(i9) United States
`(12) Patent Application Publication oo) Pub. No.: US 2008/0057086 Al
`Etter (43) Pub. Date: Mar. 6,2008
`
`US 20080057086A1
`
`(54) COLON-TARGETED ORAL FORMULATIONS
`OF CYTIDINE ANALOGS
`
`(75) Inventor:
`
`Jeffrey B. Etter, Boulder, CO
`(US)
`
`Correspondence Address:
`SWANSON & BRATSCHUN, L.L.C.
`8210 SOUTHPARK TERRACE
`LITTLETON, CO 80120
`
`Publication Classification
`
`(51) Int. CI.
`A61K 9/00 (2006.01)
`A61K 31/7068 (2006.01)
`A61P 43/00 (2006.01)
`
`(52) U.S. CI 424/400; 514/49
`
`(73) Assignee: PHARMION CORPORATION,
`Boulder, CO (US)
`
`(21) Appl. No.: 11/849,958
`
`(22) Filed: Sep. 4, 2007
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/824,320, filed on Sep.
`1, 2006.
`
`(57)
`
`ABSTRACT
`
`The present invention provides an oral formulation of a
`cytidine analog, including, 5-azacytidine, for delivery to the
`lower gastrointestinal tract, including, the large intestine;
`methods to treat diseases associated with abnormal cell
`proliferation by treatment with the oral formulations of the
`present invention; and methods to increase the bioavailabil-
`ity of a cytidine analog upon administration to a patient by
`providing an oral formulation of the present invention.
`
`siunum
`
`Ileum
`
`Intestinal Segms
`
`Colon
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0001
`
`

`

`Patent Application Publication Mar. 6,2008 Sheet 1 of 6
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0002
`
`

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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0003
`
`

`

`Patent Application Publication Mar. 6,2008 Sheet 3 of 6
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0004
`
`

`

`Patent Application Publication Mar. 6,2008 Sheet 4 of 6
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0005
`
`

`

`Patent Application Publication Mar. 6,2008 Sheet 5 of 6
`
`US 2008/0057086 Al
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0006
`
`

`

`Patent Application Publication Mar. 6,2008 Sheet 6 of 6
`
`US 2008/0057086 Al
`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0007
`
`

