(19) United States
`(12) Patent Application Publication (io) Pub. No.: US 2004/0162263 Al
`Sands et al.
`(43) Pub. Date:
`Aug. 19,2004
`
`US 20040162263A1
`
`(54) PHARMACEUTICAL FORMULATIONS
`TARGETING SPECIFIC REGIONS OF THE
`GASTROINTESINAL TRACT
`
`(75)
`
`Inventors: Howard Sands, Wilmington, DE (US);
`Sanjeev Redkar, Union City, CA (US);
`Harish Ravivarapu, Union City, CA
`(US)
`
`Correspondence Address:
`WILSON SONSINI GOODRICH & ROSATI
`650 PAGE MILL ROAD
`PALO ALTO, CA 943041050
`
`(73) Assignee: SuperGen, Inc., a Delaware Corpora(cid:173)
`tion, Dublin, CA
`
`(21) Appl. No.:
`
`10/698,983
`
`(22) Filed:
`
`Oct. 31, 2003
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/423,179, filed on Oct.
`31, 2002.
`
`Publication Classification
`
`(51)
`
`Int. Cl.7
`
`(52) U.S. Cl
`
`A61K 31/7076; A61K 31/7072;
`A61K 9/24
`514/46; 514/50; 424/471
`
`(57)
`
`ABSTRACT
`
`Oral formulations ol pharmaceuticals are provided with
`enhanced bioavailability by targeting specific regions ol the
`gastrointestinal tract. Particularly, water soluble and acid-
`labile drugs such as cytidine analogs (e.g., decitabine) and
`2'-deoxyadenosine analogs (e.g., pentostatin) are formulated
`with pH-sensitive polymers so that these drugs are prefer(cid:173)
`ably absorbed in the upper regions of the small intestine,
`such as the jejunum. In addition, drugs with poor oral
`bioavailability such as camptothecin compounds (e.g., 9-ni-
`tro-camptothecin) can also be formulated using similar
`strategies in order to significantly improve their oral bio(cid:173)
`availability. These formulations can be used to treat a wide
`variety of diseases or conditions, such hematological disor(cid:173)
`ders, benign tumors, cancer, restenosis, inflammatory dis(cid:173)
`eases, and autoimmune diseases.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0001
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 1 of 15
`
`US 2004/0162263 Al
`
`DUODENUM i-
`
`TRANSVERSE:
`COLON
`
`ASCENDING
`COLON
`
`JEJUNUM
`
`CECUM
`
`STOMACH
`
`/PANCREAS
`
`LARGE
`INTESTINE
`SMALL
`INTESTINE
`
`DESCENDING
`COLON
`
`SIGMOID
`FLEXURE
`
`, l £ UM ^APPENDIX IN RECTUM
`
`HUMAN INTESTINES
`
`FIGURE 1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0002
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 2 of 15
`
`US 2004/0162263 Al
`
`FIGURE 2
`
`Pentostatin
`
`El Saline
`• Buffered
`
`feE IC
`
`IL
`IJ
`Intestinal Region
`
`t
`
`PO
`
`1.400
`
`1.200
`
`1.000
`
`+•>
`
`1 0.800
`'55
`% 0.600
`o
`S
`
`0.400
`
`0.200
`
`0.000
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0003
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 3 of 15
`
`US 2004/0162263 Al
`
`10000.0
`
`1000.0
`
`•£• 100.0
`u
`c
`o
`o
`
`10.0
`
`1.0
`
`3000.0
`
`2500.0
`
`f
`
`^ 2000.0
`
`•S- 1500.0
`
`O 1000.0
`
`FIGURES
`
`Intravenous Administration
`
`-X— Systemic
`-O— Portal Vein
`
`200
`
`400
`
`600
`
`800
`
`Time (min)
`
`Intravenous Administration
`
`-X— Systemic
`-D— Portal Vein
`
`200
`
`400
`Time (min)
`
`-G-
`
`800
`
`600
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0004
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 4 of 15
`
`US 2004/0162263 Al
`
`1000.0
`
`I- 100.0 ^
`D)
`c
`
`O
`
`10.0
`
`1.0
`
`250.0
`
`200.0
`
`150.0
`
`FIGURE 4
`
`Oral Administration
`
`Saline
`Buffer
`
`200
`
`400
`
`600
`
`800
`
`Time (min)
`
`Oral Administration
`
`-•— Saline
`-O-Buffer
`
`400
`
`600
`
`800
`
`Time (min)
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0005
`
`

`

`Patent Application Publication Aug. 19, 2004 Sheet 5 of 15
`
`US 2004/0162263 Al
`
`FIGURES
`
`Jejuna! Administration
`
`1000.0 -I
`
`M\
`r "^-^ ^i;^
`
`- •- Saline
`—TT— Rirffcir
`i—i uLnrer
`
`-
`
`- ^T
`^~^^-_id
`
`5
`
`U
`c
`o
`O
`
`100.0 -
`
`^/^K
`
`\
`
`1
`10 0 i
`J
`
`1 0 -
`c
`)
`
`200
`
`400
`
`600
`
`800
`
`Time (min)
`
`Jejunal Administration
`
`450.0
`400.0
`350.0
`=* 300.0
`"I 250.0
`li 200.0
`O 150.0
`100.0
`50.0
`0.0
`
`-•—Saline
`-Q-Buffer
`
`200
`
`400
`Time (min)
`
`600
`
`800
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0006
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 6 of 15
`
`US 2004/0162263 Al
`
`1000.0
`
`I 1000
`
`1.0
`
`300.0 i
`
`250.0
`
`FIGURE 6
`
`lleum Administration
`
`-•—Saline
`•O—Buffer
`
`200
`
`400
`Time (min)
`
`600
`
`800
`
`lleum Administration
`
`-•—Saline
`•O— Buffer
`
`200
`
`400
`Time (min)
`
`600
`
`800
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0007
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 7 of 15
`
`US 2004/0162263 Al
`
`FIGURE?
