United States Patent [19]
`Friend et al.
`
`[54] DELIVERY OF DRUGS TO THE LOWER GI
`TRACT
`
`[75] Inventors: David R. Friend, Menlo Park; David
`Wong, San Francisco, both of Calif.
`
`[73] Assignee: Cibus Pharmaceutical, Inc.,
`Burlingame, Calif.
`
`[21] Appl. No.: 602,611
`[22]
`Filed:
`Feb. 16, 1996
`
`Related US. Application Data
`
`[63]
`
`Continuation-in-part of Ser. No. 486,974, Jun. 7, 1995, Pat.
`NO. 5,656,294.
`
`[51]
`
`Int. C1.6 ............................. .. A61K 9/24; A61K 9/34;
`A61K 9/36; A61K 38/00
`[52] US. Cl. ........................... .. 514/2; 424/851; 424/465;
`424/474; 424/475; 424/479; 424/481; 424/485;
`424/488; 514/3; 514/12; 514/21; 514/177;
`514/178; 514/179; 514/180; 514/181; 514/182;
`514/777; 514/780; 514/782; 514/960; 514/961
`[58] Field of Search ............................. .. 514/2, 3, 12, 21,
`514/177, 178, 179, 180, 181, 182, 960,
`961, 777, 780, 782; 424/85.1, 452, 461,
`465, 474, 475, 479, 481, 485, 488, 493,
`496, 500
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,629,393 12/1971 Nakamoto et al. ................... .. 424/470
`4,389,393
`6/1983 Schor et a1. .... ..
`424/480
`4,894,233
`1/1990 Sharma et al.
`424/440
`4,994,276
`2/1991 Baichwal et al. .
`424/440
`4,999,200
`3/1991 Casillan .......... ..
`424/480
`5,108,758
`4/1992 Allwood et a1. ..
`424/468
`5,128,143
`7/1992 Baichwal et al. .
`424/464
`5,422,121
`6/1995 Lehmann et al. .
`424/464
`5,445,826
`8/1995 Kuhrts ............. ..
`424/451
`5,525,634
`6/1996 Sintov et al. .
`514/777
`5,656,294
`8/1997 Friend et a1. ......................... .. 424/465
`
`FOREIGN PATENT DOCUMENTS
`
`2053569 4/1992 Canada .
`0 343 993 A1 11/1989 European Pat. Off. .
`0 371 493 A1 6/1990 European Pat. Off. .
`0 481 240 A2 4/1992 European Pat. Off. .
`0 485 840 A2 5/1992 European Pat. Off. .
`2 667 242 4/1992 France .
`2 238 243 5/1991 United Kingdom .
`WO 86/06627 11/1986 WIPO .
`WO 87/06241 10/1987 WIPO .
`WO 89/04673
`6/1989 WIPO .
`WO 91/16881 11/1991 WIPO .
`WO 92/00732
`1/1992 WIPO .
`
`OTHER PUBLICATIONS
`
`Adkin et al., “Colonic Transit of Different Sized Tablets in
`Healthy Subjects” Journal of Controlled Release (1993)
`23:147—156.
`Brondsted and Kopeck, “Hydrogels for Site—Speci?c Oral
`Drug Delivery: Synthesis and Characterization”, Biomate
`rials (1991):584—592.
`
`US005811388A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,811,388
`Sep. 22, 1998
`
`Cummings, “Short Chain Fatty Acids in the Human Colon”,
`Gut (1981), 22:763—779.
`Damgé et al., “New Approach for Oral Administration of
`Insulin With Polyalkylcyanoacrylate Nanocapsules as Drug
`Carrier” Diabetes (1968) 37:246—25 1.
`Davis et al., “Transit of Pharmaceutical Dosage Forms
`Through the Small Intestine” Gut (1986) 27:886—892.
`Feely et al., “Investigating the Gastrointestinal Transit of
`Controlled Release Mini—Matrices Using Gamma Scintiog
`raphy”, Proceed. Intern. Symp. Control. Rel. Bioact. Mater.
`(1985) 12:94—95.
`Hardy et al., (1987) “Evaluation of an Enteric—Coated
`Delayed—Release 5—Aminosalicyclic Acid Tablet in Patients
`With In?ammatory BoWel Disease” Aliment. Pharmacol.
`T herap. (1987), 1:273—280.
