111111111111111111111111111111111111111111111111111111111111111111111111111
`US008052983B2
`
`c12) United States Patent
`Ashley
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,052,983 B2
`*Nov. 8, 2011
`
`(54) METHODS OF TREATING ACNE
`
`(75)
`
`Inventor: RobertA. Ashley, Newtown, PA (US)
`
`(73) Assignee: Galdcrma Laboratories, Inc., Fort
`Worth, TX (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 215 days.
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 11/876,478
`
`(22) Filed:
`
`Oct. 22, 2007
`
`(65)
`
`Prior Publication Data
`US 2008/0171727 AI
`Jul. 17, 2008
`
`Related U.S. Application Data
`(60) Continuation of application No. 10/757,656, filed on
`Jan. 14, 2004, now abandoned, which is a division of
`application No. 10/117,709, filedonApr. 5, 2002, now
`Pat. No. 7,211,267.
`(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. Cl.
`A61K 9/68
`(2006.01)
`(52) U.S. Cl •........................................ 424/401; 514/152
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`514/528
`
`U.S. PATENT DOCUMENTS
`4,704,383 A
`1111987 McNamara et al.
`611992 Ritter
`5,122,519 A
`5,260,292 A *
`11/1993 Robinson et al. ............. 514/198
`10/1997 Tomas eta!.
`5,674,539 A
`5,827,840 A
`I 0/1998 Rarnamwthy eta!.
`5,908,838 A
`6/1999 Gans
`5,998,390 A
`12/1999 Rarnamurthy eta!.
`6,455,583 Bl *
`9/2002 Pfiugfelder eta!.
`6,673,843 B2
`1/2004 Arbiser
`3/2006 Ashley
`7,014,858 B2
`2003/0082120 AI
`5/2003 Milstein
`2003/0148945 AI
`8/2003 McNicol et al.
`2005/0239723 AI
`10/2005 Amin eta!.
`FOREIGN PATENT DOCUMENTS
`1/1991
`0 410 099 A1
`wo 83/00628
`3/1983
`wo 99/58131
`11/1999
`OTHER PUBLICATIONS
`Akamatsu, eta!. "Effect of Keigai-Rengyo-To, a Japanese Kampo
`Medicine, on N eutorphil Functions: a Possible Mechanism of Action
`ofKeigai-Rengyo-To in Acne," The Journal ofinternationalMedical
`Research, 25: 255-265 (1997).
`Baer, eta!. "High-Dose Tetracycline Therapy in Severe Acne," Arch
`Dermatol, 112:479-481 (Apr. 1976).
`
`EP
`wo
`wo
`
`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, "Effect of Doxycycline on the Generation of Reactive
`Oxygen Species: A Possible Mechanism of Action of Acne Therapy
`with Doxycycline," ActaDerm Venereol (Stockh) 72:178-178 (1992).
`Bodokh, Y. Jacome!, J. Ph. Lacour and J.P. Ortonne, "Minocycline
`Induces an Increase in the Number of Excreting Pilosebaceous Fol-
`licles in Acne Vulgaris,'' Acta Derm Venereol (Stockh), 77:255-259
`(1997).
`W. J. Cunliffe, M.D., F.R.C.P., "Evolution of a Strategy for the
`Treatment of Acne," JAm Acad Dermatol, 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
`Dermatol, 101:86-91 (1993).
`Boni E. Elewski, M.D., BethA.J. Lamb, W. Mitchell Sams, Jr., M.D.,
`and W. Ray Ganunon, M.D., "In Vivo Suppression of Neutrophil
`Chemotaxis by Systemically and Topically Administered Tetracy-
`cline," JAm Acad Dermatol, 8:807-812 (1983).
`Nancy B. Esterly, M.D., Nancy L. Furey, M.D., and Lillian E.
`Flanagan, B.S., "The Effect of Antimicrobial Agents on Leukocyte
`Chemotaxis,'' The Journal of Investigative Dermatology, 70(1 ): 51-
`55 (1978).
