Ulllted States Patent [19]
`Berliner et al.
`
`[54] DELIVERY OF DRUGS TO THE LOWER
`GASTROINTESTINAL TRACT
`[75] Inventors: David L. Berliner, Atherton; Sergio
`_
`_
`Nacht, Redwood City, both of Calif.
`
`[73] Assignee: Advanced Polymer Systems, Inc.,
`Redwood City, Calif.
`
`[21] Appl. No.: 720,335
`
`[22]
`
`.
`_
`Flled'
`
`Sep' 27’ 1996
`
`Related US. Application Data
`
`[63]
`
`Continuation-in-part of Ser. No. 432,619, May 2, 1995,
`abandoned, which is a continuation-in-part of Ser. No.
`282’836’ Jul' 29’ 1994’ abandoned
`[51] Int. Cl.6 ............................. .. A61K 9/26; A61K 9/30;
`A61K 9/48; A61K 9/52
`[52] US. Cl. ........................ .. 424/463; 424/451; 424/456;
`424/463; 424/464; 424/469; 424/474; 424/475;
`424/479; 424/482
`[58] Field of Search ................................... .. 424/451, 456,
`424/458, 461, 463, 486, 489, 499, 464,
`469, 474F482
`
`USOO5849327A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,849,327
`Dec. 15, 1998
`
`FOREIGN PATENT DOCUMENTS
`322392 A1 6/1989 European Pat. Off. .
`g ;/ 1992 European Pat‘ Off‘ '
`/1992 European Pat. Off. .
`3234331 A1 3/1984 Germany _
`291668 A 2/1986 Germany .
`91/16881 11/1991 WIPO.
`WO 91/16881
`A 11/1991 WIPO .
`WO 91/19483
`A1 12/1991 WIPO _
`
`92/00732
`WO 92/00732
`WO 97/27843
`A2 8/1997 WIPO ,
`
`1/1992 WIPO .
`1/1992 WIPO .
`
`OTHER PUBLICATIONS
`
`Ashford et al., “An Evaluation of Pectin as a Carrier for
`Drug Targeting to the Colon”, Journal of Controlled
`Release, 26, 213—220 (1993).
`Rubenstein et 311,, “In Vitro Method for Drug Release Analy
`sis from Microbially Controlled Delivery Systems”, Pro
`ceea'. Intern. Symp. Control. Rel. Bioact. Mater., 17,
`466—467 (1990)
`Rubenstein et al., “Pectic Salt as a Colonic Delivery Sys
`tern”, Proceed. Intern. Symp. Control. Rel. Bioact. Mater.,
`18, 221—222 (1991).
`
`[56]
`
`References Cited
`
`(List continued on next page.)
`
`US' PATENT DOCUMENTS
`3/1976 Hill ....................................... .. 424/230
`4/1980 DeSimone
`.... .. 424/79
`4/1980 Seidel et a1.
`424/81
`9/1980 MeitZner et al.
`521/29
`3/1986 DeCrosta et al.
`.. 525/283
`9/1987 Won ___________ __
`424/501
`2/1989 Leong et a1,
`424/487
`2/1990 Theeuwes et a1.
`424/468
`9/1992 W911 --------------- --
`- 424/78-31
`1/1993 Wnght ct a1~ -
`424/473
`5/1994 Eury """""""" "
`424501
`6/1995 Lehmann et a1.
`424/464
`8/1995 Milstein et a1.
`424/451
`4/1996 Edman et a1.
`424/493
`6/1996 Sintov et a1. ......................... .. 514/777
`
`3,946,110
`4,198,395
`4,198,396
`4,221,871
`4,575,539
`4,690,825
`4,806,360
`4,904,474
`5,145,675
`571787866
`5’316’774
`5,422,121
`5,443,841
`5,505,966
`5,525,634
`
`Primary Examiner—Gollamudi S. Kishore
`Attorney, Agent, or Firm—Heller Ehrman White &
`McAuliffe
`
`ABSTRACT
`
`[57]
`_
`_
`_
`_
`Diseases of the colon are treated by oral ingestion of a unit
`dosage form containing a plurality of porous microscopic
`beads, the pores containing an active agent or drug and
`plugged With a polysaccharide that is chemically degradable
`by colon-speci?c bacteria. The dosage form further contains
`a coating of an enteric material that remains intact until the
`dosa 6 form reaches the Colon
`g
`'
`
`34 Claims, 1 Drawing Sheet
`
`MYLAN Ex 1040, Page 1
`
`

`

`5,849,327
`Page 2
`
`OTHER PUBLICATIONS
`
`Salyers et al., “Fermentation of Mucins and Plant Polysac
`charides by Anaerobic Bacteria from the Human Colon”,
`Applied and Environmental Microbiology, 34, 529—533
`(1977).
