(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. 1026
`
`

`
`US 6,331,316 B1
`
`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 a 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 Which provides a sustained release
`composition for treating hypertensive patients, and Which
`comprises a mixture of microniZed indoramin or a pharma
`ceutically acceptable salt thereof, a Water-channeling agent,
`a Wetting agent, a disintegrant, the mixture being in the form
`of a non-compressed pellet and having an enteric coat or
`sustained release coat permeable to gastrointestinal juices.
`US. Pat. No. 5,536,507 is directed to a pharmaceutical
`
`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 of 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
`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
`
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`

`
`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.
`
`55
`
`65
`
`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.
`
`

`
`US 6,331,316 B1
`
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`
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`5
`The core employed in the pharmaceutical composition of
`As used herein “enteric coating”, is a polymer material or
`materials Which encase the medicament core. The polymeric
`the invention Will be formed of a tablet, preferably a round,
`enteric coating material in the present invention does not
`biconvex tablet, approximately 3/16 of an inch. The invention
`contain any active compound, ie any therapeutically active
`is not, hoWever, limited in the siZe of the tablet and tablets
`agent, of the present invention. Preferably, a substantial
`of varying siZes may be made. Smaller siZed tablets are
`amount or all of the enteric polymer coating material is
`advantageous, hoWever, since they pass through the stomach
`dissolved before the medicament or therapeutically active
`With more ease than larger siZed tablets. Experimentation
`agent released from the dosage form, so as to achieve
`has shoWn that the tablet of the present invention having
`delayed dissolution of the medicament core. A pH-sensitive polymer is one Which Will dissolve in intestinal
`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
`
`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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`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 enteric coating layer Will be employed.
`HoWever, unlike previously reported coatings such as that
`disclosed in US. Pat. No. 5,225,202, the novel pharmaceu
`tical composition of the present invention, as a result of the
`novel process utiliZed in making the composition of the
`present invention and the pH adjustment of the coating, does
`not require a subcoat since the need for such an insulating
`layer is eliminated by raising the pH of the aqueous coating
`suspension. Since the coating is designed to breakdown at
`pH 5.5, the enteric coating applied at pH 5 permits relatively
`rapid breakdoWn in the intestine as only a small amount of
`additional alkalinity is required to bring the pH to 5 .5.
`A preferred formulation for preparing a 50 mg uncoated
`tablet is set out beloW.
`
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`Material
`
`TABLET CORE
`
`Amount (mg) per Tablet
`
`25
`
`Drug (didanosine)
`Microcrystalline Cellulose
`Na Starch Glycolate
`Magnesium Stearate (for compaction)
`Magnesium Stearate (for tableting)
`
`Uncoated Tablet Net Weight
`
`50.00
`17.00
`2.10
`0.60
`0.30
`
`70.00
`
`Apreferred formulation for the preparation of an enteric
`?lm coating suspension to coat the uncoated 50 mg tablets
`is set out beloW.
`
`Material
`
`COATING
`
`Amount (g) per 100 g
`
`Eudragit L-30-D 55
`Diethyl Phthalate
`Puri?ed Water
`(pH adjusted to 5 r 0.1 With NaOH solution)
`
`66.67
`3.00
`qs
`
`30
`
`40
`
`45
`
`8
`prises the steps of miXing an acid labile medicament, a
`binder/?ller, such as microcrystalline cellulose, a
`disintegrant, such- as sodium starch glycolate, and a ?rst
`portion of a lubricant, such as magnesium stearate, for
`compaction, in a tumbling type blender, to prepare a dry
`blend. The blend is then screened and placed back in the
`blender for a second blending. The resulting blend is slugged
`or compacted and then siZed to form small granules. A
`second portion of magnesium stearate lubricant for tableting
`is then calculated and blended in the tumbling type blender
`With the screened granules. The resulting blend is then
`formed into tablets (uncoated) having a desired Weight and
`hardness.
`The tablets may then be coated With an enteric ?lm
`coating suspension comprising Eudragit L-30-D 55 and
`plasticiZer (diethyl phthalate), using a ?uid bed coating
`apparatus With top spray mode, such as an Aeromatic
`STREA-1 table top unit, and then dried. During preparation
`of the ?lm coating suspension, a NaOH solution is added to
`the suspension until a pH of 5010.1 is obtained. Adjustment
`of the enteric ?lm coating suspension to pH 5 eliminates the
`need for a subcoat or insulating layer. The advantage here is
`that an enteric coating at pH 5 permits relatively rapid
`breakdoWn in the intestine since only a small amount of
`alkalinity is required to bring the pH to 5.5. The suspension
`pH adjustment to 510.1 is not critical. The pH could be
`adjusted up to 5.4 as may be necessary of a speci?c
`formulation. Although a top spray mode ?uid bed apparatus
`is preferred, the invention is not limited in this respect, and
`any suitable spray coating means, including one With a
`bottom spray, or a pan type coater, may also be utiliZed.
`Depending on their siZe, the tablets may be ingested
`individually or, in another embodiment of the invention,
`may be ?lled into dissolvable, hard shell capsules, such as
`gelatin capsules of varying siZes depending on the dosage of
`medicament desired. If the tablets are to be encapsulated, a
`hydrophobic anti-adherent, such as talc, is added (range 0.1
`to 4% by Weight) to the ?lm coated tablets and blended.
`The Examples represent preferred embodiments of the
`present invention. The folloWing eXamples further describe
`the materials and methods used in carrying out the invention
`and are intended to be for illustrative purposes only, and are
`not intended to limit the scope or spirit of this invention or
`the claims in any Way. All temperatures are expressed in
`degrees Centigrade unless otherWise indicated and all mesh
`siZes are US. standard ASTM.
`
`The percentage range of the ingredients in the above
`formulations for the uncoated tablet and the enteric ?lm
`coating is set forth in the folloWing chart:
`
`EXAMPLE 1
`
`A ddl formulation for 50mg tablets having the folloWing
`composition Was prepared as described beloW.
`
`Material
`
`CORE
`
`Drug (didanosine)
`Microcrystalline Cellulose
`Na Starch Glycolate
`Magnesium Stearate
`COATING
`
`Eudragit L-30-D 55
`Diethyl Phthalate
`
`The enteric coated pharmaceutical composition in the
`form of tablets may be prepared by a process Which com
`
`% (range)
`
`55
`
`1—100
`0-40
`0—6
`0—3
`
`2-30
`0.5-6.0
`
`EXAMPLE 1
`A ddl formulation for 50 mg tablets having the following
`composition Was prepared as described beloW.
`
`60
`
`COMPOSITION
`
`A: TABLET CORE
`
`ddI
`Microcrystalline Cellulose
`Na Starch Glycolate
`Magnesium Stearate
`
`65
`
`WEIGHT %
`WEIGHT %
`OF FINAL
`OF
`COMPONENT FORMULATION
`
`71.4
`24.3
`3.0
`1.3
`
`65.763
`22.359
`2.762
`1.184
`
`

