11111111111111 111111111111111111 IIIII IIIII 1111111111111111111111111 11111111
`US007014858B2
`
`(12) United States Patent
`Ashley
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,014,858 B2
`Mar.21,2006
`
`(54) USE METHODS OF TREATING ACNE AND
`TELANGIECTASIA
`
`(75)
`
`Inventor: Robert A. Ashley, Newtown, PA (US)
`
`(73) Assignee: CollaGenex Pharmaceuticals, Inc.,
`Newton, PA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 10/272,499
`
`(22) Filed:
`
`Oct. 15, 2002
`
`(65)
`
`Prior Publication Data
`US 2003/0139380 A1
`Jul. 24,2003
`
`Related U.S. Application Data
`(63) Continuation of application No. 10/117,709, filed on
`Apr. 5, 2002.
`(60) Provisional application No. 60/281,916, filed on Apr.
`5, 2001, provisional application No. 60/325,489, filed
`on Sep. 26, 2001.
`
`(51)
`
`Int. CI.
`A61K 6/00
`(2006.01)
`A61K 9/20
`(2006.01)
`A61K 31/65
`(2006.01)
`(52) U.S. Cl. ....................... 424/401; 424/464; 514/152
`(58) Field of Classification Search ................ 424/464,
`424/465, 401,468,451, 457; 514/152
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`6/1992 Ritter
`5,122,519 A
`5,505,949 A *
`4/1996 Benitez ...................... 424/401
`10/1997 Tomas et a!.
`5,674,539 A
`
`pHOIDIDXIC!TX INDEX
`
`EP
`wo
`wo
`
`10/1998 Ramamurthy et a!. ...... 514/152
`5,827,840 A *
`5,908,838 A
`6/1999 Gans .......................... 514/152
`5,998,390 A *
`12/1999 Ramamurthy et at. ........ 514/94
`1/2000 Wirostko .................... 514/152
`6,015,803 A *
`10/2000 Parks ......................... 514/453
`6,133,310 A *
`6,664,287 B1 *
`12/2003 Avery eta!. ................ 514/436
`FOREIGN PATENT DOCUMENTS
`0 410 099 A1
`1/1991
`wo 83/00628
`3/1983
`wo 99/58131
`11/1999
`OTIIER PUBLICATIONS
`Akamatsu, et al. "Effect of Keigai-Rengyo-To, a Japanese
`Kampa Medicine, on Neutorphil Functions: a Possible
`Mechanism of Action of Keigai-Rengyo-To in Acne," The
`Journal of International Medical Research, 25:255-265
`(1997).
`Baer, et al. "High-Dose Tetracycline Therapy in Severe
`Acne," Arch Dennatol, 112:479-481 (Apr. 1976).
`Cheryl Guttman, "Emerging resistance changes face of
`antibiotic therapy for acne," Dennatology Times, Jan. 2001,
`p. 22.
`Hirohiko Akamatsu, Maid Asada, Jinro Komurra, Yasuo
`Asada, and Yulde Niwa, "Effect of Doxycycline on the
`Generation of Reactive Oxygen Species: A Possible Mecha-
`nism of Action of Acne Therapy with Doxycycline," Acta
`Derm 1knereol (Stockh) 72:178-178 (1992).
`(Continued)
`Primary Examiner-Thurman K. Page
`Assistant Examiner-S. Tran
`(74) Attorney, Agent, or Finn-Hoffmann & Baron, LLP
`
`(57)
`
`ABSTRACT
`
`A method of treating telangiectasia in a human in need
`thereof comprising administering to said human a tetracy-
`cline compound in an amount that is effective to treat
`telangiectasia, but has substantially no antibiotic activity.
`
`32 Claims, 1 Drawing Sheet
`
`100
`
`1000.-------------------------------,
`1af 7
`41~6 :1·~~\67
`2aair
`
`PHOTOIRRITANCY
`FACTOR (PIF)
`
`10
`
`23.16
`15.8
`5.38 I
`5.27
`5.17
`2. 4
`182
`1.54
`1.0 117
`1.0
`1.0
`1 1o 1 1;o 1 11o 1 1;o 1
`
`Dr. Reddy's Laboratories, Ltd., eta\.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1026
`
`Exh. 1026
`
`

`
`US 7,014,858 B2
`Page 2
`
`01HER PUBLICATIONS
`Bodokh, Y. Jacomet, J. Ph. Lacour and J.P. Ortonne,
`"Minocycline Induces an Increase in the Number of Excret-
`ing Pilosebaceous Follicles in Acne Vulgaris," Acta Derm
`Venereal (Stockh) 77:255-259 (1997).
