Connect public, paid and private patent data with Google Patents Public Datasets

Modified release dosage forms

Download PDF

Info

Publication number
US20040241236A1
US20040241236A1 US10476238 US47623804A US2004241236A1 US 20040241236 A1 US20040241236 A1 US 20040241236A1 US 10476238 US10476238 US 10476238 US 47623804 A US47623804 A US 47623804A US 2004241236 A1 US2004241236 A1 US 2004241236A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
shell
core
active
dosage
form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10476238
Inventor
Shun-Por Li
Harry Sowden
David Wynn
Narendra Parikh
Der-Yang Lee
Martin Thomas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
OMJ Ireland Ltd
Original Assignee
Johnson and Johnson Consumer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/02Apparatus specially adapted for manufacture or treatment of sweetmeats or confectionery; Accessories therefor
    • A23G3/04Sugar-cookers
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G1/00Cocoa; Cocoa products, e.g. chocolate; Substitutes therefor
    • A23G1/30Cocoa products, e.g. chocolate; Substitutes therefor
    • A23G1/50Cocoa products, e.g. chocolate; Substitutes therefor characterised by shape, structure or physical form, e.g. products with an inedible support
    • A23G1/54Composite products, e.g. layered laminated, coated, filled
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/0002Processes of manufacture not relating to composition and compounding ingredients
    • A23G3/0004Processes specially adapted for manufacture or treatment of sweetmeats or confectionery
    • A23G3/0019Shaping of liquid, paste, powder; Manufacture of moulded articles, e.g. modelling, moulding, calendering
    • A23G3/0025Processes in which the material is shaped at least partially in a mould in the hollows of a surface, a drum, an endless band, or by a drop-by-drop casting or dispensing of the material on a surface, e.g. injection moulding, transfer moulding
    • A23G3/0029Moulding processes for hollow products, e.g. opened shell
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/34Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
    • A23G3/36Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds
    • A23G3/364Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
    • A23G3/368Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins containing vitamins, antibiotics
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/34Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
    • A23G3/50Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by shape, structure or physical form, e.g. products with supported structure
    • A23G3/54Composite products, e.g. layered, coated, filled
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A23B - A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/30Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/005Coating of tablets or the like
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/06Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2095Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/282Organic compounds, e.g. fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/282Organic compounds, e.g. fats
    • A61K9/2826Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/284Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/2873Proteins, e.g. gelatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893Tablet coating processes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B30PRESSES
    • B30BPRESSES IN GENERAL
    • B30B11/00Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
    • B30B11/02Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
    • B30B11/08Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds carried by a turntable
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B30PRESSES
    • B30BPRESSES IN GENERAL
    • B30B11/00Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
    • B30B11/34Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses for coating articles, e.g. tablets
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B30PRESSES
    • B30BPRESSES IN GENERAL
    • B30B15/00Details of, or accessories for, presses; Auxiliary measures in connection with pressing
    • B30B15/30Feeding material to presses
    • B30B15/302Feeding material in particulate or plastic state to moulding presses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2068Compounds of unknown constitution, e.g. material from plants or animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5084Mixtures 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
    • YGENERAL 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
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/13Hollow or container type article [e.g., tube, vase, etc.]
    • Y10T428/1352Polymer or resin containing [i.e., natural or synthetic]

Abstract

A dosage form comprises: (a) a core comprising at least one active ingredient; and (b) a molded shell which surrounds the core, wherein the shell provides a predetermined time delay of greater than one hour for the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium and the delay is independent of the pH of the liquid medium. The weight of the shell may be at least 50 percent of the weight of the core, and the shell may have a thickness of about 500-4000 microns, or be substantially free of pores having a diameter of 0.5 to 5 microns.