`
`Colon Administration
`
`-A—Saline
`-&-Buffer
`
`200
`
`400
`
`600
`
`800
`
`Time (min)
`
`Colon Administration
`
`—A—Saline
`- A- Buffer
`
`1000.0
`
`=* 100.0
`
`1.0
`
`aKn n _
`
`300.0 •
`
`r
`1
`
`_ 250.0 -
`
`~5> 200.0 -
`
`I'sn n •
`
`ti
`o
`
`50.0 '
`
`^r
`
`--
`_
`
`—-
`
`K
`
`\
`
`K^ N i — ^ * _ __
`
`0.0 L
`\
`0
`
`.
`200
`
`m—i
`400
`
`Time (min)
`
`—i
`600
`
`%J
`
`1
`800
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0008
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 8 of 15
`
`US 2004/0162263 Al
`
`FIGURE 8
`
`IV Dose Response
`
`1400
`
`B ^i
`
`iByt,.
`
`Wfg?=;o*wm ft
`^ i^gaBfr^j
`
`1 2 00
`0
`5 1000
`.2 800
`1 600
`w
`>
`W
`
`400
`
`200
`
`3?
`
`•fgryiV
`
`^^f^
`
`it J*
`
`H
`
`J ^ - - fe
`
`JV
`
`^ i ;^
`
`^ H fv -
`
`»-r V ^ ^?
`
`F*SE
`
`XM
`
`•
`
`AUC
`
`if
`
`.
`
`Linear (AUC)
`
`S U li
`
`0.5
`
`1
`
`1.5
`
`2.5
`
`Dose (mg/kg)
`
`FIGURE 9
`
`Low IV dose (0.75 mg/kg)
`
`1000
`
`-jE 800
`
`£*- ^MT^
`
`r cr
`
`S ys
`
`• PV
`
`a p - i 'v •>«
`
`' ?-
`
`*
`
`"if"
`
`f I if £4
`
`'
`
`• a1"
`
`"?»
`
`"•
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`Time (min)
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0009
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 9 of 15
`
`US 2004/0162263 Al
`
`FIGURE 10
`
`Medium IV dose (1.5 mg/kg)
`
`1400
`
`•Sys
`
`• PV
`
`-t
`
`""rvv
`
`50
`
`100
`
`150
`Time (min)
`
`200
`
`250
`
`300
`
`FIGURE 11
`
`High dose IV dose (2.5 mg/kg)
`
`2500
`
`--*« * " »/* ^zr.
`
`Jjj 2000
`c
`~ 1500
`
`'
`
`iggj. - - r - ^ s-
`'•4» ^
`f
`\}
`,d"'3ffl
`^4!
`
`^ -m- sys «•;% -^ ' v
`. ^m:
`" ^ %•, -, rj»i -
`^
`,. 4" ?
