PATENT
`Customer No. 6449
`Attorney Docket No. 3850-125
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Application of:
`
`Roberto VILLA et al.
`
`Group Art Unit: TBD
`
`Application No.: TBD
`
`Examiner: TBD
`
`Filed: Herewith
`
`For: CONTROLLED RELEASE AND
`TASTE MASKING ORAL
`PHARMACEUTICAL COMPOSITION
`
`Confirmation No.: TBD
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`LETTER ACCOMPANYING CONTINUATION APPLICATION
`
`The present application is a continuation of application Serial No. 13/462,409 to pursue
`
`the claims as set forth in the present application.
`
`Claim Support
`
`Support for these claims can be found throughout the specification and claims of parent
`
`application Serial No. 13/462,409 as filed, for example, at least as follows, with reference to the
`
`parent patents:
`
`Claim recitation
`
`1
`
`"A controlled release oral pharmaceutical
`composition"
`
`Support in Patent
`
`Support in Patent
`
`No. 8,029,823
`
`No. 7,431,943
`
`Title of application
`
`Title of application
`
`MYLAN Ex 1059, Page 1
`
`

`

`Attorney Docket No. 3850-125
`Continuation of U.S. Application No. 13/462,409
`
`"a tablet core"
`
`col. 4, lines 46-50;
`col. 3, lines 35-36;
`col. 7, lines 35-36
`
`"budesonide in an amount effective for
`treatment of inflammatory bowel
`disease in the gastrointestinal tract"
`
`col. 5, lines 38-39;
`col. 1, lines 19-21;
`col. 2, lines 29-32
`
`col. 4, lines 59-63;
`col. 3, lines 41-42;
`col. 6, lines 49-50
`
`col. 5, lines 18-20,
`col. 1, lines 18-24;
`col. 2, lines 34-37
`
`"a lipophilic excipient"
`
`col. 3, line 28
`
`col. 3, line 33
`
`"an amphiphilic excipient"
`
`col. 3, line 22
`
`col. 3, lines 27-28
`
`"a hydrogel forming hydrophilic
`excipient"
`
`col. 3, line 34 to col.
`5, line 2
`
`col. 3, line 39 to
`col. 4, line 38
`
`"a coating on said tablet core, said coating
`comprising a gastro-resistant film"
`
`co1.4, lines 46-50
`
`co1.4, lines 49-53
`
`2 "comprising 9 mg of budesonide"
`
`col. 6, lines 20-40
`
`---
`
`Therefore, no new matter is added by the claims of the present application. Applicants
`
`respectfully request that the examination of this application proceed with the present claims.
`
`Authorization to Charge Deposit Account
`
`Please grant any extensions of time required to enter this paper and charge any additional
`
`required fees to Deposit Account No. 02-2135.
`
`Respectfully submitted,
`
`Dated: 14 September 2012 (cid:9)
`
`By (cid:9)
`
`/Jeffrey L. Ihnen/
`Jeffrey L. Ihnen
`Registration No. 28,957
`Attorney for Applicants
`607 14th Street, N.W., Suite 800
`Washington, D.C. 20005
`Phone: 202-783-6040
`Fax: 202-783-6031
`
`-2-
`
`MYLAN Ex 1059, Page 2
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`

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`Controlled Release and Taste-Masking Oral Pharmaceutical Composition
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`[0001] (cid:9)
`
`This application is a continuation of application Serial No. 13/462,409 filed on May 2,
`
`2012; which is a continuation of application Serial No. 13/249,839 filed on September 30, 2011;
`
`which is a continuation of application Serial No. 12/210,969 filed on September 15, 2008, now
`
`U.S. Patent No. 8,029,823; which is a continuation-in-part of application Serial No. 10/009,532
`
`filed on December 12, 2001, now U.S. Patent No. 7,431,943; which is the 35 U.S.C. 371
`
`national stage of International application PCT/EP00/05356 filed on June 9, 2000; which
`
`claimed priority to Italian applications MI2000A000422 and MI99A001317 filed March 3, 2000
`
`and June 14, 1999, respectively. The entire contents of each of the above-identified applications
`
`are hereby incorporated by reference.
