Europaisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`
`
`
`
` |||IlllllillIlllilllllllilillilllIiillilllllillllilll
`0 241 178 BI
`
`® Publication number:
`
`EUROPEAN PATENT SPECIFICATION
`
`9 6
`
`9
`
`Date of publication of patent specification: 08.01.92 ® Int.CI.5:A51K 9H0, A51K 47:00
`
`@ Application number: 373025142
`
`Date ofiiiing: 24.03.87
`
`
`
`® Pharmaceutical composition for treating periodontal diseases.
`
`
`
`(3}) Priority: 25.03.36 JP 6781 ores
`
`@ Date of publication of application:
`14.10.87 Butletin 87l42
`
`(£9 Proprietor: nor-no PHARMACEUTICAL co.,
`LTD.
`No. 1-3-1, Tatsuminishi
`lkuno-ltu Osaka-shi Osaka-mth)
`
`
`
`inventor: Higashi, Kiyotsugu
`1987, Ryoanii-cho
`Gojo-ehi Nara-kenlJP)
`Inventor: Kametaka, Shigeru
`968-10. Oazatakaida
`Kashiwara-shi Osaka-tub?)
`Inventor: Morisairl. Katsuhilto
`- 2-55, Oazamimatsugaoka—nlshi Sango-cho
`“coma-gun Nara-ken(JP)
`Inventor: Hayashi, Shin'ichi
`4-683-49, Nonaka
`Fujiidera-shi Osaka-tum}
`Inventor: lzumi, Reiko
`Puchishanburu 201 13-21, Tamatsukurl-
`hommachi
`
`Tennoji-cho Osakl-shi Osaka-fu(JP)
`
`Representative: Stuart. Ian Alexander et at
`MEWBURN ELLIS 8: CO. 213 Cursitor Street
`
`London E04A 130(GB)
`
`Publication ot the grant of the patent:
`03.01.92 Bulletin 9202
`
`Designated Contracting Statea:
`DE FFI GB IT
`
`References cited:
`EP-A- 0 135 022
`EP-A- O 184 389
`DE-A— 3 432 573
`FFt-A- 2148 045
`US-A— 4 568 535
`
`EP024-1178B1
`
`Note: Within nine 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
`
`Dr. Reddy's - EX1021
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`Page 1
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`Dr. Reddy's - EX1021
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`1
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`EP 0 241 17'8 Bi
`
`2
`
`Description
`
`This invention relates to a pharmaceutical com-
`position which is appiied 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 genera! term of
`various inflammatdry diseases of paradentium. The
`diseases inciude 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. peCuIiar diseases such as "juvenile para-
`dentitis'I and "acute necrotizing ulcerative gingivi-
`tis" are also included in the periodontal diseases.
`The
`paradeniitis. 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.
`The consensus of most Investigators is that
`periodontal diseases
`are
`caused by
`bacteria
`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 inc—Errol:
`ing Actinobacillus. Capnocytophaga, Fusobacterium
`and Spirochetes may be included in the causative
`pathomy case. it is an established theory
`that the periodontal diseases should not be attrib-
`uted to all bacteria present in the dental plaque.
`The periodontal diseases have previously been
`treated in several Ways. such as exhaustive scaling
`of plaques in periodontal pockets,
`root planing,
`gingivectomy to eliminate the periodontal pocket.
`or surgical curettage to excise inflammatOry tis~
`sues. These treatments have been effective to
`some extent but not satisfactory.
`On the other hand. pharmacotherapy has also
`been conducted using drugs. for example germi«
`
`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 ointr'nents).
`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 to
`be more effective than any conventional phar-
`macotherapy. For instance, J. M. Goodson et al.
`disclose the implantation of "hollow fiber“, which
`contains germicides.
`into the gingival
`region (J.
`Clinical Periodontology, 1979: 6: 33-92). M. Addy
`at al. have reported the insertion of strips. which
`were prepared from a mixture of an insclubie poly-
`mer such as polyethylmethacrylate and gerrnicides,
`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.
`59-222403).
`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
`concentration as desired.
`
`The use of the hollow fiber or insoluble poly-
`mer. as a base. causes irritation or pain to patients.
`and moreover.
`it necessitates the removal of the
`base after release of an active ingredient. which is
`often annoying. On the other hand. the strip which
`comprises a soluble polymer as a base or carrier
`permits a rapid release of an active ingredient.
`Accordingly. it does not afford a constant therapeu-
`tic effect and. therefore. has a poor practical use.
