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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1611—Inorganic compounds
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
  • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
• • 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
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
• • 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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
  • A61K9/2846—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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
  • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to a drug delivery composition.
• the present invention also relates to its use and method for making the same.
• These tablets function by allowing a fluid, such as gastric or intestinal fluid, to permeate the coating membrane and dissolve the active ingredient so it can be released through a passageway in the coating membrane by osmotic tension or if the active ingredient is insoluble in the permeating fluid, pushed through the passageway by an expanding agent such as a hydrogel.
• a fluid such as gastric or intestinal fluid
• 3,629,393 utilizes a three- component system to provide slow release tablets in which granules of an active ingredient with a hydrophobic salt of a fatty acid and a polymer are combined with granules of a hydrocolloid and a carrier and granules of a carrier and an active or a buffering agent, which are then directly compressed into tablets.
• U.S. Patent No. 3,728,445 discloses slow release tablets formed by mixing an active ingredient with a solid sugar excipient, granulating the same by moistening with a cellulose acetate phthalate solution, evaporating the solvent, recovering the granules and compressing under high pressure.
• 6,645,528 teaches porous drug matrices and methods of manufacture thereof. Such systems are at a disadvantage because they allow drug delivery via a singular unit. This presents a high risk approach to drug delivery as the single unit may be incapacitated during transit in the gastrointestinal tract or its integrity compromised leading to dose dumping. Furthermore, the singular unit tablet may be excreted intact without drug release.
• a drug delivery composition comprising extruded spheroids, the spheroids comprising: at least one active pharmaceutical ingredient; at least one extrusion-spheronization aid; at least one superdisintegrant; and at least one glidant, at least one lubricant, and/or at least one oil.
• a drug delivery composition comprising coated spheroids having inert spheroids and at least one coating for the spheroids, the coating comprising at least one active pharmaceutical ingredient and at least one superdisintegrant.
• a method for administering the drug delivery composition to a mammal to provide a timed, pulsed, chronotherapeutic, extended or controlled release of said at least one active pharmaceutical ingredient.
• a use of the drug delivery composition in a medicament for providing a mammal with a timed, pulsed, chronotherapeutic, extended or controlled release of said at least one active pharmaceutical ingredient in a medicament for providing a mammal with a timed, pulsed, chronotherapeutic, extended or controlled release of said at least one active pharmaceutical ingredient.
• a use of the drug delivery composition for providing a mammal with a timed, pulsed, chronotherapeutic, extended or controlled release of said at least one active pharmaceutical ingredient for providing a mammal with a timed, pulsed, chronotherapeutic, extended or controlled release of said at least one active pharmaceutical ingredient.
• a method for making the drug delivery composition comprising: combining dry materials of the composition to provide a homogeneous blend; combining the granules with said at least one glidant, at least one lubricant, and/or at least one oil to provide a wetted mass suitable for extrusion-spheronization; and extruding the wetted mass to form the spheroids.
• the wetted mass has a plasticity.
• the wetted mass comprises from about 1 :0.7 to about 1 :2 of the extrusion aid to said at least one glidant, at least one lubricant, and/or at least one oil.
• Figure 1 is a dissolution profile for capsules of Example 3; and Figure 2 is a dissolution profile for tablets of Example 3.
• the present invention is directed to a drug delivery composition and to a method of using and preparing same in order to control the rate and extent of delivery of active pharmaceutical ingredient(s) in mammals.
• the drug delivery composition comprises spheroids.
• the spheroids comprise at least one active pharmaceutical ingredient; at least one extrusion-spheronization aid; at least one superdisintegrant; and at least one glidant, at least one lubricant, and/or at least one oil.
• the spheroids can further comprise at least one carbomer, at least one buffering agent, at least one electrolyte, zein, and/or water.
• the spheroids of the composition can be made by extrusion, typically, an extrusion- spheronization process.
• the spheroids can comprise from about 0.1 wt% to about 80 wt% of at least one active pharmaceutical ingredient, from about 10 wt% to about 90 wt% of at least one extrusion-spheronization aid, from about 0.1 wt% to about 70 wt% of at least one superdisintegrant, from about 0.1 wt% to about 70 wt% of at least one glidant, from about 0.1 wt% to about 70 wt% of at least one lubricant, and from about 0.1 wt% to about 50 wt% of at least one oil.
• the spheroids can further comprise from about 0 wt% to about 50 wt% of at least one carbomer, from about 0 wt% to about 25 wt% of at least one buffering agent, from about 0 wt% to about 55 wt% of at least one electrolyte, from about 0 wt% to about 25 wt% of zein, and/or from about 0 wt% to about 10 wt% of water. These wt% are based on the total weight of the spheroid.
• the active pharmaceutical ingredient can also be present of from about 5 wl% to about 70 wt%; about 10 wt% to about 70 wt%; about 20 wt% to about 60 wt%; about 30 wt% to about 60 wt%; or from about 40 wt% to about 60 wt%.
