(12) INTERNATIONALAPPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(10) International Publication Number
`WO 2008/028193 A2
`
`<a>
`
`Gc
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`RP)
`
`
`
`|
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`6 March 2008 (06.03.2008)
`
`(51) International Patent Classification:
`A61K 31/7068 (2006.01)
`—A61P 43/00 (2006.01)
`A61K 9/00 (2006.01)
`
`(74) Agents: SMITH, Mary, Breen et al.; SWANSON &
`BRATSCHUN, L.L.C., 8210 SouthPark Terrace, Littleton,
`Colorado 80120 (US).
`
`(21) International Application Number:
`PCT/US2007/077557
`
`(22) International Filing Date:
`4 September 2007 (04.09.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(81)
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
`CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG,
`ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,IL,
`IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK,
`LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
`Mx, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
`PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY,
`TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`
`except US):
`(for all designated States
`(71) Applicant
`PHARMION CORPORATION [US/US]; 2525 28th
`Street, Boulder, Colorado 80301 (US).
`
`(84)
`(30) Priority Data:
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`60/824,320 1 September 2006 (01.09.2006)|US
`
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES,FI,
`FR, GB, GR, HU,IE, 1S, IT, LT, LU, LV, MC, MT, NL, PL,
`PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`Published:
`
`
`
`2008/028193A2IMITIMMIITNNININNIN0NI000000TINM
`
`wo
`
`(72)
`(75)
`
`Inventor; and
`Inventor/Applicant (for US only): ETTER, Jeffrey B.
`[US/US]; 1318 Deer Trail Rd., Boulder, Colorado 80302
`(US).
`
`— without international search report and to be republished
`uponreceipt of that report
`
`(54) Title: COLON-TARGETED ORAL FORMULATIONS OF CYTIDINE ANALOGS
`
`(57) Abstract: The present invention provides an oral formulation of a cytidine analog, including, 5-azacytidine, for delivery to the
`lowergastrointestinal tract, including, the large intestine; methods to treat diseases associated with abnormalcell proliferation by
`treatment with the oral formulations of the present invention; and methodsto increase the bioavailability of a cytidine analog upon
`administration to a patient by providing an oral formulation ofthe present invention.
`C ELG ENE 2041
`CELGENE 2041
`APOTEX v. CELGENE
`APOTEX v. CELGENE
`IPR2023-00512
`IPR2023-00512
`
`

`

`WO2008/028193
`
`PCT/US2007/077557
`
`COLON-TARGETED ORAL FORMULATIONS OF CYTIDINE ANALOGS
`
`Attorney Docket: PHAR.0S/PCT
`
`BACKGROUNDOFTHE INVENTION
`
`[0001]
`
`Cellular proliferative disorders are responsible for numerousdiseasesresulting in
`
`major morbidity and mortality and have been intensively investigated for decades. Cancernow is
`
`the second leading cause of death in the United States, and over 500,000 people die annually
`
`from this proliferative disorder.
`
`[0002]
`
`Nucleoside analogs have been usedclinically for the treatment of viral infections
`
`and proliferative disorders for decades. Most of the nucleoside analog drugsare classified as
`
`antimetabolites. After they enter cells, nucleoside analogs are successively phosphorylated to
`
`nucleoside 5'-monophosphates, 5'-diphosphates, and 5'-triphosphates. In most cases, nucleoside
`
`triphosphates are the chemical entities that inhibit DNA or RNA synthesis, either through a
`
`competitive inhibition of polymerases or through incorporation of modified nucleotides into
`
`DNA or RNAsequences. Nucleosides mayact also as their diphosphates.
`
`[0003]
`
`5-Azacytidine (also knownasazacitidine and 4-amino-1-B-D-ribofuranosyl- 1 ,3,5-
`
`triazin-2(1H)-one; Nation Service Center designation NSC-102816; CAS Registry Number 320-
`
`67-2) has undergone NCI-sponsoredtrials for the treatment of myelodysplastic syndromes
`
`(MDS). See Kornblith et al., J. Clin. Oncol. 20(10): 2441-2452 (2002) and Silvermanetal., J.
`
`Clin. Oncol. 20(10): 2429-2440 (2002). 5-Azacytidine may be defined as having a molecular
`
`formula of CsH}2N4Os, a relative molecular weight of 244.21 and a structure of:
`Ni
`
` [0004]
`
`HA
`
`N
`
`,
`NLA
`
`

