United States Patent [19]
`United States Patent [19]
`Loesche (cid:9)
`Loesche
`
`[11] Patent Number: (cid:9)
`[11] Patent Number:
`[45] Date of Patent:
`[45] Date of Patent: (cid:9)
`
`4,568,535
`4,568,535
`Feb. 4, 1986
`Feb. 4, 1986
`
`[54] COMPOSITION FOR PERIODONTAL
`[54] COMPOSITION FOR PERIODONTAL
`ADMINISTRATION
`-
`ADMINISTRATION
`[76] Inventor: Walter J, Loesche, 1814 Hermitage,
`[76] Inventor: Walter J. Loesche, 1814 Hermitage,
`Ann Arbor, Mich. 48104
`Ann Arbor, Mich. 48104
`
`[21] Appl. No.: 631,542
`[21] Appl' No': 631’542
`JuL 16 1984
`[22] Filed:
`Jul. 16, 1984
`[22] Filed: (cid:9)
`
`[63]
`[63] (cid:9)
`
`Related U.S. Application Data
`Related US. Application Data
`Continuatiommpm ofsen N0 405 790 Aug 6 1982
`Continuation-in-part of Ser. No. 405,790, Aug. 6, 1982,
`’
`’
`abandoned.
`’
`’
`abandoned_
`
` A61K 9/22; A61K 9/52
`[51] Int. C1 4 (cid:9)
`, _ , _, A61K 9/22; A61K 9/52
`[51] Int, Cl,4 _ , _ _ _ , _ _ , ,
` 424/19; 514/365;
`[52] U.S. Cl. (cid:9)
`[52] US. Cl. .................................... .. 424/19; 514/365;
`424/28
`424/28
` 424/22, 26, 28, 19,
`[58] Field of Search (cid:9)
`[58] Field of Search ..................... .. 424/22, 26, 28, 19,
`424/273 R, 52; 106/35; 514/365
`424/273 R, 52; 106/35; 514/365
`
`[56]
``[56]
`
`References Cited
`References Cited
`PUBLICATIONS
`PUBLICATIONS
`Soskolne et al., New Sustained Release Dosage Form of
`Soskolne et al., New Sustained Release Dosage Form of
`Perio, Res,
`Chlorhexidine for Dental Use, J.
`Chlorhexidine for Dental Use, J. Perio, Res,
`18:330-336.
`18:330-336.
`Primary Examiner—-Johnnie R. Brown
`Primary Examiner—Johnnie R. Brown
`Assistant Examiner—C. Joseph Faraci
`Assistant Examiner-C. Joseph Faraci
`ABSTRACT
`[57]
`ABSTRACT
`[57] (cid:9)
`A composition for periodontal administration and a
`A composition for periodontal administration and a
`method of periodontal treatment involving a slow re-
`method of periodontal treatment involving a slow re
`lease device which can be placed directly into the peri-
`lease device which can be placed directly into the peri
`odontal pocket where metronidazole, with or without
`odontal pocket where metronidazole, with or without
`antioxidants, are released over periods of days to weeks
`antioxidants, are released over periods of days to weeks
`at a cidal concentration for anaerobes in the domain of
`at a cidal concentration for anaerobes in the domain of
`the periodontal pocket.
`the periodontal pocket.
`
`2 Claims, 3 Drawing Figures
`2 Claims, 3 Drawing Figures
`
`Par Pharm., Inc., et al.
`Exhibit 1015
`Page 001
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`US. Patent Feb. 4, 1986
`U.S. Patent Feb. 4, 1986 (cid:9)
`
`Sheetl of3
`Sheet 1 of 3 (cid:9)
`
`4,568,535
`4,568,535
`
`SUPRAGINGIVAL PLAQUE
`COCCI = G RODS >
`G-RODS >MOTILE RODS
`
`3 (cid:9)
`
`GINGIVAL MARGIN PLAQUE
`G + RODS = G-RODS > COCCI
`
`POCKET PLAQUE
`G -RODS = MOTILE RODS
`> G -+ SPECIES
`
`2| / T
`
`I
`
`12
`
`14 (cid:9)
`
`8 3 5
`
`FIG. I
`
`FIG. I
`
`FIG. 18
`
`FIG. IA
`
`FIG. IA
`
`PERIODONTAL
`DISEASE
`
`PERIODONTAL D
`
`I
`
`S
`
`E
`
`A
`
`S
`
`E
`
`
`
`I
`/
`II l5
`
`15
`
`II
`
`n l3 \
`
`13
`
`2 l5
`
`y
`
`3 Y I2
`
`I .x ,
`
`. X
`
`_
`
`14
`
`l4
`
`X-8
`POCKET DEPTH (cid:9)
`Y-3
`GINGIVA TO CEJ (cid:9)
`ATTACHMENT DISTANCE - Z-5
`
`DEPTH
`POCKET
` — — —
`
`—
`
`—
`
`CINCIVA T0 CEJ -
`
`A
`
`T
`
`D
`
`T
`
`I
`
`A
`
`S
`
`C
`
`H
`
`T
`
`M
`
`A
`
`-
`E
`
`N
`
`N
`
`C
`
`T
`
`
`
`E
`
`
`
`Par Pharm., Inc., et al.
