111111 11111111 111111111111111111 11111 11111 11111 1111111111 1111111111 11111111
`US007211267B2
`
`c12) United States Patent
`Ashley
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,211,267 B2
`May 1, 2007
`
`(54) METHODS OF TREATING ACNE
`
`(75)
`
`Inventar: Robert A. Ashley, Newtown, PA (US)
`
`(73) Assignee: CollaGenex Pharmaceuticals, Inc.,
`Newton, PA (US)
`
`(") Notice:
`
`Subject to any disclaimer, the termoftbis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 10/117,709
`
`(22) Filed:
`
`Apr. 5, 2002
`
`(65)
`
`Prior Publlcation Data
`US 2003/0130240 Al
`Jul. 10, 2003
`
`Related U.S. Application Data
`(60) Provisiona1 app1ication No. 60/325,489, fi1ed on Sep.
`26, 2001, provisional application No. 60/281,916,
`fi1ed on Apr. 5, 2001.
`
`(51)
`
`Int. Cl.
`A61K 9120
`(2006.01)
`A61K 9148
`(2006.01)
`A61K 9168
`(2006.01)
`A61K 37118
`(2006.01)
`(52) U.S. Cl . ...................... 424/401; 424/440; 424/451;
`424/464; 514/152
`(58) Field of Classification Search ................ 424/401,
`424/464, 465,468,451, 457; 514/152
`See app1ication fi1e for comp1ete search history.
`References Cited
`U.S. PATENT DOCUMENTS
`4,704,383 A * 11/1987 McNamara et al ......... 514/152
`
`(56)
`
`5,122,519 A *
`5,157,046 A •
`5,413,777 A •
`5,532,227 A •
`5,674,539 A
`5,827,840 A •
`5,908,838 A •
`5,998,390 A *
`6,664,287 B2 •
`6,673,843 B2 •
`7,014,858 B2 •
`2003/0082120 Al •
`2003/0139380 Al •
`
`6/1992 Ritter ......................... 514/152
`10/1992 Van Wauwe et al ........ 514/397
`5/1995 Sheth et al ................. 424/490
`7/1996 Golub et al ................. 514/152
`10/1997 Tomas et al.
`10/1998 Ramamurthy et al. ...... 514/152
`6/1999 Gans .......................... 514/152
`12/1999 Ramamurthy et al. ........ 514/94
`12/2003 Avery et al. ................ 514/436
`112004 Arbiser ....................... 514/679
`3/2006 Ashley ....................... 424/401
`5/2003 Mitstein ...................... 424/59
`7/2003 Robert ....................... 514/152
`
`FOREIGN PATENT DOCUMENTS
`0 410 099 Al
`111991
`02006437 A
`1/1990
`wo 83/00628
`3/1983
`wo 99/58131
`1111999
`
`•
`
`EP
`JP
`wo
`wo
`
`OTHER PUBLICATIONS
`Wong et al. "Oral ibuprofen and tetracycline for the treatrnent of
`acne vulgaris" (Journal of the American Academy ofDermatology),
`pp. 1076-1081; 1984.*
`
`(Continued)
`Primary Examiner-S. Tran
`(74) Attorney, Agent, or Firm-Hoffmann & Baron, LLP
`
`(57)
`
`ABSTRACT
`
`A method of treating acne in a human in need thereof
`comprising administering systemica11y to said human a
`tetracycline compound in an amount that is effective to treat
`acne but has substantially no antibiotic activity, without
`administering a bisphosphorrate compound.
`
`31 Claims, 1 Drawing Sheet
`
`PHOTQTOX!CITY INDEX
`
`1000~-----------------------------------,
`
`PHOTO!RRITANCY
`FACTOR (PIF)
`
`100
`
`10
`
`Dr. Reddy's Laboratories, Ltd., et al.
`V.
`Galderma Laboratories, lnc.
