Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• Controlled release systems for drug delivery are often designed to administer drugs in specific areas of the body. In the case of drug delivery to or via the gastrointestinal tract, it is critical that the drug not be delivered substantially beyond the desired site of action or absorption, respectively, before it has had a chance to exert a topical effect or to pass into the bloodstream.
• a drug delivery system that adheres to the lining of the appropriate viscus, will deliver its contents to the targeted tissue as a function of proximity and duration of contact.
• An orally ingested product can adhere to either the epithelial surface or the mucus lining of the gastrointestinal tract.
• a polymeric drug delivery device adhere to the epithelium or to the mucous layer.
• Bioadhesion in the gastrointestinal tract proceeds in two stages: (1) viscoelastic deformation at the point of contact of the synthetic material into the mucus substrate, and (2) formation of bonds between the adhesive synthetic material and the mucus or the epithelial cells.
• adhesion of polymers to tissues may be achieved by (i) physical or mechanical bonds, (H) primary or covalent chemical bonds, and/or (iii) secondary chemical bonds (i.e., ionic).
• Physical or mechanical bonds can result from deposition and inclusion of the adhesive material in the crevices of the mucus or the folds of the mucosa.
• Secondary chemical bonds, contributing to bioadhesive properties, consist of dispersive interactions (i.e., Van der Waals interactions) and stronger specific interactions, which include hydrogen bonds.
• the hydrophilic functional groups primarily responsible for forming hydrogen bonds are the hydroxyl and the carboxylic acid groups.
• larger oral formulations such as tablets with the ability to adequately adhere to the gastrointestinal tract mucosa are not known.
• the larger oral formulations differ from microparticles in that dosage forms such as tablets, capsules and drug-eluting devices cannot enter into an invagination in the mucosa, whereas microparticles are generally small enough to fit into an invagination.
• larger oral formulations contact a smaller surface area of the gastrointestinal tract (particularly as a function of the ratio of contact surface area to volume of the formulation), which is expected to weaken the interaction between the larger formulation and the gastrointestinal tract.
• the present invention provides pharmaceutical dosage forms for oral delivery of a drug, comprising a drug to be delivered gastrointestinally, and a bioadhesive polymeric coating applied to at least a fraction of one surface of the dosage form.
• the coating provides the dosage form with a fracture strength of at least 100 N/m 2 as measured on rat intestine, and the dosage form has a gastrointestinal retention time of at least 4 hours in a fed beagle dog model during which the drug is released from the dosage form.
• the present invention is a tablet for oral delivery of a drug, comprising a core including a drug to be delivered gastrointestinally, and a bioadhesive polymeric coating applied to at least one surface of the tablet.
• the coating provides the tablet with a fracture strength of at least 100 N/m 2 as measured on rat intestine, and the tablet has a gastrointestinal retention time of at least 4 hours in a fed beagle dog model during which the drug is released from the tablet.
• the bioadhesive polymer coating further includes metal compounds, low molecular weight oligomers or a combination thereof that enhance the mucosal adhesion of the synthetic polymer coating.
• the bioadhesive polymeric coating does not substantially swell upon hydration.
• the present invention is a tablet for oral delivery of a drug, comprising a core including a drug to be delivered gastrointestinally, and a bioadhesive polymeric coating applied to at least one surface of the tablet.
• the coating provides the tablet with a fracture strength of at least 100 N/m 2 as measured on rat intestine, and the tablet has a gastrointestinal retention time of at least 3 hours in a fasted beagle dog model (see Example 1) during which the drug is released from the tablet.
• the bioadhesive polymer coating further includes metal compounds, low molecular weight oligomers or a combination thereof that enhance the mucosal adhesion of the synthetic polymer coating.
• the bioadhesive polymeric coating does not substantially swell upon hydration.
• the invention is a drug-eluting device for oral delivery of a drug, which includes a reservoir having a drug-containing core contained therein, one or more orifices or exit ports through which drug from the core can elute from the device, and a bioadhesive polymeric coating, applied to at least one surface of the device.
• the coating provides the device with a fracture strength of at least 100 N/m 2 as measured on rat intestine, and the device has a gastrointestinal retention time of at least 3 hours in a fasted beagle dog model during which the drug is released from the device.
• the bioadhesive polymeric coating does not substantially swell upon hydration.
• the invention is a drug-eluting device for oral delivery of a drug, which includes a reservoir having a drug-containing core contained therein, one or more orifices or exit ports through which drug from the core can elute from the device, and a bioadhesive polymeric coating, applied to at least one surface of the device.
• the coating provides the device with a fracture strength of at least 100 N/m 2 as measured on rat intestine, and the device has a gastrointestinal retention time of at least 4 hours in a fed beagle dog model during which the drug is released from the device.
• the bioadhesive polymeric coating does not substantially swell upon hydration.
• the present invention provides methods for improving the bioadhesive properties of drug delivery systems such as tablets, capsules and drug-eluting devices.
• the invention also provides methods for improving the adhesion of drug delivery systems to mucosal membranes including membranes of the gastrointestinal tract.
• the polymeric drug delivery systems of the invention have an improved ability to bind to mucosal membranes, and thus can be used to deliver a wide range of drugs or diagnostic agents in a wide variety of therapeutic applications, and/or improve uptake of the active agent across the intestinal mucosa.
• the drug delivery system comprises particles ranging in size from 0.1-10 ⁇ m.
• Bioadhesive dosage forms of the invention generally have the advantages, inter alia, of allowing for decreasing dosage levels and/or dosing frequencies of drugs.
• the bioadhesive and/or mucoadhesive systems for the local and sustained delivery of therapeutic agents allow for more efficient targeting of drugs to the required sites on the luminal surface of the gastrointestinal tract.
• dosage level and/or dosing frequencies several potential problems relating to antimicrobial agents may be reduced or avoided altogether, such as gastrointestinal irritation in some patients.
• Reduction of dosage level and/or dosing frequencies can also reduce or avoid disturbances of the normal enteric flora, which are caused by certain drugs, that may lead to drug-resistant bacterial enteritis or bacterial super-infection.
• the potential reduction in side effects and the overall ease of administration should greatly increase patient compliance, is expected to further improve the therapeutic outcome
• the present invention is an orally administrable, multi ⁇ layer, pharmaceutical tablet having an inner and one or more outer layers, each comprising a drug (e.g., a drug including a valproic moiety such as sodium valproate, divalproex sodium, valproic acid, etc.) admixed with one or more excipients. At least one of the excipients is hydrophobic, although such excipient is not required in each layer. Additional outer layers (i.e., layers other than the inner and outer layers specified above) are optionally free of the drug.
• a drug e.g., a drug including a valproic moiety such as sodium valproate, divalproex sodium, valproic acid, etc.
• excipients At least one of the excipients is hydrophobic, although such excipient is not required in each layer.
• Additional outer layers i.e., layers other than the inner and outer layers specified above) are optionally free of the drug.
• FIG. 1 is an illustration of a trilayer tablet with a bioadhesive coating.
• FIGS. 2A-2D show that the trilayer tablets described in Example 1 were retained in the stomach of beagle dogs at A) 2.5 hours (fasted animal and tablet with SpheromerTM III, a poly(butadiene-co-maleic acid) functionalized with DOPA, outer layers), B) 3.5 hours (fasted animal and tablet with SpheromerTM III outer layers), C) 5.25 hours (fed animal and tablet with SpheromerTM I, poly(fumaric-co-sebacic anhydride 20:80), outer layers) and D) 6 hours (fed animal and tablet with SpheromerTM I outer layers).
• FIG. 3 shows the pharmacokinetics of the 5-layer tablet in fed beagle dogs, as described in Example 2.
• FIGS. 4A and 4B show the release profile of sodium valproate from the tablets prepared in Example 3.
• FIG. 6 shows the release profile of levodopa from the tablet prepared in
• FIG. 7 shows the effect of repeat dosing of the trilayer tablet of Example 5 (400 mg acyclovir, administered once per 12 hrs, 2 administrations) compared to Zovirax® (200 mg, administered once per 6 hrs, 4 administrations) in 6 dogs.
• FIG. 8 shows the release profile of itraconazole from the tablet prepared in
• FIG. 9 shows the plasma levels of itraconazole following administration of tablets of Example 6 and Sporanox ® to beagle dogs in the fed state, as measured using
• FIG. 10 is a bar graph showing the fracture strength of bonds (mN/cm 2 ) formed with the bioadhesive materials, SpheromerTM II and SpheromerTM III, as compared to Carbopol 934P and Gantrez AN polymers and control (uncoated substrate).
• FIG. 11 is a bar graph of the tensile work (nJ) required to rupture the bonds formed with the bioadhesive materials, SpheromerTM II and SpheromerTM III, as compared to Carbopol 934P and Gantrez AN polymers and control (uncoated substrate).
• the present invention is directed to pharmaceutical dosage forms (e.g., tablets and drug-eluting devices) having increased gastrointestinal retention time.
• gastrointestinal residence time is the time required for a pharmaceutical dosage form (e.g., tablet or drug-eluting device) to transit through the stomach to the pyloric sphincter.
• a pharmaceutical dosage form (e.g., tablet or drug-eluting device) of the invention has a gastrointestinal residence time of at least 3 hours, at least 4 hours, at least 6 hours, at least 8 hours, or at least 12 hours. This time can be measured in either a fed or a fasted state, typically a fed state.
• the pharmaceutical dosage forms (e.g., tablets and drug-eluting devices) of the invention may also have an increased retention time in the small and/or large intestine, or in the area of the gastrointestinal tract that absorbs the drug contained in the pharmaceutical dosage form (e.g., tablet or drug-eluting device).
• pharmaceutical dosage forms (e.g., tablets or drug-eluting devices) of the invention can be retained in the small intestine (or one or two portions thereof, selected from the duodenum, the jejunum and the ileum) for at least 6 hours, at least 8 hours or at least 12 hours, such as from 16 to 18 hours.
• the increased gastrointestinal residence time may not be applicable, as the bioadhesive may not be exposed until the dosage form enters the small intestine or lower.
• These pharmaceutical dosage forms e.g., tablets and drug-eluting devices, as a whole, include a bioadhesive polymeric coating that is applied to at least one surface of the dosage form.
• Bioadhesion is defined as the ability of a material to adhere to a biological tissue for an extended period of time. Bioadhesion is one solution to the problem of inadequate residence time resulting from stomach emptying and intestinal peristalsis, and from displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate contact must exist between the bioadhesive and the receptor tissue, the bioadhesive must penetrate into the crevice of the tissue surface and/or mucus, and mechanical, electrostatic, or chemical bonds must form. Bioadhesive properties of polymers are affected by both the nature of the polymer and by the nature of the surrounding media.
• bioadhesive delivery system of the invention is for the local delivery of antimicrobial and acid lowering agents to eradicate Helicobacter pylori. Eradication of H. pylori not only cures both the gastric and duodenal ulcers but also has the potential to prevent a substantial proportion of gastric adenocarcinoma and lymphomas.
• one or more therapeutic agents including acid suppressants (ranitidine bismuth citrate, lansoprazole), mucosal defense enhancing agent (bismuth salts) and/or mucolytic agents (megaldrate) are incorporated in the bioadhesive delivery system and then administered to patients with or at risk of H. pylori infection or ulcers.
• the bioadhesive formulation includes a multi ⁇ layer core enveloped by a bioadhesive coating.
