`
`(12) United States Patent (cid:9)
`Villa et al. (cid:9)
`
`(10) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`US 9,320,716 B2
`*Apr. 26, 2016
`
`(54) CONTROLLED RELEASE AND TASTE
`MASKING ORAL PHARMACEUTICAL
`COMPOSITIONS
`
`(71) Applicant: COSMO TECHNOLOGIES
`LIMITED, Dublin (IE)
`
`(72) Inventors: Roberto Villa, Lecco (IT); Massimo
`Pedrani, Gignese (IT); Mauro Ajani,
`Milan (IT); Lorenzo Fossati, Milan (IT)
`
`(73) Assignee: COSMO TECHNOLOGIES
`LIMITED, Dublin (IE)
`
`* )
`
`Notice: (cid:9)
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 14/308,279
`
`(22) Filed: (cid:9)
`
`Jun. 18, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2014/0302139 Al (cid:9)
`
`Oct. 9, 2014
`
`(56) (cid:9)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,133,863 A
`3,800,051 A
`4,608,248 A
`4,716,041 A
`5,183,815 A
`5,320,848 A
`5,342,625 A
`5,447,729 A
`5,534,501 A
`5,541,170 A
`5,597,844 A
`5,643,602 A
`5,681,584 A
`5,811,388 A (cid:9) *
`5,840,332 A
`5,849,327 A
`5,863,910 A
`5,874,063 A
`5,908,833 A
`5,955,502 A
`5,965,167 A
`6,004,582 A
`6,042,847 A
`6,140,308 A
`6,190,692 B1
`6,214,378 B1
`6,239,120 B1 *
`6,258,377 B1
`6,368,629 B1
`
`5/1964 Tansey
`3/1974 Barnhart et al.
`8/1986 Knecht et al.
`12/1987 Kjomaes et al.
`2/1993 Saari et al.
`6/1994 Geyer
`8/1994 Hauer
`9/1995 Belenduik et al.
`7/1996 Samain
`7/1996 Rhodes et al.
`1/1997 Chauhan
`7/1997 Ulmius
`10/1997 Savastano et al.
`9/1998 Friend et al. (cid:9)
`11/1998 Lerner et al. (cid:9)
`12/1998 Berliner et al.
`1/1999 Bolonick et al.
`2/1999 Briggner et al.
`6/1999 Brattsand et al.
`9/1999 Hansen et al.
`10/1999 Sanghvi
`12/1999 Faour et al.
`3/2000 Kere et al.
`10/2000 Brattsand
`2/2001 Busetti
`4/2001 Tanida et al.
`5/2001 Hallgren et al. (cid:9)
`7/2001 New
`4/2002 Watanabe et al.
`(Continued)
`
` 424/474
` 424/464
`
` 514/174
`
`Related U.S. Application Data
`
`FOREIGN PATENT DOCUMENTS
`
`(63) Continuation of application No. 13/617,138, filed on
`Sep. 14, 2012, now Pat. No. 8,784,888, which is a
`continuation of application No. 13/462,409, filed on
`May 2, 2012, now Pat. No. 8,293,273, which is a
`continuation of application No. 13/249,839, filed on
`Sep. 30, 2011, now abandoned, which is a continuation
`of application No. 12/210,969, filed on Sep. 15, 2008,
`now Pat. No. 8,029,823, which is a
`continuation-in-part of application No. 10/009,532,
`filed as application No. PCT/EP00/05356 on Jun. 9,
`2000, now Pat. No. 7,431,943.
`
`(30) (cid:9)
`
`Foreign Application Priority Data
`
`CA (cid:9)
`DE (cid:9)
`
`11/1998
`2119253 (cid:9)
`3/1993
`41 31 562 (cid:9)
`(Continued)
`
`OTHER PUBLICATIONS
`
`Jantzen, G.M. et al., "Sustained- and Controlled-Release Drug Deliv-
`ery Systems," Modern Pharmaceutics, 3rd Edition, Revised and
`Expanded, pp. 575-609, © 1996 Marcel Dekker, Inc., 37 pages.
