United States Patent [191
`Savastano et a1.
`
`11300568158421‘
`[11] Patent Number:
`[45} Date of Patent:
`
`1
`
`5,681,584
`Oct. 28, 1997
`
`[54] CONTROLLED RELEASE DRUG DELIVERY
`DEVICE
`
`[75] Inventors: Louis Savastano. Livingston; James
`Carr. Butler. both of N .J.; Elizabeth
`Quadros. Brooklyn. N.Y.; Shailesh
`Shah. Union. N.J.; Salish Chandra
`Khanna. Bottminger. Switzerland
`
`[73] Assignee: Ciba-Geigy Corporation. Tarrytown.
`NY.
`
`[21] Appl. No.: 622,238
`[22] Filed:
`Mar. 22,1996
`
`Related US. Application Data
`
`[63] Continuation of Ser. No. 165,437, Dec. 10, 1993, aban
`doned, which is a continuation-impart of Ser. No. 52,435,
`Apr. 23, 1993, abandoned.
`
`[51] Int. cu‘ . . . . . . . . . . .
`
`. . . . . . . . . . . . .. A61K 9/24
`
`424/473; 424/468
`[52] US. Cl. ................ ..
`[58] Field of Search .................................... .. 424/473. 468
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,845,770 11/1974 Theeuwes et a1. .................... .. 128/260
`
`Davis et al “Sticking of Dosage Forms in the GI. Tract. "
`27(2):226. 1986 Feb.
`Godbillon et a1 “Investigation of Drug Absorption From the
`Gastrointestinal Tract of Man." British Journal Clinical
`Phar. (1985) vol. 19. 1135-1185.
`Davis et a1 ‘Transit of Pharmaceutical Dosage Forms
`Through the Smalll Intestine" Gut. 27:886-892. (1986).
`Theeuwes “Elementary Osmotic Pump" Journal Pharmaceu
`tical Sciences vol. 64, No. 12. (1975) 1987.-1991.
`Rubinstein et al “Gastrointestinal Physiological Variables
`Alfecting Performance of Oral Sustained Release Dosage
`Forms. Oral Sustained Release Formulations” Pergarnon
`Press. Chap. 6. p. 146, Tables 9 and 10.
`Brunton et a1 “Agents Alfecting Gastrointestinal Water Flux
`and Motility” Goodman and Gilrnan’s Pharmaceutical Basis
`of Therapeutics 8th Ed. Pergamon Press, Chap. 39, p. 915.
`Dew et a1 “an Oral Preparation to Release Drugs in the
`Human Colon” Br. J. Clin. Pharmac. 14:405-408 (1982).
`Davis et al “Biopharmaceutical Aspects of Solid Dosage
`Forms” Proceed. Intern. Symp Control. Rel. Bioact. Water.
`15: 189-190 (1988).
`Friend et a1 “Colon4peci?c Drug Delivery” Advanced
`Drug Delivery Reviews 7:149-199 (1991).
`Stevens ct al “Pulsatile Drug Delivery to GI. Tract” B.T.
`Gattefosse No. 84- 1991 (pp. 11-15).
`Verhoeven et al “The Design of a Dry-Coated Controlle
`d-Release Tablet for Oxprenolol with Microporus Polypro
`pylene Powder” Journal of Controlled Release 10:205-217
`(1989).
`Kallstrand et a1 “Membrane-Coated Tablets: A System for
`the Controlled Release of Drugs” Journal of Pharmac.
`Sciences. vol. 72; No. 7; pp. 772-775 (1983).
`Amkraut et a1 “Osmotic Delivery of Peptides and Macro
`molecules Advanoed Drug Delivery Reviews”. 4:255-276
`(1990).
`Barrow et al “Phathological In?uences on Colonic Motility
`Implications for Drug Delivery” Advanced Drug Delivery
`Reviews 7:201-218 (1991).
`Davis et al “A Comparative Study of the Gastrointestinal
`Transit of a Pellet and Tablet Formulation" International
`Journal of Pharmaceutics 21:167-177 (1984).
`Primary Examiner-D. Gabrielle Phelan
`Attorney, Agent, or Firm-Marla J. Mathias; Karen G.
