemplary anti-inflammatory agents coating can be a functional or non-functional coating. By include, but are not limited to, the known steroidal anti functional coating is meant a coating that imparts one or inflammatory and non-steroidal anti-inflammatory drugs more desirable properties to the drug carrier, Such as (NSAIDs). Exemplary steroidal anti-inflammatory agents enhanced targeting or retention at site of action, increase in include but are not limited to 21-acetoxypregnenolone, the activity of the API, or having a destired activity itself. alclometaSone, algestone, amcinonide, beclomethasone, 0107. In some embodiments, DART and/or other anti betamethasone, budesonide, chloroprednisone, clobetasol, bacterial agent can be formed as a particle. In addition to the clobetansone, clocortolone, cloprednol, corticosterone, cor API (e.g., DART and/or other anti-bacterial agent), the tisone, cortivaZol, deflazacort, desonide, desoximetaSone, particle can further comprise a compound selected from the dexamethasone, diflorasone, diflucortolone, difluprednate, group consisting of lipids, oils, polymers, peptides, proteins, enoXolone, fluazacort, flucloronide, flumethasone flunisol carbohydrates, glycolipids, phospholipids, lipoproteins, cat ide, fluocinolone acetonide, fluocinonide, fluocortin butyl, ionic molecules, and any combinations thereof. The API, fluocortolone, fluorometholone, fluperolone acetate, flu e.g., DART or other anti-bacterial agent, can be present in prednidene acetate, fluprednisolone, flurandrenolide, fluti the core of the particle and the additional component can casone propionate, formocortal, halcinonide, halobetasol form a coating layer over the core. propionate, halometasone, halopredone acetate, hydrocorta 0108. In some embodiments, the particle comprises a mate, hydrocortisone, loteprednol etabonate, maZipredone, surface modifier on the surface thereof. Generally a surface medrysone, meprednisone, methylprednisolone, mometa modifier is a molecule that can change the Surface of the Sone furcate, paramethoSone, prednicarbate, prednisolone, particle (such as by coating) in question and help in adhering prednisolone 25-diethylamino-acetate, prednisolone sodium the whole particle, hence, to the specific Surface(s). Gener phosphate, prednisone, prednival, prednylidene, rimex ally, the Surface modification does not involve chemical olone, tiXocortol, triamcinolone, triamcinolone acetonide, bonding alterations or creation of any chemical bond. The triamcinolone benetonide, triamcinolone hexacetonide, Surface modifier just physically associates with the particle. derivatives thereof and mixtures thereof. Exemplary non US 2016/0346294 A1 Dec. 1, 2016 56 steroidal anti-inflammatory agents include but are not lim isopropyl cinnamate, methyl-2,5-diisopropyl cinnamate, ited to COX inhibitors (COX-1 or COX nonspecific inhibi ethyl-2,4-diisopropyl cinnamate, methyl-2,4-diisopropyl tors) and selective COX-2 inhibitors. Exemplary COX cinnamate, propyl-p-methoxy cinnamate, isopropyl-p- inhibitors include but are not limited to salicylic acid deriva methoxy cinnamate, isoamyl-p-methoxy cinnamate, octyl tives such as aspirin, sodium salicylate, choline magnesium p-methoxy cinnamate(2-ethylhexyl-p-methoxy cinnamate), trisalicylate, Salicylate, diflunisal, SulfaSalazine and olsala 2-ethoxyethyl-p-methoxy cinnamate, cyclohexyl-p- Zine; para-aminophenol derivatives Such as acetaminophen; methoxy cinnamate, ethyl-O-cyano-B-phenyl cinnamate, indole and indene acetic acids such as indomethacin and 2-ethylhexyl-C-cyano-B-phenyl cinnamate, glyceryl mono Sulindac; heteroaryl acetic acids Such as tolmetin, dicofenac 2-ethylhexanoyl-dipara-methoxy cinnamate, methyl-bis and ketorolac, arylpropionic acids such as ibuprofen, (trimethylsiloxane)silylisopentyl trimethoxy cinnamate and naproxen, flurbiprofen, ketoprofen, fenoprofen and oxapro the like: 3-(4-methylbenzylidene)-d.l-camphor; 3-ben Zin; anthranilic acids (fenamates) such as mefenamic acid Zylidene-d.l-camphor; urocanic acid, urocanic acid ethyl and meloxicam, enolic acids such as the oxicams (piroxi ester; 2-phenyl-5-methylbenzoxazole; 2,2'-hydroxy-5-meth cam, meloxicam); alkanones such as nabumetone; deriva ylphenylbenzotriazole: 2-(2-hydroxy-5'-t-octylphenyl)ben tives thereof and mixtures thereof. Exemplary COX-2 Zotriazole; 2-(2-hydroxy-5'-methylphenylbenzotriazole; inhibitors include but are not limited to diarylsubstituted dibenZaladine; dianisoylmethane, 4-methoxy-4-t-bu furanones such as refecoxib; diaryl-substituted pyrazoles tyldibenzoylmethane; 5-(3.3-dimethyl-2-norbornylidene)-3- Such as celecoxib; indole acetic acids such as etodolac and pentane-2-one; dimorpholinopyridaZinone; and combina sulfonanilides such as nimeSulide; derivatives thereof and tions thereof. Ultraviolet light scattering agents include, for mixtures thereof. example, powders such as titanium oxide, particulate tita 0113. In some embodiments, the active agent is an anti nium oxide, Zinc oxide, particulate Zinc oxide, ferric oxide, aging agent. As used herein, the term “anti-aging agent' particulate ferric oxide, ceric oxide and the like. means a compound or composition that inhibits or reduces 0.115. In some embodiments, the active agent is an anti signs of aging, Such as wrinkles, fine lines, and other wrinkle agent, e.g., a dermatological anti-wrinkle agent. manifestations of photodamage. Examples of anti-aging Anti-wrinkle agents include, without limitations, flavonoids agentsinclude, but are not limited to, flavonoids such as Such as quercetin, hesperidin, quercitrin, rutin, tangeritin, quercetin, hesperidin, quercitrin, rutin, tangeritin, and epi and epicatechin; CoQ10; vitamin C: hydroxy acids includ catechin, CoO10; inorganic Sunscreens Such as tianium ing C-C alpha-hydroxy acids such as glycolic acid, lactic dioxide and Zinc oxide, organic Sunscreens such as octyl acid, 2-hydroxybutanoic acid, malic acid, citric acid tartaric methyl cinnamates and derivatives thereof; retinoids; vita acid, alpha-hydroxyethanoic acid, hydroxycaprylic acid and mins such as vitamin E. vitamin A, vitamin C (ascorbic the like; beta hydroxy acids including salicylic acid and acid), vitamin B, and derivatives thereof such as vitamin E polyhydroxy acids including gluconolactone (G4); and mix acetate, vitamin C palmitate, and the like; antioxidants tures of these acids. Further anti-wrinkle agents include including alpha hydroxy acid such as glycolic acid, citric retinoic acid and gamma-linolenic acid. acid, lactic acid, malic acid, mandelic acid, ascorbic acid, 0116. In some embodiments, the active agent is a skin alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, whitening or bleaching agent. Skin whitening and bleaching alpha-hydroxyisocaproic acid, atrrolactic acid, alpha-hy agentsinclude hydrogen peroxide, Zinc peroxide, sodium droxyisovaleric acid, ethyl pyruvate, galacturonic acid, glu peroxide, hydroquinone, 4-isopropylcatechol, hydroquinone copehtonic acid, glucopheptono 1.4-lactone, gluconic acid, monobenzyl ether, kojic acid; lactic acid; ascorbyl acid and gluconolactone, glucuronic acid, glucurronolactone, gly derivatives such as magnesium ascorbyl phosphate; arbutin; colic acid, isopropyl pyruvate, methyl pyruvate, mucic acid, and licorice root. Sunless tanning actives include dihydroxy pyruvia acid, saccharic acid, Saccaric acid 1.4-lactone, tar acetone (DHA); glyceryl aldehyde; tyrosine and tyrosine taric acid, and tartronic acid; beta hydroxy acids such as derivatives such as malyltyrosine, tyrosine glucosinate, and beta-hydroxybutyric acid, beta-phenyl-lactic acid, beta-phe ethyl tyrosine; phospho-DOPA, indoles and derivatives; and nylpyruvic acid; botanical extracts such as green tea, soy, mixtures thereof. Other skin whitening agents include Sugar milk thistle, algae, aloe, angelica, bitter orange, coffee, amines, such as glucosamine, N-acetyl glucosamine, glu goldthread, grapefruit, hoellen, honeysuckle, Job’s tears, cosamine Sulfate, mannosamine, N-acetyl mannosamine, lithospermum, mulberry, peony, puerarua, rice, saflower, galactosamine, N-acetylgalactosamine, their isomers (e.g., and mixtures thereof. Stereoisomers), and their salts (e.g., HCl salt); and N-acyl 0114. In some embodiments, the active agent is an ultra amino acid compounds, such as N-acyl phenylalanine, violet (UV) light absorbing or scattering agent. Ultraviolet N-acyl tyrosine, their isomers, including their D and L light absorbing agents include, for example, ultraviolet isomers, salts, derivatives, and mixtures thereof. An example absorber of benzoic acid system such as para-aminobenzoic of a suitable N-acyl amino acid is N-undecylenoyl-L-phe acid (hereinafter, abbreviated as PABA), PABA monoglyc nylalanine. erin ester, N,N-dipropoxy PABA ethyl ester, N,N-diethoxy 0117. In some embodiments, the active agent is a skin PABA ethyl ester, N,N-dimethyl PABA ethyl ester, N.N- depigmentation agent. Examples of Suitable depigmentation dimethyl PABA butyl ester, and N,N-dimethyl PABA methyl agents include, but are not limited to, soy extract; soy ester and the like; ultraviolet absorber of anthranilic acid isoflavones; retinoids such as retinol, kojic acid; kojic system Such as homomenthyl-N-acetyl anthranilate and the dipalmitate; hydroquinone; arbutin; transexamic acid; Vita like; ultraviolet absorber of salicylic acid system such as mins such as niacin and vitamin C; azelaic acid; linolenic amyl salicylate, menthyl salicylate, homomenthyl salicylate, acid and linoleic acid; placertia; licorice; and extracts Such octyl salicylate, phenyl salicylate, benzyl salicylate, p-iso as chamomile and green tea; and salts and prodrugs thereof. propanol phenyl salicylate and the like; ultraviolet absorber 0118. In some embodiments, the active agent is an anti of cinnamic acid system such as octyl cinnamate, ethyl-4- oxidant agent. As used herein, the term “antioxidant agent US 2016/0346294 A1 Dec. 1, 2016 57 refers to any molecule capable of slowing, reducing, inhib molecules which provide a sensation of cooling on applica iting, or preventing the oxidation of other molecules. tion. Some exemplary cooling agents include, but are not Examples of antioxidants include, but are not limited to, limited to, WS-3; WS-23; menthol: 3-substituted-P-men hydrophilic antioxidants, lipophilic antioxidants, and mix thanes; N-substituted-P-menthane-3-carboxamides; isop tures thereof. Non-limiting examples of hydrophilic antioxi ulegol; 3-(1-menthoxy)propane-1,2-diol, 3-(1-menthoxy)-2- dants include chelating agents (e.g., metal chelators) Such as methylpropane-1,2-diol; p-menthane-2,3-diol; p-menthane ethylenediaminetetraacetic acid (EDTA), citrate, ethylene 3.8-diol; 6-isopropyl-9-methyl-1,4-dioxaspiro4.5 decane glycol tetraacetic acid (EGTA), 1.2-bis(o-aminophenoxy) 2-methanol; menthyl Succinate and its alkaline earth metal ethane-N,N,N',N'-tetraacetic acid (BAPTA), diethylene tri salts; trimethylcyclohexanol; N-ethyl-2-isopropyl-5-methyl amine pentaacetic acid (DTPA), 2,3-dimercapto-1-propane cyclohexanecarboxamide, Japanese mint oil; peppermint sulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), oil; menthone; menthone glycerol ketal; menthyl lactate; C-lipoic acid, Salicylaldehyde isonicotinoyl hydrazone 3-(1-menthoxy)ethan-1-ol; 3-(1-menthoxy)propan-1-ol; (SIH), hexylthioethylamine hydrochloride (HTA), desferri 3-(1-menthoxy)butan-1-ol: 1-menthylacetic acid N-ethyl oxamine, salts thereof, and mixtures thereof. Additional amide: 1-menthyl-4-hydroxypentanoate, 1-menthyl-3-hy hydrophilic antioxidants include ascorbic acid (vitamin C), droxybutyrate; N.2,3-trimethyl-2-(1-methylethyl)-butana cysteine, glutathione, dihydrolipoic acid, 2-mercaptoethane mide; n-ethyl-t-2-c-6 nonadienamide: N,N-dimethyl Sulfonic acid, 2-mercaptobenzimidazole Sulfonic acid, 6-hy menthyl succinamide; menthyl pyrrolidone carboxylate; and droxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, the like. sodium metabisulfite, salts thereof, and mixtures thereof. 0122. In some embodiments, the active agent is a color Non-limiting examples of lipophilic antioxidants include ing agent. As used herein, the term “coloring agent’ means Vitamin E isomers such as C-, 3-, y-, and 8-tocopherols and any Substance that can be employed to produce a desired Cl-, 3-, y-, and 8-tocotrienols; polyphenols such as 2-tert color. Gen. Such coloring agents are approved for human butyl-4-methyl phenol, 2-tert-butyl-5-methyl phenol, and consumption pursuant an appropriate governmental agency 2-tert-butyl-6-methyl phenol; butylated hydroxyanisole and/or act, Such as the Food and Drug Administration (BHA) (e.g., 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl (FDA)/Federal Food Drug and Cosmetic Act (FD&C) in the 4-hydroxyanisole); butylhydroxytoluene (BHT); tert-butyl US or an analogous agency of the European Union. For hydroquinone (TBHQ); ascorbyl palmitate; n-propyl gallate; example, the coloring agent can be a food-grade dye or a salts thereof, and mixtures thereof. One of skill in the art will lake. A “dye' is a water soluble compound, which is appreciate that antioxidants can be classified as primary available as a powder, granule, liquid or other special antioxidants, secondary antioxidants, or metal chelators purpose form. A “lake' is a water insoluble form of a dye. based upon the mechanisms in which they act. Primary Exemplary coloring agents include, but are not limited to, antioxidants quench free radicals which are often the Source FD&C Blue No. 1 (Brilliant Blue), FD&C Blue No. 2 of oxidative pathways, whereas secondary antioxidants (Indigotine), FD&C Green No. 3 (Fast Green), FD&C Red function by decomposing the peroxides that are reactive No. 3 (Erythrosine), FD&C Red No. 40 (Allura Red), FD&C intermediates of the pathways. Metal chelators function by Yellow No. 5 (Tartrazine), FD&C Yellow No. 6 (Sunset sequestering the trace metals that promote free radical Yellow), annatto extract, anthocyanis, aronia/red fruit, beet development. In some embodiments, the antioxidant agent is juice, beet powder, beta-carotene, beta-apo-8-carotenal, resveratrol. black currant, burnt Sugar, canthaxanthin, caramel, carbo 0119. In some embodiments, the active agent is a wound medicinalis, carmine, carmine/beta-carotene, carmine blue, healing agent. As used herein, the term "wound healing carminic acid, carrot, carrot oils, chlorophyll, chlorophyllin, agent’ means active agents that are effective for promoting cochineal extract, copper-chlorophyll, copper-chlorophyllin, natural wound healing processes over days, weeks, or curcumin, curcumin/Cu-chlorophyllin, elderberry, grape, months. Exemplary wound healing agents include, but are grape skin extracts, hibiscus, lutein, mixed carotenoids, not limited to, proteinaceous growth factors, vascular paprika, paprika extract, paprika oleoresin, riboflavin, saf endothelial growth factors, anti-proliferant agent, antimicro fron, spinach, Stinging nettle, titanium dioxide, turmeric, and bials, and anti-inflammatory agents. combinations thereof. Preferred coloring agents according to 0120 In some embodiments, the active agent is a sooth the present invention are FD&C Blue No. 1 (Brilliant Blue), ing agent. As used herein, the term 'soothing agent’ means FD&C Blue No. 2 (Indigotine), FD&C Green No. 3 (Fast a molecule which helps in reducing the discomfort of the Green), FD&C Red No. 3 (Erythrosine), FD&C Red No. 40 skin and/or scalp, for example by soothing the feelings of (Allura Red), FD&C Yellow No. 5 (Tartrazine), FD&C itching. Exemplary soothing agents include, but are not Yellow No. 6 (Sunset Yellow), and any combinations limited to, aloe, avocado oil, green tea extract, hops extract, thereof. chamomile extract, colloidal oatmeal, calamine, cucumber I0123. In some embodiments; the active agent is a fra extract, Sodium palmate, Sodium palm kernelate, butyrosper grance. Exemplary fragrances include; but are not limited to, mum parkii (i.e., shea butter), menthe piperita (i.e., pepper 2,4-dimethyl-3-cyclohexene-1-carbaldehyde; isocyclocitral; mint) leaf oil, sericin, pyridoxine (a form of vitamin B6), menthone; isomenthone; ROMASCONER) (methyl 2,2-di retinyl palmitate and/or other forms of vitaminA, tocopheryl methyl-6-methylene-1-cyclohexanecarboxylate); nerone; acetate and/or other forms of vitamin E, lauryl laurate, terpineol; dihydroterpineol; terpenyl acetate; dihydroterpe hyaluronic acid, aloe barbadensis leaf juice powder, euterpe nyl acetate; dipentene; eucalyptol; hexylate; rose oxide; oleracea (i.e., acai berry) fruit extract, riboflavin (i.e., Vita PERYCOROLLE(R) ((S)-1,8-p-menthadiene-7-ol): 1-p-men min B2), thiamin HCl and/or other forms of vitamin B1, thene-4-ol: (1RS,3RS.4SR)-3-p-mentanyl acetate: (1R,2S, and/any combinations thereof. 4R)-4,6,6-trimethyl-bicyclo[3,1,1]heptan-2-ol; 0121. In some embodiments, the active agent is a cooling DOREMOXR (tetrahydro-4-methyl-2-phenyl-2H-pyran); agent. As used herein, the term “cooling agent” refers to cyclohexyl acetate; cyclanol acetate; Fructalate (1,4-cyclo US 2016/0346294 A1 Dec. 1, 2016