`(Continued)
`
`Primary Examiner — Susan Tran
`
`Jun. 14, 1999 (IT) (cid:9)
`Mar. 3, 2000 (IT) (cid:9)
`
` MI99A1317
` MI2000A0422
`
`(74) Attorney, Agent, or Firm Rothwell, Figg, Ernst &
`Manbeck P.C.
`
`(51)
`
`Int. Cl.
`A 61K 9/20 (cid:9)
`A 61K 9/28 (cid:9)
`A 61K 9/16 (cid:9)
`A 61K 9/24 (cid:9)
`A 61K 31/58 (cid:9)
`(52) U.S. Cl.
`CPC (cid:9)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`A61K 9/2866 (2013.01); A61K 9/1617
`(2013.01); A61K 9/209 (2013.01); A61K
`9/2054 (2013.01); A61K 9/2077 (2013.01);
`A61K 9/2846 (2013.01); A 61K 31/58
`(2013.01); A61K 9/1652 (2013.01)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(57) (cid:9)
`
`ABSTRACT
`
`The invention relates to an oral pharmaceutical composition
`comprising an active agent, a macroscopically homogeneous
`structure and a gastro-resistant coating. The macroscopically
`homogeneous structure comprises at least one hydrophilic
`compound and at least one lipophilic compound and/or at
`least one amphiphilic compound. The macroscopically
`homogeneous structure controls the release of the active
`ingredient, and the gastro-resistant film prevents release of
`the active agent in the stomach.
`
`29 Claims, No Drawings
`
`MYLAN Ex 1001, Page 1
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`
`
`US 9,320,716 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4/2002 Akiyama
`6,368,635 B1 (cid:9)
`5/2003 Mantelle
`6,562,363 B1 (cid:9)
`8/2003 Odidi et al.
`6,607,751 B1 (cid:9)
`7,410,651 B2 (cid:9) * 8/2008 Villa et al. (cid:9)
`7,410,652 B2 (cid:9)
`8/2008 Villa et al.
`7,431,943 B1 (cid:9) * 10/2008 Villa et al. (cid:9)
`8,029,823 B2 (cid:9) * 10/2011 Villa et al. (cid:9)
`8,787,888 B2 (cid:9) * 7/2014 Bridge et al. (cid:9)
`8,895,064 B2 (cid:9) * 11/2014 Villa et al. (cid:9)
`2006/0003006 Al (cid:9)
`1/2006 Remon et (cid:9) al.
`2006/0057200 Al (cid:9)
`3/2006 Schaeffler
`2006/0134208 Al (cid:9)
`6/2006 Villa et al.
`2009/0011010 Al (cid:9)
`1/2009 Villa et al.
`2011/0123460 Al (cid:9)
`5/2011 Wilhelm et (cid:9) al.
`2012/0021052 Al (cid:9)
`1/2012 Villa et al.
`2012/0021053 Al (cid:9)
`1/2012 Villa et al.
`2012/0220559 Al (cid:9)
`8/2012 Villa et al.
`
`FOREIGN PATENT DOCUMENTS
`
` 424/468
`
` 424/468
` 424/464
` 455/415
` 424/464
`
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`GB
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`4131562 Al (cid:9)
`0 375 063 Bl (cid:9)
`0 453 001 Al (cid:9)
`0482576 (cid:9)
`0 514 008 (cid:9)
`0 514 008 Al (cid:9)
`0514008
`935639
`63048226
`4159217
`5132416
`6510772
`6511478
`8503482
`2000510488
`2000515130
`9221328 Al
`93/00889 Al
`9305768 Al
`9412180 Al
`9516451 Al
`96/13273
`96/36318 A2
`9800169
`WO 99/11245
`WO 99/17752
`99/39700 Al
`
`3/1993
`6/1990
`10/1991
`4/1992
`11/1992
`11/1992
`11/1992
`9/1963
`2/1988
`6/1992
`5/1993
`12/1994
`12/1994
`4/1996
`8/2000
`11/2000
`12/1992
`1/1993
`4/1993
`6/1994
`6/1995
`5/1996
`11/1996
`1/1998
`3/1999
`4/1999
`8/1999
`
`OTHER PUBLICATIONS
`
`Angelucci et al., "Budesonide for Inflammatory Bowel Disease
`Treatment," Current Medicinal Chemistry, 2008, vol. 15, No. 14, pp.
`2-9.
