(12) United States Patent
`Ullah et al.
`
`US006331316B1
`US 6,331,316 B1
`Dec. 18, 2001
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) ENTERIC COATED PHARMACEUTICAL
`TABLET AND METHOD OF
`MANUFACTURING
`
`(75)
`
`Inventors: Ismat Ullah, Cranbury; Gary J. Wiley,
`Jackson, both of NJ (US)
`
`(73)
`
`Assignee:
`
`Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21)
`(22)
`
`Appl. No.
`; 09/549,455
`Apr. 14, 2000
`
`Filed:
`
`(63)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Related US. Application Data
`
`Continuation of application No. 09/118,418, ?led on Jul. 17,
`1998, now abandoned.
`
`Int. Cl.7 ............................. .. A61K 9/20; A61K 9/48;
`A61K 9/32; A61K 31/70
`US. Cl. ........................ .. 424/482; 424/464; 424/474;
`424/475; 424/451; 514/23
`Field of Search ................................... .. 424/464, 468,
`424/474, 475, 479, 482, 480, 458, 451,
`478; 514/23
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,432,996
`4,524,060
`4,556,552
`4,704,295
`4,775,536
`4,786,505
`4,794,001
`4,808,413
`4,853,230
`4,861,759
`4,920,210
`4,925,675
`4,975,283
`4,994,279
`5,026,559
`5,026,560
`5,158,777 *
`
`2/1984
`6/1985
`12/1985
`11/1987
`10/1988
`11/1988
`12/1988
`2/1989
`8/1989
`8/1989
`4/1990
`5/1990
`12/1990
`2/1991
`6/1991
`6/1991
`10/1992
`
`Zeitoun et al.
`Mughal et al.
`Porter et al.
`Porter et al.
`
`424/21
`424/19
`.. 424/32
`..... .. 424/3
`
`Patell ................................. .. 424/471
`Lovgren et al. ................... .. 424/468
`Mehta et al.
`424/458
`Joshi et al.
`424/458
`Lovgren et al.
`424/466
`Mitsuya et al. ...................... .. 514/46
`KosZalka et al. .
`
`Giannini et al. ................... .. 424/469
`
`424/470
`Patell ........... ..
`424/494
`Aoki et al. .
`424/458
`Eichel et al.
`Makino et al. .................... .. 424/494
`AbramoWitZ et al. .
`
`5,175,003 * 12/1992 Goldman .
`5,225,202 * 7/1993 Hodges et al. .
`5,254,539
`10/1993 Mitsuya et al. ...................... .. 514/46
`5,326,570
`7/1994 Rudnic et al. .
`5,350,584
`9/1994 McClelland et al. .............. .. 424/501
`5,422,121
`6/1995 Lehmann et al. .
`5,510,114
`4/1996 Borella et al. .
`5,536,507
`7/1996 AbramoWitZ et al. ............. .. 424/479
`5,556,839
`9/1996 Greene et al. .
`5,616,566
`4/1997 Mitsuya et al. ...................... .. 514/47
`5,686,106
`11/1997 Kelm et al.
`5,733,575
`3/1998 Mehra et al. ...................... .. 424/480
`
`FOREIGN PATENT DOCUMENTS
`
`0754452
`0781549
`WO94/03160
`
`1/1997 (EP) .............................. .. A61K/9/52
`7/1997 (EP) .............................. .. A61K/9/28
`2/1994 (W0).
`
`OTHER PUBLICATIONS
`
`Ishibashi et al., “Design and Evaluation of a NeW Capsule—
`Type Dosage Form for Colon—Targeted Delivery of Drugs”,
`Int’l. J. of Pharmaceutics 168 (1998) pp. 31—40.
`C.G. Wilson and Neena Washington, “Small Intestine: Tran
`sit and Absorption of Drugs”; Chapter 5—Physiological
`Pharmaceutics—Biological Barriers to Drugs Absorption;
`1989 pp. 71—90.
`
`* cited by examiner
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Brian K. Seidleck
`(74) Attorney, Agent, or Firm—Barry J. Marenberg;
`Gabriel Lopez
`(57)
`
`ABSTRACT
`
`A high drug load enteric coated pharmaceutical composition
`is provided Which includes a core in the form of a tablet and
`Which is comprised of a medicament Which is sensitive to a
`loW pH environment of less than 3, such as ddl, and having
`an enteric coating formed of methacrylic acid copolymer
`and a plasticiZer. The tablets may be of varying siZes and
`may be orally ingested individually or a plurality of tablets
`suf?cient to attain a desired dosage may be encapsulated in
`a dissolvable capsule. The tablets have excellent resistance
`to disintegration at pH less than 3 but have excellent drug
`release properties at pH greater than 4.5. A novel method of
`making said pharmaceutical composition is also disclosed.
`
`35 Claims, N0 Drawings
`
`Lupin Exh. 1030
`
`

`
`US 6,331,316 B1
`
`1
`ENTERIC COATED PHARMACEUTICAL
`TABLET AND METHOD OF
`MANUFACTURING
`
`This is a continuation of Ser. No. 09/118,418, Jul. 17,
`1998, abandoned.