hexane diethyldicarboxylate); KOUMALACTONE(R) 0.124. In some embodiments, the active agent is an anti ((3ARS,6SR,7ASR)-perhydro-3,6-dimethyl-benzoB fungal agent. Examplary antifungal agents are described furan-2-one); Natactone ((6R)-perhydro-3,6-dimethyl elsewhere in the disclosure. As used herein, the terms benzo Bfuran-2-one); 2,4,6-trimethyl-4-phenyl-1,3-diox “fungus' or “fungi' include a variety of nucleated, spore ane; 2,4,6-trimethyl-3-cyclohexene-1-carbaldehyde; (E)-3- bearing organisms which are devoid of chlorophyll. methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2- Examples include yeasts, mildews, molds, rusts, and mush ol: (1R.E)-2-ethyl-4-(2,2',3'-trimethyl-3'-cyclopenten-1'- rooms. Examples of fungi include, but are not limited to yl)-2-buten-1-ol; POLY SANTOLOOR) (1'R.E)-3,3- Aspergillus fumigates, Aspergillus flavus, Aspergillus nidu dimethyl-5-(2,2',3'-trimethyl-3'-cyclopenten-1-yl)-4- lans, Candida albicans, Candida glabrata, Candida guilli ermondii, Candida krusei, Candida lusitaniae, Candida penten-2-ol); fleuramone: PARADISONER) (methyl-(1R)- parapsilosis, Candida tropicalis, Cryptococcus neoformans, cis-3-oxo-2-pentyl-1-cyclopentane acetate); Veloutone (2.2, Issatchenkia Orientalis, Coccidioides, Paracoccidioides, 5-Trimethyl-5-pentyl-1-cyclopentanone); NIRVANOLOR Histoplasma, Blastomyces, Trichophyton rubrum, and Neu (3.3-dimethyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4- rospora crassa. In some embodiments, fungus is of the penten-2-ol): 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1- genus Malassezia (e.g., M. furfur, M. pachydermatis, M. yl)-2-pentanol; damascones: NEOBUTENONE(R) (1-(5.5- dimethyl-1-cyclohexen-1-yl)-4-penten-1-one); nectalactone globosa, M. restricta, M. sloofiae, M. Sympodialis, M. nana, ((1R)-2-[2-(4-methyl-3'-cyclohexen-1-yl)propylcyclo M. vamatoensis, M. dermatis, and M. Obtuse). In one pentanone); alpha-ionone; beta-ionone; damascenone; embodiment, the fungus is Trichophyton rubrum. DYNASCONE(R) (mixture of 1-(5,5-dimethyl-1-cyclo 0.125. In some embodiments, the active agent is an anti hexen-1-yl)-4-penten-1-one and 1-(3.3-dimethyl-1-cyclo bacterial agent. Exemplary anti-bacterial agents are hexen-1-yl)-4-penten-1-one); DORINONER) beta (1-(2,6,6- described elsewhere in the disclosure. trimethyl-1-cyclohexen-1-yl)-2-buten-1-one); 0.126 In some embodiments, the active agent is an anti ROMANDOLIDE(R) ((1S,1'R)-1-(3',3'-Dimethyl-1'-cyclo scarring agent. As used herein, an “anti-scarring agent' hexyl)ethoxycarbonyl)methyl propanoate); 2-tert-butyl-1- refers to any agent which inhibit fibrosis or scarring. Useful cyclohexyl acetate; LIMBANOLR) (1-(2.2.3,6-tetramethyl anti-scarring agents can inhibit one or more aspect of the cyclohexyl)-3-hexanol): trans-1-(2.2,6-trimethyl-1- fibrosis process. For example, in certain embodiments, the cyclohexyl)-3-hexanol; (E)-3-methyl-4-(2,6,6-trimethyl-2- anti-scarring agent inhibits inflammation; collagen produc cyclohexen-1-yl)-3-buten-2-one; terpenyl isobutyrate; tion in, or release from, cells; and/or is an anti-infective or LORYSIAR (4-(1,1-dimethylethyl)-1-cyclohexyl acetate): antifungal agent. In some embodiments, the anti-scarring 8-methoxy-1-p-menthene: HELVETOLIDER) ((1S,1'R)-2- agent is selected from the group consisting of (-)-arctigenin, 1-(3',3'-dimethyl-1'-cyclohexyl) ethoxy-2-methylpropyl 6. The device of claim 1 or claim 2 wherein the anti-scarring propanoate); para tert-butylcyclohexanone; menthenethiol: agent is selected from an angiogenesis inhibitor, a 5-HT 1-methyl-4-(4-methyl-3-pentenyl)-3-cyclohexene-1-carbal inhibitor, a beta 1 integrin antagonist, a beta tubulin inhibi dehyde; allyl cyclohexylpropionate; cyclohexyl salicylate; tor, a bisphosphonate compound selected from risedronate Methyl cedryl ketone; Verdylate: vetyverol; vetyverone: and an analogue or derivative thereof, a blocker of enzyme 1-(octahydro-2.3,8,8-tetramethyl-2-naphtalenyl)-1-etha production in Hepatitis C, a bone mineralization promoter, none; (5RS.9RS, 10SR)-2,6,9,10-tetramethyl-1-oxaspiro4. a Bruton's tyrosine kinase inhibitor, a calcineurin inhibitor, 5 deca-3,6-diene and the (5RS.9SR,10RS) isomer; 6-ethyl a calcium channel blocker, a CaM kinase 11 inhibitor, a 2,10,10-trimethyl-1-oxaspiro4.5 deca-3,6-diene; 1,2,3,5,6, caspase 3 inhibitor, a cathepsin B inhibitor, a cathepsin K 7-hexahydro-1,1,2,3,3-pentamethyl-4-indenone; inhibitor, a cathepsin L inhibitor, a CB1/CB2 receptor ago HIVERNAL(R) (a mixture of 3-(3.3-dimethyl-5-indanyl)pro nist, a CC chemokine receptor antagonist, a CD40 antago panal and 3-(1,1-dimethyl-5-indanyl)propanal); Rhubofix(R) nist, a cell cycle inhibitor, a cell cycle inhibitor, a chemokine (3',4-dimethyl-tricyclo6.2.1.0(2,7) undec-4-ene-9-spiro-2'- receptor antagonist, a chymase inhibitor, a clotting factor, a oxirane); 9/10-ethyldiene-3-oxatricyclo6.2.1.0(2,7) unde collagenase antagonist, a cual integrin inhibitor, a CXCR cane: POLYWOODR (perhydro-5,5,8A-trimethyl-2-naph antagonist, a cyclic GMP agonist, a cyclindependent kinase thalenyl acetate); octalynol; CETALOXR (dodecahydro-3a, inhibitor, a cyclooxygenase 1 inhibitor, a D2 dopamine 6,6,9a-tetramethyl-naphthoI2, 1-bfuran); tricyclo5.2.1.0(2. receptor antagonist, a DHFR inhibitor, a diuretic, a DNA 6)dec-3-en-8-yl acetate and tricyclo5.2.1.0(2,6)dec-4-en alkylating agent, a DNA methylation inhibitor, a DNA 8-yl acetate as well as tricyclo[5.2.1.0(2.6)dec-3-en-8-yl methylation promoter, a DNA methylation promoter, a DNA propanoate and tricyclo5.2.1.0(2,6) dec-4-en-8-yl propano synthesis inhibitor, a DNA topoisomerase inhibitor, a dop ate; camphor, borneol; isobornyl acetate; 8-isopropyl-6- amine antagonist, a farnesyltransferase inhibitor, a farnexyl methyl-bicyclo[2.2.2]oct-5-ene-2-carbaldehyde: Call transferase inhibitor, a fibrinogen antagonist, a G protein phopinene; cedramber (8-methoxy-2,6,6,8-tetramethyl agonist, a glycosylation inhibitor, a heat shock protein 90 tricyclo5.3.1.0(1.5) undecane); cedrene; cedrenol; cedrol; antagonist, a histamine receptor antagonist, a histone FLOREX(R) (mixture of 9-ethylidene-3-oxatricyclo[6.2.1.0 deacetylase inhibitor, a histone deacetylase inhibitor, a (2.7) undecan-4-one and 10-ethylidene-3-oxatricyclo6.2.1. JAK2 inhibitor, a JAK3 enzyme inhibitor, a JNK inhibitor, 0(2,7)undecan-4-one): 3-methoxy-7,7-dimethyl-10-meth a kinase inhibitor, a kinesin antagonist, a leukotriene inhibi ylene-bicyclo[4.3.1 decane; CEDROXYDE(R) (trimethyl tor and antagonist, a lysyl hydrolase inhibitor, a MAP kinase 13-oxabicyclo-10.1.0-trideca-4,8-diene); Ambrettolide LG inhibitor, a matrix metalloproteinase inhibitor, a microtubule ((E)-9-hexadecen-16-olide); HABANOLIDER(pentade inhibitor, a microtubule inhibitor, a muscarinic receptor cenolide); muscenone (3-methyl-(4/5)-cyclopentade inhibitor, a neurokinin antagonist, a nitric oxide agonist, a cenone); muscone; EXALTOLIDER) (pentadecanolide); nitric oxide synthase inhibitor, a NO synthase inhibitor, a EXALTONER) (cyclopentadecanone); (1-ethoxyethoxy)cy norepinephrine reuptake inhibitor, a NSAID agent, a p38 clododecane; Astrotone; LILIAL(R); rosinol; and the like. MAP kinase inhibitor, a palmitoyl-protein thioesterase US 2016/0346294 A1 Dec. 1, 2016 59 inhibitor, a PDGF receptor kinase inhibitor, a peptidylgly ZD-6474, AP-23573, synthadotin, S-0885, aplidine, cine alpha-hydroxylating monooxygenase inhibitor, a pep ixabepilone, IDN-5390, SB-2723005, ABT-518, combret tidyl-prolyl cis/trans isomerase inhibitor, a Peptidyl-Prolyl astatin, anecortave acetate, SB-715992, temsirolimus, adali Cis/Trans isomerase Inhibitor, a peroxisome proliferator mumab, erucylphosphocholine, alphastatin, etanercept, activated receptor (PPAR) agonist, a pesticide, a phos humicade, gefitinib, isotretinoin, radicicol, clobetasol pro phatase inhibitor, a phosphodiesterase inhibitor, a PKC pionate, homoharringtonine, trichostatin A, brefeldin A, inhibitor, a PKC inhibitor, a platelet activating factor antago thapsigargin, dolastatin, cerivastatin, jasplakinolide, her nist, a platelet aggregation inhibitor, a polymorphonuclear bimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, neutrophil inhibitor, a prolyl hydroxylase inhibitor, a pros loteprednol etabonate, juglone, prednisolone, puromycin, taglandin inhibitor, a protein synthesis inhibitor, a protein 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, tyrosine kinase inhibitor, a purineoreceptor P2X antagonist, Ly333531 (ruboxistaurin), and simvastatin. a pyruvate dehydrogenase activator, a Raf kinase inhibitor, I0127. In some embodiments, the active agent is a skin a RAR/RXT antagonist, a reducing agent, a retinoic acid regenerating agent. Some skin regenerating agents can act as receptor antagonist, a retinoic acid receptor antagonist, a anti-Scarring agents. selective serotonin reuptake inhibitor, a serine protease I0128. In some embodiments, the drug carrier comprises inhibitor, a serotonin receptor inhibitor, a sheddase inhibitor, an additional anti-acne agent. In some embodiments, the a sodium channel inhibitor, a steroid, a steroid, a stromelysin additional anti-acne agent can be selected from the group inhibitor, a Superoxide anion generator, a TACE inhibitor, a consisting of acetretin, adapalene(s), alitretinoin, alpha- or telomerase inhibitor, a TGF beta inhibitor, a thromboxane beta-hydroxy acids, antibiotics, antimicrobial peptides, anti A2 receptor inhibitor, a TNF-alpha antagonist, a Toll recep microbials, aZelaic acid, benzoyl peroxide, beXarotene, bile tor inhibitor, a tryptase inhibitor, a tubulin antagonist, a salts, biofilm inhibitors, clindamycin, erythromycin, etreti tumor necrosis factor antagonist, a tyrosine kinase inhibitor, nate, glycolic acid, isotretinoin, keratolytic agents, lactic a VEGF inhibitor, a vitamin D receptor agonist, amplicillin acid, lipoic acid, N-acetylcystein, natural anti-acne agents, Sodium salt, an acetylcholinesterase inhibitor, an actin octopirox, phenoxyethanol, phenoxypropanol, pyruvic acid, polymerization and stabilization promoter, an adenylate resorcinol, retinoic acid, retinoid(s), Salicylic acid, sebostats, cyclase agonist, an ALK-5 receptor antagonist, an alpha Sodium Sulfacetamide, spironolactone, Sulfur, Sulfur con adrenergic receptor antagonist, an androgen inhibitor, an taining D- or L-amino acids, tazarotene, tea tree oil, anesthetic compound, an angiotensin II receptor agonist, an tretinoin, triclosan, urea, and any combinations thereof. antibiotic selected from the group consisting of apigenin, an 0129. The drug carrier disclosed herein can comprise any anti-coagulant, an anti-emetic agent, an anti-inflammatory amount of the API (e.g., DART or other agent). For example, compound, an antimetabolite and antineoplastic agent, an the drug carrier can comprise about 0.01% to about 99% anti-microbial agent, an anti-microbial agent, an antine (w/w) of the API. For example, the particle can comprise oplastic agent, an antioxidant, an anti-proliferative agent, an between about 0.01% to about 20% (w/w) of the API. In anti-psychotic compound, an anti-spasmodic agent, an anti some embodiments, the API comprises greater than 1% thrombotic agent, an anti-viral agent, an apoptosis activator, (w/w), greater than 5% (w/w), greater than 10% (w/w), an apoptosis activator, an apoptosis antagonist, an aromatase greater than 15% (w/w), greater than 20% (w/w), greater inhibitor, an AXOR12 agonist, an elastase inhibitor, an than 25% (w/w), greater than 30% (w/w), greater than 35% elF-2a inhibitor, an elongation factor-1 alpha inhibitor, an (w/w), greater than 40% (w/w), greater than 45% (w/w), endothelial growth factor antagonist, an endothelial growth greater than 50% (w/w), greater than 55% (w/w), greater factor receptor kinase inhibitor, an endotoxin antagonist, an than 60% (w/w), greater than 65% (w/w), greater than 70% epothilone and tubulin binder, an estrogen agonist, an estro (w/w), greater than 75% (w/w), greater than 80% (w/w), gen receptor antagonist, an FGF inhibitor, an FGF receptor greater than 85% (w/w), greater than 90% (w/w), or greater kinase inhibitor, an FLT-3 kinase inhibitor, an FXR antago than 95% (w/w) of the total weight of the drug carrier. In nist, an HMGCoA reductase inhibitor, an HMGCoA reduc some embodiments, the content of API in the drug carrier tase inhibitor, an ICAM inhibitor, an IL, an IL-2 inhibitor, an can range from about 75% to about 97% (w/w). In some immunosuppressant, an inhibitor of type III receptor tyro other embodiments, the content of API in the drug carrier sine kinase, an inosine monophosphate inhibitor, an inter can range from about 3% to about 25% (w/w). leukin antagonist, an intracellular calcium flux inhibitor, an 0.130. A lipid for use in the drug carriers or formulations intracellular calcium flux inhibitor, an intracellular calcium disclosed herein can be selected from the group consisting of influx inhibitor, an irreversible inhibitor of enzyme methio fatty acids, fatty alcohols, glycerolipids (e.g., monoglycer nine aminopeptidase type 2, an isozyme selective delta ides, diglycerides, and triglycerides), phospholipids, glyc protein kinase C inhibitor, an MCP-CCR2 inhibitor, an erophospholipids, sphingolipids, sterol lipids, prenol lipids, MEK1/MEK2 inhibitor, an MIF inhibitor, an mTOR inhibi saccharolipids, polyketides, and any combination thereof. In tor, an mTOR kinase inhibitor, an NF kappa B inhibitor, an Some embodiments, the lipid can be selected from the group ornithine decarboxylase inhibitor, an S-adenosyl-L-homo consisting of 1.3-Propanediol Dicaprylate/Dicaprate; 10-un cysteine hydrolase inhibitor, an SDF-1 antagonist, an SRC decenoic acid, 1-dotriacontanol, 1-heptacosanol; 1-nonaco inhibitor, an Syk kinase inhibitor, an O-glucosidase inhibitor, sanol; 2-ethylhexanol; Androstanes; Arachidic acid; Arachi an integrin antagonist, and a immuno-modulator selected donic acid; arachidyl alcohol; Behenic acid; behenyl from Bay 11-7085, and IRAK antagonist, ICE, idazoxan alcohol; Capmul MCM C10: Capric acid; capric alcohol: hydrochloride, protein kinase B inhibitor, protein kinase C capryl alcohol; Caprylic acid; Caprylic/Capric Acid Ester of stimulant, purine nucleoside analogue, puromycin, revers Saturated Fatty Alcohol C12-C18; Caprylic/Capric Triglyc ible inhibitor of ErbB1 and ErbB2, ribonucleoside triphos eride; Caprylic/Capric Triglyceride; Ceramide phosphoryl phate reductase inhibitor, any combination thereof. In some choline (Sphingomyelin, SPH); Ceramide phosphoryletha embodiments, the anti-scarring agent can be selected from nolamine (Sphingomyelin, Cer-PE): Ceramide US 2016/0346294 A1 Dec. 1, 2016 60 phosphorylglycerol; Ceroplastic acid; Cerotic acid; Cerotic fatty acid salt. Without limitations, the fatty acid salt can be acid; ceryl alcohol; Cetearyl alcohol; Ceteth-10; cetyl alco selected from the group consisting of Zinc, Sodium, potas hol; Cholanes; Cholestanes; cholesterol, cis-11-eicosenoic sium, lithium, ammonium, copper, calcium, magnesium, acid; cis-11-octadecenoic acid, cis-13-docosenoic acid; strontium, manganese, and combinations thereof. The drug cluytyl alcohol; coenzyme Q10 (CoQ10); Dihomo-y-lino carrier can comprise any amount of the lipid component. For lenic; Docosahexaenoic acid; egg lecithin; Eicosapentaenoic example, the drug carrier can comprise between about acid; Eicosenoic acid; Elaidic acid; elaidolinolenyl alcohol: 0.01% to about 99% (w/w) of the lipid component. In some elaidolinoleyl alcohol; elaidyl alcohol; Erucic acid; erucyl embodiments, the lipid component comprises greater than alcohol; Estranes; Ethylene glycol distearate (EGDS); Ged 0.1% (w/w), greater than 0.5% (w/w), greater than 1% dic acid: geddyl alcohol; glycerol distearate (type I) EP (w/w), greater than 2% (w/w), greater than 3% (w/w), (Precirol ATO 5); Glycerol Tricaprylate/Caprate; Glycerol greater than 4% (w/w), greater than 5% (w/w), greater than Tricaprylate/Caprate (CAPTEXR 355 EP/NF); glyceryl 6% (w/w), greater than 7% (w/w), greater than 8% (w/w), monocaprylate (Capmul MCM C8 EP); Glyceryl Triacetate; greater than 9% (w/w), greater than 10% (w/w), greater than Glyceryl Tricaprylate: Glyceryl Tricaprylate/Caprate/Lau 1% (w/w), greater than 12% (w/w), greater than 13% (w/w), rate; Glyceryl Tricaprylate/Tricaprate; glyceryl tripalmitate greater than 14% (w/w), greater than 15% (w/w), greater (Tripalmitin); Henatriacontylic acid; Heneicosyl alcohol; than 16% (w/w), greater than 17% (w/w), greater than 18% Heneicosylic acid; Heptacosylic acid; Heptadecanoic acid; (w/w), greater than 19% (w/w), greater than 20% (w/w), Heptadecyl alcohol; Hexatriacontylic acid; isostearic acid; greater than 25% (w/w), greater than 30% (w/w), greater isostearyl alcohol; Lacceroic acid; Lauric acid; Lauryl alco than 35% (w/w), greater than 40% (w/w), greater than 45% hol; Lignoceric acid, lignoceryl alcohol; Linoelaidic acid; (w/w), or greater than 50% (w/w) of the total weight of the Linoleic acid; linolenyl alcohol; linoleyl alcohol; Margaric drug carrier. Typically, the content of the lipid component in acid; Mead; Melissic acid; melissyl alcohol; Montanic acid; the drug carriers are in the range of about 2-25% (w/w). montanyl alcohol; myricyl alcohol; Myristic acid; Myristo I0132) Ratio of the active agent (e.g., DART or other leic acid; Myristyl alcohol; neodecanoic acid; neoheptanoic anti-bacterial agent) to the total lipid component of the acid; neononanoic acid; Nervonic; Nonacosylic acid; Non coating layer can be any desired ratio. For example, ratio of adecyl alcohol; Nonadecylic acid; Nonadecylic acid; Oleic the active agent to the total lipid component can range from acid; oleyl alcohol; Palmitic acid; Palmitoleic acid; palmi about 100:1 to about 1:100. In some embodiments, the ratio toleyl alcohol; Pelargonic acid; pelargonic alcohol; Penta of the active agent to the total lipid component can range cosylic acid; Pentadecyl alcohol; Pentadecylic acid; Phos from about 75:1 to about 1:75, from about 50:1 to about phatidic acid (phosphatidate, PA); Phosphatidylcholine 1:50, from about 25:1 to about 1:25, from about 20:1 to (lecithin, PC): Phosphatidylethanolamine (cephalin, PE); about 1:20, from about 15:1 to about 1:15, from about 5:1 to Phosphatidylinositol (PI); Phosphatidylinositol bisphos about 1:5, or from about 25:1 to about 1:5. In some embodi phate (PIP2); Phosphatidylinositol phosphate (PIP); Phos ments, the ratio of the active agent to the total lipid com phatidylinositol triphosphate (PIP3); Phosphatidylserine ponent is about 30:1, about 25:1, about 20:1, about 15:1, (PS); polyglyceryl-6-distearate; Pregnanes; Propylene Gly about 10:1, about 5:1, or about 1:1. The ratio can be based col Dicaprate; Propylene Glycol Dicaprylocaprate; Propyl on weight, mass, or moles. ene Glycol Dicaprylocaprate; Psyllic acid; recinoleaic acid; I0133. Thickness of the coating layer can range from recinoleyl alcohol, Sapienic acid; soy lecithin; Stearic acid; nanometers to millimeters. For example, the coating layer Stearidonic; stearyl alcohol; Tricosylic acid; Tridecyl alco thickness can range from about 1 nm to about 5000 nm, from hol; Tridecylic acid; Triolein: Undecyl alcohol; undecylenic about 5 nm to about 2500 nm, from about 10 nm to about acid; Undecylic acid; Vaccenic acid; C-Linolenic acid; Y-Li 2000 nm, from about 50 nm to about 1500 nm, from about nolenic acid; a fatty acid salt of 10-undecenoic acid, ada 20 nm to about 1000 nm, from about 1 nm to about 1000 nm, palene, arachidic acid, arachidonic acid, behenic acid, from about 1 nm to about 500 nm, from about 1 nm to about butyric acid, capric acid, caprylic acid, cerotic acid, cis-11 250 nm, from about 1 nm to about 200 nm, from about 1 nm. eicosenoic acid, cis-11-octadecenoic acid, cis-13-docose to about 150 nm, from about 1 nm to about 100 nm, from noic acid, docosahexaenoic acid, eicosapentaenoic acid, about 2 nm to about 50 nm, or from about 5 nm to about 25 elaidic acid, erucic acid, heneicosylic acid, heptacosylic acid, heptadecanoic acid, isostearic acid, lauric acid, ligno I0134. In some embodiments, the drug carrier can com ceric acid, linoelaidic acid, linoleic acid, montanic acid, prise two or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) myristic acid, myristoleic acid, neodecanoic acid, neohep lipids, i.e., the carrier can comprise a first lipid and a second tanoic acid, neononanoic acid, nonadecylic acid, oleic acid, lipid. For example, the coating layer can comprise a second palmitic acid, palmitoleic acid, pelargonic acid, pentacosylic lipid that is different from the first lipid. acid, pentadecylic acid, recinoleaic acid (e.g. Zinc recino 0.135 Exemplary proteins for use in the drug carriers or leate), sapienic acid, Stearic acid, tricosylic acid, tridecylic formulations disclosed herein can include, but are not lim acid, undecylenic acid, undecylic acid, vaccenic acid, Valeric ited to, Actin, Albumin, Amaranth Protein, Ammonium acid, C.-linolenic acid, or Y-linolenic acid; paraffin, and any Hydrolyzed Animal Protein, Animal protein, Barley Protein, combinations thereof. In some embodiments, the lipid can Brazil Nut Protein, Casein, Collagen, Collagen protein be a fatty acid comprising 11 or fewer carbons. For example hydrolyzed, Conchiolin Protein, corn protein, Cottonseed the fatty acid can comprise 6, 7, 8, 9, 10, or 11 carbons. Protein, Elastin, Extensin, Fibroin, Fibronectin, Fish Pro 0131 Without wishing to be bound by a theory, it is tein, Gadidae Protein, Gelatin, Glutein, Glycoproteins, believed that fatty acid salts can be also used in the particles Hazelnut Protein, Hemoglobin, Hemp Seed Protein, Honey to potentiate anti-bacterial activity, e.g., anti-acne activity Protein, Hydrolyzed Actin, Hydrolyzed Amaranth Protein, and provide stability in compositions comprising said drug Hydrolyzed animal protein, Hydrolyzed Barley Protein, carriers. Accordingly, in Some embodiments, the lipid is a Hydrolyzed Brazil Nut Protein, Hydrolyzed Conchiolin Pro US 2016/0346294 A1 Dec. 1, 2016