`Salyers et al., “Carbohydrate Metabolism in the Human
`Colon”, Human Intestinal M icro?ora in Health and Disease,
`Chapter 6, 129—146 (1983).
`Vercellotti, et al., “Breakdown of Mucin and Plant Polysac
`charides in the Human Colon”, Can. J. Biochem., 55,
`1190—1196 (1977).
`Wilson, “The Gastrointestinal Micro?ora”, Textbook of Gas
`troenterology: Carbohydrate Metabolism, 1, 532—543
`(1991).
`Cui et al., “A Budesonide Prodrug Accelerates Treatment of
`Colitis in Rats”, Gut, 35, 1439—1446 (1994).
`Geary et al., “Vancomycin and Insulin Used as Models for
`Oral Delivery of Peptides”, Journal of Controlled Release,
`23, 65—74,(1993).
`of
`Evaluation
`Vitro
`“In
`al.,
`Haeberlin
`et
`Colon—Speci?c
`DeXamethasone—[3—D—Glucuronide for
`Drug Delivery”, Pharm. Res., 10, 1553—1562 (1993).
`
`Levine, et al. “Coating of Oral Beclomethasone Dipropi
`onate Capsules With Cellulose Acetate Phthalate Enhances
`Delivery of Topically Active Antiin?ammatory Drug to the
`Terminal Ileum”, Gastroenterology 92, 1037—1044, (1987).
`McLeod et al., “A Glucocorticoid Prodrug Facilitates Nor
`mal Mucosal Function in Rat Colitis Without Adrenal Sup
`pression”, Gastroenterology, 106, 405—413 (1994).
`Milojevic et al., “Amylose as a Coating for Drug Delivery
`to the Colon: Preparation and in Vitro Evaluation Using
`5—Aminosalicylic Acid Pellets”, Journal of Controlled
`Release, 38, 75—84 (1996).
`Rutgeerts et al., “A Comparison of Budenoside With Pred
`nisolone for Active Crohn’s Disease”,New England Journal
`of Medicine, 331, 842—845 (1994).
`Saffron, et al. “A NeW Approach to the Oral Administration
`of Insulin and Other Peptide Drugs”, Science, 233,
`1081—1084 (1986).
`TheeuWes, F. “Elementary Osmotic Pump”, Journal of
`Pharmaceutical Sciences, 64, 1987—1991 (1975).
`
`MYLAN Ex 1040, Page 2
`
`

`

`U.S. Patent
`
`Dec. 15, 1998
`
`5,849,327
`
`0 0 000090
`O
`
`21
`
`MYLAN Ex 1040, Page 3
`
`

`

`1
`DELIVERY OF DRUGS TO THE LOWER
`GASTROINTESTINAL TRACT
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part of US. Pat.
`application Ser. No. 08/432,619, ?led May 2, 1995, noW
`abandoned, Which Was a continuation-in-part of application
`Ser. No. 08/282,836, ?led Jul. 29, 1994, noW abandoned.
`The contents of both applications 08/432,619 and 08/282,
`836 are hereby incorporated herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`This invention relates to the treatment of diseases of the
`colon, such as in?ammatory boWel disease. More
`particularly, it relates to a dosage form for an active agent
`and the method of its use in topically treating disease in the
`colon.
