US20010055613A1 - Oral pulsed dose drug delivery system - Google Patents
Oral pulsed dose drug delivery system Download PDFInfo
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- US20010055613A1 US20010055613A1 US09/176,542 US17654298D US2001055613A1 US 20010055613 A1 US20010055613 A1 US 20010055613A1 US 17654298 D US17654298 D US 17654298D US 2001055613 A1 US2001055613 A1 US 2001055613A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- This invention pertains to a multiple dosage form delivery system comprising one or more amphetamine salts for administering the amphetamine salts to a recipient.
- First pass metabolism Some drugs, such as ⁇ blockers, ⁇ -estradiol, and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre-systemic metabolism. Thus, a constant/sustained oral method of delivery would result in reduced oral bioavailability.
- Biological tolerance Continuous release drug plasma profiles are often accompanied by a decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal nitroglycerin.
- Gastric irritation or drug instability in gastric fluid For compounds with gastric irritation or chemical instability in gastric fluid, the use of a sustained release preparation may exacerbate gastric irritation and chemical instability in gastric fluid.
- Pulsed dose delivery systems prepared as either single unit or multiple unit formulations, and which are capable of releasing the drug after a predetermined time, have been studied to address the aforementioned problematic areas for sustained release preparations. These same factors are also problematic in pulsed dose formulation development. For example, gastrointestinal transit times vary not only from patient to patient but also within patients as a result of food intake, stress, and illness; thus a single-unit pulsed-release system may give higher variability compared to a multiple unit system. Additionally, drug layering or core making for multiple unit systems is a time-consuming and hard-to-optimize process. Particularly challenging for formulation scientists has been overcoming two conflicting hurdles for pulsatile formulation development, i.e., lag time and rapid release.
- enteric materials e.g., cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and the Eudragit® acrylic polymers
- enteric materials which are soluble at higher pH values, are frequently used for colon-specific delivery systems. Due to their pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performance as well as inter- and intra-subject variability are major issues for using enteric coated systems as a time-controlled release of drugs.
- a retarding swellable hydrophilic coating has been used for oral delayed release systems (4,5). It was demonstrated that lag time was linearly correlated with coating weight gain and drug release was pH independent.
- Hydroxypropyl methylcellulose barriers with erodible and/or gellable characteristics formed using press coating technology for tablet dosage forms have been described to achieve time-programmed release of drugs (6).
- Tablets or capsules coated with a hydrophobic wax-surfactant layer made from an aqueous dispersion of carnauba wax, beeswax, polyoxyethylene sorbitan monooleate, and hydroxypropyl methylcellulose have been used for rapid drug release after a predetermined lag time. For example,. However, even though a two-hour lag time was achieved for the model drug theophylline at a higher coating level (60%), three hours were required for a complete release of theophylline after the lag time. (8)
- a sustained-release drug delivery system is described in U.S. Pat. No. 4,871,549.
- this system When this system is placed into dissolution medium or the gastrointestinal tract, water influx and the volume expansion of the swelling agent cause the explosion of the water permeable membrane. The drug thus releases after a predetermined time period.
- OROS® push-pull system (Alza Company) has been developed for pulsatile delivery of water-soluble and water-insoluble drugs (9, 10), e.g. the OROS-CT® system and is based on the swelling properties of an osmotic core compartment which provides a pH-independent, time-controlled drug release.
- the PulsincapTM dosage form releases its drug content at either a predetermined time or at a specific site (e.g., colon) in the gastrointestinal tract (11).
- the drug formulation is contained within a water-insoluble capsule body and is sealed with a hydrogel plug.
- the capsule cap dissolves in the gastric juice and the hydrogel plug swells.
- the swollen plug is ejected from the PulsincapTM dosage form and the encapsulated drug is released.
- a pulsatile capsule system containing captopril with release after a nominal 5-hr period was found to perform reproducibly in dissolution and gamma scintigraphy studies. However, in the majority of subjects, no measurable amounts of the drug were observed in the blood, possibly due to instability of the drug in the distal intestine. (12)
- Adderal® comprises a mixture of four amphetamine sulfate salts which, in combination, is indicated for treatment of Attention Deficit Hyperactivity Disorder in children from 3-10 years of age.
- One disadvantage of current treatment is that a tablet form is commonly used which many young children have difficulty in swallowing.
- Another disadvantage of current treatment is that two separate doses are administered, one in the morning and one approximately 4-6 hours later, commonly away from home under other than parental supervision. This current form of treatment, therefore, requires a second treatment which is time-consuming, inconvenient and may be problematic for those children having difficulties in swallowing tablet formulations.
- FIG. 1 illustrates the desired target plasma level profile of the pharmaceutical active contained within the delivery system.
- a pharmaceutical composition for delivering one or more pharmaceutically active amphetamine salts that includes:
- the immediate release and enteric release portions of the composition are present on the same core.
- the immediate release and enteric release components are present on different cores.
- composition may include a combination of the hereinabove referred to cores (one or more cores that include both components on the same core and one or more cores that include only one of the two components on the core).
- the present invention provides a composition in which there is immediate release of drug and enteric release of drug wherein the enteric release is a pulsed release and wherein the drug includes one or more amphetamine salts and mixtures thereof.
- the immediate release component releases the pharmaceutical agent in a pulsed dose upon oral administration of the delivery system.
- the enteric release coating layer retards or delays the release of the pharmaceutical active or drug for a specified time period (“lag time”) until a predetermined time, at which time the release of the drug is rapid and complete, i.e., the entire dose is released within about 30-60 minutes under predetermined environmental conditions, i.e. a particular location within the gastrointestinal tract.
- the delay or lag time will take into consideration factors such as transit times, food effects, inflammatory bowel disease, use of antacids or other medicaments which alter the pH of the GI tract.
- the lag time period is only time-dependent, i.e., pH independent.
- the lag time is preferably within 4 to 6 hours after oral administration of the delivery system.
- the present invention is directed to a composition that provides for enteric release of at least one pharmaceutically active amphetamine salt, including at least one pharmaceutically active amphetamine salt that is coated with an enteric coating wherein (1) the enteric release coating has a defined minimum thickness and/or (2) there is a protective layer between the at least one pharmaceutically active amphetamine salt and the enteric release coating and/or (3) there is a protective layer over the enteric release coating.
- Typical enteric coating levels did not meet the above requirements for the desired dosage profile of amphetamine salts. Using the typical amount of enteric coating (10-20 ⁇ ) resulted in undesired premature leakage of the drug from the delivery system into the upper gastrointestinal tract and thus no drug delivery at the desired location in the gastrointestinal tract after the appropriate lag time. Thus this coating did not meet the requirements for the drug release profile to provide full beneficial therapeutic activity at the desired time.
- the pulsed enteric release of the amphetamine salts is accomplished by employing a certain minimum thickness of the enteric coating.
- the pulsed dose delivery comprises a composition which comprises one or more pharmaceutically active amphetamine salts; an enteric coating over the one or more pharmaceutically active amphetamine salts, wherein the thickness of the enteric coating layer is at least 25 ⁇ ; a further layer of one or more pharmaceutically active amphetamine salts over the enteric coating layer; and an immediate release layer coating.
- the thicker enteric coating surprisingly provides the required delayed immediate release of the pharmaceutically active amphetamine salt at the desired time in the desired area of the gastrointestinal tract.
- FIG. 2 illustrates a model of this delivery system.
- the one or more pharmaceutically active amphetamine salts can be provided within or as a part of a core seed around which the enteric coating is applied.
- a core seed can be coated with one or more layers of one or more pharmaceutically active amphetamine salts.
- a delayed immediate release drug delivery can also be accomplished by coating the drug first with a protective layer prior to applying the enteric coating.
- the pulsed enteric release is accomplished by employing a protective layer between the drug and the enteric coating.
- the enteric coating may be of an increased thickness or may be of lower thickness.
- the object of the invention is met by providing a composition comprising one or more pharmaceutically active amphetamine salts; a protective layer coating over the one or more pharmaceutically active amphetamine salt layer(s), and an enteric coating layer over the protective coating layer; a further pharmaceutically active amphetamine salt layer and an immediate release layer coating.
- the thickness of the enteric coating is at least 25 ⁇
- the protective layer comprises an immediate release coating.
- the one or more pharmaceutically active amphetamine salts can be provided within or as a part of a core seed, during the core seed manufacturing process, around which the protective coating is applied.
- a core seed can be coated with one or more layers of one or more pharmaceutically active amphetamine salts.
- the pulsed enteric release is accomplished by employing a protective layer over the enteric coating.
- a pulsed dose release drug delivery system comprising one or more pharmaceutically active amphetamine salts; an enteric coating layer over the pharmaceutically active amphetamine salt layer(s); and a protective layer over the enteric coating; a second pharmaceutically active amphetamine salt layer; and an immediate release layer coating.
- the protective layer is comprised of one or more components, which includes an immediate release layer and a modifying layer.
- the modifying layer is preferably comprised of a semi water-permeable polymer. Applicants have surprisingly found that a semi-permeable polymer coating used in combination with an immediate release layer coating provided a delayed pulsed release drug delivery profile when layered over the enteric coating.
- the protective layer comprises a semi-permeable polymer and an immediate release coating layer.
- the modifying layer comprises a first layer of a semi-permeable polymer which is adjacent to the enteric coating layer and a second coating layer over the semi-permeable polymer coating layer comprising an immediate release polymer coating layer.
- a semi-permeable polymer which may comprise a low water-permeable pH-insensitive polymer, is layered onto the outer surface of the enteric layer, in order to obtain prolonged delayed release time.
- This semi-permeable polymer coating controls the erosion of the pH-sensitive enteric polymer in an alkaline pH environment in which a pH-sensitive polymer will dissolve rapidly.
- Another pH-sensitive layer may be applied onto the surface of a low water-permeability layer to further delay the release time.
- the composition in addition to a protective layer, comprises an acid which is incorporated into the pharmaceutical active layer or coated onto the surface of the active layer to reduce the pH value of the environment around the enteric polymer layer.
- the acid layer may also be applied on the outer layer of the pH-sensitive enteric polymer layer, followed by a layer of low water-permeability polymer. The release of the active thus may be delayed and the dissolution rate may be increased in an alkaline environment.
- the protective coating may be used both over the drug and over the enteric coating.
- the one or more pharmaceutically active amphetamine salts can be provided within or as a part of a core seed, during the core seed manufacturing process, around which the enteric coating is applied.
- a core seed can be coated with one or more layers of one or more pharmaceutically active amphetamine salts.
- the drug delivery system of the present invention as described herein preferably comprises one or a number of beads or beadlets in a dosage form, either capsule, tablet, sachet or other method of orally administering the beads.
- FIG. 1 illustrates a multiple pulse drug delivery system target plasma profile of the drug delivery system of the present invention.
- the profile reflects an immediate-release component followed by a delayed-release component.
- FIG. 2 schematically illustrates the delayed-release system of the present invention.
- FIG. 2 a graphically illustrates a pulsed dose delivery system.
- FIGS. 2 b and c graphically illustrate the drug release mechanism from the proposed delivery system.
- FIG. 3 is a plot of the percent drug released versus time from the drug-loaded pellets described in Example 1 which exemplifies the immediate release component of the present invention.
- FIG. 4 is a plot of the percent drug released versus time from the coated pellets described in Example 2 which exemplifies the immediate release component and the delayed release components of the present invention.
- FIG. 5 is a plot of the percent drug released versus time from the coated pellets of Example 3 which exemplifies the immediate release component and the delayed release components of the present invention.
- FIG. 6 illustrates the drug release profile of coated pellets described in Example 4 which exemplifies the immediate release component and the delayed release components of the present invention.
- the present invention comprises a core or starting seed, either prepared or commercially available product.
- the cores or starting seeds can be sugar spheres; spheres made from microcrystalline cellulose and any suitable drug crystals.
- the materials that can be employed in making drug-containing pellets are any of those commonly used in pharmaceutics and should be selected on the basis of compatibility with the active drug and the physicochemical properties of the pellets.
- the additives except active drugs are chosen below as examples:
- Binders such as cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer and the like.
- Disintegration agents such as corn starch, pregelatinized starch, cross-linked carboxymethylcellulose (Ac-Di-Sol), sodium starch glycolate (Explotab), cross-linked polyvinylpyrrolidone (Plasdone XL), and any disintegration agents used in tablet preparations.
- Filling agents such as lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
- Surfactants such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate, Pluronic® line (BASF), and the like.
- Solubilizer such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid sodium bicarbonate and sodium carbonate and the like.
- Stabilizers such as any antioxidation agents, buffers, acids, and the like, can also be utilized.
- Extrusion-Spheronization Drug(s) and other additives are granulated by addition of a binder solution. The wet mass is passed through an extruder equipped with a certain size screen. The extrudates are spheronized in a marumerizer. The resulting pellets are dried and sieved for further applications.
- High-Shear Granulation Drug(s) and other additives are dry-mixed and then the mixture is wetted by addition of a binder solution in a high shear-granulator/mixer. The granules are kneaded after wetting by the combined actions of mixing and milling. The resulting granules or pellets are dried and sieved for further applications.
- Solution or Suspension Layering A drug solution or dispersion with or without a binder is sprayed onto starting seeds with a certain particle size in a fluid bed processor or other suitable equipment. The drug thus is coated on the surface of the starting seeds. The drug-loaded pellets are dried for further applications.
