|Publication number||USRE33994 E|
|Application number||US 07/390,518|
|Publication date||Jul 14, 1992|
|Filing date||Aug 4, 1989|
|Priority date||Aug 16, 1983|
|Publication number||07390518, 390518, US RE33994 E, US RE33994E, US-E-RE33994, USRE33994 E, USRE33994E|
|Inventors||Richard W. Baker, James W. Brooke|
|Original Assignee||Burroughs Wellcome Co.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (42), Non-Patent Citations (14), Referenced by (57), Classifications (12), Legal Events (5)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This invention relates to a device which provides the controlled, continuous dispensing of a water-soluble beneficial agent for a predetermined period of time. Moreover, the invention relates to such a device powered by an osmotic pumping mechanism, to the preparation of such a device and to the use of such a device in the medical, veterinary and other fields.
Systems for the delivery of pharmaceutically beneficial agents are well known in the art. Dispensing systems which deliver their contents by diffusion through a permeable polymer coating or wall are well known but suffer from severe limitations. For example, many pharmaceutically beneficial agents cannot be delivered from such diffusion controlled devices. In many instances permeation rates through the permeable polymer coating are inadequate to provide useful concentrations of the beneficial agent. In many others, the beneficial agent has such a high molecular weight that it will not diffuse through the polymer coating.
Also well known are delivery systems which operate by means of an osmotic pumping mechanism. In a typical delivery system of this type the beneficial agent is contained within a continuous, semipermeable film, e.g. a capsule or a film coating, having a hole of predetermined size drilled therethrough. In operation the delivery system is placed in the appropriate aqueous environment, e.g. the stomach or cul-de-sac of the eye, whereupon it .[.imbides.]. .Iadd.imbibes .Iaddend.water through the semi-permeable film, thereby dissolving at least in part the contents of the delivery system. This causes an increase in the internal (osmotic) pressure, which results in dissolved contents being continuously pumped out of the delivery system through the hole at a controlled rate over a predetermined period of time.
The devices taught in the art have a number of deficiencies. They are, in most case, complex devices having multiple parts or requiring special fabrication steps. For example, many require the drilling of a hole through the film coating of each device. Consequently, the delivery system itself is relatively expensive to fabricate and contributes substantially to the final cost of the product.
Prior art devices each having a single passageway through which their dissolved contents are delivered have other advantages. When the beneficial agent contained and delivered by such a device is irritating to the biological tissue in the region in which the device is used, local tissue irritation could be a problem at the locus of delivery of the agent, i.e. in the vicinity of the hole through which the concentrated agent is pumped.
Alternatives to drilling individual holes through the semipermeable film have been disclosed. For example, the use of a friable, inexpandable wall has been described which fractures when it .[.imbides.]. .Iadd.imbibes .Iaddend.water to provide cracks and fissures through which the contents are then delivered. Passageways provided by erosion of bioerodible fibers incorporated in the wall of the delivery device have also been described.
There is a very large body of art describing the various delivery systems. The U.S. patents below are cited as representative of the controlled delivery system art: U.S. Pat. Nos. 3,845,770; 3,916,899; 4,016,880; 4,160,452 and 4,200,098.
The present invention provides a method and means for dispensing in a controlled, continuous manner therapeutically effective amounts of water-soluble drugs for a predetermined period of time to achieve a predetermined useful effect in animals, especially mammals, including in particular human beings. In one aspect a core comprising the desired water-soluble beneficial agent together with any desired excipient(s) including osmotic enhancing agents is film coated with a solution of a water-insoluble, water-permeable polymer, a water-permeability-modifying agent (if desired) and a water-soluble, polymer-solvent-insoluble, particulate, pore-forming material.
When the pore-forming material is soluble in the solvent used to dissolve the polymer, it can be suspended in a pore-forming material non-solvent which is compatible with the polymer solution. The polymer solution and the pore-forming material suspension can then be separately but simultaneously applied, as by spray coating in a pan coater or fluidized bed.
In another aspect of the present invention there is provided a method of simply and reproducibly mass producing osmotically driven, controlled release devices for dispensing water-soluble beneficial agents.