`As the result of an extensive study for seeking
`a novel
`therapeutical composition for periodontal
`diseases. which suitably commie the release of one
`or more active ingredients and which does not give
`any uncomfortable feelings to patients, it has been
`
`to
`
`1‘5
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`50
`
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`3
`
`EP 0 241 178 31
`
`4
`
`found that the use of a two-phase carrier base.
`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-a 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 discontinuous
`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, hydrcxyethyl cellulose. sodium
`alginate.
`propylene
`glycol
`alginste.
`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),
`polylglycolio
`acid),
`polyllacfic
`tetramethylglycolide, pclydiethylglycclide, polysa-
`caprolactone.
`poileL—decalactone),
`poly-
`(alkyleneadipate), methylaorylate! methaorylio acid
`copolymer. methylacrylatef methacryiic acid! oc-
`tylacrylate copolymer, ethylaorylatei methacrylic
`acid copolymer, methylaorylater methacrylic acidf
`methylmethacrylate
`copolymer,
`mrtltl‘lylmethacrylaterr methaorylic acid copolymer,
`
`cellulose acetate phthalate, cellulose acetate suc-
`cinate, cellulose acetate maleate. starch acetate
`phthalate. amylose acetate phthalate, methyl cel-
`Iulcse phthalate,
`hydroxypropylmethyl
`cellulose
`phthalate.
`hydroxyethyl
`ethylcellulose phthalate,
`hydroxypropylmethyf cellulose acetate succinate.
`carboxymethylethyl
`cellulose.
`polyvinylalcohol
`phthalate.
`polyvinyl
`acetate
`phthalate.
`poly-
`vinylacetal phthalate. polyvinylbutylate phthalate,
`methylmethaorylate/
`dimethylaminoethyl
`methacryiate
`copolymer.
`and
`polyvinylacetalrr
`dimethylamino acetate.
`
`
`Brief Description of the Drawing
`
`Fig. 1 shows the dissolution profile of two ac-
`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—
`scluble 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 turn to 500nm depending on the contem-
`plated release pattern of
`the active ingredient.
`However, the size range between him and 300LLm
`is generally preferred.
`0n the other hand. one or more water soluble
`
`10
`
`f5
`
`20
`
`30
`
`35
`
`40
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`5
`
`EP 0 241 178 B1
`
`6
`
`polymers are dissolved in a suitable solvent. The
`solvent may contain, if desired. one or more active
`ingredients. Subsequently, the pH of the mixture is
`adjusted,
`if necessary, and the particles obtained
`above are uniformly suspended in the mixture. The
`pharmaceutical composition of the invention in the
`form of gel is thus- obtained.
`The cempositiOn of the invention in the form of
`film or sheet is obtained by deaerating the just
`mentioned gel. and subiecting the same to the
`casting process. The film or sheet may also be
`prepared by compression molding. extrusion or
`calendaring. 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
`polymer ranges from 1:99 to 99:1 on the basis of
`dry weight. The composition of the particles: solu-
`ble polymer in a ratio of 10:90-70:30 is preferred.
`Therapeutically active ingredient or ingredients
`used for the preparation of the composition of the
`invention are selected from those effective for pre-
`vention or treatment of periodontal diseases.
`for
`example. germicides, such as chlomexidine. Ag
`protein, glyceryl iodide. phenol, benzalkonium chlo-
`ride. and cetylpyridinium chloride; antimicrobial
`agents. such as ampicillin,
`tetracycline, benzyl-
`penlclllin,
`cllndamycin;
`cefalexln,
`erythrornycin.
`chloramphenlcol, and fragiomycin sulfate:-an'ti-in-
`ilammatory
`agents,
`such
`as
`ibuprofen,
`in-
`domethacin. ketoprofen, mefenamic acid. antipy-
`rine, pranoprofen,
`ibufenac.
`tiaramide hydrochlo-
`ride, prednisolon, dexarnefhasone.
`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 length.
`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
`
`the periodontal pocket or paradentium by insertion,
`
`injection, or rubbing according to the type of for-
`mutation.
`
`The pharmaceutical composition of the inven-
`tion exhibits a desirably controlled release pattern
`of the active ingredient(sl. 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.
`{3} Selection of non-soluble polymer or poly-
`more 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 kindts) of particles
`which differ from each other in their solubilities.
`
`(5} The ratio of the amounts of particles and
`soluble polymer to be combined.
`(6) Selection of soluble polymer or polymers
`having desired viscosity.
