Docket No. PHAR.O5/PR
`
`APPLICATION DATA SHEET
`
`Publication Filing Type:
`Application Type:
`Title of Invention:
`
`New Provisional
`Provisional
`ORAL FORMULATIONS OF CYTIDINE ANALOGS
`
`Customer Number Attorney and Correspondence Address:
`
`25871
`
`INVENTORS:
`
`ETTER, Jeffrey B.
`1318 Deer Trail Rd.
`Boulder, CO 80302
`(US Citizen)
`
`ASSIGNEE:
`Pharmion Corporation
`2525 28th Street
`Boulder, Colorado 80301
`(Delaware Corporation)
`
`CELGENE 2123
`CELGENE 2123
`APOTEX v. CELGENE
`APOTEX v. CELGENE
`IPR2023-00512
`IPR2023-00512
`
`

`

`ORAL FORMULATIONSOF CYTIDINE ANALOGS
`
`Attorney Docket: PHARM.05/PR
`
`BACKGROUNDOF THE INVENTION
`
`[0001]
`
`Cellular proliferative disorders are responsible for numerousdiseases resulting in
`
`major morbidity and mortality and have been intensively investigated for decades. Cancer now 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 used clinically for the treatment of viral infections
`
`and proliferative disorders for decades. Most of the nucleoside analog drugs are 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
`
`DNAor RNAsequences. Nucleosides may act also as their diphosphates.
`
`[0003]
`
`5-Azacytidine (also known as azacitidine and 4-amino-1-B-D-ribofuranosy]-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 CgH,2N.Os, a relative molecular weight of 244.21 and a structure of:
`N
`
`H S
`
`y
`
`N
`
`NLA
`
` [0004]
`
`[0005]
`
`Azacitidine (also referred to herein as 5-azacytidine herein) is a nucleoside
`
`analog, more specifically a cytidine analog. Azacitidine is an antagonistofits related natural
`
`

`

`nucleoside, cytidine. Azacitidine, as well as decitabine, 1.e., 5-aza-2’-deoxycytidine, are
`
`antagonists of decitabine’s related natural nucleoside, deoxycytidine. The only structural
`
`difference between the analogs andtheir related natural nucleosidesis the presence of nitrogen at
`
`position 5 of the cytosine ring in place of oxygen.
`
`[0006]
`
`Other membersofthe 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-$-D-arabinofuranoside (ara-C).
`
`[0007]
`
`In general, oral delivery of members of this class of compounds has proven
`
`difficult due to combinations of chemicalinstability, enzymatic instability, and/or poortissue
`
`permeability. For example, these compounds are knownto be acid labile and thus unstable in the
`
`acidic gastric environment. In the case of azacitidine, ara-C, decitabine and gemcitabine, an
`
`enzymethoughtto be responsible for a significant portion of drug metabolism is cytidine
`
`deaminase. Strategies to improvethe 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 azacitidine 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 author states 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.
`
`Azacitidine 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
`
`pharmacodynamics ofinter peritoneal (1.P.) and peri oral (P.O.) azacitidine when administered to
`
`leukemic mice. Pharmacokinetic parameters were determined using a bioassay that did not
`
`discriminate between azacitidine andits degradation and metabolism products. Inclusion of
`
`THU with IP administration had little effect on the clearance or degradation of azacitidine.
`
`Inclusion of THU with PO administration significantly increased both C,,.x and ty. In both
`
`