`t i t"
`
`iS^i'
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`Time (min)
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0010
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 10 of 15
`
`US 2004/0162263 Al
`
`FIGURE 12
`
`PV infusion (2.5 mg/kg)
`
`SYS
`
`^36. J »
`
`-VH
`
`&xtm
`
`ml
`
`50
`
`100
`
`150
`
`200
`
`Time (min)
`
`^ J
`250
`
`300
`
`FIGURE 13
`
`PO dose 2.5 mg/kg
`
`2000
`
`1500
`
`1000
`
`£
`
`500
`
`1000
`
`£
`
`800
`
`600
`
`400
`
`200
`
`u
`
`£
`2
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`Time (min)
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0011
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 11 of 15
`
`US 2004/0162263 Al
`
`FIGURE 14
`
`USI infusion 2.5 mg/kg
`
`J? "r a *
`
`T-**
`
`, S « i«
`
`• py
`
`i C *i
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`Time (min)
`
`FIGURE 15
`
`LSI infusion 2.5 mg/kg
`
`1000
`
`^
`$sf
`?&«r*
`
`• - PV
`
`^
`Pfc
`
`*
`
`^ <%&
`
`100
`
`150
`
`200
`
`250
`
`Time (min)
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0012
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 12 of 15
`
`US 2004/0162263 Al
`
`FIGURE 16
`
`Colon infusion 2.5 mg/kg
`RS-44
`
`80
`60
`Time (min)
`
`140
`
`FIGURE 17
`
`Colon infusion 2.5 mg/kg
`RS-45
`
`1000
`
`f" -<>•< > > 41 ^ f «V
`80
`60
`Time (min)
`
`140
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0013
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 13 of 15
`
`US 2004/0162263 Al
`
`FIGURE 18
`
`10 z
`
`1
`
`0.1
`
`~
`c
`o
`ra
`i_
`c
`0)
`o
`c
`o
`o
`ro E
`w
`i5
`CL
`
`0.01
`
`JEJUNUM Administration
`
`9-NC systemic
`9-NC portal vein
`9-AC systemic
`9-AC portal vein
`
`10
`
`15
`
`20
`
`25
`
`Time (hr)
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0014
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 14 of 15
`
`US 2004/0162263 Al
`
`FIGURE 19
`
`£>
`c o
`CD 4= c
`O c o o
`
`CD
`
`ro
`w
`i5
`
`10 i
`
`1
`
`0.1
`
`0.01
`
`ILEUM Administration
`•— 9-NC systemic
`o— 9-NC portal vein
`•— 9-AC systemic
`9-AC portal vein
`
`10
`
`15
`
`Time (hr)
`
`25
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0015
`
`

`

`Patent Application Publication Aug. 19,2004 Sheet 15 of 15
`
`US 2004/0162263 Al
`
`FIGURE 20
`
`COLON Administration
`
`•— 9-NC systemic
`o— 9-NC portal vein
`•— 9-AC systemic
`v— 9-AC portal vein
`
`10 q
`
`c
`c
`o
`
`•J=>
`
`c
`a>
`o
`c
`o
`o
`ro
`E
`
`0.1
`
`0.01
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0016
`
`

`

`US 2004/0162263 Al
`
`Aug. 19, 2004
`
`PHARMACEUTICAL FORMULATIONS
`TARGETING SPECIFIC REGIONS OF THE
`GASTROINTESINAL TRACT
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`[0001] This application claims priority to U.S. Provisional
`Application No. 60/423,179, filed Oct. 31, 2002, which is
`hereby incorporated by reference herein.
`
`BACKGROUND OF THE INVENTION
`
`[0002] 1. Field of the Invention
`[0003] This invention relates to pharmaceutical formula(cid:173)
`tions for oral delivery of drugs to specific regions of the
`gastrointestinal tract for enhanced bioavailability, and more
`particularly relates to oral formulations of water-soluble,
`acid-labile drugs such as cytidine analogs (e.g., decitabine)
`and 2'-deoxyadenosine analogs (e.g., pentostatin), as well as
`drugs with poor bioavailability such as camptothecin com(cid:173)
`pounds.
`
`[0004] 2. Description of the Related Art
`[0005] 1. Decitabine
`[0006] Decitabine, 5-aza-2'-deoxycytidine, is an antago(cid:173)
`nist of its related natural nucleoside, deoxycytidine. The
`only structural difference between these two compounds is
`the presence of a nitrogen at position 5 of the cytosine ring
`in decitabine as compared to a carbon at this position for
`deoxycytidine. Two isomeric forms of decitabine can be
`distinguished. The P-anomer is the active form. The modes
`of decomposition of decitabine in aqueous solution are (a)
`conversion of the active P-anomer to the inactive a-anomer
`(Pompon et al. (1987) J. Chromat. 388:113-122); (b) ring
`cleavage of the aza-pyrimidine ring to form N-(formylami-
`dino)-N'-P-D-2'-deoxy-(ribofuranosy)-urea
`(Mojaverian
`and Repta (1984) J. Pharm. Pharmacol. 36:728-733); and (c)
`subsequent forming of guanidine compounds (Kissinger and
`Stemm (1986) J. Chromat. 353:309-318).