Description

    BACKGROUND OF THE INVENTION
  • [0001]
    1. Field of the Invention
  • [0002]
    This invention relates to modified release dosage forms such as modified release pharmaceutical compositions. More particularly, this invention relates to modified release dosage forms having a core containing at least one active ingredient and a shell surrounding the core, in which the shell provides a delay of greater than one hour for the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium such as water or gastrointestinal fluids, and the delay is independent of the pH of the liquid medium.
  • [0003]
    2. Background Information
  • [0004]
    Modified release pharmaceutical dosage forms have long been used to optimize drug delivery and enhance patient compliance, especially by reducing the number of doses of medicine the patient must take in a day. For this purpose, it is often desirable to modify the rate of release of a drug (one particularly preferred type of active ingredient) from a dosage form into the gastro-intestinal (g.i.) fluids of a patient, especially to slow the release in order to provide prolonged action of the drug in the body.
  • [0005]
    The rate at which an orally delivered pharmaceutical active ingredient reaches its site of action in the body depends on a number of factors, including the rate and extent of drug absorption through the gastro-intestinal (g.i.) mucosa. To be absorbed into the circulatory system (blood), the drug must first be dissolved in the g.i. fluids. For many drugs, diffusion across the g.i. membranes is relatively rapid compared to dissolution. In these cases, the dissolution of the active ingredient is the rate limiting step in drug absorption, and controlling the rate of dissolution allows the formulator to control the rate of drug absorption into the circulatory system of a patient.
  • [0006]
    An important objective of modified release dosage forms is to provide a desired blood concentration versus time (pharmacokinetic, or PK) profile for the drug. Fundamentally, the PK profile for a drug is governed by the rate of absorption of the drug into the blood, and the rate of elimination of the drug from the blood. The type of PK profile desired depends, among other factors, on the particular active ingredient, and physiological condition being treated.
  • [0007]
    One desirable PK profile for a number of drugs and conditions, is achieved by a dosage form that delivers a delayed release dissolution profile, in which the release of drug from the dosage form is delayed for a pre-determined time after ingestion by the patient. The delay period (“lag time”) can be followed either by prompt release of the active ingredient (“delayed burst”), or by sustained (prolonged, extended, or retarded) release of the active ingredient (“delayed then sustained”).
  • [0008]
    A particularly desirable type of delayed release PK profile is a “pulsatile” profile, in which for example, a first dose is delivered immediately, followed by a delay corresponding approximately to the time during which a therapeutic concentration of the first dose is maintained in the blood, followed by either prompt or sustained release of a subsequent dose of the same drug.
  • [0009]
    A particularly challenging aspect of the design of delayed release systems involves the predictability and repeatability of the lag time in vivo. Physiological systems, e.g. the human g.i. tract, have a high degree of inter- and intra-subject variability, for example in intestinal motility and pH. For the purpose of repeatability and predictability, it is desirable to have a delayed release mechanism that is independent of the pH of the environment in which the dosage form must release drug.
  • [0010]
    Well known mechanisms by which a dosage form (or drug delivery system) can deliver drug at a modified rate (e.g. delayed, pulsatile, sustained, prolonged, extended or retarded release) include diffusion, erosion, and osmosis.
  • [0011]
    One classic diffusion-controlled release system comprises active ingredient, distributed throughout an insoluble porous matrix through which the active ingredient must diffuse in order to be absorbed into the bloodstream of the patient. The amount of drug release (M) at a given time at sink conditions (i.e. drug concentration at the matrix surface is much greater than drug concentration in the bulk solution) depends on the area (A) of the matrix, the diffusion coefficient (D), the porosity (E) and tortuosity (T) of the matrix, the drug solubility (Cs) in the dissolution medium, time (t) and the drug concentration (Cp) in the dosage form:
  • M=A(DE/T(2Cp−ECs)(Cs)t)1/2
  • [0012]
    It will be noted in the above relationship that the amount of drug released is generally proportional to the square root of time. Assuming factors such as matrix porosity and tortuosity are constant within the dosage form, a plot of amount of drug released versus the square root of time should be linear.
  • [0013]
    A commonly used erosion-controlled release system comprises a “matrix” throughout which the drug is distributed. The matrix typically comprises a material which swells at the surface, and slowly dissolves away layer by layer, liberating drug as it dissolves. The rate of drug release, dM/dt, in these systems depends on the rate of erosion (dx/dt) of the matrix, the concentration profile in the matrix, and the surface area (A) of the system:
  • dM/dt=A{dx/dt}{f(C)}
  • [0014]
    Again, variation in one or more terms, such as surface area, typically lead to a non-constant release rate of drug. In general, the rate of drug release from erosion-controlled release systems typically follows first order kinetics.
  • [0015]
    Another type of erosion controlled delivery system utilizes materials which swell and dissolve slowly by surface erosion are additionally useful for providing a delayed release of pharmaceutical active ingredient. Delayed release is useful, for example in pulsatile or repeat action delivery systems, in which an immediate release dose is delivered, followed by a pre-determined lag time before a subsequent dose is delivered from the system. In these systems, the lag time (T1) depends on the thickness (h) of the erodible layer, and the rate of erosion (dx/dt) of the matrix, which in turn depends on the swelling rate and solubility of the matrix components:
  • T 1 =h(dx/dt)
  • [0016]
    The cumulative amount of drug (M) released from these systems at a given time generally follows the equation:
  • M=(dM/dt)(t−T 1)
  • [0017]
    where dM/dt is generally described by either the diffusion-controlled or erosion-controlled equations above, and T1 is the lag time.
  • [0018]
    It is often practical to design dosage forms that use a combination of the above mechanisms to achieve a particularly desirable release profile for a particular active ingredient.
  • [0019]
    Current delayed-release systems are limited by the available methods for manufacturing them, as well as the materials that are suitable for use with the current methods. A shell, or coating, which confers modified release properties, is typically applied via conventional methods, such as for example, spray-coating in a coating pan. Pan-coating produces a single shell which essentially surrounds the core. The single shell is inherently limited in its functionality. It is possible via pan-coating to apply multiple concentric shells, each with a different functionality, however such systems are limited in that the outer shell must first dissolve before the functionality conferred by each successive layer can be realized. Additionally, the coating compositions that can be applied via spraying are limited by their viscosity. Spray-coating methods suffer the further limitations of being time-intensive and costly. One well-known and commonly used design for providing delayed release of a drug employs an enteric coating material, either on particles containing the drug or on the surface of a dosage form. Enteric materials are generally selected from polymer systems which are soluble only in fluid environments with a certain pH range, higher than that of typical gastric fluid, for example pH greater than 5.5, greater than pH 6.0, or greater than pH 7.0. While these systems may be useful for protecting certain acid-labile active ingredients from gastric fluids, or for protecting the stomach lining from damage by certain active ingredients, they are limited in their applicability to programmed time-delay systems due to variability in gastrointestinal pH and motility.
  • [0020]
    The pH-independent delay of drug release has been achieved by conventional spray-coating methods. For example, G. Maffione et al., “High-Viscosity HPMC as a Film-Coating Agent,” Drug Development and Industrial Pharmacy (1993) 19(16), pp. 2043-2053, describes a core or tablet matrix, surrounded by a shell or coating, which provides a delayed burst dissolution profile. Coating levels were 12.5-25% of the weight of the core. A preferred coating formula employs a swellable film-former dispersed in non-aqueous solvent. Low polymer concentrations (5-10%), and the use of ethanol as a “non-solvent” were required for sprayability.
  • [0021]
    It is also known, via pan coating, to deliver a first dose of active ingredient from a coating, and a second dose of active ingredient from a core. U.S. Pat. No. 4,576,604, for example, discloses an osmotic device (dosage form) comprising a drug compartment surrounded by a wall (coating) in which the coating may comprise an immediate release dose of drug, and the inner drug compartment may comprise a sustained release dose of drug.
  • [0022]
    Alternately, conventional controlled release systems may be prepared by compression, to produce either multiple stacked layers, or core and shell configurations. Modified release dosage forms prepared via compression are exemplified in U.S. Pat. Nos. 5,738,874 and 6,294,200, and WO 99/51209.
  • [0023]
    It is possible via compression-coating to produce a pH-independent time delayed drug release. U.S. Pat. No. 5,464,633 discloses delayed-release dosage forms in which an external coating layer was applied by a compression coating process. The coating level ranged from 105 percent to 140 percent of the weight of the core in order to yield product with the desired time delayed profile.
  • [0024]
    Compression-coated dosage forms are limited by the shell thickness and shell composition. Gunsel et al., “Compression-coated and layer tablets” in Pharmaceutical Dosage Forms—Tablets, edited by H. A. Lieberman, L. Lachman, and J. B. Schwartz, (2nd ed., rev. and expanded Marcel Dekker) Inc., p. 247-284, for example, discloses the thickness of compression coated shells is typically between 800 and 1200 microns.
  • [0025]
    It is one object of this invention to provide a dosage form having a core which contains at least one active ingredient and a shell surrounding the core, in which the shell has a weight of at least 50 percent of the weight of the core, the shell provides a delay of greater than one hour for the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium, and the delay is independent of the pH of the liquid medium. Other objects, features and advantages of this invention will be apparent to those skilled in the art from the following detailed description of the invention.
  • SUMMARY OF THE INVENTION
  • [0026]
    The dosage form of this invention comprises:
  • [0027]
    (a) a core comprising at least one active ingredient; and
  • [0028]
    (b) a molded shell which surrounds the core, wherein the shell provides a predetermined time delay of greater than one hour for the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium and the delay is independent of the pH of the liquid medium.
  • [0029]
    In one embodiment, the weight of the shell is at least 50 percent of the weight of the core.
  • [0030]
    In another embodiment, the shell has a thickness from about 500 to about 4000 microns.
  • [0031]
    In another embodiment, the shell has a thickness from about 100 to 600 microns.
  • [0032]
    In another embodiment, the shell has a surface gloss of at least about 150 gloss units.
  • [0033]
    In another embodiment, the shell is substantially free of pores having a diameter of 0.5 to 5.0 microns.
  • [0034]
    In another embodiment, the shell comprises at least 30% of a thermal reversible carrier.
  • [0035]
    In another embodiment, the shell comprises at least about 10% of a film-former.
  • [0036]
    In another embodiment, the shell additionally comprises at least one active ingredient which may be the same or different than the active ingredient contained in the core.
  • [0037]
    In another embodiment, the dosage form additionally comprises an outer coating which covers at least a portion of the shell, and the outer coating comprises at least one active ingredient which may be the same or different than the active ingredient contained in the core.
  • [0038]
    In another embodiment, the core is a compressed tablet.
  • [0039]
    In another embodiment, the core comprises coated particles of at least one active ingredient.
  • [0040]
    In another embodiment, the core is made by molding.
  • [0041]
    In another embodiment, the core is substantially free of pores having a diameter of 0.5 to 5.0 microns.
  • [0042]
    In another embodiment, the core comprises at least about 30 weight percent of a thermal-reversible carrier.
  • [0043]
    In another embodiment, the core comprises a release-modifying excipient.
  • [0044]
    In another embodiment, the shell is not a compression coating applied to the core.
  • [0045]
    In another embodiment, the dosage form provides an immediate release of at least one active ingredient, followed by a delay of at least about 1 hour, followed by a burst release of at least one active ingredient.
  • [0046]
    In another embodiment, the shell is prepared using a solvent-free molding process.
  • [0047]
    In another embodiment, the shell comprises at least 30% by weight of a thermal-reversible carrier.
  • [0048]
    In another embodiment, the shell comprises up to 55% by weight of a swellable, erodible hydrophilic material.
  • [0049]
    In another embodiment, the shell is prepared using a solvent-based molding process.
  • [0050]
    In another embodiment, the shell comprises at least 10% by weight of a film-former.
  • [0051]
    In another embodiment, the shell comprises up to 55% by weight of a release-modifying excipient.
  • [0052]
    In another embodiment, the dosage form provides a delayed burst release profile of the active ingredient.
  • [0053]
    In another embodiment, the dosage form provides a delayed and sustained release profile of the active ingredient.
  • [0054]
    In another embodiment, the dosage form provides a pulsatile release profile of the active ingredient.
  • [0055]
    In another embodiment, the core or portion thereof further comprises shellac at a level of about 5 to about 15 weight percent of the core or portion thereof.
  • [0056]
    In another embodiment, the shell or portion thereof further comprises shellac at a level of about 5 to about 15 weight percent of the shell or portion thereof.
  • [0057]
    In another embodiment, the thermal reversible carrier is selected from the group consisting of polyethylene glycol, polyethylene oxide and copolymers and combinations thereof.
  • [0058]
    In another embodiment, the film former is polyethylene oxide.
  • [0059]
    In another embodiment, the release-modifying excipient is a swelling cross-linked polymer.
  • [0060]
    In another embodiment, the swelling cross-linked polymer is croscarmellose sodium.
  • [0061]
    In another embodiment, the shell further comprises a plasticizer.
  • [0062]
    In another embodiment, the plasticizer is tributyl citrate.
  • [0063]
    In another embodiment, the shell is prepared using a solvent-based molding process, and the weight of the shell is from about 10 percent to about 60 percent of the weight of the core.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0064]
    [0064]FIG. 1 depicts a cross-sectional view of one embodiment of this invention.
  • [0065]
    [0065]FIG. 2 depicts the percent release of active ingredient vs. hours for the dosage form of Example 1.
  • [0066]
    [0066]FIG. 3 depicts the percent release of active ingredient vs. hours for the dosage form of Example 2.
  • [0067]
    [0067]FIG. 4 depicts the percent release of active ingredient vs. hours for the dosage form of Example 3.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0068]
    As used herein, the term “dosage form” applies to any solid object, semi-solid, or liquid composition designed to contain a specific pre-determined amount (i.e. dose) of a certain ingredient, for example an active ingredient as defined below. Suitable dosage forms may be pharmaceutical drug delivery systems, including those for oral administration, buccal administration, rectal administration, topical or mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like. Preferably the dosage forms of the present invention are considered to be solid, however they may contain liquid or semi-solid components. In a particularly preferred embodiment, the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the gastro-intestinal tract of a human.
  • [0069]
    The active ingredient employed in the dosage forms of this invention may be found within the core, the shell or a combination thereof. Suitable active ingredients for use in this invention include for example pharmaceuticals, minerals, vitamins and other nutraceuticals, oral care agents, flavorants and mixtures thereof. Suitable pharmaceuticals include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, oral contraceptives, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof.
  • [0070]
    Suitable oral care agents include breath fresheners, tooth whiteners, antimicrobial agents, tooth mineralizers, tooth decay inhibitors, topical anesthetics, mucoprotectants, and the like.
  • [0071]
    Suitable flavorants include menthol, peppermint, mint flavors, fruit flavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueur flavors and combinations and the like.
  • [0072]
    Examples of suitable gastrointestinal agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate; stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as prucalopride, antibiotics for H. pylori, such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheals, such as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such as ondansetron, analgesics, such as mesalamine.
  • [0073]
    In one embodiment of the invention, the active ingredient may be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • [0074]
    In another embodiment, the active ingredient is selected from analgesics, anti-inflammatories, and antipyretics, e.g. non-steroidal anti-inflammatory drugs (NSAIDs), including propionic acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acid derivatives, e.g. indomethacin, diclofenac, sulindac, tolmetin, and the like; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid, flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal, and the like; and oxicams, e.g. piroxicam, sudoxicam, isoxicam, meloxicam, and the like. In a particularly preferred embodiment, the active ingredient is selected from propionic acid derivative NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof. In a particular embodiment of the invention, the active ingredient may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • [0075]
    In another embodiment of the invention, the active ingredient may be selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • [0076]
    Examples of suitable polydimethylsiloxanes, which include, but are not limited to dimethicone and simethicone, are those disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each is expressly incorporated herein by reference. As used herein, the term “simethicone” refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone.
  • [0077]
    The active ingredient or ingredients are present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dose regime, the age and weight of the patient, and other factors must be considered, as known in the art. Typically, the dosage form comprises at least about 5 weight percent, preferably, the dosage form comprises at least about 20 weight percent of the active ingredient. In one preferred embodiment, the core comprises at least about 25 weight percent (based on the weight of the core) of the active ingredient.
  • [0078]
    The active ingredient or ingredients may be present in the dosage form in any form. For example, the active ingredient may be dispersed at the molecular level, e.g. melted or dissolved, within the dosage form, or may be in the form of particles, which in turn may be coated or uncoated. If the active ingredient is in form of particles, the particles (whether coated or uncoated) typically have an average particle size of about 1-2000 microns. In one preferred embodiment, such particles are crystals having an average particle size of about 1-300 microns. In another preferred embodiment, the particles are granules or pellets having an average particle size of about 50-2000 microns, preferably about 50-1000 microns, most preferably about 100-800 microns.
  • [0079]
    In certain embodiments of the invention, at least a portion of the active ingredient may be coated with a release-modifying coating, as known in the art. This advantageously provides an additional tool for optimizing the release profile of the active ingredient from the dosage form Examples of suitable release modifying coatings are described in U.S. Pat. Nos. 4,173,626; 4,863,742; 4,980,170; 4,984,240;5,286,497, 5,912,013; 6,270,805; and 6,322,819. Commercially available modified release coated active particles may also be employed. Accordingly, all or a portion of one or more active ingredients may be coated with a release-modifying material.
  • [0080]
    In certain other embodiments of the invention, a further degree of flexibility in designing the dosage forms of the present invention can be achieved through the use of an additional outer coating overlaying the shell. The additional outer coating may be applied by known methods, for example by spraying, dipping, printing, roller coating, compression, or by molding. In such embodiments, the dosage form of the invention comprises a core containing at least one active ingredient; a molded shell which surrounds the core, wherein the shell provides a predetermined time delay of greater than one hour for the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium and the delay is independent of the pH of the liquid medium; and an outer coating which covers at least a portion of the shell. In one particularly preferred embodiment, the dosage form is a pulsatile drug delivery system, in which the outer coating comprises an active ingredient, which is released immediately (i.e. the dissolution of the active ingredient from the outer coating conforms to USP specifications for immediate release dosage forms of the particular active ingredient employed).
  • [0081]
    In embodiments in which it is desired for the active ingredient to be absorbed into the systemic circulation of an animal, the active ingredient or ingredients are preferably capable of dissolution upon contact with a fluid such as water, stomach acid, intestinal fluid or the like. In one embodiment, the dissolution characteristics of at least one active ingredient meets USP specifications for immediate release tablets containing the active ingredient. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856 (1999). In embodiments in which at least one active ingredient is released immediately, the immediately released active ingredient is preferrably contained in the shell or on the surface of the shell, e.g. in a further coating residing upon at least a portion of the shell. In another embodiment, the dissolution characteristics of at least one active ingredient are modified: e.g. controlled, sustained, extended, retarded, prolonged, delayed and the like. In embodiments in which at least one active ingredient is released in a modified manner, the modified release active ingredient is preferably contained in the core.
  • [0082]
    [0082]FIG. 1 depicts a cross-sectional view of one embodiment of this invention. In FIG. 1, a core 2 comprises an active ingredient. The core 2 is surrounded by a shell 4 which provides a delay of greater than one hour to the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium. The delay of the onset of dissolution is independent of the pH of the liquid medium. The weight of the shell material is at least 50 percent of the weight of the core material.
  • [0083]
    The core of the present invention may be prepared by any suitable method, including for example compression, or molding, and depending on the method by which it is made, typically comprises active ingredient and a variety of excipients (inactive ingredients which may be useful for conferring desired physical properties to the core).
  • [0084]
    In one embodiment, the core is prepared by the compression methods and apparatus described in copending U.S. patent application Ser. No. 09/966,509, pages 16-27, the disclosure of which is incorporated herein by reference. Specifically, the core is made using a rotary compression module comprising a fill zone, insertion zone, compression zone, ejection zone, and purge zone in a single apparatus having a double row die construction as shown in FIG. 6 of U.S. patent application Ser. No. 09/966,509. The dies of the compression module are preferably filled using the assistance of a vacuum, with filters located in or near each die. The purge zone of the compression module includes an optional powder recovery system to recover excess powder from the filters and return the powder to the dies.
  • [0085]
    In embodiments in which the core or a portion thereof is made by compression, suitable excipients include fillers, binders, disintegrants, lubricants, glidants, and the like, as known in the art. In embodiments in which the core is made by compression and additionally confers modified release of an active ingredient contained therein, the core preferably further comprises a release-modifying excipient for compression.
  • [0086]
    Suitable fillers for use in making the core, or a portion thereof, by compression include water-soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, maltose, and lactose, sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol, starch hydrolysates, which include dextrins, and maltodextrins, and the like, water insoluble plasticly deforming materials such as microcrystalline cellulose or other cellulosic derivatives, water-insoluble brittle fracture materials such as dicalcium phosphate, tricalcium phosphate and the like and mixtures thereof.
  • [0087]
    Suitable binders for making the core, or a portion thereof, by compression include dry binders such as polyvinyl pyrrolidone, hydroxypropylmethylcellulose, and the like; wet binders such as water-soluble polymers, including hydrocolloids such as alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, starches, and the like; and derivatives and mixtures thereof.
  • [0088]
    Suitable disintegrants for making the core, or a portion thereof, by compression include sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and the like.
  • [0089]
    Suitable lubricants for making the core, or a portion thereof, by compression include long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, and waxes.
  • [0090]
    Suitable glidants for making the core, or a portion thereof, by compression include colloidal silicon dioxide, and the like.
  • [0091]
    Suitable release-modifying excipients for making the core, or a portion thereof, by compression include swellable erodible hydrophilic materials, insoluble edible materials, pH-dependent polymers, and the like.
  • [0092]
    Suitable swellable erodible hydrophilic materials for use as release-modifying excipients for making the core, or a portion thereof, by compression, include water swellable cellulose derivatives, polyalkalene glycols, thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, and swelling cross-linked polymers, and derivitives, copolymers, and combinations thereof. Examples of suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC) such as those available from Dow Chemical Company under the tradename METHOCEL K4M, METHOCEL K15M, and METHOCEL K100M, hydroxyisopropylcellulose, hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples of suitable polyalkalene glyclols include polyethylene glycol. Examples of suitable thermoplastic polyalkalene oxides include poly (ethylene oxide). Examples of suitable acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL (high-molceular weight cross-linked acrylic acid homopolymers and copolymers), and the like. Examples of suitable hydrocolloids include alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan. Examples of suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof. Examples of suitable gelling starches include acid hydrolyzed starches, swelling starches such as sodium starch glycolate, and derivatives thereof. Examples of suitable swelling cross-linked polymers include cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcellose sodium.
  • [0093]
    Suitable insoluble edible materials for use as release-modifying excipients for making the core, or a portion thereof, by compression include water-insoluble polymers, and low-melting hydrophobic materials. Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof. Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like.
  • [0094]
    Suitable pH-dependent polymers for use as release-modifying excipients for making the core, or a portion thereof, by compression include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L and the like, and derivatives, salts, copolymers, and combinations thereof.
  • [0095]
    Suitable pharmaceutically acceptable adjuvants for making the core, or a portion thereof, by compression include, preservatives; high intensity sweeteners such as aspartame, acesulfame potassium, sucralose, and saccharin; flavorants; colorants; antioxidants; surfactants; wetting agents; and the like and mixtures thereof.
  • [0096]
    In certain preferred embodiments of the invention, the core, or the shell, or a portion thereof, is prepared by molding. In such embodiments, the core, or the shell, or a portion thereof, is made from a flowable material. The flowable material may be any edible material that is flowable at a temperature between about 37° C. and 250° C., and that is solid, semi-solid, or can form a gel at a temperature between about −10° C. and about 80° C., e.g. between about −10° C. and about 55° C., or between about −10° C. and about 35° C. When it is in the fluid or flowable state, the flowable material may comprise a dissolved or molten component, and optionally a solvent such as for example water or organic solvents, or combinations thereof. The solvent may be partially or substantially removed by drying.
  • [0097]
    Suitable flowable materials for making the core, or the shell, or a portion thereof by molding include those comprising thermoplastic materials; film formers; thickeners such as gelling polymers or hydrocolloids; low melting hydrophobic materials; non-crystallizable carbohydrates; and the like. Suitable molten components of the flowable material include thermoplastic materials, low melting hydrophobic materials, and the like. Suitable dissolved components for the flowable material include film formers, thickeners such as gelling polymers or hydrocolloids, non-crystallizable carbohydrates, and the like.
  • [0098]
    Suitable thermoplastic materials for use as components of the flowable material for making the core or the shell or a portion thereof by molding can be molded and shaped when heated, and include both water soluble and water insoluble polymers that are generally linear, not crosslinked, nor strongly hydrogen bonded to adjacent polymer chains. Examples of suitable thermoplastic materials include thermoplastic water swellable cellulose derivatives, thermoplastic water insoluble cellulose derivatrives, thermoplastic vinyl polymers, thermoplastic starches, thermplastic polyalkalene glycols, thermoplastic polyalkalene oxides, and amorphous sugar-glass, and the like, and derivatives, copolymers, and combinations thereof. Examples of suitable thermoplastic water swellable cellulose derivatives include hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC). Examples of suitable thermoplastic water insoluble cellulose derivatrives include cellulose acetate (CA), ethyl cellulose (EC), cellulose acetate butyrate (CAB), cellulose propionate. Examples of suitable thermoplastic vinyl polymers include, polyvinyl alcohol, polyvinyl acetate (PVA) and polyvinyl pyrrolidone (PVP). Examples of suitable thermoplastic starches are disclosed for example in U.S. Pat. No. 5,427,614, which is incorporated herein by reference. Examples of suitable thermoplastic polyalkalene glycols include polyethylene glycol; Examples of suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight from about 100,000 to about 900,000 Daltons. Other suitable thermoplastic materials include sugar in the form on an amorphous glass such as that used to make hard candy forms.
  • [0099]
    Any film former known in the art is suitable for use in the flowable material of the present invention. Examples of suitable film formers include, but are not limited to, film-forming water soluble polymers, film-forming proteins, film-forming water insoluble polymers, and film-forming pH-dependent polymers. Suitable film-forming water soluble polymers include water soluble vinyl polymers such as polyvinylalcohol, polyvinylacetate (PVA); water soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl starch, pre-gelatinized starches, and film-forming modified starches; water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose (HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); water soluble copolymers such as methacrylic acid and methacrylate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers; and derivatives and combinations thereof. Suitable film-forming proteins may be natural or chemically modified, and include gelatin, whey protein, myofibrillar proteins, coaggulatable proteins such as albumin, casein, caseinates and casein isolates, soy protein and soy protein isolates, zein; and polymers, derivatives and mixtures thereof. Suitable film-forming water insoluble polymers, include for example ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof. Suitable film-forming pH-dependent polymers include enteric cellulose derivatives, such as for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L and the like, and derivatives, salts, copolymers, and combinations thereof.
  • [0100]
    One suitable hydroxypropylmethylcellulose compound for use as a thermoplastic film-forming water soluble polymer is “HPMC 2910”, which is a cellulose ether having a degree of substitution of about 1.9 and a hydroxypropyl molar substitution of 0.23, and containing, based upon the total weight of the compound, from about 29% to about 30% methoxyl groups and from about 7% to about 12% hydroxylpropyl groups. HPMC 2910 is commercially available from the Dow Chemical Company under the tradename METHOCEL E. METHOCEL E5, which is one grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 4 to 6 cps (4 to 6 millipascal-seconds) at 20° C. in a 2% aqueous solution as determined by a Ubbelohde viscometer. Similarly, METHOCEL E6, which is another grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 5 to 7 cps (5 to 7 millipascal-seconds) at 20° C. in a 2% aqueous solution as determined by a Ubbelohde viscometer. METHOCEL E15, which is another grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 15000 cps (15 millipascal-seconds) at 20° C. in a 2% aqueous solution as determined by a Ubbelohde viscometer. As used herein, “degree of substitution” shall mean the average number of substituent groups attached to a anhydroglucose ring, and “hydroxypropyl molar substitution” shall mean the number of moles of hydroxypropyl per mole anhydroglucose.
  • [0101]
    One suitable polyvinyl alcohol and polyethylene glycol copolymer is commercially available from BASF Corporation under the tradename KOLLICOAT IR.
  • [0102]
    As used herein, “modified starches” include starches that have been modified by crosslinking, chemically modified for improved stability or optimized performance, or physically modified for improved solubility properties or optimized performance. Examples of chemically-modified starches are well known in the art and typically include those starches that have been chemically treated to cause replacement of some of its hydroxyl groups with either ester or ether groups. Crosslinking, as used herein, may occur in modified starches when two hydroxyl groups on neighboring starch molecules are chemically linked. As used herein, “pre-gelatinized starches” or “instantized starches” refers to modified starches that have been pre-wetted, then dried to enhance their cold-water solubility. Suitable modified starches are commercially available from several suppliers such as, for example, A. E. Staley Manufacturing Company, and National Starch & Chemical Company. One suitable film forming modified starch includes the pre-gelatinized waxy maize derivative starches that are commercially available from National Starch & Chemical Company under the tradenames PURITY GUM and FILMSET, and derivatives, copolymers, and mixtures thereof. Such waxy maize starches typically contain, based upon the total weight of the starch, from about 0 percent to about 18 percent of amylose and from about 100% to about 88% of amylopectin.
  • [0103]
    Another suitable film forming modified starch includes the hydroxypropylated starches, in which some of the hydroxyl groups of the starch have been etherified with hydroxypropyl groups, usually via treatment with propylene oxide. One example of a suitable hydroxypropyl starch that possesses film-forming properties is available from Grain Processing Company under the tradename, PURE-COTE B790.
  • [0104]
    Suitable tapioca dextrins for use as film formers include those available from National Starch & Chemical Company under the tradenames CRYSTAL GUM or K-4484, and derivatives thereof such as modified food starch derived from tapioca, which is available from National Starch and Chemical under the tradename PURITY GUM 40, and copolymers and mixtures thereof.
  • [0105]
    Any thickener known in the art is suitable for use in the flowable material. Examples of such thickeners include but are not limited to hydrocolloids (also referred to herein as gelling polymers), clays, gelling starches, and crystallizable carbohydrates, and derivatives, copolymers and mixtures thereof. Examples of suitable hydrocolloids (also referred to herein as gelling polymers) such as alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, whelan, rhamsan, zooglan, methyl an, chitin, cyclodextrin, chitosan. Examples of suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof. Examples of suitable gelling starches include acid hydrolyzed starches, and derivatives and mixtures thereof. Additional suitable thickening hydrocolloids include low-moisture polymer solutions such as mixtures of gelatin and other hydrocolloids at water contents up to about 30%, such as for example those used to make “gummi” confection forms. Suitable crystallizable carbohydrates include the monosaccharides and the oligosaccharides. Of the monosaccharides, the aldohexoses e.g., the D and L isomers of allose, altrose, glucose, mannose, gulose, idose, galactose, talose, and the ketohexoses e.g., the D and L isomers of fructose and sorbose along with their hydrogenated analogs: e.g., glucitol (sorbitol), and mannitol are preferred. Of the oligosaccharides, the 1,2-disaccharides sucrose and trehalose, the 1,4-disaccharides maltose, lactose, and cellobiose, and the 1,6-disaccharides gentiobiose and melibiose, as well as the trisaccharide raffinose are preferred along with the isomerized form of sucrose known as isomaltulose and its hydrogenated analog isomalt. Other hydrogenated forms of reducing disaccharides (such as maltose and lactose), for example, maltitol and lactitol are also preferred. Additionally, the hydrogenated forms of the aldopentoses: e.g., D and L ribose, arabinose, xylose, and lyxose and the hydrogenated forms of the aldotetroses: e.g., D and L erythrose and threose are preferred and are exemplified by xylitol and erythritol, respectively.
  • [0106]
    In one embodiment of the invention, the flowable material comprises gelatin as a gelling polymer. Gelatin is a natural, thermogelling polymer. It is a tasteless and colorless mixture of derived proteins of the albuminous class which is ordinarily soluble in warm water. Two types of gelatin—Type A and Type B—are commonly used. Type A gelatin is a derivative of acid-treated raw materials. Type B gelatin is a derivative of alkali-treated raw materials. The moisture content of gelatin, as well as its Bloom strength, composition and original gelatin processing conditions, determine its transition temperature between liquid and solid. Bloom is a standard measure of the strength of a gelatin gel, and is roughly correlated with molecular weight. Bloom is defined as the weight in grams required to move a half-inch diameter plastic plunger 4 mm into a 6.67% gelatin gel that has been held at 10° C. for 17 hours. In a preferred embodiment, the flowable material is an aqueous solution comprising 20% 275 Bloom pork skin gelatin, 20% 250 Bloom Bone Gelatin, and approximately 60% water.
  • [0107]
    Suitable xanthan gums include those available from C. P. Kelco Company under the tradenames KELTROL 1000, XANTROL 180, or K9B310.
  • [0108]
    “Acid-hydrolyzed starch,” as used herein, is one type of modified starch that results from treating a starch suspension with dilute acid at a temperature below the gelatinization point of the starch. During the acid hydrolysis, the granular form of the starch is maintained in the starch suspension, and the hydrolysis reaction is ended by neutralization, filtration and drying once the desired degree of hydrolysis is reached. As a result, the average molecular size of the starch polymers is reduced. Acid-hydrolyzed starches (also known as “thin boiling starches”) tend to have a much lower hot viscosity than the same native starch as well as a strong tendency to gel when cooled.
  • [0109]
    “Gelling starches,” as used herein, include those starches that, when combined with water and heated to a temperature sufficient to form a solution, thereafter form a gel upon cooling to a temperature below the gelation point of the starch. Examples of gelling starches include, but are not limited to, acid hydrolyzed starches such as that available from Grain Processing Corporation under the tradename PURE-SET B950; hydroxypropyl distarch phosphate such as that available from Grain Processing Corporation under the tradename, PURE-GEL B990, and mixtures thereof.
  • [0110]
    Suitable low-melting hydrophobic materials for use as components of the flowable material for making the core, or the shell, or a portion thereof by molding include fats, fatty acid esters, phospholipids, and waxes. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes include camauba wax, spernaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like.
  • [0111]
    Suitable non-crystallizable carbohydrates for use as components of the flowable material for making the core, or the shell, or a portion thereof by molding include non-crystallizable sugars such as polydextrose, and starch hydrolysates, e.g. glucose syrup, corn syrup, and high fructose corn syrup; and non-crystallizable sugar-alcohols such as maltitol syrup.
  • [0112]
    Suitable solvents for optional use as components of the flowable material for making the core, or the shell, or a portion thereof by molding include water; polar organic solvents such as methanol, ethanol, isopropanol, acetone, and the like; and non-polar organic solvents such as methylene chloride, and the like; and mixtures thereof.
  • [0113]
    The flowable material for making the core or the shell or a portion thereof by molding may optionally comprise adjuvants or excipients, which may comprise up to about 30% by weight of the flowable material. Examples of suitable adjuvants or excipients include plasticizers, detackifiers, humectants, surfactants, anti-foaming agents, colorants, flavorants, sweeteners, opacifiers, and the like. Suitable plasticizers for making the core, the shell, or a portion thereof, by molding include, but not be limited to polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as castor oil, rape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glyceroltributyrate; hydrogenated castor oil; fatty acids; substituted triglycerides and glycerides; and the like and/or mixtures thereof. In certain embodiments, the shell is substantially free of plasticizers, i.e. contains less than about 1%, say less than about 0.01% of plasticizers.