`

`acute and chronic IP dosing the inclusion of THU did not influence the pharmacodymamic
`
`effects of azacitidine except at the highest chronic dose which was toxic. Conversely, co-
`
`administration of THU with PO azacitidine resulted in increased efficacy at all doses except the
`
`highest chronic dose which wasagain toxic.
`
`[0010]
`Dunbar, et al describe the administration of azacitidine via IV and PO routes for
`increased production oftotal hemoglobin in a B°-thalassemic patient. 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 azacitidine via the SC and PO routes for
`
`increased production of total hemoglobin, fetal hemoglobin and F cells in sickle cell patients.
`
`Azacitidine oral bioavailability was assessed byclinical response only. Dover reportsthat oral
`
`doses of azacitidine (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 deaminase activity for several days post
`
`administration. When azacitidine was co-administered with THU goodclinical response was
`
`observed as determined by total hemoglobin, fetal hemoglobin and F cell 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 azacitidine 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 compoundshave also been
`
`described in, for example, U.S. Patent Application Publication No. 2004/0162263 (Sands, etal.)
`
`In this publication, delivery of azacitidine in an enteric-coated formulation are disclosed such
`
`that the drugs are preferably absorbed in the upper regions of the small intestine, such as the
`
`jejunum.
`
`[0013]
`
`Despite these efforts, a need remains for more effective methods and
`
`compositions which increaseoral bioavailability of this class of compounds.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0014]
`
`Figure | represents a graph showing Absolute Mucosal to Serosal Permeability of
`
`Azacitidine in Human Intestinal Tissue with and without Enzymatic Inhibition.
`
`

`

`[0015]
`
`Figure 2 represents a graph showing Relative Mucosal to Serosal Permeability of
`
`Azacitidine in Human Intestinal Tissue with and without Enzymatic Inhibition with Respect to
`
`Atenolol.
`
`[0016]
`
`Figure 3 represents a graph showing Absolute Mucosal to Serosal Permeability of
`
`Azacitidine 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
`
`Azacitidine in Human Colonic Tissue with Various Concentrations of TPGS or Labrafil without
`
`Enzymatic Inhibition.
`
`SUMMARYOF THE INVENTION
`
`[0018]
`
`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 amountof a cytidine analog and a drug release
`
`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.
`
`[0019]
`
`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 drug release 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.
`
`[0020]
`
`In another embodiment, the present invention includes a methodof 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 andincreases the bioavailability of the cytidine analog.
`
`

`

`[0021]
`
`In one embodiment, a condition to treat using the present inventionis a
`
`myelodysplastic syndrome. In one embodiment, the cytidine analog is azacitidine. In one
`
`embodiment, the drug release controlling componentis an enteric coating.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0022]
`
`The present invention is based on the surprising discovery that azacitidine and
`
`related compoundsare best absorbed in the lower gastrointestinal tract, 1.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 greater liquidity, 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 most consistent
`
`between patients in colonic tissue. Accordingly, the present invention demonstrates the
`
`preparation of a solid oral dosage form of a cytidine analog, such as azacitidine, using common
`
`pharmaceutical excipients designed for delivering pharmaceutical compositionsto the large
`
`intestine and colon. The term "absorb", "absorption", "absorbed" and the like are used to
`
`indicate transfer of a cytidine analog across a 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.
`
`[0023]
`
`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
`
`inhibitors such as THUin 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
`
`azacitidine without inclusion of an enzymatic inhibitor is possible when the target tissue to which
`
`the drug is delivered is the colon.
`
`In the case of PO delivery of azacitidine to humans, data
`
`suggests that delivery to the upper GI tract may well benefit from enzymatic inhibition, however
`
`

`

`delivery 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.
`
`[0024]
`
`Furthermore, the inventors have demonstrated the preparation of solid oral dosage
`
`forms containing excipients and coatings which possess acceptable production andstability
`
`characteristics for use as a pharmaceutical dosage form.
`
`[0025]
`
`In one embodiment, the present invention includes a controlled release
`
`pharmaceutical composition for oral administration comprising a) a therapeutically effective
`
`amount of 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.
`
`[0026]
`
`In one embodiment, the cytidine analog useful in the present invention includes
`
`any moiety whichisstructurally related to cytidine or deoxycytidine and functionally mimics
`
`and/or antagonizesthe action of cytidine or deoxycytidine. These analogs mayalso 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, andelaidic 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.
`
`[0027]
`
`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
`
`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.
`
`[0028]
`
`In one embodiment, the amounts of a cytidine analog to use in methodsofthe
`
`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 onpatient
`
`body surface area) or about 4 mg/kg (based on patient body weight) as single or divided (2-3)
`
`daily doses.
`
`[0029]
`
`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 occursprimarily in the large intestine. In
`
`one embodiment, at least about 95% of the cytidine analogis released in the large intestine, or at
`
`least about 90% of the cytidine analog is released in the large intestine. In other embodiments, at
`
`least about 80% of the cytidine analogis released in the large intestine, at least about 70% of the
`
`cytidine analogis releasedin the large intestine, at least about 60% of the cytidine analogis
`
`released in the large intestine, or at least about 50% of the cytidine analog is released in the large
`
`intestine. In other embodiments, the amount released in the intestines is at least about 40%, at
`
`least about 30%, or at least about 20% ofthe 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.
`
`[0030]
`
`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, powdersor pellets that may
`
`or may not be encapsulated. Such formats may also be referred to as the "drug core" which
`
`contains the cytidine analog. Such dosage forms are prepared using conventional methods
`
`knownto those in the field of pharmaceutical formulation and are described in the pertinent
`
`texts, e.g., in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY,20th Edition, Lippincott
`
`Williams & Wilkins, 2000). 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 methodfor forming tablets is by direct compression of a powdered,crystalline
`
`or granular composition containing the cytidine analog, alone or in combination with one or
`
`more carriers, 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 moldedrather
`
`