`2. Description of the Prior Art
`Many conditions either originate or are expressed in the
`lumen of the gastrointestinal (GI) tract or in the tissue
`intermediate to the lumen. In?ammatory boWel diseases,
`such as ulcerative colitis and Crohn’s disease, are eXamples
`of such conditions. Current therapies for in?ammatory
`boWel diseases involve systemic administration of a formu
`lation containing an active drug. Unfortunately, the drug is
`absorbed systemically even though the site Where the drug
`is needed is a localiZed area in the boWel. Thus, to achieve
`a therapeutically effective local concentration at the site of
`the disease, one must administer enough of the formulation
`that the systemic concentration is relatively high. The dis
`advantage is that high systemic concentrations can have
`damaging side effects. An eXample is the administration of
`prednisolone for in?ammatory boWel disease. Although
`administered for purposes of localiZed action, this steroid is
`absorbed systemically, and prolonged eXposure from con
`tinued systemic absorption can result in atrophy of adrenal
`glands. Steroids have also been administered by enema, but
`this does not prevent systemic absorption.
`One method of preventing systemic absorption is the use
`of prodrug techniques. The prodrug is one that is not
`absorbed until it reaches a particular region of the GI tract
`Where it is transformed to an absorbable form and thereby
`becomes active. An eXample is sulphasalaZine Which is used
`in the treatment of in?ammatory boWel disease.
`While the prodrug approach has Worked for some drugs it
`is limited in scope due to its dependence upon the chemistry
`of the prodrug and the drug, and hoW the former is trans
`formed to the latter in the GI environment. This approach
`requires the development of a neW prodrug for each active
`species, and as neW chemical entities, prodrugs require
`independent regulatory approval.
`
`SUMMARY OF THE INVENTION
`
`The disadvantages noted above are addressed by the
`present invention, Which resides in a composition and
`method for the treatment of diseases of the colon by oral
`ingestion of a drug specially formulated to pass intact
`through the stomach and to be released at a controlled rate
`for therapeutic action upon reaching the colon. These effects
`are achieved in a manner independent of the chemistry of the
`drug or of any relationship betWeen the drug itself and the
`environment of the GI tract. The formulation comprises
`microscopic beads With pores containing the drug, the pores
`
`10
`
`15
`
`20
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`25
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`35
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`40
`
`45
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`65
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`5,849,327
`
`2
`being plugged With a polysaccharide that is chemically
`degradable only by bacterial enZymes that are present in the
`colon, the beads being assembled into a unit dosage form
`suitable for oral administration yet coated With an enteric
`coating that protects that dosage form from the stomach
`environment and alloWs it to pass intact through the stomach
`and into the colon. The dosage form thus remains intact until
`it reaches the small intestine or regions close thereto, Where
`the enteric coating degrades and eXposes the polysaccharide
`that plugs the pores. While some dissolving of the polysac
`charide occurs upon eXposure in this manner, chemical
`degradation of the polysaccharide occurs only in the large
`intestine (i.e., the colon). Once the polysaccharide is
`degraded sufficiently to eXpose the active agent in the pores,
`the beads release the active agent at a rate Which is sloW and
`controlled due to the pore structure.
`The microscopic beads are rigid polymeric beads that
`remain rigid and insoluble throughout their travel through
`the GI tract, each microscopic bead containing a substan
`tially noncollapsible internal pore netWork accessible
`through openings on the surfaces of the beads. The polymer
`from Which the beads are formed can be linear or
`crosslinked. The active agent retained in the pore netWork of
`the beads is any of a Wide variety of therapeutic drugs,
`eXamples of Which are corticosteroids and non-steroidal
`anti-in?ammatory agents for treatment of in?ammatory
`boWel disease, anti-tumor agents for treatment of colonic
`malignancies, anti-parasitic agents for treatment of
`parasites, antibiotics for treatment of infections, laxatives for
`treatment of constipation, and drugs such as bismuth
`subsalicylate, trimethoprim-sulfamethoXaZole, and doXycy
`cline and various other antibiotics for treatment of diarrhea.
`The microscopic beads used in the present invention have
`previously been used as a delivery system for eXternal
`topical skin administration of active agents. When topically
`administered, the beads Were shoWn to be capable of releas
`ing the active agents at a controlled rate. It has noW been
`found that these microscopic beads When formulated With
`the polysaccharides and enteric coatings described above
`constitute a delivery system that can be administered orally
`for the safe and e?icacious treatment of diseases of the colon
`Without harm to, or substantial release of the active agent at,
`other locations along the GI tract. The inherently sloW
`release rate of active agents from the pores of the micro
`scopic beads is thus noW further combined With localiZation
`of the release. In certain cases a small degree of systemic
`absorption of the active agents may occur, but side effects
`are substantially absent since the rate of systemic absorption
`is at most very sloW due to the combination of drug,
`microbeads, pore structure, and polysaccharide in the for
`mulation.