• the extrusion-spheronization aid can also be present of from about 10 wt% to about 70 wt%; from about 20 wt% to about 70 wt%; about 30 wt% to about 70 wt%; about 40 wt% to about 70 wt%; about 50 wt% to about 70 wt%; or from about 55 wt% to about 70 wt%.
• the superdisintegrant can also be present of from about 2 wt% to about 70 wt%; from about 20 wt% to about 70 wt%; about 30 wt% to about 70 wt%; about 40 wt% to about 70 wt%; about 50 wt% to about 70 wt%; or from about 55 wt% to about 70 wt%.
• the glidant can also be present of from about 1 wt% to about 20 wt%; from about 1 wt% to about 15 wt%; from about 2 wt% to about 15 wt%; from about 5 wt% to about 15 wt%; or from about 5 wt% to about 10 wt%.
• the lubricant can also be present of from about 0.5 wt% to about 5 wt%; from about 0.5 wt% to about 4 wt%; from about 0.5 wt% to about 3 wt%; from about 0.5 wt% to about 2 wt%; or from about 1 wt% to about 2 wt%.
• the oil can also be present of from about 0.5 wt% to about 5 wt%; from about 0.5 wt% to about 4 wt%; from about 0.5 wt% to about 3 wt%; from about 0.5 wt% to about 2 wt%; or from about 1 wt% to about 2 wt%.
• Spheroids of drug delivery compositions tend to have more reproducible upper Gl transit patterns than the singular polymeric matrix tablets, for example, if dosing in the fed and fasted states is compared. Since Gl transit time is an important parameter relevant to the variability of plasma concentration during drug delivery, this makes the use of multiparticulate drug delivery compositions, such as spheroids, more desirable than singular polymeric matrix systems.
• the use of a multiparticulate drug delivery composition instead of a singular polymeric matrix tablet is more advantageous since the multiparticulate drug delivery composition can contain a plurality of spheroids containing drugs. Therefore, the loss of integrity of a few spheroids is not going to be statistically significant as compared to the singular polymeric matrix tablet of the prior art. Therefore, the delivery of many therapeutic agents will be most effective when made available as a multiparticulate drug delivery composition.
• the spheroids of the drug delivery composition described above can also be coated, for example, with at least one layer of a polymeric film coat; at least one layer of enteric coat; at least one layer of non-enteric coat; and/or at least one layer of semi-permeable membrane coat.
• the coating is from about 0.5 wt% to about 50 wt% based on the total weight of the spheroid and coating.
• the coating is from about 1 wt% to about 20 wt%, from about 1 wt% to about 10 wt%, from about 1 wt% to about 7 wt%, from about 3.5 wt% to about 7 wt%, from about 3.5 wt% to about 6 wt%, or from about 4 wt% to about 5 wt%.
• the weight percentages of the components in the coating described herein are based on the weight of the coating.
• the coatings can include: An enteric coating which can comprise at least one enteric material and at least one superdisintegrant.
• the coating further comprises at least one wicking agent, carragenaan, and at least one plasticizer.
• the coating comprises from about 10 wt% to about 90 wt% of the enteric material, such as cellulose esters or polymethacrylates; from about 0.5 wt% to about 60 wt% of the superdisintegrant; from about 0 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% of the plasticizer, such as polyethylene glycol.
• the enteric material such as cellulose esters or polymethacrylates
• the wicking agent such as microcrystalline cellulose
• the plasticizer such as polyethylene glycol
• a non-enteric coating which can comprise at least one non-enteric material and at least one superdisintegrant.
• the coating further comprises at least one wicking agent, carragenaan, and at least one plasticizer.
• the coating comprises from about 10 wt% to about 90 wt% of the non-enteric material, such as ethylcellulose and/or polyvinylacetate; from about 0.5 wt% to about 60 wt% of the superdisintegrant; from about 0 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% of the plasticizer, such as polyethylene glycol.
• a semi-permeable membrane coating which can comprise at least one semi-permeable membrane material and at least one superdisintegrant.
• the coating further comprises at least one wicking agent, carragenaan, and at least one plasticizer.
• the coating comprises from about 10 wt% to about 90 wt% of the semi-permeable membrane material, such as cellulose acetate phthalate; from about 0.5 wt% to about 60 wt% of the superdisintegrant; from about 0 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose; from about 0 wt% to about
• the enteric material can also be present in the coating of from about 5 wt% to about 90 wt%; from about 10 wt% to about 80 wt%; from about 20 wt% to about 80 wt%; from about 30 wt% to about 70 wt%; or from about 40 wt% to about 70 wt%.
• the non-enteric material can also be present in the coating of from about 5 wt% to about 90 wt%; from about 10 wt% to about 80 wt%; from about 20 wt% to about 80 wt%; from about 30 wt% to about 70 wt%; or from about 40 wt% to about 70 wt%.
• the semi-permeable membrane material can also be present in the coating of from about 5 wt% to about 90 wt%; from about 10 wt% to about 80 wt%; from about 20 wt% to about 80 wt%; from about 30 wt% to about 70 wt%; or from about 40 wt% to about 70 wt%.