`Exhibit 1015
`Page 002
`
`

`

`lUalVd 'S'11
`
`E Jo Z PaITS
`
`gEg`89c't (cid:9)
`
`FIG. 2
`PROFILE OF THREE TEETH SHOWING POCKET DEPTH AS DISTANCE
`BETWEEN GINGIVAL MARGIN 23 AND BONE LEVEL 26. NOTE THAT
`DEEP POCKETS ( 6 TO 8 MM IN DEPTH ) ARE ABOUT THE FIRST
`AND SECOND MOLARS ( TEETH 21 AND 22 ).
`
`20
`
`21 (cid:9)
`
`22
`
`23 GINGIVAL
`MARGIN
`
`i la I III I I 1
`
`26 BONE LEVELS (cid:9)
`1
`2mm (cid:9)
`i , (cid:9)
`POCKET DEPTH \ (cid:9)
`
`I (cid:9)
`
`1
`
`i
`i1
`I
`I
`,
`
`I (cid:9)
`
`/
`
`8mm
`POCKET DEPTH
`
`6mm
`POCKET DEPTH
`
`I I (cid:9)
`
`\
`
`I (cid:9)
`
`\
`
`/ (cid:9)
`I
`
`24 (cid:9)
`
`I
`
`I (cid:9)
`
`I
`I (cid:9)
`
`\ (cid:9)
`
`I
`
`r (cid:9)
`
`I (cid:9)
`/
`/ (cid:9)
`
`% (cid:9)
`
`\
`
`t
`
`I (cid:9)
`I (cid:9)
`
`TOOTH SURFACE
`BENEATH
`GINGIVAL MARGIN
`
`1I (cid:9)
`k, (cid:9)
`
`/ (cid:9)
`
`I (cid:9)
`
`I,
`
`25
`BIFURCATION
`
`1 (cid:9)
`
`I (cid:9)
`I (cid:9)
`il (cid:9)
`I (cid:9)
`I ,.....," (cid:9)
`
`/ (cid:9)
`
`/
`
`I (cid:9)
`/ (cid:9)
`I
`I /f 1 (cid:9)
`t
`/ (cid:9)
`t I
`
`25
`BIFURCATION
`
`- (cid:9)
`
`ti
`
`I
`
`I
`
`\
`N
`
`Par Pharm., Inc., et al.
`Exhibit 1015
`Page 003
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`U.S. Patent Feb. 4, 1986 (cid:9)
`
`Sheet 3 of 3 (cid:9)
`
`4,568,535
`
`FIG. 3
`
`PROFILE OF THREE TEETH SHOWING TWO CONTOURED DRUG RELEASING FILMS 36
`SUBGINGIVALLY PLACED ONLY IN THOSE SITES WHERE THE POCKET DEPTHS ARE
`6 MM OR MORE. NOTE THAT THE FILMS CAN BE PLACED OVER THE BIFURCATION
`SITES 25.
`
`30
`
`31 (cid:9)
`
`,-32
`
`8mm
`POCKET DEPTH (cid:9)
`
`t i (cid:9)
`it (cid:9)
`
`6 rani
`POCKET DEPTH
`
`it
`
` It
`
`
`
`I T
`,
`
`I
`
`It
`
`/ (cid:9)
`I
`/ (cid:9)
`
`1
`I (cid:9)
`
`X,
`
`,
`'..... 1
`
`/
`
`25
`BIFURCATION
`
`r (cid:9)
`
`%
`
`' 36 -- (cid:9)
`
`t (cid:9)
`
`%,
`t
`1
`
`1 (cid:9)
`I I,
`
`33 GINGIVAL
`MARGIN
`
`-
`
`36 BONE LEVEL)
`2mm
`POCKET DEPTH
`
`TOOTH SURFACE
`BENEATH
`GINGIVAL MARGIN
`
`25
`BIFURCATION
`
`Par Pharm., Inc., et al.
