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WO1987000044A1 - Formulations therapeutiques presentant des caracteristiques de liberation bimodales - Google Patents

Formulations therapeutiques presentant des caracteristiques de liberation bimodales Download PDF

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Publication number
WO1987000044A1
WO1987000044A1 PCT/US1986/001360 US8601360W WO8700044A1 WO 1987000044 A1 WO1987000044 A1 WO 1987000044A1 US 8601360 W US8601360 W US 8601360W WO 8700044 A1 WO8700044 A1 WO 8700044A1
Authority
WO
WIPO (PCT)
Prior art keywords
bimodal
metolose
sustained release
therapeutically active
weight
Prior art date
Application number
PCT/US1986/001360
Other languages
English (en)
Inventor
Ashok C. Shah
Original Assignee
The Upjohn Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Upjohn Company filed Critical The Upjohn Company
Publication of WO1987000044A1 publication Critical patent/WO1987000044A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to a oarrier base material to be combined with a therapeutically active medicament and formed into a solid, shaped dosage unit having a bimodal controlled release of medicament upon administration.
  • this invention relates to a carrier base material consisting of one or more bimodal hydroxypropylmethylcelluloses (B-HPMC's) having a physical and chemical structure which renders it suitable for use in sustained release therapeutic formulations with bimodal release characteristics.
  • B-HPMC's bimodal hydroxypropylmethylcelluloses
  • Forest U.S. Patent 4,369,172 hydroxypropylmethylcellulose (methoxy content of 27 to 30%, hydroxypropyl content of 9 to 12% ) is combined with ethylcellulose or sodium carboxymethylcellulose for prolonged release.
  • Another Forest U.S. Patent 3, 870,790 mentions a slow release buccal tablet of 80 to 100% hydroxypropylmethylcellulose (methoxy content 28 to 30%, hydroxypropyl content 7-12%) and 0 to 20% ethylcellulose.
  • Forest U.S. patent 4,357,469 uses a hydrolyzed and oxidated hydroxypropylmethylcellulose (methoxy content 28 to 30% hydroxypropyl content 7.5 to 12%) with up to 30% ethylcellulose or 30% sodium carboxymethylcellulose.
  • Forest German Patent DT2718-260 describes the use of a treated hydroxypropylmethylcellulose and ethylcellulose to produce a slow release formulation.
  • Forest Patents U.S. 4,226,849 and South Africa 7,805,528 claim similar slow release formulations using hydroxypropylmethylcellulose.
  • U.S. Patents U.S. 4,226,849 and South Africa 7,805,528 claim similar slow release formulations using hydroxypropylmethylcellulose.
  • hydroxypropylmethylcellulose is used for a sustained release tablet that is at least 1/3 by weight hydrophilic gum.
  • Methocels listed are E4-M, 90 HG 4,000 cps., K4-M, and K15-M.
  • U.S. Patent 4,389,393 claims a carrier base material being one or more hydroxypropylmethylcelluloses (methoxy content 16 to 24%, hydroxypropyl content 4 to 32% and average molecular weight of at least 50,000) up to
  • Patent 3,065,143 uses a cellulose product with a methoxyl content of 19 to 24% and hydroxypropyl content of 4 to 12% with the HPMC comprising at least 1/3 of the total tablet weight.
  • Patents J5-8135-807-A and J5-7062-224 use hydroxypropylmethylcellulose as a coating for tablets.
  • the effect of various METHOCEL Products on Tablet Dissolution, including F4-M, is the subject of a Dow booklet entitled Formulating Sustained Release Pharmaceutical Products with Methocel".
  • Metolose 65SH-4000 has been reported to be useful as a paint thickener, as a suspending agent in spray paints, as a thickener in paint removers, as a latex stabilizer and thickener for asphalt emulsion, as a base of jelly for an external application or ointments, as a binder for cigar leaf.
  • Metolose 65SH-1500 as a gypsum plaster additives.
  • Metolose 65SH-400 as Joint cement additive, as suspension stabilizer in vinyl chloride vinylidene polymer, as latex stabilizer, as spray paint additive, as shampoo additive to improve viscosity.
  • Metolose 65SH-50 as suspension stabilizer in vinylchlorlde vinylidene polymer.
