(12) United States Patent
`Sako et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,562,375 B1
`May 13, 2003
`
`USO06562375B1
`
`STABLE PHARMACEUTICAL
`COMPOSITION FOR ORAL USE
`
`Inventors:
`
`Kazuhiro Sako, Shizuoka (JP);
`T0y0hir0 Sawada, Shizuoka (JP);
`Keiichi Yoshihara, Shizuoka (JP);
`Tatsunobu Yoshioka, Shizuoka (JP);
`Shunsuke Watanabe, Shizuoka (JP)
`
`Yamanouchi Pharmaceuticals, Co.,
`Ltd., Tokyo (JP)
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`Appl. No.:
`Filed:
`
`09/629,405
`
`Aug. 1, 2000
`
`Related U.S. Application Data
`Provisional application No. 60/147,222, filed on Aug. 4,
`1999.
`
`Int. Cl.7 ..
`U.S. Cl.
`..
`
`......................... .. A61K 9/14; A61K 9/20
`................... .. 424/486; 424/464; 424/465;
`424/482
`Field of Search ............................... .. 424/484, 473,
`424/468, 469, 470, 486, 464, 465, 482
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,859,470 A
`5,021,053 A
`5,532,003 A
`5,650,170 A
`6,117,453 A
`
`*
`*
`*
`
`8/1989
`6/1991
`7/1996
`7/1997
`9/2000
`
`Guittard et al.
`Barclay et al.
`Wong et al.
`.............. .. 424/473
`Wright et al.
`.
`424/467
`Seth et al.
`................ .. 424/486
`
`FOREIGN PATENT DOCUMENTS
`
`O 661 045 A1
`661045 A1 *
`901787
`901787 A1 *
`4—346929
`5—92918
`
`9/1993
`7/1995
`3/1999
`3/1999
`12/1992
`4/1993
`
`.......... .. A61K/9/22
`.......... .. A6lK/9/22
`
`.......... .. A6 1K/9/28
`
`OTHER PUBLICATIONS
`
`A pamphlet of Polyox by Union Carbide.
`A pamphlet of PEO by Seitetsu Chemical lnd.
`English translation of p. 6 of the PEO pamphlet by Seitetsu
`Chemical Ind.
`*
`
`cited by examiner
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Robert M. Joynes
`(74) Attorney, Agent, or Firm—Townsend and Townsend
`and Crew LLP
`
`(57)
`
`ABSTRACT
`
`The present invention is to provide a stable pharmaceutical
`composition for oral use and preparation thereof in which
`changes are prevented in drug release at stored even under
`the exposure to light by adding yellow ferric oxide and/or
`red ferric oxide in a matrix type sustained—release prepara-
`tion eontaining a drug, hydrophilic base, and polyethylene
`oxide. The present invention is to further provide a method
`for preventing changes in drug release at stored under the
`exposure to light in a matrix type sustained—release prepa-
`ration containing a drug, hydrophilic base, and polyethylene
`oxide. The quality assurance period of the product can be
`prolonged and the product value can be improved by the
`present invention.
`
`21 Claims, N0 Drawings
`
`TEVA EXHIBIT 1041
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`RBP_TEVA05017990
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`TEVA EXHIBIT 1041
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`

`
`US 6,562,375 B1
`
`1
`STABLE PHARMACEUTICAL
`COMPOSITION FOR ORAL USE
`
`CROSS-REFERENCES TO RELATED
`APPLICATIONS
`
`This application claims priority to U.S. Ser. No. 60/147,
`222, filed Aug. 4, 1999, the disclosure of which is herein
`incorporated by reference in its entirety.
`
`TECHNICAL FIELD
`
`The present invention relates to a solid pharmaceutical
`composition for oral use with that prevents changes in drug
`release in a matrix type sustained-release preparation con-
`taining polyethylene oxide. The present
`invention also
`relates to a method of producing a stable solid pl1arn1aceu-
`tical composition for oral use that prevents changes in drug
`release in a matrix type sustained-release preparation con-
`taining polyethylene oxide. Furthermore, the present inven-
`tion relates to a method of preventing changes in drug
`release in a matrix type sustained-release preparation con-
`taining polyethylene oxide.