`Exhibit 1015
`Page 004
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`1
`1
`
`COMPOSITION FOR PERIODONTAL
`COMPOSITION FOR PERIODONTAL
`ADMINISTRATION
`ADMINISTRATION
`
`CROSS-REFERENCES
`CROSS-REFERENCES (cid:9)
`This is a continuation-in-part of Ser. No. 405,790 ?led
`This is a continuation-in-part of Ser. No. 405,790 filed
`8/6/82 now abandoned.
`8/6/82 now abandoned.
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`1. Technical Field
`1. Technical Field
`This invention relates to a composition for periodon
`This invention relates to a composition for periodon-
`tal administration that is cidal for anaerobes in the do
`tal administration that is cidal for anaerobes in the do-
`main of the periodontal pocket and to a novel method of
`main of the periodontal pocket and to a novel method of
`treatment of anaerobic infections in periodontal disease
`treatment of anaerobic infections in periodontal disease
`15
`15
`that is dependent upon the slow release of metronida
`that is dependent upon the slow release of metronida-
`zole from a plastic ?lm that is placed within the peri
`zole from a plastic film that is placed within the peri-
`odontal pocket, and which ?lm resides in such pocket
`odontal pocket, and which film resides in such pocket
`for a period of days to weeks.
`for a period of days to weeks.
`2. Description of Prior Art
`2. Description of Prior Art
`The main cause of tooth loss in adults is periodontal
`The main cause of tooth loss in adults is periodontal
`disease. Yet, surprisingly, less than one percent of the
`disease. Yet, surprisingly, less than one percent of the
`public expenditures for dental treatment is for periodon
`public expenditures for dental treatment is for periodon-
`tal disease (see J. Dent. Educ. 432320‘ (1979). This is
`tal disease (see J. Dent. Educ. 43:320, (1979). This is
`because conventional periodontal treatment is too ex
`because conventional periodontal treatment is too ex-
`pensive for most individuals, mainly due to the labor
`pensive for most individuals, mainly due to the labor
`intensive, symptomatic treatment that is usually per
`intensive, symptomatic treatment that is usually per-
`formed by highly skilled specialists. -
`formed by highly skilled specialists.
`Periodontal disease is an all-inclusive term for a vari
`Periodontal disease is an all-inclusive term for a vari-
`ety of clinical entities that are forms of either gingivitis
`ety of clinical entities that are forms of either gingivitis
`or periodontitis. Gingivitis is an in?ammation of the
`or periodontitis. Gingivitis is an inflammation of the
`gingiva or gums that can be associated with poor oral
`gingiva or gums that can be associated with poor oral
`hygiene and/or hormonal states of the host. It is as
`hygiene and/or hormonal states of the host. It is as-
`sumed, but not proven in the human, that gingivitis will
`sumed, but not proven in the human, that gingivitis will
`progress to a periodontitis, which is the form of the
`progress to a periodontitis, which is the form of the
`disease in which the infection has progressed to involve
`disease in which the infection has progressed to involve
`the oral tissues which retain the teeth in the jaw bone.
`the oral tissues which retain the teeth in the jaw bone.
`Periodontitis is the more severe form of the disease, and
`Periodontitis is the more severe form of the disease, and
`if untreated, will eventuate in the loss of the tooth.
`if untreated, will eventuate in the loss of the tooth.
`Dentists have long assumed that periodontal disease
`Dentists have long assumed that periodontal disease
`originates by the overgrowth of bacteria on the tooth
`originates by the overgrowth of bacteria on the tooth
`surfaces in aggregates known as dental plaque. If this
`surfaces in aggregates known as dental plaque. If this
`plaque persists for long periods of time on the tooth
`plaque persists for long periods of time on the tooth
`surfaces, it may in some instances calcify, forming the
`surfaces, it may in some instances calcify, forming the
`hard substance known as calculus. Numerous studies
`hard substance known as calculus. Numerous studies
`describe chemical agents which can in vitro and in vivo
`describe chemical agents which can in vitro and in vivo
`reduce plaque formation and calculus. However, none
`reduce plaque formation and calculus. However, none
`of these chemical agents has been reported to be suc
`of these chemical agents has been reported to be suc-
`cessful in treating periodontitis.