`W. J. Cunliffe, M.D., F.R.C.P., "Evolution of a Strategy for
`the Treatment of Acne, "Acad Dermata!, 16:591-9 (1987).
`E. Anne Eady, Eileen Ingham, Christina E. Walters,
`Jonathan H. Cove, and William J. Cunliffe, "Modulation of
`Comedonal Levels of Interleukin-1 in Acne Patients Treated
`with Tetracyclines," J. Invest Dermata!, 101:86-91 (1993).
`Boni E. Elewski, M.D., Beth A.J. Lamb, W. Mitchell Sams,
`Jr., M.D., and W. Ray Gammon, M.D., "In Vivo Suppression
`of Neutraphil Chemotaxis by Systemically and Topically
`Administered Tetracycline," J Am Acad Dermata!, 8:807-
`812 (1983).
`Nancy B. Esterly, M.D., Nancy L. Furey, M.D., and Lillian
`E. Flanagan, B.S., "The Effect of Antimocrabial Agents on
`Leukocyte Chemotaxis," The Journal of Investigative Der-
`matology, 70(1):51-55 (1978).
`Sainte-Marie,
`I. Tenaud, 0. Jumbou and B. Dreno,
`"Minocycline Modulation of Alpha-MSH Praduction by
`Keratinocytes In vitra," Acta Derm Venereal 79:265-267
`(1999).
`Hoshiki Miyachi, M.D., Akira Yoshioka, M.D., Sadao
`Imamura, M.D., and Yukie Niwa, M.D., "Effect of Antibi-
`otics on the Generation of Reactive Oxygen Species," J
`Invest Dermata!, 86(4):449-453 (1986).
`Gerd Plewig, M.D., and Erwin Schöpf, M.D., "Anti-Infiam-
`matory Effects of Antimicrabial Agents: An In Vivo Study,"
`The Journal of Investigative Dermatology, 65:532-536
`(1975).
`M. Toyoda and M. Morohashi, "An Overview of Topical
`Antibiolies for Acne Treatment," Dermatology, 196:130-134
`(1998).
`Sheila E. Unkles, and Curtis G. Gemmell, "Effect of
`Clindamycin, Erythramycin, Lincomycin, and Tetracycline
`on Grawth and Extracellular Lipase Praduction by
`Prapionibacteria In Vitra," Antimicrobial Agents and Che-
`motherapy, 21:39-43 (1982).
`
`G.F. Webster, K.J. McGinley, and J.J. Leyden, "Inhibition of
`Lipase Praduction in Propionibacterium acnes by Sub-
`Minimal-Inhibitory Concentrations of Tetracycline and
`Erythramycin," British Journal of Dermatology, 104:453-
`457 (1981).
`Guy F. Webster, M.D., Ph.D., Susan M. Toso, M.S., and Lutz
`Hegemann, M.D., Ph.D., "Inhibition of a Model of In Vitra
`Granuloma Formation by Tetracyclines and Ciprafioxacin,"
`Arch Dermata!., 130:748-752 (1994).
`Reynold C. Wong, M.D., Sewon Kang, M.P.H., Jan L.
`Heezen, L.P.N. John J. Voorhees, M.D., and Charles N. Ellis,
`M.D., "Oral Ibuprafen and Tetracycline for the Treatment of
`Acne Vulgaris," J AmAcadDermatol, 11:1076-1081 (1984).
`Kenneth S. Kornman and Edward H. Karl, "The Effect of
`Lang-Term Low-Dose Tetracycline Therapy on the Subgin-
`gival Micrafiora in Refractory Adult Periodontitis," J. Peri-
`odontol. 53(10) 604-610 (Oct. 1982).
`Bikowski, J.B., "Treatment of rasacea with doxycycline
`monohydrate," Curtis. 2000 Aug., 66(2): 149-152.
`Jimenez-Acosta, "Response to tetracycline of telangiecta-
`sias in male hemophilliac with human immunodeficiency
`virus infection," J. Am. Acad. DermataL Aug., 19, 1988(2 Pt
`1):369-379.
`Torresani, C., "Clarithramycin versus doxycycline in the
`treatment of rasaecea," Int. J. Clin. DermataL Dec. 1997,
`36(12):942-946.