`Holt, et al., “Effect of Gel Fibre on Gastric Emptying and
`Absorption of Glucose and Paracetamol”, Lancet (1979)
`1:636—639.
`Jain et al., “Controlled—Release Tablet Formulation of Iso
`niaZid”, Pharmazie (1992) 47:277—278.
`Khosla et al., (1989) “Gastrointestinal Transit of Non—Dis
`integrating Tablets in Fed Subj ects” International Journal of
`Pharmaceutics (1989) 53:107—117.
`Kopecek, “Polymers for Colon—Speci?c Drug Delivery”,
`Journal of Controlled Release (1992) 19:121—130.
`Latymer et al., “Measurement of Transmit Time of Digesta
`Through Sections of Gastrointestinal Tract of Pigs Fed With
`Diets Containing Various Sources of Dietary Fibre (Non—
`Starch Polysaccharides)” Arch. Anim. Nutr Berlin (1990)
`40:667—680.
`Marvola et al., “Gastrointestinal Transit and Concomitant
`Absorption of Verapamil from a Single—Unit Sustaine
`d—Release Tablet”, Drug Development and Industrial Phar
`macy (1987) 13(9—11) :1593—1609.
`Miranda et al., “High—Fiber Diets in the Treatment of
`Diabetes Mellitus” Annals of Internal Medicine (1978)
`88:482—486.
`Moore et al., “Absorption Enhancement of GroWth Hor
`mone from the Gastrointestinal Tract of Rats”, International
`Journal ofPharmaceutics (1986) 34:35—43.
`
`(List continued on next page.)
`
`Primary Examiner—Jeffrey E. Russel
`Attorney, Agent, or Firm—Cooley GodWard LLP
`[57]
`ABSTRACT
`
`Pharmaceutical compositions for orally delivering a thera
`peutically effective amount of a drug to the colon Without
`signi?cant release of the drug in the upper GI tract after oral
`administration of the composition are described. The com
`position is a unit dosage in the form of a tablet that
`comprises about 0.01% by Weight to about 10% by Weight
`of the drug that is useful in treating a colonic disorder or that
`is absorbed from the colon; about 40% by Weight to about
`98% by Weight of a hydrocolloid gum obtainable from
`higher plants; and about 2% by Weight to about 50% by
`Weight of a pharmaceutically acceptable binder. The com
`positions are useful for treating loWer GI disorders in human
`subjects by administering a suitable amount to a subject in
`need thereof. A particularly preferred aspect is the process
`for preparing such composition in the form of a tablet.
`
`30 Claims, N0 Drawings
`
`Exhibit 1009
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`5,811,388
`Page 2
`
`OTHER PUBLICATIONS
`
`McIntire et al., “Different Fibers Have Different Regional
`Effects on Lurninal Contents of Rat Colon”, Gastroenterol
`ogy (1991) 101:1274—1281.
`Price et al., “Characterization of Colonic Transit of Nondis
`integrating Tablets in Healthy Subjects”, Digestive Diseases
`and Sciences, (1993) 38(6) :1015—1021.
`Price et al., “The Effect of Meal Cornposition on the
`Gastrocolonic Response: Implications for Drug Delivery to
`the
`Colon”
`Pharmaceutical
`Research
`(1993)
`10(5):722—726.
`Rubinstein and Gliko—Kabir, “Synthesis and Swelling
`Dependent EnZyrnatic Degradation of Borax Modi?ed Guar
`Gurn for Colonic Delivery Purposes” SIP Pharma Sci
`ences (1995) 5:41—46.
`Sakr and Elsabbagh, “Effect of Particle SiZe Distribution on
`the Disintegrating Ef?ciency of Guar Gurn” Pharm. Ind.
`(1976) 38(8) :732—734.
`Salyers and Leedle, “Carbohydrate Metabolism in the
`Human Colon” Human Intestinal Micro?ora in Health and
`Disease, Chapter 6, pp. 129—146 (1983).
`Spiller et al., “Ernptying of the Terminal Ileurn in Intact
`Humans: In?uence of Meal Residue and Ileal Motility”
`Gastroentrology (1987) 92:724—729.
`
`Trenev, “We Need Friendly Bacteria” Total Health (1988)
`10:29—29.