`cessful in treating periodontitis.
`A substantial number of different types of compounds
`A substantial number of different types of compounds 50
`and compositions have been developed for use as anti
`and compositions have been developed for use as anti-
`bacterial and antiplaque agents, e.g., benzethonium
`bacterial and antiplaque agents, e.g., benzethonium
`chloride and cetyl pyridinium chloride, disclosed in
`chloride and cetyl pyridinium chloride, disclosed in
`U.S. Pat. No. 4,110,429, or as anticalculus agents, e.g.,
`U.S. Pat. No. 4,110,429, or as anticalculus agents, e.g.,
`2-phosphono-butane 1,2,4-tricarboxylic acid, disclosed
`2-phosphono-butane 1,2,4-tricarboxylic acid, disclosed 55
`in U.S. Pat. No. 4,224,308. These compounds are de
`in U.S. Pat. No. 4,224,308. These compounds are de-
`signed to be used by the individual in dentifrices, dental
`signed to be used by the individual in dentifrices, dental
`powders, pastes, mouthwashes, nonabrasive gels, chew
`powders, pastes, mouthwashes, nonabrasive gels, chew-
`ing gums, topical solutions and the like, e.g., see U.S.
`ing gums, topical solutions and the like, e.g., see U.S.
`Pat. No. 4,205,061. They are designed to be used as
`Pat. No. 4,205,061. They are designed to be used as 60
`60
`prophylactic agents, usually without requiring a pre
`prophylactic agents, usually without requiring a pre-
`scription or supervision during usage, e. g., see U.S. Pat.
`scription or supervision during usage, e.g., see U.S. Pat.
`No. 4,251,507. Often they are compounded with deter
`No. 4,251,507. Often they are compounded with deter-
`gents and other cleaning agents, and this cleaning action
`gents and other cleaning agents, and this cleaning action
`is often an important aspect of the invention, e.g., see
`is often an important aspect of the invention, e.g., see 65
`65
`U.S. Pat. Nos. 4,251,507 and 4,205,06l. None of these
`U.S. Pat. Nos. 4,251,507 and 4,205,061. None of these
`compounds or compositions are designed to be used as
`compounds or compositions are designed to be used as
`antimicrobial agents for the treatment of periodontitis,
`antimicrobial agents for the treatment of periodontitis,
`
`30
`
`35
`
`40
`
`45
`45
`
`5
`
`10
`
`20
`20
`
`25
`25
`
`4,568,535
`4,568,535
`2
`2
`nor are they formulated to be slow release devices for
`nor are they formulated to be slow release devices for
`these antimicrobial agents in vivo.
`these antimicrobial agents in vivo.
`Recent research in periodontal disease (see, for exam
`Recent research in periodontal disease (see, for exam-
`ple, Chemotherapy of Dental Plaque Infections, Oral
`ple, Chemotherapy of Dental Plaque Infections, Oral
`Sci. Rev. 9:65-107, 1976) indicates that gingivitis and
`Sci. Rev. 9:65-107, 1976) indicates that gingivitis and
`periodontitis are characterized by different types of
`periodontitis are characterized by different types of
`bacteria. Gingivitis is associated with the accumulation
`bacteria. Gingivitis is associated with the accumulation
`of gram positive cocci and actinomyces, whereas perio
`of gram positive cocci and actinomyces, whereas perio-
`dontitis is characterized by proportional increases in
`dontitis is characterized by proportional increases in
`anaerobic bacteria, such as spirochetes and black pig
`anaerobic bacteria, such as spirochetes and black pig-
`mented bacteroides (see Host-Parasite Interactions in
`mented bacteroides (see Host-Parasite Interactions in
`Periodontal Disease. R. J. Genco and S. E. Mergenha
`Periodontal Disease. R. J. Genco and S. E. Mergenha-
`gen, eds. Amer. Soc. for Microbiol. Washington, DC.
`gen, eds. Amer. Soc. for Microbiol. Washington, D.C.
`p. 27-45, 62-75, 1982). The different bacterial composi
`p. 27-45, 62-75, 1982). The different bacterial composi-
`tions of plaque associated with either gingivitis or perio
`tions of plaque associated with either gingivitis or perio-
`dontitis suggest that a mode of treatment that is effec
`dontitis suggest that a mode of treatment that is effec-
`tive in gingivitis may not be effective in periodontitis.
