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`pregelatinized starch, red iron oxide, saccharin sodium, sodium carboxymethyl ether, sodium
`chloride, sodium citrate, sodium phosphate, strawberry flavor, synthetic black iron oxide,
`synthetic red iron oxide, titanium dioxide, and white wax.
`
`Solid oral dosage forms mayoptionally be treated with coating systems(e.g. Opadry® fx film
`coating system, for example Opadry® blue (OY-LS-20921), Opadry® white (YS-2-7063),
`Opadry® white (YS-1-7040), and black ink (S-1-8106).
`
`The agents either in their free form or as a salt can be combined with a polymer such as
`polylactic-glycoloic acid (PLGA), poly-(1)-lactic-glycolic-tartaric acid (P(DLGT) (WO
`01/12233), polyglycolic acid (U.S. 3,773,919), polylactic acid (U.S. 4,767,628), poly(e-
`caprolactone) and poly(alkylene oxide) (U.S. 20030068384)to create a sustainedrelease
`formulation. Such formulations can be used to implants that release a peptide or another agent
`over a period of a few days, a few weeks or several months depending on the polymer, the
`particle size of the polymer, and the size of the implant(see, e.g., U.S. 6,620,422). Other
`sustained release formulations and polymersfor use in are described in EP 0 467 389 A2, WO
`93/24150, U.S. 5,612,052, WO 97/40085, WO 03/075887, WO 01/01964A2,U.S.5,922,356,
`WO 94/155587, WO 02/074247A2, WO 98/25642, U.S. 5,968,895, U.S. 6,180,608, U.S.
`20030171296, U.S. 20020176841, U.S. 5,672,659, U.S. 5,893,985, U.S, 5,134,122, US.
`5,192,741, U.S. 5,192,741, U.S. 4,668,506, U.S. 4,713,244, U.S. 5,445,832 U.S. 4,931,279, U.S.
`5,980,945, WO 02/058672, WO 9726015, WO 97/04744, and. US20020019446. In such
`sustained release formulations microparticles (Delie and Blanco-Prieto 2005 Molecule 10:65-80)
`ofpeptide are combined with microparticles of polymer. One or more sustainedrelease implants
`can beplaced in the large intestine, the small intestine or both. U.S. 6,011,011 and WO
`94/06452 describe a sustained release formulation providing either polyethylene glycols (i.e.
`PEG 300 and PEG 400)ortriacetin. WO 03/053401 describes a formulation which may both
`enhance bioavailability and provide controlled releaseofthe agent within the GI tract. Additional.
`controlled release formulations are described in WO 02/38129, EP 326 151, U.S. 5,236,704, WO
`02/30398, WO 98/13029; U.S. 20030064105, U.S. 20030138488A1, U.S. 20030216307A1, U.S.
`6,667,060, WO 01/49249, WO 01/49311, WO 01/49249, WO 01/4931, and U.S.5,877,224.
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`The agents can be administered,e.g., by intravenous injection, intramuscular injection,
`
`subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints),
`intradermal, buccal, ophthalmic (including intraocular), intranasaly (including using a cannula),
`intraspinally, intrathecally, or by other routes. The agents can be administeredorally,e.g., as a
`
`tablet or cachet containing a predetermined amountofthe active ingredient, gel, pellet, paste,
`
`syrup, bolus, electuary, slurry, capsule, powder, lyophilized powder, granules, sachet, as a
`solution or a suspension in an aqueousliquid or a non-aqueousliquid, as an oil-in-water liquid
`emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, ¢.g. WO 97/11682)
`via a liposomal formulation(see, e.g., EP 736299,WO 99/59550 and WO 97/13500),via
`
`formulations described in WO 03/094886, via bilosome(bile-salt based vesicular system), via a
`
`dendrimer, or in some other form. Orally administered compositions can include binders,
`lubricants, inert diluents, lubricating, surface active or dispersing agents, flavoring agents, and
`
`humectants. Orally administered formulations suchas tablets may optionally be coated or scored
`
`and may be formulated so as to provide sustained, delayed or controlledreleaseofthe active
`
`ingredient therein. The agents can also be administered transdermally(i.e. via reservoir-type or
`matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis,
`
`electroporation,ultrasound or other forms of sonophoresis, jet injection, or a combination of any
`
`of the preceding methods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:115-124)),
`The agents can be administered using high-velocity transdermalparticle injection techniques
`using the hydrogel particle formulation described in U.S. 20020061336. Additionalparticle
`formulations are described in WO 00/45792, WO 00/53160, and WO 02/19989. An example of
`a transdermal formulation containing plaster and the absorption promoter dimethylisosorbide can
`
`be found in WO 89/04179. WO 96/11705 provides formulations suitable for transdermal
`
`adminisitration. The agents can be administered in the form a suppository or by other vaginal or
`rectal means. The agents can be administered in a transmembrane formulation as described in
`WO90/07923. The agents can be administed non-invasively via the dehydratedparticicles
`described in U.S. 6,485,706. The agent can be administered in an enteric-coated drug
`formulation as described in WO 02/49621. The agents can be administered intranassaly using
`the formulation described in U.S. 5,179,079. Formulations suitable for parenteral injection are
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`described in WO 00/62759, The agents can be administered using the casein formulation
`described in U. S. 20030206939 and WO 00/06108. The agents can be administered using the
`particulate formulations described in U.S. 20020034536.