`
`BACKGROUND OF THE INVENTION
`
`[0002] (cid:9)
`
`The present invention relates to controlled release and taste masking compositions
`
`containing budesonide as active ingredient incorporated in a three-component matrix structure,
`
`i.e. a structure formed by successive amphiphilic, lipophilic or inert matrices and finally
`
`incorporated or dispersed in hydrophilic matrices. The use of a plurality of systems mechanism
`
`for the control of the dissolution of the active ingredient modulates the dissolution rate of the
`
`active ingredient in aqueous and/or biological fluids, thereby controlling the release kinetics in
`
`the gastrointestinal tract, and it also allows the oral administration of active principles having
`
`unfavourable taste characteristics or irritating action on the mucosae of the administration site,
`
`particularly in the buccal or gastric area.
`
`[0003] (cid:9)
`
`The compositions of the invention are suitable to the oral administration or the
`
`efficaciously deliver the active ingredient acting topically at some areas of the gastrointestinal
`
`tract.
`
`[0004] (cid:9)
`
`The preparation of a sustained, controlled, delayed, extended or anyhow modified
`
`release form can be carried out according to different techniques:
`
`[0005] (cid:9)
`
`1. The use of inert matrices, in which the main component of the matrix structure
`
`opposes some resistance to the penetration of the solvent due to the poor affinity towards
`
`aqueous fluids; such property being known as lipophilia.
`
`[0006] (cid:9)
`
`2. The use of hydrophilic matrices, in which the main component of the matrix
`
`structure opposes high resistance to the progress of the solvent, in that the presence of
`
`MYLAN Ex 1059, Page 3
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`

`

`2
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`strongly hydrophilic groups in its chains, mainly branched, remarkably increases
`
`viscosity inside the hydrated layer.
`
`[0007] (cid:9)
`
`3. The use of bioerodible matrices, which are capable of being degraded by the
`
`enzymes of some biological compartment.
`
`[0008] (cid:9)
`
`All the procedures listed above suffer, however, from drawbacks and imperfections.
`
`[0009] (cid:9)
`
`Inert matrices, for example, generally entail non-linear, but exponential, release of the
`
`active ingredient.
`
`[00010] Hydrophilic matrices: have a linear behaviour until a certain fraction of active
`
`ingredient has been released, then significantly deviate from linear release.
`
`[00011] Bioerodible matrices are ideal to carry out the so-called "sire-release", but they
`
`involve the problem of finding the suitable enzyme or reactive to degradation. Furthermore, they
`
`frequently release in situ metabolites that are not wholly toxicologically inert.
`
`[00012] A number of formulations based on inert lipophilic matrices have been described:
`
`Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) discloses a process making use of varying
`
`amounts of colloidal silica as a porization element for a lipophilic inert matrix in which the
`
`active ingredient is incorporated
`
`[0010] (cid:9)
`
`The same notion of canalization of an inert matrix is described in U.S. Patent No.
`
`4,608,248 in which a small amount of a hydrophilic polymer is mixed with the substances
`
`forming an inert matrix, in a non sequential compenetration of different matrix materials. EP
`
`375,063 discloses a technique for the preparation of multiparticulate granules for the controlled-
`
`release of the active ingredient which comprises co-dissolution of polymers or suitable
`
`substances to form a inert matrix with the active ingredient and the subsequent deposition of said
`
`solution on an inert carrier which acts as the core of the device. Alternatively, the inert carrier is
`
`kneaded with the solution containing the inert polymer and the active ingredient, then the
`
`organic solvent used for the dissolution is evaporated off to obtain a solid residue. The resulting
`
`structure is a "reservoir", i.e. is not macroscopically homogeneous along all the symmetry axis
`
`of the final form. The same "reservoir" structure is also described in Chem. Pharm. Bull. 46 (3),
`
`531-533, (1998) which improves the application through an annealing technique of the inert
`
`polymer layer which is deposited on the surface of the pellets.