`
`BRIEF DESCRIPTION OF THE INVENTION
`
`The present invention is directed to an enteric-coated
`pharmaceutical composition in the form of a tablet Which
`comprises an acid labile high drug load medicament, such as
`
`ddl, Which is sensitive to a loW pH environment less than
`3, and Which includes an enteric coating such as Eudragit
`L-30-D 55 and a plasticiZer, but Which does not require a
`subcoat. The tablets have excellent resistance to disintegra
`tion at pH less than 3 but have excellent drug release
`properties at pH greater than 4.5. Anovel method of making
`said pharmaceutical composition is also disclosed.
`
`10
`
`15
`
`BACKGROUND OF THE INVENTION
`
`20
`
`Enteric coatings have been used for many years to arrest
`the release of the drug from orally ingestible dosage forms.
`Depending upon the composition and/or thickness, the
`enteric coatings are resistant to stomach acid for required
`periods of time before they begin to disintegrate and permit
`sloW release of the drug in the loWer stomach or upper part
`of the small intestines. Examples of some enteric coatings
`are disclosed in US. Pat. No. 5,225,202 Which is incorpo
`rated by reference fully herein. As set forth in US. Pat. No.
`5,225,202, some examples of coating previously employed
`are beesWax and glyceryl monostearate; beesWax, shellac
`and cellulose; and cetyl alcohol, mastic and shellac, as Well
`as shellac and stearic acid (US. Pat. No. 2,809,918); poly
`vinyl acetate and ethyl cellulose (US. Pat. No. 3,835,221);
`and neutral copolymer of polymethacrylic acid esters
`(Eudragit L30D)
`W. Goodhart et al., Pharm. Tech., pp.
`64—71, April 1984); copolymers of methacrylic acid and
`methacrylic acid methylester (Eudragits), or a neutral
`copolymer of polymethacrylic acid esters containing metal
`lic stearates (Mehta et al., US. Pat. Nos. 4,728,512 and
`4,794,001).
`Most enteric coating polymers begin to become soluble at
`pH 5.5 and above, With maximum solubility rates at pHs
`greater than 6.5.
`Numerous enteric coated and/or extended release phar
`maceutical compositions and the methods of making these
`compositions have been disclosed in the art. Prior art
`compositions, hoWever, often comprise numerous extra
`ingredients in addition to the medicaments, such as ?llers,
`buffering agents, binders and Wetting agents, all of Which
`add to the bulk of the composition and reduce the amount of
`active medicament Which can be contained in the composi
`tion. The processes for preparing these aforementioned
`pharmaceutical compositions require multiple time consum
`ing steps, including subcoating and outer coating steps.
`Furthermore, many of these pharmaceutical compositions
`are intended for delivery in the loWer GI tract, ie in the
`colon, as opposed to the upper intestines, ie the duodenum
`of the small intestine.
`US. Pat. No. 5,225,202 discloses enteric coated pharma
`ceutical compositions utiliZing neutraliZed hydroxypropyl
`methylcellulose phthalate polymer (HPMCP) coating. The
`pharmaceutical compositions disclosed comprise an acid
`labile medicament core, a disintegrant, one or more buffer
`ing agents to provide added gastric protection in addition to
`the enteric coating, as Well as the enteric coating and a
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`plasticiZer. The pharmaceutical composition may also
`include one or more lactose, sugar or starch ?llers. Accord
`ing to the invention disclosed in this reference, When the
`core includes a drug Which is incompatible With the enteric
`coating layer, an additional subcoat layer Which acts as a
`physical barrier betWeen the core and outer enteric coating
`layer is employed to prevent interaction of the acid labile
`drug and the acidic enteric coat. The HPMCP enteric coating
`starts its dissolution process at pH 5.0. The process of
`preparing this pharmaceutical composition requires numer
`ous coating steps to apply the subcoat and then the enteric
`coat.
`US. Pat. No. 5,026,560 discloses a pharmaceutical com
`position and method of making said pharmaceutical
`composition, Wherein the pharmaceutical composition com
`
`prises Nonpareil
`seed core produced by coating sucrose
`With corn starch, spraying the core With an aqueous binder
`in a solution of Water or ethanol and With a spraying poWder
`containing a drug and loW substituted
`hydroxypropylcellulose, folloWed by the application of an
`enteric coating.
