Europaisches Patentamt
`
`Europaisches Patentamt Europaisches Patentamt
`European Patent Office
`
`European Patent Office European Patent Office
`Dffice europeen des brevets
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`Office europ6en des brevets Office europ6en des brevets
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`5) Publication number:
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`Publication number: Publication number:
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`
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`11 11
`11 (cid:9)11 (cid:9)
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`11111 11 1 MI (cid:9)11111 11 1 MI (cid:9)
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`0 241 1 78 B 1 0 241 1 78 B 1
`3 2 4 1 1 7 8 B l
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`©
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`EUROPEAN PATENT S P E C I F I C A T I O N
`
`EUROPEAN PATENT SPECIFICATION EUROPEAN PATENT SPECIFICATION
`
`© Date of publication of patent specification: 08.01.92 © Int. CI.5: A61 K 9/70, A61 K 4 7 / 0 0
`
`Int. CI.5: A61K 9/70, A61K 47/00 Int. CI.5: A61K 9/70, A61K 47/00
`
`0 Date of publication of patent specification: 08.01.92 0 Date of publication of patent specification: 08.01.92
`
`© Application number: 87302514.2
`
`0 Application number: 87302514.2 0 Application number: 87302514.2
`
`© Date of filing: 24.03.87
`
`0 Date of filing: 24.03.87 0 Date of filing: 24.03.87
`
`@ Pharmaceutical composition for treating periodontal diseases.
`
`0 Pharmaceutical composition for treating periodontal diseases. 0 Pharmaceutical composition for treating periodontal diseases.
`
`© Priority: 25.03.86 JP 67810/86
`
`0 Priority: 25.03.86 JP 67810/86 0 Priority: 25.03.86 JP 67810/86
`
`© Date of publication of application:
`
`0 Date of publication of application: 0 Date of publication of application:
`14.10.87 Bulletin 87/42
`
`14.10.87 Bulletin 87/42 14.10.87 Bulletin 87/42
`
`© Publication of the grant of the patent:
`
`0 Publication of the grant of the patent: 0 Publication of the grant of the patent:
`08.01.92 Bulletin 92/02
`
`08.01.92 Bulletin 92/02 08.01.92 Bulletin 92/02
`
`® Designated Contracting States:
`
`0 Designated Contracting States: 0 Designated Contracting States:
`DE FR GB IT
`
`DE FR GB IT DE FR GB IT
`
`© References cited:
`
`0 References cited: 0 References cited:
`EP-A- 0 135 022
`
`EP-A- 0 135 022 EP-A- 0 135 022
`EP-A- 0 184 389
`
`EP-A- 0 184 389 EP-A- 0 184 389
`DE-A- 3 432 573
`
`DE-A- 3 432 573 DE-A- 3 432 573
`FR-A- 2 148 045
`
`FR-A- 2 148 045 FR-A- 2 148 045
`US-A- 4 568 535
`
`US-A- 4 568 535 US-A- 4 568 535
`
`© Proprietor: ROHTO PHARMACEUTICAL CO.,
`
`0 Proprietor: ROHTO PHARMACEUTICAL CO., 0 Proprietor: ROHTO PHARMACEUTICAL CO.,
`LTD.
`
`LTD. LTD.