`
`[0011] (cid:9)
`
`To the "reservoir" structure also belong the products obtained according to the
`
`technique described in WO 93/00889 which discloses a process for the preparation of pellets in
`
`hydrophilic matrix which comprises: - dissolution of the active ingredient with gastro resistant
`
`hydrophilic polymers in organic solvents; - drying of said suspension; - subsequent kneading
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`MYLAN Ex 1059, Page 4
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`3
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`and formulation of the pellets in a hydrophilic or lipophilic matrix without distinction of
`
`effectiveness between the two types of application. EP 0 453 001 discloses a multiparticulate
`
`with "reservoir" structure inserted in a hydrophilic matrix. The basic multiparticulate utilizes
`
`two coating membranes to decrease the release rate of the active ingredient, a pH-dependent
`
`membrane with the purpose of gastric protection and a pH-independent methacrylic membrane
`
`with the purpose of slowing down the penetration of the aqueous fluid. WO 95/16451 discloses
`
`a composition only formed by a hydrophilic matrix coated with a gastro-resistant film for
`
`controlling the dissolution rate of the active ingredient.
`
`[0012] (cid:9) When preparing sustained-, controlled-release dosage forms of a medicament
`
`topically active in the gastrointestinal tract, it is important to ensure a controlled release from the
`
`first phases following administration, i.e. when the inert matrices have the maximum release rate
`
`inside the logarithmic phase, namely the higher deviation from linear release. Said object has
`
`been attained according to the present invention, through the combination of an amphiphilic
`
`matrix inside an inert matrix, the latter formulated with a lipophilic polymer in a superficial
`
`hydrophilic matrix. The compositions of the invention are characterized by the absence of a first
`
`phase in which the medicament superficially present on the matrix is quickly solubilized, and by
`
`the fact the amphiphilic layer compensate the lack of affinity of the aqueous solvent with the
`
`lipophilic compounds forming the inner inert matrix.
`
`DISCLOSURE OF THE INVENTION
`
`[0013] (cid:9)
`
`The invention provides controlled release and taste masking oral pharmaceutical
`
`compositions containing as active ingredient budesonide comprising:
`
`[0014] (cid:9)
`
`a) a matrix consisting of lipophilic compounds with melting point lower than 90°
`
`C and optionally by amphiphilic compounds in which the active ingredient is at least
`
`partially incorporated;
`
`[0015] (cid:9)
`
`[0016] (cid:9)
`
`b) an amphiphilic matrix;
`
`c) an outer hydrophilic matrix in which the lipophilic matrix and the amphiphilic
`
`matrix are dispersed;
`
`[0017] (cid:9)
`
`d) optionally other excipients.
`
`[0018] (cid:9)
`
`A particular aspect of the invention consists of controlled release oral compositions
`
`containing as active ingredient budesonide comprising:
`
`MYLAN Ex 1059, Page 5
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`4
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`[0019] (cid:9)
`
`a) a matrix consisting of amphiphilic compounds and lipophilic compounds with
`
`melting point below 90° C. in which the active ingredient is at least partially
`
`incorporated;
`
`[0020] (cid:9)
`
`b) an outer hydrophilic matrix in which the lipophilic/amphiphilic matrix is
`
`dispersed, preferably by mixing;
`
`[0021] (cid:9)
`
`c) optionally other excipients.
`
`[0022] (cid:9) A further aspect of the invention provides taste masking oral pharmaceutical
`
`compositions budesonide containing comprising:
`
`[0023] (cid:9)
`
`an inert or lipophilic matrix consisting of C6-C20 alcohols or C8-C20 fatty acids
`
`or esters of fatty acids with glycerol or sorbitol or other polyalcohols with carbon atom
`
`chain not higher than six:
`
`[0024] (cid:9)
`
`an amphiphilic matrix consisting of polar lipids of type I or II or glycols partially
`
`etherified with C1-C4 alkyl chains;
`
`[0025] (cid:9)
`
`an outer hydrophilic matrix containing the above matrices, mainly formed by
`
`saccharide, dextrin, polyalcohol or cellulose compounds or by hydrogels or their
`
`mixtures;
`
`[0026] (cid:9)
`
`optional excipients to give stability to the pharmaceutical formulation.
`
`DETAILED DISCLOSURE OF THE INVENTION
`
`[0027] (cid:9)
`
`The compositions of the invention can be prepared by a method comprising the
`
`following steps:
`
`[0028] (cid:9)
`
`a) the active ingredient, represented by budesonide, is first inglobated by simple
`
`kneading or mixing in a matrix or coating consisting of compounds having amphiphilic
`
`properties, which will be further specified below. The active ingredient can be mixed
`
`with the amphiphilic compounds without the aid of solvents or with small amounts of
`
`water-alcoholic solvents.
