IIIIIIIIIIIIIIIIIIIIIIIIIIIUS010071103B2 (12 ) United States Patent ( 10) Patent No

Home , Astromicin, Clomocycline, Estrin (compound), Nana (entertainer), Ranbezolid, Verdamicin

IIIIIIIIIIIIIIIIIIIIIIIIIIIUS010071103B2 (12 ) United States Patent ( 10) Patent No. : US 10 ,071 , 103 B2 Sengupta et al. (45 ) Date of Patent: Sep . 11 , 2018

(54 ) TREATMENTS FOR RESISTANT ACNE (58 ) Field of Classification Search CPC .. . . A61K 31 /55 ; A61K 9 /0014 ; A61K 31/ 192 ; (71 ) Applicant: VYOME BIOSCIENCES PVT. LTD ., A61K 31 /4709 ; A61K 45 /06 ; A61K New Delhi ( IN ) 47 / 02 , A61K 47 / 08 ; A61K 47 / 10 ; A61K 47 / 183 ; A61K 47 /32 , A61K 47 / 36 ; A61K (72 ) Inventors : Shiladitya Sengupta , Delhi (IN ); 47 /38 Suresh Rameshlal Chawrai, Pune USPC ...... 514 /210 . 16 ( IN ) ; Shamik Ghosh , Delhi ( IN ) ; See application file for complete search history . Sumana Ghosh , Delhi ( IN ); Nilu Jain , New Delhi ( IN ) ; Suresh Sadhasivam , ( 56 ) References Cited Salem ( IN ) ; Richard Buchta , Melbourne (AU ) ; Anamika U . S . PATENT DOCUMENTS Bhattacharyya , Delhi ( IN ) 4 , 668 ,664 A 5 / 1987 Rougier et al. 5 ,607 , 980 A 3 / 1997 McAtee et al . (73 ) Assignee: VYOME BIOSCIENNCES PVT. 6 , 255, 279 B1 7 / 2001 Christophers et al. LTD ., New Delhi (IN ) 2005 / 0209157 Al 9 /2005 Owen 2005 /0245545 Al 11/ 2005 Kase et al . Subject to any disclaimer, the term of this 2005 /0282755 Al 12 /2005 Hart et al . ( * ) Notice : 2006 / 0008538 A1 1 / 2006 Wu et al . patent is extended or adjusted under 35 2007/ 0134729 AL 6 / 2007 Christensen et al. U . S . C . 154 ( b ) by 0 days. 2007 / 0197501 A1 8 / 2007 Schulz et al . 2011/ 0144329 A1 * 6 / 2011 Shawer ...... CO7D 223 / 12 ( 21 ) Appl. No .: 15 / 115 ,143 540 /605 2016 / 0058775 A1 * 3 / 2016 Prasad ...... A61K 8 /342 ( 22 ) PCT Filed : Jan . 29 , 2015 424 / 401 ( 86 ) PCT No. : PCT/ IN2015 / 000057 FOREIGN PATENT DOCUMENTS $ 371 (c )( 1 ), CN 103524492 A 1/ 2014 ( 2 ) Date: Jul. 28 , 2016 EP 0251330 A2 1 / 1998 JP 2009196934 A 9 /2009 WO 2006 / 100495 A1 9 / 2006 (87 ) PCT Pub. No. : W02015/ 114666 WO 2007 /070518 A2 6 / 2007 PCT Pub . Date : Aug. 6, 2015 WO 2008 /035078 A1 3 / 2008 WO 2012 / 177770 A112 / 2012 wo 2012 / 177986 A2 12 / 2012 (65 ) Prior Publication Data WO 2014 / 167554 A2 10 / 2014 US 2016 /0346294 A1 Dec. 1 , 2016 WO 2014 / 195872 A112 / 2014 (30 ) Foreign Application Priority Data OTHER PUBLICATIONS Jan . 29 , 2014 ( IN ) ...... 269 /DEL /2014 Betriu et al . , “ Erythromycin and Clindamycin Resistance and Nov . 10 , 2014 ( IN ) ...... 3247 /DEL / 2014 Telithromycin Susceptibility in Streptococcus agalactiae” , Antimi crobial Agents and Chemotherapy 47 ( 3 ) : 1112 - 1114 (2003 ) . (51 ) Int. CI. Bryskier et al. , “ Dual B - lactam - fluoroquinolone compounds: a novel A61K 31 /55 ( 2006 .01 ) approach to antibacterial treatment” , Expert Opinion on Investiga A61K 31/ 192 ( 2006 .01 ) tional Drugs 6 ( 10 ) : 1479 - 1499 ( 1997 ) . Cambau et al ., “ Target specificity of the new fluoroquinolone A61K 45 / 06 ( 2006 .01 ) besifloxacin in Streptococcus pneumoniae , Staphylococcus aureus A61K 47 / 02 ( 2006 . 01 ) and Escherichia coli” , Journal of Antimicrobial Chemotherapy A61K 47 / 08 ( 2006 .01 ) 63: 443 -450 (2009 ) . A61K 47 / 10 ( 2017 .01 ) De Lucca et al. , “ Antifungal peptides : Origin , activity , and thera C07D 513 /04 ( 2006 .01 ) peutic potential" , Revista Iberoamericana de Micologia 17 : 116 - 120 A61K 31 / 4709 ( 2006 .01 ) ( 2000 ) . A61K 9 / 00 ( 2006 . 01 ) A61K 47/ 18 ( 2017 .01 ) (Continued ) A61K 4732 ( 2006 . 01 ) Primary Examiner — Yevgeny Valenrod A61K 47 / 36 ( 2006 .01 ) (74 ) Attorney, Agent, or Firm — Nixon Peabody LLP ; A61K 47 /38 ( 2006 .01 ) David S . Resnick ; Ravinderjit Braich (52 ) U . S . CI. CPC ...... A61K 31/ 55 ( 2013 .01 ) ; A61K 9 / 0014 ( 2013 . 01 ); A61K 31 / 192 (2013 . 01 ) ; A61K (57 ) ABSTRACT 31 /4709 (2013 .01 ) ; A61K 45 /06 (2013 .01 ) ; The present disclosure relates generally to novel molecules , A61K 47 / 02 ( 2013 .01 ) ; A61K 47/ 08 ( 2013 .01 ) ; compositions, and formulations for treatment of bacterial A61K 47 / 10 ( 2013. 01 ) ; A61K 47 / 183 infections in general and more specifically to bacterial ( 2013 .01 ) ; A61K 47 /32 ( 2013 .01 ) ; A61K 47 / 36 infections with antibiotic resistant pathogens. ( 2013 .01 ) ; A61K 47/ 38 ( 2013 .01 ) ; C07D 513 /04 ( 2013 .01 ) 16 Claims, 14 Drawing Sheets US 10 ,071 , 103 B2 Page 2

References Cited loproteinases in keratinocytes in response to Propionibacterium ( 56 ) acnes" , Archives of Dermatological Research 302 :745 - 756 ( 2010 ) . Liu et al. , “ Cutting Edge : All- trans Retinoic Acid Down -Regulates OTHER PUBLICATIONS TLR2 Expression and Function ” , The Journal of Immunology 174 :2467 - 2470 (2005 ) . Elitropi et al ., “ New Cephalosporins and 7a -Methoxy Cephalosporins Mouser et al. , “ Propionibacterium acnes- Reactive T Helper - 1 Cells in the Skin of Patients with Acne Vulgaris ” , The Journal of Chemistry and Biological Activities” , The Journal of Antibiotics Investigative Dermatology 121 (5 ) : 1226 - 1228 (2003 ) . 32 ( 9 ): 900 - 908 ( 1979 ) . Nagy et al ., “ Propionibacterium acnes and lipopolysaccharide induce Epand et al. , “ Diversity of antimicrobial peptides and their mecha the expression of antimicrobial peptides and proinflammatory cytokines/ nismsof action ” , Biochimica et Biophysica Acta 1462 : 11 -28 ( 1999 ). chemokines in human sebocytes ” , Microbes and Infection 8 : 2195 Haas et al. , “ Besifloxacin , a Novel Fluoroquinolone, Has Broad 2205 ( 2006 ) . Spectrum In Vitro Activity against Aerobic and Anaerobic Bacte Regoes et al . , “ Pharmacodynamic Functions : a Multiparameter ria ” , Antimicrobial Agents and Chemotherapy 53 ( 8 ) :3552 - 3560 Approach to the Design of Antibiotic Treatment Regimens ” , Anti ( 2009 ) . microbial Agents and Chemotherapy 48 ( 10 ) : 3670 - 3676 ( 2004 ) . Jeremy et al. , “ Inflammatory Events Are Involved in Acne Lesion Schlunzen et al . , " Structural basis for the interaction of antibiotics Initiation ” , Journal of Investigative Dermatology 121 ( 1 ) :20 - 27 (2003 ) . with the peptidyl transferase centre in eubacteria ” , Nature 413 :814 Kabara et al. , “ Fatty Acids and Derivatives as Antimicrobial Agents ” , 821 (2001 ) . Antimicrobial Agents and Chemotherapy 2 ( 1 ) :23 - 28 ( 1972 ). Taglietti et al . , " Novel Topical Drug Delivery Systems and Their Kato et al ., “ Comparison of In Vitro Activities of DU -6859a and Potential Use in Acne Vulgaris ” , Skin Therapy Letter 1 - 5 (2008 ) . Other Fluoroquinolones Against Japanese Isolates of Anaerobic Thiboutot et al. , “ IL - 17 : A Key Player in the P . acnes Inflammatory Bacteria ” , Clinical Infectious Diseases 23 ( Suppl 1 ) : S31 - S35 ( 1996 ) . Cascade ? " , Journal of Investigative Dermatology 134 : 307 -310 ( 2014 ) . Keren et al ., " Specialized Persister Cells and the Mechanism of Toyoda et al ., “ An Overview of Topical Antibiotics for Acne Multidrug Tolerance in Escherichia coli” , Journal of Bacteriology Treatment" , Dermatology 196 ( 1) : 130 -134 ( 1998 ). 186 ( 24 ) :8172 -8180 ( 2004 ) . Zasloff M . , “ Antimicrobial peptides of multicellular organisms” , Kim et al. , " Activation of Toll - Like Receptor 2 in Acne Triggers Nature 415 : 389 -395 ( 2002 ) . Inflammatory Cytokine Responses ” , The Journal of Immunology Miller et al. , “ SOS Response Induction by B - Lactams and Bacterial 169 : 1535 - 1541 ( 2002 ) . Defense Against Antibiotic Lethality ” , Science 305: 1629 - 1631 ( 2004 ) . Lau et al. , “ Scope and Limitations of The Co - Drug Approach to Ye et al . , " Synthesis and antibacterial activity of pyridonecarboxylic Topical Drug Delivery ” , Current Pharmaceutical Design 14 ( 8 ) :794 acid derivatives containing 2 -methyl - 5 - nitroimidazol ” , Acta 802 ( 2008 ) . Pharmaceutica Sinica 38 ( 4 ) :260 - 263 (2003 ) . Lee et al. , “ Protease -activated receptor - 2 mediates the expression of inflammatory cytokines, antimicrobial peptides , and matrix metal * cited by examiner U . S . Patent Sep . 11, 2018 Sheet 1 of 14 US 10 ,071 , 103 B2

