`Approved for use through 04/30/2013. OMB 0651-OOZI
`US. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection ofinfcrmation unless it displays a valid OMB control number.
`
`TRANSMITTAL LETTER TO THE UNITED STATES RECEIVING OFFICE
`
`
`| Date of deposit: 26 June 2013
`‘
`Express Mail mailing number: N/A
`
`File reference no.:
`1 1913-1013
`International application no. (if known): Not Yet Assigned
`
`Earliest priority date claimed (Day/Month/Year): 29 June 2012
`Customer Number”: 22,852
`
`Title of the invention: FORMULATIONS
`
`‘ Customer Number will allow access to the application in Private PAIR but cannot be used to establish or change the correspondence address.
`
`This is a new International Application
`SCREENING DISCLOSURE INFORMATION
`
`In order to assist in screening the accompanying international application for purposes of determining whether a
`license for foreign transmittal should and could be granted and for other purposes, the following information is
`supplied. (check as boxes as apply):
`The invention disclosed was not made in the United States 01" America.
`
`There is no prior US application relating to this invention.
`
`The following prior U.S. application(s) contain subject matter which is related to the invention disclosed in the
`attached international application.
`(NOTE: priority to these applications may or may not be claimed on the
`Request (flirm PCT/RO/I 01) and this listing does not constitute a claim for priority.)
`
`
`application no.
`61/666,562
`
`filed on
`
`29 June 2012
`
`application no.
`
`filed on
`
`The present international application contains additional subject matter not found in the prior U.S. application(s)
`identified above. The additional subject matter is found on pages
`throu hout
`and
`.DOES NOT ALTER
`DMIGHT BE CONSIDERED TO ALTER the general nature of the
`invention in a manner which would require the US. application to have been made available for inspection by the
`
`appropriate defense agencies under 35 U.S.C. 181 and 37 C.F.R. 5.15.
`Itemized list of contents
`
`Sheets of Request fonn: 5
`Sheets of description
`
`Return receipt postcard: N/A
`(excludin_ seuence listin ): 39
`
`Sheets of claims: 4 Power of attorney: N/A
`Certified copy of priority
`document (specify): To be prepared and transmitted to the
`
`International Bureau by the RO/U S
`Other (specify):
`l. PCT Calculation Sheet (PCT—SAFE [EASY mode])
`2. Validation Messages Sheet (PCT—SAFE [EASY mode])
`
`Check no.2 N/A
`
`'
`
`
`
`Sheets of abstract:
`
`1
`
`Sheets of drawings: N/A
`
`Sheets of sequence listing: N/A
`
`
`
`Sequence listing diskette/CD: N/A
`
`The person
`signing this
`form 13:
`
`.
`
`D Apphcant
`Attorney/Agent (Reg. No.)
`71,542
`
`RODRIGO, Christina M.
`
`Name of uerson si 'nin_
`
`El Common Representative
`
`/Christina M. RODRIGO, Reg. No. 71,542/
`
`This collection ofinformation is required by 37 CFR 1.10 and 1.412. The information is required to obtain or retain a benefit by the public, which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 15 minutes to complete, including
`gathering information, preparing, and submitting the completed form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount oftime you
`require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, US. Patent and Trademark Office, US. Department of
`Commerce, P.0. Box [450, Alexandria, VA 223134450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS.
`SEND TO: Mail Stop PCT, Commissioner for Patents, P.O. Box 1450, Alexandria. VA 22313~1450.
`
`SAN EX 1011, Page 1
`
`SAN EX 1011, Page 1
`
`
`
`Attorney Docket No: 1 1913.1013-00304
`
`FORMULATIONS
`
`The present disclosure provides certain oral pharmaceutical formulations of ibrutinib,
`
`certain methods for their administration, certain processes of their production, and certain
`
`uses of these formulations for the treatment of diseases treatable by ibrutinib such as cancer,
`
`inflammatory diseases, and autoimmune diseases.