tein, Hydrolyzed corn protein, Hydrolyzed Cottonseed Pro P08835-1), pigeon (e.g. as defined by Khan et al., 2002,1112. tein, Hydrolyzed Elastin, Hydrolyzed Extensin, Hydrolyzed J. Biol. Macromol, 30(3-4), 171-8), rabbit (e.g., see Swis Fibroin, Hydrolyzed Fibronectin, Hydrolyzed Fish Protein, sprot accession number P490 65-1), rat (e.g., see Swissprot Hydrolyzed Gadidae Protein, Hydrolyzed Gadidae Protein, accession number P02770-1), salamander (e.g., see Swis Hydrolyzed Gelatin, Hydrolyzed Hair Keratin, Hydrolyzed sprot accession number Q8UW05-1), salmon ALB1 (e.g., Hazelnut, Hydrolyzed Hazelnut Protein, Hydrolyzed Hemo see Swissprot accession number P21848-1), salmon ALB2 globin, Hydrolyzed Hemp Seed Protein, Hydrolyzed Honey (e.g., see Swissprot accession number Q03156-1), sea lam Protein, Hydrolyzed Keratin, Hydrolyzed Lupine Protein, prey (e.g., see Swissprot accession number Q91274-1 and Hydrolyzed Maple Sycamore Protein, Hydrolyzed Milk 042279-1) sheep (e.g., see Swissprot accession number Protein, Hydrolyzed Oat Protein, Hydrolyzed Pea Protein, P14639-1), Sumatran orangutan (e.g., see Swissprot acces Hydrolyzed Potato Protein, Hydrolyzed Reticulin, Hydro sion number Q5NVH5-1), tuatara (e.g., see Swissprot acces lyzed Royal Jelly Protein, Hydrolyzed Sericin, Hydrolyzed sion number Q8JIA9-1), turkey ovalbumin (e.g., see Swis Serum Protein, Hydrolyzed Sesame Protein, Hydrolyzed sprot accession number 073860-1), Western clawed frog Soy Protein, Hydrolyzed Soymilk Protein, Hydrolyzed Spi (e.g., see Swissprot accession number Q6D.I95-1), and nal Protein, Hydrolyzed Spongin, Hydrolyzed Sweet includes variants and fragments thereof as defined herein. Almond Protein, Hydrolyzed Vegetable Protein, Hydrolyzed Many naturally occurring mutant forms of albumin are Wheat Gluten, Hydrolyzed Wheat Protein, Hydrolyzed known. Many are described in Peters, (1996, All About Whey Protein, Hydrolyzed Yeast Protein, Hydrolyzed Albumin: Biochemistry, Genetics and Medical Applications, Yogurt Protein, Hydrolyzed Zein, Integrin, Jojoba protein Academic Press, Inc., San Diego, Calif., p. 170-181), con HP, Hydrolyzed, keratin, Lupine Protein, Maple Sycamore tent of which is incorporated herein by reference. The term Protein, MEADHydrolyzed Collagen, MEADHydrolyzed albumin also encompasses albumin variants, such as geneti Silk, Milk Protein, Myosin, Oat Protein, Pea Protein, polyly cally engineered forms, mutated forms, and fragments etc. sine, Potato Protein, Reticulin, Rice Quat, Royal Jelly Pro having one or more binding sites that are analogous to a tein, Sericin, Serum Protein, Sesame Protein, Silk powder, binding site unique for one or more albumins as defined Sodium Hydrolyzed Casein, Soy Protein, Soy Rice Peptides, above. By analogous binding sites in the context of the Soymilk Protein, Spinal Protein, Spongin, Sweet Almond invention are contemplated structures that are able to com Protein, Vegetable Protein, Wheat Gluten, Whey Protein, pete with each other for binding to one and the same ligand Yeast Protein, Yogurt Protein, Zein, and Zinc Hydrolyzed structure. In one embodiment, albumin is bovine serum Collagen. albumin, egg albumin, hydrolyzed lactalbumin, or lactalbu min, including variants and fragments thereof. In one 0136. In some embodiments, the protein is an albumin. The albumin can be a naturally occurring albumin, an embodiment, the protein is egg albumin. albumin related protein or a variant thereof such as a natural 0.137 The protein can comprise between about 0.01% to or engineered variant. Variants include polymorphisms, about 99% (w/w) of the drug carrier. In some embodiments, fragments such as domains and Subdomains, fragments the protein component comprises greater than 0.1% (W/w), and/or fusion proteins. An albumin can comprise the greater than 0.5% (w/w), greater than 1% (w/w), greater than sequence of an albumin protein obtained from any source. A 2% (w/w), greater than 3% (w/w), greater than 4% (w/w), number of proteins are known to exist within the albumin greater than 5% (w/w), greater than 6% (w/w), greater than family. Accordingly, the albumin can comprise the sequence 7% (w/w), greater than 8% (w/w), greater than 9% (w/w), of an albumin derived from one of serum albumin from greater than 10% (w/w), greater than 11% (w/w), greater African clawed frog (e.g., see Swissprot accession number than 12% (w/w), greater than 13% (w/w), greater than 14% P08759-1), bovine (e.g., see Swissprot accession number (w/w), greater than 15% (w/w), greater than 1.6% (w/w), P02769-1), cat (e.g., see Swissprot accession number greater than 17% (w/w), greater than 18% (w/w), greater P49064-1), chicken (e.g., see Swissprot accession number than 19% (w/w), greater than 20% (w/w), greater than 25% P19121-1), chicken ovalbumin (e.g., see Swissprot acces (w/w), greater than 30% (w/w), greater than 35% (w/w), sion number P01012-1), cobra ALB (e.g., see Swissprot greater than 40% (w/w), greater than 45% (w/w), or greater accession number Q91134-1), dog (e.g., see Swissprot than 50% (w/w) of the total weight of the drug carriers. accession number P49822-1), donkey (e.g., see Swissprot Typically, the content of the protein component in the drug accession number QSXLE4-1), European water frog (e.g., carriers are in the range of about 1-25% (w/w), about see Swissprot accession number Q9YGH6-1), blood fluke 0.1-10% (w/w), about 0.5-5% (w/w), or about 1-1.5% (e.g., see Swissprot accession number AAL08579 and (w/w). Q95VB7-1), Mongolian gerbil (e.g., see Swissprot acces 0.138 Ratio of the active agent (e.g., DART or other sion number 035090-1 and JC5838), goat (e.g., see Swis anti-bacterial agent) to the protein component can be any sprot accession number B3VHM9-1 and as available from desired ratio. For example, ratio of the active agent to the Sigma as product no. A2514 or A4164), guinea pig (e.g., see protein component can range from about 100:1 to about Swissprot accession number Q6WDN9-1), hamster (see 1:100. In some embodiments, the ratio the active agent to the DeMarco et al. (2007). International Journal for Parasitology protein can range from about 100:1 to about 1:1, from about 37(11): 1201-1208), horse (e.g., see Swissprot accession 90:1 to about 10:1, from about 85:1 to about 15:1, from number P35747-1), human (e.g., see Swissprot accession about 80:1 to about 25:1, or from 75:1 to about 50:1. In some number P02768-1), Australian Lung-fish (e.g., see Swissprot embodiments, the ratio of the active agent to the protein accession number P83517), macaque (Rhesus monkey) component is about 75:1. The ratio can be based on weight, (e.g., see Swissprot accession number Q28522-), mouse mass, or moles. (e.g., see Swissprot accession number P07724-1), North 0.139 Generally, any cationic molecule can be used in the American bull frog (e.g., see Swissprot accession number drug carriers or formulations disclosed herein. As used P21847-1), pig (e.g., see Swissprot accession number herein the term "cationic molecule' refers to a molecule that US 2016/0346294 A1 Dec. 1, 2016 62 carries a net positive charge. In some embodiments, the greater than 12% (w/w), greater than 13% (w/w), greater cationic molecule is a polyamine. Exemplary cationic mol than 14% (w/w), greater than 15% (w/w), greater than 16% ecules include, but are not limited to, Putrescine (Butane (w/w), greater than 17% (w/w), greater than 18% (w/w), 1,4-diamine), Cadaverine (Pentane-1,5-diamine), Spermi greater than 19% (w/w), greater than 20% (w/w), greater dine, Spermine, Cyclen (1,4,7,10-tetrazacyclododecane), than 25% (w/w), greater than 30% (w/w), greater than 35% Cyclam (1,4,8,11-Tetraazacyclotetradecane), Linear Poly (w/w), greater than 40% (w/w), greater than 45% (w/w), or ethyleneimine (Poly(iminoethylene)), Norspermidine, greater than 50% (w/w) of the total weight of the drug p-Phenylenediamine (1,4-diaminobenzene), Diethylenetri carriers. Typically, the content of the carbohydrate in the amine (N-(2-aminoethyl)-1,2-ethanediamine), thermosper drug carriers are in the range of about 1-25% (w/w), about mine, Tris(2-aminoethyl)amine, Hexamethylenediamine, 0.1-10% (w/w), about 0.5-5% (w/w), or about 1-1.5% Beta-lysine (3,6-diaminohexanoic acid), m-Phenylenedi (w/w). amine (1,3-diaminobenzene), Diaminopropane (1,2-Di 0144. Ratio of the active agent (e.g., DART or other aminopropane), Ethylenediamine dihydroiodide, and anti-bacterial agent) to the carbohydrate can be any desired polyamine D 400 (Polyoxyalkyleneamine D 400). ratio. For example, ratio of the active agent to the carbohy 0140. The cationic molecule can comprise between about drate can range from about 100:1 to about 1:100. In some 0.01% to about 99% (w/w) of the drug carrier. In some embodiments, the ratio the active agent to the carbohydrate embodiments, the cationic molecule comprises greater than can range from about 100:1 to about 1:1, from about 90:1 to 0.1% (w/w), greater than 0.5% (w/w), greater than 1% about 10:1, from about 85:1 to about 15:1, from about 80:1 (w/w), greater than 2% (w/w), greater than 3% (w/w), to about 25:1, or from 75:1 to about 50:1. In some embodi greater than 4% (w/w), greater than 5% (w/w), greater than ments, the ratio of the active agent to the carbohydrate is 6% (w/w), greater than 7% (w/w), greater than 8% (w/w), about 75:1. The ratio can be based on weight, mass, or greater than 9% (w/w), greater than 10% (w/w), greater than moles. 11% (w/w), greater than 12% (w/w), greater than 13% 0145. In some embodiments, the drug carrier further (w/w), greater than 14% (w/w), greater than 15% (w/w), comprises an excipient. In some embodiments, the excipient greater than 1.6% (w/w), greater than 17% (w/w), greater is a wetting agent. Without limitations, the wetting agent can than 18% (w/w), greater than 19% (w/w), greater than 20% be selected from alkyl Sulfates, e.g. sodium lauryl Sulfate, (w/w), greater than 25% (w/w), greater than 30% (w/w), Sodium Stearyl Sulfate, Sodium oleyl Sulfate and sodium greater than 35% (w/w), greater than 40% (w/w), greater cetyl sulfate, alkyl aryl Sulfonates, e.g. sodium dodecylben than 45% (w/w), or greater than 50% (w/w) of the total Zene sulfonate and dialkyl sodium sulfosuccinates, e.g. weight of the drug carriers. Typically, the content of the Sodium bis-(2-ethylhexyl)sulfo Succinate, and most prefer cationic molecule in the drug carriers are in the range of ably sodium lauryl sulfate. Further examples of the phar about 1-25% (w/w), about 0.1-10% (w/w), about 0.5-5% maceutically acceptable wetting agent include benzetho (w/w), or about 1-1.5% (w/w). nium chloride, cetylpyridinium chloride, docusatesodium, 0141 Ratio of the active agent (e.g., DART or other poloxamer, polysorbate and Sorbitan esters. anti-bacterial agent) to the protein component can be any 0146 In some embodiments, the excipient is a stabilizer, desired ratio. For example, ratio of the active agent to the e.g., a Surface stabilizer. Suitable Surfacestabilizers can protein component can range from about 100:1 to about preferably be selected from known organic and inorganic 1:100. In some embodiments, the ratio the active agent to the pharmaceutical excipients. Such excipients include various protein can range from about 100:1 to about 1:1, from about polymers, low molecular weight oligomers, natural prod 90:1 to about 10:1, from about 85:1 to about 15:1, from ucts, and Surfactants with high and low hydrophilic lipo about 80:1 to about 25:1, or from 75:1 to about 50:1. In some philic balance (HLB). Preferred surfacestabilizersinclude embodiments, the ratio of the active agent to the protein nonionic and ionic Surfactants. Two or more surfacestabi component is about 75:1. The ratio can be based on weight, lizers can be used in combination. Representative examples mass, or moles. of Surfacestabilizersinclude Sodium docusate, cetyl pyri 0142 Generally, any carbohydrate molecule can be used dinium chloride, gelatin, casein, lecithin (phosphatides), in the drug carriers or formulations disclosed herein. In some dextran, glycerol, gum acacia, cholesterol, tragacanth, embodiments, the carbohydrate is a polysaccharide. Exem Stearic acid, benzalkonium chloride, calcium Stearate, glyc plary polysaccharides include cellulose derivatives such as erol monostearate, cetostearyl alcohol, cetomacrogol emul hydroxyethyl-cellulose, hydroxy propyl-methyl-cellulose Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers and carboxymethylcellulose; glycosaminoglycans such as (e.g., macrogol ethers such as cetomacrogol 1000), poly hyaluronic acid, chondroitin Sulfate, chitin and chitosan; oxyethylene castor oil derivatives, polyoxyethylene sorbitan starch derivatives such as starch/hydroxyethyl starch; aga fatty acid esters (e.g., the commercially available Tweens(R) rose; and alginate and combinations thereof. In some such as e.g., Tween 20R) and Tween 80R(ICI Specialty embodiments, the carbohydrate can be selected from the Chemicals); polyethylene glycols (e.g., Carbowaxs 3350R) group consisting of chitosan and their derivatives, alginates and 1450R, and Carbopol 934(R) (Union Carbide)), dodecyl and their derivatives, pullulan, their derivatives trimethyl ammonium bromide, polyoxyethylene Stearates, 0143. The carbohydrate can comprise between about colloidal silicon dioxide, phosphates, sodium dodecylsul 0.01% to about 99% (w/w) of the drug carrier. In some fate, carboxymethylcellulose calcium, hydroxypropyl cellu embodiments, the carbohydrate comprises greater than 0.1% loses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl (w/w), greater than 0.5% (w/w), greater than 1% (w/w), methylcellulose (HPMC), carboxymethylcellulose sodium, greater than 2% (w/w), greater than 3% (w/w), greater than methylcellulose, hydroxyethylcellulose, hydroxypropylcel 4% (w/w), greater than 5% (w/w), greater than 6% (w/w), lulose, hydroxypropylmethyl-cellulose phthalate, noncrys greater than 7% (w/w), greater than 8% (w/w), greater than talline cellulose, magnesium aluminum silicate, trietha 9% (w/w), greater than 10% (w/w), greater than 11% (w/w), nolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone US 2016/0346294 A1 Dec. 1, 2016

