United States Patent 15
`4,568,535
`Patent Number:
`(11)
`[45]
`Feb,4,1986
`
`Date of Patent:
`Loesche
`
`(54)
`
`[76]
`
`COMPOSITION FOR PERIODONTAL
`ADMINISTRATION
`
`[56]
`
`References Cited
`
`PUBLICATIONS
`
`Inventor: Walter J, Loesche, 1814 Hermitage,
`Ann Arbor, Mich. 48104
`
`Soskolne et al., New Sustained Release Dosage Form of
`Chlorhexidine
`for Dental Use,
`J. Perio, Res,
`18:330-336.
`
`[21]
`
`Appl. No.: 631,542
`
`[22]
`
`Filed:
`
`Jul. 16, 1984
`
`[63]
`
`(S1]
`[52]
`
`[58]
`
`Related U.S. Application Data
`
`Continuation-in-part of Ser. No. 405,790, Aug.6, 1982,
`abandoned.
`
`Tint. C14 oes essstessessennes AGIK 9/22; AGIK 9/52
`TLS. Cy ceeecscetecesetsseceeceesrenenacenses 424749; 514/36%
`424/28
`Field of Search ............:::0:0000 424/72, 26, 28, 19,
`424/273 R, 52; 106/35; 514/365
`
`Primary Examiner—Johnnie R. Brown
`Assistant Examiner—C. Joseph Faraci
`
`ABSTRACT
`[57]
`A composition for periodontal administration and a
`method of periodontal treatment involving a slow re-
`lease device which can be placed directly into the peri-
`odontal pocket where metronidazole, with or without
`antioxidants, are released over periods of days to weeks
`at a cidai concentration for anaerobes in the domain of
`the pefiodontal pocket.
`
`2 Claims, 3 Drawing Figures
`
`Dr. Reddy's - EX1015
`Page 1
`
`Dr. Reddy's - EX1015
`Page 1
`
`

`

`U.S. Patent
`
`Feb.4, 1986
`
`Sheet 1 of 3
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`U.S. Patent
`
`Feb. 4, 1986
`
`Sheet 2 of 3
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`Page 3
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`

`

`U.S. Patent
`
`Feb. 4, 1986
`
`Sheet 3 of 3
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`4,568,535
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`Page 4
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`Page 4
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`

`4,568,535
`
`1
`
`COMPOSITION FOR PERIODONTAL
`ADMINISTRATION
`
`CROSS-REFERENCES
`
`Thisis a continuation-in-part of Ser. No. 405,790filed
`8/6/82 now abandoned.
`
`BACKGROUNDOF THE INVENTION
`
`1, Technical Field
`This invention relates to a composition for periodon-
`tal administration that is cidal for anaerobes in the do-
`main of the periodontal pocket and to a novel method of
`treatment of anaerobic infections in periodontal disease
`that is dependent upon the slow reiease of metronida-
`zole from a plastic film that is placed within the peri-
`odontal pocket, and which film resides in such pocket
`for a period of days to weeks.
`2. Description of Prior Art
`The main cause of tooth loss in adults is periodontal
`disease. Yet, surprisingly, less than one percent of the
`public expenditures for dental treatmentis for periodon-
`tal disease (see J. Dent. Educ. 43:320, (1979). This is
`because conventional periodontal treatmentis too ex-
`pensive for most individuals, mainly due to the labor
`intensive, symptomatic treatment that is usually per-
`formed by highly skilled specialists.
`.
`Periodontal disease is an all-inclusive term for a vari-
`ety of clinical entities that are forms of either gingivitis
`or periodontitis. Gingivitis is an inflammation of the
`gingiva or gums that can be associated with poor oral
`hygiene and/or hormonal states of the host. It is as-
`sumed, but not proven in the human,that gingivitis will
`progress to a periodontitis, which is the form of the
`disease in which the infection has progressed to involve
`the oral tissues which retain the teeth in the jaw bone.