It is contemplated that the controlled release device of the present invention also has utility in non-animal environments such as in agriculture (e.g., for the controlled delivery of fertilizers, soil trace minerals or elements, fungicides, herbicides and the like) or other environments in which it would come into contact with water from time to time or continuously.
When the device of the present invention is used, e.g., by oral administration to a human being, it comes into contact with an aqueous environment. Water is .[.imbided.]. .Iadd.imbibed .Iaddend.through the semi-permeable film coating, in the process leaching out the water-soluble particles in the film coating. The .[.imbided.]. .Iadd.imbibed .Iaddend.water dissolves the water-soluble beneficial agent as well as osmotic enhancing agents present. This sets up the osmotic gradient which actively brings in water through the semi-permeable membrane thereby increasing the pressure inside the device, resulting in the saturated (or partially saturated) solution of the beneficial agent being pumped out through the micropassageways created by the water dissolving the pore-forming, water soluble particles imbedded in the film coating of the device.
The drawings are not drawn to scale. They are set forth to illustrate the invention, and are as follows:
FIG. 1 is a view of a controlled release tablet for the delivery of a beneficial agent;
FIG. 2(a) is a sectional view taken along line 2--2 schematically illustrating the functional structure of the tablet as manufactured, i.e. before use; and
FIG. 2(b) is the same sectional view as depicted in FIG. 2(a) schematically illustrating the functional structure of the tablet after the pore-forming material has been dissolved during use.
In the drawings and specification, like parts are identified by like numbers.
The drawings illustrated here are intended to schematically represent the controlled delivery device of the invention and are not to be considered limiting. FIG. 1 represents one example of the delivery device, indicated by the numeral 10, a tablet for oral administration to an animal.
In FIG. 2(a) the tablet 10 of FIG. 1 is depicted in cross-section illustrating the structure of the tablet as manufactured. Tablet 10 comprises a water-permeable, water-insoluble film coating 11 which may contain in the film coating plasticizers and/or water-permeability-modifying agents and which has dispersed therein particulate, pore-forming material 12 and 13. The individual particles of pore-forming material 12 are in substantial contact with one another across the thickness of film 11 and, when the tablet 10 is used for its intended use, are dissolved out to form the pores 15 therethrough as shown in FIG. 2(b). The individual particles of pore-forming material 13 are not in contact with one another across the thickness of film 11 and, when the tablet 10 is used, do not form pores through film 11. The film coating 11 encompasses a core 14 which comprises at least one water-soluble beneficial agent. Core 14 may contain other desired excipients including osmotic enhancing agents when it is desired to increase the osmotic pressure developed within the tablet 10 when in use.
FIG. 2(b) depicts the same cross-section as shown in FIG. 2(a) after sufficient exposure to its environment of use to dissolve the pore-former particles.
The novel controlled delivery device of the present invention is simple in construction, permitting efficient mass production by conventional techniques. It is simple in operation, being no more complex to use than a conventional tablet or capsule.
Water-insoluble, water-permeable polymers suitable for forming the film coating of the device of the present invention include homopolymers and copolymers which are semipermeable. By semipermeable is herein meant permeable to solvent but not to solute, i.e., permeable to water but not permeable to the beneficial agent or osmotic enhancing agent dissolved therein. Suitable polymeric materials include cellulose esters such as mono-, di- and triacylates including mixed esters, cellulose ethers such as ethyl cellulose, nylons, polycarbonates, poly(dialkylsiloxanes), poly(methacrylic acid) esters, poly(acrylic acid) esters, poly(phenylene oxides), poly(vinyl alcohols), aromatic nitrogen-containing polymers, polymeric epoxides, regenerated cellulose and other membrane-forming material suitable for use in reverse osmosis or dialysis application. Some examples of such suitable film-forming materials include cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate, cellulose tripropionate, ethyl cellulose, nylon 6 and the like. The film coating, in addition to being semipermeable, must not adversely affect the beneficial agent or the animal receiving the device. The thickness of the film coating is desirably 10 to 500 μm, preferably 25 to 250 μm.
