US3039933A - Ethyl cellulose-polyethylene glycol tablet matrix - Google Patents

Ethyl cellulose-polyethylene glycol tablet matrix Download PDF

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US3039933A
US3039933A US68840357A US3039933A US 3039933 A US3039933 A US 3039933A US 68840357 A US68840357 A US 68840357A US 3039933 A US3039933 A US 3039933A
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tablet
active
ingredient
solid
matrix
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Goldman Robert
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PREMO PHARMACEUTICAL LAB Inc
PREMO PHARMACEUTICAL LABORATORIES Inc
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PREMO PHARMACEUTICAL LAB Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats

Description

United States Patent Ofitice 3,939,933 Patented June 19, 1962 3,039,933 ETHYL CELLULOSE-POLYETHYLENE GLYCOL TABLET MATRIX Robert Goldman, Cresskill, N.J., assignor to Premo Pharmaceutical Laboratories, Inc., South Hackensack, NJ., a corporation of New Jersey No Drawing. Filed Oct. 7, 1957, Ser. No. 688,403 3 Claims. (Cl. 167-82) This invention relates to a tablet having a slow protracted medicinal effect and to a method of making the same.

More particularly, it is an object of my invention to provide a tablet and method of the character described which are such that the tablet after ingestion, i.e., after being swallowed, experiences a time-controlled slow disintegration, so that an active medicinal ingredient or ingredients uniformly and finely dispersed throughout the tablet is continually discharged for assimilation by the patient.

It is another object of my invention to provide a tablet and method of the character described which make the taking of medication more convenient.

It is another object of my invention to provide a tablet and method of the character described which are such that a single tablet taken in the morning, for example, will relieve the patient entirely of the necessity of carrying a supply of medication with him during the day and also of the necessity of remembering to take the medication at prescribed intervals.

It is another object of my invention to provide a tablet and method of the character described which will provide a more uniform therapeutic response than can be achieved with doses taken at intervals. Customarily, medication is taken at widely spaced times and this results in an intermittent response characterized by an increase in intensity of action each time the medication is taken followed by a falling off of action after each dose. In accordance with the present invention, however, this is avoided, and the action of the tablet is more uniform.

It is another object of my invention to provide a tablet and method of the character described which will reduce the manufacturers costs and will enable any kind of active ingredient to be used therewith.

It is another object of my invention to provide a tablet and method of the character described which lend themselves to manufacture by comparatively unskilled labor and which do not require the use of special equipment.

It has been proposed heretofore to provide medication having an extended effective period although taken at a single dose. Such medication constituted many individual small particles of an active ingredient which were covered with coatings requiring different times for dissolution, so that after ingestion of a large number of mixed particles of such character, the release of medication was extended over a period of time determined by the varying times necessary for the different coatings to dissolve. However, such medication customarily had different rates of release time depending on the pH of the site in which it would dissolve.

It is another object of my invention to provide a tablet and method of the character described which avoid the drawback that just has been mentioned.

Other objects of my invention in part will be obvious and in part will be pointed out hereinafter.

My invention accordingly consists in the combinations of compositions and series of steps which will be exemplified in the tablets and methods hereinafter described and of which the scope of application will be indicated in the appended claims.

A medicated tablet conventionally constitutes a solid carrier and a medically active ingredient hereinafter sim ply referred to as an active ingredient. The solid carrier ordinarily is inert, that is to say, it usually has no medical function, simply serving as a diluent. It is nontoxic, tasteless and bland, and lends itself to tableting, this being a standard operation in which a mass of particles of a solid carrier and active ingredient are compacted in a die under pressure.

The present invention distinguishes from conventional tableting only in that a different and special solid carrier is used. In all other respects, that is to say, in the mixing together of the solid carrier and active ingredient or ingredients, and in the tableting operation itself, standard practice is followed.