`Periodontitis is the more severe form of the disease, and
`if untreated, will eventuate in the loss of the tooth.
`Dentists have long assumed that periodontal disease
`originates by the overgrowth of bacteria on the tooth
`surfaces in aggregates known as dental plaque. If this
`plaque persists for long periods of time on the tooth
`surfaces, it may in some instances calcify, forming the
`hard substance known as calculus. Numerous studies
`describe chemical agents which can in vitro and in vivo
`reduce plaque formation and calculus. However, none
`of these chemical agents has been reported to be suc-
`cessful in treating periodontitis.
`A substantial number ofdifferent types of compounds
`and compositions have been developed for use as anti-
`bacterial and antiplaque agents, e.g., benzethonium
`chloride and cetyl pyridinium chloride, disclosed in
`U.S. Pat. No. 4,110,429, or as anticalculus agents,e.g.,
`2-phosphono-butane 1,2,4-tricarboxylic acid, disclosed
`in U.S. Pat. No. 4,224,308. These compounds are de-
`signed to be used bythe individual in dentifrices, dental
`powders, pastes, mouthwashes, nonabrasive gels, chew-
`ing gums, topical solutions and the like, e.g., see U.S.
`Pat. No. 4,205,061. They are designed to be used as
`prophylactic agents, usually without requiring a pre-
`scription or supervision during usage, e.g., see U.S. Pat.
`No. 4,251,507. Often they are compounded with deter-
`gents and other cleaning agents, and this cleaning action
`is often an important aspect of the invention, e.g., see
`U.S. Pat. Nos. 4,251,507 and 4,205,061. None of these
`compounds or compositions are designed to be used as
`antimicrobial agents for the treatment of periodontitis,
`
`15
`
`20
`
`40
`
`45
`
`35
`
`60
`
`65
`
`2
`nor are they formulated to be slow release devices for
`these antimicrobial agents in vivo.
`Recent research in periodontal disease (see, for exam-
`ple, Chemotherapy of Dental Plaque Infections, Oral
`Sci. Rev. 9:65-107, 1976) indicates that gingivitis and
`periodontitis are characterized by different
`types of
`bacteria. Gingivitis is associated with the accumulation
`of gram positive cocci and actinomyces, whereas perio-
`dontitis is characterized by proportional
`increases in
`anaerobic bacteria, such as spirochetes and black pig-
`mented bacteroides (see Host-Parasite Interactions in
`Periodontal Disease. R. J. Genco and S. E. Mergenha-
`gen, eds. Amer. Soc. for Microbiol. Washington, D.C.
`p. 27-45, 62-75, 1982). The different bacterial composi-
`tionsof plaque associated with either gingivitis or perio-
`dontitis suggest that a mode of treatment thatis effec-
`tive in gingivitis may not be effective in periodontitis.
`This is an important factor in the present invention, as
`previous discoveries in the area of periodontal disease
`have assumed that there is no bacterial specificity in
`periodontal disease. This is now knownto be incorrect.
`These bacterial differences in plaque may explain why
`an agent effective in plaque control, such as chlorhexi-
`dine, has little effect on gingivitis and no published
`effect on periodontitis.
`Another important finding from recent periodontal
`research is that the composition of the dental plaque
`will differ accordingto its location on the tooth surface.
`Abovethe gingival or gum margin, facultative bacteria,
`such as gram positive cocci and rods, are numerically
`dominant, whereas below the gum margin, anaerobic
`motile bacteria such as spirochetes, and anaerobic gram
`negative rods including the black-pigmented bacteroi-
`des are predominant.
`In other words, two different
`microbial ecosystems are present on the same tooth
`surface.
`This is illustrated in the accompanying drawings in
`FIGS.1¢ and 15, which show a cross section of a tooth
`10, a periodontal pocket 11, and the gingiva or gum 12.
`The tooth illustrated in FIG.
