PROVISIONAL APPLICATION COVER SHEET
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`This is a request for filing a PROVISIONAL APPLICATION under 37 CFR ’l.53(c).
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`Docket Number 11913.6003-00000 - Type a plus sign (+) inside this box a
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`TITLE OF INVENTION (500 characters max)
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` FORMULATIONS
`CORRESPONDENCE ADDRESS
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`FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, L.L.P., Customer Number 22,852
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`ENCLOSED APPLICATION PARTS (check all that apply)
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`E Specification: 44 Pages
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`[:I Drawing(s):
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`[Number] Sheets/[Number] Figures
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`[Number] Pages; [Description]
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`METHOD OF PAYMENT
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`$250.00
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`herewith.
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`Total Number of Pages of specification, drawings,
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`If more
`sequence or computer listing, or other papers 45.
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`The Commissioner is hereby
`than 100 pages, add $310 for each additional 50 pages or
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`deficiency or credit any
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`The invention was made by an agency of the United States Government or under a contract with an
`agency of the United States Government.
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`E No.
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`[:I Yes, the name of the US. Government agency and the Government contract number are:
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`Respectfully submitted on behalf of the patent practitioners associated with Customer Number 22,852,
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`I
`‘09
`SIGNATURE W U
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`Date June 29,2012
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`TYPED OR PRINTED NAME Wen Li, PhD.
`Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P.
`Telephone: 650.849.6649
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`REGISTRATION NO. 62,185
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`[:1 Additional inventors are being named on separately numbered sheets attached hereto.
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`PROVISIONAL APPLICATION FILING ONLY
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`SAN EX 1014, Page 1
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`SAN EX 1014, Page 1
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`Attorney Docket No. 1 1913.6003-00000
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`FORMULATIONS
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`Inventor
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`David Goldstein
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`SAN EX 1014, Page 2
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`Attorney Docket No: 11913.6003-00000
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`FORMULATIONS
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`The present disclosure provides certain oral pharmaceutical formulations of ibrutinib,
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`certain methods for their administration, certain processes of their production, and certain
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`uses of these formulations for the treatment of diseases treatable by ibrutinib such as cancer
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`and autoimmune diseases.
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`Bruton’s tyrosine kinase (BTK) is a member of the Tec tyrosine kinase family. BTK
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`is expressed in most hematopoietic cells such as B cells, mast cells, and macrophages but not
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`in T cells, natural killer cells, and plasma cells. Btk plays a role in the development and
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`activation of B cells. Mutations in the human BTK gene cause the inherited disease X—linked
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`agammaglobulinemia (XLA), with lack of peripheral B cells and low levels of serum 1g. In
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`XLA, the primary immune deficit is B cell specific. The development of drugs which inhibit
`BTK can have therapeutic significance in the treatment of both B cell—related hematological
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`cancers (e. g. non—Hodgkin lymphoma (NHL) and B cell chronic lymphocytic leukemia (B-
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`CLL), and autoimmune diseases (eg. rheumatoid arthritis, Sjogrens syndrome, IBD, lupus,
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`and asthma).
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`PCT—32765 (ibrutinib) is disclosed in US. Patent No. 7,514,444, issued on April 7,
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`2009, and has the following structure:
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`0
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`NH2 0
`O N
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`O
`N’lv
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`Ibrutinib is an orally available drug that targets Bruton’s tyrosine kinase (BTK).
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`Ibrutinib, is an irreversible small molecule BTK inhibitor that is in Ph lb/II of clinical trials
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`in a variety of B—cell malignancies including chronic lymphocytic leukemia (CLL), small
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`lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and diffuse large B—cell
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`lymphoma (DLBCL) and multiple myeloma (cancer of plasma cells, a type of white blood
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`cell present in bone marrow). At present ibrutinib is administered orally in clinical trials, via
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`the gastrointestinal tract, at high clinical doses (420 nag/day or 840 mg/day) to patients with
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`CLL and SLL to obtain the desired thereapeutic effect. The need for such high doses of
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`Attorney Docket No: l 1913.6003—00000
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`ibrutinib may be due to low bioavailability (the oral bioavailability of ibrutinib is reported to
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`be 22.8% in rats) and may be responsible for the adverse side effects associated with the use
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`of ibrutinib such as nausea or emesis, dizziness and diarrhea. Moreover, low bioavailability
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`results in more variable absorption and potential variability of the desired therapeutic
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`response.