`
`Venter and Vorster, “Possible Metabolic Consequences of
`Fermentation in the Colon for Humans” Medical Hypotheses
`(1989) 29:161—166.
`
`Waaler et al., “Biopharrnaceutical Studies of Naftidrofuryl
`in Hydrocolloids Matrix Tablets” International Journal of
`Pharmaceutics (1992) 87:229—237.
`
`Watanabe et al., “Factors Affecting Prednisolone Release
`from Hydrogels Prepared With Water—Soluble Dietary
`Fibers, Xanthan and Locust Bean Gurns” Chem. Pharm.
`Bull. (1992) 40(2) :459—462.
`
`Woodley, “Peptidase Activity in the GI. Tract: Distribution
`BetWeen Lurninal Contents and Mucosal Tissue”, Proceed.
`Intern. Symp. Control. Rel. Bioct. Mater (1991) 18:337—338.
`
`YoshikaWa et al., “Comparison of Disapearance frorn Blood
`and Lyrnphatic Delivery of Human Fibroblast Interferon in
`Rat by Different Adrninistration Route”, J. Pharmacobio—
`Dyn. (1985) 8:206—210.
`
`000002
`
`

`

`1
`DELIVERY OF DRUGS TO THE LOWER GI
`TRACT
`
`CROSS-REFERENCE TO RELATED CASES
`
`This is a continuation-in-part application of US. patent
`application Ser. No. 08/486,974, ?led Jun. 7, 1995 now US.
`Pat. No. 5,656,294.
`
`INTRODUCTION
`
`1. Technical Field
`This invention relates to pharmaceutical compositions for
`oral administration to preferentially deliver drugs to the
`loWer gastrointestinal (GI) tract, particularly to the colon.
`2. Background
`At the present time, there are no good orally-deliverable
`drug compositions that target treatment of various colon
`diseases such as chronic in?ammatory diseases of the colon
`or diseases that require treatment by drugs that are better
`absorbed through the colon than the stomach or upper GI
`tract. Also, there are no orally-deliverable drug compositions
`for peptides that release the peptides in a colonic environ
`ment Where the peptides are not degraded to the same extent
`as peptides are degraded in the acid environment of the
`upper GI tract, particularly the stomach.
`It is also knoWn that peptides and proteins are large,
`molecules that are acid labile and polar to cause them to be
`poorly absorbed in the upper gastrointestinal tract. These
`molecules are degraded by luminal and brush border pepti
`dases and generally have very short half-lives. As a result
`they have exceedingly loW and variable bioavailability.
`Certain researchers have concluded that these molecules
`may be regionally absorbed in the colon. See, e.g., Moore,
`et al., Int. J. Pharm 34:35 (1986) discussing HGH and
`YoshikaWa, et al., J. Pharmacobiodyn. 8:291 (1985) discuss
`ing interferon. There is also evidence that there is much
`loWer peptidase activity in the colon relative to the upper
`intestinal tract (Woodley, Proc. Int. Syn. Control. Rel. Bio
`act. Mat. 18:337 (1991).
`Colon diseases include such conditions such as Crohn’s
`disease, colitis (particularly ulcerative colitis), irritable
`boWel syndrome and the like. These diseases include a
`spectrum of in?ammatory boWel disorders With overlapping
`clinical, epidemiologic and pathologic ?ndings but Without
`a de?nite etiology. Both Crohn’s disease (CD) and ulcerative
`colitis (UC) are characteriZed by chronic in?ammation at
`various sites of the GI tract, generally the colon (i.e., that
`part of the intestine from the cecum to the rectum). In
`treating these disease states, it is dif?cult to direct drugs that
`are speci?cally anti-in?ammatory in nature and act topically
`to the desired site. For example, CD seems to affect the
`terminal ileum and the cecum primarily While UC seems to
`go past the second turn in the colon and affect the splenic
`?exure.
`It One of the families of compounds that are used in the
`treatment of this family of diseases are glucocorticoids.
