L/ll/Bé
`
`Xi?
`
`4,569,837
`
`United States Patent [191
`Suzuki et al.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,569,837
`Feb. 11, 1986
`
`[54] PHARMACEUTICAL PREPARATION FOR
`REMEDY OF PERIODONTAL DISEASE AND
`PROCESS FOR PRODUCTION THEREOF
`[75] Inventors: Yoshiki Suzuki; Hiroshi Ikura, both
`of Hino; Toshihide Noguchi, Tokyo;
`Katsunori Izumizawa, Yokohama;
`Shiro Kinoshita, deceased, late of
`Tokyo, all of Japan, by Kimiko
`Kinoshita, Atsuhiro Kinoshita, heirs
`[73] Assignee: Teijin Limited, Osaka, Japan
`[21] Appl. No.: 616,510
`[22] Filed:
`Jun. 1, 1984
`[30]
`Foreign Application Priority Data
`Jun. 1, 1983 [JP]
`Japan ................................ .. 58-95752
`
`[51] Int. Cl.‘ ..................... .. A61L 15/03; A61K 9/70;
`A61K 31; A6lK 74
`[52] U.S. Cl. ...................................... .. 424/28; 424/78;
`514/953; 514/900; 514/902; 514/784
`[58] Field of Search .................. .. 424/28, 78; 514/953,
`514/900, 902, 781
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,972,995 8/1976 Tsuk et al. .......................... .. 424/28
`4,292,299 9/ 1981 Suzuki et a1. ....................... .. 424/28
`
`FOREIGN PATENT DOCUMENTS
`
`822075 9/1969 Canada ................................ .. 424/28
`56-100714 8/1981 Japan ............ ..
`424/28
`WO80/009l6 5/1980 PCT Int’l Appl.
`424/21
`WO82/0ll29 4/1982 PCT Int’l Appl. ................. .. 424/28
`Primary Examiner-Shep K. Rose
`Attorney, Agent, or Firm—Sughrue, Mion, Zinn,
`Macpeak, and Seas
`ABSTRACT
`[57]
`A pharmaceutical preparation for remedy of periodon
`tal diseases, which is in the form of a film or sheet and
`is inserted in a periodontal pocket or gingiva, said phar
`maceutical preparation comprising a water-soluble pol
`ymeric substance having a Young’s modulus of 10 to
`250 Kg/rnrn2 as determined at a temperature of 25° C.
`and a relative humidity of 65%, and a viscosity of the
`2% aqueous solution of 5 to 30,000 CP as determined at
`20° C. and a medicinal agent for remedy of periodontal
`diseases. This pharmaceutical preparation can be pre
`pared by dissolving the above-mentioned water-soluble
`polymeric substance and medicinal agent in an organic
`solvent, casting the resultant solution, and removing the
`organic solvent by drying to obtain a pharmaceutical
`preparation in the form of a ?lm or sheet.
`
`9 Claims, No Drawings
`
`Par Pharm., Inc., et al.
`Exhibit 1011
`Page 001
`
`

`

`1
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`4,569,837
`
`PHARMACEUTICAL PREPARATION FOR
`REMEDY OF PERIODONTAL DISEASE AND
`PROCESS FOR PRODUCTION THEREOF
`
`2
`ever, none of these methods have a decisive curative
`effect.
`There has recently been reported a method in which
`an antibacterial agent is included in a strip composed of
`a water-insoluble polymeric substance such as poly
`(ethyl methacrylate) and the strip is placed in a peri
`odontal pocket to kill anaerobic bacteria in the peri
`odontal pocket [M. Addy et al.; J. Periodontol, Novem
`ber, 693 (1982].
`However, according to this method, since a water
`insoluble polymeric substance is used, if the strip is left
`in the periodontal pocket, a pain or irritation is readily
`given to the affected part.