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`As stated above, at present ibrutinib is administered orally, via the gastrointestinal
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`tract, at high clinical doses (420 mg/day or 840 mg/day) to patients to obtain the desired
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`clinical benefit. It is presently disclosed that when ibrutinib is administered intraduodenally
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`versus via the gastrointestinal tract in rats, the oral bioavailability of ibrutinib unexpectedly
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`increased from 21 % to l00% as determined by AUC. This unexpected increase in oral
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`bioavailability of ibrutinib can translate into a number of desirable practical benefits. The
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`increase in oral bioavailability should enable administration of ibrutinib at a significantly
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`lower therapeutically effective dose than is currently being used. The lower variability
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`associated with this greater bioavailability should lead to a more reliable therapeutic response
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`as well as more predictable drug absorption. And avoidance of exposure of Ibtrutinib to the
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`stomach and/or use of lower therapeutically effective dose of ibrutinib can reduce or
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`altogether eliminate potential adverse side effects of this drug such as diahrrea, nausea or
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`emesis, and dizziness. US. Patent No. 7,514,444, mentioned above, discloses administration
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`of 002—5000 mg/kg andl»1500 mg of ibrutinib/per day and in clinical trials 420 or 840
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`mg/day of ibrutinib is being administered to the patients with CLL and SLL. There is no
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`reasonable expectation n the art that ibrutinib can be adminstered orally at lower efficacious
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`doses to the patients with CLL and SLL, particularly as evidenced by the 420 or 840 mg/day
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`of ibrutinib being administered in clinical trials to those patients. Moreover, other than for
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`active agents that are unstable in the stomach or at acidic pH delivery of any active agent
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`with low bioavailability further along in the gastrointestinal tract reduces the path length for
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`drug absorption and would be expected to reduce bioavailability. That is a reason why it was
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`unexpected that delivery of ibruntinib directly to the small intestine results in greater
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`bioavailability.
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`Accordingly, in one aspect, the present disclosure provides a solid oral dosage form
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`comprising:
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`(i)
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`(ii)
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`ibrutinib and/or a pharmaceutically acceptable salt thereof;
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`means for release of ibrutinib in the intestine; and
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`(iii)
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`at least one pharmaceutically acceptable excipient.
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`In one embodiment of above aspect, ibrutinib and/or a pharmaceutically acceptable
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`salt thereof is released in the small intestine.
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`In one embodiment,, ibrutinib and/or a
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`Attorney Docket No: 1 1913.6003-00000
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`pharmaceutically acceptable salt thereof is released to a region of the intestine in which the
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`pH is about 5, or 5, or greater than 5. In another embodiment, said ibrutinib and/or a
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`pharmaceutically acceptable salt thereof is released to a region of the intestine in which the
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`pH is about 5.5, or greater than about pH 5.5 or 5.5. For example, the release is in one or
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`more of the duodenum, jejunum, ileum, and colon. In one embodiment, the release is in one
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`or more of the duodenum, jejunum, or ileum. In one embodiment, the release to the above
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`regions of the intestine is achieved by coating ibrutinib and/or a pharmaceutically acceptable
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`salt thereof or the dosage form containing ibrutinib and/or a pharmaceutically acceptable salt
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`thereof with at least one coating chosen from enteric coatings and non—enteric time-delayed
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`release coatings. In one embodiment, the release to the above regions of the intestine is
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`achieved by coating ibrutinib and/or a pharmaceutically acceptable salt thereof or the dosage
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`form containing ibrutinib and/or a pharmaceutically acceptable salt thereof with at least one
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`coating chosen from enteric coatings. In one embodiment, the release to the above regions of
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`the intestine is achieved by coating ibrutinib and/or a pharmaceutically acceptable salt thereof
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`or the dosage form containing ibrutinib and/or a pharmaceutically acceptable salt thereof with
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`at least one coating chosen from enteric coatings wherein the enteric coatings are choseb
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`from polymeric coatings. When a non-enteric coating is employed, the time—delayed release
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`dosage forms are administered in fasted state and the time-delayed release coating is designed
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`to erode, burst, or become hightly permeable in about 0.3 to about 3 hours, and preferably in
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`about 0.5 to about 2 hours after administration to release ibrutinib and/or a pharmaceutically
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`acceptable salt thereof.