`These are thought to be useful in that the glucocorticoids
`have the capacity to prevent or suppress the development of
`the manifestations of this in?ammation. The thought is that
`if the drugs can be administered to the in?amed area, the
`in?ammation Will recede and the body Will ultimately be
`able to recover. Unfortunately, there are certain side effects
`the glucocorticoids exhibit if administered systemically and
`these side effects can be quite signi?cant in treating any
`disease state. Another problem stemming from these side
`effects is that there is no Way to deliver the drugs directly to
`
`10
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`15
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`20
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`25
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`30
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`35
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`40
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`45
`
`50
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`55
`
`60
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`65
`
`5,811,388
`
`2
`the af?icted portion of the colon. Most of the oral formula
`tions that are presently available disintegrate as they pass
`through the upper GI tract and thus, the steroids are absorbed
`into the body systemically and the subject being treated Will
`experience some of the undesirable side effects.
`The general approaches to delivering drugs to the loWer
`GI tract (e.g. colon) include: 1) enteric coating designed to
`release drug in the more alkaline environment of the gas
`trointestinal tract, 2) bioerodible coatings and matrices, 3)
`prodrugs, 4) timed-release systems and, 5) enteric polymeric
`material-based release systems that release drug after they
`transit through the small and reach the large intestines. A
`general discussion of these approaches and others may be
`found in PCT Patent application No. PCT/US91/03014 by
`Sintov and Rubinstein.
`It is knoWn that certain hydrocolloids have a chemical
`structure that is subject to attack by the enZymes that are
`present in the colon and Will cause the structure of the
`hydrocolloids to degrade and breakdoWn. Thus, it has been
`thought that if a composition could be prepared that Would
`be made of a drug useful for treating the colonic condition
`that Would pass through the upper GI tract Without releasing
`the drug but Would preferentially release it in the colon, the
`problem could be solved. Several attempts have been made
`to use a galactomannan-based composition (such as guar
`gum) to prepare compositions that are orally-administratable
`but Which do not deliver a drug in the upper GI tract but
`instead make it through the tract to the colon. None of these
`have been entirely successful and some are more complex
`than desired. A paper by Rubinstein and Gilko-Kabir
`describes a borax-modi?ed guar gum for colonic delivery
`purposes. HoWever, that procedure requires that guar gum be
`chemically modi?ed using borax (Which is toxic at certain
`concentrations) in various concentrations to achieve the
`desired results. Other attempts have been made using glassy
`amylose to prepare compositions. These, too, Were mini
`mally successful. Still another approach requires that a
`galactomannan (locust bean gun) be mixed With an acrylate
`resin and coated around a drug-containing core (See US.
`Pat. No. 5,422,121).
`It is also knoWn that hydrocolloids that are obtainable
`from higher plants, such as guar gum, are used to increase
`the gastric residence time and provide sustained release of a
`drug Which has the same bioavailability as the formulation
`of the drug. The concept is spelled out in co-pending
`application U.S. Ser. No. 08/348,515 ?led Dec. 1, 1994 noW
`abandoned. A broad range of hydrocolloid gum obtained
`from higher plants could be used to achieve those ends. The
`type of drug that could be used in the composition of that
`invention generally included nonpeptidic drug categories
`that exhibit a preferential WindoW of absorption in the upper
`GI tract and/or that are generally susceptible to sustained
`release. Generally these drugs are present in high concen
`trations in the compositions.
`It has noW been discovered that drugs With high thera
`peutic activity (i.e., drugs that require less than about 10%
`Weight in an orally-deliverable composition) can be deliv
`ered to the loWer GI, particularly the colon. By carefully
`controlling the amount of a hydrocolloid that is obtainable
`from higher plants, such as guar gum, a composition is
`prepared for such drugs that is particularly useful for treating
`conditions of the loWer intestinal tract, particularly chronic
`in?ammatory diseases of the colon (and other colon disor
`ders such as irritable boWel syndrome, constipation,
`diarrhea, etc.) and for delivering compounds (eg peptides)
`to the colon for better absorption. The families of com
`pounds for Which this is particularly valuable includes the
`
`000003
`
`

`

`3
`glucocorticoids, local anesthetics, anticholenergics, 5-ASA,
`stimulant laxatives, peptides, certain antibodies and certain
`vaccines. While the amount of the hydrocolloid is one factor
`to consider in preparing the compositions of this invention,
`other important factors include the particle siZe of the
`hydrocolloid, the amount and type of other ingredients, the
`design of the tablet and other factors discussed herein.