`

`WO2008/028193
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`PCT/US2007/077557
`
`[0005]
`
`Azacitidine (also referred to herein as 5-azacytidine herein) is a nucleoside
`
`analog, more specifically a cytidine analog. 5-azacytidine is an antagonist ofits related natural
`
`nucleoside, cytidine. 5-azacytidine, as well as decitabine,i.e., 5-aza-2’-deoxycytidine, are
`
`antagonists of decitabine’s related natural nucleoside, deoxycytidine. The only structural
`
`difference between the analogs andtheir related natural nucleosides is the presence of nitrogen at
`
`position 5 of the cytosine ring in place of oxygen.
`
`[0006]
`
`Other membersof the class of deoxycytidine and cytidine analogs include
`
`arabinosylcytosine (Cytarabine), 2'-deoxy-2',2'-difluorocytidine (Gemcitabine), 5-aza-2’-
`
`deoxycytidine (Decitabine), 2(1H) pyrimidine riboside (Zebularine), 2’ ,3’-dideoxy-5-fluoro-
`3’thiacytidine (Emtriva), N*-pentyloxycarbonyl-5’-deoxy-5-fluorocytidine (Capecitabine), 2’-
`cyclocytidine, arabinofuanosyl-5-azacytidine, dihydro-5-azacytidine, N*-octadecyl-cytarabine,
`
`elaidic acid cytarabine, and cytosine 1-B-D-arabinofuranoside (ara-C).
`
`[0007]
`
`In general, oral delivery of membersof this class of compoundshas proven
`
`difficult due to combinations of chemical instability, enzymatic instability, and/or poortissue
`
`permeability. For example, these compoundsare knownto be acid labile and thus unstable in the
`
`acidic gastric environment. In the case of 5-azacytidine, ara-C, decitabine and gemcitabine, an
`
`enzyme thoughtto be responsible for a significant portion of drug metabolism is cytidine
`
`deaminase. Strategies to improve the oral bioavailability of this drug class have included the use
`
`of prodrugs to modify chemical and enzymatic instability, and/or the use of enzymatic inhibitors.
`
`[0008]
`
`For example, DeSimoneet al describe the ability of 5-azacytidine to inducefetal
`
`hemoglobin production in baboons when administered via the intravenous (IV), subcutaneous
`
`(SC), or perioral (PO) route.
`
`In the case of PO administration the authorstates that co-
`
`administration of THU (tetrahydrouridine) was necessary to achieve fetal hemoglobin induction,
`
`howeverno specific data is provided on the doses or responses observed without THU. 5-
`
`azacytidine doses ranged from 0.25 mg/kg/d to 8 mg/kg/d with co-administration of 20 mg/kg/d
`
`THU. Administration of THU alone was shownto result in a significant decrease in peripheral
`
`cytidine deaminaseactivity.
`
`[0009]
`
`Neil, et al describe the effect of THU on the pharmacokinetics and
`
`pharmacodynamicsofinter peritoneal (I.P.) and peri oral (P.O.) 5-azacytidine when administered
`
`to leukemic mice. Pharmacokinetic parameters were determined using a bioassay that did not
`
`discriminate between 5-azacytidine and its degradation and metabolism products. Inclusion of
`
`