• Nos.6, 197,346, 6,217,908 and 6,365,187 include soluble and insoluble, biodegradable and nonbiodegradable polymers. These can be hydrogels or thermoplastics, homopolymers, copolymers or blends, and/or natural or synthetic polymers.
• the preferred polymers are synthetic polymers, with controlled synthesis and degradation characteristics. Particularly preferred polymers are anhydride copolymers of fumaric acid and sebacic acid (P(FA:SA)), which have exceptionally good bioadhesive properties when administered to the gastrointestinal tract.
• P(FA: SA) copolymers examples include those having a 1:99 to 99:1 ratio of fumaric acid to sebacic acid, such as 5:95 to 75:25, for example, 10:90 to 60:40 or at least 15:85 to 25:75. Specific examples of such copolymers have a 20:80 or a 50:50 ratio of fumaric acid to sebacic acid.
• Bioadhesive pharmaceutical dosage forms e.g., tablets and drug-eluting devices
• produce a bioadhesive interaction (fracture strength) of at least 100 N/m 2 (10 mN/cm 2 ) when applied to the mucosal surface of rat intestine.
• the fracture strength of the pharmaceutical dosage forms e.g., tablets and drug-eluting devices
• the fracture strength of a polymer-containing pharmaceutical dosage form e.g., tablet or drug-eluting device
• the forces described herein refer to measurements made upon rat intestinal mucosa, unless otherwise stated.
• the same adhesive measurements made on other species of animal may differ from those obtained using rats. This difference is attributed to both compositional and geometrical variations in the mucous layers of different animal species as well as cellular variations in the mucosal epithelium.
• P(FA:SA) produces stronger adhesions than polylactic acid (PLA) in rats, sheep, pigs, etc.
• the fracture strength of pharmaceutical dosage forms (e.g., tablets and drug-eluting devices) of the invention on rat intestine is generally at least 125 N/m 2 , such as at least 150 N/m 2 , at least 250 N/m 2 , at least 500 N/m 2 or at least 1000 N/m 2 .
• the fracture strength of a pharmaceutical dosage form can be measured according to the methods disclosed by Duchene et al. Briefly, the tablet is attached on one side to a tensile tester and is contacted with a testing surface (e.g., a mucosal membrane, such as rat or pig intestine) on the opposite surface.
• the tensile tester measures the force required to displace the pharmaceutical dosage form (e.g., tablet or drug-eluting device) from the testing surface.
• Common tensile testers include a Texture Analyzer and the Instron tensile tester.
• tablets are pressed using flat- faced tooling, 0.3750" (9.525 mm) in diameter. Tablet weight will depend on composition; in most cases, the tablets have a final weight of 200 mg. These tablets are then glued to a plastic 10 mm diameter probe using a common, fast-drying cyanoacrylate adhesive. Once the tablets are firmly adhered to the probe, the probe is attached to the Texture Analyzer. The Texture Analyzer is fitted with a 1 kg load cell for maximum sensitivity. The following settings are used:
• Test and Post-Test Speeds are advantageously as low as the instrument permits, in order to allow capture of a maximum number of data points.
• the Pre-Test speed is used only until the probe encounters the Trigger Force; i.e., prior to contacting the tissue.
• the Proportional, Integral, and Differential Gain are set to 0. These settings, when optimized, maintain the system at the Applied Force for the duration of the Contact Time. With soft tissue as a substrate, however, the probe and tablet are constantly driven into the deformable surface. This results in visible damage to the tissue. Thus, the probe and tablet are allowed to relax gradually from the Applied Force by setting these parameters to 0. The tracking speed, which is a measure of how rapidly the feedback is adjusted, is also set to 0.
• the tissue on which the tablets are tested is secured in the Mucoadhesive Rig; the rig is then completely immersed in a 600 mL Pyrex beaker containing 375 mL of PBS. The tissue is maintained at approximately 37 °C for the duration of the test; no stirring is used as the machine can detect the oscillations from the stir bar.
• Gurney et ah Biomaterials, 5:336-340 (1984) report that adhesion maybe affected by physical or mechanical bonds; secondary chemical bonds; and/or primary, ionic or covalent bonds.
• Park et ah "Alternative Approaches to Oral Controlled Drug Delivery: Bioadhesives and In-Situ Systems," in J. M. Anderson and S. W. Kim, Eds., "Recent Advances in Drug Delivery,” Plenum Press, New York, 1984, pp. 163-183, report a study of the use of fluorescent probes in cells to determine adhesiveness of polymers to mucin/epithelial surface, which indicates that anionic polymers with high charge density appear to be preferred as adhesive polymers.
• Mikos et ah in J. Colloid Interface ScL, 143:366-373 (1991) and Lehr et ah, J. Controlled ReI. Soc, 13:51-62 (1990) report a study of the bioadhesive properties of polyanhydrides and polyacrylic acid, respectively, in drug delivery.
• hydrophilic polymers In the past, two classes of polymers have shown useful bioadhesive properties, hydrophilic polymers and hydro gels.
• carboxylic groups e.g., poly[ acrylic acid]
• polymers with the highest concentrations of carboxylic groups are preferred materials for bioadhesion on soft tissues.
• the most promising polymers were sodium alginate, carboxymethylcellulose, hydroxymethylcellulose and methylcellulose. Some of these materials are water- soluble, while others are hydrogels.
• Rapidly bioerodible polymers such as poly[lactide-co-glycolide], polyanhydrides, and polyorthoesters, whose carboxylic groups are exposed on the external surface as their smooth surface erodes, are particularly suitable for bioadhesive drug delivery systems.
• polymers containing labile bonds such as polyanhydrides and polyesters, are well known for their hydrolytic reactivity. Their hydrolytic degradation rates can generally be altered by simple changes in the polymer backbone.
• Representative natural polymers suitable for the present invention include proteins (e.g., hydrophilic proteins), such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and polysaccharides such as cellulose, dextrans, polyhyaluronic acid, polymers of acrylic and methacrylic esters and alginic acid. These are generally less suitable for use in bioadhesive coatings due to higher levels of variability in the characteristics of the final products, as well as in degradation following administration.
• Synthetically modified natural polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocelluloses.
• Representative synthetic polymers for use in bioadhesive coatings include polyphosphazines, poly( vinyl alcohols), polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof.
• polymers suitable for use in the invention include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene
• bioerodible polymers for use in bioadhesive coatings include polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide-co- glycolide], polyanhydrides (e.g., poly(adipic anhydride)), polyorthoesters, blends and copolymers thereof.
• Polyanhydrides are particularly suitable for use in bioadhesive delivery systems because, as hydrolysis proceeds, causing surface erosion, more and more carboxylic groups are exposed to the external surface.
• polylactides erode more slowly by bulk erosion, which is advantageous in applications where it is desirable to retain the bioadhesive coating for longer durations.
• polymers that have high concentrations of carboxylic acid are preferred.
• the high concentrations of carboxylic acids can be attained by using low molecular weight polymers (MW of 2000 or less), because low molecular weight polymers contain a high concentration of carboxylic acids at the end groups.
• the polymers listed above can be obtained from sources such as Sigma Chemical Co., St. Louis, Mo., Polysciences, Warrenton, Pa., Aldrich, Milwaukee, Wis., Fluka, Ronkonkoma, N.Y., and BioRad, Richmond, Calif., or can alternatively be synthesized from monomers obtained from these suppliers using standard techniques.
• the synthetic polymer is typically selected from polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers of thereof.
• the synthetic polymer is poly(fumaric-co-sebacic) anhydride.
• Another group of polymers suitable for use as bioadhesive polymeric coatings are polymers having a hydrophobic backbone with at least one hydrophobic group pendant from the backbone. Suitable hydrophobic groups are groups that are generally non-polar. Examples of such hydrophobic groups include alkyl, alkenyl and alkynyl groups. Preferably, the hydrophobic groups are selected to not interfere and instead to enhance the bioadhesiveness of the polymers.
• a further group of polymers suitable for use as bioadhesive polymeric coatings are polymers having a hydrophobic backbone with at least one hydrophilic group pendant from the backbone.
• Suitable hydrophilic groups include groups that are capable of hydrogen bonding or electrostatically bonding to another functional group.
• Example of such hydrophilic groups include negatively charged groups such as carboxylic acids, sulfonic acids and phosponic acids, positively charged groups such as (protonated) amines and neutral, polar groups such as amides and imines.
• the hydrophilic groups are selected to not interfere and instead to enhance the bioadhesiveness of the polymers.
• the hydrophilic groups can be either directly attached to a hydrophobic polymer backbone or attached through a spacer group.
• a spacer group is an alkylene group, particularly a C 1 -C 8 alkyl group such as a C 2 -C 6 alkyl group.
• Preferred compounds containing one or more hydrophilic groups include amino acids (e.g., phenyalanine, tyrosine and derivatives thereof) and amine-containing carbohydrates (sugars) such as glucosamine.
• Polymers can be modified by increasing the number of carboxylic groups accessible during biodegradation, or on the polymer surface.
• the polymers can also be modified by binding amino groups to the polymer.
• the polymers can be modified using any of a number of different coupling chemistries available in the art to covalently attach ligand molecules with bioadhesive properties to the surface-exposed molecules of the polymeric microspheres.
• Lectins can be covalently attached to polymers to render them target specific to the mucin and mucosal cell layer.
• Useful lectin ligands include lectins isolated from: Abrus precatroius, Agaricus bisporus, Anguilla anguilla, Arachis hypogaea, Pandeiraea simplicifolia, Bauhinia purpurea, Caragan arobrescens, Cicer arietinum, Codium fragile, Datura stramonium, Dolichos biflorus, Erythrina corallodendron, Erythrina cristagalli, Euonymus europaeus, Glycine max, Helix aspersa, Helix pomatia, Lathyrus odoratus, Lens culinaris, Limulus polyphemus, Lysopersicon esculentum, Madura pomifera, Momordica charantia, Mycoplasma gallisepticum
• any positively charged ligand such as polyethyleneimine or polylysine
• a polymer may improve bioadhesion due to the electrostatic attraction of the cationic groups coating the beads to the net negative charge of the mucus.
• Any ligand with a high binding affinity for mucin could also be covalently linked to most polymers with the appropriate chemistry, such as with carbodiimidazole (CDI), and be expected to influence the binding to the gut.
• CDI carbodiimidazole
• polyclonal antibodies raised against components of mucin or else intact mucin, when covalently coupled to a polymer, would provide for increased bioadhesion.
• antibodies directed against specific cell surface receptors exposed on the lumenal surface of the intestinal tract would increase the residence time when coupled to polymers using the appropriate chemistry.
• the ligand affinity need not be based only on electrostatic charge, but other useful physical parameters such as solubility in mucin or specific affinity to carbohydrate groups.
• any of the natural components of mucin in either pure or partially purified form to the polymers generally increases the solubility of the polymer in the mucin layer.
• useful ligands include but are not limited to the following: sialic acid, neuraminic acid, n-acetyl-neuraminic acid, n- glycolylneuraminic acid, 4-acetyl-n-acetylneuraminic acid, diacetyl-n- acetylneuraminic acid, glucuronic acid, iduronic acid, galactose, glucose, mannose, fucose, any of the partially purified fractions prepared by chemical treatment of naturally occurring mucin, e.g., mucoproteins, mucopolysaccharides and mucopolysaccharide-protein complexes, and antibodies immunoreactive against proteins or sugar structure on the mucosal surface.