`
`[0029] (cid:9)
`
`b) the matrix obtained as specified under a) is incorporated in a low melting
`
`lipophilic excipient or mixture of excipients, if necessary while heating to soften and/or
`
`melt the excipient itself, which thereby incorporates the active ingredient by simple
`
`dispersion forming an inert matrix which can be reduced in size to obtain inert matrix
`
`granules containing the active ingredient particles.
`
`[0030] (cid:9)
`
`c) the inert matrix granules are subsequently mixed together with one or more
`
`hydrophilic water-swellable excipients. The mixture is then subjected to compression or
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`MYLAN Ex 1059, Page 6
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`5
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`tabletting. This way, when the tablet is contacted with biological fluids, a high viscosity
`
`swollen layer is formed, which coordinates the solvent molecules and acts as a barrier to
`
`penetration of the aqueous fluid itself inside the new structure. Said barrier antagonizes
`
`the starting "burst effect" caused by the dissolution of the medicament inglobated inside
`
`the inert matrix, which is in its turn inside the hydrophilic matrix.
`
`[0031] (cid:9)
`
`The amphiphilic compounds which can be used according to the invention comprise
`
`polar lipids of type I or II (lecithin, phosphatidylcholine, phosphatidylethanolainine), ceramides,
`
`glycol alkyl ethers such as diethylene glycol monomethyl ether (Transcutol®).
`
`[0032] (cid:9)
`
`The lipophilic matrix consists of substances selected from unsaturated or
`
`hydrogenated alcohols or fatty acids, salts, esters or amides thereof, fatty acids mono-, di-or
`
`triglycerides, the polyethoxylated derivatives thereof, waxes, ceramides, cholesterol derivatives
`
`or mixtures thereof having melting point within the range of 40° to 90° C, preferably from 60° to
`
`70° C. If desired, a fatty acid calcium salt may be incorporated in the lipophilic matrix which is
`
`subsequently dispersed in a hydrophilic matrix prepared with alginic acid, thus remarkably
`
`increasing the hydrophilic matrix viscosity following penetration of the solvent front until
`
`contact with the lipophilic matrix granules dispersed inside.
`
`[0033] (cid:9)
`
`An amphiphilic matrix with high content in active ingredient, typically from 5% to
`
`95% w/w, in particular from 20% to 70%, is first prepared by dispersing the active ingredient in
`
`a mixture of amphiphilic compounds, such as lecithin, other type II polar lipids, surfactants, or
`
`in diethylene glycol monoethyl ether; the resulting amphiphilic matrix is then mixed or kneaded,
`
`usually while hot, with lipophilic compounds suitable to form an inert matrix, such as saturated
`
`or unsaturated fatty acids, such as palmitic, stearic, myristic, lauric, laurylic, or oleic acids or
`
`mixtures thereof with other fatty acids with shorter chain, or salts or alcohols or derivatives of
`
`the cited fatty acids, such as mono-, di-, or triglycerides or esters with polyethylene glycols,
`
`alone or in combination with waxes, ceramides, cholesterol derivatives or other apolar lipids in
`
`various ratios so that the melting or softening points of the lipophilic compounds mixtures is
`
`within the range of 40° to 90° C, preferably from 60° to 70° C.
`
`[0034] (cid:9)
`
`Alternatively, the order of formation of the inert and amphiphilic matrices can be
`
`reversed, incorporating the inert matrix inside the amphiphilic compounds.
`
`[0035] (cid:9)
`
`The resulting inert lipophilic matrix is reduced into granules by an extrusion and/or
`
`granulation process, or any other known processes which retain the homogeneous dispersion and
`
`matrix structure of the starting mixture.
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`MYLAN Ex 1059, Page 7
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`6
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`[0036] (cid:9)
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`The hydrophilic matrix consists of excipients known as hydrogels, i.e. substances
`
`which when passing from the dry state to the hydrated one, undergo the so-called "molecular
`
`relaxation", namely a remarkable increase in mass and weight following the coordination of a
`
`large number of water molecules by the polar groups present in the polymeric chains of the
`
`excipients themselves. Examples of hydrogels which can be used according to the invention are
`
`compounds selected from acrylic or methacrylic acid polymers or copolymers, alkylvinyl
`
`polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins,
`
`starches and derivatives, natural or synthetic gums, alginic acid. In case of taste-masking
`
`formulations, the use of polyalcohols such as xylitol, maltitol and mannitol as hydrophilic
`
`compounds can also be advantageous.