`D'Haens, G.R. et al., "Budesonide MMXTM Is Active and Safe in
`Patients With Active Left-Sided Ulcerative Colitis," Br J Clinic
`Pharmacol., 2005, vol. 61, 3 pages.
`Sandborn, W.J., "Budesonide MMX® 9mg: Analysis of Pooled Data
`From Two Phase 3 Studies," poster, 1 page.
`Maejima, T., "Application of Tumbling Melt Granulation Method to
`Prepare Controlled-Release Beads by Coating with Mixture of Func-
`tional Non-Meltable and Meltable Materials," Chem. Pharm. Bull.,
`1998, vol. 46, No. 3, pp. 531-533, © 1998 Pharmaceutical Society of
`Japan.
`Sandborn, W.J. et al., "Budesonide MXX® 9mg for the Induction of
`Remission of Mild-to-Moderate Ulcerative Colitis (UC): Data From
`a Multicenter, Randomized, Double-Blind Placebo-Controlled Study
`in North America and India," Presentation at DDW 2011, Poster, 1
`page.
`D'Haens, G.R., et al., "Clinical Trial: Preliminary Efficacy and
`Safety Study of a New Budesonide-MMX® 9mg Extended-Release
`Tablets in Patients With Active Left-Sided Ulcerative Colitis," Jour-
`nal of Crohn's and Colitis, 2010, vol. 4, pp. 153-160, © copyright
`2009 European Crohn's and Colitis Organisation.
`
`Flanders, P. et al., The Control of Drug Release From Conventional
`Melt Granulation Matrices, Drug Development and Industrial Phar-
`macy, 1987, vol. 13, No. 6, pp. 1001-1022, © 1987 Marcel Dekker,
`Inc.
`Ferraboschi, P. et al., "Estimation and Characterisation of
`Budesonide Tablets Impurities," Journal of Pharmaceutical and Bio-
`medical Analysis 2008, vol. 47, pp. 636-640, © 2008 Elsevier B.V.
`Fiorino, G. et al„ "New Drug Delivery Systems in inflammatory
`Bowel Disease: MMXTM and Tailored Delivery to the Gut," Current
`Medicinal Chemistry, 2010, vol. 17, pp. 1851-1857, © 2010 Bentham
`Science Publlishers Ltd.
`Koutroubakis, I., "Recent Advances in the Management of Distal
`Ulcerative Colitis," World Journal of Gastrointestinal Pharmacology
`and Therapeutics, 2010, vol. 1, No. 2, pp. 43-50, © 2010 Baishideng.
`Steward, P., "Review of Pharmaceutical Controlled Release Methods
`and Devices", 1995, pp. 1-9.
`Jantzen, et al., "Sustained/Controlled-Release Drug Delivery", Mod-
`ern Pharmaceutics, 3rd Edition, pp. 582-589.
`Physical Pharmacy, Chapter 19: Drug Product Design, Oct. 1993, pp.
`515-519.
`Moro, et al., "Drug Delivery Systems: Diffusion Controlled Sys-
`tems", II Prodotto Chimico & Aerosol Selezione (The Chemical &
`Aerosol Selection), Apr. 1985, pp. 16-24.
`Brunner, M. et al., "Gastrointestinal Transit, Release and Plasma
`Pharmacokinetics of a New Oral Budesonide Formulation," British
`Journal of Clinical Pharmacology, DOI:10.1111/j.1365-2125.2005.
`02517.x, pp. 1-8, copyright 2005 Blackwell Publishing Ltd., 8 pages.
`Brunner, M. et al., "Gastrointestinal Transit and 5-ASA Release
`From a New Mesalazine Extended-Release Formulation," Alimen-
`tary Pharmacology and Therapeutics, vol. 17, pp. 395-402, copyright
`2003 Blackwell Publishing Ltd., 8 pages.
`JP Office Action dated May 6, 2010 from corresponding JP2001-
`502812-English translation included.
`Lichtenstein, G. et al., Poster, "Effect of Budesonide MMX 6 mg on
`the Hypothalamic-Pituitary-Adrenal (HPA) Axis in Patients with
`Ulcerative Colitis: Results from Phase III, 12 Month Safety and
`Extended User Study," May 2012, San Diego, CA, 1 page.