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FIGS. 15A and 15B US 10 ,071 , 103 B2 TREATMENTS FOR RESISTANT ACNE propanol; and flavinoids, these agents tend to lack in poten tial to mitigate the acne condition and may have negative RELATED APPLICATIONS side effects when devised in conventional topical formula tions . A key challenge that has limited the use of topical This application claims benefit priority of Indian Patent 5 formulations is the absence of formulations with the desired Application No. 269 /DEL / 2014 , filed Jan . 29 , 2014 and No. physicochemical properties and high drug loading, which 3247 /DEL /2014 , filed Nov. 10 , 2014 , the content of both maintains a concentration significantly higher than the MIC applications is incorporated herein by reference in their at the site of application by facilitating the right degree of entirety. penetration over time but with minimal systemic exposure . 10 A formulation that addresses these unmet needs can be a FIELD OF THE INVENTION significant advance in the treatment of acne . Furthermore , as articulated in [ Taglietti et al, 2008 ) , when The present disclosure relates generally to novel mol- it comes to the delivery of a drug to a specific site , topical ecules, compositions, and formulations for treatment of formulations that are efficacious are probably among the bacterial infections in general and more specifically to 15 most challenging products to develop . Once the product is bacterial infections with antibiotic - tolerant pathogens. applied on the skin , a complex interaction occurs between the formulation , the active compounds , and the skin itself . BACKGROUND OF THE INVENTION The penetration of the active compound ( s ) into the skin follows Fick ' s first law of diffusion , which describes the Acne vulgaris is a skin condition that affects over 85 % of 20 transfer rate of solutes as a function of the concentration of all people . Acne is a term for a medical condition of plugged the various ingredients, the size of the treatment surface pores typically occurring on the face, neck , and upper torso . area , and the permeability of the skin . However, the skin ' s Following are four primary factors that are currently known permeability can be influenced by many factors , such as the to contribute to the formation of acne vulgaris ; ( 1 ) increased drying , moisturizing, or occluding effects of the excipients sebum output resulting in oily , greasy skin ; ( 2 ) increased 25 in the formulation , which , in combination , can modulate the bacterial activity , normally due to an overabundance of release of the product at the treatment site . In acne , the site Propionibacterium acnes bacteria ; (3 ) plugging (hypercor - of action is inside the pilosebaceous unit and , therefore , an nification ) of the follicle or pilosebaceous duct ; and ( 4 ) and efficacious anti - acne formulation should facilitate the pen inflammation . The plugged pores result in blackheads , etration of the active compound ( s ) into this extremely lipo whiteheads , pimples or deeper lumps such as cysts or 30 philic environment. An effective topical formulation there nodules . Severe cases of acne can result in permanent fore needs to provide a stable chemical environment in a scarring or disfiguring . suitable dispensing container in order to accommodate mul Though acne vulgaris is multifactorial , a commensal skin tiple compounds that may have different, if not incompat bacteria ( P . acnes) plays a major role in the formation of ible , physicochemical characteristics [ Tagleitti et al, 2008 ] . acne lesion . It is an infection of pilosebacious glands, oil 35 Once applied , a topical formulation must interact with the glands in the skin . In most cases sudden breakouts of acne skin environment , which can influence the rate of the release can be correlated with sudden increased production of of the compound ( s ) in order to achieve adequate skin sebum in the affected individual. During adolescence andro - absorption , and exert additional physical effects on the skin , gen hormones play a crucial role . It leads to overproduction such as drying , occluding , or moisturizing [ Tagleitti et al, of sebum by the pilosebaceous gland . The situation gets 40 2008 ] . For example , even if an active agent is very potent , further accentuated by irregular shedding of dead skin from and is effective via a systemic route, in the case of topical lining of hair follicles . As the dead skin cells clump together administration can behave completely differently , i. e . if the in the oily environment, they can form plugs which block the desired concentration is not reached in the pilosebaceous (or pores of the hair follicles . A pore clogged by the shedding skin ) unit, it will not serve as an effective anti- acne therapy. skin is referred to as a comedo . 45 Similarly , a molecule or drug can behave entirely differently This creates a very conducive anaerobic condition for P . if formulated with different compositions, which we dem acnes bacteria to grow . Hyperproliferation of P . acnes leads onstrate later in an example . Similarly, two molecule or to destruction of follicular walls and it sends a danger signal active agents may behave entirely differently in the same to the host immune system . P . acnes may trigger an innate formulation or composition . Therefore , every new molecule immune reaction both in very early (microcomedogenic ) and 50 that needs to be formulated for topical skin application poses in late ( inflammatory ) acne lesions via the activation of Toll a novel and independent challenge as it is impossible to like receptors 2 ( TLR2 ) on inante immune cells . TLR predict which composition and ratio of active and excipients activation ultimately triggers the expression various cytok - will provide the desired efficacy benefit . ines ( like IL - 6 , IL - 8 , IL - 12 , IL - 17 etc ) and chemokines that Furthermore , an emerging condition is the evolution of stimulate recruitment of other host immune cells (Jeremy et 55 strains of P . acnes, which do not respond to the antibiotic al, 2003 ; Thibout et al, 2014 ) . Acne lesions range in severity agents such as clindamycin , tetracyclines and erythromycin from blackheads , whiteheads and pimples to more serious currently approved for the treatment of acne . While the lesions such as deeper lumps, cysts and nodules . earlier dogmawas that antibiotics failure arises due to selec Although various over - the - counter products are commer tion of ' resistant' strains, i . e . a mutation resulting in altera cially available to counteract acne condition , such as anti - 60 tion of the target of the antibiotic rendering it ineffective , acne agents for topical use , including salicylic acid ; sulfur; emerging evidence suggests that antibiotic failure is more lactic acid ; glycolic acid ; pyruvic acid ; urea ; resorcinol; complex than this simple understanding . The assumption N - acetylcysteine ; retinoic acid ; isotretinoin ; tretinoin ; ada - was that if resistance develops, i . e . the target of an antibiotic palene ; tazoretene ; antibacterials such as clindamycin , tet- is altered , it is possible to treat the condition by changing to racyclines , and erythromycin , vitamins such as folic acid 65 an alternative antibiotic , the target of which is still intact in and nicotinamide ; minerals such as zinc ; benzoyl peroxide ; the bacteria . However, recent knowledge has rendered this octopirox ; triclosan ; azelaic acid ; phenoxyethanol; phenoxy assumption as false . For example , Regoes et al, 2004 dem US 10 ,071 , 103 B2 onstrates that even in the absence of any resistance , a subset followed by moxifloxacin and ciprofloxacin . [ Cambau et al, of bacteria can just exhibit tolerance to an antibiotic , i . e . not 2009 ] . It is therefore not possible to predict the activity of a undergo lysis . This could arise due to physiological (meta molecule against a bacteria or microbe based on its simi bolic ) and morphological changes observed in bacteria larity in structure another drug that shows activity against exposed to antibiotics . For example , in a study published in 5 the same microbe or a different microbe , even though they Science , [Miller et al , 2004 ] showed that a transient induc might have similar mechanisms of action . Indeed , as shown tion of SOS response by ampicillin can protect E . coli in FIG . 1 , we observed that molecules that were verisimilar in structure had completely distinct activity against P . acnes, against the bactericidal effects of ampicillin . Regoes et al, i . e . where one was inactive the other was very potent against 2004 suggested that tolerance mechanisms could cross over both clindamycin -susceptible and - non - resistant P . acnes between some antibiotics , i . e . Antibiotic A might be ren - 10 ( FIGS . 1 A and 1B ) . In another example, which we discuss dered ineffective due to development of resistance , but it is later, we observed a non - lincosamide molecule that was very possible that Antibiotic B , which has an entirely different effective in a P . acnes strain resistant to clindamycin but not target/ mechanism of action , and is shown to be active in a active in a clindamycin -sensitive P . acnes (FIGS . 1A and different or sensitive bacterial strain , may also be rendered 1B ) . The identification of an effective drug that works ineffective in the resistant strain due to shared toleranceice 15 against both sensitive as well as clindamycin - , minocycline - , mechanisms. Indeed , massive changes in gene expression erythromycin -, or doxycycline -nonresponder P . acnes there leading to alteration in the syntheses of proteins of metabolic fore emerges through serendipity during systematic screen and stress response pathways and cell division during expo - ing in P . acnes. sure of E . coli to ampicillin and ofloxacin have been Furthermore, while an emerging problem is the develop observed , and a number of these alterations in the gene 20 ment of resistant strains of microbes that are not responding expression levels were shared between bacteria exposed to to antimicrobial compounds and compositions well known ampicillin and ofloxacin , suggesting a bacteria not respond in the art , there remains a need in the art for a more effective ing to ampicillin may not respond to ofloxacin although both antibiotic that not only works against resistant microbes but agents have different targets . We saw a similar observation also reduces the risk of development of resistance by the in screening a library of antibiotics against different strains 25 microbes to this new antibiotic . Thus molecules that are of P . acnes that are sensitive or non -responsive to clindamy efficacious antibiotics and also 'prevent ' or reduce the devel cin (a lincosamide ). As shown in FIG . 1A . the strain of P. opment of resistance can be a major advancement in the treatment of microbial diseases . acnes non - responsive to clindamycin also showed increased The inflammatory character of acne has been correlated survival capability in the presence of roxithromycin ( a with the host immune response targeting Propionibacterium macrolide ), which targets a different site from clindamycin . 30 acnes , In vitro studies demonstrate that P . acnes whole cells [Keren et al, 2004 ]. Specialized persister cells and the or cell fractions stimulate cytokine and matrix metallopro mechanism of multidrug tolerance in Escherichia coli. J. teinase release from immune cells , keratinocytes , and sebo Bacteriol. 186 : 8172 - 8180 ) suggested that random fluctua cytes [Kim et al. , 2002 ; Liu et al ., 2005 ; Nagy et al. , 2006 ; tions in gene expression are responsible for the formation of Lee et al. , 20101 Though P . acnes are long been present in specialized persister cells . As argued by Regoes et al, 2004 , 35 the follicular area , they come in direct contact with immune phenotypic tolerance to antibiotic could actually prevent cells in dermis only after follicular rupture, The innate clearance . As a result, while there remains a need in the art immune system recognizes P . acnes via TLR2 [Kim et al. , for compositions, formulations and methods for treating 2002 ], leading to the secretion of inflammatory cytokines , acne that is not responding to the currently used agents , including IL - 6 , IL - 8 , IL - 12 etc . Follicular rupture happens especially clindamycin -, minocydine - , erythromycin - , and / 40 very late in the disease process . But there are multiple or doxycycline , the probability of tolerance makes itimprob - evidences which suggest that the adaptive immune response able to predict a drug that may work against P . acnes. also has a significant role in the inflammation observed even Furthermore, it is increasingly becoming evident that in early stages of acne , resulting from the recruitment of subtle changes in chemical structure of a molecule can activated T helper 1 ( Th1) lymphocytes to early acne lesions dramatically change activity of the molecules against target 45 [Mouser et al. , 2003 ] 1 . A potential treatment of acne there protein . For example erythromycin ( a macrolide ) and clin - fore needs to resolve inflammation , and should be able to damycin bind to similar 50S ribosomal unit but crystal target these inflammatory pathways . structure [Schulzen et al , 2001 ] showed different mode of An ideal treatment for acne therefore need molecules that binding between the agents and amino acid residues present can work at two or more targets . Molecules that work against in 50S ribosomal sub -unit . There are known bacterial strains 50 both antibiotic -sensitive as well as clindamycin -, minocy of P . acnes that are resistant to clindamycin but can be either cline -, erythromycin - and doxycycline - tolerant or non - re non - responsive or susceptible to erythromycin and vice sponsive strains of P . acnes and can additionally inhibit the versa . Interestingly , telithromycin , which is a semisynthetic P . acnes -activated inflammatory mediator / s , or molecules derivative of erythromycin works well in a bacterial strain that target two or more cellular targets in these microbes that is resistant to both erythromycin and clindamycin 55 while additionally exerting an inhibitory effect on the P . [Beitru et al , 2003 ) . Similarly , in another example , the acnes - activated inflammatory mediator / s , and is formulated introduction of 8 - chloro group dramatically enhanced the in an optimal formulation that enables the desired concen potency ofmoxifloxacin but a similar change in gatifloxacin tration of the active agent on the skin or pilosebaceous had no effect against S . aureus, S . pneumonia , and E . coli. region following topical application can emerge as a pow Additionally , molecules of the same class can have different 60 erful strategy for the treatment of acne . affinity for the same protein target but in different bacteria . For example it has been found that both besifloxacin and SUMMARY moxifloxacin effectively bind to DNA gyrase than cipro floxacin in S . aureus . In contrary ciprofloxacin binding DART towards DNA gyrase is more effective in E . coli than 65 moxifloxacin or besifloxacin . Similarly , besifloxacin is A series of novel DART (Dual Action Rational Thera found to be best effective molecule against S . pneumonia peutics ) molecules were designed and synthesized for treat US 10 ,071 , 103 B2 ment of bacterial infections caused by both susceptible and the 50S sub -unit in bacteria , or causes DNA modification , resistant gram positive and gram negative bacteria and such as inducing DNA nicks while inhibiting the induction specially for curing acne and different skin and skin structure of negative supercoils in DNA ; or altering the fluidity of the infections and additionally prevent the development of resis cell membrane while exerting an activity on the DNA ; or tance . DART molecules can mount its activity through two 5 altering the levels of metal ions in a cell while inducing distinct mechanisms of action in a microbe ( such as a DNA changes . In some embodiments , the first mechanism of bacteria ) , and create less chance in mutation development at action is an anti -bacterial action and the second mechanism both target sites in the bacteria . Additionally , it can also act of action is anti - inflammatory or immunomodulatory . at the host level by modulating the immune response , such In some embodiments , the DART molecule has at least as altering the levels of inflammatory cytokines. 10 two distinct treating acne mechanisms of action and modu The design of DART comprises of two active domains. lates at least two different targets . In some embodiments , the The two active domains can be selected from different first mechanism is an antibacterial action and the second families , for example , B - lactam , B - lactam derivatives , 2 - and mechanism of action is inhibition of keratinocyte prolifera 4 - quinolones , quinolones having halogenated atom specially tion and differentiation . In some embodiments , the DART fluorine atom attached at C -6 or C - 7 position of the central 15 molecule has two distinct acne treating mechanisms of ring system , fluoroquinolone with halogenated atom spe action and wherein the first mechanism is an antibacterial cially chlorine atom attached at C -8 position of the central action and the second mechanism of action is anti - inflam ring system , tetracycline , oxazolidinone , hydroxypyridones, matory . In some embodiments , the DART molecule is effec derivatives of hydroxypyridones, pleuromutilin , azoles, tive against forms of Propionbacterium acnes that respond nitroimidazoles , monoxycarbolic acid class, fusidic acid , 20 poorly to clindamycin - , or doxycycline - , or erythromycin - , sulfonamide, sulfonamide derivatives, retinoids, different or minocycline - containing anti -acne products . In some fatty acids ( saturated , unsaturated ) , propylene glycol and embodiments , they are effective against one or more of glycerol derivatives of different fatty acids and a strategic clindamycin -, minocycline -, erythromycin -, and /or doxycy combination from each of the families . The design was made cline - tolerant or resistant strains of Propionbacterium acnes . strategically by arranging the two active domains in the right 25 In some embodiments , it prevents the development of resis steric arrangement for both the active domains to maintain tance in P . acnes . their function against bacteria or fungus . Overall these In some embodiments , the DART molecule has at least molecules possess faster bacterial killing with reduction in two distinct anti - bacterial mechanisms of action and modu inflammation and activity against resistant pathogens. These lates at least two different targets against a pathogen . Non molecules also show a lower risk of development of resis - 30 limiting examples of such pathogens are : Bartonella hense tance . lae , Borrelia burgdorferi, Campylobacter jejuni, Campy In some embodiments , the DART molecule has at least lobacter fetus, Chlamydia trachomatis, Chlamydia pneumo two chemical domains . Each of said chemical domains binds niae , Chylamydia psittaci, Simkania negevensis , to a distinct or different active site in a target cell . In a Escherichia coli ( e . g . , 0157 : H7 and K88 ) , Ehrlichia cha preferred embodiment, a third chemical domain may be 35 feensis , Clostridium botulinum , Clostridium perfringens , present. In a further preferred embodiment, said two chemi- Clostridium tetani, Enterococcus faecalis , Haemophilius cal domains may be bound together through a said third influenzae, Haemophilius ducreyi , Coccidioides immitis , domain . In some embodiments , the DART molecule has at Bordetella pertussis , Coxiella burnetii, Ureaplasma ure least two distinct or different anti -bacterial mechanisms of alyticum , Mycoplasma genitalium , Trichomatis vaginalis , action . In some embodiments , the DART molecule has at 40 Helicobacter pylori, Helicobacter hepaticus, Legionella least two distinct or different anti -acne mechanisms of pneumophila , Mycobacterium tuberculosis, Mycobacterium action . Without limitations, the DARTs can act on the same bovis , Mycobacterium africanum , Mycobacterium leprae , target or on different targets , for example , the bacteria and Mycobacterium asiaticum , Mycobacterium avium , Myco the host . In some embodiments , the DART acts on at least bacterium celatum , Mycobacterium celonae , Mycobacte two different targets . In some embodiments, at least one of 45 rium fortuitum , Mycobacterium genavense , Mycobacterium the targets is different than that affected by conventional haemophilum , Mycobacterium intracellulare , Mycobacte antibiotics . rium kansasii, Mycobacterium malmoense , Mycobacterium In some embodiments , the DART molecule has a marinum , Mycobacterium scrofulaceum , Mycobacterium B - lactam ring and a quinolone nucleus, or a quinolone simiae , Mycobacterium szulgai , Mycobacterium ulcerans , nucleus and a nitro - heterocycle, or a B - lactam ring and a 50 Mycobacterium xenopi, Corynebacterium diptheriae , Rho nitroheterocycle . dococcus equi, Rickettsia aeschlimannii , Rickettsia africae , In some embodiments , the DART has at least two distinct Rickettsia conorii, Arcanobacterium haemolyticum , Bacillus anti -bacterial mechanisms of action , for example inhibits anthracis , Bacillus cereus, Lysteria monocytogenes , Yers DNA gyrase or topoisomerase IV and transpeptidase -medi inia pestis , Yersinia enterocolitica , Shigella dysenteriae , ated cross - linking of peptidoglycans; inhibits isoprenyl 55 Neisseria meningitides , Neisseria gonorrhoeae, Streptococ pyrophosphate and transpeptidase- mediated cross - linking of cus bovis, Streptococcus hemolyticus, Streptococcus mutans, peptidoglycans ; inhibits isoprenyl pyrophosphate and DNA Streptococcus pyogenes, Streptococcus pneumoniae , gyrase of topoisomerase IV ; inhibits folate synthesis and Staphylococcus aureus, Staphylococcus epidermidis , DNA gyrase of topoisomerase IV ; inhibits folate synthesis Staphylococcus pneumoniae , Staphylococcus saprophyticus, and transpeptidase -mediated cross - linking of peptidogly - 60 Vibrio cholerae, Vibrio parahaemolyticus, Salmonella typhi, cans; inhibits DNA gyrase or topoisomerase IV and the 30S Salmonella paratyphi , Salmonella enteritidis, Treponema ribosomal sub -unit in bacteria ; inhibits DNA gyrase or pallidum , Candida , Cryptcooccus, Cryptosporidium , Giar topoisomerase IV and the 50S sub -unit in bacteria ; inhibits dia lamblia , Microsporidia , Plasmodium vivax, Pneumocys transpeptidase -mediated cross - linking of peptidoglycans tis carinii, Toxoplasma gondii, Trichophyton mentagro and the 30S or the 50S ribosomal sub -unit in bacteria ; 65 phytes, Enterocytozoon bieneusi, Cyclospora cayetanensis , inhibits folate synthesis and the 30S or the 50S sub -unit in Encephalitozoon hellem , Encephalitozoon cuniculi , among bacteria ; or inhibits isoprenyl pyrophosphate and the 30S or other bacteria , archaea , protozoa, and fungi. US 10 ,071 , 103 B2 In some embodiments , the first and second domains tionally exerting a greater efficacy by inhibiting P . acnes independently have antibacterial activity against a Staphy mediated inflammatory pathways ( i. e . dual mechanisms of lococcus species . Examples of Staphylococcus species action ) . include, but are not limited to , S . aureus group ( e . g ., S . aureus, S . simiae ) , S . auricularis group (e . g ., S. auricularis ), 5 Combinations S . carnosus group (e .g ., S. carnosus, S . condimenti, S. massiliensis, S . piscifermentans, S . simulans) , S . epidermidis The disclosure also provides formulations comprising a combination of two or more antibiotic agents . For example , group ( e . g ., S . capitis , S . caprae, S . epidermidis , S . saccha an 8 - chloro fluoroquinolone in combination with another rolyticus ), S . haemolyticus group ( e . g ., S . devriesei , S . haeŠ 10 anti- acne agent . In some embodiments , the formulation molyticus, S . hominis ), S . hyicus- intermedius group ( e . g ., S . comprises two or more different 8 - chloro fluoroquinolones . chromogenes, S . felis , S . delphini, S . hyicus, S . intermedius, In some embodiments , the formulation comprises besifloxa S . lutrae, S . microti , S . muscae , S. pseudintermedius, S . cin and a retinoid , such as adapalene . rostri , S . schleiferi ) , S . lugdunensis group ( e . g ., S . lugdunen In some embodiments , the formulation comprises an sis ), S . saprophyticus group (e . g. , S . arlettae, S. cohnii, S. 15 anti -acne agent and an anti - inflammatory agent. For equorum , S. gallinarum , S . kloosii, S . leei , S. nepalensis , S . example , the formulation can comprise an 8 -chloro fluoro saprophyticus, S . succinus , S . xylosus) , S . sciuri group ( e . g ., quinolone and an anti - inflammatory agent. S . fleurettii , S . lentus, S . sciuri, S . stepanovicii, S . vitulinus ) , In some embodiments , the two or more antibiotic agents S . simulans group ( e . g ., S . simulans ) , and S . warneri group can be a DART molecule or two or more different DART ( e. g ., S. pasteuri, S. warneri) . 20 molecules . In some embodiments , one of the two or more Without limitations, the DARTS can be in the form of antibiotic agent is a DART and the other is not a DART particles , powders , suspensions, dispersions, emulsions, molecule . liposomes, micelles , globules , solutions, vesicles, aggre As described herein , the disclosure provides formulations gates , creams, gels , and the like . comprising DART and /or non -DART antibiotic agent as the The disclosure also provides formulations comprising 25 API. As such , exemplary API' s for the formulations include DARTs as the active pharmaceutical ingredient (API ) . DARTs, anti - bacterial, anti - fungal and anti -acne agents . In some embodiments , the API can be in the form of a drug Antibiotics carrier , i .e ., the API can be nanotized , coated , made into vesicles , liposome, emulsions, and the like for the formula The disclosure also provides formulations comprising 30 tion . Without limitations the formulation or the composition antibiotic agents , which are not DARTs , as the API. In some can be formulated for administration by any appropriate embodiments , the antibiotic agent is a8 - chloro fluoroqui- route known in the art including , but not limited to , topical nolone . Exemplary 8 - chloro fluoroquinolones include , but (including buccal and sublingual) and oral or parenteral are not limited to , besifloxacin , clinafloxacin and sitafloxa routes, including intravenous, intramuscular, subcutaneous, cin . In some embodiments , the formulation comprises besi - 35 transdermal, airway ( aerosol) , pulmonary , and nasal admin floxacin as the API. istration . In various embodiments , the API can be micronized , The DARTs and formulations disclosed herein can be suspended , or solubilized . In some embodiments , the API used for treating bacterial infections due to Gram -positive or can be in the form of particles, powders , suspensions, Gram - negative bacteria . Additionally, the DARTs are effec dispersions , emulsions , liposomes , micelles , globules , solu - 40 tive against resistant forms of pathogens . Furthermore , the tions , vesicles, aggregates, and the like . In some embodi- DARTs are effective in preventing the development of ments , the API can in the form of a drug carrier. resistant forms of pathogens. Thus , the DARTs and formu In some embodiments, the API can be coated . In some lations disclosed herein can be used for treating antibiotic other embodiments , the API can be uncoated . tolerant or resistant bacterial infections . Exemplary bacterial Without limitations, the formulation can be in a form 45 infections include , but are not limited to , infection by selected from the group consisting of lotions, creams, gels , Bartonella henselae, Borrelia burgdorferi, Campylobacter emulgel , oils , serums, powders , sprays , ointments , solutions, jejuni, Campylobacter fetus , Chlamydia trachomatis , Chla suspensions , dispersions, pastes , foams, peels , films, masks, mydia pneumoniae , Chylamydia psittaci , Simkania negeven patches , sticks, rollers, cleansing liquid washes , cleansing sis , Escherichia coli ( e . g. , 0157 :H7 and K88 ) , Ehrlichia solid bars , pastes , foams, powders , shaving creams, impreg - 50 chafeensis , Clostridium botulinum , Clostridium perfringens , nated fabric ) , and the like . In some embodiments , the Clostridium tetani, Enterococcus faecalis , Haemophilius formulation is in a form selected from the group consisting influenzae , Haemophilius ducreyi, Coccidioides immitis , of gel , cream , spary , face wash , soap bar, body wash , lotion , Bordetella pertussis , Coxiella burnetii , Ureaplasma ure suspended drug loaded gel, suspended drug loaded cream , alyticum , Mycoplasma genitalium , Trichomatis vaginalis , and any combinations thereof. 55 Helicobacter pylori , Helicobacter hepaticus, Legionella In some embodiments , the API or the formulation can be pneumophila , Mycobacterium tuberculosis , Mycobacterium used to treat acne not responding to antibiotics . Specifically , bovis , Mycobacterium africanum , Mycobacterium leprae , it exerts greater efficacy against forms of Propionbacterium Mycobacterium asiaticum , Mycobacterium avium , Myco acnes that respond poorly to clindamycin - , or doxycycline - , bacterium celatum , Mycobacterium celonae , Mycobacte or erythromycin -, or minocycline -containing anti -acne prod - 60 rium fortuitum , Mycobacterium genavense , Mycobacterium ucts . haemophilum , Mycobacterium intracellulare , Mycobacte In some embodiments, the API or the formulation can be rium kansasii , Mycobacterium malmoense , Mycobacterium used to treat acne by exerting an anti - inflammatory effect. marinum , Mycobacterium scrofulaceum , Mycobacterium In some embodiments, the API or the formulation can be simiae , Mycobacterium szulgai, Mycobacterium ulcerans , used to treat acne by killing strains of Propionbacterium 65 Mycobacterium xenopi, Corynebacterium diptheriae , Rho acne that are sensitive to one or more of clindamycin - , dococcus equi, Rickettsia aeschlimannii , Rickettsia africae , minocycline -, erythromycin -, and /or doxycycline and addi Rickettsia conorii, Arcanobacterium haemolyticum , Bacillus US 10 ,071 , 103 B2 10 anthracis , Bacillus cereus, Lysteria monocytogenes , Yers - and nadifloxacin with relaxed E . coli plasmid DNA. Com inia pestis , Yersinia enterocolitica , Shigella dysenteriae , pound 91 shows greater efficacy than Nadifloxacin . Neisseria meningitides , Neisseria gonorrhoeae , Streptococ FIGS . 4A and 4B are bar graphs showing the effect of cus bovis , Streptococcus hemolyticus, Streptococcus mutans, compound 91 on P . acnes - induced cytokine IL - 6 ( FIG . 4A ) , Streptococcus pyogenes, Streptococcus pneumoniae, 5 IL - 8 ( FIG . 4B ) release in THP - 1 cells . Compound 91 exerts Staphylococcus aureus, Staphylococcus epidermidis , an anti - inflammatory activity against P . acnes - induced Staphylococcus pneumoniae, Staphylococcus saprophyticus, cytokine production . Statistical analysis was performed Vibrio cholerae. Vibrio parahaemolyticus, Salmonella typhi. using Student' s t -test ( p = 0 .05 ; * ** p = 0 .005 ) . Salmonella paratyphi , Salmonella enteritidis , Treponema FIGS . 5A and 5B are bar graphs showing the effect of pallidum , Candida , Cryptcooccus, Cryptosporidium , GiarGior 10 compound 91 on P . acnes- induced cytokine IL - la ( FIG . dia lamblia , Microsporidia , Plasmodium vivax, Pneumocys 5A ), IL - 1B (FIG . 5B ) release in THP - 1 cells . tis carinii, Toxoplasma gondii, Trichophyton mentagro FIG . 6 . is a bar graph showing the minimum inhibition phytes , Enterocytozoon bieneusi, Cyclospora cayetanensis , value for some exemplary topical gel formulations against P . Encephalitozoon hellem , Encephalitozoon cuniculi, among 15 acnes . other bacteria , archaea , protozoa , and fungi . In amongsome 15 FIG . 7 is a line graph showing the dose response curve of embodiments , infection is with a Staphylococcus speciesin some. tionsZone againstof Inhibition Pacnes (ZOI . ) of some exemplary gel formula In some embodiments , the DARTS and formulations FIG . 8 is a line graph showing the time kill kinetics of disclosed herein can be used for treating acne. In some some exemplary gel formulations against P . acnes. embodiments , the DARTS and formulations disclosed 20 FIG . 9 Graph shows the efficacy of a topical formulation herein are effective against forms of Propionbacterium ofbesifloxacin in P . acnes in an in vivo skin infection model. acnes that respond poorly to clindamycin -, or doxycycline - , Besifloxacin gel formulation has the ability to clear almost or erythromycin - , or minocycline - containing anti - acne prod 1 . 5 log CFU ( ~ 95 % ) of inoculum of clindamycin resistant P . ucts . In some embodiments , the DARTs and formulations acnes within first 24 hours . disclosed herein are effective against one or more of clin - 25 FIG . 10 is a line graph showing time kill kinetics of some damycin -, minocycline- , erythromycin - , and / or doxycy - exemplary besifloxacin formulations against P . acnes cline -tolerant or resistant strains of Propionbacterium acnes. MTCC 1951, showing that the composition of the formula For treating infections, the DART or the formulation dis - tion can change the efficacy of an antibiotic . closed herein can be administered once or daily to the FIG . 11 is a line graph showing time kill kinetics of some subject as a single dose or a plurality of doses. 30 exemplary besifloxacin formulations and besifloxacin APIs against S . aureus . BRIEF DESCRIPTION OF THE DRAWINGS FIG . 12 is a line graph showing time kill kinetics of besifloxacin against P. acnes (CCARM 9010 ). FIGS . 1A and 1B shows dose response curves of different FIG . 13 Graph shows that topical formulations with antibiotics against both MTCC1951 and CCARM 9010 35 different excipient compositions for the same antibiotic can strains of P . acnes . While MTCC1951 is killed by clindamy result in different profiles in the skin and in systemic cin , the drug has no effect on CCARM9010 . Different circulation of SD rats . Fully suspended 1 % Besifloxacin gel antibiotics behave differently and unpredictably on the dif - (VLN - F19 /BSF /GL / 068 ), fully soluble 1 % Besifloxacin gel ferent strains belong to a different family from Clindamycin . (VLN - F21 /BSF /GL /001A ) and fully suspended 1 % Besi FIGS. 1C and 1D are line graphs showing concentration 40 floxacin gel (VLN - F20 /BSF /CR /004 ) were used for com efficacy curve of DART compounds 90 , 91 , 94 , 113 , 115 and parison purpose . To be efficacious, a formulation should not 116 in both clindamycin - susceptible (MTCC 1951 ) ( FIG . only be physicochemically compatible with the antibiotic 1C ) and clindamycin - nonresponsive (CCARM 9010 ) ( FIG . but also enable a sustained concentration of the antibiotic at 1D ) P . acnes strains. The molecules have different and a concentration greater than MIC level. unpredictable activity against MTCC1951 and 45 FIGS . 14A and 14B are bar graphs showing the concen CCARM9010 strains of P . acnes . Compound 91 showed tration -dependent inhibitory effect of Besifloxacin on P . highly efficacious bacterial killing profile for both bacterial acnes - induced cytokines IL - 6 (FIG . 14A ) but not IL - 8 (FIG . strains . Compound 90 shows activity in P . acnes that do not 14B ) release in THP - 1 cells . Statistical analysis was per respond to clindamycin but is ineffective in the P . acnes formed using Student' s t- test (* p = 0 .005 ; * * p = 0 . 0005 ) . strain that responds to clindamycin . 50 FIGS . 15A and 15B are bar graph showing the combina FIGS . 2A and 2B show concentration -dependent inhibition of Besifloxacin and Adapalene increases the efficacy of tion of DNA gyrase activity ( super- coiling ) by compound inhibiting P . acnes- induced cytokines IL -6 (FIG . 15A ) but 91 . FIG . 2A – Agarose gel electrophoresis showing effect of has no effect on IL - 8 ( FIG . 15B ) release in THP - 1 cells . compound 91 on super- coiling of E . coli plasmid DNA by Statistical analysis was performed using Student' s t -test DNA Gyrase. FIG . 2B — Percentage of DNA super -coiling 55 ( * p = 0 .005 ; * * p = 0 .001 ) . by DNA gyrase in presence increasing concentrations of compound 91 . DETAILED DESCRIPTION OF THE FIG . 3A is a bar graph showing percentage of DNA INVENTION super- coiling by DNA gyrase in presence of compounds 90 , 91 , 94 , 113 , 115 and 116 with relaxed E . coli plasmid DNA . 60 Acne vulgaris is a skin condition that affects over 85 % of Compound 91 and compound 116 seemed to have the best all people . Acne is a term for a medical condition of plugged gyrase inhibiting activity among all the comparators . pores typically occurring on the face , neck , and upper torso . Though this observation is mostly correlated with MIC data Following are four primary factors that are currently known against P . acnes, yet there is some species -specific advan - to contribute to the formation of acne vulgaris ; ( 1 ) increased tages is observed with compound 91. 65 sebum output resulting in oily , greasy skin ; ( 2 ) increased FIG . 3B is a bar graph showing percentage of DNA bacterial activity, normally due to an overabundance of super - coiling by DNA gyrase in presence of compound 91 Propionibacterium acnes bacteria ; ( 3 ) plugging (hypercor US 10 ,071 , 103 B2 11 nification ) of the follicle or pilosebaceous duct; and ( 4 ) and of all cases of skin bacterial infections caused by MRSA inflammation . The plugged pores result in blackheads, species . The infections associated with MRSA species can whiteheads , pimples or deeper lumps such as cysts or not be cured with traditional penicillin - related drugs . nodules. Severe cases of acne can result in permanent Instead , MRSA must be treated with alternate antibiotics. scarring or disfiguring . 5 However as articulated in http : / / thescienceofacne . com / As articulated in http : // thescienceofacne. com / antibiotic - antibiotic - susceptibility -of - propionibacterium -acnes /“ Not susceptibility - of- propionibacterium - acnes /results from all antibiotics are created equal” . The same is true for studies over last four decades clearly demonstrate that over bacteria . Some types of antibiotics are highly effective time P . acnes bacteria has become increasingly resistant to against certain types of bacteria , while essentially worthless certain classes of antibiotics . Particularly important are 10 against others . Moreover , antibiotic susceptibility and resis observations that a significant percentage of the bacteria tance is a dynamic process that is constantly changing . Over isolated from acne patients are now resistant to the most time, certain types of bacteria may gain or lose resistance to common antibiotics used in acne treatment: Clindamycin , particular antibiotics . The primary problem with standard , Erythromycin , Tetracycline, Doxycycline and Minocycline . laboratory -based antibiotic resistance testing is that the Additionally , such resistant or antibiotic - tolerant strains can 15 susceptibility of a bacteria to an antibiotic is often different cause relapse of acne , and also cause other diease states . when it is growing on a petri dish versus when it is growing There is a need for antibiotics that can kill P . acnes while on your body . This is because bacteria are not static organ minimizing the probability of development of mutant or isms, they adapt to their environment . A P . acnes bacteria tolerant strains that can survive the antibiotic exposure , and growing in a follicle and feeding on sebum has a different those that can work against strains that are not responding to 20 metabolic profile than one growing on a petri dish and the current drugs . Additionally , if these novelmolecules can feeding on a bacterial nutrition supplement. Furthermore , target additional steps in acne formation , such as inflamma bacteria modulate expression of surface proteins , cell wall tion , then the clinical outcome in acne can be greater than structures and genes depending on their environment, and existing therapies. these changes can have a profound effect on their suscepti Skin is a major organ of the body, and performs many 25 bility to a particular antibiotic . As a result, in the case of essential functions besides acting as a barrier , such as topical antibiotics for treatment of skin bacterial conditions, maintaining homeostasis . Besides acne , there are many other a priori knowledge does not exist, i . e . there is no mechanism skin diseases that are caused by bacterial colonization of the to predict that an antibiotic will be effective against P . acnes skin . The most common bacteria for mild to moderate skin acnes or any other skin bacterial condition until it has been infection are Staphylococcus and Streptococcus e . g . , Acute 30 tested on the bacterial strain . For example , as shown in Bacterial Skin and Skin Structure Infection (ABSSSI ) . Such http : / /thescienceofacne .com / antibiotic -susceptibility -of bacteria can infect the skin of both pediatric and adult propionibacterium -acnesl , P . acnes was reported to be patients ; mainly develop during hospitalization or living in highly resistant to a nitroimidazole (metronidazole ) or a a nursing home, while gardening , or while swimming . Some tetracycline ( lymecycline ) but partially responsive to doxy people are at particular risk of developing skin infections, 35 cycline another tetracycline ) , and showing no resistance to for example , people suffering with diabetes, human immu - ciprofloxacin but resistant to another fluoroquinolone, Levo nodeficiency virus (HIV ) or AIDS or other immune disor - floxacin . It is therefore impossible to predict which antibi ders , or hepatitis , and who is undergoing chemotherapy or otic will work based on a priori activity in other bacterial treatment with other drugs that suppress the immune system . strains . There is a need for a systematic development of Common skin bacterial infections include cellulitis , ery - 40 novel antibiotics that show activity against acne . sipelas, impetigo , folliculitis , and furuncles and carbuncles . In this regard DART molecules can act as an ideal drug Cellulitis is a painful, erythematous infection of the dermis candidate to acne caused by P . acnes, and additionally for and subcutaneous tissue characterized by warmth , edema , the treatment of other skin and skin structure infections and advancing borders and is usually caused by Streptococ - caused by other bacteria such as MRSA . DARTS were cus or Staphylococcus species . Erysipelas is a superficial 45 designed to contain two distinct chemical domains , selected form of cellulitis with sharply demarcated borders and is from different families as mentioned earlier, for example a caused almost exclusively by Streptococcus . Impetigo is B - lactam ring and a quinolone nucleus , or a quinolone also caused by Streptococcus or Staphylococcus and can nucleus and nitro - heterocycle , or a B - lactam ring and a lead to lifting of the stratum corneum resulting in the nitroheterocycle , which confers two distinct mechanisms of commonly seen bullous effect. Folliculitis is an inflamma - 50 action . This creates less chance in mutation development at tion of the hair follicles, and it is most commonly caused by both target sites of bacteria resulting in less resistance Staphylococcus . If the infection of the follicle is deeper and development against these antibiotics . Some of the mol involves more follicles , it moves into the furuncle and ecules can exert additional anti - inflammatory mechanisms carbuncle stages and usually requires incision and drainage . to reduce host inflammatory response, further enhancing the Two different kinds of skin diseases occurred due to the 55 anti -acne efficacy . toxins produced by the bacteria include, Staphylococcal The embodiments of the various aspects disclosed herein Scaled Skin Syndrome ( SSSS ) which usually affects chil are based on the molecules designed by the inventors , which dren less than 5 years old , adults with kidney failure and the can act on at least two different or distinct targets. Generally , other one is Toxic Shock Syndrome. There is more chance the molecule includes at least two different or distinct of colonization of S . aureus is found with patients suffering 60 chemical domains. Each of said chemical domains binds to from eczema and atopic dermatitis , a type of inflammatory, a distinct or different active site in a target cell . The said relapsing, non - contagious, itchy skin disorder . Thus Staphy- chemical domains can be bound together through a third lococcus aureus infection plays an important role in atopic domain . As used herein , the term " chemical domain ” means dermatitis (AD ) or atopic eczema (AE ) . Unfortunately, some a part of a molecule that is involved in a desired property . strains of Staphylococcus have become resistant to methi- 65 For example, a chemical domain can be part of the molecule cillin and other similar antibiotics which are known as involved in binding of the molecule with a target or involved MRSA . Recently it has been found that more than one -half in modulating an activity of the target. US 10 , 071 , 103 B2 13 14 In some embodiments , the first and second chemical acid ; amphenicols such as chloramphenicol, azidamfenicol, domains independently have anti - bacterial or bactericidal thiamphenicol, florfenicol; nitrofurans such as furazolidone, activity. In some embodiments , the first and second domain nitrofurantoin ; streptogramins such as pristinamycin , quinu can independently comprise an antibacterial agent. As used pristin /dalfopristin virginiamycin ; other antibacterials such herein , the term " antibacterial agent” or “ antibiotic agent” is 5 as arsphenamine , fosfomycin , mupirocin , platensimycin , defined as a compound having either a bactericidal or tigecycline, trimethoprim , polymyxin , bacitracin , colistin , bacteriostatic effect upon bacteria contacted by the com - colymycin , metronidazole , cotrimoxazole and phosphono pound . As used herein , the term “ bactericidal” is defined to mycin ; and anti- mycobacterial drugs such as clofazimine , mean having a destructive killing action upon bacteria . As dapsone , capreomycin , cycloserine, ethambutol, ethiona used herein , the term " bacteriostatic ” is defined to mean 10 mide , isoniazid , pyrazinamide , rifampicin , rifabutin , rifa having an inhibiting action upon the growth of bacteria . pentine , streptomycin . in some embodiments , the antibacte Examples of antibacterial agents include, but are not limited rial agent can be selected from the group consisting of to , macrolides or ketolides such as erythromycin , azithro - azithromycin , roxithromycin , ceftaroline , cefotaxime, mycin , clarithromycin , dirithromycin , troleandomycin , spi cefoxitin , ceftriaxone, cephalothin , minocycline , nadifloxa ramycin , telithromycin , carbomycin a , josamycin , kitasamy - 15 cin , moxifloxacin , besifloxacin , ulifloxacin , prulifloxacin , cin , midecamycin acetate, oleandomycin , solithromycin , retapamulin , metronidazole, ornidazole and any combina spiramycin , troleandomycin , cethromycin , solithromycin , tions thereof . In some embodiments , antibacterial agent can spiramycin , ansamycin , oleandomycin , carbomycin and be hyaluronic acid or a derivative thereof . tylosin ; beta -lactams including penicillin , cephalosporin and in some embodiments of the DART molecule , the first and carbapenems such as carbapenem , imipenem and mero - 20 second domains independently have anti -acne activity . In penem ; monolactams such as penicillin g , penicillin V , some embodiments , the first and second chemical domains methicillin , oxacillin , cloxacillin , dicloxacillin , nafcillin , are independently an anti -acne agent . As used herein , the ampicillin , azlocillin , amoxicillin , carbenicillin , ticarcillin , term “ anti - acne agent ” refers to any chemical that is effec mezlocillin , piperacillin , azlocillin , temocillin , flucloxacil - tive in the treatment of acne and / or the symptoms associated lin , cepalothin , cephapirin , cephradine , cephaloridine , cefa - 25 therewith . Anti -acne agents are well known in the art such zolin , cefamandole, cefuroxime, cephalexin , cefprozil , cefa - as U . S . Pat. App . Pub . No . 2006 /0008538 and U . S . Pat . No . clor, loracarbef, cefoxitin , cefmetazole , cefotaxime, 5 ,607 , 980 , content of both of which is incorporated herein ceftizoxime, ceftriaxone , cefoperazone , ceftazidime, by reference . Examples of useful anti - acne agents include , cefixime , cefpodoxime, ceftibuten , cefdinir , cefpirome, but are not limited to keratolytics , such as salicylic acid , cefepime, cefadroxil , cefalothin , cefalexin , cefuroxime, 30 derivatives of salicylic acid , and resorcinol; retinoids, such cefditoren , ceftazidime, ceftizoxime, ceftaroline fosamil, as retinoic acid , tretinoin , adapalene , tazarotene; sulfur ceftaroline, ceftobiprole, aztreonam , ertapenem , doripenem containing D - and L - amino acids and their derivatives and and cilastatin ; penicillin combinations such as amoxicillin salts ; lipoic acid ; antibiotics and antimicrobials , such as clavulanate , ampicillin / sulbactam , piperacillin / tazobactam benzoyl peroxide, triclosan , chlorhexidine gluconate , and ticarcillin / clavulanate ; quinolones such as nalidixic 35 octopirox , tetracycline , 2 , 4 , 4 ' - trichloro - 2 -hydroxy diphenyl acid , oxolinic acid , norfloxacin , pefloxacin , enoxacin , ether , 3 , 4 , 4 ' - trichlorobanilide, nicotinamide, tea tree oil , ofloxacin , levofloxacin , ciprofloxacin , temafloxacin , lom rofecoxib , azelaic acid and its derivatives, phenoxyethanol, efloxacin , fleroxacin , grepafloxacin , sparfloxacin , trova - phenoxypropanol, phenoxisopropanol, ethyl acetate , clin floxacin , clinafloxacin , gatifloxacin , moxifloxacin , sitafloxa damycin , erythromycin , and meclocycline ; sebostats , such cin , ganefloxacin , gemifloxacin , pazufloxacin , besifloxacin , 40 as flavonoids; and bile salts , such as scymnol sulfate and its ulifloxacin , prulifloxacin , cinoxacin , piromidic acid , pipemi- derivatives , deoxycholate , and cholate ; and combinations dic acid , rosoxacin , rufloxacin , balofloxacin , tosufloxac in , thereof. These agents are well known and commonly used in delafloxacin , nemonoxacin ; antibacterial sulfonamides and the field of personal care . antibacterial sulphanilamides, including para - aminobenzoic In some embodiments , the anti -acne agent can be an acid , sulfadiazine , silver sulfadiazine , sulfisoxazole , sul- 45 antimicrobial peptide having activity against P . acnes . Anti famethoxazole, sulfadimethoxine , sulfadoxine , sulfame - microbial peptides are ubiquitous in nature and play an thizole and sulfathalidine , mafenide, sulfacetamide , sulfiso important role in the innate immune system ofmany species midine , sulfanilimide , sulfasalazine and [Zasloff et al ., 2002 ; and Epand et al ., 1999 ]. The antimi sulfonamidochrysoidine ; aminoglycosides such as strepto - crobial peptide can be a naturally occurring peptide or an mycin , neomycin , kanamycin , paromycin , gentamicin , 50 analog thereof, or it can be a synthetic peptide . As used tobramycin , amikacin , netilmicin , spectinomycin , sisomicin , herein an " analog ” refers to a naturally -occurring antimi dibekalin , isepamicin , dihydrostreptomycin , framycetin , crobial peptide that has been chemically modified to ribostamycin , arbekacin , bekanamycin , dibekacin , hygro - improve its effectiveness and / or reduce its toxic side effects . mycin b , verdamicin and , astromicin ; tetracyclines tetracy The antimicrobial peptide can be a peptide known to be cline , chlortetracycline, demeclocycline, minocycline , 55 effective against Gram positive bacteria . Non - limiting oxytetracycline , methacycline , doxycycline , clomocycline , examples include lantibiotics , such as nisin , subtilin , epi lymecycline, meclocycline , penimepicycline , and rolitetra - dermin and gallidermin ; defensins; attacins, such as sarco cycline ; rifamycins such as rifampicin (also called rifam - toxin ; cecropins , such as cecropin A , bactericidin , and pin ) , rifapentine , rifabutin , bezoxazin , orifamycin and rifaxi- lepidopteran ; magainins; melittins; histatins; brevinins; and min ; lincosamides such as lincomycin and clindamycin ; 60 combinations thereof. Additionally , antimicrobial peptides lipopeptide like daptomycin ; glycopeptides such as vanco - having activity against P . acnes have been reported , for mycin , telavancin and teicoplanin ; streptogramins such as example , in U . S . Pat. App . Pub . No. 2005/ 0282755 ; No . quinupristin and daflopristin ; ansamycins such as geldan 2005 /02455452 ; and No . 2005 /0209157 , and U . S . Pat. No . amycin , herbimycin , rifaximin ; oxazolidinones such as lin - 6 , 255 , 279 , content of all of which is incorporated herein by ezolid , eperezolid , posizolid , radezolid , ranbezolid , sut- 65 reference . Suitable examples of antimicrobial peptides hav ezolid and tedizolid ; pleuromutilins such as retapamulin , ing reported activity against P . acnes include , but are not tiamulin , valnemulin ; steroid antibacterials such as fusidic limited to , novispirins (Hogenhaug , supra ), and those US 10 ,071 , 103 B2 15 16 described in U . S . Pat. App . Pub . No. 2007 /0265431 , content Examples of antifungal agents include , but are not limited of which is incorporated herein by reference . In some to , azoles ( e . g . , Fluconazole , Isavuconazole , Itraconazole , embodiments , the antimicrobial peptide can be cathilicidine Ketoconazole , Miconazole , Clortrimazole , Voriconazole , and its derivatives . Posaconazole , Ravuconazole , Ciclopirox , etc . ) , polyenes In some embodiments , the anti - bacterial agent can be free 5 ( e . g ., natamycin , lucensomycin , nystatin , amphotericin B , fatty acid (FFA ) or fatty acid derivatives or fatty acid esters etc . ), echinocandins ( e . g ., Cancidas ), pradimicins ( e . g ., of propylene glycol (PG ) or glycerol (G ) derivatives and any beanomicins , nikkomycins, sordarins , allylamines, etc . ), Tri closan , Piroctone and its olamine salt , fenpropimorph , ter combinations thereof. For example , lauric acid , stearic acid , binafine, and derivatives and analogs thereof. Additional myristic acid , oleic acid , linoleic acid , myristoleic acid , 10 antifungal agents include those described , for example, in palmitooleic acid , linoleic acid , linolenic acid , sapienic acid , Int. Pat . Pub . No. WO2001/ 066551 , No. WO2002 /090354 , different polyunsaturated FAS (PUFA ), propylene glycol No . WO2000 /043390 , No . WO2010 /032652 , No . WO2003/ monolaurate , glycerol mono and/ or di laurate , propylene 008391 , No. WO2004 /018485 , No. WO2005 /006860 , No . glycol monoloeate , glycerol mono and / or di oleate and other WO2003 /086271 , No. WO2002/ 067880 ; in U . S . Pat . App . derivatives known in art . Fatty acids are well knownknown anti - 15 Pub . No . 2008 /0194661 , No. 2008 /0287440 , No. 2005 / microbial agent [Kabara et al . , 1972 ] and their activity varies 0130940 , No . 2010 /0063285 , No . 2008 /0032994 , No. 2006 / with chain length , degree of unsaturation and number of 0047135 , No . 2008 / 0182885 ; and in U . S . Pat . No. 6 , 812 , fatty acid ester present in propylene glycol or glycerol 238 ; No. 4 ,588 , 525 ; No. 6 , 235 ,728 ; No . 6 , 265 ,584 ; No . backbones. The prime target of FAs and derivatives is 4 , 942 , 162 ; and No . 6 , 362, 172 , content of all of which is bacterial cell membrane, which is non - specific in nature . 20 incorporated herein by reference. Disruption of bacterial membrane causes disruption in cel In some embodiments , the antifungal agent is a pyrithione lular electron transport activity or oxidative phosphorylation salt . Examples of useful pyrithione salts include , but are not or inhibition to a particular enzyme activity or diminishing limited to , zinc pyrithione, sodium pyrithione, potassium cellular energy production or impairment of nutrient uptake pyrithione , lithium pyrithione, ammonium pyrithione , cop or auto -oxidation of degradation products or generation of 25 per pyrithione , calcium pyrithione , magnesium pyrithione, toxic peroxidation or direct lysis of bacterial cells. Their strontium pyrithione, silver pyrithione , gold pyrithione , broad spectrum of non -specific activity makes them as a manganese pyrithione, and combinations thereof. Non -metal promising antimicrobial candidate for treatment and preven - pyrithione salts such as the ethanolamine salt , chitosan salt , tion of antimicrobial infections caused by number of gram and the disulfide salt of pyrithione (which is commercially positive and gram - negative bacteria that generates various 30 available as OMADINE MDS or OMDS ) , can also be used . skin and skin structure infections. In some embodiments , the The pyrithione salt can be used in any particulate form , FA and derivatives alone or in combination with any anti - including, but not limited to , crystalline form such as biotics or covalent conjugates with any antibiotics ( e . g . platelets , rods , needles , blocks, round and amorphous , regu DARTs ) are effective against antibiotic prone Propionbac - larly or irregularly shaped particles. terium acnes as well as P . acnes that respond poorly to 35 In some embodiments, the pyrithione salt is zinc pyrithi clindamycin - , or doxycycline- , or erythromycin - , or mino - one . Zinc pyrithione is best known for its use in treating cycline- containing anti -acne products . In some embodi dandruff and seborrhoeic dermatitis . It also has antibacterial ments , they are effective against one or more of clindamy - properties and is effective against many pathogens from the cin -, minocycline -, erythromycin - , and / or doxycycline Streptococcus and Staphylococcus genera . Its other medical tolerant or resistant strains of Propionbacterium acnes. In 40 applications include treatments of psoriasis , eczema , ring some embodiments , it prevents the development of resistant worm , fungus, athlete 's foot, dry skin , atopic dermatitis , forms of pathogens tinea , and vitiligo . In some embodiments , the first and second anti- acne In some embodiments , the antifungal agent is an antifun agents in the DART or formulations disclosed herein are gal peptide . Antifungal peptides are well known in the art selected independently from the group consisting of acetre - 45 (see for example , De Lucca et al. , 2000 ) . The antifungal tin , adapalene , alitretinoin , azelaic acid , Azithromycin , ben - peptide can be a naturally occurring peptide or an analog zoyl peroxide, Besifloxacin , bexarotene , Cefotaxime, thereof, or it can be a synthetic peptide . As used herein , the Cefoxitin , Ceftaroline, Ceftobiprole , Ceftriaxone , Cepha - term " analog ” refers to a naturally occurring antifungal lothin , clindamycin , erythromycin , etretinate , Garenoxacin , peptide that has been chemically modified to improve its glycolic acid , isotretinoin , lactic acid , Minocycline , Moxi- 50 effectiveness and/ or reduce its toxic / side effects. Exemplary floxacin , N -acetylcystein , Nadifloxacin , octopirox , phe - antifungal peptides can include , but are not limited to , noxyethanol, phenoxypropanol, Prulifloxacin , pyruvic acid , syringomycins, syringostatins , syringotoxins, nikkomycins , Radezolid (RX - 1741 ), resorcinol, Retapamulin , retinoicnoic echinocandins , pneumocadins , aculeacins, mulundocadins, acid , Roxithromycin , salicylic acid , Sitafloxacin , sodium cecropins, alpha - defensins, beta - defensins, novispirins, and sulfacetamide , spirinolactone , sulfacetamide , sulfur, tazaro - 55 combinations thereof. Other antifungal peptides include tene , tretinoin , triclosan , ulifloxacin , metronidazole , ornida - those described , for example , in U . S . Pat . No. 6 ,255 ,279 and zole , urea , and any combinations thereof. U . S . Pat. App . Pub . No. 2005/ 0239709 ; No. 2005 /0187151 ; In some embodiments , the first and second chemical No. 2005 /0282755 , and No . 2005 /0245452 , content all of domains are independently an antifungal agent. As used which is incorporated herein by reference . herein , the term “ antifungal agent” is intended to mean a 60 In some embodiments, the first chemical domain is an substance capable of inhibiting or preventing the growth , anti -bacterial agent and the second chemical domain is viability and / or reproduction of a fungal cell . Preferable anti - acne agent or an antifungal agent. antifungal agents are those capable of preventing or treating Without limitations , the first and the second chemical a fungal infection in an animal or plant. A preferable domains in the DART can be bound to each other covalently . antifungal agent is a broad spectrum antifungal agent. How - 65 One of skill in the art is well aware of different functional ever , an antifungal agent can also be specific to one or more groups in chemical domains that can be used for covalently particular species of fungus . binding a first chemical domain with a second chemical US 10 ,071 , 103 B2 17 domain . For example , the first chemical domain can com N ( R ) , C ( O ), C ( O ) O , cleavable linking group , substituted prise a functional group selected from the group consisting or unsubstituted aryl, substituted or unsubstituted heteroaryl, of an amino group , a N - substituted amino group , a carboxyl substituted or unsubstituted heterocyclic ; where R ' is hydro group , a carbonyl group , an acid anhydride group , an gen , acyl, aliphatic or substituted aliphatic . aldehyde group, a hydroxyl group , an epoxy group , a thiol , 5 In some embodiments, the first and second chemical a disulfide group , an alkenyl group , a hydrazine group , a domains are covalently bound to each other via a third hydrazide group , a semicarbazide group , a thiosemicarbaz - domain comprising at least one cleavable group . A cleavable ide group , an amide group , an aryl group , an ester group , an group is one which is sufficiently stable under a first set of ether group, a glycidyl group , a halo group , a hydride group , conditions and can be cleaved to release the two parts the an isocyanate group , a urea group , a urethane group , and any 10 cleavable group is holding together . In a preferred embodi combinations thereof for binding with the second chemical ment, the cleavable group is cleaved at least 10 times or domain . In some embodiments , the second chemical domain more , preferably at least 100 times faster under a first comprises a functional group selected from the group con - reference condition (which can , e . g ., be selected to mimic or sisting of an amino group , a N -substituted amino group , a represent intracellular conditions ) than under a second ref carboxyl group , a carbonyl group , an acid anhydride group , 15 erence condition (which can , e .g . , be selected to mimic or an aldehyde group , a hydroxyl group , an epoxy group , a represent conditions found in the blood or serum ) . thiol, a disulfide group , an alkenyl group , a hydrazine group , Cleavable groups are susceptible to cleavage agents , e. g ., a hydrazide group , a semicarbazide group , a thiosemicarba - pH , redox potential or the presence of degradative mol zide group , an amide group , an aryl group , an ester group , ecules. Generally , cleavage agents are more prevalent or an ether group , a glycidyl group , a halo group , a hydride 20 found at higher levels or activities at the desired site of group , an isocyanate group , a urea group , a urethane group , action of the molecule comprising the cleavable group . and any combinations thereof for binding with the first Examples of such degradative agents include : redox agents chemical domain . In some embodiments , the first and sec - which are selected for particular substrates or which have no ond chemical domains are bound to each other via same substrate specificity , including , e . g ., oxidative or reductive functional group . In some embodiments , the first and second 25 enzymes or reductive agents such as mercaptans , present in chemical domains are bound to each other via different cells , that can degrade a redox cleavable linking group by functional groups. reduction ; esterases; amidases ; endosomes or agents that can In some embodiments , the third domain can enhance or create an acidic environment, e . g . , those that result in a pH increase an activity of at least one of the chemical domains of five or lower ; enzymes that can hydrolyze or degrade an For example, the activity of at least one of the chemical 30 acid cleavable linking group by acting as a general acid , domains is increased or enhanced relative to when the third peptidases (which can be substrate specific ) and proteases , domain is absent. In some embodiments , the third domain and phosphatases . can increase or enhance antibacterial activity of at least one Exemplary cleavable groups include , but are not limited of the chemical domains in the DART. In some embodi- to , redox cleavable groups ( e. g ., - S - S — and C ( R )2 — ments , the third domain can increase or enhance anti - acne 35 S S - , wherein R is H or C , -C6 alkyl and at least one R is activity of at least one of the chemical domains in the DART. CZ - C6 alkyl such as CHz or CH CHZ) ; phosphate -based In some embodiments , the third domain can increase or cleavable linking groups ( e . g ., — O — P ( O ) (OR ) - 0 enhance anti- inflammatory activity of at least one of the O — P (S )( OR ) O - , 0 — P (S )( SR ) - 0 - , - S - P (O ) chemical domains in the DART. (OR ) - 0 , 0 - P ( O )( OR ) - S - , S - P ( O ) (OR ) In some embodiments , the third domain itself has bio - 40 S4 , 0 P (S ) (ORK )- S — , - S — P (S ) (OR ) - 0 - - 0 logical activity . For example , the third domain can be an P ( O ) ( R ) - 0 , 0 - P ( S ) (R ) - 0 , S — P ( O ) ( R ) active agent. In some embodiments , the third domain can 0 - , - S P ( S ) ( R ) O - , - S — P ( O ) ( R ) - S — , -O P have anti - bacterial or antifungal activity . In some embodi- ( S ) ( R ) - S — , - 0 — P ( O ) ( OH ) - 0 - - 0 - P ( S ) ( OH ) — ments, the third domain can have anti - inflammatory activity . 0 , 0 - P ( S ) (SH ) - 04 , S P ( O ) ( OH ) - 0 , The third domain of the DARTs can be a direct bond or 45 - 0 — P ( O ) (OH ) - 5 - - S - P ( O )( OH ) S - 0 — P ( S ) an atom such as oxygen or sulfur, a unit such as NR ' , C ( O ) , (OH ) — 5 — , - S — P ( S ) (OH )40 - , - 0 P ( O ) ( H ) - 0 , C ( O ) O , C ( O )NH , SS , SO , SO , , SO ,NH or a chain of atoms, 0 — P ( S ) ( H ) - 0 - , S - P ( O )( H ) O - , S - P ( S ) such as substituted or unsubstituted alkyl, substituted or ( H ) - 0 - , - S P ( O )( H ) - S — , and O — P ( S ) ( H ) - S , unsubstituted alkenyl, substituted or unsubstituted alkynyl, wherein R is optionally substituted linear or branched arylalkyl, arylalkenyl , arylalkynyl, heteroarylalkyl , het - 50 C1- C10 alkyl) ; acid cleavable groups ( e .g ., hydrazones, eroarylalkenyl, heteroarylalkynyl , heterocyclylalkyl, hetero - esters, and esters of amino acids , C = NN — and _ OC cyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, hetero (0 ) — ) ; ester -based cleavable groups ( e . g . , - C ( O ) O - ) ; cyclyl , cycloalkyl, cycloalkenyl, alkylarylalkyl, peptide - based cleavable groups, ( e . g ., groups that are alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alk cleaved by enzymes such as peptidases and proteases, e . g. , enylarylalkenyl , alkenylarylalkynyl, alkynylarylalkyl, alky - 55 NHCHR4C ( O )NHCHRPC ( O ) - , where R4 and RB are nylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, the R groups of the two adjacent amino acids ). A peptide alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylhet - based cleavable group comprises two or more amino acids . eroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylal- In some embodiments , the peptide -based cleavable group kynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, comprises the amino acid sequence that is the substrate for alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylhet- 60 a peptidase or a protease found in /secreted by P. acnes. erocyclylalkenyl, alkylhererocyclylalkynyl, alkenylhetero - In some embodiments , the cleavable group is an acid cyclylalkyl, alkenylheterocyclylalkenyl , alkenylheterocy - labile group . Generally , an acid cleavable group is cleavable clylalkynyl, alkynylheterocyclylalkyl, in an acidic environment with a pH of about 6 . 5 or lower alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, ( e . g . , about 6 . 5 , 6 . 0 , 5 .5 , 5 . 0 , 4 .5 , 4 . 0 , 3 . 5 , 3 .0 , or lower ), or alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenyl- 65 by agents such as enzymes that can act as a general acid . heteroaryl, alkynylhereroaryl, where one or more methyl- In some embodiments , the first and second chemical enes can be interrupted or terminated by O , S , S (O ), SO2, domains are covalently bound together by a third domain US 10 ,071 , 103 B2 19 20 selected from the group consisting of 11 -hydroxyundecenic Similarly , the second chemical domain can be bound to acid ; 1 , 10 -decanediol ; 1 , 3 - propanediol; 1 , 5 -pentanedil ; the first chemical domain or the domain connecting the first 10 -hydroxydecenic acid ; succinic ; lactic acid ; 3 -hydroxy and second chemical domains via a direct bond or an atom propionic acid ; and any combinations thereof. such as oxygen or sulfur, a unit such as NH , C ( O ) , C ( O ) O , In some embodiments, the third domain can be linker, 5 C ( O )NH , SS, SO , SO , , or SO , NH . e . g ., a cleavable or non - cleavable linker. The DARTs can be synthesized using methods known in The first chemical domain can be bound to the second the art . Exemplary methods for synthesizing the DARTs are chemical domain or the domain connecting the first and described in the Examples section herein . See Examples 2 to second chemical domains via a direct bond or an atom such 10 . as oxygen or sulfur, a unit such as NH , C ( O ), C ( O ) O , 10 In some embodiments , the DART can be selected from C (O )NH , SS , SO , SO2, or SO NH . those shown in Tables 1A & 1B . TABLE 1A Exemplary DARTs Set -1

It!

?? 11110 11111

HN 2 -2V

111

utiltad

Hinn

F NH HN US 10 ,071 , 103 B2 22 TABLE 1A -continued Exemplary DARTsDARTs Set- 1

NH NH2 pentington 5

y F Hinta

11.

*111110 BogenatedHN US 10 ,071 , 103 B2 23 24 TABLE 1A -continued Exemplary DARTS Set- 1

1 .

S 0

JE O NH

NH2

? poffimboHN 111 olan

NH2

HN US 10 ,071 , 103 B2 25 TABLE 1A -continued Exemplary DARTs Set - 1

*till

A S HN????

12 RS IIIIIII??

HN H 0H IIIIIII: - N US 10 ,071 , 103 B2 27 TABLE 1A -continued Exemplary DARTs Set - 1

NH , ) NH2

0 Noo

I-Z

|IT N HO NH2 OH | | other OH?? ? 17

OOHOO

NH , HO googleHON AI US 10 ,071 , 103 B2 29 TABLE 1A -continued Exemplary DARTs Set- 1

II 111811*

HN . my **11110

O OH O=0 0 5. . THN

HN . ..111Z HO

HNAHN

F HO

obferuatingHN US 10 ,071 , 103 B2 31 32 TABLE 1A -continued Exemplary DARTS Set- 1

? H??? EO 0 NH2H2 ) ya II.) HOY. HO Illlll OTHHN - NH2

HN HN

NH2

=o F

lun HN O

NH2 US 10 ,071 , 103 B2 33 34 TABLE 1A -continued Exemplary DARTs Set- 1

His)

HN OH

S NH2

F His

HN OH la NH2

OS F

Hun / N NH HN

NH US 10 ,071 , 103 B2 35 36 TABLE 1A -continued Exemplary DARTs Set - 1

???

Hi,

NH HN

NH2

S 29 HaN F HN ? NH ,

(

- ????????? ??:?III N 30

????

IIIII( NH2

- NH2 US 10 ,071 , 103 B2 38 37 TABLE 1A -continued Exemplary DARTs Set - 1

1 .. . . H N F

HN20 U1113

S 20

. HO Ilir"

NH2 US 10 ,071 , 103 B2 TABLE 1A -continued Exemplary DARTs Set- 1

s 0

?? OH HN .

?????? NHz 35

llll H

ill

- 0 ?

HN . US 10 ,071 , 103 B2 TABLE 1A -continued Exemplary DARTs Set - 1

illiti Lurral HÖN

HO •111110

lin .

NH (2 )

H?N 11 OH Both ZI. US 10 ,071 , 103 B2 44 TABLE 1A -continued Exemplary DARTs Set- 1

t111111 HN .

*11110 ) III

0 HO 0 0 NH TINTI . HO ZI

0 HO 0 0

. HN !d HO

+ N - US 10 ,071 , 103 B2 4545 TABLE 1A -continued Exemplary DARTs Set - 1

0 OH 0 0 | La CNHNH, s OH ? ?

ose 45

Apartheid 46

Hinn

HNE 111111** ON lits .

Z **111110

NH2 US 10 ,071 , 103 B2 48 TABLE 1A -continued " "Exemplary DARTs Set- " 1 " 47

F H0

IIIIIIII:

( 1iill

1111111.

} 1 { .. ????

\ NH

NH2

H0 .

??? IIIIIII ?????? ????? IIIIII US 10, 071 , 103 B2 49 ) 50 TABLE 1A -continued Exemplary DARTs Set - 1

]}

will • HO ???????•will

jilih+

? H , N ?

Ss 0 0 HO 0 0 HO I (Z ) I ( R) . HN ( I ( Z ) IE( SOH ??? zill:

CHN

H , N »IIIIil US 10 ,071 , 103 B2 51 52 TABLE 1A -continued Exemplary DARTs Set- 1 54

H??. o ?? ? ? HN

.26 . HO .01 HO qZ Z

NH ,

55 HN

Is le NH , |. . HO ZI.C ZI

S 0

Filmen HN

NH2 US 10 ,071 , 103 B2 5353 54 TABLE 1A -continued Exemplary DARTs Set -1

0 OH O

NH2 (Z ) HN . T . HO both dongengZI 58

. HO

H11 Livros HN

HN OH ON

NH2 US 10 ,071 , 103 B2 55 56 TABLE 1A -continued Exemplary DARTs Set- 1

HN OH 1Theodore -NH2

OH FerasF 62

O OH Z KO

- NH2 US 10 ,071 , 103 B2 57 5858 TABLE 1A -continued Exemplary DARTs Set- 1

Hit)

tit HN 111111 U111111

NH2

111

Units

H2N

1111111

II | | | | | HO US 10 ,071 , 103 B2 TABLE 1A - continued Exemplary DARTs Set - 1

111111* 1131 HN « illl ttililll

Intitate

HO UND UO unut

OCNH OS .. . 11H v s

HO . US 10 ,071 , 103 B2 TABLE 1A -continued Exemplary DARTs Set- 1

OE Jn. tillo *1111011 H2N A

HIH

H2NS

.Ill

2 OH 0 OFS HNHN " .L 0 ||I (2 ) HOT. HO IZ US 10 ,071 , 103 B2 63 64 TABLE 1A -continued Exemplary DARTs Set - 1

| 0 OH 0

IIIII) \ NH , H5N R11111 H0 LIIIII IIIIII

HO 0 0 s 2 HIN H2N ??? HO II ? 74

* N 1111

HN . IIIII?? :

iiiiii 111111

75 ?????0= US 10 ,071 , 103 B2 65 TABLE 1A -continued Exemplary DARTs Set- 1

HO ?

.SE NH NH2

. HO

SZ 11tll +. 111110

NH2

/ HN

-Z

*** 11110 Hitta US 10, 071 ,103 B2 TABLE1A - coiltinued Exemplary DARTs Set- 1

H ? N

{ {{ { #

1 0 1 0H1 10 10 . . "' I ? 1 (llll ulli) OH

nofiiif

5 ?MNili H , N ? ??? 48 14 US 10 ,071 , 103 B2 69 70 TABLE 1A -continued Exemplary DARTs Set - 1

OH O=

NH2 SS.

?? .UZ

both 85

N111 *

11110

O 86

111111! . . HN .

*111110 US 10 ,071 , 103 B2 72 TABLE 1A -continued Exemplary DARTs Set- 1

OH IHIII S | H ci.

HN 0 - N .

H NH2

NH2 O1111 HNT

Oz US 10 ,071 , 103 B2 | ??73 | 7474 TABLE 2A Exemplary DARTs Set - 2 00

--00

H (

92 sz ' N NO.