Essentially, my invention consists in the provision of a solid carrier which constitutes a homogeneous matrix consisting of a water-soluble material intimately, extensively, finely and thoroughly dispersed in a water-insoluble material, the active ingredient being finely, intimately, extensively and thoroughly dispersed in the matrix itself. Desirably, the two constituents of the matrix are in solid solution with one another. It is highly preferred, moreover, for the matrix to have waxy physical characteristics, so that the particles thereof have excellent coherency, thus enabling the tablet to maintain its shape, and, furthermore, permitting the tablet to slip off, i.e., readily release, from the tableting dies.

In the preferred form of my invention the water-soluble ingredient of the matrix constitutes polyethylene glycol or a water-soluble fatty acid ester thereof both of these being waxy, and the water-insoluble ingredient is ethyl cellulose.

I have found that any of the commercially available polyethylene glycols are suitable for the purposes of my invention and prefer particularly to use polyethylene glycols or the specified derivatives thereof) having an average molecular weight of between 1,000 and 20,000. A suitable water-soluble fatty acid ester of polyethylene glycol is a mono or di stearate of polyethylene glycol wherein the molecular weight of the polyethylene glycol is about 6,000.

Any of the commercially available ethyl celluloses can be used which have an ethyoxyl content of from 2.2 to 2.6 ethyoxyl groups per anhydroglucose unit. The number of such anhydroglucose units in a chain, that is to say, the molecular Weight, has no noticeable effect on the operation of my invention, and I have found that both high and low viscosity types of ethyl cellulose work equally well.

The first step in the operation of my invention is to prepare a base matrix mixture for the tablet. One satisfactory method of making the same is to dissolve the water-soluble and water-insoluble ingredients in a mutual volatile organic solvent, and then to evaporate the solvent so as to obtain a single homogeneous solid. In this solid the two materials, i.e., the water-soluble and the water-insoluble constituents, will be intimately, finely, extensively and thoroughly dispersed in one another. Thereafter, this homogeneous solid is milled, that is to say, reduced to fine particles, e.g., 20 mesh. At this stage, the matrix material is ready for mixing with the active ingredients and tableting. It can be stored for as long as desired and is at all times immediately available for incorporation in a tablet.

To make a tablet out of this material, the same is mixed with an active ingredient in any desired proportions, depending upon the desired rate of release and the desired amount of medication. Preferably, the amount of active ingredient does not exceed 40% by weight of the tablet and in no case should it exceed by weight. The mixing can be accomplished in conventional blenders and mixers, such as are presently employed in phar- 3 mac eutical houses. Thereafter, the mixture of the matrix material and the active ingredient are tableted in a known manner, i.e., between dies and under pressure. In the finished tablet, the active ingredient will be found to be finely, intimately, extensively and thoroughly dispersed through the matrix.

An example of the foregoing method consists in dissolving two pounds of polyethylene glycol (molecular weight of 6,000) with one pound of ethyl cellulose (2.42 to 2.53 ethyoxyl groups per anhydroglucose unit, the viscosity being 4 centipoises when determined in 5% concentration, using 80% toluene and 20% methanol as a solvent) in three gallons of methanol at room temperature. The solution then is evaporated in a vacuum drier at any suitable temperature in order to recover the methanol for reuse. If recovery is not desired, the solvent can be evaporated into the atmosphere at room temperature. The resulting homogeneous solid then is milled to a fineness of about 20 mesh.

An alternate method of making the matrix material is to heat the polyethylene glycol or the water-soluble fatty acid ester thereof so as to melt the same, and then to dissolve the ethyl cellulose in the now liquid material. The temperature employed for melting is a few degrees, a minimum of 5 C., above the melting temperature for the polyethylene glycol or its derivative, e.g., about 60 C. When the ethyl cellulose is completely dissolved and, preferably, after the mix is stirred, it is permitted to solidify by cooling, and it will be found that at such time the two materials are as finely, thoroughly, intimately and uniformly dispersed in one another as in the first method above described. Thereafter, the solid is milled and used in the manner already set forth.