`
`20
`
`25
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`The present invention relates to a pharmaceutical
`preparation for remedy of periodontal disease. More
`particularly, the present invention relates to a pharma
`ceutical preparation for remedy of periodontal diseases,
`which is in the form of a ?lm or sheet and is inserted in
`a periodontal pocket or gingiva, comprising a medicinal
`agent for remedy of periodontal diseases, which has
`medicinal actions such as a germicidal action, an anti
`bacterial action, a plaque-dissolving action and an anti
`in?ammatory action, and a water-soluble polymeric
`substance having a Young’s modulus of 10 to 250
`Kg/mmZ as determined at a temperature of 25° C. and a
`relative humidity of 65%, and a viscosity of 5 to 30,000
`CP as determined at 20° C. with respect to a 2% aque
`ous solution, and also relates to a process for the pro
`duction of this pharmaceutical preparation for remedy
`of periodontal diseases.
`2. Description of the Prior Art
`By “periodontal diseases” are meant all diseases oc
`curring in the periodontal tissue. The main periodontal
`diseases are gingivitis and chronic parodontitis margina
`lis. Chronic parodontitis marginalis is called “pyorrhea
`alveolaris”, and 50 to 70% of adults of thirty years and
`over suffer from this diseases more or less. Pyorrhea
`alveolaris is a chronic disease of the periodontal tissue,
`the main complaints of which are the drainage of pus
`from the gingiva, the absorption of an alveolar bone,
`and the relaxation and tottering of teeth. It was consid
`ered that the main causes of pyorrhea alveolaris are
`general disorders such as hormone imbalance, abnormal
`metabolism, and avitaminosis but it has recently been
`proved that the main cause of pyorrhea alveolaris is a
`local in?ammatory factor in the periodontal portion,
`which is due mainly to a plaque. The plaque is a bacte
`rial plexus of oral bacteria, which is deposited on a
`groove of the tooth surface, a boundary between teeth,
`or a boundary between a tooth and gingiva. In?amma
`tion is caused by bacteria in the plaque or metabolites
`thereof, and this in?ammation extends to the deep por
`tion to form a gingival pocket (periodontal pocket).
`This state is called pyorrhea alveolaris.
`As the curative means, there are adopted an antiphlo
`gistic treatment, a load relieving method, and a home
`curative treatment mainly for improving the affected
`gingival pocket and repairing the lesion of the periodon
`tal tissue. According to the antiphlogistic treatment, the
`affected gingival pocket is improved by curettage of the
`affected gingival pocket, removal of tartar or cutting or
`cauterization of the gingiva, and the affected part is
`rendered antiphlogistic by washing and the injection of
`a medicine. According to the load relieving method,
`occlusion is adjusted, and according to the home cura
`tive treatment, teeth are cleaned and gingiva is mas
`saged by the patient. Furthermore, there is adopted a
`method in which a solution of an antibacterial agent is
`irrigated or injected into the periodontal region and the
`interior of the periodontal pocket (see, for example, J.
`H. Hardy, H. N. Newman, I. D. Strahan; J. Clinical
`Periodontology, September 1982, pages 57-65). How
`
`SUMMARY OF THE INVENTION
`Accordingly, the object of the present invention is to
`provide a pharmaceutical preparation for remedy of
`periodontal diseases, which comprises a medicinal agent
`capable of killing bacteria and bacterial plexus in a peri
`odontal pocket, which are fundamental causes of peri
`odontal diseases, and of moderating in?ammation, and a
`polymeric substance which has a ?exibility such that
`the pharmaceutical preparation can be easily carried to
`the bottom of the periodontal pocket or the bottom of
`the gingival region as the boundary between the gingiva
`and teeth, such a water-solubility that, after the adminis
`tration, the pharmaceutical preparation does not give an
`alien solid feeling causing a pain or irritation in the
`affected part and such physical properties that the poly
`metic substance is dissolved in the body ?uid or extrud
`ate to form a viscous liquid which is present in the
`periodontal pocket or gingival region for a certain time
`so that the medicinal agent is made resident in a part
`within the periodontal pocket or gingival region to
`increase the curative effect.
`Another object of the present invention is to provide
`a process for the production of a pharmaceutical prepa
`ration for_ remedy of periodontal diseases.
`Other objects and advantages of the present invention
`will be apparent from the following description.