Plasticizers may be used in the semipermeable polymeric film coating of the present invention. Typical plasticizers which may be used include esters such as the phthalates, phosphates, citrates, adipates, tartrates, sebacates, succinates, glycolates, glycerolates, benzoates and myristates, sulfonamides and the like. Specific examples include dimethyl phthalate, dipropyl phthalate, di-(2-ethylhexyl) phthalate, tributyl phosphate, triacetyl phosphate, and tributyl citrate. The plasticizer must be compatible with the other materials of the film coating. It should also have a high degree of permanence, i.e., it should remain in the polymeric film and not migrate to the surface to an appreciable extent. It should also have no adverse effect on the beneficial agent or the animal receiving the device.
The term "water-permeability-modifying agent" as used herein means a compound or material which when added to the semipermeable film-forming material modifies the water permeability of the film produced therefrom, enhancing or increasing its permeability to water. Permeability-modifying agents include the poly(alkylene glycols), esters and polyesters of poly(alkylene glycols), polyhydric alcohols and esters and polyesters of polyhydric alcohols. Specific examples of suitable water-permeability-modifying agents include poly(ethylene glycols) 300, 400, 600, 1500 and 1540, poly(propylene glycol), 1,3-butyleneglycol, glycerine, ethylene glycol dipropionate, ethylene glycol butyrate and the like.
The pore-forming material must be particulate in nature, with a maximum particle size preferably not exceeding about 500 μm in its longest dimension and an average particle size from about 1 μm to about 300 μm, more preferably having an average particle size from 5 μm to about 100 μm. It must be soluble in water or aqueous media and insoluble in the organic solvent in which the polymeric film-forming material is dissolved during the film-coating process. Suitable pre-forming materials include the water-soluble sugars, e.g., lactose, sucrose, sorbitol and mannitol, and water-soluble salts, e.g., sodium carbonate, sodium chloride, calcium chloride, potassium chloride and sodium sulfate, and the like. When the device of this invention is intended for pharmaceutical use, the pore-forming material should be pharmaceutically acceptable. A portion of the beneficial agent may be used as the pore-forming material, and in certain formulations this may be preferred.
Osmotic enhancing agents are water-soluble materials having a high molar water solubility (high water solubility on a molar basis) which are capable of achieving in solution an osmotic pressure greater than that of the aqueous environment of the device of this invention when in use. Suitable osmotic enhancing agents include sugars, e.g. sucrose, lactose, fructose, mannitol and the like; salts, e.g., sodium chloride, potassium chloride, sodium carbonate and the like; as well as other water-soluble organic or inorganic compounds. When used in devices for human or veterinary use the osmotic enhancing agents should be pharmaceutically acceptable.
The delivery devices of the present invention are manufactured by standard techniques. In one embodiment tablets, which are suitable for oral administration to a mammal, containing the desired beneficial agent together with standard excipients as well as osmotic-enhancing agents, if desired, are prepared in a conventional manner. They are then coated with a controlled-porosity, water-permeable film by spraying for example in a rotating pan coater or fluidized-bed coater with a solution of the film-forming polymer, plasticizer (if desired) and permeability-modifying agent (if desired) containing the pore-forming material suspended therein until the desired film thickness is achieved.
Beneficial agents suitable for use in the devices of this invention must be water soluble and produce a beneficial effect when delivered from the device. Such beneficial agents include pharmaceutical agents for use in human and veterinary medicine, nutrients, pesticides, insecticides, fungicides, herbicides, algicides, vitamins, fertilizers, soil trace minerals or elements and the like. Specific examples include d-pseudoephedrine hydrochloride; bupropion hydrochloride; soluble potassium salts such as potassium chloride, potassium citrate, potassium gluconate, and the like; chlorpheniramine maleate; propranolol hydrochloride; cimetidine; phenylpropanolamine hydrochloride; dextromethorphan hydrobromide; ascorbic acid; aspirin; acetaminophen, codeine salts; methomyl, copper sulfate; ammonium nitrate and the like.
When used in human or veterinary medicine the devices of this invention may be administered in any appropriate manner. For example, administration by oral, subcutaneous implantation, suppository insertion, inter alia may be employed with these devices.
The following examples further illustrate but should not be construed as limiting the invention.