• the superdisintegrant can also be present in the coating of from about
• the wicking agent can also be present in the coating of from about 0.5 wt% to about 55 wt%; from about 0.5 wt% to about 50 wt%; from about 0.5 wt% to about 40 wt%; from about 5 wt% to about 40 wt%; or from about 20 wt% to about 40 wt%.
• Carragenaan can also be present in the coating of from about 0.5 wt% to about 55 wt%; from about 0.5 wt% to about 50 wt%; from about 0.5 wt% to about 40 wt%; from about 5 wt% to about 40 wt%; or from about 20 wt% to about 40 wt%.
• the plasticizer can also be present in the coating of from about 0.5 wt% to about 25 wt%; from about 1 wt% to about 20 wt%; from about 5 wt% to about 20 wt%; from about 5 wt% to about 15 wt%; or from about 1 wt% to about 5 wt%.
• the coating of the coated spheroids comprises from about 10 wt% to about 90 wt% of the enteric material, such as cellulose esters and/or polymethacrylates; from about 0.5 wt% to about 60 wt% of the superdisintegrant; from about 0.5 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol.
• the enteric material such as cellulose esters and/or polymethacrylates
• the superdisintegrant from about 0.5 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose
• the wicking agent such as microcrystalline cellulose
• plasticizer such as polyethylene glycol
• the coating of the coated spheroids comprises from about 10 wt% to about 90 wt% of the non-enteric material, such as ethylcellulose and/or polyvinylacetate; from about 0.5 wt% to about 60 wt% of the superdisintegrant; from about 0.5 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol.
• the non-enteric material such as ethylcellulose and/or polyvinylacetate
• the superdisintegrant from about 0.5 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose
• the wicking agent such as microcrystalline cellulose
• plasticizer such as polyethylene glycol
• the coating of the coated spheroids comprises from about 10 wt% to about 90 wt% of the semipermeable membrane material such as cellulose acetate phthalate; from about 0.5 wt% to about 60 wt% of a superdisintegrant; from about 0.5 wt% to about 60 wt% of a wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol.
• the semipermeable membrane material such as cellulose acetate phthalate
• a superdisintegrant from about 0.5 wt% to about 60 wt% of a wicking agent, such as microcrystalline cellulose
• a wicking agent such as microcrystalline cellulose
• plasticizer such as polyethylene glycol
• the coating of the coated spheroids comprises from about 10 wt% to about 90 wt% polyvinylacetate and/or ethylcellulose; from about 0.5 wt% to about 60 wt% of a superdisintegrant; from about 0.5 wt% to about 60 wt% of a wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol.
• the spheroids (e.g. with or without coating) of the composition may be encapsulated (e.g.
• At least one population of spheroids coated with at least one layer of a polymeric film coat are encapsulated or compressed into at least one tablet.
• at least one population of spheroids coated with at least one layer of enteric coat are encapsulated or compressed into at least one tablet.
• at least one population of spheroids coated with at least one layer of non-enteric coat are encapsulated or compressed into at least one tablet.
• at least one population of spheroids coated with at least one layer of semi-permeable membrane coat are encapsulated or compressed into at least one tablet.
• the drug delivery composition can also comprise coated inert spheroids.
• Any suitable coating of the inert spheroids is a coating composition that comprises at least one active pharmaceutical ingredient.
• the coating can include at least one active pharmaceutical ingredient and at least one superdisintegrant.
• the coating comprises from about 0.1 wt% to about 80 wt% of at least one active pharmaceutical ingredient and from about 0.5 wt% to about 60 wt% of the superdisintegrant.
• the coating can further comprise at least one wicking agent, carragenaan, at least one plasticizer, at least one electrolyte, at least one oil, at least one water soluble gellable polymer, at least one water insoluble organosoluble polymer, at least one glidant, at least one buffering agent, and water.
• wicking agent from about 0 wt% to about 60 wt% of a wicking agent; from about 0 wt% to about 60 wt% carragenaan; from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol; from about 0 wt% to about 55 wt% of at least one electrolyte, from about 0 wt% to about 55 wt% of at least one oil, from about 0 wt% to about 50 wt% at least one water soluble gellable polymer, from about 0 wt% to about 50 wt% at least one water insoluble organosoluble polymer, from about 0 wt% to about 25 wt% of at least one glidant, from about 0 wt% to about 25 wt% of at least one buffering agent, and/or from about 0 wt% to about 10 wt% of water.
• plasticizer such as polyethylene glycol
• plasticizer
• the active pharmaceutical ingredient can also be present in the coating of from about 0.5 wt% to about 90 wt%; from about 10 wt% to about 80 wt%; from about 20 wt% to about 80 wt%; from about 30 wt% to about 70 wt%; or from about 40 wt% to about 70 wt%.
• the superdisintegrant can also be present in the coating of from about 0.5 wt% to about 55 wt%; from about 0.5 wt% to about 40 wt%; from about 0.5 wt% to about 30 wt%; from about 1 wt% to about 20 wt%; or from about 10 wt% to about 20 wt%.