`IPR2015-__
`Exhibit 1016
`
`Exh. 1016
`
`

`
`US 7,211,267 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Akamatsu et al. “Effect of Doxycycline on the Generation of
`Reactive Oxygen Species” (Stockh) 1992; 721178-179.*
`Komman et al. “The Effect of Long-Term Low-Dose Tetracycline
`Therapy on the Subgingival Micro?ora in Refractory Adult
`Periodontitis” (J. Periodontol.) 53(10) 604-610; 1982*
`Stedman’s Medical Dictionary 27th Edition.*
`Webster et al., “Inhibition of lipase production in Propionibacterium
`acnes by sub-minimal-inhibitory conentrations of tetracyclin and
`erythromycin”, British Journal of Dermatology (1981), pp. 453
`457.*
`Plewig et al., “Acne1Morphogenesis and Treatment”, Spring-Verlag,
`pp. 297-301 (1975).*
`Webster et al., “Suppression of Polymorphonuclear Leukocyte
`Chemotactic Factor Production in Propionibacterium acnes by
`Subminimal Inhibitory Concentrations of Tetracycline, Ampicillin,
`Minocycline, and Erythromycin”, Antimicrobial Agents and Che
`motherapy 21(5)1770-772. 1982*
`Kenneth S. Kornman and Edward H. Karl, “The Effect of Long
`Term Low-Dose Tetracycline Therapy on the Subgingival
`Micro?ora in Refractory Adult Periodontitis,” J Periodontol.
`53(10) 604-610 (Oct. 1982).
`Akamatsu, et al. “Effect of Keigai-Rengyo-To, a Japanese Kampo
`Medicine, on Neutorphil Functions: a Possible Mechanism of
`Action of Keigai-Rengyo-To in Acne,” The Journal of International
`Medical Research, 251 255-265 (1997).
`Baer, et al. “High-Dose Tetracycline Therapy in Severe Acne,” Arch
`Dermatol, 1121479-481 (Apr. 1976).
`Cheryl Guttman, “Emerging resistance changes face of antibiotic
`therapy for acne,” Dermatology Times, Jan. 2001, p. 22.
`Hirohiko Akamatsu, Maki Asada, Jinro Komura, Yasuo Asada, and
`Yukie Niwa, “Elfect of Doxycycline on the Generation of Reactive
`Oxygen Species: A Possible Mechanism of Action of Acne Therapy
`with Doxycycline,” Acta Derm Venereol (Stockh) 721178-178
`(1992).
`Bodokh, Y. Jacomet, J. Ph. Lacour and J .P. Ortonne, “Minocycline
`Induces an Increase in the Number of Excreting Pilosebaceous
`Follicles in Acne Vulgaris,” Acta Derm Venereol (Stockh), 77:225
`259 (1997).
`W. J. Cunliffe, M.D., F.R.C.P., “Evolution of a Strategy for the
`Treatment of Acne,” JAm Acad Dermatol, 161591-9 (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 Dermatol, 101186-91 (1993).
`Boni E. Elewski, M.D., Beth A.J. Lamb, W. Mitchell Sams, Jr.,
`M.D., and Ray Gammon, M.D., “In Vivo Suppression of Neutrophil
`Chemotaxis by Systemically and Topically Administered Tetracy
`cline,” JAm Acad Dermatol, 81807-812 (1983).
`Nancy B. Esterly, M.D., Nancy L. Furey, M.D., and Lillian E.
`Flanagan, BS, “The Effect of Antimicrobial Agents on Leukocyte
`Chemotaxis,” The Journal of Investigative Dermatology, 70(1)151
`55 (1978).
`Sainte-Marie, I. Tenaud, O. Jumbou and B. Dréno, “Minocycline
`Modulation of Alpha-MSH Production by Keratinocytes In vitro,”
`Acta Derm Venereol 791265-267 (1999).
`Hoshiki Miyachi, M.D., Akira Yoshioka, M.D., Sadao Imamura,
`M.D., and Yukie Niwa, M.D., “Effect of Antibiotics on the Gen
`eration of Reactive Oxygen Species,” J Invest Dermatol, 86(4)1449
`453 (1986).