`

`WO2008/028193
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`PCT/US2007/077557
`
`THU with IP administration hadlittle effect on the clearance or degradation of 5-azacytidine.
`
`Inclusion of THU with PO administration significantly increased both Cmax and ti2.
`
`In both
`
`acute and chronic IP dosing the inclusion of THU did not influence the pharmacodymamic
`
`effects of 5-azacytidine except at the highest chronic dose which was toxic. Conversely, co-
`
`administration of THU with PO 5-azacytidine resulted in increased efficacy at all doses except
`
`the highest chronic dose which wasagaintoxic.
`
`Dunbar,et al describe the administration of 5-azacytidine via IV and POroutes
`[0010]
`for increased production of total hemoglobin in a B°-thalassemicpatient. Doses of 2 mg/kg/d IV
`
`resulted in a measurable increase to hemoglobin levels. Administration of 2 mg/d tid (three
`
`times daily) PO with co-administration of THU did notresult in increased hemoglobinlevels.
`
`[0011]
`
`Dover, et al describe administration of 5-azacytidine via the SC and PO routes for
`
`increased production of total hemoglobin, fetal hemoglobin andF cells in sickle cell patients. 5-
`
`azacytidine oral bioavailability was assessed by clinical response only. Doverreports that oral
`
`doses of 5-azacytidine (2 mg/kg/d) alone or THU (200 mg/d) alone did not result in increased F
`
`reticulocyte production. Howeveroral doses of 200 mg/d of THU were observedto result in a
`
`significant suppression of peripheral cytidine deaminaseactivity for several days post
`
`administration. When 5-azacytidine was co-administered with THU goodclinical response was
`
`
`
`observed as determined by total hemoglobin, fetal hemoglobin andFcell levels. In fact
`
`comparable clinical response was observed with doses of 2 mg/kg/d SC without THU versus 0.2
`
`mg/kg/d PO with co-administration of 200 mg/d THU. Oral doses of 5-azacytidine and THU
`
`were prepared by encapsulation at the clinical site. No information was provided with respect to
`
`excipients.
`
`[0012]
`
`Efforts to increase bioavailability of this class of compounds have also been
`
`described in, for example, U.S. Patent Application Publication No. 2004/0162263 (Sands, et al.)
`
`In this publication, delivery of 5-azacytidine in an enteric-coated formulation are disclosed such
`
`that the drugs are preferably absorbed in the upperregions of the small intestine, such as the
`
`jejunum. All U.S. patents and patent publications referenced herein are incorporated by
`
`reference herein in theirentireties.
`
`[0013]
`
`Despite these efforts, a need remains for more effective methods and
`
`compositions which increase oral bioavailability of this class of compounds.
`
`

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`WO2008/028193
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`PCT/US2007/077557
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`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0014]
`
`Figure | represents a graph showing Absolute Mucosal to Serosal Permeability of
`
`5-azacytidine in HumanIntestinal Tissue with and without Enzymatic Inhibition.
`
`[0015]
`
`Figure 2 represents a graph showing Relative Mucosal to Serosal Permeability of
`
`5-azacytidine in HumanIntestinal Tissue with and without Enzymatic Inhibition with Respect to
`
`Atenolol.
`
`[0016]
`
`Figure 3 represents a graph showing Absolute Mucosal to Serosal Permeability of
`
`5-azacytidine in Human Colonic Tissue with Various Concentrations of TPGS or Labrafil
`
`without Enzymatic Inhibition.
`
`[0017]
`
`Figure 4 represents a graph showing Relative Mucosal to Serosal Permeability of
`
`5-azacytidine in Human Colonic Tissue with Various Concentrations of TPGS or Labrafil
`
`without Enzymatic Inhibition.
`
`[0018]
`
`Figure 5 shows concentration vs time profiles of individual subjects administered
`
`an oral formulation of the present invention.
`
`[0019]
`
`Figure 6 showsconcentration vs time profiles for the 60 mg dose and the mean of
`
`the three 80 mg dosesfor individual subjects administered an oral formulation of the present
`
`invention.
`
`SUMMARYOF THE INVENTION
`
`[0020]
`
`In a first embodiment, the present invention comprises a controlled release
`
`pharmaceutical composition for oral administration for enhanced systemic delivery of a cytidine
`
`analog comprising a therapeutically effective amount of a cytidine analog and a drug release
`
`controlling component which is capable of providing release of the cytidine analog primarily in
`
`the large intestine. After ingestion by a patient, the cytidine analog is released primarily in the
`
`large intestine.
`
`[0021]
`
`In another embodiment, the present invention includes a methodfortreating a
`
`patient having a disease associated with abnormalcell proliferation. The method includesorally
`
`administering to the patient a controlled release pharmaceutical composition, comprising a
`
`therapeutically effective amountof a cytidine analog and a drugrelease controlling component
`
`whichis capable of providing release of the cytidine analog primarily in the large intestine.
`
`After ingestion by a patient the cytidine analog is released primarily in the large intestine.
`
`