-A tablet prepared in accordance with the foregoing invention Will, when ingested, be exposed to the fluids present in the alimentary canal. These are water based and, therefore, at the solid-liquid interface of the tablet and alimentary fluid a disintegrative process will be started by solution or dispersion of the water-soluble material, and also a release, therefore, of the water-insoluble material in the matrix. This will set free as much active ingredient as previously had been bound into the tablet by that amount of the water-soluble and waterinsoluble materials that have left the surface of the tablet. In other words, as the surface of the tablet gradually is disintegrated by the water present in the alimentary systern, the active ingredient content will be released into the system for assimilation thereby.

It is pointed out that the rate of disintegration of the tablet and, therefore, the rate of release of the active ingredient, can be varied by varying the composition of the matrix and, in general, the greater the percentage of water-soluble material present, the more rapid will be the rate of release and vice versa. I have found it quite simple to prepare matrices of different compositions which will give times of disintegration ranging from one hour to twenty-four hours for a single conventionally-sized tablet. As an example, a diameter tablet with oval sides containing five grains of matrix consisting of 55% ethyl cellulose and 45% polyethylene glycol, with a molecular weight of 6,000, prepared at a typical tableting compression force of 35 tons per square inch, will slowly disintegrate over a period of about four hours, it being then fully disintegrated. By varying the proportions to 50% ethyl cellulose and 50% polyethylene glycol (molecular weight 6,000), the time required for complete slow disintegration is about 2 hours. Conversely, by changing the amount of ethyl cellulose to 60% and the amount of polyethylene glycol of the same molecular weight to 40%, the time for complete slow disintegration is about 6 hours. If the amount of ethyl cellulose is 65% and that of polyethylene glycol is 35%, the time for complete slow disintegration is about 9 hours.

It also will be appreciated that the time span of dis integration may be extended or shortened bymaking the 4 weight of the tablet larger or smaller as the case may be, or by changing the shape of the tablet, the disintegration time being a function of the ratio of surface area to volume. t

It further will be appreciated that any known type of active ingredient can be utilized, examples thereof being: racemic amphetamine sulfate, dextroarn-phetamine sulfate, erythrityltetranitrate, digitoxin, acetyl salicylic acid, sodium penicillin, dihydrostreptomycin, pentobarbital, tolbutamide, aminophylline, antazoline hydrochloride, pyrilamine 'maleate, alkaloids of belladonna, bethanecholchloride, caffeine, codeine sulfate, morphine sulfate, colchicine, cortisone, meprobamate, tolazoline hydrochloride, reserpine, quinidine sulfate, quinine sulfate, pilocarpine hydrochloride progestrone, dienestrol, diethyl carbamazine citrate, ephedrine sulfate, ergonovine meleate, ethisterone, predisone, isoniazid, mercurophylline, methyltestosterone, propylthiouracil, and neostigmine bromide. The foregoing, before incorporation into the tablet, are powders. However, it even is within the scope of my invention to utilize liquid active ingredients, e.g., nitroglycerine, provided that the same are present in sufficiently small proportions to permit tableting.

As noted above, I prefer not to have the amount of active ingredient exceed by Weight of the tablet. However, this percentage can be made as small as is wanted, depending, as Will be appreciated, upon the desired rate of release of the active ingredient and the total amount present in any one tablet.

It also will be appreciated that the active ingredient may itself be carried in an inert base, particularly when very tiny amounts thereof are to be utilized, or when the active ingredient normally is supplied in such manner by chemical and pharmaceutical manufacturing concerns.

A typical example of a tablet embodying my invention is 5 mgs. of dextroamphetamine sulfate together sufficient of the matrix to make up 5 grains (325 mgs.), the matrix consisting of 65 by weight of ethyl cellulose and 35% by weight of polyethylene glycol. The tablet is compressed at 35 tons per square inch and has a diameter of A; of an inch.