`In accordance with the present invention, there is
`I provided a pharmaceutical preparation for remedy of
`periodontal diseases, which is in the form of a ?lm or
`sheet and is inserted in a periodontal pocket or gingiva,
`comprising a water-soluble polymeric substance having
`a Young’s modulus of 10 to 250 Kg/mm2 as determined
`at a temperature of 25° C. and a relative humidity of
`65%, and a viscosity of the 2% aqueous solution of 5 to
`30,000 CP as determined at 20° C. and a medicinal agent
`for remedy of periodontal diseases.
`In accordance with the present invention, there is
`also provided a process for the production the above
`mentioned pharmaceutical preparation comprising the
`steps of dissolving a water-soluble polymeric substance
`having a Young’s modulus of 10 to 250 Kg/mm2 as
`determined at a temperature of 25° C. and a relative
`humidity of 65%, and a viscosity of the 2% aqueous
`solution of 5 to 30,000 CP as determined at 20° C. and a
`medicinal agent for remedying periodontal diseases.
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`Research was carried out with a view to developing
`a pharmaceutical preparation for remedy of periodontal
`diseases such as pyorrhea alveolaris, having a ?exibility
`such as facilitating the arrival of the pharmaceutical
`preparation at the bottom of a periodontal pocket or
`gingival region, being capable of retaining a medicinal
`
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`Par Pharm., Inc., et al.
`Exhibit 1011
`Page 002
`
`

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`25
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`30
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`4,569,837
`3
`agent in the pocket for a long time, and giving no pain
`or irritation to the affected part. As the result, it was
`found that this object can be attained by the above-men
`tioned pharmaceutical preparation which is in the form
`of a film or sheet and is inserted in a periodontal pocket
`or gingiva.
`According to the present invention, a water-soluble
`polymertic substance having a Young’s modulus of 10
`to 250 Kg/mm2 as determined at a temperature of 25° C.
`and a relative humidity of 65%, and a viscosity of the
`2% aqueous solution of 5 to 30,000 CP as determined at
`20° C. is used as the base.
`By the Young’s modulus referred to in the present
`invention is meant the initial Young’s modulus
`(Kg/mmz) obtained when a sheet or ?lm having a width
`of 1 cm and a thickness about 0.25 mm is pulled in a
`tensile strength tester at a chuck distance of 2 cm. When
`a water-soluble polymeric substance having such a ?ex
`ibility that the Young’s modulus is within the above
`mentioned range is used, the obtained pharmaceutical
`preparation has a characteristic wherein the pharma
`ceutical preparation is administered, it can easily be
`guided to the bottom of a periodontal pocket or gingival
`region. By the term “periodontal pocket” used herein is
`meant a gingival pocket, that is, a groove or clearance
`formed between the tooth and gingiva by perodontitis
`or the like. Furthermore, by the term “gingival region”
`is meant a groove or clearance formed in the boundary
`between the tooth and gingiva by arti?cial means or a
`gingival portion left after curettage of a periodontal
`pocket. It is preferred that the Young’s modulus of the
`polymeric substance be 15 to 200 Kg/mmz, especially
`20 to 180 Kg/mmz.
`It is indispensable in the present invention that the
`viscosity of a 2% aqueous solution of the water-soluble
`polymeric substance should be 5 to 30,000 CP as deter
`mined at 20° C. If a water-soluble polymeric substance
`having a viscosity included within the above-mentioned
`range is used, when the pharmaceutical preparation is
`inserted into a periodontal pocket or gingival region,
`the medicinal agent can be retained at an affected part
`of the periodontal pocket or gingival region for a long
`time without ?owing-out of the medicinal agent and the
`curative effect of the medicinal agent can be exerted at
`a high efficiency. It is preferred that the viscosity of the
`polymeric substance be 10 to 27,000 CP especially 20 to
`25,000 CP.
`The base used in the present invention has the above
`mentioned Young’s modulus and viscosity and is a
`water-soluble polymeric substance having such a water
`solubility that is soluble in saliva or secreting ?uid or
`exudate in the oral cavity. Since the pharmaceutical
`preparation of the present invention comprises this
`water-soluble polymeric substance, the surface portion
`of the preparation is dissolved by saliva or the like to
`some extent after administration into the periodontal
`pocket, and therefore, the preparation becomes adapted
`to the periodontal pocket or gingival region and the
`pain or irritation given to the affected part is moderated.
`This is one of advantage attained by the pharmaceutical
`preparation of the present invention.