`
`OBJECTS OF THE INVENTION
`
`An object of this invention is to provide a unit dosage
`composition comprising a drug useful for treating loWer
`gastrointestinal disorders, particularly colonic disorders, that
`is orally-administered and delivers the major amount of the
`drug preferentially to, eg the colon of a human subject in
`need thereof.
`Another object of this invention is to provide an orally
`administered unit dosage composition comprising (a) a drug
`useful for treating loWer gastrointestinal disorders, particu
`larly colonic disorders, or (b) a drug that degrades in the
`upper GI tract, Which composition goes through the upper
`GI tract Without releasing signi?cant quantities of the drug
`to a human subject being treated and releases the majority of
`the drug to the loWer GI, e.g. colon.
`Another object of this invention is to provide a unit
`dosage composition comprising a drug useful for treating
`loWer gastrointestinal disorders, particularly colon
`disorders, that is orally-administered and minimiZes adverse
`systemic effects to a human subject being treated.
`Another object of this invention is to provide an orally
`administered, unit dosage composition that delivers the
`major amount of the drug useful for topically treating colon
`disorders to the colon so the drug is released for topical
`treatment While minimiZing systemic effects of such drug.
`Another object of this invention is to provide an orally
`administered, unit dosage composition that systemically
`delivers drugs, such as peptides, by absorption throughout
`the loWer GI or colon.
`Another object of this invention is to provide a method for
`treating a human subject through oral administration of a
`unit dosage composition that achieves the foregoing objects
`of this invention.
`Still another object of this invention is to provide a
`process for preparing a unit dosage tablet composition
`suitable for oral administration that attains the foregoing
`objects of this invention.
`Other objects of this invention Will be apparent to one of
`ordinary skill by reading the folloWing speci?cation and
`claims.
`
`SUMMARY OF THE INVENTION
`
`One aspect of this invention is a poWdered mixture useful
`for preparing a tablet for orally delivering a therapeutically
`effective amount of a drug to the loWer GI tract, particularly
`the colon, Without signi?cant release of the drug in the upper
`GI tract after oral administration of the tablet, Which com
`position comprises
`about 0.01% Weight to about 10.0% by Weight of such
`drug;
`about 40% Weight to about 98% by Weight of a hydro
`colloid gum obtainable from higher plants; and
`about 2.0% by Weight to about 50% by Weight of a
`pharmaceutically acceptable excipient, Wherein said
`mixture is free of any enteric polymeric material or
`gas-forming excipients.
`
`10
`
`15
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`20
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`25
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`30
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`40
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`5,811,388
`
`4
`Another aspect of this invention is a pharmaceutical tablet
`having an inner composition optionally coated by a
`pharmaceutically-acceptable coating (preferably an enteric
`coating), said tablet designed for orally delivering a thera
`peutically effective amount of a drug to the loWer GI tract,
`particularly the colon, Without signi?cant release of the drug
`in the upper GI tract after oral administration of the tablet,
`Which inner composition of the tablet comprises
`about 0.01% Weight to about 10.0% by Weight of a drug
`useful for treating a loWer GI tract disorder;
`about 40% to about 98% by Weight of a hydrocolloid gum
`obtainable from higher plants;
`about 2% to about 50% by Weight of a pharmaceutically
`acceptable excipient; and
`no enteric polymeric material or gas-forming excipients.
`Another aspect of this invention is a method for treating
`a disorder of the loWer GI tract, particularly the colon, in a
`human subject, Which method comprises orally
`administering to a human subject in need thereof a tablet
`described above.
`Another aspect of this invention is a method for prefer
`entially delivering a drug to the loWer GI tract, particularly
`the colon, Wherein such drug is susceptible to enZymatic
`degradation in the upper GI tract, Which method comprises
`orally-administering to a human subject in need thereof a
`tablet described above.
`Still another aspect of this invention is a process for
`preparing a composition in the form of a tablet suitable for
`oral administration to a human subject, Wherein the tablet
`composition preferentially delivers a therapeutically effec
`tive amount of such drug to the loWer GI tract, particularly
`the colon, Without signi?cant release of the drug in the upper
`GI tract, Which process comprises
`(a)mixing about 0.5% Weight to about 10.0% by Weight of
`such drug With
`about 40% Weight to about 98% by Weight of a hydro
`colloid gum obtainable from higher plant; and
`about 2% by Weight to about 50% by Weight of a
`pharmaceutically acceptable excipient to form a uni
`form mixture
`(b)forming a tablet; and
`(c)optionally coating the tablet.