Tablets containing 100 mg bupropion hydrochloride and 500 mg lactose were prepared using a conventional table press. Fifty tablets were placed in a miniature pan coater. A polymer solution was prepared by dissolving cellulose acetate (CA 383-40 from Eastman Chemical Products, Inc., Kingsport, Tenn.) and poly(ethylene glycol) (Polyglycol E-400 from Dow Chemical Co., Midland Mich.) in acetone and adding impalpable lactose (particle size: 2-20 μmm) to give a mixture containing cellulose acetate:poly(ethylene glycol):lactose in the weight % ratio of 40:40:20 and a total solids content of 50 g/L. The polymer mixture was sprayed onto the tablets in the pan coater to give film-coated tablets having a film coating weighing 27 mg each when dried.
Drug release rates were determined for the tablets by placing them in simulated gastric buffer (pH 1.5) at 37° C. and periodically measuring the bupropion hydrochloride concentration in the buffer. After 2 hr., about 45% of the bupropion hydrochloride was released; after 4 hr., about 70%; and after 6 hr., about 90%.
Tablets containing 100 mg bupropion hydrochloride and 500 mg lactose were prepared using a conventional tablet press. Fifty tablets were placed in a miniature pan coater. A polymer solution was prepared by dissolving cellulose acetate (CA 383-40) and poly (ethylene glycol) (Polyglycol E-400) in acetone and adding impalpable lactose to give a mixture containing cellulose acetate:poly(ethylene glycol):lactose in the weight % ratio of 67:13:20 and a total solids content of 50 g/L. The polymer mixture was sprayed onto the tablets in the pan coater to give film-coated tablets having film coating weighing 35 mg each when dried.
Drug release rates were determined for the tablets by placing them in simulated gastric buffer (pH 1.5) at 37° C. and periodically measuring the bupropion hydrochloride concentration of the buffer. After 2 hr., about 10% of the bupropion hydrochloride was released; after 4 hr., about 25%; after 6 hr., about 40%; and after 8 hr., about 55%.
Tablets containing 120 mg d-pseudoephedrine hydrochloride, 5 mg tripolidine hydrochloride, 125 mg lactose, and 28 mg starch were prepared using a conventional tablet press. Fifty tablets were placed in a miniature pan coater. A polymer solution was prepared by dissolving cellulose acetate (CA 398-10 from Eastman Chemical Products., Inc., Kingsport, Tenn.) and poly (ethylene glycol) (Polyglycol E-400) in acetone and adding powdered sodium carbonate (particle size: 30-200 μm) to give a mixture containing cellulose acetate:poly(ethylene glycol):sodium carbonate in the weight % ratio of 40:40:20 and a total solids content of 50 g/L. The polymer mixture was sprayed onto the tablets in the pan coater to give film-coated tablets having a film coating weighing 64 mg each when dried.
Drug release rates were determined for the tablets by placing them in simulated gastric buffer (pH 1.5) at 37° C. and periodically measuring the drug concentration. After 1 hr., about 33% of the d-pseudoephedrine hydrochloride and 32% of the triprolidine hydrochloride was released; after 2 hr., about 53% of each drug was released; after 3 hr., about 71% and 74%, respectively; and after 4 hr., about 97% and 85%, respectively.
It will be appreciated from the foregoing that what we will claim may comprise any novel feature described herein, principally, but not exclusively, for example:
