Europaisches Patentamt
`European Patent Office
`Office européen des brevets
`
`0
`
` LO
`My|
`@) Publication number:
`0 241 178 Bl
`
`@)
`
`EUROPEAN PATENT SPECIFICATION
`
`Date of publication of patent specification: 08.01.92 @) Int. cl5: A61K 9/70, A61K 47/00
`
`@) Application number: 87302514.2
`
`@) Date offiling: 24.03.87
`
`
`
`@) Pharmaceutical composition for treating periodontal diseases.
`
`
`@) Priority: 25.03.86 JP 67810/86
`@3) Proprietor: ROHTO PHARMACEUTICALCO.,
`LTD.
`No. 1-8-1, Tatsuminishi
`ikuno-ku Osaka-shi Osaka-fu(JP)
`
`@) Date of publication of application:
`14.10.87 Bulletin 87/42
`
`Publication of the grant of the patent:
`08.01.92 Bulletin 92/02
`
`@)
`
`Designated Contracting States:
`DE FR GB IT
`
`Referencescited:
`EP-A- 0 135 022
`EP-A- 0 184 389
`DE-A- 3 432 573
`FR-A- 2 148 045
`US-A- 4 568 535
`
`Inventor: Higashi, Kiyotsugu
`1987, Ryoanji-cho
`Gojo-shi Nara-ken(JP)
`inventor: Kametaka, Shigeru
`968-10, Oazatakaida
`Kashiwara-shi Osaka-fu(JP)
`Inventor: Morisaki, Katsuhiko
`- 2-55, Oazamimatsugaoka-nishi Sango-cho
`ikoma-gun Nara-ken(JP)
`inventor: Hayashi, Shin‘ichi
`4-683-49, Nonaka
`Fujiidera-shi Osaka-fu(JP)
`inventor: Izumi, Reiko
`Puchishanburu 201 13-21, Tamatsukuri-
`hommachi
`Tennoji-cho Osaki-shi Osaka-fu(JP)
`
`Ge) Representative: Stuart, lan Alexanderet al
`MEWBURNELLIS & CO. 2/3 Cursitor Street
`London EC4A 1BQ(GB)
`
`
`
`Note: Within niné months from the publication of the mention of the grant of the European patent, any person
`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
`has been paid (Art. 99(1) European patent convention).
`Rank Xerox (UK) Business Services
`
`EP0241178B1
`
`Dr. Reddy's - EX1021
`Page 1
`
`Dr. Reddy's - EX1021
`Page 1
`
`

`

`This invention relates to a pharmaceutical com-
`position which is applied to a periodontal pocket or
`paradentium for the purpose of treating periodontal
`diseases. The pharmaceutical composition may be
`provided in the form of gel, sheet, film or bar-like
`formulation to release a controlled and effective
`amount of an active ingredient at the periodontal
`pocket or paradentium.
`The “periodontal diseases" is a general term of
`various inflammatory diseases of paradentium. The
`diseases include a series of diseases exhibiting
`various syndromes which vary from each other
`according to the stage or situation of the diseases
`or
`the age of
`the patient, and have not been
`definitely subclassified. Since, however,
`the term
`“periodontal diseases" is given to any inflamma-
`tory disease which initially occurs at a marginal
`gingiva area and finally reaches an alveolar bone,
`the diseases can be roughly divided, on the basis
`of the degree of the inflammation,
`into "gingivitis"
`in which the inflammation is limited to the gingiva
`tissue, and "paradentitis" in which the inflammation
`is chronic and found even in an alveolar bone.
`However, peculiar diseases such as "juvenile para-
`denititis" and “acute necrotizing ulcerative gingivi-
`tis" are also included in the periodontal diseases.
`The
`paradentitis, which was
`once
`called
`"alveolar pyorrhea", is characterized by remarkable
`symptoms such as inflammation of gingiva, forma-
`tion of periodontal pockets, bleeding and pus dis-
`charge from said periodontal pockets, and it brings
`about resorption of alveolar bone, loose teeth, and
`shedding of teeth.
`investigators is that
`The consensus of most
`caused
`by
`bacteria
`periodontal diseases
`are
`present
`in dental plaques formed in periodontal
`pockets. Efforts have been concentrated on the
`discovery of pathogenic bacteria responsible for
`said diseases. At the present time, an attributable
`major pathogen is recognized to be certain nigral
`
`pigment-producing bacteria, such as genus Bac-
`teroides. However, other genera of bacteria includ-
`The use of the hollow fiber or insoluble poly-
`ing Actinobacillus, Capnocytophaga, Fusobacterium
`andSpirochetesmaybeincludedinthecausative
`mer, as a base, causes irritation or pain tc patients,
`and moreover,
`it necessitates the removal of the
`pathogens. In any case, it is an established theory
`that the periodontal diseases should not be attrib-
`base after release of an active ingredient, which is
`often annoying. On the other hand, the strip which
`uted to all bacteria present in the dental plaque.