  • [0114]
    In one preferred embodiment, the flowable material comprises less than 5% humectants, or alternately is substantially free of humectants, such as glycerin, sorbitol, maltitol, xylitol, or propylene glycol. Humectants have traditionally been included in pre-formed films employed in enrobing processes, such as that disclosed in U.S. Pat. Nos. 5,146,730 and 5,459,983, assigned to Banner Gelatin Products Corp., in order to ensure adequate flexibility or plasticity and bondability of the film during processing. Humectants function by binding water and retaining it in the film. Pre-formed films used in enrobing processes can typically comprise up to 45% water. Disadvantageously, the presence of humectant prolongs the drying process, and can adversely affect the stability of the finished dosage form.
  • [0115]
    In one embodiment of the invention, the core, the shell, or a portion thereof is made by the thermal setting molding method and apparatus described in copending U.S. patent application Ser. No. 09/966,450, pages 57-63, the disclosure of which is incorporated herein by reference. In this embodiment, the core, the shell, or a portion thereof is formed by injecting a starting material in flowable form into a molding chamber. The starting material preferably comprises an active ingredient and a thermal setting material at a temperature above the melting point of the thermal setting material but below the decomposition temperature of the active ingredient. The starting material is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold).
  • [0116]
    According to this method, the starting material must be in flowable form. For example, it may comprise solid particles suspended in a molten matrix, for example a polymer matrix. The starting material may be completely molten or in the form of a paste. The starting material may comprise an active ingredient dissolved in a molten material. Alternatively, the starting material may be made by dissolving a solid in a solvent, which solvent is then evaporated from the starting material after it has been molded.
  • [0117]
    The starting material may comprise any edible material which is desirable to incorporate into a shaped form, including active ingredients, nutritionals, vitamins, minerals, flavors, sweeteners, and the like. Preferably, the starting material comprises an active ingredient and a thermal setting material. The thermal setting material may be any edible material that is flowable at a temperature between about 37 and about 120° C., and that is a solid at a temperature between about 0 and about 35° C. Preferred thermal setting materials include water-soluble polymers such as polyalkylene glycols, polyethylene oxides and derivatives, and sucrose esters; fats such as cocoa butter, hydrogenated vegetable oil such as palm kernel oil, cottonseed oil, sunflower oil, and soybean oil; mono-, di-, and triglycerides, phospholipids, waxes such as carnuba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; sugar in the form on an amorphous glass such as that used to make hard candy forms, sugar in a supersaturated solution such as that used to make fondant forms; low-moisture polymer solutions such as mixtures of gelatin and other hydrocolloids at water contents up to about 30% such as those used to make “gummi” confection forms. In a particularly preferred embodiment, the thermal setting material is a water-soluble polymer such as polyethylene glycol.
  • [0118]
    In another embodiment of the invention, the core, the shell, or a portion thereof is make using the thermal cycle molding method and apparatus described in copending U.S. patent application Ser. No. 09/966,497, pages 27-51, the disclosure of which is also incorporated herein by reference. In the thermal cycle molding method and apparatus of U.S. patent application Ser. No. 09/966,497, a thermal cycle molding module having the general configuration shown in FIG. 3 therein is employed. The thermal cycle molding module 200 comprises a rotor 202 around which a plurality of mold units 204 are disposed. The thermal cycle molding module includes a reservoir 206 (see FIG. 4) for holding flowable material to make the core. In addition, the thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold units. FIGS. 55 and 56 depict such a temperature control system 600.
  • [0119]
    In certain embodiments the core or portions thereof may be molded using a solvent-free process. In such embodiments, the core may comprise active ingredient contained within an excipient matrix. The matrix typically comprises at least about 30 percent, e.g. at least about 45 weight percent of a thermal-reversible carrier, and optionally up to about 30 weight percent of various adjuvants such as for example plasticizers, gelling agents, strengthening agents, colorants, stabilizers, preservatives, and the like as known in the art. The matrix may optionally further comprise up to about 55 weight percent of one or more release-modifying moldable excipients as described below.
  • [0120]
    The core may be in a variety of different shapes. For example, the core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like. In cetrain embodiments, the core has one or more major faces. For example in embodiments wherein the core is a compressed tablet, the core surface typically has two opposing major faces formed by contact with the upper and lower punch faces in the compression machine. In such embodiments the core surface typically further comprises a “belly-band” located between the two major faces, and formed by contact with the die walls in the compression machine. Exemplary core shapes which may be employed include tablet shapes formed from compression tooling shapes described by “The Elizabeth Companies Tablet Design Training Manual,” (Elizabeth Carbide Die Co., Inc., p.7 (McKeesport, Pa.) (incorporated herein by reference) as follows (the tablet shape corresponds inversely to the shape of the compression tooling):
  • [0121]
    1. Shallow Concave.
  • [0122]
    2. Standard Concave.
  • [0123]
    3. Deep Concave.
  • [0124]
    4. Extra Deep Concave.
  • [0125]
    5. Modified Ball Concave.
  • [0126]
    6. Standard Concave Bisect.
  • [0127]
    7. Standard Concave Double Bisect.
  • [0128]
    8. Standard Concave European Bisect.
  • [0129]
    9. Standard Concave Partial Bisect.
  • [0130]
    10. Double Radius.
  • [0131]
    11. Bevel & Concave.
  • [0132]
    12. Flat Plain.
  • [0133]
    13. Flat-Faced-Beveled Edge (F.F.B.E.).
  • [0134]
    14. F.F.B.E. Bisect.
  • [0135]
    15. F.F.B.E. Double Bisect.
  • [0136]
    16. Ring.
  • [0137]
    17. Dimple.
  • [0138]
    18. Ellipse.
  • [0139]
    19. Oval.
  • [0140]
    20. Capsule.
  • [0141]
    21. Rectangle.
  • [0142]
    22. Square.
  • [0143]
    23. Triangle.
  • [0144]
    24. Hexagon.
  • [0145]
    25. Pentagon.
  • [0146]
    26. Octagon.
  • [0147]
    27. Diamond.
  • [0148]
    28. Arrowhead.
  • [0149]
    29. Bullet.
  • [0150]
    30. Barrel.
  • [0151]
    31. Half Moon.
  • [0152]
    32. Shield.
  • [0153]
    33. Heart.
  • [0154]
    34. Almond.
  • [0155]
    35. House/Home Plate.
  • [0156]
    36. Parallelogram.
  • [0157]
    37. Trapezoid.
  • [0158]
    38. FIG. 8/Bar Bell.
  • [0159]
    39. Bow Tie.
  • [0160]
    40. Uneven Triangle.
  • [0161]
    In one embodiment of the invention, the core comprises multiple portions, for example a first portion and a second portion. The portions may be prepared by the same or different methods and mated using various techniques, such as thermal cycle molding and thermal setting molding methods described herein. For example, the first and second portions may both be made by compression, or both may be made by molding. Or one portion may be made by compression and the other by molding. The same or different active ingredient may be present in the first and second portions of the core. Alternately, one or more core portions may be substantially free of active ingredients.
  • [0162]
    In certain embodiments of the invention, the core or a portion thereof may function to confer modified release properties to at least one active ingredient contained therein. In such embodiments, wherein the core or core portion is made by compression, as previously noted, the core preferably comprises a release-modifying excipient for compression. In such embodiments, wherein the core or core portion is made by molding, as previously noted, the core preferably comprises a release-modifying moldable excipient.
  • [0163]
    In embodiments in which the core or a portion thereof functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core portion preferably comprises a release-modifying compressible or moldable excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, and combinations thereof.
  • [0164]
    In embodiments in which the core or a portion thereof functions as a diffusional matrix through which active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core portion preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore-formers. Alternately, in such embodiments in which the core portion is prepared by molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated.
  • [0165]
    The shell of the present invention may be prepared by molding, using a solvent-free process, or a solvent-based process, and depending on the method by which it is made, typically comprises a variety of excipients which are useful for conferring desired properties to the shell. The shell may optionally further comprise one or more active ingredients.
  • [0166]
    In embodiments in which the shell is prepared using a solvent-free molding process, the shell will typically comprise at least about 30 percent, e.g. at least about 45 percent by weight of a thermal-reversible carrier. The shell may optionally further comprise up to about 55 weight percent of a release modifying excipient. The shell may optionally further comprise up to about 30 weight percent total of various plasticizers, adjuvants and excipients. In certain embodiments in which the shell is prepared by solvent-free molding, the release modifying excipient is preferrably selected from swellable, erodible hydrophilic materials.
  • [0167]
    In embodiments in which the shell is prepared using a solvent-based molding process, the shell will typically comprise at least about 10 weight percent, e.g. at least about 12 weight percent or at least about 15 weight percent or at least about 20 weight percent or at least about 25 weight percent of a film-former. Here, the solvent-molded shell may optionally further comprise up to about 55 weight percent of a release-modifying excipient. The solvent-molded shell portions may again also optionally further comprise up to about 30 weight percent total of various plasticizers, adjuvants, and excipients.
  • [0168]
    Suitable thermal-reversible carriers for making the core, or the shell, or a portion thereof, by solvent-free molding are thermoplastic materials typically having a melting point below about 11° C., more preferably between about 20 and about 100° C. Examples of suitable thermal-reversible carriers for solvent-free molding include thermplastic polyalkalene glycols, thermoplastic polyalkalene oxides, low melting hydrophobic materials, thermoplastic polymers, thermoplastic starches, and the like. Suitable thermoplastic polyalkylene glycols for use as thermal-reversible carriers include polyethylene glycol having molecular weight from about 100 to about 20,000, e.g. from about 100 to about 8,000, say from about 1000 to about 8,000 Daltons. Suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight from about 100,000 to about 900,000 Daltons. Suitable low-melting hydrophobic materials for use as thermal-reversible carriers include fats, fatty acid esters, phospholipids, and waxes which are solid at room temperature, fat-containing mixtures such as chocolate; and the like. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes that are solid at room temperature include camauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax. Suitable thermoplastic polymers for use as thermal-reversible carriers include thermoplastic water swellable cellulose derivatives, thermoplastic water insoluble polymers, thermoplastic vinyl polymers. Suitable thermoplastic water swellable cellulose derivatives include include hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), carboxymethylcellulose (CMC), cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxybutylcellulose (HBC), hydroxyethylcellulose (HEC), hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose, and salts, derivatives, copolymers, and combinations thereof. Suitable thermoplastic water insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, and the like and derivatives, copolymers, and combinations thereof. Suitable thermoplastic vinyl polymers include polyvinylacetate, polyvinyl alcohol, and polyvinyl pyrrolidone (PVP). Examples of suitable thermoplastic starches for use as thermal-reversible carriers include those disclosed in U.S. Pat. No. 5,427,614, which is incorporated herein by reference.
  • [0169]
    In one embodiment, the thermal-reversible carrier for making the core or the shell, or a portion thereof, by solvent-free molding is selected from polyalkylene glycols, polyalkaline oxides, and combinations thereof. In one particular such embodiment, the core or shell or portion thereof further comprises shellac as a strengthening adjuvant. Advantageously, shellac may be employed as a strengthening agent in the molded core or shell or portions thereof at a level from about 5 to about 15 weight percent of the molded portion, without imparting pH-dependency to the dissolution of the molded portion.
  • [0170]
    Suitable release-modifying moldable excipients for making the core, or a portion thereof, by solvent-free or sovent based molding include but are not limited to swellable erodible hydrophilic materials, pH-dependent polymers, pore formers, and insoluble edible materials.
  • [0171]
    In embodiments of the present invention wherein the shell is prepared by a solvent-free or solvent-based molding process, suitable release-modifying excipients are preferably selected from swellable erodible hydrophilic materials, pH dependent polymers, and insoluble edible materials.
  • [0172]
    Suitable swellable erodible hydrophilic materials for use as release-modifying excipients for making the core, or the shell, or a portion thereof by a solvent-free molding process include water swellable cellulose derivatives, polyalkalene glycols, thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, and swelling cross-linked polymers, and derivitives, copolymers, and combinations thereof. Examples of suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples of suitable polyalkalene glyclols include polyethylene glycol. Examples of suitable thermoplastic polyalkalene oxides include poly (ethylene oxide). Examples of suitable acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL (high-molceular weight cross-linked acrylic acid homopolymers and copolymers), and the like. Examples of suitable hydrocolloids include alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan. Examples of suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof. Examples of suitable gelling starches include acid hydrolyzed starches, swelling starches such as sodium starch glycolate, and derivatives thereof. Examples of suitable swelling cross-linked polymers include cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcellose sodium.
  • [0173]
    Suitable pH-dependent polymers for use as release-modifying moldable excipients for making the molded matrix or molded core or molded shell or a portion thereof by molding include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L and the like, and derivatives, salts, copolymers, and combinations thereof.
  • [0174]
    Suitable pore formers for use as release-modifying excipients for making the molded matrix, the core, the shell, or a portion thereof by molding include water-soluble organic and inorganic materials. Examples of suitable water-soluble organic materials include water soluble polymers including water soluble cellulose derivatives such as hydroxypropylmethylcellulose, and hydroxypropylcellulose; water soluble carbohydrates such as sugars, and starches; water soluble polymers such as polyvinylpyrrolidone and polyethylene glycol, and insoluble swelling polymers such as microcrystalline cellulose. Examples of suitable water soluble inorganic materials include salts such as sodium chloride and potassium chloride and the like and/or mixtures thereof.
  • [0175]
    Suitable insoluble edible materials for use as release-modifying moldable excipients for making the core, or the shell, or a portion thereof, by molding, include water-insoluble polymers, and low-melting hydrophobic materials. Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof. Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like.
  • [0176]
    In a preferred embodiment, the shell of the present invention, whether prepared by a solvent-free molding process, or by a solvent-based molding process, is substantially free of pores having a diameter of 0.5-5.0 microns. As used herein, “substantially free” means that the shell has a pore volume of less than about 0.02 cc/g, preferably less than about 0.01 cc/g, more preferably less than about 0.005 cc/g in the pore diameter range of 0.5 to 5.0 microns. In contrast, typical compressed materials have pore volumes of more than about 0.02 cc/g in this diameter range.
  • [0177]
    The pore volume, pore diameter and density of the shells used in this invention may be determined using a Quantachrome Instruments PoreMaster 60 mercury intrusion porosimeter and associated computer software program known as “Porowin.” The procedure is documented in the Quantachrome Instruments PoreMaster Operation Manual. The PoreMaster determines both pore volume and pore diameter of a solid or powder by forced intrusion of a non-wetting liquid (mercury), which involves evacuation of the sample in a sample cell (penetrometer), filling the cell with mercury to surround the sample with mercury, applying pressure to the sample cell by: (i) compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum). Intruded volume is measured by a change in the capacitance as mercury moves from outside the sample into its pores under applied pressure. The corresponding pore size diameter (d) at which the intrusion takes place is calculated directly from the so-called “Washburn Equation”: d=−(4γ(cos θ))/P where γ is the surface tension of liquid mercury, θ is the contact angle between mercury and the sample surface and P is the applied pressure.
  • [0178]
    Equipment used for pore volume measurements:
  • [0179]
    (1) Quantachrome Instruments PoreMaster 60.
  • [0180]
    (2) Analytical Balance capable of weighing to 0.0001 g.
  • [0181]
    (3) Desiccator.
  • [0182]
    Reagents used for measurements:
  • [0183]
    (1) High purity nitrogen.
  • [0184]
    (2) Triply distilled mercury.
  • [0185]
    (3) High pressure fluid (Dila AX, available from Shell Chemical Co.).
  • [0186]
    (4) Liquid nitrogen (for Hg vapor cold trap).
  • [0187]
    (5) Isopropanol or methanol for cleaning sample cells.
  • [0188]
    (6) Liquid detergent for cell cleaning.
  • [0189]
    Procedure:
  • [0190]
    The samples remain in sealed packages or as received in the dessicator until analysis. The vacuum pump is switched on, the mercury vapor cold trap is filled with liquid nitrogen, the compressed gas supply is regulated at 55 psi., and the instrument is turned on and allowed a warm up time of at least 30 minutes. The empty penetrometer cell is assembled as described in the instrument manual and its weight is recorded. The cell is installed in the low pressure station and “evacuation and fill only” is selected from the analysis menu, and the following settings are employed:
  • [0191]
    Fine Evacuation time: 1 min.
  • [0192]
    Fine Evacuation rate: 10
  • [0193]
    Coarse Evacuation time: 5 min.
  • [0194]
    The cell (filled with mercury) is then removed and weighed. The cell is then emptied into the mercury reservoir, and two tablets from each sample are placed in the cell and the cell is reassembled. The weight of the cell and sample are then recorded. The cell is then installed in the low-pressure station, the low-pressure option is selected from the menu, and the following parameters are set:
  • [0195]
    Mode: Low pressure
  • [0196]
    Fine evacuation rate: 10
  • [0197]
    Fine evacuation until: 2001 μHg
  • [0198]
    Coarse evacuation time: 10 min.
  • [0199]
    Fill pressure: Contact+0.1
  • [0200]
    Maximum pressure: 50
  • [0201]
    Direction: Intrusion And Extrusion
  • [0202]
    Repeat: 0
  • [0203]
    Mercury contact angle; 140
  • [0204]
    Mercury surface tension: 480
  • [0205]
    Data acquisition is then begun. The pressure vs. cumulative volume-intruded plot is displayed on the screen. After low-pressure analysis is complete, the cell is removed from the low-pressure station and reweighed. The space above the mercury is filled with hydraulic oil, and the cell is assembled and installed in the high-pressure cavity. The following settings are used:
  • [0206]
    Mode: Fixed rate
  • [0207]
    Motor speed: 5
  • [0208]
    Start pressure: 20
  • [0209]
    End pressure: 60,000
  • [0210]
    Direction: Intrusion and extrusion
  • [0211]
    Repeat: 0
  • [0212]
    Oil fill length: 5
  • [0213]
    Mercury contact angle: 140
  • [0214]
    Mercury surface tension: 480
  • [0215]
    Data acquisition is then begun and graphic plot pressure vs. intruded volume is displayed on the screen. After the high pressure run is complete, the low-and high-pressure data files of the same sample are merged.
  • [0216]
    The shell of the present invention, whether prepared by a solvent-free molding process, or by a solvent-based molding process, typically has a surface gloss of at least about 150 gloss units, e.g. at least about 175 gloss units, or at least about 190 gloss units, when measured according to the method set forth in Example 6 herein. In contrast, typical sprayed coatings have gloss values of less than about 150 gloss units.
  • [0217]
    Dosage forms with high surface gloss are preferred by consumers due to their aesthetic elegance and perceived swallowability. The surface gloss of the shell depends upon a number of factors, including the shell composition, the method of forming the shell, and, if a mold is used, the surface finish on the mold.
  • [0218]
    Shells of this invention may be tested for surface gloss using an instrument available from TriCor Systems Inc. (Elgin, Ill.) under the tradename TRI-COR MODEL 805A/806H SURFACE ANALYSIS SYSTEM and generally in accordance with the procedure described in “TriCor Systems WGLOSS 3.4 Model 805A/806H Surface Analysis System Reference Manual” (1996), which is incorporated by reference herein, except as modified below.
  • [0219]
    This instrument utilizes a CCD camera detector, employs a flat diffuse light source, compares samples to a reference standard, and determines average gloss values at a 60 degree incident angle. During its operation, the instrument generates a gray-scale image, wherein the occurrence of brighter pixels indicates the presence of more gloss at that given location.
  • [0220]
    The instrument also incorporates software that utilizes a grouping method to quantify gloss, i.e., pixels with similar brightness are grouped together for averaging purposes.
  • [0221]
    The “percent full scale” or “percent ideal” setting (also referred to as the “percent sample group” setting), is specified by the user to designate the portion of the brightest pixels above the threshold that will be considered as one group and averaged within that group. “Threshold,” as used herein, is defined as the maximum gloss value that will not be included in the average gloss value calculation. Thus, the background, or the non-glossy areas of a sample are excluded from the average gloss value calculations. The method disclosed in K. Fegley and C. Vesey, “The Effect of Tablet Shape on the Perception of High Gloss Film Coating Systems,” which is available at www.colorcon.com as of 18 Mar. 2002 and incorporated by reference herein, is used to minimize the effects resulting from different shell shapes, and to report a metric that is comparable across the industry. (The 50% sample group setting is selected as the setting which best approximates analogous data from surface roughness measurements.)
  • [0222]
    After initially calibrating the instrument using a calibration reference plate (190-228; 294 degree standard; no mask, rotation 0, depth 0), a standard surface gloss measurement may be created using gel-coated caplets available from McNeil-PPC, Inc. under the tradename Extra Strength TYLENOL Gelcaps. The average gloss value for a sample of such gel-coated caplets may be determined, while employing the 25 mm full view mask (190-280), and configuring the instrument to the following settings:
  • [0223]
    Rotation: 0
  • [0224]
    Depth: 0.25 inches
  • [0225]
    Gloss Threshold: 95
  • [0226]
    % Full Scale: 50%
  • [0227]
    Index of Refraction: 1.57
  • [0228]
    The average surface gloss value for the reference standard is then determined.
  • [0229]
    Each shell sample may then be independently tested in accordance with the same procedure.
  • [0230]
    The weight of the shell is preferably about 10 to about 400% of the weight of the core. In embodiments wherein the shell is prepared by a solvent-free molding process, the weight of the shell is typically from about 50 to about 400%, e.g. from about 75 to about 400%, or about 100 to about 200% percent of the weight of the core. In embodiments wherein the shell is prepared by a solvent-based molding process, the weight of the shell is typically from about 10 to about 100 percent, preferably from about 10 to about 60 percent of the weight of the core.
  • [0231]
    The shell provides a delay of greater than one hour, for example at least about 3 hours, or at least about 4 hours, or at least about 6 hours, or at least about 12 hours to the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium such as water, gastrointestinal fluid or the like. The delay period is typically controlled by the shell thickness, composition, or a combination thereof. In one embodiment the delay period is independent of the pH of the dissolution media or fluid environment. For example, the average lag-time for dissolution of active ingredient in 0.1 N HCl is not substantially different (i.e. within about 30 minutes, preferably within about 15 minutes) from the average lag-time for the dissolution of active ingredient in pH 5.6 buffer system.
  • [0232]
    Typical shell thicknesses which may be employed in this invention are about 50 to about 4000 microns. In embodiments wherein the shell is prepared by a solvent-free molding process, the shell typically has a thickness of about 500 to about 4000 microns, e.g. about 500 to about 2000 microns, say about 800 to about 1200 microns. In embodiments wherein the shell is prepared by a solvent-based molding process, the shell typically has a thickness of less than about 800 microns, e.g. about 100 to about 600 microns, say about 150 to about 400 microns.
  • [0233]
    In one embodiment of the invention, the shell additionally comprises at least one active ingredient which may be the same or different than the active ingredient contained in the core.
  • [0234]
    In another embodiment of this invention, at least one active ingredient contained within the dosage form exhibits a delayed burst release profile. By “delayed burst release profile” it is meant that the release of that particular active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, and the delay period (“lag time”) is followed by prompt (immediate) release of that active ingredient. The shell of the present invention provides for the delay period and is preferaby substantially free of the active ingredient to be released in a delayed burst manner. In such embodiments, the delayed burst active ingredient is typically contained within the core or a portion thereof. In these embodiments, the core may be prepared by compression or molding, and is formulated for immediate release, as is known in the art, so that the core is readily soluble upon contact with the dissolution medium. In such embodiments the core preferably comprises a disintegrant, and optionally comprises additional excipients such as fillers or thermoplastic materials selected from water-soluble or low-melting materials, and surfactants or wetting agents. In these embodiments, the dissolution of the burst release active ingredient, after the delay period, meets USP specifications for immediate release tablets containing that active ingredient. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856 (1999).
  • [0235]
    In another embodiment of this invention at least one active ingredient contained within the dosage form exhibits a delayed and sustained release profile. By “delayed then sustained release profile” it is meant that the release of that particular active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, and the delay period (“lag time”) is followed by sustained (prolonged, extended, or retarded) release of that active ingredient. The shell of the present invention provides for the delay period, and is preferraby substantially free of the active to be released in a delayed then sustained manner. In such embodiments, the delayed then sustained release active ingredient is preferrably contained within the core. In such embodiments the core may function for example as an eroding matrix or a diffusional matrix, or an osmotic pump. In embodiments in which the core or a portion thereof functions as a diffusional matrix through which active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core portion preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore-formers. Alternately, in such embodiments in which the core portion is prepared by molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated. In embodiments in which the core or a portion thereof functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core portion preferably comprises a release-modifying compressible or moldable excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, and combinations thereof.
  • [0236]
    In one embodiment, the shell is not a compression coating applied to the core.
  • [0237]
    This invention will be illustrated by the following examples, which are not meant to limit the invention in any way.
  • EXAMPLE 1
  • [0238]
    Dosage forms according to the invention, comprising a core within a shell, were prepared as follows.
  • [0239]
    The following ingredients were used to make the shells:
    TABLE A
    Weight Mg/
    Shell Trade Name Manufacturer percent Tablet
    Polyethylene Carbowax ® Union Carbide 45.0 250
    Glycol 3350 Corporation,
    Danbury, CT
    Polyethylene Polyox ® Union Carbide 15.0 83
    Oxide WSR N-80 Corporation,
    (MW 200,000) Danbury, CT
    Shellac Powder Regular Mantrose-Haeuser 20.0 111
    bleached Company,
    shellac Atteboro, MA
    Triethyl Citrate Morflex, Inc., 10.0 56
    Greensboro, NC
    Croscarmellose Ac-Di-Sol ® FMC Corporation, 10.0 56
    Sodium Newark, DE
  • [0240]
    The shell material was prepared as follows: a beaker was submersed in a 70° C. water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.). Polyethylene glycol (PEG) 3350 was added to the beaker and was mixed with a spatula until all PEG was melted. Shellac powder, which was screened through 40-mesh screen, was added to the molten PEG and was mixed until all powder was dispersed. Triethyl citrate was added to the molten PEG and was mixed for 1 minute. Polyethylene oxide (PEO) (MW=200,000) was added and was mixed for 10 minutes. Croscarmellose sodium was added and was mixed for 2 minutes. The shell material was provided in flowable form.
  • [0241]
    The following commercially available product was used as the core:
    TABLE B
    Weight
    Tablet Trade Name Manufacturer percent Mg/Tablet
    Pseudoephedrine Nasal CVS Pharmacy, 23.0 165
    HCL core tablet decongestant Inc., Woonsocket,
    tablet 30 mg RI
  • [0242]
    The shell was molded according to the following process: a laboratory scale (round, tablet-shaped, 0.4375″ diameter) stainless steel mold assembly was used to apply the shells to the cores. The mold assembly comprised a lower mold portion and an upper mold portion, with no temperature control. 350 to 450 mg of the molten shell material was introduced into the mold cavity formed by the lower mold portion. A pseudoephedrine HCL core tablet (Table B) was then inserted into the mold cavity. Additional molten shell material was added to fill the mold cavity and the upper mold portion was manually applied to form a molded tablet. After 10 seconds, the upper mold portion was removed, and the molded dosage form was ejected from the lower mold portion.
  • EXAMPLE 2
  • [0243]
    Dosage forms according to the invention, comprising a core within a shell, were prepared as follows.
  • [0244]
    The following ingredients were used to make the shells:
    TABLE C
    Trade Weight Mg/
    Shell Name Manufacturer percent Tablet
    Lauroyl Macrogol-32 Gelucire Gattefosse Corp., 70.0 751
    Glycerides 50/13 Westwood, NJ
    Lauroyl Macrogol-32 Gelucire Gattefosse Corp., 30.0 322
    Glycerides 44/14 Westwood, NJ
  • [0245]
    The shell material was prepared in the following manner: a beaker was submersed in a water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.) where the water temperature was set at 70° C. Lauroyl Macrogol-32 glycerides were added to the beaker and were mixed with a spatula until all the glycerides were melted. The shell material was provided in flowable form.
  • [0246]
    The shell material was applied to the cores of Example 1, using the laboratory scale mold assembly of Example 1, in the following manner: 700 to 800 mg of the molten shell material (Table C) was introduced into the mold cavity formed by the lower mold portion. A pseudoephedrine HCL core tablet (Example 1) was then inserted into the mold cavity. Additional molten mixture was added to fill the mold cavity and the upper mold portion was manually applied to form a molded tablet. After 10 seconds, the upper mold portion was removed, and the molded dosage form was ejected from the lower mold portion.
  • EXAMPLE 3
  • [0247]
    Dosage forms according to the invention, comprising a core within a shell, were prepared as follows.
  • [0248]
    The following ingredients were used to make the shells:
    TABLE D
    Weight Mg/
    Shell Trade Name Manufacturer percent Tablet
    Polyethylene Carbowax ® Union Carbide 65.0 430
    Glycol 3350 Corporation,
    Danbury, CT
    Hydroxypropyl Methocel Dow Chemical 25.0 165
    Methylcellulose K4M Perm Co., Midland,
    CR MI
    Hydroxpropylcellulose Klucel Hercules 10.0 66
    EXAF Incorporated,
    Pharm Wilmington,
    DE
  • [0249]
    The shell material was prepared in the following manner: a beaker was submersed in a water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.) where the water temperature was set at 70° C. PEG 3350 was added to the beaker and was mixed with a spatula until all PEG was melted. Hydroxypropyl methylcellulose and hydroxpropylcellulose were added to the molten PEG and mixed for 10 minutes. The shell material was provided in flowable form.
  • [0250]
    The following ingredients were used to make the cores:
    TABLE E
    Weight Mg/
    Granulation Trade Name Manufacturer percent Tablet
    Ibuprofen Albemarle Corp., 93.24 200
    Orangeburg, SC
    Sodium Starch Explotab Mendell, A Penwest 5.59 12
    Glycolate Co., Patterson, NY
    Colloidal Silicon Cab-O-Sil Cabot Corp., 0.23 0.5
    Dioxide Tuscola, IL
    Magnesium Mallinckrodt Inc., 0.93 2
    Stearate St. Louis, MO
  • [0251]
    The cores were made in the following manner: Ibuprofen was screened through a #20 mesh screen and was added to a plastic bag. Sodium starch glycolate was screened through a #30 mesh screen and was added to the plastic bag. The powder was blended by manual shaking for 2 minutes. Half of the powder was removed from the first plastic bag and was added to a second plastic bag containing colloidal silicon dioxide and magnesium stearate. The powder in the second bag was then blended by manual shaking for 1 minute and was passed a #20 mesh screen. The resultant powder blend was added to the first bag and further blended by manual shaking for 1 minute. The blend was then compressed into tablets using a Manesty Beta-press (Thomas Engineering, Inc., Hoffman Estates, Ill.) fitted with round, concave punch and die unit having 0.3125″ diameter.
  • [0252]
    The shell material was applied to the cores, using a laboratory scale metal mold assembly (0.5065″, round), made from a lower mold assembly portion comprising a lower mold cavity, and an upper mold assembly portion comprising an upper mold cavity. The dosage form was prepared in the following manner 400 to 450 mg of the molten shell material (Table D) was introduced into the lower mold cavity formed by the lower mold assembly. An ibuprofen core tablet as described above was then inserted into the lower mold cavity. Additional molten shell material was then introduced into the upper mold cavity formed by the upper mold assembly. The upper mold assembly was mated with the lower mold assembly to form a dosage form. After 60 seconds, the upper and lower mold assemblies were separated, and the dosage form was removed from the mold.
  • EXAMPLE 4
  • [0253]
    The release profiles for the active ingredients contained in the dosage forms of Examples 1-3 were compared with those of the same active ingredients from other dosage forms. Results are shown in FIGS. 2-4.
  • [0254]
    All dissolution testing was performed according to the following method:
  • [0255]
    Apparatus: USP Type I apparatus (Basket, 100 RPM).
  • [0256]
    Media: 0.1 N HCL and pH 5.6 phosphate buffer at 37° C. The pH of the buffer was switched from 0.1N HCL to pH 5.6 phosphate buffer at the 2 hour time point.
  • [0257]
    Time points: Samples were tested at 0.5, 1, 2, 3, 4, 6, and 8 hours for pseudoephedrine HCL.
  • [0258]
    Analysis: Dissolution samples were analyzed for pseudoephedrine HCL versus a standard prepared at the theoretical concentration for 100 percent released of each compound. Samples were analyzed using a HPLC equipped with a Waters® 717 Autoinjector and a Waters® 486 UV detector set at a wavelength of 214 nm. The mobile phase was prepared using 55 percent acetonitrile and 45 percent 18 mM Potassium phosphate buffer. The injection volume was 50 μL with a run time of approximately 8 minutes and a pump flow of 2.0 mL/min. The column used was a Zorbax® 300-SCX (4.6 mm×25 cm).
  • [0259]
    [0259]FIG. 2 depicts the percent release of active ingredient (pseudoephedrine HCL) vs. time (hours) for the dosage form of Example 1, as well as the percent release of pseudoephedrine vs. time (hours) for a commercially available immediate release dosage form (Nasal decongestant tablet made by CVS Pharmacy, Inc.— Table B). Curve (a) shows the release of pseudoephedrine HCl from the dosage form of Example 1. Curve (b) shows the release of pseudoephedrine HCl from the immediate release comparitor tablet. As shown in FIG. 2, the dosage form of Example 1 exhibited a delay of about 3 hours to the onset of release of active ingredient.
  • [0260]
    [0260]FIG. 3 depicts the percent release of active ingredient (pseudoephedrine HCL) vs. time (hours) from the dosage form of Example 2, as well as the percent release of pseudoephedrine vs. time (hours) from a commercially available immediate release tablet (Sudafed®). As shown in FIG. 3, the dosage form of Example 2 exhibited a delay of about 4 hours to the onset of release of active ingredient. Curve (a) shows the release rate of pseudoephedrine HCL of this invention. Curve (d) was derived from the commercially immediate release dosage forms of Sudafed® tablet (containing pseudoephedrine HCL).
  • [0261]
    [0261]FIG. 4 depicts the percent release of active ingredient (Ibuprofen) vs. time (hours) for the dosage form of Example 3. As shown in FIG. 4, the dosage form of Example 3 exhibited a delay of about 8 hours to the onset of release of active ingredient.
  • EXAMPLE 5
  • [0262]
    Dosage forms according to the invention, comprising a compressed core within a molded shell, are made in a continuous process using an apparatus comprising a compression module and a thermal cycle molding module linked in series via a transfer device as described at pages 14-16 of copending U.S. application Ser. No. 09/966,939, the disclosure of which is incorporated herein by reference. The shells are made of a shell flowable material comprising the ingredients shown in Table D above and prepared in flowable form as described in Example 3. The cores are made of the ingredients shown in Table E above and prepared as a powder as described in Example 3. The cores are first compressed on a compression module as described in copending U.S. application Ser. No. 09/966,509 at pages 16-27. The compression module is a double row, rotary apparatus, comprising a fill zone, insertion zone, compression zone, ejection zone, and purge zone as shown in FIG. 6 of U.S. application Ser. No. 09/966,509. The dies of the compression module are filled using vacuum assistance, with mesh screen filters located in die wall ports of each die.
  • [0263]
    The cores are transferred from the compression module to the thermal cycle molding module via a transfer device. The transfer device has the structure shown as 300 in FIG. 3 and described on pages 51-57 of copending U.S. application Ser. No. 09/966,414, the disclosure of which is incorporated by reference. It comprises a plurality of transfer units 304 attached in cantilever fashion to a belt 312 as shown in FIGS. 68 and 69. The transfer device rotates and operates in sync with the compression and thermal cycle molding modules to which it is coupled. Transfer units 304 comprise retainers 330 for holding the cores as they travel around the transfer device.
  • [0264]
    The thermal cycle molding module has the general configuration shown in FIG. 3 and pages 27-51 of copending U.S. application Ser. No. 09/966,497, which depicts a thermal cycle molding module 200 comprising a rotor 202 around which a plurality of mold units 204 are disposed. The thermal cycle molding module includes reservoir 206 (see FIG. 4) for holding the shell flowable material. In addition, the thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold units. FIGS. 55 and 56 of pending U.S. application Ser. No. 09/966,497 depict the temperature control system 600.
  • [0265]
    The thermal cycle molding module is of the type shown in FIG. 28A of copending U.S. application Ser. No. 09/966,497. The mold units 204 of the thermal cycle molding module comprise upper mold assemblies 214, rotatable center mold assemblies 212 and lower mold assemblies 210 as shown in FIG. 28C. Cores are continuously transferred to the mold assemblies, which then close over the cores.
  • [0266]
    Coating is performed in two steps, first and second portions of the shell portions being applied separately as shown in the flow diagram of FIG. 28B of copending U.S. application Ser. No. 09/966,497. In a first step, a first portion of shell flowable material, heated to a flowable state in reservoir 206, is injected into the mold cavities created by the closed mold assemblies. The temperature of the first portion is then decreased, hardening it over half the core. The mold assemblies separate, the center mold assembly rotates, and then the mold assemblies again close. In a second step, the second portion of the shell flowable material, heated to a flowable state in reservoir 206, is injected into the mold cavities. The temperature of the second portion is then decreased, hardening it over the other half of the core. The mold assemblies separate, and the finished dosage forms are ejected from the apparatus.
  • [0267]
    Although this invention has been illustrated by reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made which clearly fall within the scope of this invention.