`Sandborn, W.J. et al, "Once-Daily Budesonide MMX Extended
`Release Tablets Induce Remission in Patients With Mild to Moderate
`Ulcerative Colitis: Results From the CORE I Study," Gastroenterol-
`ogy 2012, Vo. 143, pp. 1218-1226.
`Travis, S. et al., Poster, "Induction of Clinical and Endoscopic Remis-
`sion with Budesonide MMX in Mild-to-Moderately Active Ulcer-
`ative Colitis, Magnitude of Response in Two Phase III Studies," Oct.
`20-24, 2012, Amsterdam, UEG Week, 1 page.
`McNally, P.R., "Literature Review: CORE I & II: Colonic Release
`Budesonide for the Induction of Remission for Mild-Moderate
`Ulcerative Colitis," Visible Human Journal of Endoscopy, vol. 13,
`Issue 1, 2014, 5 pages.
`D'Haens et al., Full page poster: ECCO Congress, Innsbruck, Aus-
`tria, Mar. 1-3, 2007, 1 page.
`D'Haens et al., Partial page poster: Digestive Disease Week, Wash-
`ington, D.C., USA, May 19-24, 2007, 1 page.
`Gen I News Highlight Positive Phase III Data Leads Co smo to Project
`U.S. and EU Filing for UC Drug in 2011; Nov. 8, 2010.
`Nicholls, A., "Bioavailability Profile of Uceris MMX Extended-
`Release Tablets Compared with Entocort EC Capsules in Healthy
`Volunteers," Journal of International Medical Research, 0(0), pp. 1-9,
`copyright The Author(s) 2013.
`Sandborn, et al., "Induction of Clinical and Endoscopic Remission of
`Mild to Moderately Active Ulcerative Colitis with Budesonide MMX
`9mg: Analysis of Pooled Data from Two Phase 3 Studies," poster, 1
`page, presented Oct. 2011 at ECCO (European Crohn's and Colitis
`Organisation).
`Santarus Submits IND for Phase III Clinical Testing of Rifamycin SV
`MMX in Travelers' Diarrhea, Dec. 30, 2009.
`Spurio et al., "Low Bioavailability and Traditional Systemic Steroids
`in IBD: Can the Former Take Over the Latter?," Journal of
`Gastrointestinal and Liver Diseases, Mar. 2013, vol. 22, No. 1, pp.
`65-71.
`
`MYLAN Ex 1001, Page 2
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`
`
`US 9,320,716 B2
`Page 3
`
`(56) (cid:9)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Travis et al., "Once-Daily Budesonide MMX in Active, Mild-to-
`Moderate Ulcerative Colitis: Results From the Randomised CORE II
`Study," Gut, published online Feb. 22, 2013, doi: 10.1136/gutjnl-
`2012-304258, 9 pages.
`Remington, The Science and Practice of Pharmacy, 21st Edition, Part
`6—Pharmacodynamics and Pharmacokinetics, Chapter 58: Basic
`Pharmacokinetics and Pharmacodynamics, pp. 1180-1183, Lip-
`pincott Williams & Wilkins, Philadelphia, 2006, 8 pages total, includ-
`ing pp. 1180-1183.
`Kshirsagar, S.J. et al., "In Vitro In Vivo Comparison of Two pH
`Sensitive Eudragit Polymers for Colon Specific Drug Delivery," Jour-
`nal of Pharmaceutical Sciences and Research, 2009, vol. 1, No. 4, pp.
`61-70.
`Campieri, M. et al., "Oral Budesonide is as Effective as Oral
`Prednisolone in Active Crohn's Disease," Gut, 1997, vol. 41, pp.
`209-214.
`
`Handbook of Pharmaceutical Excipients, Sixth Edition, Rowe, R.C.
`et al., Eds., Pharmaceutical Press and American Pharmacists Asso-
`ciation, London, 2009,14 pages, including pp. 385-387 and 697-699.
`Porro, G.B. et al., "Comparative Trial of Methylprednisolone and
`Budesonide Enemas in Active Distal Ulcerative Colitis," European
`Journal of Gastroenterology & Hepatology, 1994, vol. 6, No. 2, pp.
`125-130, © Current Science Ltd.