`McClellan, K.J., "Topical Metranidazole. Areview of its use
`in rasaea," Am. 1. Clin. DermataL May-Jun. 2000, 1(3):191-
`199.
`Quarterman, M.J., "Ocular Rosacea. Signs, symptoms and
`tear studies before and after treatment with doxycycline,"
`Arch. DermataL Jan. 1997, 133(1):49-54.
`Skidmore et aL, "Effects of Subantimicrabial-Dose Doxy-
`cycline in the Treatment of Moderate Acne," Archives of
`Dermatology 139:459-464 (Apr. 2003), XP009047590.
`
`* cited by examiner
`
`Exh. 1026
`
`

`
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`~
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`
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`
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`
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`
`I
`
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`
`COL-313
`
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`
`DOXYCYCLINE
`COL-314
`
`TETRACYCLINE
`COL-302
`
`COL-303
`
`COL-315
`
`COL-807
`
`COL-309
`
`CMT-10
`
`MINOCYCLINE
`COL-306
`
`COL-307
`
`COL-1002
`
`COL-805
`
`COL-804
`
`COL-802
`
`COL-801
`
`COL-308
`
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`jj;
`165 !,,
`547
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`23.371
`
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`41 1
`
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`
`62.67
`
`60.27
`
`1000-.------------------......--,
`
`F,IG. l PHOTOTOXICITY INDEX
`
`1
`
`10-
`
`100-
`
`PHOTOIRRITANCY
`
`FACTOR (PIF)
`
`Exh. 1026
`
`

`
`1
`USE METHODS OF TREATING ACNE AND
`TELANGIECTASIA
`
`2
`The numbering system of the multiple ring nucleus is as
`follows:
`
`US 7,014,858 B2
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`5
`
`Structure B
`
`This application is a continuation of co-pending U.S.
`application Ser. No. 10/117,709, filed Apr. 5, 2002. This
`application claims benefit of U.S. Provisional Application 10
`No. 60/281,916, filed Apr. 5, 2001; and U.S. Provisional
`Application No. 60/325,489, filed Sep. 26, 2001, all of
`which are incorporated herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`Acne is a common disease characterized by various types
`of lesions. The areas affected typically are areas of the skin
`where sebaceous glands are largest, most numerous, and
`most active. The lesions associated with acne are usually 20
`categorized as either non-infiammatory or infiammatory.
`Non-infiammatory lesions include comedones. Come-
`dones appear in two forms, open and closed. Comedones are
`thought to arise from abnormal follicular differentiation.
`Instead of undergoing shedding and discharge through the
`follicular orifice, abnormal desquamated cells (kerati-
`nocytes) become unusually cohesive, forming a micro-
`comedo or a microscopic hyperkeratotic plug in the folli-
`cular canal. The progressive accumulation of
`these
`microcomedones lead to visible comedones.
`In its mildest form, acne is a more or less superficial
`disorder characterized by slight, spotty skin irritations. In
`such cases, ordinary skin hygiene is typically a satisfactory
`treatment. In the more infiammatory types of acne, however,
`pustules; infected cysts; and in extreme cases, canalizing,
`infiamed and infected sacs appear. Without effective treat-
`ment, these lesions may become extensive and leave per-
`manent, disfiguring scars.
`Microorganisms, especially Prapianibacterium acnes, are
`strongly implicated in the pathogenesis of acne. The micro-
`organisms are thought to release microbial mediators of
`infiammation into the dermis or trigger the release of cytok-
`ines from ductal keratinocytes.
`Accordingly, the efficacy of antibiolies in treating acne is
`thought to be due, in significant part, to the direct inhibitory
`effect of the antibiolies on the growth and metabolism of
`these microorganisms. Systemically-administered tetracy-
`cline antibiotics, especially minocycline hydrochloride, are 50
`particularly effective in treating acne.
`The tetracyclines are a class of compounds of which
`tetracycline is the parent compound. Tetracycline has the
`following general structure:
`
`Structure A
`
`~(CH3)2
`
`OH
`
`CONH2
`
`OH
`
`0
`
`OH
`
`0
`
`Tetracycline, as well as the 5-hydroxy (oxytetracycline,
`e.g. Terramycin) and 7-chloro (chlorotetracycline, e.g.
`Aureomycin) derivatives, exist in nature, and are all well
`known antibiotics. Semisynthetic derivatives such as 7-dim-
`15 ethylaminotetracycline (minocycline) and 6a-deoxy-5-hy-
`droxytetracycline (doxycycline) arealso known tetracycline
`antibiotics. Natural tetracyclines may be modified without
`losing their antibiotic properties, although certain elements
`of the structure must be retained to do so.