• the wicking agent can also be present in the coating of from about 0.5 wt% to about 90 wt%; from about 0.5 wt% to about 80 wt%; from about 0.5 wt% to about 70 wl%; from about 5 wt% to about 60 wt%; or from about 20 wt% to about 60 wt%.
• Carragenaan can also be present in the coating of from about 0.5 wt% to about 90 wt%; from about 0.5 wt% to about 80 wt%; from about 0.5 wt% to about 70 wt%; from about 5 wt% to about 60 wt%; or from about 20 wt% to about 60 wt%.
• the plasticizer can also be present in the coating of from about 0.5 wt% to about 25 wt%; from about 1 wt% to about 20 wt%; from about 5 wt% to about 20 wt%; from about 5 wt% to about 15 wt%; or from about 1 wt% to about 5 wt%.
• the coating composition comprises from about 0.1 wt% to about 80 wt% of at least one active pharmaceutical ingredient; from about 0.5 wt% to about 60 wt% of a superdisintegrant; from about 0.5 wt% to about 60 wt% of a wicking agent, such as microcrystalline cellulose and/or pectin; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol.
• a wicking agent such as microcrystalline cellulose and/or pectin
• plasticizer such as polyethylene glycol
• the coating composition can further comprise from about 0 wt% to about 55 wt% of at least one electrolyte, from about 0 wt% to about 55 wt% of at least one oil, from about 0 wt% to about 90 wt% of at least one plasticizer, from about 0 wt% to about 50 wt% at least one water soluble gellable polymer, from about 0 wt% to about 50 wt% at least one water insoluble organosoluble polymer, from about 0 wt% to about 25 wt% of at least one glidant, from about 0 wt% to about 25 wt% of at least one buffering agent, and/or from about 0 wt% to about 10 wt% of water.
• the coating composition comprises from about 0.1 wt% to about 80 wt% of at least one active pharmaceutical ingredient, from about 0.1 wt% to about 50 wt% of at least one superdisintegrant, from about 0.5 wt% to about 90 wt% of a wicking agent, and from about 0.5 wt% to about 90 wt% of carrageenan.
• the coating composition comprises from about 0.1 wt% to about 80 wt% of at least one active pharmaceutical ingredient, about 0.1 wt% to about 50 wt% of at least one superdisintegrant, from about 0.5 wt% to about 90 wt% of microcrystalline cellulose, and from about 0.5 wt% to about 90 wt% of carrageenan.
• the coating composition can further comprise from about 0 wt% to about 55 wt% of at least one electrolyte, from about 0 wt% to about 55 wt% of at least one oil, from about 0 wt% to about 90 wt% polyethylene glycol, from about 0 wt% to about 50 wt% hydroxypropylmethyl cellulose, from about 0 wt% to about 50 wt% polyvinyl acetate, from about 0 wt% to about 25 wt% of at least one glidant, from about 0 wt% to about 25 wt% of at least one buffering agent, and/or from about 0 wt% to about 10 wt% of water.
• inert spheroids that may be used are any pharmaceutically acceptable, inert spheroid such as, and without being limited thereto, sugar spheroids, starch spheroids and/or cellulose spheroids.
• the spheroids and/or coated spheroids of the present invention can be any suitable size for drug delivery.
• the spheroids may have a diameter of less than about 6 mm; from about 0.01 mm to about 5.0 mm; or from about 0.15 mm to about 5 mm.
• the coating is typically applied to the spheroid to yield a surface area of about 0.1 mg/cm 2 to about 20 mg/cm 2 .
• the drug delivery composition embodiments of the present invention can be used for providing a mammal with a timed, pulsed, chronotherapeutic, extended or controlled release of at least one active pharmaceutical ingredient.
• the drug delivery composition of the present invention may be in any suitable form that provides release of the spheroids.
• the composition can be in the form of a tablet or capsule such as, encapsulating (e.g. placed within a capsule) or compressing into a tablet at least one population of spheroids.
• the tablets or capsules themselves can also be coated, for example, with a polymeric film, such as polymethacrylate copolymers, to provide a timed, pulsed, chronotherapeutic, extended or controlled release of at least one active pharmaceutical ingredient.
• a method for treating a disease for which at least one active pharmaceutical ingredient in the drug delivery composition is effective comprises administering to a mammal in need of such treatment the timed, pulsed, chronotherapeutic, controlled or extended release drug delivery composition of the present invention.
• the drug delivery composition of the present invention can be used for the treatment of hypertension, angina, diabetes, HIV AIDS, pain, depression, psychosis, microbial infections, gastro esophageal reflux disease, impotence, cancer, cardiovascular diseases, gastric/stomach ulcers, blood disorders, nausea, epilepsy, Parkinson's disease, obesity, malaria, gout, asthma, erectile dysfunction, impotence, urinary incontinence, irritable bowel syndrome, ulcerative colitis, smoking, arthritis, rhinitis, Alzheimer's disease, attention deficit disorder, cystic fibrosis, anxiety, insomnia, headache, fungal infection, herpes, hyperglycemia, hyperlipidemia, hypotension, high cholesterol, hypothyroidism, infection, inflammation, mania, menopause, multiple sclerosis, osteoporosis, transplant rejection, schizophrenia, neurological disorders.
