Attorney Docket No. 2551-1001-4
`
`UTILITY/PLANT PATENT APPLICATION TRANSMITTAL
`(Only for new nonprovisional applications under 37 CFR 1.53(b))
`To the Director of Patents
`Transmitted herewith for filing is the patent application of:
`Inventors: Roberto VILLA, Massio PEDRANI, Mauro AJANI and Lorenzo FOSSATI
`Corresponding to U.S. Patent Application No. 10/009,532, filed December 12, 2001, International Application No. PCT/EP00/05356, filed
`June 9, 2000, and Italian Patent Application Nos. MI99A001347 and MI2000A000422 filed on June 14, 1999 and March 3, 2000
`respectively, the entirety of which applications are hereby expressly incorporated by reference in the accompanying application.
`Title: CONTROLLED RELEASE AND TASTE-MASKING ORAL PHARMACEUTICAL COMPOSITION
`Enclosed are:
`
`16 (cid:9)
`
`q
`
`q
`
`a (cid:9)
`
`a (cid:9)
`
`q
`
`q
`
`q
`
`q
`
`q
`
`a (cid:9)
`
`q
`
`q
`
`a.
`b.
`
`c.
`
`q
`
`Pages of Specification containing 15 claims, (cid:9)
`Abstract of the Disclosure.
`
`Sheets of Drawings and an
`
`Submission of English translation of prior provisional application
`under 37 CFR 1.78(a)(5)
`
`Newly executed Oath or Declaration/Power of Attorney
`
`Copy of Oath or Declaration/Power of Attorney from a prior
`(continuation/divisional)
`
`application
`
`a copy of the oath or The entire disclosure of the prior application, from which
`
`
`considered as being part of the declaration is supplied as indicated in the preceding box, is
`disclosure of the accompanying application and is hereby incorporated
`by reference therein.
`q
`
`deleting inventor(s) named in Deletion of inventor(s). A signed statement attached
`the prior application (see 37 CFR 1.63 (d)(2) and 1.33(b)
`
`Application Data Sheet under 37 C.F.R. § 1.76
`
`Assignment Papers (cover sheet & document(s))
`
`An assignment to COSMO TECHNOLOGIES LIMITED for
`parent application no.
`017136, Frame 0818
`10/009,532 was recorded on December 23, 2005 at Reel
`
`Information Disclosure Statement (IDS) w/PTO-1449 - q
`
`Copy of IDS citations
`
`Preliminary Amendment
`
`Itemized Return Receipt Postcard
`
`Certified Copy of Priority Document(s)
`
`Priority of Italian application Nos. M199A001317 and M12000A000422
`June 14, 1999 and March 3, 2000, respectively
`is claimed under 35 U.S.C. § 119.
`Certified copy(s) of the priority document(s) was(were) forwarded
`to the Patent Office by the
`International Bureau during the International phase of parent application
`No. 10/009,532
`(Appendix)
`CD-ROM or CD-R in duplicate, large table or Computer Program
`
`filed in Italy on
`
`Nucleotide and/or Amino Acid Sequence Submission (if applicable,
`
`all necessary)
`
`q Computer Readable Form (CRF)
`Specification Sequence Listing on:
`i. (cid:9) q CD-ROM or CD-R (2 copies); or ii. (cid:9) q (cid:9)
`q Statement verifying identity of above copies
`
`paper
`
`Other Attachment:
`
`Y&T September 15, 2008
`
`Exhibit 1054
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`UTILITY/PLANT PATENT APPLICATION TRANSMITTAL
`(continued)
`If a CONTINUING APPLICATION, check appropriate box, and supply requisite information
`preliminary amendment or in an Application Data Sheet under 37 CFR 1.76:
`@ (cid:9)
`Continuation (cid:9) q (cid:9)
`Divisional (cid:9) q (cid:9)
`Continuation-in-part (cid:9)
`Examiner: SHEIKH, H (cid:9)
`Prior Application Information: (cid:9)
`
`below and in a
`
`Prior Appin. # 10/009,532 of
`
`Center: 1615
`Tech
`
`Attorney Docket No. 2551-1001-4
`
`, filed
`
`on (cid:9)
`
`, the entire contents
`
`q --This application is a division of co-pending Application No. (cid:9)
`of which are hereby incorporated by reference.--
`filed on December 12,
`--This application is a continuation of co-pending Application No. 10/009,532,
`@ (cid:9)
`Application No.
`2001. Application No. 10/009,532 is the national phase of PCT International
`
`contents of each of the above- PCT/EP00/05356 filed on June 9, 2000 under 35 U.S.C. § 371. The entire
`identified applications are hereby incorporated by reference.--
`CORRESPONDENCE INFORMATION
`Correspondence Address: (cid:9)
`Young & Thompson
`209 Madison Street, Suite 500
`Alexandria, VA 22314
`Telephone (703) 521-2297
`Facsimile (703) 979-4709
`
`Customer Number: (cid:9)
`00466 (cid:9)
`
`Ei (cid:9)
`
`Applicant claims small entity status under 37 C.F.R. § 1.27
`
`The filino fee has been calculated as follows:
`BASIC FILING FEES
`Large Entity
`Fee (cid:9)
`Fee
`Code (cid:9)
`($)
`1011
`300
`1111
`500
`1311
`200
`1013
`200
`1113
`300
`1313
`160
`
`Small Entity
`Fee (cid:9)
`Fee
`Code (cid:9)
`($)
`4011
`75
`2111
`255
`2311
`105
`2013
`100
`2113
`150
`2313
`80
`
`Utility filing fee
`Utility search fee
`Utility examination fee
`Plant filing fee
`Plant search fee
`Plant examination fee
`
`Fee Description
`
`SIZE FEE
`for each additional 50 sheets
`in excess of 100
`
`EXTRA CLAIM FEES
`Independent Claims
`
`Total Claims
`
`Multiple Dependent
`
`14 - 100 = (cid:9)
`
`Additional Sheets
`0 (cid:9) = (cid:9)
`0 X
`
`50
`
`Extra Claims
`1 - 3 = 0 X
`
`7 - 20 = 0 X
`
`Fee From
`Below
`$125.00
`
`$200.00
`
`$50.00
`
`Fee Paid
`
`$75.00
`$255.00
`$105.00
`$0.00
`$0.00
`$0.00
`
`$0.00
`
`$0.00
`
`$0.00
`
`$0.00
`
`Large Entity
`Fee
`Fee
`Code
`($)
`1081
`250
`1083
`250
`1201
`200
`1202
`50
`1203
`360
`ADDITIONAL FEES
`Fee
`Code
`8021
`
`Fee
`($)
`40
`
`Small Entity
`Fee
`Fee
`Code
`($)
`2081
`125
`2083
`125
`2201
`100
`2202
`25
`2203
`180
`
`Fee Description
`
`Utility Size fee sheets in excess of 100
`Plant Size fee sheets in excess of 100
`Independent claims in excess of 3
`Claims in excess of 20
`Multiple dependent claim
`
`Fee Description
`
`Recording each patent assignment per property
`
`TOTAL
`
`$0.00
`$ 435.00
`
`000002
`
`