`This method of administering the active agent is thus a
`topical administration since the active agent is not released
`from the dosage form until it reaches the site of interest. The
`agent thus contacts the site of interest directly through the
`Wall of the colon, rather than being delivered to the colon
`through the blood stream Which Would carry the agent active
`to other (not diseased) parts of the body as Well. The use of
`porous microbeads for a controlled and sustained release
`rate maXimiZes this topical effect and minimiZes systemic
`effects.
`In preferred embodiments, the dosage form is a pharma
`ceutical capsule (such as a gelatin capsule) or tablet con
`taining a multitude of microscopic beads With the selected
`active agent in the porous netWork of the individual beads,
`the polysaccharide on the surfaces of the individual beads
`and plugging the pores, and an enteric coating surrounding
`
`MYLAN Ex 1040, Page 4
`
`

`

`5,849,327
`
`3
`the capsule or tablet. The active agent can be present in the
`capsule or tablet in varying amounts not critical to this
`invention, although in most cases the amount per capsule or
`tablet Will generally be in the range of about 0.1—100 mg,
`With additional acceptable ranges about 1—100 mg, about
`3—20 mg, and about 5—20 mg.
`Examples of microscopic beads are those formed from
`styrene-divinylbenZene copolmyer, methyl methacrylate
`ethylene glycol dimethacrylate copolymer, poly(methyl
`acrylate), poly(methyl methacrylate), and polystyrene, and
`analogs thereof. Typical bead diameters are about 5—200
`microns, preferably about 10—40 microns.
`TWo of the many conditions that can be successfully
`treated by the composition and method of this invention are
`ulcerative colitis, Which affects only the large intestine (a
`portion or its entire length), and Crohn’s disease, Which
`affects both the terminal ileum and the ascending colon. A
`dosage form for ulcerative colitis according to the present
`invention is formulated so that it Will initially remain intact
`in the GI. tract and degrade only in or near the large
`intestine. For Crohn’s disease the dosage form is formulated
`to initially remain intact in the GI. tract until reaching the
`junction of the ileum With the colon Where it Will degrade
`and release the active agent.
`
`4
`Pore-plugging Polysaccharide Degradable by Colonic Bac
`teria
`As noted, one of the elements responsible for restricting
`release of the drug from the dosage form to locations in or
`near the colon is the polysaccharide that plugs the pore
`openings and seals the active agent inside the pores. The
`polysaccharide is one that is chemically degradable only by
`the action of bacteria that are speci?c to and generally
`con?ned in the colon. The degradation of the coating by
`these bacteria result in the removal of the polysaccharide
`from the pore openings and consequently the release of the
`drug. Examples of polysaccharides that meet this description
`are pectin, arabinogalactose, chitosan, chondroitin sulfate,
`cyclodextrin, dextran, galactomannan (guar gum), and
`xylan. A preferred polysaccharide is pectin.
`The amount of colon-degradable polysaccharide present
`in the formulation can vary and is not critical, although
`amounts considered optimal Will depend on the particular
`polysaccharide selected. The amount in any event Will be
`sufficient to plug the pore openings. For pectin, it has been
`shoWn that dissolution and release Will depend on the
`particular pectin composition, primarily its methoxy con
`tent. Thus, pectins With a high degree of methoxylation
`demonstrate a higher degree of protection for the dosage
`form than those pectins With a loWer degree of methoxyla
`tion. Pectin USP With a degree of methoxylation of 70% is
`an example of a preferred material Which can be obtained
`from Bulmer Pectin, UK.
`Enteric Coating
`Examples of enteric coating materials that are gastro
`resistant and yet degrade in the intestines are disclosed in
`Eury et al., US. Pat. No. 5,316,774, entitled “Blocked
`Polymeric Particles Having Internal Pore NetWorks for
`Delivering Active Substances to Selected Environments,”
`issued May 31, 1994, the contents of Which are hereby
`incorporated herein by reference. Other examples are knoWn
`to those skilled in the art.
`One class of enteric coating materials of the above
`description are those that remain intact in the environment of
`the stomach but solubiliZe at the higher pH of the intestines.
