PROVISIONAL APPLICATION COVER SHEET
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`This is a requestforfiling a PROVISIONAL APPLICATION under 37 CFR 1.53(c).
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`FORMULATIONS
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`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(checkall that apply)
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`XX] Specification: 44 Pages
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`[Number] Pages; [Description]
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`Docket Number 11913.6003-00000 [| Typeaplus sign(+) inside this box =
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`INVENTOR(s)/APPLICANT(s)
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`David Me] Redwood City, CA
`GOLDSTEIN
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`TITLE OF INVENTION(500 characters max)
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`The filing fees are submitted
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`herewith.
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`overpaymentin fees to Deposit
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`TOTAL FILING FEE
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`The invention was made by an agencyof the United States Governmentor under a contract with an
`agency of the United States Government.
`&] No.
`[-] Yes, the name of the U.S. Government agency and the Government contract number are:
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`[-] Drawing(s):
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`[Number] Sheets/[Number] Figures
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`METHOD OF PAYMENT
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`sequenceor computer listing, or other papers 45.
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`Respectfully submitted on behalf of the patentpractitioners associated with Customer Number 22,852,
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`WJ
`SIGNATURE (oe
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`Date June 29, 2012
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`TYPED OR PRINTED NAME Wen Li, Ph.D.
`Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P.
`Telephone: 650.849.6649
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`REGISTRATION NO. 62,185
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`[_] Additional inventors are being named on separately numbered sheets attached hereto.
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`PROVISIONAL APPLICATION FILING ONLY
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`Attorney Docket No. 11913.6003-00000
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`FORMULATIONS
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`Inventor
`David Goldstein
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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 formulationsof ibrutinib,
`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 autoimmunediseases.
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`Bruton’s tyrosine kinase (BTK)is a memberof 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
`in T cells, natural killer cells, and plasmacells. Btk plays a role in the development and
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`activation of B cells. Mutations in the human BTK genecausethe inherited disease X-linked
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`agammaglobulinemia (XLA), with lack of peripheral B cells and low levels of serum Ig. In
`XLA,the primary immunedeficit is B cell specific. The development of drugs which inhibit
`BTK can have therapeutic significance in the treatmentof both B cell-related hematological
`cancers (e.g. non-Hodgkin lymphoma (NHL)andBcell chronic lymphocytic leukemia (B-
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`CLL), and autoimmunediseases (e.g. rheumatoidarthritis, Sjogrens syndrome, IBD,lupus,
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`and asthma).
`PCI-32765 (ibrutinib) is disclosed in U.S. Patent No. 7,514,444, issued on April 7,
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`2009, and has the followingstructure:
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`O
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`NH> (
`OoN
`OWe
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`Ibrutinib is an orally available drug that targets Bruton's tyrosine kinase (BTK).
`Ibrutinib, is an irreversible small molecule BTK inhibitorthat is in Ph Ib/II ofclinicaltrials
`in a variety of B-cell malignancies including chronic lymphocytic leukemia (CLL), small
`lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), anddiffuse large B-cell
`lymphoma (DLBCL)and multiple myeloma (cancer of plasmacells, a type of white blood
`cell present in bone marrow). Atpresent ibrutinib is administered orally in clinicaltrials, via
`the gastrointestinaltract, at high clinical doses (420 mg/day or 840 mg/day) to patients with
`CLL and SLLto obtain the desired thereapeutic effect. The need for such high doses of
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`Attorney Docket No: 11913.6003-00000
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`ibrutinib may be due to low bioavailability (the oral bioavailability of ibrutinib is reported to
`be 22.8% in rats) and may be responsible for the adverse side effects associated with the use
`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.