`
`[0037] (cid:9)
`
`The lipophilic matrix granules containing the active ingredient are mixed with the
`
`hydrophilic compounds cited above in a weight ratio typically ranging from 100:0.5 to 100:50
`
`(lipophilic matrix: hydrophilic matrix). Part of the active ingredient can optionally be mixed
`
`with hydrophilic substances to provide compositions in which the active ingredient is dispersed
`
`both in the lipophilic and the hydrophilic matrix, said compositions being preferably in the form
`
`of tablets, capsules and/or minitablets.
`
`[0038] (cid:9)
`
`The compression of the mixture of lipophilic and/or amphiphilic matrix, hydrogel-
`
`forming compound and, optionally, active ingredient not inglobated in the lipophilic matrix,
`
`yields a macroscopically homogeneous structure in all its volume, namely a matrix containing a
`
`dispersion of the lipophilic granules in a hydrophilic matrix. A similar result can also be
`
`obtained by coating the lipophilic matrix granules with a hydrophilic polymer coating.
`
`[0039] (cid:9)
`
`The tablets obtainable according to the invention are subjected to known coating
`
`processes with a gastro-resistant film, consisting of, for example, acrylic and methacrylic acids
`
`polymers (Eudragit®) or copolymer or cellulose derivatives, such as cellulose acetophthalate.
`
`[0040] (cid:9)
`
`The composition of the invention can further contain conventional excipients, for
`
`example bioadhesive excipients such as chitosans, polyacrylamides, natural or synthetic gums,
`
`acrylic acid polymers.
`
`[0041] (cid:9)
`
`The compositions of the invention are preferably in the form of tablets, capsules or
`
`minitablets.
`
`[0042] (cid:9)
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`In terms of dissolution characteristics, contact with water or aqueous fluids causes the
`
`immediate penetration of water inside the more superficial layer of the matrix which, thanks to
`
`the presence of the aqueous solvent, swells due to the distension of the polymeric chains of the
`
`hydrogels, giving rise to a high viscosity hydrated front which prevents the further penetration of
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`MYLAN Ex 1059, Page 8
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`7
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`the solvent itself linearly slowing down the dissolution process to a well determined point which
`
`can be located at about half the thickness, until the further penetration of water would cause the
`
`disintegration of the hydrophilic layer and therefore the release of the content which, consisting
`
`of inert matrix granules, however induces the diffusion mechanism typical of these structures
`
`and therefore further slows down the dissolution profile of the active ingredient. The presence of
`
`the amphiphilic matrix inside the lipophilic matrix inert allows to prevent any unevenness of the
`
`release profile of the active ingredient. The surfactants present in the amphiphilic portion
`
`promote wettability of the porous canaliculuses which cross the inert matrix preventing or
`
`reducing resistance to penetration of the solvent inside the inert matrix. To obtain taste masking
`
`tablets, the components of the hydrophilic matrix are carefully selected to minimize the active
`
`substance release time through penetration accelerated by the canalization induced by the
`
`hydrophilic compound.
`
`EXPERIMENTAL PART
`
`[0043] (cid:9)
`
`To test the effective ability of the formulations of the invention to modify the release
`
`rate and extent of the active ingredient from the dosage form suitable for the drug
`
`administration, before any pharmacokinetic study on patients or volunteers, the dissolution test
`
`is taken as monitoring and discriminating tool. Dissolution Test Method.
`
`[0044] (cid:9)
`
`Tablets according to the present invention undergo to dissolution test to verify the
`
`formulation capacity in modulating and controlling the rate by which the active ingredient is
`
`leaked by the device or dosage form in the environmental medium, generally a buffered solution
`
`simulating gastric or intestinal juices.
`
`[0045] (cid:9)
`
`The dissolution test is performed by introducing individual tablets in a glace vessel
`
`containing from 500 to 1000 ml of a buffered solution set to different pH conditions (pH 1, 6.4
`
`and 7.2 are the pH condition generally used in this test applications), so that the whole digestive
`
`tract pH conditions, from stomach to large intestine, should be reproduced. To simulate the
`
`human body conditions, the test is carried out at a temperature of 37° C ± 2° C. and at
`
`predetermined time periods samples of the dissolution medium are withdrawn to detect the
`
`percentage of active ingredient dissolved over time.