`comprises a soluble polymer as a base or carrier
`The periodontal diseases have previously been
`permits a rapid release of an active ingredient.
`treated in several ways, such as exhaustive scaling
`Accordingly, it does not afford a constant therapeu-
`of plaques in periodontal pockets,
`root planing,
`gingivectomy to eliminate the periodontal pocket,
`tic effect and, therefore, has a poor practical use.
`As the result of an extensive study for seeking
`or surgical curettage to excise inflammatory tis-
`sues. These treatments have been effective to
`a novel
`therapeutical composition for periodontal
`diseases, which suitably controls the release of one
`some extent but not satisfactory.
`or more active ingredients and which does not give
`On the other hand, pharmacotherapy has also
`any uncomfortable feelings to patients, it has been
`been conducted using drugs,
`for example germi-
`
`70
`
`15
`
`20
`
`26
`
`30
`
`35
`
`50
`
`55
`
`1
`
`EP 0 241 178 Bi
`
`2
`
`Description
`
`cides, antiinflammatory agents, plaque solubilizing
`agents, and hemostyptics. These drugs are used in
`the form of formulations suited for internal use or
`massotherapy (e.g., dentifrices and ointments).
`However, they are not satisfactory for the purpose
`of treatment of periodontal diseases because the
`internal use hardly permits the selective migration
`of the drug to the lesional region, and the mas-
`sotherapy is not
`successful
`in solubilizing the
`plaques which are present beneath the gingival
`margin.
`Recently, strips which comprise polymers and
`active ingredients for treatment of periodontal dis-
`eases have been developed. These strips are said
`to be useful for the treatment of plaques and in-
`flammation beneath the gingival margin. The strips
`can be applied directly to the lesional region to be
`treated, and therefore, the active ingredient can be
`concentrated to the desired site selectively. This
`modified therapeutic method has been proved io
`be more effective than any conventional phar-
`macotherapy. For instance, J. M. Goodson etal.
`disclose the implantation of "hollow fiber", which
`contains germicides,
`into the gingival
`region (J.
`Clinical Periodontology, 1979: 6: 83-92). M. Addy
`et al. have reported the insertion of strips, which
`were prepared from a mixture of an insoluble poly-
`mer such as polyethyimethacrylate and germicides,
`into periodontal pockets (J. Periodontal, 693, Nov.
`1982).
`In addition,
`insertion of the strips, prepared
`from a mixture of a soluble polymer and a drug,
`into the lesional region, such as periodontal pock-
`ets, is also reported (Japan Patent Publication No.
`59-222406).
`The formulations mentioned above comprise a
`mixture of an active ingredient and a homogeneous
`polymer base. Accordingly, where such formulation
`is designed to contain two or more active ingre-
`dients which differ from each other in terms of
`
`pharmacological activity and therapeutically effec-
`tive dose,
`it has been impossible to prepare a
`formulation in which each of the plural ingredients
`may release independently and provide its suitable
`conceniration as desired.
`
`Page 2
`
`Page 2
`
`

`

`3
`
`EP 0 241 178 B1
`
`4
`
`the use of a two-phase carrier base,
`found that
`which consists of particles comprising a polymer
`having a limited solubility in water and a water
`soluble polymer used for dispersing such particles,
`meets the requirements just mentioned above.