`Kaiser; Irving M. Fishman
`[57]
`ABSTRACT
`
`A drug delivery device for delivering a drug either intermit
`tently or to a pro-selected region of the gastro-intestinal
`tract. particularly to the colon. consists of an a solid core
`comprising an active agent coated with a delay jacket, then
`coated with a semi-permeable membrane which is optionally
`drilled to provide a release ori?ce, and then optionally
`further coated with an enteric material. The device delivers
`substantially all of the active agent to the targeted site.
`
`23 Claims, N0 Drawings
`
`.
`
`
`
`
`
`
`
`4,627,851 12/1986 Wong et al. 4,693,895 4,705,515 11/1987 Wong et al. 4,857,336 9/1987 Wong et al. 8/1989 Khanna et al.
`
`
`
`
`
`1/1990 Ambegaonkar
`4,891,223
`1/1990 Shah et a1. ....... ..
`4,892,739
`.
`4,904,474 2/1990 Theewes et a1.
`5,001,161
`3/1991 Appelgren et a]. ................... .. 514/651
`
`424/408
`
`FOREIGN PATENT DOCUMENTS
`
`0366621 5/ 1990
`0425699 5/1991
`425699 5/1991
`155898
`9/1979
`8300435 2/1983
`9107949 6/1991
`9204011
`3/1992
`
`European Pat. O?'. .
`European Pat. O?'. .
`European Pat. O?". .
`United Kingdom .
`WIPO .
`
`WIPO .
`
`WIPO .
`
`OTHER PUBLICATIONS
`
`Fara et al “Evaluation of Oxprenolol and Metoprolol Oros
`Systems in the dog” Br. J. Clin Phar. 19:91S-95S (1985).
`Davis et al. “Gastrointestinal Transit of a Controlled Release
`Naproxen Tablet Formulation” J. Pharmaceuticals 32:85-90
`(1986).
`Davis et al "The Design & Evaluation of Controlled Release
`Systems for the Gastrointestinal Tract” Journal of Controlled
`Release 2:27-38 (1985).
`Remington’s Pharmaceutical Sciences 16th Ed. Mack, Eas
`ton, Pa. pp. 1594-1613 (1980).
`
`MYLAN Ex 1008, Page 1
`
`

`

`1
`CONTROLLED RELEASE DRUG DELIVERY
`DEVICE
`
`5.681.584
`
`This is a Continuation of Ser. No. 08/ 165.437. ?led Dec.
`10. 1993. now abandoned. which is a Continuation In Part
`of Ser. No. 08/052.435. ?led on Apr. 23. 1993. now aban—
`doned.
`
`FIELD OF THE INVENTION
`
`The present invention relates to tablets which are time
`controlled to release active agent intermittently or at a
`pre-selected region of the gastro-intestinal tract. speci?cally
`the colon.
`
`10
`
`2
`the gastro-intestinal tract or. in the case of controlled release
`dosage forms. deliver drug throughout the entire length of
`the gastro-intestinal tract instead of concentrating delivay
`primarily within the colon. Thus. in either case. by the time
`the dosage form reaches the colon. the drug concentration is
`diminished or even depleted. In addition. the acidic and
`enzymatic environment of the stomach may inactivate a
`substantial mount of the drug. particularly protein or
`peptide-like drugs. Even if the drug is released from the
`stomach in its active state. such drugs frequently are metabo
`lized or inactivated in the small intestine. Thus. little if any
`of the drug from these conventional dosage forms is avail
`able for producing a therapeutic result in the colon. espe
`cially if the dosage form reaches the colon essentially devoid
`of drug.
`Drug delivery to the colon is di?icult not only for the
`above mentioned facts. but also because of the uncertainty
`of the transit time from oral ingestion to arrival at this
`pre-selected site. The time of retention within the stomach is
`most variable. depending both on the size of the dosage form
`and the mount of food present at the time of ingestion. The
`drug delivery device may remain within the stomach from
`about 0.5 to about ten hours. The device then enters the
`small intestine where retention time is signi?cantly more
`constant and less dependent upon the mount of food present.
`It takes from about three to about six hours to travel the
`length of the small intestine to the beginning of the colon.
`The device may then remain within the colon from about ten
`to about fourteen hours in a subject with normal motility.