• the drug delivery composition can dissolve rapidly, instantaneously or melt in the mouth, releasing the spheroids.
• the drug delivery composition has a dissolution profile wherein from about 0 % to 50 % of active pharmaceutical ingredient(s) is released in the first hour and greater than about 70% is released in approximately 24 hours.
• various populations of spheroids may be used.
• a coated population of spheroids can be combined with an uncoated population of spheroids and encapsulated in a capsule or compressed into a tablet.
• coated spheroids with different release rates can be combined together and encapsulated in a capsule or compressed into a tablet.
• the spheroids can be prepared by extrusion-spheronization.
• drug-powder or drug solution layering can be used to coat the spheroids.
• the spheroids themselves can be inert and the coating itself contain the active pharmaceutical ingredient(s).
• liquids tend to migrate to the surface of spheroids and induce surface plasticity. At very low levels, the surface moisture contributes to lubrication and enhances spheroid movement. At high levels, and especially at reduced ratios of the extrusion-spheronization aid, the liquid may cause the spheroids to stick to one another and the spheronizer wall. It may also lead to uncontrolled granule growth and wide distribution of particle size and, therefore, the batch may be destroyed. This underscores the relationship that exists between the amount of liquid for lubrication and the production of spheroids that are free from agglomeration.
• the drug delivery composition of the present invention introduces a high margin of formulation tolerance which brings about a balance between rigidity and plasticity of the spheroids.
• spheroids within a narrow size distribution range can be manufactured conveniently and consistently. This method lowers the chance of material being discarded or reworked after a production run due to a low yield in the required size range.
• Good extrudates and spheroids can be obtained from the spheroid compositions described herein, for example, a composition comprising from about 0.1 wt% to about 80 wt% of at least one active pharmaceutical ingredient, from about 10 wt% to about 90 wt% of at least one extrusion- spheronization aid, from about 0.1 wt% to about 70 wt% of at least one superdisintegrant, from about 0.1 wt% to about 70 wt% of at least one glidant, from about 0.1 wt% to about 70 wt% of at least one lubricant, and from about 0.1 wt% to about 50 wt% of at least one oil.
• the spheroids can further comprise from about 0 wt% to about 50 wt% of at least one carbomer, from about 0 wt% to about 25 wt% of at least one buffering agent, from about 0 wt% to about 55 wt% of at least one electrolyte, from about 0 wt% to about 25 wt% of zein, and/or from about 0 wt% to about 10 wt% of water.
• extrudates are prepared by first blending the dry materials of the composition in a planetary mixer for a suitable time to provide a homogeneous blend; typically, for about 5 minutes.
• the homogeneous blend is granulated for about 5 minutes using at least one glidant, at least one lubricant, and/or at least one oil such as, for example, water, oil and, sometimes, an aqueous solution of plasticizer.
• the granulation time, end point and amount of granulation liquid is determined by the behavior (e.g. should have a plasticity) of a resultant wetted mass during extrusion-spheronization operation.
• the extrusion aid to the at least one glidant, at least one lubricant, and/or at least one oil is used to form the resultant wetted mass.
• at least one lubricant for example, from about 100 wt% : 70 wt% to about 100 wt% : 200 wt% of the extrusion aid to the at least one glidant, at least one lubricant, and/or at least one oil is used to form the resultant wetted mass.
• the wetted mass is passed through the extruder to form rods.
• the extrudates are charged onto the spheronizer rotating plate and spun at a predetermined rpm for about 30 seconds to about 5 minutes or for a suitable time to provide spheroids.
• the spheroids are harvested and dried.
• the spheroids are dried to provide spheroids having a water content of less than about 10 wt%.
• the spheroids are dried at about 4O 0 C for about 16 hours in a tray drier oven to provide a water content of less than about 10 wt%.
• the granulation solution serves as binder, and together with lubricants, oils and glidants listed above aid the extrusion-spheronization process.
• a coating composition such as, and without being limited thereto, a solution, a dispersion or a suspension of the coating composition, is coated onto the spheroids.
• the spheroids can have no coating or already have at least one coating prior to the coating with the coating composition.
• the coating composition can be applied using any suitable coating process used in the pharmaceutical industry that substantially maintains the integrity of a majority of the spheroids. For example, a fluid bed, powder layering and/or a centrifugal process may be used.
• the coating method can be repeated to provide more than one coating layer.
• the coating composition can comprise a polymeric film, an enteric material; a non-enteric material; and/or a semi-permeable membrane material.
• the resultant coating is from about 0.5 wt% to about 50 wt% based on the total weight of the spheroid and coating.
• the coating composition comprises from about 10 wt% to about 90 wt% of the enteric material, such as cellulose esters and/or polymethacrylates; from about 0.5 wt% to about 60 wt% of the superdisintegrant; from about 0.5 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol.