`
`Bruton’s tyrosine kinase (BTK) is a member of the Tec tyrosine kinase family. BTK
`
`is expressed in most hematopoietic cells such as B cells, mast cells, and macrophages, but not
`
`in T cells, natural killer cells, and plasma cells. BTK plays a role in the development and
`
`activation of B cells. Mutations in the human BTK gene cause the inherited disease X—linked
`
`agammaglobulinemia (XLA), with lack of peripheral B cells and low levels of serum Ig. In
`
`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
`
`cancers (e.g. non—Hodgkin lymphoma (NHL) and B cell chronic lymphocytic leukemia (B-
`
`CLL), and autoimmune diseases (e.g. rheumatoid arthritis, Sjogrens syndrome, IBD, lupus,
`
`and asthma).
`
`PCI—32765 (ibrutinib) is disclose d in US. Patent No. 7,514,444, issued on April 7,
`
`2009, and has the following structure:
`
`Q
`
`0
`
`NH2 0
`0 g“
`CNb
`
`Ibrutinib is an orally available drug that targets Bruton's tyrosine kinase (BTK).
`
`Ibrutinib is an irreversible small molecule BTK inhibitor that is in Ph Ib/II of clinical trials in
`
`a variety of B-cell malignancies including chronic lymphocytic leukemia (CLL), small
`
`lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B—Cell lymphoma
`
`(DLBCL) and multiple myeloma (cancer of plasma cells, a type of white blood cell present in
`
`bone marrow). At present ibrutinib is administered orally in clinical trials, via the
`
`gastrointestinal tract, at high clinical doses (420 mg/day or 840 mg/day) to patients with CLL
`
`and SLL to obtain the desired thereapeutic effect. The need for such high doses of ibrutinib
`
`_1_
`
`SAN EX 1011, Page 2
`
`10
`
`15
`
`20
`
`25
`
`SAN EX 1011, Page 2
`
`
`
`Attorney Docket No: 1 1913.1013—00304
`
`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
`
`results in more variable absorption and potential variability of the desired therapeutic
`
`response.
`
`As stated above, at present ibrutinib is administered orally, via the gastrointestinal
`
`tract, at high clinical doses (420 mg/day or 840 m g/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 increase in oral
`
`bioavailability of ibrutinib can translate into a number of desirable 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 lower variability
`
`associated with this greater bioavailability should lead to a more reliable therapeutic response
`
`as well as more predictable drug absorption. And avoidance of exposure of Ibtrutinib to the
`
`stomach and/or use of lower therapeutically effective dose of ibrutinib can reduce or
`
`altogether eliminate potential adverse side effects of this drug such as diahrrea, nausea or
`
`emesis, and dizziness. US. Patent No. 7,514,444, mentioned above, discloses administration
`
`of 0.02—5000 mg/kg and1-1500 mg of ibrutinib/per day and in clinical trials 420 or 840
`
`mg/day of ibrutinib is being administered to the patients with CLL and SLL. There is no
`
`reasonable expectation in the art that ibrutinib can be adminstered orally at lower efficacious
`
`doses to the patients with CLL and SLL, particularly as evidenced by the 420 or 840 mg/day
`
`of ibrutinib being administered in clinical trials to those patients. Moreover, other than for
`
`active agents that are unstable in the stomach or at 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. Therefore, it was
`
`unexpected to achieve delivery of ibruntinib directly to the small intestine with greater
`
`bioavailability.
`
`10
`
`15
`
`20
`
`25
`
`Accordingly, in one aspect, the present disclosure provides a solid oral dosage form
`
`30
`
`comprising:
`
`(i)
`
`(ii)
`
`ibrutinib and/or a pharmaceutically acceptable salt thereof;
`
`means for release of ibrutinib in the intestine; and
`
`(iii)
`
`at least one pharmaceutically acceptable excipient.
`
`In one embodiment of above aspect, ibrutinib and/or a pharmaceutically
`
`acceptable salt thereof is released in the small intestine.