- the core particles have a diameter in the range of about 500-1500 microns; preferably 100-800 microns.
- the core may be coated directly with a layer or layers of at least one pharmaceutically active amphetamine salts and/or the pharmaceutically active amphetamine salt may be incorporated into the core material.
- Pharmaceutical active amphetamine salts contemplated to be within the scope of the present invention include amphetamine base, all chemical and chiral derivatives and salts thereof; methylphenidate, all chemical and chiral derivatives and salts thereof; phenylpropanolamine and its salts; and all other compounds indicated for the treatment of attention deficit hyperactivity disorder (ADHD).
- ADHD attention deficit hyperactivity disorder
- a protective layer may be added on top of the pharmaceutical active containing layer and also may be provided between active layers.
- a separation or protective layer may be added onto the surface of the active-loaded core, and then the enteric layer is coated thereupon.
- Another active layer may also be added to the enteric layer to deliver an initial dose.
- a protective coating layer may be applied immediately outside the core, either a drug-containing core or a drug-layered core, by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions.
- Suitable materials for the protective layer include cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose aqueous dispersions (Aquacoat, Surelease), Eudragit RL 30D, Opadry® and the like.
- the suggested coating levels are from 1 to 6%, preferably 2-4% (w/w).
- the enteric coating layer is applied onto the cores with or without seal coating by conventional coating techniques, such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. All commercially available pH-sensitive polymers are included.
- the pharmaceutical active is not released in the acidic stomach environment of approximately below pH 4.5, but not limited to this value. The pharmaceutical active should become available when the pH-sensitive layer dissolves at the greater pH; after a certain delayed time; or after the unit passes through the stomach.
- the preferred delay time is in the range of two to six hours.
- Enteric polymers include cellulose acetate phthalate, Cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, materials known under the trade name Eudragit L12.5, L100, or Eudragit S12.5, S100 or similar compounds used to obtain enteric coatings.
- Aqueous colloidal polymer dispersions or re-dispersions can be also applied, e.g.
- the enteric polymers used in this invention can be modified by mixing with other known coating products that are not pH sensitive.
- coating products include the neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride, sold currently under the trade names EudragitRS and Eudragit RL; a neutral ester dispersion without any functional groups, sold under the trade names Eudragit NE30D and Eudragit NE30; and other pH independent coating products.
- the modifying component of the protective layer used over the enteric coating can include a water penetration barrier layer (semipermeable polymer) which can be successively coated after the enteric coating to reduce the water penetration rate through the enteric coating layer and thus increase the lag time of the drug release.
- a water penetration barrier layer semipermeable polymer
- Sustained-release coatings commonly known to one skilled in the art can be used for this purpose by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions.
- the following materials can be used, but not limited to: Cellulose acetate, Cellulose acetate butyrate, Cellulose acetate propionate, Ethyl cellulose, Fatty acids and their esters, Waxes, zein, and aqueous polymer dispersions such as Eudragit RS and RL 30D, Eudragit NE 30D, Aquacoat, Surelease, cellulose acetate latex.
- aqueous polymer dispersions such as Eudragit RS and RL 30D, Eudragit NE 30D, Aquacoat, Surelease, cellulose acetate latex.
- the combination of above polymers and hydrophilic polymers such as Hydroxyethyl cellulose, Hydroxypropyl cellulose (Klucel, Hercules Corp.), Hydroxypropyl methylcellulose (Methocel, Dow Chemical Corp.), Polyvinylpyrrolidone can also be used.
- An overcoating layer can further optionally be applied to the composition of the present invention.
- Opadry®, Opadry II® (Colorcon) and corresponding color and colorless grades from Colorcon can be used to protect the pellets from being tacky and provide colors to the product.
- the suggested levels of protective or color coating are from 1 to 6%, preferably 2-3% (w/w).
- ingredients can be incorporated into the overcoating formula, for example to provide a quicker immediate release, such as plasticizers: acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate, dibutylsebacate, triacetin, polyethylene glycols, propylene glycol and the others; lubricants: talc, colloidal silica dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, and the like.
- composition preferably in beadlet form
- Typical excipients to be added to a capsule formulation include, but are not limited to: fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler.
- fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler.
- there can be flow aids such as fumed silicon dioxide, silica gel, magnesium stearate, calcium stearate or any other material imparting flow to powders.
- a lubricant can further be added if necessary by using polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or calcium stearate.
- the composition may also be incorporated into a tablet, in particular by incorporation into a tablet matrix, which rapidly disperses the particles after ingestion.
- a filler/binder In order to incorporate these particles into such a tablet, a filler/binder must be added to a table that can accept the particles, but will not allow their destruction during the tableting process.
- Materials that are suitable for this purpose include, but are not limited to, microcrystalline cellulose (A vicel), soy polysaccharide (Emcosoy), pre-gelatinized starches (STARCH 1500, National 1551), and polyethylene glycols (Carbowax).
- the materials should be present in the range of 5-75% (w/w), with a preferred range of 25-50% (w/w).
- disintegrants are added in order to disperse the beads once the tablet is ingested.
- Suitable disintegrants include, but are not limited to: cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol), sodium starch glycolate (Explotab, Primojel), and cross-linked polyvinylpolypyrrolidone (Plasone-XL). These materials should be present in the rate of 3-15% (w/w), with a preferred range of 5-10% (w/w).
- Lubricants are also added to assure proper tableting, and these can include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behanate, and hydrogenated vegetable oil. These lubricants should be present in amounts from 0.1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).
- Tablets are formed, for example, as follows.
- the particles are introduced into a blender along with Avicel, disintegrants and lubricant, mixed for a set number of minutes to provide a homogeneous blend which is then put in the hopper of a tablet press with which tablets are compressed.
- the compression force used is adequate to form a tablet; however, not sufficient to fracture the beads or coatings.
- the multiple dosage form of the present invention can deliver rapid and complete dosages of pharmaceutically active amphetamine salts to achieve the desired levels of the drug in a recipient over the course of about 8 hours with a single oral administration.
- the levels of drug in blood plasma of the pharmaceutically active amphetamine salts will reach a peak fairly rapidly after about 2 hours, and after about 4 hours a second pulse dose is released, wherein a second fairly rapid additive increase of plasma drug levels occurs which slowly decreases over the course of the next 12 hours.
- Nonpareil seeds (30/35 mesh, Paulaur Corp., N.J.), 6.8 kg were put into a FLM-15 fluid bed processor with a 9′′ Wurster column and fluidized at 60° C.
- the suspension of mixed amphetamine salts (MAS) with 1% HPMC E5 Premium (Dow Chemical) as a binder was sprayed onto the seed under suitable conditions. Almost no agglomeration and no fines were observed with a yield of at least 98%.
- the drug-loaded cores were used to test enteric coatings and sustained release coatings. TABLE 1 Ingredients Amount (%) Nonpareil seed 88.00 mixed amphetamine salts 11.40 Methocel E5 Premium 0.60 Water *
- the following formulation was used to coat the mixed amphetamine salts loaded (MASL) pellets from Example 1 with the Eudragit® L 30D-55 (Rohm Pharma, Germany) coating dispersion.
- 2 kg of MASL pellets were loaded into a fluid bed processor with a reduced Wurster column equipped with a precision coater (MP 2/3, Niro Inc.).
- the coating dispersion was prepared by dispersing Triethyl citrate, Talc and Eudragit® L 30D-55 into water and mixing for at least 30 minutes. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized MASL pellets. The spraying was continued until the targeted coating level was achieved (20 ⁇ ). The coated pellets were dried at 30-35° C.
- the following formulation was used to coat the MASL pellets from Example 1 with the Eudragit® 4110D (Rohm Pharma, Germany) coating dispersion.
- MASL pellets (2 kg) were loaded in a fluid bed processor with a reduced Wurster column (GPGC-15, Glatt).
- the coating dispersion was prepared by dispersing Triethyl citrate, Talc and Eudragit® 4110D into water and mixing for at least 30 minutes. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized MASL pellets. The spraying was continued until the targeted coating level was achieved.
- the coated pellets were dried at 30-35° C. for 5 minutes before stopping the process.
- the enteric coated MASL pellets were tested using a USP paddle method at different pH buffers.
- the drug content was analyzed using HPLC.
- the enteric coating delayed the drug release for several hours from the coated pellets until the pH value reached 6.8 or higher, as shown below in Table 3. (Reference # AR98125-3) TABLE 3 Ingredients Amount (%) MASL pellets 70.00 Eudragit ® 4110D 26.24 Triethyl citrate 0.76 Talc 3.00 Water *
- the following formulation was selected to coat the enteric coated MASL pellets.
- Coated MASL pellets from Example 2 or coated MASL pellets from Example 3 (2 kg of either) were loaded into a fluid bed processor with a reduced Wurster column (GPGC-15, Glatt).
- the coating dispersion was prepared by mixing Surelease® (Colorcon) and water for at least 15 minutes prior to spraying. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized pellets. The spraying was continued until the targeted coating level was achieved.
- the coated pellets were coated with a thin layer of Opadry® white (Colorcon) (2%) to prevent the tackiness of the coated pellets during storage. The coated pellets were then dried at 35-40° C.
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Abstract
A multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising an immediate-release component and an enteric delayed-release component wherein (1) the enteric release coating has a defined minimum thickness and/or (2) there is a protective layer between the pharmaceutically active amphetamine salt and the enteric release coating and/or (3) there is a protective layer over the enteric release coating. The product can be composed of either one or a number of beads in a dosage form, including either capsule, tablet, or sachet method for administering the beads.
Description
- This invention pertains to a multiple dosage form delivery system comprising one or more amphetamine salts for administering the amphetamine salts to a recipient.
- Traditionally, drug delivery systems have focused on constant/sustained drug ouput with the objective of minimizing peaks and valleys of drug concentrations in the body to optimize drug efficacy and to reduce adverse effects. A reduced dosing frequency and improved patient compliance can also be expected for the controlled/sustained release drug delivery systems, compared to immediate release preparations. However, for certain drugs, sustained release delivery is not suitable and is affected by the following factors:
- First pass metabolism: Some drugs, such as β blockers, β-estradiol, and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre-systemic metabolism. Thus, a constant/sustained oral method of delivery would result in reduced oral bioavailability.
- Biological tolerance: Continuous release drug plasma profiles are often accompanied by a decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal nitroglycerin.
- Chronopharmacology and circadian rhythms: Circadian rhythms in certain physiological functions are well established. It has been recognized that many symptoms and onset of disease occur during specific time periods of the 24 hour day, e.g., asthma and angina pectoris attacks are most frequently in the morning hours (1,2).
- Local therapeutic need: For the treatment of local disorders such as inflammatory bowel disease, the delivery of compounds to the site of inflammation with no loss due to absorption in the small intestine is highly desirable to achieve the therapeutic effect and to minimize side effects.
- Gastric irritation or drug instability in gastric fluid: For compounds with gastric irritation or chemical instability in gastric fluid, the use of a sustained release preparation may exacerbate gastric irritation and chemical instability in gastric fluid.
- Drug absorption differences in various gastrointestinal segments: In general, drug absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declining in the large intestine. Compensation for changing absorption characteristics in the gastrointestinal tract may be important for some drugs. For example, it is rational for a delivery system to pump out the drug much faster when the system reaches the distal segment of the intestine, to avoid the entombment of the drug in the feces.
- Pulsed dose delivery systems, prepared as either single unit or multiple unit formulations, and which are capable of releasing the drug after a predetermined time, have been studied to address the aforementioned problematic areas for sustained release preparations. These same factors are also problematic in pulsed dose formulation development. For example, gastrointestinal transit times vary not only from patient to patient but also within patients as a result of food intake, stress, and illness; thus a single-unit pulsed-release system may give higher variability compared to a multiple unit system. Additionally, drug layering or core making for multiple unit systems is a time-consuming and hard-to-optimize process. Particularly challenging for formulation scientists has been overcoming two conflicting hurdles for pulsatile formulation development, i.e., lag time and rapid release.
- Various enteric materials, e.g., cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and the Eudragit® acrylic polymers, have been used as gastroresistant, enterosoluble coatings for single drug pulse release in the intestine (3). The enteric materials, which are soluble at higher pH values, are frequently used for colon-specific delivery systems. Due to their pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performance as well as inter- and intra-subject variability are major issues for using enteric coated systems as a time-controlled release of drugs.
- A retarding swellable hydrophilic coating has been used for oral delayed release systems (4,5). It was demonstrated that lag time was linearly correlated with coating weight gain and drug release was pH independent.
- Hydroxypropyl methylcellulose barriers with erodible and/or gellable characteristics formed using press coating technology for tablet dosage forms have been described to achieve time-programmed release of drugs (6). Barrier formulation variables, such as grade of hydroxypropyl methylcellulose, water-soluble and water-insoluble excipients, significantly altered the lag time and the release rate from the center cores.
- Special grades of hydroxypropyl methylcellulose, e.g., Metolose® 60SH, 90SH (Shin-Etsu Ltd., Japan), and Methocel® F4M (Dow Chemical Company, USA), as a hydrophilic matrix material have been used to achieve bimodal drug release for several drugs, i.e., aspirin, ibuprofen, and adinazolam (7). Bimodal release is characterized by a rapid initial release, followed by a period of constant release, and finalized by a second rapid drug release.