`McLeod, A.D. et al., "Kinetic Perspectives in Colonic Drug Deliv-
`ery," in Oral Colon-Specific Drug Delivery, pp. 106-108, (David R.
`Friend ed., CRC Press 1992).
`Akhgari, A. et al., "Statistical Optimization of Indomethacin Pellets
`Coated with pH-Dependent Methacrylic Polymers for Possible
`Colonic Drug Delivery," International Journal of Pharmaceutics,
`305, (2005), pp. 22-30, copyright 2005 Elsevier B.V.
`Remington' S Pharmaceutical Sciences (18th Edition 1990), p. 390,
`plus cover page.
`
`* cited by examiner
`
`MYLAN Ex 1001, Page 3
`
`
`
`US 9,320,716 B2
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`20 (cid:9)
`
`1
`CONTROLLED RELEASE AND TASTE
`MASKING ORAL PHARMACEUTICAL
`COMPOSITIONS
`
`2
`Hydrophilic matrices have a linear behaviour until a certain
`fraction of active ingredient has been released; then they
`significantly deviate from linear release.
`Bioerodible matrices are ideal to carry out the so-called
`5 "site-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
`This application is a continuation of application Ser. No. (cid:9)
`toxicologically inert.
`13/617,138 filed on Sep. 14, 2012, now U.S. Pat. No. 8,784, (cid:9)
`A number of formulations based on inert lipophilic matri-
`888; which is a continuation of application Ser. No. 13/462, 10 ces have been described: Drug Dev. Ind. Pharm. 13 (6), 1001-
`1022, (1987) discloses a process making use of varying
`409 filed on May 2, 2012, now U.S. Pat. No. 8,293,273; which
`is a continuation of Ser. No. 13/249,839 filed on Sep. 30, (cid:9)
`amounts of colloidal silica as a porization element for a lipo-
`2011, now abandoned; which is a continuation of application (cid:9)
`philic inert matrix in which the active ingredient is incorpo-
`Ser. No. 12/210,969 filed on Sep. 15, 2008, which reissued as (cid:9)
`rated.
`(cid:9) 15 (cid:9)
`The same notion of canalization of an inert matrix is
`U.S. Pat. No. RE43,799 from U.S. Pat. No. 8,029,823; which
`described in U.S. Pat. No. 4,608,248 in which a small amount
`is a continuation-in-part of application Ser. No. 10/009,532
`filed on Dec. 12, 2001, now U.S. Pat. No. 7,431,943; which is (cid:9)
`of a hydrophilic polymer is mixed with the substances form-
`ing an inert matrix, in a non sequential compenetration of
`the 35 U.S.C. 371 national stage of International application
`different matrix materials.
`PCT/EP00/05356 filed on Jun. 9, 2000; which claimed prior-
`EP 375,063 discloses a technique for the preparation of
`ity (cid:9)
`to Italian applications MI2000A000422 and
`MI99A001317 filed Mar. 3, 2000 and Jun. 14, 1999, respec- (cid:9)
`multiparticulate granules for the controlled-release of the
`active ingredient which comprises co-dissolution of poly-
`tively. The entire contents of each of the above-identified
`applications are hereby incorporated by reference. (cid:9)
`mers or suitable substances to form a inert matrix with the
`active ingredient and the subsequent deposition of said solu-
`The present invention relates to controlled release and
`taste-masking compositions containing one or more active 25 tion on an inert carrier which acts as the core of the device.
`principles incorporated in a three-component matrix struc- (cid:9)
`Alternatively, the inert carrier is kneaded with the solution
`ture, i.e. a structure formed by successive amphiphilic, lipo- (cid:9)
`containing the inert polymer and the active ingredient, then
`the organic solvent used for the their dissolution is evaporated
`philic or inert matrices and finally incorporated or dispersed
`in hydrophilic matrices. The use of a plurality of systems for (cid:9)
`off to obtain a solid residue. The resulting structure is a
`the control of the dissolution of the active ingredient modu- 30 "reservoir", i.e. is not macroscopically homogeneous along
`lates the dissolution rate of the active ingredient in aqueous (cid:9)
`all the symmetry axis of the final form.
`and/or biological fluids, thereby controlling the release kinet- (cid:9)
`The same "reservoir" structure is also described in Chem.