`1¢@ exhibits periodontal
`disease in which periodontal attachmentof the tooth to
`the alveolar bone has been destroyed, and a periodontal
`pocket 11 has been formed between the gum 12 and the
`root surface of the tooth. Clinical assessment of such
`deterioration of teeth is made by measuring the depth of
`the pocket. This is done by inserting a periodontal
`probeorruler, a thin metal rod (not shown),to the base
`of the pocket 14. Two measurements can be obtained
`with the probe. One, called the pocket depthx,in illus-
`tration l@ is the distance between the height of the
`gingival margin 13 to the base of the pocket 14. The
`other measurement, y,
`is the distance between the
`height of the gingival margin 13 and the cemento-
`enamel junction (CEJ)15. The CEJ is extremely valu-
`able because it gives a permanent reference mark on
`each tooth surface from which one can base further
`measurements. It enables one to divide the pocket depth
`measurement into two components: the distance be-
`tween the CEJ and the top of the gingival margin, y,
`and the distance between the CEJ and the bottom ofthe
`pocket, z. This letter measurementis called the attach-
`ment distance. As illustrated in the diseased tooth, the
`attachment distance is 5 mm and the pocket depth is 8 ,
`mm.
`
`FIG. 18 is an enlargement of a section of the type
`shown in FIG. 1a in which the periodontal pocket 11is
`now filled with bacterial plaque. Note that the plaque
`lies between the tooth and the gingiva in the space
`
`Page 5
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`Page 5
`
`

`

`4,568,535
`
`3
`called the periodontal pocket. Also note that the bacte-
`rial composition of the plaque varies according to its
`spatial relationship to the gingival margin 13. Above the
`gingival margin the plaque is known as the supragingi-
`val plaque, and it generally has equal numbers of gram
`positive (+) cocci and rods, fewer gram negative (—)
`rods and even fewer motile rods. Next comesa section
`of plaque which contains proportionally more gram
`negative (—) rods and some spirochetes. This plaqueis
`known as the gingival margin plaque. Finally, in the
`bottom of the pocket, is found a plaque which is domi-
`nated by anaerobic gram negative rods and motile rods,
`including black-pigmented bacteroides and spirochetes.
`This plaque is known as subgingival or pocket plaque
`and it is this plaque that is the etiologic agent of perio-
`dontitis.
`It is clear from this illustration and from recent elec-
`tronmicroscopic examinations of plaque that the subgin-
`gival plaque is distinct from supragingival plaque (see J.
`Periodontol. 47:1-18, 1976). This has important implica-
`tions for our invention, as previous patents for the use of
`antimicrobials described agents that are delivered to the
`supragingival plaque. It can be surmised from theillus-
`tration and now accepted as fact,
`that antimicrobial
`agents delivered in dentifrices, dental powders, pastes,
`mouthrinses, nonabrasive gels, chewing gums, topical
`solutions and the like, will minimally penetrate into the
`pocketfor a distance of about | to 3 mm. Asperiodontal
`pockets may be 12 to 13 mm in depth, it is apparent that
`the topical application of any antimicrobial agent, even
`metronidazole, to the supragingival plaque will have no
`. Or minimaleffect on the subgingival plaque and accord-
`ingly, should have little if any effect on periodontitis.
`Ourinventionis, therefore, quite distinct from the topi-
`cal application of metronidazole in wateror in vehicles,
`such as gels or pastes as disclosed in U.S. Pat. No.
`3700,685, as our invention will place the metronidazole
`directly into the periodontal pocket, whereit will be in
`contact with the bacteria in the subgingival plaque.
`Also, our invention is different from previous patent
`applications which incorporated antimicrobials in denti-
`frices, gels, powders, etc. which were designed to be
`delivered to the supragingival tooth sites, e.g., see U.S.
`Pat. Nos. 4,205,061, 4,251,507, 4,224,308 and 3,700,685
`and had as their treatment goal, the control of dental
`plaque and oral cleanliness.