`Other aspects of the invention Will be apparent to one of
`ordinary skill of the art upon reading the folloWing speci
`?cations and claims.
`
`DESCRIPTION OF SPECIFIC EMBODIMENTS
`
`The compositions of this invention are based on the
`observation that by carefully controlling the percentage of a
`hydrocolloid obtainable from a higher plant at a very high
`level in an orally-administered dosage form and combining
`it With a suitable excipient and a particular family of drugs
`at loW concentrations (i.e., less than about 10% by Weight),
`a composition can be obtained Which traverses the upper GI
`tract Without releasing any signi?cant amount of drug, but
`When it reaches the loWer GI tract, eg the colon, the drug
`is preferentially released due at least in part to the action of
`the enZymatic environment in the loWer GI tract that attacks
`the hydrocolloid to release the drug. The compositions and
`methods of this invention are of a delayed release nature (as
`compared to sustained or extended release) particularly
`useful for colonic delivery of glucocorticoids, as Well as
`other drugs (eg peptides) that might be inactivated (e.g.,
`enZymatically degraded) if released in the upper gastrointes
`tinal tract. Thus, for purposes of this application a delayed
`release composition alloWs for the release of most of the
`
`000004
`
`

`

`5,811,388
`
`6
`“higher plant” is meant an organism of the vegetable king
`dom that lacks the poWer of locomotion, has cellulose cell
`Walls, groWs by synthesis of inorganic substances and
`includes the vascular plants (or tracheophytes) of the divi
`sion Spermatophyta, particularly those of the class
`Angiospermae. The gums may be extracted from the roots,
`legumes, pods, berries, bark, etc. Thus, higher plants do not
`include algae, ?agellates, bacteria, slime molds, fungi,
`mosses, ferns, horsetails and the like. Representative hydro
`colloid gums obtainable from higher plants include guar
`gum, gum tragacanth, karaya gum (also referred to as
`kadaya gum) and locust bean gum (also referred to as carob).
`Others may be readily apparent to one of skill in the art. See,
`for example, “The Chemistry of Plant Gums and Mucilages”
`by Smith and Montgomery from ACS Monograph Series,
`No. 141, 1959, Reinhold Publishing Company and the 18th
`edition of the Merck Index. A particularly convenient and
`useful hydrocolloid is guar gum Which is a neutral polysac
`charide and consists of long galactomannan molecules With
`some side chain attachments. The hydrocolloids used in the
`subject invention generally have high viscosity exhibited
`upon hydration, are normally linear (at least about 50% by
`Weight of the compound is the backbone chain), and Will
`normally have high molecular Weight, usually about 3><105
`daltons, more usually greater than about 1><106 daltons.
`Generally, the hydrocolloid comes as a poWdered hydrocol
`loid gum and exhibits a viscosity at a 1% concentration in a
`neutral aqueous solution of at least about 75 centipoise per
`second (cps) at 25° C. after 24 hours, using a Brook?eld
`viscometer (model LDF) With a number 3 spindle at 90
`rpms, preferably at least 1><103 cps and most preferably at
`least about 2><103 cps. Generally, the viscosity increases
`With increasing molecular Weight. See Meer Corporation,
`“An Introduction to Polyhydrocolloids.” Hydrocolloid gums
`most useful are those Where the hydrocolloid is a polysac
`charide hydrocolloid Which is chemically designated as
`galactomannan. Galactomannans are polysaccharides con
`sisting of long chains of (1-4) - [3-D-mannopyranosyl units
`to Which single unit side chains of ot-D-galactopyranosyl are
`joined by (1-6) linkages. Galactomannans are found in a
`variety of plants but differ in molecular siZe and the number
`of D-galactosyl side chains. The galactomannans useful in
`this invention are commonly found in the endosperms of the
`leguminosae. Examples of the family of legumes are set
`forth in Table 1 Which shoWs the family and the percent
`endosperm content of leguminous seeds.