`Materials of this type are knoWn in the art for use as coatings
`for solid core drug formulations. The most effective enteric
`materials are polyacids having a pKa of from about 3 to 5.
`Preferred are those Whose carboxylic acid groups are trans
`formed to carboxylate groups at a pH of from about 5 to 7.
`These copolymers are resistant to gastric juices. Exemplary
`materials include fat-fatty acid mixtures, cellulose acetate
`phthalates, copolymers of methacrylic acid and methyl
`methacrylate, copolymers of methacrylic acid and
`ethylacrylate, and polymers or copolymers in general con
`taining acrylic acid or alkyl-substituted acrylic acids as
`monomers. The polymers, and particularly those containing
`acrylic acid or an alkyl-substituted acrylic acid can be
`applied to the outer surface of the dosage form either by in
`situ polymeriZation or by deposition from an aqueous dis
`persion. Examples of copolymers useful as enteric coating
`materials are listed in Table I.
`
`TABLE I
`
`Copolymer
`
`Molecular Weight Preferred Monomer Ratio
`
`poly(methacrylic acid,
`ethylacrylate)
`poly(methacrylic acid,
`methylmethacrylate)
`
`250 kD
`
`135 kD
`
`1:1
`
`1:2
`
`The coating thickness may vary and is not critical to this
`invention. In most applications and With most coating
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a cross section of a porous microscopic bead
`impregnated With an pharmacological agent in the pores,
`and the pores plugged With a polysaccharide for use in the
`formulations of this invention. The vieW shoWn in the Figure
`is that of a region close to the surface of the bead.
`FIG. 2 is a cross section of a tablet embodying a unit
`dosage form Within the scope of this invention.
`FIG. 3a is a cross section of a capsule embodying a unit
`dosage form Within the scope of this invention. FIG. 3b is an
`enlarged cross section of one of the particles contained in the
`interior of the capsule of FIG. 3a.
`
`DETAILED DESCRIPTION OF THE
`INVENTION AND PREFERRED
`EMBODIMENTS
`
`Microscopic Beads
`Microscopic beads that can be used in connection With the
`present invention are knoWn in the art and are described in
`detail in Won, US. Pat. No. 5,145,675, entitled “TWo Step
`Method for Preparation of Controlled Release
`Formulations,” issued Sep. 8, 1992, assigned to Advanced
`Polymer Systems, Inc. The disclosure of US. Pat. No.
`5,145,675 is incorporated herein by reference. One particu
`lar type of microscopic bead contemplated for use in this
`invention are co-polymers of styrene and divinylbenZene,
`Whose preparation is disclosed in Example 1.1 of US. Pat.
`No. 5,145,675. The same example also illustrates a method
`for entrapping steroids Within the porous netWork of the
`polymeric beads. Another type of microscopic bead con
`templated for use herein are copolymers of methyl meth
`acrylate and ethylene glycol dimethacrylate. The preparation
`of microscopic beads of this composition is described in
`Example 6.2 of US. Pat. No. 5,145,675. In general, the
`diameter of an individual bead is not critical and may vary.
`In most cases, hoWever, the most convenient diameter is
`from about 5 microns to about 200 microns. Particles of the
`aforementioned types are commercially available from
`Advanced Polymer Systems, Inc., of RedWood City, Calif.,
`in the form of empty particles or as particles Which have
`been loaded With the active agents utiliZed in the present
`invention.
`
`MYLAN Ex 1040, Page 5
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`5,849,327
`
`5
`materials, best results are obtained With coatings of thick
`ness in the range of from about 0.1 mm to about 1.0 mm.
`Additional Features
`The term “unit dosage form” as used herein denotes a
`formulation con?gured as a self-contained dosage contain
`ing suf?cient active agent to constitute the dosage for a
`single administration, When taken either as the sole treat
`ment or as one of a series of periodic administrations. The
`present invention contemplates any suitable dosage form
`that can be used for oral drug delivery. In this regard the
`polymeric particles carrying the drug may be incorporated
`into a variety of knoWn dosage forms, as described in, for
`example, Remington’s Pharmaceutical Sciences, Mack Pub
`lishing Company, Easton Pa., 16th Ed., 1982, the disclosure
`of Which is incorporated herein by reference. The unit
`dosage form Will contain a preselected quantity of active
`agent(s) contained Within the porous microscopic beads.