`From a review of these patents and other information
`in the literature it is apparent that an improved means of
`treating periodontitis is needed in dentistry. From a
`reading of information in theart, it is obvious that the
`basic need oftreating an anaerobic infection in the peri-
`odontal pocketis not satisfied. None of the means pres-
`ently available appears to get at the heart of the prob-
`lem, whichis finding an improved meansofdelivering
`an antimicrobial agent specific for anaerobic organisms,
`such as spirochetes and black pigmented bacteroides, to
`the periodontal pocket for continuous periods of 5 to 10
`days or more.
`Sucha delivery can be achieved with systemic anti-
`microbials. Indeed, short-term oral administration of
`metronidazole in humansand in dogs caused a sustained
`reduction of spirochetes and black pigmented bacteroi-
`des for weeks to months (see for example J. Clinical
`Periodontol. 8:29-44,
`1981,
`ibid 10:100-112 1983).
`However,as is known, such systemic usage of metroni-
`dazole can be associated with undesirable side effects,
`such as nausea. Also, there is the suggestion from animal
`toxicity studies that metronidazole is a weak tumorigen
`
`_ 0
`
`20
`
`25
`
`30
`
`40
`
`50
`
`60
`
`4
`(for example, see Proceedings of International Metroni-
`dazole Conference, Excerpta Medica, 1976). For these
`reasons, it is desirable to use the lowest possible dosage
`of metronidazole consistent with a therapeutic effect.
`The slow-release-film-metronidazole device, which is
`described in this invention, may reduce the amount of
`metronidazole necessary to treat advanced cases of
`periodontitis by as much as 99%.
`Thus,
`the present invention not only describes an
`effective means of treating anaerobic periodontal infec-
`tion, but does so at dosages that are greatly reduced
`compared to systemic or oral administration of the same
`agent(s). This safety factor is an important aspect of the
`present invention.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`It is an object of the present invention to provide
`improved means for treating periodontal
`infections,
`such as periodontitis which occur below the gingival
`margin in the periodontal pocket.
`It is another object of the invention to provide means
`of distributing metronidazole, or other antimicrobial
`agents, to the peridontal pocket that avoids the disad-
`vantages of the priorart.
`It is another object of the invention to incorporate
`metronidazole, or other antimicrobial agents, in a slow
`telease device that can be placed by the clinician di-
`rectly into the infected periodontal pocket.
`It is a further object of the invention that the slow
`release device will release metronidazole, or other anti-
`microbial agents, over a period of 5 to 10 days or more.
`It is a further object of this invention that the release
`of metronidazole, or other antimicrobial agents, by the
`slow release device will significantly reduce and/or
`eliminate the Jevels of periodontopathic bacteria resid-
`ing in the periodontal pocket.
`Other objects of this invention will be set forth in, or
`be apparent from, the following description of the in-
`vention.
`A novel means for accomplishing the foregoing ob-
`jects and other features and advantages of the present
`invention are achieved by incorporating metronidazole
`(Zenith Laboratory, Northvale, N.J.), or other antimi-
`crobial agents,
`in a polymer, such as ethylcellulose
`(Hercules, Inc., Wilmington, Del.), which can be placed
`directly into the diseased periodontal pocket by the
`clinician. Such metronidazole-ethylcellulose films will
`release metronidazole continuously into the pocket
`over a period of 7 to 14 days or more.
`The present invention concerns a composition for
`subgingival administration of an antimicrobial agent
`directly to the periodontal pocketin patients exhibiting
`periodontitis. The composition comprises a pharmaceu-
`tically acceptable polymeric matrix, such as ethylcellu-
`lose, (see J. Dent. Res. 54:1392, 1980), which contains
`metronidazole. The polymer-metronidazole combina-
`tion is formulated so that the metronidazole is slowly
`released from the polymerinto the environment of the
`periodontal pocket. For purposes of this invention one
`uses a concentration of metronidazole such that a single
`dose of the composition provides sustained release of
`metronidazole for 7 to 14 days or more. A preferred
`dosage for a periodontal pocket, for example, is one in
`which each pocket receives about two mg of metroni-
`dazole, preferably in a slow release form that releases
`from 0.01 to 0.2 mg per day for each day that the poly-
`meric device remains in the periodontal pocket.