Claims (36)

The invention claimed is:
1. A dosage form comprising:
(a) a core comprising at least one active ingredient; and
(b) a molded shell which surrounds the core, wherein the shell provides a predetermined time delay of greater than one hour for the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium and the delay is independent of the pH of the liquid medium.
2. The dosage form of claim 1, in which the shell comprises means for delaying the onset of dissolution of the active ingredient for greater than one hour upon contacting of the dosage form with a liquid medium, and the delay is independent of the pH of the liquid medium.
3. The dosage form of claim 1, wherein the weight of the shell is at least 50 percent of the weight of the core.
4. The dosage form of claim 1, wherein the shell has a thickness from about 500 to about 4000 microns.
5. The dosage form of claim 1, wherein the shell has a thickness from about 100 to 600 microns.
6. The dosage form of claim 1, wherein the shell is substantially free of pores having a diameter of 0.5 to 5.0 microns.
7. The dosage form of claim 1, wherein the shell comprises at least about 30% of a thermal reversible carrier.
8. The dosage form of claim 1, wherein the shell comprises at least about 10% of a film-former.
9. The dosage form of claim 1, in which the shell additionally comprises at least one active ingredient which may be the same or different than the active ingredient contained in the core.
10. The dosage form of claim 1, which additionally comprises an outer coating which covers at least a portion of the shell, and the outer coating comprises at least one active ingredient which may be the same or different than the active ingredient contained in the core.
11. The dosage form of claim 1, in which the core is a compressed tablet.
12. The dosage form of claim 1, in which the core comprises coated particles of at least one active ingredient.
13. The dosage form of claim 1, in which the core is prepared by molding.
14. The dosage form of claim 1, in which the core is substantially free of pores having a diameter of 0.5 to 5.0 microns.
15. The dosage form of claim 1, in which the core comprises at least about 30 weight percent of a thermal-reversible carrier.
16. The dosage form of claim 1, in which the core comprises a release-modifying excipient.
17. The dosage form of claim 1, in which the shell is not a compression coating applied to the core.
18. The dosage form of claim 1, which provides an immediate release of at least one active ingredient, followed by a delay of at least about 1 hour, followed by a burst release of at least one active ingredient.
19. The dosage form of claim 1, wherein the shell is prepared using a solvent-free molding process.
20. The dosage form of claim 1, wherein the shell comprises at least 30% by weight of a thermal-reversible carrier.
21. The dosage form of claim 1, wherein the shell comprises up to 55% by weight of a swellable, erodible hydrophilic material.
22. The dosage form of claim 1, wherein the shell is prepared using a solvent-based molding process.
23. The dosage form of claim 1, wherein the shell comprises at least 10% by weight of a film-former.
24. The dosage form of claim 1, wherein the shell comprises at least 55% by weight of a release-modifying excipient.
25. The dosage form of claim 1, wherein the dosage form comprises means for providing a delayed burst release profile of the active ingredient.
26. The dosage form of claim 1, wherein the dosage form comprises means for providing a delayed and sustained release profile of the active ingredient.
27. The dosage form of claim 1, wherein the dosage form comprises means for providing a pulsatile release profile of the active ingredient.
28. The dosage form of claim 1, wherein the core or portion thereof further comprises shellac at a level of about 5 to about 15 weight percent of the core or portion thereof.
29. The dosage form of claim 1, wherein the shell or portion thereof further comprises shellac at a level of about 5 to about 15 weight percent of the shell or portion thereof.
30. The dosage form of claim 20, wherein the thermal reversible carrier is selected from the group consisting of polyethylene glycol, polyethylene oxide and copolymers and combinations thereof.
31. The dosage form of claim 23, wherein the film former is polyethylene oxide.
32. The dosage form of claim 24, wherein the release-modifying excipient is a swelling cross-linked polymer.
33. The dosage form of claim 32, wherein the swelling cross-linked polymer is croscarmellose sodium.
34. The dosage form of claim 1, wherein the shell further comprises a plasticizer.
35. The dosage form of claim 34, wherein the plasticizer is tributyl citrate.
36. The dosage form of claim 22, wherein the weight of the shell is from about 10 percent to about 60 percent of the weight of the core.
US10476238 2001-09-28 2002-09-28 Modified release dosage forms Abandoned US20040241236A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
US09966497 US7122143B2 (en) 2001-09-28 2001-09-28 Methods for manufacturing dosage forms
US09966939 US6837696B2 (en) 2001-09-28 2001-09-28 Apparatus for manufacturing dosage forms
US09966509 US6767200B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09966450 US6982094B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09967414 US6742646B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US10476238 US20040241236A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031062 WO2003026626A3 (en) 2001-09-28 2002-09-28 Modified release dosage forms

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US10476238 US20040241236A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms

Related Parent Applications (5)

Application Number Title Priority Date Filing Date
US09966497 Continuation-In-Part US7122143B2 (en) 2001-09-28 2001-09-28 Methods for manufacturing dosage forms
US09966939 Continuation-In-Part US6837696B2 (en) 2001-09-28 2001-09-28 Apparatus for manufacturing dosage forms
US09966509 Continuation-In-Part US6767200B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09966450 Continuation-In-Part US6982094B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09967414 Continuation-In-Part US6742646B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms

Publications (1)

Publication Number Publication Date
US20040241236A1 true true US20040241236A1 (en) 2004-12-02

Family

ID=27542311

Family Applications (15)

Application Number Title Priority Date Filing Date
US10476529 Abandoned US20050019407A1 (en) 2001-09-28 2002-09-28 Composite dosage forms
US10476238 Abandoned US20040241236A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10477334 Active 2024-07-06 US7968120B2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10476504 Abandoned US20040213848A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10476530 Active 2026-09-13 US8545887B2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10432488 Abandoned US20040062804A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10476514 Abandoned US20040170750A1 (en) 2001-09-28 2002-09-28 Edible composition and dosage form comprising an edible shell
US10484485 Abandoned US20040241208A1 (en) 2001-09-28 2002-09-28 Fondant-based pharmaceutical composition
US10393871 Active 2023-06-06 US7416738B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
US10393752 Active 2025-05-06 US7635490B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
US10393610 Abandoned US20030219484A1 (en) 2001-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
US10393638 Abandoned US20030232082A1 (en) 2001-09-28 2003-03-21 Modified release dosage forms
US10393765 Abandoned US20040018327A1 (en) 2001-09-28 2003-03-21 Delayed release dosage forms
US12049628 Abandoned US20080305150A1 (en) 2001-09-28 2008-03-17 Polymer Composition And Dosage Forms Comprising The Same
US12391475 Active US7972624B2 (en) 2001-09-28 2009-02-24 Method of manufacturing modified release dosage forms

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10476529 Abandoned US20050019407A1 (en) 2001-09-28 2002-09-28 Composite dosage forms

Family Applications After (13)

Application Number Title Priority Date Filing Date
US10477334 Active 2024-07-06 US7968120B2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10476504 Abandoned US20040213848A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10476530 Active 2026-09-13 US8545887B2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10432488 Abandoned US20040062804A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10476514 Abandoned US20040170750A1 (en) 2001-09-28 2002-09-28 Edible composition and dosage form comprising an edible shell
US10484485 Abandoned US20040241208A1 (en) 2001-09-28 2002-09-28 Fondant-based pharmaceutical composition
US10393871 Active 2023-06-06 US7416738B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
US10393752 Active 2025-05-06 US7635490B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
US10393610 Abandoned US20030219484A1 (en) 2001-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
US10393638 Abandoned US20030232082A1 (en) 2001-09-28 2003-03-21 Modified release dosage forms
US10393765 Abandoned US20040018327A1 (en) 2001-09-28 2003-03-21 Delayed release dosage forms
US12049628 Abandoned US20080305150A1 (en) 2001-09-28 2008-03-17 Polymer Composition And Dosage Forms Comprising The Same
US12391475 Active US7972624B2 (en) 2001-09-28 2009-02-24 Method of manufacturing modified release dosage forms

Country Status (9)

Country Link
US (15) US20050019407A1 (en)
JP (11) JP2005535558A (en)
KR (11) KR20040037207A (en)
CN (10) CN1596101A (en)
CA (12) CA2461656A1 (en)
DE (5) DE60223269T2 (en)
EP (12) EP1429724B1 (en)
ES (3) ES2311073T3 (en)
WO (12) WO2003026628A3 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040037883A1 (en) * 2002-02-21 2004-02-26 Fang Zhou Controlled release dosage forms
US20070196484A1 (en) * 2004-03-10 2007-08-23 Kaoru Wada Poorly water-soluble drug-containing solid formulation
US20090023778A1 (en) * 2005-04-28 2009-01-22 Eisai R&D Management Co., Ltd. Composition Containing Anti-Dementia Drug
US20090142378A1 (en) 2002-02-21 2009-06-04 Biovail Laboratories International S.R.L. Controlled release dosage forms
US20100291311A1 (en) * 2007-10-05 2010-11-18 Trouve Gerard Coating composition comprising polydextrose, process for preparing same and use of coating ingestible solid forms
US20120141569A1 (en) * 2010-12-07 2012-06-07 Kimberly-Clark Worldwide, Inc. Wipe Coated with a Botanical Composition having Antimicrobial Properties
US8481565B2 (en) 2004-12-27 2013-07-09 Eisai R&D Management Co., Ltd. Method for stabilizing anti-dementia drug