• polyamino acids containing extra pendant carboxylic acid side groups such as polyaspartic acid and polyglutamic acid
• the polyamino chains would increase bioadhesion by means of chain entanglement in mucin strands as well as by increased carboxylic charge.
• polymers such as those named above, having a metal compound incorporated therein have a further improved ability to adhere to tissue surfaces, such as mucosal membranes, and are suitable for use in the invention.
• the metal compound incorporated into the polymer can be, for example, a water-insoluble metal oxide.
• Metal compounds that can be incorporated into polymers to improve their bioadhesive properties preferably are water-insoluble metal compounds, such as water-insoluble metal oxides and metal hydroxides, which are capable of becoming incorporated into and associated with a polymer to improve the bioadhesiveness of the polymer.
• a water-insoluble metal compound is defined as a metal compound with little or no solubility in water, for example, less than about 0.0 to 0.9 mg/ml.
• the water-insoluble metal compounds can be derived from a wide variety of metals, including, but not limited to, calcium, iron, copper, zinc, cadmium, zirconium and titanium.
• the water-insoluble metal compound preferably is a metal oxide or hydroxide. Water-insoluble metal compounds of multivalent metals are preferred.
• Representative metal oxides suitable for use in the compositions described herein include cobalt (II) oxide (CoO), cobalt (III) oxide (Co 2 O 3 ), selenium oxide (SeO 2 ), chromium (IV) oxide (CrO 2 ), manganese oxide (MnO 2 ), titanium oxide (TiO 2 ), lanthanum oxide (La 2 O 3 ), zirconium oxide (ZrO 2 ), silicon oxide (SiO 2 ), scandium oxide (Sc 2 O 3 ), beryllium oxide (BeO), tantalum oxide (Ta 2 Os), cerium oxide (CeO 2 ), neodymium oxide (Nd 2 O 3 ), vanadium oxide (V 2 O 5 ), molybdenum oxide (Mo 2 O 3 ), tungsten oxide (WO), tungsten trioxide (WO 3 ), samarium oxide (Sm 2 O 3 ), europium oxide (Eu 2 O 3 ), gadolinium oxide (Gd 2
• TiO 2 nickel oxide (NiO), and zinc oxide (ZnO).
• Other oxides include barium oxide (BaO) 5 calcium oxide (CaO), nickel (III) oxide (Ni 2 O 3 ), magnesium oxide (MgO), iron (II) oxide (FeO), iron (III) oxide (Fe 2 O 3 ), copper (II) oxide (CuO), cadmium oxide (CdO), and zirconium oxide (ZrO 2 ).
• Preferred properties defining the metal compound include: (a) substantial insolubility in aqueous environments, such as acidic or basic aqueous environments (such as those present in the gastric lumen); and (b) ionizable surface charge at the pH of the aqueous environment.
• the water-insoluble metal compounds can be incorporated into the polymer by one of the following mechanisms: (a) physical mixtures which result in entrapment of the metal compound; (b) ionic interaction between metal compound and polymer; (c) surface modification of the polymers which would result in exposed metal compound on the surface; and (d) coating techniques such as fluidized bed, pan coating, or any similar methods known to those skilled in the art, which produce a metal compound enriched layer on the surface.
• nanoparticles or microparticles of the water-insoluble metal compound are incorporated into the polymer.
• the metal compound is provided as a fine particulate dispersion of a water-insoluble metal oxide e.g., incorporated throughout the polymer or disposed on the surface of the polymer which is to be adhered to a tissue surface.
• the metal compound also can be incorporated in an inner layer of the polymer and exposed only after degradation or else dissolution of a "protective" outer layer.
• a tablet core containing a polymer and metal may be covered with an enteric coating designed to dissolve when exposed to gastric fluid. The metal compound- enriched core then is exposed and becomes available for binding to GI mucosa.
• Fine metal oxide particles can be produced for example by micronizing a metal oxide by mortar and pestle treatment to produce particles ranging in size, for example, from 10.0 to 300 run.
• the metal oxide particles can be incorporated into the polymer, for example, by dissolving or dispersing the particles into a solution or dispersion of the polymer.
• metal compounds which are incorporated into polymers to improve their bioadhesive properties can be metal compounds which are already approved by the FDA as either food or pharmaceutical additives, such as zinc oxide.
• Suitable polymers that can be used and into which the metal compounds can be incorporated include soluble and water-insoluble, and biodegradable and nonbiodegradable polymers, including hydrogels, thermoplastics, and homopolymers, copolymers and blends of natural and synthetic polymers, provided that they have the requisite fracture strength when mixed with a metal compound.
• representative polymers which can be used in conjunction with a metal compound include hydrophilic polymers, such as those containing carboxylic groups, including polyacrylic acid.
• Representative bioerodible poly(hydroxy acids) and copolymers thereof which can be used include poly(lactic acid), poly(glycolic acid), poly(hydroxy-butyric acid), poly(hydroxyvaleric acid), poly(caprolactone), poly(lactide-co-caprolactone), and poly(lactide-co-glycolide).
• Polymers containing labile bonds, such as polyanhydrides and polyorthoesters, can be used optionally in a modified form with reduced hydrolytic reactivity.
• Positively charged hydrogels, such as chitosan, and thermoplastic polymers, such as polystyrene also can be used.
• Representative natural polymers which also can be used include proteins, such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and polysaccharides such as dextrans, polyhyaluronic acid and alginic acid.
• Representative synthetic polymers include polyphosphazenes, polyamides, polycarbonates, polyacrylamides, polysiloxanes, polyurethanes and copolymers thereof. Celluloses also can be used. As defined herein the term "celluloses" includes naturally occurring and synthetic celluloses, such as alkyl celluloses, cellulose ethers, cellulose esters, hydroxyalkyl celluloses and nitrocelluloses.
• Exemplary celluloses include ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate and cellulose sulfate sodium salt.
• Polymers of acrylic and methacrylic acids or esters and copolymers thereof can be used.
• Representative polymers which can be used include poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
• polymers which can be used include polyalkylenes such as polyethylene and polypropylene; polyarylalkylenes such as polystyrene; poly(alkylene glycols), such as poly(ethylene glycol); poly(alkylene oxides), such as poly(ethylene oxide); and ⁇ oly(alkylene terephthalates), such as poly(ethylene terephthalate).
• polyvinyl polymers can be used, which as defined herein includes polyvinyl alcohols, polyvinyl ethers, polyvinyl esters and polyvinyl halides.
• Exemplary polyvinyl polymers include poly(vinyl acetate), polyvinyl phenol and polyvinylpyrrolidone. Water soluble polymers can also be used.
• Suitable water soluble polymers include polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyethylene glycol, copolymers of acrylic and methacrylic acid esters, and mixtures thereof. Water insoluble polymers also can be used.
• Suitable water insoluble polymers include ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, ⁇ oly(ethylene) high density, poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl isobutyl ether),
• a water insoluble polymer and a water soluble polymer are used together, such as in a mixture.
• Such mixtures are useful in controlled drug release formulations, wherein the release rate can be controlled by varying the ratio of water soluble polymer to water insoluble polymer.
• Polymers varying in viscosity as a function of temperature or shear or other physical forces also may be used.
• Poly(oxyalkylene) polymers and copolymers such as poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) or poly(ethylene oxide)- poly(butylene oxide) (PEO-PBO) copolymers, and copolymers and blends of these polymers with polymers such as poly(alpha-hydroxy acids), including but not limited to lactic, glycolic and hydroxybutyric acids, polycaprolactones, and polyvalerolactones, can be synthesized or commercially obtained.
• polyoxyalkylene copolymers are described in U.S. Patent Nos. 3,829,506, 3,535,307, 3,036,118, 2,979,578, 2,677,700 and 2,675,619.
• Polyoxyalkylene copolymers are sold, for example, by BASF under the tradename PLURONICSTM. These materials are applied as viscous solutions at room temperature or lower which solidify at the higher body temperature. Other materials with this behavior are known in the art, and can be utilized as described herein. These include KLUCELTM (hydroxypropyl cellulose), and purified konjac glucomannan gum. Other suitable polymers are polymeric lacquer substances based on acrylates and/or methacrylates, commonly called EUDRAGITTM polymers (sold by Rohm America, Inc.). Specific EUDRAGITTM polymers can be selected having various permeability and water solubility, which properties can be pH dependent or pH independent.
• EUDRAGITTM RL and EUDRAGITTM RS are acrylic resins comprising copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, which are present as salts and give rise to the permeability of the lacquer films, whereas EUDRAGITTM RL is freely permeable and EUDRAGITTM RS is slightly permeable, independent of pH. In contrast, the permeability of EUDRAGITTM L is pH-dependent. EUDRAGITTM L is an anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester.
• thermoreversible polymers include natural gel- forming materials such as agarose, agar, furcellaran, beta-carrageenan, beta-l,3-glucans such as curdlan, gelatin, or polyoxyalkylene- containing compounds, as described above.
• specific examples include thermosetting biodegradable polymers for in vivo use described in U.S. Patent No. 4,938,763, the contents of which are incorporated herein by reference.
• polymers with enhanced bioadhesive properties are provided by incorporating anhydride monomers or oligomers into one of the polymers listed above by dissolving, dispersing, or blending, as taught by U.S. Patent Nos. 5,955,096 and 6,156,348, the contents of which are incorporated herein by reference.
• the polymers may be used to form drug delivery systems which have improved ability to adhere to tissue surfaces, such as mucosal membranes.
• the anhydride oligomers are generally formed from organic diacid monomers, preferably the diacids normally found in the Krebs glycolysis cycle.
• Anhydride oligomers that enhance the bioadhesive properties of a polymer have a molecular weight of about 5000 or less, typically between about 100 and 5000 daltons, or include 20 or fewer diacid units linked by anhydride linkages and terminating in an anhydride linkage with a carboxylic acid monomer.
• the oligomers can be blended or incorporated into a wide range of hydrophilic and hydrophobic polymers including proteins, polysaccharides and synthetic biocompatible polymers, including those described above, hi one embodiment, anhydride oligomers may be combined with metal oxide particles, such as those described above, to improve bioadhesion even more than with the organic additives alone.
• Organic dyes because of their electronic charge and hydrophobicity or hydrophilicity, can either increase or decrease the bioadhesive properties of polymers when incorporated into the polymers.
• anhydride oligomer refers to a diacid or polydiacid linked by anhydride bonds, and having carboxy end groups linked to a monoacid such as acetic acid by anhydride bonds.
• the anhydride oligomers have a molecular weight less than about 5000, typically between about 100 and 5000 daltons, or are defined as including between one to about 20 diacid units linked by anhydride bonds.
• the diacids are those normally found in the Krebs glycolysis cycle.
• the oligomers can, for example, be formed in a reflux reaction of the diacid with excess acetic anhydride.
• the excess acetic anhydride is evaporated under vacuum, and the resulting oligomer, which is a mixture of species which include from about one to twenty diacid units linked by anhydride bonds, is purified by recrystallizing, for example, from toluene or other organic solvents.
• the oligomer is collected by filtration, and washed, for example, in ethers.
• the reaction produces anhydride oligomers of mono and poly acids with terminal carboxylic acid groups linked to each other by anhydride linkages.
• An anhydride oligomer is hydrolytically labile.
• the molecular weight may be, for example, on the order of 200-400 for fumaric acid oligomer (FAPP) and 2000-4000 for sebacic acid oligomer (SAPP).