`US. Pat. No. 4,524,060 recites a sloW release pharma
`
`ceutical composition Whic*******************878 0 Td(cid:10)(provides )Tj(cid:10)60.4938 Tz 3.915 0 Td(cid:10)(a )Tj(cid:10)65.775 Tz 0.907 0 Td(cid:10)(sustained )Tj(cid:10)62.963 Tz 4.096 0 Td(cid:10)(release )Tj(cid:10)63.4877 Tz 10.4816 0 0 10.4816 293.76 498.536 Tm(cid:10)(composition )Tj(cid:10)54.6989 Tz 4.579 0 Td(cid:10)(for )Tj(cid:10)53.4268 Tz 1.374 0 Td(cid:10)(treating )Tj(cid:10)60.1051 Tz 2.954 0 Td(cid:10)(hypertensive )Tj(cid:10)52.5788 Tz 4.717 0 Td(cid:10)(patients, )Tj(cid:10)66.1475 Tz 3.274 0 Td(cid:10)(and )Tj(cid:10)68.6916 Tz 1.557 0 Td(cid:10)(Which )Tj(cid:10)78.4753 Tz 8.4952 0 0 8.4952 293.76 488.7996 Tm(cid:10)(comprises )Tj(cid:10)65.9193 Tz 4.633 0 Td(cid:10)(a )Tj(cid:10)76.6816 Tz 0.735 0 Td(cid:10)(mixture )Tj(cid:10)72.9821 Tz 3.616 0 Td(cid:10)(of )Tj(cid:10)78.1614 Tz 1.187 0 Td(cid:10)(microniZed )Tj(cid:10)79.5217 Tz 5.057 0 Td(cid:10)(indoramin )Tj(cid:10)68.2735 Tz 4.661 0 Td(cid:10)(or )Tj(cid:10)65.9193 Tz 1.215 0 Td(cid:10)(a )Tj(cid:10)87.8924 Tz 0.706 0 Td(cid:10)(pharma )Tj(cid:10)56.8116 Tz 10.1388 0 0 10.1388 293.76 478.3879 Tm(cid:10)(ceutically )Tj(cid:10)60.7569 Tz 3.716 0 Td(cid:10)(acceptable )Tj(cid:10)49.3156 Tz 3.953 0 Td(cid:10)(salt )Tj(cid:10)55.7267 Tz 1.468 0 Td(cid:10)(thereof, )Tj(cid:10)55.2335 Tz 3.006 0 Td(cid:10)(a )Tj(cid:10)63.6172 Tz 0.592 0 Td(cid:10)(Water-channeling )Tj(cid:10)57.2061 Tz 6.415 0 Td(cid:10)(agent, )Tj(cid:10)60.6982 Tz 9.226 0 0 9.226 294 468.5525 Tm(cid:10)(a )Tj(cid:10)68.75 Tz 0.598 0 Td(cid:10)(Wetting )Tj(cid:10)62.866 Tz 3.2 0 Td(cid:10)(agent, )Tj(cid:10)60.6982 Tz 2.549 0 Td(cid:10)(a )Tj(cid:10)61.3652 Tz 0.624 0 Td(cid:10)(disintegrant, )Tj(cid:10)62.1434 Tz 5.073 0 Td(cid:10)(the )Tj(cid:10)69.9887 Tz 1.405 0 Td(cid:10)(mixture )Tj(cid:10)71.9707 Tz 3.2 0 Td(cid:10)(being )Tj(cid:10)58.5304 Tz 2.419 0 Td(cid:10)(in )Tj(cid:10)63.5886 Tz 0.962 0 Td(cid:10)(the )Tj(cid:10)76.9566 Tz 1.405 0 Td(cid:10)(form )Tj(cid:10)73.7813 Tz 8.6743 0 0 8.6743 293.76 458.7432 Tm(cid:10)(of )Tj(cid:10)64.5586 Tz 1.3 0 Td(cid:10)(a )Tj(cid:10)80.0395 Tz 0.858 0 Td(cid:10)(non-compressed )Tj(cid:10)63.7901 Tz 7.166 0 Td(cid:10)(pellet )Tj(cid:10)79.9297 Tz 2.767 0 Td(cid:10)(and )Tj(cid:10)77.6241 Tz 1.881 0 Td(cid:10)(having )Tj(cid:10)76.087 Tz 3.265 0 Td(cid:10)(an )Tj(cid:10)65.8762 Tz 1.383 0 Td(cid:10)(enteric )Tj(cid:10)70.3228 Tz 3.237 0 Td(cid:10)(coat )Tj(cid:10)69.17 Tz 2.13 0 Td(cid:10)(or )Tj(cid:10)63.2435 Tz 9.698 0 0 9.698 293.76 448.6574 Tm(cid:10)(sustained )Tj(cid:10)59.5118 Tz 3.762 0 Td(cid:10)(release )Tj(cid:10)62.8998 Tz 2.871 0 Td(cid:10)(coat )Tj(cid:10)70.5761 Tz 1.831 0 Td(cid:10)(permeable )Tj(cid:10)53.6195 Tz 4.182 0 Td(cid:10)(to )Tj(cid:10)58.5175 Tz 1.039 0 Td(cid:10)(gastrointestinal )Tj(cid:10)56.5657 Tz 5.89 0 Td(cid:10)(juices. )Tj(cid:10)96.5517 Tz 8.8381 0 0 8.8381 302.64 437.6321 Tm(cid:10)(US. )Tj(cid:10)61.0991 Tz 2.2 0 Td(cid:10)(Pat. )Tj(cid:10)78.4483 Tz 1.928 0 Td(cid:10)(No. )Tj(cid:10)74.4253 Tz 1.874 0 Td(cid:10)(5,536,507 )Tj(cid:10)52.0474 Tz 4.453 0 Td(cid:10)(is )Tj(cid:10)67.3222 Tz 1.059 0 Td(cid:10)(directed )Tj(cid:10)58.8362 Tz 3.666 0 Td(cid:10)(to )Tj(cid:10)63.3621 Tz 1.195 0 Td(cid:10)(a )Tj(cid:10)73.7069 Tz 0.787 0 Td(cid:10)(pharmaceutical )Tj(cid:10)69.9427 Tz 9.5143 0 0 9.5143 293.76 427.7586 Tm(cid:10)(composition )Tj(cid:10)70.0701 Tz 5.146 0 Td(cid:10)(having )Tj(cid:10)58.8589 Tz 3.052 0 Td(cid:10)(a )Tj(cid:10)68.4685 Tz 0.883 0 Td(cid:10)(delayed )Tj(cid:10)60.6607 Tz 3.405 0 Td(cid:10)(release )Tj(cid:10)64.8649 Tz 3.103 0 Td(cid:10)(coating )Tj(cid:10)63.0631 Tz 3.229 0 Td(cid:10)(or )Tj(cid:10)60.6607 Tz 1.261 0 Td(cid:10)(enteric )Tj(cid:10)63.5581 Tz 9.6762 0 0 9.6762 293.76 417.6872 Tm(cid:10)(coatings )Tj(cid:10)70.2756 Tz 3.547 0 Td(cid:10)(Wherein )Tj(cid:10)59.252 Tz 3.472 0 Td(cid:10)[(the )-363(active )]TJ(cid:10)65.315 Tz 4.316 0 Td(cid:10)(agent )Tj(cid:10)57.874 Tz 2.456 0 Td(cid:10)(in )Tj(cid:10)60.6299 Tz 1.191 0 Td(cid:10)(the )Tj(cid:10)68.7724 Tz 1.612 0 Td(cid:10)(composition )Tj(cid:10)49.6063 Tz 5.06 0 Td(cid:10)(is )Tj(cid:10)68.8274 Tz 9.226 0 0 9.226 293.76 407.6816 Tm(cid:10)(intended )Tj(cid:10)60.6982 Tz 3.616 0 Td(cid:10)(for )Tj(cid:10)63.1757 Tz 1.379 0 Td(cid:10)(release )Tj(cid:10)69.3694 Tz 2.966 0 Td(cid:10)(of )Tj(cid:10)60.6982 Tz 1.119 0 Td(cid:10)(a )Tj(cid:10)74.4932 Tz 0.624 0 Td(cid:10)(predominant )Tj(cid:10)79.4857 Tz 5.229 0 Td(cid:10)(amount )Tj(cid:10)67.2016 Tz 3.174 0 Td(cid:10)(of )Tj(cid:10)62.1434 Tz 1.067 0 Td(cid:10)(the )Tj(cid:10)71.5372 Tz 1.457 0 Td(cid:10)(drug )Tj(cid:10)54.1948 Tz 2.055 0 Td(cid:10)(at )Tj(cid:10)66.5622 Tz 8.4132 0 0 8.4132 294 397.6311 Tm(cid:10)(a )Tj(cid:10)72.2675 Tz 0.77 0 Td(cid:10)(point )Tj(cid:10)73.6938 Tz 2.567 0 Td(cid:10)(near )Tj(cid:10)68.147 Tz 2.168 0 Td(cid:10)(the )Tj(cid:10)61.8077 Tz 1.655 0 Td(cid:10)(inlet )Tj(cid:10)64.185 Tz (to )Tj(cid:10)71.3166 Tz 3.395 0 Td(cid:10)(or )Tj(cid:10)75.2787 Tz 1.227 0 Td(cid:10)(Within )Tj(cid:10)68.147 Tz 3.081 0 Td(cid:10)(the )Tj(cid:10)68.4639 Tz 1.655 0 Td(cid:10)(large )Tj(cid:10)65.5056 Tz 2.453 0 Td(cid:10)(intestine )Tj(cid:10)80.8255 Tz 3.994 0 Td(cid:10)(and )Tj(cid:10)59.4305 Tz 1.883 0 Td(cid:10)(at )Tj(cid:10)60.4938 Tz 9.2571 0 0 9.2571 294 387.6933 Tm(cid:10)(a )Tj(cid:10)97.2222 Tz 0.7 0 Td(cid:10)(pH )Tj(cid:10)69.1358 Tz 1.53 0 Td(cid:10)(of )Tj(cid:10)70.7977 Tz 1.167 0 Td(cid:10)(approximately )Tj(cid:10)63.7346 Tz 5.911 0 Td(cid:10)(6.4—7.0. )Tj(cid:10)74.1935 Tz 8.8571 0 0 8.8571 302.64 376.7364 Tm(cid:10)(Pharmaceutical )Tj(cid:10)74.5161 Tz 6.747 0 