Another example is a tablet of the same weight, 5 grains, the same size, and similar compression, containiug mgs. of pyrilamine maleate together with a suflicient quantity of the same matrix as used in example 1 to make up the 5 grain-s.

Still another example is a tablet of the same size, weight and compression, containing 2 mgs. of dienestrol together with enough of the same matrix to make up 5 grains.

A further example is a tablet of the same weight, size and compression, containing 0.5 mg. of reserpine together with enough of the matrix to make up to 5 grains.

Still another example is a tablet containing 200 mgs. of quinidine sulfate together with enough of the same matrix to make up an 8 grain tablet. Due to the size of the tablet, the same is /2 inch in diameter and is compressed to the same extent as aforesaid.

The matrix materials of my invention not only are non-toxic, bland, inert, palatable, and ingestible in the human system without any ill effects, but they can be stored for protracted periods of time without experiencing any chemical or physical deterioration.

Because the release of the active ingredient takes place by solution or dispersion at the surface of the tablet, and because the surface initially is largest directly following ingestion, the initial release of active ingredient is the fastest, and thereafter the rate of release gradually decreases. This is particularly desirable because it enables a rapid achievement of a therapeutic level of medication to be obtained, followed by a slowly decreasing rate of release which approximates the rate at which the body eliminates the medication.

It will be apparent that my novel matrix can be incorporated in standard tableting procedures without requiring the skilled help and special machinery that are necessary in varying the coatings on particles of active material, and that with very little additional expense, I can prepare a single tablet that, although taken only once a day, will give a steady substantially uniform release of active material for a rather long period of time. In addition to the foregoing, due to the fact that the disintegration of the tablet employing my new matrix is achieved by exposure to a water based liquid, the disintegration is substantially unaffected by the pH of such liquid. Thus, despite the fact that the tablet may be traversing almost the entire length of the alimentary canal, the rate of release of the medicament will not vary. In this respect the tablet differs from some conventional tablet-s which are specially coated to provide release only in regions of certain pHs and which, after they travel past such regions, will have no beneficial effect. However, it will be understood that, if desired, a tablet embodying my invention can be coated to prevent release of medicament initially and to permit start of release only at some certain part of the alimentary canal.

It thus will be seen that I have provided tablets and methods of making the same which achieve the various objects of my invention and are well adapted to meet the conditions of practical use.

As various possible embodiments might be made of the above invention and as various changes might be made in the embodiments above set forth, it is to be understood that all matter herein described is to be interpreted as illustrative and not in a limiting sense.

Having thus described my invention, I claim as new and desire to secure by Letters Patent:

1. A solid compressed tablet having a slow protracted medicinal effect, said tablet consisting of a matrix and an active ingredient, said matrix essentially constituting a solid solution of solid ethyl cellulose in a solid material selected from the class consisting of polyethylene glycol and water-soluble mono and di fatty acid esters thereof, said active ingredient being intimately, finely, extensively and thoroughly dispersed throughout said matrix, whereby when the tablet is ingested, the water based liquids in the alimentary canal will form a liquid-solid interface, with the surface of the tablet, whereupon the surface of the tablet will gradually be disintegrated by solution of the solid material selected from the class consisting of polyethylene glycol and water-soluble mono and di fatty acid esters thereof in the alimentary water-based liquids with the consequent release of the solid ethyl cellulose and of the active ingredient so that the tablet will slowly disintegrate at its surface to slowly and continually release the active ingredient at the said surface into the alimentary canal over a period of several hours and so that because the rate of release of the active ingredient is proportional to the surface area of the tablet and because the surface area of the tablet continually decreases in size the rate of release of the active ingredient slowly decreases.