`In addition to the direct antibiotic activity of tetracyclines,
`further activities of antibiotic tetracyclines have been inves-
`tigated for possible therapeutic effects on acne. For example,
`a study by Elewski et al., J. Amer. Acad. Dermata!.,
`8:807-812 (1983) suggests that acne therapy, consisting of
`25 orally-administered tetracycline at a total daily dose of 1000
`mg, may have therapeutic anti-infiammatory effects in addi-
`tion to antibiotic effects. In particular, it was found that the
`anti-infiammatory effect of tetracycline was, at least in part,
`due to inhibition of neutrophil chemotaxis induced by bac-
`30 terial chemotactic factors.
`A more recent study, performed by Eady et al., J. Invest.
`Dermata!., 101:86-91 (1993), evaluated the effects of oral
`minocycline or tetracycline therapy on the cytokine and
`microfiora content of open comedones in acne patients. The
`35 total daily dose of minocycline administered was 100 mg.
`The total daily dose of tetracycline administered was 1000
`mg.
`Eady et al. found that the therapies upregulated the
`production of bioactive IL-1a-like material and immu-
`40 nochemical IL-1ß. IL-1 is considered to be a pro-infiam-
`matory cytokine.
`Accordingly to Eady et al., no overall decrease in the
`numbers of propionibacteria/mg of comedonal material was
`45 found. It is important to note, however, that the numbers of
`propionibacteria/mg of comedonal material are not expected
`to decrease in respause to antibiotic therapy. Since the
`bacteria within comedones are encapsulated by the follicle,
`they are not susceptible to antibiotic treatment.
`Another possible activity of tetracyclines in acne therapy
`was investigated by Bodokh, 1., et al.,Acta. Derm. Veneral.,
`77:255-259 (1997). Their study was designed to evaluate
`the action of minocycline on sebaceous excretion in acne
`patients. A 100 mg daily dose of minocycline was admin-
`55 istered. A subclinical increase in seborrhoea was reported.
`The authors propose that minocycline induces an increase in
`seborrhoea via a reduction in ductal obstruction. The mecha-
`nism by which the ductal obstruction is reduced is proposed
`to be a reduction in ductal irritation. The authors suggest that
`60 the reduction of ductal irritation is due to minocycline's
`direct effect on P. acnes, or minocycline's effect on the
`lipase produced by P. acnes.
`Bodokh et al. also found that during treatment no corre-
`lation exists between seborrhoea intensity and clinical sever-
`65 ity of acne. The authors state that the lack of correlation
`shows that seborrhoea is pathogenic because it is the "cul-
`ture medium" of P. acnes. Thus, it can be concluded that the
`
`Exh. 1026
`
`

`
`US 7,014,858 B2
`
`4
`
`R8
`
`R9
`
`hydrogen
`hydrogen
`hydrogen
`
`amino
`palmitamide
`dimethylamino
`
`COL
`
`308
`311
`306
`
`R7
`
`hydrogen
`hydrogen
`hydrogen
`
`5
`
`10 For structures L, M, N or 0 the compounds indicated are as
`follows:
`
`15
`
`COL
`
`R7
`
`R8
`
`R9
`
`801
`802
`804
`805
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`acetamido
`dimethylaminoacetamido
`nitro
`amino
`
`For structure P, R8 is hydrogen and R9 is nitro.
`
`DETAILED DESCRIPTION
`
`3
`authors consider the antibiotic activity of minocycline to be
`therapeutically significant with respect to acne.
`Similarly, in a recent clinical study it was reported that
`tetracycline in sub-antibiotic doses had no clinical effect on
`acne. (Cunliffe et al., J. Am. Acad. Dermata!., 16:591-9
`(1987).) In particular, a 100 mg total daily dose of minocy-
`cline and a 1.0 g total daily dose of tetracycline were found
`to be necessary to successfully treat acne.
`The antibiotic effects of antibiolies are generally directly
`proportional to the dose administered of the antibiotics.
`Accordingly, in moderate to severe (i.e. infiammatory)
`forms of acne, oral antibiolies are typically administered at
`high doses. For example, in conventional acne therapy,
`tetracycline is administered at an initial dose of 500 to 2,000
`mg/day, followed by a maintenance dose of 250--500
`mg/day.