`
`BACKGROUND OF THE INVENTION
`
`Various sustained-release preparations have been devel-
`oped in the field of pharmaceuticals, and release of the drug
`from this preparation is an important factor of preparation
`design in terms of in vivo absorption of the drug when the
`preparation is orally taken by the patient. Stable drug release
`from the preparation, wherein the release rate is steady with
`few changes, is essential, from the time the pharmaceutical
`preparation is made until it is transported, stored and orally
`taken by the patient.
`Incidentally, various sustained-release preparations have
`been made by researchers affiliated with the applicant of the
`present patent. It goes without saying that, as with the main
`agent, in sustained-release preparations, the polymer sub-
`stance that forms a hydrogel as the main base in particular
`must be also stable in order to maintain the rate with which
`
`the drug is released (WO 94/06414).
`Polyethylene oxide can be mentioned as one polymer
`substance that forms a hydrogel. This substance is a water-
`soluble thermoplastic resin in the form of white powder or
`granules that
`is obtained by polymerization of ethylene
`oxide and that has a molecular weight of from several
`100,000s to several 1,000,000s. It is known that because it
`is extremely sticky when wet, sustained-release preparations
`containing this substance show good drug release within the
`digestive tract. Although it is a known fact that the erosion
`rate of the polymer substance or a matrix made from said
`substance has a strong elfect on this drug release rate, the
`factors that affect stability of the polyethylene oxide that is
`used as the base of sustained-release preparations, particu-
`larly factors that affect drug release, are not known.
`The present inventors performed studies of polyethylene
`oxide as the base of sustained-release preparations, and they
`discovered that erosion of the matrix made from polyethyl-
`ene oxide is accelerated when the preparation is preserved
`under exposure to light. As a result, the rate with which the
`drug is released increases over time, and there are changes
`in drug release. Therefore, the prevention of changes in drug
`release is desired.
`
`DISCLOSURE OF THE INVENTION
`
`The present invention provides a stable preparation that
`shows no changes in drug release in matrix type sustained-
`
`2
`release preparations containing polyethylene oxide at the
`preserved period under exposure to light. Moreover,
`the
`present invention provides a method of producing a stable
`preparation with which there are no changes in drug release
`in matrix type sustained-release preparations containing
`polyethylene oxide. The present invention further provides a
`method with which changes in drug release are prevented in
`matrix type sustained-release preparations containing drugs
`and polyethylene oxide at the preserved period under expo-
`sure to light.
`the present inventors
`Under the above circumstances,
`discovered that changes in drug release can be prevented at
`the preserved period even under exposure to light, if yellow
`ferric oxide or red ferric oxide, which has been used as
`coloring agent among pharmaceutical additives, was added
`by physical mixing in an amount of 10 wt %, which is in
`excess of the amount used as coloring agent (which said
`amount is very small and not more than 0.1 wt %) with drug
`and polyethylene oxide in a matrix type sustained-release
`preparation containing polyethylene oxide and was made
`into a tablet. The present inventors completed the present
`invention upon discovering that changes in drug release
`from a preparation can be prevented by adding yellow ferric
`oxide or red ferric oxide not only by means of physical
`mixing, but also by means of coating a tablet.
`The mechanism of preventing effect by adding yellow
`ferric oxide or red ferric oxide has not been discerned, but
`it is thought that the mechanism is not just a prevention of
`the degradation of polyethylene oxide by exposure to light.
`That
`is,
`the present
`inventors found that
`titanium oxide
`absorbing light at the wavelength of not more than 400 nm
`(UV) and reflecting light at the wavelength of not less than
`400 nm, or medicinal carbon absorbing light at all wave-
`length (broad range) cannot reduce changes in drug release
`in a matrix type tablet consisting of polyethylene oxide and
`polyethylene glycol even if it was added by physical mixing
`in an amount of 10 wt %, for example, per tablet weight. The
`anticipation that the stability against light can be performed
`if the wavelength (color) affecting the influence on the
`stability of polyethylene oxide is blocked. To the contrary,
`changes in drug release on the tablet could not be reduced
`even if all visual light was blocked by reflecting or by
`absorbing. This result suggested that the special wavelength
`affecting the inlluence on the stability in the visual region
`did not exist because the color of solution dissolving poly-
`ethylene oxide was colorless and clear. It had no absorbed
`wavelength in the visual region. If the special wavelength
`affecting the influence on the stability in visual region
`existed, the additive reflecting all visual light (white color)
`or the additive absorbing all visual light (black color) was
`anticipated to be able to make the stable preparation with no
`changes in drug release. To the contrary, it was an unex-
`pected result. Therefore, although there is/are unknown
`factor(s) affecting changes in drug release besides light, the
`results suggested that yellow ferric oxide, which absorbs
`light at wavelength of not more than 400 nm and reflects
`light at wavelength of not less than 400 nm, or red ferric
`oxide, which absorbs light at wavelength of not more than
`560 nm and reflects light at wavelength of not less than 560
`run, could be added in an effective amount in a matrix type
`sustained-release preparation containing at least polyethyl-
`ene oxide can reduce changes in drug release although the
`factor(s) affccting changes in drug release by compounding,
`by physical mixing or by coating tablet, may exist.