`
`[0046] (cid:9)
`
`The tablets according to the present invention, when designed to be used to treat
`
`inflammatory bowel disease, in principle have to show a good resistance, thanks to the
`
`polymeric film resistant to the low pH conditions (intended as < 5 to simulate the gastric
`
`environment) applied to cover the tablet surface, resistance which last at least for two hours; to
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`8
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`target the large intestinal sectors, also the pH condition of 6.4 shown unsuitability to determine a
`
`drug leakage from the administration device for a short exposition time and only mediums at pH
`
`7.2 have been able to determine an active ingredient dissolution at a progressive and quite
`
`constant rate during a timeframe from 6 to 12 hours; the dissolution percentage obtained with
`
`this tablet formulation were below 15% at first hour sampling, below 25% at second hour
`
`sampling, then values were in the range 25% to 55% at fourth hour and a dissolution greater
`
`than 80% was achieved at 8th hour sampling.
`
`EXAMPLE 1
`
`[0047] (cid:9)
`
`2.7 kg of budesonide, 3.0 kg of lecithin (amphiphilic matrix forming material) and 3.0
`
`kg of stearic acid (lipophilic matrix forming material) are mixing after sieving till an
`
`homogeneous mixture is obtained; then add 39.0 kg of inert, functional excipients and 9.0 kg of
`
`low viscosity hydroxypropylcellulose (binder) and mix for 10 minutes before adding purified
`
`water and kneading to a suitable consistence. Then pass the granulate through a rotating
`
`granulator equipped with the suitable screen and transfer the granulate to the fluid bed drier to
`
`lower the residual moisture content under 3%.
`
`[0048] (cid:9) After a new sieving on the dry, the granulate is added of 9.0 kg of
`
`hydroxypropylcellulose (hydrophilic matrix forming material) and the suitable amount of
`
`functional excipients (in particular, microcrystalline cellulose, lactose and silicon dioxide) and,
`
`after 15 minutes of mixing, magnesium stearate in a suitable quantity to act as lubricant is
`
`added.
`
`[0049] (cid:9)
`
`After a final blending, tablets of around 300 mg of unitary weight are generated.
`
`[0050] (cid:9)
`
`The core are then subjected to be coated with a suspension obtained introducing into a
`
`stainless steel container 5.8 kg of EudragitTM (methacrylate copolymers), 0.6 kg of triethylcitrate
`
`and 3.0 kg of dyes and talc, using alcohol as solvent.
`
`[0051] (cid:9)
`
`The mean dissolution percentage (as average of six or more tablets) obtained with this
`
`tablet formulation were around 10-20% at second hour sampling, in the range 25% to 65% at
`
`fourth hour and a dissolution greater than 80% was achieved at 8th hour sampling.
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`9
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`EXAMPLE 2
`
`[0052]
`
`Component
`
`Tablet
`Budesonide
`Stearic Acid
`Lecithin
`Microcrystalline cellulose
`Hydroxypropylcellulose
`Lactose monohydrate
`Silicon dioxide
`Magnesium stearate
`
`Coating materials
`Eudragit L100
`Eudragit S100
`Talc
`Titanium dioxiede
`Triethylcitrate
`
`Alcohol
`
`mg/tablet
`
`9.0
`10.0
`10.0
`156.0
`60.0
`50.0
`2.0
`3.0
`
`14.0
`12.0
`7.9
`4.5
`1.6
`
`q. s .
`
`[0053] (cid:9)
`
`According to the present invention, coated tablets individually weighing about 220
`
`mg are obtained.
`
`[0054] (cid:9)
`
`[0055] (cid:9)
`
`The above described dissolution test is performed on the tablets of Example 2.