`a
`It is preferred that the degree of the water solubilit
`be such that when the water-soluble polymeric sub
`stance is compression-molded into a disc having a
`weight of about 500 mg, a diameter of 13 mm and a
`thickness of about 3 to about 4 mm and the solubility is
`tested in water according to the dissolution test method
`of the Japanese Pharmacopoeia (the stirring speed is 200
`
`4
`rpm and the liquid amount is 500 ml), more than 50% of
`the polymeric substance is not dissolved out within 30
`minutes. When a water-soluble polymeric substance
`having a water solubility included within the above
`mentioned range, the residence property of the pharma
`ceutical preparation inserted in a gingival region or
`periodontal pocket is improved.
`As speci?c examples of the water-soluble polymeric
`substance, there can be mentioned lower alkyl ethers of
`cellulose such as methyl cellulose, hydroxyethyl cellu
`lose, hydroxypropyl cellulose, hydroxypropylmethyl
`cellulose and sodium carboxymethyl cellulose, water
`soluble vinyl polymers such as polyvinyl alcohol, poly
`vinyl pyrrolidone, polyacrylic acid, copolymers of
`methacrylic acid, styrene or a vinyl type ether mono
`mer with acrylic acid and salts thereof, and alginic acid
`and the salts thereof, gelatin, pullulan, starch deriva
`tives, and polyoxyalkylenes such as high molecular
`weight polyethylene glycol. Mixtures of two or more of
`these water-soluble polymeric substances also can be
`used. Among these water-soluble polymeric substances,
`lower alkyl ethers of cellulose, water-soluble vinyl pol
`ymers and mixtures of two or more of them are pre
`ferred, and methyl cellulose, sodium carboxymethyl
`cellulose, hydroxypropyl cellulose, hydroxypropyl
`methyl cellulose, polyvinyl pyrrolidone, a mixture of
`hydroxypropyl cellulose and polyacrylic acid or a salt
`thereof, and a mixture of hydroxypropyl cellulose and
`sodium carboxymethyl cellulose are especially pre
`ferred. Methyl cellulose, hydroxypropyl cellulose, and
`a mixture of hydroxypropyl cellulose and polyacrylic
`acid or its salt are most preferred.
`Any of medicines effective for prevention and rem
`edy of periodontal diseases can be used as the medicinal
`agent in the present invention. As the medicinal agent,
`there can be mentioned germicidal agents such as chlo
`rohexidine, thimerosal, silver protein, chloramine, io
`dine glycerin, iogloform, boric acid, paraformaldehyde,
`phenol, hexylres'orcinol, benzalkonium chloride, benze
`thonium
`chloride,
`chlorhexidine
`gluconate,
`phenododecium bromide, dequalinium chloride, cetyl
`pyridinium chloride, and povidone iodine, antibacterial
`agents such as tetracycline, tetracycline hydrochloride,
`benzylpenicillin, ampicillin, carbenicillin, acetylkitasa
`mycin, amoxyeillin, bacitracin, cephalotin sodium,
`cephaloridine, cephalexin, erythromycin, chloramphen
`icol, oxytetracycline hydrochloride, doxycycline hy
`drochloride, polymyxin B sulfate, fradiomycin sulfate,
`and gentamicin sulfate, plaque-dissolving agents such as
`lysozyme chloride, amylase, dextranase, and protease,
`anti-in?ammatory agents such as sulpyrine, antipyrine,
`aspirin, phenylbutazone, meprizole, oxyphenbutazone,
`fenbufen, mefenamic acid, flurbiprofen, diclofenac so
`dium, ketoprofen, naproxen, tiaramid hydrochloride,
`benzydamine hydrochloride, alclofenac, ibufenac, peri
`soxalcitrate,
`ibuprofen,
`indomethacin, aluminum
`?ufenamate, thinoridine hydrochloride, clofezone, dex
`amethasone, triamcinolone acetonide, and prostaglan
`din, antihistaminic agents such as diphenhydramine
`hydrochloride, chlorpheniramine maleate, and clemas
`tine, antibiotic agents such as sulfathiazole, sul?somi
`dine, and acetylfuratrizine, and local anesthetic agents
`such as ethyl aminobenzoate and tetracaine hydrochlo
`ride. Mixtures of two or more of these medicinal agents
`may be used. Among these medicinal agents, germicidal
`agents, antibacterial agents, plaque-dissolving agents,
`and anti-inflammatory agents are preferred.
