US2809917A - Sustained release pharmaceutical tablets - Google Patents
Sustained release pharmaceutical tablets Download PDFInfo
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- US2809917A US2809917A US541031A US54103155A US2809917A US 2809917 A US2809917 A US 2809917A US 541031 A US541031 A US 541031A US 54103155 A US54103155 A US 54103155A US 2809917 A US2809917 A US 2809917A
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
Definitions
- enteric coating is one which will resist the action of the gastric juices in the stomach and will not dissolve therein or be otherwise ailected thereby so that the drug which is incorporated in the tablet will pass through the stomach and into the intestine.
- enteric coating is of such a nature that it will be dissolved very readily in the intestinal fluids so that the drug which has been enclosed in the enteric coating will become eiiective in the intestinal tract rather than in the stomach.
- Such tablets are merely de layed action tablets.
- enteric coated tablet is also used when it is desirable to introduce the medicament into the patients intestinal tract without discharging any of the medicament into the stomach.
- enteric coatings are not particularly accurate and the enteric coatings now in use are not always completely reliable.
- enteric coatings using the in vitro method of Maney and Kuever have shown that most available enteric coatings dissolved to an appreciable extent in the gastric juices of the stomach or at least are attacked by such gastric juices to such an extent as to lose physical or structural strength, a factor which has been hitherto overlooked.
- peristalic action is severe enough to disrupt the physically weakened enteric coating and the drug or medicament enters the system with a surge, as has been discovered by blood level studies.
- enteric coatings however eflicient or inefficient they may be, merely withhold the medicament for some time-delay period and then release it to the patients system in the same surge dose as though the period of time delay had not occurred. In other words, the patient ultimately gets the surge.
- a pharmaceutical preparation adapted for sustained minute-incremental dosage can be made by intimately mixing various enteric water insoluble excipients, such as shellac, with powdered drugs to form a somewhat pasty mass which is then spread on drying trays and dried to produce a rough granular material.
- This granular material is crushed and remixed with the excipieat to form a pasty mass which is then spread on trays and dried again to form a rough granular material.
- This procedure of crushing, mixing with excipient, and traydrying is repeated a number of times and finally the end product is screened to produce a granule of substantially uniform size.
- the machine should also be provided with two conventional feeding hoppers located at spaced positions along the path of movement of the die plate.
- Each die-cavity is initially filled with a suitable quantity of the granules prepared as above described and the punch driven into the die recess to compress the granules.
- the punch upon being withdrawn, leaves the die-cavity about halffilled.
- a quantity of plain drug i. e. not formed into slow-release granules, is charged into the unfilled portion of the die-cavity.
- the punch is again driven into the diecavity, compressing the second filling and the whole tablet into a firm two-ply or laminated tablet.
- Example I 3 lbs. of dicalcium phosphate and 1 lb. d-amphetamine sulfate is mixed in the dry. To this mixture, wax-free shellac (3 lb. cut-U. S. P. grade) is slowly added with agitation and in sufficient amount to produce a pasty mass which is spread out on cloth drying trays and air dried for 7-10 hours. The resulting product, when removed from the drying trays, forms a free flowing granular mass in which the granules have an average size of wheat grains. These granules are then crushed to about the size of coarse sugar and again mixed with enough shellac (of the type above) until a pasty mass results.
- wax-free shellac 3 lb. cut-U. S. P. grade
- This mass is again placed on cloth drying trays and the above procedure repeated for a total of eleven times, using a total of about 1 gallon of shellac.
- the first four mixing-drying steps are repeated over a time cycle which involves about 7 to 10 hour drying periods and all subsequent mixing-drying steps include about to 22 hour drying periods. These time periods can be speeded up by placing the drying trays in a hot room.
- the hot room should be maintained at about 100 to 120 F. with a relative humidity not in excess of and the material dried until the granules are hard and frangible, that is to say, will form fine-grained particles upon crushing.
- Final yield' is approximately 15 .lbs. of granules of heterogeneous and irregular shapes.