  • Metolose 90SH-100 as suspension stabilizer in vinylchlorlde vinylidene polymer, as molding binder for pencil or crayons.
  • Metolose 90SH-15000 as cement mortar additive, as tile cement additive, as gypsum plaster additive, as plaster additive, as molding product of gypsum cement.
  • Metolose 60SH-4000 as paint remover additive, as shampoo additive, as binder for the extrusion molding of ceramic condenser and ferrite alumina porcelains.
  • Methocel F4-M as additive to general adhesives, dust stickers, spray stickers, caulking compounds, tile and grout adhesives, toothpastes, pie fillings, cements, creams, ointments, ophthalmic preparations, and suspensions.
  • the present invention is directed toward a carrier base material for therapeutically active medicaments in a solid dosage formulation that produces a bimodal controlled release profile characterized by a rapid initial release of aedicament followed by a substantially constant rate of release for a period of time, after which the release rate is greater than the constant rate previously observed.
  • a carrier base material and bimodal controlled release formulation prepared therefrom over conventional sustained release formulations are substantial.
  • Conventional sustained release formulations may exhibit a zero order release profile, where the rate of release of therapeutic agent is essentially constant, or a profile in which the release rate decreases with time.
  • An objective of the bimodal controlled release formulation of this invention is to provide for a more uniform delivery of therapeutic agent since it is now possible to increase the rate of drug release at a point when the body's ability to absorb a medicament decreases, thus providing more uniform delivery of the therapeutic agent.
  • Another object of the present invention is to provide a bimodal formulation giving therapeutic blood levels similar to those produced by administration of two smaller doses over an extended period of time.
  • the bimodal release profile of the active ingredient from the carrier of the present invention can be controlled according to the particlar therapeutic agent and its intended therapeutic effect since the initial rate of release, initial time of rate change, and the final release rate for a specific drug, are all a property of the particular B-HPMC(s) utilized. These parameters can be selectively modified by the addition of various excipients that include, but are not limited to, non-bimodal hydroxypropylmethylcellulose (HPMC's), hydroxypropylcelluloses, lactose, starch, binders, fillers, disintegrating agents and other pharmaceutical compounding agents.
  • HPMC's non-bimodal hydroxypropylmethylcellulose
  • the active ingredient can be any type of therapeutic agent which lends itself to controlled release administration.
  • agents include antihistamines, laxatives, vitamins, decongestants, gastrointestinal sedatives, anti-inflammatory substances, antacids, anti-infectives, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, psyehotropics, antimanics, stimulants, antidiarrheal preparations, antianginal drugs, vasoconstrictors, anticoagulants, antithrombotic drugs, analgesics, anti-pyretics, hypnotics, sediatives, anti-emetics, anti-nauseants, anticonvulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, anti-spasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, anabolic drugs, erythropoietic drugs, anti-as
  • sustained release tablets with bimodal release characteristics consists of thorough mixing of a therapeutic agent with one or more of the hydroxypropylmethylcellulose ethers of the present invention, and any other ingredients wMch are. conventional in tablet making - such as magnesium stearate, stearic acid, Cab-O-sil (colloidal 3ilicon dioxide) etc. Release rate modifiers, as mentioned previously, are also added at this time, if they are desined. All ingredients are mixed thoroughly. The mixture, in an amount sufficient to make a uniform batch of matrix tablets, is subjected to tableting on conventional tableting machines.
  • hydroxypropylmethylcellulose ethers effective for the present purpose are the bimodal hydroxypropylmethylcellulose ethers (B-HPMC's), with a methoxy content of 19 to 30%, a hydro xypropyoxy content of from 4 to 12%, a viscosity of from 40 to 19,000 cps, an average molecular weight of from 20,000 to 140,000, and demonstrates a bimodal release profile in accordance with the assay described in Procedure I. Accordingly, any hydroxypropylmethylcellulose ether having the foregoing specifications, and exhibiting a bimodal release profile in accordance with Procedure I represents a B-HPMC.
  • B-HPMC's bimodal hydroxypropylmethylcellulose ethers
  • hydroxypropylmethylcellulose ethers which can be used as B-HPMC's include, but are not limited to, Metolose 65SH-50, 400, 1500 and 4000, Metolose 60SH-4000 and Metolose 90SH-100 and 15,000, all available from Shin-Etsu Ltd., Japan, as well as Methocel F4-M available from the Dow Chemical Company.