`
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`Par Pharm., Inc., et al.
`Exhibit 1011
`Page 003
`
`

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`4,569,837
`5
`The amount used of the medicinal agent may be ap
`propriately determined according to the intensity of the
`pharmacological activity of the medicinal agent used
`and the symptoms of the periodontal disease to be
`treated.
`The pharmaceutical preparation of the invention of
`this application is inserted into the periodontal pocket
`or gingival region, and it is administered in the form of
`a ?lm or sheet. The size, shape, and thickness of the
`pharmaceutical preparation can be changed according
`to the condition of the periodontal disease to be treated
`and they are not particularly critical. Ordinarily, the
`size, shape, and thickness of the pharmaceutical prepa
`ration are changed according to the size of the peri
`odontal pocket of the patient or the condition of the
`gingiva. For example, a rectangular pharmaceutical
`preparation having a length of 5 to 15 mm, a width of
`0.5 to 2.0 mm, and a thickness of 0.1 to 0.4 mm is used
`for a periodontal pocket, and a rectangular pharmaceu
`tical preparation having a width of 10 to 30 mm, a
`20
`length of 20 to 60 mm, and a thickness of 0.1 to 0.3 mm
`is used for a gingival portion left after curettage of a
`periodontal portion.
`A plasticizer may be incorporated into the pharma
`ceutical preparation of the present invention according
`to need. As the plasticizer, there can be mentioned, for
`example, diethyl phthalate, dibutyl phthalate, butylph
`thalylbutyl glycolate, ethylene glycol, diethylene gly
`col, triethylene glycol, dipropylene glycol, polyethyl
`ene glycol, glycerin, and triacetin. When the plasticizer
`is incorporated, a pharmaceutical preparation in the
`form of a soft ?lm or sheet suitable for administration
`into a periodontal pocket is obtained.
`Furthermore, there may be used a colorant such as a
`tar pigment, a taste- or smell-improving agent such as
`citric acid, fumaric acid, tartaric acid or menthol, and
`an antioxidant such as butylhydroxytoluene, propyl
`gallate or butylhydroxyanisole, according to need.
`The pharmaceutical preparation of the present inven
`tion can be produced by dissolving the above-men
`tioned water-soluble polymeric substance and the
`above-mentioned medicinal agent for remedy of peri
`odontal diseases in a solvent, casting the obtained solu
`tion and removing the solvent by drying.
`Any of these solvents capable of dissolving the re
`spective components of the pharmaceutical preparation
`therein and inert to these components can be used in the
`present invention. For example, there can be mentioned
`alcohol type solvents such as methanol, ethanol, and
`isopropanol; ketone type solvents such as acetone and
`methylethyl ketone; chlorinated hydrocarbon type sol
`vents such as methylene chloride, dichloroethane and
`l,1,l-trichloroethane; and water. A mixture of two or
`more of these solvents can be used. An alcohol type
`solvent is preferred among these solvents.
`It is preferred that the water-soluble polymeric sub
`stance be dissolved in the solvent in such an amount that
`the concentration is 3 to 50%, especially 5 to 40%,
`though the preferred concentration suitable for the
`production differs to some extent according to the mo
`lecular weight of the water-soluble polymeric sub
`stance. The medicinal agent is dissolved in an amount
`determined according to the intensity of the pharmaco
`logical activity of the medicinal agent. A plasticizer, a
`colorant, a taste- or smell-improving agent, and an anti
`oxidant are dissolved in the solvent according to need.
`When the formed solution contains insoluble solids,
`they are removed by ?ltration, and it is preferred that
`
`40
`
`6
`the solution be allowed to stand still or be in vacuo for
`a while so that the solution is suf?ciently deaerated. The
`solution is then cast. This casting is accomplished ac
`cording to a method in which the solution is uniformly
`cast on a metal plate or glass plate, or by using a drum
`type ?lm preparing apparatus customarily adopted in a
`solution casting method for production of ?lms or an
`endless belt type ?lm preparing apparatus.