`DE-A-3 432 573 and US-A-4 693 887 disclose
`pharmaceutical composition having two polymeric
`phases, one hydrophobic and one hydrophilic, the
`combination being insoluble in water and thus suit-
`able for water-insoluble implants. A drug partitions
`itself between the phases. The hydrophilic phase
`has a different composition from the disccntinuous
`phase employed in the present
`Thus the present invention provides:
`a controlled-release pharmaceutical composi-
`tion in the form of gel, sheet, film, or bar to be
`inserted or placed into a periodontal pocket
`for
`treating a periodontal disease, said composition
`comprising a therapeutically effective amount of at
`least one active ingredient effective for the treat-
`ment of the periodontal disease, said active ingre-
`dient being dispersed in a two-phase carrier con-
`sisting of
`(a) a continuous phase consisting of a water-
`soluble polymer capable of dissolving in water
`at a concentration of more than 1% by weight
`irrespective of pH, and
`(b) a discontinuous phase consisting of solid
`particles composed of a polymer capable of
`dissolving in water at a concentration of at least
`about 0.1% and not more than about 1.0% by
`weight; or solid particles composed of a polymer
`capable of dissolving in water at a concentration
`of more than 1% by weight only at a pH higher
`than 4 or lower than 6
`said particles having an average size ranging from
`1 um to 500 um and being dispersed in said
`water-soluble polymer, with the weight ratio of said
`particles to said water-soluble polymer
`ranging
`from 1:99 to 99:1 on a dry weight basis, said water-
`soluble polymer being selected from the
`methyl cellulose, hydroxypropyl cellulose, so-
`dium carboxymethyl
`cellulose,
`hydroxypropyl-
`methyl cellulose, hydroxyethyl cellulose, sodium
`alginate,
`propylene
`glycol
`alginate,
`pullulan,
`tragacanth, xanthan gum, chitosan, polyethylene
`oxide, polyvinyl alcohol, polyacrylic acid, poly-
`methacrylic acid, and salts thereof, and said solid
`particles being selected from
`poly-
`acid),
`poly(glycolic
`acid),
`poly(lactic
`tetramethylglycolide, polydiethylglycolide, poly-e-
`caprolactone,
`poly(DL-decalactone),
`poly-
`({alkyleneadipate), methylacrylate/ methacrylic acid
`copolymer, methylacrylate/ methacrylic acid/ oc-
`tylacrylate copolymer, ethylacrylate/ methacrylic
`acid copolymer, methylacrylate/ methacrylic acid/
`methylmethacrylate
`copolymer,
`methylmethacrylate/ methacrylic acid copolymer,
`
`cellulose acetate phthalate, cellulose acetate suc-
`cinate, cellulose acetate maleate, starch acetate
`phthalate, amylose acetate phthalate, methyl cel-
`lulose
`phthalate,
`hydroxypropylmethyl
`cellulose
`phthalate,
`hydroxyethyl
`ethylcellulose phthalate,
`hydroxypropylmethy! cellulose acetate succinate,
`carboxymeihylethyl
`cellulose,
`polyvinylalcohol
`phthalate,
`polyvinyl
`acetate
`phthalate,
`poly-
`vinylacetal phthalate, polyvinylbutylate phthalate,
`methylmethacrylate/
`dimethylaminoethy]
`methacrylate
`copolymer,
`and
`polyvinylacetal/
`dimethylamino acetate.
`
`Briet Description of the Drawing
`
`1 shows the dissolution profile of two ac-
`Fig.
`tive ingredients contained in the pharmaceutical
`composition of the invention which is in the form of
`a film. Fig. 2 shows the dissolution profile of two
`active ingredients contained in a conventional com-
`position.
`"Water soluble polymer" or "soluble polymer"
`denotes any polymer which dissolves in an aque-
`ous medium, particularly in water,
`in a concentra-
`tion of more than 1% by weight, irrespective of pH.
`For
`the purpose of simplicity,
`the polymers
`usable for the discontinuous phase are hereinafter
`referred to as "non-soluble polymer" as a whole.
`The soluble polymer used in the present inven-
`tion must be fabricated into a semi-solid or a solid
`material. The non-soluble polymer should have a
`property suitable for being fabricated into particles.
`Both soluble and non-soluble polymers employed
`in the present application should be, of course,
`physiologically acceptable.
`The pharmaceutical composition of the present
`invention may be prepared by dispersing one or
`more of active ingredients into a non-soluble poly-
`mer, or both of a soluble polymer and a non-
`soluble polymer, and mixing these polymers, and
`finally forming the resultant mixture into a solid
`material of a film, sheet or bar-like shape, or into a
`semi-solid material such as gel or ointment.
`In more detail, one or more non-soluble poly-
`mers is dissolved, as the first step,
`in an appro-
`priate organic solvent. To the resultant solution is
`dissolved or dispersed one or more active ingre-
`dients, and the mixture is formed into film or sheet
`by casting method. The resultant solid material
`is
`ground into particles.
`The particles are also obtainable by spray dry-
`ing, Wuster coating, Coacervation, or Drying in
`liquid phase. The average particle size may range
`from 1m to 500m depending on the contem-
`plated release pattern of
`the active ingredient.
`However, the size range between 1um and 300m
`is generally preferred.
`On the other hand, one or more water soluble
`
`10
`
`18
`
`20
`
`26
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Page 3
`
`Page 3
`
`

`

`5
`
`EP 0 241 178 B1
`
`6
`
`polymers are dissolved in a suitable solvent. The
`solvent may contain, if desired, one ar more active
`ingredients. Subsequently, the pH of the mixture is
`adjusted,
`if necessary, and the particles obtained
`above are uniformly suspendedin the mixture. The
`pharmaceutical composition of the invention in the
`form of gel is thus obtained.