2. A solid compressed tablet having a slow protracted medicinal effect, said tablet consisting of a matrix and an active ingredient, said matrix essentially constituting a solid mutual solution of solid polyethylene glycol having a molecular Weight of between 1,000 and 20,000 and solid ethyl cellulose having an ethyoxyl content of from 2.2 to 2.6 ethyoxyl groups per anhydroglucose unit, said active ingredient being intimately, finely, extensively and thoroughly dispersed throughout said matrix, whereby when the tablet is ingested, the water-based liquids in the alimentary canal will form a liquid-solid interface, with the surface of the tablet, whereupon the surface of the tablet will gradually be disintegrated by solution of the solid material selected from the class consisting of polyethylene glycol and water-soluble mono and di fatty acid esters thereof in the alimentary water-based liquids with the consequent release of the solid ethyl cellulose and of the active ingredient so that the tablet will' slowly disintegrate at its surface to slowly and continually release the active ingredient at the said surface into the alimentary canal over a period of several hours and so that because the rate of release of the active ingredient is proportional to the surface area of the tablet and because the surface area of the tablet continually decreases in size the rate of release of the active ingredient slowly decreases.

3. A solid compressed tablet having a slow protracted medicinal effect, said tablet consisting of a matrix and an active ingredient, said matrix essentially constituting a solid solution of a solid fatty acid ester of a polyethylene glycol having a molecular weight of between 1,000 and 20,000 and solid ethyl cellulose having an ethyoxyl content of from 2.2 to 2.6 ethyoxyl groups per anhydroglucose unit, said active ingredient being intimately, finely, extensively and thoroughly dispersed throughout said matrix, whereby when the tablet is ingested, the water-based liquids in the alimentary canal will form a liquid-solid interface, with the surface of the tablet, whereupon the surface of the tablet will gradually be disintegrated by solution of the solid material selected from the class consisting of polyethylene glycol and Water-soluble mono and di fatty acid esters thereof in the alimentary waterbased liquids with the consequent release of the solid ethyl cellulose and of the active ingredient so that the tablet will slowly disintegrate at its surface to slowly and continually release the active ingredient at the said surface into the alimentary canal over a period of several hours and so that because the rate of release of the active ingredient is proportional to the surface area of the tablet and because the surface area of the tablet continually decreases in size the rate of release of the active ingredient slowly decreases.

References Cited in the file of this patent UNITED STATES PATENTS 2,410,417 Andersen Nov. 5, 1946 2,550,622 Taub Apr. 24, 1951 2,736,682 Hermelin Feb. 28, 1956 2,791,530 Dallavis et a1. May 7, 1957 2,793,979 Svedres May 28, 1957 2,798,837 Sahyun July 9, 1957 2,805,977 Robinson Sept. 10, 1957 2,809,917 Hermelin Oct. 15, 1957 2,894,289 Harper et al. July 14, 1959 2,987,445 Levesque June 6, 1961 FOREIGN PATENTS 109,438 Australia Ian. 11, 1940 OTHER REFERENCES McClelland: Chemical and Engineering News, 23:3, February 10, 1945, page 249 relied upon.

Lesser: Drug and Cos. Ind., vol. 62, No. 6, June 1948, p. 752.

Miller: The Use of Polyethylene Glycol as a Binder in Tablet Compression, J.A.P.A Sci. Ed., vol. 43, No. 8, August 1954, pages 486-488.

Claims (1)