`Asstated above, at present ibrutinib is administered orally, via the gastrointestinal
`tract, at high clinical doses (420 mg/day or 840 mg/day)to patients to obtain the desired
`clinical benefit. It is presently disclosed that when ibrutinib is administered intraduodenally
`versus via the gastrointestinal tract in rats, the oral bioavailability of ibrutinib unexpectedly
`increased from 21 % to 100% as determined by AUC. This unexpected increasein oral
`bioavailability of ibrutinib can translate into a numberofdesirable practical benefits. The
`increase in oral bioavailability should enable administration of ibrutinib at a significantly
`lower therapeutically effective dose than is currently being used. The lowervariability
`associated with this greater bioavailability should lead to a morereliable therapeutic response
`as well as morepredictable drug absorption. And avoidance of exposure ofIbtrutinib to the
`stomach and/or use of lower therapeutically effective dose of ibrutinib can reduce or
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`altogether eliminate potential adverseside effects of this drug such as diahrrea, nausea or
`emesis, and dizziness. U.S. Patent No. 7,514,444, mentioned above, discloses administration
`of 0.02-5000 mg/kg and1-1500 mgofibrutinib/per day andin clinical trials 420 or 840
`mg/day of ibrutinib is being administered to the patients with CLL and SLL. Thereis no
`reasonable expectationn theart that ibrutinib can be adminstered orally at lowerefficacious
`doses to the patients with CLL and SLL,particularly as evidenced by the 420 or 840 mg/day
`of ibrutinib being administered in clinicaltrials to those patients. Moreover, other than for
`active agents that are unstable in the stomachorat acidic pH delivery of any active agent
`with low bioavailability further along in the gastrointestinal tract reduces the path length for
`drug absorption and would be expected to reduce bioavailability. That is a reason whyit was
`unexpected that delivery of ibruntinib directly to the small intestine results in greater
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`bioavailability.
`Accordingly, in one aspect, the present disclosure provides a solid oral dosage form
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`comprising:
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`ibrutinib and/or a pharmaceutically acceptable salt thereof;
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`meansfor release of ibrutinib in the intestine; and
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`at least one pharmaceutically acceptable excipient.
`(iii)
`In one embodiment of aboveaspect, ibrutinib and/or a pharmaceutically acceptable
`salt thereof is released in the small intestine.
`In one embodiment, ibrutinib and/or a
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`pharmaceutically acceptablesalt thereof is released to a region ofthe intestine in which the
`pH is about5, or5, or greater than 5. In another embodiment, said ibrutinib and/or a
`pharmaceutically acceptable salt thereof is released to a region ofthe intestine in whichthe
`pHis about 5.5, or greater than about pH 5.5 or 5.5. For example, the release is in one or
`more of the duodenum, jejunum, ileum, and colon. In one embodiment, the release is in one
`or more of the duodenum,jejunum,or ileum. In one embodiment, the release to the above
`regions ofthe intestine is achieved by coating ibrutinib and/or a pharmaceutically acceptable
`salt thereof or the dosage form containing ibrutinib and/or a pharmaceutically acceptablesalt
`thereof with at least one coating chosen from enteric coatings and non-enteric time-delayed
`release coatings. In one embodiment, the release to the above regionsofthe intestineis
`achieved by coating ibrutinib and/or a pharmaceutically acceptable salt thereof or the dosage
`form containing ibrutinib and/or a pharmaceutically acceptable salt thereof with at least one
`coating chosen from enteric coatings. In one embodiment,the release to the above regions of
`the intestine is achieved by coating ibrutinib and/or a pharmaceutically acceptablesalt thereof
`or the dosage form containing ibrutinib and/or a pharmaceutically acceptable salt thereof with
`at least one coating chosen from enteric coatings wherein the enteric coatings are choseb
`from polymeric coatings. When a non-enteric coating is employed, the time-delayed release
`dosage forms are administered in fasted state and the time-delayed release coating is designed
`to erode, burst, or become hightly permeable in about 0.3 to about 3 hours, and preferably in
`about 0.5 to about 2 hours after administration to release ibrutinib and/or a pharmaceutically
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`acceptablesalt thereof.
`In a second aspect, the present disclosure providesa solid oral dosage form
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`ibrutinib and/or a pharmaceutically acceptable salt thereof;
`(i)
`(ii)|meansfor increasing the oral bioavailability of ibrutinib, as measured by the
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`area underthe curve (AUC), as compared to whensaid ibrutinib and/or said pharmaceutically
`acceptable salt thereof are administered in an immediate release dosage form; and
`(iii)
`at least one pharmaceutically acceptable excipient.