• FAPP fumaric acid oligomer
• SAPP sebacic acid oligomer
• the anhydride bonds can be detected by Fourier transform infrared spectroscopy by the characteristic double peak at 1750 cm “1 and 1820 cm '1 , with a corresponding disappearance of the carboxylic acid peak normally at 1700 cm "1 .
• the oligomers can be made from diacids described, for example, in U.S. Patent Nos. 4,757,128, 4,997,904 and 5,175,235, the disclosures of which are incorporated herein by reference.
• monomers such as sebacic acid, bis(p-carboxy-phenoxy)propane, isophthalic acid, fumaric acid, maleic acid, adipic acid or dodecanedioic acid can
• Organic dyes because of their electronic charge and hydrophilicity or hydrophobicity, can alter the bioadhesive properties of a variety of polymers when incorporated into the polymer matrix or bound to the surface of the polymer.
• a partial listing of dyes that affect bioadhesive properties include, but are not limited to: acid fuchsin, alcian blue, alizarin red s, auramine o, azure a and b, Bismarck brown y, brilliant cresyl blue aid, brilliant green, carmine, cibacron blue 3GA, congo red, cresyl violet acetate, crystal violet, eosin b, eosin y, erythrosin b, fast green fcf, giemsa, hematoylin, indigo carmine, Janus green b, Jenner's stain, malachite green oxalate, methyl blue, methylene blue, methyl green, methyl violet 2b,
• Polymers having an aromatic group which contains one or more hydroxyl groups grafted onto them or coupled to individual monomers are also suitable for use in the bioadhesive coatings of the invention, as described in U.S. Provisional Application No. 60/528,042, filed December 9, 2003, U.S. Application No. 11/009,327, filed December 9, 2004, and WO 2005/056708, the contents of which are incorporated herein by reference.
• Such polymers can be biodegradable or non- biodegradable polymers.
• the polymer can be hydrophobic.
• the aromatic group is catechol or a derivative thereof and the polymer contains reactive functional groups, so that a hydroxyl-substituted aromatic group can be readily attached.
• the polymer is a polyanhydride and the aromatic compound is the catechol derivative DOPA.
• the molecular weight of the suitable polymers and percent substitution of the polymer with the aromatic group may vary greatly.
• the degree of substitution varies based on the desired adhesive strength, it may be as low as 10%, 25% or 50%, or up to 100% substitution.
• about 10 to about 40%, such as about 20% to about 30% of the monomers in the polymeric backbone are substituted with at least one aromatic group.
• the resulting polymer typically has a molecular weight ranging from about 1 to 2,000 kDa.
• the polymer that forms that backbone of the bioadhesive material can be a biodegradable polymer.
• biodegradable polymers include synthetic polymers such as poly hydroxy acids, such as polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butyric acid), poly( valeric acid), poly(caprolactone), poly(hydroxybutyrate), poly(lactide-co-glycolide) and poly(lactide-cocaprolactone), and natural polymers such as alginate and other polysaccharides, collagen and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof. In general, these materials degrade either by enzymatic hydrolysis or exposure to water in vivo and by surface or bulk erosion. The foregoing materials may be used alone, as physical mixtures (
• Suitable polymers can formed by first coupling the aromatic compound to the monomer and then polymerizing.
• the monomers may be polymerized to form a polymer backbone, including biodegradable and non-biodegradable polymers.
• Suitable polymer backbones include, but are not limited to, polyanhydrides, polyamides, polycarbonates, polyalkylenes, polyalkylene oxides such as polyethylene glycol, polyalkylene terephthalates such as poly(ethylene terephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyethylene, polypropylene, polyvinyl acetate), poly(vinyl chloride), polystyrene, polyvinyl halides, polyvinylpyrrolidone, polyhydroxy acids, polysiloxanes, polyurethanes and copolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocellulloses, poly
• a suitable polymer backbone can be a known bioadhesive polymer that is hydrophilic or hydrophobic.
• Hydrophilic polymers include CARBOPOLTM, polycarbopb.il, cellulose esters, and dextran.
• Non-biodegradable polymers are also suitable as polymer backbones.
• preferred non-biodegradable polymers include ethylene vinyl acetate, poly(methacrylic acid), copolymers of maleic anhydride with other unsaturated polymerizable monomers, e.g., poly(butadiene maleic anhydride), polyamides, copolymers and mixtures thereof and dextran, cellulose and derivatives thereof.
• Hydrophobic polymer backbones include polyanhydrides, poly(ortho)esters, and polyesters such as polycaprolactone.
• the polymer is sufficiently hydrophobic that it is not readily water soluble.
• the polymer may be soluble up to less than about 1% w/w in water, preferably about 0.1% w/w in water at room temperature or body temperature.
• the polymer is a polyanhydride, such as a poly(butadiene maleic anhydride) or another copolymer of maleic anhydride.
• Polyanhydrides maybe formed from dicarboxylic acids, as described in U.S. Patent No. 4,757,128 to Domb et ah, incorporated herein by reference.
• Suitable diacids include aliphatic dicarboxylic acids, aromatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acid, combinations of aromatic, aliphatic and aromatic-aliphatic dicarboxylic acids, aromatic and aliphatic heterocyclic dicarboxylic acids, and aromatic and aliphatic heterocyclic dicarboxylic acids in combination with aliphatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, and aromatic dicarboxylic acids of more than one phenyl group.
• Suitable monomers include sebacic acid (SA), fumaric acid (FA), bis(p- carboxyphenoxy)propane (CPP), isophthalic acid (IPh), and dodecanedioic acid (DD).
• a wide range of molecular weights are suitable for the polymer that forms the backbone of the bioadhesive material.
• the molecular weight may be as low as about 200 Da (for oligomers) up to about 2,000 kDa.
• the polymer has a molecular weight of at least 1,000 Da, more preferably at least 2,000 Da, most preferably the polymer has a moecular weight of up to 20 kDa or up to 200 kDa.
• the molecular weight of the polymer may be up to 2,000 kDa (e.g., 20 kDa to 1,000 kDa or 2,00O kDa).
• the range of substitution on the polymer can vary greatly and depends on the polymer used and the desired bioadhesive strength. For example, a butadiene maleic anhydride copolymer that is 100% substituted with DOPA will have the same number of DOPA molecules per chain length as a 67% substituted ethylene maleic anhydride copolymer. Typically, the polymer has a percentage substitution ranging from 10% to 100%, more typically ranging from 20% to 30%.
• the polymers and copolymers that form the backbone of the bioadhesive material typically include reactive functional groups that interact with the functional groups on the aromatic compound.
• the polymer or monomer that forms the polymeric backbone contains accessible functional groups that easily react or interact with molecules contained in the aromatic compounds, such as amines and thiols.
• the polymer contains amino reactive moieties, such as aldehydes, ketones, carboxylic acid derivatives, cyclic anhydrides, alkyl halides, aryl azides, isocyanates, isothiocyanates, succinimidyl esters or a combination thereof.
• the aromatic compound containing one or more hydroxy! groups is catechol or a derivative thereof.
• the aromatic compound is a polyhydroxy aromatic compound, such as a trihydroxy aromatic compound (e.g., phloroglucinol) or a multihydroxy aromatic compound (e.g., tannin).
• the catechol derivative may contain a reactive group, such as an amino, thiol, or halide group.
• a preferred catechol derivative is 3,4-dihydroxyphenylalanine (DOPA), which contains a primary amine. Tyrosine, the immediate precursor of DOPA, which differs only by the absence of one hydroxyl group in the aromatic ring, can also be used. Tyrosine is capable of conversion (e.g., by hydroxylation) to the DOPA form.
• a particularly preferred aromatic compound is an amine-containing aromatic compound, such as an amine-containing catechol derivative (e.g., dopamine).
• Two general methods are used to form the polymer product, hi one example, a compound containing an aromatic group which contains one or more hydroxyl groups is grafted onto a polymer.
• the polymeric backbone is a biodegradable polymer.
• the aromatic compound is coupled to individual monomers and then polymerized.
• Any chemistry which allows for the conjugation of a polymer or monomer to an aromatic compound containing one or more hydroxyl groups can be used, for example, if the aromatic compound contains an amino group and the monomer or polymer contains an amino reactive group, this modification to the polymer or monomer is performed through a nucleophilic addition or a nucleophilic substitution reaction, such as a Michael-type addition reaction, between the amino group in the aromatic compound and the polymer or monomer. Additionally, other procedures can be used in the coupling reaction.
• carbodiimide and mixed anhydride based procedures form stable amide bonds between carboxylic acids or phosphates and amino groups
• bifunctional aldehydes react with primary amino groups
• bifunctional active esters react with primary amino groups
• divinylsulfone facilitates reactions with amino, thiol, or hydroxy groups.
• L-DOPA is grafted to maleic anhydride copolymers by reacting the free amine in L-DOPA with the maleic anhydride bond in the copolymer.
• polymers can be used as the backbone of the bioadhesive material, as described above. Additional representative polymers include 1:1 random copolymers of maleic anhydride with ethylene, vinyl acetate, styrene, or butadiene. In addition, a number of other compounds containing aromatic rings with hydroxy suhstituents, such as tyrosine or derivatives of catechol, can be used in this reaction.
• the polymers are prepared by conjugate addition of a compound containing an aromatic group that is attached to an amine to one or more monomers containing an amino reactive group.
• the monomer is an acrylate or the polymer is acrylate.
• the monomer can be a diacrylate such as 1,4-butanediol diacrylate, 1,3-propanediol diacrylate, 1,2-ethanediol diacrylate, 1,6-hexanediol diacrylate, 2,5-hexanediol diacrylate or 1,3-propanediol diacrylate.
• the monomer and the compound containing an aromatic group are each dissolved in an organic solvent (e.g., THF, CH 2 Cl 2 , methanol, ethanol, CHCl 3 , hexanes, toluene, benzene, CCl 4 , glyme, diethyl ether, etc.) to form two solutions.
• an organic solvent e.g., THF, CH 2 Cl 2 , methanol, ethanol, CHCl 3 , hexanes, toluene, benzene, CCl 4 , glyme, diethyl ether, etc.
• the molecular weight of the synthesized polymer can be controlled by the reaction conditions (e.g., temperature, starting materials, concentration, solvent, etc) used in the synthesis.
• a monomer such as 1,4-phenylene diacrylate or 1,4-butanediol diacrylate having a concentration of 1.6 M
• DOPA or another primary amine containing aromatic molecule are each dissolved in an aprotic solvent such as DMF or DMSO to form two solutions.
• the solutions are mixed to obtain a 1 : 1 molar ratio between the diacrylate and the amine group and heated to 56 0 C to form a bioadhesive material.
• Preferred bioadhesive coatings do not appreciably swell upon hydration, such that they do not substantially inhibit or block movement (e.g., of ingested food) through the gastrointestinal tract, as compared to the polymers disclosed by Duchene et ah
• polymers that do not appreciably swell upon hydration include one or more hydrophobic regions, such as a polymethylene region (e.g., (CEb) n , where n is 4 or greater).
• the swelling of a polymer can be assessed by measuring the change in volume when the polymer is exposed to an aqueous solution.
• Polymers that do not appreciably swell upon hydration expand in volume by 50% or less when fully hydrated. Preferably, such polymers expand in volume by less than 25%, less than 20%, less than 15%, less than 10% or less than 5%.
• the bioadhesive coatings are mucophilic.