`By selection of suitable conditions in regard to
`the above variables,
`there is obtained the phar-
`maceutical composition of the invention which re-
`leases one or more of active ingredients in the
`manner as contemplated. Since the surface of the
`composition of the invention is mainly composed of
`water soiubie polymer. it does not give any uncom-
`fortabte feeling to patients.
`The following examples are presented by way
`of itlustration of specific embodiments of the phar-
`maceutical composition of the invention.
`In exam-
`ples. part or parts are represented by weight basis.
`
`Example 1
`
`Polyhactic 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 50cm.
`The particles (to 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.
`
`10
`
`f5
`
`20
`
`30
`
`4c
`
`45
`
`50
`
`Example 2
`
`55
`
`it 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 BDum.
`
`Page 4
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`

`

`7
`
`EP 0 241 178 31
`
`3
`
`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
`product in a gel form.
`
`Example 3
`
`The particles produced in Example 2 (20
`parts}. methyl cellulose (80 parts) and tetracycline
`hydrochloride (5 pans) are uniformly admixed. and
`the resulting mixture is pressed to a sheet having a
`500le thicknesa.
`
`Experiment:
`
`The controlled release of an active ingredient
`was evaluated for a pharmaceutical composition of
`the invention which contains two kinds of active
`
`ingredients.
`
`
`Method fl materials
`
`(1) Preparation of Sample
`
`1 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
`105nm to 177nm in size.
`
`35
`
`0n the other hand. hydroxypropyl cellulose
`(viscosity of 2% aqueous solution is 1000 to 4000
`cp at 20' 0) (one part) was dissolved in water (as
`parts). In the solution was dissolved tetracaine hy-
`drochloride (0.03 part}.
`The hydroxypropyl cellulose solution and the
`particles are uniformly admixed at a weight ratio of
`10020.5, 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 300nm
`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 300nm thickness,
`which was employed as a reference.
`
`{2) Evaluation of Dissolution Hate
`
`The dissolution rates 01 the active ingredients
`released from the films obtained above were mea-
`
`45
`
`55
`
`sored using a phosphate butter (500ml), pl-l 7.2, at
`37°C.
`in accordance with the Rotating Basket
`Method (100 rpm) of Japanese Pharmacopoeia (X).
`
`Results
`
`10
`
`$5
`
`20
`
`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 ot 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 term of a sustained
`release formulation may be obtained where a sin-
`gle active ingredient is employed rather than two
`active ingredients as employed in 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 polymer being
`selected from the
`
`methyl cellulose, hydroxypropyl cellulose.
`sodium carboxymethyl
`cellulose,
`hydrox-
`ypropylmethyl cellulose, hydroxyethyl cellu-
`lose, sodium alginate, propylene glycol al-
`
`Page 5
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`9
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`I
`
`EP D 241 178 Bi
`
`10
`
`tragacanth, xanthan gum.
`pullulan,
`ginate,
`chitosan, polyethylene oxide, polyvinyl alcohol.
`polyacrylic acid. polymethacrylic
`acid, and
`salts hereof, and said solid particles being
`selected from
`
`poly(glycolic acid), polyllactic acid), poly-
`tetramethylglycolide.
`polydiethylglycolide.
`poly-e-caprolactone,
`polleL-deoalactone).
`poly(alkyleneadipate).
`methylacrylatel
`methacrylic acid copolymer. methylacrylatei
`melhacrylic
`acidi
`cctylacrylate
`copolymer.
`ethylacrylate! methacrylic
`acid
`copolvmer.
`methylacrylatei methacrylic
`acid} methyl-
`methacrylate copolymer. methylmethacrylatel’
`methacrylic acid copolymer, cellulose acetate
`phthalate. cellulose acetate succinate, cellulose
`acetate maleate.
`starch
`acetate phthalate.
`amylase acetate phthalate. methyl cellulose
`phthalate.
`hydroxypropylmethyl
`cellulose
`phthalate,
`hydroxyethyl
`ethylceilulose
`phthalate, hydroxypropylmethyl cellulose ace-
`tate succinate. carboxymethylethyl cellulose.
`polyvinylalcohol phthalate, polyvinyl acetate
`phthalate, polyvinylacetal phthalate, polyvinyl-
`butylate
`phthalate,
`methylmethacrylatei
`dimethylaminoethyl methacrylate copolymer.
`and polyvinylacetall dimethylamino acetate.
`
`2.
`
`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 One is 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
`planed 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.
`
`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:
`
`(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 8 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) andlor Step (2].