`
`The agents, alone or in combination with othersuitable components, can be administered by
`pulmonary route utilizing several techniques includingbut not limited to intratracheal instillation
`(delivery of solution into the lungs by syringe), intratracheal delivery ofliposomes,insufflation
`(administration ofpowder formulation by syringe or any other similar device into the lungs) and
`aerosol inhalation, Aerosols (¢.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs),
`and dry-powder inhalers (DPIs)) can also be used in intranasal applications. Aerosol
`formulationsare stable dispersions or suspensionsofsolid material and liquid droplets in a
`gaseous medium and can beplaced into pressurized acceptable propellants, such as
`hydrofluroalkanes (FAs, i.e. HEA-134a and HFA-227,or a mixture thereof),
`dichlorodifluoromethane(or other chlorofluocarbon propellants such as a mixture ofPropellants
`11, 12, and/or 114), propane, nitrogen, and the like. Pulmonary formulations may include
`permeation enhancers suchas fatty acids, saccharides, chelating agents, enzyme inhibitors(e.g.,
`proteaseinhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat),
`preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but
`possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositionsas it can
`improve the function of the metering valve and in some cases also improvethestability ofthe
`dispersion. Pulmonary formulations mayalso include surfactants which include but are not
`limited to bile salts and those described in U.S. 6,524,557 and references therein. The
`surfactants described in U.S. 6,524,557, e.g., a C8-C16 fatty acid salt, a bile salt, a phospholipid,
`or alkyl saccaride are advantageous in that some of them also reportedly enhance absorption of
`the peptide in the formulation. Also suitable in the invention are dry powder formulations
`comprising a therapeutically effective amount of active compound blended with an appropriate
`carrier and adapted for use in connection with a dry-powderinhaler. Absorption enhancers
`which can be added to dry powder formulationsof the present invention include those described
`in U.S. 6,632,456. WO 02/080884 describes new methods for the surface modification of
`
`powders. Aerosol formulations may include U.S. 5,230,884, U.S. 5,292,499, WO 017/8694,
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`WO 01/78696, U.S. 2003019437, U. S. 20030165436, and WO 96/40089 (which includes
`
`vegetable oil). Sustained release formulations suitable for inhalation are described in U.S.
`
`20010036481A1, 20030232019A1, and U.S. 20040018243A1 as well as in WO 01/13891, WO
`
`02/067902, WO 03/072080, and WO 03/079885. Pulmonary formulations containing
`
`microparticles are described in WO 03/015750, U.S. 20030008013, and WO 00/00176.
`
`Pulmonary formulations containing stable glassy state powder are described in U.S.
`
`20020141945 and U.S. 6,309,671. Other aerosol formulations are desribed in EP 1338272A1
`
`WO 90/09781, U.S, 5,348,730, U.S. 6,436,367, WO 91/04011, and U.S.6,294,153 and U.S.
`6,290,987 describes a liposomal based formulation that can be administered via aerosol or other
`means. Powder formulations for inhalation are described in U.S. 20030053960 and WO
`
`01/60341. The agents can be administered intranasally as described in U.S. 20010038824.