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`In a second aspect, the present disclosure provides a solid oral dosage form
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`comprising:
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`(i)
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`(ii)
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`ibrutinib and/or a pharmaceutically acceptable salt thereof;
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`means for increasing the oral bioavailability of ibrutinib, as measured by the
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`area under the curve (AUC), as compared to when said ibrutinib and/or said pharmaceutically
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`acceptable salt thereof are administered in an immediate release dosage form; and
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`(iii)
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`at least one pharmaceutically acceptable excipient.
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`In one embodiment of the second aspect, the increase in the oral bioavailability of
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`ibrutinib and/or a pharmaceutically acceptable salt thereof is due to the release of the
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`ibrutinib and/or a pharmaceutically acceptable salt thereof in the intestine. In another
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`embodiment of the second aspect, the increase in the oral bioavailability of ibrutinib and/or a
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`pharmaceutically acceptable salt thereof is due to the release of the ibrutinib and/or a
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`pharmaceutically acceptable salt thereof in the small intestine. In another embodiment of the
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`second aspect, ibrutinib and/or a pharmaceutically acceptable salt thereof is released in in
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`SAN EX 1014, Page 5
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`Attorney Docket No: 11913.6003-00000
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`one or more of the duodenum, jejunum, or ileum.
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`In one embodiment, the release to the
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`above regions of the intestine is achieved by coating ibrutinib and/or a pharmaceutically
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`acceptable salt thereof or a a dosage form containing ibrutinib and/or a pharmaceutically
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`acceptable salt thereof with at least one coating chosen from enteric coatings and a non—
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`enteric time—delayed release coatings. When the delayed release dosage forms are
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`administered in fasted state, the time-delayed release coating is designed to erode, burst, or
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`become very permeable in about 0.3 to about 3 hours, and preferably in about 0.5 to about 2
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`hours after administration to release ibrutinib and/or a pharmaceutically acceptable salt
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`thereof. When the dosage form comprised of said compound is coated with a non-enteric
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`coating, it is generally administered in the fasted state to avoid variability or delays in gastric
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`emptying with meals and the resulting variability in the initiation of efficacious plasma
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`levels.
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`In a third aspect, the present disclosure provides a solid oral dosage form comprising:
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`(i)
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`(ii)
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`ibrutinib and/or a pharmaceutically acceptable salt thereof;
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`at least one coating chosen from enteric coatings and non-enteric time-delayed
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`release coatings; and
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`(ii)
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`at least one pharmaceutically acceptable excipient.
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`In one embodiment,the said at least one coating is chosen from enteric coatings. In
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`one embodiment,the said at least one coating is chosen from polymeric coatings.
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`In one
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`2O
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`embodiment, the said at least one coating is chosen from enteric coatings where the enteric
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`coating is a polymer which erodes to release ibrutinib and/or a pharmaceutically acceptable
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`salt thereof at about pH 5 and above. In another embodiment, ibrutinib and/or a
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`pharmaceutically acceptable salt thereof is released at about pH 5.5 and above or from about
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`5.5 to about 6.5. In yet another embodiment of the third aspect, ibrutinib and/or a
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`pharmaceutically acceptable salt thereof is released in one or more of the duodenum,
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`jejunum, or ileum. In one embodiment, of the third aspect and embodiments contained
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`therein the dosage form is coated. In one embodiment, of the third aspect and embodiments
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`contained therein said ibrutinib and said pharmaceutically acceptable salt thereof are coated.