`Thus. the time span necessary to delay release of the drug
`from an orally administered dosage form until the beginning
`of the colon is wide. However. the time span can be
`considerably narrowed by measuring the time from arrival in
`the small intestine instead of from the time of ingestion.
`Drug delivery in the stomach may be prevented by the use
`of an enteric coating which is resistant to the gastric ?uids.
`As such a coating is not soluble in ?uids with an acidic pH.
`such as that of the stomach. application to the outside of the
`dosage form inhibits release prior to reaching the higher pH
`of the small intestine. Once the dosage form reaches the
`small intestine and the enteric coating dissolves. drug
`release needs to be delayed only an additional three to six
`hours to result in substantially no active agent being deliv
`ered before the colon.
`Although some drug may reach the colon passively.
`conventional peroral dosage forms are not designed to
`deliver their contents speci?cally to the colon. Generally.
`they are formulated to be immediate release devices which
`disintegrate in the stomach. duodenum. or small intestine.
`allowing the drug to be immediately exposed to the local
`environment.
`More recently. controlled release dosage forms. for
`example Orally Releasing Osmotic Systems or OROS®
`(Alza Corporation). have been developed (US. Pat. No.
`3.845.770). Although the bene?ts of controlled release are
`significant. such as reduction in the number of doses and
`steady drug levels in the blood. they are generally no more
`elfective than conventional tablets in delivering the active
`agent primarily to the colon.
`Several delivery forms have been developed which
`attempt to deliver active agent primarily to the colon. These
`methods rely upon either the environmental conditions sur
`rounding the system. particularly pH. bacterial count and/or
`time.
`Wong. et at. (U.S. Pat. Nos. 4.627.851; 4.693.895; and
`4.705.515) disclose a tri-laminated core in which the ?rst
`
`25
`
`BACKGROUND OF THE INVENTION
`Parametric drug delivery refers to drug release in syn
`chrony with its temporal requirements or optimal absorption
`site. thereby maximizing therapeutic elfect while simulta
`neously minimizing side-effects or in vivo degradation. An
`example of parametric drug delivery is delivery of a drag to
`a pre-selected region of the gastro-intestinal tract. such as
`the colon. Another example is delivery of a drug intermit
`tently at pro-selected times such that the patient receives the
`drug when needed.
`Delivery of a bene?cial drug in the colon has been the
`goal of various research projects in the pharmaceutical
`industry. The reasons for this are multi-fold. To begin with.
`many drugs are rendered inetfective by the enzymes present
`in the ?uids of the upper gastro-intestinal tract. particularly
`protein or peptide-like drugs. In addition. some drugs are
`more readily or more predictably absorbed by the colonic
`tissue than by that in the upper gastro-intestinal tract.
`Delivery of a bene?cial drug in the colon is also thera
`peutically indicated to treat diseased colonic tissue. In such
`circumstances. the drug should not be absorbed prior to
`localization in the colon lest its concentrations be dimin
`ished or even depleted prior to reaching the intended site of
`action. Such treatment would be bene?cial for a variety of
`colonic diseases including in?ammatory bowel disease. coli
`tis ulcerosa. enteritis. regionalis Crohn. chronic nonspeci?c
`colitis. and diverticulitis.
`Prior treatments have been attempted rectally using sup
`positories and enemas. Rectal administration. while often
`more effective than oral administration. is limited in that
`most rectally administrable dosage forms are capable of
`producing the intended result only in the immediate area. not
`reaching the upper portions of the colon. This is because the
`length of the colon reached is volume dependent. usually
`reaching only as far as the splenic ?exure. In addition. rectal
`administration is messy and inconvenient. as well as not
`readily acceptable to the general patient population.
`Furthermore. if the patient sulfcrs from severe in?ammation
`of the rectum he may experience di?iculty with retention
`enemas.
`Thus. an orally administrable dosage form to treat colonic
`diseases would usually be preferred and is often required.
`Orally administrable treatments. using tablets. capsules. and
`the like. have been attempted. However. to reach the colon
`intact. the dosage form must withstand the rigors of the
`transit through the gastro-intestinal tract. These rigors
`include at least a million-fold variation in hydrogen ion
`concentration. wide variations in osmotic pressure from the
`surrounding ?uids. a variety of enzymes. and a strong
`mechanical grinding force.