`Clearly, the state-of-the-art teaching is that the clinical
`efficacy of systemically-administered tetracyclines in the
`treatment of acne is due, at least in significant part, to the
`antibiotic effects of the tetracyclines. In addition to their 20
`antibiotic effects, it has been proposed that tetracyclines
`reduce the number of infiammatory lesions (papules, pus-
`tules and nodules) by a variety of non-antibiotic mecha-
`nisms. Such mechanisms include interfering with the
`chemotaxis of polymorphonuclear leukocytes (PMN) into 25
`the infiammatory lesion, inhibition of PMN derived colla-
`genase, and by scavenging reactive oxidative species pro-
`duced by resident infiammatory cells.
`There is no disclosure in the prior art of using either a
`sub-antibiotic dose of an antibiotic tetracycline compound, 30
`or of using a non-antibiotic tetracycline compound for the
`treatment of acne.
`The use of tetracycline antibiotics, however, can lead to
`undesirable side effects. For example, the lang term admin-
`istration of antibiotic tetracyclines can reduce or eliminate
`healthy microbial fiora, such as intestinal fiora, and can lead
`to the production of antibiotic resistant organisms or the
`overgrowth of yeast and fungi.
`Accordingly, there is a need for an effective treatment of
`acne which causes fewer undesirable side effects produced
`by the systemically-administered antibiolies used in conven-
`tional acne therapy.
`SUMMARY OF INVENTION
`
`The present invention provides methods of treating acne.
`As used herein, the term "acne" is a disorder of the skin
`characterized by papules, pustules, cysts, nodules, come-
`dones, and other blemishes or skin lesions. These blemishes
`and lesions are often accompanied by infiammation of the
`skin glands and pilosebaceous follicles, as well as, micro-
`bial, especially bacterial, infection.
`For the purposes of this specification, acne includes all
`known types of acne. Same types of acne include, for
`example, acne vulgaris, cystic acne, acne atrophica, bromide
`35 acne, chlorine acne, acne conglobata, acne cosmetica, acne
`detergicans, epidemic acne, acne estivalis, acne fulminans,
`halogen acne, acne indurata, iodide acne, acne keloid, acne
`mechanica, acne papulosa, pomade acne, premenstral acne,
`acne pustulosa, acne scorbutica, acne scrofulosorum, acne
`40 urticata, acne varioliformis, acne venenata, propionic acne,
`acne excoriee, gram negative acne, steroid acne, nodulocys-
`tic acne and acne rosacea. Acne rosacea is characterized by
`infiammatory lesions ( erythema) and telangiectasia.
`Telangiectasia is abnormally and permanently dilated
`45 blood vessels associated with a number of diseases. For
`example, facial telangiectasia is associated with age, acne
`rosacea, sun exposure, and alcohol use. Other diseases
`associated with telangiectasia include, for example, sclero-
`derma, hereditary hemorrhagic telangiectasia (Olser-Rendu
`syndrome ), Ataxia-Telangiectasia, spider angioma, cutis
`marmorata telangiectasia congenita, Bloom syndrome, Klip-
`pel-Trenaunay-Weber syndrome, Sturge-Weber disease,
`Xeroderma pigmentosa and Nevus fiammeus.
`Telangietcasia can develop anywhere within the body, but
`can be easily seen in the skin, mucous membranes and
`whites of the eyes. Same forms of telangiectasia may be
`asymptomatic, however, some forms of telangiectasia bleed
`readily and cause significant problems. For example, telang-
`iectasia can occur in the brain and cause problems from
`60 bleeding.
`The present invention is effective in treating telangiectasia
`caused by any disease or condition. The method comprises
`the administration of a tetracycline compound, to a human,
`in an amount which is effective for the treatment of telang-
`iectasia, but which has substantially no antibiotic activity.
`The present invention is particularly effective in treating
`comedones, e.g., reducing the number of comedones. Both
`
`50
`
`The present invention provides a method of treating acne
`in a human in need thereof. The method comprises admin-
`istering systemically to the human a tetracycline compound
`in an amount that is effective to treat acne but has substan-
`tially no antibiotic activity (i.e. substantially no antimicro-
`bial activity), without administering a bisphosphonate com-
`pound.