`Gerd Plewig, M.D., and Erwin Schopf, M.D., “Anti-In?ammatory
`Effects of Antimicrobial Agents: An In Vivo Study,” The Journal of
`Investigative Dermatology, 651532-536 (1975).
`
`M. Toyoda and M. Morohashi, “An Overview of Topical Antibiotics
`for Acne Treatment,” Dermatology, 1961130-134 (1998).
`Sheila E. Unkles, and Curtis G. Gemmell, “Effect of Clindamycin,
`Erythromycin, Lincomycin, and Tetracycline on Growth and
`Extracellular Lipase Production by Propionibacteria In Vitro,” Anti
`microbial Agents and Chemotherapy, 21139-43 (1982).
`GE Webster, K.J. McGinley, and J .J . Leyden, “Inhibition of Lipase
`Production in Propionibacterium acnes by Sub-Minimal-Inhibitory
`Concentrations of Tetracycline and Erythromycin,” British Journal
`ofDermatology, 1041453-457 (1981).
`Guy F. Webster, M.D., Ph.D., Susan M. Toso, MS, and LutZ
`Hegemann, M.D., Ph.D., “Inhibition of a Model of In Vitro Granu
`loma Formation by Tetracyclines and Cipro?oxacin,” Arch
`Dermatol., 1301748-752 (1994).
`Reynold C. Wong, M.D., Sewon Kang, M.P.H., Jan L. HeeZen,
`L.PN., John J. Voorhees, M.D., and Charles N. Ellis, M.D., “Oral
`Ibuprofen and Tetracycline for the Treatment of Acne Vulgaris,” J
`Am Acad Dermatol, 1111076-1081 (1984).
`Skidmore et al., “Effects of Subantimicrobial-Dose Doxycycline in
`the Treatment of Moderate Acne,” Archives of Dermatology
`1391459-464 (Apr. 2003), XP009047590.
`Bikowski, J .B., “Treatment of rosacea with doxycycline
`monohydrate,” Curtis. 2000 Aug., 66(2)1149-152
`Jimenez-Acosta, “Response to tetracycline of telangiectasias in
`male hemophiliac with human immunode?ciency virus infection,”
`J. Am. Acad. Dermatol. Aug. 1988, 19(2 Pt. 1)1369-379.
`Torresani, C., “Clarithromycin versus doxycycline in the treatment
`of rosacea,” Int. J. Clin. Dermatol. Dec. 1997, 36(12)1942-946.
`McClellan, K.J., “Topical MetronidaZole. A rewiew of its use in
`rosaea,” Am. J. Clin. Dermatol. May-Jun. 2000, 1(3)1191-199.
`Quarterman, M.J., “Ocular Rosacea. Signs, symptoms and tear
`studies before and after treatment with doxycycline,” Arch.
`Dermatol. Jan. 1997, l33(l)149-54.
`Akarnatsu, et al. “Effects of subminimal inhibitory concentrations
`of minocycline on neutrophil chemotactic factor production in
`comedonal bacteria, neutrophil phagocytosis and oxygen metabo
`lism,” Arch Dermatol Res 2831 524-528 (1991).
`Bikowski, et al. “Treatment of rosacea with doxycycline
`monohydrate” Cutis, 661 149-152 (Aug 2000).
`Golub, et al. “Tetracyclines inhibit connective tissue breakdown:
`New therapeutic implications for an old family of drugs” Critical
`Reviews in Oral Biology and Medicine, 2(2): 297-322 (1991).
`Illig “Positive side effects of antibiotic and antimicrobial substances
`in therapy” Infection 7 (Suppl.6)1 S 584-588 (1979) (English
`translation. Original document in German.)
`Knight, et al. “A follow-up of tetracycline-treated rosacea” British
`Journal ofDermatology 931 577-580 (1975).
`Marks, et al. “Comparative effectiveness of tetracycline and
`ampicillin in rosacea” The Lancet, 1049-1052 (Nov. 13, 1971).