`

`US 2008/0057086 Al
`
`Mar. 6, 2008
`
`COLON-TARGETED ORAL FORMULATIONS
`OF CYTIDINE ANALOGS
`
`RELATED APPLICATIONS
`
`[0001] This application is a non-provisional of U.S. Patent
`Application Ser. No. 60/824,320, filed Sep. 1, 2006, entitled
`"Oral Formulations of Cytidine Analogs", which is incor-
`porated by reference herein in its entirety.
`
`BACKGROUND OF THE INVENTION
`
`[0002] Cellular proliferative disorders are responsible for
`numerous diseases resulting in major morbidity and mortal-
`ity 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.
`[0003] Nucleoside analogs have been used clinically for
`the treatment of viral infections and proliferative disorders
`for decades. Most of the nucleoside analog drugs are clas-
`sified 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 incorpo-
`ration of modified nucleotides into DNA or RNA sequences.
`Nucleosides may act also as their diphosphates.
`[0004] 5-Azacytidine (also known as azacitidine and
`4-amino-l-P-D-ribofuranosyl-l,3,5-triazin-2(lH)-one;
`Nation Service Center designation NSC-102816; CAS Reg-
`istry Number 320-67-2) has undergone NCI-sponsored trials
`for the treatment of myelodysplastic syndromes (MDS). See
`Komblith et al, J. Clin. Oncol. 20(10): 2441-2452 (2002)
`and Silverman et al, J. Clin. Oncol. 20(10): 2429-2440
`(2002). 5-Azacytidine may be defined as having a molecular
`formula of C8H12N405, a relative molecular weight of
`244.21 and a structure of:
`
`NHj
`
`N ^N
`
`N ^O
`
`HO.
`
`OH
`
`OH
`
`[0005] Azacitidine (also referred to herein as 5-azacyti-
`dine herein) is a nucleoside analog, more specifically a
`cytidine analog. 5-azacytidine is an antagonist of its related
`natural nucleoside, cytidine. 5-azacytidine, as well as decit-
`abine, i.e., 5-aza-2'-deoxycytidine, are antagonists of decit-
`abine's related natural nucleoside, deoxycytidine. The only
`structural difference between the analogs and their related
`natural nucleosides is the presence of nitrogen at position 5
`of the cytosine ring in place of oxygen.
`[0006] Other members of the class of deoxycytidine and
`cytidine analogs include arabinosylcytosine (Cytarabine),
`
`2'-deoxy-2',2'-difluorocytidine (Gemcitabine), 5-aza-2'-
`deoxycytidine (Decitabine), 2(1 H) pyrimidine riboside (Ze-
`bularine), 2',3'-dideoxy-5-fluoro-3'thiacytidine (Emtriva),
`N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine (Capecit-
`abine), 2'-cyclocytidine, arabinofuanosyl-5-azacytidine,
`dihydro-5-azacytidine, N4-octadecyl-cytarabine, elaidic
`acid cytarabine, and cytosine 1-P-D-arabinofuranoside (ara-
`C).
`[0007] In general, oral delivery of members of this class of
`compounds has proven difficult due to combinations of
`chemical instability, enzymatic instability, and/or poor tissue
`permeability. For example, these compounds are known to
`be acid labile and thus unstable in the acidic gastric envi-
`ronment. In the case of 5-azacytidine, ara-C, decitabine and
`gemcitabine, an enzyme thought to be responsible for a
`significant portion of drug metabolism is cytidine deami-
`nase. 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 enzy-
`matic inhibitors.
`[0008] For example, DeSimone et al describe the ability of
`5-azacytidine to induce fetal hemoglobin production in
`baboons when administered via the intravenous (IV), sub-
`cutaneous (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, however no specific data is provided
`on the doses or responses observed without THU. 5-azacy-
`tidine 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 shown to result in a significant decrease in
`peripheral cytidine deaminase activity.
`[0009] Neil, et al describe the effect of THU on the
`pharmacokinetics and pharmacodynamics of inter peritoneal
`(LP) and peri oral (P.O.) 5-azacytidine when administered to
`leukemic mice. Pharmacokinetic parameters were deter-
`mined using a bioassay that did not discriminate between
`5-azacytidine and its degradation and metabolism products.
`Inclusion of THU with IP administration had little effect on
`the clearance or degradation of 5-azacytidine. Inclusion of
`THU with PO administration significantly increased both
`C and t1/2. 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 was again toxic.
`[0010] Dunbar, et al describe the administration of 5-aza-
`cytidine via IV and PO routes for increased production of
`total hemoglobin in a p0-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 not result in increased
`hemoglobin levels.
`[0011] Dover, et al describe administration of 5-azacyti-
`dine via the SC and PO routes for increased production of
`total hemoglobin, fetal hemoglobin and F cells in sickle cell
`patients. 5-azacytidine oral bioavailability was assessed by
`clinical response only. Dover reports 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. How-
`ever oral doses of 200 mg/d of THU were observed to result
`in a significant suppression of peripheral cytidine deaminase
`activity for several days post administration. When 5-aza-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0008
`
`