- Tablets or capsules coated with a hydrophobic wax-surfactant layer, made from an aqueous dispersion of carnauba wax, beeswax, polyoxyethylene sorbitan monooleate, and hydroxypropyl methylcellulose have been used for rapid drug release after a predetermined lag time. For example,. However, even though a two-hour lag time was achieved for the model drug theophylline at a higher coating level (60%), three hours were required for a complete release of theophylline after the lag time. (8)
- A sustained-release drug delivery system is described in U.S. Pat. No. 4,871,549. When this system is placed into dissolution medium or the gastrointestinal tract, water influx and the volume expansion of the swelling agent cause the explosion of the water permeable membrane. The drug thus releases after a predetermined time period.
- The OROS® push-pull system (Alza Company) has been developed for pulsatile delivery of water-soluble and water-insoluble drugs (9, 10), e.g. the OROS-CT® system and is based on the swelling properties of an osmotic core compartment which provides a pH-independent, time-controlled drug release.
- The Pulsincap™ dosage form releases its drug content at either a predetermined time or at a specific site (e.g., colon) in the gastrointestinal tract (11). The drug formulation is contained within a water-insoluble capsule body and is sealed with a hydrogel plug. Upon oral administration, the capsule cap dissolves in the gastric juice and the hydrogel plug swells. At a controlled and predetermined time point, the swollen plug is ejected from the Pulsincap™ dosage form and the encapsulated drug is released. A pulsatile capsule system containing captopril with release after a nominal 5-hr period was found to perform reproducibly in dissolution and gamma scintigraphy studies. However, in the majority of subjects, no measurable amounts of the drug were observed in the blood, possibly due to instability of the drug in the distal intestine. (12)
- Adderal® comprises a mixture of four amphetamine sulfate salts which, in combination, is indicated for treatment of Attention Deficit Hyperactivity Disorder in children from 3-10 years of age. One disadvantage of current treatment is that a tablet form is commonly used which many young children have difficulty in swallowing. Another disadvantage of current treatment is that two separate doses are administered, one in the morning and one approximately 4-6 hours later, commonly away from home under other than parental supervision. This current form of treatment, therefore, requires a second treatment which is time-consuming, inconvenient and may be problematic for those children having difficulties in swallowing tablet formulations.
- Accordingly, in view of a need for successfully administering a multiple pulsed dose of amphetamine salts and mixtures thereof, the present invention provides an oral multiple pulsed dose delivery system for amphetamine salts and mixtures thereof. FIG. 1 illustrates the desired target plasma level profile of the pharmaceutical active contained within the delivery system.
- In accordance with a preferred embodiment of the present invention, there is provided a pharmaceutical composition for delivering one or more pharmaceutically active amphetamine salts that includes:
- (a) one or more pharmaceutically active amphetamine salts that are covered with an immediate release coating, and
- (b) one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating wherein (1) the enteric release coating has a defined minimum thickness and/or (2) there is a protective layer between the at least one pharmaceutically active amphetamine salt and the enteric release coating and/or (3) there is a protective layer over the enteric release coating.
- In one embodiment, the immediate release and enteric release portions of the composition are present on the same core.
- In another embodiment, the immediate release and enteric release components are present on different cores.
- It is also contemplated that the composition may include a combination of the hereinabove referred to cores (one or more cores that include both components on the same core and one or more cores that include only one of the two components on the core).
- The present invention provides a composition in which there is immediate release of drug and enteric release of drug wherein the enteric release is a pulsed release and wherein the drug includes one or more amphetamine salts and mixtures thereof.
- The immediate release component releases the pharmaceutical agent in a pulsed dose upon oral administration of the delivery system.
- The enteric release coating layer retards or delays the release of the pharmaceutical active or drug for a specified time period (“lag time”) until a predetermined time, at which time the release of the drug is rapid and complete, i.e., the entire dose is released within about 30-60 minutes under predetermined environmental conditions, i.e. a particular location within the gastrointestinal tract.
- The delay or lag time will take into consideration factors such as transit times, food effects, inflammatory bowel disease, use of antacids or other medicaments which alter the pH of the GI tract.
- In a preferred embodiment, the lag time period is only time-dependent, i.e., pH independent. The lag time is preferably within 4 to 6 hours after oral administration of the delivery system.
- In one aspect, the present invention is directed to a composition that provides for enteric release of at least one pharmaceutically active amphetamine salt, including at least one pharmaceutically active amphetamine salt that is coated with an enteric coating wherein (1) the enteric release coating has a defined minimum thickness and/or (2) there is a protective layer between the at least one pharmaceutically active amphetamine salt and the enteric release coating and/or (3) there is a protective layer over the enteric release coating.
- In attempting to provide for enteric release of an amphetamine salt, applicants found that use of an enteric release coating as generally practiced in the art did not provide effective enteric release.
- Typical enteric coating levels did not meet the above requirements for the desired dosage profile of amphetamine salts. Using the typical amount of enteric coating (10-20μ) resulted in undesired premature leakage of the drug from the delivery system into the upper gastrointestinal tract and thus no drug delivery at the desired location in the gastrointestinal tract after the appropriate lag time. Thus this coating did not meet the requirements for the drug release profile to provide full beneficial therapeutic activity at the desired time.
- Surprisingly, applicants found that using a thicker application of enteric coating on the formulation allowed for the second pulsed dose to be released only and completely at the appropriate time in the desired predetermined area of the gastrointestinal tract, i.e., in the intestine.
- This was surprising because an increase in thickness of about 5-101μ of enteric coatings above a minimum thickness of about 10-20μ typically does not have a significant effect on release of drug from within such coatings. Enteric coatings typically are pH dependent and will only dissolve/disperse when exposed to the appropriate environment. Typically, application of a thicker coating (greater than 20μ) will only marginally increase the time for complete release at the appropriate environmental condition i.e., for a brief period of time (20 minutes). Using the typical coating, applicants could not achieve the desired result—rather, the coating leaked before the predetermined time in an inappropriate environment resulting in significant loss of the therapeutic agent.
- Accordingly, in one aspect, the pulsed enteric release of the amphetamine salts is accomplished by employing a certain minimum thickness of the enteric coating.
- In one embodiment of the invention, the pulsed dose delivery comprises a composition which comprises one or more pharmaceutically active amphetamine salts; an enteric coating over the one or more pharmaceutically active amphetamine salts, wherein the thickness of the enteric coating layer is at least 25μ; a further layer of one or more pharmaceutically active amphetamine salts over the enteric coating layer; and an immediate release layer coating. The thicker enteric coating surprisingly provides the required delayed immediate release of the pharmaceutically active amphetamine salt at the desired time in the desired area of the gastrointestinal tract. FIG. 2 illustrates a model of this delivery system.
- In this aspect, the one or more pharmaceutically active amphetamine salts can be provided within or as a part of a core seed around which the enteric coating is applied. Alternatively, a core seed can be coated with one or more layers of one or more pharmaceutically active amphetamine salts.
- It has further been discovered that a delayed immediate release drug delivery can also be accomplished by coating the drug first with a protective layer prior to applying the enteric coating.
- Thus, in another embodiment, the pulsed enteric release is accomplished by employing a protective layer between the drug and the enteric coating. When using a protective coating, the enteric coating may be of an increased thickness or may be of lower thickness.
- Thus, in another aspect, the object of the invention is met by providing a composition comprising one or more pharmaceutically active amphetamine salts; a protective layer coating over the one or more pharmaceutically active amphetamine salt layer(s), and an enteric coating layer over the protective coating layer; a further pharmaceutically active amphetamine salt layer and an immediate release layer coating. In a preferred embodiment of this aspect, the thickness of the enteric coating is at least 25μ, and the protective layer comprises an immediate release coating.
- With respect to this embodiment of the invention, the one or more pharmaceutically active amphetamine salts can be provided within or as a part of a core seed, during the core seed manufacturing process, around which the protective coating is applied. Alternatively, a core seed can be coated with one or more layers of one or more pharmaceutically active amphetamine salts.
- In another embodiment, the pulsed enteric release is accomplished by employing a protective layer over the enteric coating.
- Accordingly, in this embodiment of the present invention, there is provided a pulsed dose release drug delivery system comprising one or more pharmaceutically active amphetamine salts; an enteric coating layer over the pharmaceutically active amphetamine salt layer(s); and a protective layer over the enteric coating; a second pharmaceutically active amphetamine salt layer; and an immediate release layer coating.
- In one aspect of this embodiment, the protective layer is comprised of one or more components, which includes an immediate release layer and a modifying layer. The modifying layer is preferably comprised of a semi water-permeable polymer. Applicants have surprisingly found that a semi-permeable polymer coating used in combination with an immediate release layer coating provided a delayed pulsed release drug delivery profile when layered over the enteric coating.
- Thus, in this embodiment, the protective layer comprises a semi-permeable polymer and an immediate release coating layer. In a preferred embodiment, the modifying layer comprises a first layer of a semi-permeable polymer which is adjacent to the enteric coating layer and a second coating layer over the semi-permeable polymer coating layer comprising an immediate release polymer coating layer.
- In one aspect of this embodiment, a semi-permeable polymer, which may comprise a low water-permeable pH-insensitive polymer, is layered onto the outer surface of the enteric layer, in order to obtain prolonged delayed release time. This semi-permeable polymer coating controls the erosion of the pH-sensitive enteric polymer in an alkaline pH environment in which a pH-sensitive polymer will dissolve rapidly. Another pH-sensitive layer may be applied onto the surface of a low water-permeability layer to further delay the release time.
- In a still further aspect of the invention, in addition to a protective layer, the composition comprises an acid which is incorporated into the pharmaceutical active layer or coated onto the surface of the active layer to reduce the pH value of the environment around the enteric polymer layer. The acid layer may also be applied on the outer layer of the pH-sensitive enteric polymer layer, followed by a layer of low water-permeability polymer. The release of the active thus may be delayed and the dissolution rate may be increased in an alkaline environment.
- In a further embodiment, the protective coating may be used both over the drug and over the enteric coating.
- With respect to this embodiment of the invention, the one or more pharmaceutically active amphetamine salts can be provided within or as a part of a core seed, during the core seed manufacturing process, around which the enteric coating is applied. Alternatively, a core seed can be coated with one or more layers of one or more pharmaceutically active amphetamine salts.
- The drug delivery system of the present invention as described herein preferably comprises one or a number of beads or beadlets in a dosage form, either capsule, tablet, sachet or other method of orally administering the beads.
- FIG. 1 illustrates a multiple pulse drug delivery system target plasma profile of the drug delivery system of the present invention. The profile reflects an immediate-release component followed by a delayed-release component.
- FIG. 2 schematically illustrates the delayed-release system of the present invention.
- FIG. 2a graphically illustrates a pulsed dose delivery system.
- FIGS. 2b and c graphically illustrate the drug release mechanism from the proposed delivery system.
- FIG. 3 is a plot of the percent drug released versus time from the drug-loaded pellets described in Example 1 which exemplifies the immediate release component of the present invention.
- FIG. 4 is a plot of the percent drug released versus time from the coated pellets described in Example 2 which exemplifies the immediate release component and the delayed release components of the present invention.
- FIG. 5 is a plot of the percent drug released versus time from the coated pellets of Example 3 which exemplifies the immediate release component and the delayed release components of the present invention.
- FIG. 6 illustrates the drug release profile of coated pellets described in Example 4 which exemplifies the immediate release component and the delayed release components of the present invention.
- The present invention comprises a core or starting seed, either prepared or commercially available product. The cores or starting seeds can be sugar spheres; spheres made from microcrystalline cellulose and any suitable drug crystals.
- The materials that can be employed in making drug-containing pellets are any of those commonly used in pharmaceutics and should be selected on the basis of compatibility with the active drug and the physicochemical properties of the pellets. The additives except active drugs are chosen below as examples:
- Binders such as cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer and the like.
- Disintegration agents such as corn starch, pregelatinized starch, cross-linked carboxymethylcellulose (Ac-Di-Sol), sodium starch glycolate (Explotab), cross-linked polyvinylpyrrolidone (Plasdone XL), and any disintegration agents used in tablet preparations.
- Filling agents such as lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
- Surfactants such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate, Pluronic® line (BASF), and the like.
- Solubilizer such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid sodium bicarbonate and sodium carbonate and the like.
- Stabilizers such as any antioxidation agents, buffers, acids, and the like, can also be utilized.
- Methods of Manufacturing the Core Include
- a. Extrusion-Spheronization—Drug(s) and other additives are granulated by addition of a binder solution. The wet mass is passed through an extruder equipped with a certain size screen. The extrudates are spheronized in a marumerizer. The resulting pellets are dried and sieved for further applications.
- b. High-Shear Granulation—Drug(s) and other additives are dry-mixed and then the mixture is wetted by addition of a binder solution in a high shear-granulator/mixer. The granules are kneaded after wetting by the combined actions of mixing and milling. The resulting granules or pellets are dried and sieved for further applications.
- c. Solution or Suspension Layering—A drug solution or dispersion with or without a binder is sprayed onto starting seeds with a certain particle size in a fluid bed processor or other suitable equipment. The drug thus is coated on the surface of the starting seeds. The drug-loaded pellets are dried for further applications.
- For purposes of the present invention, the core particles have a diameter in the range of about 500-1500 microns; preferably 100-800 microns.