`Furthermore. most of these orally administered dosage
`forms result in delivery of the drug in the upper portion of
`
`35
`
`45
`
`55
`
`65
`
`MYLAN Ex 1008, Page 2
`
`

`

`5.681.584
`
`3
`layer is composed of an insoluble. but semi-permeable
`composition. the second is a microporous combination of
`water insoluble polymer and osmotic solute. and the third
`contains an enteric composition. This dosage form has a
`delayed onset of delivery for a period of about two hours
`after it exits the stomach. after which only about 50% of the
`drug is released within twenty-four hours. This drug delivery
`time scheme is insu?icient to insure that the bulk of the drug
`is delivered to the colon.
`Theeuwes. et al. (US. Pat. No. 4.904.474) disclose a
`dosage form which has a two-layered internal compartment
`with a ?rst layer of the drug in an excipient layer adjacent
`to an exit passageway and a second layer of a push com
`ponent. The internal compartment is surrounded by a semi
`permeable wall and then an enteric layer. Theeuwes’s dos
`age form results in a delay of the onset of delivery in
`intestinal ?uid for a period of about two hours. This repre
`sents a delay period too short. and a delivery rate too slow
`to insure the bulk of the drug is delivered to the colon.
`Ring. et at. (WO 91/07949) disclose a tablet core coated
`with two laminates. The outer laminate is an erodible acrylic
`polymer and the inner laminate consists primarily of amy
`lose in the glassy state which can only be degraded in the
`presence of fecal micro?orae.
`The instant parametric drug delivery devices can also be
`used to deliver a drug intermittently at pre-selected times
`such that the patient receives the drug when needed. This is
`of particular importance in treating diseases which have
`symptoms which do not remain constant throughout the day
`and night.
`For example. blood pressure is known to follow a circa
`dian rhythm during a 24-hour period In some subjects the
`highest pressure occurs in the morning shortly after the
`individual awakes. suggesting that it would be appropriate to
`deliver an antihypertensive agent such as a B-blOCkCl' to such
`a patient su?iciently before awakening so as to mitigate the
`effects of the disease at the most appropriate time interval.
`In order to accomplish this without disturbing the patient’s
`sleep. it is necessary to administer the drug in the evening in
`a form that is activated just before the patient arises.
`Another example is the treatment of asthma with the agent
`theophylline. The drug has a rather narrow therapeutic index
`with minimum e?‘ective blood concentrations of 6-10 ug/ml
`and toxic levels of approximately 20 pg/rnl. However. the
`serum theophylline concentrations required to produce
`maximum physiological bene?t may ?uctuate with the
`degree of bronchospasm present and are variable. Asthma
`often exhibits more serious symptoms in the evening. while
`theophylline absorption may change due to posture and
`changes in the circadian rhythm. This suggests that the
`nighttime dosing need not be identical to the daytime dosing
`regimen. and it is recommended that the extended release
`formulation not be given in the evening. Thus. a sustained
`acting dosage form for the day. with a bolus dose of
`theophylline at bedtime combined into a single peroral drug
`delivery system requiring once per day dosing in the evening
`is of possible bene?t.
`Many controlled release dosage forms are created by the
`use of special water insoluble membranes which either limit
`the ?ow of gastro-intestinal juices into the system. or
`modulate the release of dissolved substances out of the
`system. Application of such a membrane was initially
`accomplished by thin layer. spray application of lacquer
`coatings made with organic solvents. These processes
`allowed the manufacturer to achieve the desired membrane
`qualities in short time using few components. However. it
`
`15
`
`20
`
`25
`
`50
`
`55
`
`65
`
`4
`was eventually realized that the processes were often dan
`gerous in that excessive use of organic solvents were capable
`of causing irreversible harm to the environment and pro
`duced dosage fonns which contained extraneous. undesir
`able residuals.
