MAIL STOP AF
`AMENDMENT AFTER FINAL
`EXPEDITED PROCESSING
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Appl. No. (cid:9)
`Applicant (cid:9)
`Filed (cid:9)
`TC/A.U. (cid:9)
`Examiner (cid:9)
`
`: 13/617,138
`: Roberto VILLA et al.
`: 14 September 2012
`: 1615
`: Susan T. Tran
`
`Docket No. (cid:9)
`Customer No. (cid:9)
`Confirmation No. (cid:9)
`
`: 3850-125
`: 06449
`: 7811
`
`AMENDMENT AFTER FINAL
`
`MAIL STOP AF
`Director of the United States Patent
`and Trademark Office
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`
`Dear Sir:
`
`In response to the Office Action dated 6 March 2013, please amend this application as
`
`follows:
`
`Amendment to the Specification begins on page 2 of this paper.
`
`Amendments to the Claims begin on page 34 of this paper.
`
`Remarks begin on page 36 of this paper.
`
`Exhibit 1015
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`AMENDMENT TO THE SPECIFICATION
`
`Please amend the specification as follows:
`
`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, now U.S. Patent No. 8,293,273; 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 which reissued as U.S. Patent No. RE43,799 from
`
`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 mucosac of the administration site,
`
`particularly in the buccal or gastric area.
`
`2
`
`000002
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`

`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`[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
`
`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 arc 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 Dcv. Md. Pharin. 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.
`
`/1,608,218 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
`
`3
`
`000003
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`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`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 Chcin. Pharin. 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
`.. •
`
`ess 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 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 multiparticulatc 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 95/16'151 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)
`
`dicament 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 arc characterized by the absence of a first
`
`phase in which the medicament superficially present on the matrix is quickly solubilizcd, and by
`
`4
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`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`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;
`
`b) an amphiphilic matrix;
`
`[0015] (cid:9)
`
`[0016]
`
`matrix arc 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:
`
`[0019]
`
`: " : : • ' : (cid:9)
`
`• ' : (cid:9)
`
`: : : ' (cid:9)
`
`: " : : • ' :
`
`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
`
`5
`
`000005
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`

`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`[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
`
`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
`
`6
`
`000006
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`

`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`triglycerides, the polyethoxylated derivatives thereof, waxes, ceramides, cholesterol derivatives
`
`or mixtures thereof having melting point within the range of 110° 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
`
`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
`
`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 /10° 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
`
`[0036] (cid:9)
`
`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
`
`7
`
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`

`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`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 arc 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 minitablcts.
`
`[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,
`
`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 arc preferably in the form of tablets, capsules or
`
`minitablcts.
`
`[0042]
`
`t .1
`
`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
`
`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
`
`8
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`000008
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`(cid:9)
`

`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`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 a5
`
`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, 6/1
`
`and 7.2 arc 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 target the large
`
`intestinal sectors, also the pH condition of 6/1 shown unsuitability to determine a drug leakage
`
`9
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`Application No.: 13/617,138
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`
`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 (cid:9) hour
`
`sampling.
`
`low viscosity hydroxypropylcellulose (binder) and mix for 10 minutes before adding purified (cid:9)(cid:9)
`functional excipients (in particular, microcrystallinc cellulose, lactose and silicon dioxide) and, (cid:9)(cid:9)
`
`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 (cid:9) an
`
`homogeneous mixture is obtained; then add 39.0 kg of inert, functional excipients and 9.0 kg (cid:9) of
`
`water and kneading to a suitable consistence. Then pass the granulate through a rotating (cid:9)
`
`granulator equipped with the suitable screen and transfer the granulate to the fluid bed drier (cid:9) 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 (cid:9) of
`
`hydroxypropylcellulose (hydrophilic matrix forming material) and the suitable amount (cid:9) of
`
`after 15 minutes of mixing, magnesium stearate in a suitable quantity to act as lubricant is added. (cid:9)
`
`[0049] (cid:9)
`
`[0050] (cid:9)
`
`After a final blending, tablets of around 300 mg of unitary weight are generated.
`
`The core arc then subjected to be coated with a suspension obtained introducing into (cid:9) a
`
`.stainless steel container 5.8 kg of EudragitTM (methacrylate copolymers), 0.6 kg of triethylcitratc
`
`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
`
`- • - .1"
`fourth hour and a dissolution greater than 80% was achieved at 8th hour sampling.
`
`10
`
`000010
`
`(cid:9)
`(cid:9)
`(cid:9)
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`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`[0052]
`
`EXAMPLE 2
`
`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
`
`cl• (cid:9)
`
`•
`
`[0053] (cid:9)
`
`According to the present invention, coated tablets individually weighing about 220 mg
`
`arc 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 6/1 (cid:9)
`after 2 hours at pH 7.2 (cid:9)
`after 'I hours at pH 7.2 (cid:9)
`after 8 hours at pH 7.2 (cid:9)
`
`resistant (<5%)
`resistant (<5%)
`15%
`37%
`91%
`
`[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
`
`EXAMPLE 3
`
`11
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`Application No.: 13/617,138
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`
`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,
`
`hydroxypropylmethylcellulose (35.0 kg) and other excipients, including magnesium stwrate 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 arc 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 arc obtained.
`
`[0059] (cid:9)
`
`The results of the above described dissolution test arc the following (indicated as
`
`average value of at least six tablets):
`
`after 2 hours at pH 1 (cid:9)
`after 1 hour at pH 6/1 (cid:9)
`after 2 hours at pH 7.2 (cid:9)
`after /I hours at pH 7.2 (cid:9)
`after 8 hours at pH 7.2 (cid:9)
`
`resistant (<5%)
`resistant (<5%)
`9%
`28%
`86%
`
`EXAMPLE /1
`
`[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 arc added. The components arc mixed until
`
`homogeneous dispersion of the matrices, then added with 2/150 g of microcrystalline cellulose,
`
`12
`
`000012
`
`