`No. 1-8-1, Tatsuminishi
`
`No. 1-8-1, Tatsuminishi No. 1-8-1, Tatsuminishi
`Ikuno-ku Osaka-shi Osaka-fu(JP)
`
`Ikuno-ku Osaka-shi Osaka-fu(JP) Ikuno-ku Osaka-shi Osaka-fu(JP)
`
`© Inventor: Higashi, Kiyotsugu
`
`0 Inventor: Higashi, Kiyotsugu 0 Inventor: Higashi, Kiyotsugu
`1987, Ryoanji-cho
`
`1987, Ryoanji-cho 1987, Ryoanji-cho
`Gojo-shi Nara-ken(JP)
`
`Gojo-shi Nara-ken(JP) Gojo-shi Nara-ken(JP)
`Inventor: Kametaka, Shigeru
`
`Inventor: Kametaka, Shigeru Inventor: Kametaka, Shigeru
`968-10, Oazatakaida
`
`968-10, Oazatakaida 968-10, Oazatakaida
`Kashiwara-shi Osaka-fu(JP)
`
`Kashiwara-shi Osaka-fu(JP) Kashiwara-shi Osaka-fu(JP)
`Inventor: Morisaki, Katsuhiko
`
`Inventor: Morisaki, Katsuhiko Inventor: Morisaki, Katsuhiko
`2-55, Oazamimatsugaoka-nishi Sango-cho
`
`2-55, Oazamimatsugaoka-nishi Sango-cho 2-55, Oazamimatsugaoka-nishi Sango-cho
`Ikoma-gun Nara-ken(JP)
`
`Ikoma-gun Nara-ken(JP) Ikoma-gun Nara-ken(JP)
`Inventor: Hayashi, Shin'ichi
`
`Inventor: Hayashi, Shin'ichi Inventor: Hayashi, Shin'ichi
`4-683-49, Nonaka
`
`4-683-49, Nonaka 4-683-49, Nonaka
`Fujiidera-shi Osaka-fu(JP)
`
`Fujiidera-shi Osaka-fu(JP) Fujiidera-shi Osaka-fu(JP)
`Inventor: Izumi, Reiko
`
`Inventor: Izumi, Reiko Inventor: Izumi, Reiko
`Puchishanburu 201 13-21, Tamatsukuri-
`
`Puchishanburu 201 13-21, Tamatsukuri-Puchishanburu 201 13-21, Tamatsukuri-
`hommachi
`
`hommachi hommachi
`Tennoji-cho Osaki-shi Osaka-fu(JP)
`
`Tennoji-cho Osaki-shi Osaka-fu(JP) Tennoji-cho Osaki-shi Osaka-fu(JP)
`
`® Representative: Stuart, Ian Alexander et al
`
`0 Representative: Stuart, Ian Alexander et al 0 Representative: Stuart, Ian Alexander et al
`MEWBURN ELLIS & CO. 2/3 Cursitor Street
`
`MEWBURN ELLIS & CO. 2/3 Cursitor Street MEWBURN ELLIS & CO. 2/3 Cursitor Street
`London EC4A 1BQ(GB)
`
`London EC4A 1B0(GB) London EC4A 1B0(GB)
`
`CM
`O Note: Within nine months from the publication of the mention of the grant of the European patent, any person
`
`Note: Within nine months from the publication of the mention of the grant of the European patent, any person Note: Within nine months from the publication of the mention of the grant of the European patent, any person
`n may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition
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`may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition
`shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee
`Uj
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`shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee
`has been paid (Art. 99(1) European patent convention).
`
`has been paid (Art. 99(1) European patent convention). has been paid (Art. 99(1) European patent convention).
`Rank Xerox (UK) Business Services
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`Rank Xerox (UK) Business Services Rank Xerox (UK) Business Services
`
`EP 0 241 178 B1
`EP 0 241 178 B1
`
`00
`00
`
`Par Pharm., Inc., et al.
`Exhibit 1021
`Page 001
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`1
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`EP 0 241 178 B1
`EP 0 241 178 B1 (cid:9)
`EP 0 241 178 B1 (cid:9)
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`2
`2
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`Description
`Description
`Description
`
`This invention relates to a pharmaceutical com-
`This invention relates to a pharmaceutical com-
`This invention relates to a pharmaceutical com-
`position which is applied to a periodontal pocket or
`position which is applied to a periodontal pocket or
`position which is applied to a periodontal pocket or
`paradentium for the purpose of treating periodontal
`paradentium for the purpose of treating periodontal
`paradentium for the purpose of treating periodontal
`diseases. The pharmaceutical composition may be
`diseases. The pharmaceutical composition may be
`diseases. The pharmaceutical composition may be
`provided in the form of gel, sheet, film or bar-like
`provided in the form of gel, sheet, film or bar-like
`provided in the form of gel, sheet, film or bar-like
`formulation to release a controlled and effective
`formulation to release a controlled and effective
`formulation to release a controlled and effective
`amount of an active ingredient at the periodontal
`amount of an active ingredient at the periodontal
`amount of an active ingredient at the periodontal
`pocket or paradentium.