1. A SOLID COMPRESSED TABLET HAVING A SLOW PROTRACTED MEDICINAL EFFECT, SAID TABLET CONSISTING OF A MATRIX AND AN ACTIVE INGREDIENT, SAID MATRIX ESSENTIALLY CONSTITUTING A SOLID SOLUTION OF SOLID ETHYL CELLULOSE IN A SOLID MATERIAL SELECTED FROM THE CLASS CONSISTING OF POLYETHYLENE GLYCOL AND WATER-SOLUBLE MONO AND DI FATTY ACID ESTERS THEREOF, SAID ACTIVE INGREDIENT BEING INTIMATELY, FINELY, EXTENSIVELY AND THOROUGHLY DISPERSED THROUGHOUT SAID MATRIX, WHEREBY WHEN THE TABLET IS INGESTED, THE WATER BASED LIQUIDS IN THE ALIMENTARY CANAL WILL FORM A LIQUID-SOLID INTERFACE, WITH THE SURFACE OF THE TABLET, WHEREUPON THE SURFACE OF THE TABLET WILL GRADUALLY BE DISINTERGRATED BY SOLUTION OF THE SOLID MATERIAL SELECTED FROM THE CLASS CONSISTING OF POLYETHYLENE GLYCOL AND WATER-SOLUBLE MONO AND DI FATTY ACID ESTERS THEREOF IN THE ALIMENTARY WATER-BASED LIQUIDS WITH THE CONSEQUENT RELEASE OF THE SOLID ETHYL CELLULOSE AND OF THE ACTIVE INGREDIENT SO THANT THE TABLET WILL SLOWLY DISINTEGRATE AT ITS SURFACE TO SLOWLY AND CONTINUALLY RELEASE THE ACTIVE INGREDIENT AT THE SAID SURFACE INTO THE ALIMENTARY CANAL OVER A PERIOD OF SEVERAL HOURS AND SO THAT BECAUSE THE RATE OF RELEASE OF THE ACTIVE INGREDIENT IS PROPORTIONAL TO THE SURFACE AREA OF THE TABLET AND BECAUSE THE SURFACE AREA OF THE TABLET CONTINUALLY DECREASES IN SIZE THE RATE OF RELEASE OF THE ACTIVE INGREDIENT SLOWLY DECREASES.
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3096248A (en) * 1959-04-06 1963-07-02 Rexall Drug & Chemical Company Method of making an encapsulated tablet
US3371015A (en) * 1962-06-28 1968-02-27 Haessle Ab Pharmaceutical core compositions with thin rapidly disintegrating coatings
US3538214A (en) * 1969-04-22 1970-11-03 Merck & Co Inc Controlled release medicinal tablets
FR2035801A1 (en) * 1968-05-21 1970-12-24 American Home Prod
US3854480A (en) * 1969-04-01 1974-12-17 Alza Corp Drug-delivery system
US3909444A (en) * 1971-08-05 1975-09-30 Ncr Co Microcapsule
US3938515A (en) * 1971-12-20 1976-02-17 Alza Corporation Novel drug permeable wall
US4308251A (en) * 1980-01-11 1981-12-29 Boots Pharmaceuticals, Inc. Controlled release formulations of orally-active medicaments
GB2164556A (en) * 1983-04-09 1986-03-26 Nikken Chemicals Co Ltd Sustained release pharmaceutical tablet of theophylline and production process therefor
US4673527A (en) * 1985-05-20 1987-06-16 Autotrol Corporation Tablet granulation
US4704284A (en) * 1982-08-12 1987-11-03 Pfizer Inc. Long-acting matrix tablet formulations
US4764378A (en) * 1986-02-10 1988-08-16 Zetachron, Inc. Buccal drug dosage form
US4960765A (en) * 1980-03-20 1990-10-02 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
US4980173A (en) * 1980-03-20 1990-12-25 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
US5082655A (en) * 1984-07-23 1992-01-21 Zetachron, Inc. Pharmaceutical composition for drugs subject to supercooling
US20120058965A1 (en) * 2010-06-17 2012-03-08 Goddard Iii William A Methods and systems for modulating hormones and related methods, agents and compositions