`Pharmaceutically acceptable non-toxic dosage forms are
`prepared using conventional excipients, such as pharmaceu
`tical grades of mannitol, lactose, starch, magnesium stearate,
`sodium saccharin, talcum, cellulose, glucose, sucrose,
`magnesium, carbonate, and the like. Such compositions may
`be in the form of solutions, suspensions, tablets, pills,
`capsules, poWders, and the like.
`As noted above, the invention ?nds utility in the treatment
`of diseases of the colon. One type of disease to Which the
`dosage form and method of this invention are particularly
`Well suited is in?ammatory boWel disease. Examples of
`drugs to be utiliZed for treatment of in?ammatory boWel
`disease are hydrocortisone, beclomethasone dipropionate,
`tixocortol pivalate, budesonide, dexamethasone, prednisone,
`prednisolone and triamcinolone acetonide. Non-steroidal
`anti-in?ammatory agents such as amino salicylate and sul
`fasalaZine are also contemplated. Recent clinical studies
`have shoWn that ulcerative colitis can also be treated With
`cyclosporine, a drug usually given to transplant patients, and
`this is contemplated for use herein as Well. Prodrugs are
`another class of drugs contemplated for use herein, Where
`they are placed in the pores of the microscopic beads in the
`same manner as the active drugs described above. Examples
`of prodrugs are dexamethasone-succinate-dextran
`(Gastroenterology, 1994, 106:2 405—413), budesonide-[3
`glucuronide (Gut, 1994, 35: 1439—1446), and
`dexamethasone-[3-D-glucuronide (Pharm. Res., 1993, 10:
`1553 . 1562).
`In compositions for the treatment of colonic
`malignancies, any suitable anti-tumor agent knoWn in the art
`for the treatment of localiZed malignancies can be incorpo
`rated in the dosage form. Examples of anti-tumor agents
`suitable for use in this invention are methotrexate,
`5-?uorouracil, and similarly functioning anti-neoplastic
`agents, such as tamoxifen, cyclophosphamide, mercaptopu
`rine etoposide, indomethacin, semustine, ?uorouracil, ?oxu
`ridine and mitomycin. For the treatment of infections of the
`colon, antibiotics (including antibacterials) Which are suit
`able for use in this invention include sulphanilamides and
`their derivatives, and other antibiotics speci?cally designed
`to treat particular bacterial infections associated With food
`ingestion. Additional examples include sulfonamides,
`nor?oxacin, chloramphenicol, tetracyclines and vancomy
`cin.
`For treatment of parasites, suitable anti-parasitic agents
`can be used, such as diloxanide furoate, metronidaZole,
`quinacrine, tetracyclines, iodoquinol, dehydroemetine,
`amphotericin B, mebendaZole and thiabendaZole.
`For a further understanding of the invention, reference is
`made to FIGS. 1, 2 and 3.
`
`10
`
`15
`
`20
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`25
`
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`35
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`
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`A cross section of a region close to the surface of an
`impregnated microscopic bead 11 for use in the composition
`and method of this invention is shoWn in FIG. 1. The bead
`itself is a polymeric matrix 12 With an internal netWork of
`pores. Residing in the pores is an active pharmacological
`agent 13, and the pore openings are plugged With the
`polysaccharide 14 that is degradable by colon-speci?c
`enzymes.
`A multitude of impregnated microscopic beads such as
`those shoWn in FIG. 1 are shoWn in FIG. 2, Where the beads
`are combined into a compressed tablet 20, shoWn in cross
`section. The individual beads 11 occupy the interior of the
`tablet, and the polysaccharide 21 that is degradable by
`colon-speci?c enZymes not only coats the beads and plugs
`their pore openings, but also ?lls the volume in betWeen the
`beads. The exterior of the tablet is the enteric coating
`material 22, coating the tablet.