? ? H0 | 93

--00

??? US 10 ,071 , 103 B2 75 76 TABLE 2A -continued Exemplary DARTs Set- 2

94 thagenF 95

' N NO2NO TV

OH US 10 ,071 , 103 B2 78 TABLE 2A -continued Exemplary DARTs Set- 2

' N NO HO

NO ,

100 TON

H II ci

I) US 10 ,071 , 103 B2 79 80 TABLE 2A - continued Exemplary DARTs Set- 2 101 LA NO2NO2

? OH

N 102

ON N N

OH organ??OH 103

NO2 Z

wystanie?? O

104 S

onthe sporte OH

105

OH oryOH outlet US 10, 071 , 103 B2 TABLE 2A -continued Exemplary DARTs Set- 2 106

HO lilE

/ , HO

( 1) 107

, HO

H0 LI, a > 108

(1 ) 109 | 0

LI Y 0 = US 10 ,071 , 103 B2 83 84 TABLE 2A -continued Exemplary DARTs Set -2

110 - OH

AOHOH

Coo 111

HOM

NH tot s HOOC

112

' N NO2

S N

HOOC

113 O K= as-00

F US 10 ,071 , 103 B2 85 86 TABLE 2A - continued Exemplary DARTs Set- 2

114

F bronne 115 O2N ' N

H2C OH

116

ON H2C OH

117

shorte 118

OH RocheF US 10 ,071 , 103 B2 8787 88 TABLE 2A - continued Exemplary DARTs Set -2 119

NO2

OH F Praca 120

ergottenF m 121

122 muuableOH

O 123 F ??

mnyonge 124 manyolmyotl OH US 10 ,071 , 103 B2 89 90 TABLE 2A -continued Exemplary DARTS Set - 2

125

126

127

128

0 F OH

129 munionot OH US 10 ,071 , 103 B2

TABLE 2A -continued Exemplary DARTs Set- 2 X 130

OH oca 131 ZO quoteOH 132

R = Lauric acid , oleic , palmitoleic acid , myrstoleic acid , linoleic acid , linolenic acid 133