`Millar, et al. “A general practice study investigating the effect of
`minocycline (Minocine) 50 mg bd for 12 weeks in the treatment of
`acne vulgaris” The British Journal of Clinical Practice 41(8)1882
`886 (Aug. 1987).
`Plewig, et al. Acne.‘ Morphogenesis and Treatment, Springer-Verlag
`297-301 (1975).
`Webster, et al. “Suppression of Polymorphonuclear Leukocyte
`Chemotactic Factor Production in Propionibacterium acnes by
`Subminimal Inhibitory Concentrations of Tetracycline, Ampicillin,
`Minocycline, and Erythromycin” Antimicrobial Agents and Che
`motherapy 21(5)1770-772 (1982).
`* cited by examiner
`
`Exh. 1016
`
`

`
`U.S. Patent
`
`May 1, 2007
`
`US 7,211,267 B2
`
`FIG. 1 eumolommuuax
`1000
`
`PHOTOIRRITANCY
`FACTOR (PlF)
`
`Exh. 1016
`
`

`
`US 7,211,267 B2
`
`1
`METHODS OF TREATING ACNE
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`2
`The numbering system of the multiple ring nucleus is as
`folloWs:
`
`Structure B
`
`This application claims the bene?t of US. Provisional
`Application No. 60/281,916, ?led Apr. 5, 2001, and US.
`Provisional Application No. 60/325,489, ?led Sep. 26, 2001,
`both of Which are incorporated herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`Acne is a common disease characterized by various types
`of lesions. The areas a?fected typically are areas of the skin
`Where sebaceous glands are largest, most numerous, and
`most active. The lesions associated With acne are usually
`categorized as either non-in?ammatory or in?ammatory.
`Non-in?ammatory 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 ori?ce, 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 super?cial
`disorder characterized by slight, spotty skin irritations. In
`such cases, ordinary skin hygiene is typically a satisfactory
`treatment. In the more in?ammatory types of acne, hoWever,
`pustules; infected cysts; and in extreme cases, canalizing,
`in?amed and infected sacs appear. Without e?fective treat
`ment, these lesions may become extensive and leave per
`manent, dis?guring scars.
`Microorganisms, especially Propionibaclerium acnes, are
`strongly implicated in the pathogenesis of acne. The micro
`organisms are thought to release microbial mediators of
`in?ammation into the dermis or trigger the release of cytok
`ines from ductal keratinocytes.
`Accordingly, the e?icacy of antibiotics in treating acne is
`thought to be due, in signi?cant part, to the direct inhibitory
`effect of the antibiotics on the groWth and metabolism of
`these microorganisms. Systemically-administered tetracy
`cline antibiotics, especially minocycline hydrochloride, are
`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
`
`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
`ethylaminotetracycline (minocycline) and 60t-deoxy-5-hy
`droxytetracycline (doxycycline) are also knoWn tetracycline
`antibiotics. Natural tetracyclines may be modi?ed 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.
`DermaZoL, 8:807*812 (1983) suggests that acne therapy,
`consisting of orally-administered tetracycline at a total daily
`dose of 1000 mg, may have therapeutic anti-in?ammatory
`effects in addition to antibiotic effects. In particular, it Was
`found that the anti-in?ammatory effect of tetracycline Was,
`at least in part, due to inhibition of neutrophil chemotaxis
`induced by bacterial chemotactic factors.
`A more recent study, performed by Eady et al., J. Invest.
`DermaZoL, 101:86*91 (1993), evaluated the effects of oral
`minocycline or tetracycline therapy on the cytokine and
`micro?ora content of open comedones in acne patients. The
`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-lot-like material and immu
`nochemical IL-1[3. IL-1 is considered to be a pro-in?am
`matory cytokine.