`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
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`/100 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 arc then subjected to coating using a suspension containing polyacrylatc 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):
`
`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 arc mixed with 10 g of
`
`toy 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
`
`extruded into small granules. The inert matrix granules arc loaded into a mixer in which 30 g of
`
`carbopol 971 P and 65 g of hydroxypropyl methylcellulose "arc 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 arc film coated with cellulose acetophthalate or
`
`istancc 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
`
`13
`
`000013
`
`

`

`[0065] (cid:9)
`
`50 g of diethylene glycol monoethyl ether are homogeneously distributed on 500 g of
`
`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`microcrystalline cellulose; then 100 g of Budesonide are added, mixing to complete
`•
`
`- All (cid:9) ; (cid:9)
`
`
`
`' ; " ; : '' •
`
`- (cid:9)
`
`• : : - : (cid:9)
`
`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.
`[0067] (cid:9)
`with 2450 g of microcrystallinc cellulose, 400 g of lactose, 100 g of colloidal silica and 50 g of
`
`V V ...
`
`magnesium stwrate. 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 arc dispersed in a granulator/kneader with 35 g of diethylene
`
`glycol monocthyl 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
`
`of magnesium stearatc.
`
`[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%.
`
`[0071] (cid:9)
`
`120 g of octylonium bromide arc 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
`
`EXAMPLE D
`
`melted.
`
`14
`
`000014
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`

`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`The system is heated to carry out the granulation of the active ingredient in the inert
`[0072] (cid:9)
`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 microcrystallinc cellulose.
`The final mixture is tabletted to unitary weight of 200 mg/tablet equivalent to 120 mg
`[0073] (cid:9)
`of active ingredient.
`The resulting tablets, when subjected to dissolution test in simulated enteric juice,
`[0074] (cid:9)
`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%.
`
`EXAMPLE E
`12 g of diethylene glycol monoethyl ether arc loaded on 6 g of microcrystalline
`[0075] (cid:9)
`cellulose and 6 grams of calcium carbonate, then 100 g of Gabapentin arc added and the mixture
`is homogenized. After that, 800 g of Gabapentin are added which are dispersed in a
`granulator/kneader with '1.5 g of white wax and 5 g of stearic acid. The system is heated to carry
`out the granulation of the active ingredient in the inert matrix. The resulting 916.5 g of
`formulation arc added with 39.5 g of hydroxypropyl methylcellulose, 10 g of alginic acid, 11 g
`of magnesium stearate and 6 g of syloid. The final mixture is tabletted to unitary weight of 1000
`mg/tablet equivalent to 900 mg of active ingredient.
`
`EXAMPLE F
`50 g (25 g) of carbidopa and 200 g (100 g) of lcvodopa arc dispersed in a
`[0076] (cid:9)
`granulator/kneader with 60 g (30 g) of stearic acid and 30 g (15 g) of yellow wax, in which 10
`(5) g of diethylene glycol monoethyl ether had previously been melted.
`The system is heated to carry out the granulation of the active ingredient in the inert
`[0077] (cid:9)
`matrix. The resulting 3'10 g (170 g) of formulation arc added with 20 g (10 g) of hydroxypropyl
`
`magnesium stearate.
`
`[0078] (cid:9)
`
`The final mixture is tabletted to unitary weight of 400 (200) mg/tablet equivalent to 50
`(25) mg of carbidopa and 200 (-100) mg di lcvodopa.
`
`15
`
`000015
`
`

`

`Application No.: 13/617,138
`Attorney Docket No. 3850-125
`
`EXAMPLE G
`'1 g of Nimesulide are solubilised in 50 g of diethylene glycol monoethyl ether, then
`
`[0079] (cid:9)
`
`100 g of microcrystallinc cellulose arc added to obtain a homogeneous mixture.
`
`[0080] (cid:9)
`
`The resulting mixture is added in a granulator/kneader with 196 g of Nimesulide, 50 g
`
`of stearic acid and 25 g of carnauba wax. The system is heated to carry out the granulation of the
`
`active ingredient in the inert and amphiphilic matrix system.
`
`[0081] (cid:9)
`
`'125 g of the resulting granulate arc added with 60 g of hydroxypropyl methylcellulose,
`
`5 g of policarbophil and 10 g of magnesium stearate.
`
`[0082] (cid:9)
`
`The final mixture is tabletted to unitary weight of 500 mg/tablet equivalent to 200 mg
`
`of active ingredient.
`
`[0083] (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 1 hour no more
`• .
`- - (cid:9)
`• (cid:9) .
`
`than 25%, after 2 hours no more than '10%, after
`
`more than 90%.
`
`E