`Additionally, the present invention provides methods for
`reducing the number of comedones, inhibiting oxidation of
`melanin, and/or inhibiting lipid-associated abnormal folli-
`cular differentiation in a human in need thereof. These 55
`methods comprise administering systemically to the human
`a tetracycline compound in an amount that is effective for its
`purpose, e.g., to reduce the number of comedones, to inhibit
`oxidation of melanin, and/or to inhibit lipid-associated
`abnormal follicular differentiation, but has substantially no
`antibiotic activity.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the photoirritancy factor (PIF) for some 65
`tetracycline compounds. For structure K, the compounds
`indicated are as follows:
`
`Exh. 1026
`
`

`
`US 7,014,858 B2
`
`50
`
`5
`open and closed comedones can be treated in accordance
`with the methods of this invention.
`The present invention can also be used to treat certain
`other types of acneiform dermal disorders, e.g. perioral
`dermatitis, seborrheic dermatitis in the presence of acne, 5
`gram negative folliculitis, sebaceous gland dysfunction,
`hiddradenitis suppurativa, pseudo-folliculitis barbae, or fol-
`liculitis.
`The method comprises the administration of a tetracycline
`compound to a human in an amount which is effective for its 10
`purpose e.g., the treatment of acne, including reducing the
`number of comedones, but which has substantially no anti-
`biotic activity.
`The tetracycline compound can be an antibiotic or non-
`antibiotic compound. The tetracycline compound has the 15
`general tetracycline structure indicated above, or a deriva-
`tive thereof.
`Same examples of antibiotic (i.e. antimicrobial) tetracy-
`cline compounds include doxycycline, minocycline, tetra-
`cycline, oxytetracycline, chlortetracycline, demeclocycline, 20
`lymecycline and their pharmaceutically acceptable salts.
`Doxycycline is preferably administered as its hyclate salt or
`as a hydrate, preferably monohydrate.
`Non-antibiotic tetracycline compounds are structurally
`related to the antibiotic tetracyclines, but have had their 25
`antibiotic activity substantially or completely eliminated by
`chemical modification. For example, non-antibiotic tetracy-
`cline compounds are capable of achieving antibiotic activity
`comparable to that of tetracycline or doxycycline at con-
`centrations at least about ten times, preferably at least about 30
`twenty five times, greater than that of tetracycline or doxy-
`cycline, respectively.
`Examples of chemically modified non-antibiotic tetracy-
`clines ( CMTs)
`include 4-de( dimethylamino )tetracycline
`(CMT-1), tetracyclinonitrile (CMT-2), 6-demethyl-6-deoxy-
`4-de( dimethylamino )tetracycline ( CMT-3), 7 -chloro-4-de
`( dimethylamino )tetracycline (CMT-4), tetracycline pyrazole
`( CMT-5),
`4-hydroxy-4-de( dimethylamino )tetracycline
`( CMT-6),
`4-de( dimethylamino-12a-deoxytetracycline
`(CMT-7), 6-deoxy-5a-hydroxy-4-de(dimethylamino )tetra- 40
`cycline
`( CMT-8), 4-de( dimethylamino )-12a-deoxyanhy-
`drotetracycline ( CMT-9), 4-de( dimethylamino )minocycline
`(CMT-10).
`Further examples of chemically modified non-antibiotic
`tetracyclines include Structures C-Z. (See Index of Struc- 45
`tures.) Tetracycline derivatives, for purposes of the inven-
`tion, may be any tetracycline derivative, including those
`compounds disclosed generically or specifically in co-pend-
`ing U.S. patent application Ser. No. 09/573,654 filed on May
`18, 2000, which are herein incorporated by reference.
`tetracycline compound
`The minimal amount of the
`administered to a human is the lowest amount capable of
`providing effective treatment of acne. Effective treatment is
`a reduction or inhibition of the blemishes and lesions
`associated with acne. The amount of the tetracycline com-
`pound is such that it does not significantly prevent the
`growth of microbes, e.g. bacteria.
`Two ways in which to describe the administered amount
`of a tetracycline compound is by daily dose, and by serum
`level.
`For example, tetracycline compounds that have signifi-
`cant antibiotic activity may be administered in a dose (i.e.
`amount) which is 10-80% of the antibiotic dose. More
`preferably, the antibiotic tetracycline compound is admin-
`istered in a dose which is 40-70% of the antibiotic dose.
`Same examples of antibiotic doses of members of the
`tetracycline family include 50, 75, and 100 mg/day of
`
`6
`doxycycline; 50, 75, 100, and 200 mg/day of minocycline;
`250 mg of tetracycline one, two, three, or four times a day;
`1000 mg/day of oxytetracycline; 600 mg/day of demeclo-
`cycline; and 600 mg/day of lymecycline.