`

`UTILITY/PLANT PATENT APPLICATION TRANSMITTAL
`(continued)
`
`Attorney Docket No. 2551-1001-4
`
`•
`
`The fees in the amount 435.00 are being paid online simultaneously herewith by credit card.
`
`q
`The Director is hereby authorized to charge indicated fees and credit any overpayment to Deposit account No.
`25-0120 in the name of Young & Thompson, as described below. A duplicate copy of this sheet is enclosed.
`
`[S] (cid:9)
`
`The Director is hereby authorized in this, concurrent, and future submissions, to charge payment or credit any
`overpayment to Deposit Account No. 25-0120 for any additional fee required under 37 C.F.R. §§ 1.16 or 1.17.
`
`/Robert A. Madsen/
`Robert A. Madsen, Reg. No. 58,543
`Young & Thompson
`209 Madison Street, Suite 500
`Alexandria, VA 22314
`Telephone (703) 521-2297
`
`RAM/abs
`
`Date: September 15, 2008
`
`000003
`
`

`

`Application Data Sheet
`
`Application Information
`
`Application Type:: (cid:9)
`
`Subject Matter:: (cid:9)
`
`Suggested Classification::
`
`Suggested Group Art Unit::
`
`Regular
`
`Utility
`
`CD-ROM or CD-R?:: (cid:9)
`
`None
`
`Number of CD disks::
`
`Number of Copies of CDs::
`
`Sequence Submission?:: (cid:9)
`
`None
`
`Computer Readable Form (CRF):: (cid:9)
`
`No
`
`Number of copies of CRF:: (cid:9)
`
`0
`
`Title:: (cid:9)
`
`CONTROLLED RELEASE AND TASTE
`
`MASKING ORAL PHARMACEUTICAL
`
`COMPOSITION
`
`Attorney Docket Number:: (cid:9)
`
`2551-1001-3
`
`Request for Early (cid:9)
`
`Publication?::
`
`No
`
`Request for Non-Publication?:: (cid:9)
`
`No
`
`Suggested Drawing Figure::
`
`Total Drawing Sheets::
`
`Small Entity?:: (cid:9)
`
`Latin Name::
`
`Yes
`
`Variety Denomination Name::
`
`Petition Included?:: (cid:9)
`
`No
`
`Petition Type::
`
`Licensed US Gov't Agency::
`
`Contract or Grant Numbers::
`
`Secrecy Order in Parent (cid:9)
`
`No
`
`Appl.?::
`
`Page #1 (cid:9)
`
`Initial 9/15/08
`
`000004
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`