R = FA -ester of propylene glycole and glyceol and their derivatives

The present invention also provides formulations com - otic agent as the API. For example , the present invention prising DART as the API. Various features of the formula describes the use of 8 - chloro fluoroquinolones for the treat tions are described in more detail vide infra . 60 ment of acne conditions, especially those caused by resistant forms of P . acnes . It is a sub class of fluoroquinolones where Antibiotics (Non -DART ) C8 position is substituted with chlorine . Thus , in some embodiments , the disclosure provides a formulation com The present invention also envisages compounds which prising 8 - chloro fluoroquinolone as the API. Exemplary are not DARTs. Accordingly , the invention also provides 65 8 - chloro fluoroquinolones include , but are not limited to , formulations comprising an antibiotic agent which is not a besifloxacin , sitafloxacin , and clinafloxacin . In some DART, i .e ., a formulation comprising a non -DART antibi embodiments , the formulation comprises besifloxacin . US 10 ,071 , 103 B2 93 94 Generally , themicronized API has a size in the range from about 0 . 2 um to about 15 um . In some embodiments , the micronized API has a size in the range from about 1 um to ?? about 10 um . In some embodiments , the micronized API has a size in the range from about 1 . 5 um to about 9 um . In some embodiments , the micronized API has a size in the range from about 2 um to about 8 um . In some embodiments , the API is in the form of a particle and comprises a surface modifier on the surface thereof. HN 10 Generally a surface modifier is a molecule that can change RY the surface of the particle ( such as by coating ) in question 8 - Chloro fluoroquinolones and help in adhering the whole particle , hence , to the specific surface ( s ) . Generally, the surface modification does not R1 = H , F involve chemical bonding alterations or creation of any R2 = H , Cyclopropyl 15 chemical bond . The surface modifier just physically associ Examples - ates with the particle . O The surface modifier can be selected from the group F consisting of lipids, oils , polymers , peptides , proteins, car ?? bohydrates, glycolipids, phospholipids , lipoproteins, cat 20 ionic molecules, and any combinations thereof. The surface modifier can form a coating layer on the particle surface . Without limitations, the particle can be partially or fully coated with the surface modifier. Some non - limiting exemplary formulations comprising a TUR 25 micronized antibiotic agent, e . g . , besifloxacin , are described ?? ? in Examples 18 - 20 and shown in Table 18 . In some embodiments , the formulation can be a spray Besifloxacin formulation . Exemplary non -limiting spray formulations are described in Example 23 and Table 19 . In some embodi 30 ments , the formulation can be in the form of a face wash . OH Exemplary non - limiting face wash formulations are described in Example 24 , and Table 20 . In some embodi ments , the formulation can be in the form of a soap bar. Exemplary non - limiting soap bar formulations are described 35 in Example 25 and Table 21 . In some embodiments , the formulation can be in the form of a body wash . Exemplary H N non - limiting body wash formulations are described in 07Clinafloxacin Example 26 , and Table 22 . In some embodiments , the formulation can be in the form of a lotion . Exemplary 40 non -limiting lotion formulations are described in Example F 27 , and Table 23 . OH Surfactants are known to solubilize hydrophobic sub stances by reducing the interfacial tension . Accordingly , in some embodiments , the antibiotic agent can be solubilized 45 with a surfactant before forming the formulation . In - addition to surfactants , co - solvents or co - surfactants can also help in . solubilization of the poorly water - soluble compounds by HN A increasing the wetting property or reducing the interfacial tension of the hydrophobic molecule . Some exemplary Sitafloxacin 50 surfactants and co - surfactants can include , but are not lim ited to , sodium lauryl sulfate , tween 80 , tween 20 , span 20 , and any combinations thereof. Exemplary co -solvents for Without wishing to be bound by a theory , micronization solubilizing the antibiotic agent, such as besifloxacin , can of an antibiotic agent, such as besifloxacin , can have an include propylene glycol monocaprylate and diethylene gly impact on its bioactivity . For example , micronization can col monoethyl ether. Additional surfactants , co - surfactants enhance antibiotic agent ' s bioactivity or its retention at a and co - solvents that are amenable for solubilizing the anti desired site . Further, micronization can also affect the anti biotic agent are described elsewhere in the disclosure . With biotic agent' s stability and amounts in a formulation . More out wishing to be bound by a theory, solubilizing the over , micronization can also allow optimizing properties of antibiotic agent, e . g . , besifloxacin , can provide formulations formulations comprising micronized besifloxacinkaç?n . Accord - 60 that are within FDA prescription guidelines and limits of ingly , without limitations, the API in the formulation , ( e . g . , inactive excipients or ingredients . Non - limiting exemplary the antibiotic agent) can be in the form of particles, powders , formulations comprising a solubilized API, e . g . , antibiotic suspensions, dispersions , emulsions , liposomes, micelles, agent such as besifloxacin , are described in Examples 28 , 31 globules , solutions , vesicles , aggregates , and the like . and 33 , and shown in Tables 24 , 27 and 30 - 32 . In some embodiments , the API , for example , but not 65 Preparation of drug - loaded ( suspended form ) gel via limited to , besifloxacin or DART, can be micronized , i .e . , conventionalmethods usually leads to exposure of the drug formed as a particle . to a wide range of pH conditions, which can lead to , in some US 10 ,071 , 103 B2 95 96 instances, solubilization of the drug , and then reprecipita second anti - biotic agent are micronized . In some embodi tion . This solubilization -reprecipitation phenomenon in ments , the first anti -biotic agent is micronized and the most cases leads to change in original particle size, impurity second anti -biotic agent is solubilized . In some embodi profile or crystal pattern , or others. In order to circumvent ments , the first antibiotic agent is micronized and the this issue , the inventors have used an inventive approach to 5 second antibiotic agent is suspended in the formulation . In prepare different suspended drug -loaded formulations . Thus, some embodiments , the first anti -biotic agent is solubilized in some embodiments , the formulation is in form of a and the second anti -biotic agent is micronized . In some suspended gel with negligible or minimal drug solubiliza embodiments , both the first anti -biotic agent the second tion -reprecipitation . In the suspended drug formulations, the anti -biotic agent are solubilized . In some embodiments , the API particles are dispersed in a carrier media , such as, but 10 first anti -biotic agent is solubilized and the second anti not limited to , glycerol, and processed to the desired for biotic agent is suspended . In some embodiments , the first mulation . Exemplary suspended gel formulations are anti -biotic agent is suspended and the second anti -biotic described in Example 24 , 26 , 28 , 29 , 30 , 31 and 32 and agent is micronized . In some embodiments, the first anti shown in Tables 25 , 27 , 29 , 33 , 34 , 37 and 38 . Exemplary biotic agent is suspended and the second anti -biotic agent is suspended drug loaded cream formulations are described in 15 solubilized . In some embodiments , both the first anti -biotic Examples 30 and 32 and Tables 26 and 28 . agent and the second antibiotic agent are suspended . In addition to the various components , the formulation In some embodiments , the formulation comprises besi can also comprise one or more viscosity modifiers . In some floxacin and adapalene , wherein besifloxacin is solubilized embodiments , the viscosity modifier is a polymer . Exem - and adapalene is suspended . In some other embodiments , the plary polymeric viscosity modifiers include, but are not 20 formulation comprises besifloxacin and adapalene, wherein limited to , carbopol, hydroxypropyl cellulose , hydroxypro - both the besifloxacin and adapalene are solubilized . Exem pyl methyl cellulose , hydroxyethyl cellulose , and sodium plary formulation comprising both besifloxacin and ada hyaluronate . In some other embodiments , the viscosity palene are described in Examples 18 , 23 - 27 and 31 and modifier is a non -polymeric viscosity modifier or gelling Tables 18 -23 and 27 . agent. Additional exemplary viscosity modifiers are 25 It is noted that various formulations features discussed in described elsewhere in the disclosure . Exemplary formula - more detail vide infra are applicable to the formulation tions comprising various viscosity modifiers are described in comprising two or more antibiotic agents described herein . Example 33 and Tables 29 -32 . According to published literature there may be some kind Features Applicable to DART, Non -DART , and of physical and / or chemical interaction between carbopol 30 Combination APIs and fluoroquinolones . For which , there may be a need to prepare formulations without carbopol or carbopol- like Furthermore, as articulated in http : // thescienceo polymers to avoid any incompatibility issues during the facne . com /antibiotic - susceptibility -of - propionibacterium product shelf life . Accordingly , in some embodiments , the acnes/ ) . “ The second major limitation of treatment of acne is formulation is essentially free ofd viscosity modifiers. 35 that antibiotics are not evenly dispersed throughout the Exemplary formulations that are essentially free of a vis different tissues in the body. Many antibiotics do not effec cosity modifier are described in Example 32 and Table 28 . tively accumulate in the follicle and /or sebaceous glands, In some embodiments , the API can be coated with a and therefore do not effectively reach the bacteria respon molecule selected from the group consisting of lipids , oils , sible for acne. Even if a bacteria is highly susceptible to a polymers, peptides , proteins , carbohydrates, glycolipids, 40 particular antibiotic in lab - based testing , if that antibiotic phospholipids , lipoproteins , cationic molecules , and any does not make it to the site of infection at a sufficient combinations thereof. Without limitations, the API can be concentration , it is not going to be an effective treatment. As partially or fully coated with the coating molecule . Exem - a result there can be major differences in the effectiveness of plary formulations comprising coated or non - coated API are oral antibiotics and topical antibiotics used in acne treat described in Example 46 and Tables 52 and 53 . 45 ments . This extends to all bacterial diseases of the skin . It is noted that various formulations features discussed in There is a need to develop unique optimal topical formula more detail vide infra are applicable to the formulation tions and is described later. comprising antibiotic agent, e . g ., besifloxacin , described Skin , e . g ., micro - cracks, sweat or secretion pores , and hair herein . follicles can act as reservoirs for drug carriers of particular 50 sizes . Efficacy of active agents , e . g ., antifungal and antibac Combination terial formulations can be enhanced using infundibular delivery . A drug carrier can enhance the delivery of active In some embodiments , the formulation comprises two or agent on sebum filled hair follicles and also exhibit fuso more antibiotic agents . For example , the formulation can genecity of such drug carriers to lipophilic microbial cell comprise two or more different anti -acne agents . In some 55 wall / cell membrane . This allows retention of the drug carrier embodiments , the formulation comprises an 8 - chloro fluo - on the skin , followed by slow and continuous release of the roquinolones alone or in combination with another anti - acne DART or antibacterial agent from the drug carrier. Exem agent. Exemplary 8 - chloro fluoroquinolones include , but are plary drug carriers include, but are not limited to micropar not limited to , besifloxacin , sitafloxacin , and clinafloxacin . ticles, nanoparticles , vesicles , liposomes, emulsions, glob In some embodiments , the formulation comprises besifloxa - 60 ules , and solutions . cin . In some embodiments , the formulation comprises besi - In addition to the API ( e. g ., DART and /or other anti floxacin and adapalene . bacterial agent) , the drug carrier can further comprise one or Without limitations, the two or more antibiotic agents can more additional components . For example , the drug carrier be in the same form or different forms. For example , the first can further comprise a compound selected from the group and second anti - biotic agents can be independently micron - 65 consisting of lipids, oils , polymers, peptides , proteins , car ized , suspended , or solubilized for the API. Accordingly , in bohydrates, glycolipids, phospholipids, lipoproteins, cat some embodiments , both the first antibiotic agent and the ionic molecules, and any combinations thereof. The API, US 10 ,071 , 103 B2 97 98 e . g . , DART or other anti -bacterial agent, can be present in and non - steroidal anti - inflammatory drugs (NSAIDs ) . the core of the drug carrier and the additional component can Exemplary steroidal anti - inflammatory agents include but form a coating layer over the core . Without limitation , the are not limited to 21- acetoxypregnenolone , alclometasone , coating can be a functional or non - functional coating . By algestone , amcinonide , beclomethasone , betamethasone , functional coating is meant a coating that imparts one or 5 budesonide , chloroprednisone , clobetasol, clobetansone, more desirable properties to the drug carrier , such as clocortolone , cloprednol, corticosterone , cortisone , cortiva enhanced targeting or retention at site of action , increase in zol, deflazacort , desonide , desoximetasone, dexamethasone , the activity of the API, or having a desired activity itself. diflorasone, diflucortolone , difluprednate , enoxolone , flu In some embodiments , DART and /or other anti -bacterial azacort , flucloronide , flumethasone flunisolide , fluocinolone agent can be formed as a particle . In addition to the API ( e . g . , 10 acetonide , fluocinonide , fluocortin butyl, fluocortolone, DART and /or other anti -bacterial agent) , the particle can fluorometholone, fluperolone acetate , fluprednidene acetate , further comprise a compound selected from the group con - fluprednisolone , flurandrenolide , fluticasone propionate , for sisting of lipids , oils , polymers , peptides, proteins, carbo mocortal, halcinonide, halobetasol propionate , halometa hydrates , glycolipids, phospholipids, lipoproteins, cationic sone , halopredone acetate , hydrocortamate , hydrocortisone , molecules, and any combinations thereof. The API, e . g ., 15 loteprednol etabonate, mazipredone , medrysone, mepred DART or other anti - bacterial agent, can be present in the nisone , methylprednisolone, mometasone furcate , param core of the particle and the additional component can form ethosone , prednicarbate , prednisolone , prednisolone 25 -di a coating layer over the core . ethylamino - acetate , prednisolone sodium phosphate , In some embodiments , the particle comprises a surface prednisone, prednival, prednylidene , rimexolone , tixocortol , modifier on the surface thereof. Generally a surface modifier 20 triamcinolone , triamcinolone acetonide, triamcinolone is a molecule that can change the surface of the particle benetonide, triamcinolone hexacetonide , derivatives thereof ( such as by coating ) in question and help in adhering the and mixtures thereof. Exemplary nonsteroidal anti - inflam whole particle , hence , to the specific surface (s ). Generally , matory agents include but are not limited to COX inhibitors the surface modification does not involve chemical bonding (COX - 1 or COX nonspecific inhibitors ) and selective alterations or creation of any chemical bond . The surface 25 COX - 2 inhibitors . Exemplary COX inhibitors include but modifier just physically associates with the particle . are not limited to salicylic acid derivatives such as aspirin , The surface modifier can be selected from the group sodium salicylate , choline magnesium trisalicylate , salicy consisting of lipids, oils , polymers, peptides, proteins, car - late , diflunisal , sulfasalazine and olsalazine ; para -aminophe bohydrates, glycolipids , phospholipids , lipoproteins , cat- nol derivatives such as acetaminophen ; indole and indene ionic molecules , and any combinations thereof . The surface 30 acetic acids such as indomethacin and sulindac ; heteroaryl modifier can form a coating layer on the particle surface . acetic acids such as tolmetin , dicofenac and ketorolac ; Without limitations, the particle can be partially or fully arylpropionic acids such as ibuprofen , naproxen , flurbipro coated with the surface modifier . fen , ketoprofen , fenoprofen and oxaprozin , anthranilic acids In some embodiments , the drug carriers and formulations (fenamates ) such as mefenamic acid and meloxicam ; enolic disclosed herein can further comprise an active agent, i . e ., an 35 acids such as the oxicams (piroxicam , meloxicam ) ; active agent in addition to the DART and / or anti -bacterial alkanones such as nabumetone ; derivatives thereof and agent. As used herein , the term “ active agent” means a mixtures thereof. Exemplary COX - 2 inhibitors include but compound or composition that has a particular desired are not limited to diarylsubstituted furanones such as refe activity. For example , an active agent can be a therapeutic coxib ; diarylsubstituted pyrazoles such as celecoxib ; indole compound . Without limitations the active agent can be 40 acetic acids such as etodolac and sulfonanilides such as selected from the group consisting of small organic or nimesulide ; derivatives thereof and mixtures thereof. inorganic molecules , saccharines , oligosaccharides , poly . In some embodiments , the active agent is an anti - aging saccharides, peptides ; proteins , peptide analogs and deriva - agent. As used herein , the term “ anti - aging agent” means a tives, peptidomimetics , nucleic acids, nucleic acid analogs compound or composition that inhibits or reduces signs of and derivatives , antibodies , antigen binding fragments of 45 aging , such as wrinkles , fine lines , and other manifestations antibodies , lipids, extracts made from biological materials , of photodamage. Examples of anti -aging agents include , but naturally occurring or synthetic compositions , and any com - are not limited to , flavonoids such as quercetin , hesperidin , binations thereof. quercitrin , rutin , tangeritin , and epicatechin ; CoQ10 ; inor In some embodiments, the active agent can be selected ganic sunscreens such as tianium dioxide and zinc oxide ; from the group consisting of antifungal agents , antibacterial 50 organic sunscreens such as octyl -methyl cinnamates and agents , antimicrobial agents , anti -acne agents , antioxidant derivatives thereof ; retinoids; vitamins such as vitamin E , agents , cooling agents , soothing agents , wound healing vitamin A , vitamin C (ascorbic acid ), vitamin B , and deriva agents , anti - inflammatory - agents , penetration enhancers , tives thereof such as vitamin E acetate , vitamin C palmitate , permeation enhancers, antioxidants , anti -aging agents , anti - and the like ; antioxidants including alpha hydroxy acid such wrinkle agents , skin whitening or bleaching agents , ultra - 55 as glycolic acid , citric acid , lactic acid , malic acid , mandelic violet (UV ) light absorbing or scattering agents , skin depig acid , ascorbic acid , alpha -hydroxybutyric acid , alpha -hy mentation agents , regenerative agents , scar healing agents , droxyisobutyric acid , alpha -hydroxyisocaproic acid , atrro dyes or coloring agents , deodorizing agents , fragrances, lactic acid , alpha -hydroxyisovaleric acid , ethyl pyruvate , keratolytic agent , and any combinations thereof. In some galacturonic acid , glucopehtonic acid , glucopheptono 1 , 4 embodiments , the active agent can be a keratolytic agent. 60 lactone , gluconic acid , gluconolactone , glucuronic acid , In some embodiments , the active agent is an anti - inflam - glucurronolactone, glycolic acid , isopropyl pyruvate , methyl matory agent . As used herein the term “ anti - inflammatory pyruvate , mucic acid , pyruvia acid , saccharic acid , saccaric agent” refers to a compound ( including its analogs , deriva - acid 1 , 4 - lactone, tartaric acid , and tartronic acid ; beta tives , prodrugs and pharmaceutically salts ) which can be hydroxy acids such as beta -hydroxybutyric acid , beta - phe used to treat inflammation or inflammation related disease or 65 nyl- lactic acid , beta - phenylpyruvic acid ; botanical extracts disorder. Exemplary anti - inflammatory agents include, but such as green tea, soy , milk thistle , algae , aloe, angelica , are not limited to , the known steroidal anti- inflammatory bitter orange , coffee, goldthread , grapefruit, hoellen , honey US 10 ,071 , 103 B2 99 100 suckle , Job ' s tears , lithospermum , mulberry , peony , puer- N - acyl tyrosine , their isomers, including their D and L arua , rice, safflower, and mixtures thereof. isomers , salts , derivatives , and mixtures thereof. An example In some embodiments, the active agent is an ultraviolet of a suitable N -acyl amino acid is N - undecylenoyl- L - phe (UV ) light absorbing or scattering agent. Ultraviolet light nylalanine . absorbing agents include , for example , ultraviolet absorber 5 In some embodiments , the active agent is a skin depig of benzoic acid system such as para -aminobenzoic acid mentation agent. Examples of suitable depigmentation ( hereinafter , abbreviated as PABA ) , PABA monoglycerin agents include , but are not limited to , soy extract ; soy ester, N , N - dipropoxy PABA ethyl ester, N , N -diethoxy i soflavones ; retinoids such as retinol; kojic acid ; kojic PABA ethyl ester, N , N - dimethyl PABA ethyl ester, N , N - dipalmitate ; hydroquinone ; arbutin ; transexamic acid ; vita dimethyl PABA butyl ester , and N , N - dimethyl PABA methyl 10 mins such as niacin and vitamin C ; azelaic acid ; linolenic ester and the like ; ultraviolet absorber of anthranilic acid acid and linoleic acid , placertia ; licorice ; and extracts such system such as homomenthyl- N -acetyl anthranilate and the as chamomile and green tea ; and salts and prodrugs thereof. like ; ultraviolet absorber of salicylic acid system such as In some embodiments , the active agent is an antioxidant amyl salicylate , menthyl salicylate , homomenthyl salicylate , agent. As used herein , the term “ antioxidant agent” refers to octyl salicylate , phenyl salicylate , benzyl salicylate , p - iso - 15 any molecule capable of slowing , reducing , inhibiting, or propanol phenyl salicylate and the like ; ultraviolet absorber preventing the oxidation of other molecules . Examples of of cinnamic acid system such as octyl cinnamate , ethyl- 4 antioxidants include, but are not limited to , hydrophilic isopropyl cinnamate , methyl- 2 , 5 - diisopropyl cinnamate , antioxidants , lipophilic antioxidants , and mixtures thereof. ethyl- 2 , 4 - diisopropyl cinnamate , methyl- 2 , 4 -diisopropyl Non - limiting examples of hydrophilic antioxidants include cinnamate , propyl- p -methoxycinnamate , isopropyl- p - 20 chelating agents ( e . g ., metal chelators ) such as ethylenedi methoxy cinnamate , isoamyl- p -methoxy cinnamate , octyl - aminetetraacetic acid (EDTA ) , citrate , ethylene glycol tet p -methoxy cinnamate ( 2 - ethylhexyl - p -methoxy cinnamate ) , raacetic acid (EGTA ) , 1 , 2 -bis ( o - aminophenoxy ) ethane- N , N , 2 - ethoxyethyl- p -methoxy c innamate , cyclohexyl - p - N ', N ' -tetraacetic acid (BAPTA ) , diethylene triamine methoxycinnamate , ethyl - a -cyano - ß -phenyl cinnamate , pentaacetic acid (DTPA ), 2 , 3 - dimercapto - 1 -propanesulfonic 2 -ethylhexyl - a -cyano - B - phenyl cinnamate , glyceryl mono - 25 acid (DMPS ) , dimercaptosuccinic acid (DMSA ), a - lipoic 2 - ethylhexanoyl- dipara -methoxycinnamate , methyl- bis acid , salicylaldehyde isonicotinoyl hydrazone ( SIH ) , hexyl ( trimethylsiloxane )silylisopentyl trimethoxy cinnamate and thioethylamine hydrochloride (HTA ), desferrioxamine, salts the like ; 3 - (4 '- methylbenzylidene )- d ,l - camphor ; 3- ben - thereof, and mixtures thereof. Additional hydrophilic anti zylidene- d , l - camphor ; urocanic acid , urocanic acid ethyl oxidants include ascorbic acid ( vitamin C ) , cysteine , gluta ester ; 2 -phenyl - 5 -methylbenzoxazole ; 2 , 2 ' -hydroxy - 5 -meth - 30 thione , dihydrolipoic acid , 2 -mercaptoethane sulfonic acid , ylphenylbenzotriazole ; 2 - ( 2 - hydroxy - 5 '- t - octylphenyl) ben - 2 -mercaptobenzimidazole sulfonic acid , 6 -hydroxy - 2 , 5 , 7 , 8 zotriazole ; 2 - (2 -hydroxy -5 ' -methylphenylbenzotriazole ; tetramethylchroman -2 - carboxylic acid , sodium meta dibenzaladine ; dianisoylmethane , 4 -methoxy - 4 '- t -bu bisulfite, salts thereof, and mixtures thereof. Non - limiting tyldibenzoylmethane ; 5 -( 3 , 3 - dimethyl- 2 - norbornylidene ) -3 examples of lipophilic antioxidants include vitamin E iso pentane - 2 -one ; dimorpholinopyridazinone ; and combina - 35 mers such as a - , B - , Y - , and d - tocopherols and a -, B -, Y - , and tions thereof. Ultraviolet light scattering agents include , for d - tocotrienols ; polyphenols such as 2 -tert - butyl- 4 -methyl example , powders such as titanium oxide , particulate tita phenol, 2 - tert - butyl- 5 -methyl phenol, and 2 - tert - butyl -6 nium oxide , zinc oxide , particulate zinc oxide , ferric oxide , methyl phenol; butylated hydroxyanisole (BHA ) ( e . g . , particulate ferric oxide , ceric oxide and the like . 2 - tert -butyl - 4 -hydroxyanisole and 3 - tert- butyl - 4 - hydroxy In some embodiments , the active agent is an anti -wrinkle 40 anisole ); butylhydroxytoluene (BHT ) ; tert -butylhydroqui agent, e . g . , a dermatological anti -wrinkle agent. Anti - none ( TBHQ ) ; ascorbyl palmitate ; n - propyl gallate ; salts wrinkle agents include , without limitations, flavonoids such thereof; and mixtures thereof. One of skill in the art will as quercetin , hesperidin , quercitrin , rutin , tangeritin , and appreciate that antioxidants can be classified as primary epicatechin ; CoQ10 ; vitamin C ; hydroxy acids including antioxidants , secondary antioxidants , or metal chelators C . -C30 alpha -hydroxy acids such as glycolic acid , lactic 45 based upon the mechanisms in which they act . Primary acid , 2 - hydroxy butanoic acid , malic acid , citric acid tartaric antioxidants quench free radicals which are often the source acid , alpha -hydroxyethanoic acid , hydroxycaprylic acid and of oxidative pathways , whereas secondary antioxidants the like; beta hydroxy acids including salicylic acid and function by decomposing the peroxides that are reactive polyhydroxy acids including gluconolactone (G4 ) ; and mix intermediates of the pathways . Metal chelators function by tures of these acids . Further anti -wrinkleagentsinclude ret - 50 sequestering the trace metals that promote free radical inoic acid and gamma- linolenic acid . development. In some embodiments , the antioxidant agent is In someembodiments , the active agent is a skin whitening resveratrol. or bleaching agent. Skin whitening and bleaching agents In some embodiments , the active agent is a wound healing include hydrogen peroxide, zinc peroxide, sodium peroxide , agent. As used herein , the term “ wound healing agent” hydroquinone, 4 - isopropylcatechol, hydroquinone 55 means active agents that are effective for promoting natural monobenzyl ether, kojic acid ; lactic acid ; ascorbyl acid and wound healing processes over days , weeks , or months . derivatives such as magnesium ascorbyl phosphate ; arbutin ; Exemplary wound healing agents include, but are not lim and licorice root. Sunless tanning actives include dihydroxy - ited to , proteinaceous growth factors , vascular endothelial acetone (DHA ); glyceryl aldehyde; tyrosine and tyrosine growth factors , anti- proliferant agent, antimicrobials , and derivatives such as malyltyrosine, tyrosine glucosinate , and 60 anti- inflammatory agents . ethyl tyrosine ; phospho -DOPA , indoles and derivatives ; and In some embodiments , the active agent is a soothing mixtures thereof. Other skin whitening agents include sugar agent. As used herein , the term “ soothing agent” means a amines , such as glucosamine , N -acetyl glucosamine , glu - molecule which helps in reducing the discomfort of the skin cosamine sulfate , mannosamine , N -acetyl mannosamine , and /or scalp , for example by soothing the feelings of itching . galactosamine , N -acetyl galactosamine , their isomers ( e . g ., 65 Exemplary soothing agents include , but are not limited to , stereoisomers ) , and their salts ( e . g ., HC1 salt ) ; and N -acyl aloe , avocado oil , green tea extract , hops extract, chamomile amino acid compounds, such as N -acyl phenylalanine , extract , colloidal oatmeal, calamine , cucumber extract , US 10 , 071 , 103 B2 101 102 sodium palmate , sodium palm kernelate , butyrospermum nyl acetate ; dipentene ; eucalyptol ; hexylate ; rose oxide ; parkii ( i . e . , shea butter ) , menthe piperita (i . e . , peppermint ) PERYCOROLLE? (( S ) - 1 , 8 - p -menthadiene - 7 - ol ) ; 1 - p -men leaf oil, sericin , pyridoxine (a form of vitamin B6 ), retinyl thene - 4 - ol; ( 1RS ,3RS ,4SR ) - 3 - p - mentanyl acetate; ( 1R ,2S , palmitate and / or other forms of vitamin A , tocopheryl 4R ) - 4 , 6 , 6 - trimethyl- bicyclo [ 3 , 1 , 1 ]heptan - 2 - ol; acetate and /or other forms of vitamin E , lauryl laurate , 5 DOREMOX® ( tetrahydro -4 -methyl - 2 - phenyl- 2H -pyran ); hyaluronic acid , aloe barbadensis leaf juice powder, euterpe cyclohexyl acetate ; cyclanol acetate; Fructalate ( 1 , 4 - cyclo oleracea ( i. e . , acai berry ) fruit extract, riboflavin ( i. e ., vita - hexane diethyldicarboxylate ) ; KOUMALACTONE? min B2 ) , thiamin HCl and /or other forms of vitamin B1, (( 3ARS , 6SR , 7ASR ) -perhydro - 3 ,6 -dimethyl - benzo [B ] and/ any combinations thereof. furan - 2 - one ); Natactone ( (6R )- perhydro -3 ,6 -dimethyl In some embodiments , the active agent is a cooling agent. 10 benzo [B ] furan - 2 -one ); 2, 4 ,6 - trimethyl- 4 - phenyl- 1, 3 -diox As used herein , the term “ cooling agent” refers to molecules ane; 2 , 4 ,6 - trimethyl - 3 -cyclohexene - 1 -carbaldehyde ; ( E ) -3 which provide a sensation of cooling on application . Some methyl- 5 - ( 2 , 2 , 3 - trimethyl- 3 -cyclopenten - 1 - yl ) - 4 -penten - 2 exemplary cooling agents include, but are not limited to , ol; ( 1 'R , E ) - 2 -ethyl - 4 - ( 2 ', 2 ', 3 ' - trimethyl - 3 ' -cyclopenten - 1 ' WS - 3 ; WS -23 ; menthol; 3 -substituted - P -menthanes ; N - sub - yl )- 2 -buten - 1 - ol; POLYSANTOL® ( I 'R , E ) - 3 , 3 - dimethyl stituted - P -menthane - 3 - carboxamides ; isopulegol ; 3 - ( 1 -men - 15 5 - ( 2 ', 2 ', 3 ' -trimethyl - 3 - cyclopenten - 1 '- yl) - 4 - penten - 2 - ol) ; thoxy )propane - 1 ,2 -diol ; 3 - ( 1 -menthoxy )- 2 -methylpropane fleuramone ; PARADISONE® (methyl - 1R ) -cis - 3 -oxo - 2 1, 2 -diol ; p -menthane - 2 , 3 -diol ; p -menthane - 3 , 8 - diol; pentyl- 1 -cyclopentane acetate ); Veloutone ( 2 , 2 , 5 - Trimethyl 6 - isopropyl- 9 -methyl - 1, 4 -dioxaspiro [4 , 5 ] decane- 2 -metha - 5 -pentyl - 1 -cyclopentanone ); NIRVANOL® (3 , 3 -dimethyl nol; menthyl succinate and its alkaline earth metal salts ; 5 - ( 2 , 2 , 3 - trimethyl- 3 - cyclopenten - 1 -yl ) - 4 -penten - 2 -ol ) ; trimethylcyclohexanol; N - ethyl- 2 - isopropyl- 5 -methylcyclo - 20 3 -methyl - 5 - (2 , 2 ,3 - trimethyl- 3 -cyclopenten - 1 -yl ) - 2 -penta hexanecarboxamide ; Japanese mint oil ; peppermint oil ; nok damascones ; NEOBUTENONE? ( 1 - ( 5 , 5 - dimethyl- 1 menthone ; menthone glycerol ketal; menthyllactate ; 3 - ( 1 - cyclohexen - 1 - yl) - 4 -penten - 1 - one ); nectalactone ( ( 1 ' R ) - 2 - [ 2 menthoxy )ethan - 1 -ol ; 3 -( 1 -menthoxy )propan - 1- ol ; 3- ( 1 - (4 '- methyl - 3 -cyclohexen - 1' - yl ) propyl ]cyclopentanone ); menthoxy )butan - 1 -ol ; 1 -menthylacetic acid N -ethylamide ; alpha -ionone ; beta - ionone ; damascenone ; DYNASCONE® 1 -menthyl - 4 -hydroxypentanoate ; l -menthyl - 3 -hydroxybu - 25 (mixture of 1 - ( 5 , 5 -dimethyl - 1 - cyclohexen - 1 - yl) - 4 -penten - 1 tyrate ; N , 2 , 3 - trimethyl- 2 - ( 1 -methylethyl ) -butanamide ; one and 1 - ( 3 , 3 - dimethyl- 1 - cyclohexen - 1 - yl) - 4 - penten - 1 n -ethyl - t- 2 - c -6 nonadienamide; N ,N -dimethyl menthyl suc - one ) ; DORINONE® beta ( 1 -( 2 ,6 ,6 - trimethyl- 1 -cyclohexen cinamide; menthyl pyrrolidone carboxylate ; and the like. 1 - yl) - 2 - buten - 1 - one ) ; ROMANDOLIDE? ( 18 , 1 'R ) - [ 1 - ( 3 ', In some embodiments , the active agent is a coloring 3 ' - Dimethyl- 1 ' - cyclohexyl ethoxycarbonyl) methyl agent. As used herein , the term “ coloring agent” means any 30 propanoate ) ; 2 - tert -butyl - 1 - cyclohexyl acetate ; LIMBA substance that can be employed to produce a desired color. NOL® ( 1 - ( 2 , 2 , 3 , 6 - tetramethyl- cyclohexyl) - 3 -hexanol ) ; Gen . Such coloring agents are approved for human con - trans - 1 -( 2 , 2 ,6 -trimethyl - 1 - cyclohexyl) - 3 -hexanol ; ( E ) - 3 sumption pursuant an appropriate governmental agency and / methyl- 4 - ( 2 ,6 , 6 - trimethyl- 2 -cyclohexen - 1 -yl ) - 3 -buten - 2 or act, such as the Food and Drug Administration (FDA ) one ; terpenyl isobutyrate ; LORYSIA® ( 4 - ( 1 , 1 - dimethyl Federal Food Drug and Cosmetic Act (FD & C ) in the US or 35 ethyl) - 1 - cyclohexyl acetate ) ; 8 -methoxy - 1 - p -menthene ; an analogous agency of the European Union . For example , HELVETOLIDE? ( 15 , 1' R ) - 2 - [ 1 - ( 3 ', 3 -dimethyl - 1 '- cyclo the coloring agent can be a food - grade dye or a lake . A “ dye” hexyl) ethoxy ] - 2 -methylpropyl propanoate ) ; para tert -butyl is a water soluble compound , which is available as a powder, cyclohexanone; menthenethiol; 1 -methyl - 4 -( 4 -methyl - 3 granule , liquid or other special purpose form . A “ lake” isa p entenyl) - 3 - cyclohexene - 1 - carbaldehyde ; allyl water insoluble form of a dye . Exemplary coloring agents 40 cyclohexylpropionate ; cyclohexyl salicylate ; Methyl cedryl include, but are not limited to , FD & C Blue No. 1 (Brilliant ketone; Verdylate ; vetyverol ; vetyverone; 1 - ( octahydro - 2 , 3 , Blue ), FD & C Blue No . 2 ( Indigotine ), FD & C Green No . 3 8 , 8 - tetramethyl- 2 -naphtalenyl ) - 1 - ethanone ; (5RS , ORS , (Fast Green ) , FD & C Red No . 3 ( Erythrosine ) , FD & C Red 10SR ) - 2 , 6 , 9 , 10 - tetramethyl- 1 -oxaspiro [ 4 . 5 ]deca - 3 , 6 - diene No. 40 (Allura Red ) , FD & C Yellow No. 5 ( Tartrazine ) , and the (5RS , 9SR , 10RS ) isomer; 6 - ethyl- 2 , 10 , 10 - trimethyl FD & C Yellow No . 6 (Sunset Yellow ) , annatto extract, antho - 45 1 -oxaspiro [4 . 5 ]deca - 3 , 6 - diene; 1 , 2 , 3 , 5 ,6 , 7 -hexahydro - 1 , 1 , 2 , cyanis , aronia / redfruit , beet juice , beet powder, beta - caro - 3 , 3 -pentamethyl - 4 - indenone ; HIVERNAL® ( a mixture of tene , beta -apo - 8 - carotenal , black currant, burnt sugar , can - 3 - ( 3 , 3 - dimethyl- 5 - indanyl) propanal and 3 - ( 1 , 1 - dimethyl- 5 thaxanthin , caramel , carbo medicinalis , carmine , carmine / indanyl ) propanal) ; Rhubofix® ( 3 ', 4 -dimethyl - tricyclo beta - carotene, carmine blue , carminic acid , carrot , carrot 6 . 2 . 1. 0 ( 2 , 7 ) undec -4 - ene - 9 -spiro - 2 ' -oxirane ); 9 / 10 - ethyl oils , chlorophyll , chlorophyllin , cochineal extract, copper- 50 diene - 3 - oxatricyclo [6 . 2 . 1 . 0 ( 2 , 7 ) ] undecane ; POLYWOOD chlorophyll, copper -chlorophyllin , curcumin , curcumin /Cu - (perhydro - 5 , 5 , 8A - trimethyl - 2 - naphthalenyl acetate ) ; octaly chlorophyllin , elderberry, grape, grape skin extracts , hibis - nol; CETALOX® ( dodecahydro - 3a, 6 , 6 , 9a -tetramethyl cus, lutein , mixed carotenoids, paprika , paprika extract , naphtho [2 , 1- b ]furan ) ; tricyclo [ 5 .2 .1 . 0 ( 2 ,6 )] dec - 3 - en - 8 -yl paprika oleoresin , riboflavin , saffron , spinach , stinging acetate and tricyclo [5 .2 . 1. 0 (2 , 6 ) ]dec -4 -en - 8 -yl acetate as nettle, titanium dioxide , turmeric , and combinations thereof. 55 well as tricyclo [ 5 . 2 . 1 . 0 ( 2 , 6 ) ]dec - 3 - en -8 - yl propanoate and Preferred coloring agents according to the present invention tricyclo [ 5 . 2 . 1 . 0 ( 2 ,6 ) ] dec- 4 - en - 8 - yl propanoate ; camphor; are FD & C Blue No. 1 (Brilliant Blue ), FD & C Blue No . 2 borneol; isobornyl acetate ; 8 - isopropyl -6 -methyl - bicyclo ( Indigotine ) , FD & C Green No . 3 (Fast Green ) , FD & C Red [ 2 . 2 . 2 ]oct - 5 - ene - 2 - carbaldehyde ; camphopinene ; cedramber No. 3 (Erythrosine ), FD & C Red No . 40 (Allura Red ) , FD & C (8 -methoxy - 2 ,6 ,6 , 8 -tetramethyl - tricyclo [ 5 . 3 .1 . 0 ( 1 ,5 ) ]unde Yellow No. 5 ( Tartrazine) , FD & C Yellow No . 6 (Sunset 60 cane ) ; cedrene ; cedrenol; cedrol; FLOREX® ( mixture of Yellow ) , and any combinations thereof. 9 - ethylidene - 3 - oxatricyclo [6 . 2 . 1 . 0 ( 2 , 7 ) ] undecan - 4 - one and In some embodiments ; the active agent is a fragrance . 10 - ethylidene - 3 - oxatricyclo 6 . 2 . 1 . 0 ( 2 , 7 ) Jundecan - 4 - one ) ; Exemplary fragrances include ; but are not limited to , 2 , 4 3 -methoxy - 7 ,7 - dimethyl- 10 -methylene -bicyclo [4 .3 . 1 ]de dimethyl - 3 -cyclohexene - 1 -carbaldehyde ; isocyclocitral ; cane ; CEDROXYDE? (trimethyl - 13 -oxabicyclo -[ 10 . 1 .0 ) menthone ; isomenthone ; ROMASCONE® (methyl 2 , 2 - di- 65 trideca - 4 , 8 -diene ) ; Ambrettolide LG ( ( E ) - 9 -hexadecen - 16 methyl- 6 -methylene - 1 - cyclohexanecarboxylate ) ; nerone ; olide ) ; HABANOLIDE? ( pentadecenolide ) ; muscenone terpineol; dihydroterpineol; terpenyl acetate ; dihydroterpe ( 3 -methyl - ( 4 / 5 ) - cyclopentadecenone ) ; muscone; EXAL US 10 , 071 , 103 B2 103 104 TOLIDE® (pentadecanolide ); EXALTONE® ( cyclopenta kinase inhibitor, a peptidylglycine alpha - hydroxylating decanone ) ; ( 1 - ethoxyethoxy ) cyclododecane; Astrotone ; monooxygenase inhibitor, a peptidyl- prolyl cis / trans LILIAL® ; rosinol; and the like. isomerase inhibitor , a Peptidyl- Prolyl Cis / Trans isomerase In some embodiments , the active agent is an antifungal Inhibitor , a peroxisome proliferator- activated receptor agent. Examplary antifungal agents are described elsewhere 5 ( PPAR ) agonist, a pesticide , a phosphatase inhibitor, a in the disclosure . As used herein , the terms " fungus ” or p hosphodiesterase inhibitor , a PKC inhibitor, a PKC inhibi “ fungi” include a variety ofnucleated , spore -bearing organ - tor, a platelet activating factor antagonist, a platelet aggre isms which are devoid of chlorophyll. Examples include gation inhibitor, a polymorphonuclear neutrophil inhibitor, a yeasts , mildews, molds , rusts , and mushrooms. Examples of prolyl hydroxylase inhibitor, a prostaglandin inhibitor, a fungi include , but are not limited to Aspergillus fumigates , 10 protein synthesis inhibitor, a protein tyrosine kinase inhibi Aspergillus flavus , Aspergillus nidulans , Candida albicans, tor, a purineoreceptor P2X antagonist, a pyruvate dehydro Candida glabrata , Candida guilliermondii , Candida krusei, genase activator, a Raf kinase inhibitor, a RAR /RXT antago Candida lusitaniae, Candida parapsilosis, Candida tropi nist, a reducing agent, a retinoic acid receptor antagonist , a calis , Cryptococcus neoformans, Issatchenkia orientalis , retinoic acid receptor antagonist, a selective serotonin Coccidioides , Paracoccidioides , Histoplasma, Blastomyces, 15 reuptake inhibitor , a serine protease inhibitor, a serotonin Trichophyton rubrum , and Neurospora crassa . In some receptor inhibitor, a sheddase inhibitor , a sodium channel embodiments , fungus is of the genus Malassezia (e .g ., M . inhibitor , a steroid , a steroid , a stromelysin inhibitor, a furfur, M . pachydermatis , M . globosa , M . restricta , M . superoxide anion generator, a TACE inhibitor , a telomerase slooffiae , M . sympodialis , M . nana , M . yamatoensis , M . inhibitor, a TGF beta inhibitor, a thromboxane A2 receptor dermatis , and M . obtuse ) . In one embodiment, the fungus is 20 inhibitor , a TNF - alpha antagonist, a Toll receptor inhibitor, Trichophyton rubrum . a tryptase inhibitor, a tubulin antagonist , a tumor necrosis In some embodiments , the active agent is an antibacterial factor antagonist , a tyrosine kinase inhibitor, a VEGF inhibi agent. Exemplary anti -bacterial agents are described else tor, a vitamin D receptor agonist , ampicillin sodium salt, an where in the disclosure . acetylcholinesterase inhibitor, an actin polymerization and In some embodiments , the active agent is an anti - scarring 25 stabilization promoter, an adenylate cyclase agonist , an agent. As used herein , an “ anti - scarring agent” refers to any ALK - 5 receptor antagonist , an alpha adrenergic receptor agent which inhibit fibrosis or scarring. Useful anti - scarring antagonist, an androgen inhibitor, an anesthetic compound , agents can inhibit one or more aspect of the fibrosis process . an angiotensin Il receptor agonist, an antibiotic selected For example , in certain embodiments, the anti -scarring agent from the group consisting of apigenin , an anti -coagulant , an inhibits inflammation ; collagen production in , or release 30 anti- emetic agent, an anti - inflammatory compound , an anti from , cells ; and /or is an anti - infective or antifungal agent. In metabolite and antineoplastic agent, an anti -microbial agent, some embodiments , the anti -scarring agent is selected from an anti -microbial agent, an anti - neoplastic agent, an anti the group consisting of ( - ) -arctigenin , 6 . The device of claim oxidant, an anti- proliferative agent , an anti- psychotic com 1 or claim 2 wherein the anti -scarring agent is selected from pound , an anti - spasmodic agent, an antithrombotic agent, an an angiogenesis inhibitor, a 5 -HT inhibitor, a beta 1 integrin 35 anti - viral agent, an apoptosis activator, an apoptosis activa antagonist , a beta tubulin inhibitor , a bisphosphonate com - tor, an apoptosis antagonist , an aromatase inhibitor, an pound selected from risedronate and an analogue or deriva - AXOR12 agonist , an elastase inhibitor, an elF - 2a inhibitor, tive thereof, a blocker of enzyme production in Hepatitis C , an elongation factor - 1 alpha inhibitor, an endothelial growth a bone mineralization promoter, a Bruton ' s tyrosine kinase factor antagonist , an endothelial growth factor receptor inhibitor, a calcineurin inhibitor , a calcium channel blocker , 40 kinase inhibitor, an endotoxin antagonist , an epothilone and a CaM kinase II inhibitor, a caspase 3 inhibitor, a cathepsin tubulin binder , an estrogen agonist , an estrogen receptor B inhibitor, a cathepsin K inhibitor , a cathepsin L inhibitor , antagonist, an FGF inhibitor, an FGF receptor kinase inhibi a CB1/ CB2 receptor agonist, a CC chemokine receptor tor, an FLT -3 kinase inhibitor, an FXR antagonist, an HMG antagonist, a CD40 antagonist , a cell cycle inhibitor, a cell CoA reductase inhibitor, an HMGCoA reductase inhibitor, cycle inhibitor, a chemokine receptor antagonist , a chymase 45 an ICAM inhibitor, an IL , an IL - 2 inhibitor, an immuno inhibitor, a clotting factor, a collagenase antagonist , a cual suppressant, an inhibitor of type III receptor tyrosine kinase , integrin inhibitor , a CXCR antagonist , a cyclic GMP agonist , an inosine monophosphate inhibitor, an interleukin antago a cyclin dependent kinase inhibitor , a cyclooxygenase 1 nist, an intracellular calcium flux inhibitor , an intracellular inhibitor, a D2 dopamine receptor antagonist , a DHFR calcium flux inhibitor, an intracellular calcium influx inhibi inhibitor , a diuretic , a DNA alkylating agent , a DNA meth - 50 tor , an irreversible inhibitor of enzymemethionine amino ylation inhibitor , a DNA methylation promoter, a DNA peptidase type 2 , an isozyme selective delta protein kinase methylation promoter, a DNA synthesis inhibitor, a DNA C inhibitor , an MCP - CCR2 inhibitor, an MEK1/MEK 2 topoisomerase inhibitor, a dopamine antagonist, a farnesyl- inhibitor, an MIF inhibitor , an mTOR inhibitor, an mTOR transferase inhibitor, a farnexyl transferase inhibitor, a kinase inhibitor , an NF kappa B inhibitor, an ornithine fibrinogen antagonist, a G protein agonist , a glycosylation 55 decarboxylase inhibitor, an S - adenosyl- L -homocysteine inhibitor, a heat shock protein 90 antagonist , a histamine hydrolase inhibitor, an SDF - 1 antagonist , an SRC inhibitor, receptor antagonist, a histone deacetylase inhibitor, a histone an Syk kinase inhibitor , an a - glucosidase inhibitor, an deacetylase inhibitor, a JAK2 inhibitor, a JAK3 enzyme Integrin antagonist , and a immuno -modulator selected from inhibitor, a JNK inhibitor, a kinase inhibitor, a kinesin Bay 11 - 7085 , and IRAK antagonist , ICE , idazoxan hydro antagonist, a leukotriene inhibitor and antagonist, a lysyl 60 chloride , protein kinase B inhibitor , protein kinase C stimu hydrolase inhibitor, a MAP kinase inhibitor, a matrix met lant, purine nucleoside analogue, puromycin , reversible alloproteinase inhibitor, a microtubule inhibitor , a microtu - inhibitor of ErbB1 and ErbB2, ribonucleoside triphosphate bule inhibitor, a muscarinic receptor inhibitor, a neurokinin reductase inhibitor, any combination thereof. In some antagonist , a nitric oxide agonist , a nitric oxide synthase embodiments , the anti -scarring agent can be selected from inhibitor, a NO synthase inhibitor, a norepinephrine reuptake 65 ZD -6474 , AP - 23573 , synthadotin , S - 0885 , aplidine , inhibitor , a NSAID agent, a p38 MAP kinase inhibitor, a ixabepilone , IDN -5390 , SB - 2723005, ABT- 518 , combret palmitoyl- protein thioesterase inhibitor , a PDGF receptor a statin , anecortave acetate, SB -715992 , temsirolimus , adali US 10 ,071 , 103 B2 105 106 mumab , erucylphosphocholine , alphastatin , etanercept, acid ; Eicosenoic acid ; Elaidic acid ; elaidolinolenyl alcohol; humicade , gefitinib , isotretinoin , radicicol, clobetasol pro elaidolinoleyl alcohol; elaidyl alcohol; Erucic acid ; erucyl pionate, homoharringtonine , trichostatin A , brefeldin A , alcohol; Estranes ; Ethylene glycol distearate (EGDS ) ; Ged thapsigargin , dolastatin , cerivastatin , jasplakinolide , her dic acid ; geddyl alcohol; glycerol distearate ( type I ) EP bimycin A , pirfenidone , vinorelbine, 17 - DMAG , tacrolimus , 5 ( Precirol ATO 5 ) ; Glycerol Tricaprylate /Caprate ; Glycerol loteprednol etabonate , juglone , prednisolone, puromycin , Tricaprylate /Caprate (CAPTEX® 355 EP /NF ) ; glyceryl 3 -BAABE , cladribine ,mannose - 6 -phosphate , 5 -azacytidine , monocaprylate ( Capmul MCM C8 EP ) ; Glyceryl Triacetate ; Ly333531 ( ruboxistaurin ) , and simvastatin . Glyceryl Tricaprylate ; Glyceryl Tricaprylate/ Caprate /Lau In some embodiments , the active agent is a skin regen - rate ; Glyceryl Tricaprylate / Tricaprate ; glyceryl tripalmitate erating agent. Some skin regenerating agents can act as 10 ( Tripalmitin ) ; Henatriacontylic acid ; Heneicosyl alcohol; anti - scarring agents . Heneicosylic acid ; Heptacosylic acid ; Heptadecanoic acid ; In some embodiments , the drug carrier comprises an Heptadecyl alcohol; Hexatriacontylic acid ; isostearic acid ; additional anti -acne agent. In some embodiments , the addi isostearyl alcohol; Lacceroic acid ; Lauric acid ; Lauryl alco tional anti- acne agent can be selected from the group con - hol ; Lignoceric acid ; lignoceryl alcohol; Linoelaidic acid ; sisting of acetretin , adapalene (s ), alitretinoin , alpha - or beta - 15 Linoleic acid ; linolenyl alcohol; linoleyl alcohol; Margaric hydroxy acids , antibiotics, antimicrobial peptides , acid ; Mead ; Melissic acid ; melissyl alcohol; Montanic acid ; antimicrobials , azelaic acid , benzoyl peroxide , bexarotene , montanyl alcohol; myricyl alcohol ; Myristic acid ; Myristo bile salts , biofilm inhibitors , clindamycin , erythromycin , leic acid ; Myristyl alcohol; neodecanoic acid ; neoheptanoic etretinate , glycolic acid , isotretinoin , keratolytic agents , lac acid ; neononanoic acid ; Nervonic ; Nonacosylic acid ; Non tic acid , lipoic acid , N - acetylcystein , natural anti - acne 20 adecyl alcohol; Nonadecylic acid ; Nonadecylic acid ; Oleic agents , octopirox , phenoxyethanol, phenoxypropanol , pyru - acid ; oleyl alcohol; Palmitic acid ; Palmitoleic acid , palmi vic acid , resorcinol, retinoic acid , retinoid ( s ) , salicylic acid , toleyl alcohol ; Pelargonic acid ; pelargonic alcohol; Penta sebostats , sodium sulfacetamide, spironolactone , sulfur , sul cosylic acid ; Pentadecyl alcohol; Pentadecylic acid ; Phos fur containing D - or L - amino acids, tazarotene , tea tree oil, phatidic acid (phosphatidate , PA ) ; Phosphatidylcholine tretinoin , triclosan , urea , and any combinations thereof. 25 (lecithin , PC ) ; Phosphatidylethanolamine ( cephalin , PE ) ; The drug carrier disclosed herein can comprise any Phosphatidylinositol (PI ) ; Phosphatidylinositol bisphos amountof the API (e .g . , DART or other agent) . For example , phate (PIP2 ); Phosphatidylinositol phosphate (PIP ); Phos the drug carrier can comprise about 0 .01 % to about 99 % phatidylinositol triphosphate (PIP3 ); Phosphatidylserine ( w /w ) of the API. For example , the particle can comprise (PS ) ; polyglyceryl- 6 -distearate ; Pregnanes ; Propylene Gly between about 0 . 01 % to about 20 % ( w / w ) of the API. In 30 col Dicaprate ; Propylene Glycol Dicaprylocaprate ; Propyl some embodiments , the API comprises greater than 1 % ene Glycol Dicaprylocaprate ; Psyllic acid ; recinoleaic acid ; ( w / w ), greater than 5 % ( w /w ), greater than 10 % ( w /w ), recinoleyl alcohol; Sapienic acid ; soy lecithin ; Stearic acid ; greater than 15 % ( w /w ), greater than 20 % (w /w ), greater Stearidonic ; stearyl alcohol; Tricosylic acid ; Tridecyl alco than 25 % ( w / w ) , greater than 30 % ( w / w ) , greater than 35 % hol; Tridecylic acid ; Triolein ; Undecyl alcohol; undecylenic ( w / w ), greater than 40 % (w /w ), greater than 45 % ( w /w ), 35 acid ; Undecylic acid ; Vaccenic acid ; a - Linolenic acid ; y -Li greater than 50 % ( w / w ) , greater than 55 % ( w / w ) , greater nolenic acid ; a fatty acid salt of 10 -undecenoic acid , ada than 60 % ( w / w ), greater than 65 % ( w / w ) , greater than 70 % palene , arachidic acid , arachidonic acid , behenic acid , ( w / w ) , greater than 75 % ( w / w ) , greater than 80 % ( w / w ) , butyric acid , capric acid , caprylic acid , cerotic acid , cis - 11 greater than 85 % ( w / w ) , greater than 90 % ( w / w ), or greater eicosenoic acid , cis - 11 - octadecenoic acid , cis - 13 -docose than 95 % ( w / w ) of the total weight of the drug carrier . In 40 noic acid , docosahexaenoic acid , eicosapentaenoic acid , some embodiments, the content of API in the drug carrier elaidic acid , erucic acid , heneicosylic acid , heptacosylic can range from about 75 % to about 97 % ( w / w ) . In some acid , heptadecanoic acid , isostearic acid , lauric acid , ligno other embodiments , the content of API in the drug carrier ceric acid , linoelaidic acid , linoleic acid , montanic acid , can range from about 3 % to about 25 % ( w / w ) . myristic acid , myristoleic acid , neodecanoic acid , neohep A lipid for use in the drug carriers or formulations 45 tanoic acid , neononanoic acid , nonadecylic acid , oleic acid , disclosed herein can be selected from the group consisting of palmitic acid , palmitoleic acid , pelargonic acid , pentacosylic fatty acids, fatty alcohols , glycerolipids ( e . g . , monoglycer - acid , pentadecylic acid , recinoleaic acid ( e . g . zinc recino ides , diglycerides , and triglycerides ) , phospholipids, glyc - leate ) , sapienic acid , stearic acid , tricosylic acid , tridecylic erophospholipids, sphingolipids , sterol lipids , prenol lipids, acid , undecylenic acid , undecylic acid , vaccenic acid , valeric saccharolipids , polyketides, and any combination thereof . In 50 acid , a - linolenic acid , or y - linolenic acid ; paraffin ; and any some embodiments , the lipid can be selected from the group combinations thereof. In some embodiments , the lipid can consisting of 1 , 3 - Propanediol Dicaprylate /Dicaprate ; 10 - un - be a fatty acid comprising 11 or fewer carbons. For example decenoic acid ; 1 -dotriacontanol ; 1 -heptacosanol ; 1 - nonaco - the fatty acid can comprise 6 , 7 , 8 , 9 , 10 , or 11 carbons . sanol; 2 - ethyl hexanol; Androstanes ; Arachidic acid ; Arachi- Without wishing to be bound by a theory , it is believed donic acid ; arachidyl alcohol; Behenic acid ; behenyl 55 that fatty acid salts can be also used in the particles to alcohol; Capmul MCM C10 ; Capric acid ; capric alcohol; potentiate anti -bacterial activity , e . g ., anti- acne activity and capryl alcohol; Caprylic acid ; Caprylic / Capric Acid Ester of provide stability in compositions comprising said drug car Saturated Fatty Alcohol C12 - C18 ; Caprylic / Capric Triglyc - riers . Accordingly , in some embodiments , the lipid is a fatty eride ; Caprylic / Capric Triglyceride; Ceramide phosphoryl - acid salt. Without limitations, the fatty acid salt can be choline ( Sphingomyelin , SPH ) ; Ceramide phosphoryletha- 60 selected from the group consisting of zinc , sodium , potas nolamine ( Sphingomyelin , Cer -PE ) ; Ceramide s ium , lithium , ammonium , copper , calcium , magnesium , phosphorylglycerol; Ceroplastic acid ; Cerotic acid ; Cerotic strontium , manganese , and combinations thereof. The drug acid ; ceryl alcohol; Cetearyl alcohol, Ceteth - 10 ; cetyl alco carrier can comprise any amountof the lipid component. For hol; Cholanes ; Cholestanes ; cholesterol; cis - 11 - eicosenoic example , the drug carrier can comprise between about acid ; cis - 11 -octadecenoic acid ; cis - 13 - docosenoic acid ; 65 0 .01 % to about 99 % ( w / w ) of the lipid component. In some cluytyl alcohol; coenzyme Q10 (CoQ10 ) ; Dihomo - y - lino - embodiments, the lipid component comprises greater than lenic ; Docosahexaenoic acid ; egg lecithin ; Eicosapentaenoic 0 . 1 % ( w / w ), greater than 0 . 5 % ( w / w ) , greater than 1 % US 10 ,071 , 103 B2 107 108 (w /w ), greater than 2 % (w / w ), greater than 3 % ( w /w ), Protein , Hydrolyzed Sesame Protein , Hydrolyzed Soy Pro greater than 4 % ( w / w ), greater than 5 % ( w / w ) , greater than tein , Hydrolyzed Soymilk Protein , Hydrolyzed Spinal Pro 6 % ( w / w ), greater than 7 % (w /w ), greater than 8 % ( w / w ), tein , Hydrolyzed Spongin , Hydrolyzed Sweet Almond Pro greater than 9 % ( w / w ), greater than 10 % ( w / w ), greater than tein , Hydrolyzed Vegetable Protein , Hydrolyzed Wheat 11 % ( w / w ) , greater than 12 % ( w / w ) , greater than 13 % 5 Gluten , Hydrolyzed Wheat Protein , Hydrolyzed Whey Pro ( w / w ) , greater than 14 % ( w / w ) , greater than 15 % ( w / w ) , tein , Hydrolyzed Yeast Protein , Hydrolyzed Yogurt Protein , greater than 16 % ( w / w ) , greater than 17 % ( w / w ) , greater Hydrolyzed Zein , Integrin , Jojoba protein HP, Hydrolyzed , than 18 % ( w / w ) , greater than 19 % ( w / w ), greater than 20 % keratin , Lupine Protein , Maple Sycamore Protein , MEA ( w / w ), greater than 25 % ( w / w ) , greater than 30 % ( w / w ) , Hydrolyzed Collagen , MEA -Hydrolyzed Silk , Milk Protein , greater than 35 % ( w / w ) , greater than 40 % ( w / w ) , greater 10 Myosin , Oat Protein , Pea Protein , polylysine , Potato Protein , than 45 % ( w / w ) , or greater than 50 % ( w / w ) of the total Reticulin , Rice Quat, Royal Jelly Protein , Sericin , Serum weight of the drug carrier. Typically , the content of the lipid Protein , Sesame Protein , Silk powder, Sodium Hydrolyzed component in the drug carriers are in the range of about Casein , Soy Protein , Soy Rice Peptides, Soymilk Protein , 2 - 25 % (w / w ). Spinal Protein , Spongin , Sweet Almond Protein , Vegetable Ratio of the active agent ( e . g ., DART or other anti - 15 Protein , Wheat Gluten , Whey Protein , Yeast Protein , Yogurt bacterial agent ) to the total lipid component of the coating Protein , Zein , and Zinc Hydrolyzed Collagen . layer can be any desired ratio . For example , ratio of the In some embodiments , the protein is an albumin . The active agent to the total lipid component can range from albumin can be a naturally occurring albumin , an albumin about 100 : 1 to about 1: 100 . In some embodiments , the ratio related protein or a variant thereof such as a natural or of the active agent to the total lipid component can range 20 engineered variant . Variants include polymorphisms, frag from about 75 : 1 to about 1 :75 , from about 50 : 1 to about ments such as domains and subdomains, fragments and /or 1 :50 , from about 25 :1 to about 1: 25 , from about 20 : 1 to fusion proteins. An albumin can comprise the sequence of an about 1 : 20 , from about 15 : 1 to about 1 : 15 , from about 5 : 1 to albumin protein obtained from any source . A number of about 1 : 5 , or from about 25 : 1 to about 1 : 5 . In some embodi- proteins are known to exist within the albumin family . ments , the ratio of the active agent to the total lipid com - 25 Accordingly , the albumin can comprise the sequence of an ponent is about 30 : 1 , about 25 : 1 , about 20 : 1 , about 15 : 1 , albumin derived from one of serum albumin from African about 10 : 1 , about 5 : 1 , or about 1 : 1 . The ratio can be based clawed frog ( e . g . , see Swissprot accession number P08759 on weight, mass , or moles . 1 ) , bovine ( e . g . , see Swissprot accession number P02769- 1 ) , Thickness of the coating layer can range from nanometers cat ( e . g ., see Swissprot accession number P49064 - 1 ), to millimeters . For example, the coating layer thickness can 30 chicken ( e . g . , see Swissprot accession number P19121 - 1 ) , range from about 1 nm to about 5000 nm , from about 5 nm chicken ovalbumin ( e . g . , see Swissprot accession number to about 2500 nm , from about 10 nm to about 2000 nm , from P01012 - 1 ) , cobra ALB ( e . g . , see Swissprot accession num about 50 nm to about 1500 nm , from about 20 nm to about ber 091134 - 1 ) , dog ( e . g ., see Swissprot accession number 1000 nm , from about 1 nm to about 1000 nm , from about 1 P49822 - 1 ) , donkey ( e . g ., see Swissprot accession number nm to about 500 nm , from about 1 nm to about 250 nm , from 35 QSXLE4 - 1 ) , European water frog ( e . g ., see Swissprot acces about 1 nm to about 200 nm , from about 1 nm to about 150 sion number Q9YGH6 - 1 ) , blood fluke ( e . g . , see Swissprot nm , from about 1 nm to about 100 nm , from about 2 nm to accession number AAL08579 and Q95VB7 - 1 ) , Mongolian about 50 nm , or from about 5 nm to about 25 nm . gerbil (e . g. , see Swissprot accession number 035090 -1 and In some embodiments , the drug carrier can comprise two JC5838 ) , goat ( e . g . , see Swissprot accession number or more ( e . g . , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , or more ) lipids, i. e ., 40 B3VHM9- 1 and as available from Sigma as product no . the carrier can comprise a first lipid and a second lipid . For A2514 or A4164 ) , guinea pig ( e . g . , see Swissprot accession example , the coating layer can comprise a second lipid that number Q6WDN9- 1 ) , hamster (see DeMarco et al. ( 2007) . is different from the first lipid . International Journal for Parasitology 37 ( 11 ): 1201 - 1208 ), Exemplary proteins for use in the drug carriers or formu horse ( e . g ., see Swissprot accession number P35747 - 1 ) , lations disclosed herein can include , but are not limited to , 45 human ( e . g ., see Swissprot accession number P02768 - 1 ) , Actin , Albumin , Amaranth Protein , Ammonium Hydrolyzed Australian Lung - fish ( e . g ., see Swissprot accession number Animal Protein , Animal protein , Barley Protein , Brazil Nut P83517 ) , macaque (Rhesus monkey ) ( e . g . , see Swissprot Protein , Casein , Collagen , Collagen protein hydrolyzed , accession number 028522 - ) , mouse ( e . g . , see Swissprot Conchiolin Protein , corn protein , Cottonseed Protein , Elas - accession number P07724 - 1 ) , North American bull frog tin , Extensin , Fibroin , Fibronectin , Fish Protein , Gadidae 50 ( e . g ., see Swissprot accession number P21847 - 1 ) , pig ( e . g . , Protein , Gelatin , Glutein , Glycoproteins, Hazelnut Protein , see Swissprot accession number P08835 - 1 ) , pigeon (e . g. as Hemoglobin , Hemp Seed Protein , Honey Protein , Hydro defined by Khan et al, 2002 , 1112 . J . Biol. Macromol, lyzed Actin , Hydrolyzed Amaranth Protein , Hydrolyzed 30 ( 3 -4 ), 171- 8 ), rabbit (e . g. , see Swissprot accession num animal protein , Hydrolyzed Barley Protein , Hydrolyzed ber P490 65 - 1 ), rat (e . g . , see Swissprot accession number Brazil Nut Protein , Hydrolyzed Conchiolin Protein , Hydro - 55 P02770 - 1 ) , salamander ( e . g ., see Swissprot accession num lyzed corn protein , Hydrolyzed Cottonseed Protein , Hydro ber ( 8UW05 - 1 ) , salmon ALB1 ( e . g . , see Swissprot acces lyzed Elastin , Hydrolyzed Extensin , Hydrolyzed Fibroin , sion number P21848 - 1 ) , salmon ALB2 ( e . g . , see Swissprot Hydrolyzed Fibronectin , Hydrolyzed Fish Protein , Hydro accession number 003156 - 1 ) , sea lamprey ( e . g . , see Swis lyzed Gadidae Protein , Hydrolyzed Gadidae Protein , Hydro - sprot accession number 091274 - 1 and 042279 - 1 ) sheep lyzed Gelatin , Hydrolyzed Hair Keratin , Hydrolyzed Hazel - 60 ( e . g ., see Swissprot accession number P14639 - 1 ) , Sumatran nut, Hydrolyzed Hazelnut Protein , Hydrolyzed Hemoglobin , orangutan ( e . g . , see Swissprot accession number Q5NVH5 Hydrolyzed Hemp Seed Protein , Hydrolyzed Honey Protein , 1 ), tuatara ( e . g . , see Swissprot accession number Q8JIA9 - 1 ) , Hydrolyzed Keratin , Hydrolyzed Lupine Protein , Hydro turkey ovalbumin (e .g . , see Swissprot accession number lyzed Maple Sycamore Protein , Hydrolyzed Milk Protein , 073860- 1 ) , Western clawed frog ( e . g ., see Swissprot acces Hydrolyzed Oat Protein , Hydrolyzed Pea Protein , Hydro - 65 sion number Q6D . 195 - 1 ) , and includes variants and frag lyzed Potato Protein , Hydrolyzed Reticulin , Hydrolyzed ments thereof as defined herein . Many naturally occurring Royal Jelly Protein , Hydrolyzed Sericin , Hydrolyzed Serum mutant forms of albumin are known .Many are described in US 10 ,071 , 103 B2 109 110 Peters , (1996 , All About Albumin : Biochemistry , Genetics greater than 7 % ( w / w ) , greater than 8 % (w / w ), greater than and Medical Applications, Academic Press , Inc ., San Diego , 9 % ( w / w ), greater than 10 % ( w / w ) , greater than 11 % ( w / w ) , Calif ., p . 170 - 181 ), content of which is incorporated herein greater than 12 % ( w / w ), greater than 13 % ( w / w ) , greater by reference . The term albumin also encompasses albumin than 14 % ( w / w ) , greater than 15 % ( w / w ) , greater than 16 % variants, such as genetically engineered forms, mutated 5 ( w / w ) , greater than 17 % ( w / w ) , greater than 18 % ( w / w ) , forms, and fragments etc . having one or more binding sites greater than 19 % ( w / w ) , greater than 20 % ( w / w ) , greater that are analogous to a binding site unique for one or more albumins as defined above . By analogous binding sites in the than 25 % ( w / w ), greater than 30 % ( w / w ) , greater than 35 % context of the invention are contemplated structures that are ( w / w ) , greater than 40 % ( w / w ) , greater than 45 % ( w / w ) , or able to compete with each other for binding to one and the 10 greater than 50 % ( w / w ) of the total weight of the drug same ligand structure. In one embodiment, albumin is carriers . Typically, the content of the cationic molecule in bovine serum albumin , egg albumin , hydrolyzed lactalbu the drug carriers are in the range of about 1 - 25 % ( w / w ) , min , or lactalbumin , including variants and fragments about 0 . 1 - 10 % ( w / w ) , about 0 . 5 - 5 % ( w / w ) , or about 1 - 1 . 5 % thereof. In one embodiment, the protein is egg albumin . ( w / w ) . The protein can comprise between about 0 .01 % to about 15 Ratio of the active agent ( e . g ., DART or other anti bacterial agent) to the protein component can be any desired protein99 % (w /componentw ) of the drug comprises carrier. greaterIn some than embodiments 0 . 1 % ( w ,/ wthe ), ratio . For example , ratio of the active agent to the protein greater than 0 . 5 % ( w / w ) , greater than 1 % ( w / w ) , greater than component can range from about 100 : 1 to about 1 : 100 . In 2 % (w /w ), greater than 3 % (w /w ), greater than 4 % (w /w ), some embodiments , the ratio the active agent to the protein greater than 5 % ( w / w ) , greater than 6 % ( w / w ) , greater than 20 can range from about 100 : 1 to about 1 : 1 , from about 90 : 1 to 7 % ( w / w ) , greater than 8 % ( w / w ), greater than 9 % ( w / w ) , about 10 : 1, from about 85 : 1 to about 15 : 1 , from about 80 : 1 greater than 10 % ( w / w ), greater than 11 % ( w / w ), greater to about 25 : 1 , or from 75 : 1 to about 50 : 1 . In some embodi than 12 % ( w / w ), greater than 13 % ( w / w ), greater than 14 % ments , the ratio of the active agent to the protein component ( w / w ) , greater than 15 % ( w / w ) , greater than 16 % ( w / w ) , is about 75 : 1 . The ratio can be based on weight, mass , or greater than 17 % ( w / w ), greater than 18 % ( w / w ) , greater 25 moles . than 19 % ( w / w ) , greater than 20 % ( w / w ), greater than 25 % Generally , any carbohydrate molecule can be used in the ( w /w ), greater than 30 % ( w / w ) , greater than 35 % ( w / w ) , drug carriers or formulations disclosed herein . In some greater than 40 % ( w / w ) , greater than 45 % ( w / w ) , or greater embodiments , the carbohydrate is a polysaccharide . Exem than 50 % ( w / w ) of the total weight of the drug carriers . plary polysaccharides include cellulose derivatives such as Typically , the content of the protein component in the drug 30 hydroxyethylcellulose, hydroxypropyl- methyl - cellulose carriers are in the range of about 1 - 25 % ( w / w ) , about and carboxymethylcellulose ; glycosaminoglycans such as 0 . 1 - 10 % ( w / w ) , about 0 . 5 - 5 % ( w / w ), or about 1 - 1 . 5 % hyaluronic acid , chondroitin sulfate , chitin and chitosan ; ( w / w ) . starch derivatives such as starch /hydroxyethyl starch ; aga Ratio of the active agent ( e . g ., DART or other anti - rose ; and alginate and combinations thereof. In some bacterial agent ) to the protein component can be any desired 35 embodiments , the carbohydrate can be selected from the ratio . For example , ratio of the active agent to the protein group consisting of chitosan and their derivatives , alginates component can range from about 100 : 1 to about 1 : 100 . In and their derivatives , pullulan , their derivatives some embodiments , the ratio the active agent to the protein The carbohydrate can comprise between about 0 .01 % to can range from about 100 : 1 to about 1 : 1 , from about 90 : 1 to about 99 % ( w / w ) of the drug carrier . In some embodiments , about 10 : 1, from about 85 : 1 to about 15 : 1 , from about 80 : 1 40 the carbohydrate comprises greater than 0 . 1 % (w /w ), greater to about 25 : 1 , or from 75 : 1 to about 50 : 1 . In some embodi - than 0 . 5 % ( w / w ) , greater than 1 % ( w / w ) , greater than 2 % ments , the ratio of the active agent to the protein component ( w / w ) , greater than 3 % ( w / w ) , greater than 4 % ( w / w ) , is about 75 : 1. The ratio can be based on weight, mass , or greater than 5 % ( w / w ) , greater than 6 % ( w / w ) , greater than moles . 7 % ( w / w ) , greater than 8 % ( w / w ) , greater than 9 % ( w / w ) , Generally , any cationic molecule can be used in the drug 45 greater than 10 % ( w / w ) , greater than 11 % ( w / w ), greater carriers or formulations disclosed herein . As used herein the than 12 % ( w / w ) , greater than 13 % ( w / w ) , greater than 14 % term “ cationic molecule ” refers to a molecule that carries a ( w / w ) , greater than 15 % ( w / w ) , greater than 16 % ( w / w ) , net positive charge . In some embodiments , the cationic greater than 17 % ( w / w ) , greater than 18 % ( w / w ) , greater molecule is a polyamine . Exemplary cationic molecules than 19 % ( w / w ), greater than 20 % ( w / w ) , greater than 25 % include , but are not limited to , Putrescine (Butane - 1 , 4 - 50 ( w / w ) , greater than 30 % ( w / w ) , greater than 35 % ( w / w ) , diamine ), Cadaverine (Pentane - 1 , 5 - diamine ), Spermidine , greater than 40 % ( w / w ), greater than 45 % ( w / w ) , or greater Spermine , Cyclen ( 1 , 4 , 7 , 10 -tetrazacyclododecane ) , Cyclam than 50 % ( w / w ) of the total weight of the drug carriers . ( 1 , 4 , 8 , 11 - Tetraazacyclotetradecane ), Linear Polyethyl Typically , the content of the carbohydrate in the drug eneimine (Poly ( iminoethylene )) , Norspermidine , p -Phe carriers are in the range of about 1 -25 % ( w /w ), about nylenediamine ( 1 , 4 - diaminobenzene) , Diethylenetriamine 55 0 . 1 - 10 % ( w / w ), about 0 .5 - 5 % ( w / w ) , or about 1 - 1 . 5 % ( N - ( 2 - aminoethyl) - 1 , 2 - ethanediamine ), thermospermine , ( w / w ) . Tris ( 2 - aminoethyl) amine , Hexamethylenediamine, Beta - ly Ratio of the active agent ( e . g ., DART or other anti sine (3 ,6 -diaminohexanoic acid ), m -Phenylenediamine (1 , 3 - bacterial agent) to the carbohydrate can be any desired ratio . diaminobenzene ) , Diaminopropane ( 1 , 2 -Diaminopropane ) , For example , ratio of the active agent to the carbohydrate Ethylenediamine dihydroiodide , and polyamine D 400 60 can range from about 100 : 1 to about 1 : 100 . In some embodi (Polyoxyalkyleneamine D 400 ) . ments , the ratio the active agent to the carbohydrate can The cationic molecule can comprise between about 0 .01 % range from about 100 : 1 to about 1 : 1 , from about 90 : 1 to to about 99 % ( w / w ) of the drug carrier . In some embodi- about 10 : 1 , from about 85 : 1 to about 15 : 1 , from about 80 : 1 ments , the cationic molecule comprises greater than 0 . 1 % to about 25 : 1 , or from 75 : 1 to about 50 : 1 . In some embodi ( w / w ) , greater than 0 . 5 % ( w / w ) , greater than 1 % ( w / w ) , 65 ments , the ratio of the active agent to the carbohydrate is greater than 2 % ( w / w ) , greater than 3 % ( w / w ) , greater than about 75 : 1 . The ratio can be based on weight, mass, or 4 % ( w / w ), greater than 5 % ( w / w ) , greater than 6 % ( w / w ), moles. US 10 ,071 , 103 B2 111 112 In some embodiments , the drug carrier further comprises methylglucamide ; n -noyl B - D - glucopyranoside ; octanoyl an excipient . In some embodiments , the excipient is a N -methylglucamide ; n - octyl- ß -D - glucopyranoside; octyl wetting agent. Without limitations, the wetting agent can be B - D - thioglucopyranoside ; and the like . Most of these sur selected from alkyl sulfates, e . g . sodium lauryl sulfate , facestabilizers are known pharmaceutical excipients and are sodium stearyl sulfate , sodium oleyl sulfate and sodium 5 described in detail in the Handbook of Pharmaceutical cetyl sulfate , alkyl aryl sulfonates, e . g . sodium dodecylben - Excipients , published jointly by the American Pharmaceu zene sulfonate and dialkyl sodium sulfosuccinates , e . g . tical Association and The Pharmaceutical Society of Great sodium bis -( 2 - ethylhexyl) sulfosuccinate , and most prefer - Britain ( The Pharmaceutical Press, 1986 ), content of which ably sodium lauryl sulfate . Further examples of the phar - is incorporated herein by reference in its entirety . In one maceutically acceptable wetting agent include benzetho - 10 embodiment, the excipient is sodium docusate . nium chloride, cetylpyridinium chloride , docusatesodium , Generally , the drug carriers have an average diameter of poloxamer , polysorbate and sorbitan esters . from about 5 nm to about 20 ,000 nm . In some embodiments , In some embodiments , the excipient is a stabilizer , e . g . , a the drug carriers have an average diameter of from about 5 surface stabilizer. Suitable surfacestabilizers can preferably nm to about 5 , 000 nm . In some embodiments , the drug be selected from known organic and inorganic pharmaceu - 15 carriers have an average diameter of from about 50 nm to tical excipients . Such excipients include various polymers , about 2500 nm . In some embodiments , the drug carriers low molecular weight oligomers , natural products , and sur- have an average diameter of from about 100 nm to about factants with high and low hydrophilic lipophilic balance 2000 nm . In some embodiments , the drug carriers have an (HLB ). Preferred surfacestabilizers include nonionic and average diameter of from about 150 nm to about 1700 nm . ionic surfactants . Two or more surfacestabilizers can be used 20 In some embodiments , the drug carriers have an average in combination . Representative examples of surfacestabiliz diameter of from about 200 nm to about 1500 nm . In some ers include sodium docusate , cetyl pyridinium chloride, embodiment, the drug carriers have an average diameter of gelatin , casein , lecithin (phosphatides ) , dextran , glycerol, about 260 nm . In one embodiment, the drug carriers have an gum acacia , cholesterol, tragacanth , stearic acid , benzalko average diameter of about 30 nm to about 150 nm . In some nium chloride , calcium stearate , glycerol monostearate , 25 embodiments , the drug carriers have an average diameter of cetostearyl alcohol , cetomacrogol emulsifying wax , sorbitan about 100 nm to about 1000 nm , from about 200 nm to about esters , polyoxyethylene alkyl ethers (e . g ., macrogol ethers 800 nm , from about 200 nm to about 700 nm , or from about such as cetomacrogol 1000 ), polyoxyethylene castor oil 300 nm to about 700 nm . derivatives, polyoxyethylene sorbitan fatty acid esters ( e . g ., Generally , the drug carriers disclosed herein can be of any the commercially available Tweens® such as e . g . , Tween 30 shape or form , e . g . , spherical, rod , elliptical, cylindrical , 20® and Tween 80® ( ICI Specialty Chemicals )) ; polyeth capsule , or disc . ylene glycols ( e . g . , Carbowaxs 3350 and 1450® , and In some embodiments , the drug carrier can be micro -sized Carbopol 934® (Union Carbide ) ) , dodecyl trimethyl ammo and have a size of about 1 um to about 1000 um . In some nium bromide , polyoxyethylene stearates , colloidal silicon embodiments , the drug carrier can be nano -sized and have dioxide , phosphates , sodium dodecylsulfate , carboxymeth - 35 size of about 0 . 1 nm to about 1000 nm . In some embodi ylcellulose calcium , hydroxypropyl celluloses ( e . g . , HPC , ments , the drug carrier is a microparticle or a nanoparticle . HPC - SL , and HPC - L ), hydroxypropyl methylcellulose As used herein , the term “ microparticle ” refers to a particle ( HPMC ) , carboxymethylcellulose sodium , methylcellulose , having a particle size of about 1 um to about 1000 um . As hydroxyethylcellulose , hydroxypropylcellulose , hydroxy - used herein , the term “ nanoparticle” refers to particle having propylmethyl- cellulose phthalate , noncrystalline cellulose , 40 a particle size of about 0 . 1 nm to about 1000 nm . magnesium aluminum silicate , triethanolamine , polyvinyl It will be understood by one of ordinary skill in the art that alcohol (PVA ) , polyvinylpyrrolidone (PVP ) , 4 -( 1 , 1 , 3 , 3 -te - particles usually exhibit a distribution of sizes around the tramethylbutyl) - phenol polymer with ethylene oxide and indicated “ size .” Unless otherwise stated , the terms " drug formaldehyde (also known as tyloxapol, superione , and carrier size” and “ particle size” as used herein refer to the triton ), poloxamers ( e . g . , Pluronics F68® and F108® , which 45 mode of a size distribution of drug carriers or particles , i. e ., are block copolymers of ethylene oxide and propylene the value that occurs most frequently in the size distribution . oxide ) ; poloxamines ( e . g ., Tetronic 908® , also known as Methods for measuring the drug carrier or particle size are Poloxamine 908® , which is a tetrafunctional block copoly known to a skilled artisan , e . g. , by dynamic light scattering mer derived from sequential addition of propylene oxide and ( such as photocorrelation spectroscopy, laser diffraction , ethylene oxide to ethylenediamine (BASF Wyandotte Cor- 50 low - angle laser light scattering (LALLS ) , and medium poration , Parsippany, N . J .) ) ; a charged phospholipid such as angle laser light scattering (MALLS ) ) , light obscuration dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate methods ( such as Coulter analysis method ) , or other tech ( DOSS ); Tetronic 1508® ( T - 1508 ) (BASF Wyandotte Cor- niques ( such as rheology, and light or electron microscopy ). poration ) , dialkylesters of sodium sulfosuccinic acid ( e . g ., In some embodiments , the drug carrier can be substan Aerosol OT® , which is a dioctyl ester of sodium sulfosuc - 55 tially spherical. What is meant by “ substantially spherical” cinic acid ( American Cyanamid ) ) ; Duponol P® , which is a is that the ratio of the lengths of the longest to the shortest sodium lauryl sulfate (DuPont ) ; Tritons X -200® , which is an perpendicular axes of the drug carrier cross section is less alkyl aryl polyether sulfonate (Rohm and Haas ) ; Crodestas than or equal to about 1 . 5 . Substantially spherical does not F - 1 10® , which is a mixture of sucrose stearate and sucrose require a line of symmetry . Further , the drug carriers can distearate ( Croda Inc . ) ; p - isononylphenoxypoly - ( glycidol) , 60 have surface texturing , such as lines or indentations or also known as Olin -IOG® or Surfactant 10 -G® (Olin protuberances that are small in scale when compared to the Chemicals , Stamford , Conn . ); Crodestas SL -40® ( Croda , overall size of the drug carrier and still be substantially Inc . ) ; decanoyl- N -methylglucamide ; n - decyl B - D - glucopy spherical. In some embodiments , the ratio of lengths ranoside ; n -decyl B - D -maltopyranoside ; n - dodecyl B - D - glu - between the longest and shortest axes of the drug carrier is copyranoside ; n -dodecyl B - D - maltoside ; heptanoyl- N -meth - 65 less than or equal to about 1 . 5 , less than or equal to about ylglucamide ; n -heptyl - B - D - glucopyranoside ; n - heptyl 1 . 45 , less than or equal to about 1 . 4 , less than or equal to thioglucoside; n -hexyl B -D -glucopyranoside ; nonanoyl- N - about 1. 35 , less than or equal to about 1. 30 , less than or US 10 ,071 , 103 B2 113 114 equal to about 1 . 25 , less than or equal to about 1 . 20 , less than than the active agent or the additional component formsone or equal to about 1 . 15 less than or equal to about 1 . 1 . or more coating layers on the drug carrier core ; ( 8 ) lipo Without wishing to be bound by a theory , surface contact is somes comprising the active agent; ( 9 ) emulsions, e . g . , minimized in drug carriers that are substantially spherical, oil/ water / oil or water/ oil/ water emulsions ; ( 10 ) micelles ; which minimizes the undesirable agglomeration of the drug 5 ( 11) globules ; ( 12 ) suspensions ; ( 13 ) dispersions ; ( 14 ) carriers upon storage . Many crystals or flakes have flat vesicles ; ( 15 ) aggregates; and ( 16 ) drug carrier comprising surfaces that can allow large surface contact areas where any of the drug carriers of ( 1 ) - ( 15 ) and further comprising agglomeration can occur by ionic or non - ionic interactions. one or more layers of a material other than the active agent A sphere permits contact over a much smaller area . or the additional component. In drug carriers of ( 16 ) , the In some embodiments , the drug carriers have substantially 10 further layer can be the outermost layer, a first layer on the the same particle size . Drug carriers having a broad size core , interspersed between the layers described in ( 1 ) - ( 15 ) , distribution where there are both relatively big and small or any combinations thereof. Without limitations, the coat drug carriers allow for the smaller drug carriers to fill in the ing layer can comprise components other than indicated gaps between the drug carriers , thereby creating new contact above. For example, the above indicated coating component surfaces . A broad size distribution can result in larger 15 can be mixed with other molecules or compositions to form spheres by creating many contact opportunities for binding the coating layer. This can be useful in instances wherein the agglomeration . The drug carriers described herein are within specified componentmay not be able to form a coating layer a narrow size distribution , thereby minimizing opportunities by itself . In some embodiments , the particle comprises a for contact agglomeration . What is meant by a “ narrow size core comprising the active agent and the additional compo distribution ” is a particle size distribution that has a ratio of 20 nent forms one or more ( e . g . , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 or the volume diameter of the 90th percentile of the small more ) coating layers on the core . spherical particles to the volume diameter of the 10th In some embodiments , the drug carrier can be in the form percentile less than or equal to 5 . In some embodiments , the of a liposome. As used herein , a liposome is a structure volume diameter of the 90th percentile of the small spherical having lipid - containing membranes enclosing an aqueous particles to the volume diameter of the 10th percentile is less 25 interior. Liposomes can have one or more lipid membranes . than or equal to 4 . 5 , less than or equal to 4 , less than or equal Oligolamellar, large vesicles and multilamellar vesicles have to 3 . 5 , less than or equal to 3 , less than or equal to 2 . 5 , less multiple , usually concentric , membrane layers. Liposomes than or equal to 2 , less than or equal to 1 . 5 , less than or equal with several nonconcentric membranes, i . e ., several smaller to 1 . 45 , less than or equal to 1 . 40 , less than or equal to 1 . 35 , vesicles contained within a larger vesicle , are termed mul less than or equal to 1 . 3 , less than or equal to 1 .25 , less than 30 tivesicular vesicles . or equal to 1 .20 , less than or equal to 1 . 15 , or less than or Liposomes can further comprise one or more additional equal to 1. 1. lipids and / or other components such as sterols , e . g . , choles Geometric Standard Deviation (GSD ) can also be used to terol. Additional lipids can be included in the liposome indicate the narrow size distribution . GSD calculations compositions for a variety of purposes, such as to prevent involved determining the effective cutoff diameter (ECD ) at 35 lipid oxidation , to stabilize the bilayer, to reduce aggregation the cumulative less than percentages of 15 . 9 % and 84 . 1 % . during formation or to attach ligands onto the liposome GSD is equal to the square root of the ratio of the ECD less surface . Any of a number of additional lipids and /or other than 84 .17 % to ECD less than 15 . 9 % . The GSD has a narrow components can be present , including amphipathic , neutral, size distribution when GSD < 2 . 5 . In some embodiments, cationic , anionic lipids, and programmable fusion lipids . GSD is less than 2 , less than 1 .75 , or less than 1 .5 . In one 40 Such lipids and/ or components can be used alone or in embodiment, GSD is less than 1 . 8 . combination . In addition to the lipids , the liposome can While , the drug carriers are discussed in terms of coated comprise one or more of the additives described in the particles , there are at least eight types of drug carriers that disclosure . can be formulated with the active agent and one or more Liposome compositions can be prepared by a variety of additional components . Different types of drug carriers can 45 methods that are known in the art. See e . g . , U . S . Pat . Nos . be as follows: ( ( 1 ) drug carriers comprising a core formed by 4 ,235 ,871 ; 4 ,737 , 323; 4 ,897 ,355 and 5 , 171, 678 ; published the active agent to which the additional component absorbs / International Applications WO 96 / 14057 and WO 96 /37194 ; adsorbs or the additional component forms one or more Feigner , P . L . et al. , Proc. Natl . Acad . Sci. , USA ( 1987 ) coating layers on the drug carrier core; (2 ) drug carriers 8 : 7413 - 7417 , Bangham , et al. M . Mol. Biol. ( 1965 ) 23 : 238 , comprising a generally homogeneous mixture of the active 50 Olson , et al. Biochim . Biophys. Acta (1979 ) 557: 9 , Szoka, et agent and the additional component; ( 3 ) drug carriers com - al. Proc. Natl . Acad . Sci. ( 1978 ) 75 : 4194 , Mayhew , et al. prising a core comprising a generally homogeneous mixture Biochim . Biophys . Acta ( 1984 ) 775 : 169 , Kim , et al. Biochim . of the active agent and the additional component, and the Biophys. Acta ( 1983 ) 728 : 339 , and Fukunaga , et al. Endo additional component forms one or more coating layers on crinol. ( 1984 ) 115 : 757 . the drug carrier core ; ( 4 ) drug carriers comprising a core 55 In some embodiments , the drug carrier can be micelle. As formed by the additional component and the active agent used herein , “ micelles ” are a particular type of molecular forms one or more coating layers on the drug carrier core ; assembly in which amphipathic molecules are arranged in a ( 5 ) drug carriers comprising a core comprising a generally spherical structure such that all hydrophobic portions on the homogeneous mixture of the active agent and the additional molecules are directed inward , leaving the hydrophilic por component, and the active agent forms one or more coating 60 tions in contact with the surrounding aqueous phase . The over the drug carrier core ; ( 6 ) drug carrier comprising a core converse arrangement. of material other than the active agent and the additional In some embodiments, the drug carrier can be an emul component, and a mixture of the active agent and the sion . As used herein , " emulsion ” is a heterogeneous system additional component forms one or more coating layers on of one liquid dispersed in another in the form of droplets . the drug carrier core ; ( 7 ) drug carriers comprising a core 65 Emulsions are often biphasic systems comprising two comprising a generally homogeneous mixture of the active immiscible liquid phases intimately mixed and dispersed agent and the additional component, and a material other with each other . Either of the phases of the emulsion can be US 10 ,071 , 103 B2 115 116 a semisolid or a solid , as is the case of emulsion - style In some embodiments , the formulation comprises 8 - chloro ointment bases and creams. The active agent can be present besifloxacin and another anti - acne agent as the API. In one as a solution in either the aqueous phase , oily phase or itself embodiment, the formulation comprises besifloxacin and as a separate phase . adapalene as the API. In some embodiments , the drug carrier can be formulated 5 The formulations disclosed herein can comprise several as microemulsions. As used herein , " microemulsion ” refers types of cosmetically - acceptable topical vehicles including , to a system of water , oil and amphiphile which is a single but not limited to solutions, colloidal suspensions , disper optically isotropic and thermodynamically stable liquid sions , emulsions (microemulsions , nanoemulsions , multiple solution . Microemulsions also include thermodynamically and non -aqueous emulsions ) , hydrogels , and vesicles ( lipo stable , isotropically clear dispersions of two immiscible 10 somes , niosomes , novasomes ) . Components and formula liquids that are stabilized by interfacial films of surface - tion methods of suitable cosmetically -acceptable topical active molecules . vehicles are well known in the art and are described , for The application of emulsion formulations via dermato example , in U . S . Pat. No . 6 ,797 ,697 and U . S . Pat. App . Pub . logical , oral and parenteral routes and methods for their No . 2005 /0142094 and No. 2005 / 0008604 , Int. Pat . App . manufacture have been reviewed in the literature , for 15 Pub . No. 2006 / 029818 and No . 2000 / 062743 , content of all example see Idson , in Pharmaceutical Dosage Forms, Lie - of which is incorporated herein by reference . Those skilled berman , Rieger and Banker ( Eds. ) , 1988 , Marcel Dekker , in the art will appreciate the various methods for producing Inc ., New York , N . Y . , volume 1 , p . 199 ; Rosoff, in Pharma- these various product forms. ceutical Dosage Forms, Lieberman , Rieger and Banker In some embodiments , the formulation can be in the form ( Eds . ), 1988 , Marcel Dekker, Inc . , New York , N . Y ., volume 20 of a cream , oil , lotion , serum , gel, sunscreen , nail varnish , 1 , p . 245 ; and Block , in Pharmaceutical Dosage Forms, ointment, foam , spray, aerosol, powder, stick , solution , Lieberman , Rieger and Banker (Eds .) , 1988 ,Marcel Dekker , suspension , dispersion , paste , peel, and impregnated fabric Inc . , New York , N . Y . , volume 1 , p . 335 , contents of which ( e . g . a “ wipe” or tissue ). Generally , the composition com are herein incorporated by reference in their entirety . prises an effective amount of the active agent. As used here , The drug carrier can be fabricated using methods and 25 the term “ effective amount” is that amount of the formula instruments well known in the art . For example , the drug tion containing the active agent necessary to achieve the carriers can be made using microprecipitation , encapsula desired improvement. In some embodiments , the formula tion , deaggregation , hybrid of deaggregation and encapsu - tion is a topical formulation . lation , homogenization , hybrid of deaggregation and hot In some embodiments , the formulation can be in a form homogenization , or any combinations thereof. In some 30 selected from the group consisting of lotions, creams, gels , embodiments , the process of making the particles comprises emulgel, oils , serums, powders , sprays , ointments, solutions , the step of selecting particles of a desired size . suspensions, dispersions , pastes, foams, peels , films, masks, patches , sticks, rollers , cleansing liquid washes , cleansing Formulation Features Applicable to DART, solid bars, pastes , foams, powders , shaving creams, impreg Non -DART and Combination API 35 nated fabric ( e . g . a " wipe” or tissue ) , and the like . In some embodiments , the formulation is an antibacterial The disclosure provides a composition or formulation formulation . In some embodiments , the composition is an comprising a DART. The disclosure also provides a com - anti -bacterial composition in the form of a skin care com position or formulation comprising an antibacterial agent as position . As defined herein , the term “ skin care composi the API, wherein the antibacterial agent is not a DART 40 tion ” refers to materials applied topically to the skin that molecule . In some embodiments , the formulation comprises benefit , improve , or enhance the condition of the skin , or two or more different APIs , e. g . , two different DARTs , two treat skin suffering from an infectious or diseased condition . different anti -bacterial agents which are not DART , or a Such skin care compositions include bases such as soap DART molecule and an antibacterial agent which is not a bases , cosmetic bases , medicament bases , cream bases , DART. In some embodiments , the DART or the antibacterial 45 emollient bases , and combinations thereof, as well as other agent is formulated as drug carrier for the API. Without bases known in the art. limitations the formulation or the composition can be for- Without limitations, the formulation can comprise any mulated for administration by any appropriate route known desired amount of the API. For example , the formulation can in the art including , but not limited to , topical ( including comprise from about 0 .01 % to about 99 % ( w / w or w / v ) of buccal and sublingual) and oral or parenteral routes, includ - 50 the API. In some embodiments , the formulation can com ing intravenous, intramuscular, subcutaneous, transdermal, prise from about 0 . 1 % to about 75 % ( w / w or w / v ) , from airway ( aerosol) , pulmonary, nasal, and rectal administra about 1 % to about 50 % ( w / w or w / v ) , from about 1 . 5 % to tion . Exemplary modes of administration include , but are not about 40 % ( w / w or w / v ) , API. In some embodiments , the limited to , topical, injection , infusion , instillation , inhala - formulation can comprise from about 2 . 5 % , 3 % , 3 . 5 % , 4 % , tion , or ingestion . “ Injection ” includes , without limitation , 55 4 . 5 % , 5 % , 7 . 5 % , 10 % , 12 .5 % , 15 % , 17 . 5 % , 20 % , 22 . 5 % , or intravenous , intramuscular, intra - arterial, intrathecal, intra - 25 % ( w / w or w /v ) of the API. ventricular, intracapsular , intraorbital, intracardiac , intrader - In some embodiments , the formulation can comprises, in mal, intraperitoneal, intralymphnodal , transtracheal, subcu - addition to the API, one or more zinc compounds. Without taneous, subcuticular , intra -articular , sub capsular , wishing to be bound by a theory , zinc compounds can help subarachnoid , intraspinal, intracerebral , spinal, and intrac - 60 to suppress sebum secretion and reduce acne inflammation . issternal injection and infusion . In some embodiments , the Exemplary zinc compounds include, but are not limited to , formulation can be in the form of an oral dosage , injectable , zinc acetate , zinc methionine , zinc pyrrolidone carboxylic aerosolae or inhalant. acid , zinc sulfide , zinc gluconate , zinc picolinate , zinc In some embodiments , the formulation can comprise two sulphate , zinc citrate , etc . Without limitations, the formula or more ( e . g . , two , three , four, five or more ) different 65 tion can comprise any desired amount of the zinc compound . antibacterial agents as the API. For example , the formula - For example , the formulation can comprise from about tion can comprise two different anti - acne agents as the API. 0 .01 % to about 99 % ( w / w or w / v ) of the zinc compound . In US 10 ,071 , 103 B2 117 118 some embodiments , the formulation can comprise from less than about 5 % , and most preferably less than about 3 % about 0 . 1 % to about 75 % ( w /w or w /v ), from about 1 % to by weight of the total composition . Such components about 50 % ( w / w or w /v ) , from about 1 . 5 % to about 40 % include , but are not limited to surfactants , emollients , mois ( w /w or w / v ), from about 2 % to about 25 % ( w / w or w / v ) , or turizers, stabilizers , film - forming substances , fragrances , from about 2 . 5 % to about 25 % (w /w or w /v ) of the zinc 5 colorants , chelating agents , preservatives , antioxidants , pH compound . In some embodiments , the formulation can com - adjusting agents antimicrobial agents , water - proofing prise from about 2 .5 % , 3 % , 3 .5 % , 4 % , 4 . 5 % , 5 % , 7 .5 % , agents , dry feel modifiers, vitamins, plant extracts , hydroxy 10 % , 12 . 5 % , 15 % , 17 .5 % , 20 % , 22 . 5 % , or 25 % (w /w or acids ( such as alpha - hydroxy acids and beta -hydroxy acids) , w / v ) of the zinc compound . and sunless tanning agents . In some embodiments, the formulation can further com - 10 The formulation can comprise one or more of the follow prise one or more excipients . Without limitations, the excipi- ing basic cosmetic raw materials , including , but not limited ent can be selected from the group consisting of emulsifiers, to hydrocarbons, esters , fatty alcohols , fatty acids, emulsi preservatives, surfactants , oils , lipids , waxes , stabilizers , fying agents , humectants , viscosity modifiers , and silicone rheology modifiers or thickening agents ( gelling agent) , based materials. The formulations can contain a wide range emollients , moisturizers , conditioning agents , fragrances / 15 of these basic components . The total concentration of added perfumes, potentiating agents , preservatives , opacifiers , ingredients usually is less than 50 % , preferably less than antioxidants , cooling agents , film forming agents , abrasives, 20 % , and most preferably less than 10 % by weight of the exfoliating agents , colorants , pH modifiers , solvents , total formulation . Those skilled in the art will appreciate the vehicle, penetration enhancers , permeation enhancers, pearl various concentrations and combinations for employing izing agents , and any combinations thereof. Amount of the 20 these basic components to achieve the desired product form . excipients in the formulation can range from about 5 % to Suitable lipids which can be used include one or more of 99 .99 % (w /w or w / v ). In some embodiments , the formula - hydrocarbons, fatty alcohols , fatty acids , glycerides or esters tion comprises one or more GRAS ingredients . of fatty acids with C -C36 alkanols . Hydrocarbons can Generally , the pH of intended use of the formulation will include paraffin or petroleum jelly . Fatty alcohols can generally range from about PH 2 to about pH10 , from about 25 include decanol, dodecanol, tetradecanol, hexadecanol or pH 3 to about pH 9 , from about pH 4 and about pH 8 , or from octadecanol. Fatty acids can include C6 -C24 alkanoic acids about pH 5 .0 to about pH 7 .5 or from about pH 5 to about such as hexanoic acid , octanoic acid , decanoic acid , dode 6 . 5 . Suitable pH adjusting agents which can be used include canoic acid , tetradecanoic acid , hexadecanoic acid , octade one or more of organic or inorganic acids and bases includ canoic acid , unsaturated fatty acids such as oleic acid and ing sodium hydroxide, potassium hydroxide , ammonium 30 linoleic acid . Glycerides can include olive oil , castor oil , hydroxide , phosphate buffers , citric acid , acetic acid , sesame oil, caprylic / capric acid triglyceride or glycerol fumaric acid , hydrochloric acid , malic acid , nitric acid , mono - , di - and tri -esters with palmitic and / or stearic acid . phosphoric acid , propionic acid , sulfuric acid , tartaric acid , Esters of fatty acids can include C , - Can alkanols such as triethyl amine , and the like . beeswax , carnauba wax , cetyl palmitate , lanolin , isopropyl Typically , the cosmetically acceptable medium for skin 35 myristate , isopropyl stearate , oleic acid decyl ester, ethyl care compositions comprises water and other solvents which oleate and C . - C , , alkanoic acid esters and the like . include , but are not limited to , mineral oils and fatty alco - Suitable hydrocarbons include , but are not limited to hols . The cosmetically - acceptable medium is from about mineral oil, isohexadecane, squalane , hydrogenated poly 10 % to about 99. 99 % by weight of the composition , pref- isobutene , petrolatum , paraffin , microcrystalline wax , and erably from about 50 % to about 99 % by weight of the 40 polyethylene . Suitable oils can include one or more of composition , and can , in the absence of other additives, form almond oil, apricot seed oil, borage oil , canola oil, coconut the balance of the composition . oil , corn oil , cotton seed oil , fish oil, jojoba bean oil , lard oil , As used herein the term " cosmetically acceptable linseed oil, boiled macadamia nut oil , mineral oil , olive oil, medium ” refers to formulations that are used to treat skin , peanut oil , safflower oil , sesame oil , soybean oil , squalane , hair and /or nails and contain one ormore ingredients used by 45 sunflower seed oil , tricaprylin ( 1 , 2 , 3 trioctanoyl glycerol) , those skilled in the art to formulate products used to treat wheat germ oil and the like . The preferred quantity of oil skin . The cosmetically acceptable medium can be in any used is in the range of about 5 to about 25 % w / w , and more suitable form , i . e . , a liquid , cream , emulsion , gel , thickening preferably in the range of about 5 % to about 20 % w / w of the lotion or powder and will typically contain water , and can composition . contain a cosmetically acceptable solvent and /or one or 50 Suitable esters which can be used include , but are not more surfactants . limited to isopropyl palmitate , octyl stearate , caprylic /capric The formulation can comprise one or more conventional triglyceride, plant waxes (Canelilla , Caranauba ) , vegetable functional cosmetic or dermatological additives or adju - oils ( natural glycerides ) and plant oils ( Jojoba ) . vants , providing that they do not interfere with the mildness , Suitable fatty alcohols which can be used include, but are performance or aesthetic characteristics desired in the final 55 not limited to myristyl, cetyl, stearyl, isostearyl, and behe products . The CTFA ( The Cosmetic , Toiletry , and Fragrance nyl. Association ; now known as the Personal Care Products Suitable emulsifying agents which can be used include , Council ) International Cosmetic Ingredient Dictionary and but are not limited to anionic ( TEA / K stearate ( trietha Handbook , Eleventh Edition (2006 ), and McCutcheon ' s nolamine /potassium stearate ), sodium lauryl stearate , Functional Materials , North America and Internationals 60 sodium cetearyl sulfate , and beeswax /Borax ) , nonionic Editions , MC Publishing Co . ( 2007 ) describe a wide variety ( glycerol distearate , PEG (polyethyleneglycol ) - 100 Stear of cosmetic and pharmaceutical ingredients commonly used ate , Polysorbate 20 , steareth 2 and steareth 20 ), and cationic in skin care compositions, which are suitable for use in the (distearyldimethylammonium chloride, behenalkonium compositions of the present invention . The compositions of chloride and steapyrium chloride ) , polymeric (acrylates / C the present invention can contain a wide range of these 65 10 - 30 alkyl acrylate crosspolymer , polyacrylamide, poly additional, optional components. The total concentration of quaternium - 37 , propylene glycol, dicaprylate / dicaparate and added ingredients usually is less than about 20 % , preferably PPG - 1 Trideceth - 6 ), and silicone based materials (alkyl US 10 ,071 , 103 B2 119 120 modified dimethicone copolyols ) , and polyglyceryl esters , a tradename for a family of polyethoxylated fatty acid and ethoxylated di- fatty esters. Additional suitable emulsi - commercially available from a number of suppliers, such as fiers/ surfactant can include one or more of ionic polysorbate polyoxyethylene monostearate (Myrj 49 ) and the like . surfactant, Tween® 20 , Tween® 40 , Tween® 60 , Tween® Tween is the tradename for a family of polyoxyethylene 80 , Nonylphenol Polyethylene Glycol Ethers, (alkylphenol - 5 sorbitan or polysorbate surfactants , such as polyoxyethylene hydroxypolyoxyethylene ) , Poly (oxy - 1 ,2 -ethanediyl ), alpha - sorbitan trioleate ( Tween 85 ) and polysorbate 80 ( Tween 80 ) ( 4 -nonylphenol ) - omega -hydroxy - , branched (i . e . Tergitol® commercially available from a number of suppliers. Azone NP -40 Surfactant) , Nonylphenol Polyethylene Glycol Ether is a tradename for 1 -Dodecylhexahydro - 2 h - Azepin - 2 -One . mixtures ( i. e . Tergitol® NP - 70 (70 % AQ ) Surfactant) , phe In some embodiments , the formulation comprises one or noxypolyethoxyethanols and polymers thereof such as Tri - 10 more penetration enhancers . Exemplary penetration enhanc ton® , Poloxamer® , Spans® , Tyloxapol® , different grades ers include , but are not limited to fatty acids, bile salts , of Brij , sodium dodecyl sulfate and the like . The preferred chelating agents , surfactants , and non - surfactants . Exem quantity of the emulsifiers /surfactant used is in the range of plary penetration enhancers include dimethyl sulfoxide ; about 0 . 1 % to about 10 % w / w of the composition . isopropyl myristate ; decyl, undecyl or dodecyl alcohol; Exemplary humectants for use include, but are not limited 15 propylene glycol, polyethylene glycol; C9, C10 , C11 , C12 to propylene glycol, sorbitol, butylene glycol, butylene or C12 - 15 fatty alcohols ; azone ; alkyl pyrrolidones ; glycol , hexylene glycol, acetamide MEA ( acetyletha - diethoxy glycol ( Transcutol) ; lecithin ; etc . Surfactants can nolamine ), honey , and sodium PCA ( sodium - 2 -pyrrolidone also be used as penetration enhancers . carboxylate ), sorbitol, triacetin , and the like . The formulation disclosed herein can further comprise Viscosity modifiers which can be used in the composi - 20 one or more optional components known for use in personal tions of the invention include , but are not limited to xanthum care products , provided that the optional components are gum , magnesium aluminum silicate , cellulose gum , and physically and chemically compatible with the essential hydrogenated castor oil. components described herein , or do not otherwise unduly Suitable thickening agents which can be used include one impair product stability , aesthetics or performance . Indi or more of cellulose polymer, a carbomer polymer , a car - 25 vidual concentrations of such optional components can bomer derivative , a cellulose derivative , polyvinyl alcohol, range from about 0 . 001 % to about 10 % by weight of the poloxamers , polysaccharides and the like. compositions . Suitable emollients which can be used include one or Non - limiting examples of optional components for use in more of caprylic / capric triglycerides, castor oil, ceteareth - the composition include a deposition aid , cationic polymers , 20 , ceteareth - 30 , cetearyl alcohol, ceteth 20 , cetostearyl 30 nonionic polymers , dispersed particles , conditioning agents alcohol, cetyl alcohol, cetyl stearyl alcohol, cocoa butter , ( silicones and organic conditioning oils ), humectant, sus diisopropyl adipate, glycerin , glyceryl monooleate , glyceryl pending agent, additional anti- dandruff actives, viscosity monostearate , glyceryl stearate, isopropyl myristate , isopro modifiers, dyes, nonvolatile solvents or diluents (water pyl palmitate , lanolin , lanolin alcohol, hydrogenated lanolin , soluble and insoluble ) , pearlescent aids, additional surfac liquid paraffins , linoleic acid , mineral oil, oleic acid , white 35 tants or nonionic cosurfactants , pediculocides, pH adjusting petrolatum , polyethylene glycol, polyoxyethylene glycol agents , perfumes, preservatives, chelants , proteins, skin fatty alcohol ethers , polyoxypropylene 15 - stearyl ether , pro - active agents , sunscreens, UV absorbers , vitamins, antioxi pylene glycol stearate , squalane, steareth - 2 or - 100 , stearic dants , preserving agents , fillers , surfactants , UVA and / or acid , stearyl alcohol, urea and the like . UVB sunscreens , fragrances, viscosifying agents , wetting Suitable preservatives which can be used include one or 40 agents , anionic polymers , nonionic polymers, amphoteric more of phenoxyethanol, parabens (such as methylparaben polymers, viscosity / foam stabilizers , opacifying/ pearlizing and propylparaben ) , propylene glycols , sorbates , urea agents , sequestering agents , stabilizing agents , humectants , derivatives ( such as diazolindinyl urea ), and the like. anti - static agents , antifreezing agents, buffering agents , Suitable chelating agents which can be used include one dyes , and pigments . These adjuvants are well known in the or more of disodium EDTA , edetate trisodium , edetate 45 field of cosmetics and are described in many publications, tetrasodium , diethyleneamine pentaacetate and the like . for example see Harry ' s Book of Cosmeticology, 8th edition , In some embodiments , the formulation comprises one or Martin Rieger, ed . , Chemical Publishing , New York (2000 ) . more of alcohols like C , -C1 alcohols , diols and triols , The compositions disclosed herein can also include a glycerol, methanol, ethanol, propanol, octanol and the like . deposition aid . The deposition aid is included to effectively In some embodiments , the formulation comprises one or 50 enhance deposition of the composition components . The more permeation enhancers . Exemplary permeation enhanc - deposition aid can comprise any material that enhances the ers include anionic surfactants , such as sodium lauryl sulfate deposition of the composition components onto the hair , and sodium laurate ; cationic surfactants , such as scalp , or skin . In some embodiments , the deposition aids are cetylpyridium chloride ; non - ionic surfactants , such as cationic polymers . The concentration of the deposition aid in poloxamer , Brij , Span , Myrj , and Tween ; bile salts ; sodium 55 the composition should be sufficient to effectively enhance glycodeoxycholate ; sodium glycocholate , sodium taurode - the deposition of the components and typically range from oxycholate , sodium taurocholate , Azone® ; fatty acids, such about 0 .05 % to about 5 % , preferably from about 0 . 075 % to as oleic and caprylic acid ; cyclodextrins, such as a - , B -, about 2. 5 % , more preferably from about 0 .1 % to about y -cyclodextrin , methylated ß - cylcodextrins; chelators , such 1 . 0 % , by weight of the composition . as EDTA , sodium citrate and poly acrylates ; polymers , such 60 The compositions disclosed herein can comprise a cat as chitosan , trimethyl chitosan and cationic amino acids , ionic polymer . Concentrations of the cationic polymer in the such as poly - L - arginine and L -lysine . Brij is the tradename composition typically range from about 0 . 05 % to about 3 % , for a family of nonionic polyoxyethylene commercially preferably from about 0 .075 % to about 2. 0 % , more prefer available from a number of suppliers. Span is the tradename a bly from about 0 . 1 % to about 1 . 0 % , by weight of the for a family of sorbitan surfactants , such as sorbitan trioleate 65 composition . Preferred cationic polymers will have cationic (Span 85 ) and sorbitan tristearate (Span 65 ) and the like , charge densities of at least about 0 . 9 meq / gm , preferably at commercially available from a number of suppliers . Myrj is least about 1. 2 meq /gm , more preferably at least about 1. 5 US 10 ,071 , 103 B2 121 122 meq /gm , but also preferably less than about 7 meq/ gm ,more Other suitable cationic polymers for use in the composi preferably less than about 5 meq/ gin . The average molecular tion include polysaccharide polymers , such as cationic cel weight of such suitable cationic polymers will generally be lulose derivatives and cationic starch derivatives . Preferred between about 10 ,000 and 10 million , preferably between cationic cellulose polymers are salts of hydroxyethyl cellu about 50 ,000 and about 5 million , more preferably between 5 lose reacted with trimethyl ammonium substituted epoxide , about 100 , 000 and about 3 million . referred to in the industry (CTFA ) as Polyquaternium 10 and available from Amerchol Corp . (Edison , N . J . , USA ) in their Suitable cationic polymers for use in the compositions Polymer LR , JR , and KG series of polymers. Other suitable contain cationic nitrogen containing moieties such as qua types of cationic cellulose include the polymeric quaternary ternary ammonium or cationic protonated amino moieties . 10 ammonium salts of hydroxyethyl cellulose reacted with The cationic protonated amines can be primary , secondary, lauryl dimethyl ammonium - substituted epoxide referred to or tertiary amines (preferably secondary or tertiary ), depend in the industry (CTFA ) as Polyquaternium 24 . These mate ing upon the particular species and the selected pH of the rials are available from Amerchol Corp . under the tradename composition . Any anionic counterions can be used in asso Polymer LM - 200 . ciation with the cationic polymers so long as the polymers 15 Other suitable cationic polymers include cationic guar remain soluble in water , in the composition , or in a coacer gum and derivatives thereof, such as guar hydroxypropylt vate phase of the composition , and so long as the counte rimonium chloride, specific examples of which include the rions are physically and chemically compatible with the Jaguar series commercially available from Rhone- Poulenc essential components of the composition or do not otherwise Incorporated and the N -Hance series commercially available unduly impair product performance, stability or aesthetics . 20 from Aqualon Division of Hercules, Inc. Other suitable Non limiting examples of such counterions include halides cationic polymers include quaternary nitrogen - containing ( e . g . , chloride, fluoride , bromide , iodide ) , sulfate and meth cellulose ethers , some examples of which are described in ylsulfate . Non limiting examples of cationic polymers are U . S . Pat. No. 3 , 962, 418 . Other suitable cationic polymers described in the CTFA Cosmetic Ingredient Dictionary , 3rd include copolymers of etherified cellulose , guar and starch , edition , edited by Estrin , Crosley , and Haynes , ( The Cos - 25 some examples of which are described in U . S . Pat . No . metic , Toiletry , and Fragrance Association , Inc ., Washing - 3 , 958 , 581 . When used , the cationic polymers herein are ton , D . C . ( 1982 ) ) . either soluble in the composition or are soluble in a complex Non limiting examples of suitable cationic polymers coacervate phase in the composition formed by the cationic include copolymers of vinyl monomers having cationic polymer and the anionic , amphoteric and / or zwitterionic protonated amine or quaternary ammonium functionalities 30 detersive surfactant component described hereinbefore . with water soluble spacer monomers such as acrylamide , Complex coacervates of the cationic polymer can also be methacrylamide, alkyl and dialkyl acrylamides , alkyl and formed with other charged materials in the composition . dialkylmethacrylamides , alkyl acrylate , alkyl methacrylate , Polyalkylene glycols having a molecular weight of more vinyl caprolactone or vinyl pyrrolidone . than about 1000 are useful herein . Polyethylene glycol Suitable cationic protonated amino and quaternary ammo - 35 polymers useful herein are PEG - 2M ( also known as Polyox nium monomers , for inclusion in the cationic polymers of WSR® N - 10 , which is available from Union Carbide and as the composition herein , include vinyl compounds substi - PEG - 2 ,000 ); PEG -5M (also known as Polyox WSR? N - 35 tuted with dialkylaminoalkyl acrylate , dialkylaminoalkyl and Polyox WSR® N - 80 , available from Union Carbide and methacrylate , monoalkylaminoalkyl acrylate , monoalky - as PEG - 5 , 000 and Polyethylene Glycol 300 , 000 ) ; PEG - 7M laminoalkyl methacrylate , trialkyl methacryloxyalkyl 40 ( also known as Polyox WSR® N -750 available from Union ammonium salt, trialkyl acryloxyalkyl ammonium salt , dial Carbide ) ; PEG - 9M ( also known as Polyox WSR® N - 3333 lyl quaternary ammonium salts , and vinyl quaternary ammo available from Union Carbide ) ; and PEG - 14 M (also known nium monomers having cyclic cationic nitrogen -containing as Polyox WSR® N - 3000 available from Union Carbide ) . rings such as pyridinium , imidazolium , and quaternized The composition can also include dispersed particles. The pyrrolidone , e . g . , alkyl vinyl imidazolium , alkyl vinyl pyri - 45 can include at least 0 . 025 % by weight of the dispersed dinium , alkyl vinyl pyrrolidone salts . particles , more preferably at least 0 .05 % , still more prefer Other suitable cationic polymers for use in the composi - ably at least 0 . 1 % , even more preferably at least 0 . 25 % , and tions include copolymers of 1 - vinyl - 2 -pyrrolidone and 1 - vi - yetmore preferably at least 0 . 5 % by weight of the dispersed nyl- 3 -methylimidazolium salt ( e . g . , chloride salt ) ( referred particles. In some embodiments , it is preferable to incorpo to in the industry by the Cosmetic , Toiletry, and Fragrance 50 rate no more than about 20 % by weight of the dispersed Association , “ CTFA ” , as Polyquaternium - 16 ) ; copolymers particles , more preferably no more than about 10 % , still of 1 - vinyl- 2 - pyrrolidone and dimethylaminoethylmethacry - more preferably no more than 5 % , even more preferably no late ( referred to in the industry by CTFA as Polyquaternium more than 3 % , and yet more preferably no more than 2 % by 11) ; cationic diallyl quaternary ammonium containing poly - weight of the dispersed particles. mers , including , for example , dimethyldiallylammonium 55 Conditioning agents include any material which is used to chloride homopolymer , copolymers of acrylamide and dim - give a particular conditioning benefit to skin . The condi ethyldiallylammonium chloride ( referred to in the industry tioning agents useful in the compositions of the present by CTFA as Polyquaternium 6 and Polyquaternium 7 , invention typically comprise a water insoluble , water dis respectively ); amphoteric copolymers of acrylic acid includ - persible , non - volatile , liquid that forms emulsified , liquid ing copolymers of acrylic acid and dimethyldiallylammo- 60 particles or are solubilized by the surfactant micelles, in the nium chloride ( referred to in the industry by CTFA as anionic detersive surfactant component (described above ) . Polyquaternium 22 ), terpolymers of acrylic acid with dim - Suitable conditioning agents for use in the composition are ethyldiallylammonium chloride and acrylamide ( referred to those conditioning agents characterized generally as sili in the industry by CTFA as Polyquaternium 39 ) , and ter cones ( e . g . , silicone oils , cationic silicones, silicone gums, polymers of acrylic acid with methacrylamidopropyl trim - 65 high refractive silicones , and silicone resins ) , organic con ethylammonium chloride and methylacrylate (referred to in ditioning oils ( e . g . , hydrocarbon oils , polyolefins , and fatty the industry by CTFA as Polyquaternium 47) . esters) or combinations thereof, or those conditioning agents US 10 , 071 , 103 B2 123 124 which otherwise form liquid , dispersed particles in the ethylsiloxane , (polydimethylsiloxane ) (methylvinylsilox aqueous surfactant matrix herein . ane ) copolymer, polydimethylsiloxane ) (diphenyl siloxane ) The conditioning agent of the compositions can be an (methylvinylsiloxane ) copolymer and mixtures thereof . insoluble silicone conditioning agent . The silicone condi - Other non - volatile , insoluble silicone fluid conditioning tioning agent particles can comprise volatile silicone, non - 5 agents that are suitable for use in the compositions of the volatile silicone , or combinations thereof. Preferred are present invention are those known as “ high refractive index non -volatile silicone conditioning agents . If volatile sili - silicones, " having a refractive index of at least about 1 .46 , cones are present, they will typically be incidental to their preferably at least about 1 . 48 , more preferably at least about use as a solvent or carrier for commercially available forms 1 . 52 , more preferably at least about 1 . 55 . The refractive of non - volatile silicone material ingredients, such as silicone 10 index of the polysiloxane fluid will generally be less than gums and resins . The silicone conditioning agent particles about 1 . 70 , typically less than about 1 .60 . In this context, can comprise a silicone fluid conditioning agent and can also polysiloxane " fluid ” includes oils as well as gums. comprise other ingredients , such as a silicone resin to Silicone fluids suitable for use in the compositions of the improve silicone fluid deposition efficiency or enhance present invention are disclosed in U . S . Pat. No. 2 , 826 , 551 , glossiness of the hair . 15 U . S . Pat. No. 3 , 964 ,500 , U . S . Pat. No . 4 ,364 , 837 , British The concentration of the silicone conditioning agent typi- Pat. No . 849 ,433 , and Silicon Compounds, Petrarch Sys cally ranges from about 0 .01 % to about 10 % , by weight of tems, Inc . ( 1984 ). the composition , preferably from about 0 . 1 % to about 8 % , Silicone resins can be included in the silicone condition more preferably from about 0 . 1 % to about 5 % , more pref- ing agent of the compositions of the present invention . These erably from about 0 . 2 % to about 3 % . Non - limiting examples 20 resins are highly cross- linked polymeric siloxane systems. of suitable silicone conditioning agents , and optional sus - The cross - linking is introduced through the incorporation of pending agents for the silicone , are described in U . S . Reis - trifunctional and tetrafunctional silanes with monofunc sue Pat . No . 34, 584 , U . S . Pat . No . 5 , 104 , 646 , and U . S . Pat. tional or difunctional, or both , silanes during manufacture of No . 5 , 106 ,609 . The silicone conditioning agents for use in the silicone resin . the compositions of the present invention preferably have a 25 Silicone materials and silicone resins in particular, can viscosity , as measured at 25° C . , from about 20 to about conveniently be identified according to a shorthand nomen 2 ,000 ,000 centistokes ( “ csk ” ), more preferably from about clature system known to those of ordinary skill in the art as 1, 000 to about 1 , 800 ,000 csk , even more preferably from “MDTQ ” nomenclature . Under this system , the silicone is about 50 ,000 to about 1 , 500 ,000 csk , more preferably from described according to presence of various siloxane mono about 100 , 000 to about 1 , 500 ,000 csk . 30 mer units which make up the silicone. Briefly , the symbol M The dispersed silicone conditioning agent particles typi - denotes the monofunctional unit (CH2 ) 2SiOos ; D denotes cally have a volume average particle diameter ranging from the difunctional unit (CH3 ) 2SiO ; T denotes the trifunctional about 0 .01 um to about 50 um . For small particle application unit (CH3 ) SiOs; and Q denotes the quadra - or tetra - func to hair , the volume average particle diameters typically tional unit SiO2. Primes of the unit symbols (e . g . M ', D ', T, range from about 0 . 01 um to about 41 um , preferably from 35 and Q ') denote substituents other than methyl , and must be about 0 . 01 um to about 2 um , more preferably from about specifically defined for each occurrence . 0 .01 um to about 0 .51 um . For larger particle application to Preferred silicone resins for use in the compositions of the hair , the volume average particle diameters typically range present invention include , but are not limited to MQ , MT, from about 5 um to about 125 um , preferably from about 10 MTQ , MDT and MDTQ resins. Methyl is a preferred um to about 90 um , more preferably from about 15 um to 40 silicone substituent. Especially preferred silicone resins are about 70 um , more preferably from about 20 um to about 50 MQ resins, wherein the M : Q ratio is from about 0 . 5 : 1 . 0 to um . about 1 . 5 : 1 . 0 and the average molecular weight of the Background material on silicones including sections dis - silicone resin is from about 1000 to about 10 , 000 . cussing silicone fluids, gums, and resins, as well as manu - The conditioning component of the compositions of the facture of silicones, are found in Encyclopedia of Polymer 45 present invention can also comprise from about 0 .05 % to Science and Engineering , vol . 15 , 2d ed . , pp 204 - 308 , John about 3 % , by weight of the composition , preferably from Wiley & Sons , Inc. ( 1989 ) . about 0 . 08 % to about 1 . 5 % , more preferably from about Silicone fluids include silicone oils , which are flowable 0 . 1 % to about 1 % , of at least one organic conditioning oil as silicone materials having a viscosity , as measured at 25° C ., the conditioning agent, either alone or in combination with less than 1 , 000 , 000 csk , preferably from about 5 csk to about 50 other conditioning agents , such as the silicones ( described 1 , 000 ,000 csk , more preferably from about 100 csk to about above ) . 600 , 000 csk . Suitable silicone oils for use in the composi Suitable organic conditioning oils for use as conditioning tions of the present invention include polyalkyl siloxanes , agents in the compositions of the present invention include , polyaryl siloxanes, polyalkylaryl siloxanes , polyether silox - but are not limited to , hydrocarbon oils having at least about ane copolymers , and mixtures thereof. 55 10 carbon atoms, such as cyclic hydrocarbons , straight chain Other insoluble , non - volatile silicone fluids having hair aliphatic hydrocarbons ( saturated or unsaturated ) , and conditioning properties can also be used . branched chain aliphatic hydrocarbons (saturated or unsatu Other silicone fluids suitable for use in the compositions rated ) , including polymers and mixtures thereof. Straight are the insoluble silicone gums. These gums are polyor - chain hydrocarbon oils preferably are from about C to about ganosiloxane materials having a viscosity , as measured at 60 C19 . Branched chain hydrocarbon oils , including hydrocar 25° C . , of greater than or equal to 1 ,000 , 000 csk . Silicone bon polymers , typically will contain more than 19 carbon gums are described in U . S . Pat. No. 4 , 152 ,416 ; Noll and atoms. Walter, Chemistry and Technology of Silicones, New York : Specific non - limiting examples of these hydrocarbon oils Academic Press ( 1968 ) ; and in General Electric Silicone include paraffin oil , mineral oil, saturated and unsaturated Rubber Product Data Sheets SE 30 , SE 33 , SE 54 and SE 76 . 65 dodecane , saturated and unsaturated tridecane , saturated and Specific non -limiting examples of silicone gums for use in unsaturated tetradecane , saturated and unsaturated pentade the compositions of the present invention include polydim cane, saturated and unsaturated hexadecane , polybutene , US 10 ,071 , 103 B2 125 126 polydecene, and mixtures thereof. Branched chain isomers polyethylene glycol mono - and di - fatty acid esters , propyl of these compounds, as well as of higher chain length e ne glycol mono - and di- fatty acid esters , polypropylene hydrocarbons , can also be used , examples of which include glycol monooleate , polypropylene glycol 2000 monostear highly branched , saturated or unsaturated , alkanes such as ate , ethoxylated propylene glycol monostearate , glyceryl the permethyl- substituted isomers , e . g ., the permethyl- sub - 5 mono - and di - fatty acid esters , polyglycerol poly - fatty acid stituted isomers of hexadecane and eicosane , such as 2 , 2 , 4 , esters, ethoxylated glyceryl monostearate , 1 , 3 -butylene gly 4 , 6 ,6 , 8 , 8 - dimethyl - 10 -methylundecane and 2 ,2 , 4 , 4 , 6 , 6 - dim - col monostearate , 1 , 3 -butylene glycol distearate , polyoxy ethyl- 8 -methylnonane , available from Permethyl ethylene polyol fatty acid ester, sorbitan fatty acid esters , Corporation . Hydrocarbon polymers such as polybutene and and polyoxyethylene sorbitan fatty acid esters . polydecene are preferred . A preferred hydrocarbon polymer 10 Still other fatty esters suitable for use in the compositions is polybutene , such as the copolymer of isobutylene and of the present invention are glycerides, including , but not butene . A commercially available material of this type is limited to ,mono - , di- , and tri - glycerides, preferably di- and L - 14 polybutene from Amoco Chemical Corporation . tri - glycerides, more preferably triglycerides. For use in the Organic conditioning oils for use in the compositions of compositions described herein , the glycerides are preferably the present invention can also include liquid polyolefins, 15 the mono -, di- , and tri- esters of glycerol and long chain more preferably liquid poly - a - olefins, more preferably carboxylic acids, such as C10 to C22 carboxylic acids. A hydrogenated liquid poly - a -olefins . Polyolefins for use variety of these types of materials can be obtained from herein are prepared by polymerization of C4 to about C14 vegetable and animal fats and oils , such as castor oil, olefenic monomers, preferably from about C6 to about C12 . safflower oil , cottonseed oil , corn oil , olive oil , cod liver oil , Non - limiting examples of olefenic monomers for use in 20 almond oil, avocado oil , palm oil, sesame oil , lanolin oil and preparing the polyolefin liquids herein include ethylene , soybean oil . Synthetic oils include , but are not limited to , propylene, 1 - butene , 1 -pentene , 1 -hexene , 1 - octene, 1 - de - triolein and tristearin glyceryl dilaurate . cene, 1 -dodecene , 1 - tetradecene, branched chain isomers Other fatty esters suitable for use in the compositions of such as 4 -methyl - 1 - pentene, and mixtures thereof. Also the present invention are water insoluble synthetic fatty suitable for preparing the polyolefin liquids are olefin con - 25 esters . taining refinery feedstocks or effluents . Preferred hydroge Specific non - limiting examples of suitable synthetic fatty nated a - olefin monomers include , but are not limited to : esters for use in the compositions of the present invention 1 -hexene to 1 - hexadecenes, 1 - octene to 1 -tetradecene , and include : P - 43 (C8 -C10 triester of trimethylolpropane ) , mixtures thereof. MCP -684 ( tetraester of 3 , 3 - diethanol- 1 , 5 pentadiol) , MCP Other suitable organic conditioning oils for use as the 30 121 (C8 - C10 diester of adipic acid ), all of which are conditioning agent in the compositions of the present inven - available from Mobil Chemical Company . tion include , but are not limited to , fatty esters having at least Also suitable for use in the compositions herein are the 10 carbon atoms. These fatty esters include esters with conditioning agents described by the Procter & Gamble hydrocarbyl chains derived from fatty acids or alcohols ( e . g . Company in U . S . Pat. Nos. 5 ,674 ,478 , and 5 ,750 , 122. Also mono - esters , polyhydric alcohol esters , and di- and tri- 35 suitable for use herein are those conditioning agents carboxylic acid esters ). The hydrocarbyl radicals of the fatty described in U . S . Pat . No . 4 , 529, 586 (Clairol ) , U . S . Pat. No . esters hereof can include or have covalently bonded thereto 4 , 507 , 280 ( Clairol ) , U . S . Pat. No. 4 ,663 , 158 ( Clairol ) , U . S . other compatible functionalities , such as amides and alkoxy Pat. No . 4 , 197 , 865 ( L 'Oreal ) , U . S . Pat. No. 4 , 217 , 914 moieties ( e . g . , ethoxy or ether linkages, etc . ) . ( L ' Oreal) , U . S . Pat. No . 4 , 381 ,919 ( L ' Oreal) , and U . S . Pat . Specific examples of preferred fatty esters include, but are 40 No . 4 , 422, 853 ( L 'Oreal ) . not limited to : isopropyl isostearate , hexyl laurate , isohexyl The compositions can contain a humectant. The humec laurate , isohexyl palmitate , isopropyl palmitate , decyl tants can be selected from the group consisting of polyhydric oleate , isodecyl oleate , hexadecyl stearate , decyl stearate , alcohols , water soluble alkoxylated nonionic polymers , and dihexyldecyl adipate , lauryl lactate , myristyl lactate , cetyl mixtures thereof. The humectants , when used herein , are lactate , oleyl stearate, oleyl oleate , oleyl myristate , lauryl 45 preferably used at levels by weight of the composition of acetate , cetyl propionate , and oleyl adipate . from about 0 . 1 % to about 20 % ,more preferably from about Other fatty esters suitable for use in the compositions of 0 . 5 % to about 5 % . the present invention are mono -carboxylic acid esters of the Polyhydric alcohols useful herein include glycerin , sor general formula R 'COOR , wherein R ' and R are alkyl orb itol, propylene glycol, butylene glycol, hexylene glycol, alkenyl radicals , and the sum of carbon atoms in R ' and R is 50 ethoxylated glucose , 1 , 2 -hexane diol, hexanetriol, dipropyl at least 10 , preferably at least 22 . ene glycol, erythritol, trehalose , diglycerin , xylitol, maltitol , Still other fatty esters suitable for use in the compositions maltose , glucose, fructose , sodium chondroitin sulfate , of the present invention are di- and trialkyl and alkenyl sodium hyaluronate , sodium adenosine phosphate , sodium esters of carboxylic acids , such as esters of C4 to C8 lactate , pyrrolidone carbonate , glucosamine , cyclodextrin , dicarboxylic acids ( e . g . C1 to C22 esters , preferably C1 to 55 and mixtures thereof. C6 , of succinic acid , glutaric acid , and adipic acid ) . Specific Water soluble alkoxylated nonionic polymers useful non - limiting examples of di- and trialkyl and alkenyl esters herein include polyethylene glycols and polypropylene gly of carboxylic acids include isocetyl stearyol stearate , diiso - cols having a molecular weight of up to about 1000 such as propyl adipate , and tristearyl citrate . In some embodiments , those with CTFA names PEG - 200 , PEG - 400 , PEG - 600 , the composition comprises ester of at least one of lauric acid , 60 PEG - 1000 , and mixtures thereof. and succinic acid have additional anti - acne and / anti - inflam - The compositions of the present invention can further matory properties . comprise a suspending agent at concentrations effective for Other fatty esters suitable for use in the compositions of suspending water- insoluble material in dispersed form in the the present invention are those known as polyhydric alcohol compositions or for modifying the viscosity of the compo esters . Such polyhydric alcohol esters include alkylene gly - 65 sition . Such concentrations range from about 0 . 1 % to about col esters , such as ethylene glycol mono and di -fatty acid 10 % , preferably from about 0 . 3 % to about 5 . 0 % , by weight esters, diethylene glycol mono - and di- fatty acid esters, of the compositions. US 10 ,071 , 103 B2 127 128 Suitable suspending agents include crystalline suspending honey , hydrogenated starch hydrolysates, hydrolyzed corn agents that can be categorized as acyl derivatives , long chain starch , lactamide MEA , lactic acid , lactose lysine PCA , amine oxides , or combinations thereof. These suspending mannitol, methyl gluceth - 10 , methyl gluceth - 20 , PCA , PEG - 2 lactamide , PEG - 10 propylene glycol, polyamino agents are described in U .S . Pat. No . 4 ,741 ,855 . nino 5 acids, polysaccharides, polyamino sugar condensate , potas The compositions can contain also vitamins and amino 5 siumag PCA , propylene glycol, propylene glycol citrate, sac acids such as: water soluble vitamins such as vitamin B1, charide hydrolysate , saccharide isomerate , sodium aspartate , B2 , B6 , B12 , C , pantothenic acid , pantothenyl ethyl ether, sodium lactate , sodium PCA , sorbitol, TEA - lactate , TEA panthenol, biotin , and their derivatives, water soluble amino PCA , urea , xylitol, panthenol, petrolatum , mineral oil, lano acids such as asparagine , alanine, tryptophan , glutamic acid 10 lin , lanolin alcohol, tocopherol, esters of tocopherol, alkyl and their salts , water insoluble vitamins such as vitamin A , polydimethylsiloxanes , vegetable oils , hydrogenated veg D , E , and their derivatives, water insoluble amino acids such etable oils , fatty acid esters, beeswax , hydrolyzed keratin , as tyrosine, tryptamine, and their salts . hydroxyethyl urea , carboxylic acid amides , mucopolysac The formulations disclosed herein can also contain pig - charides, and quaternized nitrogen moisturizing agents . ment materials such as nitroso ,monoazo , diazo , carotenoid , 15 Examples of quaternary nitrogen moisturizing agents triphenyl methanes , triaryl methanes , xanthenes , quinolines , include, but are not limited to , hydroxypropyl bis - hydroxy oxazines , azines, anthraquinones, indigoids , thionindigoids, ethyldimonium chloride (available as COLATM Moist 200 quinacridones , phthalocyianines , botanicals , and natural col- from Colonial Chemicals , Inc . ), moisturizing agents ors including water soluble dye components . The composi- described in U . S . Pat. No . 6 , 869 , 977 ( content of which is tions of the present invention can also contain chelating 20 incorporated herein by reference ) , choline salts described in agents . U . S . Pat . Nos. 6 ,475 , 965 and 6 , 265 , 364 ( contents of both of In one embodiment, the formulation is a moisturizer which are incorporated herein by reference ) , carnitine , and cream / gel base . For example , the formulation comprises at combinations thereof. The moisturizing agent can be present least one moisturizing agent. Generally, the formulation can in the formulation in any desired amount to give a desired comprise from about 0 .01 % (by weight ) to about 50 % (by 25 level of moisturization . In some embodiments , the moistur weight ) of the moisturizing agents to impart a moisturizing izing agent can be preset in an amount of 0 to about 5 . In benefit upon use . It is noted that dryness is one of prime another embodiment, the quaternary nitrogen moisturizing concerns of art known anti - acne topical products . Exem agent is present in an amount of about 0 . 1 to about 1 % by plary moisturizing agents include, but are not limited to , weight . In another embodiment, the moisturizing agent is N - Acetyl ethanolamine , aloe vera gel , arginine PCA , chito - 30 present at about 1 % by weight. san PCA , copper PCA , Corn glycerides, dimethyl imidazo In some embodiments , the formulation comprises at least lidinone, fructose , glucamine, glucose , glucose glutamate , one of glycolic acid , lactic acid , sulfur , salicylic acid , and glucuronic acid , glutamic acid , glycereth - 7 , glycereth - 12 , resorcinol. glycereth - 20 , glycereth - 26 , glycerin , honey, hydrogenated Some exemplary formulations are described in Tables 2 - 5 . TABLE 2 Some exemplary cream formulations. Phase Ingredients A B C Method of preparation ??? 0 . 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 5 . 0 % — 2 ) All ingredients of Macrogol 5 . 0 % 5 . 0 % phase B were mixed and Cetostearyl Ether 2 stirred to get uniform Span 20 1 . 0 % — solution , then phase B Apifil 5 . 0 % was also heated to 70 - 80° C . Pemulen TR 1 0 . 5 % 0 . 5 % with continuous Macrogol 5 . 0 % 5 . 0 % stirring Cetostearyl Ether 20 3 ) Phase A was added Tween 20 5 . 0 % into phase B with Glycerol 5 . 0 % 10 . 0 % 5 . 0 % continuous stirring at Water q . s . to 100 q . s . to 100 q . s . to 100 70 -80° C . Preservative 0 . 1 % 0 . 1 % 0 . 1 % 4 ) Ingredients of phase OA 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