Families Citing this family (243)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US6607751B1 (en) * 1997-10-10 2003-08-19 Intellipharamaceutics Corp. Controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum
WO1999051208A1 (en) * 1998-04-03 1999-10-14 Bm Research A/S Controlled release composition
US20090149479A1 (en) * 1998-11-02 2009-06-11 Elan Pharma International Limited Dosing regimen
DE10026698A1 (en) 2000-05-30 2001-12-06 Basf Ag Self-emulsifying drug formulation and use of this formulation
US20040234602A1 (en) 2001-09-21 2004-11-25 Gina Fischer Polymer release system
EP1429744A1 (en) 2001-09-21 2004-06-23 Egalet A/S Morphine polymer release system
EP1429724B1 (en) 2001-09-28 2013-11-06 McNeil-PPC, Inc. Dosage form containing a confectionery composition
US9358214B2 (en) 2001-10-04 2016-06-07 Adare Pharmaceuticals, Inc. Timed, sustained release systems for propranolol
GB0203296D0 (en) 2002-02-12 2002-03-27 Glaxo Group Ltd Novel composition
US7169450B2 (en) 2002-05-15 2007-01-30 Mcneil-Ppc, Inc. Enrobed core
US20060083791A1 (en) 2002-05-24 2006-04-20 Moerck Rudi E Rare earth metal compounds methods of making, and methods of using the same
US20040161474A1 (en) * 2002-05-24 2004-08-19 Moerck Rudi E. Rare earth metal compounds methods of making, and methods of using the same
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
US8637512B2 (en) 2002-07-29 2014-01-28 Glaxo Group Limited Formulations and method of treatment
DE602004025159D1 (en) * 2003-03-26 2010-03-04 Egalet As Matrix preparations for the controlled administration of drugs
US20060159758A1 (en) * 2002-12-11 2006-07-20 Rajesh Gandhi Coating composition for taste masking coating and methods for their application and use
GB0229258D0 (en) * 2002-12-16 2003-01-22 Boots Healthcare Int Ltd Medicinal compositions
US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US20050220870A1 (en) * 2003-02-20 2005-10-06 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
EP2301526B1 (en) 2003-03-26 2016-03-23 Egalet Ltd. Morphine controlled release system
EP1615626B1 (en) * 2003-04-24 2009-10-14 Jagotec Ag Tablet with coloured core
EP1631251B1 (en) 2003-04-24 2011-06-15 Jagotec AG Delayed release tablet with defined core geometry
EP1633328A4 (en) * 2003-05-29 2008-07-09 Glykon Technologies Group Llc Method and composition for stable and controlled delivery of (-)-hydroxycitric acid
EP2112920A1 (en) * 2003-06-26 2009-11-04 Isa Odidi Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
DK1648421T3 (en) 2003-07-24 2017-12-04 Glaxosmithkline Llc Orally soluble films
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Abuse-proofed dosage form
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
WO2005016278A3 (en) * 2003-08-12 2005-05-19 Advancis Pharmaceuticals Corp Antibiotic product, use and formulation thereof
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
GB0320854D0 (en) 2003-09-05 2003-10-08 Arrow No 7 Ltd Buccal drug delivery
EP1944008A3 (en) * 2004-09-24 2008-07-23 BioProgress Technology Limited Additional improvements in powder compaction and enrobing
KR20070057977A (en) * 2004-09-24 2007-06-07 바이오프로그레스 테크놀로지 리미티드 Additional improvement in powder compaction and enrobing
US8627828B2 (en) 2003-11-07 2014-01-14 U.S. Smokeless Tobacco Company Llc Tobacco compositions
CN102669810B (en) 2003-11-07 2014-11-05 美国无烟烟草有限责任公司 Tobacco compositions
US7879354B2 (en) * 2004-01-13 2011-02-01 Mcneil-Ppc, Inc. Rapidly disintegrating gelatinous coated tablets
US8067029B2 (en) 2004-01-13 2011-11-29 Mcneil-Ppc, Inc. Rapidly disintegrating gelatinous coated tablets
US20050196448A1 (en) * 2004-03-05 2005-09-08 Hai Yong Huang Polymeric compositions and dosage forms comprising the same
US20050196442A1 (en) * 2004-03-05 2005-09-08 Huang Hai Y. Polymeric compositions and dosage forms comprising the same
US20050196446A1 (en) * 2004-03-05 2005-09-08 Huang Hai Y. Polymeric compositions and dosage forms comprising the same
US20050196447A1 (en) * 2004-03-05 2005-09-08 Huang Hai Y. Polymeric compositions and dosage forms comprising the same
US8545881B2 (en) * 2004-04-19 2013-10-01 Eurand Pharmaceuticals, Ltd. Orally disintegrating tablets and methods of manufacture
DK1758557T3 (en) * 2004-05-11 2011-10-24 Egalet Ltd Swellable dosage form comprising gellan gum
US7622137B2 (en) * 2004-05-21 2009-11-24 Accu-Break Technologies, Inc. Dosage forms contained within a capsule or sachet
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8815916B2 (en) 2004-05-25 2014-08-26 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060002986A1 (en) * 2004-06-09 2006-01-05 Smithkline Beecham Corporation Pharmaceutical product
ES2427169T3 (en) * 2004-06-09 2013-10-29 Glaxosmithkline Llc Apparatus for pharmaceutical production
US20050281876A1 (en) * 2004-06-18 2005-12-22 Shun-Por Li Solid dosage form for acid-labile active ingredient
DE102004032051A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH A process for preparing a secured against misuse, solid dosage form
US8394409B2 (en) 2004-07-01 2013-03-12 Intellipharmaceutics Corp. Controlled extended drug release technology
US8609198B2 (en) * 2004-07-21 2013-12-17 Hewlett-Packard Development Company, L.P. Pharmaceutical dose form with a patterned coating and method of making the same
US20060153918A1 (en) * 2004-07-26 2006-07-13 Lerner E I Dosage forms with an enterically coated core tablet
US7621734B2 (en) 2004-07-28 2009-11-24 Mars, Incorporated Apparatus and process for preparing confectionery having an inclusion therein using forming rolls and a forming pin
US20060024361A1 (en) * 2004-07-28 2006-02-02 Isa Odidi Disintegrant assisted controlled release technology
US20060024368A1 (en) * 2004-07-30 2006-02-02 Reza Fassihi Compressed composite delivery system for release-rate modulation of bioactives
US20060039976A1 (en) * 2004-08-23 2006-02-23 Isa Odidi Controlled release composition using transition coating, and method of preparing same
EP1639899A1 (en) * 2004-08-23 2006-03-29 Friesland Brands B.V. Powdered, cold-water soluble/dispersible, foamable composition
EP1799453B1 (en) * 2004-09-30 2012-09-05 MonoSolRX, LLC Multi-layer films having uniform content
EP1809305A4 (en) * 2004-10-15 2009-12-30 Altairnano Inc Phosphate binder with reduced pill burden
US20060087051A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20060088587A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20060088593A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20070281022A1 (en) * 2004-10-27 2007-12-06 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US8383159B2 (en) 2004-10-27 2013-02-26 Mcneil-Ppc, Inc. Dosage forms having a microreliefed surface and methods and apparatus for their production
US20060088586A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20070190133A1 (en) * 2004-10-27 2007-08-16 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
GB0423964D0 (en) * 2004-10-28 2004-12-01 Jagotec Ag Dosage form
US20060093560A1 (en) * 2004-10-29 2006-05-04 Jen-Chi Chen Immediate release film coating
RU2007115537A (en) * 2004-11-04 2008-12-10 Астразенека Аб (Se) New formulations of proton pump inhibitors in the form of modified release pellets
WO2006049565A1 (en) * 2004-11-04 2006-05-11 Astrazeneca Ab New modified release tablet formulations for proton pump inhibitors
WO2006055886A3 (en) 2004-11-19 2006-11-16 Smithkline Beecham Corp Method for customized dispensing of variable dose drug combination products for individualizing of therapies
US7404708B2 (en) * 2004-12-07 2008-07-29 Mcneil-Ppc, Inc. System and process for providing at least one opening in dosage forms
US7530804B2 (en) * 2004-12-07 2009-05-12 Mcneil-Ppc, Inc. System and process for providing at least one opening in dosage forms
US20070129402A1 (en) * 2004-12-27 2007-06-07 Eisai Research Institute Sustained release formulations
EP1838287B1 (en) * 2005-01-07 2012-05-23 Sandoz Ag Process for preparing granulates comprising amoxicillin
US20080187581A1 (en) * 2005-03-16 2008-08-07 Subhash Pandurang Gore Delivery System For Mulitple Drugs
CA2605185A1 (en) * 2005-04-06 2006-10-12 Mallinckrodt Inc. Matrix-based pulse release pharmaceutical formulation
US20080069870A1 (en) * 2005-04-12 2008-03-20 Elan Corporation Pic Controlled Release Compositions Comprising a Cephalosporin for the Treatment of a Bacterial Infection
US8673352B2 (en) * 2005-04-15 2014-03-18 Mcneil-Ppc, Inc. Modified release dosage form
US20060233882A1 (en) * 2005-04-15 2006-10-19 Sowden Harry S Osmotic dosage form
CN101287411B (en) 2005-04-28 2013-03-06 普罗秋斯生物医学公司 Pharma-informatics system
US9756874B2 (en) 2011-07-11 2017-09-12 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
US9161918B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US20090123637A1 (en) * 2005-05-18 2009-05-14 Laboratoires Goemar Novel Food Ingredient and Products Containing the Same
CA2611081C (en) * 2005-06-03 2016-05-31 Egalet A/S A drug delivery system for delivering active substances dispersed in a dispersion medium
US7884136B2 (en) 2005-06-27 2011-02-08 Biovail Laboratories International S.R.L. Modified-release formulations of a bupropion salt
US20070009573A1 (en) * 2005-07-07 2007-01-11 L N K International Method of forming immediate release dosage form
DE102005034043A8 (en) * 2005-07-18 2007-07-12 Südzucker AG Mannheim/Ochsenfurt Isomaltulose and carnitine
US20070015834A1 (en) * 2005-07-18 2007-01-18 Moshe Flashner-Barak Formulations of fenofibrate containing PEG/Poloxamer
CA2619643A1 (en) * 2005-08-17 2007-02-22 Altairnano, Inc. Treatment of chronic renal failure and other conditions in domestic animals: compositions and methods
KR20080075113A (en) * 2005-10-14 2008-08-14 하. 룬트벡 아크티에 셀스카브 Stable pharmaceutical formulations containing escitalopram and bupropion
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
WO2007086846A1 (en) * 2006-01-24 2007-08-02 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
JP2007224012A (en) * 2006-01-30 2007-09-06 Fujifilm Corp Enzymatically crosslinked protein nanoparticle
US20070184111A1 (en) * 2006-02-03 2007-08-09 Pharmavite Llc Hybrid tablet
US20070190131A1 (en) * 2006-02-10 2007-08-16 Perry Ronald L Press-fit rapid release medicament and method and apparatus of manufacturing
US20070224258A1 (en) * 2006-03-22 2007-09-27 Bunick Frank J Dosage forms having a randomized coating
KR20090009214A (en) * 2006-03-28 2009-01-22 맥네일-피피씨, 인코포레이티드 Non-homogenous dosage form coatings
US9561188B2 (en) 2006-04-03 2017-02-07 Intellipharmaceutics Corporation Controlled release delivery device comprising an organosol coat
EP2010162A4 (en) * 2006-04-03 2013-01-09 Isa Odidi Drug delivery composition
US20140010860A1 (en) * 2006-05-12 2014-01-09 Isa Odidi Abuse and alcohol resistant drug composition
US20070293587A1 (en) * 2006-05-23 2007-12-20 Haley Jeffrey T Combating sinus, throat, and blood infections with xylitol delivered in the mouth
US8865133B2 (en) * 2006-05-23 2014-10-21 Orahealth Corporation Bi-Layer Pressed Powders Oral Adhering Tablet with Acacia gum adhesive
JP2009541341A (en) * 2006-06-19 2009-11-26 エーシーシーユー−ブレイク テクノロジーズ,インク. The dosage form of segments form medicament
DK2049123T4 (en) 2006-08-03 2016-11-28 Horizon Pharma Ag LATE discharge-glucocorticoid treatment of rheumatoid ILLNESS
EP2292229B1 (en) 2006-08-25 2012-05-23 Purdue Pharma LP Tamper resistant oral pharmaceutical dosage forms comprising an opioid analgesic
US8399230B2 (en) 2006-10-12 2013-03-19 Kemin Industries, Inc. Heat-stable enzyme compositions
EP1916006A1 (en) * 2006-10-19 2008-04-30 Albert Schömig Implant coated with a wax or a resin
US8580855B2 (en) * 2006-10-20 2013-11-12 Mcneil-Ppc, Inc. Acetaminophen / ibuprofen combinations and method for their use
US20080113021A1 (en) * 2006-10-25 2008-05-15 Robert Shen Ibuprofen composition
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
CA2674536C (en) * 2007-01-16 2016-07-26 Egalet A/S Use of i) a polyglycol and ii) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse
US7767248B2 (en) 2007-02-02 2010-08-03 Overly Iii Harry J Soft chew confectionary with high fiber and sugar content and method for making same
GB0702974D0 (en) * 2007-02-15 2007-03-28 Jagotec Ag Method and apparatus for producing a tablet
JP5224790B2 (en) * 2007-03-02 2013-07-03 株式会社明治 Solid food and a method of manufacturing the same
CA2677076C (en) * 2007-03-02 2017-09-12 Meda Pharmaceuticals Inc. Compositions comprising carisoprodol and methods of use thereof
DE102007011485A1 (en) 2007-03-07 2008-09-11 Grünenthal GmbH Dosage form with impeded abuse
US20080292692A1 (en) * 2007-05-21 2008-11-27 Shira Pilch Impermeable Capsules
US20080300322A1 (en) * 2007-06-01 2008-12-04 Atlantic Pharmaceuticals, Inc. Delivery vehicles containing rosin resins
CA2687192C (en) 2007-06-04 2015-11-24 Egalet A/S Controlled release pharmaceutical compositions for prolonged effect
EP2157968B1 (en) * 2007-06-11 2017-01-18 Encapsys, Llc Benefit agent containing delivery particle
US20080317677A1 (en) * 2007-06-22 2008-12-25 Szymczak Christopher E Laser Marked Dosage Forms
US20080317678A1 (en) * 2007-06-22 2008-12-25 Szymczak Christopher E Laser Marked Dosage Forms
US20090004248A1 (en) * 2007-06-29 2009-01-01 Frank Bunick Dual portion dosage lozenge form
WO2009023672A3 (en) * 2007-08-13 2009-12-30 Abuse Deterrent Pharmaceutical Llc Abuse resistant drugs, method of use and method of making
US20090060983A1 (en) * 2007-08-30 2009-03-05 Bunick Frank J Method And Composition For Making An Orally Disintegrating Dosage Form
EP2197448A4 (en) * 2007-09-12 2010-11-17 Elan Pharma Int Ltd Dosing regimen
US8741329B2 (en) * 2007-09-21 2014-06-03 Merck Sharp & Dohme B.V. Drug delivery system
US20090105561A1 (en) * 2007-10-17 2009-04-23 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Medical or veterinary digestive tract utilization systems and methods
US8303573B2 (en) 2007-10-17 2012-11-06 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8789536B2 (en) 2007-10-17 2014-07-29 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
CA2702904A1 (en) 2007-10-19 2009-04-23 Otsuka Pharmaceutical Co., Ltd. Matrix-type pharmaceutical solid preparation
US8808276B2 (en) * 2007-10-23 2014-08-19 The Invention Science Fund I, Llc Adaptive dispensation in a digestive tract
US20090163894A1 (en) * 2007-10-31 2009-06-25 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Medical or veterinary digestive tract utilization systems and methods
US8333754B2 (en) * 2007-10-31 2012-12-18 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8707964B2 (en) * 2007-10-31 2014-04-29 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090110716A1 (en) * 2007-10-31 2009-04-30 Frank Bunick Orally disintegrative dosage form
US8808271B2 (en) * 2007-10-31 2014-08-19 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8109920B2 (en) * 2007-10-31 2012-02-07 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090137866A1 (en) * 2007-11-28 2009-05-28 Searete Llc, A Limited Liability Corporation Of The State Delaware Medical or veterinary digestive tract utilization systems and methods
US8771643B2 (en) 2008-01-04 2014-07-08 Schabar Research Associates Llc Use of analgesic potentiating compounds to potentiate the analgesic properties of an analgesic compound
WO2009092601A1 (en) 2008-01-25 2009-07-30 Grünenthal GmbH Pharmaceutical dosage form
WO2009154810A3 (en) * 2008-02-25 2010-03-11 Dr. Reddy's Laboratories Ltd. Delivery systems for multiple active agents
US8372432B2 (en) 2008-03-11 2013-02-12 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
WO2009114648A1 (en) 2008-03-11 2009-09-17 Depomed Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
WO2009137648A8 (en) * 2008-05-09 2010-05-27 Aptapharma, Inc. Multilayer proton pump inhibitor tablets
EP2273983B1 (en) 2008-05-09 2016-07-20 Grünenthal GmbH Process for the preparation of an intermediate powder formulation and a final solid dosage form under usage of a spray congealing step
US20110165290A1 (en) * 2008-05-14 2011-07-07 Cadbury Adams Usa Llc Confectionery with enzymatically manipulated texture
WO2009146537A1 (en) * 2008-06-02 2009-12-10 Pharmascience Inc. Multilayer control-release drug delivery system
KR200452140Y1 (en) * 2008-06-20 2011-02-08 주식회사 부성시스템 Control device for nonwoven open/closed device of vinyl house
CN102159163B (en) * 2008-07-14 2014-09-10 波利皮得有限公司 Sustained-release drug carrier composition
KR200450450Y1 (en) * 2008-07-16 2010-10-04 이봉석 The case of position limit switch
JP2011530529A (en) * 2008-08-07 2011-12-22 アバントール パフォーマンス マテリアルズ, インコーポレイテッドJ T Baker Incorporated Sustained-release composition containing a rubber and sugar alcohols
US8038424B2 (en) 2008-09-22 2011-10-18 Xerox Corporation System and method for manufacturing sold ink sticks with an injection molding process
FR2936952A1 (en) * 2008-10-09 2010-04-16 Monique Bellec Product, useful as nutritional supplements, comprises a composition in powder/anhydrous liquid form, having active ingredient and gelling agent e.g. lecithin and alginic acid, where composition is enclosed in edible water-soluble envelope
CA2742759C (en) 2008-11-05 2016-06-07 Polibiotech Srl Dry granulation in a gas stream
WO2010067478A1 (en) * 2008-12-12 2010-06-17 株式会社ミツヤコーポレーション Food and method for processing the same
EP2391369A1 (en) * 2009-01-26 2011-12-07 Nitec Pharma AG Delayed-release glucocorticoid treatment of asthma
CA2751667C (en) 2009-02-06 2016-12-13 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
WO2010088911A1 (en) * 2009-02-06 2010-08-12 Egalet A/S Pharmaceutical compositions resistant to abuse
WO2010093854A1 (en) * 2009-02-13 2010-08-19 Romark Laboratories L.C. Controlled release pharmaceutical formulations of nitazoxanide
WO2010132205A1 (en) * 2009-05-12 2010-11-18 Bpsi Holdings, Llc. Film coatings containing fine particle size detackifiers and substrates coated therewith
WO2010133961A1 (en) 2009-05-22 2010-11-25 Inventia Healthcare Private Limited Extended release compositions of cyclobenzaprine
WO2010149169A3 (en) 2009-06-24 2011-06-16 Egalet A/S Controlled release formulations
CN105126179A (en) 2009-07-14 2015-12-09 波利皮得有限公司 Sustained-release drug carrier composition
JP5592371B2 (en) * 2009-07-24 2014-09-17 モンデリーズ・ジャパン株式会社 Multiple regions confectionery and a method of manufacturing the same
EP2461811B1 (en) 2009-08-05 2016-04-20 Idenix Pharmaceuticals LLC. Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv
US20120141584A1 (en) * 2009-08-26 2012-06-07 Aptapharma, Inc. Multilayer Minitablets
CN102596252A (en) * 2009-08-31 2012-07-18 蒂宝制药公司 Gastric retentive pharmaceutical compositions for immediate and extended release of acetaminophen
RU2012112595A (en) 2009-09-01 2013-10-10 Родиа Операсьон The polymer compositions
US8871263B2 (en) * 2009-09-24 2014-10-28 Mcneil-Ppc, Inc. Manufacture of tablet in a die utilizing radiofrequency energy and meltable binder
US20110070286A1 (en) * 2009-09-24 2011-03-24 Andreas Hugerth Process for the manufacture of nicotine-comprising chewing gum and nicotine-comprising chewing gum manufactured according to said process
US8313768B2 (en) * 2009-09-24 2012-11-20 Mcneil-Ppc, Inc. Manufacture of tablet having immediate release region and sustained release region
EP2316432A1 (en) * 2009-10-30 2011-05-04 ratiopharm GmbH Compound containing fesoterodine and roughage
WO2011056764A1 (en) 2009-11-05 2011-05-12 Ambit Biosciences Corp. Isotopically enriched or fluorinated imidazo[2,1-b][1,3]benzothiazoles
CN103405341A (en) * 2009-12-02 2013-11-27 普罗秋斯数字健康公司 Integrated ingestible event marker system with pharmaceutical product
CA2782285A1 (en) 2009-12-02 2011-06-09 Luigi Mapelli Fexofenadine microcapsules and compositions containing them
CN102639122A (en) * 2009-12-07 2012-08-15 麦克内尔-Ppc股份有限公司 Partial dip coating of dosage forms for modified release
WO2011075615A1 (en) 2009-12-18 2011-06-23 Idenix Pharmaceuticals, Inc. 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors
WO2011078993A1 (en) * 2009-12-21 2011-06-30 Aptapharma, Inc. Functionally-coated multilayer tablets
US8795726B2 (en) 2010-01-19 2014-08-05 Polypid Ltd. Sustained-release nucleic acid matrix compositions
WO2011094890A1 (en) 2010-02-02 2011-08-11 Argusina Inc. Phenylalanine derivatives and their use as non-peptide glp-1 receptor modulators
CN102821757B (en) 2010-02-03 2016-01-20 格吕伦塔尔有限公司 Preparation of a powdered pharmaceutical composition by an extruder
GB201003731D0 (en) * 2010-03-05 2010-04-21 Univ Strathclyde Immediate/delayed drug delivery
GB201003766D0 (en) 2010-03-05 2010-04-21 Univ Strathclyde Pulsatile drug release
GB201003734D0 (en) * 2010-03-05 2010-04-21 Univ Strathclyde Delayed prolonged drug delivery
US20130059062A1 (en) * 2010-03-11 2013-03-07 Ramakant Kashinath Gundu Device For The Manufacture Of A Dosage Form With A Hole And Method Of Manufacture
WO2011112689A9 (en) 2010-03-11 2011-12-22 Ambit Biosciences Corp. Salts of an indazolylpyrrolotriazine
US8486013B2 (en) * 2010-03-18 2013-07-16 Biotronik Ag Balloon catheter having coating
US9743688B2 (en) * 2010-03-26 2017-08-29 Philip Morris Usa Inc. Emulsion/colloid mediated flavor encapsulation and delivery with tobacco-derived lipids
KR20130063512A (en) 2010-05-12 2013-06-14 스펙트럼 파마슈티컬즈 인크 Lanthanum carbonate hydroxide, lanthanum oxycarbonate and methods of their manufacture and use
US20110280936A1 (en) * 2010-05-17 2011-11-17 Aptapharma, Inc. Self Breaking Tablets
WO2011161666A3 (en) * 2010-06-21 2012-03-29 White Innovation Ltd. Enclosed liquid capsules
US20110318411A1 (en) 2010-06-24 2011-12-29 Luber Joseph R Multi-layered orally disintegrating tablet and the manufacture thereof
ES2579942T3 (en) 2010-09-01 2016-08-17 Ambit Biosciences Corporation Pirazolilaminoquinazolina optically active and pharmaceutical compositions and methods of use thereof
CA2809983A1 (en) 2010-09-01 2012-03-08 Ambit Biosciences Corporation Hydrobromide salts of a pyrazolylaminoquinazoline
RU2607499C2 (en) 2010-09-02 2017-01-10 Грюненталь Гмбх Destruction-resistant dosage form containing anionic polymer
CA2819859A1 (en) 2010-12-06 2012-06-14 Follica, Inc. Methods for treating baldness and promoting hair growth
WO2012080833A3 (en) 2010-12-13 2012-09-07 Purdue Pharma L.P. Controlled release dosage forms
WO2012080050A1 (en) 2010-12-14 2012-06-21 F. Hoffmann-La Roche Ag Solid forms of a phenoxybenzenesulfonyl compound
CN103338753A (en) 2011-01-31 2013-10-02 细胞基因公司 Pharmaceutical compositions of cytidine analogs and methods of use thereof
WO2012109398A1 (en) 2011-02-10 2012-08-16 Idenix Pharmaceuticals, Inc. Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating hcv infections
US20120252721A1 (en) 2011-03-31 2012-10-04 Idenix Pharmaceuticals, Inc. Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor
WO2012170578A1 (en) * 2011-06-06 2012-12-13 Oak Crest Institute Of Science Drug delivery device employing wicking release window
US9084439B2 (en) * 2011-09-22 2015-07-21 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US9629392B2 (en) 2011-09-22 2017-04-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US9474303B2 (en) 2011-09-22 2016-10-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
KR101384055B1 (en) * 2012-02-02 2014-04-14 한국원자력연구원 Burst type lagged-release controlled composition and preparation method thereof
US20130225697A1 (en) 2012-02-28 2013-08-29 Grunenthal Gmbh Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
KR20140138293A (en) 2012-03-16 2014-12-03 액시킨 파마수티컬스 인코포레이티드 3,5-diaminopyrazole kinase inhibitors
US20130261372A1 (en) * 2012-03-30 2013-10-03 Elwha LLC, a limited liability company of the State of Delaware Device, System, and Method for Delivery of Sugar Glass Stabilized Compositions
WO2013165961A4 (en) * 2012-04-30 2013-12-27 Carnegie Mellon University A water-activated, ingestible battery
US9233491B2 (en) 2012-05-01 2016-01-12 Johnson & Johnson Consumer Inc. Machine for production of solid dosage forms
US9445971B2 (en) * 2012-05-01 2016-09-20 Johnson & Johnson Consumer Inc. Method of manufacturing solid dosage form
US9511028B2 (en) 2012-05-01 2016-12-06 Johnson & Johnson Consumer Inc. Orally disintegrating tablet
JPWO2013183497A1 (en) * 2012-06-05 2016-01-28 武田薬品工業株式会社 A dry-coated tablet
WO2014006004A1 (en) 2012-07-06 2014-01-09 Egalet Ltd. Abuse deterrent pharmaceutical compositions for controlled release
CN102824640A (en) * 2012-08-06 2012-12-19 济南圣泉唐和唐生物科技有限公司 Capsule shell and preparation method thereof
US20140193546A1 (en) * 2013-01-09 2014-07-10 Alexander Vigneri Coated chocolate confection with improved dye acceptance
DE102013004263A1 (en) 2013-03-13 2014-09-18 Martin Lipsdorf Fast-dissolving oral dosage form and method for manufacturing the same
CA2906945A1 (en) * 2013-03-15 2014-09-18 Incube Labs, Llc Multi-stage biodegradable drug delivery platform
US9470489B2 (en) * 2013-05-14 2016-10-18 Kerry Thaddeus Bowden Airsoft marking round
CA2913209A1 (en) 2013-05-29 2014-12-04 Grunenthal Gmbh Tamper resistant dosage form with bimodal release profile
US9796576B2 (en) 2013-08-30 2017-10-24 Proteus Digital Health, Inc. Container with electronically controlled interlock
RU2016114523A (en) 2013-09-18 2017-10-23 Аксикин Фармасьютикалз, Инк. Pharmaceutically acceptable salts of 3,5-kinase inhibitors diaminopirazolnyh
WO2015042375A1 (en) 2013-09-20 2015-03-26 Idenix Pharmaceuticals, Inc. Hepatitis c virus inhibitors
US20160317449A1 (en) * 2013-12-23 2016-11-03 Xiaoguang WEN Double-layer tablet and preparation method thereof
KR20160107254A (en) 2014-01-10 2016-09-13 존슨 앤드 존슨 컨수머 인코포레이티드 Process for making tablet using radiofrequency and lossy coated particles
US9375033B2 (en) 2014-02-14 2016-06-28 R.J. Reynolds Tobacco Company Tobacco-containing gel composition
WO2015134560A1 (en) 2014-03-05 2015-09-11 Idenix Pharmaceuticals, Inc. Solid forms of a flaviviridae virus inhibitor compound and salts thereof
JP2017508816A (en) 2014-03-20 2017-03-30 カペラ セラピューティクス,インコーポレーテッド Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer
CA2949422A1 (en) 2014-05-26 2015-12-03 Grunenthal Gmbh Multiparticles safeguarded against ethanolic dose-dumping
US9546163B2 (en) 2014-12-23 2017-01-17 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
DE202016008309U1 (en) * 2015-01-22 2017-07-14 Pfeifer & Langen GmbH & Co. KG Cellobiosehaltige sugar mass
US20160222328A1 (en) * 2015-01-30 2016-08-04 Follmann Gmbh & Co. Kg Thermally opening stable core/shell microcapsules
USD765828S1 (en) 2015-02-19 2016-09-06 Crossford International, Llc Chemical tablet
US9839212B2 (en) 2015-04-16 2017-12-12 Bio-Lab, Inc. Multicomponent and multilayer compacted tablets
CA2983642A1 (en) 2015-04-24 2016-10-27 Grunenthal Gmbh Tamper-resistant dosage form with immediate release and resistance against solvent extraction
WO2017159653A1 (en) * 2016-03-15 2017-09-21 アステラス製薬株式会社 Tablet