`Sainte-Marie, I. Tenaud, 0. Jumbou and B. Dreno, "Minocycline
`Modulation of Alpha-MSH Production by Keratinocytes In vitro,"
`Acta Derm Venereo/79:265-267 (1999).
`Hoshiki Miyachi, M.D., Akira Yoshioka, M.D., Sadao Imamura,
`M.D., and Yukie Niwa, M.D., "Effect of Antibiotics on the Genera-
`tion of Reactive Oxygen Species," J Invest Dermatol, 86(4):449-453
`(1986).
`Gerd Plewig, M.D., and Erwin Schopf, M.D., "Anti-Inflammatory
`Effects of Antimicrobial Agents: An In Vivo Study,'' The Journal of
`Investigative Dermatology, 65:532-536 (1975).
`M. Toyoda and M. Morohashi, "An Overview of Topical Antibiotics
`for Acne Treatment," Dermatology, 196:130-134 (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, 21:39-43 (1982).
`G.F. 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
`of Dermatology, 104:453-457 (1981).
`Guy F. Webster, M.D., Ph.D., Susan M. Toso, M.S., and Lutz
`Hegemann, M.D., "Inhibition of a Model of In Vitro Granuloma
`Formation by Tetracyclines and Ciprofioxacin,'' Arch Dermatol.,
`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
`Ibuprofen and Tetracycline for the Treatment of Acne Vulgaris," JAm
`AcadDermatol, 11:1076-1081 (1984).
`Kenneth S. Kornman and Edward H. Karl, "The Effect ofLong-Term
`Low-Dose Tetracycline Therapy on the Subgingival Microfiora in
`Refractory Adult Periodontitis,'' J. Periodontol., 53(10):604-610
`(Oct. 1982).
`
`(Continued)
`
`Primary Examiner- Susan Tran
`(74) Attorney, Agent, or Firm- Hoffman & Baron, LLP
`
`ABSTRACT
`(57)
`A method of treating acne in a human in need thereof com-
`prising administering systemically to said human a tetracy-
`cline compound in an amount that is effective to treat acne but
`has substantially no antibiotic activity, without administering
`a bisphosphonate compound.
`
`11 Claims, 1 Drawing Sheet
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-_ _
`Exhibit 1036
`
`Exh. 1036
`
`

`
`US 8,052,983 B2
`Page 2
`
`OTHER PUBLICATIONS
`Bikowski, J .B., “Treatment of rosacea with doxycycline
`monohydrate,” Curtis. Aug. 2000, 66(2):l49-152.
`Jimenez-Acosta, “Response to tetracycline of telangiectasias in male
`hemophiliac with human immunode?ciency virus infection,” J. Am.
`Acad. Dermatol.Aug. 1988, l9(2 Pt. l):369-379.
`Torresani, C ., “Clarithromycin versus doxycycline in the treatment of
`rosacea,” Int. J. Clin. Dermatol. Dec. 1997, 36(12):942-946.
`McClellan, K.J., “Topical Metronidazole. A review of its use in
`rosaea,” Am. J. Clin. Dermatol. May-Jun. 2000, l(3):l9l-l99.
`Quarterman, M.J., “Ocular Rosacea. Signs, symptoms and tear stud
`ies before and after treatment with doxycycline,” Arch. Dermatol.
`Jan. 1997, l33(l):49-54.
`Skidmore et al., “Effects of Subantimicrobial-Dose Doxycycline in
`the Treatment of Moderate Acne,” Archives of Dermatology
`1391459-464 (Apr. 2003), XP009047590.
`Akamatsu, 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 283:524-528 (1991).
`Bikowski, et al. “Treatment of rosacea with doxycycline
`monohydrate” Cutis, 661149-152 (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): S 584-588 (1979) (English trans
`lation. Original document in German.)
`Knight, et al. “A follow-up of tetracycline-treated rosacea” British
`Journal of Dermatology 93:577-580 (1975).
`Marks, et al. “Comparative effectiveness of tetracycline and ampicil
`lin in rosacea” The Lancet, 1049-1052 (Nov. 13, 1971).