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`In a fourth aspect, the present disclosure provides a solid oral dosage from
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`comprising:
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`(i)
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`about 20 mg to about 450 mg of ibrutinib and/or a pharmaceutically
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`acceptable salt thereof;
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`(ii)
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`at least one coating chosen from an enteric coating and/or a non—enteric time—
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`delayed release coating; and
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`(iii)
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`at least one pharmaceutically acceptable excipient;
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`SAN EX 1014, Page 6
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`Attorney Docket No: 11913.6003-00000
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`wherein said oral dosage form increases the oral bioavailability, as measured by the
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`area under the curve (AUC), of said ibrutinib and/or said pharmaceutically acceptable salt
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`thereof by at least 20% as compared to the bioavailability obtained from an immediate release
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`solid oral dosage form comprising the same dose of said ibrutinib and/or said
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`pharmaceutically acceptable salt thereof and said at least one pharmaceutically acceptable
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`excipient under same conditions . In embodiment the increase in bioavailability is at least
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`30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% , or 100%. In one
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`embodiment the increase in bioavailability is independently at least 70%, or 75%, or 80%, or
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`85%, or 90% , 95% or 100% .
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`In one embodiment of one to fouth aspect and embodiments contained therein, the
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`dosage from contains from about 20 mg to about 450 mg of said ibrutinib and/or said
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`pharmaceutically acceptable salt thereof. In another embodiment of fouth aspect and
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`embodiments contained therein, the dosage form contains from about 20 mg to about 420 mg
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`of said ibrutinib and/or said pharmaceutically acceptable salt thereof. In another embodiment
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`of fourth aspect and embodiments contained therein, the dosage form contains from about 20
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`or 30 mg to about 300 or 350 mg of said ibrutinib and/or said pharmaceutically acceptable
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`salt thereof. In another embodiment of fourth aspect and embodiments contained therein, the
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`dosage form contains from about 50 mg to about 200, or 220, or 250 mg of said ibrutinib
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`and/or said pharmaceutically acceptable salt thereof.
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`In one embodiment, the solid oral dosage forms disclosed above are coated with at
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`least one coating chosen from enteric coatings and non-enteric time—delayed release coatings.
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`Within this embodiment, in one embodiment, the at least one coating is chosen from enteric
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`coatings. Within the above embodiments, the enteric coatings are chosen from polymeric
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`coatings.
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`In another embodiment, the solid oral dosage form disclosed above comprise ibrutinib
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`and/ a pharmaceutically acceptable salt thereof that are coated with at least one coating
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`chosen from enteric coatings and non—enteric time—delayed release coatings. Within this
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`embodiment, in one embodiment, the at least one coating is chosen from enteric coatings.
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`Within the above embodiments, the enteric coatings are chosen from polymeric coatings.
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`In one embodiment, the solid oral dosage forms are a tablet or capsule. When the
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`dosage form is capsule, ibrutinib and/or a pharmaceutically acceptable salt thereof can be
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`present in a non-solid form. In another embodiment, the solid oral dosage form disclosed
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`above comprise ibrutinib.
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`The therapeutically effective amount of ibrutinib and/or a pharmaceutically
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`acceptable salt thereof when administered into the intestine by bypassing the stomach can be
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`SAN EX 1014, Page 7
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`Attorney Docket No: 11913.6003-00000
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`from about 20 mg per day to about 450 mg/day, or 20 mg/day to about 420 mg/day; or about
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`20 mg/day or 30 mg/day to about 300 or 350 mg/day; or about 30 or 50 mg/day to about 200,
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`or 220 or 250 mg/day; or about 30 or 50 mg/day to about 100 or 150 mg/day and can be
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`administered in single or multiple doses. Accordingly, any of the formulation disclosed
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`herein, can contain from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,
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`90, 95, 100,110,115,120,125,130,135,140,l45,150,155,160,175,170,175,l80,185,
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`190, 195, 200, 225, 250, 300, 325, 350, 375, 400, 425, or 450 milligrams ofibrutinib or a
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`pharmaceutically acceptable salt thereof. In one embodiment, the tablets or capsules can
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`contain about 20, 25, 30, 50, 75, 100, 150, 200, or 220 milligrams of ibrutinib and/or a
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`pharmaceutically acceptable salt thereof.
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`In one embodiment, any of the formulations disclosed herein contain, unless stated
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`otherwise, one or more pharmaceutically acceptable excipient(s) such as glidants, polymers,
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`binders, surfactants, disintegrants, diluents, buffering agents, antiadherents, retardants,
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`solubilizers, antioxidants, antifoaming agents, fillers, flavors, colors, lubricants, sorbents,
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`plasticizers, or sweeteners, preservatives, or mixtures thereof, which facilitate processing of
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`ibrutinib and/or a pharmaceutically acceptable salt thereof or into preparations which can be
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`used pharmaceutically. Any of the well-known techniques and excipients may be used as
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`suitable and as understood in the art, see for example, Remington: The Science and Practice
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`of Pharmacy, Nineteenth Ed., (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John
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`E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA. 1975;
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`Liberman, H. A. and Lachman, L., Eds, Pharmaceutical Dosage Forms, Marcel Decker, New
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`York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh
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`Ed. (Lippincott Williams & Wilkins 1999), which are herein incorporated by reference in
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`their entirety.