`Whenever organic solvent is used in a pharmaceutical
`process. measures need to be taken to protect the opm'ators
`who produce the dosage forms and the environment from
`overexposure to the hazardous. often teratogenic and carci
`nogenic materials. Additional precautions are necessary to
`protect personnel. equipment and facilities from harm due to
`the ignition of explosive vapors. Even if these immediate
`problems can be solved through engineering means. it is still
`possible for detectable levels of residual solvent to remain in
`the ?nished dosage form. the long term etfects of which are
`either undesirable or not yet established
`Several manufacturers of coating equipment responded to
`the challenge of minimizing the dangers of using hazardous
`solvents by building machines which contained and con
`trolled the exhaust vapors from organic solvent coating
`processes. Despite the capability of these machines to mini
`mize the problems of explosion and exposure hazards. the
`equipment is complicated. costly to operate. and requires
`rather expensive maintenance even on a murine basis. It also
`does not address the problem of residual solvent remaining
`in the ?nished dosage form. This is ameliorated by storing
`the coated tablets in containers at high temperatures and
`humidities in order to draw the solvent out of the tablets;
`however. solvent extraction from ?nished dosage forms adds
`costs to the manufacturing process in additional capital
`equipment expenditures. processing time and analytical
`requirements.
`The impetus for seeking new manufacturing techniques is
`obvious. The US. Food and Drug Administration and Envi
`ronmental Protection Agency are continuously urging all
`manufacturers to reduce. and wherever possible. to eliminate
`the use of organic solvents in manufacturing.
`Rather than pursuing costly engineering solutions to the
`problem. raw material suppliers were encouraged to develop
`aqueous dispersions of the materials most frequently
`employed to produce ?lm coatings for tablets. pellets and
`particulate dosage forms. Aqueous dispersions allow utili
`zation of existing equipment and familiar processes. thus
`avoiding the expenses of capital investments. maintenance.
`process validation and retraining of personnel.
`SUMMARY OF THE INVENTION
`It is accordingly an object of the present invention to
`provide a delivery device for the oral administration of a
`pharmaceutically acceptable active agent to a warm-blooded
`animal. either intermittently at pre-selected times or to a
`pre-selected region of the gastro-intestinal tract. particularly
`to the lower portion of the small intestine and/or the colon.
`more particularly to the colon.
`It is another object of this invention to provide a dosage
`form for delivering substantially all of a therapeutic drug to
`the colon.
`It is yet another object of this invention to provide a
`dosage form which comprises a core tablet coated with a
`delay jacket for delaying the delivery of the drug to insure
`the time required for the dosage form to travel through the
`small intestine.
`It is still yet another object of this invention to provide a
`dosage form in which the semi-permeable membrane may
`be applied without the use of organic solvents. ie. aqueously.
`yet is still strong enough to resist the hydrostatic pressures
`of the ordinary osmotic core.
`
`MYLAN Ex 1008, Page 3
`
`

`

`5,681,584
`
`-continued
`
`Time (hrs)
`
`Fluid
`
`Total Amount Released (%)
`
`6
`8
`10
`12
`18
`24
`
`intestinal
`intestinal
`intestinal
`intestinal
`intestinal
`intestinal
`
`0-20
`0-50
`10-80
`20-100
`50-109
`70-1 15
`
`5
`It is a further object of this invention to provide a dosage
`form which comprises an enteric coating over a semi
`permeable wall for further delaying the delivery of the active
`agent dining the time required for the dosage form to travel
`through the stomach.
`It is still a further object of this invention to provide a
`dosage form which resists dissolution in gastric ?uid for at
`least two hours. further delays initiation of active agent
`release for at least three hours. and releases at least 70% of
`its active agent within twenty-four hours.
`It is yet still a further object of this invention to provide
`a delivery device which delivers drag intermittently at
`pro-selected times.
`These. and other objects apparent to those skilled in the
`art from the following detailed description. am accom
`plished by the present invention which pertains to the
`delivery of a therapeutic drug to a pro-selected region of the
`gastro-intestinal tract. particularly the colon. by means of a
`drug delivery device. This drug delivery device comprises:
`a) a solid core comprising an active agent;
`b) a delay jacket coated over the core;
`c) a semi-permeable membrane coated over the delay
`jacket. the membrane optionally having a release ori
`?ce; and optionally
`d) an enteric coating over the semi-permeable membrane.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`This invention pertains to an osmotic delivery device for
`the oral administration of a pharmaceutically acceptable
`active agent to a warm-blooded animal. either intermittently
`at pro-selected times or to a pre-selected region of the
`gastro-intestinal tract. particularly to the lower portion of the
`small intestine and/or the colon. more particularly to the
`colon. This drug delivery device comprises:
`a) a solid core comprising an active agent;
`b) a delay jacket coated over the core;
`c) a semi-permeable membrane coated over the delay
`jacket. the membrane optionally having a release ori
`?ce; and optionally
`d) an enteric coating over the semi-permeable membrane.