Td(cid:10)(compositions )Tj(cid:10)82.1935 Tz 5.88 0 Td(cid:10)(Which )Tj(cid:10)69.6774 Tz 3.008 0 Td(cid:10)(include )Tj(cid:10)63.2258 Tz 3.523 0 Td(cid:10)(a )Tj(cid:10)79.7849 Tz 0.921 0 Td(cid:10)(medica )Tj(cid:10)88.7153 Tz 8.2286 0 0 8.2286 293.76 366.72 Tm(cid:10)(ment )Tj(cid:10)88.4722 Tz 2.421 0 Td(cid:10)(Which )Tj(cid:10)55.9028 Tz 2.975 0 Td(cid:10)(is )Tj(cid:10)74.7396 Tz 0.962 0 Td(cid:10)(unstable )Tj(cid:10)68.0556 Tz 3.938 0 Td(cid:10)(in )Tj(cid:10)80.2083 Tz 1.167 0 Td(cid:10)(an )Tj(cid:10)69.6759 Tz 1.312 0 Td(cid:10)(acidic )Tj(cid:10)83.0808 Tz 2.829 0 Td(cid:10)(environment )Tj(cid:10)81.4236 Tz 5.804 0 Td(cid:10)(such )Tj(cid:10)68.0556 Tz 2.304 0 Td(cid:10)(as )Tj(cid:10)69.6759 Tz 1.137 0 Td(cid:10)(the )Tj(cid:10)73.2143 Tz 9.6 0 0 9.6 293.76 356.558 Tm(cid:10)(stomach )Tj(cid:10)70.8333 Tz 3.45 0 Td(cid:10)(and )Tj(cid:10)75 Tz 1.6 0 Td(cid:10)(Which )Tj(cid:10)47.9167 Tz 2.6 0 Td(cid:10)(is )Tj(cid:10)63.8889 Tz 0.925 0 Td(cid:10)(not )Tj(cid:10)66.6667 Tz 1.5 0 Td(cid:10)(adequately )Tj(cid:10)61.1111 Tz 4.325 0 Td(cid:10)(buffered, )Tj(cid:10)60.4167 Tz 3.625 0 Td(cid:10)(Will )Tj(cid:10)61.9048 Tz 1.775 0 Td(cid:10)(require )Tj(cid:10)71.888 Tz 9.181 0 0 9.181 294 346.6414 Tm(cid:10)(an )Tj(cid:10)62.2407 Tz 1.412 0 Td(cid:10)(enteric )Tj(cid:10)64.4813 Tz 3.137 0 Td(cid:10)(protective )Tj(cid:10)67.8423 Tz 4.444 0 Td(cid:10)(coating )Tj(cid:10)56.639 Tz 3.398 0 Td(cid:10)(to )Tj(cid:10)69.7095 Tz 1.255 0 Td(cid:10)(prevent )Tj(cid:10)63.4855 Tz 3.451 0 Td(cid:10)(release )Tj(cid:10)69.7095 Tz 3.241 0 Td(cid:10)(of )Tj(cid:10)71.888 Tz 1.333 0 Td(cid:10)(such )Tj(cid:10)75.4167 Tz 9.6 0 0 9.6 293.76 336.8799 Tm(cid:10)(medicament )Tj(cid:10)60.8333 Tz 4.85 0 Td(cid:10)(prior )Tj(cid:10)56.25 Tz 2.15 0 Td(cid:10)(to )Tj(cid:10)66.1458 Tz 1.05 0 Td(cid:10)(reaching )Tj(cid:10)59.7222 Tz 3.525 0 Td(cid:10)(the )Tj(cid:10)56.0606 Tz 1.45 0 Td(cid:10)(intestines. )Tj(cid:10)59.7296 Tz 9.2082 0 0 9.2082 302.64 325.515 Tm(cid:10)(ddl, )Tj(cid:10)60.8*********************also knoWn as didanosine or 2‘,3‘-dideoxyinosine,
`
`and marketed by Bristol-Myers Squibb Co. under the brand
`name Videx®), is an acid labile drug Which has the formula
`
`0
`
`HN
`
`k |
`
`N
`
`N
`
`>
`
`N
`
`HOCHZ
`o
`
`H H
`
`H
`H
`H H
`
`and Which has been shoWn to be effective in the treatment of
`patients With the HIV virus Which causes AIDS. The com
`position and method of inhibiting HIV replication With
`2‘,3‘-dideoxyinosine have been reported. See US. Pat. Nos.
`4,861,759, 5,254,539 and 5,616,566, Which are incorporated
`by reference herein. More recently, Videx® has become
`Widely used as a component of the neW therapeutic cocktails
`used to treat AIDS. It is also an acid labile medicament
`sensitive to a loW pH environment and Will degrade in the
`stomach.