`Millar, et al. “A general practice study investigating the effect of
`minocycline (Minocin) 50 mg bd for 12 weeks in the treatment of
`acne vulgaris” The British Journal of Clinical Practice 4 1(8): 882-886
`(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 Sub
`minimal Inhibitory Concentrations of Tetracycline, Ampicillin,
`Minocycline, and Erythromycin” Antimicrobial Agents and Chemo
`therapy 2l(5):770-772 (1982).
`* cited by examiner
`
`Exh. 1036
`
`

`
`US. Patent
`
`NOV. 8, 2011
`
`US 8,052,983 B2
`
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`Exh. 1036
`
`

`
`1
`METHODS OF TREATING ACNE
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`US 8,052,983 B2
`
`2
`The numbering system of the multiple ring nucleus is as
`follows:
`
`Structure B
`
`This application is a continuation of US. application Ser.
`No. 10/757,656 ?led on Jan. 14, 2004, now abandoned which
`is a divisional application of US. application Ser. No. 10/ 1 17,
`709, ?led onApr. 5, 2002, now U.S.Pat.No. 7,211,267 which
`claims the bene?t of US. Provisional Application No.
`60/281,916, ?led Apr. 5, 2001, and US. Provisional Appli
`cation No. 60/325,489, ?led Sep. 26, 2001. All of the afore
`mentioned applications are incorporated herein by reference
`in their entireties.
`
`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 catego
`rized 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 follicular
`canal. The progressive accumulation of these microcome
`dones lead to visible comedones.
`In its mildest form, acne is a more or less super?cial dis
`order characterized by slight, spotty skin irritations. In such
`cases, ordinary skin hygiene is typically a satisfactory treat
`ment. In the more in?ammatory types of acne, however, pus
`tules; infected cysts; and in extreme cases, canaliZing,
`in?amed and infected sacs appear. Without effective treat
`ment, these lesions may become extensive and leave perma
`nent, 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 tetracycline
`antibiotics, especially minocycline hydrochloride, are par
`ticularly effective in treating acne.
`The tetracyclines are a class of compounds of which tetra
`cycline is the parent compound. Tetracycline has the follow
`ing 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.
`Dermalol., 8:807-812 (1983) suggests that acne therapy, con
`sisting 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.
`Dermalol., 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 produc
`tion of bioactive IL-la-like material and immunochemical
`IL-1[3. IL-1 is considered to be a pro-in?ammatory 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 bacte
`ria 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., Acta. Derm. Venerol.,
`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 adminis
`tered. A subclinical increase in seborrhoea was reported. The
`authors propose that minocycline induces an increase in seb
`orrhoea via a reduction in ductal obstruction. The mechanism
`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 P. acnes, or minocycline’s effect on the lipase pro
`duced by P. acnes.
`Bodokh et al. also found that during treatment no correla
`tion exists between seborrhoea intensity and clinical severity
`of acne. The authors state that the lack of correlation shows
`that seborrhoea is pathogenic because it is the “culture
`medium” of P. acnes. Thus, it can be concluded that the
`authors consider the antibiotic activity of minocycline to be
`therapeutically signi?cant with respect to acne.
`
`20
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`25
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`30
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`35
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`40
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`45
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`50
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`55
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`60
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`65
`
`Exh. 1036
`
`

`
`US 8,052,983 B2
`
`3
`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. Dermalol., 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, tetracy
`cline 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
`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, pustules
`and nodules) by a variety of non-antibiotic mechanisms. Such
`mechanisms include interfering with the chemotaxis of poly
`morphonuclear leukocytes (PMN) into the in?ammatory
`lesion, inhibition of PMN derived collagenase, and by scav
`enging reactive oxidative species produced 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 treat
`ment 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 administer
`ing systemically to the human a tetracycline compound in an
`amount that is effective to treat acne but has substantially no
`antibiotic activity (i.e. substantially no antimicrobial activ
`ity), without administering a bisphosphonate compound.
`Additionally, the present invention provides methods for
`reducing the number of comedones, inhibiting oxidation of
`melanin, and/ or inhibiting lipid-associated abnormal follicu
`lar differentiation in a human in need thereof. These methods
`comprise administering systemically to the human a tetracy
`cline 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 folli
`cular differentiation, but has substantially no antibiotic activ
`ity.