(PVP), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with um. As used herein, the term “nanoparticle' refers to particle ethylene oxide and formaldehyde (also known as tyloxapol, having a particle size of about 0.1 nm to about 1000 nm. Superione, and triton), poloxamers (e.g., Pluronics F68(R) and 0150. It will be understood by one of ordinary skill in the F108(R), which are block copolymers of ethylene oxide and art that particles usually exhibit a distribution of sizes propylene oxide); poloxamines (e.g., Tetronic 908 R, also around the indicated "size.” Unless otherwise stated, the known as Poloxamine 908R, which is a tetrafunctional terms “drug carrier size' and “particle size' as used herein block copolymer derived from sequential addition of pro refer to the mode of a size distribution of drug carriers or pylene oxide and ethylene oxide to ethylenediamine (BASF particles, i.e., the value that occurs most frequently in the Wyandotte Corporation, Parsippany, N.J.)); a charged phos size distribution. Methods for measuring the drug carrier or pholipid such as dimyristoyl phophatidylglycerol, dioctyl particle size are known to a skilled artisan, e.g., by dynamic sulfosuccinate (DOSS); Tetronic 1508(R) (T-1508) (BASF light scattering (Such as photocorrelation spectroscopy, laser Wyandotte Corporation), dialkylesters of sodium sulfosuc diffraction, low-angle laser light scattering (LALLS), and cinic acid (e.g., Aerosol OTR), which is a dioctyl ester of medium-angle laser light scattering (MALLS)), light obscu Sodium SulfoSuccinic acid (American Cyanamid)); Duponol ration methods (such as Coulter analysis method), or other P(R), which is a sodium lauryl sulfate (DuPont); Tritons techniques (such as rheology, and light or electron micros X-200R, which is an alkyl aryl polyether sulfonate (Rohm copy). and Haas); Crodestas F-1 10R, which is a mixture of sucrose 0151. In some embodiments, the drug carrier can be Stearate and Sucrose distearate (Croda Inc.), p-isononylphe substantially spherical. What is meant by “substantially noxypoly-(glycidol), also known as Olin-IOGR) or Surfac spherical is that the ratio of the lengths of the longest to the tant 10-GR(Olin Chemicals, Stamford, Conn.); Crodestas shortest perpendicular axes of the drug carrier cross section SL-40R (Croda, Inc.); decanoyl-N-methylglucamide; n-de is less than or equal to about 1.5. Substantially spherical cyl B-D-glucopyranoside; n-decyl B-D-maltopyranoside; does not require a line of symmetry. Further, the drug n-dodecyl B-D-glucopyranoside; n-dodecyl B-D-maltoside; carriers can have Surface texturing, such as lines or inden heptanoyl-N-methylglucamide; n-heptyl-B-D-glucopyrano tations or protuberances that are Small in Scale when com side; n-heptyl B-D-thioglucoside; n-hexyl B-D-glucopyrano pared to the overall size of the drug carrier and still be side; nonanoyl-N-methylglucamide; n-noyl B-D-glucopyra Substantially spherical. In some embodiments, the ratio of noside; octanoyl-N-methylglucamide; n-octyl-f-D- lengths between the longest and shortest axes of the drug glucopyranoside; octyl B-D-thioglucopyranoside; and the carrier is less than or equal to about 1.5, less than or equal like. Most of these surfacestabilizers are known pharmaceu to about 1.45, less than or equal to about 1.4, less than or tical excipients and are described in detail in the Handbook equal to about 1.35, less than or equal to about 1.30, less than of Pharmaceutical Excipients, published jointly by the or equal to about 1.25, less than or equal to about 1.20, less American Pharmaceutical Association and The Pharmaceu than or equal to about 1.15 less than or equal to about 1.1. tical Society of Great Britain (The Pharmaceutical Press, Without wishing to be bound by a theory, surface contact is 1986), content of which is incorporated herein by reference minimized in drug carriers that are substantially spherical, in its entirety. In one embodiment, the excipient is sodium which minimizes the undesirable agglomeration of the drug docusate. carriers upon storage. Many crystals or flakes have flat 0147 Generally, the drug carriers have an average diam Surfaces that can allow large Surface contact areas where eter of from about 5 nm to about 20,000 nm. In some agglomeration can occur by ionic or non-ionic interactions. embodiments, the drug carriers have an average diameter of A sphere permits contact over a much smaller area. from about 5 nm to about 5,000 nm. In some embodiments, 0152. In some embodiments, the drug carriers have sub the drug carriers have an average diameter of from about 50 stantially the same particle size. Drug carriers having a nm to about 2500 nm. In some embodiments, the drug broad size distribution where there are both relatively big carriers have an average diameter of from about 100 nm to and Small drug carriers allow for the Smaller drug carriers to about 2000 nm. In some embodiments, the drug carriers fill in the gaps between the drug carriers, thereby creating have an average diameter of from about 150 nm to about new contact Surfaces. A broad size distribution can result in 1700 nm. In some embodiments, the drug carriers have an larger spheres by creating many contact opportunities for average diameter of from about 200 nm to about 1500 nm. binding agglomeration. The drug carriers described herein In some embodiment, the drug carriers have an average are within a narrow size distribution, thereby minimizing diameter of about 260 nm. In one embodiment, the drug opportunities for contact agglomeration. What is meant by a carriers have an average diameter of about 30 nm to about “narrow size distribution' is a particle size distribution that 150 nm. In some embodiments, the drug carriers have an has a ratio of the volume diameter of the 90th percentile of average diameter of about 100 nm to about 1000 nm, from the small spherical particles to the volume diameter of the about 200 nm to about 800 nm, from about 200 nm to about 10th percentile less than or equal to 5. In some embodi 700 nm, or from about 300 nm to about 700 nm. ments, the volume diameter of the 90th percentile of the 0148 Generally, the drug carriers disclosed herein can be small spherical particles to the volume diameter of the 10th of any shape or form, e.g., spherical, rod, elliptical, cylin percentile is less than or equal to 4.5, less than or equal to drical, capsule, or disc. 4, less than or equal to 3.5, less than or equal to 3, less than 0149. In some embodiments, the drug carrier can be or equal to 2.5, less than or equal to 2, less than or equal to micro-sized and have a size of about 1 um to about 1000 um. 1.5, less than or equal to 1.45, less than or equal to 1.40, less In some embodiments, the drug carrier can be nano-sized than or equal to 1.35, less than or equal to 1.3, less than or and have size of about 0.1 nm to about 1000 nm. In some equal to 1.25, less than or equal to 1.20, less than or equal embodiments, the drug carrier is a microparticle or a nano to 1.15, or less than or equal to 1.1. particle. As used herein, the term “microparticle' refers to a 0153. Geometric Standard Deviation (GSD) can also be particle having a particle size of about 1 um to about 1000 used to indicate the narrow size distribution. GSD calcula US 2016/0346294 A1 Dec. 1, 2016 64 tions involved determining the effective cutoff diameter 0156 Liposomes can further comprise one or more addi (ECD) at the cumulative less than percentages of 15.9% and tional lipids and/or other components such as sterols, e.g., 84.1%. GSD is equal to the square root of the ratio of the cholesterol. Additional lipids can be included in the lipo ECD less than 84.17% to ECD less than 15.9%. The GSD Some compositions for a variety of purposes, such as to has a narrow size distribution when GSD-2.5. In some prevent lipid oxidation, to stabilize the bilayer, to reduce embodiments, GSD is less than 2, less than 1.75, or less than aggregation during formation or to attach ligands onto the liposome Surface. Any of a number of additional lipids 1.5. In one embodiment, GSD is less than 1.8. and/or other components can be present, including amphip 0154 While, the drug carriers are discussed in terms of athic, neutral, cationic, anionic lipids, and programmable coated particles, there are at least eight types of drug carriers fusion lipids. Such lipids and/or components can be used that can be formulated with the active agent and one or more alone or in combination. In addition to the lipids, the additional components. Different types of drug carriers can liposome can comprise one or more of the additives be as follows: (1) drug carriers comprising a core formed by described in the disclosure. the active agent to which the additional component absorbs/ 0157 Liposome compositions can be prepared by a vari adsorbs or the additional component forms one or more ety of methods that are known in the art. See e.g., U.S. Pat. coating layers on the drug carrier core; (2) drug carriers Nos. 4,235,871; 4,737,323; 4,897,355 and 5,171,678; pub comprising a generally homogeneous mixture of the active lished International Applications WO 96/14057 and WO agent and the additional component; (3) drug carriers com 96/37194: Felgner, P. L. et al., Proc. Natl. Acad. Sci., USA prising a core comprising a generally homogeneous mixture (1987) 8:7413-7417, Bangham, et al. M. Mol. Biol. (1965) of the active agent and the additional component, and the 23:238, Olson, et al. Biochim. Biophys. Acta (1979) 557:9, additional component forms one or more coating layers on Szoka, et al. Proc. Natl. Acad Sci. (1978) 75:4194, Mayhew, the drug carrier core; (4) drug carriers comprising a core et al. Biochim. Biophys. Acta (1984) 775: 169, Kim, et al. formed by the additional component and the active agent Biochim. Biophys. Acta (1983) 728:339, and Fukunaga, et al. forms one or more coating layers on the drug carrier core; Endocrinol. (1984) 115:757. (5) drug carriers comprising a core comprising a generally 0158. In some embodiments, the drug carrier can be homogeneous mixture of the active agent and the additional micelle. As used herein, “micelles' are a particular type of component, and the active agent forms one or more coating molecular assembly in which amphipathic molecules are over the drug carrier core; (6) drug carrier comprising a core arranged in a spherical structure Such that all hydrophobic of material other than the active agent and the additional portions on the molecules are directed inward, leaving the component, and a mixture of the active agent and the hydrophilic portions in contact with the Surrounding aque additional component forms one or more coating layers on ous phase. The converse arrangement. the drug carrier core; (7) drug carriers comprising a core 0159. In some embodiments, the drug carrier can be an comprising a generally homogeneous mixture of the active emulsion. As used herein, "emulsion' is a heterogeneous agent and the additional component, and a material other system of one liquid dispersed in another in the form of than the active agent or the additional component forms one droplets. Emulsions are often biphasic systems comprising or more coating layers on the drug carrier core; (8) lipo two immiscible liquid phases intimately mixed and dis Somes comprising the active agent; (9) emulsions, e.g., persed with each other. Either of the phases of the emulsion oil/water/oil or water/oil/water emulsions; (10) micelles; can be a semisolid or a Solid, as is the case of emulsion-style (11) globules; (12) Suspensions; (13) dispersions; (14) ointment bases and creams. The active agent can be present vesicles; (15) aggregates; and (16) drug carrier comprising as a solution in either the aqueous phase, oily phase or itself any of the drug carriers of (1)-(15) and further comprising as a separate phase. one or more layers of a material other than the active agent 0160. In some embodiments, the drug carrier can be or the additional component. In drug carriers of (16), the formulated as microemulsions. As used herein, “microemul further layer can be the outermost layer, a first layer on the sion” refers to a system of water, oil and amphiphile which core, interspersed between the layers described in (1)-(15), is a single optically isotropic and thermodynamically stable or any combinations thereof. Without limitations, the coat liquid Solution. Microemulsions also include thermody ing layer can comprise components other than indicated namically stable, isotropically clear dispersions of two above. For example, the above indicated coating component immiscible liquids that are stabilized by interfacial films of can be mixed with other molecules or compositions to form Surface-active molecules. the coating layer. This can be useful in instances wherein the 0.161 The application of emulsion formulations via der specified component may not be able to form a coating layer matological, oral and parenteral routes and methods for their by itself. In some embodiments, the particle comprises a manufacture have been reviewed in the literature, for core comprising the active agent and the additional compo example see Idson, in Pharmaceutical Dosage Forms, Lie nent forms one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or berman, Rieger and Banker (Eds.), 1988, Marcel Dekker, more) coating layers on the core. Inc., New York, N.Y., volume 1, p. 199: Rosoff, in Pharma 0155. In some embodiments, the drug carrier can be in ceutical Dosage Forms, Lieberman, Rieger and Banker the form of a liposome. As used herein, a liposome is a (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume structure having lipid-containing membranes enclosing an 1, p. 245; and Block, in Pharmaceutical Dosage Forms, aqueous interior. Liposomes can have one or more lipid Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, membranes. Oligolamellar, large vesicles and multilamellar Inc., New York, N.Y., volume 1, p. 335, contents of which vesicles have multiple, usually concentric, membrane layers. are herein incorporated by reference in their entirety. Liposomes with several nonconcentric membranes, i.e., sev 0162 The drug carrier can be fabricated using methods eral Smaller vesicles contained within a larger vesicle, are and instruments well known in the art. For example, the drug termed multivesicular vesicles. carriers can be made using microprecipitation, encapsula US 2016/0346294 A1 Dec. 1, 2016 tion, deaggregation, hybrid of deaggregation and encapsu formulation containing the active agent necessary to achieve lation, homogenization, hybrid of deaggregation and hot the desired improvement. In some embodiments, the formu homogenization, or any combinations thereof. In some lation is a topical formulation. embodiments, the process of making the particles comprises (0167. In some embodiments, the formulation can be in a the step of selecting particles of a desired size. form selected from the group consisting of lotions, creams, gels, emulgel, oils, serums, powders, sprays, ointments, Formulation Features Applicable to DART, Solutions, Suspensions, dispersions, pastes, foams, peels, Non-DART and Combination API films, masks, patches, Sticks, rollers, cleansing liquid 0163 The disclosure provides a composition or formu washes, cleansing Solid bars, pastes, foams, powders, shav lation comprising a DART. The disclosure also provides a ing creams, impregnated fabric (e.g. a “wipe' or tissue), and composition or formulation comprising an anti-bacterial the like. agent as the API, wherein the anti-bacterial agent is not a (0168. In some embodiments, the formulation is an anti DART molecule. In some embodiments, the formulation bacterial formulation. In some embodiments, the composi comprises two or more different APIs, e.g., two different tion is an anti-bacterial composition in the form of a skin DARTs, two different anti-bacterial agents which are not care composition. As defined herein, the term "skin care DART, or a DART molecule and an anti-bacterial agent composition” refers to materials applied topically to the skin which is not a DART. In some embodiments, the DART or that benefit, improve, or enhance the condition of the skin, the antibacterial agent is formulated as drug carrier for the or treat skin Suffering from an infectious or diseased con API. Without limitations the formulation or the composition dition. Such skin care compositions include bases such as can be formulated for administration by any appropriate Soap bases, cosmetic bases, medicament bases, cream bases, route known in the art including, but not limited to, topical emollient bases, and combinations thereof, as well as other (including buccal and Sublingual) and oral or parenteral bases known in the art. routes, including intravenous, intramuscular, Subcutaneous, 0169. Without limitations, the formulation can comprise transdermal, airway (aerosol), pulmonary, nasal, and rectal any desired amount of the API. For example, the formulation administration. Exemplary modes of administration include, can comprise from about 0.01% to about 99% (w/w or w/v) but are not limited to, topical, injection, infusion, instilla of the API. In some embodiments, the formulation can tion, inhalation, or ingestion. "Injection' includes, without comprise from about 0.1% to about 75% (w/w or w/v), from limitation, intravenous, intramuscular, intra-arterial, intrath about 1% to about 50% (w/w or w/v), from about 1.5% to ecal, intraventricular, intracapsular, intraorbital, intracar about 40% (w/w or w/v), API. In some embodiments, the diac, intradermal, intraperitoneal, intralymphnodal, transtra formulation can comprise from about 2.5%. 3%, 3.5%, 4%, cheal, Subcutaneous, Subcuticular, intra-articular, Sub 4.5%. 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, or capsular, Subarachnoid, intraspinal, intracerebral, spinal, and 25% (w/w or w/v) of the API. intracissternal injection and infusion. In some embodiments, (0170. In some embodiments, the formulation can com the formulation can be in the form of an oral dosage, prises, in addition to the API, one or more Zinc compounds. injectable, aerosol or inhalant. Without wishing to be bound by a theory, Zinc compounds 0164. In some embodiments, the formulation can com can help to Suppress sebum secretion and reduce acne prise two or more (e.g., two, three, four, five or more) inflammation. Exemplary Zinc compounds include, but are different anti-bacterial agents as the API. For example, the not limited to, Zinc acetate, Zinc methionine, Zinc pyrroli formulation can comprise two different anti-acne agents as done carboxylic acid, Zinc sulfide, Zinc gluconate, Zinc the API. In some embodiments, the formulation comprises picolinate, Zinc Sulphate, Zinc citrate, etc. Without limita 8-chlorobesifloxacin and another anti-acne agent as the API. tions, the formulation can comprise any desired amount of In one embodiment, the formulation comprises besifloxacin the Zinc compound. For example, the formulation can com and adapalene as the API. prise from about 0.01% to about 99% (w/w or w/v) of the 0.165. The formulations disclosed herein can comprise Zinc compound. In some embodiments, the formulation can several types of cosmetically-acceptable topical vehicles comprise from about 0.1% to about 75% (w/w or w/v), from including, but not limited to Solutions, colloidal suspensions, about 1% to about 50% (w/w or w/v), from about 1.5% to dispersions, emulsions (microemulsions, nanoemulsions, about 40% (w/w or w/v), from about 2% to about 25% (w/w multiple and non-aqueous emulsions), hydrogels, and or w/v), or from about 2.5% to about 25% (w/w or w/v) of vesicles (liposomes, niosomes, novasomes). Components the Zinc compound. In some embodiments, the formulation and formulation methods of Suitable cosmetically-accept can comprise from about 2.5%, 3%, 3.5%, 4%, 4.5%. 5%, able topical vehicles are well known in the art and are 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, or 25% (w/w described, for example, in U.S. Pat. No. 6,797,697 and U.S. or w/v) of the Zinc compound. Pat. App. Pub. No. 2005/0142094 and No. 2005/0008604, (0171 In some embodiments, the formulation can further Int. Pat. App. Pub. No. 2006/0298.18 and No. 2000/062743, comprise one or more excipients. Without limitations, the content of all of which is incorporated herein by reference. excipient can be selected from the group consisting of Those skilled in the art will appreciate the various methods emulsifiers, preservatives, Surfactants, oils, lipids, waxes, for producing these various product forms. stabilizers, rheology modifiers or thickening agents (gelling 0166 In some embodiments, the formulation can be in agent), emollients, moisturizers, conditioning agents, fra the form of a cream, oil, lotion, serum, gel, Sunscreen, nail grances/perfumes, potentiating agents, preservatives, opaci varnish, ointment, foam, spray, aerosol, powder, Stick, solu fiers, antioxidants, cooling agents, film forming agents, tion, Suspension, dispersion, paste, peel, and impregnated abrasives, exfoliating agents, colorants, pH modifiers, Sol fabric (e.g. a “wipe' or tissue). Generally, the composition vents, vehicle, penetration enhancers, permeation enhancers, comprises an effective amount of the active agent. As used pearlizing agents, and any combinations thereof. Amount of here, the term “effective amount' is that amount of the the excipients in the formulation can range from about 5% US 2016/0346294 A1 Dec. 1, 2016 66 to 99.99% (w/w or w/v). In some embodiments, the formu ciate the various concentrations and combinations for lation comprises one or more GRAS ingredients. employing these basic components to achieve the desired 0172 Generally, the pH of intended use of the formula product form. tion will generally range from about pH 2 to about pH 10. 0177 Suitable lipids which can be used include one or from about pH 3 to about pH 9, from about pH 4 and about more of hydrocarbons, fatty alcohols, fatty acids, glycerides pH 8, or from about pH 5.0 to about pH 7.5 or from about or esters of fatty acids with C-C alkanols. Hydrocarbons pH 5 to about 6.5. Suitable pH adjusting agents which can can include paraffin or petroleum jelly. Fatty alcohols can be used include one or more of organic or inorganic acids include decanol, dodecanol, tetradecanol, hexadecanol or and bases including Sodium hydroxide, potassium hydrox octadecanol. Fatty acids can include C-C alkanoic acids ide, ammonium hydroxide, phosphate buffers, citric acid, Such as hexanoic acid, octanoic acid, decanoic acid, dode acetic acid, fumaric acid, hydrochloric acid, malic acid, canoic acid, tetradecanoic acid, hexadecanoic acid, octade nitric acid, phosphoric acid, propionic acid, Sulfuric acid, canoic acid, unsaturated fatty acids such as oleic acid and tartaric acid, triehtyl amine, and the like. linoleic acid. Glycerides can include olive oil, castor oil, 0173 Typically, the cosmetically acceptable medium for sesame oil, caprylic/capric acid triglyceride or glycerol skin care compositions comprises water and other solvents mono-, di- and tri-esters with palmitic and/or Stearic acid. which include, but are not limited to, mineral oils and fatty Esters of fatty acids can include C-C alkanols such as alcohols. The cosmetically-acceptable medium is from beeswax, carnauba wax, cetyl palmitate, lanolin, isopropyl about 10% to about 99.99%, by weight of the composition, myristate, isopropyl Stearate, oleic acid decyl ester, ethyl preferably from about 50% to about 99% by weight of the oleate and C-C alkanoic acid esters and the like. composition, and can, in the absence of other additives, form 0.178 Suitable hydrocarbons include, but are not limited the balance of the composition. to mineral oil, isohexadecane, squalane, hydrogenated poly 0.174 As used herein the term "cosmetically acceptable isobutene, petrolatum, paraffin, microcrystalline wax, and medium' refers to formulations that are used to treat skin, polyethylene. Suitable oils can include one or more of hair and/or nails and contain one or more ingredients used by almond oil, apricot seed oil, borage oil, canola oil, coconut those skilled in the art to formulate products used to treat oil, corn oil, cotton seed oil, fish oil, jojoba bean oil, lard oil, skin. The cosmetically acceptable medium can be in any linseed oil, boiled macadamia nut oil, mineral oil, olive oil, Suitable form, i.e., a liquid, cream, emulsion, gel, thickening peanut oil, safflower oil, sesame oil, Soybean oil, squalane, lotion or powder and will typically contain water, and can Sunflower seed oil, tricaprylin (1.2.3 trioctanoyl glycerol), contain a cosmetically acceptable solvent and/or one or wheat germ oil and the like. The preferred quantity of oil more surfactants. used is in the range of about 5 to about 25% w/w, and more 0.175. The formulation can comprise one or more con preferably in the range of about 5% to about 20% w/w of the ventional functional cosmetic or dermatological additives or composition. adjuvants, providing that they do not interfere with the 0.179 Suitable esters which can be used include, but are mildness, performance or aesthetic characteristics desired in not limited to isopropyl palmitate, octyl Stearate, caprylic/ the final products. The CTFA (The Cosmetic, Toiletry, and capric triglyceride, plant waxes (Canelilla, Caranauba), Veg Fragrance Association; now known as the Personal Care etable oils (natural glycerides) and plant oils (Jojoba). Products Council) International Cosmetic Ingredient Dic 0180 Suitable fatty alcohols which can be used include, tionary and Handbook, Eleventh Edition (2006), and but are not limited to myristyl, cetyl, Stearyl, isostearyl, and McCutcheon's Functional Materials, North America and behenyl. Internationals Editions, MC Publishing Co. (2007) describe 0181 Suitable emulsifying agents which can be used a wide variety of cosmetic and pharmaceutical ingredients include, but are not limited to anionic (TEA/K stearate commonly used in skin care compositions, which are Suit (triethanolamine/potassium Stearate), sodium lauryl Stearate, able for use in the compositions of the present invention. The Sodium cetearyl Sulfate, and beeswax/Borax), nonionic compositions of the present invention can contain a wide (glycerol di-stearate, PEG (polyethyleneglycol)-100 Stear range of these additional, optional components. The total ate, Polysorbate 20, steareth 2 and steareth20), and cationic concentration of added ingredients usually is less than about (distearyldimethylammonium chloride, behenalkonium 20%, preferably less than about 5%, and most preferably chloride and steapyrium chloride), polymeric (acrylates/C less than about 3% by weight of the total composition. Such 10-30 alkyl acrylate crosspolymer, polyacrylamide, poly components include, but are not limited to Surfactants, quatemium-37, propylene glycol, dicaprylate/dicaparate and emollients, moisturizers, stabilizers, film-forming Sub PPG-1 Trideceth-6), and silicone based materials (alkyl stances, fragrances, colorants, chelating agents, preserva modified dimethicone copolyols), and polyglyceryl esters, tives, antioxidants, pH adjusting agents, antimicrobial and ethoxylated di-fatty esters. Additional suitable emulsi agents, water-proofing agents, dry feel modifiers, Vitamins, fiers/surfactant can include one or more of ionic polysorbate plant extracts, hydroxy acids (such as alpha-hydroxy acids surfactant, Tween(R) 20, Tween R 40, Tween R. 60, Tween(R) and beta-hydroxy acids), and Sunless tanning agents. 80, Nonylphenol Polyethylene Glycol Ethers, (alkylphenol 0176 The formulation can comprise one or more of the hydroxypolyoxyethylene), Poly(oxy-1,2-ethanediyl), alpha following basic cosmetic raw materials, including, but not (4-nonylphenol)-omega-hydroxy-, branched (i.e. Tergitol(R) limited to hydrocarbons, esters, fatty alcohols, fatty acids, NP-40 Surfactant), Nonylphenol Polyethylene Glycol Ether emulsifying agents, humectants, viscosity modifiers, and mixtures (i.e. Tergitol(R) NP-70 (70% AQ) Surfactant), phe silicone-based materials. The formulations can contain a noxypolyethoxyethanols and polymers thereof Such as Tri wide range of these basic components. The total concentra ton R, Poloxamer R, Spans(R), Tyloxapolr), different grades tion of added ingredients usually is less than 50%, preferably of Brij, sodium dodecyl sulfate and the like. The preferred less than 20%, and most preferably less than 10% by weight quantity of the emulsifiers/surfactant used is in the range of of the total formulation. Those skilled in the art will appre about 0.1% to about 10%/w/w of the composition. US 2016/0346294 A1 Dec. 1, 2016 67