`

`US 2008/0057086 Al
`
`Mar. 6, 2008
`
`cytidine was co-administered with THU good clinical
`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 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 upper regions of the small
`intestine, such as the jejunum. All U.S. patents and patent
`publications referenced herein are incorporated by reference
`herein in their entireties.
`[0013] Despite these efforts, a need remains for more
`effective methods and compositions which increase oral
`bioavailability of this class of compounds.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0014] FIG. 1 represents a graph showing Absolute
`Mucosal to Serosal Permeability of 5-azacytidine in Human
`Intestinal Tissue with and without Enzymatic Inhibition.
`[0015] FIG. 2 represents a graph showing Relative
`Mucosal to Serosal Permeability of 5-azacytidine in Human
`Intestinal Tissue with and without Enzymatic Inhibition with
`Respect to Atenolol.
`[0016] FIG. 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] FIG. 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] FIG. 5 shows concentration vs time profiles of
`individual subjects administered an oral formulation of the
`present invention.
`[0019] FIG. 6 shows concentration vs time profiles for the
`60 mg dose and the mean of the three 80 mg doses for
`individual subjects administered an oral formulation of the
`present invention.
`
`SUMMARY OF THE INVENTION
`
`[0020] In a first embodiment, the present invention com-
`prises 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 inges-
`tion by a patient, the cytidine analog is released primarily in
`the large intestine.
`[0021] In another embodiment, the present invention
`includes a method for treating a patient having a disease
`associated with abnormal cell proliferation. The method
`includes orally administering to the patient a controlled
`release pharmaceutical composition, comprising a therapeu-
`tically 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.
`[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 amount of 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 component is an
`enteric coating.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0024] The present invention is based on the surprising
`discovery that 5-azacytidine and related compounds are best
`absorbed in the lower gastrointestinal 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 greater
`liquidity, and the fact that typically the greater part of
`absorption of nutrients takes place therein. However, the
`inventors have found that in the case for cytidine analogs,
`absorption is greatest and most consistent between patients
`in colonic tissue. Accordingly, the present invention dem-
`onstrates the preparation of a solid oral dosage form of a
`cytidine analog, such as 5-azacytidine, using common phar-
`maceutical excipients designed for delivering pharmaceuti-
`cal compositions to the large intestine and colon. The term
`"absorb", "absorption", "absorbed" and the like are used to
`indicate transfer of a cytidine analog across a relevant tissue,
`such as, for example, intestinal tissue. In some embodi-
`ments, absorbed cytidine analogs are taken up by the blood
`stream making the cytidine analog available at least partially
`systemically. In some embodiments, absorption occurs with-
`out 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 requirement to
`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, for-
`mulations of the present invention obviate the need to utilize
`enzymatic inhibitors such as THU in formulations to
`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 may result in instability, or unde-
`sirable, pharmacological, toxicological or other effects.
`Accordingly, oral delivery of 5-azacytidine without inclu-
`sion 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 5-azacytidine 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
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0009
`
`