`Accordingly to Eady et al., no overall decrease in the
`numbers of propionibacteria/mg of comedonal material Was
`found. It is important to note, hoWever, that the numbers of
`propionibacteria/mg of comedonal material are not expected
`to decrease in response 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, I., et al., Acla. Derm. Venerol,
`77z255i259 (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
`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
`the reduction of ductal irritation is due to minocycline’s
`direct effect on R acnes, or minocycline’s effect on the
`lipase produced by R acnes.
`Bodokh et al. also found that during treatment no corre
`lation exists betWeen seborrhoea intensity and clinical sever
`ity of acne. The authors state that the lack of correlation
`shoWs that seborrhoea is pathogenic because it is the “cul
`ture medium” of R acnes. Thus, it can be concluded that the
`
`20
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`25
`
`30
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`35
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`40
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`45
`
`50
`
`55
`
`60
`
`65
`
`Exh. 1016
`
`

`
`3
`authors consider the antibiotic activity of minocycline to be
`therapeutically signi?cant 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. (Cunlilfe et al., J. Am. Acad. DermaZoL, 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 antibiotics are generally directly
`proportional to the dose administered of the antibiotics.
`Accordingly, in moderate to severe (i.e. in?ammatory)
`forms of acne, oral antibiotics 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 25(k500
`mg/day.
`Clearly, the state-of-the-art teaching is that the clinical
`e?icacy of systemically-administered tetracyclines in the
`treatment of acne is due, at least in signi?cant part, to the
`antibiotic effects of the tetracyclines. In addition to their
`antibiotic effects, it has been proposed that tetracyclines
`reduce the number of in?ammatory 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
`the in?ammatory lesion, inhibition of PMN derived colla
`genase, and by scavenging reactive oxidative species pro
`duced by resident in?ammatory cells.
`There is no disclosure in the prior art of using either a
`sub-antibiotic dose of an antibiotic tetracycline compound,
`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 long term admin
`istration of antibiotic tetracyclines can reduce or eliminate
`healthy microbial ?ora, such as intestinal ?ora, 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 antibiotics used in conven
`tional acne therapy.
`
`SUMMARY OF INVENTION
`
`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
`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 di?ferentiation, but has substantially no
`antibiotic activity.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`FIG. 1 shoWs the photoirritancy factor (PIF) for some
`tetracycline compounds. For structure K, the compounds
`indicated are as folloWs:
`
`65
`
`US 7,211,267 B2
`
`COL
`
`R7
`
`R8
`
`R9
`
`308
`311
`306
`
`hydrogen
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`hydrogen
`
`amino
`palrnitarnide
`dirnethylarnino
`
`10
`
`For structures L, M, N or O the compounds indicated are as
`folloWs:
`
`COL
`
`R7
`
`R8
`
`R9
`
`801
`802
`804
`805
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`acetarnido
`dimethylarninoacetarnido
`nitro
`amino
`
`For structure P, R8 is hydrogen and R9 is nitro.
`
`DETAILED DESCRIPTION
`
`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 in?ammation of the
`skin glands and pilosebaceous follicles, as Well as, micro
`bial, especially bacterial, infection.
`For the purposes of this speci?cation, acne includes all
`knoWn types of acne. Some types of acne include, for
`example, acne vulgaris, cystic acne, acne atrophica, bromide
`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
`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
`in?ammatory lesions (erythema) and permanent dilation of
`blood vessels (telangectasia).
`The present invention is particularly effective in treating
`comedones, e.g., reducing the number of comedones. Both
`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, eg perioral
`dermatitis, seborrheic dermatitis in the presence of acne,
`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
`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
`general tetracycline structure indicated above, or a deriva
`tive thereof.
`Some examples of antibiotic (i.e. antimicrobial) tetracy
`cline compounds include doxycycline, minocycline, tetra
`cycline, oxytetracycline, chlor‘tetracycline, demeclocycline,
`
`Exh. 1016
`
`

`
`US 7,211,267 B2
`
`5
`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
`antibiotic activity substantially or completely eliminated by
`chemical modi?cation. 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
`tWenty ?ve times, greater than that of tetracycline or doxy
`cycline, respectively.