0182 Exemplary humectants for use include, but are not 0190. In some embodiments, the formulation comprises limited to propylene glycol, Sorbitol, butylene glycol, buty one or more penetration enhancers. Exemplary penetration lene glycol, hexylene glycol, acetamide MEA (acetyletha enhancers include, but are not limited to fatty acids, bile nolamine), honey, and sodium PCA (Sodium-2-pyrrolidone salts, chelating agents, Surfactants, and non-surfactants. carboxylate), sorbitol, triacetin, and the like. Exemplary penetration enhancers include dimethyl sulfox 0183 Viscosity modifiers which can be used in the com ide; isopropyl myristate; decyl, undecyl or dodecyl alcohol; positions of the invention include, but are not limited to propylene glycol; polyethylene glycol; C9, C10, C11, C12 Xanthum gum, magnesium aluminum silicate, cellulose or C12-15 fatty alcohols; azone; alkyl pyrrolidones: gum, and hydrogenated castor oil. diethoxy glycol (Transcutol); lecithin; etc. Surfactants can 0184 Suitable thickening agents which can be used also be used as penetration enhancers. include one or more of cellulose polymer, a carbomer (0191 The formulation disclosed herein can further com polymer, a carbomer derivative, a cellulose derivative, poly prise one or more optional components known for use in vinyl alcohol, poloxamers, polysaccharides and the like. personal care products, provided that the optional compo 0185. Suitable emollients which can be used include one nents are physically and chemically compatible with the or more of caprylic/capric triglycerides, castor oil, ceteareth essential components described herein, or do not otherwise 20, ceteareth-30, cetearyl alcohol, ceteth 20, cetostearyl unduly impair product stability, aesthetics or performance. alcohol, cetyl alcohol, cetyl Stearyl alcohol, cocoa butter, Individual concentrations of Such optional components can diisopropyl adipate, glycerin, glyceryl monooleate, glyceryl range from about 0.001% to about 10% by weight of the monostearate, glyceryl Stearate, isopropyl myristate, isopro compositions. pyl palmitate, lanolin, lanolin alcohol, hydrogenated lanolin, 0.192 Non-limiting examples of optional components for liquid paraffins, linoleic acid, mineral oil, oleic acid, white use in the composition include a deposition aid, cationic petrolatum, polyethylene glycol, polyoxyethylene glycol polymers, nonionic polymers, dispersed particles, condition fatty alcohol ethers, polyoxypropylene 15-stearyl ether, pro ing agents (silicones and organic conditioning oils), humec pylene glycol Stearate, squalane, Steareth-2 or -100, Stearic tant, Suspending agent, additional anti-dandruff actives, vis acid, Stearyl alcohol, urea and the like. cosity modifiers, dyes, nonvolatile solvents or diluents (water soluble and insoluble), pearlescent aids, additional 0186 Suitable preservatives which can be used include Surfactants or nonionic coSurfactants, pediculocides, pH one or more of phenoxyethanol, parabens (such as methyl adjusting agents, perfumes, preservatives, chelants, proteins, paraben and propylparaben), propylene glycols, Sorbates, skin active agents, sunscreens, UV absorbers, vitamins, urea derivatives (such as diazolindinyl urea), and the like. antioxidants, preserving agents, fillers, Surfactants, UVA 0187 Suitable chelating agents which can be used and/or UVB Sunscreens, fragrances, viscosifying agents, include one or more of disodium EDTA, edetate trisodium, wetting agents, anionic polymers, nonionic polymers, edetate tetrasodium, diethyleneamine pentaacetate and the amphoteric polymers, viscosity/foam stabilizers, opacify like. ing/pearlizing agents, sequestering agents, stabilizing 0188 In some embodiments, the formulation comprises agents, humectants, anti-static agents, antifreezing agents, one or more of alcohols like C-C alcohols, diols and buffering agents, dyes, and pigments. These adjuvants are triols, glycerol, methanol, ethanol, propanol, octanol and the well known in the field of cosmetics and are described in like. many publications, for example see Harry's Book of Cos 0189 In some embodiments, the formulation comprises melicology, 8th edition, Martin Rieger, ed., Chemical Pub one or more permeation enhancers. Exemplary permeation lishing, New York (2000). enhancers include anionic Surfactants, such as sodium lauryl 0193 The compositions disclosed herein can also include Sulfate and Sodium laurate; cationic Surfactants, such as a deposition aid. The deposition aid is included to effectively cetylpyridium chloride; non-ionic Surfactants, such as enhance deposition of the composition components. The poloxamer, Brij, Span, Myr, and Tween; bile salts; sodium deposition aid can comprise any material that enhances the glycodeoxycholate; sodium glycocholate, Sodium taurode deposition of the composition components onto the hair, oxycholate, sodium taurocholate, AZone R; fatty acids. Such Scalp, or skin. In some embodiments, the deposition aids are as oleic and caprylic acid; cyclodextrins, such as C.-, 3-, cationic polymers. The concentration of the deposition aid in Y-cyclodextrin, methylated B-cylcodextrins; chelators. Such the composition should be sufficient to effectively enhance as EDTA, Sodium citrate and polyacrylates; polymers. Such the deposition of the components and typically range from as chitosan, trimethyl chitosan and cationic amino acids, about 0.05% to about 5%, preferably from about 0.075% to Such as poly-L-arginine and L-lysine. Brij is the tradename about 2.5%, more preferably from about 0.1% to about for a family of nonionic polyoxyethylene commercially 1.0%, by weight of the composition. available from a number of suppliers. Span is the tradename 0194 The compositions disclosed herein can comprise a for a family of Sorbitan Surfactants, such as Sorbitan trioleate cationic polymer. Concentrations of the cationic polymer in (Span 85) and sorbitan tristearate (Span 65) and the like, the composition typically range from about 0.05% to about commercially available from a number of suppliers. Myri is 3%, preferably from about 0.075% to about 2.0%, more a tradename for a family of polyethoxylated fatty acid preferably from about 0.1% to about 1.0%, by weight of the commercially available from a number of Suppliers. Such as composition. Preferred cationic polymers will have cationic polyoxyethylene monostearate (Myril 49) and the like. charge densities of at least about 0.9 med/gm, preferably at Tween is the tradename for a family of polyoxyethylene least about 1.2 med/gm, more preferably at least about 1.5 Sorbitan or polysorbate surfactants, such as polyoxyethylene med/gm, but also preferably less than about 7 med/gm, more sorbitan trioleate (Tween 85) and polysorbate 80 (Tween 80) preferably less than about 5 meq/gin. The average molecular commercially available from a number of Suppliers. AZone weight of Such suitable cationic polymers will generally be is a tradename for 1-Dodecylhexahydro-2h-Azepin-2-One. between about 10,000 and 10 million, preferably between US 2016/0346294 A1 Dec. 1, 2016