`

`US 2008/0057086 Al
`
`Mar. 6, 2008
`
`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 sta-
`bility 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
`amount of a cytidine analog and b) a drug release controlling
`component for providing the release of the cytidine analog
`primarily in the large intestine. The controlled release phar-
`maceutical 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 which is struc-
`turally related to cytidine or deoxycytidine and functionally
`mimics and/or antagonizes the action of cytidine or deoxy-
`cytidine. These analogs may also be called cytidine deriva-
`tives 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'-difluorocy-
`tidine, 5-aza-2'-deoxy-2'-fluorocytidine, 2'-deoxy-2',2'-dif-
`luorocytidine (also called gemcitabine), or cytosine 1-P-D-
`arabinofuranoside (also called ara-C), 2(1 H) pyrimidine
`riboside (also called zebularine), 2'-cyclocytidine, arabino-
`fuanosyl-5-azacytidine, dihydro-5-azacytidine, N4-octade-
`cyl-cytarabine, and elaidic acid cytarabine. In one embodi-
`ment, 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 known in the art. In
`one embodiment, methods to manufacture include methods
`as disclosed in U.S. Ser. No. 10/390,526 (U.S. Pat. No.
`7,038,038); U.S. Ser. No. 10/390,578 (U.S. Pat. No. 6,887,
`855); U.S. Ser. No. 11/052,615 (U.S. Pat. No. 7,078,518);
`U.S. Ser. No. 10,390,530 (U.S. Pat. No. 6,943,249); and
`U.S. Ser. 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 methods of the present invention and in the
`oral formulations of the present invention include a thera-
`peutically effective amount. Therapeutic indications are dis-
`cussed more fully herein below. Precise amounts for thera-
`peutically 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/m2 (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 composi-
`tions of the present invention include a drug release con-
`trolling component. The drug release controlling component
`is 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 analog is 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 analog is released in the large
`
`intestine, at least about 70% of the cytidine analog is
`released in the large intestine, at least about 60% of the
`cytidine analog is 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% of the cytidine analog. The term "release" refers
`to the process whereby the 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 plural-
`ity of granules, beads, powders or 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
`known to 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).
`[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 process-
`ing 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 more carriers, additives, or the
`like. As an alternative to direct compression, tablets can be
`prepared using wet-granulation or dry-granulation pro-
`cesses. Tablets may also be molded rather than compressed,
`starting with a moist or otherwise tractable material; par-
`ticularly, 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 amount of plasticizer such as
`glycerol. As an alternative to gelatin, the capsule shell may
`be made of a carbohydrate material. The capsule composi-
`tion may additionally include colorings, flavorings and
`opacifiers as required.
`[0035] The cytidine analog in one embodiment is prepared
`as a controlled release tablet or capsule which includes a
`drug core comprising the pharmaceutical composition and
`optional excipients (described elsewhere herein). Option-
`ally, a "seal coat", described elsewhere herein, is applied to
`the drug core before addition of the drug release component.
`The drug release component is formulated to provide for
`release of the cytidine analog primarily in the large intestine
`(colon). In one embodiment, minimal release of the cytidine
`analog occurs in the upper reaches of the gastrointestinal
`tract, e.g., the stomach and small intestine.
`[0036] The small intestine extends from the pylorus to the
`colic valve where it ends in the large intestine. The small
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0010
`
`