`
`10
`
`3‘5
`
`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
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`1. Composition
`liberation
`a
`pharrnaceutique
`contrfilée sous la forme de gel. teuille. pelli-
`cule ou barre a insérer ou placer dans une
`poche parodontale pour
`le traitement d'une
`parodontopathie.
`ladite composition compre-
`nant one quantité therapeutique etficace d‘au
`moins un ingredient actif efficace pour le traito-
`ment de la parodontopathie,
`ledit
`ingredient
`actit étant dispersé clans on support a deux
`phases constitué do
`(a) une phase continue formée d'un poly-
`mers hydrosoluble capable de se dissoudre
`clans l'eau a one concentration de plus de 1
`es en poids quel que soit le pH. at
`{b} une phase discontinue tormée de parti-
`cules solides constituées d‘un polymers ca-
`pable de se dissoudre dans l'eau a une
`concentration d'au moins environ 0,1 % et
`d‘au plus environ 1.0 °/o en poids ; ou de
`particules solides oonstituées d‘un polymers
`capable de se dissoudre dans l'eau a une
`concentration de plus de 1
`“A: an poids
`uniquement a on pH supérieur a 4 cu inte-
`rieur a B.
`lesdites particules ayant one taille moyenne
`comprise entre 1 urn st 500 am at étant
`dispersées clans ledit polymére hydrosoluble,
`Ie rapport en poids desdites particules audit
`polymers hydrosoluble étant compris entre
`1:99 at 99:1 en poids sec. ledit polymers hy-
`drosoluble étant choisi parmi ceux qui suivent :
`métbylcellulose. hydroxypropylcellulose. car-
`
`Page 6
`
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`
`

`

`11
`
`EP0241 178 B1
`
`12
`
`boxyrnéthylcellulose sodique, hydroxypropyl-
`méthylcellulose. hydroxyéthylcellulosei alginate
`de sodium, alginate de propylene-glycol. pullu-
`lane, gomme adragante. gornrne de xanthane.
`chitosane. poly(oxyde d'éthylene]. alcool poly-
`vinylique, acids polyacrylique, acids polymé-
`thacrylique et leurs sets. at lesdites particmes
`solides étant chcisies parrni ceux qui suivent :
`po|y(acide glycolique), poly(acicle Iactique), po-
`Iytétramétl-Iylglycclide,
`polydiéthylglycolide,
`poly-e-caproiactone,
`poly(DL—décalactone}.
`poly(adipate d'aikyléne). copolymere acryiate
`de méthyletacide méthacrylique. ccpolymere
`acrylate
`de
`méthyiefacide
`mémacryliquaiacryiate d'octyle.
`copolymere
`acrylate d'éthylefacide méthacrylique. copoly-
`mere
`acrylate
`de
`méthyielacide
`méthacryliqusiméthacrylate de méthyle. copo-
`lymere méthacrylate do methylefacide metha-
`crylique. acétophtalate de cellulose, acétosuc-
`cinate de cellulose, acetomateate de cellulose.
`acétophtalate d'amidon, acétophtaiate d’amylo-
`se, phtalate de me‘thylcellulose. phtalate d'hy-
`droxypropylméthylcellulose.
`phtalate
`d'hy-
`droxyéthyle‘thylcellulose. aoétosuccinate d'hy-
`droxypropylme‘thylcellulose.
`carboxyrnéthylé-
`thylcellulose. phtaiate d‘alcocl polyvinylique,
`acetophtalate de poiyuinyle, phtalate de polyvi-
`nytaoétal. butyrophtalate de polyvinyle, oopoly-
`mere méthacrylate de methylennéthacrylate de
`diméthylaminoéthyle
`et
`po|yvinylacétalfdiméthylamlnoacétate.
`
`Composition salon la revendication 1I dans la-
`quelle deux ingredients actifs sont disperses
`dens Iedit support.
`
`Composition selon Ia revendication 1, conte-
`nant au moins deux ingredients actifs dont l'un
`so trouve dans la phase continue at
`l'autre
`clans la phase discontinue. de sorte qu'ils aient
`des profile de liberation difiérents.
`
`Utilisation du support a deux phases selon la
`revendication 1 cornme support pour preparer
`une composition pharmaceutique a Iibération
`conbfilée sous la forme de gel, feuille. pelli-
`culs ou barre a insérer ou placer dans une
`pcche parodontele pour le traitement de paro-
`dontopathies, une quantité thérapeutique effi-
`cace d‘au moins un ingredient actif, efficace
`pour Ie traitement de la parodontopathie, etant
`disperses clans ledit support a deux phases.