`Accordingly, the present invention relates to 1) a stable
`pharmaceutical composition for oral use comprising a yel-
`low ferric oxide and/or a red ferric oxide in an effective
`
`TEVA EXHIBIT 1041
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`RBP_TEVA05017991
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`TEVA EXHIBIT 1041
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`

`
`US 6,562,375 B1
`
`3
`amount to stabilize a matrix type sustained-release prepara-
`tion containing a drug, hydrophilic base, and polyethylene
`oxide. Moreover,
`the present
`invention relates to 2) the
`stable pharmaceutical composition for oral use according to
`the above-mentioned 1), wherein the amount of yellow ferric
`oxide and/or red ferric oxide added is not less than 0.3 wt %
`per tablet weight. The present invention also relates to 3) the
`stable pharmaceutical composition for oral use according to
`the above-mentioned 1) or 2), wherein the amount of yellow
`ferric oxide added is present
`from 1 to 20 wt % per
`preparation weight. In addition, the present invention relates
`to 4) the stable pharmaceutical composition for oral use
`according to the above-mentioned 1) or 2), wherein the
`amount of red ferric oxide added is present from 5 to 20 wt
`% per preparation weight. The present invention relates to 5)
`a method of producing a stable pharmaceutical composition
`for oral use comprising adding yellow ferric oxide and/or
`rcd fcrric oxide in an amount cffcctivc to stabilize a matrix
`type sustained-release preparation to a mixture drug, hydro-
`philic base, and polyethylene oxide. Moreover, the present
`invention relates to 6) the method of producing a stable
`pharmaceutical composition for oral use according to the
`above-mentioned 5), wherein yellow ferric oxide and/or red
`ferric oxide is added by one or two or more means selected
`from film coating, granulation and mixing. Furthermore, the
`present invention relates to 7) the method of producing a
`stable pharmaceutical composition for oral use according to
`the above-mentioned 5) or 6), wherein the amount of yellow
`ferric oxide and/or red ferric oxide added is not less than 0.3
`wt % per tablet weight. The present invention also relates to
`8) a method of preventing changes in drug release by adding
`yellow ferric oxide and/or red ferric oxide in an amount
`effective to stabilize a matrix type sustained-release prepa-
`ration containing a drug, hydrophilic base, and polyethylene
`oxide. The present invention further relates to 9) a use of
`yellow ferric oxide and/or red ferric oxide in an amount
`effective to stabilize a matrix type sustained-release prepa-
`ration containing a drug, hydrophilic base, and polyethylene
`oxide in order to prevent changes in drug release.
`is a
`it
`The term ‘a matrix preparation’ signifies that
`preparation that contains polyethylene oxide as a base of a
`sustained-release preparation, wherein a drug and hydro-
`philic base are dispersed in said polyethylene oxide.