(a) A delivery system for the controlled release of a water-soluble beneficial agent comprising (i) a core containing said agent and (optionally) an osmotic enhancing agent and excipients, and (ii) encompassing said core a water-insoluble, water-permeable, polymeric film containing discrete, water-soluble, particles which during use of the system dissolve in the aqueous environment thereof to leave pores in said film, and (optionally) containing a water-permeability-enhancing amount of a water-permeability-modifying agent and a plasticizer;
(b) A method of preparing a device as defined in (a) above substantially as hereinbefore described:
(c) A method of delivering a water-soluble beneficial agent in a controlled, continuous manner using a device as defined in (a) above.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US2011587 *||Mar 24, 1934||Aug 20, 1935||Kelp Ol Lab Inc||Coating for medical compound|
|US2987445 *||Oct 10, 1958||Jun 6, 1961||Rohm & Haas||Drug composition|
|US3143463 *||Dec 21, 1959||Aug 4, 1964||Lundbeck & Co As H||1-(para-halophenyl)-2-loweralkyl-amino propane: weight reducing composition and method|
|US3146169 *||Jun 8, 1962||Aug 25, 1964||Burroughs Wellcome Co||Pharmaceutical formulations and their manufacture|
|US3538214 *||Apr 22, 1969||Nov 3, 1970||Merck & Co Inc||Controlled release medicinal tablets|
|US3773920 *||Jul 14, 1971||Nov 20, 1973||Nikken Chemicals Co Ltd||Sustained release medicinal composition|
|US3819706 *||Nov 30, 1970||Jun 25, 1974||Burroughs Wellcome Co||Meta chloro substituted-alpha-butylamino-propiophenones|
|US3885046 *||Aug 23, 1973||May 20, 1975||Burroughs Wellcome Co||Meta chloro or fluoro substituted alpha-T-butylaminopropionphenones in the treatment of depression|
|US4016880 *||Mar 4, 1976||Apr 12, 1977||Alza Corporation||Osmotically driven active agent dispenser|
|US4060598 *||Oct 28, 1975||Nov 29, 1977||Boehringer Mannheim G.M.B.H.||Tablets coated with aqueous resin dispersions|
|US4116241 *||Dec 15, 1976||Sep 26, 1978||Alza Corporation||Osmotic system with laminated wall comprising structurally different semipermeable lamina|
|US4135514 *||Mar 9, 1977||Jan 23, 1979||Alza Corporation||Osmotic releasing system for administering ophthalmic drug to eye of animal|
|US4173626 *||Dec 11, 1978||Nov 6, 1979||Merck & Co., Inc.||Sustained release indomethacin|
|US4256108 *||May 21, 1979||Mar 17, 1981||Alza Corporation||Microporous-semipermeable laminated osmotic system|
|US4309405 *||Jan 30, 1981||Jan 5, 1982||American Home Products Corporation||Sustained release pharmaceutical compositions|
|US4327725 *||Nov 25, 1980||May 4, 1982||Alza Corporation||Osmotic device with hydrogel driving member|
|US4347176 *||Apr 14, 1980||Aug 31, 1982||Burroughs Wellcome Co.||Compounds and methods of making same|
|US4347177 *||Apr 14, 1980||Aug 31, 1982||Burroughs Wellcome Co.||Compounds and methods of making them|
|US4347178 *||Apr 14, 1980||Aug 31, 1982||Burroughs Wellcome Co.||Compounds and methods of making|
|US4347257 *||Aug 11, 1980||Aug 31, 1982||Burroughs Wellcome Co.||Prolactin suppression in mammals|
|US4347382 *||Apr 15, 1980||Aug 31, 1982||Burroughs Wellcome Co.||3H Labeled compounds|
|US4355179 *||Apr 14, 1980||Oct 19, 1982||Burroughs Wellcome Co.||Radioactive nuclide labeled propiophenone compounds|
|US4356165 *||Apr 14, 1980||Oct 26, 1982||Burroughs Wellcome Co.||Bupropion radioimmunoassay, and kit|
|US4393078 *||Mar 15, 1982||Jul 12, 1983||Burroughs Wellcome Co.||Bupropion and ethanol|
|US4435449 *||Jul 6, 1982||Mar 6, 1984||Burroughs Wellcome Co.||Treatment of minimal brain dysfunction (MBD)|
|US4439194 *||Sep 8, 1981||Mar 27, 1984||Merck & Co., Inc.||Water and drug delivery system for suppository use|
|US4439196 *||Mar 18, 1982||Mar 27, 1984||Merck & Co., Inc.||Osmotic drug delivery system|