`tive in gingivitis may not be effective in periodontitis.
`This is an important factor in the present invention, as
`This is an important factor in the present invention, as
`previous discoveries in the area of periodontal disease
`previous discoveries in the area of periodontal disease
`have assumed that there is no bacterial speci?city in
`have assumed that there is no bacterial specificity in
`periodontal ‘disease. This is now known to be incorrect.
`periodontal disease. This is now known to be incorrect.
`These bacterial differences in plaque may explain why
`These bacterial differences in plaque may explain why
`an agent effective in plaque control, such as chlorhexi
`an agent effective in plaque control, such as chlorhexi-
`dine, has little effect on gingivitis and no published
`dine, has little effect on gingivitis and no published
`effect on periodontitis.
`effect on periodontitis.
`Another important ?nding from recent periodontal
`Another important finding from recent periodontal
`research is that the composition of the dental plaque
`research is that the composition of the dental plaque
`will differ according to its location on the tooth surface.
`will differ according to its location on the tooth surface.
`Above the gingival or gum margin, facultative bacteria,
`Above the gingival or gum margin, facultative bacteria,
`such as gram positive cocci and rods, are numerically
`such as gram positive cocci and rods, are numerically
`dominant, whereas below the gum margin, anaerobic
`dominant, whereas below the gum margin, anaerobic
`motile bacteria such as spirochetes, and anaerobic gram
`motile bacteria such as spirochetes, and anaerobic gram
`negative rods including the black-pigmented bacteroi
`negative rods including the black-pigmented bacteroi-
`des are predominant. In other words, two different
`des are predominant. In other words, two different
`microbial ecosystems are present on the same tooth
`microbial ecosystems are present on the same tooth
`surface.
`surface.
`This is illustrated in the accompanying drawings in
`This is illustrated in the accompanying drawings in
`FIGS. la and lb, which show a cross section of a tooth
`FIGS. 1a and 1b, which show a cross section of a tooth
`10, a periodontal pocket 11, and the gingiva or gum 12.
`10, a periodontal pocket 11, and the gingiva or gum 12.
`The tooth illustrated in FIG. 1a exhibits periodontal
`The tooth illustrated in FIG. la exhibits periodontal
`disease in which periodontal attachment of the tooth to
`disease in which periodontal attachment of the tooth to
`the alveolar bone has been destroyed, and a periodontal
`the alveolar bone has been destroyed, and a periodontal
`pocket 11 has been formed between the gum 12 and the
`pocket 11 has been formed between the gum 12 and the
`root surface of the tooth. Clinical assessment of such
`root surface of the tooth. Clinical assessment of such
`deterioration of teeth is made by measuring the depth of
`deterioration of teeth is made by measuring the depth of
`the pocket. This is done by inserting a periodontal
`the pocket. This is done by inserting a periodontal
`probe or ruler, a thin metal rod (not shown), to the base
`probe or ruler, a thin metal rod (not shown), to the base
`of the pocket 14. Two measurements can be obtained
`of the pocket 14. Two measurements can be obtained
`with the probe. One, called the pocket depth x, in illus
`with the probe. One, called the pocket depth x, in illus-
`tration 1a is the distance between the height of the
`tration la is the distance between the height of the
`gingival margin 13 to the base of the pocket 14. The
`gingival margin 13 to the base of the pocket 14. The
`other measurement, y, is the distance between the
`other measurement, y, is the distance between the
`height of the gingival margin 13 and the cemento
`height of the gingival margin 13 and the cemento-
`enamel junction (CEJ)15. The CEJ is extremely valu
`enamel junction (CEJ)15. The CEJ is extremely valu-
`able because it gives a permanent reference mark on
`able because it gives a permanent reference mark on
`each tooth surface from which one can base further
`each tooth surface from which one can base further
`measurements. It enables one to divide the pocket depth
`measurements. It enables one to divide the pocket depth
`measurement into two components: the distance be
`measurement into two components: the distance be-
`tween the CEJ and the top of the gingival margin, y,
`tween the CEJ and the top of the gingival margin, y,
`and the distance between the CE] and the bottom of the
`and the distance between the CEJ and the bottom of the
`pocket, 2. This letter measurement is called the attach
`pocket, z. This letter measurement is called the attach-
`ment distance. As illustrated in the diseased tooth, the
`ment distance. As illustrated in the diseased tooth, the
`attachment distance is 5 mm and the pocket depth is 8
`attachment distance is 5 mm and the pocket depth is 8 ,
`mm.