`
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`
`5
`active ingredient in the loWer GI, particularly the colon
`Without releasing any signi?cant amount of the drug in the
`upper GI tract as the composition travels through the entire
`GI tract. This is different than a sustained release composi
`tion that releases the active on a regular (i.e. constant) basis
`throughout the GI. Generally, a relatively high percentage of
`the hydrocolloid gum obtainable from higher plants is
`present, namely at least 50% to about 98% (depending in
`part on the purity of the commercially-available gum), With
`a lesser amount of a pharmaceutically acceptable excipient
`that provides lubricating, binding and/or disintegrating capa
`bility for the composition as Well as providing a minimal
`hardness for the tablet so that it can be prepared pharma
`ceutically. This amount is less than about 50% but more than
`about 2% by Weight of the composition. The remainder is a
`drug present at a level that is therapeutically effective and
`depends on the relative activity of the drug and its interac
`tion With the composition. The drug may be useful for
`treating conditions of the loWer GI, particularly the colon
`(e.g., in?ammatory diseases) or other conditions requiring
`drugs that are better absorbed from the colon.
`The Compositions
`One aspect of this invention is an orally-deliverable tablet
`having an inner composition optionally surrounded by a
`pharmaceutically-acceptable coating. The tablet preferen
`tially delivers a therapeutically effective amount of a suit
`able drug to the loWer GI, eg the colon, Without signi?cant
`release of the drug in the upper GI tract upon oral admin
`istration of the composition to a subject in need thereof. The
`inner composition of the tablet comprises about 0.01%
`Weight to about 10.0% by Weight of a suitable drug (e.g., for
`treating in?ammatory colonic disorders); about 50% by
`Weight to about 98% by Weight of a hydrocolloid gum
`obtainable from higher plants; and about 2% by Weight to
`about 50% by Weight of a pharmaceutically acceptable
`excipient such as a binder. Other optional materials may be
`present that Will assist in establishing the desired character
`istics of the pharmaceutical composition. These include
`materials that may enhance absorption of the drug in the
`loWer GI, may protect the drug against degradation, may
`prevent dissolution, and the like. Optionally surrounding the
`inner composition of the tablet is a coating that is preferably
`of enteric polymeric material.
`The solid tablet of this invention is designed to take
`advantage of (1) the protective characteristics of the hydro
`colloid obtainable from higher plants in the upper GI and (2)
`the disintegrative characteristics of the hydrocolloid in the
`loWer GI. Thus, the inner composition of the tablet may be
`one of several designs: (a) it may be a matrix of a thera
`peutically effective amount of the active ingredient uni
`formly dispersed throughout in combination With a high
`percentage of the hydrocolloid and a generally lesser amount
`of other excipients; (b) it may have a core, in Which the
`active ingredient is concentrated, surrounded by a layer of
`material that is free of the active ingredient and that has a
`high percentage of the hydrocolloid and a generally lesser
`amount of other excipients; (c) it may have a concentration
`gradient of the active ingredient such that there is a greater
`amount in the core of the tablet With lesser amounts in
`multiple layers surrounding the core and very little or no
`active ingredient in the outer layer. Whether the design of the
`tablet is that of (a), (b) or (c) above, the speci?city for
`regional delivery to the loWer GI, especially the colon, is
`enhanced by enterically coating the tablet With an appropri
`ate enteric coating material.
`The hydrocolloid that is used in the subject invention is a
`hydrocolloid that is obtainable from higher plants. By
`
`TABLE 1
`
`50
`
`Estimated Endosperm Content of leguminous Seeds
`
`Family
`
`Acacia
`Astragalos
`Baryxylum
`Caesalpinia
`Cassia
`Cercidium
`Ceratonia (carob)
`Chamaecrista
`Colvillea
`Crotalaria
`Cyamopsis (guar)
`Cytisus
`Dalea
`Daubentonia
`Delonix
`Desmanthus
`
`55
`
`60
`
`65
`
`Endo-
`sperm % Family
`
`Endo
`sperm %
`
`1-15
`2-3
`30
`8-40
`10-60
`20
`50
`8-15
`30
`8-25
`50
`15
`20
`10-15
`25
`15
`
`Glottidium
`Glymnocladus
`Indigofera
`Lespedeza
`Leucaena
`Lotus
`Lysiloma
`Melilotus
`Mimosa
`Onomis
`Parkinsonia
`Parryella
`Prosopis
`Schrankia
`Sesbania
`Sophora
`
`2
`15
`20
`1-4
`15
`2-4
`4
`8-12
`3-30
`25
`25
`20
`15
`12
`20
`20-25
`
`000005
`
`

`

`5,811,388
`
`7
`
`TABLE l-continued
`
`Estimated Endosperm Content of Leguminous Seeds
`
`Family
`
`Desmodium
`Gleditsia
`
`Endo-
`sperm % Family
`
`2
`30
`
`Trifolium
`Virgilia
`
`Endo
`sperm %
`
`3—10
`20
`
`Table 2 shows the approximate composition of some
`galactomannans from legume seeds and the percentage of
`anhydromannose residues versus the anhydrogalactose resi
`dues. As can be seen from Table 2, the percentage of
`anhydromannose may vary from about 50% to about 90%
`(e. g. 86%) of the composition of the galactomannan With the
`percent anhydrogalactose varying from about 10% (eg
`14%) to about 50%.