`The composition of the invention in the form of
`film or sheet
`is obtained by deaerating the just
`mentioned gel, and subjecting the same to the
`casting process. The film or sheet may also be
`prepared by compression molding, extrusion or
`calendering. The most suitable forming process
`among others
`is
`selected depending on
`the
`physico-chemical properties of the polymers em-
`ployed.
`the invention is
`The bar-like composition of
`prepared in the similar manner as the film or sheet,
`but through extrusion.
`The weight ratio of the particles to the soluble
`(5) The ratio of the amounts of particles and
`soluble polymer to be combined.
`polymer ranges from 1:99 to 99:1 on the basis of
`{6) Selection of soluble polymer or polymers
`dry weight. The composition of the particles: solu-
`ble polymerin a ratio of 10:90-70:30 is preferred.
`having desired viscosity.
`By selection of suitable conditions in regard to
`Therapeutically active ingredient or ingredients
`the above variables,
`there is obtained the phar-
`used for the preparation of the composition of the
`invention are selected from those effective for pre-
`maceutical composition of the invention which re-
`leases one or more of active ingredients in the
`vention or treatment of periodontal diseases,
`for
`manner as contemplated. Since the surface of the
`example, germicides, such as chlorhexidine, Ag
`protein, glyceryl iodide, phenol, benzalkonium chlo-
`composition of the invention is mainly composed of
`ride, and cetylpyridinitum chloride;
`antimicrobial
`water soluble polymer, it does not give any uncom-
`fortable feeling to patients.
`agents, such as ampicillin,
`tetracycline, benzyl-
`penicillin,
`clindamycin;
`cefalexin,
`erythromycin,
`The following examples are presented by way
`
`chloramphenicol, and fragiomycin sulfate;.anti-in- of illustration of specific embodiments of the phar-
`flammatory
`agents,
`such
`as_
`ibuprofen,
`in-
`maceutical composition of the invention.
`In exam-
`ples, part or parts are represented by weight basis.
`domethacin, ketoprofen, mefenamic acid, antipy-
`rine, pranoprofen,
`ibufenac,
`tiaramide hydrochlio-
`ride, prednisolon, dexamethasone,
`triamcinolone
`acetonide, and prostaglandine; plaque solubilizing
`agents,
`such
`as
`dextranase,
`protease,
`and
`amylase; collagenase inhibitors obtained from the
`extraction of crude drugs, such as gambir-catechu
`known by the name of “asenyaku”; local anesthet-
`ics, such as tetracaine hydrochloride and ethyl
`aminobenzoate;
`antihistaminic agents,
`such as
`chlorphenilamine maleate and diphenhydramine;
`and hemostatic agents such as tranexamic acids.
`The solid composition of the invention in the
`form of
`film, sheet or bar can be prepared in
`different sizes. However, the convenient size of the
`film or sheet may be 0.1-0.5 mm in thickness, 0.5-
`3 mm in width, and 10-50 mm in length. The size
`of the bar may generally range from 0.5 to 1.5 mm
`in diameter and from 10 to 50 mm in
`Jength.
`Furthermore, the composition of the invention may
`be cut in suitable size by the user depending on
`several
`factors, such as severity of the disease,
`and the width and depth of the locus to be applied.
`The composition of the invention can be applied to
`
`Example 2
`
`/ methyl methacrylate
`acid
`Methacrylic
`copolymer (1:2 molar ratio) (80 parts) is dissolved
`in ethanol
`(1000 parts).
`In the solution are sus-
`pended or dissolved indomethacin (5 parts) and
`triacetin (20 parts), and the mixture is cast into a
`sheet, which is then pulverized into particles having
`an average size of 80um.
`
`Page 4
`
`the periodontal pocket or paradentium by insertion,
`injection, or rubbing according to the type of for-
`mulation.
`The pharmaceutical composition of the inven-
`tion exhibits a desirably controlled release pattern
`of the active ingredient(s). Such controlled release
`is attained by careful selection of a particular con-
`dition with respect to the following variables.
`(1) Distribution ratio of an active ingredient be-
`tween the particles. and the soluble polymer.
`(2) The particle size to be dispersed in the
`soluble polymer.
`(8) Selection of non-soluble polymer or poly-
`mers which permits the modification of both the
`solubility of particles and diffusion velocity of an
`active ingredient in the particles in the manner
`as desired.