`Pharm. Bull. 46 (3), 531-533, (1998) which improves the
`ics in the gastrointestinal tract, and it also allows the oral
`administration of active principles having unfavourable taste (cid:9)
`application through an annealing technique of the inert poly-
`characteristics or irritating action on the mucosae of the 35 mer layer which is deposited on the surface of the pellets.
`administration site, particularly in the buccal area. (cid:9)
`To the "reservoir" structure also belong the products
`The compositions of the invention can contain active prin- (cid:9)
`obtained according to the technique described in WO
`ciples belonging to the therapeutical classes of analgesics, (cid:9)
`93/00889 which discloses a process for the preparation of
`antiinflammatories, cardioactives, tranquillizers, antihyper- (cid:9)
`pellets in hydrophilic matrix which comprises:
`tensives, disinfectants and topical antimicrobials, antiparkin- (cid:9) 40 (cid:9)
`dissolution of the active ingredient with gastro-resistant
`hydrophilic polymers in organic solvents;
`son drugs, antihistamines and are suitable to the oral admin-
`drying of said suspension;
`istration or for acting topically at some areas of the
`gastrointestinal tract. (cid:9)
`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"
`The preparation of a sustained, controlled, delayed or any- (cid:9)
`structure inserted in a hydrophilic matrix. The basic multi-
`how modified release form can be carried out according to (cid:9)
`particulate utilizes two coating membranes to decrease the
`different known techniques: (cid:9)
`release rate of the active ingredient, a pH-dependent mem-
`1. The use of inert matrices, in which the main component 50 brave with the purpose of gastric protection and a pH-inde-
`of the matrix structure opposes some resistance to the (cid:9)
`pendent methacrylic membrane with the purpose of slowing
`penetration of the solvent due to the poor affinity
`down the penetration of the aqueous fluid.
`towards aqueous fluids; such property being known as
`WO 95/16451 discloses a composition only formed by a
`lipophilia. (cid:9)
`hydrophilic matrix coated with a gastro-resistant film for
`2. The use of hydrophilic matrices, in which the main 55 controlling the dissolution rate of the active ingredient.
`component of the matrix structure opposes high resis- (cid:9)
`When preparing sustained-, controlled-release dosage
`tance to the progress of the solvent, in that the presence
`forms of a medicament topically active in the gastrointestinal
`of strongly hydrophilic groups in its chains, mainly (cid:9)
`tract, it is important to ensure a controlled release from the
`branched, remarkably increases viscosity inside the
`first phases following administration, i.e. when the inert
`hydrated layer. (cid:9)
`60 matrices have the maximum release rate inside the logarith-
`3. The use of bioerodible matrices, which are capable of
`mic phase, namely the higher deviation from linear release.
`being degraded by the enzymes of some biological com- (cid:9)
`Said object has been attained according to the present
`partment. (cid:9)
`invention, through the combination of an amphiphilic matrix
`All the procedures listed above suffer, however, from draw- (cid:9)
`inside an inert matrix, the latter formulated with a lipophilic
`backs and imperfections. (cid:9)
`65 polymer in a superficial hydrophilic matrix. The composi-
`Inert matrices, for example, generally entail non-linear, but
`tions of the invention are characterized by the absence of a
`exponential, release of the active ingredient. (cid:9)
`first phase in which the medicament superficially present on
`
`TECHNOLOGICAL BACKGROUND
`
`45 (cid:9)
`
`MYLAN Ex 1001, Page 4
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`(cid:9)
`(cid:9)
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`US 9,320,716 B2
`
`3
`the matrix is quickly solubilized, and by the fact the
`amphiphilic layer compensate the lack of affinity of the aque-
`ous solvent with the lipophilic compounds forming the inner
`inert matrix.
`
`DISCLOSURE OF THE INVENTION
`
`5
`
`4
`caused by the dissolution of the medicament inglobated
`inside the inert matrix, which is in its turn inside the hydro-
`philic matrix.
`The amphiphilic compounds which can be used according
`to the invention comprise polar lipids of type I or II (lecithin,
`phosphatidylcholine, phosphatidylethanolamine), ceram-
`ides, glycol alkyl ethers such as diethylene glycol monom-
`ethyl ether (Transcutol®).