`Such device with an enteric coating thus resists dissolu
`tion in gastric ?uid for at least two hours and thereafter
`limits the release of active agent in intestinal ?uid to
`approximately ten percent or less for at least three hours
`after the device passes through the pylorus due to the delay
`jacket. The device thus allows for controlled continuous
`release of the active agent in the pro-selected region of the
`gastro-intestinal tract at a predetermined average rate. pref
`erably at a rate of about 5 percent to about 25 percent by
`weight per hour. In addition. the device allows for substan
`tially all of the active agent to be released at the pre-selected
`region of the gastro-intestinal tract. preferably 70—100%
`within twenty-four hours of ingestion.
`Preferably. the basic device releases its active agent in
`vitro according to the following scheme. where time is hours
`from inception corresponding to in vivo release of active
`agent from time of ingestion:
`
`35
`
`45
`
`50
`
`55
`
`Tune (hrs)
`
`Fluid
`
`Total Amount Released (96)
`
`2
`5
`
`gastric
`intestinal
`
`0-4
`0-10
`
`65
`
`10
`
`20
`
`25
`
`Thus. the colonic delivery device would deliver from about
`50% to about 100%. more particularly from about 60% to
`about 90%. most particularly from about 70% to about 80%
`of its active agent to the colon.
`The solid core comprises an active agent and may option
`ally include other pharmaceutically acceptable excipients
`including osmotic agents. lubricants. glidants. wetting
`agents. binders. ?llers. and suspending/thickening agents.
`Any core which would be suitable for an OROS-type system
`may be used in the present invention. including the various
`modi?cations currently lmown in the art such as MOCOSTM
`and push-pull OROS.
`As used herein. MOCOS refers to a mono-compartmental
`system. such as that described in U.S. Pat. No. 4.857.336.
`hereby incorporated by reference. in which the elementary
`OROS has been modi?ed in that the core comprises a
`hydrogel in addition to an active agent and an osmotic agent;
`and push-pull OROS refers to a system. such as that
`described in U.S. Pat. No. 4.111.202 (equivalent to Great
`Britain Patent 1.551.898). hereby incorporated by reference.
`in which the core has a drug layer immediately adjacent to
`the release ori?ce. a “push” layer consisting of hydrogels
`and osmotic agents beneath the drug layer. and an optional
`partition layer between the two.
`Active agents useful in the present invention include. but
`are not limited to. proteins and peptides. antiasthmatics.
`antianginals. corticosteroids. 5-lipoxygenase inhibitors.
`antihypertensives. and leukotriene B4 receptor antagonists.
`Proteins and peptides include. but are not limited to. trans
`forming growth factors (TGF). immunoglobulin E (IgE)
`binding factors. interleukins. interferons (IFN). insulin-like
`growth factors (IGF). milk growth factors. anticoagulants.
`and parathyroid hormones (PTH). Speci?c active agents
`include. but are not limited to theophylline. IGF-I. P'I‘H
`(1-34) and analogues thereof. TGFWTGFBI. TGFWTTGFm.
`IFNw hybrid IFNa. IFNT hirudin. heparin. calcitonin.
`S-aminosalicylic acid. CGS 23885. CGS 25019C. CGS
`26529. Zileuton. ONO-LB 457. beclomethasone
`dipropionate. betamethasone-17-valerate. prednisolone
`metasulfobenzoate. tixocortol pivalate. budesonide.
`?uticasone. metoprolol fumarate. metoprolol tartrate. tet
`rahydroaminoacridine (THA). galanthamine. ursodiol. clo
`mipramiue hydrochloride. terbutaline sulfate.