`
`Page 6
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`Page 6
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`

`

`4,568,535
`
`5
`A preferred anti-periodontitis formulation is given
`hereinafter by way of example and is presented for the
`purpose ofillustration but not of limitation.
`In this regard, the invention contemplates a preferred
`embodiment in which metronidazole comprises 1
`to
`20% wt/wtof the ethylcellulose film. Such a film is
`achieved by slowly dissolving 20 g of metronidazole
`(Zenith Laboratory) in chloroform, followed by 80 g of
`ethylcellulose Type N-22 (Hercules, Inc.), so as to form
`a slurry. Ethylcellulose Type N-7 or N-7NF may also
`be used. This slurry is then poured or cast into molds,
`which determine the thickness of the film. The chloro-
`form is allowed to evaporate, leaving behind a thin film
`in which the metronidazole is enmeshed within the
`matrix of the ethylcellulose. This metronidazoie-ethyl-
`cellulose film acts as a slow release device for metroni-
`dazole, as is described in the following test procedure.
`A circular disc of the film, measuring 5 mm in diame-
`ter and 0.3 mm thick was placed on a bacteriological
`agar medium in a Petri plate that had been previously
`inoculated with Bacteroides gingivalis, a bactcrium com-
`monly found in the subgingival plaque and a suspected
`periodontal pathogen. This bacterium or germ subse-
`quently grew on this medium, except in the vicinity of
`the disc. In the vicinity of the disc there was a zone of
`no growth that measured from | to 1.5 cm in diameter.
`This zone ofinhibition would have been larger, except
`that the disc was removed after one day and placed on
`a second agarplate that also had been previously inocu-
`lated with B. gingivalis. After a zone of bacterial inhibi-
`tion was noted about the site where the disc had been
`placed. This disc was subsequently transferred sequen-
`tially to other agar plates, inoculated with B. gingivalis
`and each time a zone ofinhibition was noted. The sup-
`ply of metronidazole in the disc was eventually ex-
`hausted after 70 days incubation on agar medium, dur-
`ing which time it was transferred about 55 times. If the
`disc was madethicker,i.e., about 0.5 mmthick,it could
`be incubated about 110 days before its supply of metro-
`nidazole was exhausted. During this period the disc was
`transferred about 75 times to fresh bacteriological me-
`dium newly inoculated with B. gingivalis. Thus the
`length of time that the disc can release the metronida-
`zole is a factor of the film thickness provided that the
`composition remains unchanged. In other trials the
`discs were abie to similarly inhibit Bacteroides interme-
`dius and the anaerobic spirochete known as Treponema
`denticola. These three species ofbacteria are representa-
`tive of the anaerobic black pigmented bacteroides spe-
`cies and spirochetes respectively that are associated
`with periodontitis. The fact that these bacteria were
`inhibited by the disc containing 20% metronidazole,
`80% ethylcellulose after 70 to 110 days of incubation
`during which 55 to 75 serial transfers of the disc oc-
`curred, attests to the fact that the formulation described
`in this invention acts as a slow release device for the
`metronidazole.
`As it is well knownin the periodontal literature, the
`absence ofblack pigmented bacteroides and spirochetes
`is associated with periodontal health, and the propor-
`tional increase of these organisms is associated with
`periodontal disease (see J. Clin. Periodontol. 5:115-132,
`1978; Host-Parasite Interactions in Periodontal Disease.
`R. J. Genco and §. E. Mergenhagen, eds. Amer. Soc.
`for Microbiol. Washington, D.C. pp. 27-45, 62-75,
`1982). Thus, antimicrobial agents, which suppress these
`microbes, have therapeutic value in the treatment of
`periodontitis. Indeed, in studies in which systemic met-
`
`10
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`25
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`30
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`40
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`45
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`50
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`6
`ronidazole was given for one week and compared to
`placebo medication, the metronidazole treatment was
`associated with a significant improvement in periodon-
`tal health, as evident by pocket reduction and decreased
`proportions of spirochetes and black pigmented bacte-
`roides, (J. Clin. Periodontol. 8:29-44, 1980; J. Periodon-
`tol. 55:325, 1984).