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US2410417A (en) * 1944-03-04 1946-11-05 Lever Brothers Ltd Vitamin and mineral dietary supplement and method of making
US2550622A (en) * 1947-07-11 1951-04-24 Benjamin Clayton Ointment base and iodine ointment
US2736682A (en) * 1954-10-11 1956-02-28 Victor M Hermelin Method of making a prolonged action medicinal tablet
US2791530A (en) * 1953-08-31 1957-05-07 Abbott Lab Stabilized fumagillin compositions
US2793979A (en) * 1953-03-30 1957-05-28 Smith Kline French Lab Method of making a sustained release pharmaceutical tablet and product of the method
US2798837A (en) * 1952-11-20 1957-07-09 Sahyun Melville Achlorhydria composition
US2805977A (en) * 1955-01-04 1957-09-10 Smith Kline French Lab Sustained release pharmaceutical preparation
US2809917A (en) * 1955-10-17 1957-10-15 Victor M Hermelin Sustained release pharmaceutical tablets
US2894289A (en) * 1956-03-01 1959-07-14 Dow Chemical Co Method of making permeselective membranes
US2987445A (en) * 1958-10-10 1961-06-06 Rohm & Haas Drug composition

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2410417A (en) * 1944-03-04 1946-11-05 Lever Brothers Ltd Vitamin and mineral dietary supplement and method of making
US2550622A (en) * 1947-07-11 1951-04-24 Benjamin Clayton Ointment base and iodine ointment
US2798837A (en) * 1952-11-20 1957-07-09 Sahyun Melville Achlorhydria composition
US2793979A (en) * 1953-03-30 1957-05-28 Smith Kline French Lab Method of making a sustained release pharmaceutical tablet and product of the method
US2791530A (en) * 1953-08-31 1957-05-07 Abbott Lab Stabilized fumagillin compositions
US2736682A (en) * 1954-10-11 1956-02-28 Victor M Hermelin Method of making a prolonged action medicinal tablet
US2805977A (en) * 1955-01-04 1957-09-10 Smith Kline French Lab Sustained release pharmaceutical preparation
US2809917A (en) * 1955-10-17 1957-10-15 Victor M Hermelin Sustained release pharmaceutical tablets
US2894289A (en) * 1956-03-01 1959-07-14 Dow Chemical Co Method of making permeselective membranes
US2987445A (en) * 1958-10-10 1961-06-06 Rohm & Haas Drug composition

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3096248A (en) * 1959-04-06 1963-07-02 Rexall Drug & Chemical Company Method of making an encapsulated tablet
US3371015A (en) * 1962-06-28 1968-02-27 Haessle Ab Pharmaceutical core compositions with thin rapidly disintegrating coatings
FR2035801A1 (en) * 1968-05-21 1970-12-24 American Home Prod
US3854480A (en) * 1969-04-01 1974-12-17 Alza Corp Drug-delivery system
US3538214A (en) * 1969-04-22 1970-11-03 Merck & Co Inc Controlled release medicinal tablets
US3909444A (en) * 1971-08-05 1975-09-30 Ncr Co Microcapsule
US3938515A (en) * 1971-12-20 1976-02-17 Alza Corporation Novel drug permeable wall
US4308251A (en) * 1980-01-11 1981-12-29 Boots Pharmaceuticals, Inc. Controlled release formulations of orally-active medicaments
US5013727A (en) * 1980-03-20 1991-05-07 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
US4960765A (en) * 1980-03-20 1990-10-02 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
US4980173A (en) * 1980-03-20 1990-12-25 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
US4704284A (en) * 1982-08-12 1987-11-03 Pfizer Inc. Long-acting matrix tablet formulations
GB2164556A (en) * 1983-04-09 1986-03-26 Nikken Chemicals Co Ltd Sustained release pharmaceutical tablet of theophylline and production process therefor
US5082655A (en) * 1984-07-23 1992-01-21 Zetachron, Inc. Pharmaceutical composition for drugs subject to supercooling
US4673527A (en) * 1985-05-20 1987-06-16 Autotrol Corporation Tablet granulation
US4764378A (en) * 1986-02-10 1988-08-16 Zetachron, Inc. Buccal drug dosage form
US20120058965A1 (en) * 2010-06-17 2012-03-08 Goddard Iii William A Methods and systems for modulating hormones and related methods, agents and compositions
US8796233B2 (en) * 2010-06-17 2014-08-05 California Institute Of Technology Methods and systems for modulating hormones and related methods, agents and compositions

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