  • Various grades of Methocel A, E and K tested do not demonstrate a bimodal release profile nor has Metolose SM-1500, a brand of methylcellulose. See, for example, the cumulative and differential plots of a 200 mg flurbiprofen/Methocel 30% K15-M of FIGURES 3 and 4.
  • B-HPMC hydroxypropylmethylcellulose
  • the bimodal hydroxypropylmethylcelluloses (B-HPMC's) of the present invention can be optionally mixed with about 0 to 50% by weight of the total formulation of a non-bimodal hydroxypropylmethylcellulose, or methylcellulose, sodium carboxymethylcellulose or other cellulsoe ether.
  • B-HPMC's for example, two or more B-HPMC's, one or more non-bimodal HPMC, or other cellulose ethers in combination with one or more B-HPMC can be mixed to provide bimodal formulations of various specific release characteristics. See e g. Example 11 and 12. Procedure 1 Determination of Bimodal Hydroxypropylmethyl-cellulose (B-HPMC's) Utilizing Standard In Vitro Assay Procedures
  • hydroxypropylmethylcelluloses to produce a bimodal release profile can be readily evaluated in accordance with the following procedure.
  • One Hundred 300 mg Aspirin tablets are prepared from the following types and amounts of ingredients:
  • Release rates are determined using an automated spin filter dissolution apparatus, J. Pharm. Sci. 63. 110, (1974), or other dissolution test device using the following conditions: Media: 1,000 ml of 0.05 M phosphate buffer, pH 7.2
  • Release rates are plotted (cumulative and/ or differential plots) and evaluated for the presence of a bimodal profile characterized by a rapid initial release of drug followed by am essentially constant rate of release .for a period of time, after which the release rate is greater than the constant rate previously observed.
  • An HPMC that produces a bimodal release rate is a B-HPMC.
  • Metolose 65SH-4000 is a B-HPMC.
  • Examples 1-3 Bimodal Controlled Release 200 mg flurbiprofen tablets containing 40% bimodal hydroxypropylmethylcellulose were prepared from the following ingredients:
  • Example 1 Bimodal Controlled Release 200 mg flurbiprofen tablets containing 40% bimodal hydroxypropylmethylcellulose were prepared from the following ingredients:
  • Example 1 Bimodal Controlled Release 200 mg flurbiprofen tablets containing 40% bimodal hydroxypropylmethylcellulose were prepared from the following ingredients:
  • Example 1
  • Table 1 shows the percent drug dissolved per hour, and the rate of dissolution for Examples 1-3.
  • Examples 4-9 show the effect of varying the amount of a bimodal hydroxypropylmethylcellulose used on 200 mg flurbiprofen formulations.
  • Tablets are prepared and tested as stated in Examples 1-3. Tablet weight ranges from 241 mg to 527 mg. Table 2 shows the percent drug dlssolved per hour, and rate of dissolution for Examples 4-9.
  • Examples 10-12 show the effect of a modifying excipient, Metolose SM-1500 (methylcellulose, USP; 1500 cps), on 30 mg adinazolam mesylate formulations containing the bimodal hydroxypropylmethylcellulose, Metolose 65SH-4000.
  • Metolose SM-1500 methylcellulose, USP; 1500 cps
  • Example 10 show the effect of a modifying excipient, Metolose SM-1500 (methylcellulose, USP; 1500 cps), on 30 mg adinazolam mesylate formulations containing the bimodal hydroxypropylmethylcellulose, Metolose 65SH-4000.
  • Example 10 shows the effect of a modifying excipient, Metolose SM-1500 (methylcellulose, USP; 1500 cps), on 30 mg adinazolam mesylate formulations containing the bimodal hydroxypropylmethylcellulose, Metolose 65SH-4000.