`
`Utilisation salon ia revendication 4. dans la-
`quelle deux ingredients actifs sont disperses
`cans Iedit support.
`
`6. Utilisation selon Ia revendication 5. dans la-
`
`quelle un ingredient actif est disperse dans la
`phase continue at l‘autre ingredient actit est
`disperse dans la phase discontinue.
`
`Prooédé pour preparer la composition pharma-
`ceutique a liberation controlée de la revendica~
`tion 1, 2 cc 3. qui comprend les stapes suivan-
`tes :
`
`(1} preparer des particules de polymers en
`utilisant un polymers capable de se dissou-
`dre clans I'eau a une concentration d‘au
`
`moins environ 0.1 % et d'au plus environ
`1.0 % en poids cu” un polymers capable de
`se dissoudre dans I'eau a une concentration
`
`de plus de 1 so on poids uniquement a un
`pH supérieur a 4 cu un pH inférieur a 6
`Iedit polymers étant spécifié dans la reven-
`dication 1 ;
`
`(2) mélanger unifonnérnent Ies particules et
`un polymers capable de se dissoudre dans
`I‘eau a une concentration de plus de 1 9t.
`en poids quel que soit le pH, ledit polymére
`étant spéciiié dans la revendication 1
`;
`(3) transformer ie mélange pour former une
`composition pharmaceutique sous la forme
`de gel. feuille. pellicule ou barre,
`clans lequel au moins un ingredient actif.
`efficaoe pour la traitement de parodontopa-
`thies. est ajouté dans I'Etape (1) etiou I'Eta-
`pa (2).
`
`Proce'de' selon la revendication 7, dans quuel
`an ingredient actif est ajouté dans I'Etape (1)
`et un autre ingredient est ajoute dans I'Etape
`(2).
`
`Patentansprii che
`
`1. Pharmazeutisches Pr§parat mit kontrollierter.
`verzifigerter Freigabe in Form eines Gels, einer
`Folie bzw. Platte. eines Films oder eines Sta-
`bes. else in eine periodontale Tasche singe-
`setzt oder eingesetzt wird. fur die Behandlung
`einer periodontalen Krankheit, dadurch ge-
`kennzeichnet. dais das Praparat eine thera-
`peutisch wirksame Mange von mindestens ei-
`nem aktiven Bestandteil. der fLir die Behand-
`lung der periodontalen Krankheit wirksam ist.
`enthalt. wobei der aktive Bestandteil in einem
`Zweiphasen-Trager dispergiert ist. der sue
`{a} einer kontinuierlichen Phase. die aus ei-
`nem wasserloslichen Polymeren, welches
`sich in Wasser in einer Konzentration von
`
`ilber 1 Gem-es, unabhangig vorn pH-Wert.
`losen kann, besteht. und
`
`(b) einer diskontinuierlichen Phase, die aus
`festen Teilchen, dis aus einem Polymeren,
`
`1'0
`
`#5
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
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`Page 7
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`

`13
`
`EP0241 178 B1
`
`14
`
`das sich in Waseer in einer Konzentration
`
`van mindestens etwa 0.1 Gem-$3 und nicht
`mehr als etwa 1,0 Gew.-% Ifisen kann. be-
`stehen, uder aus fasten Teilchen. die aus
`einem Polymeren, das sich in Wesser in
`einer Konzentration von fiber 1 Gew.-% nur
`
`bei einem pH-Wert fiber 4 oder niedriger
`ale 8 [Been kann. besteht,
`besteht, wobei die Teilchen eine durchschnittli-
`che Teilchengrfifle im Bereich von 1 pm his
`500 um aufweisen und in dem genannten was-
`serlfislichen Polymeren dispergiert sind. das
`Gewichtsverhfiltnis der Teilchen zu dem was-
`eerlfislichen Polymeren im Bereich van 1:99
`bis 99:1 eui Trockengewichtsbasis Eiegt, dae
`waseerltisriche Polymers auegewfihlt wird aus
`der Gruppe:
`Hydroxypropylcellulose.
`Methylcellwose.
`Natriumcarbowmethylcelluloee,
`Hydmxypro-
`pylmethyloellulose. Hydroxyemylceiiulose. Na-
`triumalginat.
`Propylenglykolalginat.
`Pullulan,
`Traganthgurnrni. Xanthangurnmi. Chitosan, Po-
`lyethylenoxid. Polyvinylalkahol. Pclyacwlsfi