`Then, the solvent is removed by drying. Drying is
`accomplished by air-drying, standing at room tempera
`ture or heating, or according to the drying method
`customarily adopted in a ?lm preparing apparatus. In
`view of the stability of the base and medicinal agent, it
`is preferred that drying the accomplished by air-drying
`or standing at room temperature. Thus, a pharmaceuti
`cal preparation in the form of a ?lm or sheet is obtained.
`The ?lm or sheet is cut into a desired shape. Thus, the
`intended pharmaceutical preparation is obtained.
`Methods other than the above~mentioned method
`may be adopted for the production of a pharmaceutical
`preparation in the form of a ?lm or sheet according to
`the present invention. For example, there may be
`adopted a calender method in which a mixture of a
`water-soluble polymeric substance and a medicinal
`agent is rolled between heated rolls to form a ?lm or
`sheet, and a melt extrusion method in which a mixture
`of a water-soluble polymeric substance and a medicinal
`agent is heated and melted and the melt is extruded by
`a screw to form a ?lm or sheet.
`The obtained pharmaceutical preparation in the form
`of a ?lm or sheet may be sterilized by heating or by
`ethylene oxide or radiation.
`As described in detail hereinbefore, according to the
`present invention, a pharmaceutical preparation in the
`form of a film or sheet which comprises a water-soluble
`polymeric substance having speci?c Young’s modulus
`and viscosity and a medicinal agent for remedy of peri
`odontal diseases, and this pharmaceutical preparation
`has a ?exibility such that it can be easily guided to the
`bottom of a periodontal pocket or gingival region and a
`property such that the medicinal agent can be retained
`within a local part of a periodontal pocket or gingival
`region and the pharmaceutical preparation moderates
`pains and irritations given to affected parts. Thus, excel
`lent effects can be attained according to the present
`invention.
`
`EXAMPLES
`The present invention will now be described in detail
`with reference to, but is by no means limited to, the
`following Examples.
`
`Example 1
`100 g of hydroxypropyl cellulose having a viscosity
`of 2080 C? as determined at 20° C. (2% aqueous solu
`tion) and a Young’s modulus of about 40 kg/mm2 as
`determined at a temperature of 25° C. and relative hu
`midity of 65% 1 g of chlorhexidine gluconate were
`gradually incorporated and dissolved with stirring in
`1000 g of ethanol. The solution was allowed to stand
`still overnight to effect deaeration, the solution was cast
`on a clean glass plate, and the thickness was uniformal
`ized by using a doctor knife. The cast solution was
`air-dried and forcibly dried at 40° C. to obtain a pharma
`ceutical preparation in the form of a ?lm having a thick
`ness of 0.26 mm. The concentration of chlorhexidine
`gluconate in the pharmaceutical preparation was
`0.98%. The Young’s modulus of the ?lm was about 40
`
`5
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`Page 004
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`7
`Kg/mm2 as determined at a temperature of 25° C. and a
`relative humidity of 65%.
`Example 2
`100 g of hydroxypropyl cellulose having a viscosity
`of 2080 C? as determined at 20° C. (2% aqueous solu
`tion) and a Young’s modulus of 48.2 Kg/mm2 as deter
`mined at a temperature of 25° C. and a relative humidity
`of 65% and 1.0 g of chlorhexidine were gradually incor
`porated and dissolved with stirring into 1000 g of etha
`nol. The solution was allowed to stand still overnight to
`effect deaeration and cast on a clean glass plate. The
`thickness was uniformalized by using a doctor knife, .
`and the cast solution was air-dried and forcibly dried at
`40° C. to obtain a pharmaceutical preparation in the
`form of a ?lm having a thickness of 0.26 mm. The con
`centration of chlorhexidine in the obtained pharmaceu
`tical preparation was 0.98%.