`The usage of a metronidazole-ethylcellulose film, as
`embodiedin this invention, will achieve the same thera-
`peutic result, but at much lower dosages. For example,
`a standard art-recognized systemic treatment for perio-
`dontitis by the oral route using oral tablets requires a
`total of about 5250 to 7000 mg of metronidazole. How-
`ever, non-systemic treatment for periodontitis with the
`slow release composition of the present invention uses
`only about 2.4 mg per periodontal pocket. As patients
`with the most advanced casesof periodontitis may have
`about 20 diseased pockets, and if the metronidazole
`discs are placed in each of these pockets, then the total
`dosage of metronidazole would be about 50 mg. This
`total dosage is less than 1% of the total systemic (oral)
`dose and reflects a substantial safety factor over sys-
`temic treatment with oral metronidazole. Thus, another
`aspect ofthe present inventionis its outstanding safety
`factor relative to systemic administration.
`This is possible because the nature of the invention
`allows the metronidazole to be placed exactly in and to
`the depths of the pockets where the periodontitis exists.
`Theclinician diagnoses the site where the periodontitis
`exists and then cuts or contours the metronidazole-
`ethylcellulose film for each of the individual pockets, so
`that its resulting contour matches the dimensions and
`contour of each pocket in turn so that the resulting
`contoured film can be placed completely and match-
`ingly within all of the pockets below the gingival mar-
`gin. This is illustrated in FIG. 2, which shows a premo-
`lar 20, a first molar 21 and a second molar 22. The
`gingival margin 23 is that level of gum which is seen
`about the teeth. The pocket is that space below the
`gingival margin where the tooth was formerly attached
`to its supporting tissue. As shown and as expressed
`dimensionally the difference between the gingival mar-
`gin and the base of the pocket, i.e. pocket depth 24,
`about the first and second molars ranges from 6 to 8
`mm, and about the premolar, ranges from about 2 to 4
`mm. The metronidazole-ethylcellulose film is con-
`toured by the dentist to fit subgingivally in those sites
`about the molars that have pockets of 6 or more mm.
`This is shown in FIG. 3, where two such contoured
`films 36 have been placed in the pockets aboutthe first
`and second molars. Note in particular the area on the
`teeth where the roots separate or bifurcate. These bifur-
`cations 25, are notoriously difficult to treat by conven-
`tional mechanical debridementand are completely inac-
`cessible to antimicrobials delivered by mouthrinses,
`dentifrices, gels, etc. However, the film can be placed
`over and within the bifurcations, thus delivering the
`metronidazole to this part of the tooth that usually is
`refractory to most forms of conventional periodontal
`therapy. Thus, another aspect ofthe presentinventionis
`that bifurcations and trifurcations (root separation on
`the maxillary or upper teeth) can be exposed to thera-
`peutic levels of metronidazole for periodsoftime suffi-
`cient to treat an anaerobic infection.
`The placement ofthe films in this fashion below the
`gum line is novel to this invention and has not been
`described in previous patents devoted to antimicrobials
`
`Page 7
`
`Page 7
`
`

`

`4,568,535
`
`8
`isms such as spirochetes and black pigmented bacteroi-
`des. The invention involves the incorporation of metro-
`nidazole an antimicrobial which has a specific spectrum
`of activity against anaerobic bacteria, into an ethylcellu-
`lose film in such a way that the metronidazole is slowly
`released. The metronidazole ethylcellulose film is
`placed by the clinician directly into the periodontal
`pocket of 6 mm or more depth andleft in situ for peri-
`ods of 7 to 14 days or more during which time the
`metronidazole is continuously released at bacteriocidal
`levels for anaerobes. This manner of application assures
`that furcation sites on molars will be exposed to thera-
`peutic levels of metronidazole. The release kinetics of
`the metronidazole can be controlled by the dimensions
`of the film and by the addition of polyethylene glycol.