`
`20
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`30
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`35
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`40
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`45
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`50
`
`55
`
`60
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the photoirritancy factor (PIF) for some
`tetracycline compounds. For structure K, the compounds
`indicated are as follows:
`
`65
`
`COL
`
`R7
`
`R8
`
`R9
`
`3 08
`3 1 1
`3 06
`
`hydrogen
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`hydrogen
`
`amino
`palmitarnide
`dimethylarnino
`
`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, microbial,
`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, premenstrual acne,
`acne pustulosa, acne scorbutica, acne scrofulosorum, acne
`urticata, acne varioliformis, acne venenata, propionic acne,
`acne excoriee, gram negative acne, steroid acne, nodulocystic
`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, e. g. perioral dermatitis,
`seborrheic dermatitis in the presence of acne, gram negative
`folliculitis, sebaceous gland dysfunction, hiddradenitis sup
`purativa, pseudo-folliculitis barbae, or folliculitis.
`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 antibi
`otic activity.
`The tetracycline compound can be an antibiotic or non
`antibiotic compound. The tetracycline compound has the
`general tetracycline structure indicated above, or a derivative
`thereof.
`Some examples of antibiotic (i.e. antimicrobial) tetracy
`cline compounds include doxycycline, minocycline, tetracy
`cline, oxytetracycline, chlortetracycline, demeclocycline,
`lymecycline and their pharmaceutically acceptable salts.
`Doxycycline is preferably administered as its hyclate salt or
`as a hydrate, preferably monohydrate.
`
`Exh. 1036
`
`

`
`US 8,052,983 B2
`
`20
`
`25
`
`5
`Non-antibiotic tetracycline compounds are structurally
`related to the antibiotic tetracyclines, but have had their anti
`biotic 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 concen
`trations at least about ten times, preferably at least about
`twenty ?ve times, greater than that of tetracycline or doxycy
`cline, 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-120t-deoxytetracycline
`(CMT-7), 6-deoxy-5(x-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 C-Z. (See Index of Struc
`tures.)
`Tetracycline derivatives, for purposes of the invention, may
`be any tetracycline derivative, including those compounds
`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 admin
`istered 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 compound 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 administered 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 doxy
`cycline; 50, 75, 100, and 200 mg/day ofminocycline; 250 mg
`45
`of tetracycline one, two, three, or four times a day; 1000
`mg/day of oxytetracycline; 600 mg/day of demeclocycline;
`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 come
`dones, doxycycline is administered in a daily amount of from
`about 30 to about 60 milligrams, but maintains a concentra
`tion 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®.
`Example 38 below summarizes a clinical study using 20
`mg doxycycline hyclate tablets administered twice a day. A
`65
`signi?cant reduction in the number of comedones was
`observed. This reduction in the number of comedones is
`
`6
`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 tetracycline
`concentration which is 10-80% of the minimum antibiotic
`serum concentration. The minimum antibiotic serum concen
`tration is the lowest concentration known to exert a signi?cant
`antibiotic effect.
`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 minocycline
`serum levels ranging from 0.74 to 4.45 pg/ml over a period of
`an hour. The average level is 2.24 pg/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
`pg/ml. Five hundred milligrams of tetracycline HCl admin
`istered every six hours over a twenty-four hour period pro
`duces a serum concentration level of 4 to 5 pg/ml.
`In one embodiment, the tetracycline compound can be
`administered in an amount which results in a serum concen
`tration between about 0.1 and 10.0 ug/ml, more preferably
`between 0.3 and 5.0 ug/ml. For example, doxycycline is
`administered in an amount which results in a serum concen
`tration between about 0.1 and 0.8 ug/ml, more preferably
`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 pg/ml for doxycycline; 0.8 11ng for minocy
`cline; and 0.5 11ng 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 11ng to about 10 ug/ml.
`The actual preferred amounts of tetracycline compounds in
`a speci?ed case will vary according to the particular compo
`sitions formulated, the mode of application, the particular
`sites of application, and the subject being treated.