`Example 3
`20
`80 g of hydroxypropyl cellulose having a viscosity of
`2080 CP as determined at 20° C. (2% aqueous solution)
`and a Young’s modulus of 48.2 Kg/mm2 as determined
`at a temperature of 25° C. and a relative humidity of
`25
`65% and 20 g of tetracycline hydrochloride were grad
`ually incorporated and dissolved with stirring in 960 g
`of ethanol. The solution was allowed to stand still over
`night to effect deaeration, and the solution was cast on
`a clean glass plate and the thickness was uniformalized
`by using a doctor knife. The cast solution was air-dried
`and forcibly dried at 40° C. to obtain a pharmaceutical
`preparation in the form of a ?lm having a thickness of
`0.25 mm. The concentration of tetracycline hydrochlo
`ride in the pharmaceutical preparation was 19.8%.
`Example 4
`100 g of hydroxypropyl cellulose having a viscosity
`of 200 GP as determined at 20° C. (2% aqueous solu
`tion) and a Young’s modulus of 39.1 Kg/mm2 as deter
`mined at a temperature of 25° C. and a relative humidity
`of 65% and l g of cetyl pyridinium chloride were grad
`ually incorporated and dissolved with stirring in 960 g
`of ethanol. The solution was allowed to stand still over
`night to effect deaeration and cast on a clean glass sheet.
`The thickness was uniformalized by using a doctor knife
`and the cast solution was air-dried and forcibly dried at
`40° C. to obtain a pharmaceutical preparation in the
`form of a ?lm having a thickness of 0.27 mm. The con
`centration cetyl pyridinium chloride in the pharmaceu
`tical preparation was 1.0%.
`Example 5
`75 g of hydroxypropyl cellulose having a viscosity of
`200 C? as determined at 20° C. (2% aqueous solution)
`and a Young’s modulus of 39.1 Kg/mm2 as determined
`at a temperature of 25° C. and a relative humidity of
`65%, 25 g of sodium polyacrylate and 10 g of amoxycil
`lin were gradually incorporated and dissolved with
`stirring in 960 g of an aqueous solution of ethanol. The
`60
`solution was allowed to stand still overnight to effect
`deaeration and cast on a clean glass plate, the thickness
`was uniformalized by using a doctor knife, and the cast
`solution was air-dried and forcibly dried at 40° C. to
`obtain a pharmaceutical preparation in the form of a
`?lm having a thickness of 0.28 mm. The concentration
`of amoxycillin in the pharmaceutical preparation was
`8.5%.
`
`65
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`4,569,837
`
`8
`Example 6
`90 g of methyl cellulose having a viscosity of 4160 CP
`as determined at 20° C. (2% aqueous solution) and a
`Young’s modulus of 125 Kg/mm2 as determined at a
`temperature of 25° C. and a relative humidity of 65%
`and 10 g of fradiomycin sulfate were incorporated and
`dissolved with stirring in 1000 g of ethanol, and the
`solution was allowed to stand still overnight to effect
`deaeration. The solution was cast on a clean glass plate,
`the thickness was uniformalized by using a doctor knife,
`and the cast solution was air-dried and forcibly dried at
`40° C. to obtain a pharmaceutical preparation in the
`form of a ?lm having a thickness of 0.20 mm. The con
`centration of fradiomycin sulfate in the pharmaceutical
`preparation was 9.8%.
`Example 7
`95 g of methyl cellulose having a viscosity of 4160 CP
`as determined at 20° C. (2% aqueous solution) and a
`Young’s modulus of 125 Kg/mm2 as determined at a
`temperature of 25° C. and a relative humidity of 65%
`and 5 g of ketoprofen were gradually incorporated and
`dissolved with stirring in 1000 g of ethanol. The solu
`tion was allowed to stand still overnight to effect deaer
`ation and cast on a clean glass plate. The thickness was
`uniformalized by using a doctor knife and the cast solu
`tion was air-dried and forcibly dried at 40° C. to obtain
`a pharmaceutical preparation in the form of a ?lm hav
`ing a thickness of 0.29 mm. The concentration of keto
`profen in the pharmaceutical preparation was 4.8%.
`Example 8
`95 g of methyl cellulose having a viscosity of 9670 CP
`as determined at 20° C. (2% aqueous solution) and a
`Young’s modulus of 130 Kg/mm2 as determined at a
`temperature of 25° C. and a relative humidity of 65%
`and 5 g of indomethacin were gradually incorporated
`and dissolved with stirring in 960 g of ethanol. The
`solution was allowed to stand still overnight to effect
`deaeration, the solution was cast on a clean glass plate,
`and the thickness was uniformalized by using a doctor
`knife. The cast solution was air-dried and forcibly dried
`at 40° C. to obtain a pharmaceutical preparation in the
`form of a ?lm having a thickness of 0.25 mm. The con
`centration of indomethacin in the pharmaceutical prep
`aration was 5.0%.