`The activity of metronidazole can be enhanced by the
`usage of reducing agents.
`DESCRIPTION OF THE PREFERRED
`EMBODIMENT
`
`7
`in plaque control, e.g., see U.S. Pat. Nos. 3,700,685,
`4,205,061, 4,224,308 and 4,251,507.
`Metronidazole’s -action can be counteracted by the
`presence of oxygen. As bleeding is a commonfinding in
`periodontitis and the oxygen contained in blood may
`reduce the activity of the released metronidazole, a
`preferred embodimentof the compositions of the inven-
`tion includes an antioxidant that is compatible with the
`formulation. For this purpose, one may use one or more
`of a wide variety of pharmaceutically-acceptable anti-
`oxidant agents that provide the desired oxidation reduc-
`tion potential for optimal bactericidal action of metroni-
`dazole. Such antioxidants include agents such as ascor-
`bic acid, sodium thiosulfate, dithiothreitol, cysteine,
`thioglycollate and glutathione. Anti-oxidants that are
`recognized as safe for use as food additives, such as
`ascorbic acid and sodium thiosulfate, are preferred. One
`uses an amount of anti-oxidant sufficient, when the
`composition is administered to the subgingival site or
`pocket site, to enhance or maintain the anaerobic state
`of the site during the period of treatment. A preferred
`composition is one in which the concentration ofanti-
`oxidant is in the range from about 0.1 to about 1% by
`weight of the composition. This usage of an antioxidant
`to enhancethe action of metronidazole is novel to this
`invention.
`As indicated, the composition of the invention com-
`prises a pharmaceutically acceptable polymer that is
`solid at body temperatures. The polymer can be se-
`lected from naturally occurring and synthetic poly-
`. meric materials and manufactured in composition forms
`. as inserts or containers by known methods. Thus, the
`invention contemplates use of matrices composed of
`any of a wide variety of art-recognized polymeric mate-
`rials, such matrices and their method of manufacture
`being described, for example, by Shel] et al. in their U.S.
`Pat. No. 4,304,765, incorporated herewith by reference.
`The matrix in solid form suitably is adapted for osmotic
`release, as described in U.S. Pat. No. 4,303,765, or it
`Inay be bicerodible, such that the active components are
`.. Slowly released over a prolonged period of time, for
`example, from five to 15 days. A preferred polymeric
`matrix is a solid form comprising ethylcellulose, prefer-
`ably constituting from about 79 to about 98 percent by
`weight of the composition. The solid form matrix or
`insert is manufactured, sized, shaped, structured and
`adapted for easy insertion and comfortable prolonged
`retention in the periodontal pocket. The matrix can
`have any geometric shape, and its dimensions can vary
`to conform to the subgingival site. The lower limit on
`the size of the matrix is governed by the amount of
`metronidazole to be housed and administered to elicit
`the desired pharmacological and periodontal response,
`as well as the smallest size of matrix that can be conve-
`niently inserted and maintained in the pocket.
`In anotheraspect, the invention concerns a method of
`periodontal treatment which comprises administering
`subgingivally a composition according to the invention
`in unit dose form within at least one periodontal pocket
`in one or more quadrants of the dentition. A preferred
`embodiment of the method is one where the metronida-
`zole content of the composition is in a form adapted for
`sustained release.
`
`..
`
`35
`
`40
`
`45
`
`The invention and best modeof practicing the sameis
`given hereafter by way of example andis presented for
`the purposeofillustration, but not of limitation.
`EXAMPLE1
`
`Sustained Release Solid Form
`
`Component
`Metronidazole
`
`Parts by Weight
`1 to 20
`
`Antioxidant, Ascorbic Acid 0.0 to 1.0
`Ethyl] Cellulose (Type N22, N7, or N-7NF)* 80 to 98
`*Manufactured by Hercules, Inc., Delaware.