`
`

`
`US 6,331,316 B1
`
`15
`
`25
`
`35
`
`3
`Videx® is generally available in a variety of oral dosages,
`including CheWable/Dispersible Buffered Tablets in
`strengths of 25, 50, 100 or 150 mg of didanosine. Each tablet
`is buffered With calcium carbonate and magnesium hydrox
`ide. Videx® tablets also contain aspartame, sorbitol, micro
`crystalline cellulose, Polyplasdone®, mandarin-orange
`?avor, and magnesium stearate. Videx® Buffered PoWder
`for Oral Solution is supplied for oral administration in
`single-dose packets containing 100, 167 or 250 mg of
`didanosine. Packets of each product strength also contain a
`citrate phosphate buffer (composed of dibasic sodium
`phosphate, sodium citrate, and citric acid) and sucrose. A
`Videx® Pediatric PoWder for Oral Solution is also available
`and Which is supplied for oral administration in 4- or
`8-ounce glass bottles containing 2 or 4 grams of didanosine
`respectively, and is to be mixed With commercial antacid
`before oral ingestion.
`With particular emphasis on the tablets, Whether ingested
`alone or as part of a combination (“cocktail”) therapy
`regimen, the current cheWable/dispersible buffered tablets
`are not conducive from a patient ease of use standpoint.
`Whereas the other products Which are a part of the AIDS
`therapeutic cocktail are capsules or tablets and easily
`sWalloWed, the Videx® (referred to herein as “ddl”)
`CheWable/Dispersible Buffered Tablets must be thoroughly
`cheWed, manually crushed, or uniformly dispersed in Water
`before administration. Because ddl degrades rapidly at
`acidic pH, ddl, in its cheWable/dispersible form and its
`buffered poWder for oral solution, contains buffering agents
`and is administered With antacids in the pediatric poWder
`form. HoWever, the presence of the large quantities of
`antacid components in the formulation can lead to signi?
`cant GI imbalance as noted by severe diarrhea. Many
`patients also complain about cheWing the large ddl tablets
`(dose=2 tablets of 2.1 g each), the taste of the ddl or the time
`required to disperse the tablets and the volume of ?uid (4 02)
`required for the dose. All these factors, coupled With the fact
`that other nucleoside analog drugs are marketed in a more
`convenient dosage presentation (i.e. capsule or smaller
`tablets), necessitate the development of an innovative dos
`age form of ddl Which is easy to sWalloW and does not cause
`discomforting side effects.
`Accordingly, there is provided a tablet comprising a
`medicament core and having a coating Which prevents
`release of the medicament in the stomach and alloWs for
`release of the drug in the small intestine thereby eliminating
`the need for an antacid Which may cause GI imbalance upon
`chronic use. Thus, pharmaceutical compositions Which
`include a medicament Which is unstable in an acid environ
`ment such as the stomach Will require such a protective
`coating to prevent release of such medicament prior to
`reaching the intestines.
`
`45
`
`DESCRIPTION OF THE INVENTION
`
`In accordance With the present invention, an enteric
`coated, high drug load pharmaceutical composition, and a
`method of making said pharmaceutical composition, is
`provided Which includes a medicament Which may degrade
`in a loW pH environment but Which is protected from doing
`so by the enteric coating. The pharmaceutical composition
`of the invention, Which is advantageously in the form of
`tablets, includes a core Which comprises a medicament, such
`as ddl, Which is sensitive to a loW pH environment and
`optionally a binder or ?ller, a disintegrant or sWelling agent,
`and a lubricant. The core further comprises an enteric
`coating surrounding the core Which includes a methacrylic
`acid copolymer and a plasticiZer.
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`4
`The novel enteric coated pharmaceutical of the invention
`Will provide for protection of the medicament or therapeu
`tically active agent, such as ddl, at pH’s less than 3 (such as
`found in the stomach) but Will permit drug release at a pH
`of 4.5 or higher (such as found in the upper intestines).
`Accordingly, the pharmaceutical composition of the
`invention Will usually include drugs Which are chemically
`unstable in acidic environments. The pharmaceutical com
`position of the invention provides excellent protection in
`very acidic environments (pH<3) While not delaying the
`rapid release in regions of pH greater than 4, Whether this be
`the upper intestine or the duodenum.
`Most of the enteric coating materials knoWn in the art are
`acidic in nature and hence may cause chemical instability
`When in contact With acid labile ingredients. This is espe
`cially true under high temperature and humid conditions
`experienced during an aqueous coating process. To mini
`miZe this acid caused instability, a protective coat or subcoat
`is usually applied betWeen the particles, beadlets, pellets,
`tablets, etc., and the enteric coat. This protective coat
`physically separates the acid labile drug from the acidic
`enteric coat, and hence improves stability of the formulation.
`The process of applying such a subcoat, hoWever, often
`entails multiple burdensome and time-consuming steps.
`Furthermore, the subcoat can cause a delay in drug release.