`- 2 _
`
`In another embodiment, ibrutinib
`
`SAN EX 1011, Page 3
`
`SAN EX 1011, Page 3
`
`
`
`Attorney Docket No: 1 1913.1013—00304
`
`and/or a pharmaceutically acceptable salt thereof is released to a region of the intestine in
`
`which the pH is about 5, or 5, or greater than 5. In another embodiment, said ibrutinib and/or
`
`a pharmaceutically acceptable salt thereof is released to a region of the intestine in which the
`
`pH is about 5.5, or greater than about pH 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 of
`
`the intestine is 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 and non-enteric time-delayed release
`
`coatings. In one embodiment, the release to the above regions of the intestine is 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 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 wherein the enteric coatings are chosen
`
`from polymeric coatings. In another embodiment, the enteric coating is is an anionic polymer
`
`such as polymethacrylates (e. g., methacrylic acid ethacrylate poly, methacrylic acid methyl
`
`methacrylate poly); cellulose—based polymers (e.g., cellulose acetate phthalate (CAP),
`
`cellulose acetate trimellitate (CAT), cellulose acetate succinate (CAS), hydroxypropylmethyl—
`
`cellulose phthalate (HPMCP), and hydroxypropylmethylcellulose acetate succinate
`
`(HPMCAS)) or polyvinyl derivatives such as polyvinyl acetate phthalate (PVAP).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 or in about 0.5 to about 2 hours after
`
`administration to release ibrutinib and/or a pharmaceutically acceptable salt thereof.
`
`In a second aspect, the present disclosure provides a solid oral dosage form
`
`comprising:
`
`(i)
`
`(ii)
`
`ibrutinib and/or a pharmaceutically acceptable salt thereof;
`
`means for increasing the oral bioavailability of ibrutinib, as measured by the
`
`area under the curve (AUC), as compared to when said 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 embodiment of 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
`_ 3 _
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`SAN EX 1011, Page 4
`
`SAN EX 1011, Page 4
`
`
`
`Attorney Docket No: 1 1913.1013-00304
`
`ibrutinib and/or a pharmaceutically acceptable salt thereof in the intestine. In another
`
`embodiment of 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 thereof in the small intestine. In another embodiment of the
`
`second aspect, ibrutinib and/or a pharmaceutically acceptable salt thereof is released in one
`
`or more of the duodenum, jejunum, or ileum. In one embodiment, the release to the 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 forms are administered in fasted state, the
`
`time—delayed release coating is designed to erode, burst, or become very permeable in about
`
`0.3 to about 3 hours or in about 0.5 to about 2 hours after administration to release ibrutinib
`
`and/or a pharmaceutically acceptable salt thereof. When the dosage form comprised of said
`
`compound is 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 the resulting variability in
`
`the initiation of efficacious plasma levels.
`
`In a third aspect, the present disclosure provides a solid oral dosage form comprising:
`
`(i)
`
`(ii)
`
`ibrutinib and/or a pharmaceutically acceptable salt thereof;
`
`at least one coating chosen from enteric coatings and non—enteric time—delayed
`
`10
`
`15
`
`20
`
`release coatings; and
`
`(ii)
`
`at least one pharmaceutically acceptable excipient.
`
`In one embodiment, the said at least one coating is chosen from enteric coatings. In
`
`one embodiment,the said at least one coating is chosen from polymeric coatings.
`
`In one
`
`embodiment, the said at least one coating is chosen from enteric coatings where the enteric
`
`coating is a polymer which erodes to 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 above or from about
`
`5 .5 to about 6.5.
`
`In yet another embodiment of the third aspect, ibrutinib and/or a
`
`pharmaceutically acceptable salt thereof is released in one or more of the duodenum,
`
`jejunum, or ileum. In one embodiment of the third aspect and embodiments contained therein
`
`the dosage form is coated. In one embodiment of the third aspect and embodiments
`
`contained therein said ibrutinib and/or said pharmaceutically acceptable salt thereof are
`
`25
`
`3O
`
`coated.