`Examples of the maximum non-antibiotic doses of tetra-
`cyclines based on steady-state pharmacokinetics are as fol-
`lows: 20 mg/twice a day for doxycycline; 38 mg of minocy-
`cline one, two, three or four times a day; and 60 mg of
`tetracycline one, two, three or four times a day.
`In a preferred embodiment, to reduce the number of
`comedones, doxycycline is administered in a daily amount
`of from about 30 to about 60 milligrams, but maintains a
`concentration in human plasma below the threshold for a
`significant antibiotic effect.
`In an especially preferred embodiment, doxycycline
`hyclate is administered at a 20 milligram dose twice daily.
`Such a formulation is sold for the treatment of periodontal
`disease by CollaGenex Pharmaceuticals, Inc. of Newtown,
`Pa. under the trademark Periostat®.
`Example 38 below summarizes a clinical study using 20
`mg doxycycline hyclate tablets administered twice a day. A
`significant reduction in the number of comedones was
`observed. This reduction in the number of comedones is
`unexpected. The reduction is particularly unexpected since,
`as can be seen from the microbiology results in Example 38,
`the treatment with doxycycline resulted in no reduction of
`skin microfiora vis-a -vis a placebo control.
`The administered amount of a tetracycline compound
`described by serum levels follows.
`An antibiotic tetracycline compound is advantageously
`administered in an amount that results in a serum tetracy-
`cline concentration which is 10-80% of the minimum anti-
`biotic serum concentration. The minimum antibiotic serum
`35 concentration is the lowest concentration known to exert a
`significant antibiotic effect.
`Same examples of the approximate antibiotic serum con-
`centrations of members of the tetracycline family follow.
`For example, a single dose of two 100 mg minocycline
`HCl tablets administered to adult humans results in minocy-
`cline serum levels rauging from 0.74 to 4.45 ,ug!ml over a
`period of an hour. The average level is 2.24 ,ug!ml.
`Two hundred and fifty milligrams of tetracycline HCl
`administered every six hours over a twenty-four hour period
`produces a peak plasma concentration of approximately 3
`,ug!ml. Five hundred milligrams of tetracycline HCl admin-
`istered every six hours over a twenty-four hour period
`produces a serum concentration level of 4 to 5 ,ug/ml.
`In one embodiment, the tetracycline compound can be
`administered in an amount which results in a serum con-
`centration between about 0.1 and 10.0 ,ug/ml, more prefer-
`ably between 0.3 and 5.0 ,ug/ml. For example, doxycycline
`is administered in an amount which results in a serum
`55 concentration between about 0.1 and 0.8 ,ug/ml, more pref-
`erably between 0.4 and 0.7 ,ug!ml.
`Same examples of the plasma antibiotic threshold levels
`of tetracyclines based on steady-state pharmacokinetics are
`as follows: 1.0 ,ug/ml for doxycycline; 1.0 ,ug/ml for minocy-
`60 cline; and 0.5 ,ug/ml for tetracycline.
`Non-antibiotic tetracycline compounds can be used in
`higher amounts than antibiotic tetracyclines, while avoiding
`the indiscriminate killing of microbes, and the emergence of
`resistant microbes. For example, 6-demethyl-6-deoxy-4-de
`65 (dimethylamino)tetracycline (CMT-3) may be administered
`in doses of about 40 to about 200 mg/day, or in amounts that
`result in serum levels of about 1.55 ,ug/ml to about 10 ,ug/ml.
`
`Exh. 1026
`
`

`
`US 7,014,858 B2
`
`8
`Structure K
`
`5
`
`7
`The actual preferred amounts of tetracycline compounds
`in a specified case will vary according to the particular
`compositions formulated, the mode of application, the par-
`ticular sites of application, and the subject being treated.
`The tetracycline compounds can be in the form of phar-
`maceutically acceptable salts of the compounds. The term
`"pharmaceutically acceptable salt" refers to a salt prepared
`from tetracycline compounds and pharmaceutically accept-
`able non-toxic acids or bases. The acids may be inorganic or 10
`organic acids of tetracycline compounds. Examples of inor-
`ganic acids include hydrochloric, hydrobromic, hydroiodic,
`sulfuric, and phosphoric acids. Examples of organic acids
`include carboxylic and sulfonic acids. The radical of the
`organic acids may be aliphatic or aromatic. Same examples 15
`of organic acids include formic, acetic, phenylacetic, pro-
`pionic, succinic, glycolic, glucuronic, maleic,
`furoic,
`glutamic, benzoic, anthranilic, salicylic, phenylacetic, man-
`delic, embonic (pamoic), methanesulfonic, ethanesulfonic,
`panthenoic, benzenesulfonic, stearic, sulfanilic, alginic, tar- 20
`taric, citric, gluconic, gulonic, arylsulfonic, and galacturonic
`acids. Appropriate organic bases may be selected, for
`example,
`from N,N-dibenzylethylenediamine, chlorop-
`rocaine, choline, diethanolamine, ethylenediamine, meglu-
`mine (N-methylglucamine), and procaine.