`
`(4) The use of one or more kind(s) of particles
`which differ from each other in their solubilities.
`
`Example 1
`
`Poly(lactic acid) (10 parts) and tetracycline hy-
`drochloride (2 parts) are dissolved in methylene
`chloride (100 parts). Flow casting of the resultant
`mixture yields a sheet, which is ground into par-
`ticles having an average size of 50m.
`The particles (10 parts) and hydroxypropyl cel-
`lulose (10 parts) are uniformly admixed. The mix-
`ture is blended with water, extruded with pressure,
`and dried. The bar-like shaped product of 1.0 mm
`diameter is thus obtained.
`
`70
`
`15
`
`20
`
`26
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Page 4
`
`

`

`7
`
`EP 0 241 178 B1
`
`8
`
`Hydroxypropyl cellulose (10 parts) is dissolved
`in water (1000 parts), and tetracycline (25 parts) is
`added to the resultant solution, after adjusting to
`pH 6.0 by addition of hydrochloric acid. The resul-
`tant mixture (80 parts) is uniformly admixed with
`the particles obtained above (20 parts) to yield the
`productin a gel form.
`
`Example 3
`
`(20
`2
`The particles produced in Example
`parts), methyl cellulose (80 parts) and tetracycline
`hydrochloride (5 parts) are uniformly admixed, and
`the resulting mixture is pressed to a sheet having a
`500u.m thickness.
`
`Experiment 1
`
`The controlled release of an active ingredient
`was evaluated for a pharmaceutical composition of
`the invention which contains two kinds of active
`
`ingredients.
`
`Method and materials
`
`(1) Preparation of Sample
`
`/ methyl methacrylate
`acid
`Methacrylic
`ratio)
`(80 parts) was dis-
`copolymer
`(1:2 molar
`solved in ethanol (1000 parts). Triacetin (20 parts)
`and tetracycline hydrochloride (6 parts) were then
`mixed with the resultant solution. The mixture was
`cast on a Teflon tray and dried at 40°C. The
`resultant sheet was pulverized into particles of
`105um to 177um in size.
`On the other hand, hydroxypropyl cellulose
`(viscosity of 2% aqueous solution is 1000 to 4000
`cp at 20°C) (one part) was dissolved in water (99
`parts). In the solution was dissolved tetracaine hy-
`drochloride (0.03 part).
`The hydroxypropyl cellulose solution and the
`particles are uniformly admixed at a weightratio of
`100:0.5, and the mixture is deaerated, cast on a
`Teflon tray with care to ensure the constant thick-
`ness, and air-dried to yield a film having 300um
`thickness.
`In a solution of hydroxypropyl cellulose (1
`part) dissolved in water (100 parts) were dissolved
`tetracycline hydrochloride (0.02 part) and tetracaine
`hydrochloride (0.02 parts), and the mixture was
`adjusted to pH 6, deaerated, cast on a Teflon tray,
`air-dried to obtain a film having 300m thickness,
`which was employed as a reference.
`
`(2) Evaluation of Dissolution Rate
`
`The dissolution rates of the active ingredients
`released from the films obtained above were mea-
`
`sured using a phosphate buffer (500ml), pH 7.2, at
`37°C,
`in accordance with the Rotating Basket
`Method (100 rpm) of Japanese Pharmacopoeia (%).
`
`Results
`
`The dissolution profiles of the film of the inven-
`tion and that of
`the reference are respectively
`shown in Fig.
`1 and Fig. 2 of the accompanying
`drawing. The abscissa indicates immersion time
`and the ordinate indicates the dissolution rate. Fig.
`1 shows that two active ingredients were released
`from the film with different release patterns while
`Fig. 2 shows the same and identical release pattern
`of the two active ingredients. Thus, this experiment
`illustrates that the composition of the invention per-
`mits separate control of the release patterns of two
`active ingredients. It also teaches that the composi-
`tion of
`the invention in the form of a sustained
`release formulation may be obtained where a sin-
`gle active ingredient is employed rather than two
`active ingredients as employedin this experiment.
`
`Claims
`
`1. A controlled-released pharmaceutical composi-
`tion in the form of gel, sheet, film, or bar to be
`inserted or placed into a periodontal pocket for
`treating a periodontal disease, said composi-
`tion
`comprising a
`therapeutically
`effective
`amount of at least one active ingredient effec-
`tive for
`the treatment or the periodontal dis-
`ease, said active ingredient being dispersed in
`a two-phase carrier consisting of
`(a) a continuous phase consisting of a
`water-soluble polymer capable of dissolving
`in water at a concentration of more than 1%
`by weight irrespective of pH, and
`(b) a discontinuous phase consisting of solid
`particles composed of a polymer capable of
`dissolving in water at a concentration of at
`least about 0.1% and not more than about
`1.0% by weight; or solid particles com-
`posed of a polymer capable of dissolving in
`water at a concentration of more than 1%
`by weight only at a pH higher than 4 or
`lower than 6.