`
`TABLE 2
`
`Approximate Composition of Some Galactomannans from Legume Seeds
`
`Name of Seed
`
`Caesalpinia spinosa (tara)
`Caesalpinia cacalaco (huizache)
`Ceratonia siliqua (carob, locust bean)
`Cercidiam torregyanam (palo verde)
`Delonix regia (?ame tree)
`cyamopsis tetragonolobus (guar)
`Gleditsia triacanthos (honey locust)
`Gymnocladus dioica (Kentucky coffee)
`Sophora japonica
`Desmanthus illinoensis (prairie-mimosa)
`Indigofera hirsata (indigo)
`Cassia leptocarpa (senna)
`Crotalaria intermedia (rattlebox)
`Crotalaria juncea (rattlebox)
`Crotalia striata (rattlebox)
`Trigonella foenum graecum (fenugreek)
`Medicago sativa (alfalfa)
`
`Anhydro-
`mannose %
`
`Anhydro
`galactose %
`
`71
`69
`80-86
`73
`79
`64
`71
`71
`81
`70
`72
`65
`64
`60
`60
`52
`66
`
`26
`28
`20-14
`22
`19
`36
`26
`26
`16
`26
`23
`21
`28
`40
`40
`48
`33
`
`Preferably, the galactomannan that is most useful in this
`invention is derived from the cyamopsis tetragonolobus,
`commonly referred to as guar. This exhibits a percentage
`mannose residue of about 64% With a percent galactose
`residue of about 36%. Commercially available guar gum is
`about 66—82% galactomannan polysaccharide With impuri
`ties making up the remainder of the composition. According
`to the National Formulary (NF) standards the guar gum may
`contain up to 15% W Water, up to 10% W protein, up to 7%
`W acid insoluble material and up to about 1.5% ash. Sources
`of commercially available guar gum are Aqualon Company,
`Wilmington, Del.; Meer Corporation, Cincinnati, Ohio;
`Stein Hall & Company; and TIC Gums, Inc., Belcamp, Md.
`Other hydrocolloids may be readily apparent to one of
`skill in the art. See for example “The Chemistry of Plant
`Gums and Mucilages” by Smith and Montgomery from the
`A.C.S. Monograph series, #141, 1959, Reinhold Publishing
`Co. and the Eighteenth Edition of The Merck Index.
`In general, the amount of the hydrocolloid that Will be
`used is an amount that alloWs the composition to traverse the
`upper GI tract Without signi?cant disintegration and Without
`releasing signi?cant amounts of drug in the upper GI tract,
`i.e. to provide a delayed-release pro?le. Asigni?cant amount
`in this case is more than about 20%, thus more than about
`80% of the drug Will be released in the loWer GI tract.
`Generally, that amount of hydrocolloid Will be more than
`about 50% but less than about 98%. More preferably, the
`amount Will be betWeen about 60% to about 95% by Weight
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`of the hydrocolloid gum. Depending on individual
`variability, Whether a subject has eaten or has fasted, and
`other factors, a tablet Will traverse the stomach and upper
`intestinal tract in about 3 to 6 hours. During this time, little
`drug (less than 20%, preferably less than 10%) is released
`from the tablet of this invention. Once the tablet reaches the
`loWer GI particularly the colon, the release of the drug is
`triggered by enzymatic degradation of the galactomannan
`gum. Once release is triggered, the release rate is relatively
`rapid for certain drugs, e.g., about 80—90% of the drug
`release occurs in about 2—4 hours or so, While other drugs
`such as