`pocket or paradentium.
`pocket or paradentium.
`The "periodontal diseases" is a general term of
`The "periodontal diseases" is a general term of
`The "periodontal diseases" is a general term of
`various inflammatory diseases of paradentium. The
`various inflammatory diseases of paradentium. The
`various inflammatory diseases of paradentium. The
`diseases include a series of diseases exhibiting
`diseases include a series of diseases exhibiting
`diseases include a series of diseases exhibiting
`various syndromes which vary from each other
`various syndromes which vary from each other
`various syndromes which vary from each other
`according to the stage or situation of the diseases
`according to the stage or situation of the diseases
`according to the stage or situation of the diseases
`or the age of the patient, and have not been
`or the age of the patient, and have not been
`or the age of the patient, and have not been
`definitely subclassified. Since, however, the term
`definitely subclassified. Since, however, the term
`definitely subclassified. Since, however, the term
`"periodontal diseases" is given to any inflamma-
`"periodontal diseases" is given to any inflamma-
`"periodontal diseases" is given to any inflamma-
`tory disease which initially occurs at a marginal
`tory disease which initially occurs at a marginal
`tory disease which initially occurs at a marginal
`gingiva area and finally reaches an alveolar bone,
`gingiva area and finally reaches an alveolar bone,
`gingiva area and finally reaches an alveolar bone,
`the diseases can be roughly divided, on the basis
`the diseases can be roughly divided, on the basis
`the diseases can be roughly divided, on the basis
`of the degree of the inflammation, into "gingivitis"
`of the degree of the inflammation, into "gingivitis"
`of the degree of the inflammation, into "gingivitis"
`in which the inflammation is limited to the gingiva
`in which the inflammation is limited to the gingiva
`in which the inflammation is limited to the gingiva
`tissue, and "paradentitis" in which the inflammation
`tissue, and "paradentitis" in which the inflammation
`tissue, and "paradentitis" in which the inflammation
`is chronic and found even in an alveolar bone.
`is chronic and found even in an alveolar bone.
`is chronic and found even in an alveolar bone.
`However, peculiar diseases such as "juvenile para-
`However, peculiar diseases such as "juvenile para-
`However, peculiar diseases such as "juvenile para-
`dentitis" and "acute necrotizing ulcerative gingivi-
`dentitis" and "acute necrotizing ulcerative gingivi-
`dentitis" and "acute necrotizing ulcerative gingivi-
`tis" are also included in the periodontal diseases.
`tis" are also included in the periodontal diseases.
`tis" are also included in the periodontal diseases.
`The paradentitis, which was once called
`The paradentitis, which was once called
`The paradentitis, which was once called
`"alveolar pyorrhea", is characterized by remarkable
`"alveolar pyorrhea", is characterized by remarkable
`"alveolar pyorrhea", is characterized by remarkable
`symptoms such as inflammation of gingiva, forma-
`symptoms such as inflammation of gingiva, forma-
`symptoms such as inflammation of gingiva, forma-
`tion of periodontal pockets, bleeding and pus dis-
`tion of periodontal pockets, bleeding and pus dis-
`tion of periodontal pockets, bleeding and pus dis-
`charge from said periodontal pockets, and it brings
`charge from said periodontal pockets, and it brings
`charge from said periodontal pockets, and it brings
`about resorption of alveolar bone, loose teeth, and
`about resorption of alveolar bone, loose teeth, and
`about resorption of alveolar bone, loose teeth, and
`shedding of teeth.
`shedding of teeth.
`shedding of teeth.