`said particles having an average size ranging
`from 1 um to 500 um and being dispersed in
`said water-soluble polymer, with the weight
`ratio of said particles to said water-soluble
`polymer ranging from 1:99 to 99:1 on a dry
`weight basis, said water-soluble palymer being
`selected from the
`methyl cellulose, hydroxypropy! cellulose,
`sodium carboxymethyl
`cellulose,
`hydrox-
`ypropylmethyl
`cellulose, hydroxyethyl cellu-
`lose,
`sodium alginate, propylene glycol al-
`
`10
`
`18
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Page 5
`
`Page 5
`
`

`

`9
`
`EP 0 241 178 B1
`
`10
`
`tragacanth, xanthan gum,
`pullulan,
`ginate,
`chitosan, polyethylene oxide, polyvinyl alcohol,
`polyacrylic acid, polymethacrylic
`acid,
`and
`salts thereof, and said solid particles being
`selected from
`
`poly(glycolic acid), poly(lactic acid), poly-
`tetramethylglycolide,
`polydiethylglycolide,
`poly-e-caprolactone,
`poly(DL-decalactone),
`poly{alkyleneadipate),
`methylacrylate/
`methacrylic acid copolymer, methylacrylate/
`methacrylic
`acid/
`octylacrylate
`copolymer,
`ethylacrylate/ methacrylic
`acid
`copolymer,
`methylacrylate/. methacrylic
`acid/ methyl-
`methacrylate copolymer, methylmethacrylate/
`methacrylic acid copolymer, cellulose acetate
`phthalate, cellulose acetate succinate, cellulose
`acetate maleate,
`starch
`acetate
`phthalate,
`amylose acetate phthalate, methyl cellulose
`phthalate,
`hydroxypropylmethy!
`cellulose
`phthalate,
`hydroxyethyl
`ethylcellulose
`phthalate, hydroxypropylmethyl cellulose ace-
`tate succinate, carboxymethylethyl cellulose,
`polyvinylaicohol phthalate, polyvinyl acetate
`phthalate, polyvinylacetal phthalate, polyvinyl-
`butylate
`phihalate,
`methylmethacrylate/
`dimethylaminoethy! methacrylate copolymer,
`and polyvinylacetal/ dimethylamino acetate.
`
`(1) preparing polymer particles using a
`polymer capable of dissolving in water at a
`concentration of at least about 0.1% and not
`more than about 1.0% by weight or a poly-
`mer capable of dissolving in water only at a
`pH higher than 4 or a pH lower than 6 at a
`concentration of more than 1% by weight,
`said polymer being specified in Claim 1.
`{2) uniformly admixing the particles and a
`polymer capable of dissolving in water at a
`concentration of more than 1% by weight
`irrespective of
`pH,
`said polymer being
`specified in Claim 1.
`(3) processing the mixture to form a phar-
`maceutical composition in the form of gel,
`sheet,
`film or bar, wherein at
`least one
`active ingredient effective for the treatment
`of the periodontal disease is added in Step
`(1) and/or Step (2).
`
`70
`
`18
`
`20
`
`8.
`
`The process of Claim 7, wherein one active
`ingredient
`is added in Step (1) and another
`ingredient is added in Step (2).
`
`25
`
`Revendications
`
`2.
`
`3.
`
`The composition of claim 1 wherein two active
`ingredients are dispersed in said carrier.
`
`The composition of claim 1 having at least two
`active ingredients whereof one is in the con-
`tinuous phase and oneis in the discontinuous
`phase, whereby they have different release
`profiles.
`
`the two-phase carrier according to
`Use of
`Claim 1 as a carrier for preparing a controlled-
`release pharmaceutical
`composition in
`the
`form of gel, sheet, film or bar to be inserted or
`placed into a periodontal pocket for treating a
`periodontal disease, a therapeutically effective
`amount of at least one active ingredient effec-
`tive for tile treatment of the periodontal disease
`being dispersed in said two-phase carrier.
`
`Use according to claim 4 wherein two active
`ingredients are dispearsed in said carrier.
`
`6.
`
`Use according to claim 5 wherein one active
`ingredient is dispersed in the continuous phase
`and the other active ingredient is dispersed in
`the discontinuouse phase.