- These particles can then be coated in a fluidized bed apparatus with an alternating sequence of coating layers.
- The core may be coated directly with a layer or layers of at least one pharmaceutically active amphetamine salts and/or the pharmaceutically active amphetamine salt may be incorporated into the core material. Pharmaceutical active amphetamine salts contemplated to be within the scope of the present invention include amphetamine base, all chemical and chiral derivatives and salts thereof; methylphenidate, all chemical and chiral derivatives and salts thereof; phenylpropanolamine and its salts; and all other compounds indicated for the treatment of attention deficit hyperactivity disorder (ADHD).
- A protective layer may be added on top of the pharmaceutical active containing layer and also may be provided between active layers. A separation or protective layer may be added onto the surface of the active-loaded core, and then the enteric layer is coated thereupon. Another active layer may also be added to the enteric layer to deliver an initial dose.
- A protective coating layer may be applied immediately outside the core, either a drug-containing core or a drug-layered core, by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. Suitable materials for the protective layer include cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose aqueous dispersions (Aquacoat, Surelease), Eudragit RL 30D, Opadry® and the like. The suggested coating levels are from 1 to 6%, preferably 2-4% (w/w).
- The enteric coating layer is applied onto the cores with or without seal coating by conventional coating techniques, such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. All commercially available pH-sensitive polymers are included. The pharmaceutical active is not released in the acidic stomach environment of approximately below pH 4.5, but not limited to this value. The pharmaceutical active should become available when the pH-sensitive layer dissolves at the greater pH; after a certain delayed time; or after the unit passes through the stomach. The preferred delay time is in the range of two to six hours.
- Enteric polymers include cellulose acetate phthalate, Cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, materials known under the trade name Eudragit L12.5, L100, or Eudragit S12.5, S100 or similar compounds used to obtain enteric coatings. Aqueous colloidal polymer dispersions or re-dispersions can be also applied, e.g. Eudragit L 30D-55, Eudragit L100-55, Eudragit S100, Eudragit preparation 4110D (Rohm Pharma); Aquateric, Aquacoat CPD 30 (FMC); Kollicoat MAE 30D and 30DP (BASF); Eastacryl 30D (Eastman Chemical).
- The enteric polymers used in this invention can be modified by mixing with other known coating products that are not pH sensitive. Examples of such coating products include the neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride, sold currently under the trade names EudragitRS and Eudragit RL; a neutral ester dispersion without any functional groups, sold under the trade names Eudragit NE30D and Eudragit NE30; and other pH independent coating products.
- The modifying component of the protective layer used over the enteric coating can include a water penetration barrier layer (semipermeable polymer) which can be successively coated after the enteric coating to reduce the water penetration rate through the enteric coating layer and thus increase the lag time of the drug release. Sustained-release coatings commonly known to one skilled in the art can be used for this purpose by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. For example, the following materials can be used, but not limited to: Cellulose acetate, Cellulose acetate butyrate, Cellulose acetate propionate, Ethyl cellulose, Fatty acids and their esters, Waxes, zein, and aqueous polymer dispersions such as Eudragit RS and RL 30D, Eudragit NE 30D, Aquacoat, Surelease, cellulose acetate latex. The combination of above polymers and hydrophilic polymers such as Hydroxyethyl cellulose, Hydroxypropyl cellulose (Klucel, Hercules Corp.), Hydroxypropyl methylcellulose (Methocel, Dow Chemical Corp.), Polyvinylpyrrolidone can also be used.
- An overcoating layer can further optionally be applied to the composition of the present invention. Opadry®, Opadry II® (Colorcon) and corresponding color and colorless grades from Colorcon can be used to protect the pellets from being tacky and provide colors to the product. The suggested levels of protective or color coating are from 1 to 6%, preferably 2-3% (w/w).
- Many ingredients can be incorporated into the overcoating formula, for example to provide a quicker immediate release, such as plasticizers: acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate, dibutylsebacate, triacetin, polyethylene glycols, propylene glycol and the others; lubricants: talc, colloidal silica dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, and the like.
- The composition, preferably in beadlet form, can be incorporated into hard gelatin capsules, either with additional excipients, or alone. Typical excipients to be added to a capsule formulation include, but are not limited to: fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler. In addition, there can be flow aids such as fumed silicon dioxide, silica gel, magnesium stearate, calcium stearate or any other material imparting flow to powders. A lubricant can further be added if necessary by using polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or calcium stearate.
- The composition may also be incorporated into a tablet, in particular by incorporation into a tablet matrix, which rapidly disperses the particles after ingestion. In order to incorporate these particles into such a tablet, a filler/binder must be added to a table that can accept the particles, but will not allow their destruction during the tableting process. Materials that are suitable for this purpose include, but are not limited to, microcrystalline cellulose (A vicel), soy polysaccharide (Emcosoy), pre-gelatinized starches (STARCH 1500, National 1551), and polyethylene glycols (Carbowax). The materials should be present in the range of 5-75% (w/w), with a preferred range of 25-50% (w/w).
- In addition, disintegrants are added in order to disperse the beads once the tablet is ingested. Suitable disintegrants include, but are not limited to: cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol), sodium starch glycolate (Explotab, Primojel), and cross-linked polyvinylpolypyrrolidone (Plasone-XL). These materials should be present in the rate of 3-15% (w/w), with a preferred range of 5-10% (w/w).
- Lubricants are also added to assure proper tableting, and these can include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behanate, and hydrogenated vegetable oil. These lubricants should be present in amounts from 0.1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).
- Tablets are formed, for example, as follows. The particles are introduced into a blender along with Avicel, disintegrants and lubricant, mixed for a set number of minutes to provide a homogeneous blend which is then put in the hopper of a tablet press with which tablets are compressed. The compression force used is adequate to form a tablet; however, not sufficient to fracture the beads or coatings.
- It will be appreciated that the multiple dosage form of the present invention can deliver rapid and complete dosages of pharmaceutically active amphetamine salts to achieve the desired levels of the drug in a recipient over the course of about 8 hours with a single oral administration.
- In so doing, the levels of drug in blood plasma of the pharmaceutically active amphetamine salts will reach a peak fairly rapidly after about 2 hours, and after about 4 hours a second pulse dose is released, wherein a second fairly rapid additive increase of plasma drug levels occurs which slowly decreases over the course of the next 12 hours.
- The following examples are presented to illustrate and do not limit the invention.
- The following formulation was used to layer the drug onto sugar spheres. Nonpareil seeds (30/35 mesh, Paulaur Corp., N.J.), 6.8 kg were put into a FLM-15 fluid bed processor with a 9″ Wurster column and fluidized at 60° C. The suspension of mixed amphetamine salts (MAS) with 1% HPMC E5 Premium (Dow Chemical) as a binder was sprayed onto the seed under suitable conditions. Almost no agglomeration and no fines were observed with a yield of at least 98%. The drug-loaded cores were used to test enteric coatings and sustained release coatings.
TABLE 1 Ingredients Amount (%) Nonpareil seed 88.00 mixed amphetamine salts 11.40 Methocel E5 Premium 0.60 Water * - The following formulation was used to coat the mixed amphetamine salts loaded (MASL) pellets from Example 1 with the Eudragit® L 30D-55 (Rohm Pharma, Germany) coating dispersion. 2 kg of MASL pellets were loaded into a fluid bed processor with a reduced Wurster column equipped with a precision coater (
MP 2/3, Niro Inc.). The coating dispersion was prepared by dispersing Triethyl citrate, Talc and Eudragit® L 30D-55 into water and mixing for at least 30 minutes. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized MASL pellets. The spraying was continued until the targeted coating level was achieved (20μ). The coated pellets were dried at 30-35° C. for 5 minutes before stopping the process. The enteric coated PPA pellets were tested at different pH buffers by a USP paddle method. The drug content was analyzed using HPLC. The results showed that the enteric coating delayed the drug release from the coated pellets until after exposure topH 6 or higher (see Table 2 below). (Reference #AR98125-4)TABLE 2 Ingredients Amount (%) MASL pellets 40.00 Eudragit ® L 30D-55 24.88 Triethyl citrate 2.52 Talc 2.60 Water * - The following formulation was used to coat the MASL pellets from Example 1 with the Eudragit® 4110D (Rohm Pharma, Germany) coating dispersion. MASL pellets (2 kg) were loaded in a fluid bed processor with a reduced Wurster column (GPGC-15, Glatt). The coating dispersion was prepared by dispersing Triethyl citrate, Talc and Eudragit® 4110D into water and mixing for at least 30 minutes. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized MASL pellets. The spraying was continued until the targeted coating level was achieved. The coated pellets were dried at 30-35° C. for 5 minutes before stopping the process. The enteric coated MASL pellets were tested using a USP paddle method at different pH buffers. The drug content was analyzed using HPLC. The enteric coating delayed the drug release for several hours from the coated pellets until the pH value reached 6.8 or higher, as shown below in Table 3. (Reference # AR98125-3)
TABLE 3 Ingredients Amount (%) MASL pellets 70.00 Eudragit ® 4110D 26.24 Triethyl citrate 0.76 Talc 3.00 Water * - The following formulation was selected to coat the enteric coated MASL pellets. Coated MASL pellets from Example 2 or coated MASL pellets from Example 3 (2 kg of either) were loaded into a fluid bed processor with a reduced Wurster column (GPGC-15, Glatt). The coating dispersion was prepared by mixing Surelease® (Colorcon) and water for at least 15 minutes prior to spraying. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized pellets. The spraying was continued until the targeted coating level was achieved. The coated pellets were coated with a thin layer of Opadry® white (Colorcon) (2%) to prevent the tackiness of the coated pellets during storage. The coated pellets were then dried at 35-40° C. for 10 minutes before discharging from the bed. The drug dissolution from both coated pellets was performed using a USP paddle method at different pH buffers. The drug content was analyzed using HPLC. The results are shown below in Table 4. The 8% Surelease coating slightly sustained the drug release from Eudragit L 30D-55 coated pellets at pH 7.5 buffer, while the Surelease coating delayed the drug release up to 2 hours after the buffer switched from
pH 1 to pH 7.5. (Reference ## AR98I25-1)TABLE 4 Ingredients Amount, kg Enteric coated MASL pellets 90.00 Surelease ® 8.00 Opadry white 2.00 Water * - 1. B.Lemmer, “Circadian Rhythms and Drug Delivery”,J. Controlled Release, 16, 63-74 (1991)
- 2. B. Lemmer, “Why are so many Biological Systems Periodic?” inPulsatile Drug Delivery: Current Applications and Future Trends, R Gurny, H E Junginger and N A Peppas, eds. (Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, Germany 1993) pp.11-24
- 3. X. Xu and P I Lee, “Programmable Drug Delivery from an Erodible Association Polymer System”,Pharm. Res. 10(8), 1144-1152 (1993)
- 4. A. Gazzaniga, M E Sangalli, and F Giodano, “Oral Chonotropic Drug Delivery Systems: Achievement of Time and/or Site Specificity”,Eur J Pharm. Biopharm., 40(4), 246-250 (1994)
- 5. A Gazzaniga, C Busetti, L Moro, M E Sangalli and F Giordano, “Time Dependent Oral Delivery Systems for Colon Targeting”,S.T.P. Pharma Sciences 5(1), 83-88 (1996)
- 6. U Conte, L Maggi, M L Torre, P Giunchedi and A Lamanna, “Press-coated Tablets for Time programmed Release of Drugs”,Biomaterials, 14(13), 1017-1023 (1993)
- 7. A C Shah International Patent Application WO87/00044
- 8. P S Walia, P Jo Mayer Stout and R Turton, “Preliminary Evaluation of an Aqueous Wax Emulsion for Controlled Release Coating”,Pharm Dev Tech, 3(1), 103-113 (1998)
- 9. F Theeuwes, “Oros Osmotic System Development”,Drug Dev Ind Pharm 9(7), 1331-1357 (1983)
- 10. F Theeuwes, “Triggered, Pulsed and Programmed Drug Delivery” inNovel Drug Delivery and its Therapeutic Application, L F Prescott and W S Nimmos. eds. (Wiley, N.Y., 1989) pp. 323-340
- 11. M McNeil, A Rashid and H Stevens, “International Patent App WO90/09168
- 12. I R Wilding, S S Davis, M Bakhshaee, H N E Stevens, R A Sparrow and J Brennan, “Gastrointestinal Transit and Systemic Absorption of Captopril from a Pulsed Release Formulation”, Pharm Res 9(5), 654-657 (1992)
Claims (13)
1. A pharmaceutical composition for enteric delivery of one or more pharmaceutically active amphetamine salts comprising:
(a) one or more pharmaceutically active amphetamine salts covered with an immediate release coating; and
(b) one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating wherein the enteric release coating has a thickness of at least 25μ.
2. The pharmaceutical composition of wherein the one or more pharmaceutically active amphetamine salts are coated onto a core.
claim 1
3. The pharmaceutical composition of wherein the one or more pharmaceutically active amphetamine salts are incorporated into a core.
claim 1
4. The pharmaceutical composition of , wherein the immediate release and enteric release portions of the composition are present on a single core.
claim 1
5. The pharmaceutical composition of , wherein the immediate release and enteric release components are present on different cores.
claim 1
6. A pharmaceutical composition for enteric delivery of one or more pharmaceutically active amphetamine salts comprising:
(a) one or more pharmaceutically active amphetamine salts covered with an immediate release coating;
(b) one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating; and
(c) a protective layer between the at least one pharmaceutically active amphetamine salt and the enteric release coating.