about 50,000 and about 5 million, more preferably between ionic cellulose derivatives and cationic starch derivatives. about 100,000 and about 3 million. Preferred cationic cellulose polymers are salts of hydroxy 0.195 Suitable cationic polymers for use in the compo ethyl cellulose reacted with trimethyl ammonium substituted sitions contain cationic nitrogen containing moieties such as epoxide, referred to in the industry (CTFA) as Polyduater quaternary ammonium or cationic protonated amino moi nium 10 and available from Amerchol Corp. (Edison, N.J., eties. The cationic protonated amines can be primary, sec USA) in their Polymer LR, JR, and KG series of polymers. ondary, or tertiary amines (preferably secondary or tertiary), Other suitable types of cationic cellulose include the poly depending upon the particular species and the selected pH of meric quaternary ammonium salts of hydroxyethyl cellulose the composition. Any anionic counterions can be used in reacted with lauryl dimethyl ammonium-substituted epoxide association with the cationic polymers so long as the poly referred to in the industry (CTFA) as Polyduaternium 24. mers remain soluble in water, in the composition, or in a These materials are available from Amerchol Corp. under coacervate phase of the composition, and so long as the the tradename Polymer LM-200. counterions are physically and chemically compatible with 0200. Other suitable cationic polymers include cationic the essential components of the composition or do not guar gum and derivatives thereof. Such as guar hydroxypro otherwise unduly impair product performance, stability or pyltrimonium chloride, specific examples of which include aesthetics. Non limiting examples of Such counterions the Jaguar series commercially available from Rhone-Pou include halides (e.g., chloride, fluoride, bromide, iodide), lenc Incorporated and the N-Hance series commercially Sulfate and methylsulfate. Non limiting examples of cationic available from Aqualon Division of Hercules, Inc. Other polymers are described in the CTFA Cosmetic Ingredient Suitable cationic polymers include quaternary nitrogen-con Dictionary, 3rd edition, edited by Estrin, Crosley, and taining cellulose ethers, some examples of which are Haynes. (The Cosmetic, Toiletry, and Fragrance Associa described in U.S. Pat. No. 3,962,418. Other suitable cationic tion, Inc., Washington, D.C. (1982)). polymers include copolymers of etherified cellulose, guar 0196. Non limiting examples of suitable cationic poly and starch, some examples of which are described in U.S. mers include copolymers of vinyl monomers having cationic Pat. No. 3,958,581. When used, the cationic polymers herein protonated amine or quaternary ammonium functionalities are either soluble in the composition or are soluble in a with water Soluble spacer monomers such as acrylamide, complex coacervate phase in the composition formed by the methacrylamide, alkyl and dialkyl acrylamides, alkyl and cationic polymer and the anionic, amphoteric and/or Zwit dialkyl methacrylamides, alkyl acrylate, alkyl methacrylate, terionic detersive surfactant component described hereinbe vinyl caprolactone or vinyl pyrrolidone. fore. Complex coacervates of the cationic polymer can also 0.197 Suitable cationic protonated amino and quaternary be formed with other charged materials in the composition. ammonium monomers, for inclusion in the cationic poly 0201 Polyalkylene glycols having a molecular weight of mers of the composition herein, include vinyl compounds more than about 1000 are useful herein. Polyethylene glycol substituted with dialkylaminoalkyl acrylate, dialkylamino polymers useful herein are PEG-2M (also known as Polyox alkyl methacrylate, monoalkylaminoalkyl acrylate, mono WSRR) N-10, which is available from Union Carbide and as alkylaminoalkyl methacrylate, trialkyl methacryloxyalkyl PEG-2,000); PEG-5M (also known as Polyox WSR(R) N-35 ammonium salt, trialkyl acryloxyalkyl ammonium salt, dial and Polyox WSR(R) N-80, available from Union Carbide and lyl quaternary ammonium salts, and vinyl quaternary ammo as PEG-5,000 and Polyethylene Glycol 300,000); PEG-7M nium monomers having cyclic cationic nitrogen-containing (also known as Polyox WSR(R) N-750 available from Union rings such as pyridinium, imidazolium, and quaternized Carbide); PEG-9M (also known as Polyox WSR(R) N-3333 pyrrolidone, e.g., alkyl vinyl imidazolium, alkyl vinyl pyri available from Union Carbide); and PEG-14 M (also known dinium, alkyl vinyl pyrrolidone salts. as Polyox WSR(R) N-3000 available from Union Carbide). 0198 Other suitable cationic polymers for use in the 0202 The composition can also include dispersed par compositions include copolymers of 1-vinyl-2-pyrrolidone ticles. The can include at least 0.025% by weight of the and 1-vinyl-3-methylimidazolium salt (e.g., chloride salt) dispersed particles, more preferably at least 0.05%, still (referred to in the industry by the Cosmetic, Toiletry, and more preferably at least 0.1%, even more preferably at least Fragrance Association, “CTFA', as Polyduaternium-16); 0.25%, and yet more preferably at least 0.5% by weight of copolymers of 1-vinyl-2-pyrrolidone and dimethylamino the dispersed particles. In some embodiments, it is prefer ethyl methacrylate (referred to in the industry by CTFA as able to incorporate no more than about 20% by weight of the Polyduaternium-11); cationic diallyl quaternary ammonium dispersed particles, more preferably no more than about containing polymers, including, for example, dimethyldial 10%, still more preferably no more than 5%, even more lylammonium chloride homopolymer, copolymers of acry preferably no more than 3%, and yet more preferably no lamide and dimethyldiallylammonium chloride (referred to more than 2% by weight of the dispersed particles. in the industry by CTFA as Polyduaternium 6 and Poly 0203 Conditioning agents include any material which is quaternium 7, respectively); amphoteric copolymers of used to give a particular conditioning benefit to skin. The acrylic acid including copolymers of acrylic acid and dim conditioning agents useful in the compositions of the present ethyldiallylammonium chloride (referred to in the industry invention typically comprise a water insoluble, water dis by CTFA as Polyduaternium 22), terpolymers of acrylic acid persible, non-volatile, liquid that forms emulsified, liquid with dimethyldiallylammonium chloride and acrylamide particles or are solubilized by the surfactant micelles, in the (referred to in the industry by CTFA as Polyduaternium 39), anionic detersive surfactant component (described above). and terpolymers of acrylic acid with methacrylamidopropyl Suitable conditioning agents for use in the composition are trimethylammonium chloride and mefhylacrylate (referred those conditioning agents characterized generally as sili to in the industry by CTFA as Polyduaternium 47). cones (e.g., silicone oils, cationic silicones, silicone gums, 0199. Other suitable cationic polymers for use in the high refractive silicones, and silicone resins), organic con composition include polysaccharide polymers, such as cat ditioning oils (e.g., hydrocarbon oils, polyolefins, and fatty US 2016/0346294 A1 Dec. 1, 2016 69 esters) or combinations thereof, or those conditioning agents York: Academic Press (1968); and in General Electric Sili which otherwise form liquid, dispersed particles in the cone Rubber Product Data Sheets SE 30, SE 33, SE 54 and aqueous Surfactant matrix herein. SE 76. Specific non-limiting examples of silicone gums for 0204 The conditioning agent of the compositions can be use in the compositions of the present invention include an insoluble silicone conditioning agent. The silicone con polydimethylsiloxane, (polydimefhylsiloxane) (methylvii ditioning agent particles can comprise volatile silicone, nylsiloxane) copolymer, polydimethylsiloxane) (diphenyl non-volatile silicone, or combinations thereof. Preferred are siloxane) (methylvinylsiloxane) copolymer and mixtures non-volatile silicone conditioning agents. If volatile sili thereof. cones are present, they will typically be incidental to their 0210. Other non-volatile, insoluble silicone fluid condi use as a solvent or carrier for commercially available forms tioning agents that are Suitable for use in the compositions of non-volatile silicone material ingredients, such as silicone of the present invention are those known as “high refractive gums and resins. The silicone conditioning agent particles index silicones, having a refractive index of at least about can comprise a silicone fluid conditioning agent and can also 1.46, preferably at least about 1.48, more preferably at least comprise other ingredients, such as a silicone resin to about 1.52, more preferably at least about 1.55. The refrac improve silicone fluid deposition efficiency or enhance tive index of the polysiloxane fluid will generally be less glossiness of the hair. than about 1.70, typically less than about 1.60. In this 0205 The concentration of the silicone conditioning context, polysiloxane “fluid includes oils as well as gums. agent typically ranges from about 0.01% to about 10%, by 0211 Silicone fluids suitable for use in the compositions weight of the composition, preferably from about 0.1% to of the present invention are disclosed in U.S. Pat. No. about 8%, more preferably from about 0.1% to about 5%, 2,826,551, U.S. Pat. No. 3,964,500, U.S. Pat. No. 4,364,837, more preferably from about 0.2% to about 3%. Non-limiting British Pat. No. 849,433, and Silicon Compounds, Petrarch examples of Suitable silicone conditioning agents, and Systems, Inc. (1984). optional Suspending agents for the silicone, are described in 0212 Silicone resins can be included in the silicone U.S. Reissue Pat. No. 34,584, U.S. Pat. No. 5,104,646, and conditioning agent of the compositions of the present inven U.S. Pat. No. 5,106,609. The silicone conditioning agents tion. These resins are highly cross-linked polymeric siloxane for use in the compositions of the present invention prefer systems. The cross-linking is introduced through the incor ably have a viscosity, as measured at 25°C., from about 20 poration of trifunctional and tetrafunctional silanes with to about 2,000,000 centistokes (“csk'), more preferably monofunctional or difunctional, or both, silanes during from about 1,000 to about 1,800,000 csk, even more pref manufacture of the silicone resin. erably from about 50,000 to about 1,500,000 csk, more 0213 Silicone materials and silicone resins in particular, preferably from about 100,000 to about 1,500,000 csk. can conveniently be identified according to a shorthand 0206. The dispersed silicone conditioning agent particles nomenclature system known to those of ordinary skill in the typically have a Volume average particle diameter ranging art as “MDTO nomenclature. Under this system, the sili from about 0.01 um to about 50 m. For small particle cone is described according to presence of various siloxane application to hair, the Volume average particle diameters monomer units which make up the silicone. Briefly, the typically range from about 0.01 um to about 41 um, pref symbol M denotes the monofunctional unit (CH)SiOos; D erably from about 0.01 um to about 2 um, more preferably denotes the difunctional unit (CH)SiO; T denotes the from about 0.01 um to about 0.51 Lum. For larger particle trifunctional unit (CH)SiO5, and Q denotes the quadra- or application to hair, the Volume average particle diameters tetra-functional unit SiO. Primes of the unit symbols (e.g. typically range from about 5 um to about 125um, preferably M", D', T, and Q') denote substituents other than methyl, and from about 10 um to about 90 m, more preferably from must be specifically defined for each occurrence. about 15um to about 70 um, more preferably from about 20 0214 Preferred silicone resins for use in the composi um to about 50 Lum. tions of the present invention include, but are not limited to 0207 Background material on silicones including sec MQ, MT, MTQ, MDT and MDTO resins. Methyl is a tions discussing silicone fluids, gums, and resins, as well as preferred silicone substituent. Especially preferred silicone manufacture of silicones, are found in Encyclopedia of resins are MQ resins, wherein the M:Q ratio is from about Polymer Science and Engineering, Vol. 15, 2d ed., pp 0.5:1.0 to about 1.5:1.0 and the average molecular weight of 204-308, John Wiley & Sons, Inc. (1989). the silicone resin is from about 1000 to about 10,000. 0208 Silicone fluids include silicone oils, which are 0215. The conditioning component of the compositions flowable silicone materials having a viscosity, as measured of the present invention can also comprise from about 0.05% at 25°C., less than 1,000,000 csk, preferably from about 5 to about 3%, by weight of the composition, preferably from csk to about 1,000,000 csk, more preferably from about 100 about 0.08% to about 1.5%, more preferably from about csk to about 600,000 csk. Suitable silicone oils for use in the 0.1% to about 1%, of at least one organic conditioning oil as compositions of the present invention include polyalkyl the conditioning agent, either alone or in combination with siloxanes, polyaryl siloxanes, polyalkylaryl siloxanes, other conditioning agents, such as the silicones (described polyether siloxane copolymers, and mixtures thereof. Other above). insoluble, non-volatile silicone fluids having hair condition 0216 Suitable organic conditioning oils for use as con ing properties can also be used. ditioning agents in the compositions of the present invention 0209. Other silicone fluids suitable for use in the com include, but are not limited to, hydrocarbon oils having at positions are the insoluble silicone gums. These gums are least about 10 carbon atoms, such as cyclic hydrocarbons, polyorganosiloxane materials having a viscosity, as mea straight chain aliphatic hydrocarbons (saturated or unsatu sured at 25°C., of greater than or equal to 1,000,000 csk. rated), and branched chain aliphatic hydrocarbons (saturated Silicone gums are described in U.S. Pat. No. 4,152,416: Noll or unsaturated), including polymers and mixtures thereof. and Walter, Chemistry and Technology of Silicones, New Straight chain hydrocarbon oils preferably are from about C US 2016/0346294 A1 Dec. 1, 2016 70 to about C19. Branched chain hydrocarbon oils, including C6, of Succinic acid, glutaric acid, and adipic acid). Specific hydrocarbon polymers, typically will contain more than 19 non-limiting examples of di- and tri-alkyl and alkenyl esters carbon atoms. of carboxylic acids include isocetyl Stearyol Stearate, diiso 0217 Specific non-limiting examples of these hydrocar propyl adipate, and tristearyl citrate. In some embodiments, bon oils include paraffin oil, mineral oil, Saturated and the composition comprises ester of at least one of lauric acid, unsaturated dodecane, Saturated and unsaturated tridecane, and Succinic acid have additional anti-acne and/anti-inflam saturated and unsaturated tetradecane, Saturated and unsatu matory properties. rated pentadecane, Saturated and unsaturated hexadecane, 0224. Other fatty esters suitable for use in the composi polybutene, polydecene, and mixtures thereof. Branched tions of the present invention are those known as polyhydric chain isomers of these compounds, as well as of higher chain alcohol esters. Such polyhydric alcohol esters include alky length hydrocarbons, can also be used, examples of which lene glycol esters, such as ethylene glycol mono and di-fatty include highly branched, saturated or unsaturated, alkanes acid esters, diethylene glycol mono- and di-fatty acid esters, Such as the permethyl-substituted isomers, e.g., the perm polyethylene glycol mono- and di-fatty acid esters, propyl ethyl-substituted isomers of hexadecane and eicosane. Such ene glycol mono- and di-fatty acid esters, polypropylene as 2, 2, 4, 4, 6, 6, 8, 8-dimethyl-10-methylundecane and 2. glycol monooleate, polypropylene glycol 2000 monostear 2, 4, 4, 6, 6-dimethyl-8-methylnonane, available from Per ate, ethoxylated propylene glycol monostearate, glyceryl methyl Corporation. Hydrocarbon polymers such as poly mono- and di-fatty acid esters, polyglycerol poly-fatty acid butene and polydecene are preferred. A preferred hydrocar esters, ethoxylated glyceryl monostearate, 1,3-butylene gly bon polymer is polybutene, Such as the copolymer of col monostearate, 1,3-butylene glycol distearate, polyoxy isobutylene and butene. A commercially available material ethylene polyol fatty acid ester, sorbitan fatty acid esters, of this type is L-14 polybutene from Amoco Chemical and polyoxyethylene Sorbitan fatty acid esters. Corporation. 0225. Still other fatty esters suitable for use in the com 0218 Organic conditioning oils for use in the composi positions of the present invention are glycerides, including, tions of the present invention can also include liquid poly but not limited to, mono-, di-, and tri-glycerides, preferably olefins, more preferably liquid poly-C-olefins, more prefer di- and tri-glycerides, more preferably triglycerides. For use ably hydrogenated liquid poly-C-olefins. Polyolefins for use in the compositions described herein, the glycerides are herein are prepared by polymerization of C4 to about C14 preferably the mono-, di-, and tri-esters of glycerol and long olefenic monomers, preferably from about C6 to about C12. chain carboxylic acids, such as C10 to C22 carboxylic acids. 0219 Non-limiting examples of olefenic monomers for A variety of these types of materials can be obtained from use in preparing the polyolefin liquids herein include eth vegetable and animal fats and oils, such as castor oil, ylene, propylene, 1-butene, 1-pentene, 1-hexene, 1-octene, safflower oil, cottonseed oil, corn oil, olive oil, cod liver oil, 1-decene, 1-dodecene, 1-tetradecene, branched chain iso almond oil, avocado oil, palm oil, Sesame oil, lanolin oil and mers such as 4-mefhyl-1-pentene, and mixtures thereof. soybean oil. Synthetic oils include, but are not limited to, Also Suitable for preparing the polyolefin liquids are olefin triolein and tristearin glyceryl dilaurate. containing refinery feedstocks or effluents. Preferred hydro 0226. Other fatty esters suitable for use in the composi genated a-olefin monomers include, but are not limited to: tions of the present invention are water insoluble synthetic 1-hexene to 1-hexadecenes, 1-octene to 1-tetradecene, and fatty esters. mixtures thereof. 0227 Specific non-limiting examples of suitable syn 0220. Other suitable organic conditioning oils for use as thetic fatty esters for use in the compositions of the present the conditioning agent in the compositions of the present invention include: P-43 (C8-C10 triester of trimethylolpro invention include, but are not limited to, fatty esters having pane), MCP-684 (tetraester of 3,3-diethanol-1.5 pentadiol), at least 10 carbon atoms. These fatty esters include esters MCP 121 (C8-C10 diester of adipic acid), all of which are with hydrocarbyl chains derived from fatty acids or alcohols available from Mobil Chemical Company. (e.g. mono-esters, polyhydric alcohol esters, and di- and 0228. Also suitable for use in the compositions herein are tri-carboxylic acid esters). The hydrocarbyl radicals of the the conditioning agents described by the Procter & Gamble fatty esters hereof can include or have covalently bonded Company in U.S. Pat. Nos. 5,674,478, and 5,750,122. Also thereto other compatible functionalities, such as amides and Suitable for use herein are those conditioning agents alkoxy moieties (e.g., ethoxy or ether linkages, etc.). described in U.S. Pat. No. 4,529,586 (Clairol), U.S. Pat. No. 0221) Specific examples of preferred fatty esters include, 4,507,280 (Clairol), U.S. Pat. No. 4,663,158 (Clairol), U.S. but are not limited to: isopropyl isostearate, hexyl laurate, Pat. No. 4,197,865 (L'Oreal), U.S. Pat. No. 4,217,914 isohexyl laurate, isohexyl palmitate, isopropyl palmitate, (L'Oreal), U.S. Pat. No. 4,381.919 (L'Oreal), and U.S. Pat. decyl oleate, isodecyl oleate, hexadecyl Stearate, decyl Stear No. 4,422,853 (L'Oreal). ate, dihexyldecyl adipate, lauryl lactate, myristyl lactate, 0229. The compositions can contain a humectant. The cetyl lactate, oleyl Stearate, oleyl oleate, oleyl myristate, humectants can be selected from the group consisting of lauryl acetate, cetyl propionate, and oleyl adipate. polyhydric alcohols, water soluble alkoxylated nonionic 0222. Other fatty esters suitable for use in the composi polymers, and mixtures thereof. The humectants, when used tions of the present invention are mono-carboxylic acid herein, are preferably used at levels by weight of the esters of the general formula R'COOR, wherein R' and Rare composition of from about 0.1% to about 20%, more pref alkyl or alkenyl radicals, and the Sum of carbon atoms in R erably from about 0.5% to about 5%. and R is at least 10, preferably at least 22. 0230 Polyhydric alcohols useful herein include glycerin, 0223 Still other fatty esters suitable for use in the com Sorbitol, propylene glycol, butylene glycol, hexylene glycol, positions of the present invention are di- and tri-alkyl and ethoxylated glucose, 1.2-hexane diol, hexanetriol, dipropyl alkenyl esters of carboxylic acids, such as esters of C4 to C8 ene glycol, erythritol, trehalose, diglycerin, Xylitol, maltitol, dicarboxylic acids (e.g. C1 to C22 esters, preferably C1 to maltose, glucose, fructose, sodium chondroitin Sulfate, US 2016/0346294 A1 Dec. 1, 2016

Sodium hyaluronate, Sodium adenosine phosphate, sodium prime concerns of art known anti-acne topical products. lactate, pyrrolidone carbonate, glucosamine, cyclodextrin, Exemplary moisturizing agents include, but are not limited and mixtures thereof. to, N-Acetyl ethanolamine, aloe Vera gel, arginine PCA, 0231 Water soluble alkoxylated nonionic polymers use chitosan PCA, copper PCA, Corn glycerides, dimethyl imi ful herein include polyethylene glycols and polypropylene dazolidinone, fructose, glucamine, glucose, glucose gluta mate, glucuronic acid, glutamic acid, glycereth-7, glycereth glycols having a molecular weight of up to about 1000 such 12, glycereth-20, glycereth-26, glycerin, honey, as those with CTFA names PEG-200, PEG-400, PEG-600, hydrogenated honey, hydrogenated Starch hydrolysates, PEG-1000, and mixtures thereof. hydrolyzed corn starch, lactamide MEA, lactic acid, lactose 0232. The compositions of the present invention can lysine PCA, mannitol, methyl gluceth-10, methyl gluceth further comprise a Suspending agent at concentrations effec 20, PCA, PEG-2 lactamide, PEG-10 propylene glycol, tive for Suspending water-insoluble material in dispersed polyamino acids, polysaccharides, polyamino Sugar conden form in the compositions or for modifying the Viscosity of sate, potassium PCA, propylene glycol, propylene glycol the composition. Such concentrations range from about citrate, saccharide hydrolysate, saccharide isomerate, 0.1% to about 10%, preferably from about 0.3% to about Sodium aspartate, sodium lactate, Sodium PCA, Sorbitol, 5.0%, by weight of the compositions. TEA-lactate, TEA-PCA, urea, xylitol, panthenol, petrola 0233 Suitable suspending agents include crystalline sus tum, mineral oil, lanolin, lanolin alcohol, tocopherol, esters pending agents that can be categorized as acyl derivatives, of tocopherol, alkyl polydimethylsiloxanes, vegetable oils, long chain amine oxides, or combinations thereof. These hydrogenated vegetable oils, fatty acid esters, beeswax, suspending agents are described in U.S. Pat. No. 4,741,855. hydrolyzed keratin, hydroxyethyl urea, carboxylic acid 0234. The compositions can contain also vitamins and amides, mucopolysaccharides, and quaternized nitrogen amino acids such as: water soluble vitamins such as vitamin moisturizing agents. Examples of quaternary nitrogen mois B1, B2, B6, B12, C, pantothenic acid, pantothenyl ethyl turizing agents include, but are not limited to, hydroxypro ether, panthenol, biotin, and their derivatives, water soluble pyl bis-hydroxyethyldimonium chloride (available as amino acids such as asparagine, alanine, tryptophan, gluta COLATMMoist 200 from Colonial Chemicals, Inc.), mois mic acid and their salts, water insoluble vitamins such as turizing agents described in U.S. Pat. No. 6,869,977 (content vitaminA, D, E, and their derivatives, water insoluble amino of which is incorporated herein by reference), choline salts acids such as tyrosine, tryptamine, and their salts. described in U.S. Pat. Nos. 6,475,965 and 6,265,364 (con 0235. The formulations disclosed herein can also contain tents of both of which are incorporated herein by reference), pigment materials such as nitroso, monoaZO, diaZO, carote camitine, and combinations thereof. The moisturizing agent noid, triphenyl methanes, triaryl methanes, Xanthenes, qui can be present in the formulation in any desired amount to nolines, oxazines, azines, anthraquinones, indigoids, thion give a desired level of moisturization. In some embodi indigoids, quinacridones, phthalocyianines, botanicals, and ments, the moisturizing agent can be preset in an amount of natural colors including water soluble dye components. The 0 to about 5. In another embodiment, the quaternary nitrogen compositions of the present invention can also contain moisturizing agent is present in an amount of about 0.1 to chelating agents. about 1% by weight. In another embodiment, the moistur 0236. In one embodiment, the formulation is a moistur izing agent is present at about 1% by weight. izer cream/gel base. For example, the formulation comprises 0237. In some embodiments, the formulation comprises at least one moisturizing agent. Generally, the formulation at least one of glycolic acid, lactic acid, Sulfur, Salicylic acid, can comprise from about 0.01% (by weight) to about 50%, and resorcinol. (by weight) of the moisturizing agents to impart a moistur 0238. Some exemplary formulations are described in izing benefit upon use. It is noted that dryness is one of Tables 2-5. TABLE 2 Some exemplary cream formulations. Phase Ingredients A. B C Method of preparation A. API O.2% 2% 5%. 1) All ingredients of Cetostearyl alcohol 10.0% 10.0% phase A were mixed and Cetyl alcohol 10.0% heated at 70-80° C. Stearyl alcohol S.0% 2) All ingredients of Macrogol S.O% 5.0% phase B were mixed and Cetostearyl Ether 2 stirred to get uniform Span 20 1.0% Solution, then phase B Apifil S.O% was also heated to 70-80° C. B Pemulen TR 1 O.S9/o 0.5% with continuous Macrogol S.O% 5.0% stirring Cetostearyl Ether 20 3) Phase A was added Tween 20 S.0% into phase B with Glycerol S.O% 10.0% 5.0% continuous stirring at Water q.S. to 100 q.S. to 100 q.S. to 100 70-80° C. C Preservative O.1% O.1% 0.1% 4) Ingredients of phase D Citric acid NaOH q.S. to pH q.S. to pH q.S. to pH C was added into pre formed cream at 40° C. with continuous stirring 5) Finally phase D was added to get desired pH US 2016/0346294 A1 Dec. 1, 2016 72

TABLE 3 Some exemplary emugel formulations. Phase Ingredients A. B Method of preparation A. API O.1% 190 10% 1) All ingredients of Olive Oil S.0% phase A was mixed and Castor Oil S.0% heated at 70-80° C. Stearyl alcohol 2.0% 2.0% 2) All ingredients of Oleyl alcohol 2.0% 20% phase B was mixed and Liquid Paraffin 6.0% 6.0% stirred to get uniform Span 20 2.0% Solution, then phase B Steareth 2 2.0% 2.0% was also heated to 70-80° C. B Tween 20 8.0% with continuous Steareth 20 2.0% 2.0% stirring Carbopol 1.0% 1.0% 3) Phase A was added Pemulen into phase B with Propylene glycol S.0% S.0% S.0% continuous stirring at Water q.S. to 100% q.S. to 100% q.S. to 100% 70-80° C. C Preservative O.1% O.1% 4) Ingredients of phase D Citric acid NaOH q.S. to pH q.S. to pH q.S. to pH C was added into pre formed emulsion at 40° C. with continuous stirring 5) Finally phase D was added to get desired pH

TABLE 4 Some exemplary gel formulations. Phase Ingredients A. B C Method of preparation A. API O.O1% O.S9/o 296 1) Ingredients of phase Ethanol 10.0% S.0% S.0% A was mixed to B Tween 20 2.0% 2.0% Solubilize drug Steareth 20 2.0% 2) All ingredients of Carbopol 1.0% 1.0% phase B was mixed and Pemulen O.S9/o stirred to get uniform Propylene glycol 10.0% 20.0% 15.0% Solution, Water q.S. to 100% q.S. to 100% q.S. to 100%. 3) Phase A was added C Preservative O.1% O.1% O.1% into phase B with D Citric acid/NaOH q.S. to pH q.S. to pH q.S. to pH continuous stirring TEA 4) Ingredients of phase C was added into pre formed emulsion with continuous stirring 5) Finally phase D was added to get desired pH

TABLE 5 Some exemplary lotion formulations. Phase Ingredients A. B C Method of preparation A. API O.02% 1.5% 3% 1) All ingredients of Liquid paraffin S.0% 10.0% 15.0% phase A was mixed and Olive oil 1.0% 1.0% 1.0% heated at 70-80° C. Glyceryl Stearate 2.0% 1.0% 2) All ingredients of B Tween 20 2.0% S.0% 10.0% phase B was mixed and Pemulen O.S9/o stirred to get uniform Ultrez, 21 1.0% 2.0% Solution, then phase B Ethanol S.0% S.0% S.0% was also heated to 70-80° C. Propylene glycol 10.0% 10.0% 10.0% with continuous Water q.S. to 100% q.S. to 100% q.S. to 100% stirring Preservative O.1% O.1% O.1% 3) Phase A was added s Citric acid NaOH q.S. to pH q.S. to pH q.S. to pH into phase B with TEA continuous stirring at 70-80° C. 4) Ingredients of phase C was added into pre formed lotion at 40° C. with continuous stirring US 2016/0346294 A1 Dec. 1, 2016

TABLE 5-continued Some exemplary lotion formulations. Phase Ingredients A. B C Method of preparation 5) Finally phase D was added to get desired pH