`

`Applicant Information
`
`Applicant Authority Type:: (cid:9)
`
`Inventor
`
`Primary Citizenship Country:: (cid:9)
`
`ITALY
`
`Status:: (cid:9)
`
`Given Name:: (cid:9)
`
`Middle Name::
`
`Family Name:: (cid:9)
`
`Name Suffix::
`
`City of Residence:: (cid:9)
`
`State or Province of
`
`Residence::
`
`Full Capacity
`
`ROBERTO
`
`VILLA
`
`LECCO
`
`Country of Residence:: (cid:9)
`
`ITALY
`
`Street of Mailing (cid:9)
`
`VIA COL DI LANA 26
`
`Address:
`
`City of Mailing Address:: (cid:9)
`
`LECCO
`
`State or Province of Mailing Address::
`
`Country of Mailing Address:: (cid:9)
`
`ITALY
`
`Postal or Zip Code of Mailing Address::
`
`Applicant Authority Type:: (cid:9)
`
`Inventor
`
`Primary Citizenship Country:: (cid:9)
`
`ITALY
`
`Status:: (cid:9)
`
`Given Name:: (cid:9)
`
`Middle Name::
`
`Family Name:: (cid:9)
`
`Name Suffix::
`
`City of Residence::
`
`State or Province of
`
`Residence::
`
`Full Capacity
`
`MASSIMO
`
`PEDRANI
`
`CIGNESE (VERBANIA)
`
`Country of Residence:: (cid:9)
`
`ITALY
`
`Street of Mailing (cid:9)
`
`SALITA ROGNONI 18
`
`Address:
`
`City of Mailing Address::
`
`CIGNESE (VERBANIA)
`
`Page #2 (cid:9)
`
`Initial 9/15/08
`
`000005
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`(cid:9)
`(cid:9)
`

`

`State or Province of Mailing Address::
`
`Country of Mailing Address:: (cid:9)
`
`ITALY
`
`Postal or Zip Code of Mailing Address::
`
`Applicant Authority Type:: (cid:9)
`
`Inventor
`
`Primary Citizenship Country:: (cid:9)
`
`ITALY
`
`Status:: (cid:9)
`
`Given Name:: (cid:9)
`
`Middle Name::
`
`Family Name:: (cid:9)
`
`Name Suffix::
`
`City of Residence:: (cid:9)
`
`State or Province of
`
`Residence::
`
`Full Capacity
`
`MAURO
`
`AJANI
`
`MILANO
`
`Country of Residence:: (cid:9)
`
`ITALY
`
`Street of Mailing (cid:9)
`
`VIA CAROZZI 5
`
`Address:
`
`City of Mailing Address:: (cid:9)
`
`MILANO
`
`State or Province of Mailing Address::
`
`Country of Mailing Address:: (cid:9)
`
`ITALY
`
`Postal or Zip Code of Mailing Address::
`
`Applicant Authority Type:: (cid:9)
`
`Inventor
`
`Primary Citizenship Country:: (cid:9)
`
`ITALY
`
`Status:: (cid:9)
`
`Given Name:: (cid:9)
`
`Middle Name::
`
`Family Name:: (cid:9)
`
`Name Suffix::
`
`City of Residence:: (cid:9)
`
`State or Province of
`
`Residence::
`
`Full Capacity
`
`LORENZO
`
`FOSSATI
`
`MILANO
`
`Country of Residence:: (cid:9)
`
`ITALY
`
`Street of Mailing (cid:9)
`
`VIA CRETA 6
`
`Page #3 (cid:9)
`
`Initial 9/15/08
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`000006
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`