Citations (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US542614A (en) * 1895-07-09 Office
US3760804A (en) * 1971-01-13 1973-09-25 Alza Corp Improved osmotic dispenser employing magnesium sulphate and magnesium chloride
US4173626A (en) * 1978-12-11 1979-11-06 Merck & Co., Inc. Sustained release indomethacin
US4513019A (en) * 1983-07-06 1985-04-23 Seppic Film-forming compositions for enveloping solid forms, particularly pharmaceutical or food products or seeds, and products obtained, coated with said compositions
US4576604A (en) * 1983-03-04 1986-03-18 Alza Corporation Osmotic system with instant drug availability
US4656024A (en) * 1980-10-28 1987-04-07 Claude Laruelle Galenical administration form of METOCLOPRAMIDE, method for its preparation and medicament comprising the new form
US4803081A (en) * 1986-04-11 1989-02-07 Aktiebolaget Hassle New pharmaceutical preparations with extended release
US4816262A (en) * 1986-08-28 1989-03-28 Universite De Montreal Controlled release tablet
US4863742A (en) * 1986-06-20 1989-09-05 Elan Corporation Plc Controlled absorption pharmaceutical composition
US4874614A (en) * 1985-03-25 1989-10-17 Abbott Laboratories Pharmaceutical tableting method
US4906478A (en) * 1988-12-12 1990-03-06 Valentine Enterprises, Inc. Simethicone/calcium silicate composition
US4931286A (en) * 1989-04-19 1990-06-05 Aqualon Company High gloss cellulose tablet coating
US4980170A (en) * 1988-06-30 1990-12-25 Klinge Pharma Gmbh Pharmaceutical formulation as well as a process for its preparation
US4984240A (en) * 1988-12-22 1991-01-08 Codex Corporation Distributed switching architecture for communication module redundancy
US5030452A (en) * 1989-01-12 1991-07-09 Pfizer Inc. Dispensing devices powered by lyotropic liquid crystals
US5032406A (en) * 1989-02-21 1991-07-16 Norwich Eaton Pharmaceuticals, Inc. Dual-action tablet
US5100676A (en) * 1990-02-02 1992-03-31 Biosurface Technology, Inc. Cool storage of cultured epithelial sheets
US5100675A (en) * 1989-05-03 1992-03-31 Schering Corporation Sustained release tablet comprising loratadine, ibuprofen and pseudoephedrine
US5146730A (en) * 1989-09-20 1992-09-15 Banner Gelatin Products Corp. Film-enrobed unitary-core medicament and the like
US5158777A (en) * 1990-02-16 1992-10-27 E. R. Squibb & Sons, Inc. Captopril formulation providing increased duration of activity
US5194464A (en) * 1988-09-27 1993-03-16 Takeda Chemical Industries, Ltd. Enteric film and preparatoin thereof
US5200194A (en) * 1991-12-18 1993-04-06 Alza Corporation Oral osmotic device
US5229134A (en) * 1989-12-05 1993-07-20 Laboratories Smith Kline & French Pharmaceutical compositions
US5275822A (en) * 1989-10-19 1994-01-04 Valentine Enterprises, Inc. Defoaming composition
US5286497A (en) * 1991-05-20 1994-02-15 Carderm Capital L.P. Diltiazem formulation
US5397574A (en) * 1993-10-04 1995-03-14 Andrx Pharmaceuticals, Inc. Controlled release potassium dosage form
US5415868A (en) * 1993-06-09 1995-05-16 L. Perrigo Company Caplets with gelatin cover and process for making same
US5427614A (en) * 1992-02-14 1995-06-27 Warner-Lambert Company Starch based formulations
US5464633A (en) * 1994-05-24 1995-11-07 Jagotec Ag Pharmaceutical tablets releasing the active substance after a definite period of time
US5516527A (en) * 1989-01-12 1996-05-14 Pfizer Inc. Dispensing device powered by hydrogel
US5558879A (en) * 1995-04-28 1996-09-24 Andrx Pharmaceuticals, Inc. Controlled release formulation for water soluble drugs in which a passageway is formed in situ
US5738874A (en) * 1992-09-24 1998-04-14 Jagotec Ag Pharmaceutical tablet capable of liberating one or more drugs at different release rates
US5807579A (en) * 1995-11-16 1998-09-15 F.H. Faulding & Co. Limited Pseudoephedrine combination pharmaceutical compositions
US5824338A (en) * 1996-08-19 1998-10-20 L. Perrigo Company Caplet and gelatin covering therefor
US5912013A (en) * 1991-07-23 1999-06-15 Shire Laboratories, Inc. Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
US6099865A (en) * 1998-07-08 2000-08-08 Fmc Corporation Croscarmellose taste masking
US6103260A (en) * 1997-07-17 2000-08-15 Mcneil-Ppc, Inc. Simethicone/anhydrous calcium phosphate compositions
US6110499A (en) * 1997-07-24 2000-08-29 Alza Corporation Phenytoin therapy
US6146662A (en) * 1991-06-27 2000-11-14 Alza Corporation System for delaying drug delivery up to seven hours
US6270805B1 (en) * 1998-11-06 2001-08-07 Andrx Pharmaceuticals, Inc. Two pellet controlled release formulation for water soluble drugs which contains an alkaline metal stearate
US6294200B1 (en) * 1996-02-06 2001-09-25 Jagotec Ag Pharmaceutical tablet suitable to deliver the active substance in subsequent and predeterminable times
US6322819B1 (en) * 1998-10-21 2001-11-27 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
US20020028240A1 (en) * 2000-04-17 2002-03-07 Toyohiro Sawada Timed-release compression-coated solid composition for oral administration
US6365185B1 (en) * 1998-03-26 2002-04-02 University Of Cincinnati Self-destructing, controlled release peroral drug delivery system
US6517866B1 (en) * 1997-07-01 2003-02-11 Pfizer Inc. Sertraline salts and sustained-release dosage forms of sertraline
US20030068367A1 (en) * 2001-09-28 2003-04-10 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030070903A1 (en) * 2001-09-28 2003-04-17 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030072799A1 (en) * 2001-09-28 2003-04-17 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030086973A1 (en) * 2001-09-28 2003-05-08 Sowden Harry S Systems, methods and apparatuses for manufacturing dosage forms
US20030124183A1 (en) * 2001-09-28 2003-07-03 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US6899896B2 (en) * 1999-12-23 2005-05-31 Pfizer Inc Hydrogel-driven layered drug dosage form