|US4507323 *||Jul 25, 1984||Mar 26, 1985||Burroughs Wellcome Co.||Treatment of psychosexual dysfunctions|
|US4519801 *||Jul 12, 1982||May 28, 1985||Alza Corporation||Osmotic device with wall comprising cellulose ether and permeability enhancer|
|US4539198 *||Jul 7, 1983||Sep 3, 1985||Rowell Laboratories, Inc.||Solid pharmaceutical formulations for slow, zero order release via controlled surface erosion: expanded range|
|US4557925 *||Sep 5, 1984||Dec 10, 1985||Ab Ferrosan||Membrane-coated sustained-release tablets and method|
|US4571395 *||Aug 24, 1984||Feb 18, 1986||Burroughs Wellcome Co.||Lorazepam and bupropion, compositions and methods|
|US4687660 *||Aug 15, 1984||Aug 18, 1987||Burroughs Wellcome Co.||Pharmaceutical delivery system|
|US4769027 *||Feb 24, 1987||Sep 6, 1988||Burroughs Wellcome Co.||Delivery system|
|US4798826 *||Nov 6, 1985||Jan 17, 1989||Burroughs Wellcome Co.||Benzodiazepine tranquilizer combinations and the use thereof|
|AT280478B *||Title not available|
|AT305498B *||Title not available|
|EP0086093A1 *||Feb 4, 1983||Aug 17, 1983||Ono Pharmaceutical Co., Ltd.||Long-lasting three layered pharmaceutical film preparations|
|EP0111144A1 *||Oct 31, 1983||Jun 20, 1984||Merrell Dow Pharmaceuticals Inc.||Sustained release solid dosage forms having non-uniform distribution of active ingredient|
|EP0159604A2 *||Apr 5, 1985||Oct 30, 1985||Toyo Boseki Kabushiki Kaisha||Sustained-release preparation applicable to mucous membrane in oral cavity|
|GB1326995A *||Title not available|
|GB2025227A *||Title not available|
|1||Asol & Hoover "Remington's Pharmaceutical Sciences," 15th edition, 1975, Mack Publishing Company, Easton, Pa., pp. 1608-1617.|
|2||*||Asol & Hoover Remington s Pharmaceutical Sciences, 15th edition, 1975, Mack Publishing Company, Easton, Pa., pp. 1608 1617.|
|3||*||Journal of Pharmaceutical Sciences, Jul. 1983, vol. 72, No. 7, pp. 772 775.|
|4||Journal of Pharmaceutical Sciences, Jul. 1983, vol. 72, No. 7, pp. 772-775.|
|5||Lieberman & Lachman "Pharmaceutical Dosage Forms: Tablets", vol. 3, 1982, Marcel Dekker, Inc. N.Y., N.Y., pp. 73-117.|
|6||*||Lieberman & Lachman Pharmaceutical Dosage Forms: Tablets , vol. 3, 1982, Marcel Dekker, Inc. N.Y., N.Y., pp. 73 117.|
|7||*||Webster s New Collegiate Dictionary, G. & C. Merriam Co., Springfield, Mass., U.S.A. 1956, p. 3.|
|8||*||Webster s New International Dictionary of the English Language, 2nd edition, Unabridged, G & C Merriam Company, Springfield, Mass., 1939, p. 2540.|
|9||*||Webster s Third New International Dictionary of the English Language Unabridged, G & C Merriam Company, Springfield, Mass., 1963, p. 2302.|
|10||Webster's New Collegiate Dictionary, G. & C. Merriam Co., Springfield, Mass., U.S.A. 1956, p. 3.|
|11||Webster's New International Dictionary of the English Language, 2nd edition, Unabridged, G & C Merriam Company, Springfield, Mass., 1939, p. 2540.|
|12||Webster's Third New International Dictionary of the English Language Unabridged, G & C Merriam Company, Springfield, Mass., 1963, p. 2302.|
|13||*||Wellbutrin: Comprehensive Bibliography of Published Literature Nov. 13, 1989, pp. 1 91.|
|14||Wellbutrin: Comprehensive Bibliography of Published Literature Nov. 13, 1989, pp. 1-91.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US5427798 *||Aug 12, 1993||Jun 27, 1995||Burroughs Wellcome Co.||Controlled sustained release tablets containing bupropion|
|US5541231 *||Aug 25, 1994||Jul 30, 1996||Glaxo Wellcome Inc.||Stabilized Pharmaceutical|
|US5731000 *||Jul 29, 1994||Mar 24, 1998||Glaxo Wellcome Inc.||Stabilized pharmaceutical composition containing bupropion|
|US5763493 *||Jun 21, 1996||Jun 9, 1998||Glaxo Wellcome Inc.||Stabilized pharmaceutical|