`There are no special restrictions to the drug used in the
`present invention as long as it is a drug used in sustained-
`release preparations that contain polyethylene oxide as one
`of its base components. Anti-inflammatory, antipyretic anti-
`spasmodics or analgesics such as indomethacin, diclofenac,
`diclofenac sodi11m, codeine,
`ibuprofen, phenylbutazone,
`oxyplienbutazone, mepirizole, aspirin, ethenzamide,
`acetaminophen, aminopyrine, phenacetin, butylscopolamine
`bromide, morphine, etomidoline, pentazocine, fenoprofen
`calcium, naproxen, selecxip, valdecxip, and tolamadol, anti-
`rheumatism drugs such as etodolac, anti-tuberculoses drugs
`such as isoniazide and ethambutol hydrochloride, cardio-
`vascular drugs such as isosorbide dinitrate, nitroglycerin,
`nifedipine, barnidipine hydrochloride, nicardipine
`hydrochloride, dipyridamole, amrinone,
`indenolol
`hydrochloride, hydralazine hydrochloride, methyldopa,
`furosemide, spironolactone, guanethidine nitrate, reserpine,
`amosulalol hydrochloride,
`lisinopril, metoprolol,
`pilocarpine, and talcetin, antipsychotic drugs such as chlo-
`rpromazine hydrochloride, amitriptyline hydrochloride,
`nemonapride, haloperidol, moperone hydrochloride,
`perphenazine, diazepam,
`lorazepam, chlorodiazepoxide,
`adinazolam, alprazolam, methylphenidate, myrnasipran,
`peroxetin, risperidone, and sodium valproate, anti-emetics
`
`4
`such as metoclopramide, lamocetron hydrochloride, granis-
`etron hydrochloride, ondansetron hydrochloride, and aza-
`cetron hydrochloride, antihistamines such as chlorphe-
`niramine maleate and diphenhydramine hydrochloride,
`vitamins suh as thiamine nitrate,
`tocopherol acetate,
`cycothiamine, pyridoxal phosphate, cobarnamide, ascortic
`acid, and nicotinamide, anti—gout drugs such as allopurinol,
`colchicine, and probenecide, anti-Parkinson’s disease drugs
`such as levodopa and selegrine, sedatives and hypnotics
`such as amobarbital, bromuralyl urea, midazolam, and chlo-
`ral hydrate, antineoplastics such as fluorouracil, carmofur,
`acralvidine hydrochloride, cyclophosphamide, and thiodepa,
`anti-allergy drugs such as pseudoephedrine and terfenadine,
`decongestants such as plienylpropanolamine and
`ephedorine, diabetes mellitus drugs such as acetohexamide,
`insulin, tolbutamide, desmopressin, and glipizide, diuretics
`such as hydrochlorothiazide, polythiazide, and triamterene,
`bronchodilatos such as aminophyllinc, formotcrol fumaratc,
`and theophylline, antitussives such as codeine phosphate,
`noscapine, dimorfan phosphate, and dextromethorphan,
`anti-arrhythmics, such as quinidine nitrate, digitoxin, pro-
`pafenone hydrochloride, and procainamide, topical anesthet-
`ics such as ethyl aminobenzoate, lidocaine, and dibucaine
`hydrochloride, anti-convulsants such as phenytoin,
`ethosuximide, and primidone, synthetic glucocorticoids
`such as hydrocortisone, prednisolone,
`triamcinolone, and
`betametliasone, antiulceratives such as famotidine, raniti-
`dine hydrochloride, cimetidine, sucralfate, sulpiride,
`teprenone, plaunotol, 5-aminosalicylic acid, sulfasalazine,
`omeprazole, and lansoprazol, central nervous system drugs,
`such as indeloxazine, idebenone, thiapride hydrochloride,
`bifemelane hydrocide, and calcium homopantothenate, anti-
`hyperlipoproteinemics such as pravastatin sodium,
`simvastatin, lovastatin, and atorvastatin, antibiotics such as
`ampicillin hydrochloride, phthalylsulfacetamide, cefotetan,
`and josamycin, BPH therapeutic agents such as tamsulosin
`hydrochloride, doxazosin mesylate, and terazosin
`hydrochloride, drugs affecting uterine motility such as
`branylcast, zafylcast, albuterol, ambroxol, budesonide, and
`reproterol, peripheral circulation improvers of prostaglandin
`I derivatives such as beraprost sodium, anticoagulants,
`hypotensives, agents for treatment of cardiac insufficiency,
`agents used to treat the various complications of diabetes,
`peptic ulcer therapeutic agents, skin ulcer therapeutic agents,
`agents used to treat hyperlipemia, tocolytics, etc., can be
`mentioned as such a drug. The drug can be used in its free
`form or as a pharmaceutically acceptable salt. Moreover, one
`or a combination of two or more drugs can be used in the
`present invention.
`Thcrc arc no particular restrictions to the ratio in which
`the drug used in the present invention is added as long as it
`is the amount that is normally used pharmacologically for
`treatment or for prophylaxis, but it is preferably 85 wt % or
`less, particularly 80 wt % or less, of the entire preparation.