  • Tablets are prepared in Examples 13, 14 and 15 by mixing flurbiprofen, metoloses, and color in a P-K blender for 5 min. The mixed are then dry granulated by slugging. The stearic acid and Cab-O- Sil are added to the dry sized granules and blended for another 5 min. Mixos are then compressed on a Beta Press. The theoretical tablet weight is 311.28 mg. Table 4 shows the percent drug dissolved versus time and the rate for the tablets.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Matériau de base porteur destiné à être combiné avec un médicament thérapeutiquement actif et formé dans une unité de dosage solide de forme prédéterminée permettant de contrôler la libération du médicament lors de son administration. Plus précisément, la présente invention se rapporte à un matériau de base porteur formé d'une ou de plusieurs hydroxypropylméthylcellulose(s) (B-HPMC) bimodales ayant une structure physique et chimique qui rend ledit matériau utilisable dans des formulations thérapeutiques de libération soutenue présentant des caractéristiques de libération bimodales.
PCT/US1986/001360 1985-07-02 1986-06-18 Formulations therapeutiques presentant des caracteristiques de liberation bimodales WO1987000044A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75112585A 1985-07-02 1985-07-02
US751,125 1985-07-02

Publications (1)

Publication Number Publication Date
WO1987000044A1 true WO1987000044A1 (fr) 1987-01-15

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EP (1) EP0227814A1 (fr)
WO (1) WO1987000044A1 (fr)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2613224A1 (fr) * 1987-04-06 1988-10-07 Alza Corp Forme posologique bicouche a liberation prolongee
US4994276A (en) * 1988-09-19 1991-02-19 Edward Mendell Co., Inc. Directly compressible sustained release excipient
US5009895A (en) * 1990-02-02 1991-04-23 Merck & Co., Inc. Sustained release with high and low viscosity HPMC
GR1000252B (el) * 1988-09-02 1992-05-12 Alza Corp Μορφη δοσολογιας συνισταμενη απο ταχεια απελευθερωση δραστικου παραγοντα ακολουθουμενη απο βραδεια απελευθερωση δραστικου παραγοντα.
US5128143A (en) * 1988-09-19 1992-07-07 Edward Mendell Co., Inc. Sustained release excipient and tablet formulation
US5135757A (en) * 1988-09-19 1992-08-04 Edward Mendell Co., Inc. Compressible sustained release solid dosage forms
US5169639A (en) * 1988-09-19 1992-12-08 Edward Mendell Co., Inc. Controlled release verapamil tablets
US5232704A (en) * 1990-12-19 1993-08-03 G. D. Searle & Co. Sustained release, bilayer buoyant dosage form
EP0581676A3 (fr) * 1992-07-30 1995-06-07 Mendell Co Inc Edward Complexes hydrophiles agglomérés ayant des propriétés de libération multiphase.
US5472710A (en) * 1988-04-16 1995-12-05 Schwarz Pharma Ag Pharmaceutical preparation to be administered orally with controlled release of active substance and method for its manufacture
FR2766707A1 (fr) * 1997-07-30 1999-02-05 Galenix Dev Composition contenant de l'hydroxypropylcellulose, de l'hydroxypropylmethyl-cellulose et/ou de l'ethylcellulose a titre d'agents desintegrants, et procede d'obtention
FR2766708A1 (fr) * 1997-07-30 1999-02-05 Galenix Dev Composition contenant de l'hydroxypropylcellulose, de l'hydroxypropylmethylcellulose et/ou de l'ethylcellullose a titre d'agents desintegrants, et procede d'obtention
US5948437A (en) * 1996-05-23 1999-09-07 Zeneca Limited Pharmaceutical compositions using thiazepine
US6042847A (en) * 1995-05-19 2000-03-28 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Three-phase pharmaceutical form with constant and controlled release of amorphous active ingredient for single daily application
US6210710B1 (en) 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