`

`WO2008/028193
`
`PCT/US2007/077557
`
`[0022]
`
`In another embodiment, the present invention includes a method of increasing the
`
`bioavailability of a cytidine analog upon administration to a patient, comprising the following
`
`steps. First, provided is a controlled release pharmaceutical composition, comprising a
`
`therapeutically effective amountof a cytidine analog and a drug release controlling component
`
`capable of providing release of the cytidine analog primarily in the large intestine. Second, the
`
`patient ingests the composition, whereupon the composition contacts the biological fluids of the
`
`patient's body and increases the bioavailability of the cytidine analog.
`
`[0023]
`
`In one embodiment, a condition to treat using the present invention is a
`
`myelodysplastic syndrome.
`
`In one embodiment, the cytidine analog is 5-azacytidine.
`
`In one
`
`embodiment, the drug release controlling componentis an enteric coating.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0024]
`
`The present invention is based on the surprising discovery that 5-azacytidine and
`
`related compoundsare best absorbedin the lowergastrointestinal tract, i.e., the large intestine
`
`(colon). Conventionally, it is expected that the upper gastrointestinal tract is the more desirable
`
`location for absorption, due to greater surface area,relatively greaterliquidity, and the fact that
`
`typically the greater part of absorption of nutrients takes place therein. However, the inventors
`
`have foundthat in the case for cytidine analogs, absorption is greatest and mostconsistent
`
`betweenpatients in colonic tissue. Accordingly, the present invention demonstrates the
`
`preparation of a solid oral dosage form of a cytidine analog, such as 5-azacytidine, using
`
`common pharmaceutical excipients designed for delivering pharmaceutical compositions to the
`
`large intestine and colon. The term "absorb", "absorption", "absorbed" and the like are used to
`
`indicate transfer of a cytidine analog acrossa relevanttissue, such as, for example,intestinal
`
`tissue.
`
`In some embodiments, absorbed cytidine analogs are taken up by the blood stream
`
`making the cytidine analog available at least partially systemically.
`
`In some embodiments,
`
`absorption occurs without substantive degradation (i.e., undesirable chemical modification of) of
`
`the cytidine analog.
`
`[0025]
`
`Furthermore, the inventors have demonstrated that inclusion of THU (taught by
`
`others as a requirementto facilitate bioavailability of this drug class) is not necessary to achieve
`
`useful oral bioavailability of cytidine analogs via delivery in the large intestine and colon.
`
`Accordingly, formulations of the present invention obviate the need to utilize enzymatic
`
`