`
`US 6,331,316 B1
`
`9
`
`-continued
`
`EXAMPLE 1
`A ddl formulation for 50 mg tablets having the following
`composition was prepared as
`
`COMPOSITION
`
`B: COATING (Based on 8% coat)
`
`Eudragit L-30-D 55 (dry basis)
`Diethyl Phthalate
`(pH adjusted to 5.0 r 0.1)
`
`WEIGHT %
`WEIGHT %
`OF FINAL
`OF
`COMPONENT FORMULATION
`
`87
`13
`
`6.892
`1.039
`
`The preparation of ddl tablets was commenced by adding
`ddl, microcrystalline cellulose, sodium starch glycolate and
`a ?rst portion of magnesium stearate for compaction, into a
`tumbling type blender . The ingredients were blended for
`1012 minutes. Prior to blending, any of the initial ingredi
`ents which were lumpy, were passed through a #20 mesh
`screen.
`The blended mixture was then passed through a #40 size
`
`mesh screen and re-placed into the tumbling type blender
`and blended again for 1012 minutes. The resulting blend
`was then slugged using a %“ ?at face punches. The slugs
`were then passed through #10 and #20 size mesh screens for
`sizing.
`A second portion of magnesium stearate needed for
`tableting was then calculated and placed into the tumbling
`type blender with the granulation prepared for the sizing of
`the slugs and blended for 1012 minutes. The resulting blend
`was then tableted to obtain the desired tablet weight and
`hardness.
`To prepare suf?cient quantities of ?lm coating suspension
`to coat the tablets, Eudragit L-30-D 55 was ?ltered through
`a #60 mesh screen to remove any lumps present therein. The
`?ltered Eudragit was weighed and then added with stirring
`to a tarred vessel containing one-half the amount of water
`required. The mixture was continuously stirred for 5 minutes
`or until a uniform mixture was visually evident. With
`continuous stirring, diethyl phthalate was added to the vessel
`and stirring continued for 20 minutes or until a uniform was
`
`dardized using pH 4 and pH 7 buffers. With continued
`stirring, a NaOH solution was added to the vessel until a pH
`of 5 .0101 was obtained. The formula weight of the coating
`suspension was adjusted using water and stirring was con
`tinued for an additional 10 minutes.
`The tablet coating procedure utilized a ?uid bed apparatus
`with a top spray mode and appropriate distribution plate to
`allow ?uidization of the product (tablet) in the center.
`Before coating, the tablets were pre-warmed in the coat
`ing unit to a temperature between 45—50° C. An inlet
`temperature of 50:2 ° C. was determined to be adequate.
`The spray rate was adjusted to allow uniform coating and
`adequate drying of the coat. An 810.5% weight gain due to
`the ?lm coat was determined to be suf?cient. After coating,
`the tablets were dried for approximately 10 minutes at an
`inlet temperature of approximately 50° C.
`The so formed enteric coated ddl product was found
`give excellent protection against gastric acid (at pH of 3) but
`had excellent release of ddl at pH’s above 5.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`EXAMPLE 2
`Apre