• a polymer that does not appreciably swell upon hydration e.g., a hydrophobic polymer
• a polymer that does swell or a hydrophilic substance e.g., CarbopolTM, poly(acrylic acid), small organic acids such as citric acid, maleic acid, fumaric acid, hydrophilic drugs, ionic and non-ionic detergents, sugars, salts such as NaCl, disintegrants
• the amount of swelling or hydration in the polymer does not substantially interfere with bioadhesiveness.
• the amount of swellable polymer or hydrophilic substance is selected to sufficiently hydrate the non-swellable polymer to enhance its bioadhesiveness.
• the weight ratio of swellable to non-swellable polymer or hydrophilic substance to non-swellable polymer can be varied in order to obtain a coating that combines a desired amount of swelling (e.g., for faster adhesion) with longer-lasting adhesion, such as from 5:1 to 1:5 or 2:1 to 1:2.
• the swellable polymer and/or hydrophilic substance can comprise about 1% to about 30% by weight of a bioadhesive coating.
• the bioadhesive polymeric coating consists of two layers, an inner bioadhesive layer that does not substantially swell upon hydration and an outer bioadhesive layer that is readily hydratable and optionally bioerodable, such as one comprised of Carbopol .
• the bioadhesive polymers discussed above can be mixed with one or more plasticizers or thermoplastic polymers. Such agents typically increase the strength and/or reduce the brittleness of polymeric coatings.
• plasticizers include dibutyl sebacate, polyethylene glycol, triethyl citrate, dibutyl adipate, dibutyl fumarate, diethyl phthalate, ethylene oxide-propylene oxide block copolymers such as PluronicTM F68 and di(sec-butyl) fumarate.
• thermoplastic polymers include polyesters, poly(caprolactone), polylactide, poly(lactide-co-glycolide), methyl methacrylate (e.g., EUDRAGITTM), cellulose and derivatives thereof such as ethyl cellulose, cellulose acetate and hydroxypropyl methyl cellulose (HPMC) and large molecular weight polyanhydrides.
• the plasticizers and/or thermoplastic polymers are mixed with a bioadhesive polymer to achieve the desired properties.
• the proportion of plasticizers and thermoplastic polymers, when present, is from 0.5% to 40% by weight.
• the bioadhesive polymer coating in a dry packaged form of a tablet, is a hardened shell.
• a pharmaceutical dosage form (e.g., tablet or a drug-eluting device) can have one or more coatings in addition to the bioadhesive polymeric coating, e.g., covering the surface of the bioadhesive coating. These coatings and their thickness can, for example, be used to control where in the gastrointestinal tract the bioadhesive coating becomes exposed.
• the additional coating prevents the bioadhesive coating from contacting the mouth or esophagus.
• the additional coating remains intact until reaching the small intestine (e.g., an enteric coating).
• coatings include methylmethacrylates, zein, cellulose acetate, cellulose phthalate, HMPC, sugars, enteric polymers, gelatin and shellac. Premature exposure of a bioadhesive layer or dissolution of a tablet in the mouth can be prevented with a layer or coating of hydrophilic polymers such as HPMC or gelatin.
• Coatings used in tablets of the invention typically include a pore former to render the coating permeable to the drug.
• Pharmaceutical dosage forms (e.g., tablets and drug-eluting devices) of the invention can be coated by a wide variety of methods. Suitable methods include compression coating, coating in a fluidized bed or a pan and hot melt (extrusion) coating. Such methods are well known to those skilled in the art.
• the invention also includes multi-layer tablets comprising a first, a second and a third layer, where each layer includes one or more drugs and one or more excipients, where the first layer forms the core of the table, the second layer is adjacent to one side of the first layer and the third layer is adjacent to the opposite side of the first layer.
• At least one layer of the tablet includes a hydrophobic excipient and at least one drug in the tablet is hygroscopic, deliquescent or both.
• at least one hygroscopic and/or deliquescent drug and at least one hydrophobic excipient are present (e.g., blended together) in at least one layer of a tablet.
• hydrophobic excipients include celluloses, particularly cellulose acetate and ethyl cellulose, stearic acid, magnesium stearate, glycerol monostearate, fatty acids and salts thereof, monoglycerides, diglycerides, triglycerides, oil, colloidal silicon dioxide and talc.
• Such tablets optionally include one excipient present in an amount sufficient to be at least partially rate-controlling with respect to release of the drug from the tablet.
• a rate-controlling excipient e.g., a rate- controlling polymer
• the amount of rate-controlling excipient is selected relative to the amount of drug in the tablet.
• the weight of the rate-controlling excipient is about two times to about five times, such as about two times to about three times greater than the weight of the drug.
• the inner and outer layers contain different proportions of each component (including the drug(s)), thereby establishing a gradient-type composition.
• the first (inner) layer contains the greatest weight percentage of the drug(s).
• the second and third layers and any additional layers present contain lesser amounts of drug.
• the additional layers can, for example, contain no drug or contain successively lesser amounts of drug.
• layers the same distance away from the first or inner layer will contain approximately equal amount of drug, such that the tablet is essentially symmetrical about the inner layer.
• the drugs can both be present in one or more layers or the different drugs are present in separate layers (i.e., the drugs are not mixed together in one layer).
• bioadhesive tablets and particularly bioadhesive multiparticulates and nanoparticles are desirable. Drugs absorbed in these sites avoid first-pass metabolism by liver and degradation by GIT enzymes and harsh pH conditions typically present in the stomach and small intestine. Drugs absorbed in the buccal and sublingual compartments benefit from rapid onset of absorption, typically within minutes of dosing. Particularly suitable are bioadhesive particulates in fast-dissolving dosage forms, e.g., OraSolv (Cima Labs) that disintegrate within 30 sec after dosing and release the bioadhesive particules.
• OraSolv OraSolv
• Target release profiles include immediate release (IR) and combinations of zero-order controlled release (CR) kinetics and first-order CR kinetics.
• IR immediate release
• CR zero-order controlled release
• first-order CR kinetics Preferably, pharmaceutical formulations targeting the buccal and sublingual regions are constructed such that the formulation disintegrates before passing into the esophagus.
• bioadhesive, gastroretentive drug delivery systems are the option of choice.
• Bioadhesive tablets and multiparticulates are formulated to reside for durations greater than 3 hrs and optimally greater than 4, 5 or even 6 hrs in the fed state.
• Drug release profiles from these systems are tailored to match the gastric residence times, so that greater than 85% of the encapsulated drug is released during the gastric residence time.
• Target release profiles include zero-order CR kinetics, first-order CR kinetics and combinations of IR and CR kinetics.
• enteric-coated, bioadhesive drug delivery systems are preferred. Such systems are particularly well suited for topical delivery of therapeutics to Crohn's disease patients.
• Enteric-coated, bioadhesive tablets and multiparticulates are formulated to reside in the stomach for durations less than 3 hrs in the fed state and less than 1 hr in the fasted state, during which time less than 10% of the encapsulated drug is released, due to the enteric coating. Following gastric emptying, the enteric coating dissipates, revealing the underlying bioadhesive coating. Dissipation of the enteric coating is typically controlled by pH and/or time duration.
• Typical enteric polymers utilizing pH as a control are Eudragit polymers manufactured by Rohm America: Eudragit LlOO- 55 dissolves at pH values greater than 5.5, typically found in duodenum; Eudragit LlOO dissolves at pH values exceeding 6.0, typically found in jejunum; Eudragit SlOO dissolves at pH values exceeding 7.0, typically found in ileum and the ileocecal junction.
• Time may be used to control unmasking of the bioadhesive coating.
• Coatings that dissolve after 3 hrs when the dosage form is administered in the fed state and after 1-2 hrs when the dosage form is administered in the fasted state are suitable for bioadhesive delivery systems to small intestine. Erosion of soluble polymer layers is one means to achieve a time-triggered, enteric dissolution. Polymers such as HPMC, HPC, PVP, PVA or combinations of the above maybe used as time-delayed, enteric coatings and timing of the dissolution of the coating can be increased by applying thicker coating weights.
• non-permeable coatings of insoluble polymers can be used as enteric coatings for delayed/modified release (DR/MR) by inclusion of soluble pore formers in the coating, e.g., PEG, PVA, sugars, salts, detergents, triethyl citrate, triacetin, etc., at levels ranging from 0.5 to 50% w/w of the coating and most preferably from 5 to 25% w/w of the coating.
• rupturable coating systems e.g., Pulsincap, that use osmotic forces of swelling from hydrophilic polymers to rupture enteric membranes to reveal underlying bioadhesive coatings.
• Target release profiles for the small intestine include: no more than 10% drug release during the first 3 hrs post-dosing followed by either IR kinetics, zero-order CR kinetics, first-order CR kinetics and combinations of IR and CR kinetics.
• bioadhesive drug delivery systems are preferred. Such systems are particularly well suited for topical delivery of therapeutics to patients with Inflammatory Bowel Disease (IBD) including Crohn's disease and Ulcerative Colitis.
• IBD Inflammatory Bowel Disease
• Enteric-coated, bioadhesive tablets and multiparticulates are formulated to reside in the stomach for durations less than 3 hrs in the fed state and less than 1 hr in the fasted state, during which time less than 10% of the encapsulated drug is released, due to the enteric coating. Following gastric emptying, the enteric coating dissipates, revealing the underlying bioadhesive coating.
• Suitable means of controlling dissipation include pH, time duration and enzymatic action of colonic bacteria.
• enteric polymers for delivery to the lower gastrointestinal tract utilizing pH as a control are Eudragit polymers manufactured by Rohm America: Eudragit SlOO and FS dissolves at pH values exceeding 7.0, typically found in ileum and the ileocecal junction.
• Time may be used to control unmasking the bioadhesive coating.
• Coatings that dissolve after 4-5 hrs when the dosage form is administered in the fasted state and after 5-8 hrs when the dosage form is administered in the fed state are suitable for bioadhesive delivery systems to the lower small intestine and colon. Erosion of soluble polymer layers is one means to achieve a time-triggered, enteric dissolution. Polymers such as HPMC, HPC, PVP, PVA or combinations of the above may be used as time-delayed, enteric coatings and timing of the dissolution of the coating can be increased by applying thicker coating weights.
• non-permeable coatings of insoluble polymers e.g., cellulose acetate, ethylcellulose
• enteric coatings for delayed/modified release DR/MR
• soluble pore formers e.g., PEG, PVA, sugars, salts, detergents, triethyl citrate, triacetin, etc.
• coatings of polymers that are susceptible to enzymatic cleavage by colonic bacteria are another means of ensuring release to distal ileum and ascending colon.
• Materials such as calcium pectinate can be applied as coatings to tablets and multiparticulates and disintegrate in the lower gastrointestinal tract, due to bacterial action.
• Calcium pectinate capsules for encapsulation of bioadhesive multiparticulates are also available.
• Target release profiles for the lower gastrointestinal tract include: no more than 10% drug release during the first 4-5 hrs (fasted state) and 5-8 hrs (fed state) hrs post-dosing followed by either IR kinetics, zero-order CR kinetics, first-order CR kinetics and combinations of IR and CR kinetics.
• multi-layer tablets of the invention exhibit an approximately zero-order release of drag in in vitro testing and/or in vivo administration.
• zero-order release advantageously occurs over about 6-12 hours, particularly 8-10 hours.
• zero-order release advantageously occurs over about 8-16 hours, particularly 10-14 hours.
• zero-order release advantageously occurs over about 16-30 hours, particularly 22-26 hours.
• the tablet comprises at least one solid inner layer and two solid outer layers, each comprising one or more drugs and one or more pharmaceutical polymers and/or pharmaceutical excipients.