TABLE 3 Some exemplary emugel formulations. Phase Ingredients A B C Method of preparation ??? 0 . 1 % 1 % 10 % 1 ) All ingredients of Olive Oil 5 . 0 % phase A was mixed and Castor Oil 5 . 0 % heated at 70 - 80° C . Stearyl alcohol 2 . 0 % 2 . 0 % 2 ) All ingredients of US 10 ,071 , 103 B2 129 130 TABLE 3 -continued Some exemplary emugel formulations. Phase Ingredients ? ? C Method of preparation 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 . Tween 20 $8 . 0 % with continuous Steareth 20 2 . 0 % 2 . 0 % stirring Carbopol 1 . 0 % 1 . 0 % 3 ) Phase A was added Pemulen 0 .5 % into phase B with Propylene glycol 5 . 0 % 5 . 0 % 5 . 0 % continuous stirring at Water q . s . to 100 % q . s . to 100 % q . s . to 100 % 70 - 80° C . Preservative 0 . 1 % 0 . 1 % 0 . 1 % 4 ) Ingredients of phase OA 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 MethodMethod of preparationaration | ??? 0 .01 % 0 . 5 % 2 % 1 ) Ingredients of phase Ethanol 10 . 0 % 5 . 0 % 5 . 0 % A was mixed to 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 0 . 5 % 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 o Preservative 0 . 1 % 0 . 1 % 0 . 1 % into phase B with 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 ??? 0 .02 % 1 . 5 % 3 % 1 ) All ingredients of Liquid paraffin 5 . 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 Tween 20 2 . 0 % 5 . 0 % 10 . 0 % phase B was mixed and Pemulen 0 . 5 % — stirred to get uniform Ultrez 21 1 . 0 % — 2 . 0 % solution , then phase B Ethanol 5 . 0 % 5 . 0 % 5 . 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 0 . 1 % 0 . 1 % 0 . 1 % 3 ) Phase A was added Do 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 5 ) Finally phase D was added to get desired pH