|US6110973||Jan 28, 1999||Aug 29, 2000||Sepracor||Methods for treating obesity and weight gain using optically pure (-)-bupropion|
|US6210716||Feb 26, 1999||Apr 3, 2001||Andrx Pharmaceuticals, Inc.||Controlled release bupropion formulation|
|US6221917||Dec 30, 1997||Apr 24, 2001||American Home Products Corporation||Pharmaceutical composition containing bupropion hydrochloride and a stabilizer|
|US6242496||Sep 28, 1999||Jun 5, 2001||American Home Products Corporation||Pharmaceutical composition containing bupropion hydrochloride and a stabilizer|
|US6277887||Apr 20, 2000||Aug 21, 2001||Sepracor, Inc.||Methods for treating Parkinson's disease using optically pure (−)-bupropion|
|US6280763||May 10, 1999||Aug 28, 2001||Pierce Management, Llc||Apparatus and method for transdermal delivery of bupropion|
|US6337328||Aug 18, 2000||Jan 8, 2002||Sepracor, Inc.||Bupropion metabolites and methods of use|
|US6342496||Feb 22, 2000||Jan 29, 2002||Sepracor Inc.||Bupropion metabolites and methods of use|
|US6369113||Jun 27, 2001||Apr 9, 2002||Sepracor, Inc.||Method for treating depression using optically pure (−)-bupropion|
|US6451860||Feb 19, 2002||Sep 17, 2002||Sepracor, Inc.||Methods for treating depression and other disorders using optically pure (−)-bupropion|
|US6458374||Jan 28, 1999||Oct 1, 2002||Sepracor, Inc.||Methods and compositions for treating chronic disorders using optically pure (+)-bupropion|
|US6482987||Apr 2, 2001||Nov 19, 2002||Clonmel Healthcare, Ltd.||Pharmaceutical composition containing bupropion hydrochloride and a stabilizer|
|US6495605||Mar 13, 2001||Dec 17, 2002||Sepracor Inc.||Methods and compositions for aiding in smoking cessation and for treating pain and other disorders using optically pure (+)-bupropion|
|US6734213||May 17, 2002||May 11, 2004||Smithkline Beecham Corporation||Pharmaceutically active morpholinol|
|US6855820||May 17, 2002||Feb 15, 2005||Smithkline Beecham Corporation||Pharmaceutically active morpholinol|
|US6899896||Dec 20, 2000||May 31, 2005||Pfizer Inc||Hydrogel-driven layered drug dosage form|
|US6905708||May 9, 2003||Jun 14, 2005||Andrx Pharmaceuticals, Inc.||Controlled release oral dosage form|
|US6998400||May 17, 2002||Feb 14, 2006||Smithkline Beecham Corporation||Pharmaceutically active morpholinol|
|US7098206||May 17, 2002||Aug 29, 2006||Smithkline Beecham Corporation||Pharmaceutically active morpholinol|
|US7241805||Jun 27, 2006||Jul 10, 2007||Biovail Laboratories, Inc.||Modified release formulations of a bupropion salt|
|US7537784||Jun 13, 2006||May 26, 2009||Biovail Laboratories International Srl||Modified release tablet of bupropion hydrochloride|
|US7569605||Oct 16, 2006||Aug 4, 2009||Forest Laboratories Holdings Limited||Methods of treating central nervous system disorders with a low dose combination of escitalopram and bupropion|
|US7674479||Jul 25, 2007||Mar 9, 2010||Intelgenx Corp.||Sustained-release bupropion and bupropion/mecamylamine tablets|
|US7767789||Jun 2, 2006||Aug 3, 2010||University Hopitals of Cleveland||Truncated proteins as cancer markers|
|US7771750||Mar 1, 2005||Aug 10, 2010||Andrx Pharmaceuticals, Llc||Controlled release oral dosage form|
|US7884136||Jun 27, 2006||Feb 8, 2011||Biovail Laboratories International S.R.L.||Modified-release formulations of a bupropion salt|
|US8518652||Apr 28, 2010||Aug 27, 2013||Uniformed Services University of the Health Sciences, an Institution of Higher Learning within the Department of Defense.||Truncated proteins as cancer markers|
|US8545880 *||Feb 8, 2002||Oct 1, 2013||Andrx Pharmaceuticals, Llc||Controlled release oral dosage form|