`
`A process for preparing the controlled-released
`pharmaceutical composition of Claim 1, 2 or 3
`which comprises the following steps:
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`1, Composition
`libération
`a4
`pharmaceutique
`contrélée sous la forme de gel, feuille, pelli-
`cule ou barre @ insérer ou placer dans une
`poche parodontale pour
`le traitement d'une
`parodontopathie,
`ladite composition compre-
`nant une quantité thérapeutique efficace d'au
`moins un ingrédient actif efficace pourle traite-
`ment de la parodontopathie,
`ledit
`ingrécient
`actif étant dispersé dans un support 4 deux
`phases constitué de
`(a) une phase continue formée d'un poly-
`mere hydrosoluble capable de se dissoudre
`dans l'eau @ une concentration de plus de 1
`% en poids quel que soit le pH, et
`(b) une phase discontinue formée de parti-
`cules solides constituées d'un polymére ca-
`pable de se dissoudre dans l'eau 4 une
`concentration d'au moins environ 0,1 % et
`d’au plus environ 1,0 % en poids ; ou de
`particules solides constituées d'un polymére
`capable de se dissoudre dans l'eau & une
`concentration de plus de 1 % en poids
`uniquement @ un pH supérieur 4 4 ou infé-
`rieur 4 6,
`lesdites particules ayant une taille moyenne
`comprise entre 1 um et 500 um et étant
`dispersées dans ledit polymére hydrosoluble,
`le rapport en poids desdites particules audit
`polymére hydrosoluble étant compris entre
`1:99 et 99:1 en poids sec,
`ledit polymére hy-
`drosoluble étant choisi parmi ceux qui suivent:
`méthylicsllulose, hydroxypropylcellulose, car-
`
`Page 6
`
`Page 6
`
`

`

`11
`
`EP 0 241 178 B1
`
`12
`
`boxyméthylcellulose sodique, hydroxypropyl-
`méthylcellulose, hydroxyéthylcellulose, alginate
`de sodium, alginate de propyléne-glycol, pullu-
`lane, gormme adragante, gomme de xanthane,
`chitosane, poly(oxyde d'éthyléne), alcool poly-
`vinylique, acide polyacrylique, acide polymé-
`thacrylique et leurs sels, et lesdites particules
`solides étant choisies parmi ceux qui suivent :
`poly{acide glycolique), poly(acide lactique), po-
`lytétraméthylglycolide,
`polydiéthylglycolide,
`poly-e-caprolactone,
`poly(DL-décalactone),
`poly(adipate d'alkyléne), copolymére acrylate
`de méthyle/acide méthacrylique, copolymére
`acrylate
`de
`méthyle/acide
`méthacrylique/acrylate d'octyle,
`copolymére
`acrylate d'éthyle/acide méthacrylique, copoly-
`mere
`acrylate
`de
`méthyle/acide
`méthacrylique/méthacrylate de méthyle, copo-
`lymére méthacrylate de méthyle/acide métha-
`crylique, acstophtalate de cellulose, acétosuc-
`cinate de cellulose, acétomaléate de cellulose,
`acétophtalate d'amidon, acétophtalate d'amylo-
`se, phtalate de méthyicellulose, phtalate d'hy-
`droxypropylméthylcellulose,
`phtalate
` d'hy-
`droxyéthyléthyicellulose, acétosuccinate d'hy-
`droxypropylméthylceliulose,
`carboxyméthylé-
`thylcellulose, phtalate d'alcool polyvinylique,
`acétophtalate de polyvinyle, phtalate de polyvi-
`nylacétal, butyrophtalate de polyvinyle, copoly-
`mére méthacrylate de méthyle/méthacrylate de
`diméthylaminoéthyle
`et
`polyvinylacétal/diméthylaminoacétate.
`
`Composition selon la revendication 1, dansla-
`quelle deux ingrédients actifs sont dispersés
`dans ledit support.
`
`Composition selon la revendication 1, conte-
`nant au moins deux ingrédients actifs dont I'un
`se trouve dans la phase continue et
`l'autre
`dans la phase discontinue, de sorte qu'ils aient
`des profils de libération différents.
`
`Utilisation du support 4 deux phases selon la
`revendication 1 comme support pour préparer
`une composition pharmaceutique 4 libération
`contrélée sous la forme de gel, feuille, pelli-
`cule ou barre 4 insérer ou placer dans une
`poche parodontale pour le traitement de paro-
`dontopathies, une quantité thérapeutique effi-
`cace d'au moins un ingrédient actif, efficace
`pour le traitement de la parodontopathie, étant
`dispersée dans ledit support & deux phases.