`
`The agents can be incorporated into microemulsions, which generally are thermodynamically
`
`stable, isotropically clear dispersions of two immiscible liquids, such as oil and water, stabilized
`
`by an interfacial film of surfactant molecules (Encyclopedia ofPharmaceutical Technology
`
`(New York: Marcel Dekker, 1992), volume 9), For the preparation ofmicroemulsions, surfactant
`
`(emulsifier), co-surfactant (co-emulsifier), an oil phase and a water phase are necessary. Suitable
`
`surfactants include any surfactants that are useful in the preparation of emulsions,e.g.,
`
`emulsifiers that are typically used in the preparation of creams. The co-surfactant (or "co-
`
`emulsifer") is generally selected from the group of polyglycerol derivatives, glycerol derivatives
`
`and fatty alcohols. Preferred emulsifier/co-emulsifier combinations are generally although not
`
`necessarily selected from the group consisting of: glyceryl monostearate and polyoxyethylene
`
`stearate; polyethylene glycol and ethylene glycol palmitostearate; and caprilic and capric
`triglycerides and oleoyl macrogolglycerides. The water phase includes not only water butalso,
`typically, buffers, glucose, propylene glycol, polyethylene glycols, preferably lower molecular
`
`weight polyethylene glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the like, while
`the oil phase will generally comprise, for example,fatty acid esters, modified vegetable oils,
`silicone oils, mixtures of mono- di- andtriglycerides, mono- and di-esters ofPEG (e.g., oleoyl
`
`macrogol glycerides), etc.
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`The agents of the invention can be incorporated into pharmaceutically-acceptable nanoparticle,
`nanosphere, and nanocapsule formulations (Delie and Blanco-Prieto 2005 Molecule 10:65-80).
`Nanocapsules can generally entrap compoundsin a stable and reproducible way (Henry-
`Michelland et al., 1987; Quintanar-Guerrero et al., 1998; Douglaset al., 1987). To avoid side
`effects due to intracellular polymeric overloading,ultrafine particles (sized around 0.1 um) can
`
`be designed using polymers able to be degradedin vivo(e.g. biodegradable polyalkyl-
`cyanoacrylate nanoparticles), Such particles are described in the prior art (Couvreur et al, 1980;
`1988; zur Muhlenet al., 1998; Zambaux et al. 1998; Pinto-Alphandry et al., 1995 and U.S. Pat.
`
`No.5,145,684).
`
`Theagents of the invention can be formulated with pH sensitive materials which mayinclude
`those described in WO04041195 (including the seal and enteric coating described therein) and
`pH-sensitive coatings that achieve delivery in the colon including those described in US4910021
`and W09001329. US4910021 describes using a pH-sensitive material to coat a capsule.
`
`W09001329 describes using pH-sensitive coatings on beads containing acid, where the acid in
`
`the bead core prolongs dissolution of the pH-sensitive coating. U. S. Patent No. 5,175, 003
`discloses a dual mechanism polymer mixture composed of pH-sensitive enteric materials and
`film-formingplasticizers capable of conferring permeability to the enteric material, for use in
`drug-delivery systems; a matrix pellet composed of a dual mechanism polymer mixture
`
`permeated with a drug and sometimes covering a pharmaceutically neutral nucleus; a membrane-
`coated pellet comprising a matrix pellet coated with a dual mechanism polymer mixture
`envelopeofthe same ordifferent composition; and a pharmaceutical dosage form containing
`matrix pellets. The matrix pellet releases acid-soluble drugs by diffusion in acid pH and by
`disintegration at pH levels ofnominally about 5.0 or higher. The agents of the invention may be
`formulated in the pH triggered targeted control release systems described in WO04052339. The
`
`agents of the invention may be formulated according to the methodology described in any of
`
`W003105812 (extruded hyrdratable polymers); WO0243767 (enzyme cleavable membrane
`
`translocators); WO03007913 and WO03086297 (mucoadhesive systems), WO02072075(bilayer
`
`laminated formulation comprising pH lowering agent and absorption enhancer), WO04064769
`(amidated peptides); WO05063156 (solid lipid suspension with pseudotropic and/or thixotropic
`
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`properties upon melting); WO03035029 and WO03035041 (erodible, gastric retentive dosage
`
`forms); US5007790 and U$5972389 (sustained release dosage forms); WO04112711 (oral
`
`extended release compositions); WO05027878, WO002072033, and WO02072034 (delayed
`
`release compositions with natural or synthetic gum); WO005030182 (controlled release
`
`formulations with an ascending rate of release); WO05048998 (microencapsulation system); US
`
`Patent 5,952, 314 (biopolymer); US5108758 (glassy amylose matrix delivery); US 5840860
`
`(modified starch based delivery). JP10324642 (delivery system comprising chitosan and gastric
`resistant material such as wheat gliadin or zein); US5866619 and US6368629 (saccharide
`
`containing polymer); US 6531152 (describes a drug delivery system containing a water soluble
`core (Ca pectinate or other water-insoluble polymers) and outer coat which bursts (eg
`.