`There are no special restrictions to the polyethylene oxide
`used in the present inventions as long as it can control
`release of the drug from the preparation. Examples of this
`polyethylene oxides (also referred to below as PEO) include
`POLYOX® WSR-303 (viscosity-average molecular weight:
`7,000,000, viscosity: 7,500—10,000 cP (centipoise: 1% aque-
`ous solution at 25° C.)), POLYOX® WSR Coagulant
`(viscosity-average molecular weight: 5,000,000, viscosity:
`5,500—7,500 cP (1% aqueous solution at 25° C.)),
`POLYOX® WSR-301 (viscosity-average molecular weight:
`4,000,000, viscosity: 1,650—5,500 CF (1% aqueous solution
`at 25° C.)), and POLYOX® WSRN-60K (viscosity-average
`molecular weight: 2,000,000, viscosity: 2,000—4,000 CP (2%
`
`TEVA EXHIBIT 1041
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05017992
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`TEVA EXHIBIT 1041
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`
`

`
`,_
`3
`
`US 6,562,375 B1
`
`aqueous solution at 25° C.)) (all made by Union Carbide),
`ALKOX® E-75 (viscosity-average molecular weight:
`2,000,000 to 2,500,000, viscosity: 40-70 cP (0.5% aqueous
`solution at 25° C.)), ALKOX® E-100 (viscosity-average
`molecular weight: 2,500,000 to 3,000,000, viscosity:
`90-110 cP (0.5% aqueous solution at 25° C.)), ALKOX®
`E-130 (viscosity-average molecular weight: 3,000,000 to
`3,500,000, viscosity: 130-140 cP (0.5% aqueous solution at
`25° C.)), ALKOX® E-160 (viscosity-average molecular
`weight: 3,600,000 to 4,000,000, viscosity: 150-160 cP
`(0.5% aqueous solution at 25° C.)), and ALKOX® E-240
`(viscosity-average molecular weight: 4,000,000 to 5,000,
`000, viscosity: 200-240 cP (0.5% aqueous solution at 25°
`(all made by Mcisci Kagaku (Chcmical)), PEO-8
`(viscosity-average molecular weight: 1,700,000 to 2,200,
`000, viscosity: 20-70 cP (0.5% aqueous solution at 25 ° C.)),
`PEO-15 (viscosity-average molecular weight: 3,300,000 to
`3,800,000, viscosity: 130-250 cP (0.5% aqueous solution at
`25° C.)), and PEO-18 (viscosity-average molecular weight:
`4,300,000 to 4,800,000, viscosity: 250-480 cP (0.5% aque-
`ous solution at 25°
`(all made by Seitetsu Kagaku
`(Chemical Industry) Co., Ltd.), etc. Moreover, the PEO used
`in the present invention preferably has a high viscosity at the
`time of gelling, or has a high viscosity-average molecular
`weight. This PEO is preferably, for instance, one with a
`viscosity of 2,000 cP or higher as an aqueous 2% solution
`(25° C.) or one that has a viscosity-avcragc molecular
`weight of 2,000,000 or higher. One or a combination of two
`or more with different molecular weights, grades, etc., can
`be used as the PEO of the present invention.
`There are no special restrictions to the ratio of polyeth-
`ylene oxide added in the present invention as long as it is the
`amount with which release of drug from the preparation
`usually can be controlled. However, 10 to 95 wt % in terms
`of total preparation, or 15 to 90 wt % in terms of total
`preparation, is preferably used. The amount of PEO added is
`preferably 70 mg or more, particularly 100 mg or more, per
`1 unit preparation.
`The present invention relates to a pharmaceutical com-
`position for oral use, wherein yellow ferric oxide and/or red
`ferric oxide are/is added in a matrix type sustained-release
`preparation containing a drug, hydrophilic base, and poly-
`ethylene oxide. The mechanism of this preparation is dis-
`cussed in WO 94/06414. It is said that because the prepa-
`ration absorbs water retained in the upper digestive tract and
`thereby almost completely gels (not less than 70%, prefer-
`ably not less than 80%) and moves to the lower digestive
`tract as the surface of the preparation is being worn away
`with drug being released by further erosion,
`the drug is
`continually and thoroughly released and absorbed. As a
`result, sustained release performance is realized, even in the
`colon where there is little water.