• the enteric material such as cellulose esters and/or polymethacrylates
• the superdisintegrant from about 0.5 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose
• the wicking agent such as microcrystalline cellulose
• plasticizer such as polyethylene glycol
• the coating composition comprises from about 10 wt% to about 90 wt% of the non-enteric material, such as ethylcellulose and/or polyvinylacetate; from about 0.5 wt% to about 60 wt% of the superdisintegrant; from about 0.5 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol.
• the non-enteric material such as ethylcellulose and/or polyvinylacetate
• the superdisintegrant from about 0.5 wt% to about 60 wt% of the wicking agent, such as microcrystalline cellulose
• the wicking agent such as microcrystalline cellulose
• plasticizer such as polyethylene glycol
• the coating composition comprises from about 10 wt% to about 90 wt% of the semi-permeable membrane material such as cellulose acetate phthalate; from about 0.5 wt% to about 60 wt% of a superdisintegrant; from about 0.5 wt% to about 60 wt% of a wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol.
• the semi-permeable membrane material such as cellulose acetate phthalate
• a superdisintegrant from about 0.5 wt% to about 60 wt% of a wicking agent, such as microcrystalline cellulose
• a wicking agent such as microcrystalline cellulose
• plasticizer such as polyethylene glycol
• the coating composition comprises from about 10 wt% to about 90 wt% polyvinylacetate and/or ethylcellulose; from about 0.5 wt% to about 60 wt% of a superdisintegrant; from about 0.5 wt% to about 60 wt% of a wicking agent, such as microcrystalline cellulose; from about 0 wt% to about 60 wt% carragenaan and from about 0 wt% to about 25 wt% plasticizer, such as polyethylene glycol.
• the coating composition comprises from about 0.1 wt% to about 80 wt% of at least one active pharmaceutical ingredient and from about 0.5 wt% to about 60 wt% of the superdisintegrant.
• the coating can further comprise at least one wicking agent, carragenaan, at least one plasticizer, at least one electrolyte, at least one oil, at least one water soluble gellable polymer, at least one water insoluble organosoluble polymer, at least one glidant, at least one buffering agent, and water.
• a solution, a dispersion or a suspension of the coating composition is coated onto the inert spheroids.
• the spheroids can have no coating or already have at least one coating prior to coating with the coating composition.
• the coating composition can be applied using any suitable coating process used in the pharmaceutical industry that substantially maintains the integrity of a majority of the spheroids. For example, a fluid bed, powder layering and/or a centrifugal process may be used.
• the inert spheroids can be, for example, sugar, starch and/or cellulose spheroids.
• the coating composition can be applied using powder layering in a coating pan.
• the coating composition is added to the inert spheroids while rotating the coating pan.
• the solution is evaporated leaving behind layers of active pharmaceutical ingredient(s) surrounding the spheroids.
• the spheroids can be further coated.
• the coated spheroids can also be further coated with one or more layers of a polymeric film.
• the active pharmaceutical ingredient refers to chemical or biological molecules providing a therapeutic, diagnostic, or prophylactic effect in vivo.
• Active pharmaceutical ingredients contemplated for use in the compositions described herein include the following categories and examples of drugs and alternative forms of these drugs such as alternative salt forms, free acid forms, free base forms, and hydrates: analgesics/antipyretics (e.g., aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine, oxycodone, codeine, dihydrocodeine bitartrate, pentazocine, hydrocodone bitartrate, levorphanol, diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol, choline salicylate, butalbital
• drugs are generally considered to be water soluble.
• Other drugs include albuterol, adapalene, doxazosin mesylate, mometasone furoate, ursodiol, amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride, valrubicin, albendazole, conjugated estrogens, medroxyprogesterone acetate, nicardipine hydrochloride, Zolpidem tartrate, amlodipine besylate, ethinyl estradiol, rubitecan, amlodipine besylate/benazepril hydrochloride, paroxetine hydrochloride, paclitaxel, atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate, fentanyl, pramipexole dihydrochloride, Vitamin D 3 and related analogues,
• any suitable extrusion- spheronization aids such as microcrystalline cellulose, pectin and ethylcellulose.
• any superdisintegrants that can improve and modulate the release of the active pharmaceutical ingredient(s) are suitable.
• sodium starch glycolate, sodium croscarmellose, homopolymer of cross-linked N-vinyl-2- pyrrolidone, and alginic acid a cross-linked cellulose, a cross-linked polymer, a cross-linked starch, ion-exchange resin, crospovidone and combinations thereof.
• any suitable glidant such as talc, silicon dioxide, starch, calcium silicate, Cabosil, Syloid, and silicon dioxide aerogels.
• silicon dioxide is used.
• any suitable lubricant are water, alkali stearates such as magnesium stearate, calcium stearate, zinc stearate, polyethylene glycol, adipic acid, hydrogenated vegetable oils, sodium chloride, sterotex, glycerol monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, light mineral oil and the like may be employed.
• Waxy fatty acid esters such as glyceryl behenate, sold as "Compritol” products, can be used.