7. The pharmaceutical composition of wherein the one or more pharmaceutically active amphetamine salts are coated onto a core.
claim 6
8. The pharmaceutical composition of wherein the one or more pharmaceutically active amphetamine salts are incorporated into a core.
claim 6
9. The pharmaceutical composition of wherein the enteric release coating has a minimum thickness of 25μ.
claim 6
10. A pharmaceutical composition for delivering one or more pharmaceutically active amphetamine salts comprising:
(a) one or more pharmaceutically active amphetamine salts covered with an immediate release coating;
(b) one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating; and
(c) a protective layer over the enteric release coating.
11. The pharmaceutical composition of wherein the one or more pharmaceutically active amphetamine salts are coated onto a core.
claim 10
12. The pharmaceutical composition of wherein the one or more pharmaceutically active amphetamine salts are incorporated into a core.
claim 10
13. The composition of wherein the pharmaceutically active amphetamine salt is selected from amphetamine base, salts, chemical and chiral derivatives thereof; methylphenidate derivatives and salts thereof; and phenylpropanolamine hydrochloride chemical and chiral derivatives and salts thereof.
claim 1
Applications Claiming Priority (1)
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US09/176,542 US6322819B1 (en) | 1998-10-21 | 1998-10-21 | Oral pulsed dose drug delivery system |
Publications (1)
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US20010055613A1 true US20010055613A1 (en) | 2001-12-27 |
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US09/176,542 Ceased US6322819B1 (en) | 1998-10-21 | 1998-10-21 | Oral pulsed dose drug delivery system |
US09/807,462 Ceased US6605300B1 (en) | 1998-10-21 | 1999-10-20 | Oral pulsed dose drug delivery system |
US11/091,010 Expired - Lifetime USRE41148E1 (en) | 1998-10-21 | 1999-10-20 | Oral pulsed dose drug delivery system |
US10/172,705 Abandoned US20030124188A1 (en) | 1998-10-21 | 2002-06-14 | Oral pulsed dose drug delivery system |
US10/758,417 Abandoned US20040219213A1 (en) | 1998-10-21 | 2004-01-16 | Oral pulsed dose drug delivery system |
US11/091,011 Expired - Lifetime USRE42096E1 (en) | 1998-10-21 | 2005-03-24 | Oral pulsed dose drug delivery system |
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US09/176,542 Ceased US6322819B1 (en) | 1998-10-21 | 1998-10-21 | Oral pulsed dose drug delivery system |
US09/807,462 Ceased US6605300B1 (en) | 1998-10-21 | 1999-10-20 | Oral pulsed dose drug delivery system |
US11/091,010 Expired - Lifetime USRE41148E1 (en) | 1998-10-21 | 1999-10-20 | Oral pulsed dose drug delivery system |
US10/172,705 Abandoned US20030124188A1 (en) | 1998-10-21 | 2002-06-14 | Oral pulsed dose drug delivery system |
US10/758,417 Abandoned US20040219213A1 (en) | 1998-10-21 | 2004-01-16 | Oral pulsed dose drug delivery system |
US11/091,011 Expired - Lifetime USRE42096E1 (en) | 1998-10-21 | 2005-03-24 | Oral pulsed dose drug delivery system |
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EP (2) | EP1977736A1 (en) |
JP (2) | JP2002527468A (en) |
AT (1) | ATE427101T1 (en) |
AU (1) | AU1214500A (en) |
CA (1) | CA2348090C (en) |
DE (1) | DE69940673D1 (en) |
ES (1) | ES2323910T3 (en) |
HK (1) | HK1038701A1 (en) |
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US20040224020A1 (en) * | 2002-12-18 | 2004-11-11 | Schoenhard Grant L. | Oral dosage forms with therapeutically active agents in controlled release cores and immediate release gelatin capsule coats |
US20060210610A1 (en) * | 2002-11-14 | 2006-09-21 | Davidson Robert S | Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use |
US20070154547A1 (en) * | 2005-12-30 | 2007-07-05 | Flanner Henry H | Gastric release pulse system for drug delivery |
US20070275040A1 (en) * | 2003-03-28 | 2007-11-29 | Innozen, Inc. | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
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US10398644B2 (en) | 2002-11-14 | 2019-09-03 | Cure Pharmaceutical Corporation | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
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Families Citing this family (200)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010055613A1 (en) | 1998-10-21 | 2001-12-27 | Beth A. Burnside | Oral pulsed dose drug delivery system |
US20090149479A1 (en) * | 1998-11-02 | 2009-06-11 | Elan Pharma International Limited | Dosing regimen |
US20060240105A1 (en) * | 1998-11-02 | 2006-10-26 | Elan Corporation, Plc | Multiparticulate modified release composition |
DK1126826T6 (en) * | 1998-11-02 | 2019-06-24 | Alkermes Pharma Ireland Ltd | Multiparticulate modified release of methylphenidate |
DE19855421C2 (en) * | 1998-11-02 | 2001-09-20 | Alcove Surfaces Gmbh | Implant |
US20030170181A1 (en) * | 1999-04-06 | 2003-09-11 | Midha Kamal K. | Method for preventing abuse of methylphenidate |
ES2226886T3 (en) * | 1999-08-31 | 2005-04-01 | Grunenthal Gmbh | FORM OF ADMINISTRATION OF DELAYED ACTION CONTAINING SQUARINATE OF TRAMADOL. |
US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
NZ529928A (en) | 1999-10-29 | 2005-10-28 | Euro Celtique Sa | Controlled release hydrocodone formulations |
EP1233761B1 (en) * | 1999-11-22 | 2007-03-28 | ALZA Corporation | Osmotic dosage form comprising first and second coats |
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US6544555B2 (en) | 2000-02-24 | 2003-04-08 | Advancis Pharmaceutical Corp. | Antibiotic product, use and formulation thereof |
US7674480B2 (en) * | 2000-06-23 | 2010-03-09 | Teva Pharmaceutical Industries Ltd. | Rapidly expanding composition for gastric retention and controlled release of therapeutic agents, and dosage forms including the composition |
US6500457B1 (en) * | 2000-08-14 | 2002-12-31 | Peirce Management, Llc | Oral pharmaceutical dosage forms for pulsatile delivery of an antiarrhythmic agent |
US20020068078A1 (en) | 2000-10-13 | 2002-06-06 | Rudnic Edward M. | Antifungal product, use and formulation thereof |
KR101045144B1 (en) | 2000-10-30 | 2011-06-30 | 유로-셀티크 소시에떼 아노뉨 | Controlled release hydrocodone formulations |
US20030190360A1 (en) | 2001-03-13 | 2003-10-09 | Baichwal Anand R. | Chronotherapeutic dosage forms containing glucocorticosteroid and methods of treatment |
AU2002256092C1 (en) * | 2001-04-05 | 2009-10-15 | Collagenex Pharmaceuticals, Inc. | Controlled delivery of tetracycline compounds and tetracycline derivatives |
US20020187192A1 (en) * | 2001-04-30 | 2002-12-12 | Yatindra Joshi | Pharmaceutical composition which reduces or eliminates drug abuse potential |
AR034813A1 (en) * | 2001-07-20 | 2004-03-17 | Novartis Ag | PHARMACEUTICAL COMPOSITIONS AND USE OF THE SAME |
MXPA04002980A (en) * | 2001-09-28 | 2005-06-20 | Johnson & Johnson | Dosage forms having an inner core and outer shell with different shapes. |
US7838026B2 (en) | 2001-09-28 | 2010-11-23 | Mcneil-Ppc, Inc. | Burst-release polymer composition and dosage forms comprising the same |
US7122143B2 (en) | 2001-09-28 | 2006-10-17 | Mcneil-Ppc, Inc. | Methods for manufacturing dosage forms |
US20040253312A1 (en) * | 2001-09-28 | 2004-12-16 | Sowden Harry S. | Immediate release dosage form comprising shell having openings therein |
US6837696B2 (en) * | 2001-09-28 | 2005-01-04 | Mcneil-Ppc, Inc. | Apparatus for manufacturing dosage forms |
US20040146559A1 (en) * | 2002-09-28 | 2004-07-29 | Sowden Harry S. | Dosage forms having an inner core and outer shell with different shapes |
US20030228368A1 (en) * | 2001-09-28 | 2003-12-11 | David Wynn | Edible solid composition and dosage form |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
AR040682A1 (en) | 2002-07-25 | 2005-04-13 | Pharmacia Corp | DOSAGE FORM ONCE A DAY OF PRAMIPEXOL |
US6913768B2 (en) * | 2002-09-24 | 2005-07-05 | Shire Laboratories, Inc. | Sustained release delivery of amphetamine salts |
US20040062778A1 (en) * | 2002-09-26 | 2004-04-01 | Adi Shefer | Surface dissolution and/or bulk erosion controlled release compositions and devices |
US7807197B2 (en) | 2002-09-28 | 2010-10-05 | Mcneil-Ppc, Inc. | Composite dosage forms having an inlaid portion |
US7988993B2 (en) * | 2002-12-09 | 2011-08-02 | Andrx Pharmaceuticals, Inc. | Oral controlled release dosage form |
US20040208931A1 (en) * | 2002-12-30 | 2004-10-21 | Friend David R | Fast dissolving films for oral administration of drugs |
US20040220277A1 (en) * | 2003-02-10 | 2004-11-04 | Couch Richard A. | Enantiomeric amphetamine compositions |
US20040186180A1 (en) | 2003-03-21 | 2004-09-23 | Gelotte Cathy K. | Non-steroidal anti-inflammatory drug dosing regimen |
PL1615622T3 (en) | 2003-04-07 | 2012-12-31 | Supernus Pharmaceuticals Inc | Once daily formulations of doxycyclines |
US8802139B2 (en) | 2003-06-26 | 2014-08-12 | Intellipharmaceutics Corp. | Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient |
WO2005009364A2 (en) | 2003-07-21 | 2005-02-03 | Advancis Pharmaceutical Corporation | Antibiotic product, use and formulation thereof |
CA2533178C (en) | 2003-07-21 | 2014-03-11 | Advancis Pharmaceutical Corporation | Antibiotic product, use and formulation thereof |
CA2533292C (en) | 2003-07-21 | 2013-12-31 | Advancis Pharmaceutical Corporation | Antibiotic product, use and formulation thereof |
DE10361596A1 (en) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
DE10336400A1 (en) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Anti-abuse dosage form |
DE102005005446A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Break-resistant dosage forms with sustained release |
WO2005016311A1 (en) | 2003-08-11 | 2005-02-24 | Advancis Pharmaceutical Corporation | Robust pellet |
AU2004264356B2 (en) | 2003-08-12 | 2011-01-27 | Shionogi, Inc. | Antibiotic product, use and formulation thereof |
JP5686494B2 (en) | 2003-08-29 | 2015-03-18 | シオノギ インコーポレイテッド | Antibiotic preparations, their use and preparation |
EP1663169A4 (en) | 2003-09-15 | 2010-11-24 | Middlebrook Pharmaceuticals In | Antibiotic product, use and formulation thereof |
EP1663175B1 (en) * | 2003-09-19 | 2012-03-28 | Sun Pharma Advanced Research Company Limited | Oral drug delivery system |
US10213387B2 (en) | 2003-09-19 | 2019-02-26 | Sun Pharma Advanced Research Company Ltd. | Oral drug delivery system |
US10226428B2 (en) | 2003-09-19 | 2019-03-12 | Sun Pharma Advanced Research Company Ltd. | Oral drug delivery system |
NZ545921A (en) | 2003-09-19 | 2009-09-25 | Penwest Pharmaceuticals Co | Delayed released dosage forms |
US20050069590A1 (en) * | 2003-09-30 | 2005-03-31 | Buehler Gail K. | Stable suspensions for medicinal dosages |
US20050074514A1 (en) * | 2003-10-02 | 2005-04-07 | Anderson Oliver B. | Zero cycle molding systems, methods and apparatuses for manufacturing dosage forms |
JP5610663B2 (en) * | 2003-11-04 | 2014-10-22 | スパーナス ファーマシューティカルズ インコーポレイテッド | Trospium once a day dosage form |
WO2005044238A1 (en) * | 2003-11-07 | 2005-05-19 | Ranbaxy Laboratories Limited | Modified release solid dosage form of amphetamine salts |
DE10353186A1 (en) * | 2003-11-13 | 2005-06-16 | Röhm GmbH & Co. KG | Multilayer dosage form containing a modulatory substance in relation to the release of active ingredient |
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 |
JP2005239696A (en) * | 2004-01-30 | 2005-09-08 | Daiichi Suntory Pharma Co Ltd | Medicinal hard capsule preparation blended with inorganic substance |
US20050196447A1 (en) * | 2004-03-05 | 2005-09-08 | Huang Hai Y. | Polymeric compositions and dosage forms comprising the same |
US20050196448A1 (en) * | 2004-03-05 | 2005-09-08 | Hai Yong Huang | 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 |