`
`[0007] Decitabine possesses multiple pharmacological
`characteristics. At a molecular level, it is S-phase dependent
`for incorporation into DNA. At a cellular level, decitabine
`can induce cell differentiation and exert hematological tox-
`icity. Despite having a short half life in vivo, decitabine has
`an excellent tissue distribution.
`
`[0008] The most prominent function of decitabine is its
`ability to specifically and potently inhibit DNAmethylation.
`Methylation of cytosine to 5-methylcytosine occurs at the
`level of DNA. Inside the cell, decitabine is first converted
`into its active form, the phosphorylated 5-aza-deoxycyti-
`dine, by deoxycytidine kinase which is primarily synthe(cid:173)
`sized during the S phase of the cell cycle. The affinity of
`decitabine for the catalytical site of deoxycytidine kinase is
`similar to the natural substrate, deoxycytidine. Momparler et
`al. (1985) 30:287-299. After conversion to its triphosphate
`form by deoxycytidine kinase, decitabine is incorporated
`into replicating DNA at a rate similar to that of the natural
`substrate, dCTP Bouchard and Momparler (1983) Mol.
`Pharmacol. 24:109-114.
`
`[0009]
`Incorporation of decitabine into the DNA strand
`has a hypomethylation effect. Each class of differentiated
`cells has its own distinct methylation pattern. After chro(cid:173)
`
`mosomal duplication, in order to conserve this pattern of
`methylation, the 5-methylcytosine on the parental strand
`serves to direct methylation on the complementary daughter
`DNA strand. Substituting the carbon at the 5 position of the
`cytosine for a nitrogen interferes with this normal process of
`DNA methylation. The replacement of 5-methylcytosine
`with decitabine at a specific site of methylation produces an
`irreversible inactivation of DNAmethyltransferase, presum(cid:173)
`ably due to formation of a covalent bond between the
`enzyme and decitabine. Juttermann et al. (1994) Proc. Natl.
`Acad. Sci. USA 91:11797-11801. By specifically inhibiting
`DNA methyltransferase, the enzyme required for methyla(cid:173)
`tion, the aberrant methylation of the tumor suppressor genes
`can be prevented.
`[0010] Decitabine is commonly supplied as a sterile lyo-
`philized powder for injection, together with buffering salt,
`such as potassium dihydrogen phosphate, and pH modifier,
`such as sodium hydroxide. For example, decitabine is sup(cid:173)
`plied by SuperGen, Inc., as lyophilized powder packed in 20
`mL glass vials, containing 50 mg of decitabine, monobasic
`potassium dihydrogen phosphate, and sodium hydroxide.
`When reconstituted with 10 mL of sterile water for injection,
`each mL contain 5 mg of decitabine, 6.8 mg of KH2P04, and
`approximately 1.1 mg NaOH. The pH of the resulting
`solution is 6.5-7.5. The reconstituted solution can be further
`diluted to a concentration of 1.0 or 0.1 mg/mL in cold
`infusion fluids, i.e., 0.9% Sodium Chloride; or 5% Dextrose;
`or 5% Glucose; or Lactated Ringer's. The unopened vials
`are typically stored under refrigeration (2-8° C; 36-46° R),
`in the original package.
`
`[0011] Decitabine
`to
`typically administrated
`is most
`patients by injection, such as by a bolus I.V. injection,
`continuous I.V. infusion, or I.V. infusion. The length of I.V.
`infusion is limited by decitabine's decomposition in aqueous
`solutions.
`[0012] It has been found that when 5-azacytidine (azaC) is
`orally administered (8 mg/kg) to repeatedly phlebotomized
`baboon (PCV less than 20%) there is no elevation in the fetal
`hemoglobin levels (Hb F), indicating very minimal oral
`bioavailability. DeSimone et al (1985) American. J. of Hem.
`18:283-288. AzaC is more active when administered
`parenterally than orally in the treatment of L1210 leukemic
`mice due to poor bioavailability. Neil at al (1975) Cancer
`Chemother. Rep. 59:459-465. In L1210 leukemic mice,
`peroral doses of cytarabine (cytosine arbinaoside) required
`to elicit an anti-tumor effect are about 3 to 10 times those
`required when administered parenterally. Neil et al. (1970)
`Cancer Research 30:2166-2172. The poor bioavailability of
`such cytidine analogs is presumably due to the degradation
`of the cytidine analog by cytidine deaminases as well as their
`inherent chemical instability in the acidic gastric environ(cid:173)
`ment.
`[0013] 2. 2'-Deoxyadenosine Analogs
`[0014] Certain 2'-deoxyadenosine analogs have been
`found to have very useful clinical pharmacological benefits.