`

`Address::
`
`City of Mailing Address:: (cid:9)
`
`MILANO
`
`State or Province of Mailing Address::
`
`Country of Mailing Address:: (cid:9)
`
`ITALY
`
`Postal or Zip Code of Mailing Address:: 20152
`
`Correspondence Information
`
`Correspondence Customer
`
`00466
`
`Number::
`
`Representative Information
`
`Representative Customer
`
`00466
`
`Number::
`
`Domestic Priority Information
`
`Application::
`
`Continuity
`
`Parent
`
`Parent Filing
`
`Type::
`
`Application::
`
`Date::
`
`This application Continuation of 10/009,532
`
`12/12/01
`
`10/009,532
`
`National Stage of PCT/EP00/05356
`
`6/9/00
`
`Foreign Priority Information
`
`Country::
`
`Application
`
`Filing Date::
`
`Priority
`
`Number::
`
`Claimed::
`
`ITALY
`
`ITALY
`
`MI99A001317
`
`6/14/99
`
`MI2000A000422
`
`3/3/00
`
`Yes
`
`Yes
`
`Page #4 (cid:9)
`
`Initial 9/15/08
`
`000007
`
`(cid:9)
`

`

`Assignment Information
`
`Assignee Name:: (cid:9)
`
`COSMO TECHNOLOGIES LIMITED
`
`Street of Mailing (cid:9)
`
`2 DUNCAIRN TERRACE, BRAY CO
`
`Address:
`
`City of Mailing Address:: (cid:9)
`
`WICKLOW
`
`State or Province of Mailing Address::
`
`Country of Mailing Address:: (cid:9)
`
`IRELAND
`
`Postal or Zip Code of Mailing Address::
`
`Page #5 (cid:9)
`
`Initial 9/15/08
`
`000008
`
`

`

`Controlled Release and Taste-Masking Oral Pharmaceutical Composition
`
`Controlled Release and Taste-Masking Oral Pharmaceutical Composition
`
`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.
`
`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.
`
`TECHNOLOGICAL BACKGROUND
`
`The preparation of a sustained, controlled, delayed, extended or anyhow modified release form can
`
`be carried out according to different techniques:
`
`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.
`
`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.
`
`3. The use of bioerodible matrices, which are capable of being degraded by the anzimes of some
`
`biological compartment.
`
`All the procedures listed above suffer, however, from drawbacks and imperfections.
`
`000009
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`

`

`2
`
`2551-1001-4
`
`Inert matrices, for example, generally entail non-linear, but exponential, release of the active
`
`ingredient.
`
`Hydrophilic matrices: have a linear behaviour until a certain fraction of active ingredient has been
`
`released, then significantly deviate from linear release.
`
`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.
`
`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
`
`The same notion of canalization of an inert matrix is described in U.S. Pat. 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 their 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.
`
`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 bydrophilic matrix which
`
`000010
`
`

`

`3
`
`2551-1001-4
`
`comprises: -dissolution of the active ingredient with gastro resistant hydrophilic polymers in organic
`
`solvents; -diying 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 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. 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
`
`The invention provides controlled release and taste masking oral pharmaceutical compositions
`
`containing as active ingredient budesonide comprising:
`
`a) a matrix consisting of lipophilic compounds with melting point lower than 90[deg.] C. and optionally
`
`by amphiphilic compounds in which the active ingredient is at least partially incorporated;
`
`b) an amphiphilic matrix;
`
`c) an outer hydrophilic matrix in which the lipophilic matrix and the amphiphilic matrix are dispersed;
`
`d) optionally other excipients.
`
`000011
`
`

`

`4
`
`2551-1001-4
`
`A particular aspect of the invention consists of controlled release oral compositions containing as
`
`active ingredient budesonide comprising:
`
`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;
`
`b) an outer hydrophilic matrix in which the lipophilic/amphiphilic matrix is dispersed, preferably by
`
`mixing;
`
`c) optionally other excipients.
`
`A further aspect of the invention provides taste masking oral pharmaceutical compositions
`
`budesonide containing comprising:
`
`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:
`
`an amphiphilic matrix consisting of polar lipids of type I or II or glycols partially etherified with C1-04
`
`alkyl chains;
`
`an outer hydrophilic matrix containing the above matrices, mainly formed by saccharide, dextrin,
`
`polyalcohol or cellulose compounds or by hydrogels or their mixtures;
`
`optional excipients to give stability to the pharmaceutical formulation.
`
`DETAILED DISCLOSURE OF THE INVENTION
`
`The compositions of the invention can be prepared by a method comprising the following steps:
`
`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.
`
`000012
`
`