`
`There are no particular restrictions to said hydrophilic
`base as long as it can be dissolved before the polyethylene
`oxide used in the present invention gels. The amount of
`water needed to dissolve 1 g of this hydrophilic base is
`preferably 5 ml or less (at 20:5° C.), more preferably 4 ml
`or less (at the same temperature). Examples of said hydro-
`philic base include polyethylene glycol (for instance, Mac-
`rogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000,
`and Macrogol 20000 (all made by Nihon Yushi)), polyvinyl
`pyrrolidone (for instance, water-soluble polymers such as
`PVP® K30 (BASF)), sugar alcohols, such as D-sorbitol and
`xylitol, saccharides such as sucrose, maltose,
`lactulose,
`D-fructose, dextran (for instance, Dextran 40), and glucose,
`surfactants such as polyoxyethylene hydrogenated castor oil
`(for instance, Cremophor® RII40 (BASE) IICO-40, IICO-
`
`6
`60 (Nikko Chemicals), polyoxyethylene polyoxypropylene
`glycol (for instance, Pluronic® F68 (Asahi Denka), etc.) or
`polyoxyethylene sorbitan higher fatty acid esters (such as
`Tween 80 (Kanto Kagaku(Chemical)), etc.), salts, such as
`sodium chloride and magnesium chloride, organic acids
`such as citric acid and tartaric acid, amino acids such as
`glycine, [3-aniline, lysine hydrochloride, and amino saccha-
`rides such as meglumine, etc. Polyethylene glycol, sucrose
`and polyvinyl pyrrolidone are preferred and polyethylene
`glycol (particularly Macrogol 6000) is further preferred.
`Moreover, one or a combination of 2 or more hydrophilic
`bases can be used in the present invention.
`When the hydrophilic base is added in the present
`invention, the ratio used is preferably 5 to 80 wt % per total
`preparation, particularly 5 to 60 wt %, per total preparation.
`The yellow ferric oxide and/or red ferric oxide used in the
`present invention can be used alone or in combination.
`There are no special restrictions to the ratio at which
`yellow ferric oxide and/or red ferric oxide of the present
`invention is added as long as it is an amount that can usually
`stabilize a matrix type sustained-release preparation and
`reduce the changes in drug release. This ratio dilfers depend-
`ing on the type of substance and the method of addition, but
`it is preferably 1 to 20 wt %, particularly 3 to 15 wt %, with
`physical mixing in the matrix per preparation weight. For
`instance, as for red ferric oxide, it is preferably 5 to 20 wt
`%, particularly 10 to 15 wt %, per prepration weight. As for
`yellow ferric oxide, it is preferably 1 to 20 wt %, particularly
`3 to 10 wt %, per preparation weight. When used in film
`coating, it is preferably 0.3 to 2 wt %, particularly 0.5 to 1.5
`wt %, per tablet weight. The concentration of yellow ferric
`oxide or red ferric oxide contained in the film is preferably
`5 to 50 wt %, particularly 10 to 20 wt %, per tablet weight.
`The term “physical mixing in the matrix” used here means
`a means with which, for instance, drug, polyethylene oxide
`and yellow ferric oxide and/or red ferric oxide are uniformly
`dispersed and as a result, the drug and yellow ferric oxide
`and/or red ferric oxide are uniformly dispersed in PEO as the
`main base of the sustained-release preparation. Moreover,
`the term “film coating” means that, for instance, yellow
`ferric oxide and/or red ferric oxide is dissolved or suspended
`in a water-soluble polymer solution of hydroxypropylmethyl
`cellulose, etc., and this is applied as a thin film to a tablet that
`has been separately prepared. Yellow ferric oxide and/or red
`ferric oxide of the present invention can be also contained as
`usual in the preparation. For instance, it can be added as a
`film by film coating, as granules by granulation or as part of
`the matrix (for instance, around the polyethylene oxide).
`There are no special restrictions to the method of reducing
`changes in drug release from a pharmaceutical composition
`for oral use containing polyethylene oxide of the present
`invention as long as it means that said yellow ferric oxide
`and/or red ferric oxide will be added. For instance, film
`coating, granulation, mixing, etc. are mentioned. The means
`can be performed by one or by a combination of two or
`more.