• the amount of drag and/or excipient differs among the inner and outer layers.
• the one or more inner layers can comprise at least 34% of the total amount of the drag in the tablet and one or more polymer(s) and/or excipients(s)
• each of the two outer layers can comprise not more than 33% of the total amount of drug in the tablet and one or more polymer(s) and/or excipients(s).
• the multi-layer tablet consists of a solid inner layer and two solid outer layers, each comprising a drag and one or more pharmaceutical polymers or pharmaceutical excipients, wherein at least one polymer or excipient is hydrophobic. Tablets of this embodiment preferably provide approximately zero- order or linear release kinetics. In still another embodiment, the multi-layer tablet is enteric coated.
• One or more layers of the tablet can contain permeation enhancers to provide permeability enhancement of drags through mucosal lining of the gastrointestinal tract (GIT).
• GIT gastrointestinal tract
• An absorption enhancer facilitates the uptake of a drag across the gastrointestinal epithelium.
• Absorption enhancers include compounds that improve the ability of a drag to be solubilized in the aqueous environment in which it is originally released and/or in the lipophilic environment of the mucous layer lining of the intestinal walls.
• Absorption enhancers further include compounds that increase disorder of the hydrophobic region of the membrane exterior of intestinal cells, promote leaching of membrane proteins that results in increased transcellular transport, or widen the pore radius between cells for increased paracellular transport.
• absorption enhancers examples include sodium caprate, ethylenediamine tetra(acetic acid) (EDTA), citric acid, lauroylcarnitine, palmitoylcarnitine, tartaric acid and other agents known to increase GI permeability.
• EDTA ethylenediamine tetra(acetic acid)
• citric acid examples include citric acid, lauroylcarnitine, palmitoylcarnitine, tartaric acid and other agents known to increase GI permeability.
• absorption enhancers include sodium salicylate, sodium 5-methoxysalicylate, indomethacin, diclofenac, polyoxyethylene ethers, sodium laurylsulfate, quaternary ammonium compounds, sodium deoxycholate, sodium cholate, octanoic acid, decanoic acid, glyceryl- 1 -monooctanoate, glyceryl- 1 -monodecanoate, DL-phenylalanine ethylacetoacetate enamine, chlorpromazine, D-myristoyl-L-propyl-L-prolyl-glycinate, concanavaline A 9 DL- ⁇ -glycerophosphate, and 3-amino- 1 -hydroxypropylidene- 1,1- diphosphonate.
• the tablet is coated to provide additional control over diffusion of the drug or exposure of the tablet to the gastrointestinal tract (e.g., with an enteric coating).
• the diffusion-limiting coating can be a pharmaceutically- accepted polymeric coating material, such as methylmethacrylates (EudragitsTM,
• the coatings can be applied using a variety of techniques including fiuidized-bed coating, pan-coating and dip-coating.
• Multi-layer tablets of the invention can include a bioadhesive coating, as described above.
• a bioadhesive (such as those described above) can be included in one or more layers of the tablet.
• Multi -layer tablets of the invention are readily prepared, hi one example, the drug(s) is/are mixed with a compressible sugar and granulated with a binder solution of compressible sugar in purified water. Subsequent to drying, the granules are mixed with different amounts of colloidal silicon dioxide (CabosilTM) and magnesium stearate. The granules are mixed in different proportions with stearic acid or monosterate (30, 50, 70%, for example) and then fed into a multilayer tableting machine (such as a Korsch or Fette tableting machine) to yield a trilayer tablet. Additional layers, often with varying amount of drug granules (e.g., greater drug concentration in the center layer and decreasing in each subsequent outer layer), can readily be added. In certain embodiments, the outermost layers do not include a drug.
• the outermost layers do not include a drug.
• FIG. 1 illustrates a trilayer capsule shape tablet (10) including a first drug layer (14), second drug layer (16) and third drug layer (18).
• the capsule shape tablet (10) is partially enveloped in a bioadhesive polymeric plug (12) such that drug layer- ends (20a and 20b) remain exposed for drug release.
• a drug concentration gradient between the three drug layers allows a predetermined hybrid release profile to be achieved.
• the cores of pharmaceutical dosage forms (e.g., tablets and drug-eluting devices) of the invention contain one or more excipients, carriers or diluents. These excipients, carriers or diluents can be selected, for example, to control the disintegration rate of a pharmaceutical dosage form (e.g., tablet or drug-eluting device).
• a pharmaceutical dosage form e.g., tablet or drug-eluting device.
• the release time of a tablet is at least 25% of the gastrointestinal, small intestine and/or large intestine retention time, at least 50% of the gastrointestinal, small intestine and/or large intestine retention time or at least 75% of the gastrointestinal, small intestine and/or large intestine retention time.
• any vehicle or carrier conventionally employed and which is inert with respect to the active agent, and preferably does not interfere with bioadhesiveness in embodiments where that characteristic is desired, may be utilized for preparing and administering the pharmaceutical compositions of the present invention.
• Illustrative of such vehicles and carriers are those described, for example, in Remington's Pharmaceutical Sciences, 18th ed. (1990), the disclosure of which is incorporated herein by reference.
• the formulations of the present invention for use in a subject comprise the drug, optionally together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients.
• the carriers or diluents must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the drug with the carrier or diluent which constitutes one or more accessory ingredients, hi general, the formulations are prepared by uniformly and intimately bringing into association the agent with the carriers and then, if necessary, dividing the product into unit dosages thereof.
• Examples of carriers and diluents include pharmaceutically accepted hydrogels such as alginate, chitosan, methylmethacrylates, cellulose and derivatives thereof (microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose, ethylcellulose), agarose and PovidoneTM, kaolin, magnesium stearate, starch, lactose, sucrose, density-controlling agents such as barium sulfate and oils, dissolution enhancers such as aspartic acid, citric acid, glutamic acid, tartartic acid, sodium bicarbonate, sodium carbonate, sodium phosphate, glycine, tricine and TRIS.
• pharmaceutically accepted hydrogels such as alginate, chitosan, methylmethacrylates, cellulose and derivatives thereof (microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose, ethylcellulose), agarose and PovidoneTM
• the tablet typically includes at least one polymer or excipient.
• the polymer may be degradable or non-degradable. Suitable degradable polymers include polyesters, such as poly(lactic acid) (p[LA]), poly ⁇ actide-co-glycolide) (p[LGA]) 5 poly(caprolactone) (p[CL]); polyanhydrides such as poly(fumaric-co-sebacic anhydride) (p[FASA]) in molar ratios of 20:80 to 90:10, poly(carboxyphenoxypropane-co-sebacic anhydride) (p[CPPSA]), poly(adipic anhydride) (p[AA]); polyorthoesters; polyamides; and polyimides.
• polyesters such as poly(lactic acid) (p[LA]), poly ⁇ actide-co-glycolide) (p[LGA]) 5 poly(caprolactone) (p[CL]
• polyanhydrides such as poly(fum
• Suitable polymers include hydrogel-based polymers such as agarose, alginate, and chitosan.
• Suitable non-degradable polymers include polystyrene, polyvinylphenol, and polymethylmethacrylates (EudragitsTM).
• the excipients, carriers or diluents can also be selected to control the time until a pharmaceutical dosage form (e.g., tablet or drug-eluting device) detaches from a mucosal membrane.
• a pharmaceutical dosage form e.g., tablet or drug-eluting device
• the addition of one or more disintegrating agents will reduce the time until a pharmaceutical dosage form (e.g., tablet or drug-eluting device) detaches.
• an agent that interferes with the mucosa-tablet/device adhesion can be used to control the time until detachment occurs.
• Suitable excipients include stabilizers, plasticizers, wetting agents, antitack agents, tack agents, foam agents, antifoam agents, binders, fillers, extenders, flavorants, dispersants, surfactants, solubilizers, solubilization inhibitors, glidants, lubricants, antiadherents, adherents, coatings, protective agents, sorbents, suspending agents, crystallization inhibitors, recrystallization inhibitors, disintegrants, acidulants, diluents, alkalizing agents, antioxidants, preservatives, colorants, electrolytes, solvents, antisolvents, accelerating agents, and/or retarding agents.
• Examples include alginate, chitosan, methylmethacrylates (EudragitsTM), celluloses (especially microcrystalline cellulose, hydroxypropylmethylcellulose, ethylcellulose etc), agarose, PovidoneTM, lactose, microcrystalline cellulose, kaolin starch, magnesium stearate, stearic acid, glycerol monostearate, sucrose, compressible sugar, lactose and barium sulfate.
• EudragitsTM methylmethacrylates
• celluloses especially microcrystalline cellulose, hydroxypropylmethylcellulose, ethylcellulose etc
• agarose PovidoneTM
• lactose lactose
• microcrystalline cellulose kaolin starch
• magnesium stearate stearic acid
• glycerol monostearate sucrose
• compressible sugar lactose and barium sulfate.
• a wide variety of drugs can be included in pharmaceutical dosage forms (e.g., tablets and drug-eluting devices) of the invention.
• Such pharmaceutical dosage forms typically contain at least 1 mg of a drug.
• These pharmaceutical dosage forms can also contain at least 2 mg, at least 5 mg, at least 10 mg, at least 25 mg, at least 50 mg, at least 100 mg, at least 500 mg or at least 1000 mg of a drug (e.g., 2 mg to 1000 mg).
• Drugs suitable for use herein can be small organic molecules (e.g., non- polymeric molecules having a molecular weight of 2000 Da or less, such as 1000 Da or less), peptides or polypeptides and nucleic acids.
• Drugs may be classified using the Biopharmaceutical Classification System (BCS), which separates pharmaceuticals for oral administration into four classes depending on their solubility and their absorbability through the intestinal cell layer.
• BCCS Biopharmaceutical Classification System
• drug substances are classified as follows:
• Class I drugs of the BCS system are highly soluble and highly permeable in the gastrointestinal (GI) tract. Sometimes BCS Class I drugs may be micronized to sizes less than 2 microns to increase the rate of dissolution.
• Class ⁇ drugs are drugs that are particularly insoluble, or slow to dissolve, but that readily are absorbed from solution by the lining of the stomach and/or the intestine. Therefore, prolonged exposure to the lining of the GI tract is required to achieve absorption.
• Many of the known Class II drugs are hydrophobic, and have historically been difficult to administer. Moreover, because of their hydrophobicity, there tends to be a significant variation in absorption depending on whether the patient is fed or fasted at the time of taking the drug.
• Class III drugs include biologic agents that have good water solubility and poor GI permeability, such as proteins, peptides, polysaccharides, nucleic acids, nucleic acid oligomers and viruses.
• Class IV drugs are lipophilic drugs with poor GI permeability. Both Class III and IV drugs are often problematic or unsuitable for sustained release or controlled release. Class III and Class IV drugs are characterized by poor biomembrane permeability and are commonly delivered parenterally. Traditional approaches to parenteral delivery of poorly soluble drugs include using large volumes of aqueous diluents, solubilizing agents, detergents, non-aqueous solvents, or non-physiological pH solutions. These formulations, however, can increase the systemic toxicity of the drug composition or damage body tissues at the site of administration.
• the drug is selected from hormones, enzymes, antigens, digestive aids, ulcer treatments (e.g., bismuth subsalicylate optionally in combination with antibiotics effective against H. pylori), antihypertensives, enzyme inhibitors, antiparasitics (e.g., antimalarials such as atovaquone), spermicides, anti-hemorrhoidal treatments, and radiopaque compounds.