`In one embodimentofthe second aspect, the increase in the oral bioavailability of
`ibrutinib and/or a pharmaceutically acceptablesalt thereof is due to the release of the
`ibrutinib and/or a pharmaceutically acceptable salt thereofin the intestine. In another
`embodimentof the second aspect, the increase in the oral bioavailability of ibrutinib and/or a
`pharmaceutically acceptable salt thereof is due to the release of the ibrutinib and/or a
`pharmaceutically acceptable salt thereofin the small intestine. In another embodimentof the
`second aspect, ibrutinib and/or a pharmaceutically acceptable salt thereof is released in in
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`In one embodiment,the release to the
`one or more of the duodenum,jejunum,or ileum..
`above regions of the intestine is achieved by coating ibrutinib and/or a pharmaceutically
`acceptable salt thereof or a a dosage form containing ibrutinib and/or a pharmaceutically
`acceptable salt thereof with at least one coating chosen from enteric coatings and a non-
`enteric time-delayed release coatings. When the delayed release dosage formsare
`administered in fasted state, the time-delayed release coating is designed to erode, burst, or
`become very permeablein about 0.3 to about 3 hours, and preferably in about0.5 to about 2
`hoursafter administration to release ibrutinib and/or a pharmaceutically acceptablesalt
`thereof. When the dosage form comprised of said compoundis coated with a non-enteric
`coating,it is generally administered in the fasted state to avoid variability or delays in gastric
`emptying with meals and theresulting 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:
`(i)
`ibrutinib and/or a pharmaceutically acceptable salt thereof;
`(ii)
`at least one coating chosen from enteric coatings and non-enteric time-delayed
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`release coatings; and
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`at least one pharmaceutically acceptable excipient.
`(ii)
`In one embodiment,thesaid at least one coating is chosen from enteric coatings. In
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`In one
`one embodiment,the said at least one coating is chosen from polymeric coatings.
`embodiment, the said at least one coating is chosen from enteric coatings wherethe enteric
`coating is a polymer which erodesto release ibrutinib and/or a pharmaceutically acceptable
`salt thereof at about pH 5 and above.In another embodiment, ibrutinib and/or a
`pharmaceutically acceptable salt thereof is released at about pH 5.5 and aboveor from about
`5.5 to about 6.5. In yet another embodimentofthe third aspect, ibrutinib and/or a
`pharmaceutically acceptable salt thereof is released in one or more of the duodenum,
`jejunum,orileum. In one embodiment, ofthe third aspect and embodimentscontained
`therein the dosage form is coated. In one embodiment, ofthe third aspect and embodiments
`contained therein said ibrutinib and said pharmaceutically acceptable salt thereof are coated.
`In a fourth aspect, the present disclosure provides a solid oral dosage from
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`about 20 mg to about 450 mgofibrutinib and/or a pharmaceutically
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`acceptable salt thereof;
`(ii)
`at least one coating chosen from anenteric coating and/or a non-enteric time-
`delayed release coating; and
`(iii)
`at least one pharmaceutically acceptable excipient,
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`wherein said oral dosage form increases the oral bioavailability, as measured by the
`area under the curve (AUC), ofsaid ibrutinib and/or said pharmaceutically acceptablesalt
`thereof by at least 20% as compared to the bioavailability obtained from an immediate release
`solid oral dosage form comprising the samedoseof said ibrutinib and/or said
`pharmaceutically acceptable salt thereof and said at least one pharmaceutically acceptable
`excipient under same conditions . In embodimentthe increase in bioavailability is at least
`30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% , or 100%. In one
`embodimentthe increasein bioavailability is independently at least 70%, or 75%, or 80%, or
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`85%, or 90% , 95% or 100% .