`The consensus of most investigators is that
`The consensus of most investigators is that
`The consensus of most investigators is that
`periodontal diseases are caused by bacteria
`periodontal diseases are caused by bacteria
`periodontal diseases are caused by bacteria
`present in dental plaques formed in periodontal
`present in dental plaques formed in periodontal
`present in dental plaques formed in periodontal
`pockets. Efforts have been concentrated on the
`pockets. Efforts have been concentrated on the
`pockets. Efforts have been concentrated on the
`discovery of pathogenic bacteria responsible for
`discovery of pathogenic bacteria responsible for
`discovery of pathogenic bacteria responsible for
`said diseases. At the present time, an attributable
`said diseases. At the present time, an attributable
`said diseases. At the present time, an attributable
`major pathogen is recognized to be certain nigral
`major pathogen is recognized to be certain nigral
`major pathogen is recognized to be certain nigral
`pigment-producing bacteria, such as genus Bac-
`pigment-producing bacteria, such as genus Bac-
`pigment-producing bacteria, such as genus Bac-
`teroides. However, other genera of bacteria includ-
`teroides. However, other genera of bacteria includ-
`teroides. However, other genera of bacteria includ-
`ing Actinobacillus, Capnocytophaga, Fusobacterium
`ing Actinobacillus, Capnocytophaga, Fusobacterium
`ing Actinobacillus, Capnocytophaga, Fusobacterium
`and Spirochetes may be included in the causative
`and Spirochetes may be included in the causative
`and Spirochetes may be included in the causative
`pathogens. In any case, it is an established theory
`pathogens. In any case, it is an established theory
`pathogens. In any case, it is an established theory
`that the periodontal diseases should not be attrib-
`that the periodontal diseases should not be attrib-
`that the periodontal diseases should not be attrib-
`uted to all bacteria present in the dental plaque.
`uted to all bacteria present in the dental plaque.
`uted to all bacteria present in the dental plaque.
`The periodontal diseases have previously been
`The periodontal diseases have previously been
`The periodontal diseases have previously been
`treated in several ways, such as exhaustive scaling
`treated in several ways, such as exhaustive scaling
`treated in several ways, such as exhaustive scaling
`of plaques in periodontal pockets, root planing,
`of plaques in periodontal pockets, root planing,
`of plaques in periodontal pockets, root planing,
`gingivectomy to eliminate the periodontal pocket,
`gingivectomy to eliminate the periodontal pocket,
`gingivectomy to eliminate the periodontal pocket,
`or surgical curettage to excise inflammatory tis-
`or surgical curettage to excise inflammatory tis-
`or surgical curettage to excise inflammatory tis-
`sues. These treatments have been effective to
`sues. These treatments have been effective to
`sues. These treatments have been effective to
`some extent but not satisfactory.
`some extent but not satisfactory.
`some extent but not satisfactory.
`On the other hand, pharmacotherapy has also
`On the other hand, pharmacotherapy has also
`On the other hand, pharmacotherapy has also
`been conducted using drugs, for example germi-
`been conducted using drugs, for example germi-
`been conducted using drugs, for example germi-
`
`5
`5 (cid:9)
`5 (cid:9)
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`10
`-to (cid:9)
`-to (cid:9)
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`15
`/5 (cid:9)
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`25
`25 (cid:9)
`25 (cid:9)
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`30
`30 (cid:9)
`30 (cid:9)
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`35
`35 (cid:9)
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`40 (cid:9)
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`
`cides, antiinflammatory agents, plaque solubilizing
`cides, antiinflammatory agents, plaque solubilizing
`cides, antiinflammatory agents, plaque solubilizing
`agents, and hemostyptics. These drugs are used in
`agents, and hemostyptics. These drugs are used in
`agents, and hemostyptics. These drugs are used in
`the form of formulations suited for internal use or
`the form of formulations suited for internal use or
`the form of formulations suited for internal use or
`massotherapy (e.g., dentifrices and ointments).
`massotherapy (e.g., dentifrices and ointments).
`massotherapy (e.g., dentifrices and ointments).