`
`The results are the following (indicated as average value):
`
`after 2 hours at pH 1 (cid:9)
`after 1 hour at pH 6.4 (cid:9)
`after 2 hours at pH 7.2 (cid:9)
`after 4 hours at pH 7.2 (cid:9)
`after 8 hours at pH 7.2 (cid:9)
`
`resistant (<5%)
`resistant (<5%)
`15%
`37%
`91%
`
`EXAMPLE 3
`
`[0056] (cid:9)
`
`Budesonide (3.0 kg) is mixed with soybean Lecithin (5.0 kg) till an homogeneous
`
`mixture is obtained. Then carnauba wax (2.0 kg) and stearic acid (2.0 kg) sieved through a fine
`
`screen are added. After mixing, the powders are added with other functional excipients and
`
`kneaded with a binder solution obtained by dissolving medium viscosity polyvinylpyrrolidone in
`
`water. After drying in a fluid bed and milling throughout a suitable screen,
`
`MYLAN Ex 1059, Page 11
`
`

`

`10
`
`hydroxypropylmethylcellulose (35.0 kg) and other excipients, including magnesium stearate as
`
`lubricant, in a suitable quantity are added and the mixture is blended until an homogeneous
`
`powder dispersion is obtained.
`
`[0057] (cid:9)
`
`The powder mixture is subjected to compression in a rotating tableting machine and
`
`the tablets so obtained are coated in a pan coat with a gastroresistant composition containing
`
`EudragitTM, plasticizers, dyes and pigments.
`
`[0058] (cid:9)
`
`According to the present example, coated tablets individually weighing around 105
`
`mg are obtained.
`
`[0059] (cid:9)
`
`The results of the above described dissolution test are the following (indicated as
`
`average value of at least six tablets):
`
`after 2 hours at pH 1 (cid:9)
`after 1 hour at pH 6.4 (cid:9)
`after 2 hours at pH 7.2 (cid:9)
`after 4 hours at pH 7.2 (cid:9)
`after 8 hours at pH 7.2 (cid:9)
`
`resistant (<5%)
`resistant (<5%)
`9%
`28%
`86%
`
`EXAMPLE 4
`
`[0060] (cid:9)
`
`50 g of diethylene glycol monoethyl ether are homogeneously distributed on 500 g of
`
`microcrystalline cellulose; then 100 g of Budesonide are added, mixing to complete
`
`homogenization. This mix is further added with 400 g of Budesonide, then dispersed in a
`
`blender containing 100 g of carnauba wax and 100 g of stearic acid preheated at a temperature of
`
`60° C. After kneading for 5 minutes, the mixture is cooled to room temperature and extruded in
`
`granules of size below 1 mm. A suitable mixer is loaded with the matrix granules prepared as
`
`above and the following amounts of hydrophilic excipients: 1500 g of hydroxypropyl
`
`methylcellulose and 500 g of PolycarbophilTM are added. The components are mixed until
`
`homogeneous dispersion of the matrices, then added with 2450 g of microcrystalline cellulose,
`
`400 g of lactose, 100 g of colloidal silica and 50 g of magnesium stearate. After further 5 minute
`
`mixing, the mix is tableted to unitary weight of 250 mg/tablet.
`
`[0061] (cid:9)
`
`Tablets are then subjected to coating using a suspension containing polyacrylate and
`
`poly methacrylate copolymers in addition to other dyes, plasticizers and colouring agents in
`
`solvent (ethylic alcohol).
`
`[0062] (cid:9)
`
`The results of the dissolution test performed on these coated tablets are the following
`
`(indicated as average value of at least six tablets):
`
`MYLAN Ex 1059, Page 12
`
`

`

`11
`
`after 2 hours at pH 1 (cid:9)
`after 1 hour at pH 6.4 (cid:9)
`after 2 hours at pH 7.2 (cid:9)
`after 4 hours at pH 7.2 (cid:9)
`after 8 hours at pH 7.2 (cid:9)
`
`resistant (<5%)
`resistant (<5%)
`11%
`32%
`76%
`
`EXAMPLE A
`
`[0063] (cid:9)
`
`500 g of 5-aminosalicylic-acid and 20 g of octylonium bromide are mixed with 10 g
`
`of soy lecithin dissolved in 50 g of a water:ethyl alcohol 1:3 mixture at about 50° C. After
`
`homogenization and drying, the granules of the resulting matrix are treated in a kneader with
`
`20 g of carnauba wax and 50 g of stearic acid, heating until homogeneous dispersion, then cold-
`
`extruded into small granules. The inert matrix granules are loaded into a mixer in which 30 g of
`
`carbopol 971 P and 65 g of hydroxypropyl methylcellulose "are sequentially added." After a
`
`first mixing step for homogeneously dispersing the powders, 60 g of microcrystalline cellulose
`
`and 5 g of magnesium stearate are added. After mixing, the final mixture is tabletted to unitary
`
`weight of 760 mg/tablet. The resulting tablets are film-coated with cellulose acetophthalate or
`
`polymethacrylates and a plasticizer to provide gastric resistance and prevent the early release of
`
`product in the stomach.