`These include, but are not limited to, 2'-deoxycoformycin
`(also referred to as dCF, pentostatin, or NIPENT®), an
`inhibitor of adenosine deaminase; fludarabine monophos-
`phate (FLU), a fluorinated analogue of adenine that is
`relatively resistant to adenosine-deaminase and 2-chloro-2'-
`deoxyadenosine (also known as cladribine or 2CDA) a drug
`also resistant to adenosine deaminase through introduction
`of a chlorine at the 2 carbon.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0017
`
`

`

`US 2004/0162263 Al
`
`Aug. 19, 2004
`
`[0015] In humans, these compounds are assumed to act
`through a number of adenosine related pathways, particu(cid:173)
`larly the adenosine deaminase (ADA) pathway. A genetic
`deficiency of ADA may cause severe combined immunode(cid:173)
`ficiency. Dighiero, G., "Adverse and beneficial immunologi-
`cal effects of purine nucleoside analogues,"//emato/ Cell
`Ther, 38:575-581 (1996).
`
`dosage forms. However, the art recognized serious problems
`with the development of an oral dosage form. Chief among
`these is that adenosine analogs have been known for years
`to be susceptible to acid-catalyzed glycosidic cleavage.
`Therefore, one of skill in the art would expect that an orally
`administered adenosine analog would be cleaved in the
`stomach, and rendered inactive.
`
`[0016] While the exact nature of the ADA pathway inter(cid:173)
`vention seems unclear, it may be that analogs of adenosine
`resistant to cellular deamination might mimic the ADA-
`deficient state. Lack of ADA seems to lead to a build up of
`deoxyadenosine and adenosine triphosphate in the cell, thus
`fatally accelerating DNA strand breaks in the cell. Under
`normal conditions, cells are continuously breaking and
`rejoining DNA. When this physiological process is acceler(cid:173)
`ated by the effect of excess adenosine triphosphate, it leads
`to consumption of NAD for poly-ADP-ribose synthesis.
`This polymer is produced from nicotinamide adenosine
`dinucleotides (NAD) in a reaction catalyzed by the chroma-
`tin-associated poly(ADP-ribose) synthetase, leading to a
`depletion of the NAD content of the cell. This depletion
`induces a profound alteration of cellular reducing power,
`because of lethal ADP and ATP depletion.
`
`[0017] The result is programmed cell death through acti(cid:173)
`vation of a Ca2+, Mg2+-dependent endonuclease. Hence, it
`appears that nucleoside analogs according to the invention
`can act on cells, with preferential lymphocytic activity, via
`an apoptotic process. The fact that supplementation of a cell
`medium with the NAD precursor of nicotinamide or 3-ami-
`nobenzamide, an inhibitor of poly (ADP-ribose) synthetase,
`prevented NAD depletion and reduces 2CDA toxicity, tends
`to support this hypothesis.
`
`[0018] The various 2'-deoxyadenosine analogs affect the
`ADA pathway in different manners. DCF, for example, has
`been shown to be an quasi-irreversible inhibitor of ADA. By
`favoring the predominance of deoxycytidine kinase (DCK)
`over the dephosphorylating enzyme 5-nucleotidase in lym(cid:173)
`phocytes it induces a preferential accumulation of deoxy-
`adenosine-5'-triphosphate (dATP). By comparison, FLU and
`2CDA are rather resistant to the enzyme. Both drugs are
`initially phosphorylated by DCK and contribute to the
`accumulation of cellular adenosine triphosphate surrogates.
`As noted above, the accumulation of adenosine triphosphate,
`whether by the presumed DCF mechanism, or the FLU or
`2CDA mechanism, promotes the apoptotic death of the cell.
`
`[0019] A problem with administering these 2-deoxyad-
`enosine analogs is their dosage form. Currently, these ana(cid:173)
`logs are available only in an intravenous (IV) dosage form.
`While this dosage form is customary, especially for use in
`oncology indications, it is limiting in a variety of ways. For
`example, IV dosing is expensive. It requires a highly trained
`medical professional to administer the IV dose. The dosing
`involves expensive equipment and materials. Additionally,
`IV dosing presents increased possibilities of infection,
`through use of contaminated equipment or accidental con(cid:173)
`tamination, for example. This is a special concern in health
`care settings where increased incidences of antibiotic resis(cid:173)
`tant bacteria are being noted.
`
`[0020] A seemingly natural solution to the IV dosage
`problem is the development of an oral dosage form. Such a
`dosage form alleviates most, if not all, of the above-men(cid:173)
`tioned problems associated with IV or other parenteral
`
`[0021] For example, investigators studying 2'-deoxycofor-
`mycin have not considered oral administration of the drug
`worth studying because of its known acid lability. Marvin
`M. Chassin et al. Biochemical Pharmacology 28:1849-1855
`(1979). Likewise, other researchers have reported on the
`acid lability of 2'-deoxycoformycin. L. A. al-Razzak et al.