• Other useful commercial lubricants include "Stear-O-Wet" and "Myvatex TL".
• magnesium stearate, talc and/or glycerol monostearate can be used, for example, one or more selected from Almond Oil, Apricot Kernel Oil, Avocado Oil, Black Currant Oil, 14% GLA, Borage Oil, 20% GLA, Canola Oil, Carrot Oil, Castor Oil, Clove Leaf Oil, coconut Oil, Corn Oil, Cottonseed Oil, Evening Primrose Oil, 9% GLA, Flaxseed Oil, 55% ALA, Grapeseed Oil, Hazelnut Oil, Hemp Oil, ALA / GLA, Hydrogenated Oils, Jojoba Oil, Golden Jojoba Oil, Water-white Kukui Nut Oil, Macadamia Nut Oil, Oat Oil, Olive Oil, Extra Virgin Olive Oil Pomace/"B” grade, Olive Oil, Pure/NF, Palm Oil, Parsley Seed Oil, Peach Kernel Oil, Peanut Oil, Pecan Oil, Pistachio Oil, Pumpkinseed Oil, Rice Bran Oil, Rose Hip Seed Oil,
• the wicking agent creates channels or pores.
• examples include microcrystalline cellulose, pectin, colloidal silicon dioxide, kaolin, titanium dioxide, alumina, sodium lauryl sulfate, low molecular weight polyvinyl pyrrolidone, polyester and polyethylene.
• electrolytes any suitable electrolyte can be used such as one or more salts capable of providing, sodium (Na + ), potassium (K + ), chloride (Cl " ), calcium (Ca 2+ ), magnesium (Mg 2+ ), bicarbonate (HCO 3 " ), phosphate (PO 4 2" ), and sulfate (SO 4 2" ) ions.
• polymeric films examples include polymethacrylates copolymer and enteric materials.
• enteric polymers useful in the present invention include esters of cellulose and its derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polymethacrylates, polyvinyl acetate phthalate, methacrylic acid-methacrylate copolymers and shellac.
• methacrylic acid copolymers are sold under the trademark Eudragit (L100, S100, L30D 55) manufactured by Rhom Pharma, Cellacefate (cellulose acetate phthalate) from Eastman Chemical Co., Aquateric (cellulose acetate phthalate aqueous dispersion) from FMC Corp. and hydroxypropyl methylcellulose acetate succinate aqueous dispersion from Shin Etsu K. K.
• Example of non-enteric materials include cellulose ethers and ethylcellulose.
• semi-permeable membrane materials includes cellulose acetate phthalate and cellulose acetate.
• plasticizers include polyethylene glycol, dibutyl sebacate, triethyl citrate, castor oil, glyceryl monostearate, diethyl phthalate, and glyceryl trihepthanoate.
• timed release pulsed release
• chronotherapeutic release extended release
• controlled release the release of the drug from the dosage form at such a rate that when a dose of the drug is administered in the timed release, pulsed release, chronotherapeutic release, extended release or controlled- release form, blood (e.g., plasma) concentrations (levels) of the drug are maintained within the therapeutic range but below toxic levels over a selected period of time.
• the articles “a”, “an”, “the”, and “said” are intended to mean that there are one or more of the elements unless the context dictates otherwise.
• the term “a compound” and “at least one compound” may include a plurality of compounds, including mixtures thereof.
• the terms “comprising”, “having”, “including” are intended to be open-ended and mean that there may be additional elements other than the listed elements.
• Example 1 Controlled Release Methylphenidate HCI Spheroids This was a two step process in which immediate release spheroids were manufactured by an extrusion-spheronization process followed by application of a controlled release coating on the spheroids to form controlled release spheroids.
• QS Used as aqueous granulating solution (Aquacoat ) QS was typically about 100 wt% to about 200 wt%
• the materials were charged into a planetary mixer and blended for about 5 minutes.
• the resultant homogeneous blend was granulated for about 3 minutes with the sufficient quantity of water with respect to Formulation I and Formulation II, while an aqueous suspension of ethylcellulose (commercial brand AquacoatTM) was used for Formulation III.
• the wet mass was extruded using a Caleva extruder Model 25.
• the extrudates were spheronised in about 500 gram quantities in a Caleva spheroniser Model 240.
• the wet spheroids were dried at about 4O 0 C in a tray dryer oven to LOD (loss on drying) of less than about 2 wt%.
• spheroids from Formulation Il were coated with an aqueous dispersion composed of about 500 g of AquacoatTM (e.g. ethylcellulose dispersion), about 40 g LustreClearTM (e.g. carrageenan and microcrystalline cellulose), about 36 g of dibutyl sabate, and about 114 g of water.
• AquacoatTM e.g. ethylcellulose dispersion
• LustreClearTM e.g. carrageenan and microcrystalline cellulose
• the spheroids were coated to a weight gain of about 6% of the spheroid weight.
• spheroids from Formulation III were coated with an aqueous dispersion composed of about 350 g of AquacoatTM (e.g. ethylcellulose dispersion), about 36 g of dibutyl sabate, 2Og of pigment and about 72 g of water.