`

`US 2008/0057086 Al
`
`Mar. 6, 2008
`
`intestine is about 6 meters long and is 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 jejunum (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.
`[0037] Indigestible food passes into the large intestine. By
`the time ingested material leaves the small intestine, virtu-
`ally 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 colon is divided into four parts:
`the ascending, transverse, descending, and sigmoid. The
`substantial release of the cytidine compound of the present
`invention may occur in any portion of the large intestine. In
`one embodiment, release primarily occurs at the upper
`regions of the large intestine, such as, for example, at the
`distal ileum, cecum, and/or the ascending colon.
`[0038] It is known that there are major variations in acidity
`in the gastrointestinal tract. The stomach is 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. The
`transit time through the small intestine is approximately
`three hours. In contrast, the transit time through the large
`intestine is approximately 35 hours.
`[0039] Methods by which to formulate compositions to
`target specific regions of the gastrointestinal tract are known
`in the art, described in numerous publications, and all
`references specifically cited within the present document are
`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 pro-
`cess in the gastrointestinal tract. A drug release controlling
`component may take advantage of processes and/or condi-
`tions within the gastrointestinal tract and in specific regions
`of the gastrointestinal tract such as, for example, osmotic
`pressure, hydrodynamic pressure, vapor pressure, mechani-
`cal action, 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.
`[0040] Optionally, pharmaceutical compositions of the
`present invention including drug cores may further comprise
`a seal coating material that seals the drug to prevent decom-
`position due to exposure to moisture, such as hydroxypro-
`pylmethylcellulose. Accordingly, the drug core of the phar-
`maceutical composition (containing the cytidine analog)
`may first be sealed with the seal coating material and then
`coated with the drug release controlling component to
`prevent decomposition of the cytidine analog by exposure to
`moisture. Seal coating materials include, in one embodi-
`
`ment, acetyltributyl citrate, acetyltriethyl citrate, calcium
`carbonate, carauba wax, cellulose acetate, cellulose acetate
`phthalate, cetyl alcohol, chitosan, ethylcellulose, fructose,
`gelatin, glycerin, glyceryl behenate, glyceryl palmitostear-
`ate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,
`hydroxypropyl cellulose, hypromellose, hypromellose
`phthalate, isomalt, latex particles, maltitol, maltodextrin,
`methylcellulose, microcrystalline wax, paraffin, poloxamer,
`polydextrose, polyethylene glycol, polyvinyl acetate phtha-
`late, polyvinyl alcohol, povidone, shellac, shellac with
`stearic acid, sodium carboxymethyl cellulose, sucrose, tita-
`nium oxide, tributyl citrate, triethyl citrate, vanillin, white
`wax, xylitol, yellow wax, and zein. Compositions of the
`present invention may also include film forming agents,
`which include, for example, ammonium alginate, calcium
`carbonate, chitosan, chlorpheniramine maleate, copovidone,
`dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dim-
`ethyl phthalate, ethyl lactate, ethylcellulose, gelatin, hydrox-
`yyethyl cellulose, hydroxypropyl cellulose, hypromellose,
`hypromellose acetate succinate, maltodextrin, polydextrose,
`polyethylene glycol, polyethylene oxide, polymethylacry-
`lates, poly(methylvinyl ether/maleic anhydride), polyviny-
`lacetate phthalate, triethyl citrate, and vanillin. The amount
`of seal coating will vary in accordance with factors known
`by those of skill in the art. The amount of seal coat is, in one
`embodiment, about 1% w/w of the drug core; about 2%, w/w
`of the drug core, about 3%, w/w, of the drug core, about 4%,
`w/w, of the drug core; about 5% w/w of the drug core; about
`6%, w/w of the drug core, about 7%, w/w, of the drug core,
`about 8%, w/w/, of the drug core; about 9% w/w of the drug
`core; about 10%, w/w of the drug core, about 11%, w/w, of
`the drug core, about 12%, w/w, of the drug core; about 14%
`w/w of the drug core; about 16%, w/w of the drug core,
`about 18%, w/w, of the drug core, about 20%, w/w, of the
`drug core; or more, if determined to be appropriate. Seal
`coats may also be applied at amounts between about 1% and
`about 10% w/w of the drug core, between about 2% and 9%
`w/w of the drug core, between about 3% and 8% w/w of the
`drug core, between about 4% and 7% w/w of the drug core,
`and between about 5% and about 6% w/w of the drug core.
`[0041] In one embodiment, drug release controlling com-
`ponents 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 coat-
`ings of either the same or different types of coatings. In
`choosing an appropriate coating or mixture thereof, the
`formulations practitioner may consider a number of vari-
`ables 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 (which is influ-
`enced by thickness of the coatings and/or additional com-
`ponents in the coatings); time of transit through the gas-
`trointestinal tract, and whether the coatings can be degraded
`by the patent's digestive enzymes or require enzymes
`present only in bacteria residing in the lower intestine. As an
`example of a combination drug release controlling compo-
`nent is, 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
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1026-0011
`
`

`

`US 2008/0057086 Al
`
`Mar. 6, 2008
`
`component to delay drug release for a predetermined period.
`The thickness of the inner layer can be adjusted to determine
`the lag time.
`[0042] Methods by which skilled practitioners can assess
`where a drug is released in the gastrointestinal tract of either
`animal models or human volunteers are known in the art,
`and include scintigraphic studies, testing in biorelevant
`medium which simulates the fluid in relevant portions of the
`gastrointestinal tract, among others.
`[0043] In one embodiment, a drug release controlling
`component may include an enteric coating. The term
`"enteric coating" refers to a coating that allows a cytidine
`analog formulation to pass through the stomach substantially
`intact and subsequently disintegrate substantially in the
`intestines. In one embodiment, the disintegration occurs in
`the large intestine.
`[0044] The coating of pH-sensitive (enteric) polymers to
`tablets, capsules and other oral formulations of the present
`invention provided delayed release and protect the active
`drug from gastric fluid. In general, enteric coatings should
`be able to withstand the lower pH values of the stomach and
`small intestine and be able to disintegrate at the neutral or
`slightly alkaline pH of the large intestine. Enteric coatings
`are