0239. Without wishing to be bound by a theory, the additional compound selected from the group consisting formulation disclosed herein can provide at least 1.2x of lipids, oils, polymers, peptides, proteins, carbohy increase in area under the curve in a concentration on the drates, glycolipids, phospholipids, lipoproteins, cationic skin vs time plot compared with formulations known in the molecules, and any combinations thereof. art. Further, the formulation can kill at least 20% more P. 0246 2. The formulation of claim 1, wherein the drug acnes as compared to direct application of an antibiotic. carrier is coated or uncoated. 0240. The formulations disclosed herein provide formu 0247 3. The formulation of paragraph 1 or 2, wherein the lation technological advances (size optimization, Surface drug carrier has a size of about 5 nm to about 20 Lum. modification, and formulation innovations) to improve 0248 4. The formulation of paragraph 1 or 3, wherein the specificity & efficacy by enhancing penetration & delivery drug carrier has a size of about 5 nm to about 5 um. to the target site (sebaceous glands); improving retention to 0249 5. The formulation of any of paragraphs further exhibit sustained effect; or easy entry into biofilm enveloped comprising a Surface modifier on the Surface of the drug bacteria. carrier. 0241 The disclosure further provides the use of the 0250) 6. The formulation of any of paragraphs 1-5, DARTs and formulations discloses herein for treating or wherein the surface modifier is selected from the group preventing at least one bacterial infection condition in a consisting of lipids, oils, polymers, peptides, proteins, Subject. The method generally comprising administering a carbohydrates, glycolipids, phospholipids, lipoproteins, DART or formulation disclosed herein to a subject in need cationic molecules, and any combinations thereof. thereof. In some embodiments, the method is for treating an 0251 7. The formulation of any of paragraphs 1-6, acne condition in a subject. wherein the carrier or excipient is selected from the group 0242. The term "acne' includes inflammatory diseases of consisting of emulsifiers, preservatives, Surfactants, oils, the pilosebaceous follicles and/or skin glands, and com lipids, waxes, stabilizers, rheology modifiers or thicken monly is characterized by papules, pustules, cysts, nodules, ing agents (gelling agent), emolients, moisturizers, con comedones, other blemishes or skin lesions. The term ditioning agents, fragrances/perfumes, potentiating "acne as used herein includes all known types of acne. agents, preservatives, opacifiers, antioxidants, cooling Some types of acne which can be treated with the compo agents, film forming agents, abrasives, exfoliating agents, sition of the present invention are, for example, acne Vul colorants, pH modifiers, solvents, vehicle, penetration garis, acne comedo, papular acne, premenstrual acne, pre enhancers, pearlizing agents, and any combinations adolescent acne, acne Venenata, acne cosmetica, pomade thereof. acne, acne detergicans, acne excoriee, gram negative acne, 0252 8. The formulation of any of paragraphs 1-4, pseudofolliculitis barbae, folliculitis, perioral dermatitis, wherein the surface of the drug carrier is substantially free hiddradenitis Suppurativa, cystic acne, acne atrophica, bro of surface modifier. mide acne, chlorine acne, acne conglobata, acne detergicans, 0253) 9. The formulation of any of paragraphs 1-8, com epidemic acne, acne estivalis, acne fulminans, halogen acne, prising from about 0.1% to about 50% (w/w or w/v) of the acne indurata, iodide acne, acne keloid, acne mechanica, carrier or excipient. acne papulosa, pomade acne, premenstral acne, acne pustu 0254 10. The formulation of any of paragraphs 1-9, losa, acne scorbutica, acne scrofulosorum, acne urticata, wherein the formulation is formulated for topical, oral or acne varioliformis, acne venenata, propionic acne, acne parenteral administration. excoriee, gram negative acne, Steroid acne, nodulocystic 0255 11. The formulation of any of paragraphs 1-10, acne and acne rosacea. wherein the formulation is an oral dosage, injectable, 0243 Without wishing to be bound by a theory, microni aerosol or inhalant, lotion, cream, gel, emulgel, oil, Zation of besifloxacin can have an impact on its bioactivity. serum, powder, spray, ointment, Solution, Suspension, For example, microniztion can enhance besifloxacin’s bio dispersion, paste, foam, peel, films, mask, patch, Stick, activity or its retention at a desired site. Further, microni roller, impregnated fabric (e.g. a “wipe' or tissue), or any Zation can also effect besifloxacins stability and amounts in combination thereof. a formulation. Moreover, micronization can also allow opti 0256 12. The formulation of any of paragraphs 1-11, mizing properties of formulations comprising micronized further comprising a second anti-acne agent. besifloxacin. 0257 13. The formulation of any of paragraphs 1-12, 0244 Embodiments of the various aspects disclosed wherein the second anti-acne agent is selected from the herein can also be described by one or more of the numbered group consisting of 8-chloro fluroquinolones, acetretin, paragraphs: adapalene(s), alitretinoin, alpha- or beta-hydroxy acids, 0245 1. A formulation comprising an anti-acne agent and antibiotics, antimicrobial peptides, antimicrobials, azelaic at least one carrier or excipient, wherein the anti-acne acid, benzoyl peroxide, bexarotene, bile salts, biofilm agent is in the form of a drug carrier comprising the inhibitors, clindamycin, erythromycin, etretinate, glycolic anti-acne agent and at least one additional compound, said acid, isotretinoin, keratolytic agents, lactic acid, lipoic US 2016/0346294 A1 Dec. 1, 2016 74

acid, N-acetylcystein, natural anti-acne agents, octopirox, 0272. 28. The formulation of any of paragraphs 1-27, phenoxyethanol, phenoxypropanol, pyruvic acid, resorci wherein the additional active agent drug carrier has a size nol, retinoic acid, retinoid(s), Salicylic acid, sebostats, of about 100 nm to about 25 m. Sodium Sulfacetamide, Spironolactone, Sulfur, Sulfur con 0273 29. The formulation of any of paragraphs 1-28, taining D- or L-amino acids, tazarotene, tea tree oil, wherein the additional active agent drug carrier comprises tretinoin, triclosan, urea, and any combinations thereof. a surface modifier on the surface thereof. 0258 14. The formulation of any of paragraphs 1-13, 0274 30. The formulation of any of paragraphs 1-29, wherein the formulation comprises an 8-chlorofluoroqui wherein the surface modifier of the additional active agent nolone alone or in combination with another anti-acne drug carrier is selected from the group consisting of lipids, agent. oils, polymers, peptides, proteins, carbohydrates, glyco 0259 15. The formulation of any of paragraphs 1-14, lipids, phospholipids, lipoproteins, cationic molecules, wherein the formulation comprises besifloxacin and ada and any combinations thereof. palene. 0275 31. The formulation of any of paragraphs 1-30, 0260 16. The formulation of any of paragraphs 1-14, wherein the Surface of the additional active agent drug wherein the formulation comprises 8-chlorofluoroqui carrier is substantially free of surface modifier. nolone and an anti-inflammatory agent. 0276 32. The formulation of any of paragraphs 1-31, 0261) 17. The formulation of any of paragraphs 1-14, wherein the formulation further comprises a Zinc com wherein the formulation comprises 8-chlorofluoroqui pound. nolone and retinoic acid or retinoid. 0277 33. A formulation comprising an antibacterial agent 0262. 18. The formulation of any of paragraphs 1-17, and at least one carrier or excipient, wherein the antibac wherein the second anti-acne agent is in the form of a drug terial agent is in the form of a drug carrier comprising the carrier comprising the second anti-acne agent and at least antibacterial agent and at least one additional compound, one additional compound, said additional compound said additional compound selected from the group con Selected from the group consisting of lipids, oils, poly sisting of lipids, oils, polymers, peptides, proteins, car mers, peptides, proteins, carbohydrates, glycolipids, bohydrates, glycolipids, phospholipids, lipoproteins, cat phospholipids, lipoproteins, cationic molecules, and any combinations thereof. ionic molecules, and any combinations thereof. 0263. 19. The formulation of any of paragraphs 1-18, 0278 34. The formulation of paragraph 33, wherein the wherein the second anti-acne agent drug carrier has a size drug carrier has a size of about 5 nm to about 100 um. of about 5 nm to about 50 lum. (0279. 35. The formulation of paragraph 33 or 34, wherein 0264. 20. The formulation of any of paragraphs 1-19, the drug carrier has a size of about 100 nm to about 25um. wherein the second anti-acne agent drug carrier has a size 0280 36. The formulation of any of paragraphs 33-35 of about 100 nm to about 25 um further comprising a Surface modifier on the Surface of the 0265 21. The formulation of any of paragraphs 1-20, drug carrier. wherein the second anti-acne agent drug carrier comprises 0281 37. The formulation of any of paragraphs 33-36, a surface modifier on the surface thereof. wherein the surface modifier is selected from the group 0266 22. The formulation of any of paragraphs 1-21, consisting of lipids, oils, polymers, peptides, proteins, wherein the Surface modifier of the second anti-acne agent carbohydrates, glycolipids, phospholipids, lipoproteins, drug carrier is selected from the group consisting of lipids, cationic molecules, and any combinations thereof. oils, polymers, peptides, proteins, carbohydrates, glyco 0282) 38. The formulation of any of paragraphs 33-37, lipids, phospholipids, lipoproteins, cationic molecules, wherein the surface of the drug carrier is substantially free and any combinations thereof. of surface modifier. 0267. 23. The formulation of any of paragraphs 1-20, 0283 39. The formulation of any of paragraphs 33-38, wherein the Surface of the second anti-acne agent drug wherein the carrier or excipient is selected from the group carrier is substantially free of surface modifier. consisting of emulsifiers, preservatives, Surfactants, oils, 0268 24. The formulation of any of paragraphs 1-23, lipids, waxes, stabilizers, rheology modifiers or thicken further comprising an additional active agent. ing agents (gelling agent), emolients, moisturizers, con 0269. 25. The formulation of any of paragraphs 1-24, ditioning agents, fragrances/perfumes, potentiating wherein the additional active agent is an anti-inflamma agents, preservatives, opacifiers, antioxidants, cooling tory-agent, penetration enhancer, anti-oxidant, anti-aging agents, film forming agents, abrasives, exfoliating agents, agent, anti-wrinkle agent, skin whitening or bleaching colorants, pH modifiers, solvents, vehicle, penetration agent, ultraviolet (UV) light absorbing or scattering agent, enhancers, pearlizing agents, and any combinations skin depigmentation agent, skin regenerative agent, scar thereof. healing agent, or any combination thereof 0284 40. The formulation of any of paragraphs 33-39, 0270 26. The formulation of any of paragraphs 1-25, comprising from about 5% to about 99% (w/w or w/v) of wherein the additional active agent is in the form of a drug the carrier or excipient. carrier comprising a compound selected from the group 0285) 41. The formulation of any of paragraphs 33-40, consisting of lipids, oils, polymers, peptides, proteins, wherein the formulation is formulated for topical, oral or carbohydrates, glycolipids, phospholipids, lipoproteins, parenteral administration. cationic molecules, and any combinations thereof. 0286 42. The formulation of any of paragraphs 33-41, 0271 27. The formulation of any of paragraphs 1-26, wherein the formulation is an oral dosage, injectable, wherein the additional active agent drug carrier has a size aerosol or inhalant, lotion, cream, gel, emulgel, oil, of about 5 nm to about 100 um. serum, powder, spray, ointment, Solution, Suspension, US 2016/0346294 A1 Dec. 1, 2016 75

dispersion, paste, foam, peel, films, mask, patch, Stick, lipids, phospholipids, lipoproteins, cationic molecules, roller, impregnated fabric (e.g. a “wipe' or tissue), or any and any combinations thereof. combination thereof. 0303 59. The formulation of any of paragraphs 33-56, 0287 43. The formulation of any of paragraphs 33-42 wherein Surface of the additional active agent drug carrier further comprising a second antibacterial agent. is substantially free of surface modifier. 0288 44. The formulation of any of paragraphs 33–43, 0304) 60. The formulation of any of paragraphs 33-59, wherein the second antibacterial agent is in the form of a wherein the formulation further comprises a Zinc com drug carrier. pound. 0289 45. The formulation of any of paragraphs 33-44, 0305 61. The formulation of any of paragraphs 33-60, wherein the second antibacterial agent drug carrier further wherein the formulation comprises a moisturizing agent. comprises a compound selected from the group consisting (0306 62. A Dual Action Rational Therapeutic (DART) of lipids, oils, polymers, peptides, proteins, carbohy molecule that has two distinct anti-bacterial mechanisms drates, glycolipids, phospholipids, lipoproteins, cationic of action. molecules, and any combinations thereof. 0307 63. A DART molecule that has a B-lactam ring and 0290 46. The formulation of any of paragraphs 33-45, a quinolone nucleus, or a quinolone nucleus and a nitro wherein the second antibacterial agent drug carrier has a heterocycle, or a B-lactam ring and a nitroheterocycle. size of about 5 nm to about 100 Lum. 0308) 64. The molecule of paragraph 62, wherein the 0291 47. The formulation of any of paragraphs 33-46, molecule inhibits DNA gyrase or topoisomerase IV and wherein the second antibacterial agent drug carrier has a transpeptidase-mediated cross-linking of peptidoglycans. size of about 100 nm to about 25 um. (0309 65. The molecule of paragraph 62 or 63, wherein 0292) 48. The formulation of any of paragraphs 33-47, the molecule inhibits isoprenyl pyrophosphate and trans wherein the second antibacterial agent drug carrier com peptidase-mediated cross-linking of peptidoglycans. prises a surface modifier on the surface thereof. 0310) 66. The molecule of any of paragraphs 62-64, 0293 49. The formulation of any of paragraphs 33-48, wherein the molecule inhibits isoprenyl pyrophosphate wherein the surface modifier of the second antibacterial and DNA gyrase of topoisomerase IV. agent drug carrier is selected from the group consisting of 0311. 67. The molecule of any of paragraphs 62-65, lipids, oils, polymers, peptides, proteins, carbohydrates, wherein the molecule inhibits folate synthesis and DNA glycolipids, phospholipids, lipoproteins, cationic mol gyrase of topoisomerase IV. ecules, and any combinations thereof. 0312 68. The molecule of any of paragraphs 62-66, 0294 50. The formulation of any of paragraphs 33-47, wherein the molecule inhibits folate synthesis and trans wherein the Surface of the second antibacterial agent drug peptidase-mediated cross-linking of peptidoglycans. carrier is substantially free of surface modifier. 0313. 69. The molecule of any of paragraphs 62-67 that 0295) 51. The formulation of any of paragraphs 33-50 inhibits DNA gyrase or topoisomerase IV and the 30S further comprising an additional active agent. Sub-unit in bacteria. 0296 52. The formulation of any of paragraphs 33-51, 0314. 70. The molecule of any of paragraphs 62-68, wherein the additional active agent is an anti-inflamma wherein the molecule inhibits DNA gyrase or topoi tory-agent, penetration enhancer, permeation enhancer, somerase IV and the 50S sub-unit in bacteria. anti-oxidant, anti-aging agent, anti-wrinkle agent, skin 0315 71. The molecule of any of paragraphs 62-69, whitening or bleaching agent, ultraviolet (UV) light wherein the molecule inhibits transpeptidase-mediated absorbing or scattering agent, skin depigmentation agent, cross-linking of peptidoglycans and the 30S or the 50S skin regenerative agent, Scar healing agent, or any com Sub-unit in bacteria. bination thereof 0316 72. The molecule of any of paragraphs 62-70, 0297 53. The formulation of any of paragraphs 33-52, wherein the molecule inhibits folate synthesis and the 30S wherein the additional active agent is in the form of a drug or the 50S sub-unit in bacteria. carrier. 0317 73. The molecule of any of paragraphs 62-71, 0298 54. The formulation of any of paragraphs 33-53, wherein the molecule inhibits isoprenyl pyrophosphate wherein the additional active agent drug carrier further and the 30S or the 50S sub-unit in bacteria. comprises a compound selected from the group consisting 0318 74. A Dual Action Rational Therapeutic (DART) of lipids, oils, polymers, peptides, proteins, carbohy molecule that has two distinct anti-acne mechanisms of drates, glycolipids, phospholipids, lipoproteins, cationic action. molecules, and any combinations thereof. 0319 75. The molecule of paragraph 73, wherein the 0299 55. The formulation of any of paragraphs 33-54, molecule modulates at least two different targets. wherein the additional active agent drug carrier has a size 0320) 76. The molecule of paragraph 73 or 74 wherein of about 5 nm to about 100 um. the first mechanism is an antibacterial action and the 0300 56. The formulation of any of paragraphs 33-55, second mechanism of action is inhibition of keratinocyte wherein the additional active agent drug carrier has a size proliferation and differentiation. of about 100 nm to about 25 Lum. 0321) 77. The molecule of any of paragraphs 73-75, 0301 57. The formulation of any of paragraphs 33-56, wherein the first mechanism is an antibacterial action and wherein the additional active agent drug carrier comprises the second mechanism of action is anti-inflammatory. a surface modifier on the surface thereof. 0322 78. A Dual Action Rational Therapeutic (DART) 0302) 58. The formulation of any of paragraphs 33-57, molecule which includes two chemical domains, each wherein the surface modifier of the additional active agent said chemical domain binding to a distinct active site in drug carrier is selected from the group consisting of lipids, target cells, wherein said chemical domains are bound oils, polymers, peptides, proteins, carbohydrates, glyco together through a third domain. US 2016/0346294 A1 Dec. 1, 2016 76

0323 79. The molecule of paragraph 77, wherein the 0340 95. The molecule of any of paragraphs 62-93, third domain is a linker. wherein the surface modifier is a compound selected from 0324 80. The molecule of paragraph 77 or 78, wherein the group consisting of lipids, oils, polymers, peptides, the third domain is a cleavable linker. proteins, carbohydrates, glycolipids, phospholipids, lipo 0325 81. The molecule of paragraph 77 or 78, wherein proteins, cationic molecules, and any combination the third domain is a non-cleavable linker. thereof. 0326 82. The molecule of paragraphs 77-80, wherein 0341 96. A formulation comprising a dual action rational said third domain is 11-hydroxyundecenic acid; 1,10 therapeutic molecule of any of paragraphs 62-94 and at decanediol; 1,3-propanediol; 1.5-pentanedil; 10-hy least one carrier or excipient. droxydecenic acid; Succinic; lactic acid; 3-hydroxypropi 0342 97. The formulation of paragraph 95, wherein the onic acid; or any combination thereof. carrier or excipient is selected from the group consisting 0327 83. The molecule of any of paragraphs 77-81. of emulsifiers, preservatives, Surfactants, oils, lipids, wherein the third domain increases an activity of at least waxes, stabilizers, rheology modifiers or thickening one of the two chemical domains. agents (gelling agent), emollients, moisturizers, condi 0328 84. The molecule of any of paragraphs 77-82, tioning agents, fragrances/perfumes, potentiating agents, wherein the third domain has antibacterial or anti-inflam preservatives, opacifiers, antioxidants, cooling agents, matory activity. film forming agents, abrasives, exfoliating agents, colo 0329 85. The molecule of any of paragraphs 62-83, rants, pH modifiers, solvents, vehicle, penetration enhanc wherein the molecule is in the form of a drug carrier. ers, permeation enhancers, pearlizing agents, and any 0330 86. The molecule of any of paragraphs 62-84, combinations thereof. wherein the drug carrier has a 0343 98. The formulation of paragraph 95 or 96 com 0331 size of about 5um to about 100 um prising from about 5% to about 99% (w/w or w/v) of the 0332 87. The molecule of any of paragraphs 62-85, carrier or excipient. wherein the drug carrier has a size of about 100 nm to 0344) 99. The formulation of any of paragraphs 95-97, about 25 m. wherein the formulation is formulated for topical, oral or 0333 88. The molecule of any of paragraphs 62-86, parenteral administration. wherein the drug carrier further comprises a compound 0345 100. The formulation of any of paragraphs 95-98, Selected from the group consisting of lipids, oils, poly wherein the formulation is an oral dosage, injectable, mers, peptides, proteins, carbohydrates, glycolipids, aerosol or inhalant, lotion, cream, gel, emulgel, oil, phospholipids, lipoproteins, cationic molecules, and any serum, powder, spray, ointment, Solution, Suspension, combinations thereof. dispersion, paste, foam, peel, films, mask, patch, Stick, 0334 89. The molecule of any of paragraphs 62-87, roller, impregnated fabric (e.g. a “wipe' or tissue), or any wherein the drug carrier further comprises an additional combination thereof. active agent. 0346) 101. The formulation of any of paragraphs 95-99 0335 90. The molecule of paragraph 88, wherein the further comprising a second anti-acne agent. additional active agent is an anti-inflammatory-agent, 0347 102. The formulation of any of paragraphs 95-100, keratolytic agent, penetration enhancer, anti-oxidant, anti wherein the second anti-acne agent is selected from the aging agent, anti-wrinkle agent, skin whitening or bleach group consisting of acetretin, adapalene(s), alitretinoin, ing agent, ultraviolet (UV) light absorbing or scattering alpha- or beta-hydroxy acids, antibiotics, antimicrobial agent, skin depigmentation agent, skin regenerative agent, peptides, antimicrobials, azelaic acid, benzoyl peroxide, Scar healing agent, or any combination thereof. bexarotene, bile salts, biofilm inhibitors, clindamycin, 0336 91. The molecule of any of paragraphs 62-89, erythromycin, etretinate, glycolic acid, isotretinoin, kera wherein surface of the drug carrier is substantially free of tolytic agents, lactic acid, lipoic acid, N-acetylcystein, surface modifier. natural anti-acne agents, octopirox, phenoxyethanol, phe 0337 92. The molecule of any of paragraphs 62-90, noxypropanol, pyruvic acid, resorcinol, retinoic acid, ret wherein the drug carrier further comprises an additional inoid(s), salicylic acid, sebostats, sodium sulfacetamide, anti-acne agent. spironolactone, Sulfur, Sulfur containing D- or L-amino 0338 93. The molecule of any of paragraphs 62-91, acids, tazarotene, tea tree oil, tretinoin, triclosan, urea, and wherein the second anti-acne agent is selected from the any combinations thereof. group consisting of acetretin, adapalene(s), alitretinoin, 0348 103. The formulation of any of paragraphs 95-101, alpha- or beta-hydroxy acids, antibiotics, antimicrobial wherein the second anti-acne agent is in the form of a drug peptides, antimicrobials, azelaic acid, benzoyl peroxide, carrier. bexarotene, bile salts, biofilm inhibitors, clindamycin, 0349 104. The formulation of any of paragraphs 95-102, erythromycin, etretinate, glycolic acid, isotretinoin, kera wherein the second anti-acne agent drug carrier further tolytic agents, lactic acid, lipoic acid, N-acetylcystein, comprises a compound selected from the group consisting natural anti-acne agents, octopirox, phenoxyethanol, phe of lipids, oils, polymers, peptides, proteins, carbohy noxypropanol, pyruvic acid, resorcinol, retinoic acid, ret drates, glycolipids, phospholipids, lipoproteins, cationic inoid(s), Salicylic acid, sebostats, sodium sulfacetamide, molecules, and any combinations thereof. spironolactone, Sulfur, Sulfur containing D- or L-amino 0350 105. The formulation of any of paragraphs 95-103, acids, tazarotene, tea tree oil, tretinoin, triclosan, urea, and wherein the second anti-acne agent drug carrier has a size any combinations thereof. of about 5 nm to about 100 um. 0339) 94. The molecule of any of paragraphs 62–92, 0351 106. The formulation of any of paragraphs 94-103, wherein the drug carrier further comprises a surface wherein the second anti-acne agent drug carrier has a size modifier on the surface thereof. of about 100 nm to about 25 lum. US 2016/0346294 A1 Dec. 1, 2016 77