`
`Other additives that are pharmaceutically acceptable can
`be added as needed to the pharmaceutical composition of the
`present invention. For instance, one or a combination of two
`or more of fillers such as lactose, mannitol, potato starch,
`wheat starch, rice starch, corn starch, crystalline cellulose,
`methyl cellulose, gum Arabic, etc., Viscosity-mcreasmg
`agents, such as carboxymethyl cellulose, carboxymethyl
`cellulose calcium, carboxymethyl cellulose, etc., lubricants
`such as stearic acid, calcium stearate, magnesium stearate,
`talc, magnesium metasilicoaluminate, calcium hydrogen
`
`TEVA EXHIBIT 1041
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`RBP_TEVA05017993
`
`TEVA EXHIBIT 1041
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 6,562,375 B1
`
`7
`phosphate, anhydrous calcium hydrogen phosphate, etc.,
`fluidizers such as silicon dioxide hydrate,
`light silic
`anhydride, dry aluminum hydroxide, etc., surfactants such as
`sodium laurylsulfate sucrose fatty acid esters, etc., coating
`agents such as zein, hydroxypropyl methyl cellulose,
`hydroxypropyl cellulose, etc., flavorings such as 1-menthol,
`menlha oil, fennel oil, etc., preservatives such as sodium
`sorbate, potassium sorbate, methyl parabenzoate, ethyl
`parabenzoate, etc., buffers such as citric acid, succinic acid,
`glycine, aspartic acid, alanine, arginine and its salts, mag-
`nesium oxide, zinc oxide, magnesium hydroxide, phospho-
`ric acid, boric acid its salts, etc., can be added as needed.
`There are no special restrictions to the method of produc-
`ing pharmaceutical preparations consisting of the pharma-
`ceutical composition of the present invention as long as it is
`a method that is 11s1Ially suitable for hydrogel preparations.
`For instance, the tableting method whereby yellow ferric
`oxide and/or red ferric oxide and various additives, such as
`hydrophilic base, etc., as needed are mixed with the drug and
`PEO. This mixture may be compression molded, encapsu-
`latcd under pressure, cxtrusion molded, or injection molded.
`Injection molding methods include, e.g., molding and curing
`after melting the mixture. In addition, coating, such as
`conventional sugar coating and film coating after molding,
`can be performed as needed. It is also possible to fill the
`product into capsules after molding.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`The present invention will now be explained in further
`detail while referring to a Comparative Example, Examples
`and Experiments, b11t the present invention is not limited to
`these descriptions.
`
`Comparative Examples
`
`Polyethylene oxide (Polyox ® WSR303)
`Macrogol 6000
`
`150 (parts by weight)
`30
`
`The polyethylene oxide and Macrogol 6000 were mixed
`with a mortar and pestle and made into tablets with an oil
`press at a tableting pressure of 1
`ton/punch to obtain
`uncoated tablets with a diameter of 8 mm and tablet weight
`of 180 mg.
`
`EXAMPLE 1
`
`Polyethylene oxide (Polyox ® WSR303)
`Macrogol 6000
`
`150 (parts by weight)
`30
`
`The polyethylene oxide and Macrogol 6000 were mixed
`with a mortar and pestle and made into tablets with an oil
`press at a tableting pressure of 1 ton/punch to obtain tablets
`with a diameter of 8 mm and tablet weight of 180 mg.
`Eight grams hydroxypropylmethyl cellulose 2910 (TC-
`SR) and 1.5 g Macrogol 6000 were dissolved in 88.5 g
`purified water and then 2.0 g yellow ferric oxide were
`dispersed in this to obtain the coating liquid. The uncoated
`tablets that had been made were coated with 3% of this
`solution per
`tablet weight using a film coating device
`HCT-mini, Freund Sangyo) to obtain the tablets of the
`present invention.
`
`8
`EXAMPLE 2
`
`Film coating of uncoated tablets made in Example I was
`performed with the following coating solution:
`
`Eight grams hydroxypropylmethyl cellulose 2910 (TC-
`SR) and 1.5 g Macrogol 6000 were dissolved in 88.5 g pure
`water and then 2.0 g red ferric oxide were dispersed in this
`to obtain the coating liquid. The uncoated tablets that had
`been made in Example 1 were coated with 3% of this
`solution per tablet weight using a film coating device
`(HCT-mini, Freund Sangyo) to obtain the tablets of the
`present invention.