`
`[0064] (cid:9)
`
`The resulting tablets, when subjected to dissolution test in simulated enteric juice,
`
`have shown a release of the active principles having the following profile: after 60 minutes no
`
`more than 30%, after 180 minutes no more than 60%, after 5 hours no more than 80%.
`
`EXAMPLE B
`
`[0065] (cid:9)
`
`50 g of diethylene glycol monoethyl ether are homogeneously distributed on 500 g of
`
`microcrystalline cellulose; then 100 g of Budesonide are added, mixing to complete
`
`homogenization. This mix is further added with 400 g of Budesonide, then dispersed in a
`
`blender containing 100 g of carnauba wax and 100 g of stearic acid preheated at a temperature of
`
`60°C. After kneading for 5 minutes, the mixture is cooled to room temperature and extruded in
`
`granules of size below 1 mm.
`
`[0066] (cid:9)
`
`A suitable mixer is loaded with the matrix granules prepared as above and the
`
`following amounts of hydrophilic excipients: 1500 g of hydroxypropyl methylcellulose and 500
`
`g of policarbophil.
`
`MYLAN Ex 1059, Page 13
`
`

`

`12
`
`[0067] (cid:9)
`
`The components are mixed until homogeneous dispersion of the matrices, then added
`
`with 2450 g of microcrystalline cellulose, 400 g of lactose, 100 g of colloidal silica and 50 g of
`
`magnesium stearate. After further 5 minute mixing, the mix is tabletted to unitary weight of
`
`250 mg/tablet.
`
`EXAMPLE C
`
`[0068] (cid:9)
`
`850 g of metformin are dispersed in a granulator/kneader with 35 g of diethylene
`
`glycol monoethyl ether previously melted with 100 g of stearic acid and 55 g of carnauba wax.
`
`The system is heated to carry out the granulation of the active ingredient in the inert matrix. The
`
`resulting 1040 g of formulation are added with 110 g of hydroxypropyl methylcellulose and 20 g
`
`of magnesium stearate.
`
`[0069] (cid:9)
`
`The final mixture is tabletted to unitary weight of 1170 mg/tablet equivalent to 850
`
`mg of active ingredient.
`
`[0070] (cid:9)
`
`The resulting tablets, when subjected to dissolution test in simulated enteric juice,
`
`have shown a release of the active principles having the following profile: after 60 minutes no
`
`more than 35%, after 180 minutes no more than 60%, after 5 hours no more than 80%.
`
`EXAMPLE D
`
`[0071] (cid:9)
`
`120 g of octylonium bromide are dispersed in a granulator/kneader with 30 g of
`
`stearic acid and 15 g of beeswax in which 10 g of diethylene glycol monoethylene had
`
`previously been melted.
`
`[0072] (cid:9)
`
`The system is heated to carry out the granulation of the active ingredient in the inert
`
`matrix. The resulting 10 g of formulation are added with 5 g of hydroxypropyl methylcellulose
`
`and 5 g of policarbophyl, 2 g of magnesium stearate and 3 g of microcrystalline cellulose.
`
`[0073] (cid:9)
`
`The final mixture is tabletted to unitary weight of 200 mg/tablet equivalent to 120 mg
`
`of active ingredient.
`
`[0074] (cid:9)
`
`The resulting tablets, when subjected to dissolution test in simulated enteric juice,
`
`have shown a release of the active principles having the following profile: after 60 minutes no
`
`more than 25%; after 180 minutes no more than 50%; after 5 hours no more than 70%.
`
`[0075] (cid:9)
`
`12 g of diethylene glycol monoethyl ether are loaded on 6 g of microcrystalline
`
`cellulose and 6 grams of calcium carbonate, then 100 g of Gabapentin are added and the mixture
`
`EXAMPLE E
`
`MYLAN Ex 1059, Page 14
`
`

`

`13
`
`is homogenized. After that, 800 g of Gabapentin are added which are dispersed in a
`
`granulator/kneader with 4.5 g of white wax and 5 g of stearic acid. The system is heated to carry
`
`out the granulation of the active ingredient