`7:452-460 (1990).
`
`[0022] Other adenosine analogs may be expected to have
`similar acid lability characteristics. A. Tarasiuk et al. Arch.
`Immunol. Ther. Exp. (Warsz) 42:13-15 (1994); T. Ono
`Nucleic Acids Res. 25:4581-4588 (1997).
`[0023] 3. Camptothecin Compounds
`[0024] The original Camptothecin was isolated from the
`plant, Camptotheca acuminata, in the 1960's (Wall, M. et al.
`(1966) J. Am. Chem. Soc. 88: 3888-3890). Camptothecin
`has a pentacyclic ring system with only one asymmetric
`center in ring E with a 20(S)-configuration. The pentacyclic
`ring system includes a pyrrole quinoline moiety (rings A, B
`and C), a conjugated pyridone (ring D), and a six-membered
`lactone (ring E) with an a-hydoxyl group.
`
`[0025] Camptothecin itself is highly lipophilic and poorly
`water-soluble. Sodium camptothecin that is solubilized by
`sodium hydroxide in water was used in clinical trials in the
`early 70's and found to have antitumor activity. However,
`this formulation of camptothecin administered via i.v.
`caused unpredictable side effects such as myelosuppression
`and hemorrhagic cystitis. Clinical trials with sodium camp(cid:173)
`tothecin were eventually discontinued because of these
`toxicities and the lack of consistent antitumor activity.
`
`[0026] Continued evaluation of this agent showed that the
`sodium carboxylate salt is only 10% as potent as the native
`camptothecin with the closed lactone ring intact (Wall et al.
`in (1969) "International Symposium on Biochemistry and
`Physiology of the Alkaloids, Mothes et al. eds. Academic
`Verlag, Berlin, 77; Giovanella et al. (1991) Cancer Res.
`51:3052). Studies also showed that camptothecin and its
`derivatives undergo an alkaline hydrolysis of the E-ring
`lactone, resulting in a carboxylate form of camptothecin. At
`pH levels below 7.0, the lactone E-ring form of camptoth(cid:173)
`ecin predominates. However, intact lactone ring E and
`a-hydoxyl group have been shown to be essential for
`antitumor activity of camptothecin and its derivatives.
`
`[0027] Camptothecin and its derivatives have been shown
`to inhibit DNA topoisomerase I by stabilizing the covalent
`complex ("cleavable complex") of enzyme and strand-
`cleaved DNA. Inhibition of topoisomerase I by camptoth(cid:173)
`ecin induces protein-associated DNA single-stran breaks
`which occur during the S-phase of the cell cycle. Since the
`S-phase is relatively short compared to other phases of the
`cell cycle, longer exposure to camptothecin should result in
`increased cytotoxicity of tumor cells. Studies indicate that
`only the closed lactone form of the drug helps stabilize the
`cleavable complex, leading to inhibition of the cell cycle and
`apoptosis.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0018
`
`

`

`US 2004/0162263 Al
`
`Aug. 19, 2004
`
`[0028] To preserve the lactone form of camptothecin,
`camptothecin and its water insoluble derivatives have been
`dissolved in N-methyl-2-pyrrolidinone in the presence of an
`acid (U.S. Pat. No. 5,859,023). Upon dilution with an
`acceptable parenteral vehicle, a stable solution of camptoth(cid:173)
`ecin was obtained. The concentrated solution of camptoth(cid:173)
`ecin was also filled in gel capsules for oral administration.
`It is believed that such formulations increase the amount of
`lipophilic lactone form of camptothecin that diffuse through
`the cellular and nuclear membranes in tumor cells.
`
`SUMMARY OF THE INVENTION
`
`[0029] The present invention provides innovative oral
`formulations of pharmaceuticals with enhanced bioavail-
`ability by targeting specific regions of the gastrointestinal
`tract. Particularly, water soluble and acid-labile drugs such
`as cytidine analogs (e.g., decitabine and 5'-azacytidine) and
`2'-deoxyadenosine analogs (e.g., pentostatin) are formulated
`with pH-sensitive polymers so that these drugs are prefer(cid:173)
`ably absorbed in the upper regions of the small intestine,
`such as the jejunum. In addition, drugs with poor oral
`bioavailability such as camptothecin compounds (e.g., 9-ni-
`tro-camptothecin) can also be formulated using similar
`strategies in order to significantly improve their oral bio(cid:173)
`availability.
`
`[0030] In one aspect of the invention, a pharmaceutical
`composition is provided. The pharmaceutical composition
`comprises: a water-soluble, acid-labile drug enteric-coated
`with a coating material that dissolves at pH above about 5.2.