`However, they are not satisfactory for the purpose
`However, they are not satisfactory for the purpose
`However, they are not satisfactory for the purpose
`of treatment of periodontal diseases because the
`of treatment of periodontal diseases because the
`of treatment of periodontal diseases because the
`internal use hardly permits the selective migration
`internal use hardly permits the selective migration
`internal use hardly permits the selective migration
`of the drug to the lesional region, and the mas-
`of the drug to the lesional region, and the mas-
`of the drug to the lesional region, and the mas-
`is not successful
`in solubilizing the
`sotherapy
`sotherapy is not successful in solubilizing the
`sotherapy is not successful in solubilizing the
`plaques which are present beneath the gingival
`plaques which are present beneath the gingival
`plaques which are present beneath the gingival
`margin.
`margin.
`margin.
`Recently, strips which comprise polymers and
`Recently, strips which comprise polymers and
`Recently, strips which comprise polymers and
`active ingredients for treatment of periodontal dis-
`active ingredients for treatment of periodontal dis-
`active ingredients for treatment of periodontal dis-
`eases have been developed. These strips are said
`eases have been developed. These strips are said
`eases have been developed. These strips are said
`to be useful for the treatment of plaques and in-
`to be useful for the treatment of plaques and in-
`to be useful for the treatment of plaques and in-
`flammation beneath the gingival margin. The strips
`flammation beneath the gingival margin. The strips
`flammation beneath the gingival margin. The strips
`can be applied directly to the lesional region to be
`can be applied directly to the lesional region to be
`can be applied directly to the lesional region to be
`treated, and therefore, the active ingredient can be
`treated, and therefore, the active ingredient can be
`treated, and therefore, the active ingredient can be
`concentrated to the desired site selectively. This
`concentrated to the desired site selectively. This
`concentrated to the desired site selectively. This
`20 modified therapeutic method has been proved to
`20 (cid:9) modified therapeutic method has been proved to
`20 (cid:9) modified therapeutic method has been proved to
`be more effective than any conventional phar-
`be more effective than any conventional phar-
`be more effective than any conventional phar-
`macotherapy. For instance, J. M. Goodson et al.
`macotherapy. For instance, J. M. Goodson et al.
`macotherapy. For instance, J. M. Goodson et al.
`disclose the implantation of "hollow fiber", which
`disclose the implantation of "hollow fiber", which
`disclose the implantation of "hollow fiber", which
`contains germicides, into the gingival region (J.
`contains germicides, into the gingival region (J.
`contains germicides, into the gingival region (J.
`Clinical Periodontology, 1979: 6: 83-92). M. Addy
`Clinical Periodontology, 1979: 6: 83-92). M. Addy
`Clinical Periodontology, 1979: 6: 83-92). M. Addy
`et al. have reported the insertion of strips, which
`et al. have reported the insertion of strips, which
`et al. have reported the insertion of strips, which
`were prepared from a mixture of an insoluble poly-
`were prepared from a mixture of an insoluble poly-
`were prepared from a mixture of an insoluble poly-
`mer such as polyethylmethacrylate and germicides,
`mer such as polyethylmethacrylate and germicides,
`mer such as polyethylmethacrylate and germicides,
`into periodontal pockets (J. Periodontal, 693, Nov.
`into periodontal pockets (J. Periodontal, 693, Nov.
`into periodontal pockets (J. Periodontal, 693, Nov.
`1982). In addition, insertion of the strips, prepared
`1982). In addition, insertion of the strips, prepared
`1982). In addition, insertion of the strips, prepared
`from a mixture of a soluble polymer and a drug,
`from a mixture of a soluble polymer and a drug,
`from a mixture of a soluble polymer and a drug,
`into the lesional region, such as periodontal pock-
`into the lesional region, such as periodontal pock-
`into the lesional region, such as periodontal pock-
`ets, is also reported (Japan Patent Publication No.
`ets, is also reported (Japan Patent Publication No.
`ets, is also reported (Japan Patent Publication No.
`59-222406).
`59-222406).
`59-222406).