US20050196442A1 (en) * | 2004-03-05 | 2005-09-08 | Huang Hai Y. | Polymeric compositions and dosage forms comprising the same |
TWI354569B (en) * | 2004-05-28 | 2011-12-21 | Bristol Myers Squibb Co | Coated tablet formulation and method |
US20050265955A1 (en) * | 2004-05-28 | 2005-12-01 | Mallinckrodt Inc. | Sustained release preparations |
US7712288B2 (en) | 2004-05-28 | 2010-05-11 | Narayanan Ramasubramanian | Unified ingestion package and process for patient compliance with prescribed medication regimen |
US8394409B2 (en) | 2004-07-01 | 2013-03-12 | Intellipharmaceutics Corp. | Controlled extended drug release technology |
DE102004032049A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Anti-abuse, oral dosage form |
JP2008505124A (en) | 2004-07-02 | 2008-02-21 | アドバンシス ファーマスーティカル コーポレイション | Pulse delivery tablets |
JP4785847B2 (en) | 2004-08-13 | 2011-10-05 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Tablet formulation with extended release comprising pramipexole or a pharmaceutically acceptable salt thereof, process for its production and use thereof |
BRPI0513848A (en) * | 2004-08-13 | 2008-05-20 | Boehringer Ingelheim Int | Pramipexole prolonged-release pellet formulation or a pharmaceutically acceptable salt thereof, method of manufacture thereof and use thereof |
US10624858B2 (en) | 2004-08-23 | 2020-04-21 | Intellipharmaceutics Corp | Controlled release composition using transition coating, and method of preparing same |
US9149472B2 (en) * | 2004-08-31 | 2015-10-06 | Jack William Schultz | Controlled release compositions for treatment of cognitive, emotional and mental ailments and disorders |
US7350479B2 (en) * | 2004-09-10 | 2008-04-01 | United States Of America As Represented By The Secretary Of The Army | System and method for controlling growth of aquatic plants utilizing bio-eroding means implanted in triploid grass carp |
US20080020041A1 (en) * | 2004-10-19 | 2008-01-24 | Ayres James W | Enteric Coated Compositions that Release Active Ingredient(s) in Gastric Fluid and Intestinal Fluid |
US20070281022A1 (en) * | 2004-10-27 | 2007-12-06 | 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 |
US20060088587A1 (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 |
US20060087051A1 (en) * | 2004-10-27 | 2006-04-27 | Bunick Frank J | 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 |
US8383159B2 (en) * | 2004-10-27 | 2013-02-26 | Mcneil-Ppc, Inc. | Dosage forms having a microreliefed surface and methods and apparatus for their production |
US20060121112A1 (en) * | 2004-12-08 | 2006-06-08 | Elan Corporation, Plc | Topiramate pharmaceutical composition |
GB0427455D0 (en) * | 2004-12-15 | 2005-01-19 | Jagotec Ag | Dosage forms |
NZ555693A (en) | 2004-12-27 | 2010-10-29 | Eisai R&D Man Co Ltd | Matrix type sustained-release preparation containing donepezil |
DE102005005449A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
ITBO20050123A1 (en) * | 2005-03-07 | 2005-06-06 | Alfa Wassermann Spa | GASTRORESISTIC PHARMACEUTICAL FORMULATIONS CONTAINING RIFAXIMINA |
US20060204575A1 (en) * | 2005-03-11 | 2006-09-14 | Hengsheng Feng | Amphetamine formulations |
BRPI0609505A2 (en) * | 2005-03-29 | 2010-04-13 | Rihm Gmbh | multiparticulate pharmaceutical form comprising pellets with a matrix that influences the delivery of a modulating substance |
CN101111230B (en) * | 2005-03-29 | 2010-05-19 | 赢创罗姆有限责任公司 | Multiparticulate pharmaceutical form comprising pellets having a modular effect in relation to active ingredient release |
CA2605185A1 (en) * | 2005-04-06 | 2006-10-12 | Mallinckrodt Inc. | Matrix-based pulse release pharmaceutical formulation |
WO2006110807A1 (en) * | 2005-04-12 | 2006-10-19 | Elan Pharma International Limited | 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 |
CA2604617C (en) * | 2005-04-28 | 2014-06-17 | Eisai R&D Management Co., Ltd. | Composition containing anti-dementia drug |
US20070077300A1 (en) * | 2005-09-30 | 2007-04-05 | Wynn David W | Oral compositions containing a salivation inducing agent |
US8357394B2 (en) | 2005-12-08 | 2013-01-22 | Shionogi Inc. | Compositions and methods for improved efficacy of penicillin-type antibiotics |
US8778924B2 (en) | 2006-12-04 | 2014-07-15 | Shionogi Inc. | Modified release amoxicillin products |
US10064828B1 (en) * | 2005-12-23 | 2018-09-04 | Intellipharmaceutics Corp. | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
US20070196399A1 (en) * | 2006-02-21 | 2007-08-23 | Shin-Etsu Chemical Co., Ltd. | Enteric-coated preparation covered with enteric coating material for site-specific delivery of drug to site within the small intestine |
CN101400343B (en) | 2006-03-16 | 2012-01-11 | 特瑞斯制药股份有限公司 | Modified release formulations containing drug-ion exchange resin complexes |
US9561188B2 (en) | 2006-04-03 | 2017-02-07 | Intellipharmaceutics Corporation | Controlled release delivery device comprising an organosol coat |
WO2007115305A2 (en) | 2006-04-04 | 2007-10-11 | Cogentus Pharmaceuticals, Inc. | Oral dosage forms including an antiplatelet agent and an acid inhibitor |
US20070238942A1 (en) * | 2006-04-10 | 2007-10-11 | Esophamet Corp. | Apparatus and method for detecting gastroesophageal reflux disease (gerd) |
US8518926B2 (en) | 2006-04-10 | 2013-08-27 | Knopp Neurosciences, Inc. | Compositions and methods of using (R)-pramipexole |
US20070259930A1 (en) * | 2006-04-10 | 2007-11-08 | Knopp Neurosciences, Inc. | Compositions and methods of using r(+) pramipexole |
US8299052B2 (en) | 2006-05-05 | 2012-10-30 | Shionogi Inc. | Pharmaceutical compositions and methods for improved bacterial eradication |
US10960077B2 (en) | 2006-05-12 | 2021-03-30 | Intellipharmaceutics Corp. | Abuse and alcohol resistant drug composition |
BRPI0621633A2 (en) | 2006-05-12 | 2011-12-13 | Shire Llc | pharmaceutical composition, method for treating attention deficit hyperactivity disorder (ADHD) and sustained release pharmaceutical composition |
US8846100B2 (en) * | 2006-05-12 | 2014-09-30 | Shire Llc | Controlled dose drug delivery system |
EP2465500A1 (en) | 2006-05-16 | 2012-06-20 | Knopp Neurosciences, Inc. | Therapeutically effective amounts of R(+) and S(-) pramipexole for use in the treatment of parkinson's disease |
CA2652251A1 (en) | 2006-05-16 | 2007-11-29 | Knopp Neurosciences, Inc. | Compositions of r(+) and s(-) pramipexole and methods for using the same |
PE20080907A1 (en) * | 2006-08-31 | 2008-08-22 | Novartis Ag | EXTENDED RELEASE GASTRO-RETENTIVE ORAL DRUG DELIVERY SYSTEM FOR VALSARTAN |
ITMI20061692A1 (en) | 2006-09-05 | 2008-03-06 | Alfa Wassermann Spa | USE OF POLYOLS TO OBTAIN STYLE POLYMORPHIC FORMS OF RIFAXIMINA |
AU2007309281B2 (en) * | 2006-10-20 | 2013-10-31 | Johnson & Johnson Consumer Inc. | Acetaminophen / ibuprofen combinations |
US8524695B2 (en) | 2006-12-14 | 2013-09-03 | Knopp Neurosciences, Inc. | Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same |
US20100104621A1 (en) * | 2007-02-21 | 2010-04-29 | Connected Health Systems, Llc | Treating adhd and other diseases involving inflammation |
US8519148B2 (en) * | 2007-03-14 | 2013-08-27 | Knopp Neurosciences, Inc. | Synthesis of chirally purified substituted benzothiazole diamines |
US20080268047A1 (en) * | 2007-04-24 | 2008-10-30 | Xavier University Of Louisiana | Controlled Release Multiple Layer Coatings |
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 |
US8478862B2 (en) * | 2007-07-13 | 2013-07-02 | Front Porch, Inc. | Method and apparatus for internet traffic monitoring by third parties using monitoring implements |
US7953851B2 (en) * | 2007-07-13 | 2011-05-31 | Front Porch, Inc. | Method and apparatus for asymmetric internet traffic monitoring by third parties using monitoring implements |
EP2044932A1 (en) * | 2007-10-04 | 2009-04-08 | Laboratorios del Dr. Esteve S.A. | Mechanical protective layer for solid dosage forms |
EP2044929A1 (en) * | 2007-10-04 | 2009-04-08 | Laboratorios del Dr. Esteve S.A. | Oral fast distintegrating tablets |
US20090110716A1 (en) * | 2007-10-31 | 2009-04-30 | Frank Bunick | Orally disintegrative dosage form |
CN101917975B (en) * | 2007-12-21 | 2013-05-08 | 麦克内尔-Ppc股份有限公司 | Manufacture of tablet |
EP2242485A4 (en) * | 2008-02-15 | 2013-05-08 | Sun Pharma Advanced Res Co Ltd | Oral controlled release tablet |
PT2276473T (en) | 2008-04-18 | 2016-12-15 | Intec Pharma Ltd | Gastroretentive drug delivery for carbidopa/levodopa |
EP2309999A1 (en) * | 2008-06-26 | 2011-04-20 | McNeil-PPC, Inc. | Coated particles containing pharmaceutically active agents |
US9009838B2 (en) * | 2008-07-24 | 2015-04-14 | Front Porch, Inc. | Method and apparatus for effecting an internet user's privacy directive |
KR20110071064A (en) | 2008-08-19 | 2011-06-28 | 크놉 뉴로사이언시스 인코포레이티드 | Compositions and methods of using (r)-pramipexole |
WO2010061696A1 (en) | 2008-11-25 | 2010-06-03 | 日産自動車株式会社 | Conductive member and solid state polymer fuel cell using same |
ES2562925T3 (en) | 2008-12-04 | 2016-03-09 | Intec Pharma Ltd. | Gastroretentive drug administration system of zaleplón |
CA2765876A1 (en) * | 2009-06-19 | 2010-12-23 | Knopp Neurosciences, Inc. | Compositions and methods for treating amyotrophic lateral sclerosis |
PT2456424E (en) | 2009-07-22 | 2013-09-30 | Gruenenthal Gmbh | Oxidation-stabilized tamper-resistant dosage form |
NZ596667A (en) | 2009-07-22 | 2013-09-27 | Gruenenthal Chemie | Hot-melt extruded controlled release dosage form |
US8313768B2 (en) | 2009-09-24 | 2012-11-20 | Mcneil-Ppc, Inc. | Manufacture of tablet having immediate release region and sustained release region |
US8858210B2 (en) | 2009-09-24 | 2014-10-14 | Mcneil-Ppc, Inc. | Manufacture of variable density dosage forms utilizing radiofrequency energy |
US8784781B2 (en) | 2009-09-24 | 2014-07-22 | Mcneil-Ppc, Inc. | Manufacture of chewing gum product with radiofrequency |
GB201002612D0 (en) * | 2010-02-16 | 2010-03-31 | Jagotec Ag | Improvements in or relating to organic compounds |
US20120076865A1 (en) | 2010-03-24 | 2012-03-29 | Jazz Pharmaceuticals, Inc. | Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances |
EP2560624B1 (en) * | 2010-04-23 | 2018-07-04 | KemPharm, Inc. | Therapeutic formulation for reduced drug side effects |
KR101872189B1 (en) * | 2010-06-16 | 2018-06-29 | 다케다 파마슈티칼스 유에스에이, 인코포레이티드 | Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors |
MX2013002377A (en) | 2010-09-02 | 2013-04-29 | Gruenenthal Gmbh | Tamper resistant dosage form comprising inorganic salt. |
US10905652B2 (en) | 2011-03-23 | 2021-02-02 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9603809B2 (en) | 2011-03-23 | 2017-03-28 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
US10292937B2 (en) | 2011-03-23 | 2019-05-21 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
US9119809B2 (en) | 2011-03-23 | 2015-09-01 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9498447B2 (en) | 2011-03-23 | 2016-11-22 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US8927010B2 (en) | 2011-03-23 | 2015-01-06 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
WO2012129551A1 (en) * | 2011-03-23 | 2012-09-27 | Ironshore Pharmaceuticals & Development, Inc. | Methods and compositions for treatment of attention deficit disorder |
US11241391B2 (en) | 2011-03-23 | 2022-02-08 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US8916588B2 (en) | 2011-03-23 | 2014-12-23 | Ironshore Pharmaceuticals & Development, Inc. | Methods for treatment of attention deficit hyperactivity disorder |
US9283214B2 (en) | 2011-03-23 | 2016-03-15 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
EP2726066B1 (en) | 2011-06-28 | 2021-03-31 | Neos Therapeutics, LP | Dosage forms of amphetamine for oral administration |