`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 triglycer-
`ides, the polyethoxylated derivatives thereof, waxes, ceram-
`ides, cholesterol derivatives or mixtures thereof having a
`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 remark-
`ably increasing the hydrophilic matrix viscosity following
`penetration of the solvent front until contact with the lipo-
`philic matrix granules dispersed inside.
`According to an embodiment of the invention, an
`amphiphilic matrix with high content in active ingredient,
`typically from 5 to 95% w/w, is first prepared by dispersing
`the active ingredient or the mixture of active ingredients in a
`mixture of amphiphilic compounds, such as lecithin, other
`type II polar lipids, surfactants, or in diethylene glycol mono-
`ethyl ether; the resulting amphiphilic matrix is then mixed or
`kneaded, usually while hot, with lipophilic compounds suit-
`able 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.
`Alternatively, the order of formation of the inert and
`amphiphilic matrices can be reversed, incorporating the inert
`matrix inside the amphiphilic compounds.
`The resulting inert lipophilic matrix is reduced into gran-
`ules by an extrusion and/or granulation process, or any other
`known processes which retain the homogeneous dispersion
`and matrix structure of the 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 mol-
`ecules 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 meth-
`acrylic acid polymers or copolymers, alkylvinyl polymers,
`hydroxyalkyl celluloses, carboxyalkyl celluloses, polysac-
`charides, dextrins, pectins, starches and derivatives, natural or
`synthetic gums, alginic acid.
`In case of taste-masking formulations, the use of polyal-
`cohols such as xylitol, maltitol and mannitol as hydrophilic
`compounds can also be advantageous.
`The lipophilic matrix granules containing the active ingre-
`dient 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 sub-
`
`10
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`15
`
`The invention provides controlled release and taste mask-
`ing oral pharmaceutical compositions containing an active
`ingredient, comprising:
`a) a matrix consisting of lipophilic compounds with melt-
`ing point lower than 90° C. and optionally by amphiphilic
`compounds in which the active ingredient is at least partially
`incorporated;
`b) optionally an amphiphilic matrix;
`c) an outer hydrophilic matrix in which the lipophilic
`matrix and the optional amphiphilic matrix are dispersed;
`d) optionally other excipients.
`A particular aspect of the invention consists of controlled
`release oral compositions containing one or more active 20
`ingredients comprising:
`a) a matrix consisting of amphiphilic compounds and lipo-
`philic 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/ 25
`amphiphilic matrix is dispersed;
`c) optional other excipients.
`A further aspect of the invention provides taste masking
`oral pharmaceutical compositions containing one or more
`active ingredients 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 35
`II or glycols partially etherified with Cl -C4 alkyl chains;
`an outer hydrophilic matrix containing the above matrices,
`mainly formed by saccharide, dextrin, polyalcohol or cellu-
`lose compounds or by hydrogels;
`optional excipients to give stability to the pharmaceutical 40
`formulation.
`
`30
`
`DETAILED DISCLOSURE OF THE INVENTION
`
`The compositions of the invention can be prepared by a 45
`method comprising the following steps:
`a) the active ingredient is first inglobated by simple knead-
`ing or mixing in a matrix or coating consisting of compounds
`having amphiphilic properties, which will be further specified
`below. The active principle(s) can be mixed with the 50
`amphiphilic compounds without the aid of solvents or with
`small amounts of water-alcoholic solvents.
`b) The matrix obtained in a) is incorporated in a low melt-
`ing lipophilic excipient or mixture of excipients, while heat-
`ing to soften and/or melt the excipient itself, which thereby 55
`incorporates the active ingredient by simple dispersion. After
`cooling at room temperature an inert matrix forms, which can
`be reduced in size to obtain inert matrix granules containing
`the active ingredient particles.
`c) The inert matrix granules are subsequently mixed 60
`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 bio-
`logical fluids, a high viscosity swollen layer is formed, which
`coordinates the solvent molecules and acts as a barrier to 65
`penetration of the aqueous fluid itself inside the new struc-
`ture. Said barrier antagonizes the starting "burst effect"
`
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`US 9,320,716 B2
`
`EXAMPLE 1
`
`5
`6
`stances to provide compositions in which the active ingredi-
`distension of the polymeric chains of the hydrogels, giving
`ent is dispersed both in the lipophilic and the hydrophilic
`rise to a high viscosity hydrated front which prevents the
`matrix, said compositions being preferably in the form of
`further penetration of the solvent itself linearly slowing down
`tablets, capsules and/or minitablets.