Family Cites Families (386)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US231163A (en) * 1880-08-17 hamlin
US3371136A (en) 1968-02-27 United States Borax Chem Detergent tablet forming machine
US582438A (en) * 1897-05-11 John scheidler
US231117A (en) * 1880-08-10 Folding boat
US231024A (en) * 1880-08-10 Machine for lining sheets of straw-board
US599865A (en) * 1898-03-01 Emanuel l
US231129A (en) * 1880-08-10 wiesebrook
US231062A (en) * 1880-08-10 Felt hat
US966450A (en) * 1909-06-18 1910-08-09 John W S Jones Couch or bed.
US966509A (en) * 1909-06-25 1910-08-09 Charles A Wulf Flushing-valve.
US967414A (en) * 1910-02-11 1910-08-16 William W Hallam Railway-rail.
US966939A (en) * 1910-05-02 1910-08-09 James V Mitchell Sash-lock.
US996497A (en) * 1911-03-30 1911-06-27 Kokomo Sanitary Mfg Co Tank-cover fastener.
US1036647A (en) 1911-06-19 1912-08-27 St Louis Briquette Machine Company Briquet-machine.
US1437816A (en) 1922-07-26 1922-12-05 Howard S Paine Process for preparing fondant or chocolate soft cream centers
US1505827A (en) * 1923-04-25 1924-08-19 Villasenor Eduardo Tablet-making machine
US1900012A (en) 1925-09-04 1933-03-07 Western Cartridge Co Process of and apparatus for making wads
US2307371A (en) 1941-08-13 1943-01-05 Ray O Vac Co Molding process
US2415997A (en) 1946-01-12 1947-02-18 John W Eldred Article handling apparatus
US2823789A (en) 1952-05-06 1958-02-18 Gilman Engineering & Mfg Corp Parts feeder ribbon
US2996431A (en) * 1953-12-16 1961-08-15 Barry Richard Henry Friable tablet and process for manufacturing same
US2849965A (en) 1954-04-15 1958-09-02 John Holroyd & Company Ltd Machines for use in the production of coated tablets and the like
GB759081A (en) 1954-04-15 1956-10-10 John Holroyd And Company Ltd Improvements relating to machines for the production of coated tablets and the like
US2966431A (en) 1956-03-24 1960-12-27 Basf Ag Separation of filter material from carbon black
US2946298A (en) 1957-11-13 1960-07-26 Arthur Colton Company Compression coating tablet press
US2931276A (en) 1958-02-10 1960-04-05 Jagenberg Werke Ag Methods of and means for producing, processing, and for treating articles
GB866681A (en) 1958-05-22 1961-04-26 May & Baker Ltd N-substituted piperidines
GB936386A (en) 1959-01-16 1963-09-11 Wellcome Found Pellets for supplying biologically active substances to ruminants
US2963993A (en) 1959-01-20 1960-12-13 John Holroyd & Company Ltd Machines for making coated tablets by compression
US3096248A (en) 1959-04-06 1963-07-02 Rexall Drug & Chemical Company Method of making an encapsulated tablet
US3029752A (en) 1959-07-20 1962-04-17 Stokes F J Corp Tablet making machine
GB888038A (en) * 1959-12-16 1962-01-24 William Warren Triggs C B E Medicinal tablet
GB972128A (en) * 1960-01-21 1964-10-07 Wellcome Found Pellets for supplying biologically active substances to ruminants and the manufacture of such pellets
GB990784A (en) 1960-05-23 1965-05-05 Dunlop Rubber Co Improvements in or relating to balls
US3173876A (en) * 1960-05-27 1965-03-16 John C Zobrist Cleaning methods and compositions
GB994742A (en) * 1960-09-09 1965-06-10 Wellcome Found Pharmaceutical tablets containing anthelmintics, and the manufacture thereof
US3108046A (en) 1960-11-25 1963-10-22 Smith Kline French Lab Method of preparing high dosage sustained release tablet and product of this method
NL271831A (en) * 1960-11-29
BE611639A (en) * 1960-12-28
US3430535A (en) 1961-08-25 1969-03-04 Independent Lock Co Key cutter
NL297357A (en) 1962-08-31
US3185626A (en) 1963-03-06 1965-05-25 Sterling Drug Inc Tablet coating method
US3279995A (en) 1963-05-31 1966-10-18 Allen F Reid Shaped pellets
US3276586A (en) * 1963-08-30 1966-10-04 Rosaen Filter Co Indicating means for fluid filters
US3300063A (en) 1965-01-25 1967-01-24 Mayer & Co Inc O Vacuum gripping apparatus
FR1603314A (en) * 1965-02-23 1971-04-05 Pharmaceutical tablets - having a core and a matrix material
US3328840A (en) * 1965-04-23 1967-07-04 Pentronix Inc Powder compacting press
US3279360A (en) 1965-09-13 1966-10-18 Miehle Goss Dexter Inc Machine for printing on cylindrical articles
US3330400A (en) 1966-03-08 1967-07-11 Miehle Goss Dexter Inc Mechanism for transferring cylindrical articles
GB1212535A (en) 1966-10-12 1970-11-18 Shionogi & Co Method and apparatus for producing molded article
US3458968A (en) 1966-11-16 1969-08-05 Lester Gregory Jr Dispensing and feed mechanism
GB1144915A (en) 1966-11-24 1969-03-12 Armour Pharma Improvements in or relating to pastille formulations
US3546142A (en) * 1967-01-19 1970-12-08 Amicon Corp Polyelectrolyte structures
US3656518A (en) 1967-03-27 1972-04-18 Perry Ind Inc Method and apparatus for measuring and dispensing predetermined equal amounts of powdered material
US3563170A (en) 1968-04-16 1971-02-16 Reynolds Metals Co Machine for marking the exterior cylindrical surfaces of cans in a continous nonidexing manner
US3605479A (en) 1968-05-08 1971-09-20 Textron Inc Forming press
US3584114A (en) 1968-05-22 1971-06-08 Hoffmann La Roche Free-flowing powders
NL6808619A (en) * 1968-06-19 1969-12-23
US3541006A (en) * 1968-07-03 1970-11-17 Amicon Corp Ultrafiltration process
FR1581088A (en) 1968-07-17 1969-09-12
US3567043A (en) 1968-08-05 1971-03-02 Sun Chemical Corp Transfer assembly for use with container printing machines
US3627583A (en) * 1969-04-29 1971-12-14 Sucrest Corp Direct compression vehicles
US3604417A (en) * 1970-03-31 1971-09-14 Wayne Henry Linkenheimer Osmotic fluid reservoir for osmotically activated long-term continuous injector device
US3640654A (en) * 1970-06-25 1972-02-08 Wolverine Pentronix Die and punch assembly for compacting powder and method of assembly
US3832252A (en) * 1970-09-29 1974-08-27 T Higuchi Method of making a drug-delivery device
DE2063409B2 (en) 1970-12-23 1975-07-10 C.H. Boehringer Sohn, 6507 Ingelheim
US3811552A (en) 1971-01-11 1974-05-21 Lilly Co Eli Capsule inspection apparatus and method
US3995631A (en) * 1971-01-13 1976-12-07 Alza Corporation Osmotic dispenser with means for dispensing active agent responsive to osmotic gradient
US3726622A (en) * 1971-08-20 1973-04-10 Wolverine Pentronix Compacting apparatus
DE2157465C3 (en) 1971-11-19 1975-04-24 Werner & Pfleiderer, 7000 Stuttgart
GB1371244A (en) * 1971-12-09 1974-10-23 Howorth Air Conditioning Ltd Machines acting on continuously running textile yarns
BE794951A (en) * 1972-02-03 1973-05-29 Parke Davis & Co Packaging soluble in water
US3851751A (en) 1972-04-26 1974-12-03 Jones & Co Inc R A Method and apparatus for forming, filling and sealing packages
US3975888A (en) 1972-04-26 1976-08-24 R. A. Jones & Company, Inc. Method and apparatus for forming, filling and sealing packages
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3912441A (en) 1972-12-13 1975-10-14 Yasuo Shimada Compressing roll in rotary power compression molding machine
US3851638A (en) 1973-02-02 1974-12-03 Kam Act Enterprises Inc Force multiplying type archery bow
DE2309202A1 (en) * 1973-02-21 1974-08-29 Schering Ag Dosage forms including microencapsulated drug-drug
US3832525A (en) * 1973-03-26 1974-08-27 Raymond Lee Organization Inc Automatic heating device to prevent freezing of water supply lines
US3916899A (en) * 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US3884143A (en) 1973-09-04 1975-05-20 Hartnett Co R W Conveyor link for tablet printing apparatus
DE2401419A1 (en) 1974-01-12 1975-07-17 Bosch Gmbh Robert Vehicle with a hydrostatic and mechanical drive-
US3891375A (en) 1974-01-21 1975-06-24 Vector Corp Tablet press
GB1497044A (en) 1974-03-07 1978-01-05 Prodotti Antibiotici Spa Salts of phenyl-alkanoic acids
US3988403A (en) * 1974-07-09 1976-10-26 Union Carbide Corporation Process for producing molded structural foam article having a surface that reproducibly and faithfully replicates the surface of the mold
US4139589A (en) * 1975-02-26 1979-02-13 Monique Beringer Process for the manufacture of a multi-zone tablet and tablet manufactured by this process
US4230693A (en) * 1975-04-21 1980-10-28 Armour-Dial, Inc. Antacid tablets and processes for their preparation
FR2312247B1 (en) * 1975-05-30 1978-08-18 Parcor
US4097606A (en) 1975-10-08 1978-06-27 Bristol-Myers Company APAP Tablet containing an alkali metal carboxymethylated starch and processes for manufacturing same
US4077407A (en) * 1975-11-24 1978-03-07 Alza Corporation Osmotic devices having composite walls
ES456627A1 (en) 1976-03-10 1978-01-16 Aco Laekemedel Ab A method for producing and packaging in one etapade dosage units in solid form.
GB1548022A (en) * 1976-10-06 1979-07-04 Wyeth John & Brother Ltd Pharmaceutial dosage forms
US4111202A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for the controlled and delivery of agent over time
US4218433A (en) * 1977-03-03 1980-08-19 Nippon Kayaku Kabushiki Kaisha Constant-rate eluting tablet and method of producing same
US4139627A (en) * 1977-10-06 1979-02-13 Beecham Inc. Anesthetic lozenges
DE2752971C2 (en) 1977-11-28 1982-08-19 Lev Nikolaevic Moskva Su Koskin
GB2030042A (en) 1978-09-21 1980-04-02 Beecham Group Ltd Antacid fondant
DE2849494A1 (en) * 1978-11-15 1980-05-29 Voss Gunter M A process for the production of pharmaceutical-blanks
US4198390A (en) * 1979-01-31 1980-04-15 Rider Joseph A Simethicone antacid tablet
US4304232A (en) * 1979-03-14 1981-12-08 Alza Corporation Unit system having multiplicity of means for dispensing useful agent
US4271142A (en) * 1979-06-18 1981-06-02 Life Savers, Inc. Portable liquid antacids
US4286497A (en) * 1979-06-18 1981-09-01 Shamah Alfred A Ratchet-securable toggle retainer
JPS5827162B2 (en) 1979-08-24 1983-06-08 Yakuruto Honsha Kk
DE2936040C2 (en) * 1979-09-06 1982-05-19 Meggle Milchindustrie Gmbh & Co Kg, 8094 Reitmehring, De
NL7906689A (en) 1979-09-06 1981-03-10 Dawsonville Corp Nv Tatou device.
US4273793A (en) * 1979-10-26 1981-06-16 General Foods Corporation Apparatus and process for the preparation of gasified confectionaries by pressurized injection molding
US4271206A (en) 1979-10-26 1981-06-02 General Foods Corporation Gasified candy having a predetermined shape
US4683256A (en) * 1980-11-06 1987-07-28 Colorcon, Inc. Dry edible film coating composition, method and coating form
US4543370A (en) 1979-11-29 1985-09-24 Colorcon, Inc. Dry edible film coating composition, method and coating form
US4318746A (en) * 1980-01-08 1982-03-09 Ipco Corporation Highly stable gel, its use and manufacture
US4473526A (en) * 1980-01-23 1984-09-25 Eugen Buhler Method of manufacturing dry-pressed molded articles
US4292017A (en) 1980-07-09 1981-09-29 Doepel Wallace A Apparatus for compressing tablets
US4362757A (en) 1980-10-22 1982-12-07 Amstar Corporation Crystallized, readily water dispersible sugar product containing heat sensitive, acidic or high invert sugar substances
US4327076A (en) * 1980-11-17 1982-04-27 Life Savers, Inc. Compressed chewable antacid tablet and method for forming same
US4327725A (en) * 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4340054A (en) * 1980-12-29 1982-07-20 Alza Corporation Dispenser for delivering fluids and solids
FI821579L (en) * 1981-05-12 1982-11-13 Ici Plc The compositions farmaceutisk
US5002970A (en) * 1981-07-31 1991-03-26 Eby Iii George A Flavor masked ionizable zinc compositions for oral absorption
US4372942A (en) * 1981-08-13 1983-02-08 Beecham Inc. Candy base and liquid center hard candy made therefrom
DE3144678C2 (en) 1981-11-10 1993-01-07 Buehler, Eugen, Dipl.-Ing., 8877 Burtenbach, De
JPS58152813A (en) * 1982-03-08 1983-09-10 Sumitomo Chem Co Ltd Tablet having clear carved seal and its preparation
US4449983A (en) * 1982-03-22 1984-05-22 Alza Corporation Simultaneous delivery of two drugs from unit delivery device
DK151608C (en) * 1982-08-13 1988-06-20 Benzon As Alfred A process for preparing a pharmaceutical oral controlled release multiple-
US4517205A (en) * 1983-01-03 1985-05-14 Nabisco Brands, Inc. Co-deposited two-component hard candy
US4882167A (en) 1983-05-31 1989-11-21 Jang Choong Gook Dry direct compression compositions for controlled release dosage forms
US4533345A (en) * 1983-06-14 1985-08-06 Fertility & Genetics Associates Uterine catheter
US4749575A (en) 1983-10-03 1988-06-07 Bio-Dar Ltd. Microencapsulated medicament in sweet matrix
US4781714A (en) 1983-11-02 1988-11-01 Alza Corporation Dispenser for delivering thermo-responsive composition
GB2182559B (en) 1983-11-02 1989-10-25 Alza Corp Dispenser for delivering thermo-responsive composition
NL194820C (en) 1983-11-02 2003-04-03 Alza Corp A composition for the delivery of a thermo-responsive composition.
DE3404108C2 (en) 1984-02-07 1988-01-14 Kilian & Co Gmbh, 5000 Koeln, De
US4518335A (en) * 1984-03-14 1985-05-21 Allied Corporation Dilatant mold and dilatant molding apparatus
US4564525A (en) * 1984-03-30 1986-01-14 Mitchell Cheryl R Confection products
JPS60217106A (en) * 1984-04-12 1985-10-30 Nobuyuki Takahashi Inorganic-powder freezing molding method
US4757090A (en) 1986-07-14 1988-07-12 Mallinckrodt, Inc. Direct tableting acetaminophen compositions
US4661521A (en) 1984-04-30 1987-04-28 Mallinckrodt, Inc. Direct tableting acetaminophen compositions
US4528335A (en) * 1984-05-18 1985-07-09 Phillips Petroleum Company Polymer blends
US4666212A (en) * 1984-06-15 1987-05-19 Crucible S.A. Metal value recovery
US4610884A (en) 1984-06-29 1986-09-09 The Procter & Gamble Company Confectionery cremes
US4643894A (en) 1984-07-24 1987-02-17 Colorcon, Inc. Maltodextrin coating
US4828841A (en) * 1984-07-24 1989-05-09 Colorcon, Inc. Maltodextrin coating
US4894234A (en) 1984-10-05 1990-01-16 Sharma Shri C Novel drug delivery system for antiarrhythmics
JPH0456007B2 (en) * 1984-10-23 1992-09-07 Shinetsu Chem Ind Co
US4684534A (en) * 1985-02-19 1987-08-04 Dynagram Corporation Of America Quick-liquifying, chewable tablet
US4627971A (en) * 1985-04-22 1986-12-09 Alza Corporation Osmotic device with self-sealing passageway
CA1234717A (en) * 1985-06-28 1988-04-05 Leslie F. Knebl Moist chewing gum composition
GB8517073D0 (en) 1985-07-05 1985-08-14 Hepworth Iron Co Ltd Pipe pipe couplings &c
GB8518301D0 (en) * 1985-07-19 1985-08-29 Fujisawa Pharmaceutical Co Hydrodynamically explosive systems
DK8603837A (en) 1985-08-13 1987-02-14
US4665116A (en) 1985-08-28 1987-05-12 Turtle Wax, Inc. Clear cleaner/polish composition
US4663147A (en) * 1985-09-03 1987-05-05 International Minerals & Chemical Corp. Disc-like sustained release formulation
US5188840A (en) * 1985-09-26 1993-02-23 Chugai Seiyaku Kabushiki Kaisha Slow-release pharmaceutical agent
US4898733A (en) 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
US4853249A (en) 1985-11-15 1989-08-01 Taisho Pharmaceutical Co., Ltd. Method of preparing sustained-release pharmaceutical/preparation
US5229164A (en) * 1985-12-19 1993-07-20 Capsoid Pharma Gmbh Process for producing individually dosed administration forms
JPS62230600A (en) 1986-03-31 1987-10-09 Toyo Tire & Rubber Co Forklift with expansible fork
DE3610878A1 (en) 1986-04-01 1987-10-08 Boehringer Ingelheim Kg Moldings of pellets
US4873231A (en) 1986-04-08 1989-10-10 Smith Walton J Decreasing the toxicity of an ibuprofen salt
US4857330A (en) 1986-04-17 1989-08-15 Alza Corporation Chlorpheniramine therapy
GB8610572D0 (en) 1986-04-30 1986-06-04 Haessle Ab Pharmaceutical preparation
US4960416A (en) * 1986-04-30 1990-10-02 Alza Corporation Dosage form with improved delivery capability
GB8610573D0 (en) * 1986-04-30 1986-06-04 Haessle Ab Pharmaceutical formulations of acid labile substances
US5200196A (en) * 1986-05-09 1993-04-06 Alza Corporation Improvement in pulsed drug therapy
US4802924A (en) 1986-06-19 1989-02-07 Colorcon, Inc. Coatings based on polydextrose for aqueous film coating of pharmaceutical food and confectionary products
US4762719A (en) * 1986-08-07 1988-08-09 Mark Forester Powder filled cough product
DE3629994A1 (en) 1986-09-03 1988-03-17 Weissenbacher Ernst Rainer Pro Device for administration of medicaments in body cavities or on body surfaces
US4803076A (en) * 1986-09-04 1989-02-07 Pfizer Inc. Controlled release device for an active substance
CA1290526C (en) 1986-11-07 1991-10-15 Marianne Wieser Mold and die operation
DE3640574C2 (en) 1986-11-27 1988-09-15 Katjes Fassin Gmbh + Co. Kg, 4240 Emmerich, De
US4828845A (en) * 1986-12-16 1989-05-09 Warner-Lambert Company Xylitol coated comestible and method of preparation
ES2031491T3 (en) 1987-01-13 1992-12-16 Pharmaidea Srl Tablet for pharmaceutical use able to release active substances at successive times.
US4801461A (en) * 1987-01-28 1989-01-31 Alza Corporation Pseudoephedrine dosage form
US4820524A (en) * 1987-02-20 1989-04-11 Mcneilab, Inc. Gelatin coated caplets and process for making same
US5200193A (en) 1987-04-22 1993-04-06 Mcneilab, Inc. Pharmaceutical sustained release matrix and process
US4808413B1 (en) 1987-04-28 1991-09-10 Squibb & Sons Inc
US4792448A (en) 1987-06-11 1988-12-20 Pfizer Inc. Generic zero order controlled drug delivery system
US4813818A (en) * 1987-08-25 1989-03-21 Michael Sanzone Apparatus and method for feeding powdered materials
US4978483A (en) 1987-09-28 1990-12-18 Redding Bruce K Apparatus and method for making microcapsules
US4996061A (en) * 1987-10-07 1991-02-26 Merrell Dow Pharmaceuticals Inc. Pharmaceutical composition for piperidinoalkanol-decongestant combination
US4851226A (en) * 1987-11-16 1989-07-25 Mcneil Consumer Products Company Chewable medicament tablet containing means for taste masking
US4894236A (en) * 1988-01-12 1990-01-16 Choong-Gook Jang Direct compression tablet binders for acetaminophen
CA1330886C (en) 1988-01-22 1994-07-26 Bend Research Inc. Osmotic system for delivery of dilute solutions
ES2053821T5 (en) * 1988-02-03 2001-03-01 Nestle Sa synergistic antioxidant composition.
US4929446A (en) 1988-04-19 1990-05-29 American Cyanamid Company Unit dosage form
US5279660A (en) * 1988-05-24 1994-01-18 Berol Nobel Stenungsund Ab Use of viscosity-adjusting agent to counteract viscosity decrease upon temperature increase of a water-based system
US4999226A (en) 1988-06-01 1991-03-12 Merrell Dow Pharmaceuticals Inc. Pharmaceutical compositions for piperidinoalkanol-ibuprofen combination
GB8820353D0 (en) 1988-08-26 1988-09-28 Staniforth J N Controlled release tablet
WO1990002546A1 (en) 1988-09-09 1990-03-22 The Ronald T. Dodge Company Pharmaceuticals microencapsulated by vapor deposited polymers and method
JPH0816051B2 (en) 1988-12-07 1996-02-21 エスエス製薬株式会社 Sustained-release suppositories
US5610214A (en) 1988-12-29 1997-03-11 Deknatel Technology Corporation, Inc. Method for increasing the rate of absorption of polycaprolactone
US5006297A (en) * 1989-02-22 1991-04-09 Acushnet Company Method of molding polyurethane covered golf balls
US4956182A (en) 1989-03-16 1990-09-11 Bristol-Myers Company Direct compression cholestyramine tablet and solvent-free coating therefor
CA2015478A1 (en) * 1989-04-28 1990-10-28 Kishor B. Parekh Subcoated simulated capsule-like medicament
US4960169A (en) * 1989-06-20 1990-10-02 Modien Manufacturing Co. Baffle for tubular heat exchanger header
US4992277A (en) * 1989-08-25 1991-02-12 Schering Corporation Immediate release diltiazem formulation
EP0419410A3 (en) * 1989-09-19 1991-08-14 Ciba-Geigy Ag Alkanophenones
DK469989D0 (en) * 1989-09-22 1989-09-22 Bukh Meditec pharmaceutical preparation
US5178878A (en) * 1989-10-02 1993-01-12 Cima Labs, Inc. Effervescent dosage form with microparticles
US5223264A (en) * 1989-10-02 1993-06-29 Cima Labs, Inc. Pediatric effervescent dosage form
JPH03139496A (en) * 1989-10-25 1991-06-13 Sanshin Ind Co Ltd Ship propulsion machinery
US5169645A (en) 1989-10-31 1992-12-08 Duquesne University Of The Holy Ghost Directly compressible granules having improved flow properties
US5223266A (en) * 1990-01-24 1993-06-29 Alza Corporation Long-term delivery device with early startup
US4980169A (en) * 1990-05-03 1990-12-25 Warner-Lambert Company Flavor enhancing and increasing efficacy of cough drops
US4983394A (en) * 1990-05-03 1991-01-08 Warner-Lambert Company Flavor enhancing and medicinal taste masking agent
US5213738A (en) 1990-05-15 1993-05-25 L. Perrigo Company Method for making a capsule-shaped tablet
US5089270A (en) * 1990-05-15 1992-02-18 L. Perrigo Company Capsule-shaped tablet
US5075114A (en) 1990-05-23 1991-12-24 Mcneil-Ppc, Inc. Taste masking and sustained release coatings for pharmaceuticals
US5464631A (en) 1990-06-27 1995-11-07 Warner-Lambert Company Encapsulated dosage forms
US5133892A (en) * 1990-10-17 1992-07-28 Lever Brothers Company, Division Of Conopco, Inc. Machine dishwashing detergent tablets
US5228916A (en) 1990-11-05 1993-07-20 Mcneil-Ppc, Inc. Apparatus for creating a gelatin coating
US5503673A (en) * 1990-11-05 1996-04-02 Mcneil-Ppc, Inc Apparatus for dip coating product
US5436026A (en) * 1990-11-05 1995-07-25 Mcneil-Ppc, Inc. Discharge and transfer system for apparatus for gelatin coating tablets
US5538125A (en) * 1990-11-05 1996-07-23 Mcneil-Ppc, Inc. Indexing and feeding systems for apparatus for gelatin coating tablets
US5683719A (en) 1990-11-22 1997-11-04 British Technology Group Limited Controlled release compositions
US5098715A (en) * 1990-12-20 1992-03-24 Burroughs Wellcome Co. Flavored film-coated tablet
US5232706A (en) * 1990-12-31 1993-08-03 Esteve Quimica, S.A. Oral pharmaceutical preparation containing omeprazol
DE4101873C2 (en) * 1991-01-23 1993-12-09 Isis Pharma Gmbh Orally administrable dosage form for the treatment of central dopamine deficiency
US5378475A (en) 1991-02-21 1995-01-03 University Of Kentucky Research Foundation Sustained release drug delivery devices
EP0573462B1 (en) * 1991-02-27 1996-09-25 Janssen Pharmaceutica N.V. A method of highlighting intagliations in tablets
CA2061520C (en) * 1991-03-27 2003-04-22 Bayer Corporation Delivery system for enhanced onset and increased potency
WO1993014158A1 (en) * 1992-01-17 1993-07-22 Berwind Pharmaceutical Services, Inc. Film coatings and film coating compositions based on cellulosic polymers and lactose
CA2068402C (en) * 1991-06-14 1998-09-22 Michael R. Hoy Taste mask coatings for preparation of chewable pharmaceutical tablets
CA2524168A1 (en) 1991-06-17 1992-12-23 Altana Pharma Ag Oral-administration forms of a medicament containing pantoprazole
US5314696A (en) * 1991-06-27 1994-05-24 Paulos Manley A Methods for making and administering a blinded oral dosage form and blinded oral dosage form therefor
US5190927A (en) * 1991-07-09 1993-03-02 Merck & Co., Inc. High-glyceryl, low-acetyl gellan gum for non-brittle gels
US5200191A (en) 1991-09-11 1993-04-06 Banner Gelatin Products Corp. Softgel manufacturing process
US5405617A (en) * 1991-11-07 1995-04-11 Mcneil-Ppc, Inc. Aliphatic or fatty acid esters as a solventless carrier for pharmaceuticals
US5407686A (en) * 1991-11-27 1995-04-18 Sidmak Laboratories, Inc. Sustained release composition for oral administration of active ingredient
US5200195A (en) * 1991-12-06 1993-04-06 Alza Corporation Process for improving dosage form delivery kinetics
DK171536B1 (en) 1991-12-06 1996-12-23 Rasmussen Kann Ind As Window frame of extruded profile members
US5209746A (en) * 1992-02-18 1993-05-11 Alza Corporation Osmotically driven delivery devices with pulsatile effect
US5221278A (en) * 1992-03-12 1993-06-22 Alza Corporation Osmotically driven delivery device with expandable orifice for pulsatile delivery effect
US5656296A (en) * 1992-04-29 1997-08-12 Warner-Lambert Company Dual control sustained release drug delivery systems and methods for preparing same
US5260068A (en) * 1992-05-04 1993-11-09 Anda Sr Pharmaceuticals Inc. Multiparticulate pulsatile drug delivery system
CA2096575C (en) 1992-05-21 2003-05-13 Charles A. Stevens Novel simethicone containing pharmaceutical compositions
EP0572731A1 (en) * 1992-06-01 1993-12-08 THE PROCTER & GAMBLE COMPANY Chewable preparation containing a decongestant
US5317849A (en) 1992-08-07 1994-06-07 Sauter Manufacturing Corporation Encapsulation equipment and method
CA2142982A1 (en) 1992-09-30 1994-04-14 Julian Belknap Lo Articles for sustained release of medications
DE69332801D1 (en) * 1992-11-30 2003-04-30 Kv Pharm Co A taste masked pharmaceutical substances
US5375963A (en) 1993-01-19 1994-12-27 Wohlwend; Clayton E. Multipurpose lifting apparatus
US5456920A (en) 1993-02-10 1995-10-10 Takeda Chemical Industries, Ltd. Uncoated tablets and method of producing the same
US5391378A (en) * 1993-02-22 1995-02-21 Elizabeth-Hata International, Inc. Two-part medicinal tablet and method of manufacture
JP2524955B2 (en) 1993-04-22 1996-08-14 トーワ株式会社 Resin encapsulation molding method and apparatus for electronic components
DK0621032T3 (en) * 1993-04-23 2000-10-23 Novartis Ag Pharmaceutical form with controlled release
DK0699436T4 (en) 1993-05-10 2013-04-08 Euro Celtique Sa Controlled release preparation
JP3054989B2 (en) * 1993-06-19 2000-06-19 八幡 貞男 Adiabatic expression container
BE1007193A5 (en) * 1993-06-21 1995-04-18 Zambon Spa PHARMACEUTICAL SALTS CONTAINING ACID S (+) - 2- (4-isobutylphenyl) PROPIONIC WITH BASIC AMINO.
WO1995002396A1 (en) 1993-07-12 1995-01-26 Smithkline Beecham Corporation Matrix-entrapped beadlet preparation
CA2164344C (en) * 1993-08-30 2004-06-29 Stanley Lech Tablet coating based on a melt-spun mixture of a saccharide and a polymer
US5518551A (en) * 1993-09-10 1996-05-21 Fuisz Technologies Ltd. Spheroidal crystal sugar and method of making
US5622719A (en) * 1993-09-10 1997-04-22 Fuisz Technologies Ltd. Process and apparatus for making rapidly dissolving dosage units and product therefrom
US6020002A (en) * 1994-06-14 2000-02-01 Fuisz Technologies Ltd. Delivery of controlled-release system(s)
US5433951A (en) * 1993-10-13 1995-07-18 Bristol-Myers Squibb Company Sustained release formulation containing captopril and method
US5500227A (en) * 1993-11-23 1996-03-19 Euro-Celtique, S.A. Immediate release tablet cores of insoluble drugs having sustained-release coating
GB2284760B (en) * 1993-11-23 1998-06-24 Euro Celtique Sa A method of preparing pharmaceutical compositions by melt pelletisation
DE4341442C2 (en) * 1993-12-04 1998-11-05 Lohmann Therapie Syst Lts Device for the controlled release of active ingredients and their use
US5458887A (en) * 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
US6060639A (en) * 1994-03-04 2000-05-09 Mentor Corporation Testicular prosthesis and method of manufacturing and filling
US5453920A (en) * 1994-03-08 1995-09-26 Eubanks; William W. Trouble light having a shroud with see-through opening
US5559110A (en) 1994-03-09 1996-09-24 The Dupont Merck Pharmaceutical Company Pharmaceutical formulations of cyclic urea type compounds
JPH07281423A (en) * 1994-04-07 1995-10-27 Konica Corp Plate making method of printing plate
RU2160094C2 (en) 1994-07-08 2000-12-10 Астра Актиеболаг Tabletted multicomponent medicinal form, method of preparation thereof, package, and method for inhibiting gastric acid secretion and/or treating gastrointestinal inflammatory diseases
CN1152671C (en) * 1994-07-08 2004-06-09 阿斯特拉曾尼卡有限公司 Multiple unit pharmaceutical preparation containing proton pump inhibitor
US5788979A (en) * 1994-07-22 1998-08-04 Inflow Dynamics Inc. Biodegradable coating with inhibitory properties for application to biocompatible materials
EP0769935A1 (en) 1994-07-26 1997-05-02 Apr Applied Pharma Research S.A. Pharmaceutical compositions based on chewing gum and a method for the preparation thereof
US5849327A (en) 1994-07-29 1998-12-15 Advanced Polymer Systems, Inc. Delivery of drugs to the lower gastrointestinal tract
US6177125B1 (en) * 1994-08-03 2001-01-23 Gunter M. Voss Method of producing coated tablets
DE9414065U1 (en) * 1994-08-31 1994-11-03 Roehm Gmbh Thermoplastic material for intestinal juice-soluble pharmaceutical enclosures
DE4431653C2 (en) 1994-09-06 2000-01-20 Lohmann Therapie Syst Lts The coated tablet for controlled release of active substances, a process for their preparation and their use
US5733575A (en) * 1994-10-07 1998-03-31 Bpsi Holdings, Inc. Enteric film coating compositions, method of coating therewith, and coated forms
US5614578A (en) 1994-10-28 1997-03-25 Alza Corporation Injection-molded dosage form
GB9421837D0 (en) * 1994-10-28 1994-12-14 Scherer Corp R P Process for preparing solid pharmaceutical dosage forms
US5593696A (en) * 1994-11-21 1997-01-14 Mcneil-Ppc, Inc. Stabilized composition of famotidine and sucralfate for treatment of gastrointestinal disorders
US5756123A (en) * 1994-12-01 1998-05-26 Japan Elanco Co., Ltd. Capsule shell
US5626896A (en) * 1994-12-09 1997-05-06 A.E. Staley Manufacturing Co. Method for making liquid-centered jelly candies
US5582838A (en) * 1994-12-22 1996-12-10 Merck & Co., Inc. Controlled release drug suspension delivery device
DE4446468A1 (en) * 1994-12-23 1996-06-27 Basf Ag A process for the preparation of coated tablets
US6471994B1 (en) * 1995-01-09 2002-10-29 Edward Mendell Co., Inc. Pharmaceutical excipient having improved compressibility
ES2094694B1 (en) 1995-02-01 1997-12-16 Esteve Quimica Sa New pharmaceutically stable of a benzimidazole compound formulation and production process.
ES2124956T3 (en) * 1995-02-07 1999-02-16 Hermann Kronseder Transport star for containers.
US6013281A (en) 1995-02-09 2000-01-11 Astra Aktiebolag Method of making a pharmaceutical dosage form comprising a proton pump inhibitor
US5736159A (en) * 1995-04-28 1998-04-07 Andrx Pharmaceuticals, Inc. Controlled release formulation for water insoluble drugs in which a passageway is formed in situ
US5827874A (en) 1995-05-05 1998-10-27 Meyer; Hans Methods of treating pain and inflammation with proline
EP1075838A3 (en) * 1995-05-09 2001-03-21 Phoqus Limited Powder coating method and composition for electrostatic coating of pharmceutical substrates
EP0743267B1 (en) * 1995-05-13 1999-02-03 Hermann Kronseder Star coneyor for vessels
US5627971A (en) 1995-06-01 1997-05-06 Northern Telecom Limited Machine method for determining the eligibility of links in a network
US5578336A (en) * 1995-06-07 1996-11-26 Monte; Woodrow C. Confection carrier for vitamins, enzymes, phytochemicals and ailmentary vegetable compositions and method of making
US5654005A (en) * 1995-06-07 1997-08-05 Andrx Pharmaceuticals, Inc. Controlled release formulation having a preformed passageway
CN1191480A (en) * 1995-06-09 1998-08-26 R·P·谢勒公司 Soft gelatin capsules contg. particulate material
US5614207A (en) 1995-06-30 1997-03-25 Mcneil-Ppc, Inc. Dry mouth lozenge
GB9517031D0 (en) * 1995-08-19 1995-10-25 Procter & Gamble Confection compositions
ES2220989T3 (en) * 1995-09-21 2004-12-16 Pharma Pass Ii Llc New composition containing acid labile and procedure for preparing benzimidazole.
WO1997014415A1 (en) * 1995-10-19 1997-04-24 F.H. Faulding & Co. Limited Analgesic immediate and controlled release pharmaceutical composition
DE19539361A1 (en) 1995-10-23 1997-04-24 Basf Ag A process for producing multilayer, solid drug forms for oral or rectal administration
DE69614959D1 (en) * 1995-11-07 2001-10-11 Acma Spa Device and method for the forming of product groups which are classified led, with predetermined intervals,
US5733578A (en) * 1995-11-15 1998-03-31 Edward Mendell Co., Inc. Directly compressible high load acetaminophen formulations
JP3220373B2 (en) 1995-11-28 2001-10-22 バイエル薬品株式会社 Sustainability Nifuejipin formulation
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
DK0813424T4 (en) 1996-01-08 2009-11-09 Astrazeneca Ab Oral pharmaceutical dosage forms comprising a proton pump inhibitor and an antacid agent or alginate
DE69628551D1 (en) 1996-01-08 2003-07-10 Astrazeneca Ab Orally applicable pharmaceutical dosage forms containing a protonenpunpeninibitor and a non-steroidal drug antiinflamatorischen
US5879728A (en) * 1996-01-29 1999-03-09 Warner-Lambert Company Chewable confectionary composition and method of preparing same
US6245351B1 (en) * 1996-03-07 2001-06-12 Takeda Chemical Industries, Ltd. Controlled-release composition
US5711691A (en) * 1996-05-13 1998-01-27 Air Packaging Technologies, Inc. Self-closing and self-sealing valve device for use with inflatable structures
US5827535A (en) 1996-06-21 1998-10-27 Banner Pharmacaps, Inc. Graphically impressed softgel and method for making same
US5797898A (en) 1996-07-02 1998-08-25 Massachusetts Institute Of Technology Microchip drug delivery devices
US5916881A (en) * 1996-10-07 1999-06-29 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo High trehalose content syrup
US5807580A (en) 1996-10-30 1998-09-15 Mcneil-Ppc, Inc. Film coated tablet compositions having enhanced disintegration characteristics
KR20080083074A (en) 1998-06-03 2008-09-12 알자 코포레이션 Methods and devices for providing prolonged drug therapy
US6077539A (en) * 1996-11-12 2000-06-20 Pozen, Inc. Treatment of migraine headache
GB9624110D0 (en) * 1996-11-20 1997-01-08 Molins Plc Transferring rod like articles
US5830801A (en) * 1997-01-02 1998-11-03 Motorola, Inc. Resistless methods of gate formation in MOS devices
DE19710213A1 (en) 1997-03-12 1998-09-17 Basf Ag A process for producing solid combination drug forms
US5837301A (en) 1997-04-28 1998-11-17 Husky Injection Molding Systems Ltd. Injection molding machine having a high speed turret
US6210710B1 (en) * 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
US6149939A (en) * 1997-05-09 2000-11-21 Strumor; Mathew A. Healthful dissolvable oral tablets, and mini-bars
JP2001524131A (en) * 1997-05-09 2001-11-27 セイジ、ファーマスーティカルズ、インク Stable oral pharmaceutical dosage form
JP2000515559A (en) * 1997-06-25 2000-11-21 アイ・ピー・アール・インシティチュート・フォー・ファーマシューティカル・リサーチ・エー・ジー Weight loss method
ES2235337T3 (en) 1997-07-09 2005-07-01 Swiss Caps Rechte Und Lizenzen Ag Method and device for producing a multilayer pharmaceutical form, physiologically tolerable.
US5942034A (en) * 1997-07-24 1999-08-24 Bayer Corporation Apparatus for the gelatin coating of medicaments
DE19733505A1 (en) * 1997-08-01 1999-02-04 Knoll Ag Rapid-acting analgesic
US6096340A (en) * 1997-11-14 2000-08-01 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6602522B1 (en) 1997-11-14 2003-08-05 Andrx Pharmaceuticals L.L.C. Pharmaceutical formulation for acid-labile compounds
DK1035834T3 (en) * 1997-12-05 2002-07-08 Alza Corp Osmotic dosage form comprising a first and second coating
US6485748B1 (en) * 1997-12-12 2002-11-26 Andrx Pharmaceuticals, Inc. Once daily pharmaceutical tablet having a unitary core
US6022554A (en) * 1997-12-15 2000-02-08 American Home Products Corporation Polymeric microporous film coated subcutaneous implant
EP1047407A4 (en) 1997-12-19 2007-05-02 Smithkline Beecham Corp Process for manufacturing bite-dispersion tablets
US6432442B1 (en) * 1998-02-23 2002-08-13 Mcneil-Ppc, Inc. Chewable product
US6110500A (en) 1998-03-25 2000-08-29 Temple University Coated tablet with long term parabolic and zero-order release kinetics
US6372254B1 (en) * 1998-04-02 2002-04-16 Impax Pharmaceuticals Inc. Press coated, pulsatile drug delivery system suitable for oral administration
US6394094B1 (en) * 1998-05-01 2002-05-28 Enhance Pharmaceuticals, Inc. Method for injection molding manufacture of controlled release devices
US6365183B1 (en) * 1998-05-07 2002-04-02 Alza Corporation Method of fabricating a banded prolonged release active agent dosage form
EP1077065B1 (en) 1998-05-15 2004-08-04 Chugai Seiyaku Kabushiki Kaisha Controlled release formulations
CA2332922C (en) * 1998-05-22 2008-02-12 Bristol-Myers Squibb Company Enteric coated pharmaceutical composition and method of manufacturing
US6106267A (en) * 1998-06-05 2000-08-22 Aylward; John T. Apparatus for forming a compression-molded product
US6103257A (en) 1998-07-17 2000-08-15 Num-Pop, Inc. System for delivering pharmaceuticals to the buccal mucosa
CA2337885C (en) 1998-07-17 2008-01-08 Bristol-Myers Squibb Company Enteric coated pharmaceutical tablet and method of manufacturing
FR2781152B1 (en) * 1998-07-20 2001-07-06 Permatec Tech Ag Use of an acrylic type polymer as a disintegrant
DE19834180A1 (en) * 1998-07-29 2000-02-03 Benckiser Nv A composition for use in a dishwasher
US6200590B1 (en) * 1998-08-10 2001-03-13 Naphcare, Inc. Controlled, phased-release suppository and its method of production
US6174548B1 (en) * 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
DE19840256A1 (en) * 1998-09-03 2000-03-09 Basf Ag Widely applicable, continuous method for preparing coated solid dosage forms, comprises extruding mixture of drug and thermoplastic binder then applying coating composition in liquid or vapor form
US5997905A (en) 1998-09-04 1999-12-07 Mcneil-Ppc Preparation of pharmaceutically active particles
US6602521B1 (en) 1998-09-29 2003-08-05 Impax Pharmaceuticals, Inc. Multiplex drug delivery system suitable for oral administration
JP3449253B2 (en) * 1998-10-29 2003-09-22 シオノギクオリカプス株式会社 Method for producing a rigid capsule
US6165512A (en) 1998-10-30 2000-12-26 Fuisz Technologies Ltd. Dosage forms containing taste masked active agents
CA2346988C (en) 1998-11-05 2009-02-10 Astrazeneca Ab Pharmaceutical formulation comprising omeprazole
US6183681B1 (en) * 1998-12-07 2001-02-06 Centurion International, Inc. Multi-stage insert molding method
US6727200B2 (en) * 2000-08-31 2004-04-27 Mra Laboratories, Inc. High dielectric constant very low fired X7R ceramic capacitor, and powder for making
ES2175863T3 (en) 1999-02-10 2002-11-16 Suwelack Skin & Health Care Ag lyophilized product containing beta-1,3 glucan from Euglena, their preparation and use.
US6248361B1 (en) 1999-02-26 2001-06-19 Integ, Ltd. Water-soluble folic acid compositions
DE19913692A1 (en) * 1999-03-25 2000-09-28 Basf Ag Mechanically stable pharmaceutical dosage forms containing liquid or semisolid surface-active substances
US6090401A (en) * 1999-03-31 2000-07-18 Mcneil-Ppc, Inc. Stable foam composition
JP3716901B2 (en) * 1999-04-14 2005-11-16 シオノギクオリカプス株式会社 Cellulose ether film
US6248760B1 (en) * 1999-04-14 2001-06-19 Paul C Wilhelmsen Tablet giving rapid release of nicotine for transmucosal administration
DE19925710C2 (en) 1999-06-07 2002-10-10 Byk Gulden Lomberg Chem Fab New formulation and dosage form comprising an acid-labile proton pump inhibitor
US6375963B1 (en) 1999-06-16 2002-04-23 Michael A. Repka Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof
US6555139B2 (en) * 1999-06-28 2003-04-29 Wockhardt Europe Limited Preparation of micron-size pharmaceutical particles by microfluidization
US6174547B1 (en) * 1999-07-14 2001-01-16 Alza Corporation Dosage form comprising liquid formulation
US20020102309A1 (en) * 1999-09-14 2002-08-01 Jane C. I. Hirsh Controlled release formulation for administration of an anti-inflammatory naphthalene derivative
DE19954420A1 (en) * 1999-11-12 2001-05-31 Lohmann Therapie Syst Lts Preparation, consisting of a film, foil-like or wafer-like administration form with a two-layer structure and integrated marking
DE19960494A1 (en) * 1999-12-15 2001-06-21 Knoll Ag Apparatus and method for producing solid forms containing active substance
DE19963569B4 (en) 1999-12-29 2006-11-16 Reckitt Benckiser N.V. A composition for use in a dishwasher
US6599532B2 (en) * 2000-01-13 2003-07-29 Osmotica Corp. Osmotic device containing alprazolam and an antipsychotic agent
US6274162B1 (en) 2000-01-14 2001-08-14 Bpsi Holdings, Inc. Elegant film coating system
US6627223B2 (en) 2000-02-11 2003-09-30 Eurand Pharmaceuticals Ltd. Timed pulsatile drug delivery systems
FR2807034B1 (en) 2000-03-29 2002-06-14 Roquette Freres Mannitol used pneumatic and process for its manufacture
US6372252B1 (en) 2000-04-28 2002-04-16 Adams Laboratories, Inc. Guaifenesin sustained release formulation and tablets
GB0011382D0 (en) 2000-05-11 2000-06-28 Reckitt Benekiser N V Process and press for the production of tablets
US20030086972A1 (en) 2000-08-09 2003-05-08 Appel Leah E. Hydrogel-driven drug dosage form
US20020064550A1 (en) * 2000-09-07 2002-05-30 Akpharma, Inc. Edible candy compositions and methods of using same
GB0027471D0 (en) * 2000-11-08 2000-12-27 Smithkline Beecham Plc Processes
US6649187B2 (en) 2001-02-16 2003-11-18 Bristol-Myers Squibb Pharma Company Use of polyalkylamine polymers in controlled release devices
US20030070584A1 (en) * 2001-05-15 2003-04-17 Cynthia Gulian Dip coating compositions containing cellulose ethers
US20040219211A1 (en) 2001-07-16 2004-11-04 Bruno Criere Pharmeceutical formulation comprising a proton pump inhibitor and antacids
US6558722B2 (en) * 2001-07-18 2003-05-06 Wm. Wrigley Jr. Company Use of powdered gum in making a coating for a confection
GB0120835D0 (en) 2001-08-28 2001-10-17 Smithkline Beecham Plc Process
US20030059466A1 (en) * 2001-09-14 2003-03-27 Pawan Seth Delayed release tablet of venlafaxin
EP1429724B1 (en) 2001-09-28 2013-11-06 McNeil-PPC, Inc. Dosage form containing a confectionery composition
US20030066068A1 (en) 2001-09-28 2003-04-03 Koninklijke Philips Electronics N.V. Individual recommender database using profiles of others
US7323192B2 (en) * 2001-09-28 2008-01-29 Mcneil-Ppc, Inc. Immediate release tablet
WO2003063840A3 (en) 2002-01-25 2003-09-04 Warren Hall Transmucosal delivery of proton pump inhibitors
ES2327034T3 (en) 2002-03-26 2009-10-23 Euro-Celtique S.A. Gel compositions coated with sustained release.
EP1372040B1 (en) * 2002-06-11 2008-03-05 ASML Netherlands B.V. Lithographic apparatus and device manufacturing method
US6906340B2 (en) * 2002-10-25 2005-06-14 Ritdisplay Corporation Organic light-emitting diode and material applied thereto
US20050008695A1 (en) * 2003-05-21 2005-01-13 Control Delivery Systems, Inc. Compositions and methods for delivering a biologically active agent
US20050074514A1 (en) * 2003-10-02 2005-04-07 Anderson Oliver B. Zero cycle molding systems, methods and apparatuses for manufacturing dosage forms