`
`In a fourth aspect, the present disclosure provides a solid oral dosage from
`
`35
`
`comprising:
`
`_ 4 _
`
`SAN EX 1011, Page 5
`
`SAN EX 1011, Page 5
`
`
`
`Attorney Docket No: 11913.1013—00304
`
`(i)
`
`about 20 mg to about 450 mg of ibrutinib and/or a pharmaceutically
`
`acceptable salt thereof;
`
`(ii)
`
`at least one coating chosen from an enteric coating and/or a non—enteric time—
`
`delayed release coating; and
`
`(iii)
`
`at least one pharmaceutically acceptable excipient;
`
`wherein said oral dosage form increases the oral bioavailability, as measured by the
`
`area under the curve (AUC), of said ibrutinib and/or said pharmaceutically acceptable salt
`
`thereof by at least 20% as compared to the bioavailability obtained from an immediate release
`
`solid oral dosage form comprising the same dose of said ibrutinib and/or said
`
`pharmaceutically acceptable salt thereof and said at least one pharmaceutically acceptable
`
`excipient under the same conditions . In one embodiment, the increase in bioavailability is at
`
`least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or
`
`100%. In another embodiment the increase in bioavailability is independently at least 70%, or
`
`75%, or 80%, or 85%, or 90% , 95% or 100% .
`
`In one embodiment of the first to fourth aspect and embodiments contained therein,
`
`the dosage form contains from about 20 mg to about 450 mg of said ibrutinib and/or said
`
`pharmaceutically acceptable salt thereof. In another embodiment of the fouth aspect and
`
`embodiments contained therein, 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 the fourth aspect and embodiments contained therein, the dosage form contains from about
`
`20 or 30 mg to about 300 or 350 mg of said ibrutinib and/or said pharmaceutically acceptable
`
`salt thereof. In another embodiment of the fourth aspect and embodiments contained therein,
`
`the dosage form contains from about 50 mg to about 200, or 220, or 250 mg of said 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
`
`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.
`
`Within the above embodiments, the enteric coating is an anionic polymer such as
`_ 5 _
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`SAN EX 1011, Page 6
`
`SAN EX 1011, Page 6
`
`
`
`Attorney Docket No: 11913.1013-00304
`
`polymethacrylates (e.g., methacrylic acid ethacrylate poly, methacrylic acid methyl
`
`methacrylate poly); cellulose—based polymers (e.g., cellulose acetate phthalate (CAP),
`
`cellulose acetate trimellitate (CAT), cellulose acetate succinate (CAS), hydroxypropylmethyl—
`
`cellulose phthalate (HPMCP), and hydroxypropylmethylcellulose acetate succinate
`
`(HPMCAS)) or polyvinyl derivatives such as polyvinyl acetate phthalate (PVAP).
`
`In one embodiment, the solid oral dosage forms are 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 comprises ibrutinib.
`
`The therapeutically effective amount of ibrutinib and/or a pharmaceutically
`
`acceptable salt thereof when administered into the intestine by bypassing the stomach can be
`
`from about 20 mg per 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 formulations disclosed
`
`herein can contain from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,
`
`90, 95,100,110,115,120,125,130,135,140,145,150,155,160,175,170,175,180,185,
`
`190, 195, 200, 225, 250, 300, 325, 350, 375, 400, 425, or 450 milligrams of ibrutinib or a
`
`pharmaceutically acceptable salt thereof. In one embodiment, the tablets or capsules can
`
`contain about 20, 25, 30, 50, 75, 100, 150, 200, or_220 milligrams of ibrutinib and/or a
`
`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 thereof or into 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, Twenty—first Ed, (Pharmaceutical Press, 2005); Liberman, H. A., Lachman, L.,
`
`and Schwartz, J .B. Eds., Pharmaceutical Dosage Forms, Vol. 1—2 Taylor & Francis 1990;
`
`and R.I. Mahato, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Second
`
`Ed. (Taylor & Francis, 2012).
`
`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
`_ 6 _
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SAN EX 1011, Page 7
`
`SAN EX 1011, Page 7
`
`
`
`Attorney Docket No: l 1913.1013-00304
`
`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, and the like. The
`
`acids, bases, and buffers are added in an amount required to maintain pH of the composition
`
`in an acceptable range.