`The tetracycline compounds can be in the form of pharma
`ceutically acceptable salts of the compounds. The term “phar
`maceutically acceptable salt” refers to a salt prepared from
`tetracycline compounds and pharmaceutically acceptable
`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, propionic,
`succinic, glycolic, glucuronic, maleic, furoic, glutamic, ben
`zoic, anthranilic, salicylic, phenylacetic, mandelic, embonic
`(pamoic), methanesulfonic, ethanesulfonic, panthenoic, ben
`zenesulfonic, stearic, sulfanilic, alginic, tartaric, citric, glu
`conic, gulonic, arylsulfonic, and galacturonic acids. Appro
`priate organic bases may be selected, for example, from N,N
`dibenzylethylenediamine,
`chloroprocaine,
`choline,
`diethanolamine, ethylenediamine, meglumine (N-methylglu
`camine), and procaine.
`
`30
`
`35
`
`40
`
`50
`
`55
`
`60
`
`Exh. 1036
`
`

`
`US 8,052,983 B2
`
`20
`
`30
`
`35
`
`7
`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. Nevertheless,
`it is believed that the ability of tetracyclines, such as doxycy
`cline, to inhibit oxidation of melanin and to inhibit lipid
`associated abnormal follicular differentiation prevents kera
`tinocytes from becoming cohesive, thereby inhibiting the
`formation of comedones.
`Preferably, the tetracycline compounds have low phototox
`icity, or are administered in an amount that results in a serum
`level at which the phototoxicity is acceptable. Phototoxicity
`is a chemically-induced photosensitivity. Such photosensitiv
`ity renders skin susceptible to damage, e. g. sunburn, blisters,
`accelerated aging, erythemas and eczematoid lesions, upon
`exposure to light, in particular ultraviolet light. The preferred
`amount of the tetracycline compound produces no more pho
`totoxicity than is produced by the administration of a 40 mg
`25
`total daily dose of doxycycline.
`Phototoxicity can be evaluated in terms of a photoirritancy
`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 values
`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 tetracycline.
`Some non-antibiotic tetracyclines having low phototoxic
`ity include, but are not limited to, tetracycline compounds
`having the general formulae:
`S TRUCTURE K
`wherein: R7, R8, and R9 taken together in each case, have the
`following meanings:
`
`40
`
`hydrogen
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`hydrogen
`
`amino
`palmitarnide
`dimethylarnino
`
`and
`
`STRUCTURE L STRUCTURE M
`
`STRUCTURE N STRUCTURE 0
`wherein: R7, R8, and R9 taken together in each case, have the
`following meanings:
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`acetalnido
`dimethylalninoacetarnido
`nitro
`amino
`
`45
`
`50
`
`55
`
`60
`
`65
`
`and
`
`STRUCTURE P
`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 bispho sphonates include, as non-limiting examples,
`alendronate ((4-amino-1-hydroxybutylidene) bisphosphonic
`acid), clodronate (dichloromethane diphosphonic acid),
`etidronate ((1-hydroxyethylidene) diphosphanic acid) and
`pamidronate ((3-amino-1-hydroxypropylidene) bisphospho
`nic acid); also risedronate ([-hydroxy-2-(3-pyridinyl)eth
`ylidene]bisphosphonic acid), tiludronate, i.e., tiludronic acid
`([(4-chlorophenyl) thio]methylene]bisphosphonic acid) and
`zolendronate.
`The tetracycline compounds may, for example, be admin
`istered systemically. For the purposes of this speci?cation,
`“systemic administration” means administration to a human
`by a method that causes the compounds to be absorbed into
`the bloodstream.
`For example, the tetracyclines compounds can be admin
`istered orally by any method known in the art. For example,
`oral administration can be by tablets, capsules, pills, troches,
`elixirs, suspensions, syrups, wafers, chewing gum and the
`like.
`Additionally, the tetracycline compounds can be adminis
`tered enterally or parenterally, e.g., intravenously; intramus
`cularly; subcutaneously, as injectable solutions or suspen
`sions; intraperitoneally; or rectally. Administration can also
`