`A cross section of a capsule 30 is shoWn in FIG. 3a,
`representing a second dosage form as an alternative to the
`tablet 20 of FIG. 2. The capsule is holloW, With its void space
`31 ?lled With a multitude of loose particles 32, one of Which
`is shoWn in enlarged cross section in FIG. 3b. The particles
`are formed by dispersing drug-impregnated microbeads
`such as those represented by FIG. 1 (minus the polysaccha
`ride coating) in liquid polysaccharide, solidifying the
`polysaccharide, and granulating the solidi?ed mass into
`particles. Each particle 32 thus consists of a multitude of
`drug-impregnated microbeads 33 dispersed through a matrix
`of solid polysaccharide 34, i.e., the same polysaccharide that
`is used in the tablet of FIGS. 1 and 2. The capsule 35 is
`gelatin, coated With the enteric material 36.
`The folloWing examples are offered for purposes of
`illustration only.
`
`EXAMPLE 1
`
`Tablets containing a suitable amount of a corticosteroid
`entrapped in a MICROSPONGE® (registered trademark of
`Advanced Polymer Systems, Inc. of RedWood City, Calif.,
`applied to its polymeric microbeads having an internal
`porous netWork) system are prepared With the folloWing
`general formulation:
`
`Tablet Component
`
`MICROSPONGE ® System With corticosteroid
`Pectin
`Dibasic Calcium Phosphate
`EUDRAGIT 1005
`Magnesium Stearate
`
`Weight
`
`250 mg
`200 mg
`100 mg
`100 mg
`10 mg
`
`EUDRAGIT 100S is a poly(methylnethacrylate-co
`methacrylic acid) blocking agent for enteric coating from
`Rohm Pharma GmbH, Darmstadt, West Germany.
`
`A) Hvdrocortisone 10% in Acrvlates Copolymer
`
`(Formula per gram of entrapment)
`Hydrocortisone
`Acrylates Copolymer (APS Type E 101)
`
`100 mg
`900 mg
`
`APS Type E 101, E 140, and E 104 are polymer beads
`formed from a copolymer of methl methacrylate-ethylene
`glycol dimethacrylate, available from Advanced Polymer
`Systems, Inc., RedWood City, Calif. The polymers differ by
`particle siZe and porosity and all are Within the range of
`about 8 to 25 microns in diameter.
`
`MYLAN Ex 1040, Page 6
`
`

`

`5,849,327
`
`8
`solution in ethanol, isopropanol or acetone is sloWly added
`to the tumbling tablets to obtain a uniform coating by
`evaporation of the solvent.
`
`7
`This entrapment is prepared as described in US. Pat. No.
`5,145,675. Namely, a 5% W/W hydrocortisone solution is
`prepared by adding 600 mg of hydrocortisone to 12 g of
`ethanol and then heated to 65° C. Small volumes of this
`solution (less than 1 mL) are then added to 4.5 g of blank
`polymer Type E 101 in an amber bottle and then sloWly
`stirred using a spatula for several seconds. This is repeated
`until a total of 5 g of solution has been added. The bottle is
`capped and then placed on a roller mill for one hour to mix
`the contents. The polymer is then dried in an oven at 65° C.
`for 2.5 hours. Due to the loW solubility of hydrocortisone in
`the organic solvents used to prepare the entrapment, to
`achieve adequate levels of drug in the polymer to make it
`suitable for therapy, this process is repeated for a second
`entrapment step With drying of entrapped polymer in the
`oven at 50° C. overnight.
`
`B) Beclomethasone 5% in Acrvlates Copolymer
`
`(Formula per gram of entrapment)
`
`Beclomethasone Dipropionate
`Acrylates Copolymer (APS Type E 140)
`
`50 mg
`950 mg
`
`A 2.5% W/W beclomethasone solution is prepared by
`adding 300 mg of beclomethasone to 12 g of ethanol and
`then heated to 65° C. Small volumes of this solution (less
`than 1 mL) are then added to 4.75 g of blank polymer in an
`amber bottle and then sloWly stirred using a spatula for
`several seconds. This is repeated until a total of 5 g of
`solution has been added. The bottle is capped and then
`placed on a roller mill for one hour to mix the contents. The
`polymer is then dried in an oven at 65 ° C. for 2.5 hours. This
`process is repeated for the second entrapment step With
`drying of entrapped microsphere polymer in the oven at 50°
`C. overnight.