`aminoglutethimide. deferoxamine mesylate. estradiol.
`isoniazid. methyltestosterone. metyrapone. and rifampin. Of
`particular importance are theophylline. IGF-I. PTH (1-34)
`and analogues thereof. TGFwTGFpl. TGFp2.TGFp3.IFNa.
`hybrid IFNG. IFNY. hirudin. heparin. calcitonin.
`S-aminosalicylic acid. CGS 23885. CGS 25019C. CGS
`26529. Zileuton. ONO-LB 457. beclomethasone
`dipropionate. betamethasone-l7-valerate. prednisolone
`metasulfobenzoate. tixocortol pivalate. budesonide.
`?uticasone. and metoprolol. Virtually any other active agent
`which is known to be colonically absorbable or used to
`topically treat the colon can be used as an active agent in the
`present invention as long as it is compatible with the system
`components.
`As used herein. the active agents CGS 23885. 25019C.
`CGS 26529. Zileuton. ONO-LB 457 are de?ned as follows:
`
`MYLAN Ex 1008, Page 4
`
`

`

`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`7
`CGS 23885 refers to N-hydroxy-N-((6-phenoxy-2H-1
`benzopyran-3-yl)methyl)-urea; CGS 25019C refers to 4-[5
`[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N.N
`bis(1-methylethyl)benzarnide (Z)-2-butenedioate; CGS
`26529 refers to N-[2-[[2-[[4-(4-?uorophenyl)phenyl]
`methyl]- 1 .2.3 .4-tetrahydro-1-oxo-6-isoquinolinyl]oxo]
`ethyl]-N-hydroxyurea; Zileuton refers to l-(l-benzolb]
`thien-2-ylethyl)-l-hydroxyurea; ONO-LB 457 refers to
`5-[2-(2-carboxyethyl)-3-{6-(para-methoxyphenyl)-5E
`hexenyl}oxyphenoxy] valeric acid.
`The core may include an osmotic agent if necessary or
`desirable to effect the desired release pro?le. The active
`agent. for example. metoprolol fumarate. may be su?iciently
`soluble to induce an internal hydrostatic pressure acceptable
`to eliminate the need for any additional osmotic agent.
`Typically. however. an additional compound will be
`included as the osmotic agent so as to promote the disso
`lution and release of the core active agent. The osmotic agent
`is a water-soluble compound which induces a hydrostatic
`pressure after water penetrates the semi-permeable mem
`brane to drive out the active agent as a solution or a
`suspension. Suitable osmotic agents include any number of
`agents having a suitably high solubility and dissolution rate.
`The osmotic agent may be selected from any pharmaceuti
`cally acceptable chemical entity which is inert to the system.
`Suitable osmotic agents include pharmaceutically accept
`able salts of inorganic and organic acids or nonionic organic
`acids of particularly high water solubility. e.g. carbohydrates
`such as sugar. or amino acids. or another active agent
`possessing suitable solubility.
`Examples of such water-soluble compounds for inducing
`osmosis in the core include inorganic salts such as sodium.
`potassium or magnesium chloride. or sodium or potassium
`hydrogen or dihydrogen phosphate; salts of organic acids
`such as sodium alginate. sodium ascorbate. sodium
`benzoate. sodium citrate. edetate disodium. sodium
`fumarate. sodium or potassium acetate. or magnesium suc
`cinate; organic acids such as alginic acid. ascorbic acid.
`citric acid. edetic acid. malic acid. or sorbic acid; carbohy
`drates such as dexlrates. sorbitol. xylitol. maltitol. mannitol.
`arabinose. ribose. xylose. glucose. dextrose. fructose.
`galactose. mannose. sucrose. maltose. lactose. or ra?inose;
`Warm-soluble amino acids such as glycine. leucine. alanine
`or methionine; or miscellaneous others such as magnesium
`sulfate. magnesium carbonate. urea. saccharin. sodium
`saccharin. glycerin. hexylene glycol. polyethylene glycol. or
`propylene glycol; and mixtures thereof.
`Additional core excipients may include tabletting
`lubricants. glidants. wetting agents to aid in dissolution of
`the components. binders. and suspending/thickening agents.