`In one embodimentofone to fouth aspect and embodiments contained therein, the
`dosage from contains from about 20 mg to about 450 mg ofsaid ibrutinib and/or said
`pharmaceutically acceptable salt thereof. In another embodimentof fouth aspect and
`embodiments containedtherein, the dosage form contains from about 20 mg to about 420 mg
`of said ibrutinib and/or said pharmaceutically acceptable salt thereof. In another embodiment
`of fourth aspect and embodiments contained therein, the dosage form contains from about 20
`or 30 mg to about 300 or 350 mgofsaid ibrutinib and/or said pharmaceutically acceptable
`salt thereof. In another embodimentof fourth aspect and embodiments containedtherein, the
`dosage form contains from about 50 mg to about 200, or 220, or 250 mgofsaid ibrutinib
`and/or said pharmaceutically acceptable salt thereof.
`In one embodiment, the solid oral dosage forms disclosed above are coated with at
`least one coating chosen from enteric coatings and non-enteric time-delayed release coatings.
`Within this embodiment, in one embodiment, the at least one coating is chosen from enteric
`coatings. Within the above embodiments, the enteric coatings are chosen from polymeric
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`coatings.
`In another embodiment, the solid oral dosage form disclosed above comprise ibrutinib
`and/ a pharmaceutically acceptable salt thereof that are coated with at least one coating
`chosen from enteric coatings and non-enteric time-delayed release coatings. Within this
`embodiment, in one embodiment,the at least one coating is chosen from enteric coatings.
`Within the above embodiments, the enteric coatings are chosen from polymeric coatings.
`In one embodiment, the solid oral dosage formsare a tablet or capsule. When the
`dosage form is capsule, ibrutinib and/or a pharmaceutically acceptable salt thereof can be
`present in a non-solid form. In another embodiment,the solid oral dosage form disclosed
`above comprise ibrutinib.
`Thetherapeutically effective amount ofibrutinib and/or a pharmaceutically
`acceptable salt thereof when administered into the intestine by bypassing the stomach can be
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`from about 20 mgper day to about 450 mg/day, or 20 mg/day to about 420 mg/day; or about
`20 mg/day or 30 mg/day to about 300 or 350 mg/day; or about 30 or 50 mg/day to about 200,
`or 220 or 250 mg/day; or about 30 or 50 mg/day to about 100 or 150 mg/day and can be
`administered in single or multiple doses. Accordingly, any of the formulation disclosed
`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, 145, 150, 155, 160, 175, 170, 175, 180, 185,
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`190, 195, 200, 225, 250, 300, 325, 350, 375, 400, 425, or 450 milligrams of ibrutinib or a
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`pharmaceutically acceptable salt thereof. In one embodiment,the tablets or capsules can
`contain about 20, 25, 30, 50, 75, 100, 150, 200, or 220 milligramsof ibrutinib and/or a
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`pharmaceutically acceptable salt thereof.
`In one embodiment, any of the formulations disclosed herein contain, unless stated
`otherwise, one or more pharmaceutically acceptable excipient(s) such as glidants, polymers,
`binders, surfactants, disintegrants, diluents, buffering agents, antiadherents, retardants,
`solubilizers, antioxidants, antifoaming agents,fillers, flavors, colors, lubricants, sorbents,
`plasticizers, or sweeteners, preservatives, or mixtures thereof, which facilitate processing of
`ibrutinib and/or a pharmaceutically acceptable salt thereoforinto preparations which can be
`used pharmaceutically. Any of the well-known techniques and excipients may be used as
`suitable and as understood in the art, see for example, Remington: The Science and Practice
`of Pharmacy, Nineteenth Ed., (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John
`E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA. 1975;
`Liberman, H. A. and Lachman,L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New
`York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh
`Ed. (Lippincott Williams & Wilkins 1999), which are herein incorporated by reference in
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`their entirety.
`In certain embodiments, the formulations may include one or more pH adjusting
`agents or buffering agents, for example, acids such as acetic, boric, citric, lactic, phosphoric
`and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate,
`sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and
`buffers such as citrate/dextrose, sodium bicarbonate, ammonium chloride, andthelike. The
`acids, bases and buffers are added in an amount required to maintain pH of the composition
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`in an acceptable range.
`In certain embodiments, the formulations may also include one or moresalts in an
`amountthat is required to bring osmolality of the composition into an acceptable range. Such
`salts include those having sodium, potassium or ammonium cations and chloride,citrate,
`ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions. Suitable
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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),
`butylated hydroxyanisole, sodium ascorbate, and tocopherolor derivatives thereof. In certain
`embodiments, antioxidants enhance chemicalstability where required.