US6242003B1 (en) 2000-04-13 2001-06-05 Novartis Ag Organic compounds
US6322819B1 (en) 1998-10-21 2001-11-27 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
US6372252B1 (en) 2000-04-28 2002-04-16 Adams Laboratories, Inc. Guaifenesin sustained release formulation and tablets
US6913768B2 (en) 2002-09-24 2005-07-05 Shire Laboratories, Inc. Sustained release delivery of amphetamine salts
US6955821B2 (en) 2000-04-28 2005-10-18 Adams Laboratories, Inc. Sustained release formulations of guaifenesin and additional drug ingredients
US6960356B1 (en) 1997-09-19 2005-11-01 Ranbaxy Laboratories Limited Orally administered drug delivery system providing temporal and spatial control
US8303987B2 (en) 2001-04-11 2012-11-06 Novartis Ag Pharmaceutical compositions comprising fluvastatin
US9545399B2 (en) 2012-08-15 2017-01-17 Tris Pharma, Inc. Methylphenidate extended release chewable tablet
US9675704B2 (en) 2006-03-16 2017-06-13 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US11278506B2 (en) 2015-10-09 2022-03-22 Rb Health (Us) Llc Pharmaceutical formulation
US11590081B1 (en) 2017-09-24 2023-02-28 Tris Pharma, Inc Extended release amphetamine tablets
US11590228B1 (en) 2015-09-08 2023-02-28 Tris Pharma, Inc Extended release amphetamine compositions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4167558A (en) * 1976-02-13 1979-09-11 Hoffmann-La Roche Inc. Novel sustained release tablet formulations
US4369172A (en) * 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
US4389393A (en) * 1982-03-26 1983-06-21 Forest Laboratories, Inc. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4167558A (en) * 1976-02-13 1979-09-11 Hoffmann-La Roche Inc. Novel sustained release tablet formulations
US4369172A (en) * 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
US4389393A (en) * 1982-03-26 1983-06-21 Forest Laboratories, Inc. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose
US4389393B1 (fr) * 1982-03-26 1985-10-22

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR880100214A (en) * 1987-04-06 1989-01-31 Alza Corp Dosage form comprising parallel laminare
BE1001699A3 (fr) * 1987-04-06 1990-02-13 Alza Corp Forme de dosage comprenant des lamelles paralleles.
FR2613224A1 (fr) * 1987-04-06 1988-10-07 Alza Corp Forme posologique bicouche a liberation prolongee
US5472710A (en) * 1988-04-16 1995-12-05 Schwarz Pharma Ag Pharmaceutical preparation to be administered orally with controlled release of active substance and method for its manufacture
GR1000252B (el) * 1988-09-02 1992-05-12 Alza Corp Μορφη δοσολογιας συνισταμενη απο ταχεια απελευθερωση δραστικου παραγοντα ακολουθουμενη απο βραδεια απελευθερωση δραστικου παραγοντα.
US4994276A (en) * 1988-09-19 1991-02-19 Edward Mendell Co., Inc. Directly compressible sustained release excipient
US5128143A (en) * 1988-09-19 1992-07-07 Edward Mendell Co., Inc. Sustained release excipient and tablet formulation
US5135757A (en) * 1988-09-19 1992-08-04 Edward Mendell Co., Inc. Compressible sustained release solid dosage forms
US5169639A (en) * 1988-09-19 1992-12-08 Edward Mendell Co., Inc. Controlled release verapamil tablets
US5009895A (en) * 1990-02-02 1991-04-23 Merck & Co., Inc. Sustained release with high and low viscosity HPMC
EP0440462A1 (fr) * 1990-02-02 1991-08-07 Merck & Co. Inc. Libération prolongée par de l'HPMC à haute et basse viscosité
US5232704A (en) * 1990-12-19 1993-08-03 G. D. Searle & Co. Sustained release, bilayer buoyant dosage form
US5478574A (en) * 1992-07-30 1995-12-26 Edward Mendell Co., Inc. Agglomerated hydrophilic complexes with multi-phasic release characteristics
EP0581676A3 (fr) * 1992-07-30 1995-06-07 Mendell Co Inc Edward Complexes hydrophiles agglomérés ayant des propriétés de libération multiphase.