`
`C) Budesonide 5% in Acrvlates Copolymer
`
`(Formula per gram of entrapment)
`
`Budesonide
`Acrylates Copolymer (APS Type E 104)
`
`50 mg
`950 mg
`
`A 2.5% W/W budesonide solution is prepared by adding
`300 mg of budesonide to 12 g of tetrahydrofuran and then
`heated to 65° C. Small volumes of this solution (less than 1
`mL) are then added to 4.75 g of blank polymer in an amber
`bottle and then sloWly stirred using a spatula for several
`seconds. This is repeated until a total of 5 g of solution has
`been added. The bottle is capped and then placed on a roller
`mill for one hour to mix the contents. The polymer is then
`dried in an oven at 65 ° C. overnight. This process is repeated
`for a second entrapment to obtain the desired payload.
`Tablets are prepared by mixing the indicated amount of
`polymer entrapment containing the drug and the other
`ingredients listed in the formulation, except the Eudragit.
`Tablets are produced by compression compaction using a
`stainless steel mold and a suitable hydraulic press.
`These tablets are then pan-coated With the Eudragit 100S
`to provide an enteric coating that Will alloW the tablets to
`traverse through the stomach Without disintegration or pre
`mature release of the drug. To coat the tablets, they are
`placed in a suitably heated rotating drum at about 40°—45°
`C. and, While rotating, an appropriate amount of an Eudragit
`
`(Formula per Capsule)
`
`MICROSPONGE ® System With corticosteroid
`Pectin (or other suitable polysaccharide)
`
`250 mg
`150 mg
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Polymer containing the entrapped corticosteroid is pre
`pared as described in Example 1 A), B) or C) above.
`Apectin solution is prepared by dissolving 1.5 g of pectin
`(moistened With 0.5 mL of ethanol to facilitate dissolution)
`in 30 ml of Water heated to about 50° C. The suspension is
`maintained at this temperature With gentle stirring until a
`clear viscous solution is obtained.
`Then, 2.5 g of microspheres containing the corticosteroid
`is placed in a suitable glass or metal container such that it
`can be rotated While heated and its contents stirred to prevent
`agglomeration. The pectin solution is then added sloWly and
`in small portions to the polymer, While rotating the vessel
`and continue heating. As the mixture dries, more pectin
`solution is added until completion. A granular material, With
`granules about 0.6—1.0 mm in diameter is obtained. Larger
`clumps are easily broken into smaller particles With a glass
`rod or other suitable utensil.
`The dry material thus obtained is divided into 400 mg
`portions and each portion is placed into a gelatin capsule.
`Alternatively, if smaller capsules are desired, 200 mg por
`tions can be used.
`These capsules, properly sealed, are then placed in a
`mildly heated coating pan (about 40° C.) and, While rotating,
`an EUDRAGIT 100S solution in ethanol, isopropanol or
`acetone is sloWly added to the tumbling capsules to obtain
`a uniform coating When the solvent evaporates.
`Similar examples of tablet or capsule con?gurations can
`be designed by using polymeric entrapments of other drugs
`like anti-tumor agents, antibacterials, etc., in MICRO
`SPONGE® Systems of different polymer compositions,
`particle siZe, and porosities as described in US. Pat. No.
`5,145,675.
`The folloWing examples illustrate the safety of the dosage
`form and method.
`
`EXAMPLE 3
`
`This example is a study involving the gastrointestinal tract
`in subjects With ileostomy. The subjects Were all given a
`capsule similar to that described in Example 2 Wherein the
`porous microscopic beads Were loaded With 14C
`hydrocortisone.
`In this study, 14C-hydrocortisone Was measured in both
`the urine and ileal effluent for 3—5 days after ingestion of a
`capsule containing the test material. In three of the subjects,
`the urine and ileal ef?uents Were collected frequently so that
`the elimination of 14C could be timed. The ileal ef?uents
`from one subject Were accidentally destroyed during the
`drying process. Thus, only the data from four subjects can be
`evaluated.
`
`Tables II and III list the percentages of 14C recovered in
`the ileal effluent and urine for each of the four subjects
`Whose ileal effluent was not destroyed. Table III shoWs
`recovery for the entire collection, While Table IV shoWs the
`timing of the excretion in ileal effluent or urine.
`
`MYLAN Ex 1040, Page 7
`
`

`

`9
`
`TABLE II
`
`Recovery of 14C-Hvdrocortisone in Entire Collection
`
`Percent Recovered
`
`Subject
`
`Ileal Effluent