`The formulations mentioned above comprise a
`The formulations mentioned above comprise a
`The formulations mentioned above comprise a
`mixture of an active ingredient and a homogeneous
`mixture of an active ingredient and a homogeneous
`mixture of an active ingredient and a homogeneous
`polymer base. Accordingly, where such formulation
`polymer base. Accordingly, where such formulation
`polymer base. Accordingly, where such formulation
`is designed to contain two or more active ingre-
`is designed to contain two or more active ingre-
`is designed to contain two or more active ingre-
`dients which differ from each other in terms of
`dients which differ from each other in terms of
`dients which differ from each other in terms of
`pharmacological activity and therapeutically effec-
`pharmacological activity and therapeutically effec-
`pharmacological activity and therapeutically effec-
`tive dose, it has been impossible to prepare a
`tive dose, it has been impossible to prepare a
`tive dose, it has been impossible to prepare a
`formulation in which each of the plural ingredients
`formulation in which each of the plural ingredients
`formulation in which each of the plural ingredients
`may release independently and provide its suitable
`may release independently and provide its suitable
`may release independently and provide its suitable
`concentration as desired.
`concentration as desired.
`concentration as desired.
`The use of the hollow fiber or insoluble poly-
`The use of the hollow fiber or insoluble poly-
`The use of the hollow fiber or insoluble poly-
`mer, as a base, causes irritation or pain to patients,
`mer, as a base, causes irritation or pain to patients,
`mer, as a base, causes irritation or pain to patients,
`and moreover, it necessitates the removal of the
`and moreover, it necessitates the removal of the
`and moreover, it necessitates the removal of the
`base after release of an active ingredient, which is
`base after release of an active ingredient, which is
`base after release of an active ingredient, which is
`often annoying. On the other hand, the strip which
`often annoying. On the other hand, the strip which
`often annoying. On the other hand, the strip which
`comprises a soluble polymer as a base or carrier
`comprises a soluble polymer as a base or carrier
`comprises a soluble polymer as a base or carrier
`permits a rapid release of an active ingredient.
`permits a rapid release of an active ingredient.
`permits a rapid release of an active ingredient.
`Accordingly, it does not afford a constant therapeu-
`Accordingly, it does not afford a constant therapeu-
`Accordingly, it does not afford a constant therapeu-
`tic effect and, therefore, has a poor practical use.
`tic effect and, therefore, has a poor practical use.
`tic effect and, therefore, has a poor practical use.
`As the result of an extensive study for seeking
`As the result of an extensive study for seeking
`As the result of an extensive study for seeking
`a novel therapeutical composition for periodontal
`a novel therapeutical composition for periodontal
`a novel therapeutical composition for periodontal
`diseases, which suitably controls the release of one
`diseases, which suitably controls the release of one
`diseases, which suitably controls the release of one
`or more active ingredients and which does not give
`or more active ingredients and which does not give
`or more active ingredients and which does not give
`any uncomfortable feelings to patients, it has been
`any uncomfortable feelings to patients, it has been
`any uncomfortable feelings to patients, it has been
`
`45
`45 (cid:9)
`45 (cid:9)
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`so
`50 (cid:9)
`50 (cid:9)
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`55 (cid:9)
`55 (cid:9)
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`2
`2
`2
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`Par Pharm., Inc., et al.
`Exhibit 1021
`Page 002
`
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`

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`EP 0 241 178 B1
`EP 0 241 178 B1 (cid:9)
`EP 0 241 178 B1 (cid:9)
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`found that the use of a two-phase carrier base,
`found that the use of a two-phase carrier base,
`found that the use of a two-phase carrier base,
`which consists of particles comprising a polymer
`which consists of particles comprising a polymer
`which consists of particles comprising a polymer
`having a limited solubility in water and a water
`having a limited solubility in water and a water
`having a limited solubility in water and a water
`soluble polymer used for dispersing such particles,
`soluble polymer used for dispersing such particles,
`soluble polymer used for dispersing such particles,
`meets the requirements just mentioned above.
`meets the requirements just mentioned above.