• the drug is an antifungal agent (e.g., itraconazole, fluoconazole, terconazole, ketoconazole, saperconazole, griseofulvin, griseoverdin).
• the drug is an antineoplastic agent.
• the drug is an antiviral agent (e.g., acyclovir).
• antiviral agent e.g., acyclovir
• Other classes of drug suitable for inclusion in pharmaceutical dosage forms (e.g., tablets and drug- eluting devices) of the invention include steroids (e.g, danazol), immunosuppressants (e.g., cyclosporine), CNS active agents, cardiovascular agents, anti-depressant agents, anti-psychotic agents, anti-epileptic agents (e.g., carbamazepine), agents for treating a movement disorder (e.g., valproic acid and salts thereof) and anti-migraine agents (e.g., triptans such as sumatriptan).
• steroids e.g, danazol
• immunosuppressants e.g., cyclosporine
• CNS active agents e.g., cardiovascular agents, anti-depressant agents, anti-psychotic agents, anti-epileptic agents (e.
• Drugs advantageously incorporate include antibiotics, antivirals (especially protease inhibitors alone or in combination with nucleosides for treatment of HTV or Hepatitis B or C), anti-parasites (helminths, protozoans), anti-cancer (referred to herein as "chemotherapeutics", including cytotoxic drugs such as cisplatin and carboplatin, BCNU, 5FU, methotrexate, adriamycin, camptothecin, and taxol), antibodies and bioactive fragments thereof (including humanized, single chain, and chimeric antibodies), antigen and vaccine formulations, peptide drugs, antiinflammatories, and oligonucleotide drugs (including antisense, aptamers, ribozymes, external guide sequences for ribonuclease P, and triplex forming agents).
• Examples of other useful drugs for use in bioadhesive pharmaceutical dosage forms include ulcer treatments such as CarafateTM from Marion Pharmaceuticals, neurotransmitters such as L-DOPA, antihypertensives or saluretics such as Metolazone from Searle Pharmaceuticals, carbonic anhydrase inhibitors such as Acetazolamide from Lederle Pharmaceuticals, insulin like drugs such as glyburide, a blood glucose lowering drug of the sulfonylurea class, synthetic hormones such as Android F from Brown
• Antigens can be microencapsulated in one or more types of bioadhesive polymer, and subsequently compressed into a tablet or filled into a capsule or the reservoir of a drug-eluting device, to provide a vaccine.
• the vaccines can be produced to have different retention times in the gastrointestinal tract. The different retention times, among other factors, can stimulate production of more than one type (IgG, IgM, IgA, IgE, etc.) of antibody.
• a radio-opaque material such as barium is coated with polymer.
• Radioactive materials or magnetic materials could be used in place of or in addition to the radio-opaque materials.
• examples of other materials include gases or gas-emitting compounds that are radioopaque.
• Bioadhesive pharmaceutical dosage forms (e.g., tablets and drug-eluting devices) of the invention are especially useful for treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. In ulcerative colitis, inflammation is restricted to the colon, whereas in Crohn's disease, inflammatory lesions may be found throughout the gastrointestinal tract, from the mouth to the rectum.
• Sulfasalazine is one of the drugs that is used for treatment of the above diseases.
• Sulfasalazine is cleaved by bacteria within the colon to sulfapyridine, an antibiotic, and to 5-amino salicylic acid, an anti-inflammatory agent.
• the 5-amino salicylic acid is the active drug and it is needed locally. Direct administration of the degradation product (5-amino salicylic acid) may be more beneficial.
• a bioadhesive drug delivery system could improve the therapy by retaining the drug for a prolonged time in the intestinal tract. For Crohn's disease, retention of 5-aminosalicylic acid in the upper intestine is of great importance, since bacteria cleave the sulfasalazine in the colon, the only way to treat inflammations in the upper intestine is by local administration of 5-aminosalicylic acid.
• Drugs particularly useful in the treatment of H. pylori include antibiotics such as amoxicillin, tetracycline, metronidazole and clarithromycin; H 2 blockers such as cimetidine, ranitidine, famotidine, and nizatidine; proton pump inhibitors such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprozole; and stomach-lining protectors such as bismuth subsalicylate.
• antibiotics such as amoxicillin, tetracycline, metronidazole and clarithromycin
• H 2 blockers such as cimetidine, ranitidine, famotidine, and nizatidine
• proton pump inhibitors such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprozole
• stomach-lining protectors such as bismuth subsalicylate.
• Multi-layer tablets of the invention are broadly useful for drug delivery, as they are compatible with a large number of different drugs.
• Suitable drugs include sodium valproate, valproic acid, divalproex sodium, antibiotics, non-steroidal anti ⁇ inflammatory drugs ("NSAIDS"), such as methyl salicylate, antiulcerative agents such as bismuth subsalicylate alone or in combination with antibiotics effective against organisms such as H. pylori, digestive supplements and cofactors, and vitamins.
• NSAIDS non-steroidal anti ⁇ inflammatory drugs
• the drug contains a valproic moiety.
• Sodium valproate is used for the treatment of generalized, partial or other epilepsy.
• Valproic acid is used for the treatment of generalized and partial seizures.
• Valproic acid and sodium valproate typically have a 1:1 dosing relationship.
• Side effects of treatment include occasional sedation (especially if given as part of polytherapy), ataxia and tremor and liver dysfunction; increased appetite with associated weight gain is the most common side effect. Nausea has been reported but is alleviated by taking the dose after food.
• the normal monotherapy dosage in adults is 600 mg daily in divided doses increased by 200 mg every 3 days until control is achieved up to a maximum of 2.5 g daily in divided doses.
• the usual dose range is 1-2 g daily in divided doses.
• the normal dose in children over 20 kg is 400 mg daily in divided doses, irrespective of weight, increased until control is achieved up to a maximum of 35 mg/kg/day in divided doses.
• the normal dose in children up to 20 kg is 20 mg/kg daily in divided doses.
• multi ⁇ layer tablets of the invention (optionally coated with a bioadhesive) reduce or eliminate the need to administer multiple daily doses of valproate drugs. Generally, doses of valproate drugs are increased only if plasma concentrations are monitored.
• sodium valproate Because drugs such as phenytoin, carbamazepine and phenobarbitone increase the metabolism of sodium valproate, the dose required will be higher by 5-10 mg/kg/day. Once these agents have been withdrawn, the dose of sodium valproate can be reduced slightly as long as seizure control is maintained. Sustained release sodium valproate formulations are interchangeable with other dosage forms only when seizure control has been achieved, as long as the same total daily dose is given.
• a class of drugs that is suitable for use in pharmaceutical dosage forms are hygroscopic and/or deliquescent drugs.
• hygroscopic refers to substances that absorb significant amounts of atmospheric moisture when exposed to conditions of normal ambient relative humidity (RH), for example 10-50% RH.
• RH normal ambient relative humidity
• delivery refers to substances that tend to undergo gradual dissolution and/or liquefaction due to attraction ⁇ nd/or absorption of moisture from air when exposed to these conditions.
• Non-limiting examples of hygroscopic and/or deliquescent drugs suitable for use in the present invention include acetylcholine chloride, acetylcamitine, actinobolin, aluminum methionate, aminopentamide, aminopyrine hydrochloride, ammonium bromide, ammonium valerate, amobarbital sodium, anthiolimine, antimony sodium tartrate, antimony sodium thioglycollate, aprobarbital, arginine, aspirin, atropine N-oxide, avoparcin, azithromycin monohydrate, betahistine mesylate, betaine, bethanechol chloride, bismuth subnitrate, bupropion, butamirate, buthalital sodium, butoctamide, cacodylic acid, calcium chloride, calcium glycerophosphate, calcium iodide, carbachol, carnitine, caspofungin, ceruletide, chlorophyllin sodium-copper salt,
• More than one type of drug can be present in a pharmaceutical dosage form (e.g., tablet or a drug-eluting device) of the invention.
• the drugs can be evenly distributed throughout a medicament or can be heterogeneously distributed in a medicament, such that one drug is fully or partially released before a second drug.
• Pharmaceutical dosage forms e.g., tablets, capsules, drug-eluting devices
• Pharmaceutical dosage forms typically weigh at least 5 mg.
• Tablets, capsules and drug-eluting devices can also weigh at least 10 mg, at least 15 mg, at least 25 mg, at least 50 mg, at least 100 mg, at least 500 mg or at least 1000 mg.
• such objects weigh 10 mg to 500 mg.
• the pharmaceutical dosage forms typically contain between 10 and 70% of therapeutic, diagnostic or prophylactic agent (referred to generally as "drug") by weight of a dosage form, or between 30 and 90% by weight of the core of a dosage form, where each coating makes up between 1-10%, preferably 5-6%, by weight of the dosage form, up to a total of about 30% by weight.
• the coating can include drug, in ratios of, for example, from 5 and 50% by weight of the coating, preferably between 20 and 40% by weight of the coating, while still retaining rate control.
• Pharmaceutical dosage forms typically measure at least 2 mm in one direction.
• pharmaceutical dosage forms can measure at least 5 mm, at least 10 mm, at least 15 mm or at least 20 mm in one direction.
• the diameter of the pharmaceutical dosage forms is 2 to 40 mm, preferably 10 to 30 mm such as 20 to 26 mm.
• Mini- tablets have a diameter of 2 mm to about 5 mm.
• Such pharmaceutical dosage forms can measure at least 2 mm, at least 5 mm, at least 10 mm, at least 15 mm or least 20 mm in a second direction and, optionally, a third direction.
• pharmaceutical dosage forms of the invention ranges in size from about 2 to about 50 mm in length, from about 2 mm to about 15 mm in depth, and from about 2 mm to about 15 mm in width.
• the pharmaceutical dosage form is of a size that facilitates swallowing by a subject.
• the volume of a typical pharmaceutical dosage form of the invention is at least 0.008 mL, at least 0.01 mL, at least 0.05 mL, at least 0.1 mL, at least 0.125 mL, at least 0.2 mL, at least 0.3 mL, at least 0.4 mL or at least 0.5 mL, such as from 0.008 mL to 0.5 mL.
• the tablet is a trilayer tablet having an inner core that includes one or more drugs in an appropriate matrix of excipients (e.g., HPMC, MCC, lactose) and is surrounded on two sides by a bioadhesive polymeric coating, which optionally is mixed with the one or more drugs.
• excipients e.g., HPMC, MCC, lactose
• Preferred bioadhesive polymeric coatings are a DOPA-BMA (poly(butadiene-co-maleic acid)) polymer and a mixture of poly(fumaric-co-sebacic) anhydride and EudragitTM RS PO.
• the tablet is a longitudinally compressed tablet containing precompressed inserts of the drug and excipients and optionally a permeation enhancer. Drug is only released at the edge of this tablet, which can result in zero- order kinetics.
• the tablet is comprised of a multiplicity of bioadhesive-coated microspheres that have been compressed into a tablet core and subsequently coated with a bioadhesive coating and one or more additional coatings (e.g., enteric coatings).
• the tablet includes a cavity through all or part of the tablet.
• a cavity extending through a tablet creates a channel open at both ends.
• Such tablets can be coated, for example, with a compression coating (e.g., enteric, bioadhesive, combinations, etc.) on all or selected surfaces.
• a compression coating e.g., enteric, bioadhesive, combinations, etc.
• One example is a tablet having a channel through the tablet where the channel is uncoated.