`mm.
`FIG. lb is an enlargement of a section of the type
`FIG. 1b is an enlargement of a section of the type
`shown in FIG. 1a in which the periodontal pocket 11 is
`shown in FIG. la in which the periodontal pocket 11 is
`now ?lled with bacterial plaque. Note that the plaque
`now filled with bacterial plaque. Note that the plaque
`lies between the tooth and the gingiva in the space
`lies between the tooth and the gingiva in the space
`
`Par Pharm., Inc., et al.
`Exhibit 1015
`Page 005
`
`

`

`4,568,535
`4,568,535
`4
`3
`4
`3
`(for example, see Proceedings of International Metroni
`(for example, see Proceedings of International Metroni-
`called the periodontal pocket. Also note that the bacte
`called the periodontal pocket. Also note that the bacte-
`dazole Conference, Excerpta Medica, 1976). For these
`dazole Conference, Excerpta Medica, 1976). For these
`rial composition of the plaque varies according to its
`rial composition of the plaque varies according to its
`spatial relationship to the gingival margin 13. Above the
`reasons, it is desirable to use the lowest possible dosage
`reasons, it is desirable to use the lowest possible dosage
`spatial relationship to the gingival margin 13. Above the
`gingival margin the plaque is known as the supragingi
`of metronidazole consistent with a therapeutic effect.
`of metronidazole consistent with a therapeutic effect.
`gingival margin the plaque is known as the supragingi-
`val plaque, and it generally has equal numbers of gram
`The slow-release-?lm-metronidazole device, which is
`The slow-release-film-metronidazole device, which is
`val plaque, and it generally has equal numbers of gram 5
`positive (+) cocci and rods, fewer gram negative (—)
`described in this invention, may reduce the amount of
`described in this invention, may reduce the amount of
`positive (+) cocci and rods, fewer gram negative (—)
`metronidazole necessary to treat advanced cases of
`rods and even fewer motile rods. Next comes a section
`metronidazole necessary to treat advanced cases of
`rods and even fewer motile rods. Next comes a section
`periodontitis by as much as 99%.
`of plaque which contains proportionally more gram
`of plaque which contains proportionally more gram
`periodontitis by as much as 99%.
`negative (—) rods and some spirochetes. This plaque is
`Thus, the present invention not only describes an
`Thus, the present invention not only describes an
`negative ( —) rods and some spirochetes. This plaque is
`effective means of treating anaerobic periodontal infec
`known as the gingival margin plaque. Finally, in the
`effective means of treating anaerobic periodontal infec-
`known as the gingival margin plaque. Finally, in the 10
`tion, but does so at dosages that are greatly reduced
`bottom of the pocket, is found a plaque which is domi
`tion, but does so at dosages that are greatly reduced
`bottom of the pocket, is found a plaque which is domi-
`nated by anaerobic gram negative rods and motile rods,
`compared to systemic or oral administration of the same
`compared to systemic or oral administration of the same
`nated by anaerobic gram negative rods and motile rods,
`including black-pigmented bacteroides and spirochetes.
`agent(s). This safety factor is an important aspect of the
`agent(s). This safety factor is an important aspect of the
`including black-pigmented bacteroides and spirochetes.
`present invention.
`This plaque is known as subgingival or pocket plaque
`present invention.
`This plaque is known as subgingival or pocket plaque
`and it is this plaque that is the etiologic agent of perio
`and it is this plaque that is the etiologic agent of perio- 15
`dontitis.
`dontitis.
`It is clear from this illustration and from recent elec-
`It is clear from this illustration and from recent elec
`tronmicroscopic examinations of plaque that the subgin
`tronmicroscopic examinations of plaque that the subgin-
`gival plaque is distinct from supragingival plaque (see J.
`gival plaque is distinct from supragingival plaque (see J.