`hydrophobic polymer-Eudragrit)); US 6234464; US 6403130 (coating with polymercontaining
`
`casein and high methoxy pectin; WO0174175 (Maillard reaction product); WO05063206
`
`(solubility increasing formulation); WO04019872 (transferring fusion proteins). The agents of
`the invention may be formulated using gastrointestinal retention system technology (GIRES;
`
`Merrion Pharmaceuticals). GIRES comprises a controlled-release dosage form inside an
`
`inflatable pouch, which is placed in a drug capsule for oral administration. Upon dissolution of
`
`the capsule, a gas-generating system inflates the pouch in the stomach whereit is retained for 16-
`
`24 hours,all the time releasing agents of the invention.
`
`The agents of the invention can be formulated in an osmotic device including the ones disclosed
`
`in US4503030, US5609590 and US5358502. US4503030 discloses an osmotic device for
`
`dispensing a drug to certain pH regionsof the gastrointestinal tract. More particularly, the-
`
`invention relates to an osmotic device comprising a wall formed of a semi-permeable pH
`sensitive composition that surrounds a compartment containing a drug, with a passageway
`
`through the wall connecting the exterior of the device with the compartment. The device delivers
`
`the drug at a controlled rate in the region of the gastrointestinal tract having a pH ofless than 3.5,.
`
`and the device self- destructs and releases all its drug in the region of the gastrointestinal tract
`
`having a pH greater than 3.5, thereby providingtotal availability for drug absorption.U.S.
`
`Patent Nos. 5,609, 590 and 5, 358,502 disclose.an osmotic bursting device for dispensing a
`
`beneficial agent to an aqueous environment. The device comprises a beneficial agent and
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`osmagent surrounded at least in part by a semi-permeable membrane. The beneficial agent may
`also function as the osmagent. The semi-permeable membrane is permeable to water and
`substantially impermeable to the beneficial agent and osmagent. A trigger meansis attached to
`
`the semi-permeable membrane(e. g. , joins two capsule halves). The trigger meansis activated
`
`by a pH offrom 3 to 9 andtriggers the eventual, but sudden, delivery of the beneficial agent.
`
`These devices enable the pH-iriggered release of the beneficial agent core as a bolus by osmotic
`
`bursting.
`The agents ofthe invention may be formulatedbased on the invention described in U. S. Patent
`No. 5,316, 774 which discloses a composition for the controlled release of an active substance
`
`comprising a polymeric particle matrix, where each particle defines a network of internal pores.
`
`The active substance is entrapped within the pore network together with a blocking agent having
`
`physical and chemical characteristics selected to modify the release rate of the active substance
`
`from the internal pore network. In one embodiment, drugs may be selectively delivered to the
`
`intestines using an enteric material as the blocking agent. The enteric material remains intact in
`
`the stomach but degrades under the pH conditionsofthe intestines. In another embodiment, the
`
`sustained release formulation employs a blocking agent, which remains stable under the expected
`
`conditions of the environment to which the active substance is to be released. The use ofpH-
`
`sensitive materials alone to achieve site-specific delivery is difficult because of leaking ofthe
`
`beneficial agent prior to the release site or desired delivery timeandit is difficult to achieve long
`
`time lags before release of the active ingredient after exposure to high pH (because ofrapid
`dissolution or degradation ofthe pH-sensitive materials).
`
`The agents may also be formulated in a hybrid system which combines pH-sensitive materials
`
`and osmotic delivery systems. These hybrid devices provide delayedinitiation of sustained-
`
`release of the beneficial agent. In one device a pH-sensitive matrix or coating dissolves releasing
`
`osmotic devices that provide sustained release of the beneficial agent see U. S. Patent Nos.