`

`than compressed, starting with a moist or otherwise tractable material; particularly, compression
`
`and granulation techniques are used in one embodiment.
`
`[0031]
`
`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,
`
`com 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.
`
`[0032]
`
`The cytidine analog in one embodimentis preparedas a tablet or capsule which
`
`represents a drug core comprising the pharmaceutical composition and the pharmaceutical
`
`composition is a controlled release pharmaceutical composition, and as such, comprisesat least
`
`one additional component comprising a drug release controlling component. Accordingly, the
`
`formulations of the present invention are formulated with a drug release controlling component
`
`in order to provide for release of the cytidine analog primarily in the large intestine. In one
`
`embodiment, minimal release of the cytidine analog occurs in the upper reachesof the
`
`gastrointestinaltract, e.g., the stomach and small intestine.
`
`[0033]
`
`The small intestine extends from the pylorus to the colic valve where it 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
`
`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 jeyunum (middle section). Specialized cells contain digestive
`
`enzymes, carrier proteins and other secretions. Blood vessels transport nutrients away from the
`
`intestine to the liver in the first instance.
`
`

`

`[0034]
`
`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 of the 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 compoundof the
`
`present invention mayoccurin any portion of the large intestine. In one embodiment, release
`
`primarily occurs at the upper regionsof the large intestine, such as, for example,at the distal
`
`ileum, cecum, and/or the ascending colon.
`
`[0035]
`
`It is known that there are major variations in acidity in the gastrointestinal tract.
`
`The stomachis a region of high acidity (about pH 1 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
`
`to 6.5. The large intestine and the colon are about pH 6.4 to 7.0. Thetransit time through the
`
`small intestine is approximately three hours. In contrast, the transit time throughthe large
`
`intestine is approximately 35 hours.
`
`[0036]
`
`Methods by which to formulate compositionsto target specific regions of the
`
`gastrointestinal tract are knownin the art, described in numerous publications, andall references
`
`specifically cited within the present documentare incorporated by reference herein. For
`
`example, release of drug in the gastrointestinal tract may be accomplished by choosing a drug
`
`release controlling component to work together with some physical, chemical or biochemical
`
`process in the gastrointestinal tract. A drug release controlling component may take advantage
`
`of processes and/or conditions within the gastrointestinal tract and in specific regions of the
`
`gastrointestinal tract such as, for example, osmotic pressure, hydrodynamic pressure, vapor
`
`pressure, mechanicalaction, hydration status, pH, bacterial flora, and enzymes. Specific U.S.
`
`Patents incorporated by reference herein include, among others, U.S. Pat. No. 3,952,741, U.S.
`
`Pat. No. 5,464,633, U.S. Pat. No. 5,474,784, U.S. Pat. No. 5,112,621.
`
`[0037]
`
`Optionally, pharmaceutical compositions of the present invention may further
`
`comprise a seal coating material that seals the drug to prevent decomposition due to exposure to
`
`moisture, such as hydroxylpropylmethylcellulose. Accordingly, the core of the pharmaceutical
`
`composition (containing the cytidine analog) mayfirst be sealed with the seal coating material
`
`and then coating with the drug release controlling componentto prevent decomposition of the
`
`cytidine analog by exposure to moisture. Seal coating materials include, in one embodiment,
`
`