`Suitable lubricants include. but are not limited to. calcium
`stearate. glyceryl behenate. hydrogenated vegetable oils.
`magnesium stearate. mineral oil. polyethylene glycol.
`sodium stearyl fumarate. stearic acid. talc. and zinc stearate.
`Suitable glidants include. but are not limited to. fused or
`colloidal silicon dioxide. calcium silicate. magnesium
`silicate. talc. and silica hydrogel. Suitable wetting agents
`include. but are not limited to. benzalkonium chloride.
`benzethonium chloride. cetylpyridinium chloride. docusate
`sodium. lecithin. nonoxynol 9. nonoxynol l0. octoxynol 9.
`poloxamer. polyoxyl 3S castor oil. polyoxyl 40 hydroge
`nated castor oil. polyoxyl 50 stearate. polyoxyl 10 oleyl
`ether. polyoxyl 2O cetostearyl ether. polyoxyl 40 stearate.
`polysorbate 20. polysorbate 40. polysorbate 60. polysorbate
`80. sodium lauryl surfate. sorbitan esters. polyoxyethylene
`sorbitan fatty acid esters. and 'Iyloxapol (4-(l.1.3.3
`tetramethylbutyhphenol polymer with formaldehyde and
`
`5.681.584
`
`8
`oxirane). Suitable binders include. but are not limited to.
`acacia. alginic acid. carboxymethylcellulose sodium.
`dextrin. ethylcellulose. gelatin. glucose. giar gum. hydroxy
`ethyl cellulose. hydroxypropyl methylcellulose. hydrox
`ypropyl magnesium aluminum silicate. methylcellulose.
`microcrystalline cellulose. polyethylene oxide.
`polyrnethylmethacylates. polyvinylpyrrolidone. pregelati
`nized starch. sodium alginate. syrup. and zein. Suitable
`suspending/thickening agents include acacia. agar. alginic
`acid. bentonite. carbomer. carboxymethylcellulose calcium.
`carageenan. carboxymethylcellulose sodium. corn starch.
`dextn'n. gelatin. guar guru. hydroxyethyl cellulose. hydrox
`ypropyl cellulose. hydroxypropyl methylcellulose. kaolin.
`lecithin. magnesium aluminum silicate. methylcellulose.
`microcrystalline cellulose. pectin. poloxamer. polyethylene
`glycol alginate. polyethylene oxide. polyvinyl alcohol.
`polyvinylpyrrolidone. vinyl acetate. powdered cellulose.
`pregelatinized starch. propylene glycol alginate. silicon
`dioxide. sodium alginate. tragacanth. and xanthan gum.
`The delay jacket is included to impede the dis solution and
`release of the active agent for the time necessary for the drug
`delivery device to travel through the small intestine. It
`comprises soluble materials. but may contain insoluble
`materials as well. The delay jacket must be capable of
`attracting water across the semi-permeable membrane while
`at the same time hindering the water from reaching the
`active core for the designated period of delay. Thus. the
`delay jacket will typically contain both water soluble.
`osmotically active components and insoluble and/or
`swellable components. The soluble osmotic agents leach out
`of the jacket and a suspension of at least some of the
`insoluble and/or swellable components remains. The active
`agent will later di?use through this remaining suspension
`and thus the release of the active agent is dependent not only
`upon the composition of the inner core. but also upon the
`composition of the jacket.
`The delay jacket typically comprises a binder. an osmotic
`agent. and a tablet lubricant. Suitable binders include. but
`are not limited to. acacia. alginic acid. carboxymethylcellu
`lose sodium. dextrin. ethylcellulose. gelatin. glucose. guar
`gum. hydroxyethyl cellulose. hydroxypropyl
`methylcellulose. hydroxypropyl magnesium aluminum
`silicate. methylcellulose. microcrystalline cellulose. poly
`ethylene oxide. polymethylmethacrylates.
`polyvinylpyrrolidone. pregelatinized starch. sodium
`alginate. syrup. and zein. Suitable osmotic agents include.
`but are not limited to. inorganic salts such as sodium.
`potassium or magnesium chloride. or sodium or potassium
`hydrogen or dihydrogen phosphate; salts of organic acids
`such as sodium alginate. sodium ascorbate. sodium
`ben