`

`WO2008/028193
`
`PCT/US2007/077557
`
`inhibitors such as THU in formulationsto increase bioavailability of cytidine analogs.
`
`Avoidance of enzymatic inhibitors is a desirable attribute for a therapeutic dosage form since
`
`such inclusion increases the formulation cost and complexity, and mayresult in instability, or
`
`undesirable, pharmacological, toxicological or other effects. Accordingly, oral delivery of 5-
`
`azacytidine without inclusion of an enzymatic inhibitor is possible whenthe target tissue to
`
`which the drugis delivered is the colon.
`
`In the case of PO delivery of 5-azacytidine to humans,
`
`data suggests that delivery to the upper GI tract may well benefit from enzymatic inhibition,
`
`howeverdelivery to the colon does not require the inclusion of such an inhibitor. Targeting to
`
`the colon may be achieved with commercially available and pharmaceutically acceptable
`
`coatings such as, for example, enteric coatings.
`
`[0026]
`
`Furthermore, the inventors have demonstrated the preparation of solid oral dosage
`
`forms containing excipients and coatings which possess acceptable production and stability
`
`characteristics for use as a pharmaceutical dosage form.
`
`[0027]
`
`In one embodiment, the present invention includes a controlled release
`
`pharmaceutical composition for oral administration comprising a) a therapeutically effective
`
`amountof a cytidine analog and b) a drug release controlling componentfor providing the
`
`release of the cytidine analog primarily in the large intestine. The controlled release
`
`pharmaceutical compositions of the present invention will in one embodiment lack THU.
`
`[0028]
`
`In one embodiment, the cytidine analog useful in the present invention includes
`
`any moiety whichis structurally related to cytidine or deoxycytidine and functionally mimics
`
`and/or antagonizes the action of cytidine or deoxycytidine. These analogs may also be called
`
`cytidine derivatives herein.
`
`In one embodiment, cytidine analogs to use with the present
`
`invention include 5-aza-2’-deoxycytidine (decitabine), 5-azacytidine, 5-aza-2'-deoxy-2',2'-
`
`difluorocytidine, 5-aza-2'-deoxy-2'-fluorocytidine, 2'-deoxy-2',2'-difluorocytidine (also called
`
`gemcitabine), or cytosine 1-B-D-arabinofuranoside (also called ara-C), 2(1H) pyrimidine
`
`riboside (also called zebularine), 2’-cyclocytidine, arabinofuanosyl-5-azacytidine, dihydro-5-
`azacytidine, N*-octadecyl-cytarabine, and elaidic acid cytarabine.
`In one embodiment,is 5-
`
`azacytidine and 5-aza-2’-deoxycytidine The definition of cytidine analog used herein also
`
`includes mixtures of cytidine analogs.
`
`[0029]
`
`Cytidine analogs useful in the present invention may be manufactured by any
`
`methods knownin the art.
`
`In one embodiment, methods to manufacture include methods as
`
`

`

`WO2008/028193
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`PCT/US2007/077557
`
`disclosed in U.S. Serial No. 10/390,526 (U.S. Patent No. 7,038,038); U.S. Serial No. 10/390,578
`
`(U.S. Patent No. 6,887,855); U.S. Serial No. 11/052615 (U.S. Patent No. 7,078,518); U.S. Serial
`
`No. 10390530 (U.S. Patent No. 6,943,249); and U.S. Serial No. 10/823,394,all incorporated by
`
`reference herein in their entireties.
`
`[0030]
`
`In one embodiment, the amounts of a cytidine analog to use in methodsof the
`
`present invention andin the oral formulations of the present invention include a therapeutically
`
`effective amount. Therapeutic indications are discussed more fully herein below. Precise
`
`amounts for therapeutically effective amounts of the cytidine analog in the pharmaceutical
`
`compositions of the present invention will vary depending on the age, weight, disease and
`
`condition of the patient. For example, pharmaceutical compositions may contain sufficient
`quantities of a cytidine analog to provide a daily dosage of about 150 mg/m7(based on patient
`
`body surface area) or about 4 mg/kg (based on patient body weight) as single or divided (2-3)
`
`daily doses.
`
`[0031]
`
`The controlled release pharmaceutical compositions of the present invention
`
`include a drug release controlling component. The drug release controlling componentis
`
`adjusted such that the release of the cytidine analog occurs primarily in the large intestine.
`
`In
`
`one embodiment,at least about 95% of the cytidine analogis released in the large intestine, orat
`
`least about 90% of the cytidine analog is released in the large intestine.
`
`In other embodiments,at
`
`least about 80% ofthe cytidine analogis released in the large intestine, at least about 70% of the
`
`cytidine analogis released in the large intestine, at least about 60% of the cytidine analogis
`
`released in the large intestine, or at least about 50% ofthe cytidine analogis released in the large
`
`intestine.
`
`In other embodiments, the amountreleased in the intestines is at least about 40%, at
`
`least about 30%, or at least about 20% of the cytidine analog. The term "release" refers to the
`
`process wherebythe cytidine analog is made available for uptake by or transport across the
`
`epithelial cells that line the large intestine and is made available to the body.
`
`[0032]
`
`The pharmaceutical compositions of the present invention are intended for oral
`
`delivery. Oral delivery includes formats such as tablets, capsules, caplets, solutions, suspensions
`
`and/or syrups, and may also comprise a plurality of granules, beads, powdersorpellets that may
`
`or may not be encapsulated. Such formats mayalso be referred to as the "drug core” which
`
`contains the cytidine analog. Such dosage formsare prepared using conventional methods
`
`knownto those in the field of pharmaceutical formulation and are described in the pertinent
`
`