`

`acetyltributyl citrate, acetyltriethyl citrate, calcium carbonate, carauba wax, cellulose acetate,
`
`cellulose acetate phthalate, cetyl alcohol, chitosan, ethylcellulose, fructose, gelatin, glycerin,
`
`glyceryl behenate, glyceryl palmitostearate, hydroxyethyl cellulose, hydroxyethylmethyl
`
`cellulose, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, isomalt, latex
`
`particles, maltitol, maltodextrin, methylcellulose, microcrystalline wax, paraffin, poloxamer,
`
`polydextrose, polyethylene glycol, polyvinyl acetate phthalate, polyvinyl alcohol, povidone,
`
`shellac, shellac with stearic acid, sodium carboxymethylcellulose, sucrose, titanium oxide,
`
`tributyl citrate, triethyl citrate, vanillin, white wax, xylitol, yellow wax, and zein. Compositions
`
`of the present invention mayalso include film forming agents, which include, for example,
`
`ammonium alginate, calctum carbonate, chitosan, chlorpheniramine maleate, copovidone,
`
`dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, ethyl lactate,
`
`ethylcellulose, gelatin, hydroxyyethyl cellulose, hydroxypropyl cellulose, hypromellose,
`
`hypromellose acetate succinate, maltodextrin, polydextrose, polyethylene glycol, polyethylene
`
`oxide, polymethylacrylates, poly(methylvinyl ether/maleic anhydride), polyvinylacetate
`
`phthalate, triethyl citrate, and vanillin.
`
`[0038]
`
`In one embodiment, drug release controlling components include, for example,
`
`coatings, matrices, or physical changes. Coatings are used in one embodiment. Coatings
`
`include, for example, enteric coatings, time delay coatings, bacterially degradable coatings, and
`
`mixtures thereof. The pharmaceutical composition may comprise multiple coatings of either the
`
`sameor different types of coatings. In choosing an appropriate coating or mixture thereof, the
`
`formulations practitioner may consider a numberofvariables influencing the location in which a
`
`drug will become available in the gastrointestinal tract, e.g., the pH at which coatings dissolve;
`
`the time of dissolution (whichis influenced by thickness of the coatings and/or additional
`
`components in the coatings); time of transit through the gastrointestinal tract, and whether the
`
`coatings can be degraded bythe patent’s digestive enzymesor require enzymespresentonly in
`
`bacteria residing in the lowerintestine. As an example of a combination drug release controlling
`
`componentis, for example, an inner core with two polymeric layers. The outer layer, an enteric
`
`coating, may be chosen to dissolve at a pH level above 5. The inner layer, may be made up of
`
`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 determine the lag time.
`
`10
`
`

`

`[0039]
`
`Methods by whichskilled practitioners can assess where a drugis released in the
`
`gastrointestinal tract of either animal models or human volunteers are knownin the art, and
`
`include scintigraphic studies, testing in biorelevant medium whichsimulates the fluid in relevant
`
`portions of the gastrointestinal tract, among others.
`
`[0040]
`
`In one embodiment, a drug release controlling component mayinclude an enteric
`
`coating. The term "enteric coating" refers to a coating that allows a cytidine analog formulation
`
`to pass through the stomachsubstantially intact and subsequently disintegrate substantially in the
`
`intestines. In one embodiment, the disintegration occursin the large intestine.
`
`[0041]
`
`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. In general, enteric coatings should be able to withstand the lower pH values of the
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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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`pharmaceutically active compositions with enteric coatings is well knownin theart 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 andinclude a
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`number of pH-sensitive polymers. The pH dependent coating polymer may be selected from
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`those enteric coatings knownto those skilled in the art. Such polymers may be one or moreof
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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 phthalate,
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`hydroxymethylmethylcellulose acetate succinate, hydroxypropylcellulose acetate phthalate,
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`cellulose acetate terephthalate, cellulose acetate isophthalate, and includes the various grades of
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`each polymer such as HPMCAS-LF, HPMCAS-MEFand HPMCAS-HG,or mixturesthereof.
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`Other enteric coatings suitable for the present invention include acetyltributyl citrate, carbomers,
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`guar gum, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, tributyl
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`citrate, triethyl citrate, white wax, and zein.
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`11
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`