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`In certain embodiments, the formulations may include one or more pH adjusting
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`agents or buffering agents, for example, acids such as acetic, boric, citric, lactic, phosphoric
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`and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate,
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`sodium citrate, sodium acetate, sodium lactate and tris—hydroxymethylaminomethane; and
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`buffers such as citrate/dextrose, sodium bicarbonate, ammonium chloride, and the like. The
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`acids, bases and buffers are added in an amount required to maintain pH of the composition
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`in an acceptable range.
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`In certain embodiments, the formulations may also include one or more salts in an
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`amount that is required to bring osmolality of the composition into an acceptable range. Such
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`salts include those having sodium, potassium or ammonium cations and chloride, citrate,
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`ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfrte anions. Suitable
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`Attorney Docket No: l l913.6003—00000
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`salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and
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`ammonium sulfate.
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`In certain embodiments, the formulations may also include one or more antioxidants,
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`preferably non-thiol antioxidants, e,g., ascorbic acid, butylated hydroxytoluene (BHT),
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`butylated hydroxyanisole, sodium ascorbate, and tocopherol or derivatives thereof. In certain
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`embodiments, antioxidants enhance chemical stability where required.
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`In certain embodiments, the formulations may also include one or more antifoaming
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`agents. The foaming agent(s) are added to reduce foaming during processing which can
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`result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair
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`processing. Examples of suitable anti—foaming agents include silicon emulsions or sorbitan
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`sesquoleate.
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`In certain embodiments, the formulations may also include one or more
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`preservatives. Preservatives are used to inhibit microbial activity. Suitable preservatives
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`include mercury—containing substances such as merfen and thiomersal, stabilized chlorine
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`dioxide,and quaternary ammonium compounds such as benzalkonium chloride,
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`cetyltrimethylammonium bromide, and cetylpyridinium chloride.
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`In certain embodiments, the formulations may also include one or more binders.
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`Binders impart cohesive qualities. Exemplary binders include, e.g., alginic acid and salts
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`thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e. g.,
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`Methocel®), hydroxypropylmethylcellul0se, hydroxyethylcellulose, hydroxypropylcellulose
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`(e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e. g.,
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`Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide
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`acids; bentonites; gelatin; polyvinyl—pyrrolidone/vinyl acetate copolymer; crosspovidone;
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`povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g.,
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`Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and
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`lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum mucilage of isapol
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`husks, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL—lO),
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`larch arabogalactan, Veegum®, polyethylene glycol, polyethylene oxide, waxes, sodium
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`alginate, and the like. In general, binder levels of about 10 to about 70% are used in powder—
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`filled gelatin capsule formulations. Binder usage level in tablet formulations varies on
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`whether direct compression, wet granulation, or roller compaction process is used to make
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`the tablet, and/or on types of other excipients used to make the formulation e. g, fillers which
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`itself can act as moderate binder.