`The tetracycline compounds mentioned above, especially
`doxycycline and minocycline, are unexpectedly effective in
`reducing the number of comedones when administered at a
`dose which has substantially no antibiotic effect. Preferably
`the reduction is at least about 20% greater than for a placebo
`control, more preferably at least about 30% greater than for
`a placebo control, most preferably at least about 40% greater
`than for a placebo control, and optimally at least about 50%
`greater than for a placebo control.
`The inventors are not certain of, and do not wish to be
`limited by, any particular mechanism of action. Neverthe-
`less, it is believed that the ability of tetracyclines, such as
`doxycycline, to inhibit oxidation of melanin and to inhibit
`lipid-associated abnormal follicular differentiation prevents 40
`keratinocytes from becoming cohesive, thereby inhibiting
`the formation of comedones.
`Preferably, the tetracycline compounds have low photo-
`toxicity, or are administered in an amount that results in a
`serum level at which the phototoxicity is acceptable. Pho-
`totaxicity is a chemically-induced photosensitivity. Such
`photosensitivity renders skin susceptible to damage, e.g.
`sunburn, blisters, accelerated aging, erythemas and eczema-
`toid lesions, upon exposure to light, in particular ultraviolet
`light. The preferred amount of the tetracycline compound
`produces no more phototoxicity than is produced by the
`administration of a 40 mg total daily dose of doxycycline.
`Phototaxicity can be evaluated in terms of a photoirri-
`tancy factor (PIF), as described in the examples. APIF value
`of about 1.0 indicates that a compound is considered to have
`no measurable phototoxicity.
`The low phototoxic derivatives preferably have PIF val-
`ues no greater than about 5, preferably no greater than about 60
`2, more preferably no greater than about 1.5, most preferably
`no greater than about 1.2, and optimally about 1.
`Same antibiotic tetracyclines having low phototoxicity
`include, for example, minocycline and tetracyline.
`Same non-antibiotic tetracyclines having low phototox-
`icity include, but are not limited to, tetracycline compounds
`having the general formulae:
`
`wherein: R7, R8, and R9 taken tagether in each case, have
`the following meanings:
`
`R7
`
`hydrogen
`hydrogen
`hydrogen
`
`RS
`
`hydrogen
`hydrogen
`hydrogen
`
`R9
`
`amino
`palmitamide
`dimethylamino
`
`and
`
`STRUCTURE L
`STRUCTURE N
`
`STRUCTURE M
`STRUCTURE 0
`
`wherein: R7, R8, and R9 taken tagether in each case, have
`the following meanings:
`
`R7
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`RS
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`R9
`
`acetamido
`dimethylaminoacetamido
`nitro
`amino
`
`and
`
`Structure P
`
`25
`
`30
`
`35
`
`wherein: R8, and R9 taken tagether are, respectively, hydro-
`gen and nitro.
`The tetracycline compounds are administered without
`administering a bisphosphonate compound. Bisphospha-
`nales compounds are related to inorganic pyrophosphonic
`acid. The bisphosphonates
`include, as non-limiting
`examples, alendronate ( ( 4-amino-1-hydroxybutylidene) bis-
`phosphonic acid), clodronate (dichloromethane diphospho-
`45 nie acid), etidronate ((1-hydroxyethylidene) diphosphanic
`acid) and pamidronate ((3-amino-1-hydroxypropylidene)
`bisphosphonic acid); also risedronate ([ -hydroxy-2-(3-py-
`ridinyl)ethylidene] bisphosphonic acid), tiludronate, i.e.,
`tiludronic acid ([( 4-chlorophenyl) thio] methylene] bispho-
`50 sphonic acid) and zolendronate.
`The tetracycline compounds may, for example, be admin-
`istered systemically. For the purposes of this specification,
`"systemic administration" means administration to a human
`by a method that causes the compounds to be absorbed into
`55 the bloodstream