`The ethylcellulose is dissolved in chloroform and
`then after complete dissolution, the metronidazole and
`antioxidant are added. The resulting mixture is cast on
`glass plates and after evaporation of the chloroform,the
`residual film is removed from the plate. Films of vary-
`ing thickness and containing varying amountse.g., from
`one to 20 percent, of metronidazole can be prepared.
`The films are to be cut to approximate the dimensions of
`the pocket (for example, 8 mm long by 3 mm wide by
`0.5 mm thick) and then placed within the pocket by the
`dentist (See FIG. 3).
`Thelatter film weighs about 12 mg. If metronidazole
`comprises 20 percent of this weight, then about 2.4 mg
`of metronidazole is added via the film to each infected
`pocket. If the patient has 20 such deep pockets, then
`about 50 mg (202.4 mg) of metronidazole is needed to
`treat the periodontalinfection over a 7 to 14 day period.
`This dosage is about one one-hundredth (1/100th) the
`dosage of metronidazole currently given systemically to
`treat periodontal infections. ‘This reduction in dosageis
`one of the important advantages of the the present in-
`vention over the systemic route of administration.
`Other solid state polymers can be substituted in the
`composition to provide for equivalent or comparable
`sustained release of metronidazole in the pocket.
`Amongthese preferred are Wynathene, a soft and elas-
`tomeric vinyl acetate-ethylene copolymer and the bio-
`degradable polymer, polycaprolactone, as described in
`U.S. Pat. No. 4,304,765 (J. Dent. Res. 60:Spec. Iss.
`IADR Abstracts, p.274).
`In a modification of the invention, for faster sustained
`release, polyethylene glycol is dissolved in the chloro-
`form with the other components, so as to give a final
`concentration of 10 percent. The 10 percent polyethyl-
`
`Page 8
`
`SUMMARY
`
`65
`
`The Invention describes a novel method oftreating
`advanced forms of periodontal disease that are associ-
`ated with the proportional increase of anaerobic organ-
`
`Page 8
`
`

`

`4,568,535
`
`9
`ene glycol will result in a controlled faster release of the
`metronidazole from the polymer, which is especially
`useful in the prompt treatment of active periodontal
`infections. It should be obvious to anyone familiar with
`the art that metronidazole derivatives, such as those
`described in U.S. Pat. No.
`3,700,685 other ni-
`troimidazoles active against anaerobes, as well as other
`antimicrobial agents, such as chlorhexidine, fluoride,
`tetracyclines, penicillin and other compounds, could be
`incorporated singly or in various combinations in such a
`slow release device for the treatment of periodontitis.
`The above formulations may optionally include ex-
`cipient components, such self-sterilizing agents, flavor-
`ing agents, coloring or visualizing agents, and thelike,
`in suitable proportion.
`When compositionsof this invention are placed in the
`periodontal pocket that exhibits bleeding and high pro-
`portions of spirochetes and black pigmented bacteroi-
`des in the subgingival plaque, highly favorable results
`are observed. For purposes of clinical proof of this
`result, human subjects of widely varied age groups,
`whohaveactive periodontitis with pockets of 6 mm or
`more, can be used. Evidence ofclinical effectiveness
`can be obtained in the following manner. Patients with
`6 to 30 sites with pockets depths of 6 mm or more will
`be randomly assigned to one of two groups. Patients in
`group one will have ethylcellulose films containing
`metronidazole placed into these deep pockets, whereas
`patients in group two will have ethylcellulose films
`without metronidazole placed within their deep pock-
`ets. The film that is designated to be placed in the
`pocket will be contoured by the clinician so that it can
`be placed below the gingival margin, so as to occupy
`the majority of the space in the periodontal pocket (See
`FIG.3). Prior to placementof these filmsin the pocket,
`the pocket depth and attachment distance will be mea-
`sured as described previously, and an aliquot of plaque
`will be removed for microscopic and cultural analysis.
`The microscopic analysis will determine the numbers
`and proportions of various spiroc