`
`4,578, 075, 4,681, 583, and 4,851, 231. A second device consists of a semipermeable coating
`
`made of a polymerblend of aninsoluble and a pH-sensitive material. As the pH increases, the
`
`permeability of the coating increases, increasingtherate of release of beneficial agent see U.S.
`
`Patent Nos. 4,096, 238,4, 503,030, 4, 522, 625, and 4,587, 117,
`
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`The agents of the invention may bef formulated in terpolumers according to U. S. Patent No.
`5,484, 610 which discloses terpolymers whichare sensitive to pH and temperature whichare
`
`useful carriers for conducting bioactive agents through the gastric juices of the stomach in a
`
`protected form. The terpolymers swell at the higher physiologic pH of the intestinal tract causing
`
`release of the bioactive agents into the intestine. The terpolymers are linear and are made up of
`
`35 to 99 wt % of a temperature sensitive component, which imparts to the terpolymer LCST
`
`(lower critical solution temperature) properties below body temperatures, 1 to 30 wt % of a pH
`
`sensitive component having a pKa in the range of from 2 to 8 which functions through ionization
`
`or deionization of carboxylic acid groups to prevent the bioactive agent from beinglost at low
`
`pH butallows bioactive agent release at physiological pH of about 7.4 and a hydrophobic
`component whichstabilizes the LCST below body temperatures and compensatesfor bioactive
`agent effects on the terpolymers. The terpolymers provide for safe bioactive agent loading, a»
`
`simple procedure for dosage form fabrication and the terpolymerfunctions as a protective carrier
`
`in the acidic environment of the stomach and also protects the bioactive agents from digestive
`
`enzymesuntil the bioactive agent is released in the intestinaltract.
`
`The agents of the invention may be formulated in pH sensitive polymers according to those
`
`described in U. S. Patent No. 6,103, 865. U.S. Patent No. 6,103, 865 discloses pH-sensitive
`
`polymers containing sulfonamide groups, which can be changedin physical properties, such as
`
`swellability and solubility, depending on pH and which can be applied for a drug-delivery
`
`system, bio-material, sensor, and thelike, and a preparation method therefore. The pH-sensitive
`
`polymers are prepared by introduction of sulfonamide groups, various in pKa, to hydrophilic
`
`groups of polymers either through coupling to the hydrophilic groups of polymers, such as °
`
`acrylamide, N, N- dimethylacrylamide, acrylic acid, N-isopropylacrylamide andthelike or
`
`copolymerization with other polymerizable monomers. These pH-sensitive polymers may have a
`structure of linear polymer, grafted copolymer, hydrogel or interpenetrating network polymer.
`
`The agents of the invention may be formulated according U. S. Patent No. 5, 656, 292 which
`discloses a composition for pH dependent or pH regulated controlled release of active
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`ingredients especially drugs. The composition consists of a compactable mixture ofthe active
`
`ingredient and starch molecules substituted with acetate and dicarboxylate residues. The
`
`preferred dicarboxylate acid is succinate. The average substitution degree ofthe acetate residue
`
`is at least 1 and 0. 2-1. 2 for the dicarboxylate residue. The starch molecules can havethe acetate -
`
`and dicarboxylate residues attached to the same starch molecule backboneorattached to separate
`
`starch molecule backbones. The present invention also discloses methods for preparing said
`
`starch acetate dicarboxylates by transesterification or mixing of starch acetates and starch
`
`dicarboxylates respectively.
`
`The agents. of the invention may be formulated according to the methods described in U. 8S.
`Patent Nos: 5,554, 147,5, 788, 687, and 6,306, 422 which disclose a methodfor the controlled
`
`release of 2 biologically active agent wherein the agent is released from a hydrophobic, pH-
`
`sensitive polymer matrix. The polymer matrix swells when the environment reaches pH 8.5,
`
`releasing the active agent. A polymer of hydrophobic and weakly acidic comonomersis
`
`disclosed for use in the controlled release system. Also disclosed is a specific embodiment in
`
`which the controlled release system may be used. The pH-sensitive polymer is coated onto a
`
`latex catheter used in ureteral catheterization. A ureteral catheter coated with a pH-sensitive
`
`polymer having an antibiotic or urease inhibitor trapped within its matrix will release the active
`
`agent when exposed to high pH urine.