Without wishing to be bound by a theory , the formulation formulation can kill at least 20 % more P. acnes as compared disclosed herein can provide at least 1 . 2x increase in area 65 to direct application of an antibiotic . under the curve in a concentration on the skin vs time plot The formulations disclosed herein provide formulation compared with formulations known in the art. Further , the technological advances (size optimization , surface modifi US 10 ,071 , 103 B2 131 132 cation , and formulation innovations ) to improve specificity agent) , emollients, moisturizers, conditioning agents , fra & efficacy by enhancing penetration & delivery to the target grances/ perfumes , potentiating agents, preservatives, opaci site ( sebaceous glands ) ; improving retention to exhibit sus - fiers , antioxidants , cooling agents, film forming agents , tained effect; or easy entry into biofilm enveloped bacteria . abrasives , exfoliating agents, colorants , pH modifiers, sol The disclosure further provides the use of the DARTs and 5 vents, vehicle , penetration enhancers , pearlizing agents , and formulations discloses herein for treating or preventing at any combinations thereof. least one bacterial infection condition in a subject. The 8 . The formulation of any of paragraphs 1 - 4 , wherein the method generally comprising administering a DART or surface of the drug carrier is substantially free of surface formulation disclosed herein to a subject in need thereof. In modifier. some embodiments , the method is for treating an acne 10 9 . The formulation of any of paragraphs 1 - 8 , comprising condition in a subject . from about 0 . 1 % to about 50 % ( w / w or w / v ) of the carrier The term “ acne ” includes inflammatory diseases of the or excipient. pilosebaceous follicles and /or skin glands, and commonly is 10 . The formulation of any of paragraphs 1 - 9 , wherein the characterized by papules, pustules, cysts , nodules , come formulation is formulated for topical, oral or parenteral dones , other blemishes or skin lesions. The term “ acne” as 15 administration . used herein includes all known types of acne . Some types of 11 . The formulation of any of paragraphs 1 - 10 , wherein the acne which can be treated with the composition of the formulation is an oral dosage, injectable , aerosol or inhal present invention are , for example , acne vulgaris , acne ant, lotion , cream , gel, emulgel, oil , serum , powder , spray, comedo , papular acne, premenstrual acne , preadolescent ointment, solution , suspension , dispersion , paste , foam , acne , acne venenata , acne cosmetica , pomade acne , acne 20 peel , films, mask , patch , stick , roller, impregnated fabric detergicans , acne excoriee , gram negative acne , pseudofol ( e . g . a " wipe” or tissue ) , or any combination thereof. liculitis barbae , folliculitis , perioral dermatitis , hiddradenitis 12 . The formulation of any of paragraphs 1 - 11 , further suppurativa , cystic acne , acne atrophica, bromide acne , comprising a second anti -acne agent. chlorine acne, acne conglobata , acne detergicans, epidemic 13 . The formulation of any of paragraphs 1 - 12 , wherein the acne , acne estivalis , acne fulminans , halogen acne , acne 25 second anti -acne agent is selected from the group con indurata , iodide acne , acne keloid , acne mechanica , acne sisting of 8 - chloro fluroquinolones , acetretin , adapalene papulosa , pomade acne , premenstral acne , acne pustulosa , ( s ) , alitretinoin , alpha - or beta -hydroxy acids, antibiotics , acne scorbutica , acne scrofulosorum , acne urticata , acne antimicrobial peptides , antimicrobials , azelaic acid , ben varioliformis , acne venenata , propionic acne , acne excoriee , zoyl peroxide , bexarotene , bile salts , biofilm inhibitors , gram negative acne, steroid acne , nodulocystic acne and 30 clindamycin , erythromycin , etretinate , glycolic acid , isot acne rosacea . retinoin , keratolytic agents , lactic acid , lipoic acid , N - ace Without wishing to be bound by a theory , micronization tylcystein , natural anti -acne agents , octopirox , phenoxy of besifloxacin can have an impact on its bioactivity . For ethanol, phenoxypropanol, pyruvic acid , resorcinol, example , microniztion can enhance besifloxacin ' s bioactiv retinoic acid , retinoid ( s ) , salicylic acid , sebostats , sodium ity or its retention at a desired site . Further , micronization 35 sulfacetamide , spironolactone , sulfur, sulfur containing can also effect besifloxacin ' s stability and amounts in a D - or L - amino acids, tazarotene , tea tree oil, tretinoin , formulation . Moreover, micronization can also allow opti - triclosan , urea , and any combinations thereof. mizing properties of formulations comprising micronized 14 . The formulation of any of paragraphs 1 - 13 , wherein the besifloxacin . formulation comprises an 8 -chloro fluoroquinolone alone Embodiments of the various aspects disclosed herein can 40 or in combination with another anti -acne agent. also be described by one or more of the numbered para - 15 . The formulation of any of paragraphs 1 - 14 , wherein the graphs: formulation comprises besifloxacin and adapalene . 1 . A formulation comprising an anti -acne agent and at least 16 . The formulation of any of paragraphs 1 - 14 , wherein the one carrier or excipient, wherein the anti -acne agent is in formulation comprises 8 - chlorofluoroquinolone and an the form of a drug carrier comprising the anti - acne agent 45 anti - inflammatory agent . and at least one additional compound , said additional 17 . The formulation of any of paragraphs 1 - 14 , wherein the compound selected from the group consisting of lipids, formulation comprises 8 - chlorofluoroquinolone and ret oils , polymers , peptides, proteins, carbohydrates , glyco - inoic acid or retinoid . lipids, phospholipids , lipoproteins, cationic molecules, 18 . The formulation of any of paragraphs 1 - 17 , wherein the and any combinations thereof. second anti - acne agent is in the form of a drug carrier 2 . The formulation of claim 1 , wherein the drug carrier is comprising the second anti - acne agent and at least one coated or uncoated . additional compound , said additional compound selected 3 . The formulation of paragraph 1 or 2 , wherein the drug from the group consisting of lipids, oils , polymers , pep carrier has a size of about 5 nm to about 20 um . tides, proteins, carbohydrates, glycolipids, phospholipids , 4 . The formulation of paragraph 1 or 3, wherein the drug 55 lipoproteins , cationic molecules , and any combinations carrier has a size of about 5 nm to about 5 um . thereof. 5 . The formulation of any of paragraphs further comprising 19. The formulation of any of paragraphs 1 - 18 , wherein the a surface modifier on the surface of the drug carrier . second anti -acne agent drug carrier has a size of about 5 6 . The formulation of any of paragraphs 1 -5 , wherein the nm to about 50 um . surface modifier is selected from the group consisting of 60 20 . The formulation of any of paragraphs 1 - 19 , wherein the lipids , oils , polymers , peptides, proteins, carbohydrates , second anti -acne agent drug carrier has a size of about 100 glycolipids, phospholipids, lipoproteins, cationic mol nm to about 25 um ecules , and any combinations thereof. 21 . The formulation of any of paragraphs 1 - 20 , wherein the 7 . The formulation of any of paragraphs 1 - 6 , wherein the second anti - acne agent drug carrier comprises a surface carrier or excipient is selected from the group consisting of 65 modifier on the surface thereof. emulsifiers , preservatives, surfactants , oils , lipids , waxes , 22 . The formulation of any of paragraphs 1 - 21 , wherein the stabilizers , rheology modifiers or thickening agents (gelling surface modifier of the second anti -acne agent drug carrier US 10 ,071 , 103 B2 133 134 is selected from the group consisting of lipids , oils , of emulsifiers , preservatives , surfactants , oils , lipids , polymers , peptides, proteins, carbohydrates , glycolipids, waxes , stabilizers , rheology modifiers or thickening phospholipids, lipoproteins , cationic molecules , and any agents ( gelling agent) , emollients , moisturizers , condi combinations thereof. tioning agents , fragrances/ perfumes , potentiating agents , 23 . The formulation of any of paragraphs 1 - 20 , wherein the 5 preservatives , opacifiers, antioxidants , cooling agents , surface of the second anti - acne agent drug carrier is film forming agents , abrasives, exfoliating agents , colo substantially free of surface modifier . 24 . The formulation of any of paragraphs 1 -23 , further rants , pH modifiers , solvents , vehicle , penetration enhanc comprising an additional active agent. ers , pearlizing agents , and any combinations thereof 25 . The formulation of any of paragraphs 1 - 24 , wherein the 10 40 . The formulation of any of paragraphs 33 - 39 , comprising additional active agent is an anti - inflammatory - agent , from about 5 % to about 99 % ( w / w or w / v ) of the carrier penetration enhancer , antioxidant, anti - aging agent, anti or excipient. wrinkle agent, skin whitening or bleaching agent, ultra 41. The formulation of any of paragraphs 33 - 40 , wherein the violet (UV ) light absorbing or scattering agent, skin formulation is formulated for topical , oral or parenteral depigmentation agent, skin regenerative agent, scar heal- 15 administration . ing agent, or any combination thereof 42. The formulation of any of paragraphs 33 -41 , wherein the 26 . The formulation of any of paragraphs 1 -25 , wherein the formulation is an oral dosage , injectable , aerosol or inhal additional active agent is in the form of a drug carrier ant, lotion , cream , gel , emulgel, oil, serum , powder , spray , comprising a compound selected from the group consist ointment, solution , suspension , dispersion , paste , foam , ing of lipids, oils , polymers , peptides, proteins, carbohy - 20 peel, films, mask , patch , stick , roller, impregnated fabric drates , glycolipids, phospholipids, lipoproteins, cationic (e .g . a “ wipe ” or tissue ), or any combination thereof molecules, and any combinations thereof. 43 . The formulation of any of paragraphs 33 -42 further 27 . The formulation of any of paragraphs 1 -26 , wherein the comprising a second antibacterial agent. additional active agent drug carrier has a size of about 5 44 . The formulation of any of paragraphs 33 - 43 , wherein the nm to about 100 um . 25 second antibacterial agent is in the form of a drug carrier. 28 . The formulation of any of paragraphs 1 -27 , wherein the 45 . The formulation of any of paragraphs 33 - 44 , wherein the additional active agent drug carrier has a size of about 100 second antibacterial agent drug carrier further comprises nm to about 25 um . a compound selected from the group consisting of lipids, 29 . The formulation of any of paragraphs 1 - 28 , where in the oils, polymers, peptides, proteins, carbohydrates, glyco additional active agent drug carrier comprises a surface 30 modifier on the surface thereof. lipids, phospho lipids, lipoproteins, cationic molecules , 30 . The formulation of any of paragraphs 1 - 29 , wherein the and any combinations thereof surface modifier of the additional active agent drug carrier 46 . The formulation of any of paragraphs 33 - 45 , wherein the is selected from the group consisting of lipids, oils , second antibacterial agent drug carrier has a size of about polymers , peptides , proteins , carbohydrates, glycolipids , 35 5 nm to about 100 phospholipids, lipoproteins, cationic molecules, and any 47 . The formulation of any of paragraphs 33 -46 , wherein the combinations thereof. second antibacterial agent drug carrier has a size of about 31 . The formulation of any of paragraphs 1 - 30 , wherein the 100 nm to about 25 um . surface of the additional active agent drug carrier is 48 . The formulation of any of paragraphs 33 - 47 , wherein the substantially free of surface modifier . 40 second antibacterial agent drug carrier comprises a sur 32 . The formulation of any of paragraphs 1 - 31 , wherein the face modifier on the surface thereof formulation further comprises a zinc compound . 49 . The formulation of any of paragraphs 33 - 48 , wherein the 33 . A formulation comprising an antibacterial agent and at surface modifier of the second antibacterial agent drug least one carrier or excipient, wherein the antibacterial carrier is selected from the group consisting of lipids , oils , agent is in the form of a drug carrier comprising the 45 polymers , peptides , proteins , carbohydrates, glycolipids , antibacterial agent and at least one additional compound , phospholipids, lipoproteins, cationic molecules, and any said additional compound selected from the group con - combinations thereof . sisting of lipids, oils , polymers, peptides, proteins , car- 50 . The formulation of any ofparagraphs 33 -47 , wherein the bohydrates , glycolipids, phospholipids, lipoproteins , cat- surface of the second antibacterial agent drug carrier is ionic molecules , and any combinations thereof . 50 substantially free of surface modifier. 34 . The formulation of paragraph 33 , wherein the drug 51 . The formulation of any of paragraphs 33 -50 further carrier has a size of about 5 nm to about 100 um . comprising an additional active agent. 35 . The formulation of paragraph 33 or 34 , wherein the drug 52. The formulation of any of paragraphs 33 -51 , wherein the carrier has a size of about 100 nm to about 25 gam . additional active agent is an anti - inflammatory -agent , 36 . The formulation of any of paragraphs 33 -35 further 55 penetration enhancer , permeation enhancer , anti -oxidant , comprising a surface modifier on the surface of the drug anti - aging agent , anti- wrinkle agent, skin whitening or carrier. bleaching agent, ultraviolet (UV ) light absorbing or scat 37 . The formulation of any of paragraphs 33 - 36 , wherein the tering agent, skin depigmentation agent, skin regenerative surface modifier is selected from the group consisting of agent, scar healing agent, or any combination thereof lipids, oils , polymers, peptides, proteins, carbohydrates, 60 53 . The formulation of any of paragraphs 33 -52 , wherein the glycolipids , phospholipids, lipoproteins, cationic mol- additional active agent is in the form of a drug carrier . ecules , and any combinations thereof. 54 . The formulation of any of paragraphs 33 - 53 , wherein the 38 . The formulation of any of paragraphs 33 -37 , wherein the additional active agent drug carrier further comprises a surface of the drug carrier is substantially free of surface compound selected from the group consisting of lipids , modifier 65 oils , polymers , peptides , proteins , carbohydrates , glyco 39. The formulation of any of paragraphs 33 - 38 , wherein the lipids, phospholipids , lipoproteins, cationic molecules , carrier or excipient is selected from the group consisting and any combinations thereof. US 10 ,071 , 103 B2 135 136 55 . The formulation of any of paragraphs 33 -54 , wherein the 77 . The molecule of any of paragraphs 73 -75 , wherein the additional active agent drug carrier has a size of about 5 first mechanism is an antibacterial action and the second nm to about 100 um . mechanism of action is anti - inflammatory . 56 . The formulation of any of paragraphs 33 -55 , wherein the 78 . A Dual Action Rational Therapeutic (DART ) molecule additional active agent drug carrier has a size of about 1005 which includes two chemical domains, each said chemical nm to about 25 domain binding to a distinct active site in target cells , 57 . The formulation of any of paragraphs 33 - 56 , wherein the wherein said chemical domains are bound together additional active agent drug carrier comprises a surface through a third domain . modifier on the surface thereof. 79 . The molecule of paragraph 77 , wherein the third domain 58 . The formulation of any of paragraphs 33 -57 , wherein the " is a linker. surface modifier of the additional active agent drug carrier 80 . The molecule of paragraph 77 or 78 , wherein the third is selected from the group consisting of lipids , oils , domain is a cleavable linker . polymers , peptides , proteins, carbohydrates , glycolipids , 81. The molecule of paragraph 77 or 78 , wherein the third phospholipids, lipoproteins , cationic molecules , and any is domain is a non -cleavable linker. combinations thereof. 82 . The molecule of paragraphs 77 -80 , wherein said third 59 . The formulation of any of paragraphs 33 - 56 , wherein domain is 11- hydroxyundecenic acid ; 1 , 10 -decanediol ; surface of the additional active agent drug carrier is 1, 3 -propanediol ; 1, 5 -pentanedil ; 10 -hydroxydecenic acid ; substantially free of surface modifier . succinic ; lactic acid ; 3- hydroxypropionic acid ; or any 60 . The formulation of any of paragraphs 33 -59 , wherein the 20 combination thereof. formulation further comprises a zinc compound . 83 . The molecule of any of paragraphs 77 - 81, wherein the 61. The formulation of any of paragraphs 33 -60 , wherein the third domain increases an activity of at least one of the formulation comprises a moisturizing agent . two chemical domains . 62 . A Dual Action Rational Therapeutic (DART ) molecule 84 . The molecule of any of paragraphs 77 - 82 , wherein the that has two distinct anti - bacterial mechanisms of action . 25 third domain has antibacterial or anti- inflammatory activ 63 . A DART molecule that has a B - lactam ring and a ity . quinolone nucleus , or a quinolone nucleus and a nitro - 85 . The molecule of any of paragraphs 62 -83 , wherein the heterocycle , or a B - lactam ring and a nitroheterocycle . molecule is in the form of a drug carrier . 64 . The molecule of paragraph 62 , wherein the molecule 86 . The molecule of any of paragraphs 62 - 84 , wherein the inhibits DNA gyrase or topoisomerase IV and transpep - 30 drug carrier has a size of about 5 um to about 100 um tidase -mediated cross- linking of peptidoglycans. 87 . The molecule of any of paragraphs 62 - 85 , wherein the 65 . The molecule of paragraph 62 or 63 , wherein the drug carrier has a size of about 100 nm to about 25 um . molecule inhibits isoprenyl pyrophosphate and transpep - 88 . The molecule of any of paragraphs 62 - 86 , wherein the tidase -mediated cross -linking of peptidoglycans. drug carrier further comprises a compound selected from 66 . The molecule of any of paragraphs 62 -64 , wherein the 35 the group consisting of lipids, oils , polymers , peptides, molecule inhibits isoprenyl pyrophosphate and DNA proteins, carbohydrates, glycolipids, phospholipids, lipo gyrase of topoisomerase IV . proteins, cationic molecules , and any combinations 67 . The molecule of any of paragraphs 62 -65 , wherein the thereof. molecule inhibits folate synthesis and DNA gyrase of 89. The molecule of any of paragraphs 62 - 87 , wherein the topoisomerase IV . 40 drug carrier further comprises an additional active agent. 68 . The molecule of any of paragraphs 62 -66 , wherein the 90 . The molecule of paragraph 88 , wherein the additional molecule inhibits folate synthesis and transpeptidase - active agent is an anti- inflammatory - agent , keratolytic mediated cross - linking of peptidoglycans . agent, penetration enhancer, anti -oxidant , anti -aging 69 . The molecule of any of paragraphs 62 -67 that inhibits agent, anti- wrinkle agent, skin whitening or bleaching DNA gyrase or topoisomerase IV and the 30S sub - unit in 45 agent, ultraviolet (UV ) light absorbing or scattering agent, bacteria . skin depigmentation agent, skin regenerative agent, scar 70 . The molecule of any of paragraphs 62 -68 , wherein the healing agent, or any combination thereof. molecule inhibits DNA gyrase or topoisomerase IV and 91. The molecule of any of paragraphs 62 - 89 , wherein the 50S sub - unit in bacteria . surface of the drug carrier is substantially free of surface 71. The molecule of any of paragraphs 62 -69 , wherein the 50 modifier. molecule inhibits transpeptidase -mediated cross - linking 92 . The molecule of any of paragraphs 62 - 90 , wherein the of peptidoglycans and the 30S or the 50S sub -unit in drug carrier further comprises an additional anti- acne bacteria . agent. 72 . The molecule of any of paragraphs 62 -70 , wherein the 93 . The molecule of any of paragraphs 62- 91, wherein the molecule inhibits folate synthesis and the 30S or the 50S 55 second anti -acne agent is selected from the group con sub - unit in bacteria . sisting of acetretin , adapalene ( s ), alitretinoin , alpha - or 73 . The molecule of any of paragraphs 62 -71 , wherein the beta -hydroxy acids, antibiotics, antimicrobial peptides , molecule inhibits isoprenyl pyrophosphate and the 30S or antimicrobials , azelaic acid , benzoyl peroxide , bexaro the 50S sub - unit in bacteria . tene , bile salts , biofilm inhibitors , clindamycin , erythro 74 . A Dual Action Rational Therapeutic (DART ) molecule 60 mycin , etretinate , glycolic acid , isotretinoin , keratolytic that has two distinct anti - acne mechanisms of action . agents , lactic acid , lipoic acid , N - acetylcystein , natural 75 . The molecule of paragraph 73 , wherein the molecule anti -acne agents , octopirox , phenoxyethanol, phenoxy modulates at least two different targets . propanol, pyruvic acid , resorcinol, retinoic acid , 76 . The molecule of paragraph 73 or 74 wherein the first retinoid ( s ) , salicylic acid , sebostats , sodium sulfacet mechanism is an antibacterial action and the second 65 amide , spironolactone , sulfur, sulfur containing D - or mechanism of action is inhibition of keratinocyte prolif L - amino acids, tazarotene , tea tree oil , tretinoin , triclosan , eration and differentiation . urea , and any combinations thereof US 10 ,071 , 103 B2 137 138 94 . The molecule of any of paragraphs 62 - 92 , wherein the 107 . The formulation of any of paragraphs 95 - 105 , wherein drug carrier further comprises a surface modifier on the the second anti -acne agent drug carrier comprises a sur surface thereof . face modifier on the surface thereof 95 . The molecule of any of paragraphs 62 -93 , wherein the 108 . The formulation of any of claims 95 - 106 , wherein the surface modifier is a compound selected from the group 5 surface modifier of the second anti -acne agent drug carrier consisting of lipids, oils , polymers , peptides , proteins , is selected from the group consisting of lipids , oils , carbohydrates, glycolipids , phospholipids, lipoproteins, polymers , peptides , proteins, carbohydrates, glycolipids, cationic molecules , and any combination thereof. phospholipids, lipoproteins, cationic molecules , and any 96 . A formulation comprising a dual action rational thera combinations thereof. peutic molecule of any of paragraphs 62 - 94 and at least 109 . The formulation of any of paragraphs 95 - 105 , wherein one carrier or excipient. surface of the second anti- acne agent is substantially free 97 . The formulation of paragraph 95 , wherein the carrier or of surface modifier . excipient is selected from the group consisting of emul- 110 . The formulation of any of paragraphs 95 - 108 further sifiers , preservatives, surfactants , oils , lipids, waxes, sta - 16 comprising an additional active agent. bilizers, rheology modifiers or thickening agents ( gelling 1 11. The formulation of any of paragraphs 95 - 109 , wherein agent ), emollients , moisturizers , conditioning agents , fra the additional active agent is an anti - inflammatory -agent , grances / perfumes , potentiating agents , preservatives , penetration enhancer, antioxidant , anti -aging agent, anti opacifiers , antioxidants , cooling agents , film forming wrinkle agent, skin whitening or bleaching agent, ultra agents , abrasives, exfoliating agents , colorants , pH modi- 20 violet (UV ) light absorbing or scattering agent, skin fiers , solvents , vehicle, penetration enhancers, permeation depigmentation agent, skin regenerative agent, scar heal enhancers , pearlizing agents , and any combinations ing agent, or any combination thereof thereof. 112 . The formulation of any of paragraphs 95 - 110 , wherein 98 . The formulation of paragraph 95 or 96 comprising from the additional active agent is in the form of a drug carrier. about 5 % to about 99 % ( w / w or w / v ) of the carrier or 25 113 . The formulation of any of paragraphs 95 - 111 , wherein excipient. the additional active agent drug carrier further comprises a compound selected from the group consisting of lipids , 99 . The formulation of any of paragraphs 95 - 97 , wherein the oils, polymers , peptides, proteins , carbohydrates , glyco formulation is formulated for topical, oral or parenteral lipids , phospholipids, lipoproteins , cationic molecules , administration . wherein 30 and any combinations thereof 100 . The formulation of any of paragraphs 95 - 98 , wherein 30 114 . The formulation of any of paragraphs 95 - 112 , wherein the formulation is an oral dosage , injectable , aerosol or the additional active agent drug carrier has a size of about inhalant, lotion , cream , gel , emulgel, oil , serum , powder, 5 nm to about 100 um . spray, ointment, solution , suspension , dispersion , paste , 11115 . The formulation of any of paragraphs 95 - 113 , wherein foam , peel, films, mask , patch , stick , roller, impregnated 35 the additional active agent drug carrier has a size of about fabric ( e . g . a " wipe” or tissue ) , or any combination 100 nm to about 25 um thereof. 116 . The formulation of any of paragraphs 95 - 114 , wherein 101. The formulation of any of paragraphs 95 - 99 further the additional active agent drug carrier comprises a sur comprising a second anti -acne agent. face modifier on the surface thereof 102 . The formulation of any of paragraphs 95 - 100 , wherein 40 117 . The formulation of any of paragraphs 95 - 115 , wherein the second anti - acne agent is selected from the group the surface modifier of the additional active agent drug consisting of acetretin , adapalene( s ), alitretinoin , alpha carrier is selected from the group consisting of lipids, oils , or beta -hydroxy acids, antibiotics, antimicrobial peptides , polymers , peptides , proteins , carbohydrates, glycolipids , antimicrobials , azelaic acid , benzoyl peroxide , bexaro phospholipids, lipoproteins , cationic molecules , and any tene , bile salts , biofilm inhibitors, clindamycin , erythro - 45 combinations thereof. mycin , etretinate , glycolic acid , isotretinoin , keratolytic 118 . The formulation of any of paragraphs 95 - 114 , wherein agents, lactic acid , lipoic acid , N -acetylcystein , natural surface of the additional active agent drug carrier is anti -acne agents , octopirox , phenoxyethanol, phenoxy - substantially free of surface modifier . propanol, pyruvic acid , resorcinol, retinoic acid , 119 . The formulation of any of paragraphs 95 - 117 , wherein retinoid ( s ), salicylic acid , sebostats , sodium sulfacet - 50 the formulation further comprises a zinc compound. amide , spironolactone , sulfur, sulfur containing D - or 120 . A method of treating acne condition in a subject L - amino acids , tazarotene , tea tree oil , tretinoin , triclosan , comprising administering a therapeutically effective urea , and any combinations thereof amount of a formulation of any of paragraphs 1 -61 and 103 . The formulation of any of paragraphs 95 - 101 , wherein 95 - 118 . the second anti - acne agent is in the form of a drug carrier. 55 121. Themethod of any of paragraph 119 , wherein the acne 104 . The formulation of any of paragraphs 95 - 102, wherein condition is caused by antibiotic susceptible bacterial the second anti -acne agent drug carrier further comprises strain . a compound selected from the group consisting of lipids, 122 . The method of paragraph 119 or 120 , wherein the acne oils , polymers , peptides, proteins, carbohydrates, glyco condition is caused by antibiotic resistant bacteria . lipids , phospholipids , lipoproteins , cationic molecules, 60 123 . The method of any of paragraphs 119 - 121, wherein the and any combinations thereof acne condition is caused by clindamycin - , tetracycline - , 105 . The formulation of any of paragraphs 95 - 103 , wherein doxycycline- , or erythromycin - resistant Propionbacte the second anti -acne agent drug carrier has a size of about rium acnes. 5 nm to about 100 um . 124 . The method of any of paragraphs 119 - 122 , wherein the 106 . The formulation of any of paragraphs 94 - 103, wherein 65 acne condition is caused by clindamycin - , tetracycline - , the second anti -acne agent drug carrier has a size of about doxycycline -, or erythromycin -tolerant Propionbacterium 100 nm to about 25 um . acnes . US 10 ,071 , 103 B2 139 140 125 . A method of treating a bacterial infection in a subject required by context , singular terms shall include pluralities comprising administering a therapeutically effective and plural terms shall include the singular . amount of a formulation of any of paragraphs 1 -61 and Unless defined otherwise , all technical and scientific 95 - 118 . terms used herein have the same meaning as those com 126 . The method of paragraph 124 , wherein the infection is 5 monly understood to one of ordinary skill in the art to which caused by a pathogen selected from the group consisting this invention pertains. Although any known methods , of Bartonella henselae , Borrelia burgdorferi, Campy devices , and materials can be used in the practice or testing lobacter jejuni, Campylobacterfetus, Chlamydia tracho - of the invention , the methods, devices, and materials in this matis , Chlamydia pneumoniae , Chylamydia psittaci, Sim - regard are described herein . kania negevensis , Escherichia coli ( e . g ., 0157 :H7 and 10 As used herein , the term “herein ” is means the whole of K88 ), Ehrlichia chafeensis , Clostridium botulinum , the disclosure and as such is not meant to be limited to a Clostridium perfringens, Clostridium tetani, Enterococ - particular section or subsection of the disclosure . cus faecalis , Haemophilius influenzae , Haemophilius As used herein the term " comprising ” or “ comprises” is ducreyi, Coccidioides immitis , Bordetella pertussis, Cox - used in reference to compositions, methods, and respective iella burnetii , Ureaplasma urealyticum , Mycoplasma 15 component( s ) thereof, that are essential to the invention , yet genitalium , Trichomatis vaginalis , Helicobacter pylori, open to the inclusion of unspecified elements , whether Helicobacter hepaticus, Legionella pneumophila , Myco essential or not. bacterium tuberculosis , Mycobacterium bovis , Mycobac - The singular terms “ a , " " an , ” and “ the ” include plural terium africanum , Mycobacterium leprae , Mycobacte - referents unless context clearly indicates otherwise . Simi rium asiaticum , Mycobacterium avium , Mycobacterium 20 larly , the word “ or” is intended to include “ and ” unless the celatum , Mycobacterium celonae , Mycobacterium fortui context clearly indicates otherwise . tum , Mycobacterium genavense, Mycobacterium haemo Other than in the operating examples , or where otherwise philum , Mycobacterium intracellulare , Mycobacterium indicated , all numbers expressing quantities of ingredients kansasii , Mycobacterium malmoense , Mycobacterium or reaction conditions used herein should be understood as marinum , Mycobacterium scrofulaceum , Mycobacterium 25 modified in all instances by the term “ about. ” The term simiae , Mycobacterium szulgai, Mycobacterium ulcerans, “ about ” when used in connection with percentages can Mycobacterium xenopi, Corynebacterium diptheriae , mean - 5 % , + 4 % , + 3 % , 2 . 5 % , + 2 % , + 1. 5 % , + 1 % , or + 0 . 5 % Rhodococcus equiw , RickettsiaRickettsia geschlimanniiaeschlimannii ., Rickettsia of the value being referred to . africae , Rickettsia conorii, Arcanobacterium haemolyti - Although methods and materials similar or equivalent to cum , Bacillus anthracis , Bacillus cereus, Lysteria mono - 30 those described herein can be used in the practice or testing cytogenes, Yersinia pestis , Yersinia enterocolitica , Shi- of this disclosure , suitable methods and materials are gella dysenteriae , Neisseria meningitides, Neisseria described below . The term " comprises” means “ includes ." gonorrhoeae , Streptococcus bovis , Streptococcus hemo - The abbreviation , " e . g .” is derived from the Latin exempli lyticus, Streptococcus mutans , Streptococcus pyogenes, gratia , and is used herein to indicate a non - limiting example . Streptococcus pneumoniae , Staphylococcus aureus, 35 Thus , the abbreviation “ e . g . " is synonymous with the term Staphylococcus epidermidis , Staphylococcus pneumo - “ for example . ” niae , Staphylococcus saprophyticus, Vibrio cholerae , The terms “ decrease ” , “ reduced ” , “ reduction ” , “ decrease " Vibrio parahaemolyticus, Salmonella typhi, Salmonella or " inhibit ” are all used herein generally to mean a decrease paratyphi, Salmonella enteritidis , Treponema pallidum , by a statistically significant amount. However , for avoidance Candida , Cryptcooccus, Cryptosporidium , Giardia lam - 40 of doubt, “ reduced ” , “ reduction ” or “ decrease” or “ inhibit” blia , Microsporidia , Plasmodium vivax , Pneumocystis means a decrease by at least 10 % as compared to a reference carinii, Toxoplasma gondii, Trichophyton mentagro - level , for example a decrease by at least about 20 % , or at phytes, Enterocytozoon bieneusi, Cyclospora cayetanen - least about 30 % , or at least about 40 % , or at least about 50 % , sis , Encephalitozoon hellem , Encephalitozoon cuniculi , or at least about 60 % , or at least about 70 % , or at least about among other bacteria , archaea , protozoa , and fungi. 45 80 % , or at least about 90 % or up to and including a 100 % 127 . The method of paragraph 124 or 125 , wherein the decrease ( e . g . absent level as compared to a reference infection is by an antibiotic resistant bacterial strain . sample ) , or any decrease between 10 - 100 % as compared to 128 . The method of any of paragraphs 124 or 125 , wherein a reference level. the infection is by an antibiotic susceptible bacterial The terms “ increased ” , “ increase” or “ enhance ” or “ acti strain . 50 vate ” are all used herein to generally mean an increase by a 129 . The method of any of paragraphs 124 - 127 , wherein the statically significant amount; for the avoidance of any doubt, formulation is administered once or daily to said subject the terms“ increased ” , “ increase” or “ enhance ” or “ activate ” as a single dose or a plurality of doses . means an increase of at least 10 % as compared to a reference level , for example an increase of at least about 20 % , or at Some Selected Definitions 55 least about 30 % , or at least about 40 % , or at least about 50 % , or at least about 60 % , or at least about 70 % , or at least about For convenience , certain terms employed herein , in the 80 % , or at least about 90 % or up to and including a 100 % specification , examples and appended claims are collected increase or any increase between 10 - 100 % as compared to herein . Unless stated otherwise , or implicit from context, the a reference level, or at least about a 2 - fold , or at least about following terms and phrases include the meanings provided 60 a 3 - fold , or at least about a 4 - fold , or at least about a 5 - fold below . Unless explicitly stated otherwise , or apparent from or at least about a 10 - fold increase , or any increase between context, the terms and phrases below do not exclude the 2 - fold and 10 - fold or greater as compared to a reference meaning that the term or phrase has acquired in the art to level . which it pertains. The definitions are provided to aid in The term " statistically significant” or “ significantly ” describing particular embodiments , and are not intended to 65 refers to statistical significance and generally means at least limit the claimed invention , because the scope of the inven - two standard deviation ( 2SD ) away from a reference level. tion is limited only by the claims. Further , unless otherwise The term refers to statistical evidence that there is a differ US 10 , 071 , 103 B2 141 142 ence . It is defined as the probability of making a decision to EXAMPLES reject the null hypothesis when the null hypothesis is actu ally true . Example 1 The term " globule ” as used herein refers to spherical or quasi- spherical globes , balls or other shaped particles of a 5 substance such as form in biphasic suspensions or emul Screening of antibiotics against P . acnes strains shows sions . Also included in the meaning of the term " globule ” that the response is unpredictable in both clindamycin are finely divided particles of a solid material. sensitive and non -responder strains The disclosure is further illustrated by the following Examples 2 - 15 and Tables 6 - 15 describe some exemplary examples which should not be construed as limiting . The 10 DART molecules , their synthesis , formulations and uses . examples are illustrative only , and are not intended to limit , in any manner , any of the aspects described herein . The Example 2 : Synthesis of DART Molecule 9 ( from following examples do not in any way limit the invention . Table 1A )