`Periodontol. 47:1-18, 1976). This has important implica
`Periodontol. 47:1-18, 1976). This has important implica- 20
`tions for our invention, as previous patents for the use of
`tions for our invention, as previous patents for the use of
`antimicrobials described agents that are delivered to the
`antimicrobials described agents that are delivered to the
`supragingival plaque. It can be surmised from the illus-
`supragingival plaque. It can be surmised from the illus
`tration and now accepted as fact, that antimicrobial
`tration and now accepted as fact, that antimicrobial
`agents delivered in dentifrices, dental powders, pastes,
`agents delivered in dentifrices, dental powders, pastes, 25
`25
`mouthrinses, nonabrasive gels, chewing gums, topical
`mouthrinses, nonabrasive gels, chewing gums, topical
`solutions and the like, will minimally penetrate into the
`solutions and the like, will minimally penetrate into the
`pocket for a distance of about 1 to 3 mm. As periodontal
`pocket for a distance of about 1 to 3 mm. As periodontal
`pockets may be 12 to 13 mm in depth, it is apparent that
`pockets may be 12 to 13 mm in depth, it is apparent that
`the topical application of any antimicrobial agent, even
`the topical application of any antimicrobial agent, even 30
`metronidazole, to the supragingival plaque will have no
`metronidazole, to the supragingival plaque will have no
`or minimal effect on the subgingival plaque and accord-
`_ or minimal effect on the subgingival plaque and accord
`ingly, should have little if any effect on periodontitis.
`ingly, should have little if any effect on periodontitis.
`Our invention is, therefore, quite distinct from the topi
`Our invention is, therefore, quite distinct from the topi-
`cal application of metronidazole in water or in vehicles, 35
`cal application of metronidazole in water or in vehicles,
`35
`such as gels or pastes as disclosed in U.S. Pat. No.
`such as gels or pastes as disclosed in US Pat. No.
`3700,685, as our invention will place the metronidazole
`3700,685, as our invention will place the metronidazole
`directly into the periodontal pocket, where it will be in
`directly into the periodontal pocket, where it will be in
`contact with the bacteria in the subgingival plaque.
`contact with the bacteria in the subgingival plaque.
`Also, our invention is different from previous patent 40
`Also, our invention is different from previous patent
`40
`applications which incorporated antimicrobials in denti
`applications which incorporated antimicrobials in denti-
`frices, gels, powders, etc. which were designed to be
`. frices, gels, powders, etc. which were designed to be
`delivered to the supragingival tooth sites, e.g., see U.S.
`delivered to the supragingival tooth sites, e.g., see US.
`Pat. Nos. 4,205,061, 4,251,507, 4,224,308 and 3,700,685
`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 45
`and had as their treatment goal, the control of dental
`45
`plaque and oral cleanliness.
`plaque and oral cleanliness.
`From a review of these patents and other information
`From a review of these patents and other information
`in the literature it is apparent that an improved means of
`in the literature it is apparent that an improved means of
`treating periodontitis is needed in dentistry. From a
`treating periodontitis is needed in dentistry. From a
`reading of information in the art, it is obvious that the 50
`reading of information in the art, it is obvious that the
`50
`basic need of treating an anaerobic infection in the peri-
`basic need of treating an anaerobic infection in the peri
`odontal pocket is not satisfied. None of the means pres-
`odontal pocket is not satis?ed. None of the means pres
`ently available appears to get at the heart of the prob-
`ently available appears to get at the heart of the prob
`lem, which is finding an improved means of delivering
`lem, which is finding an improved means of delivering
`an antimicrobial agent speci?c for anaerobic organisms,
`an antimicrobial agent specific for anaerobic organisms, 55
`55
`such as spirochetes and black pigmented bacteroides, to
`such as spirochetes and black pigmented bacteroides, to
`the periodontal pocket for continuous periods of 5 to 10
`the periodontal pocket for continuous periods of 5 to 10
`days or more.
`days or more.
`Such a delivery can be achieved with systemic anti-
`Such a delivery can be achieved with systemic anti
`microbials. Indeed, short-term oral administration of 60
`microbials. Indeed, short-term oral administration of
`60
`metronidazole in humans and in dogs caused a sustained
`metronidazole in humans and in dogs caused a sustained
`reduction of spirochetes and black pigmented bacteroi
`reduction of spirochetes and black pigmented bacteroi-
`des for weeks to months (see for example J. Clinical
`des for weeks to months (see for example J. Clinical
`Periodontol. 8:29-44, 1981, ibid 10:100-112 1983).
`Periodontol. 8:29-44, 1981, ibid 10:100-112 1983).