0352 107. The formulation of any of paragraphs 95-105, 0368 123. The method of any of paragraphs 119-121, wherein the second anti-acne agent drug carrier comprises wherein the acne condition is caused by clindamycin-, a surface modifier on the surface thereof. tetracycline-, doxycycline-, or erythromycin-resistant 0353. 108. The formulation of any of claims 95-106, Propionbacterium acnes. wherein the Surface modifier of the second anti-acne agent 0369 124. The method of any of paragraphs 119-122. drug carrier is selected from the group consisting of lipids, wherein the acne condition is caused by clindamycin-, oils, polymers, peptides, proteins, carbohydrates, glyco tetracycline-, doxycycline-, or erythromycin-tolerant Pro lipids, phospholipids, lipoproteins, cationic molecules, pionbacterium acnes. and any combinations thereof. 0370 125. A method of treating a bacterial infection in a 0354 109. The formulation of any of paragraphs 95-105, Subject comprising administering a therapeutically effec wherein surface of the second anti-acne agent is Substan tive amount of a formulation of any of paragraphs 1-61 tially free of surface modifier. and 95-118. 0355 110. The formulation of any of paragraphs 95-108 further comprising an additional active agent. 0371) 126. The method of paragraph 124, wherein the infection is caused by a pathogen selected from the group 0356. 111. The formulation of any of paragraphs 95-109, consisting of Bartonella hemselae, Borrelia burgdorferi, wherein the additional active agent is an anti-inflamma Campylobacter jejuni, Campylobacterfetus, Chlamydia tory-agent, penetration enhancer, anti-oxidant, anti-aging trachomatis, Chlamydia pneumoniae, Chylamydia psit agent, anti-wrinkle agent, skin whitening or bleaching taci, Simkania negevensis, Escherichia coli (e.g., O157: agent, ultraviolet (UV) light absorbing or scattering agent, H7 and K88), Ehrlichia chafeensis, Clostridium botuli skin depigmentation agent, skin regenerative agent, scar num, Clostridium perfiringens, Clostridium tetani, healing agent, or any combination thereof. Enterococcus faecalis, Haemophilius influenzae, Haemo 0357 112. The formulation of any of paragraphs 95-110, philius ducreyi, Coccidioides immitis, Bordetella pertus wherein the additional active agent is in the form of a drug sis, Coxiella burnetii, Ureaplasma urealyticum. Myco carrier. plasma genitalium, Trichomatis vaginalis, Helicobacter 0358 113. The formulation of any of paragraphs 95-111, pylori, Helicobacter hepaticus, Legionella pneumophila, wherein the additional active agent drug carrier further Mycobacterium tuberculosis, Mycobacterium bovis, comprises a compound selected from the group consisting Mycobacterium africanum, Mycobacterium leprae, of lipids, oils, polymers, peptides, proteins, carbohy Mycobacterium asiaticum, Mycobacterium avium, Myco drates, glycolipids, phospholipids, lipoproteins, cationic bacterium cellatum, Mycobacterium celonae, Mycobacte molecules, and any combinations thereof. rium fortuitum, Mycobacterium genavense, Mycobacte rium haemophilum, Mycobacterium intracellulare, 0359 114. The formulation of any of paragraphs 95-112, Mycobacterium kansasii, Mycobacterium malmoense, wherein the additional active agent drug carrier has a size Mycobacterium marinum, Mycobacterium scrofiuliaceum, of about 5 nm to about 100 um. Mycobacterium simiae, Mycobacterium Szulgai, Myco 0360. 115. The formulation of any of paragraphs 95-113, bacterium ulcerans, Mycobacterium xenopi, Corynebac wherein the additional active agent drug carrier has a size terium diptheriae, Rhodococcus equi, Rickettsia aeschli of about 100 nm to about 25 Lum. mannii, Rickettsia africae, Rickettsia Conorii, 0361) 116. The formulation of any of paragraphs 95-114, Arcanobacterium haemolyticum, Bacillus anthracis, wherein the additional active agent drug carrier comprises Bacillus cereus, Lysteria monocytogenes, Yersinia pestis, a surface modifier on the surface thereof. Yersinia enterocolitica, Shigella dysenteriae, Neisseria 0362 117. The formulation of any of paragraphs 95-115, meningitides, Neisseria gonorrhoeae, Streptococcus wherein the surface modifier of the additional active agent bovis, Streptococcus hemolyticus, Streptococcus mutans, drug carrier is selected from the group consisting of lipids, Streptococcus pyogenes, Streptococcus pneumoniae, oils, polymers, peptides, proteins, carbohydrates, glyco Staphylococcus aureus, Staphylococcus epidermidis, lipids, phospholipids, lipoproteins, cationic molecules, Staphylococcus pneumoniae, Staphylococcus saprophyti and any combinations thereof. cus, Vibrio cholerae, Vibrio parahaemolyticus, Salmo nella typhi, Salmonella paratyphi, Salmonella enteritidis, 0363 118. The formulation of any of paragraphs 95-114, Treponema pallidum, Candida, CryptcoOccus, Cryp wherein Surface of the additional active agent drug carrier tosporidium, Giardia lamblia, Microsporidia, Plasmo is substantially free of surface modifier. dium vivax, Pneumocystis carinii, Toxoplasma gondii, 0364. 119. The formulation of any of paragraphs 95-117. Trichophyton mentagrophytes, Enterocytozoon bieneusi, wherein the formulation further comprises a Zinc com Cyclospora Cayetanensis, Encephalitozoon hellem, pound. Encephalitozoon cuniculi, among other bacteria, archaea, 0365 120. A method of treating acne condition in a protozoa, and fungi. Subject comprising administering a therapeutically effec tive amount of a formulation of any of paragraphs 1-61 0372 127. The method of paragraph 124 or 125, wherein and 95-118. the infection is by an antibiotic resistant bacterial strain. 0366 121. The method of any of paragraph 119, wherein 0373) 128. The method of any of paragraphs 124 or 125, the acne condition is caused by antibiotic Susceptible wherein the infection is by an antibiotic susceptible bacterial Strain. bacterial Strain. 0367. 122. The method of paragraph 119 or 120, wherein 0374 129. The method of any of paragraphs 124-127, the acne condition is caused by antibiotic resistant bac wherein the formulation is administered once or daily to teria. said Subject as a single dose or a plurality of doses. US 2016/0346294 A1 Dec. 1, 2016

SOME SELECTED DEFINITIONS 20%, or at least about 30%, or at least about 40%, or at least 0375 For convenience, certain terms employed herein, in about 50%, or at least about 60%, or at least about 70%, or the specification, examples and appended claims are col at least about 80%, or at least about 90% or up to and lected herein. Unless stated otherwise, or implicit from including a 100% decrease (e.g. absent level as compared to context, the following terms and phrases include the mean a reference sample), or any decrease between 10-100% as ings provided below. Unless explicitly stated otherwise, or compared to a reference level. apparent from context, the terms and phrases below do not 0383. The terms “increased, “increase' or “enhance' or exclude the meaning that the term or phrase has acquired in “activate are all used herein to generally mean an increase the art to which it pertains. The definitions are provided to by a statically significant amount; for the avoidance of any aid in describing particular embodiments, and are not doubt, the terms “increased, “increase' or "enhance' or intended to limit the claimed invention, because the scope of “activate” means an increase of at least 10% as compared to the invention is limited only by the claims. Further, unless a reference level, for example an increase of at least about otherwise required by context, singular terms shall include 20%, or at least about 30%, or at least about 40%, or at least pluralities and plural terms shall include the singular. about 50%, or at least about 60%, or at least about 70%, or 0376 Unless defined otherwise, all technical and scien at least about 80%, or at least about 90% or up to and tific terms used herein have the same meaning as those including a 100% increase or any increase between 10-100% commonly understood to one of ordinary skill in the art to as compared to a reference level, or at least about a 2-fold, which this invention pertains. Although any known meth or at least about a 3-fold, or at least about a 4-fold, or at least ods, devices, and materials can be used in the practice or testing of the invention, the methods, devices, and materials about a 5-fold or at least about a 10-fold increase, or any in this regard are described herein. increase between 2-fold and 10-fold or greater as compared 0377 As used herein, the term “herein is means the to a reference level. whole of the disclosure and as such is not meant to be limited 0384 The term “statistically significant’ or “signifi to a particular section or Subsection of the disclosure. cantly refers to statistical significance and generally means 0378. As used herein the term “comprising or “com at least two standard deviation (2SD) away from a reference prises' is used in reference to compositions, methods, and level. The term refers to statistical evidence that there is a respective component(s) thereof, that are essential to the difference. It is defined as the probability of making a invention, yet open to the inclusion of unspecified elements, decision to reject the null hypothesis when the null hypoth whether essential or not. esis is actually true. 0379 The singular terms “a,” “an,” and “the include (0385. The term “globule” as used herein refers to spheri plural referents unless context clearly indicates otherwise. cal or quasi-spherical globes, balls or other shaped particles Similarly, the word 'or' is intended to include “and” unless of a Substance Such as form in biphasic Suspensions or the context clearly indicates otherwise. emulsions. Also included in the meaning of the term “glob 0380. Other than in the operating examples, or where ule' are finely divided particles of a solid material. otherwise indicated, all numbers expressing quantities of (0386 The disclosure is further illustrated by the follow ingredients or reaction conditions used herein should be ing examples which should not be construed as limiting. The understood as modified in all instances by the term “about.” examples are illustrative only, and are not intended to limit, The term “about when used in connection with percentages in any manner, any of the aspects described herein. The can mean+5%, +4%, +3%, 2.5%, +2%, +1.5%, +1%, or following examples do not in any way limit the invention. +0.5% of the value being referred to. EXAMPLES 0381 Although methods and materials similar or equiva lent to those described herein can be used in the practice or Example. 1 testing of this disclosure, Suitable methods and materials are described below. The term “comprises' means “includes.” 0387 Screening of antibiotics against P. acnes strains The abbreviation, "e.g. is derived from the Latin exempli shows that the response is unpredictable in both clindamy gratia, and is used herein to indicate a non-limiting example. cin-sensitive and non-responder strains Thus, the abbreviation “e.g. is synonymous with the term (0388. Examples 2-15 and Tables 6-15 describe some “for example.” exemplary DART molecules, their synthesis, formulations 0382. The terms “decrease”, “reduced, “reduction', and uses. “decrease' or “inhibit are all used herein generally to mean a decrease by a statistically significant amount. However, for Example 2 avoidance of doubt, “reduced, “reduction' or “decrease' or “inhibit means a decrease by at least 10% as compared to Synthesis of DART Molecule 9 (from Table 1A) a reference level, for example a decrease by at least about 0389) O 1.

1.5 Pentane diol -- O NH2 DCC, HOBt, DMAP, DCM, RT, 16 h

O OH US 2016/0346294 A1 Dec. 1, 2016 79

-continued

F OH

3 DCC, HOBt, DMAP, DCM, RT, 16 h

h F

0390 Step 1. Synthesis of 2: To a solution of 1 (1 g, 2.33 0391) Step 2. Synthesis of DART, 9: To a solution of 3 mmol) in mixture of dichloromethane (10 ml) and dimeth (0.72 g, 1.55 mmol) in mixture of dichloromethane (10 ml) ylformamide (1 ml) was added N,N-dicyclohexylcarbodi and dimethylformamide (1 ml) was added dicyclohexylcar imide (0.627 g, 3.04.1 mmol) followed by N-Hydroxyben bodiimide (0.415 g, 2.05 mmol) followed by N-Hydroxy Zatriazole (0.316 g, 2.33 mmol) slowly at ice cold condition benzatriazole (0.209 g, 1.55 mmol) at RT to provide turbid and stirred at RT for 2 h to obtain turbid suspension. To this suspension. The reaction mixture was stirred for 3 hr at RT turbid solution pentanediol (0.85 ml, 8.18 mmol) was added and compound 2 (0.79 g, 1.55 mmol) was added to this followed by 4-dimethylaminopyridine (0.284 g, 2.33 mmol). turbid solution followed by addition of 4-dimethylamin The final reaction mixture was stirred at RT for 16 h. The opyridine (0.189 g 1.55 mmol). The final solution was white precipitate was filtered and extracted with ethyl stirred at RT for 16 h. The precipitate was filtered, and the acetate. The filtrate was washed with brine solution, dried filtrate was extracted with ethyl acetate. The organic layer over Sodium Sulphate and evaporated to get crude mass. The was washed with brine solution and dried over sodium crude product was purified by flash column chromatography sulphate to obtain the crude product. The crude product was eluting with 1% methanol/dichloromethane to obtain pure purified by flash column chromatography to get the final compound, 2 (0.9 g, 80% yield). product (9) in 50-60% isolated yield. US 2016/0346294 A1 Dec. 1, 2016 80

Example 2 compound was eluted with 1-3% methanol/dichloromethane to obtain pure compound, 4 (1.2g, 82% yield). Synthesis of DART Molecule 87 (from Table 1A) 0394 Step-2: Synthesis of DART, 87: To a solution of 0392 Compound 4 (1 g, 1.72 mmol) in dichloromethane (10 ml)

11 Bromoundecanoic acid Her O NH2

O OH

DCC, HOBt, DMAP, DCM, RT, 16 h

0393 Step 1. Synthesis of 4: 11-Bromoundecanoic acid and 1 ml dimethylformamide was added dicyclohexylcar (1.33 g, 5.04 mmol) was pre-mixed with the methanol (0.1 bodiimide (0.461 g, 2.23 mmol) followed by N-Hydroxy ml) was added into a stirred mixture of 1 (1 g, 2.52 mmol), benzatriazole (0.232 g, 1.72 mmol) at RT to provide turbid potassium carbonate (0.243 g, 1.764 mmol), and dipotas suspension. The reaction mixture was stirred for 1 hr at RT. sium-hydrogenphosphate (0.175 g, 1 mmol) in N,N-dim To this turbid solution 5 (0.67 g, 1.72 mmol) was added ethylacetamide (15 ml) at 0-5°C. The reaction mixture was followed by DMAP (0.210 g, 1.72 mmol) and the reaction stirred at 0°C. for 5 hr and extracted with ethyl acetate (50 mixture was stirred at RT for 16 h. The suspension was ml). The final solution was washed with 3% aqueous sodium filtered and washed with brine solution. The organic layer bicarbonate solution (10 ml) followed by brine solution (10 was dried over sodium sulphate and evaporated to obtain the ml). The organic solvent was evaporated to give crude mass crude mass. Finally the crude was purified by flash column and finally purified by flash column chromatography. The chromatography using 2-5% methanol/dichloromethane as US 2016/0346294 A1 Dec. 1, 2016

eluent to obtain the pure compound, 87 with 60-65% iso column chromatography. The final compound was eluted lated yield. with 1-2% methanol/dichloromethane mixture. The com pound was used for the next step without further character Example 3 ization. Synthesis of DART Molecule 90 (from Table 1B) Synthesis of 7-(4-1-Chloromethyl-2-(2-methyl-5- nitro-imidazol-1-yl)-ethoxycarbonylmethyl-piper 0395 Bromo-acetic acid 1-chloromethyl-2-(2-methyl-5- azin-1-yl)-6-fluoro-1-methyl-4-oxo-4H-2-thia-8b nitro-imidazol-1-yl)-ethyl ester (II) was synthesized accord aza-cyclobutaanaphthalene-3-carboxylic acid (1) ing to the following scheme. 0397 To a stirred solution of 6-Fluoro-1-methyl-4-oxo 7-piperazin-1-yl-4H-2-thia-8b-aza-cyclobutaanaphtha lene-3-carboxylic acid, (III) (0.071 g, 0.2 mmol) in dimeth ylformamide (10 ml) was added potassium carbonate (0.04 g, 0.3 mmol) followed by addition of compound (II) (0.1 g, 0.3 mmol) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with ethylacetate, washed two times with water and finally dried over sodium C OH sulphate to obtain the crude mass. The crude was purified by I flash column chromatography while eluting with 3-5% --- methanol/dichloromethane mixture to obtain the pure com - up DCC, PMP. 16h pound (1), i.e., Compound 90 from Table 1, with 30% HO 45% isolated yield. 0398 H-NMR (400 MHz, DMSO) 8 ppm: 2.19 (3H, d, ^\ N O J-=6.4 HZ, CH), 2.57 (3H, s, CH), 2.7 (4H, m, 2xCH), 3.1-3.3 (2H, s, COCH2), 3.32 (4H, m, 2xCH), 3.77-3.90 \U/ \ OH (2H, ddd, J–3.6 Hz, J-12.4 Hz, J-35.2 HZ, CHCI), 4.40-4.56 (1H, dd, J =9.6 Hz, J-14 Hz CHN), 4.76 (1H, d, ON N F O J=14 Hz, CHN), 5.44 (1H, d, 0.1=5.6 Hz. CHOCO), 6.0–6.11 III (1H, q, J=6 Hz, J-12.4 Hz, CHSN), 6.4 (1H, d, J=6.8 Hz K2CO3, DMF, 3 h Ar H), 7.8 (1H, d. J=14 Hz, Ar-H), 8.04 (1H, s, Ar H). 30-35% ESI-MS (m/z): 609 (M+H)". Example 4

Synthesis of DART Molecule 91 from Table 1B 0399 2-Methyl-5-nitro-1-oxiranylmethyl-1H-imidazole (IV) was synthesized according to the following scheme.

N 20% NaOH Ho DCM, 0° C.-RT, 3 h 90%

Note: Compound 1 in the scheme corresponds to compound 90 from Table 1B in \ u 0396 To a stirred solution of 1-Chloro-3-(2-methyl-5- (>N \U/ OH nitro-imidazol-1-yl)-propan-2-ol, (I) (0.79, 3.6 mmol) in ON F O dichloromethane (10 ml) was added dicyclohexylcarbadi HC III imide (DCC) (0.9 g, 4.31 mmol) followed by bromoacetic K2CO3, Acetone + Water, acid (0.5g, 3.6 mmol) and DMAP(0.44g, 3.6 mmol) at RT. 50° C., 20 h. O The reaction mixture was stirred at RT for 16 h. The 25-30% precipitate was removed by filtration and the organic layer IV was evaporated to get the crude that was purified by flash US 2016/0346294 A1 Dec. 1, 2016

-continued Example 5 Synthesis of DART Molecule 94 from Table 1B - y NO 0402

OH Nun N). S lo F

O OH 2

Note: Compound 2 in the scheme corresponds to compound 91 from Table 1B