`In certain embodiments, the formulations may also include one or more antifoaming
`agents. The foaming agent(s) are added to reduce foaming during processing which can
`result in coagulation of aqueous dispersions, bubblesin the finished film, or generally impair
`processing. Examples ofsuitable anti-foaming agents includesilicon emulsionsor sorbitan
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`sesquoleate.
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`In certain embodiments, the formulations may also include one or more
`preservatives. Preservatives are used to inhibit microbial activity. Suitable preservatives
`include mercury-containing substances such as merfen and thiomersal, stabilized chlorine
`dioxide,and quaternary ammonium compoundssuch as benzalkonium chloride,
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`cetyltrimethylammonium bromide, and cetylpyridinium chloride.
`In certain embodiments, the formulations may also include one or more binders.
`Binders impart cohesive qualities. Exemplary binders include,e.g., alginic acid andsalts
`thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose(¢.g.,
`Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
`(e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose(e.g.,
`Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide
`acids; bentonites; gelatin; polyvinyl-pyrrolidone/vinyl acetate copolymer; crosspovidone;
`povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose(¢.g.,
`Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and
`lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum mucilage of isapol
`husks, polyvinylpyrrolidone(e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10),
`larch arabogalactan, Veegum®, polyethylene glycol, polyethylene oxide, waxes, sodium
`alginate, and the like. In general, binder levels of about 10 to about 70% are used in powder-
`filled gelatin capsule formulations. Binder usagelevel in tablet formulationsvaries on
`whether direct compression, wet granulation, or roller compaction processis used to make
`the tablet, and/or on types of other excipients used to makethe formulation e.g, fillers which
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`itself can act as moderate binder.
`In certain embodiments, the formulations may also include dispersing agents and/or
`viscosity modulating agents. Dispersing agents and/or viscosity modulating agents include
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`materials that control the diffusion and homogeneity of a drug through liquid mediaor a
`granulation method or blend method.In some embodiments, these agents also facilitate the
`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,
`polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and the carbohydrate-based
`dispersing agents, for example, hydroxypropylcelluloses (e.g., HPC, H--PC-SL, and HPC-L),
`hydroxypropyl methylcelluloses (e.g., HPMC K100, RPMC K4M, HPMC K15M,and HPMC
`K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethyl-cellulose,
`hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropyl-
`methylcellulose acetate stearate (HPMCAS), noncrystalline cellulose, magnesium. aluminum
`silicate, triethanolamine, polyvinyl] alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer
`(S630), 4-(1, 1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde
`(also knownas tyloxapol), polyethylene oxide (e.g., PolyOx or PEO), poloxamers which are
`block copolymers of ethylene oxide and propyleneoxide(e.g., Pluronics F68®, F88®, and
`F108®; and poloxamines(e.g., Tetronic 908®, also known as Poloxamine 908®, which is a
`block copolymer derived from sequential addition of propylene oxide and ethylene oxide to
`ethylenediamine (BASF Corporation, Parsippany, N.J.)), polyvinylpyrrolidone K12, K17,
`K25, or K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), 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, polysorbate-80, sodium alginate,
`gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan
`gum, sugars, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate,
`povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans and combinations
`thereof. Dispersing agents particularly useful in liposomal dispersions and self-emulsifying
`dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs,
`natural phosphatidyl glycerol from eggs, cholesterol and isopropy! myristate.
`In certain embodiments, the formulations mayalso include one or more "diluents"
`which refers to chemical compoundsthat are used to dilute the compound ofinterestprior to
`delivery. Diluents can also be usedto stabilize compounds because they can provide a more
`stable environmentSalts dissolved in buffered solutions (which also can provide pH control
`or maintenance) are utilized as diluents in theart, including, but not limited to a phosphate
`buffered saline solution. In certain embodiments, diluents increase bulk of the composition to
`facilitate compression orcreate sufficient bulk for homogenousblend for capsulefilling.