US5670168A (en) * 1992-07-30 1997-09-23 Edward Mendell Co., Inc. Agglomerated hydrophilic complexes with multi-phasic release characteristics
US5472711A (en) * 1992-07-30 1995-12-05 Edward Mendell Co., Inc. Agglomerated hydrophilic complexes with multi-phasic release characteristics
US6042847A (en) * 1995-05-19 2000-03-28 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Three-phase pharmaceutical form with constant and controlled release of amorphous active ingredient for single daily application
US5948437A (en) * 1996-05-23 1999-09-07 Zeneca Limited Pharmaceutical compositions using thiazepine
US6210710B1 (en) 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
FR2766707A1 (fr) * 1997-07-30 1999-02-05 Galenix Dev Composition contenant de l'hydroxypropylcellulose, de l'hydroxypropylmethyl-cellulose et/ou de l'ethylcellulose a titre d'agents desintegrants, et procede d'obtention
FR2766708A1 (fr) * 1997-07-30 1999-02-05 Galenix Dev Composition contenant de l'hydroxypropylcellulose, de l'hydroxypropylmethylcellulose et/ou de l'ethylcellullose a titre d'agents desintegrants, et procede d'obtention
US6531151B1 (en) 1997-07-30 2003-03-11 Galenix Developpement Composition containing hydroxypropylmethylcellulose and/or ethylcellulose as disintegrants and process for producing it
US6960356B1 (en) 1997-09-19 2005-11-01 Ranbaxy Laboratories Limited Orally administered drug delivery system providing temporal and spatial control
USRE42096E1 (en) 1998-10-21 2011-02-01 Shire LLC, USA Oral pulsed dose drug delivery system
US6322819B1 (en) 1998-10-21 2001-11-27 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
USRE41148E1 (en) * 1998-10-21 2010-02-23 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
US6605300B1 (en) 1998-10-21 2003-08-12 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
EP1977736A1 (fr) 1998-10-21 2008-10-08 Shire LLC Système d'administration de médicament par dose pulsée par voie orale
US6432447B2 (en) 2000-04-13 2002-08-13 Novartis Ag Organic compounds
US6242003B1 (en) 2000-04-13 2001-06-05 Novartis Ag Organic compounds
US6372252B1 (en) 2000-04-28 2002-04-16 Adams Laboratories, Inc. Guaifenesin sustained release formulation and tablets
US6955821B2 (en) 2000-04-28 2005-10-18 Adams Laboratories, Inc. Sustained release formulations of guaifenesin and additional drug ingredients
US8303987B2 (en) 2001-04-11 2012-11-06 Novartis Ag Pharmaceutical compositions comprising fluvastatin
US6913768B2 (en) 2002-09-24 2005-07-05 Shire Laboratories, Inc. Sustained release delivery of amphetamine salts
US10086087B2 (en) 2006-03-16 2018-10-02 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US9675704B2 (en) 2006-03-16 2017-06-13 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US9675703B2 (en) 2006-03-16 2017-06-13 Tris Pharma, Inc Modified release formulations containing drug - ion exchange resin complexes
US9545399B2 (en) 2012-08-15 2017-01-17 Tris Pharma, Inc. Methylphenidate extended release chewable tablet
US9844545B2 (en) 2012-08-15 2017-12-19 Tris Pharma, Inc. Methylphenidate extended release chewable tablet
US9844544B2 (en) 2012-08-15 2017-12-19 Tris Pharma, Inc Methylphenidate extended release chewable tablet
US10507203B2 (en) 2012-08-15 2019-12-17 Tris Pharma, Inc Methylphenidate extended release chewable tablet
US10857143B2 (en) 2012-08-15 2020-12-08 Tris Pharma, Inc Methylphenidate extended release chewable tablet
US11103494B2 (en) 2012-08-15 2021-08-31 Tris Pharma, Inc Methylphenidate extended release chewable tablet
US11103495B2 (en) 2012-08-15 2021-08-31 Tris Pharma, Inc Methylphenidate extended release chewable tablet
US11633389B2 (en) 2012-08-15 2023-04-25 Tris Pharma, Inc Methylphenidate extended release chewable tablet
US11590228B1 (en) 2015-09-08 2023-02-28 Tris Pharma, Inc Extended release amphetamine compositions
US11278506B2 (en) 2015-10-09 2022-03-22 Rb Health (Us) Llc Pharmaceutical formulation
US12257218B2 (en) 2015-10-09 2025-03-25 Rb Health (Us) Llc Pharmaceutical formulation
US11590081B1 (en) 2017-09-24 2023-02-28 Tris Pharma, Inc Extended release amphetamine tablets
US12076441B2 (en) 2017-09-24 2024-09-03 Tris Pharma, Inc. Extended release amphetamine tablets

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