`
`5.
`
`Utilisation selon la revendication 4, dans la-
`quelle deux ingrédients actifs sont dispersés
`dans ledit support.
`
`Utilisation selon la revendication 5, dans la-
`quelle un ingrédient actif est dispersé dans la
`phase continue et
`l'autre ingrédient actif est
`dispersé dans la phase discontinue.
`
`Procédé pour préparer la composition pharma-
`ceutique 4 libération contrélée de la revendica-
`tion 1, 2 ou 3, qui comprend les 4tapes suivan-
`tes:
`(1) préparer des particules de polymére en
`utilisant un polymére capable de se dissou-
`dre dans l'eau &@ une concentration d’au
`moins environ 0,1 % et d’au plus environ
`1,0 % en poids ou un polymére capable de
`se dissoudre dans l'eau a une concentration
`de plus de 1 % en poids uniquement 4 un
`pH supérieur & 4 ou un pH inférieur & 6
`ledit polymére éiant spécifié dans la reven-
`dication 1
`;
`(2) mélanger uniformémentles particules et
`un polymére capable de se dissoudre dans
`l'eau A une concentration de plus de 1 %
`en poids quel que soit le pH,ledit polymére
`étant spécifié dans la revendication 1
`;
`(3) transformer le mélange pour former une
`composition pharmaceutique sous la forme
`de gel, feuille, pellicule ou barre,
`dans lequel au moins un ingrédient actif,
`efficace pour le traitement de parodontopa-
`thies, est ajouté dans I'Etape (1) et/ou I’Eta-
`pe (2).
`
`Procédé selon la revendication 7, dans lequel
`un ingrédient actif est ajouté dans I"Etape (1)
`et un autre ingrédient est ajouté dans |'Etape
`(2).
`
`70
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Patentanspriiche
`
`40
`
`1.
`
`45
`
`50
`
`55
`
`Pharmazeutisches Praparat mit kontrollierter,
`verzogerter Freigabe in Form eines Gels, einer
`Folie bzw. Platte, eines Films oder eines Sta-
`bes, das in eine periodontale Tasche einge-
`setzt oder eingesetzt wird, fiir die Behandlung
`einer periodontalen Krankheit, dadurch ge-
`kennzeichnet, da®8 das Praparat eine thera-
`peutisch wirksame Menge von mindestens ei-
`nem aktiven Bestandteil, der fiir die Behand-
`lung der periodontalen Krankheit wirksam ist,
`enthalt, wobei der aktive Bestandteil
`in einem
`Zweiphasen-Trager dispergiert ist, der aus
`{a) einer kontinuierlichen Phase, die aus ei-
`nem wasserldslichen Polymeren, welches
`sich in Wasser in einer Konzentration von
`Uber 1 Gew.-%, unabhangig vom pH-Wert,
`lésen kann, besteht, und
`(b) einer diskontinuierlichen Phase, die aus
`festen Teilchen, die aus einem Polymeren,
`
`Page 7
`
`Page 7
`
`

`

`13
`
`EP 0 241 178 B1
`
`14
`
`das sich in Wasser in einer Konzentration
`von mindestens etwa 0,1 Gew.-% und nicht
`mehr als etwa 1,0 Gew.-% lésen kann, be-
`stehen, oder aus festen Teilchen, die aus
`einem Polymeren, das sich in Wasser in
`einer Konzentration von Uber 1 Gew.-% nur
`
`10
`
`15
`
`26
`
`30
`
`35
`
`40
`
`45
`
`tiber 4 oder niedriger
`bei einem pH-Wert
`als 6 [6sen kann, besteht,
`besteht, wobei die Teilchen eine durchschnittli-
`che Teilchengréfe im Bereich von 1 um bis
`500 um aufweisen und in dem genannten was-
`serldslichen Polymeren dispergiert sind, das
`Gewichtsverhaltnis der Teilchen zu dem was-
`serléslichen Polymeren im Bereich von 1:99
`bis 99:1 auf Trockengewichtsbasis liegt, das
`wasserlésliche Polymere ausgewdahlt wird aus
`Verwendung nach Anspruch 4, dadurch ge-
`der Gruppe:
`kennzeichnet, da8 zwei aktive Bestandteile in
`Hydroxypropylcellulose,
`Methylcellulose,
`dem Trager dispergiert sind.
`Natriumcarboxymethylcellulose,|Hydroxypro-
`20
`pylmethylcellulose, Hydroxyethylceliulose, Na-
`triumalginat,
`Propylenglykolalginat,
`Pullulan,
`Traganthgummi, Xa