`Examples of chemically modi?ed non-antibiotic tetracy
`clines (CMTs) include 4-de(dimethylamino)tetracycline
`(CMT-l), 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- 1 20t-deoxytetracycline
`(CMT-7), 6-deoxy-5ot-hydroxy-4-de(dimethylamino)tetra
`cycline (CMT-8), 4-de(dimethylamino)-120t-deoxyanhy
`drotetracycline (CMT-9), 4-de(dimethylamino)minocycline
`(CMT-10).
`Further examples of chemically modi?ed non-antibiotic
`tetracyclines include Structures CiZ. (See Index of Struc
`tures.)
`Tetracycline derivatives, for purposes of the invention,
`may be any tetracycline derivative, including those com
`pounds disclosed generically or speci?cally in co-pending
`U.S. patent application Ser. No. 09/573,654 ?led on May 18,
`2000, Which are herein incorporated by reference.
`The minimal amount of the tetracycline compound
`administered to a human is the loWest amount capable of
`providing effective treatment of acne. E?fective 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 signi?cantly 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 signi?
`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.
`Some examples of antibiotic doses of members of the
`tetracycline family include 50, 75, and 100 mg/day of
`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
`signi?cant 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®.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`Example 38 beloW summarizes a clinical study using 20
`mg doxycycline hyclate tablets administered tWice a day. A
`signi?cant 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 micro?ora 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
`concentration is the loWest concentration knoWn to exert a
`signi?cant antibiotic e?fect.
`Some 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 ranging 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 ?fty 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
`concentration betWeen about 0.1 and 0.8 ug/ml, more pref
`erably betWeen 0.4 and 0.7 ug/ml.
`Some examples of the plasma antibiotic threshold levels
`of tetracyclines based on steady-state pharmacokinetics are
`as folloWs: 1.0 ug/ml for doxycycline; 0.8 ug/ml for minocy
`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
`(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.
`The actual preferred amounts of tetracycline compounds
`in a speci?ed 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
`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. Some examples
`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
`taric, citric, gluconic, gulonic, arylsulfonic, and galacturonic
`acids. Appropriate organic bases may be selected, for
`
`Exh. 1016
`
`

`
`US 7,211,267 B2
`
`7
`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
`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
`totoxicity 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.
`Phototoxicity can be evaluated in terms of a photoirri
`tancy factor (PIF), as described in the examples. A PIF 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
`2, more preferably no greater than about 1.5, mo st preferably
`no greater than about 1.2, and optimally about 1.
`Some antibiotic tetracyclines having loW phototoxicity
`include, for example, minocycline and tetracyline.
`Some non-antibiotic tetracyclines having loW phototox
`icity include, but are not limited to, tetracycline compounds
`having the general formulae:
`
`Structure K
`
`Wherein: R7, R8, and R9 taken together in each case, have
`the folloWing meanings:
`
`R7
`
`hydrogen
`hydrogen
`hydrogen
`
`and
`
`R8
`
`hydrogen
`hydrogen
`hydrogen
`
`R9
`
`amino
`palmitamide
`dimethylarnino
`
`STRUCTURE L
`STRUCTURE N
`
`STRUCTURE M
`STRUCTURE 0
`
`10
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`wherein: R7, R8, and R9 taken together in each case, have
`the folloWing meanings:
`
`60
`
`R7
`
`hydrogen
`hydrogen
`
`R8
`
`hydrogen
`hydrogen
`
`R9
`
`acetarnido
`dimethylarninoacetarnido
`
`65
`
`-c ontinued
`
`R7
`
`hydrogen
`hydrogen
`
`and
`
`R8
`
`hydrogen
`hydrogen
`
`S TRUC TURE P
`
`R9
`
`nitro
`amino
`
`Wherein: R8, and R9 taken together are, respectively, hydro
`gen and nitro.
`The tetracycline compounds are administered Without
`administering a bisphosphonate compound. Bisphospho
`nates 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