• the subject dosage formulations comprise an inner core, which comprises one or more drugs, excipients, and/or aborption enhancers that have been compressed to a form a solid, such as a tablet.
• an inner core which comprises one or more drugs, excipients, and/or aborption enhancers that have been compressed to a form a solid, such as a tablet.
• powdered drug formulations of the invention can be compressed to form a solid.
• a drug can be used that in its pure form, under ambient conditions, is a liquid, hi some embodiments, the liquid drug that is incorporated into a compressed inner core of the invention is present as a free base or free acid.
• the drug is a liquid drug (e.g., nicotine, valproic acid)
• the drug is preferably incorporated into a dosage form of the invention after it has been absorbed onto an absorbent material, such as kaolin clay or Cabosil (colloidal silicon dioxide).
• a solubilized form of an insoluble drug is incorporated into a dosage form of the invention.
• Solubilized forms of insoluble drugs maybe aqueous-based or oil-based.
• a water-insoluble drug may be dissolved in an organic solvent and then absorbed onto an absorbent material, such as a synthetic aluminosilicate or silicate, which can absorb certain organic solvents while still retaining the properties of a solid.
• Capsules of the invention can be constructed in a multitude of ways.
• capsules can be filled with liquid, paste, powder, granules and/or beads.
• Granules and beads are optionally coated with a bioadhesive and/or other coating described herein.
• a capsule coated with a bioadhesive can either have the bioadhesive on the surface, or the bioadhesive can be coated with one or more layers that delay exposure of the bioadhesive to ambient conditions (e.g., to prevent the capsule from adhering to an upper portion or upper portion of the gastrointestinal tract).
• Capsules can include one or more excipients disclosed herein.
• Capsules or tablets can be incorporated into standard pharmaceutical dosage forms such as gelatin capsules and tablets.
• Gelatin capsules available in sizes 000, 00, 0, 1, 2, 3, 4, and 5, from manufacturers such as Capsugel ® , may be filled with capsules or tablets and administered orally.
• capsules or tablets may be dry blended or wet-granulated with diluents such as microcrystalline cellulose, lactose, colloidal silicon dioxide (e.g., CabosilTM) and binders such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and directly compressed to form tablets.
• diluents such as microcrystalline cellulose, lactose, colloidal silicon dioxide (e.g., CabosilTM) and binders such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and directly compressed to form tablets.
• the drug-eluting device includes an inner reservoir comprising the effective agent; a first coating layer, which is essentially impermeable to the passage of the effective agent; and a second coating layer, which is permeable to the passage of the effective agent.
• the first coating layer covers at least a portion of the inner reservoir; however, at least a small portion of the inner reservoir is not coated with the first coating layer (e.g., there are one or more pores in the first coating layer).
• the second coating layer essentially completely covers the first coating layer and the uncoated portion of the inner reservoir.
• the first coating layer is a non- bioerodable or a slowly bioerodable polymer (e.g., a polymer having a polymethylene backbone).
• the second coating can be either a bioadhesive polymeric coating or a coating between the first coating and the bioadhesive polymeric coating.
• the drug-eluting device includes a multilayer core, often a bilayer, formed of polymer matrices that swell upon contact with the fluids of the stomach. At least one layer of the multilayer core includes a drug. A portion of the polymer matrices are surrounded by a band of insoluble material that prevents the covered portion of the polymer matrices from swelling and provides a segment of the dosage form that is of sufficient rigidity to withstand the contractions of the stomach. As a result, release of the drug is regulated by escape of the drug through one or more pores in the device.
• the core and the band of soluble material are coated with a bioadhesive polymeric coating.
• the drug-eluting device is an osmotic delivery system.
• the reservoir of such devices contains osmotic agents to draw water across a semi-permeable membrane and a swelling polymer to push drug out of the device at a controlled rate.
• drug-eluting devices of the invention release the drug contained therein with zero-order kinetics. EXEMPLIFICATION
• Trilayer tablets were prepared by sequentially filling a 0.3287 X 0.8937 "00 capsule" die (Natoli Engineering) with 333 mg of either SpheromerTM I or SpheromerTM III Bioadhesive polymer, followed by 233 mg of a blend of hydroxypropylmethylcellulose (HPMC) 4000 cps and 100 mg of barium sulfate, followed by an outer layer of 333 mg of either SpheromerTM I or III bioadhesive polymer. Trilayer tablets were prepared by direct compression at 2000 psi for 1 second using a Globepharma Manual Tablet Compaction Machine (MTCM-I). The tablets were administered to female beagles that were fasted for 24 hrs.
• MTCM-I Globepharma Manual Tablet Compaction Machine
• Trilayer tablets with SpheromerTM I or III in the bioadhesive layers remained in the stomach of fasted dogs for up to 3.5 hrs and resided in the stomach of fed dogs in excess of 6 hrs, as shown in FIGS. 2A-D.
• the tablets did not mix with food contents and remained in contact with stomach mucosa at the same location until they passed into the small intestine.
• the innovator drug Sporanox (Johnson & Johnson) is an immediate release dosage form containing 100 mg of itraconazole.
• an AUC of 22,000 ng/mPhr "1 , C ma ⁇ of 1200 ng/ml and T max of 1.5 hrs were obtained.
• Itraconazole is a Biopharmaceutical Classification System Class 2 drug that has negligible water solubility and good GI permeability. It is slightly soluble in water at pH ⁇ 3.5, limiting the site of GI absorption to duodenum and upper jejunum.
• the gastroretentive bioadhesive formulation described in this example delivered itraconazole for an extended period of time to the absorptive site in duodenum and upper jejunum.
• the 8 hr gastrointestinal residence time observed by fluoroscopy corresponds to the maximum itraconazole plasma concentration achieved at T max of 8 hrs.
• Granulation 180.0 g of sodium valproate (Katwijk Chemie BV) were granulated using a binder solution prepared previously by dissolving 1O g of ethyl cellulose (10-FP, NF Premium) and 1O g of polyvinylpyrrolidone, K- 15 in 667 mL of ethanol. Binder solution was applied onto the drug in a bench top fluidized-bed spray-coating unit (Vector Corp. model MFL.01).
• the granulation was dried and blended with 1% colloidal silicon dioxide. The granulation was stored in a 1 -Liter glass jar containing DesiPak dessicant until used.
• the granulation sodium valproate was blended with various excipients to achieve the sodium valproate inner and outer layers compositions as shown below.
• the granulation was initially blended with ethyl cellulose or SpheromerTM I (p(FA:SA)) or SpheromerTM III (DOPA grafted on BMA) in a blender for 5 minutes followed by blending with magnesium stearate for additional 5 minutes.
• Trilayer tablets were compressed on the GlobePharma MCTM-I manual tablet press using 0.328" x 0.8937" capsule shaped, deep concave punches. First 200 mg of outer blend was added to the die cavity and pre-compressed, then 987.2 mg of inner blend was added to the die cavity and pre-compressed again, and finally the 200 mg outer blend was added and compressed at 3000 psi for Is.
• Trilayer tablets were tested for dissolution testing in a USP I apparatus using pH 6.8 PBS buffer at 100 rpm and 37 0 C.
• the dissolution profiles for the lots including SpheromerTM I and III are shown in FIGS. 4A and 4B, respectively. These dissolution profiles indicate that sodium valproate is released from the tablet in two phases, immediate release (outer layers) and sustained release (inner layer).
• Bioadhesive tablets were tested for release profile in 0.1 N HCl at 37 ⁇ 0.5 0 C, in the USP II dissolution apparatus at 50 rpm.
• the in vitro release profile of levodopa from the trilayer tablets is shown in FIG. 6, which confirm that there is an immediate release of levodopa (from the outer layers), followed by a sustained release of levodopa (from the inner layer).
• Acyclovir is categorized as a Class 3 drug according to the Biopharmaceutical Classification system, because of its moderate water solubility and low bioavailability (10-20%).
• the drug is soluble only at acidic pH (pKa 2.27) limiting absorption in the gastrointestinal tract to duodenum and jejunum. There is no effect of food on drug absorption. Peak plasma levels are reached 3 to 4 hours following an oral dose. Bioavailability decreases with increasing drug dose. Elimination from plasma has a terminal half-life of 2.5 to 3.3 hours.
• Zovirax is normally dosed at either 200 mg every 4 hrs or 400 mg every 12 hrs, depending on the antiviral indication.
• a trilayer tablet controlled release (CR) formulation includes an inner core and an outer bioadhesive coating.
• the controlled-release inner core blend contains 400 mg of acyclovir blended with glutamic acid, functioning as an acidulant, and Ethocel.
• the outer bioadhesive coating contains SpheromerTM III and excipients.
• the inner core blend is sandwiched between outer bioadhesive layers and direct compressed to create a bioadhesive, trilayer tablet.
• the trilayer tablet is designed to reside in the stomach for greater than 6 hrs in the fed state and release acyclovir downstream, in a controlled manner, to the duodenum and upper jejunum, the main absorptive sites.
• Serum acyclovir was determined by LC/MS/MS. Turbulent flow chromatography using a 2300 HTLCTM system (Cohesive Technologies, Franklin, MA) was coupled to tandem-mass spectrometry (MS/MS) performed on a triple stage quadropole from Perkin Elmer SCIEX API 365 (Sciex, Concord, Ontario, Canada) with an atmospheric pressure ionization (API) chamber. The limit of detection of acyclovir in dog plasma was 10 ng/ml.
• acyclovir maximum observed concentration (Cmax), time at which Cmax was observed (tmax), and area under the plasma concentration versus time curve (AUC) carried out to 48 hrs (AUC0-t).
• the effect of repeat dosing on plasma drug levels is shown in FIG. 7.
• Bioadhesive, trilayer tablets containing 100 mg itraconazole in the central core layer were compressed using 0.3287 X 0.8937" capsule-shaped dies (Natoli Engineering) at 3000 psi for 3 seconds in a GlobePharma Manual Tablet Compaction Machine (MTCM-I), as described above.
• the composition of the tablet was as follows: Dru La er Com osition
• the trilayer tablets were tested for dissolution release profile in 900 mL of simulated gastric fluid (SGF), pH 1.2 in a USP II apparatus at 100 rpm. The results are shown in FIG. 8. Approximately 50% of the itraconazole was released within 8 hrs and 85% was released within 16 hrs. In contrast, dissolution of Sporanox ® (approx. 85% drug release) occurred within 60 minutes.
• SGF simulated gastric fluid
• Sporanox ® capsules and the bioadhesive trilayer tablets, each containing lOOmg of itraconazole, were administered to cohorts of six beagle dogs in the fed state and plasma levels of itraconazole were measured using LC/MS/MS.
• bioadhesive trilayer tablets were able to achieve an AUC similar to that of the Sporanox ® capsules.
• itraconazole is a Class II drug, known to be absorbed only in the upper small intestine.
• the longer Tmax of the bioadhesive Spherazole formulation, compared to the Sporanox capsule, is characteristic of a controlled release formulation, as well as indicative of retention in the gastrointestinal tract.
• Pig intestine was cut into at least 1 in 2 sections, mounted into a perforated, plastic holder with the mucus side up and submerged in phosphate buffered saline (PBS, pH 6.8). A fresh piece of tissue was used for each test. A polymer-coated support was mounted on the Texture Analyzer, and brought into contact with the pig intestine sample. An uncoated support was used as the control. After 7 minutes, the support was lifted away from the sample tissue and the load versus deformation curve was plotted. Instrumental settings are listed in the table below:

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