AR087360A1 (en) | 2011-07-29 | 2014-03-19 | Gruenenthal Gmbh | PROOF OF HANDLING TABLET PROVIDING IMMEDIATE RELEASE OF PHARMACY |
MX348054B (en) | 2011-07-29 | 2017-05-25 | Gruenenthal Gmbh | Tamper-resistant tablet providing immediate drug release. |
EP2768481A4 (en) * | 2011-10-21 | 2015-07-08 | Subhash Desai | Compositions for reduction of side effects |
CA2758556A1 (en) * | 2011-11-17 | 2013-05-17 | Pharmascience Inc. | Pharmaceutical composition of amphetamine mixed salts |
US9512096B2 (en) | 2011-12-22 | 2016-12-06 | Knopp Biosciences, LLP | Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds |
RS57913B1 (en) | 2012-04-18 | 2019-01-31 | Gruenenthal Gmbh | Tamper resistant and dose-dumping resistant pharmaceutical dosage form |
US9511028B2 (en) | 2012-05-01 | 2016-12-06 | Johnson & Johnson Consumer Inc. | Orally disintegrating tablet |
US9445971B2 (en) | 2012-05-01 | 2016-09-20 | Johnson & Johnson Consumer Inc. | Method of manufacturing solid dosage form |
US9233491B2 (en) | 2012-05-01 | 2016-01-12 | Johnson & Johnson Consumer Inc. | Machine for production of solid dosage forms |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
EP2884961B1 (en) | 2012-08-15 | 2019-03-06 | Tris Pharma Inc. | Methylphenidate extended release chewable tablet |
US9662313B2 (en) | 2013-02-28 | 2017-05-30 | Knopp Biosciences Llc | Compositions and methods for treating amyotrophic lateral sclerosis in responders |
US8652527B1 (en) | 2013-03-13 | 2014-02-18 | Upsher-Smith Laboratories, Inc | Extended-release topiramate capsules |
US9101545B2 (en) | 2013-03-15 | 2015-08-11 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
JP6445537B2 (en) | 2013-05-29 | 2018-12-26 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Tamper-resistant dosage forms containing one or more particles |
RS61539B1 (en) | 2013-07-12 | 2021-04-29 | Knopp Biosciences Llc | Treating elevated levels of eosinophils and/or basophils |
JP6449871B2 (en) | 2013-07-12 | 2019-01-09 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Anti-modified dosage form containing ethylene-vinyl acetate polymer |
US9468630B2 (en) | 2013-07-12 | 2016-10-18 | Knopp Biosciences Llc | Compositions and methods for treating conditions related to increased eosinophils |
CA2921381A1 (en) | 2013-08-13 | 2015-02-19 | Knopp Biosciences Llc | Compositions and methods for treating chronic urticaria |
WO2015023786A1 (en) | 2013-08-13 | 2015-02-19 | Knopp Biosciences Llc | Compositions and methods for treating plasma cell disorders and b-cell prolymphocytic disorders |
BR112016010482B1 (en) | 2013-11-26 | 2022-11-16 | Grünenthal GmbH | PREPARATION OF A PHARMACEUTICAL COMPOSITION IN POWDER BY MEANS OF CRYOMING |
ES2750323T3 (en) | 2014-01-10 | 2020-03-25 | Johnson & Johnson Consumer Inc | Method for manufacturing a tablet using radio frequency and loss coated particles |
WO2015173195A1 (en) | 2014-05-12 | 2015-11-19 | Grünenthal GmbH | Tamper resistant immediate release capsule formulation comprising tapentadol |
JP2017516789A (en) | 2014-05-26 | 2017-06-22 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Multiparticulates protected against ethanol overdose |
US10398662B1 (en) | 2015-02-18 | 2019-09-03 | Jazz Pharma Ireland Limited | GHB formulation and method for its manufacture |
JP2018506590A (en) * | 2015-02-27 | 2018-03-08 | シンギュレイト・セラピューティクス・リミテッド・ライアビリティ・カンパニーCingulate Therapeutics LLC | Tripulse-release activator formulation |
EA035434B1 (en) | 2015-04-24 | 2020-06-15 | Грюненталь Гмбх | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
US10142086B2 (en) | 2015-06-11 | 2018-11-27 | At&T Intellectual Property I, L.P. | Repeater and methods for use therewith |
US11590228B1 (en) | 2015-09-08 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine compositions |
US10842750B2 (en) | 2015-09-10 | 2020-11-24 | Grünenthal GmbH | Protecting oral overdose with abuse deterrent immediate release formulations |
US20170296476A1 (en) * | 2016-04-15 | 2017-10-19 | Grünenthal GmbH | Modified release abuse deterrent dosage forms |
US11602512B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
US11504347B1 (en) | 2016-07-22 | 2022-11-22 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
US11602513B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
UY37341A (en) | 2016-07-22 | 2017-11-30 | Flamel Ireland Ltd | FORMULATIONS OF GAMMA-MODIFIED RELEASE HYDROXIBUTIRATE WITH IMPROVED PHARMACOCINETICS |
US20180263936A1 (en) | 2017-03-17 | 2018-09-20 | Jazz Pharmaceuticals Ireland Limited | Gamma-hydroxybutyrate compositions and their use for the treatment of disorders |
US10493026B2 (en) | 2017-03-20 | 2019-12-03 | Johnson & Johnson Consumer Inc. | Process for making tablet using radiofrequency and lossy coated particles |
US11033508B2 (en) | 2017-06-14 | 2021-06-15 | SpecGx LLC | Delayed sustained release pharmaceutical compositions |
US11590081B1 (en) | 2017-09-24 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine tablets |
US20190110992A1 (en) | 2017-10-13 | 2019-04-18 | Grünenthal GmbH | Modified release abuse deterrent dosage forms |
KR20210094513A (en) | 2018-11-19 | 2021-07-29 | 재즈 파마슈티칼즈 아일랜드 리미티드 | Alcohol-Resistant Drug Formulations |
CA3127871A1 (en) | 2019-03-01 | 2020-09-10 | Flamel Ireland Limited | Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state |
US11583510B1 (en) | 2022-02-07 | 2023-02-21 | Flamel Ireland Limited | Methods of administering gamma hydroxybutyrate formulations after a high-fat meal |
US11779557B1 (en) | 2022-02-07 | 2023-10-10 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
Family Cites Families (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2099402A (en) | 1934-01-17 | 1937-11-16 | Pratt Food Company | Pill or tablet |
US2738303A (en) | 1952-07-18 | 1956-03-13 | Smith Kline French Lab | Sympathomimetic preparation |
US2881113A (en) * | 1957-01-29 | 1959-04-07 | Ortho Pharma Corp | Therapeutically active compositions containing amphetamines |
US2993836A (en) * | 1958-02-20 | 1961-07-25 | Dow Chemical Co | Sustained release tablets |
US3048526A (en) | 1958-08-04 | 1962-08-07 | Wander Company | Medicinal tablet |
US3066075A (en) * | 1960-07-25 | 1962-11-27 | G W Carnrick Co | Compositions comprising amphetamine and carboxymethyl cellulose in chemically combined form |
NL297631A (en) * | 1963-06-03 | |||
US3365365A (en) | 1965-08-09 | 1968-01-23 | Hoffmann La Roche | Repeat action pharmaceutical compositions in the form of discrete beadlets |
DE2322883A1 (en) | 1973-05-07 | 1974-11-28 | Roehm Gmbh | WATER-SOLUBLE POLYMERIZES |
US4049791A (en) | 1974-06-21 | 1977-09-20 | Delco Chemical Company, Inc. | Prolonged acting appetite suppressant and anti-obesity compositions containing amphetamine adipate, dextroamphetamine adipate, amphetamine sulfate and dextroamphetamine sulfate as the active agents |
FR2470599A1 (en) | 1979-12-07 | 1981-06-12 | Panoz Donald | IMPROVEMENTS IN PROCESSES FOR THE PREPARATION OF GALENIC SHAPES WITH DELAYED ACTION AND PROGRAMMED RELEASE AND GALENIC FORMS OF MEDICAMENTS THUS OBTAINED |
ZA825384B (en) | 1981-07-31 | 1983-05-25 | Tillott J B Ltd | Orally administrable pharmaceutical compositions |
JPS5982311A (en) | 1982-11-04 | 1984-05-12 | Shionogi & Co Ltd | Sustained release preparation of cephalexin |
US4765989A (en) | 1983-05-11 | 1988-08-23 | Alza Corporation | Osmotic device for administering certain drugs |
US4917899A (en) | 1983-12-22 | 1990-04-17 | Elan Corporation Plc | Controlled absorption diltiazem formulation |
IE56999B1 (en) | 1983-12-22 | 1992-03-11 | Elan Corp Plc | Pharmaceutical formulation |
US5364620A (en) | 1983-12-22 | 1994-11-15 | Elan Corporation, Plc | Controlled absorption diltiazem formulation for once daily administration |
US5002776A (en) | 1983-12-22 | 1991-03-26 | Elan Corporation, Plc | Controlled absorption diltiazem formulations |
US4894240A (en) | 1983-12-22 | 1990-01-16 | Elan Corporation Plc | Controlled absorption diltiazem formulation for once-daily administration |
US4728512A (en) | 1985-05-06 | 1988-03-01 | American Home Products Corporation | Formulations providing three distinct releases |
EP0227814A1 (en) | 1985-07-02 | 1987-07-08 | The Upjohn Company | Therapeutic formulations with bimodal release characteristics |
GB8518301D0 (en) | 1985-07-19 | 1985-08-29 | Fujisawa Pharmaceutical Co | Hydrodynamically explosive systems |
JPS62103012A (en) * | 1985-10-23 | 1987-05-13 | Eisai Co Ltd | Multi-layered granule |
EP0230654B1 (en) | 1985-12-28 | 1992-03-18 | Sumitomo Pharmaceuticals Company, Limited | Sustained pulsewise release pharmaceutical preparation |
US4794001A (en) | 1986-03-04 | 1988-12-27 | American Home Products Corporation | Formulations providing three distinct releases |
US4723958A (en) | 1986-05-23 | 1988-02-09 | Merck & Co., Inc. | Pulsatile drug delivery system |
DE3712095A1 (en) | 1987-04-10 | 1988-10-20 | Lentia Gmbh | BINDER-FREE GRANULES WITH DELAYED DELIVERY OF ACTIVE SUBSTANCES |
DE3827214A1 (en) | 1988-08-11 | 1990-02-15 | Roehm Gmbh | RETARDED MEDICAMENT AND METHOD FOR THE PRODUCTION THEREOF |
US5202128A (en) | 1989-01-06 | 1993-04-13 | F. H. Faulding & Co. Limited | Sustained release pharmaceutical composition |
US5275819A (en) | 1989-02-06 | 1994-01-04 | Amer Particle Technologies Inc. | Drug loaded pollen grains with an outer coating for pulsed delivery |
AU629915B2 (en) | 1989-02-16 | 1992-10-15 | British Technology Group Limited | Dispensing device |
KR920702383A (en) | 1989-08-28 | 1992-09-03 | 원본미기재 | Biocorrosive polymers useful for controlling the release of therapeutic agents |
JPH03148215A (en) | 1989-11-01 | 1991-06-25 | Nippon Shinyaku Co Ltd | Laminated formulation |
JPH0674206B2 (en) | 1989-12-28 | 1994-09-21 | 田辺製薬株式会社 | Controlled release formulation and process for producing |
US5229131A (en) | 1990-02-05 | 1993-07-20 | University Of Michigan | Pulsatile drug delivery system |
JP2558396B2 (en) | 1990-06-28 | 1996-11-27 | 田辺製薬株式会社 | Controlled release formulation |
US5232705A (en) * | 1990-08-31 | 1993-08-03 | Alza Corporation | Dosage form for time-varying patterns of drug delivery |
US5156850A (en) * | 1990-08-31 | 1992-10-20 | Alza Corporation | Dosage form for time-varying patterns of drug delivery |
US5422121A (en) | 1990-11-14 | 1995-06-06 | Rohm Gmbh | Oral dosage unit form |
JPH04230625A (en) | 1990-12-27 | 1992-08-19 | Standard Chem & Pharmaceut Corp Ltd | Method for production of finely dispersed tablet composition consisting of microcapsule containing sprayed and dried sodium dichlofenac and having enteric coating |
EP0569534B1 (en) * | 1991-01-30 | 1994-09-28 | Alza Corporation | Osmotic device for delayed delivery of agent |
US5226902A (en) | 1991-07-30 | 1993-07-13 | University Of Utah | Pulsatile drug delivery device using stimuli sensitive hydrogel |
US5407686A (en) * | 1991-11-27 | 1995-04-18 | Sidmak Laboratories, Inc. | Sustained release composition for oral administration of active ingredient |
EP0553777B1 (en) * | 1992-01-29 | 2002-04-24 | Takeda Chemical Industries, Ltd. | Fast dissolving tablet and its production |
US5328697A (en) * | 1992-02-10 | 1994-07-12 | Mallinckrodt Veterinary, Inc. | Compositions and processes for the sustained release of drugs |
US5308348A (en) * | 1992-02-18 | 1994-05-03 | Alza Corporation | Delivery devices with pulsatile effect |
US5260068A (en) | 1992-05-04 | 1993-11-09 | Anda Sr Pharmaceuticals Inc. | Multiparticulate pulsatile drug delivery system |
US5322697A (en) * | 1992-05-28 | 1994-06-21 | Meyer James H | Composition and method for inducing satiety |
NZ253999A (en) * | 1992-08-05 | 1996-07-26 | Faulding F H & Co Ltd | Pelletised substained release medicament |