`A process is thus described by Which tablets, beadlets,
`pellets, and/or particles containing acid labile drugs can be
`successfully aqueous enteric coated Without application of
`the protective coat or subcoat. This process involves raising
`the pH of the enteric coating suspension solution by using
`alkaliZing agents. The pH of the coating suspension is raised
`beloW the point Where enteric integrity of the polymer could
`be lost. The process may also involve the inclusion of
`binders, such as sodium carboxymethylcellulose, ?llers,
`such as microcrystalline cellulose, disintegrants, such as
`sodium starch glycolate, and other excipients, such as mag
`nesium oxide, Which are relatively alkaline in nature, in the
`formulations of cores intended for enteric coating. Raising
`the pH of the coating suspension provides a more stable
`composition for the acid labile drug in the core. As a result,
`there is no incompatibility and no need for a protective
`subcoat betWeen the acid labile drug and the acidic enteric
`coat. This process not only eliminates the costly additional
`subcoating step, but alloWs quicker release of the drug since
`the added subcoat layer delays drug release.
`The process of the present invention illustrates the prepa
`ration of high (up to 99.5%) potency (uncoated) tablets, for
`acid labile drugs, such as ddl, using an aqueous process. No
`specialiZed equipment is required as conventional blending,
`compacting, tableting, and coating equipment Was found to
`be adequate for tablet formation and coating.
`In the digestive tract, the coated tablets pass through the
`stomach ?rst. The transit time for the stomach is approxi
`mately tWo hours and the pH of this region is approximately
`1 to 3. The enteric coating component alloWs the medica
`ment core to remain substantially intact and thus prevents
`the pharmacologically active substance from being released
`in this region or the acid from penetrating through to the
`tablet core. The tablets then pass through the small intestine
`Wherein the majority of the enteric coating component Will
`dissolve and release the pharmacologically active substance
`therein. In normal flow direction therethrough, the small
`intestine consists of the duodenum, jejunum and ileum.
`Transit time through the small intestine is approximately 2—4
`hours and the pH of these regions is approximately 5 to
`approximately 7.2.
`
`

`
`5
`As used herein “enteric coating”, is a polymer material or
`materials Which encase the medicament core. The polymeric
`enteric coating material in the present invention does not
`contain any active compound, ie any therapeutically active
`agent, of the present invention. Preferably, a substantial
`amount or all of the enteric polymer coating material is
`dissolved before the medicament or therapeutically active
`agent is released from the dosage form, so as to achieve
`delayed dissolution of the medicament core. A suitable
`pH-sensitive polymer is one Which Will dissolve in intestinal
`juices at the higher pH levels (pH greater than 4.5), such as
`Within the small intestine and therefore permit release of the
`pharmacologically active substance in the regions of the
`small intestine and not in the upper portion of the GI tract,
`such as the stomach.
`The polymer coating material is selected such that the
`therapeutically active agent Will be released When the dos
`age form reaches the small intestine or a region in Which the
`pH is greater than pH 4.5. Preferred coating pH-sensitive
`materials, Which remain intact in the loWer pH environs of
`the stomach, but Which disintegrate or dissolve at the pH
`commonly found in the small intestine of the patient. The
`enteric polymer coating material begins to dissolve in an
`aqueous solution at pH betWeen about 4.5 to about 5.5. The
`pH-solubility behavior of the enteric polymers of the present
`invention are such that signi?cant dissolution of the enteric
`polymer coating Will not occur until the dosage form has
`emptied from the stomach. The pH of the small intestine
`gradually increases from about 4.5 to about 6.5 in the
`duodenal bulb to about 7.2 in the distal portions of the small
`intestine (ileum). In order to provide predictable dissolution
`corresponding to the small intestine transit time of about 3
`hours and permit reproducible release therein, the coating
`should begin to dissolve Within the pH range of the duode
`num and continue to dissolve at the pH range Within the
`small intestine. Therefore, the amount of enteric polymer
`coating should be such that it is substantially dissolved
`during the approximate three hour transit time Within the
`small intestine.
`The pharmaceutical medicament present in the core Will
`be an acid labile drug such as ddl, pravastatin, erythromycin,
`digoxin, pancreatin, ddA, (2‘,3‘-dideoxyadenosine) ddC, (
`2‘,3‘-dideoxycytosine) and the like. The present invention is
`not limited to these drugs and other drugs may be used as
`Well. The invention is particularly adapted to pharmaceutical
`compositions, such as tablets, Which contain ddl as the
`medicament. ddl Will be present in an amount of about up to
`about 95% of the composition in the coated tablets.
`One or more binders or ?llers may be present in the core.
`Microcrystalline cellulose (PH-101) is the preferred binder
`most suitable for use herein. Examples of other binders
`Which may be used include sodium carboxymethylcellulose
`AvicelTM PH101,AvicelTM RC 591, AvicelTM CL-611, (FMC
`Corp), CeolusTM (FMC Corp.), ProSolvTM (EdWard Mendell
`Co.) MethocelTM E-5 (DoW Corp.), Starch 1500 (Colorcon,
`Ltd.), Hydroxypropyl Methylcellulose (HPMC) (Shin-Etsu
`Chemical Co., Ltd.), Polyvinylpyrrolidone, Potassium Algi
`nate and Sodium Alginate.