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`WO2008/028193
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`PCT/US2007/077557
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`texts, e.g., in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 20th Edition, Lippincott
`
`Williams & Wilkins, 2000).
`
`[0033]
`
`Tablets and capsules represent the most convenient oral dosage forms, in which
`
`case solid pharmaceutical carriers are employed. Tablets are used in one embodiment. Tablets
`
`may be manufactured using standard tablet processing procedures and equipment. One method
`
`for forming tablets is by direct compression of a powdered,crystalline or granular composition
`
`containing the cytidine analog, alone or in combination with one or morecarriers, additives, or
`
`the like. As an alternative to direct compression, tablets can be prepared using wet-granulation or
`
`dry-granulation processes. Tablets may also be molded rather than compressed,starting with a
`
`moist or otherwise tractable material; particularly, compression and granulation techniques are
`
`used in one embodiment.
`
`[0034]
`
`In another embodiment, capsules may be used. Soft gelatin capsules may be
`
`prepared in which capsules contain a mixture of the active ingredient and vegetable oil or non-
`
`aqueous, water miscible materials such as, for example, polyethylene glycol and the like. Hard
`
`gelatin capsules may contain granules of the active ingredient in combination with a solid,
`
`pulverulent carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch,
`
`corn starch, amylopectin, cellulose derivatives, or gelatin. A hard gelatin capsule shell can be
`
`prepared from a capsule composition comprising gelatin and a small amountofplasticizer such
`
`as glycerol. As an alternative to gelatin, the capsule shell may be made of a carbohydrate
`
`material. The capsule composition may additionally include colorings, flavorings and opacifiers
`
`as required.
`
`[0035]
`
`The cytidine analog in one embodimentis prepared as a controlled release tablet
`
`or capsule which includes a drug core comprising the pharmaceutical composition and optional
`
`excipients (described elsewhere herein). Optionally, a "seal coat", described elsewhere herein, is
`
`applied to the drug core before addition of the drug release component. The drug release
`
`componentis formulated to provide for release of the cytidine analog primarily in the large
`
`intestine (colon).
`
`In one embodiment, minimalrelease of the cytidine analog occurs in the upper
`
`reachesof the gastrointestinal tract, e.g., the stomach and small intestine.
`
`[0036]
`
`The small intestine extends from the pylorus to the colic valve whereit ends in
`
`the large intestine. The small intestine is about 6 meters long andis divisible into three portions:
`
`the duodenum,the jejunum, and the ileum. The small intestine is especially adapted for transport
`
`