`meets the requirements just mentioned above.
`DE-A-3 432 573 and US-A-4 693 887 disclose
`DE-A-3 432 573 and US-A-4 693 887 disclose
`DE-A-3 432 573 and US-A-4 693 887 disclose
`pharmaceutical composition having two polymeric
`pharmaceutical composition having two polymeric
`pharmaceutical composition having two polymeric
`phases, one hydrophobic and one hydrophilic, the
`phases, one hydrophobic and one hydrophilic, the
`phases, one hydrophobic and one hydrophilic, the
`combination being insoluble in water and thus suit-
`combination being insoluble in water and thus suit-
`combination being insoluble in water and thus suit-
`able for water-insoluble implants. A drug partitions
`able for water-insoluble implants. A drug partitions
`able for water-insoluble implants. A drug partitions
`itself between the phases. The hydrophilic phase
`itself between the phases. The hydrophilic phase
`itself between the phases. The hydrophilic phase
`has a different composition from the discontinuous
`has a different composition from the discontinuous
`has a different composition from the discontinuous
`phase employed in the present
`phase employed in the present
`phase employed in the present
`Thus the present invention provides:
`Thus the present invention provides:
`Thus the present invention provides:
`a controlled-release pharmaceutical composi-
`a controlled-release pharmaceutical composi- (cid:9)
`a controlled-release pharmaceutical composi- (cid:9)
`tion in the form of gel, sheet, film, or bar to be
`tion in the form of gel, sheet, film, or bar to be
`tion in the form of gel, sheet, film, or bar to be
`inserted or placed into a periodontal pocket for
`inserted or placed into a periodontal pocket for
`inserted or placed into a periodontal pocket for
`treating a periodontal disease, said composition
`treating a periodontal disease, said composition
`treating a periodontal disease, said composition
`comprising a therapeutically effective amount of at
`comprising a therapeutically effective amount of at
`comprising a therapeutically effective amount of at
`least one active ingredient effective for the treat-
`least one active ingredient effective for the treat-
`least one active ingredient effective for the treat-
`ment of the periodontal disease, said active ingre-
`ment of the periodontal disease, said active ingre-
`ment of the periodontal disease, said active ingre-
`dient being dispersed in a two-phase carrier con-
`dient being dispersed in a two-phase carrier con-
`dient being dispersed in a two-phase carrier con-
`sisting of
`sisting of
`sisting of
`(a) a continuous phase consisting of a water-
`(a) a continuous phase consisting of a water-
`(a) a continuous phase consisting of a water-
`soluble polymer capable of dissolving in water
`soluble polymer capable of dissolving in water
`soluble polymer capable of dissolving in water
`at a concentration of more than 1% by weight
`at a concentration of more than 1% by weight
`at a concentration of more than 1% by weight
`irrespective of pH, and
`irrespective of pH, and
`irrespective of pH, and
`(b) a discontinuous phase consisting of solid
`(b) a discontinuous phase consisting of solid
`(b) a discontinuous phase consisting of solid
`particles composed of a polymer capable of
`particles composed of a polymer capable of
`particles composed of a polymer capable of
`dissolving in water at a concentration of at least
`dissolving in water at a concentration of at least
`dissolving in water at a concentration of at least
`about 0.1% and not more than about 1.0% by
`about 0.1% and not more than about 1.0% by
`about 0.1% and not more than about 1.0% by
`weight; or solid particles composed of a polymer
`weight; or solid particles composed of a polymer
`weight; or solid particles composed of a polymer
`capable of dissolving in water at a concentration