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`[0042]
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`In one embodiment, the pH dependent coating is selected from the group
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`consisting of methacrylic acid copolymers of varying threshold pH (suchas, but not limited to
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`EUDRAGITS 100 (a cationic copolymer of dimethyl aminoethyl methacrylate and neutral
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`methacrylic acid esters manufactured by Rohm Pharma GmbH of Darmstadt, Germany)).
`
`[0043]
`
`Multiple coatings of enteric polymers maybeutilized. In one embodiment, the
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`first coating (closest to the core) is an enteric coating that will survive until the dosage form
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`arrives at the large intestine/colon. To target the large intestine, in one embodimentan enteric
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`coating comprises a series of methacrylic acid anionic copolymers known as EUDRAGITS. The
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`EUDRAGITS filmsare colorless, transparent and brittle. In one embodiment, the enteric
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`coating comprises EUDRAGIT S100. The EUDRAGITS coatings are insoluble in pure water,
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`in buffer solutions below a pH of 6.0 andalso in natural and artificial gastric juices. They are
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`slowly soluble in the region of the digestive tract where the juices are neutral to weakly alkaline
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`(i.e., the large intestine and the colon) and in buffer solutions above a pH of 7.0. Mixtures of
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`these various enteric polymers recited above, can be used in the present invention. Further, the
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`use of plasticizers is included in one embodiment with the enteric polymer coatings useful
`
`herein.
`
`[0044]
`
`As knownin the art and discussed in sources such as Patel et al. "Colon Specific
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`Delivery" Drug Delivery Technology (2006) Vol. 6 62-71, and Khanetal., J. Controlled Release
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`1999; 58:215-222, the disintegration rates of enteric coated tablets are dependent on the polymer
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`combination usedto coatthe tablets, the pH of the disintegration media, and the coating level of
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`the tablets (i.e., thickness of the coating). The presence of plasticizer and the nature of the salts
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`in the dissolution medium also influence the dissolution rate. A numberof specific formulations
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`effective for release in the colon in human volunteers, using in vivo scintigraphic studies, is
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`disclosed in Patel et al., and are incorporated by reference herein.
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`[0045]
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`The enteric coating may also be modified through the inclusion of an edible acid
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`to retard or slow the dissolution of the coating in the intestines. Any edible acid may be used.
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`Representative edible acids include acetic acid, benzoic acid, fumaric acid, sorbic acid, propionic
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`acid, hydrochloric acid, citric acid, malic acid, tartaric acid, isocitric acid, oxalic acid, lactic acid,
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`the phosphoric acids and mixtures thereof. One embodimentincludes fumaric acid and malic
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`acids. The weight percent of the edible acid in the enteric coating solution (polymer, plasticizer,
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`anti-tack agents, water and the like) can range from about 5 to about 40%, with 10 to 30%
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`12
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`present in one embodimentand 10 to 25% in another embodiment. Thoseskilled in the art will
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`readily be able to determine the exact amountof edible acid to include in the coating solution,
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`depending upon the pKaof the particular edible acid and the desired delay in dissolution of the
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`enteric coating. After application of the enteric coating solution, as further described below, the
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`percent of edible acid in the coating will range from about 10 to about 80 weight % of the
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`coating; 20 to 60% in one embodiment; and 25-50% in another.
`
`[0046]
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`Enteric coatings can be obtained from a number of manufacturers, such as, for
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`example, Rohm Pharma GmbH of Darmstadt, Germany (EUDRAGIT). Particular blends of pH
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`sensitive polymers and types can be selected by oneofskill in the art. As an example, the
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`manufacturer of EUDRAGITpolymers teaches that the EUDRAGITgradesfor sustained release
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`formulations are based on cop