|US8703191||Jul 25, 2007||Apr 22, 2014||Intelgenx Corp.||Controlled-release pharmaceutical tablets|
|US8747898||Jul 14, 2010||Jun 10, 2014||Andrx Pharmaceuticals, Llc||Controlled release oral dosage form|
|US8932628||Jun 13, 2007||Jan 13, 2015||Valeant International Bermuda||Modified release formulations of a bupropion salt|
|US20020052340 *||Nov 16, 2001||May 2, 2002||Jerussi Thomas P.||Bupropion metabolites and methods of their synthesis and use|
|US20030022942 *||Jul 26, 2002||Jan 30, 2003||Sepracor, Inc.||Methods and compositions for treating depression and other disorders using optically pure (-)-bupropion|
|US20030032643 *||May 17, 2002||Feb 13, 2003||Ascher John A.||Pharmaceutically active morpholinol|
|US20030134906 *||May 31, 2002||Jul 17, 2003||Valpharma S.A.||Modified release pharmaceutical composition containing bupropion HCI as active substance|
|US20030161874 *||Feb 8, 2002||Aug 28, 2003||Boyong Li||Controlled release oral dosage form|
|US20050096311 *||Oct 30, 2003||May 5, 2005||Cns Response||Compositions and methods for treatment of nervous system disorders|
|US20050118286 *||Oct 22, 2004||Jun 2, 2005||Cns Response||Compositions and methods for treatment of nervous system disorders|
|US20050147678 *||Mar 1, 2005||Jul 7, 2005||Boyong Li||Controlled release oral dosage form|
|US20050238718 *||Aug 8, 2003||Oct 27, 2005||Werner Oberegger||Modified-release tablet of bupropion hydrochloride|
|US20060058300 *||Oct 20, 2005||Mar 16, 2006||Sepracor Inc.||Intermediates of bupropion metabolites synthesis|
|US20060189612 *||Apr 20, 2006||Aug 24, 2006||Smithkline Beecham Corporation||Pharmaceutically active morpholinol|
|US20060228415 *||Jun 13, 2006||Oct 12, 2006||Biovail Laboratories International S.R.L.||Modified release tablet of bupropion hydrochloride|
|US20070020706 *||Jun 2, 2006||Jan 25, 2007||University Hospitals Of Cleveland||Truncated proteins as cancer markers|
|US20070112075 *||Oct 16, 2006||May 17, 2007||Forest Laboratories, Inc.||Stable pharmaceutical formulations containing escitalopram and bupropion|
|US20080026060 *||Jul 25, 2007||Jan 31, 2008||Zerbe Horst G||Controlled-release pharmaceutical tablets|
|US20080031948 *||Jul 25, 2007||Feb 7, 2008||Zerbe Horst G||Sustained-release bupropion and bupropion/mecamylamine tablets|
|US20080038348 *||Jun 13, 2007||Feb 14, 2008||Bioavail Laboratories International S.R.L.||Modified release formulations of a bupropion salt|
|EP2266590A2||Feb 24, 2003||Dec 29, 2010||Shire LLC||Active agent delivery sytems and methods for protecting and administering active agents|
|EP2316468A1||Feb 24, 2003||May 4, 2011||Shire LLC||Delivery system and methods for protecting and administering dextroamphetamine|
|EP2316469A1||Feb 24, 2003||May 4, 2011||Shire LLC||Delivery system and methods for protecting and administering dextroamphetamine|
|WO1994004138A1 *||Aug 13, 1993||Mar 3, 1994||Wellcome Found||Sustained release tablets containing bupropion|
|WO1995003791A1 *||Jul 29, 1994||Feb 9, 1995||Sanyasi Raju Kalidindi||Stabilized pharmaceutical composition containing bupropion|
|U.S. Classification||424/465, 514/964, 604/892.1, 604/890.1, 424/469, 424/468, 424/473|
|International Classification||A61K31/135, A61K9/28|
|Cooperative Classification||A61K9/2853, A61K31/135|
|Apr 16, 1990||AS||Assignment|
Owner name: THIOKOL CORPORATION, A CORP. OF DE, UTAH
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:CHI, MINN-SHONG;REEL/FRAME:005274/0292
Effective date: 19890828
|Jan 30, 1995||FPAY||Fee payment|
Year of fee payment: 8
|Feb 9, 1999||FPAY||Fee payment|
Year of fee payment: 12
|Jun 29, 2001||AS||Assignment|
|Jul 3, 2001||AS||Assignment|