`

`5
`
`2551-1001-4
`
`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.
`
`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. 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<R> ) 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 triglycerids, the polyethoxylated derivatives thereof, waxes, ceramides,
`
`cholesterol derivatives or mixtures thereof having melting point within the range of 40 to90° 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. An amphiphilic matrix with high content in
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`active ingredient, typically from 5 to 95% w/w, in particular from 20 to 70%, is first prepared by
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`dispersing the active ingredient in a mixture of amphiphilic compounds, such as lecithin, other type II
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`polar lipids, surfactants, or in diethylene glycol monoethyl ether; the resulting amphiphilic matrix is
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`then mixed or Icneaded, usually while hot, with lipophilic compounds suitable to form an inert matrix,
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`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
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`the cited fatty acids, such as mono-, di-, or triglycerids or esters with polyethylene glycols, alone or in
`
`combination with waxes, ceramides, cholesterol derivatives or other apolar lipids in various ratios so
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`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. Alternatively, the order of formation of the inert and amphiphilic
`
`matrices can be reversed, incorporating the inert matrix inside the amphiphilic compounds. The
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`resulting inert lipophilic matrix is reduced into granules by an extrusion and/or granulation process, or
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`any other known processes which retain the homogeneous dispersion and matrix structure of the
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`starting mixture. 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. The
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`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. The
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`compression of the mixture of lipophilic and/or amphiphilic matrix, hydrogel-forming compound and,
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`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. The tablets obtainable according to the invention are
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`subjected to known coating processes with a gastro-resistant film, consisting of, for example, acrylic
`
`and methacrylic acids polymers(Eudragit (R)) or copolymer or cellulose derivatives, such as cellulose
`
`acetophthalate. 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.
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`The compositions of the invention are preferably in the form of tablets, capsules or minitablets. In
`
`terms of dissolution characteristics, contact with water or aqueous fluids causes the immediate
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`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 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
`
`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.
`
`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.
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`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.
`
`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 6.4 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
`
`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%.
`
`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)
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`and, after 15 minutes of mixing, magnesium stearate in a suitable quantity to act as lubricant is
`
`added.
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`After a final blending, tablets of around 300 mg of unitary weight are generated.
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`The core are then subjected to be coated with a suspension obtained introducing into a stainless steel
`
`container 5.8 kg of Eudragit(TM) (methacrylate copolymers), 0.6 kg of triethylcitrate and 3.0 kg of
`
`dyes and talc, using alcohol as solvent.
`
`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.
`
`EXAMPLE 2
`
`Component mg/tablet
`
`Tablet
`
`Budesonide (cid:9)
`
`Stearic Acid (cid:9)
`
`Lecithin (cid:9)
`
`Microcristalline cellulose (cid:9)
`
`Hydroxypropylcellulose (cid:9)
`
`Lactose monohydrate (cid:9)
`
`Silicon dioxide (cid:9)
`
`Magnesium stearate (cid:9)
`
`Coating materials
`
`Eudragit L100 (cid:9)
`
`Eudragit S100 (cid:9)
`
`Talc (cid:9)
`
`Titanium dioxiede (cid:9)
`
`9.0
`
`10.0
`
`10.0
`
`156.0
`
`60.0
`
`50.0
`
`2.0
`
`3.0
`
`14.0
`
`12.0
`
`7.9
`
`4.5
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`Triethylcitrate (cid:9)
`
`Alcohol (cid:9)
`
`1.6
`
`q.s.
`
`According to the present invention, coated tablets individually weighing about 220 mg are obtained.
`
`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
`
`resistant (<5%)
`
`after 1 hour at pH 6.4 resistant (<5%)
`
`after 2 hours at pH 7.2 15%
`
`after 4 hours at pH 7.2 37%
`
`after 8 hours at pH 7.2 91%
`
`EXAMPLE 3
`
`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 polyvinylpirrolidone in water. After drying in a fluid bed and
`
`milling throughout a suitable screen, hydroxypropylmethylcellulose (35.0 kg) and other excipients,
`
`including magnesium stearate as lubricant, in a suitable quantity are added and the mixture is
`
`blended till an homogeneous powder dispersion is obtained.
`
`The powder mixture is subjected to compression in a rotating tabletting machine and the tablets so
`
`obtained are coated in a pan coat with a gastroresistant composition containing Eudragit(TM),
`
`plasticizers, dyes and pigments.
`
`According to the present example, coated tablets individually weighing around 105 mg are obtained.
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`The results of the above described dissolution test are the following (indicated as average value of at
`
`least six tablets):
`
`after 2 h