US5260069A (en) | 1992-11-27 | 1993-11-09 | Anda Sr Pharmaceuticals Inc. | Pulsatile particles drug delivery system |
JP2916978B2 (en) * | 1993-08-25 | 1999-07-05 | エスエス製薬株式会社 | Controlled release initiation type formulation |
US6103262A (en) | 1994-01-27 | 2000-08-15 | G. D. Searle & Company | Modified-release metronidazole compositions and methods for making and using same |
US5395626A (en) * | 1994-03-23 | 1995-03-07 | Ortho Pharmaceutical Corporation | Multilayered controlled release pharmaceutical dosage form |
US5411745A (en) | 1994-05-25 | 1995-05-02 | Euro-Celtique, S.A. | Powder-layered morphine sulfate formulations |
US5582855A (en) | 1994-07-01 | 1996-12-10 | Fuisz Technologies Ltd. | Flash flow formed solloid delivery systems |
FR2723536A1 (en) * | 1994-08-11 | 1996-02-16 | Seth Pawan | COMPOSITION FOR SELECTIVE RELEASE OF AN ACTIVE INGREDIENT |
US5733575A (en) | 1994-10-07 | 1998-03-31 | Bpsi Holdings, Inc. | Enteric film coating compositions, method of coating therewith, and coated forms |
US5731314A (en) * | 1995-01-06 | 1998-03-24 | Bencherif; Merouane | Pharamceutical compositions for prevention and treatment of tourette's syndrome |
GB9514451D0 (en) | 1995-07-14 | 1995-09-13 | Chiroscience Ltd | Sustained-release formulation |
CA2228625C (en) * | 1995-08-16 | 2003-11-18 | Osi Specialties, Inc. | Stable silane compositions on silica carrier |
US5908850A (en) * | 1995-12-04 | 1999-06-01 | Celgene Corporation | Method of treating attention deficit disorders with d-threo methylphenidate |
US5922736A (en) * | 1995-12-04 | 1999-07-13 | Celegene Corporation | Chronic, bolus administration of D-threo methylphenidate |
US5837284A (en) | 1995-12-04 | 1998-11-17 | Mehta; Atul M. | Delivery of multiple doses of medications |
JPH09267035A (en) | 1996-01-30 | 1997-10-14 | Kanegafuchi Chem Ind Co Ltd | Production of nuclear particle |
US5773031A (en) * | 1996-02-27 | 1998-06-30 | L. Perrigo Company | Acetaminophen sustained-release formulation |
JP3929522B2 (en) | 1996-03-14 | 2007-06-13 | 塩野義製薬株式会社 | Sustained release formulation of poorly water-soluble drugs |
JP4224866B2 (en) | 1996-07-18 | 2009-02-18 | 大正製薬株式会社 | Base with controlled dissolution time |
US5846568A (en) * | 1996-09-19 | 1998-12-08 | Xyrofin Oy | Directly compressible lactitol and method |
HRP970493A2 (en) * | 1996-09-23 | 1998-08-31 | Wienman E. Phlips | Oral delayed immediate release medical formulation and method for preparing the same |
ES2262174T3 (en) | 1996-09-30 | 2006-11-16 | Alza Corporation | DOSAGE FORM AND DRUG ADMINISTRATION PROCEDURE. |
US5891474A (en) * | 1997-01-29 | 1999-04-06 | Poli Industria Chimica, S.P.A. | Time-specific controlled release dosage formulations and method of preparing same |
US5840329A (en) | 1997-05-15 | 1998-11-24 | Bioadvances Llc | Pulsatile drug delivery system |
US5885616A (en) | 1997-08-18 | 1999-03-23 | Impax Pharmaceuticals, Inc. | Sustained release drug delivery system suitable for oral administration |
US6350470B1 (en) | 1998-04-29 | 2002-02-26 | Cima Labs Inc. | Effervescent drug delivery system for oral administration |
US5945123A (en) * | 1998-04-02 | 1999-08-31 | K-V Pharmaceutical Company | Maximizing effectiveness of substances used to improve health and well being |
US20010055613A1 (en) * | 1998-10-21 | 2001-12-27 | Beth A. Burnside | Oral pulsed dose drug delivery system |
DK1126826T6 (en) | 1998-11-02 | 2019-06-24 | Alkermes Pharma Ireland Ltd | Multiparticulate modified release of methylphenidate |
US6673367B1 (en) | 1998-12-17 | 2004-01-06 | Euro-Celtique, S.A. | Controlled/modified release oral methylphenidate formulations |
AU4221300A (en) * | 1999-04-06 | 2000-10-23 | Kamal K. Midha | Pharmaceutical dosage form for pulsatile delivery of (d-threo)-methylphenidate and a second cns stimulant |
NZ517465A (en) * | 1999-09-02 | 2003-10-31 | Nostrum Pharmaceuticals Inc | Controlled release pellet formulation |
US6749867B2 (en) | 2000-11-29 | 2004-06-15 | Joseph R. Robinson | Delivery system for omeprazole and its salts |
US6913768B2 (en) | 2002-09-24 | 2005-07-05 | Shire Laboratories, Inc. | Sustained release delivery of amphetamine salts |
-
1998
- 1998-10-21 US US09/176,542 patent/US20010055613A1/en active Granted
- 1998-10-21 US US09/176,542 patent/US6322819B1/en not_active Ceased
-
1999
- 1999-10-20 AT AT99970594T patent/ATE427101T1/en not_active IP Right Cessation
- 1999-10-20 EP EP08157737A patent/EP1977736A1/en not_active Withdrawn
- 1999-10-20 US US09/807,462 patent/US6605300B1/en not_active Ceased
- 1999-10-20 EP EP99970594A patent/EP1123087B1/en not_active Expired - Lifetime
- 1999-10-20 CA CA002348090A patent/CA2348090C/en not_active Expired - Lifetime
- 1999-10-20 WO PCT/US1999/024554 patent/WO2000023055A1/en active Application Filing
- 1999-10-20 JP JP2000576830A patent/JP2002527468A/en active Pending
- 1999-10-20 DE DE69940673T patent/DE69940673D1/en not_active Expired - Lifetime
- 1999-10-20 US US11/091,010 patent/USRE41148E1/en not_active Expired - Lifetime
- 1999-10-20 ES ES99970594T patent/ES2323910T3/en not_active Expired - Lifetime
- 1999-10-20 AU AU12145/00A patent/AU1214500A/en not_active Abandoned
-
2002
- 2002-01-15 HK HK02100312.9A patent/HK1038701A1/en unknown
- 2002-06-14 US US10/172,705 patent/US20030124188A1/en not_active Abandoned
-
2004
- 2004-01-16 US US10/758,417 patent/US20040219213A1/en not_active Abandoned
-
2005
- 2005-03-24 US US11/091,011 patent/USRE42096E1/en not_active Expired - Lifetime
-
2008
- 2008-06-18 JP JP2008159637A patent/JP2008303223A/en not_active Withdrawn
Cited By (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8999372B2 (en) | 2002-11-14 | 2015-04-07 | Cure Pharmaceutical Corporation | Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use |
US10398644B2 (en) | 2002-11-14 | 2019-09-03 | Cure Pharmaceutical Corporation | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
US20060210610A1 (en) * | 2002-11-14 | 2006-09-21 | Davidson Robert S | Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use |
US9517271B2 (en) | 2002-12-13 | 2016-12-13 | Durect Corporation | Oral drug delivery system |
US20040161382A1 (en) * | 2002-12-13 | 2004-08-19 | Yum Su Il | Oral drug delivery system |
US8951556B2 (en) | 2002-12-13 | 2015-02-10 | Durect Corporation | Oral drug delivery system |
US8945614B2 (en) | 2002-12-13 | 2015-02-03 | Durect Corporation | Oral drug delivery system |
US20090023690A1 (en) * | 2002-12-13 | 2009-01-22 | Durect Corporation | Oral drug delivery system |
US20090023689A1 (en) * | 2002-12-13 | 2009-01-22 | Durect Corporation | Oral drug delivery system |
US8133507B2 (en) | 2002-12-13 | 2012-03-13 | Durect Corporation | Oral drug delivery system |
US8147870B2 (en) | 2002-12-13 | 2012-04-03 | Durect Corporation | Oral drug delivery system |
US8153152B2 (en) | 2002-12-13 | 2012-04-10 | Durect Corporation | Oral drug delivery system |
US8168217B2 (en) | 2002-12-13 | 2012-05-01 | Durect Corporation | Oral drug delivery system |
US8354124B2 (en) | 2002-12-13 | 2013-01-15 | Durect Corporation | Oral drug delivery system |
US9918982B2 (en) | 2002-12-13 | 2018-03-20 | Durect Corporation | Oral drug delivery system |
US8420120B2 (en) | 2002-12-13 | 2013-04-16 | Durect Corporation | Oral drug delivery system |
US9233160B2 (en) | 2002-12-13 | 2016-01-12 | Durect Corporation | Oral drug delivery system |
US8974821B2 (en) | 2002-12-13 | 2015-03-10 | Durect Corporation | Oral drug delivery system |
US20040224020A1 (en) * | 2002-12-18 | 2004-11-11 | Schoenhard Grant L. | Oral dosage forms with therapeutically active agents in controlled release cores and immediate release gelatin capsule coats |
US9155698B2 (en) | 2003-03-28 | 2015-10-13 | Cure Pharmaceutical Corporation | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
US8840919B2 (en) * | 2003-03-28 | 2014-09-23 | Cure Pharmaceutical Corporation | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
US20070275040A1 (en) * | 2003-03-28 | 2007-11-29 | Innozen, Inc. | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
WO2007079082A2 (en) * | 2005-12-30 | 2007-07-12 | Advancis Pharmaceutical Corporation | Gastric release pulse system for drug delivery |
US20070154547A1 (en) * | 2005-12-30 | 2007-07-05 | Flanner Henry H | Gastric release pulse system for drug delivery |
US9125803B2 (en) | 2005-12-30 | 2015-09-08 | Shionogi Inc. | Gastric release pulse system for drug delivery |
WO2007079082A3 (en) * | 2005-12-30 | 2008-03-27 | Advancis Pharmaceutical Corp | Gastric release pulse system for drug delivery |
US8415401B2 (en) | 2007-12-06 | 2013-04-09 | Durect Corporation | Oral pharmaceutical dosage forms |
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US9655861B2 (en) | 2007-12-06 | 2017-05-23 | Durect Corporation | Oral pharmaceutical dosage forms |
US9616055B2 (en) | 2008-11-03 | 2017-04-11 | Durect Corporation | Oral pharmaceutical dosage forms |
US10328068B2 (en) | 2008-11-03 | 2019-06-25 | Durect Corporation | Oral pharmaceutical dosage forms |
US9884056B2 (en) | 2008-11-03 | 2018-02-06 | Durect Corporation | Oral pharmaceutical dosage forms |
US9555113B2 (en) | 2013-03-15 | 2017-01-31 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US10300142B2 (en) | 2013-03-15 | 2019-05-28 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US9572885B2 (en) | 2013-03-15 | 2017-02-21 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US9907851B2 (en) | 2013-03-15 | 2018-03-06 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US9855333B2 (en) | 2013-03-15 | 2018-01-02 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US10449159B2 (en) | 2014-10-31 | 2019-10-22 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10507186B2 (en) | 2014-10-31 | 2019-12-17 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
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US10111839B2 (en) | 2014-10-31 | 2018-10-30 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
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US10500162B2 (en) | 2014-10-31 | 2019-12-10 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10292938B2 (en) | 2014-10-31 | 2019-05-21 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10512613B2 (en) | 2014-10-31 | 2019-12-24 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10512612B2 (en) | 2014-10-31 | 2019-12-24 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10568841B2 (en) | 2014-10-31 | 2020-02-25 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10688060B2 (en) | 2014-10-31 | 2020-06-23 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
CN110381926A (en) * | 2017-03-09 | 2019-10-25 | 德维科制药瑞士公司 | Novel dosage forms |
US20200155471A1 (en) * | 2018-11-19 | 2020-05-21 | Purdue Pharma | Methods and Compositions Particularly for Treatment of Attention Deficit Disorder |
US10722473B2 (en) * | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
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EP1123087A4 (en) | 2004-02-11 |
EP1123087A1 (en) | 2001-08-16 |
US20040219213A1 (en) | 2004-11-04 |
US6322819B1 (en) | 2001-11-27 |
EP1977736A1 (en) | 2008-10-08 |
WO2000023055A9 (en) | 2000-08-31 |
CA2348090C (en) | 2004-04-13 |
ES2323910T3 (en) | 2009-07-27 |
ATE427101T1 (en) | 2009-04-15 |
EP1123087B1 (en) | 2009-04-01 |
WO2000023055A1 (en) | 2000-04-27 |
JP2008303223A (en) | 2008-12-18 |
US20030124188A1 (en) | 2003-07-03 |
US6605300B1 (en) | 2003-08-12 |
DE69940673D1 (en) | 2009-05-14 |
USRE41148E1 (en) | 2010-02-23 |
JP2002527468A (en) | 2002-08-27 |
HK1038701A1 (en) | 2002-03-28 |
AU1214500A (en) | 2000-05-08 |
CA2348090A1 (en) | 2000-04-27 |
USRE42096E1 (en) | 2011-02-01 |
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