`The core of the composition of the invention may also
`include one or more disintegrants or sWelling agents, such as
`sodium starch glycolate marketed under the trademark
`EXPLOTAB (EdWard Mendell Co.), Ac-Di-Sol (cross
`linked sodium carboxymethylcellulose) (FMC Corp), cros
`carmellose sodium, corn starch, or cross linked polyvi
`nylpyrrolidone. A lubricant such as magnesium stearate,
`may also be used in the preparation of the uncoated tablet,
`speci?cally as a lubricant for the compaction and tableting
`process.
`
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`6
`The core employed in the pharmaceutical composition of
`the invention Will be formed of a tablet, preferably a round,
`biconvex tablet, approximately 3/16 of an inch. The invention
`is not, hoWever, limited in the siZe of the tablet and tablets
`of varying siZes may be made. Smaller siZed tablets are
`advantageous, hoWever, since they pass through the stomach
`With more ease than larger siZed tablets. Experimentation
`has shoWn that the tablet of the present invention having
`core comprising ddl as the medicament, has the same
`bioavailability as the beadlet disclosed in co-pending US.
`Application Ser. No. 09/083,597, Which Was ?led on May
`22, 1998. Depending upon the siZe of the tablets, they may
`be ingested individually, or a plurality of tablets suf?cient to
`attain a particular dosage may be encapsulated in a dissolv
`able capsule.
`In an alternative embodiment of the present invention, the
`core can be prepared from a Wet granulation process, using
`any of the Wet granulation binders (if necessary) commonly
`used in the art, such as pregelatiniZed starch,
`polyvinylpyrrolidone,
`HPMC
`sodium
`carboxymethycellulose, potassium or sodium alginate. The
`Wet granulation process comprises the steps of preparing
`granules suitable for tableting by blending a mixture com
`prising the medicament, a binder, and optionally, a disinte
`grant and ?ller; adding a predetermined amount of Water or
`granulation solvent to form a Wet mass blend; siZing the Wet
`mass blend into granules to aid drying; drying the Wet
`granules to remove excess moisture; siZing the dried gran
`ules into granules suitable for tableting, and adding
`lubricant, one or more ?llers, one or more dry binders,
`optionally a disintegrant, and other excipients necessary for
`tableting the granules.
`The enteric coating according to the present invention Will
`include methacrylic acid copolymer, a plasticiZer, and a
`suf?cient quantity of NaOH to adjust the pH of the suspen
`sion. Other alkaliZing agents, such as potassium hydroxide,
`calcium carbonate, sodium carboxymethylcellulose, magne
`sium oxide, and magnesium hydroxide can also be used.
`In forming the enteric coated pharmaceutical composition
`of the invention, an enteric coating solution of Eudragit
`L-30-D 55 Will be employed. Eudragit L-30-D 55 is an
`aqueous acrylic resin dispersion, an anionic copolymer
`derived from methacrylic acid and ethyl acrylate With a ratio
`of free carboxyl groups to the ester of approximately 1:1,
`and a mean molecular Weight of approximately 250,000, is
`supplied as an aqueous dispersion containing 30% W/W of
`dry lacquer substance, and is marketed by Rohm-Pharma
`Co., Germany. As an aqueous-based coating, no dangerous
`or environmentally harmful organic solvents are utiliZed.
`Although Eudragit L-30-D-55 is the preferred coating
`polymer, the invention is not limited in this respect and other
`enteric coating polymers knoWn in the art, such as hydrox
`ypropyl methylcellulose phthalate HP50 (HPMCP-HP50)
`(USP/NF 220824), HP55 (HPMCP-HP55)(USP/NF type
`200731) and HP55S available from Shin Etsu Chemical,
`CoatericTM (polyvinyl acetate phthalate)(Colorcon Ltd.),
`SuretericTM (polyvinyl acetate phthalate)(Colorcon, Ltd.), or
`AquatericTM (cellulose acetate phthalate)(FMC Corp.), and
`the like may be employed
`The enteric coating Will also preferably contain a plasti
`ciZer Which is preferably diethyl phthalate, although the
`invention is not limited in this respect and other plasticiZers
`may be used such as triethyl citrate (Citro?ex-2), triacetin,
`tributyl sebecate, or polyethylene glycol.
`The enteric coating employed in the present invention is
`substantially easier to process than previously reported
`
`6,331,316 B1
`
`

`
`US 6,331,316 B1
`
`7
`coating systems, and is especially advantageous for coating
`small diameter, loW mass particles (tablets) With minimal
`processing problems (sticking/picking) Without the need for
`organic solvents.
`In general, Where the core includes a drug Which is
`incompatible With the enteric coating layer, a subcoat layer
`Which may be comprised of one or more ?lm-formers or
`plasticiZers, and Which acts as a physical barrier betWeen the
`core and the outer enter