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`In certain embodiments, the formulations may also include dispersing agents and/0r
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`viscosity modulating agents. Dispersing agents and/or viscosity modulating agents include
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`Attorney Docket No: 11913.6003—00000
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`materials that control the diffusion and homogeneity of a drug through liquid media or a
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`granulation method or blend method. In some embodiments, these agents also facilitate the
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`effectiveness of a coating or eroding matrix. Exemplary diffusion facilitators/dispersing
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`agents include, e.g., hydrophilic polymers, electrolytes, Tween®60 or 80, PEG,
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`polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and the carbohydrate-based
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`dispersing agents, for example, hydroxypropyl celluloses (e. g., HPC, H——PC—SL, and HPC—L),
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`hydroxypropyl methylcelluloses (e. g., HPMC K100, RPMC K4M, HPMC K15M, and HPMC
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`KIOOM), carboxymethylcellulose sodium, methylcellulose, hydroxyethyl—cellulose,
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`hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropyl-
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`methylcellulose acetate stearate (HPMCAS), noncrystalline cellulose, magnesium. aluminum
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`silicate, triethanolamine, polyvinyl alcohol (PVA), Vinyl pyrrolidone/vinyl acetate copolymer
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`(S630), 4~(l, l ,3,3—tetramethylbutyl)—phenol polymer with ethylene oxide and formaldehyde
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`(also known as tyloxapol), polyethylene oxide ( e.g., PolyOx or P130), poloxamers which are
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`block copolymers of ethylene oxide and propylene oxide (e. g., Pluronics F68®, F88®, and
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`F108®; and poloxamines (e. g., Tetronic 908®, also known as Poloxamine 908®, which is a
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`block copolymer derived from sequential addition of propylene oxide and ethylene oxide to
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`ethylenediamine (BASF Corporation, Parsippany, N.J.)), polyvinylpyrrolidone K12, K17,
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`K25, or K30, polyvinylpyrrolidone/vinyl acetate copolymer (S—630), polyethylene glycol,
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`e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or
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`about 3350 to about 4000, or about 5400 to about 7000, polysorbate—SO, sodium alginate,
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`gums, such as, e. g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan
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`gum, sugars, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate,
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`povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans and combinations
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`thereof. Dispersing agents particularly useful in liposomal dispersions and self—emulsifying
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`25
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`dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs,
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`natural phosphatidyl glycerol from eggs, cholesterol and isopropyl myristate.
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`In certain embodiments, the formulations may also include one or more "diluents"
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`which refers to chemical compounds that are used to dilute the compound of interest prior to
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`delivery. Diluents can also be used to stabilize compounds because they can provide a more
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`stable environment Salts dissolved in buffered solutions (which also can provide pH control
`
`or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate
`
`buffered saline solution. In certain embodiments, diluents increase bulk of the composition to
`
`facilitate compression or create sufficient bulk for homogenous blend for capsule filling.
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`Such compounds include e. g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline
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`35
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`cellulose such as Avicel®.; dibasic calcium phosphate, dicalcium phosphate dihydrate;
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`SAN EX 1014, Page 10
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`SAN EX 1014, Page 10
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`Attorney Docket No: 1 1913.6003 -00000
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`tricalcium phosphate, calcium phosphate; anhydrous lactose, spray—dried lactose;
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`pregelatinized starch, compressible sugar, such as Di—Pac® (Amstar); hydroxypropyl-
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`methylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents,
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`confectioner’s sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate;
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`calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose,
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`calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the
`
`like.
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`In certain embodiments, the formulations may also include one or more
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`"disintegrants" which facilitate the breakup or disintegration of the dosage form when it
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`10
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`comes in contact with the gastrointestinal fluid. Examples of disintegration agents include a
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`starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such
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`as National 1551 or sodium starch glycolate such as Promogel®. or Explotab®, a cellulose
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`such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PHlOl, Avicel®
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`PH 102, Avicel® PH105, Elceme® P100, Emcocel®, Vivacel®, and Solka—Floc®,
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`15
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`methylcellulose, croscarmellose, or a cross—linked cellulose, such as cross-linked sodium
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`carboxymethyl-cellulose (Ac—Di—Sol®), cross—linked carboxymethylcellulose, or cross-linked
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`croscarmellose, a cross—linked starch such as sodium starch glycolate, a cross—linked polymer
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`such as crosspovidone, a cross~linl<ed polyvinylpyrrolidone, alginate such as alginic acid or a
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`salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium
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`20
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`aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth,
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`sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation—
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`exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination
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`starch, and the like.
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`In certain embodiments, the formulations may also include erosion facilitators which
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`25
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`include materials that control the erosion of a particular material in gastrointestinal fluid.
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`Exemplary erosion facilitators include, e. g., hydrophilic polymers, electrolytes, proteins,
`
`peptides, and amino acids.
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`In certain embodiments, the formulations may also include one or more filling agents
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`which include compounds such as lactose, xylitol, lactitol, mannitol, sorbitol, calcium
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`30
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`carbonate, calcium phosphate, dibasic calcium phOSphate, calcium sulfate, microcrystalline
`
`cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch,
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`sucrose, sodium chloride, polyethylene glycol, and the like.