`

`WO2008/028193
`
`PCT/US2007/077557
`
`and absorption of nutrients and other molecules from ingested material, passing through the
`
`lining of the small intestine into the blood. The surface cells of the small intestine are highly
`
`specialized for digestion and absorption of nutrients. Almost all the body's nutrient absorption
`
`occurs in the small intestine, along its three sub-divisions: the duodenum,jejunum, and ileum.
`
`Sites for absorption of specific nutrients (eg: iron, vitamin.B12) are located in these divisions,
`
`but most absorption occurs in the jejunum (middle section). Specialized cells contain digestive
`
`enzymes, carrier proteins and othersecretions. Blood vessels transport nutrients away from the
`
`intestine to the liver in thefirst instance.
`
`[0037]
`
`Indigestible food passes into the large intestine. By the time ingested material
`
`leaves the small intestine, virtually all nutrient absorption will have occurred. The large intestine
`
`extends from the end ofthe ileum (distal ileum) to the anus. The large intestine is divided into
`
`the cecum, colon, rectum, and anal canal. The colonis divided into four parts: the ascending,
`
`transverse, descending, and sigmoid. The substantial release of the cytidine compoundofthe
`
`present invention may occurin any portion of the large intestine.
`
`In one embodiment, release
`
`primarily occurs at the upperregionsof the large intestine, such as, for example, at the distal
`
`ileum, cecum, and/or the ascending colon.
`
`[0038]
`
`It is knownthat there are major variations in acidity in the gastrointestinal tract.
`
`The stomachis a region of high acidity (about pH | to 3). Specific glands and organs emptying
`
`into the small intestine raise the pH of the material leaving the stomach to approximately pH 6.0
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`to 6.5. The large intestine and the colon are about pH 6.4 to 7.0. Thetransit time through the
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`small intestine is approximately three hours.
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`In contrast, the transit time through the large
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`intestine is approximately 35 hours.
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`[0039]
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`Methodsby which to formulate compositions to target specific regions of the
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`gastrointestinal tract are knownin the art, described in numerouspublications, andall references
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`specifically cited within the present documentare incorporated by reference herein. For
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`example, release of drug in the gastrointestinal tract may be accomplished by choosing a drug
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`release controlling component to work together with some physical, chemical or biochemical
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`processin the gastrointestinal tract. A drug release controlling component may take advantage
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`of processes and/or conditions within the gastrointestinal tract and in specific regions of the
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`gastrointestinal tract such as, for example, osmotic pressure, hydrodynamic pressure, vapor
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`pressure, mechanical action, hydration status, pH, bacterial flora, and enzymes. Specific U.S.
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`PCT/US2007/077557
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`Patents incorporated by reference herein include, among others, U.S. Pat. No. 3,952,741, U.S.
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`Pat. No. 5,464,633, U.S. Pat. No. 5,474,784, U.S. Pat. No. 5,112,621.
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`[0040}
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`Optionally, pharmaceutical compositions of the present invention including drug
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`cores may further comprise a seal coating material that seals the drug to prevent decomposition
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`due to exposure to moisture, such as hydroxylpropylmethylcellulose. Accordingly, the drug core
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`of the pharmaceutical composition (containing the cytidine analog) mayfirst be sealed with the
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`seal coating material and then coated with the drug release controlling componentto prevent
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`decomposition of the cytidine analog by exposure to moisture. Seal coating materials include,in
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`one embodiment, acetyltributyl citrate, acetyltriethyl citrate, calcium carbonate, carauba wax,
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`cellulose acetate, cellulose acetate phthalate, cetyl alcohol, chitosan, ethylcellulose, fructose,
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`gelatin, glycerin, glyceryl behenate, glyceryl palmitostearate, hydroxyethyl cellulose,
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`hydroxyethylmethyl! cellulose, hydroxypropyl cellulose, hypromellose, hypromellose phthalate,
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`isomalt, latex particles, maltitol, maltodextrin, methylcellulose, microcrystalline wax, paraffin,
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`poloxamer, polydextrose, polyethylene glycol, polyvinyl acetate phthalate, polyvinyl alcohol,
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`povidone,shellac, shellac with stearic acid, sodium carboxymethylcellulose, sucrose,titanium
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`oxide, tributyl citrate, triethyl citrate, vanillin, white wax, xylitol, yellow wax, and zein.
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`Compositionsof the present invention may also include film forming agents, which include, for
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`example, ammonium alginate, calcium carbonate, chitosan, chlorpheniramine maleate,
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`copovidone, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, ethyl
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`lactate, ethylcellulose, gelatin, hydroxyyethy] cellulose, hydroxypropyl cellulose, hypromellose,
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`hypromellose acetate succinate, maltodextrin, polydextrose, polyethylene glycol, polyethylene
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`oxide, polymethylacrylates, poly(methylvinyl ether/maleic anhydride), polyvinylacetate
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`phthalate, triethyl citrate, and vanillin. The amountof seal coating will vary in accordance with
`
`factors knownbythose ofskill in the art. The amountof seal coat is, in one embodiment, about
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`1% w/w ofthe drug core; about 2%, w/w of the drug core, about 3%, w/w,of the drug core,