`However, as is known, such systemic usage of metroni- 65
`However, as is known, such systemic usage of metroni
`65
`dazole can be associated with undesirable side effects,
`dazole can be associated with undesirable side effects,
`such as nausea. Also, there is the suggestion from animal
`such as nausea. Also, there is the suggestion from animal
`toxicity studies that metronidazole is a weak tumorigen
`toxicity studies that metronidazole is a weak tumorigen
`
`DETAILED DESCRIPTION OF THE
`DETAILED DESCRIPTION OF THE
`INVENTION
`INVENTION
`It is an object of the present invention to provide
`It is an object of the present invention to provide
`improved means for treating periodontal infections,
`improved means for treating periodontal infections,
`such as periodontitis which occur below the gingival
`such as periodontitis which occur below the gingival
`margin in the periodontal pocket.
`margin in the periodontal pocket.
`It is another object of the invention to provide means
`It is another object of the invention to provide means
`of distributing metronidazole, or other antimicrobial
`of distributing metronidazole, or other antimicrobial
`agents, to the peridontal pocket that avoids the disad
`'agents, to the peridontal pocket that avoids the disad-
`vantages of the prior art.
`vantages of the prior art.
`It is another object of the invention to incorporate
`It is another object of the invention to incorporate
`metronidazole, or other antimicrobial agents, in a slow
`metronidazole, or other antimicrobial agents, in a slow
`release device that can be placed by the clinician di
`release device that can be placed by the clinician di-
`rectly into the infected periodontal pocket.
`rectly into the infected periodontal pocket.
`It is a further object of the invention that the slow
`It is a further object of the invention that the slow
`release device will release metronidazole, or other anti-
`release device will release metronidazole, or other anti
`microbial agents, over a period of 5 to 10 days or more.
`microbial agents, over a period of 5 to 10 days or more.
`It is a further object of this invention that the release
`It is a further object of this invention that the release
`of metronidazole, or other antimicrobial agents, by the
`of metronidazole, or other antimicrobial agents, by the
`slow release device will signi?cantly reduce and/or
`slow release device will significantly reduce and/or
`eliminate the levels of periodontopathic bacteria resid
`eliminate the levels of periodontopathic bacteria resid-
`ing in the periodontal pocket.
`ing in the periodontal pocket.
`Other objects of this invention will be set forth in, or
`Other objects of this invention will be set forth in, or
`be apparent from, the following description of the in
`be apparent from, the following description of the in-
`vention.
`vention.
`A novel means for accomplishing the foregoing ob-
`A novel means for accomplishing the foregoing ob
`jects and other features and advantages of the present
`jects and other features and advantages of the present
`invention are achieved by incorporating metronidazole
`invention are achieved by incorporating metronidazole
`(Zenith Laboratory, Northvale, N.J.), or other antimi-
`(Zenith Laboratory, Northvale, N.J.), or other antimi
`crobial agents, in a polymer, such as ethylcellulose
`crobial agents, in a polymer, such as ethylcellulose
`(Hercules, Inc., Wilmington, Del.), which can be placed
`(Hercules, Inc., Wilmington, Del.), which can be placed
`directly into the diseased periodontal pocket by the
`directly into the diseased periodontal pocket by the
`clinician. Such metronidazole-ethylcellulose ?lms will
`clinician. Such metronidazole-ethylcellulose films will
`release metronidazole continuously into the pocket
`release metronidazole continuously into the pocket
`over a period of 7 to 14 days or more.
`over a period of 7 to 14 days or more.
`The present invention concerns a composition for
`The present invention concerns a composition for
`subgingival administration of an antimicrobial agent
`subgingival administration of an antimicrobial agent
`directly to the periodontal pocket in patients exhibiting
`directly to the periodontal pocket in patients exhibiting
`periodontitis. The composition comprises a pharmaceu
`periodontitis. The composition comprises a pharmaceu-
`tically acceptable polymeric matrix, such as ethylcellu
`tically acceptable polymeric matrix, such as ethylcellu-
`lose, (see J. Dent. Res. 54:1392, 1980), which contains
`lose, (see J. Dent. Res. 54:1392, 1980), which contains
`metronidazole. The polymer-metronidazole combina»
`metronidazole. The polymer-metronidazole combina-
`tion is formulated so that the metronidazole is slowly
`tion is formulated so that the metronidazole is slowly
`released from the polymer into the environment of the
`released from the polymer into the environment of the
`periodontal pocket. For purposes of this invention one
`periodontal pocket. For purposes of this invention one
`uses a