`
`Example 9
`90 g of methyl cellulose having a viscosity of 15 CP
`as determined at 20° C. (2% aqueous solution) and a
`Young’s modulus of 151 Kg/mm2 as determined at a
`temperature of 25° C. and a relative humidity of 65%,
`10 g of sodium carboxymethyl cellulose and 1 part by
`weight of clemastine fumarate were gradually incorpo
`rated and dissolved with stirring in 960 g of 90% aque
`ous ethanol. The solution was allowed to stand still
`overnight to effect deaeration, the solution was cast on
`a clean glass plate, and the thickness was uniformalized
`by using a doctor knife. The cast solution was air-dried
`and forcibly dried at 40° C. to obtain a pharmaceutical
`preparation in the form of a ?lm having a thickness of
`0.30 mm. The concentration of clemastine fumarate in
`the pharmaceutical preparation was 1.0%.
`Example 10
`100 g of hydroxyethyl cellulose having a viscosity of
`5140 CP as determined at 20° C. (2% aqueous solution)
`
`Par Pharm., Inc., et al.
`Exhibit 1011
`Page 005
`
`

`

`4,569,837
`9
`and a Young’s modulus of 50 Kg/mm2 as determined at
`a temperature of 25° C. and a relative humidity of 65%
`and l g of ethyl aminobenzoate were gradually incorpo
`rated and dissolved with stirring in 960 g of ethanol.
`The solution was allowed to stand still overnight to
`effect deaeration, cast on a clean glass plate, and the
`thickness was uniformlaized by using a doctor knife.
`The cast solution was air-dried and forcibly dried at 40°
`C. to obtain a pharmaceutical preparation in the form of
`a ?lm having a thickness of 0.30 mm. The concentration
`of ethyl aminobenzoate in the pharmaceutical prepara
`tion was 0.95%.
`
`Example 1 l
`100 g of hydroxyethyl cellulose having a viscosity of
`5140 CP as determined at 20° C. (2% aqueous solution)
`and a Young’s modulus of 50 kg/mm2 as determined at
`a temperature of 25 ° C. and a relative humidity of 65 %
`and l g of dequalinium chloride were gradually incor
`porated and dissolved with stirring in 960 g of ethanol.
`The solution was allowed to stand still overnight to
`effect deaeration, cast on a clean glass plate, and the
`thickness was uniformalized by using a doctor knife and
`the cast solution was air-dried and forcibly dried at 40°
`C. to obtain a pharmaceutical preparation in the form of
`a ?lm having a thickness of 0.26 mm. The concentration
`of dequalinium chloride in the pharmaceutical prepara
`tion was 0.95%.
`
`20
`
`Example 12
`100 g of hydroxypropyl cellulose having a viscosity
`of 2080 CP as determined at 20° C. (2% aqueous solu
`tion) and a Young’s modulus of 48.2 kg/mm2 as deter
`mined at a temperature of 25 ° C. and a relative humidity
`of 65% and 1.0 g of chlorhexidine gluconate were grad
`ually incorporated and dissolved with stirring into 1000
`g of water. The solution was deaerated in vacuo for 2
`hrs and cast on a clean glass plate. The thickness was
`uniformalized by using a doctor knife, and the cast
`solution was air-dried and forcibly dried at 40° C. to
`obtain a pharmaceutical preparation on the form of a
`?lm having a thickness of 0.25 mm. The concentration
`of chlorhexidine in the obtained pharmaceutical prepa- -
`ration was 0.98%.
`
`35
`
`Example 13
`Filmy pharmaceutical preparations prepared in Ex
`amples l and 2 were cut into a width of 1 mm and a
`length of 10 mm, and cut pieces were inserted in peri
`odontal pockets of 10 patients suffering from pyorrhea
`alveolaris and the pain, drainage of pus, swelling, ?are,
`fever, and loose feeling'were checked before and after
`the administration. Effects were observed in all