`the dissolution process to a well determined point which can
`The compression of the mixture of lipophilic and/or 5
`be located at about half the thickness, until the further pen-
`amphiphilic matrix, hydrogel-forming compound and,
`etration of water would cause the disintegration of the hydro-
`optionally, active ingredient not inglobated in the lipophilic
`philic layer and therefore the release of the content which,
`matrix, yields a macroscopically homogeneous structure in
`consisting of inert matrix granules, however induces the dif-
`all its volume, namely a matrix containing a dispersion of the
`fusion mechanism typical of these structures and therefore
`lipophilic granules in a hydrophilic matrix. A similar result 1
`o further slows down the dissolution profile of the active ingre-
`can also be obtained by coating the lipophilic matrix granules
`dient.
`with a hydrophilic polymer coating.
`The presence of the amphiphilic matrix inside the lipo-
`The tablets obtainable according to the invention can
`philic matrix inert allows to prevent any unevenness of the
`optionally be subjected to known coating processes with a
`release profile of the active ingredient. The surfactants
`gastro-resistant film, consisting of, for example, methacrylic 1
`5 present in the amphiphilic portion promote wettability of the
`acids polymers (Eudragit®) or cellulose derivatives, such as
`porous canaliculuses which cross the inert matrix preventing
`cellulose acetophthalate.
`or reducing resistance to penetration of the solvent inside the
`Active ingredients which can conveniently be formulated
`inert matrix.
`according to the invention comprise:
`To obtain taste masking tablets, the components of the
`analgesics, such as acetaminophen, phenacetin, sodium 2
`o hydrophilic matrix are carefully selected to minimize the
`salicylate; antitussives, such as dextromethorphan, codeine
`active substance release time through penetration accelerated
`phosphate;
`by the canalization induced by the hydrophilic compound.
`bronchodilators, such as albuterol, procaterol;
`The following Examples illustrate the invention in greater
`antipsychotics, such as haloperidol, chlorpromazine;
`detail.
`antihypertensives and coronary-dilators, such as isosor- 25
`bide mono- and dinitrate, captopril;
`selective P2 antagonists such as salbutamol, terbutaline,
`ephedrine, orciprenaline sulfate;
`calcium antagonists, such as nifedipine, nicardipine, dilt-
`iazem, verapamil;
`antiparkinson drugs, such as pergolide, carpidopa,
`levodopa;
`non steroid anti-inflammatory drugs, such as ketoprofen,
`ibuprofen, diclofenac, diflunisal, piroxicam, naproxen,
`ketorolac, nimesulide, thiaprophenic acid, mesalazine
`(5-aminosalicylic acid); antihistamines, such as terfenedine,
`loratadine;
`antidiarrheals and intestinal antiinflammatories, such as
`loperamide, 5-aminosalicylic, olsalazine, sulfasalazine,
`budeno side ;
`spasmolytics such as octylonium bromide;
`anxiolytics, such as chlordiazepoxide, oxazepam,
`medazepam, alprazolam, donazepam, lorazepan;
`oral antidiabetics, such as glipizide, metformin, phen-
`formin, gilclazide, glibenclamide;
`cathartics, such as bisacodil, sodium picosulfate;
`antiepileptics, such as valproate, carbamazepine, pheny-
`loin, gabapentin;
`antitumorals, such as flutamide, etoposide;
`oral cavity disinfectants or antimicrobials, such as benza- so
`lkonium chloride, cetylpyridinium chloride or tibezonium
`iodide, and some amino derivatives such as benzydamine and
`chlorhexidine as well as the salts and derivatives thereof;
`sodium fluoride.
`The compositions of the invention can further contain con-
`ventional excipients, for example bioadhesive excipients
`such as chitosans, polyacrylamides, natural or synthetic
`gums, acrylic acid polymers.
`The compositions of the invention can contain more than
`one active ingredient, each of them being optionally con-
`tained in the hydrophilic matrix or in the