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`about 4%, w/w,of the drug core; about 5% w/w ofthe drug core; about 6%, w/w ofthe drug
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`core, about 7%, w/w,of the drug core, about 8%, w/w/, of the drug core; about 9% w/w of the
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`drug core; about 10%, w/w of the drug core, about 11%, w/w, of the drug core, about 12%, w/w,
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`of the drug core; about 14% w/w ofthe drug core; about 16%, w/w of the drug core, about 18%,
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`w/w, of the drug core, about 20%, w/w, of the drug core; or more, if determined to be
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`appropriate. Seal coats may also be applied at amounts between about 1% and about 10% w/w
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`10
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`PCT/US2007/077557
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`of the drug core, between about 2% and 9% w/w ofthe drug core, between about 3% and 8%
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`w/w of the drug core, between about 4% and 7% w/w of the drug core, and between about 5%
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`and about 6% w/w ofthe drug core.
`
`[0041]
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`In one embodiment, drug release controlling components include, for example,
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`coatings, matrices, or physical changes. Coatings are used in one embodiment. Coatings
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`include, for example, enteric coatings, time delay coatings, bacterially degradable coatings, and
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`mixtures thereof. The pharmaceutical composition may comprise multiple coatings of either the
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`sameordifferent types of coatings.
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`In choosing an appropriate coating or mixture thereof, the
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`formulations practitioner may consider a numberof variables influencing the location in which a
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`drug will become available in the gastrointestinal tract, e.g., the pH at which coatings dissolve;
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`the time of dissolution (whichis influenced by thickness of the coatings and/or additional
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`componentsin the coatings); time of transit through the gastrointestinal tract, and whetherthe
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`coatings can be degradedbythe patent’s digestive enzymesor require enzymespresent only in
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`bacteria residing in the lower intestine. As an example of a combination drug release controlling
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`componentis, for example, an inner core with two polymeric layers. The outer layer, an enteric
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`coating, may be chosento dissolve at a pH level above 5. The innerlayer, may be made up of
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`hydroxypropylmethylcellulose to act as a time delay componentto delay drug release for a
`
`predetermined period. The thickness of the inner layer can be adjusted to determinethe lag time.
`
`[0042]
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`Methodsby whichskilled practitioners can assess where a drug is released in the
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`gastrointestinal tract of either animal models or human volunteers are knownin the art, and
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`include scintigraphic studies, testing in biorelevant medium which simulates the fluid in relevant
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`portions of the gastrointestinal tract, among others.
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`[0043]
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`In one embodiment, a drug release controlling component mayinclude an enteric
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`coating. The term "enteric coating” refers to a coating that allows a cytidine analog formulation
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`to pass through the stomachsubstantially intact and subsequently disintegrate substantially in the
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`intestines.
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`In one embodiment, the disintegration occursin the large intestine.
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`[0044]
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`The coating of pH-sensitive (enteric) polymers to tablets, capsules and otheroral
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`formulations of the present invention provided delayed release and protect the active drug from
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`gastric fluid.
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`In general, enteric coatings should be able to withstand the lowerpH valuesofthe
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`stomach and small intestine and be able to disintegrate at the neutral or slightly alkaline pH of
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`the large intestine. Enteric coatings are a well known class of compounds. Coating
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`1]
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`pharmaceutically active compositions with enteric coatings is well knownin the art to enable
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`pharmaceutical compositions to bypass the stomach andits low acidity. Enteric coatings
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`generally refer to a class of compoundsthat dissolve at or above a particular pH and include a
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`numberof pH-sensitive polymers. The pH dependent coating polymer maybe selected from
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`those enteric coatings knownto those skilled in the art. Such polymers may be one or more of
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`the group comprising hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate
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`(PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer,
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`carboxymethyl cellulose, methacrylic acid copolymer(such as, for example, a cationic
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`copolymerof dimethyl aminoethyl methacrylate and neutral methacrylic esters), polyvinyl
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`acetate phthalate, cellulose acetate trimellitate, shellac, cellulose acetate phthalate (CAP), starch
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`glycolate, polacrylin, methyl cellulose acetate phthalate, hydroxylmethylcellulose