? ?

1 , 5 Pentane diol O NH2 . DCC , HOBt, DMAP , DCM RT, 16 h ortayano 0

HO F

? ? IN

NH2 DCC, HOBT , DMAP , DCM or yourRT, 16 h OH 2 .

? ? on S NH2 that US 10 , 071, 103 B2 143 144 Step 1 . Synthesis of 2 : To a solution of 1 ( 1 g , 2 .33 mmol) suspension . The reaction mixture was stirred for 3 hr at RT in mixture of dichloromethane ( 10 ml) and dimethylforma and compound 2 ( 0 . 79 g , 1 . 55 mmol) was added to this mide (1 ml) was added N , N -dicyclohexylcarbodiimide ( 0 .627 g, 3 .041 mmol) followed by N -Hydroxybenzatriazole turbid solution followed by addition of 4 -dimethylamin ( 0 .316 g , 2 . 33 mmol) slowly at ice cold condition and stirredred 5 opyridineopy ( 0. 189 g 1. 55 mmol ). The final solution was at RT for 2 h to obtain turbid suspension . To this turbid stirred at RT for 16 h . The precipitate was filtered , and the solution pentanediol ( 0 .85 ml, 8 .18 mmol) was added fol - filtrate was extracted with ethyl acetate . The organic layer lowed by 4 -dimethylaminopyridine ( 0 .284 g , 2 .33 mmol) . was washed with brine solution and dried over sodium The final reaction mixture was stirred at RT for 16 h . The sulphate to obtain the crude product . The crude product was white precipitate was filtered and extracted with ethyl purified by flash column chromatography to get the final acetate . The filtrate was washed with brine solution , dried over sodium sulphate and evaporated to get crude mass . The product ( 9 ) in 50 -60 % isolated yield . crude product was purified by flash column chromatography eluting with 1 % methanol/ dichloromethane to obtain pure Example 2 : Synthesis of DART Molecule 87 ( from compound , 2 (0 .9 g, 80 % yield ). Table 1A )

- NH H 0 11- bromoundecanoic acid K2CO3, K2HPO4 , CH3OH NH2 0° C ., 5 h

0 OH

ANH ilIH NH2

NH DCC , HOBT, DMAP , DCM RT, 16 h

HO ry o veri 4 G

ANH H O ) NH2 0

0 HN OH

Step 2 . Synthesis of DART, 9 : To a solution of 3 (0 .72 g , Step 1 . Synthesis of 4 : 11- Bromoundecanoic acid ( 1. 33 g , 1 . 55 mmol) in mixture of dichloromethane ( 10 ml) and 5 .04 mmol) was pre -mixed with the methanol ( 0 . 1 ml) was dimethylformamide (1 ml) was added dicyclohexylcarbodi- 65 added into a stirred mixture of 1 ( 1 g , 2. 52 mmol) , potassium imide ( 0 .415 g , 2 . 05 mmol) followed by N -Hydroxybenza carbonate ( 0 .243 g , 1 . 764 mmol) , and dipotassium -hydro triazole (0 .209 g , 1. 55 mmol) at RT to provide turbid genphosphate (0 .175 g, 1 mmol) in N ,N -dimethylacetamide US 10 , 071 , 103 B2 145 146 ( 15 ml) at 0 - 5° C . The reaction mixture was stirred at 0° C . -continued for 5 hr and extracted with ethyl acetate (50 ml) . The final solution was washed with 3 % aqueous sodium bicarbonate solution ( 10 ml) followed by brine solution ( 10 ml) . The organic solvent was evaporated to give crude mass and 5 finally purified by flash column chromatography. The com N NO2 pound was eluted with 1 - 3 % methanol/ dichloromethane to obtain pure compound , 4 ( 1 . 2 g , 82 % yield ). Step - 2 : Synthesis of DART , 87 : To a solution of Com - 10 pound 4 ( 1 g , 1. 72 mmol) in dichloromethane ( 10 ml) and 1 ml dimethylformamide was added dicyclohexylcarbodiim ide (0 .461 g , 2 .23 mmol) followed by N -Hydroxybenzatri N azole ( 0 .232 g , 1 . 72 mmol) at RT to provide turbid suspen sion . The reaction mixture was stirred for 1 hr at RT. To this ?? turbid solution 5 (0 .67 g , 1. 72 mmol) was added followed by F DMAP ( 0 . 210 g , 1 .72 mmol ) and the reaction mixture was stirred at RT for 16 h . The suspension was filtered and Note : Compound 1 in the scheme corresponds to compound 90 from washed with brine solution . The organic layer was dried over 20 Table 1B sodium sulphate and evaporated to obtain the crude mass. Finally the crude was purified by flash column chromatog - To a stirred solution of 1 - Chloro - 3 -( 2 -methyl - 5 -nitro raphy using 2 - 5 % methanol/ dichloromethane as eluent toto imiimidazol - 1 -yl ) - propan - 2 -ol , ( I) (0 .79 g , 3 . 6 mmol) in dichlo obtain the pure compound , 87 with 60 -65 % isolated yield . 25 romethane ( 10 ml) was added dicyclohexylcarbadiimide (DCC ) (0 . 9 g , 4 .31 mmol) followed by bromoacetic acid Example 3 : Synthesis of DART Molecule 90 ( from (0 . 5 g , 3 . 6 mmol) and DMAP ( 0 .44 g , 3 .6 mmol) at RT. The Table 1B ) reaction mixture was stirred at RT for 16 h . The precipitate Bromo - acetic acid 1 - chloromethyl1- 2 - ( 2 -methyl - 5 -nitro nitro - 30* was removed by filtration and the organic layer was evapo imidazol- 1 - yl) - ethyl ester ( II ) was synthesized according to rated to get the crude that was purified by flash column Forthe following schemeple. my chromatography . The final compound was eluted with 1 - 2 % on methanol /dichloromethane mixture . The compound was 35 used for the next step without further characterization . Synthesis of 7 - { 4 - [ 1 -Chloromethyl - 2 - ( 2 -methyl - 5 nitro -imidazol - 1 - yl) - ethoxycarbonylmethyl] -piper azin - 1 -yl } - 6 - fluoro - 1 -methyl - 4 -oxo - 4H - 2 - thia -8b ' N 40 aza - cyclobuta [ a ] naphthalene - 3 - carboxylic acid ( 1 ) To a stirred solution of 6 - Fluoro - 1 -methyl - 4 -oxo - 7 -pip erazin - 1 -yl -4H - 2 - thia - 8b -aza -cyclobuta [ a ]naphthalene - 3 ?? 45 carboxylic acid , (III ) (0 .071 g, 0 . 2 mmol ) in dimethylfor DCC , DMP, 16 h mamide ( 10 ml) was added potassium carbonate (0 .04 g , 0 .3 HO 45 % mmol) followed by addition of compound ( II ) ( 0 . 1 g , 0 . 3 mmol ) and the reaction mixture was stirred at RT for 3 h . 50 The reaction mixture was diluted with ethylacetate , washed two times with water and finally dried over sodium sulphate to obtain the crude mass . The crude was purified by flash column chromatography while eluting with 3 - 5 % methanol/ HN 55 dichloromethane mixture to obtain the pure compound ( 1 ) , i. e ., Compound 90 from Table 1 , with 30 % isolated yield . OH ' H -NMR (400 MHz , DMSO ) 8 ppm : 2 .19 (3H , d , J = 6 . 4 ON N F Hz, CH3 ), 2 . 57 (3H , s , CH3) , 2 . 7 (4H , m , 2xCH2) , 3 . 1 - 3 . 3 III 60 ( 2H , s , COCH2) , 3 .32 (4H , m , 2xCH2) , 3 .77 - 3 . 90 (2H , ddd , K2CO3, DMF, 3 h Jq = 3 .6 Hz, J2 = 12 . 4 Hz, Jz = 35 . 2 Hz, CH , C1) , 4 .40 - 4 . 56 ( 1H , 30 - 35 % dd , J = 9 .6 Hz, J2 = 14 Hz CHN ) , 4 . 76 ( 1H , d , J = 14 Hz, 3044 CHN ), 5 .44 (1H , d , J = 5. 6 Hz CHOCO ), 6 .0 -6 .11 (1H , q , Br 65 J1 = 6 Hz, J2 = 12 . 4 Hz, CHSN ) , 6 . 4 ( 1H , d , J = 6 . 8 Hz Ar — H ) , 7 .8 (1H , d , J = 14 Hz, Ar — H ), 8 . 04 (1H , s , Ar — H ) . ESI- MS ( m / z ): 609 ( M + H ) * . US 10 ,071 , 103 B2 147 148 Example 4 : Synthesis of DART Molecule 91 from was added potassium carbonate ( 0 . 11 g, 0 . 19 mmol) dis Table 1B solved in water ( 5 ml) , followed by addition of epoxy ornidazole , ( II ) (0 . 15 g, 0 .82 mmol) . The reaction mixture 2 -Methyl - 5 -nitro - 1- oxiranylmethyl- 1H -imidazole ( IV ) 5 was heated at 50° C . for 20 hr. After completion , the reaction was synthesized according to the following scheme. mixture was evaporated and extracted twice with dichlo romethane. The combined organic layer was dried over sodium sulphate and evaporated to obtain the crude mass . 10 The crude mass was purified by column chromatography by ON ' N 20 % NaOH eluting with 10 - 12 % methanol/ dichloromethane mixture to DCM , 0° C .- RT , 3 h obtain the pure compound (2 ), i. e ., Compound 91 from Table 90 % 1 , with 25 - 30 % isolated yield . ' H -NMR (400 MHZ, DMSO ) is 8 ppm : 2 . 12 (3H , d , J= 6 .4 Hz, CH3) , 2. 46 (3H , s, CHz) , 2 . 58 - 2 . 60 ( 2H , t, J = 5 .6 Hz CH2N ) , 2 .66 (4H , m , 2xCH2) , 3 . 2 (4H , m , 2xCH2) , 3 . 9 - 4 .1 (2H , m , 2xCH N ), 4 .63 (1H , d , yonL J = 14 Hz , CHOH ) , 5 .15 (1H , d , J= 5 . 2 Hz OH ), 6 .39 ( 1H ,

HN d , J= 6 .4 Hz, CHSN ) 6 . 93 (1H , d , J = 7 .2 Hz, Ar - H ), 7 .79 OH (1H , d , J= 14 Hz, Ar — H ) , 8 .04 (1H , s, Ar — H ). ESI- MS ( m / z ): 532. 95 ( M + H ) .

III Example 5 : Synthesis of DART Molecule 94 from K2CO3, Acetone + Water, - 25 Table 1B 50° C ., 20 h T22 25 - 30 % 30 NO2 ON ' N

OH S OH 35 DCC , HOBt, OH DMAP, RT, 16 h 60 -65 % OH 40 2 Note: toate Compound 2 in the scheme corresponds to compound 91 from Table 1B

To a stirred solution of 1 -Chloro - 3 - ( 2 -methyl - 5 - nitro - 454 N NO imidazol- 1 - yl) - propan - 2 - ol, ( I) ( 0 . 5 g , 2 .27 mmol) in dichlo romethane (8 ml) was added 20 % Sodium hydroxide (4 ml) at 0° C . The reaction mixture was stirred for 3 h at 0° C . After 3 h the reaction mixture was extracted twice with 50 dichloromethane , the organic layers were combined , washed with brine and finally dried over sodium sulphate to obtain pure product with 90 % isolated yield . ' H - NMR (400 MHz , 5 CDC13 ) dppm : 2 .517 ( 3H , S , CHz) , 2 . 52 ( 1H , m , CH2) , 55 Note1B : Compound 5 in the scheme corresponds to compound 94 from Table 2 .88 ( 1H , m , CH ) , 3 . 38 (1H , m , CH ) , 4 . 17 - 4 . 23 ( 1H , dd , J = 6 Hz, Jz = 15. 2 Hz CH2) , 4 .85 - 4 .89 ( 1H , d , J = 14 . 8 CH2) . Synthesis of 6 - Fluoro -1 -methyl - 7 -[ 4 -( 5 -methyl - 2 Synthesis of 6 - Fluoro - 7 - { 4 - [ 2 -hydroxy - 3 -( 2 -methyl oxo - [ 1 , 3 ] dioxol- 4 - ylmethyl) -piperazin - 1 - yl) - 4 - oxo 5 - nitro - imidazol- 1 - yl) - propyl] - piperazin - 1 - yl) - 1 60 4H - 2 - thia - 8b - aza - cyclobuta [ a ]naphthalene - 3 - carbox methyl- 4 - oxo -4H - 2 -thia -8b -aza -cyclobuta [ a ]naph ylic acid 1 -chloromethyl - 2 -( 2 -methyl - 5 -nitro thalene - 3 - carboxylic acid ( 2 ) imidazol- 1 -yl ) - ethyl ester ( 5 ) To a stirred solution of 6 -Fluoro - 1 -methyl - 4 -oxo - 7 -pip - a To a stirred solution of 6 - Fluoro - 1 -methyl - 7 - [ 4 - ( 5 erazin - 1 - yl- 4H - 2 -thia - 8b - aza -cyclobuta [ a ]naphthalene - 3 - methyl - 2 - oxo - ( 1, 3 ]dioxol - 4 - ylmethyl) -piperazin - 1 - yl) - 4 carboxylic acid, ( III ) ( 0 . 2 g , 0 . 57 mmol ) in acetone ( 15 ml) 0X0 - 4H - 2 - thia - 8b - aza - cyclobuta [ a ] naphthalene - 3 - carbox US 10 , 071 , 103 B2 149 150 ylic acid , (V ) (0 .5 g , 1. 08 mmol) in DMF (20 ml) was added dropwise to a stirred solution of 4 -bromo - 1 -butene ( 0 . 5 g , DCC (0 . 3 g , 1 .41 mmol) and HOBt (0 .146 g, 1. 083 mmol) 3 .7 mmol) in 20 ml of dichloromethane. After addition , the followed by addition of 1 - Chloro - 3 - ( 2 -methyl - 5 - nitro - imi11 mixture was stirred at 25° C . for 16 h , to precipitate dazol- 1 - yl) -propan - 2 -ol , ( I ) ( 0 . 285 g , 1 . 3 mmol) and DMAP 5 3 - chlorobenzoic acid . Finally the reaction mixture was evaporated to dryness under vacuum , dissolved in ethyl ( 0 . 13 g , 1 .08 mmol) at room temperature . The reaction acetate , washed initially with 4 % sodium dithionate fol mixture was stirred at RT for 16 h . The precipitate was lowed by saturated sodium bicarbonate and water . Finally removed by filtration and the organic layer was evaporated the organic layer was dried over sodium sulphate , evapo to get the crude mass . Finally it was purified by flash column rated and dried under vacuo to obtain the final compound (1 ) chromatography eluting with 2 - 4 % methanol/ dichlorometh with 90 % isolated yield . ' H -NMR (400 MHz, CDC13 ) ane mixture to obtain the pure compound , (5 ), i .e ., Com oppm : 2 . 10 ( m , 2H , CH2) 2 . 58 ( s , 1H , OCH . ) 2 . 82 ( 1H , m , pound 94 from Table 1 , with 60 % isolated yield . ' H - NMR OCH ) , 3 . 09 ( m , 1H , CH ) 3 . 55 ( t , J = 6 . 4 , 2H , CH2 - Br) . (400 MHz, DMSO ) Oppm : 2 .03 (3H , d , J = 5. 6 Hz , CH3) , 2 . 12 (3H , s , CH3) , 2 . 5 (3H , s , CH3) , 2 .62 (4H , m , 2xCH2) , 3 .22 15 Synthesis of 4 -Bromo - 1 -( 2 -methyl - 5 - nitro - imidazol (4H , m , 2xCH _ ), 3 . 95 - 4 . 06 ( 2H , m , CH C1 ), 4 . 49 - 4 . 52 ( 1H , 1 -yl ) -butan - 2 -ol (II ) t, J = 10 Hz , CHN ) 4 .77 ( 1H , d , J = 13 . 2 Hz, CHN ) , 5 .63 ( 1H , To a stirred solution of 2 -methyl -5 - nitro - 1H -imidazole d , J = 4 .4 Hz, CHOCO ), 6 . 15 (1H , m , CHSN ), 6 . 78 (1H , d , 20 ( 0 . 8 g , 6 . 3 mmol ) in dry ethyl acetate was added anhydrous J = 7. 2 , Ar — H ), 7 .68 (1H , d, J= 14 , Ar — H ), 7 .9 (1H , s, 20 Aluminium chloride ( 1. 67 g, 12 .5 mmol) at 0° C . and Ar – H ). allowed to stir for 15 min to dissolve 2 -methyl - 5 -nitro - 1H Example 6 : Synthesis of DART Molecule 116 from imidazole . After that 4 -bromo - 1 , 2 - epoxybutane ( I ), ( 1 . 9 g , Table 1B 12 .5 mmol) was added dropwise into the reaction mixture and the reaction was continued for 5 h at 0° C . The reaction mixture was slowly added into Ice water and pH was adjusted to 1 by adding concentrated HCl. The organic layer 3 - Cloroperbenzoic acid was separated , washed with saturated sodium bicarbonate Br Dichloromethane , RT. 16 h 30 followed by water. The aqueous layer obtained from the first 90 % separation adjusted to pH 7. 4 using liquor ammonia and 2 -Methyl - 5 -nitro - 1H - imidazole extracted with ethyl acetate . The combined organic layer Bir Anhy, AlCl3 , Ethylacetate , was dried over sodium sulphate and evaporated in vacuo to 0° C ., 5 h 35 obtain crude compound rude was purified by flash column 50 % chromatography while eluting with 2 -3 % methanol/ dichlo romethane mixture to obtain the pure compound ( II ) with OH 50 % isolated yield . ESI- MS ( m / z ): 277 ( M ) * . 40 Synthesis of 6 -Fluoro -7 - {4 -[ 3 -hydroxy -4 -( 2 -methyl HN 5 - nitro -imidazol - 1 - yl) - butyl ] - piperazin - 1 - yl} - 1 methyl- 4 -oxo -4H -2 - thia -8b -aza -cyclobuta [a ]naph N NO2 thalene -3 -carboxylic acid (116 ) ( III) ? 45 Br - K2CO3, DMF, RT , 16 h 45 20 % To a stirred solution of 6 - Fluoro - 1 -methyl - 4 - oxo - 7 - pip OH erazin - 1 -yl - 4H - 2 - thia - 8b - aza - cyclobuta [ a ]naphthalene - 3 carboxylic acid , ( III ) ( 3 g , 8 .6 mmol) in DMF ( 30 ml) was 50 adadded potassium carbonate (1 . 20 g, 8 .6 mmol) followed by addition of compound ( II ) ( 2 g , 7 .2 mmol) and the reaction OH mixture was stirred at RT for 16 h . The reaction mixture was N ' N diluted with ethyl acetate , washed twice with water and H2C 55 finally dried over sodium sulphate to obtain the crude mass . The crude was purified by flash column chromatography HO while eluting with 3 - 5 % methanol/ dichloromethane mixture to obtain the pure compound ( 116 ) with 20 % isolated yield . (116 ) 60 ' H -NMR (400 MHz , DMSO ) dppm : 1 .61 - 1 .68 (2H , m , CH ), 2 . 12 (3H , d , J= 6 Hz , CHZ ), 2. 46 ( 3H , S , CH3) , 2 .57 ( 4H , m , 2xCH , ) , 3 . 2 ( 4H , m , 2xCH , ) , 3 . 8 - 4 . 1 (2H , m , Synthesis of 4 -Bromo - 1, 2 - Epoxybutane (1 ) 2x' CH2N ), 4. 44 ( 1H , m , CHOH ), 5 . 2 (1H , bs, CHOH ), 6 . 4 ( 1H , 4 , J1 = 5 .6 Hz, J2= 11 . 6 Hz, CHSN ) 6 . 91 ( 1H , d , J = 7 , A Solution of 3 -Chloroperbenzoic acid (55 - 75 % pure, Ar – H ), 7 .78 ( 1H , d , J = 13 .6 Hz, Ar — H ) , 8 .04 (1H , S, 1 .60 g , 9. 25 mmol) in 10 ml dichloromethane was added Ar - H ). ESI- MS ( m /z ): 547 .08 ( M + H )* . US 10 ,071 , 103 B2 151 152 Example 7 : Synthesis of DART Molecule 113 from Table 1B