`
`10
`
`15
`
`In certain embodiments, the formulations may also include one or more salts in an
`
`amount that 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
`
`salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and
`
`ammonium sulfate.
`
`In certain embodiments, the formulations may also include one or more antioxidants,
`
`such as non—thiol antioxidants, e,g., ascorbic acid, butylated hydroxytoluene (BHT), butylated
`
`hydroxyanisole, sodium ascorbate, and tocopherol or derivatives thereof. In certain
`
`embodiments, antioxidants enhance chemical stability 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, bubbles in the finished film, or generally impair
`
`processing. Examples of suitable anti—foaming agents include silicon emulsions or sorbitan
`
`20
`
`sesquoleate.
`
`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 compounds such as benzalkonium chloride, cetyltrimethylammonium
`
`25
`
`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 and salts
`
`thereof; cellulose derivatives, such as carboxymethylcellulose, methylcellulose (e.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 (e.g.,
`
`Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and
`
`35
`
`lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum mucilage of isapol
`_ 7 _
`
`SAN EX 1011, Page 8
`
`SAN EX 1011, Page 8
`
`
`
`Attorney Docket No: 11913.1013-00304
`
`husks, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL—lO),
`
`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 usage level in tablet formulations varies on
`
`whether direct compression, wet granulation, or roller compaction process is used to make
`
`the tablet, and/or on types of other excipients used to make the formulation e.g, fillers which
`
`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
`
`materials that control the diffusion and homogeneity of a drug through liquid media or a
`
`granulation method or blend method. In some embodiments, these agents also facilitate the
`
`effectiveness of a coating or eroding matrix. Exemplary diffusion facilitators/dispersin g
`
`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, hydroxypropyl celluloses (e.g., HPC, H—-PC-SL, and HPC—L),
`
`hydroxypropyl methylcelluloses (e.g., HPMC K100, RPMC K4M, HPMC K15M, and HPMC
`
`KlOOM), 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 known as tyloxapol), polyethylene oxide ( e. g., PolyOx or PEO), poloxamers which are
`
`block copolymers of ethylene oxide and propylene oxide (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 (5—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—SO, sodium a1 ginate,
`
`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 isopropyl myristate.
`_ 8 _
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`SAN EX 1011, Page 9
`
`SAN EX 1011, Page 9
`
`
`
`Attorney Docket No: 11913.1013—00304
`
`In certain embodiments, the formulations may also include one or more "diluents"
`
`which refers to chemical compounds that are used to dilute the compound of interest prior to
`
`delivery. Diluents can also be used to stabilize compounds because they can provide a more
`
`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.
`
`Such compounds include e.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline
`
`cellulose such as Avicel®.; dibasic calcium phosphate, dicalcium phosphate dihydrate;
`
`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
`
`like.
`
`In certain embodiments, the formulations may also include one or more
`
`"disintegrants" which facilitate the breakup or disintegration of the dosage form when it
`
`comes in contact with the gastrointestinal fluid. Examples of 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, methylcrystalline 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
`
`aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth,
`
`sodium starch 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, and the like.
`
`In certain embodiments, the formulations may also include erosion facilitators which
`
`include materials that control the erosion of a particular material in gastrointestinal fluid.
`
`Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins,
`_ 9 _
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`SAN EX 1011, Page 10
`
`SAN EX 1011, Page 10
`
`
`
`Attorney Docket No: 11913.1013-00304
`
`peptides, and amino acids.
`
`In certain embodiments, the formulations may also include one or more filling agents
`
`which include compounds such as lactose, 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 the like.
`
`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,
`
`banana, orange, pear, peach, peppermint, peppermint cream, Powder, raspberry, root beer,
`
`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 combination of 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 formulation or first incorporated into one or more
`
`polymers.
`
`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,
`
`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
`
`stearyl lumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as
`
`hydrogenated soybean oil, highe