`capable of dissolving in water at a concentration
`capable of dissolving in water at a concentration
`of more than 1 % by weight only at a pH higher
`of more than 1% by weight only at a pH higher
`of more than 1% by weight only at a pH higher
`than 4 or lower than 6
`than 4 or lower than 6
`than 4 or lower than 6
`said particles having an average size ranging from
`said particles having an average size ranging from
`said particles having an average size ranging from
`1 u.m to 500 urn and being dispersed in said
`1 p.m to 500 ktm and being dispersed in said
`1 p.m to 500 ktm and being dispersed in said
`water-soluble polymer, with the weight ratio of said
`water-soluble polymer, with the weight ratio of said
`water-soluble polymer, with the weight ratio of said
`particles to said water-soluble polymer ranging
`particles to said water-soluble polymer ranging
`particles to said water-soluble polymer ranging
`from 1 :99 to 99:1 on a dry weight basis, said water-
`from 1:99 to 99:1 on a dry weight basis, said water-
`from 1:99 to 99:1 on a dry weight basis, said water-
`soluble polymer being selected from the
`soluble polymer being selected from the
`soluble polymer being selected from the
`methyl cellulose, hydroxypropyl cellulose, so-
`methyl cellulose, hydroxypropyl cellulose, so-
`methyl cellulose, hydroxypropyl cellulose, so-
`dium
`cellulose, hydroxypropyl-
`carboxymethyl
`dium carboxymethyl cellulose, hydroxypropyl-
`dium carboxymethyl cellulose, hydroxypropyl-
`methyl cellulose, hydroxyethyl cellulose, sodium
`methyl cellulose, hydroxyethyl cellulose, sodium
`methyl cellulose, hydroxyethyl cellulose, sodium
`alginate, pullulan,
`propylene glycol
`alginate,
`alginate, propylene glycol alginate, pullulan,
`alginate, propylene glycol alginate, pullulan,
`tragacanth, xanthan gum, chitosan, polyethylene
`tragacanth, xanthan gum, chitosan, polyethylene
`tragacanth, xanthan gum, chitosan, polyethylene
`oxide, polyvinyl alcohol, polyacrylic acid, poly-
`oxide, polyvinyl alcohol, polyacrylic acid, poly-
`oxide, polyvinyl alcohol, polyacrylic acid, poly-
`methacrylic acid, and salts thereof, and said solid
`methacrylic acid, and salts thereof, and said solid
`methacrylic acid, and salts thereof, and said solid
`particles being selected from
`particles being selected from
`particles being selected from
`poly(glycolic acid), poly(iactic acid), poly-
`poly(glycolic acid), poly(lactic acid), poly-
`poly(glycolic acid), poly(lactic acid), poly-
`tetramethylglycolide, polydiethylglycolide, poly-e-
`tetramethylglycolide, polydiethylglycolide, poly-6-
`tetramethylglycolide, polydiethylglycolide, poly-6-
`poly-
`poly(DL-decalactone),
`caprolactone,
`poly-
`poly-
`poly(DL-decalactone), (cid:9)
`poly(DL-decalactone), (cid:9)
`caprolactone, (cid:9)
`caprolactone, (cid:9)
`(alkyleneadipate), methylacrylate/ methacrylic acid
`(alkyleneadipate), methylacrylate/ methacrylic acid
`(alkyleneadipate), methylacrylate/ methacrylic acid
`copolymer, methylacrylate/ methacrylic acid/ oc-
`copolymer, methylacrylate/ methacrylic acid/ oc-
`copolymer, methylacrylate/ methacrylic acid/ oc-
`tylacrylate copolymer, ethylacrylate/ methacrylic
`tylacrylate copolymer, ethylacrylate/ methacrylic
`tylacrylate copolymer, ethylacrylate/ methacrylic
`acid copolymer, methylacrylate/ methacrylic acid/
`acid copolymer, methylacrylate/ methacrylic acid/
`acid copolymer, methylacrylate/ methacrylic acid/
`copolymer,
`methylmethacrylate
`copolymer,
`copolymer,
`methylmethacrylate (cid:9)
`methylmethacrylate (cid:9)
`methylmethacrylate/ methacrylic acid copolymer,
`methylmethacrylate/ methacrylic acid copolymer,
`methylmethacrylate/ methacrylic acid copolymer,
`
`5
`5
`5
`
`cellulose acetate phthalate, cellulose acetate suc-
`cellulose acetate phthalate, cellulose acetate suc-
`cellulose acetate phth