`[0031] According to the invention, the solubility of the
`drug is preferably above 1 mg/ml in water or aqueous
`solution, more preferably above 5 mg/ml in water or aque(cid:173)
`ous solution, and most preferably above 10 mg/ml in water
`or aqueous solution.
`[0032] Also according to the invention, the drug is labile
`preferably at pH lower than 5.0, more preferably at pH lower
`than 4.0, and most preferably at pH lower than 2.0.
`[0033] Examples of the drug includes, but are not limited
`to, cytidine analogs or derivatives such as 5-azacytidine and
`5-aza-2'-deoxycytidine (or decitabine), and 2'-deoxyadenos-
`ine analogs and derivatives such as 2'-deoxycoformycin (or
`pentostatin), fludarabine monophosphate, and 2-chloro-2'-
`deoxyadenosine (or cladribine).
`
`[0034] The coating material for enteric-coating of the drug
`is pH-sensitive and preferably or selectively dissolves at a
`threshold pH above about 5.2, optionally at pH above about
`5.5, optionally at pH above about 5.8, optionally at pH above
`about 6.0, optionally at pH above about 6.2, optionally at pH
`above about 6.5, optionally at pH above about 6.5, and most
`preferably at pH above about 6.8, or optionally at pH above
`about 7.0. The pharmaceutical composition is preferred to
`substantially disintegrate in an aqueous medium at a pH
`equal or above the threshold pH within 3 hours, optionally
`within 2 hours, optionally within 1 hour, more preferably
`within 30 min, and most preferably within 15 mm.
`
`[0035] Examples of such a coating material include, but
`are not limited to, cellulose phthalates that selectively dis(cid:173)
`solve at pH above 5.6, the Eudragit® family of polymers
`(e.g., Eudragit L30D with threshold pH of 5.6, Eudragit L
`with threshold pH of 6.0, and Eudragit S with threshold pH
`of 6.8), Aquateric with threshold pH of 5.8, polyvinylacetate
`
`phthalate (PVAP) that releases drug at pH values above
`about 5.0, Shellac® that releases the drug at about pH7.0,
`and cellulose acetate phthalate (CAP) with threshold pH of
`6.0.
`[0036] In a preferred embodiment, the drug is enteric-
`coated with Eudragit L100 with the threshold pH of 6.0 or
`L100-55 with a threshold pH of 5.5.
`[0037] Also according to the invention, the pharmaceuti(cid:173)
`cal composition is preferred not to substantially disintegrate
`in an acidic, aqueous medium at pH 1.0-3.0 for at least 1
`hour, more preferred not to substantially disintegrate in an
`acidic, aqueous medium at pH 1.2-2.0 for at least 1 hour,
`more preferably for at least 2 hours, and most preferably for
`at least 3 hours. Optionally, the pharmaceutical formulation
`does not substantially disintegrate in an acidic, aqueous
`medium at pH 1.2-1.5 for at least 1 hour, more preferably for
`at least 2 hours, and most preferably for at least 3 hours. The
`composition is considered to be substantially disintegrated if
`at least 50% of the composition disintegrates, e.g., under(cid:173)
`goes rupture.
`
`[0038] In addition, the pharmaceutical composition pref(cid:173)
`erably disintegrates substantially in an aqueous medium at
`pH 5.2-7.5 within 1 hour, more preferably disintegrates
`substantially in an aqueous medium at pH 6.0-7.2 within 30
`minutes, and most preferably disintegrates substantially in
`an aqueous medium at pH 6.5-7.0 within 15 minutes.
`
`[0039] The amount of the enteric-coating material is pref(cid:173)
`erably 1-10% w/w in the composition, more preferably
`2-8% w/w in the composition, and most preferably 3-6%
`w/w in the composition.
`[0040] The pharmaceutical composition may be in a form
`of tablet or capsule. In a preferred embodiment, the com(cid:173)
`position is in a form of tablet. The hardness of the tablet
`without the enteric-coat is preferably at least 4 kp, more
`preferably at least 8 kp, and most preferably 10 kp. The size
`of the tablet is preferably 5-20 mm, more preferably 8-15
`mm, and most preferably 10-13 mm.
`
`[0041] In any of the above dosage forms, the concentra(cid:173)
`tion of the drug is preferably 0.1-20% w/w, optionally
`1-10% w/w, or optionally 2-5% w/w.
`[0042] Optionally, the pharmaceutical composition may
`further comprise a seal-coating material that seals the drug
`to prevent decomposition due to exposure to moisture, such
`as hydroxy propylmethylcellulose. Optionally, the pharma(cid:173)
`ceutical composition may further comprise buffer salt such
`as potassium or sodium phosphate in an amount sufhcient to
`maintain the pH of the local environment to be 5.2-7.0 when
`the pharmaceutical composition is dissolved in the GI tract.