`
`EXAMPLE 3
`
`Film coating of uncoated tablets made in Example 1 was
`performed with the following coating solution:
`
`Eight grams hydroxypropylmethyl cellulose 2910 (TC-
`SR) and 1.5 g Macrogol 6000 were dissolved in 88.5 g pure
`water and then 2.0 g yellow ferric oxide and 0.5 g titanium
`oxide were dispersed in this to obtain the coating liquid. The
`uncoated tablets that had been made were coated with 3% of
`this solution per tablet weight using a film coating device
`(HCT-mini, Freund Sangyo) to obtain the tablets of the
`present invention.
`
`EXAMPLE 4
`
`Film coating of uncoated tablets made in Example 1 was
`performed with the following coating solution:
`
`Eight grams hydroxypropylmethyl cellulose 2910 (TC-
`SR) and 1.5 g Macrogol 6000 were dissolved in 88.5 g pure
`water and then 2.0 g red ferric oxide and 0.5 g titanium oxide
`were dispersed in this to obtain the coating liquid. The
`uncoated tablets that had been made were coated with 3% of
`this solution per tablet weight using a film coating device
`(HCT-mini, Freund Sangyo) to obtain the tablets of the
`present invention.
`
`EXAMPLE 5
`
`Polyethylene oxide (Polyox ® WSR303)
`Macrogol 6000
`Red ferric oxide
`
`150 (parts by weight)
`30
`20
`
`The polyethylene oxide, Macrogol 6000 and red ferric
`oxide were mixed with a mortar and pestle and then made
`into tablets using an oil press at a tablcting pressure of 1
`ton/punch to obtain the tablets of the invention with a
`diameter of 8 mm and a tablet weight of 200 mg.
`
`EXAMPLE 6
`
`Polyethylene oxide (Polyox ® WSR303)
`Macrogol 6000
`Yellow ferric oxide
`
`150 (parts by weight)
`30
`20
`
`The polyethylene oxide, Macrogol 6000, and yellow
`ferric oxide were mixed with a mortar and pestle and then
`made into tablets using an oil press at a tableting pressure of
`1 ton/punch to obtain tablets of the present invention with a
`diameter of 8 mm and tablet weight of 200 mg.
`
`TEVA EXHIBIT 1041
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05017994
`
`TEVA EXHIBIT 1041
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 6,562,375 B1
`
`9
`EXAMPLE 7
`
`Polyethylene oxide (Polyox ® WSR303)
`Macrogol 6000
`Yellow ferric oxide
`
`150 (parts by weight)
`30
`9.5
`
`The polyethylene oxide, Macrogol 6000, and yellow
`ferric oxide were mixed with a mortar and pestle and then
`made into tablets using an oil press at a tableting pressure of
`1 ton/punch to obtain tablets of the present invention with a
`diameter of 8 mm and tablet weight of 189.5 mg.
`[Experiment] (Stability at the Preserved Period Under Expo-
`sure to Light)
`The tablets obtained in the Comparative Example and
`Examples 1 through 7 were introduced to a plastic dish and
`exposed to light. Light exposure was performed by exposure
`to light for 8 weeks using Option 1 according to ICH
`guidelines (D65, which is the international standard for
`outdoor light in accordance with ISOl 0977) so that the total
`illumination intensity would be 1,200,000 Lux-hr. The fol-
`lowing experiment was performed using tablets that had
`been exposed to light and tablets that had been stored for the
`same amount of time protected from light.
`Matrix Erosion Experiment
`The experiment was performed with a paddle speed at 200
`rpm in accordance with Japan Pharmacopoeia Dissolution
`Experimental Methods, Method No. 2 (Paddle Method)
`using 500 ml purified water as the experimental solution. Six
`hours after starting the experiment, the tablets were removed
`from the flask and dried for 4 days in a dryer at 40° C. to
`evaporate the water content of the matrix tablet. The matrix
`erosion percentage was calculated from the difference
`between initial weight of the tablet and dry weight using
`formula (I) (Table 1).
`Matrix erosion percentage=(initial weight—dry weight)/initial
`weight><100
`(formula I)
`
`TABLE 1
`
`Matrix erosion ex ge