`
`The agents of the invention may be formulated in/with bioadhesive polymers according to US
`
`Patent No. 6,365, 187. Bioadhesive polymersin the form of, or as a coating on, microcapsules
`
`containing drugs or bioactive substances which mayserve for therapeutic, or diagnostic purposes
`
`in diseases of the gastrointestinal tract, are described in US6365187. The polymeric
`microspheresall have a bioadhesive force ofat least 11 mN/cm? (110 N/m2) Techniques for the
`fabrication of bioadhesive microspheres, as well as a method for measuring bioadhesive forces
`
`between microspheres and selected segments of the gastrointestinal tract in vitro are also
`described. This quantitative method provides a means to establish a correlation between the
`
`chemical nature, the surface morphology and the dimensions of drug-loaded microspheres on
`
`one hand and bioadhesive forces on the other, allowing the screening of the most promising
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`materials from a relatively large group of natural and synthetic polymers which, from theoretical
`consideration, should be used for making bioadhesive microspheres. Solutions of medicament in
`
`buffered saline and similar vehicles are commonly employed to generate an aerosol in a
`
`nebulizer. Simple nebulizers operate on Bernoulli’s principle and employ a stream ofair or
`oxygen to generate the spray particles. More complex nebulizers employ ultrasoundto create the
`spray particles. Both types are well known in the art and are described in standard textbooks of
`pharmacy such as Sprowls’ American Pharmacy.and Remington’s The Science and Practice of
`Pharmacy. Other devices for generating aerosols employ compressed gases, usually
`' hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any
`necessary excipients in a pressurized container, these devices are likewise described in standard
`
`textbooks such as Sprowls and Remington.
`
`The agents can be a free acid or base, or a pharmacologically acceptable salt thereof, Solids can
`be dissolved ordispersed immediately prior to administration or earlier. In some circumstances
`the preparations include a preservative to prevent the growth of microorganisms. The
`pharmaceutical formssuitable for injection can include sterile aqueous or organic solutions or
`dispersions which include, e.g., water, an alcohol, an organic solvent, an oil or other solvent or
`dispersant(e.g, glycerol, propylene glycol, polyethylene glycol, and vegetable oils). The
`formulations may contain antioxidants, buffers, bacteriostats, and solutes that render the
`formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous
`
`sterile suspensions that can include suspending agents, solubilizers, thickening agents,
`stabilizers, and preservatives. Pharmaceutical agentscan besterilized by filter sterilization or by
`othersuitable means. The agent can be fused to immunoglobulins or albumin, or incorporated
`into a lipsome to improve half-life. The agent can also be conjugated to polyethylene glycol
`(PEG)chains. Methods for pegylation and additional formulations containing PEG-conjugates
`(i.e, PEG-based hydrogels, PEG modified liposomes) can be found in Harris and Chess, Nature
`Reviews Drug Discovery 2: 214-221 and the references therein. Peptides can also be modified
`with allyl groups(e.g., C1-C20 straight or branched alkyl groups); fatty acid radicals; and
`combinations ofPEG,alkyl groups and fatty acid radicals (see U.S. Patent 6,309,633; Soltero et
`al., 2001 Innovations in Pharmaceutical Technology 106-110). The agent can be administered
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`via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International), The
`
`agents can be delivered transmucosally(i.e, across a mucosal surface such as the vagina, eye or
`nose) using formulations such as that described in U.S. 5,204,108. The agents can be formulated
`in microcapsulesas described in WO 88/01165. The agent can be administered intra-orally
`using the formulations described in U.S. 20020055496, WO 00/47203, and U.S. 6,495,120, The
`
`agent can be delivered using nanoemulsion formulations described in WO 01/91728A2.
`
`Controlled release formulations
`
`In general, one can provide for controlled release of the agents described herein through the use
`of a wide variety ofpolymeric carriers and controlled release systems including erodible and
`non-erodible matrices, osmotic control devices, various reservoir devices, enteric coatings and
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`multiparticulate control devices.