V NO ,

OH Lauric acid , DCC , DMAP HOBT, DMF, RT , 16 h

) ??OH

N NO ,

OH 113

Synthesis of 7 - { 4 -[ 2 -Dodecanoyloxy - 3 - ( 2 -methyl - 5 - 40 Example 8 : Synthesis of DART Molecule 115 from nitro - imidazol- 1 - yl) -propyl ] - piperazin - 1 -yl ) -6 Table 1B fluoro - 1 -methyl - 4 -oxo -4H - 2 - thia - 8b - aza -cyclobuta [ a ]naphthalene - 3 -carboxylic acid ( 113 ) To a solution of 91 ( 0 . 5 g , 0 . 94 mmol) in dimethylfor - 45 3- Cloroperbenzoic acid mamide ( 15 ml) was added N , N - dicyclohexylcarbodiimide Br Dichloromethane ,RT , ( 0 .29 g , 1 .41 mmol) followed by N -hydroxybenzatriazole 6 -bromo - 1 - Hexene 16 h ( 0 . 13 g , 0 .94 mmol) slowly at ice cold condition and stirred 90 % at RT for 10 min to obtain turbid suspension . To this turbid solution lauric acid ( 0 . 28 g , 1 .5 mmol) was added followed 50 2 -Methyl - 5 -nitro - 1H - imidazole by 4 - dimethylaminopyridine ( 0 . 115 g , 0 . 94 mmol) . The final ~ BrBr Anhy, AlCl3 , Ethylacetate , reaction mixture was stirred at RT for 16 h . The white 0° C . , 5 h precipitate was filtered and extracted with ethyl acetate . The 50 % filtrate was washed with water and brine solution , dried over sodium sulphate and evaporated to get crude mass . The crude product was purified by flash column chromatography eluting with 2 - 3 % methanol/ dichloromethane to obtain pure OH compound 113 with 35 % isolated yield . ' H -NMR (400 MHz, CDC13 ) oppm : 0. 86 (3H , t, J= 6 Hz, CH3) , 1 .05 - 1. 38 60 ( 18H , m , - CH2) , 1 .48 - 1 . 70 (4H , m , - CH2) , 1 .90 - 1 .93 ( 2H , HN d , J= 11. 6 Hz, CH3) , 2 . 16 - 2. 22 (3H , m , CH3) , 2 .53 (3H , s, N NO2 CH ), 2 .58 - 2 .69 (2H , m , CH , N ) , 2 .69 - 2 . 87 (4H , m , 2xCH , ) , Br _ ( III ) 3 .2 - 3 . 4 (4H , m , 2xCH , ) , 4 . 1 - 4 . 25 ( 2H , m , 2xCH , N ) , 5 . 0 K2CO3, DMF, RT, 16 h ( 1H , s , CHOH ), 6 .09 ( 1H , d , J = 5 . 2 Hz, CHSN ), 6 .41 ( 1H , d , 65 OH 20 % J = 6 .8 Hz Ar — H ), 7 .92 ( 1H , d , J= 14 . 8 Hz , Ar - H ), 8. 04 ( 1H , (II ) S , Ar – H ). ESI- MS (m /z ): 715 .2 ( M + H ) US 10 ,071 , 103 B2 153 154 -continued sulphate to obtain the crude mass . The crudewas purified by S 0 flash column chromatography while eluting with 3 - 5 % methanol/ dichloromethane mixture to obtain the pure com OL pound ( 115 ) with 20 % isolated yield . ' H -NMR (400 MHz, 5 DMSO ) 8 ppm : 1. 61 - 1 .68 (6H , m , CH2) , 2 . 1 (3H , d , J = 6 Hz , H2C CHZ) , 2 . 44 ( 3H , s , CHZ) , 2 .54 ( 4H , m , 2xCH , ) , 3 . 2 (4H , m , 2xCH , ), 3 . 9 - 4 . 1 ( 2H , m , 2xCH , N ) , 4 . 38 ( 1H , d , J = 14 , ?? CHOH ), 5 . 2 ( 1H , d , J= 4 .4 , OH ), 6 .38 ( 1H , d , J= 5 .6 Hz , T CHSN ) 6 . 9 ( 1H , d , J = 6 . 8 , Ar — H ) , 7 .78 ( 1H , d , J= 14 Hz, ( 115 ) Ar — H ), 8 .02 (1H , s, Ar – H ) . ESI- MS (m /z ) : 575 (M + H ) Example 9: Synthesis of DART Molecule 119 from Table 1B Synthesis of 2 -( 4 -bromobutyl ) - oxirane (1 ) 15 A Solution of 3 -Chloroperbenzoic acid ( 55 - 75 % pure , 4 . 54 g , 18 .39 mmol) in 20 ml dichloromethane was added dropwise to a stirred solution of 6 - bromo- 1 - hexane ( 2 g , NO2 4 - toulenesulfonylchloride 12 . 26 mmol) in 20 ml of dichloromethane. After addition , 20 Et3N , DMAP , Dry DCM the mixture was stirred at 25° C . for 16 h , to precipitate ?? RT, 3 hr 3 - chlorobenzoic acid . Finally the reaction mixture was evaporated to dryness under vacuum , dissolved in ethyl acetate , washed initially with 4 % sodium dithionate fol lowed by saturated sodium bicarbonate and water. Finally 25 the organic layer was dried over sodium sulphate, evapo HN rated and dried under vacuo to obtain the final compound ( 1 ) with 90 % isolated yield . 1H -NMR (400 MHz, CDC12 ) 8 ppm : ' H - NMR (400 MHz, CDC1z ) 8 ppm : 1 .48 - 1 . 6 (6H , m , OH CH , ) 2 . 47 ( 1H , d , J = 2 . 4 , OCH ) 2 .75 ( t , J = 4 , 1H , OCH ), 30 L NO2 F 2 . 91 ( bs, 1H , OCH . ) 3 .41 ( t, J = 6 . 4 , 2H , CH2 – Br) ( II ) OTS DMF, 90° C ., 16 h Synthesis of 6 - Bromo -1 - ( 2 -methyl - 5 -nitro -imidazol 1- yl ) - hexan -2 -ol ( II) 35 Je To a stirred solution of 2 -methyl - 5 -nitro - 1H - imidazole ( 0 . 7 g , 5 . 5 mmol) in dry ethyl acetate was added anhydrous aluminium chloride ( 1 .46 g , 11 mmol) at 0° C . and allowed to stir for 15 min to dissolve 2 -methyl - 5 -nitro - 1H - imidazole . After that 6 - bromo - 1 , 2 - epoxyhexane ( I ) , ( 1 .96 g , 11. 02 40 mmol ) was added dropwise into the reaction mixture and the NU reaction was continued for 5 h at 0° C . The reaction mixture was slowly added into Ice water and pH was adjusted to 1 OH by adding concentrated HCl. The organic layer was sepa F rated , washed with saturated sodium bicarbonate followed 45 by water . The aqueous layer obtained from the first separa ( 119 ) tion adjusted to pH 7 .4 using liquid . ammonia and extracted with ethyl acetate . The combined organic layer was dried over sodium sulphate and evaporated in vacuo to obtain Synthesis of 2 - ( 2 -Methyl - 5 -nitro - 1H - imidazol- 1 -yl ) ethyl crude compound Crude was purified by flash column chro - 50 4 -methylbenzenesulfonate (1 ) : To a stirred solution of 2 -( 2 matography while eluting with 2 - 3 % methanol/dichlo Methyl - 5 - nitro - imidazol- 1 - yl) - ethanol ( 4 g , 16 . 86 mmol) in romethanero mixture to obtain the pure compound (II ) with dichloromethane (50 ml) was added triethylamine ( 7 .3 ml) , 50 % isolated yield . ESI- MS ( m / z ) : 305 . 95 ( M + H ) 4 -toulenesulfonylchloride (6 .42 g , 33 .72 mmol) followed by Synthesis of 6 -Fluoro - 7 - { 4 - [ 5 -hydroxy -6 - ( 2 -methyl - 55 4 - dimethylaminopyridine (0 . 2 g, 1. 68 mmol) at 0° C . The 5 - nitro - imidazol- 1 -yl ) - hexyl ] - piperazin - 1 - yl) - 1 reaction mixture was stirred at RT for 3 h . After completion , methyl- 4 -oxo -4H - 2 - thia - 8b -aza - cyclobuta [ a ]naph reaction mixture was washed with water , 5 % HC1, sat . thalene - 3 -carboxylic acid ( 115 ) NaHCO3 and water . The organic layer was dried over Na2SO4 and evaporated to get crude mass. The crude was To a stirred solution of 6 - Fluoro - 1 -methyl - 4 -oxo - 7 -pip - 60 purified by flash column chromatography by eluting with carboxylicerazin - 1- yl - 4Hacid - , 2 -( thia III ) - 8B(1 . - 10aza g - ,cyclobuta 3. 16 mmol a naphthalene) in dimethylfor- 3 . 2 - 3 % methanol/ dichloromethane to obtain pure compound mamide ( 30 ml) was added potassium carbonate ( 0 .43 g, with 90 % isolated yield ' H -NMR (400 MHz, CDC13 ) dppm : 3 . 16 mmol) followed by addition of compound ( II ) ( 0 . 85 g , 2 .45 (3H , s, Ar - CHZ) , 2 .51 (3H , S, CH3) , 4 . 37 (2H , d , 2 .63 mmol) and the reaction mixture was stirred at RT for 16 65 J = 4 . 8 Hz, CH2) , 4 .54 ( 2H , d , J = 4 .8 Hz, CH2) , 7 . 29 ( 2H , d , h . The reaction mixture was diluted with ethyl acetate , J = 8 . 4 Hz, ArH ), 7 .60 (2H , d , J= 8 .4 Hz, ArH ) , 7 .81 ( 1H , s , washed twice with water and finally dried over sodium ArH ) . US 10 , 071 , 103 B2 155 156 Synthesis of 6 - Fluoro - 1 -methyl - 7 - { 4 - [ 2 - ( 2 -methyl Method : 5 - nitro -imidazol - 1 - yl) - ethyl] - piperazin - 1 - yl) - 4 - oxo P. acnes were cultured in Brain Heart Infusion Agar 4H -2 - thia -8b -aza -cyclobuta [a ]naphthalene - 3 -carbox (BHIA ) at 37° C . for 48 hours under anaerobic condition . For MIC test, BHIbroth ( 100 ul) was added into all 96 wells ylic acid ( 119) 5 and 100 ul of broth containing drug was added to first well To a stirred solution of 6 - Fluoro - 1 -methyl - 4 -oxo - 7 - pip ( 1A to 1H ) and serial ( double ) dilution was carried out for erazin - 1 - yl - 4H - 2 - thia - 8B -aza - cyclobutala ]naphthalene - 3 - up to 10 wells ( column 1 to column 10 of 96 well plate ) . For carboxylic acid , ( II ) ( 5 . 16 g , 14 .76 mmol) in dimethylfor - bacterial inoculum , P . acnes culture turbidity was adjusted to mamide ( 100 ml) was added potassium carbonate ( 2 .03 g 0 . 5 McFarland standard (approximately 1. 5x10 ' cells /ml ) 14 .76 mmol) followed by addition of compound ( I ) ( 2 g . 7 . 2 10 and further diluted ( 100 times with sterile BHI broth ) . mmol) and the reaction mixture was heated at 90° C . for 16 Diluted P . acnes suspension ( 100 ul) was added to each well h . The reaction mixture was diluted with ethyl acetate , except sterility control wells ( column 12 of 96 -well plate ) . washed twice with water and finally dried over sodium The plates were incubated at 37° C . for 48 h under sulphate to obtain the crude mass . The crude was purified by anaerobic condition for P . acnes and 37° C . for 24 h for S . flash column chromatography while eluting with 4 - 5 % 15 aureus The plates were read under Bio -Rad plate reader at methanol/ dichloromethane mixture to obtain the pure com - 595 nm for optical density to generate the dose - response pound ( 119 ) with 20 % isolated yield . ' H -NMR (400 MHz, curves. The MIC of the test compound was recorded by CDC1z) dppm : 2 . 12 ( 3H , d , J = 6 . 4 Hz, CH ) , 2 .52 ( 3H , s , addition of Alamar blue dye . CH , ), 2 .64 (4H , m , 2xCH , ), 2 .72 ( 2H , t , J = 6 Hz, CH , ), Results : 3 . 11 - 3 . 18 (4H . m . 2xCH . ) . 4 . 43 - 4 . 49 ( 2H . m . CH . N ) . 5 . 8 - 20 Table 6 and FIGS . 1C and 1D showed MIC and dose 5 . 9 ( 1H , q , J, = 6 . 4 Hz, Jo = 12 . 8 Hz, CHSN ) . 6 . 3 ( 1H , d , J = 6 . 8 response curves of different compounds in both susceptible Hz , Ar - H ), 7 .92 (1H , s, Ar - H ), 7 .95 ( 1H , S , Ar - H ). and resistant P . acnes strains . The results showed that compound 91 showed lower MIC value and faster bacterial ESI- MS (m /z ): 503 (M + H ) killing profile for both bacterial strains (clindamycin - sus Example 10 : Antimicrobial Susceptibility of 25 ceptible and resistant P . acnes ) in comparison to all other Clindamycin Sensitive and Resistant P . acnes compounds. In contrast compounds 115 and 116 , which are only marginally different from 91 , exhibited more than The antimicrobial susceptibility of P . acnes strains against double MIC values for both P . acnes strains in comparison various antibiotics was determined by micro broth dilution to MIC value obtained with compound 91 . Similarly , com method as follows. 30 pounds 113 and 94 hardly showed any activity against P . Methods: acnes , which could indicate the importance and involvement P . acnes (MTCC 1951 and CCARM9010 ) were cultured of free carbonyl and carboxylic groups towards better activ in Brain Heart Infusion Agar (BHIA ) at 37° C . for 48 hours ity of the compound . Interestingly the compound 90 was under anaerobic condition . For MIC test , BHI broth ( 100 ul) found to be not active in clindamycin - susceptible P . acnes was added into all 96 wells and 100 ul of broth containing 35 but showed promising activity in clindamycin — nonre different concentrations of cephalothin , cefoxitime, pruli - sponder P . acnes strain as observed in the dose -response floxacin , nadifloxacin , roxitrhromycin , clindamycin and curves of FIGS . 1C and 1D . besifloxacin were added to first well of each row ( 1A to 1H ) In presence of S . aureus strain all compounds 90 , 91 , 115 and serial (double ) dilution was carried out for up to 10 wells and 116 have similar activity but compound 113 showed ( column 1 to column 10 of 96 well plate ) . For bacterial 40 least activities thatmight be due to steric constrains involved inoculum , P . acnes culture turbidity was adjusted to 0 . 5 during binding to the target protein ( Table 6 ) . McFarland standard ( approximately 1. 5x108 ) and further Conclusions: diluted (100 times with sterile BHI broth ). Diluted P . acnes Compound 91 is a potent anti -acne agent, and an effica suspension ( 100 ul) was added to each well except sterility cious drug against treatment of both clindamycin - suscep control wells (column 12 of 96 well plate ) . Inoculated plates 45 tible . In clindamycin resistant P . acnes strain also , it showed were incubated at 37° C . for 72 hours under anaerobic the highest activity which is better than in the susceptible condition . After incubation , MIC was determined by adding strain . The same is also reflected in the dose response curve Alamar blue dye . ( FIGS . 1C and 1D ) . In both strains, at a very low concen Results : tration , all P. acnes bacterium were killed , indicating it The MIC results on P . acnes strains susceptible to clin - 50 overcomes allmechanisms of antibiotic non - responsiveness , damycin indicated that the strain is susceptible to all the i . e . can overcome mechanisms underlying tolerance ( de antibiotics (FIG . 1A ) . Interestingly , Clindamycin resistant scribed in introduction ) as well as resistance . This suggests strain was also resistant to a macrolide, Roxithromycin . the structure of compound 91 is unique that shows higher (FIG . 1B ) bio -efficacy in comparison to all other compounds against 55 both susceptible and resistant P . acnes strains . The wide Example 11 : Determination of Minimum Inhibitory variability in outcome with structurally - related molecules Concentration (MIC ) and Dose Response Curve for also highlight the fact that it is not possible to predict Compounds 90 , 91, 94 , 113 , 115 and 116 in Both efficacy just because of structural similarities . Similarly, the Clindamycin -Susceptible (MTCC1951 ) and higher MIC value for compound 91 against S . aureus in Clindamycin - Nonresponsive ( CCARM 9010 ) P. 60 comparison to P . acnes proves the specificity of compound acnes Strains and Laboratory S . aureus Strains 91 towards a particular bacterial strain , and that results seen in a bacterial species is not portable to another disease Materials : causing bacteria . Brain heart infusion broth , P . acnes strains (MTCC 1951 Purity and bio -activity of compounds 90 , 91, 94, 113 , 115 & CCARM 9010 ), S . aureus MTCC 6908 , 96 wells plate , 65 and 116 ( from Table 1A & 1B ) Autoclave , Incubator, Anaerobic box with anaerobic gas The purity of all above mentioned DART molecules were pack , Plate reader (595 nm ) , Alamar blue . evaluated by HPLC and their bio -activity were evaluated in US 10 , 071 , 103 B2 157 158 both P . acnes susceptible and resistant strains and S . aureus compound 116 as observed in dose response curve ( FIGS . susceptible strain . The results are shown in Table 6 . 1C & 1D ) proved that compound 91 might have unique mode of activity as compared to others . TABLE 6 When compound 91 was compared with the known HPLC purity and MIC values of compounds for both clindamycin - 5 fluoroquinolone nadifloxacin , the former showed better effi susceptible and resistant P . acnes strains and a laboratory S . aureus strain . cacy of inhibiting DNA super -coiling by DNA gyrase than nadifloxacin at both the concentrations tested ( FIG . 3B ) . MIC Conclusions : The results obtained from DNA gyrase activity assay Susceptible Resistant Susceptible P . acnes (1951 ) P. acnes (9010 ) S. aureus (6908 ) 10 suggest that compound 91 is the most potent in binding Molecules strain ( ug/ ml ) strain (ug / ml ) strain (ug / ml ) DNA gyrase and inhibiting its action . Thus , the mechanism of inhibition of bacterial growth is by impeding the DNA 90 1 . 7 0 .9 1 . 0 gyrase function , thus preventing important cellular functions 91 0 . 2 0 . 1 1 . 5 94 3 . 0 3 . 0 2 . 8 and eventually cellular death . This compound shows a better 113 8 . 2 8 . 0 > 8 . 2 15 antibacterial efficacy and binding affinity in comparison to a 115 0 . 4 0 . 8 1 . 6 known fluoroquinolone, nadifloxacin . These results are in 116 0 . 4 0 . 8 1 .64 accordance with the results obtained from the MIC data and dose response curves . Example 12 : DNA Gyrase Activity Assay with 20 Example 13: Mutant Prevention Concentration Compounds 90 , 91, 94 , 113 , 115 and 116 with E . (MPC ) of Compound 91 in Comparison to the coli DNA Gyrase Other Known Fluoroquinolonesles Materials : Materials : K 25 Brain heart infusion broth , P. acnes MTCC 1951, Petri DNA gyrase assay kit ( Topogen Inc. ), proteinase K , plate , Autoclave, Incubator, Anaerobic box with anaerobic chloroform , isoamyl alcohol, different test compounds, aga gas pack . rose gel electrophoresis system Method: Method : P . acnes were cultured in Brain Heart Infusion Agar DNA super -coiling activity was assayed using DNA 30 . (BHIA ) at 37° C . for 48 h under anaerobic condition . 3 to 4 gyrase assay kit ( Topogen Inc . ) with relaxed pHOT1 E . coli Petri plates containing 48 h P . acnes culture was suspended plasmid DNA according to manufacturer ' s protocol. The in sterile Phosphate buffer saline, PBS (pH 7 .2 ) and turbidity standard reaction mixture ( 20 ul) contained 35 mM Tris -HCI was adjusted to optical density of 1 at 600 nm ( 109 cells /ml ) . (pH 7 . 5 ) , 24 mM KC1, 4 mM MgCl2 , 2 mM dithiothreitol, 50 ml of this culture suspension was centrifuged at 4000 rpm 1 .8 mM spermidine, 1 mM ATP, 6 . 5 % glycerol, 0 .1 mg/ml 35 for 40 min . The supernatant was discarded and pellet resus bovine serum albumin (BSA ), 10 ug /ml relaxed PHOT1 pended in 250 ul of sterile PBS . 50 ul of these cell suspen plasmid DNA and 1 U of DNA gyrase . The reaction mixture sions ( 1010 cells ) was spread over the plates containing was incubated at 37° C . for 1 h in presence of selected various concentrations of antibiotics (around MIC range ). compounds/ fluoroquinolone at different concentrations . The Plates were incubated at 37° C . for 48 h and the lowest reaction was terminated by addition of 1 /5 volume of loading 40 concentration of the drug that allowed no growth was taken dye ( 4 ul) followed by proteinase K (50 ug /ml ) and again as its MPC . If thin film was observed in higher antibiotic incubated at 37° C . for half an hour. 20 ul chloroform / concentration plates then thin film was further sub - cultured isoamyl alcohol ( 24 : 1 ) was added to each tube and vortexed on drug free plates The growth obtained on drug free plates briefly . Thereafter, the blue aqueous phase was separated out were then sub - cultured on plates containing drugs (at the and analyzed by 1 % agarose gel electrophoresis . The gel 45 concentration at which the thin film was isolated ) . If growth was stained by ethidium bromide for half an hour and was not observed in these plates at the end of the incubation destained with water for 15 mins. The gel was then visual- period then the same concentration was confirmed to be the ized in a trans - illuminator and photographed MPC for the said compound . Results : Compounds Inhibit Super - Coiling Activity of Results : DNA Gyrase : 50 The Table 7 showed the value of MPC and the ratio of Compound 91 with the best MIC value was first chosen MPC and MIC of compound 91 along with other known for assessing its effect on DNA gyrase activity . The intensity fluoroquinolones and clindamycin against P. acnes. The of supercoiled band was observed at five different concen - MPC /MIC ratio indicates that compound 91 is almost 3 trations ( in the range from 0 . 25 uM to 5 uM ) (FIG . 2A ) . times more active in preventing development of resistance There was a decrease in super - coiled band in presence of 55 against P . acnes than known anti - acne antibiotic , nadifloxa compound 91 ( nearly around 54 . 3 % at 0 . 25 uM to about 2 % cin , new generation fluoroquinolone , ulifloxacin and 2 times in presence of 5 uM of compound 91 ) as compared to with respect to clindamycin . MPC /MIC ratios are found to compared to the untreated control ( 100 % ) ( FIG . 2B ) . be close with besifloxacin and compound 91. This concludes Further, all the compounds 90 , 91 , 94 , 113 , 115 and 116 both besifloxain and compound 91 are effective molecules were tested at two concentrations 1 uM and 2 . 5 uM to check 60 for treatment and preventing P . acnes and ideal for prevent their effect on DNA gyrase activity . FIG . 3A showed that all ing resistance development against pathogen . the compounds were able to inhibit the super- coiling activity Conclusions: of DNA gyrase . However , compounds 91 and 116 are highly Unlike MIC testing , which typically uses an inoculum potent in this respect as compared to the other compounds size of approximately 104 - 10° cfu /ml , the calculation of the showing that minor structural difference between compound 65 MPC needs a large inoculums ( approximately 10° - 1010 91 and 116 does not affect much in gyrase binding affinity. cfu /ml ) . This high inoculum is chosen to ensure the presence But higher bacterial killing efficacy of compound 91 than of first - step resistant mutants within the susceptible bacterial US 10 ,071 , 103 B2 159 160 population . Moreover , MPC /MIC for compound 91 is only cin Susceptible P . acnes 1951 ( A ), Clindamycin -Nonre 1 . 5 whereas it is almost 8 for nadifloxacin . The narrower the sponder P . acnes 9010 ( B ) and Laboratory S . aureus Strain window between MIC and MPC of an antibiotic molecule ( B ) . the lesser than chance of selective growth of mutants in an in vivo situation . This implies that compound 91 may be 5 TABLE 8 more effective than other known anti -acne agents in pre venting development of resistance in targeted microbes. ZOI ( cm ) P . acnes 1951 (susceptible ) Samples 1 ug 2 ug 4 ug 8 ug TABLE 7 - 10 Formulation A (Compound 91 ) 0. 95 1. 40 2. 30 2 .75 Mutation prevention concentration (MPC ) and ratio of Formulation E (Placebo ) 0 0 0 0 MPC /MIC of the compound 91 and comparison with known fluoroquinolones and lincosamide MIC MPC TABLE 9 Molecules (ug / ml ) (ug /ml ) MPC /MIC 15 - ZOI (cm ) P . acnes 9010 Clindamycin 0 . 02 0 . 13 6 . 5 (clindamycin resistant) Compound 91 0 . 2 0 . 3 - 0 . 6 1 . 5 - 3 Besifloxacin 0 . 5 Samples 1 ug 2 ug 4 ug 8 ug Ulifloxacin 0 . 13 1 . 2 9 . 2 . Nadifloxacin 0 . 13 1 . 2 9 . 2 Formulation A (Compound 91 ) 1 .60 1. 85 2 . 15 2. 45 Formulation E (Placebo ) Example 14 : Zone of Inhibition ( ZOI) of Topical Gel Formulation with Compound 91 in Comparison TABLE 10 with Other Marketed Formulations 25 ZOI ( cm ) S. aureus 6908 Materials: Samples 1 ug 2 ug 4 ug 8 ug Brain heart infusion broth , S . aureus MTCC 6908 , P. Formulation A (Compound 91 ) 0 0 . 80 1. 10 1 .20 acnes strains (MTCC 1951 and CCARM 9010 ) , 96 wells Formulation E ( Placebo ) 0 0 0 0 plate , Autoclave , Incubator, Anaerobic box with anaerobic 3 gas pack , Plate reader (595 nm ), Alamar blue. Method : Example 15 : Determination of Anti- Inflammatory For ZOI test , 100 ul of bacterial suspension (0 .5 McFar Potential of Compound 91 in THP - 1 Cells land standard equal ) was spread on BHA plates. Test 38 samples ( formulations ) were dissolved in water/ solvent Stimulated by P . acnes based on the solubility . Sterile disc ( 6 mm ) were loaded with Here we selected compound 91 to test anti - inflammatory 10 ul of test samples (with various concentrations of the assay as it showed lower MIC and effective gyrase binding compound ) and were placed on the plates containing bac - followed by faster bacterial killing profiles . Anti - inflamma terial culture . The plates were incubated at 37° C . for 48 h 40 tory activity of compound 91 in THP - 1 cells stimulated with under anaerobic condition for P . acnes and 37° C . for 24 h P . acnes ( ATCC 6919 ) was studied . for S . aureus, followed by their ZOI measurements . Method : Preparation of Stimulant for Inflammation : P . Results : acnes culture suspension was prepared in PBS and the cell The ZOI (measured in cm ) of the different test samples are number in the suspension was adjusted to approximately shown for P . acnes 1951 ( susceptible , Table 8 ), P . acnes 45 5x108 CFU /ml by measuring the cell density using a Den 9010 ( resistant, Table 9 ) and S . aureus ( susceptible , Table s imat. The bacterial suspension was then heat killed at 80° 10 ) . The formulation with compound 91 showed bacterial c . for 30 min and stored at - 80° C . until further use . killing profiles against both bacterial strains indicate that ELISA to Study Inflammatory Response in THP - 1 Cells : compound 91 retain its activity in presence of other excipi Cells were seeded in a 96 -well format (2x10 THP - 1 cells ents present in the formulation . Interestingly ZOI data 50 per well ) in media containing 10 % FBS . The cells were showed fast bacterial killing with resistant P . acnes as stimulated to induce inflammatory cytokines using 3 McFar compared to susceptible P. acnes specially at low drug land equivalent heat -killed P . acnes . Cells in control wells concentration ( 1 - 2 ug ) supported by dose response curve as were treated with PBS . One hour after induction with P . seen in FIGS . 1C and 1D as well as DNA - gyrase assays acnes, test agents were added to the induced cells at appro ( FIGS. 2A & 3A ) . Compound 91 also works in case of S . 55 priate concentrations to be tested ( compound 91 at 25 aureus strain and ZOI results support MIC values as seen in ug/ ml ) . The plates were incubated at 37° C . for 24 hours . Table 6 . After 24 h , the plates were centrifuged to pellet the cells and Conclusions : the supernatants were collected . The cell culture superna Formulation with compound 91 has activity against cer- tants thus obtained were analyzed for levels of cytokines tain gram -positive bacterial strains. In case of P . acnes, both 60 ( IL - 1a , IL - 1B , IL - 6 and IL - 8 ) by ELISA using R & D Sys clindamycin - susceptible and clindamycin non -responder tems kits for individual cytokines following the manufac strains, the formulation remains active with compound 91 turer ' s instructions . and preferably more efficacious in clindamycin -nonre Results : Compound 91 Exerts Anti - Inflammatory Action sponder P. acnes supporting the fact drug specific bio - Through the Reduction of IL - 6 in P. acnes - Induced THP - 1 activity . 65 Cells : Tables 8 - 10 . Zone of Inhibition ( ZOI) of Topical Gel For - THP -1 cells , induced using heat killed P. acnes , were mulation with Compound 91 in Comparison for Clindamy- treated with 25 ug/ ml of compound 91 following which the US 10 ,071 , 103 B2 161 162 levels of IL - la , IL - 1B , IL - 6 and IL - 8 were analyzed in the formulation with fast onset of action would finally allow culture supernatant . At the tested concentration , compound reduction of dose and duration of therapy hence ensuring 91 caused a significant reduction (nearly 60 % ) in P . acnes better patient compliance . These formulations would not be induced IL -6 levels (FIG . 4A and Table 11 ). Dexametha - restricted to treat infections caused by P. acnes ( susceptible sone , the known anti- inflammatory agent, used as a positive 5 and resistant strain ) but also other skin bacterial infections or control, showed nearly 100 % reduction in IL - 6 levels . The skin and skin structure infections or impetigo or atopic THP - 1 cells showed 90 % viability when treated with 25 dermatitis or rosacea caused by different family of gram ug/ ml of compound 91 (data not shown ) . Compound 91 did positive anaerobic bacteria such as staphylococcus sp. , not have an effect on IL -8 levels in the P. acnes- induced streptococcus sp . and others ( susceptible and resistant THP - 1 cells ( FIG . 4B ) . The results presented in FIGS . 5A 10 strain ) .More importantly this formulation should work well and 5B show that compound 91 had a small effect on P . against resistant bacteria and prevent any further develop acnes- induced IL - la and IL - 1B levels ( approximately ment of resistance 20 -25 % reduction as compiled in Table 11 ) . These results suggest that compound 91 is an effective anti - inflammatory 15 Composition Example 1 agent in a scenario specific to P . acnes - induced inflamma tion . Topical formulation with partially suspended API (com Conclusions : pound 91 ) in gel formulation using hydroxyethyl cellulose The results obtained from the DNA gyrase activity assays (HEC ) as a gelling agent, at pH 5 . 0 - 5 . 5 . ( Table 12 ) ( cell- free system ) and the anti- inflammatory assays in 20 THP - 1 cells indicate that compound 91 has a dual mode of TABLE 12 action . One of the mechanism of anti -bacterial effect is Composition mediated by targeting the bacterial DNA gyrase in addition Ingredients to induction of DNA damage from the nitroheterocycle Function ( % w / w ) moiety , while its anti- inflammatory properties are evident 25 Phase A Compound 91 Active 1. 0 Diethylene glycol Solvent 10 . 0 from its action on inflammatory mediators in mammalian monoethyl ether cells . In the context of acne , this dual mode of action may Polyethylene Humectant 5 .0 aid in reducing bacterial population as well as diminishing glycol 400 inflammation at the site of lesions thereby providing faster Propylene glycol Humectant 5 . 0 Phase B Hydroxyethyl Rheology 1 . 7 cure and better patient compliance . 30 cellulose modifier Purified Water Vehicle q . s to 100 TABLE 11 Phase C Benzyl alcohol Preservative 1 . 0 Phase D Citric acid pH modifier q .s Percentage reduction by compound 91 in P . acnes induced different cytokine IL - 14 , IL - 1B , IL - 6 and IL - 8 release in THP - 1 cells considering 100 % cytokines formation from P . acnes induced cells. 35 Method of Preparation : 1 . Hydroxylethyl cellulose was added in portions into Cytokines Dexamethasone ( 25 ug/ ml ) Compound 91 ( 25 ug/ ml ) measured volume of water by maintaining stirring 1L - 1B 64. 73 % 20 . 49 % speed at 100 - 150 rpm . The mixture was allowed to 1L - la 53. 83 % 27 .51 % swell for 1 hour at 80 - 100 rpm . (Phase B ) 1L - 6 99 . 54 % 56 . 76 % 4040 2 . In a separate vessel , polyethylene glycol 400 , propyl 1L - 8 58 .78 % 14 .65 % ene glycol, and diethylene glycol monoethyl ether were mixed together and compound 91 was added into the mixture in portions at 400 rpm for ~ 40 - 45 min to get a Example 16 : Topical Formulations with Effective uniform dispersion . ( Phase A ) DART Molecule , 91 45* 3 . The drug dispersion ( Phase A ) was transferred slowly Both cream and gel formulation was made with effective into phase B and allowed to stir at ~ 50 - 100 rpm for ~ 30 DART compound 91 where concentration of active is typi min to form homogenous mixture . cally in the range from about 0 . 5 % to about 3 % by weight 4 . Finally , benzyl alcohol was added into the final mixture or alternatively 0 . 5 % to 2 % or most preferably 1 . 0 % to 50 and mixed for further 30 minutes at 50 - 100 rpm to 1 . 5 % . The formulation was maintained at pH typically obtain a white - to - slightly yellow gel formulation . ranges from pH 4 . 0 to 8 . 0 or preferably at pH 4 . 0 to 6 . 5 or 5 . Finally pH of the gel was maintained at 5 . 0 to 5 . 5 using most preferably at pH 5 .0 to 6 .0 . The concentration of active citric acid solution . is sufficient to reduce , treat , or prevent skin infections as Composition Example 2 well as inflammation at the targeted tissues caused by P . 55 acnes, S . aureus or S . epidermis or other related anaerobic gram positive bacteria . Topical formulation with partially suspended API (com Based on the solubility profiles of compound 91, fully or pound 91) in gel formulation using carbopol 980 as a gelling partially in different solvents such as dimethyl isosorbide , agent at pH 5 . 0 - 5 . 5 . ( Table 13 ) diethylene glycol monoethyl ether , PEG 400 , propylene 60 glycol, benzyl alcohol , and pH 4 .0 acetate buffer , three TABLE 13 different formulation strategies were adopted to obtain Composition improved pharmacokinetics/ pharmacodynamics profiles , Ingredients Function ( % w / w ) high skin penetration properties and better drug deposition Phase A Compound 91 Active 1 . 0 characteristics, These should result in faster reduction in 65 Diethylene glycol solvent 10 . 0 bacterial population along with quicker reduction in host monoethyl ether immune response , such as inflammation . Such effective US 10 ,071 , 103 B2 163 164 TABLE 13 -continued 4 . Finally ethylenediaminetetraacetic acid dehydrate , ben zyl alcohol and propyl gallate were added to the final Composition mixture and stirred for 30 min at 50 - 100 rpm to obtain Ingredients Function ( % w / w ) white - to -slightly yellow gel formulation . Polyethlene Humectant 5 . 0 5 glycol 400 5 5 . The prepared gel was maintained at pH 5 .0 to 5 . 5 using Propylene glycol Humectant 5 .0 citric acid solution . Phase B Carbopol 980 Rheology 0 . 6 modifier Composition Example 4 Purified Water Vehicle q .s to 100 Triethanolamine pH modifier 9 .s 10 Topical formulation with fully suspended API ( compound Phase C Benzyl alcohol Preservative 1 . 0 91) in gel formulation using hydroxyethyl cellulose (HEC ) Method of Preparation : as a gelling agent at pH 5 .0 - 5. 5 . ( Table 15 ) 1 . Gelling agent, carbopol 980 was added in portions to a measured volume of water stirring at 100 - 150 rpm . 15 TABLE 15 2 . pH of the gel mixture was adjusted to 5 .5 by adding Composition triethanolamine solution to allow swelling of carbopol Ingredients Function ( % w / w ) 980 in water . (Phase B ) Phase A Compound 91 Active 1 . 0 3 . In a separate vessel, polyethylene glycol, propylene Glycerol Humectant 10 . 0 glycol and diethylene glycol monoethyl ether were 30 Purified Water Vehicle 10 . 0 mixed together and compound 91 was added into the Phase B Hydroxyethyl Rheology 1. 7 mixture in portions while stirring at 400 rpm for ~ 40 - 45 cellulose modifier min to get uniform dispersion . (Phase A ) Purified Water Vehicle q .s to 100 4 . This drug dispersion ( Phase A ) was added slowly into Phase C Sodium sulfite Preservative 1 . 0 phase B at 50 - 100 rpm stirring speed for about 30 min . Phase D Citric acid pH modifier q . s 5 . Finally , benzyl alcoholwas added into the finalmixture and allowed to stir for further 30 minutes at 50 - 100 rpm Method of Preparation : to obtain a white -to -slightly yellow gel formulation . 1 . Hydroxyethyl cellulose was added in portions into 6 . After preparation of gel , pH was measured and final pH measured volume of water by maintaining stirring was maintained at 5 . 0 - 5 . 5 . speed at 100 - 150 rpm . The mixture was allowed to 30 swell for 1 h at 80 - 100 rpm . (Phase B ) Composition Example 3 2 . In a separate vessel, aqueous solution of glycerol was Topical formulation with partially suspended API (com made and compound 91 was added into the mixture in pound 91 ) in gel formulation using propyl gallate as anti portions at 400 rpm for ~ 40 - 45 min to get a uniform oxidant and EDTA as a buffering agent/ chelating agent at pH 35 dispersion . (Phase A ) 5 . 0 - 5 . 5 . ( Table 14 ) 3 . The drug dispersion (Phase A ) was transferred slowly into phase B and allowed to stir at ~ 50 - 100 rpm for ~ 30 TABLE 14 min to form homogenous mixture . 4 . Finally , propyl paraben was added into the final mixture Composition 40 and mixed for further 30 min at 50 - 100 rpm to obtain Ingredients Function ( % w / w ) a white - to - slightly yellow gel formulation . Phase A Compound 91 Active 1 . 0 5 . Finally pH of the gel was maintained at 5. 0 to 5 . 5 using Diethyleneglycol monoethyl Solvent 10 . 0 citric acid solution . ether Polyethlene glycol 400 Humectant 5 . 0 Propylene glycol Humectant 5 . 0 45 Composition Example 5 Phase B Hydroxyethyl cellulose Rheology 1. 7 modifier Topical formulation with partially suspended API (com Purified Water Vehicle q . s to 100 Phase C Ethylenediaminetetraacetic Chelating 0 . 10 pound 91 ) in cream formulation at pH 5 .0 - 5 .5 ( Table 16 ) acid dehydrate agent /buffering agent 50 TABLE 16 Benzyl alcohol Preservative 1 . 0 Propyl gallate Anti -oxidant 1 . 0 Composition Phase D Citric solution pH modifier q .s Ingredients Function ( % w / w ) Phase A Compound 91 Active 1 . 00 Method of Preparation : 55 Cyclopentasiloxane Emollient and 3 . 00 humectants 1 . Hydroxyethyl cellulose was added in portions into Cetostearyl alcohol Emollient 2 . 50 measured volume of water by maintaining stirring PEG - 2 Stearyl ether Emulsifier 2 . 00 speed at 100 - 150 rpm and allowed to swell for 1 hour PEG -21 Stearyl ether Emulsifier 2 . 00 at 80 - 100 rpm . (Phase B ) Dimethylisosorbide Solubilizer 5 . 00 Phase B Hydroxyethyl Rheology 1 . 7 2 . In a separate vessel , polyethylene glycol 400 , propyl- 60 cellulose modifier ene glycol, and diethylene glycolmonoethyl ether were Purified Water Vehicle q . s to 100 mixed together and compound 91 was added into the Phase C Ethylenediaminetetra Chelating 0 . 10 mixture in portions while stirring at 400 rpm for ~ 40 -45 acetic acid dihydrate agent Benzyl alcohol Preservative 1 . 00 min to get uniform dispersion . (Phase A ) Phase D Citric acid ( 20 % w / w pH modifier q .s 3 . The drug dispersion (Phase A ) was added into Phase B 65 * * solution in water ) and allowed to stir at ~ 50 - 100 rpm for about 30 minutes . US 10 ,071 , 103 B2 165 166 Method of Preparation : Example 17 : Determination of Minimum Inhibitory Concentration (MIC ) of Different Compounds and 1 . Hydroxyethyl cellulose was added in portions into their Formulations Against P. acnes Strains by measured volume of water by maintaining stirring Using Micro - Broth Dilution Method speed at 500 rpm and heated at 50 -55° C . (Phase B ) 5 2 . In a separate vessel , PEG - 2 Stearyl ether, PEG -21 Stearyl ether and cetostearyl alcohol were heated at Materials : 50 - 55° C . Cyclopentasiloxane and dimethylisosorbide Brain heart infusion broth , P . acnes strains (MTCC & were added into the mixture while stirring at 400 rpm . CCARM ) , 96 wells plate , Autoclave, Incubator, Anaerobic Compound 91 was added into the final mixture in 10 box with anaerobic gas pack , Plate reader (600 nm ), Alamar portions at 400 rpm for – 5 - 10 min to get uniform dispersion at 50° C . (Phase A ) Method : P. acnes MTCC( 3297, MTCC 1951 & CCARM 9010 ) are 3 . The drug dispersion (Phase A ) was added slowly into cultured in Brain Heart Infusion (BHI ) Broth at 37° C . for Phase B and allowed to stir at ~ 300 -400 rpm for about" 15 48 - 72 h under anaerobic condition . The test compounds/ 20 - 30 min till temperature reach at 40° C . formulations are initially diluted with suitable solvent and 4 . Finally ethylenediaminetetraacetic acid dihydrate and further diluted with BHI broth to get the required concen benzyl alcohol were added to the final mixture and trations. Samples ( 100 ul) of different concentrations (pre stirred for ~ 30 min at 400 rpm to obtain white - to pared by serial dilution ) are added to 96 -well plate . To the slightly yellow cream formulation . 20 wells , 100 ul of P . acnes BHI broth culture is added ?culture turbidity adjusted against 0 . 5 McFarland standard (approx 5 . Finally pH of the cream formulation is adjusted to 5 .0 1 .5x10° ) , and further diluted 100 - fold with sterile BHI to 5 . 5 using citric acid solution . broth ]. In addition Growth Control and Sterility Control are created using 100 ul each of P . acnes BHI broth culture and Composition Example 6 25 plain BHI broth , respectively . Plates are incubated at 37° C . for 48 -72 hrs under anaero Topical formulation with partially suspended API ( com - bic condition . The plate is read under Bio -Rad plate reader pound 91 ) in cream formulation at pH 5 . 0 -5 .5 ( Table 17 ) @ 595 nm for optical density to generate the dose -response curves . The MIC of the test compound is recorded by TABLE 17 30 addition of Alamar blue dye. Composition Examples 18 -22 and Tables 18 -223 describe some exem Ingredients plary novel formulations comprising stand - alone API ( e . g ., Function ( % w / w ) besifloxacin ) , either alone or in combination with adapalene . Phase Compound 91 Active 1 . 00 Cyclopentasiloxane Emollient and 3 . 00 35 humectant Example 18 : Micronized Besifloxacin Particle Cetostearyl alcohol Emollient 2 . 50 Dispersions (D1 ) PEG - 20 Sorbitan Emulsifier 2 . 00 monolaurate Sorbitan monolaurate Emulsifier 2 . 00 Preparation : Dimethylisosorbide Solubilizer 5 . 00 Phase B Carbopol 980 Rheology 0 . 6 40 Besifloxacin is dispersed in surfactant solution ( 2 % aque modifier ous solution of poloxamer 407 ). The resulting suspension is Purified Water Vehicle q .s to 100 passed through high pressure homogenizer at about 800 bar. Triethanolamine pH modifier q . The output dispersion is collected in a beaker and recycled Phase C Benzyl alcohol Preservative 1 . 00 10 times to yield a dispersion of appropriately sized particles 43 (particle size range of 2 um to 8 um ). The size distribution is determined by MasterSizer (Malvern Instruments ) and Method of Preparation : mean particle size found to be 4 . 1 um [Dv ( 10 )- 0 .8 um , Dv 1 . Gelling agent, carbopol 980 was added in portions to a (90 ) - 8 . 9 um ] . measured volume of water stirring at 100 - 150 rpm . 2 . pH of the gel mixture was adjusted to 5 . 5 with Example 19: Preparation ofGel and /Cream triethanolamine solution to allow swelling of carbopol Formulations Loaded with Besifloxacin Alone , and 980 in water and heated 50 - 55° C . (Phase B ) its Combination with Adapalene 3 . In a separate vessel, PEG - 20 Sorbitan monolaurate , sorbitan monolaurate , cetostearyl alcohol, Cyclopenta - 55 Gel and /Cream formulations containing besifloxacin are siloxane and dimethylisosorbide were added and formulated as per the compositions shown in Table 18 . heated at 50 -55° C . by maintaining stirring at 400 - 500 These gel formulations have off -white to slightly yellow rpm . To this final mixture compound 91 was added in appearance with the pH of 5 - 5 . 5 and viscosity of around portions at 400 rpm for -5 - 10 min to get uniform dis 5000 mPa . s . The formulations consist of besifloxacin 60 equivalent to 1 % w / w , in three different forms ( 1 ) micron persion at 50° C . (Phase A ) ized suspended besifloxacin HCl ( Table 18 , GLI , GL2 ), (2 ) 4 . The drug dispersion ( Phase A ) was slowly transferred fully solublised besifloxacin HCl ( Table 18 , GL4 ) and (3 ) into Phase B at 50 -55° C . by maintaining stirring speed besifloxacin particles suspended in cream formulation with 400 rpm and was cooled to 40° C . within 20 - 30 min . out sizing (CM1 ) . In addition to stand alone besifloxacin 5 . Finally , benzyl alcohol was added to the finalmixture 65 formulation , besifloxacin is combined with the adapalene and allowed to cool to room temperature to finally ( 0 . 1 % ) ( Table 18 , GL1) to provide both the anti - acne and obtain a white - to -slightly yellow cream formulation . keratolytic activity in patients suffering from acne. US 10 ,071 , 103 B2 167 168 TABLE 18 4 . PART C : Swell the carbopol separately in water for 2 Gel and /Cream Formulations for Compositions GL1, GL2 , GL3 , GL4 and CM1 5 . Add PART C into PART A / B and mix well for 20 min . Composition ( % ) 5 Example 21 : Minimum Inhibitory Concentration of in -House Besifloxacin Gels ( 1 % ) and its Sr . No . Ingredient GL1 GL2 GL3 GL4 CM1 Combination with Adapalene ( 0 . 1 % ) Water Carbopol 940 q. q. q. q. qs Method : Carbopol 980 NF0 0 0 80 . 0 . 6 10 Minimum inhibitory concentration of the test gels ( Table Hydroxy Propyl OOP 1 0 Cellulose - H 18 , GL1 and GL2 ) are determined by micro broth dilution auAWN Allantoin 0 . 2 0 . 2 0 .. 2 0 00 Besifloxacin HCl 1 (D1 ) 1 (D1 ) 0 1 1 method against P . acnes MTCC 1951 ( strain susceptible to ( equivalent to Clindamycin ) . BHIbroth and BHI agar media were prepared besifloxacin ) as per the manufacturer ' s instruction and autoclaved at 121° Adapalene 0 . 1 0 0 C . for 15 minutes . P . acnes culture is grown in Brain Heart Triethanolamine Infusion agar (BHIA ) at 37° C . for 48 h under anaerobic Sodium hydroxide 0 . 15 0 . 3 Glycerol condition . For MIC determination testing , gels are dissolved 11OOOO Propylene Glycol 5 in the solvent and further diluted with BHI broth . Then , 96 12 PEG 400 13 Poloxamer 407 0 .2 2 0. 2 20 wells plate are filled with 100 ul of BHI broth containing 14 Sod . Lauryl drug with different concentration to get the final concentra Sulphate tions of 0 . 06 , 0 . 13 , 0 . 25 , 0 . 5 , 1 and 2 ug /ml in different lanes Tween 80 Tween 20 ( lane 1 to lane 6 ) . Remaining lanes of the 96 well plate are va diethylene glycol used as growth control and sterility control. Finally , P . acnes monoethyl ether 25 culture suspension (approx 1. 5x109 ) is added in all the wells 18 CetylCetyl Alcohol oooooooooooouuu0 0 0 ooooooTaoFoo0 ONNUUNooooooouooo2 except sterility control wells and plate is incubated at 37° C . 19 LightLight Liquid 0 Ooooooooooooouuuono0 0 0 5 Paraffin for 48 - 72 h under anaerobic condition . At the end of 72 h , 20 CyclopentasiloxaneCyclopentasiloxane 0 0 0 0 5 Alamar blue solution ( 20 ul) is added into the wells and 21 Steareth 22 0 0 0 0 2 incubated at 37° C . for 2 h . Plate is visualized for bacterial 22 Steareth 21 0 0 0 0 2 30 BHT 30 inhibitions and MIC values of the tested samples are deter 24 Disodium EDTA 0 . 1 0 .05 mined . Gel formulation containing Besifloxacin alone, Besi 25 Phenoxyethanol 0 . 5 0 . 5 0 . 6 0 . 5 floxacin combination with adapalene and their placebo are analyzed for MIC determinations and results are shown in Method of Preparation : FIG . 6 . ( 1 ) Allantoin is heated to 50° C . to dissolve completely Results : and cooled down to RT . Minimum inhibitory concentration (MIC ) assay showed ( 2 ) Carbopol is added to above mixture and allowed to thatMIC values of the besifloxacin in both the formulations swell for 1 to 2 h . (GL1 and GL2 ) were found to be similar in the range of 0 . 13 ( 3 ) Dispersion ofmicronized Besifloxacin and adapalene powder is added to the swelled carbopol mixture and 40 ug/ ml to 0 .25 ug /ml (FIG . 6 ) . allowed to stir for 30 min at 400 rpm . ( 4 ) Then , glycerol, propylene glycol, PEG 400 , polox Example 22 : Dose Response Curve (Using Zones amer 407 is added followed by the addition of disodium of Inhibition ) ofGel Containing Besifloxacin EDTA solubilized in water and then add phenoxyetha Alone , its Combination Containing Adapalene nol to the above stirring mixture . After addition of all 45 Against P . acnes the ingredients, the mixture is allowed to stir for 30 min . Agar well -diffusion method is employed to run Zone of ( 5 ) Above mixture is neutralized with triethanolamine and Inhibition (ZOI ) assays . ZOI is employed to assess the allowed is stirring for 2 - 3 h at 800 rpm . potency of formulations ( Table 1 , GL1 and GL2 ) consist of 50 Besifloxacin alone and its combination with adapalene to Example 20 : Preparation of Cream Formulations inhibit the growth of microorganisms under study. ZOI ( CM1) Loaded with Besifloxacin HC1 values , determined at different API concentrations, can be used to derive dose - response - curves (DRCs ) for efficacy Cream formulation containing suspended Besifloxacin comparison of different formulations . particles are formulated as per the compositions shown in 55 Method : Table 18 . This gel formulation has off -white to slightly P . acnes cultured in Brain Heart Infusion (BHI ) Broth yellow appearance with the pH of 5 - 5 .5 and viscosity of (37° C ., 48 h ) under appropriate condition to get the desired 3060 mPa .s . CFU count, to be used to inoculate the plates . TSA plates are Procedure : spreaded with 100 ul of 0 . 5 McFarland equal bacterial 1 . Part A : Disperse Besifloxacin in glycerin and deionized 60 suspension . Sterile disc (6 mm ) are loaded with various water in the main vessel and heat to 70° C . concentration of gel formulations (equivalent to different 2 . Part B : Heat in cetyl Alcohol, light liquid paraffin , Besifloxacin concentration of 0 . 12 , 0 .25 , 0 . 5 and 1 ug /ml ) cyclopentasiloxane , steareth 2 , and steareth 21 and in a and / or controls ( 100 ul each ) and then disc has been placed separate vessel to 70° C . above the spreaded plates . Thereafter, the treated plates are 3 . Add PART B into PART A with continuous mixing at 65 incubated at 37° C . for 24 h . Readouts are taken after 24 h 70° C . and allow to mix for 15 min . Cool the batch with and effect of combination of two different APIs on anti- acne mixing to 45° C . activity is measured using Zone of Inhibition studies .