`Such compoundsincludee.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline
`cellulose such as Avicel®.; dibasic calcium phosphate, dicalctum phosphate dihydrate;
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`tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose;
`pregelatinized starch, compressible sugar, such as Di-Pac® (Amstar); hydroxypropyl-
`methylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents,
`confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate;
`calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose,
`calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the
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`like.
`
`In certain embodiments, the formulations may also include one or more
`"disintegrants" which facilitate the breakupor disintegration of the dosage form whenit
`comesin contact with the gastrointestinal fluid. Examplesof disintegration agents include a
`starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such
`as National 1551 or sodium starch glycolate such as Promogel®. or Explotab®, a cellulose
`such as a wood product, methylerystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel®
`PH 102, Avicel® PH105, Elceme® P100, Emcocel®, Vivacel®, and Solka-Floc®,
`methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium
`carboxymethyl-cellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked
`croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer
`such as crosspovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a
`salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium
`aluminumsilicate), a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth,
`sodiumstarch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-
`exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination
`
`starch, andthelike.
`In certain embodiments, the formulations may also include erosion facilitators which
`include materials that control the erosion ofa particular material in gastrointestinal fluid.
`Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins,
`
`peptides, and amino acids.
`In certain embodiments, the formulations may also include one or morefilling agents
`which include compoundssuch aslactose, xylitol, lactitol, mannitol, sorbitol, calcium
`carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline
`cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch,
`sucrose, sodium chloride, polyethylene glycol, and thelike.
`In certain embodiments, the formulations may also include one or more flavoring
`agents and/or "sweeteners" e.g., acacia syrup, acesulfameK,alitame, anise, apple, aspartame,
`banana, orange, pear, peach, peppermint, peppermint cream, Powder, raspberry, root beer,
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`Attorney Docket No: 11913.6003-00000
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`rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream,
`stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium,
`mannitol, talin, sylitol, sucralose, sorbitol, tagatose, tangerine, thaumatin, vanilla, walnut,
`watermelon, wild cherry, xylitol, or any combinationof thereof. these flavoring ingredients,
`e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,
`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 formulationor first incorporated into one or more
`
`polymers.
`In certain embodiments, the formulations may also include one or moreplasticizers
`which are compoundsused 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,
`triethyl citrate, dibutyl sebacate,triethyl cellulose andtriacetin. In some embodiments,
`plasticizers can also function as dispersing agents or wetting agents.
`In certain embodiments, the formulations may also include one or morelubricants and
`glidants which are compoundsthat prevent, reduce or inhibit adhesion orfriction of
`materials. Exemplary lubricants include,e.g., stearic acid, calcium hydroxide, talc, sodium
`stearyl lumerate, a hydrocarbon such as mineraloil, or hydrogenated vegetable oil suchas
`hydrogenated soybeanoil, higher fatty acids and their alkali-metal and alkaline earth metal
`salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol,
`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
`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 certain embodiments, the formulations may also include one or more solubilizers
`which include compounds such astriacetin,triethylcitrate, ethyl oleate, ethyl caprylate,
`sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-
`methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, organic alcohols such
`as ethanol, n-butanol, isopropyl alcohol, hydroxypropylmethyl cellulose, hydroxypropylbeta
`cyclodextrins, cholesterol, bile salts, propylene glycol, polyethylene glycol 200-600,
`glycofurol, transcutol, dimethyl isosorbide andthelike.
`In certain embodiments, the formulations may also include one or more suspending
`agents which include compoundssuchas celluloses, such as, ¢.g., sodium
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`Attorney Docket No: 11913.6003-00000
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`carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, or
`
`hydroxyethylcellulose, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K112,
`polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinyl
`pyrrolidone/viny] 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, povidoneandthe like.
`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
`polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60)
`hydrogenated castor oil; and polyoxyethylene alkylethers and alkylpheny]ethers,e.g.
`octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to enhance
`
`physical stability or for other purposes.
`In certain embodiments, the formulations may also include one or more wetting
`agents which include compoundssuchasoleic acid, glyceryl monostearate, sorbitan
`monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan
`monooleate, polyoxyethy