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`Matrix devices are a commondevice for controlling the release of various agents. In such
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`devices, the agents described herein are generally present as a dispersion within the polymer
`matrix, and are typically formed by the compression of a polymer/drug mixture or by dissolution
`or melting. The dosagerelease properties ofthese devices may be dependent uponthe solubility
`of the agent in the polymer matrix or, in the case of porous matrices, the solubility in the sink
`solution within the pore network, and the tortuosity of the network. In one instance, when
`utilizing an erodible polymeric matrix, the matrix imbibes water and forms an aqueous-swollen
`gel that entraps the agent. The matrix then gradually erodes, swells, disintegrates or dissolves in
`' the GItract, thereby controlling release of one or more ofthe agents described herein. In non-
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`erodible devices, the agent is released by diffusion through an inert matrix.
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`Agents described herein can be incorporatedinto an erodible or non-erodible polymeric matrix
`controlled release device. By an erodible matrix is meant aqueous-erodible or water-swellable or
`aqueous-soluble in the sense of being either erodible or swellable or dissolvable in pure water or
`requiring the presence of an acid or base to ionize the polymeric matrix sufficiently to cause
`erosion or dissolution. When contacted with the aqueous environmentof use, the erodible
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`agent described herein. The aqueous-swollen matrix gradually erodes, swells, disintegrates or
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`dissolves in the environmentof use, thereby controlling the release of a compound described
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`herein to the environmentof use.
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`The erodible polymeric matrix into which an agent described herein can be incorporated may
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`generally be described as a set of excipients that-are mixed with the agent following its formation
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`that, when contacted with the aqueous environmentof use imbibes water and forms a water-
`swollen gel or matrix that entraps the drug form. Drug release may occur by a variety of
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`mechanisms, for example, the matrix may disintegrate or dissolve from around particles or
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`granules of the agent or the agent may dissolve in the imbibed aqueoussolution and diffuse from
`the tablet, beads or granules ofthe device. One ingredient of this water-swollen matrix is the
`water-swellable, erodible, or soluble polymer, which may generally be described as an
`osmopolymer, hydrogel or water-swellable polymer. Such polymers may be linear, branched, or
`crosslinked. The polymers may be homopolymers or copolymers. In certain embodiments, they
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`may be synthetic polymers derived from vinyl, acrylate, methacrylate, urethane, ester and oxide
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`monomers. In other embodiments, they can be derivatives of naturally occurring polymers such
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`as polysaccharides(e.g. chitin, chitosan, dextran and pullulan; gum agar, gum arabic, gum
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`karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum and
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`scleroglucan), starches(e.g. dextrin and maltodextrin), hydrophilic colloids (e.g. pectin),
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`phosphatides(e.g. lecithin), alginates (e.g. ammonium alginate, sodium, potassium or calcium
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`alginate, propylene glycolalginate), gelatin, collagen, and cellulosics. Cellulosics are cellulose
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`polymerthat has been modified by reactionof at least a portion of the hydroxyl groups on the
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`saccharide repeat units with a compoundto form an ester-linked or an ether-linked substituent.
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`For example, the cellulosic ethyl cellulose has an ether linked ethyl substituent attached to the
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`saccharide repeat unit, while the cellulosic cellulose acetate has an ester linked acetate
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`substituent. In certain embodiments, the cellulosics for the erodible matrix comprises aqueous-
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`soluble and aqueous-erodible cellulosics can include, for example, ethyl cellulose (EC),
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`methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose
`(HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP),
`cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl
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`cellulose (HPMC), HPMCP, HPMCAS,hydroxypropyl methyl cellulose acetate trimellitate
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`(HPMCAT), and ethylhydroxy ethylcellulose (EHEC), In certain embodiments, the cellulosics
`comprises various grades of low viscosity (MW less than or equal to 50,000 daltons, for
`example, the Dow Methocel™series E5, BISLV, ESOLV and K100LY)and high viscosity (MW
`greater than 50,000 daltons, for example, E4MCR, ELOMCR, K4M, K15M and K100M andthe
`Methocel™ K series) HPMC.Other commercially available types ofHPMC includethe Shin
`Etsu Metolose 90SHseries,
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`The choice ofmatrix material can have a large effect on the maximum drug concentration
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`attained by the device as well as the maintenance of a high drug concentration. The matrix
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`material can be a concentration-enhancing polymer, for example, as described in WO05/011634.
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`Other materials useful as the erodible matrix material include, but are not limited to, pullulan,
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`polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters,
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`polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid
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`(EUDRAGITO,Rohm America, Inc., Piscataway, New Jersey) and other acrylic acid derivatives
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`such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate,
`ethylme