`Examples of such buffer salts include, but are not limited to,
`KH2P04 and Na2HP04.
`
`[0043]
`In another aspect of the invention, a pharmaceuti(cid:173)
`cal composition for delivering a camptothecin compound in
`vivo is provided. The pharmaceutical composition com(cid:173)
`prises: a camptothecin compound enteric-coated with an
`enteric coating material that dissolves at pH above 5.2.
`
`[0044] The enteric coating material for enteric-coating of
`the camptothecin compound is pH-sensitive and preferably
`or selectively dissolves at pH above about 5.2, preferably at
`pH above about 5.8, more preferably at pH above about 6.0,
`and most preferably at pH above about 6.4.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1021-0019
`
`

`

`US 2004/0162263 Al
`
`Aug. 19, 2004
`
`[0045] The enteric coating material for enteric-coating of
`the drug is pH-sensitive and preferably or selectively dis(cid:173)
`solves at a threshold pH above about 5.2, optionally at pH
`above about 5.5, optionally at pH above about 5.8, option(cid:173)
`ally at pH above about 6.0, optionally at pH above about 6.2,
`optionally at pH above about 6.5, optionally at pH above
`about 6.5, and most preferably at pH above about 6.8,
`optionally at pH above about 7.0, optionally at pH above
`about 7.2, or optionally at pH above about 7.5. The phar(cid:173)
`maceutical composition is preferred to substantially disin(cid:173)
`tegrate in an aqueous medium at a pH equal or above the
`threshold pH within 3 hours, optionally within 2 hours,
`optionally within 1 hour, more preferably within 30 min, and
`most preferably within 15 min.
`
`[0046] Examples of such a coating material include, but
`are not limited to, cellulose phthalates that selectively dis(cid:173)
`solve at pH above 5.6, the Eudragit® family of polymers
`(e.g., Eudragit L30D with threshold pH of 5.6, Eudragit L
`with threshold pH of 6.0, and Eudragit S with threshold pH
`of 6.8), Aquateric with threshold pH of 5.8, polyvinylacetate
`phthalate (PVAP) that releases drug at pH values above
`about 5.0, Shellac® that releases the drug at about pH7.0,
`and cellulose acetate phthalate (CAP) with threshold pH of
`6.0.
`
`[0047]
`In a preferred embodiment, the drug is enteric-
`coated with Eudragit L100 with the threshold pH of 6.0 or
`Eudragit L100-55 with a threshold pH of 5.5.
`[0048] Also according to the invention, the pharmaceuti(cid:173)
`cal composition is preferred not to substantially disintegrate
`in an acidic, aqueous medium at pH 1.0-3.0 for at least 1
`hour, more preferred not to substantially disintegrate in an
`acidic, aqueous medium at pH 1.2-2.0 for at least 1 hour,
`more preferably for at least 2 hours, and most preferably for
`at least 3 hours. Optionally, the pharmaceutical formulation
`does not substantially disintegrate in an acidic, aqueous
`medium at pH 1.2-1.5 for at least 1 hour, more preferably for
`at least 2 hours, and most preferably for at least 3 hours. The
`composition is considered to be substantially disintegrated if
`at least 50% of the composition disintegrates, e.g., under(cid:173)
`goes rupture.
`
`[0049]
`In addition, the pharmaceutical composition pref(cid:173)
`erably disintegrates substantially in an aqueous medium at
`pH 5.2-7.5 within 1 hour, more preferably disintegrates
`substantially in an aqueous medium at pH 6.0-7.2 within 30
`minutes, and most preferably disintegrates substantially in
`an aqueous medium at pH 6.5-7.0 within 15 minutes.
`
`[0050] The amount of the enteric-coating material is pref(cid:173)
`erably 1-10% w/w in the composition, more preferably
`2-8% w/w in the composition, and most preferably 3-6%
`w/w in the composition.
`
`[0051] The camptothecin compound may be the original
`20(S)-camptothecin isolated from the plant, Camptotheca
`acuminata, analogs of 20(S)-camptothecin, derivatives of
`20(S)-camptothecin, prodrugs of 20(S)-camptothecin, and
`pharmaceutically active metabolites of 20(S)-camptothecin.
`
`[0052] Examples of camptothecin derivatives include, but
`are not limited to, 9-nitro-20(S)-camptothecin, 9-amino-
`20(S)-camptothecin,
`9-methyl-camptothecin,
`9-chloro-
`camptothecin, 9-flouro-camptothecin, 7-ethyl camptothecin,
`10-methyl-camptothecin,
`10-chloro-camptothecin,
`10-bromo-camptothecin, 10-fluoro-ca