• AquacoatTM e.g. ethylcellulose dispersion
• the spheroids were coated to a weight gain of about
• Coating was done in a UniGlatt fluid bed coater using a top spray assembly.
• the coated spheroids were dried in a tray dryer oven for about 2 hours at about 6O 0 C.
• a coated population of spheroids were combined with an uncoated population of spheroids and encapsulated in a capsule or compressed into a tablet.
• coated spheroids with different release rates were combined together and encapsulated in a capsule or compressed into a tablet.
• Water QS QS QS was typically about 100 wt% to about 200 wt%
• the materials were charged into a planetary mixer and blended for about 5 minutes.
• the resultant homogeneous blend was granulated for about 3 minutes with the sufficient quantity of water.
• the wet mass was extruded using a Caleva extruder Model 25.
• the extrudates were spheronised in about 500 gram quantities in a Caleva spheroniser Model 240.
• the wet spheroids were dried at about 4O 0 C in a tray dryer oven to LOD (loss on drying) of less than about 2 wt%.
• Type 1 is made of a blend of 10 wt% Formulation IV, 45 wt% Formulation IVa and 45 wt% Formulation Va.
• Type 2 is made of a blend of 30 wt% Formulation IV, and 70 wt% Formulation Va.
• Type 3 is made of a blend of 40 wt% Formulation IVa and 60 wt% Formulation Va.
• QS was typically about 100 wt% to about 200 wt%
• Carvedilol and crospovidone were slowly added to an aqueous solution of LustreClearTM and/or OpadryTM and mixed well.
• Sugar spheres (18-20 mesh) were coated with the drug suspension in a UniGlatt fluid bed coater.
• the spheroids were coated to a weight gain of about 10% of the spheroid weight.
• the spheroids were dried to LOD (loss on drying) of less than about 2 wt%.
• spheroids from Formulation Vl were coated with an aqueous dispersion composed of about 500 g of AquacoatTM (e.g. ethylcellulose dispersion), about 40 g LustreClearTM (e.g. carrageenan and microcrystalline cellulose), about 35.5 g of dibutyl sabate, and about 114 g of water.
• AquacoatTM e.g. ethylcellulose dispersion
• LustreClearTM e.g. carrageenan and microcrystalline cellulose
• spheroids from Formulation VII were coated with an aqueous dispersion composed of about 500 g of AquacoatTM (e.g. ethylcellulose dispersion), about 40 g LustreClearTM (e.g. carrageenan and microcrystalline cellulose), about 36 g of dibutyl sabate, and about 114 g of water.
• the spheroids were coated to a weight gain of about 6% of the spheroid weight.
• About 100Og of the spheroids from Formulation VIII were coated with an aqueous dispersion composed of about 500 g of AquacoatTM (e.g. ethylcellulose dispersion), about 40 g LustreClearTM (e.g. carrageenan and microcrystalline cellulose), about 36 g of dibutyl sabate, and about 114 g of water.
• the spheroids were coated to a weight gain of about 6% of the spheroid weight.
• spheroids from Formulation Vl were coated with an aqueous dispersion composed of about 400 g of Eudragit NE30DTM and about 60 g of talc to a weight gain of about 6% of the spheroid weight.
• spheroids from Formulation VII were coated with an aqueous dispersion composed of about 400 g of Eudragit NE30DTM and about 60 g of talc to a weight gain of about 6% of the spheroid weight.
• spheroids from Formulation VIII were coated with an aqueous dispersion composed of about 400 g of Eudragit NE30DTM and about 60 g of talc to a weight gain of about 6% of the spheroid weight.
• Coating was done in a UniGlatt fluid bed coater using a top spray assembly.
• the coated spheroids were dried in a tray dryer oven for about 2 hours at about 6O 0 C.
• the controlled release spheroids were coated with an aqueous dispersion composed of about 1142 g of Eudragit L30D55TM (e.g. methacrylic acid copolymer), about 137 g of glycerol monostearate, about 41 g of triacetyl citrate, and about 679 g of water and/or an aqueous dispersion composed of about 1142 g of cellulose esters, about 137 g of glycerol monostearate, about 41 g of triacetyl citrate, and about 679 g of water to a weight gain sufficient to give a lag time of about 1 hour to about 12 hours as desired.
• Figure 1 shows a dissolution profile for these capsules.
• the controlled release coated population of spheroids and/or inert spheroids were compressed into a tablet and the tablet was coated an aqueous dispersion composed of about 1142 g of Eudragit L30D55TM (e.g. methacrylic acid copolymer), about 137 g of glycerol monostearate, about 41 g of triacetyl citrate, and about 679 g of water and/or an aqueous dispersion composed of about 1142 g of cellulose esters, about 137 g of glycerol monostearate, about 41 g of triacetyl citrate, and about 679 g of water to a weight gain sufficient to give a lag time of about 1 hour to about 12 hours as desired.
• Figure 2 shows a dissolution profile for these tablets.

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