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`In certain embodiments, the formulations may also include one or more flavoring
`
`agents and/or "sweeteners" e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame,
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`banana, orange, pear, peach, peppermint, peppermint cream, Powder, raspberry, root beer,
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`SAN EX 1014, Page 11
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`SAN EX 1014, Page 11
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`Attorney Docket No: 1 1913.6003—00000
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`rum, saccharin, safrole, sorbitol, Spearmint, Spearmint cream, strawberry, strawberry cream,
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`stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium,
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`mannitol, talin, sylitol, sucralose, sorbitol, tagatose, tangerine, thaumatin, vanilla, walnut,
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`watermelon, wild cherry, xylitol, or any combination of thereof. these flavoring ingredients,
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`e. g., anise—menthol, cherry—anise, cinnamon-orange, cherry—cinnamon, chocolate—mint,
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`honey—lemon, lemon-lime, lemon-mint, menthol—eucalyptus, orange-cream, vanilla-mint, and
`
`mixtures thereof. The flavoring agent may be incorporated with or without a polymeric
`
`coating or may be mixed directly in a formulation or first incorporated into one or more
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`polymers.
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`15
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`In certain embodiments, the formulations may also include one or more plasticizers
`
`which are compounds used to soften the enteric or delayed release coatings to make them less
`
`brittle. Suitable plasticizers include, e. g., polyethylene glycols such as PEG 300, PEG 400,
`
`PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid,
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`triethyl citrate, dibutyl sebacate, triethyl cellulose and triacetin. In some embodiments,
`
`plasticizers can also function as dispersing agents or wetting agents.
`
`In certain embodiments, the formulations may also include one or more lubricants and
`
`glidants which are compounds that prevent, reduce or inhibit adhesion or friction of
`
`materials. Exemplary lubricants include, e. g., stearic acid, calcium hydroxide, talc, sodium
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`steaiyl lumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as
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`20
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`hydrogenated soybean oil, higher fatty acids and their alkali—metal and alkaline earth metal
`
`salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol,
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`talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a
`
`polyethylene glycol (e. g., PEG4000) or a methoxypolyethylene glycol such as Carbowax®,
`
`sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or
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`25
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`sodium lauryl sulfate, colloidal silica such as Syloid®, Cab-O—Sil®, a starch such as corn
`
`starch, silicone oil, a surfactant, and the like.
`
`In ceitain embodiments, the formulations may also include one or more solubilizers
`
`which include compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,
`
`sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-
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`30
`
`methylpyrrolidone, N—hydroxyethylpyrrolidone, polyvinylpyrrolidone, organic alcohols such
`
`as ethanol, n—butanol, isopropyl alcohol, hydroxypropylmethyl cellulose, hydroxypropyl beta
`
`cyclodextrins, cholesterol, bile salts, propylene glycol, polyethylene glycol 200-600,
`
`glycofurol, transcutol, dimethyl isosorbide and the like.
`
`In certain embodiments, the formulations may also include one or more suspending
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`35
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`agents which include compounds such as celluloses, such as, e.g., sodium
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`SAN EX 1014, Page 12
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`SAN EX 1014, Page 12
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`Attorney Docket No: l l9l3.6003—00000
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`carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, or
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`hydroxyethylcellulose, polyvinylpyrrolidone, e. g., polyvinylpyrrolidone K112,
`
`polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinyl
`
`pyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g., the polyethylene
`
`glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000,
`
`or about 5400 to about 7000, hydroxymethylcellulose acetate stearate, polysorbate—80,
`
`sodium alginate, gums, such as, e. g., gum tragacanth and gum acacia, guar gum, xanthans,
`
`including xanthan gun, sugars, polyethoxylated sorbitan monolaurate, polyethoxylated
`
`sorbitan monolaurate, povidone and the like.
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`10
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`In certain embodiments, the formulations may also include one or more surfactants
`
`which include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80,
`
`triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate,
`
`polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide
`
`and propylene oxide, e.g., Pluronic® (BASF), and the like. Some other surfactants include
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`15
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`polyoxyethylen