Patent Citations (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US542614A (en) * 1895-07-09 Office
US3760804A (en) * 1971-01-13 1973-09-25 Alza Corp Improved osmotic dispenser employing magnesium sulphate and magnesium chloride
US4173626A (en) * 1978-12-11 1979-11-06 Merck & Co., Inc. Sustained release indomethacin
US4656024A (en) * 1980-10-28 1987-04-07 Claude Laruelle Galenical administration form of METOCLOPRAMIDE, method for its preparation and medicament comprising the new form
US4576604A (en) * 1983-03-04 1986-03-18 Alza Corporation Osmotic system with instant drug availability
US4513019A (en) * 1983-07-06 1985-04-23 Seppic Film-forming compositions for enveloping solid forms, particularly pharmaceutical or food products or seeds, and products obtained, coated with said compositions
US4874614A (en) * 1985-03-25 1989-10-17 Abbott Laboratories Pharmaceutical tableting method
US4803081A (en) * 1986-04-11 1989-02-07 Aktiebolaget Hassle New pharmaceutical preparations with extended release
US4863742A (en) * 1986-06-20 1989-09-05 Elan Corporation Plc Controlled absorption pharmaceutical composition
US4816262A (en) * 1986-08-28 1989-03-28 Universite De Montreal Controlled release tablet
US4980170A (en) * 1988-06-30 1990-12-25 Klinge Pharma Gmbh Pharmaceutical formulation as well as a process for its preparation
US5194464A (en) * 1988-09-27 1993-03-16 Takeda Chemical Industries, Ltd. Enteric film and preparatoin thereof
US4906478A (en) * 1988-12-12 1990-03-06 Valentine Enterprises, Inc. Simethicone/calcium silicate composition
US4984240A (en) * 1988-12-22 1991-01-08 Codex Corporation Distributed switching architecture for communication module redundancy
US5030452A (en) * 1989-01-12 1991-07-09 Pfizer Inc. Dispensing devices powered by lyotropic liquid crystals
US5516527A (en) * 1989-01-12 1996-05-14 Pfizer Inc. Dispensing device powered by hydrogel
US5032406A (en) * 1989-02-21 1991-07-16 Norwich Eaton Pharmaceuticals, Inc. Dual-action tablet
US4931286A (en) * 1989-04-19 1990-06-05 Aqualon Company High gloss cellulose tablet coating
US5100675A (en) * 1989-05-03 1992-03-31 Schering Corporation Sustained release tablet comprising loratadine, ibuprofen and pseudoephedrine
US5146730A (en) * 1989-09-20 1992-09-15 Banner Gelatin Products Corp. Film-enrobed unitary-core medicament and the like
US5459983A (en) * 1989-09-20 1995-10-24 Banner Gelatin Products Corp. Tablet enrobing apparatus
US5275822A (en) * 1989-10-19 1994-01-04 Valentine Enterprises, Inc. Defoaming composition
US5229134A (en) * 1989-12-05 1993-07-20 Laboratories Smith Kline & French Pharmaceutical compositions
US5100676A (en) * 1990-02-02 1992-03-31 Biosurface Technology, Inc. Cool storage of cultured epithelial sheets
US5158777A (en) * 1990-02-16 1992-10-27 E. R. Squibb & Sons, Inc. Captopril formulation providing increased duration of activity
US5286497A (en) * 1991-05-20 1994-02-15 Carderm Capital L.P. Diltiazem formulation
US6146662A (en) * 1991-06-27 2000-11-14 Alza Corporation System for delaying drug delivery up to seven hours
US5912013A (en) * 1991-07-23 1999-06-15 Shire Laboratories, Inc. Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
US5200194A (en) * 1991-12-18 1993-04-06 Alza Corporation Oral osmotic device
US5427614A (en) * 1992-02-14 1995-06-27 Warner-Lambert Company Starch based formulations
US5738874A (en) * 1992-09-24 1998-04-14 Jagotec Ag Pharmaceutical tablet capable of liberating one or more drugs at different release rates
US5415868A (en) * 1993-06-09 1995-05-16 L. Perrigo Company Caplets with gelatin cover and process for making same
US5397574A (en) * 1993-10-04 1995-03-14 Andrx Pharmaceuticals, Inc. Controlled release potassium dosage form
US5464633A (en) * 1994-05-24 1995-11-07 Jagotec Ag Pharmaceutical tablets releasing the active substance after a definite period of time
US5558879A (en) * 1995-04-28 1996-09-24 Andrx Pharmaceuticals, Inc. Controlled release formulation for water soluble drugs in which a passageway is formed in situ
US5807579A (en) * 1995-11-16 1998-09-15 F.H. Faulding & Co. Limited Pseudoephedrine combination pharmaceutical compositions
US6294200B1 (en) * 1996-02-06 2001-09-25 Jagotec Ag Pharmaceutical tablet suitable to deliver the active substance in subsequent and predeterminable times
US5824338A (en) * 1996-08-19 1998-10-20 L. Perrigo Company Caplet and gelatin covering therefor
US6517866B1 (en) * 1997-07-01 2003-02-11 Pfizer Inc. Sertraline salts and sustained-release dosage forms of sertraline
US6103260A (en) * 1997-07-17 2000-08-15 Mcneil-Ppc, Inc. Simethicone/anhydrous calcium phosphate compositions
US6110499A (en) * 1997-07-24 2000-08-29 Alza Corporation Phenytoin therapy
US6365185B1 (en) * 1998-03-26 2002-04-02 University Of Cincinnati Self-destructing, controlled release peroral drug delivery system
US6099865A (en) * 1998-07-08 2000-08-08 Fmc Corporation Croscarmellose taste masking
US6322819B1 (en) * 1998-10-21 2001-11-27 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
US6270805B1 (en) * 1998-11-06 2001-08-07 Andrx Pharmaceuticals, Inc. Two pellet controlled release formulation for water soluble drugs which contains an alkaline metal stearate
US6899896B2 (en) * 1999-12-23 2005-05-31 Pfizer Inc Hydrogel-driven layered drug dosage form
US20020028240A1 (en) * 2000-04-17 2002-03-07 Toyohiro Sawada Timed-release compression-coated solid composition for oral administration
US20030068367A1 (en) * 2001-09-28 2003-04-10 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030070903A1 (en) * 2001-09-28 2003-04-17 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030072799A1 (en) * 2001-09-28 2003-04-17 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030086973A1 (en) * 2001-09-28 2003-05-08 Sowden Harry S Systems, methods and apparatuses for manufacturing dosage forms
US20030124183A1 (en) * 2001-09-28 2003-07-03 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US6767200B2 (en) * 2001-09-28 2004-07-27 Mcneil-Ppc, Inc. Systems, methods and apparatuses for manufacturing dosage forms

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040037883A1 (en) * 2002-02-21 2004-02-26 Fang Zhou Controlled release dosage forms
US8323692B2 (en) 2002-02-21 2012-12-04 Valeant International Bermuda Controlled release dosage forms
US20090142378A1 (en) 2002-02-21 2009-06-04 Biovail Laboratories International S.R.L. Controlled release dosage forms
US7780987B2 (en) 2002-02-21 2010-08-24 Biovail Laboratories International Srl Controlled release dosage forms
US20070196484A1 (en) * 2004-03-10 2007-08-23 Kaoru Wada Poorly water-soluble drug-containing solid formulation
US8481565B2 (en) 2004-12-27 2013-07-09 Eisai R&D Management Co., Ltd. Method for stabilizing anti-dementia drug
US8507527B2 (en) 2004-12-27 2013-08-13 Eisai R & D Management Co., Ltd. Method for stabilizing anti-dementia drug
US20090023778A1 (en) * 2005-04-28 2009-01-22 Eisai R&D Management Co., Ltd. Composition Containing Anti-Dementia Drug
US20100291311A1 (en) * 2007-10-05 2010-11-18 Trouve Gerard Coating composition comprising polydextrose, process for preparing same and use of coating ingestible solid forms
US8741051B2 (en) * 2007-10-05 2014-06-03 Société d'Exploitation de Produits pour les Industries Chimiques SEPPIC Coating composition comprising polydextrose, process for preparing same and use of coating ingestible solid forms
US20120141569A1 (en) * 2010-12-07 2012-06-07 Kimberly-Clark Worldwide, Inc. Wipe Coated with a Botanical Composition having Antimicrobial Properties

Also Published As

Publication number Publication date Type
EP1438028A1 (en) 2004-07-21 application
US20030232082A1 (en) 2003-12-18 application
ES2444549T3 (en) 2014-02-25 grant
JP2005508330A (en) 2005-03-31 application
US20040241208A1 (en) 2004-12-02 application
CA2461354A1 (en) 2003-04-03 application
DE60239945D1 (en) 2011-06-16 grant
WO2003026625A1 (en) 2003-04-03 application
EP1429745A2 (en) 2004-06-23 application
DE60223269T2 (en) 2008-08-21 grant
KR20040045030A (en) 2004-05-31 application
WO2003026624A9 (en) 2004-05-06 application
US7968120B2 (en) 2011-06-28 grant
CN1638740A (en) 2005-07-13 application
US20080305150A1 (en) 2008-12-11 application
ES2295427T3 (en) 2008-04-16 grant
CN1592612A (en) 2005-03-09 application
KR20040066094A (en) 2004-07-23 application
WO2003026629A3 (en) 2004-03-04 application
CA2447984A1 (en) 2003-04-03 application
KR20040037208A (en) 2004-05-04 application
CA2446760A1 (en) 2003-04-03 application
KR20040045032A (en) 2004-05-31 application
US20030235616A1 (en) 2003-12-25 application
EP1429743A1 (en) 2004-06-23 application
JP2005508326A (en) 2005-03-31 application
CN1592610A (en) 2005-03-09 application
WO2003026614A9 (en) 2004-02-26 application
CN1596104A (en) 2005-03-16 application
WO2003026612A3 (en) 2003-06-26 application
CN1592611A (en) 2005-03-09 application
KR20040045026A (en) 2004-05-31 application
JP2005508329A (en) 2005-03-31 application
CA2461870A1 (en) 2003-04-03 application
EP1429746A2 (en) 2004-06-23 application
US8545887B2 (en) 2013-10-01 grant
US20040213848A1 (en) 2004-10-28 application
EP1432404A1 (en) 2004-06-30 application
JP2005509604A (en) 2005-04-14 application
CN1596100A (en) 2005-03-16 application
JP2005535558A (en) 2005-11-24 application
WO2003026616A1 (en) 2003-04-03 application
WO2003026629A2 (en) 2003-04-03 application
JP2005508325A (en) 2005-03-31 application
WO2003026627A1 (en) 2003-04-03 application
US20030232083A1 (en) 2003-12-18 application
WO2003026624A1 (en) 2003-04-03 application
WO2003026628A3 (en) 2003-05-01 application
CN100408029C (en) 2008-08-06 grant
CA2461659A1 (en) 2003-04-03 application
EP1429738B1 (en) 2007-10-31 grant
CA2461354C (en) 2010-04-27 grant
WO2003026626A3 (en) 2003-10-16 application
CN1607945A (en) 2005-04-20 application
JP2005529059A (en) 2005-09-29 application
ES2311073T3 (en) 2009-02-01 grant
WO2003026613A1 (en) 2003-04-03 application
CA2461865A1 (en) 2003-04-03 application
EP1438018B1 (en) 2010-08-11 grant
WO2003026625A9 (en) 2004-05-06 application
JP2005508327A (en) 2005-03-31 application
KR20040037207A (en) 2004-05-04 application
KR20040037203A (en) 2004-05-04 application
EP1429724B1 (en) 2013-11-06 grant
US7635490B2 (en) 2009-12-22 grant
WO2003026612A2 (en) 2003-04-03 application
CA2461682A1 (en) 2003-04-03 application
KR20040037206A (en) 2004-05-04 application
EP1463489A1 (en) 2004-10-06 application
CN1592613A (en) 2005-03-09 application
WO2003026615A3 (en) 2003-07-31 application
CA2446759A1 (en) 2003-04-03 application
US20040170750A1 (en) 2004-09-02 application
EP1429737A1 (en) 2004-06-23 application
KR20040045034A (en) 2004-05-31 application
US20050266084A1 (en) 2005-12-01 application
CA2461659C (en) 2010-12-07 grant
WO2003026614A1 (en) 2003-04-03 application
CA2461653A1 (en) 2003-04-03 application
WO2003026626A2 (en) 2003-04-03 application
DE60228281D1 (en) 2008-09-25 grant
WO2003026630A1 (en) 2003-04-03 application
EP1438030A2 (en) 2004-07-21 application
CN100364515C (en) 2008-01-30 grant
JP2005511515A (en) 2005-04-28 application
EP1438018A1 (en) 2004-07-21 application
EP1429742B1 (en) 2011-05-04 grant
JP2005509605A (en) 2005-04-14 application
US20030219484A1 (en) 2003-11-27 application
CA2461684A1 (en) 2003-04-03 application
JP2005508328A (en) 2005-03-31 application
US7416738B2 (en) 2008-08-26 grant
US20090155372A1 (en) 2009-06-18 application
DE60237294D1 (en) 2010-09-23 grant
US20040213849A1 (en) 2004-10-28 application
KR20040045033A (en) 2004-05-31 application
US20040018327A1 (en) 2004-01-29 application
US7972624B2 (en) 2011-07-05 grant
US20050019407A1 (en) 2005-01-27 application
WO2003026628A2 (en) 2003-04-03 application
DE60223269D1 (en) 2007-12-13 grant
CA2461656A1 (en) 2003-04-03 application
WO2003026615A2 (en) 2003-04-03 application
EP1429724A1 (en) 2004-06-23 application
CN1596102A (en) 2005-03-16 application
EP1429746B1 (en) 2008-08-13 grant
CA2461616A1 (en) 2003-04-03 application
EP1429742A2 (en) 2004-06-23 application
CN1596101A (en) 2005-03-16 application
EP1429738A2 (en) 2004-06-23 application
KR20040045031A (en) 2004-05-31 application
US20040062804A1 (en) 2004-04-01 application

Similar Documents

Publication Publication Date Title
US20030086973A1 (en) Systems, methods and apparatuses for manufacturing dosage forms
US20030124183A1 (en) Systems, methods and apparatuses for manufacturing dosage forms
US20030068367A1 (en) Systems, methods and apparatuses for manufacturing dosage forms
US5770225A (en) Process of preparing a subcoated simulated capsule-like medicament
US20030070584A1 (en) Dip coating compositions containing cellulose ethers
US20080286344A1 (en) Solid form
WO2003026637A2 (en) Dosage form for treatment of diabetes mellitus
US20030108607A1 (en) Film forming compositions containing sucralose
US7217381B2 (en) Systems, methods and apparatuses for manufacturing dosage forms
US20030215585A1 (en) Enrobed core
US20040265372A1 (en) Soft tablet containing high molecular weight cellulosics
US20050271724A1 (en) Sugar coatings and methods therefor
WO2008140460A1 (en) Solid form
US20080311201A1 (en) Modified release solid or semi-solid dosage forms
US20050074514A1 (en) Zero cycle molding systems, methods and apparatuses for manufacturing dosage forms
US20050152971A1 (en) Rapidly disintegrating gelatinous coated tablets
US20040253312A1 (en) Immediate release dosage form comprising shell having openings therein
US20050281876A1 (en) Solid dosage form for acid-labile active ingredient
US20030219484A1 (en) Immediate release dosage form comprising shell having openings therein
WO2008140459A1 (en) Solid form
US20110142905A1 (en) Coated tablets with remaining degradation surface over the time
US20050152970A1 (en) Rapidly disintegrating gelatinous coated tablets
WO2006047695A2 (en) Dosage forms having a microreliefed surface and methods and apparatus for their production
US20030229158A1 (en) Polymer composition and dosage forms comprising the same
US20040129174A1 (en) Burst-release polymer composition and dosage forms comprising the same

Legal Events

Date Code Title Description
AS Assignment

Owner name: MCNEIL-PPC, INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LI, SHUN-POR;SOWDEN, HARRY S.;WYNN, DAVID;AND OTHERS;REEL/FRAME:015288/0770;SIGNING DATES FROM 20040416 TO 20040426

AS Assignment

Owner name: OMJ IRELAND LTD., PUERTO RICO

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MCNEIL-PPC, INC.;REEL/FRAME:020133/0338

Effective date: 20071119