- the granules are precisely uniform in constituency. In other words, any given weight of granules will be found to contain the same dosage of amphetamine. Of course, each batch should be assayed and the actual amphetamine content by weight or percentage determined. It has been found that by following a standardized manufacturing procedure, successive batches of granules have closely similar assays well within admissible limits of pharmaceutical accuracy. However, this is not overly important since the granules thus formed are measured into capsules or tableted by conventional procedure for administration to the patient and any variations in con 4 tent can be taken into account in making up the capsule or tablet.
- slow-release granules are then formed into a two-ply or laminated tablet with plain or untreated amphetamine sulfate in the initial-dosage portion as above described.
- Example II A dry mixture of 12 oz. d-amplretamin'e sulfate, 8 oz. secobarbital and 3 lbs. 8 oz'. dicalcium phosphate is taken up with shellac as per Example I employing approximately 1 gal. shellac in eleven successive mixing-drying steps. Yield approximately 16 lbs. of granules.
- slow-release granules are then formed into a two-ply or laminated tablet with plain or untreated amphetamine sulfate in the initial-dosage portion as above described.
- Example III A dry mixture of 2 lbs. pentobarbituric acid, 1 lb. phenobarbital and 6 oz. d-amphetamine sulfate, 3 lbs. dicalcium phosphate is taken up in shellac as per Example I employing nine successive mixing drying steps.
- slow release granules are then formed into a two-ply or laminated tablet with a plain or untreated mixture of pentobarbituric acid, d-amphetamine sulfate, and dicalcium phosphate in the above named proportions in the initial-dosage portion, as above described.
- liquid excipients such as a mixture of castor oil, stearic acid, and confectioners glaze (i. e. shellac) can be employed in practicing the herein described invention.
- a minimum of such steps is two and a practical maximum is fifteen, since additional mixing drying steps resulting in such a slow rate of drug absorption by the patient has been found to be impractical for presently known medical purposes.
- the method or" making a laminated tablet having a layer containing an immediate release medicated preparation and a layer containing a delayed release medicated preparation having a slow but continuous and attenuated solubility in the gastro-intestinal tract comprises intimately mixing a powdered drug and an enteric water insoluble excipient to produce a pasty mass, drying the mass slowly Without agitation in such a manner as to produce a rough granular material, breaking up the rough granular material by light crushing, whereby to reduce it to granular particles, said mixing, drying and crushing operations constituting one cycle, and remixing the granular particles with an additional quantity of the excipient to produce a pasty mass, redrying such pasty mass slowly and without agitation in such a manner as to produce a granular material, again breaking up the rough granular material by light crushing, whereby to reduce it again to granular particles, said second mixing,-drying and crushing operations constituting a second cycle, said process consisting of not less than three nor more
- enteric water insoluble excipient comprises a mixture of shellac and stearic acid.
- a pharmaceutical preparation comprising a single tablet having two laminated layers attached integrally to each other, one layer containing a medicated preparation in readily assimilable form for immediate release into a patients system and the other layer containing a medicated preparation having a slow but continuous and attenuated solubility in the gastro-intestinal tract, said last-mentioned preparation containing a solid mass of dry discrete granules, each said granule being made by intimately mixing a powdered drug and an enteric water insoluble excipient to produce a pasty mass, drying the mass slowly without agitation in such a manner as to produce a rough granular material, breaking up the rough granular material by light crushing, whereby to reduce it to granular particles, said mixing, drying and crushing operations constituting one cycle, and remixing the granular particles with an additional quantity of the excipient to produce a pasty mass, redrying such pasty mass slowly and without agitation in such a manner as to produce a granular material, again breaking up
- enteric water insoluble excipient comprises a mixture of shellac and stearic acid.
Description
SUSTAINED RELEASE PHARMACEUTECAL TABLETS Victor M. Hermelin, University City, Me.
No Drawing. Application October 17, 1955, Serial No. 541,031
6 Claims. (Cl. 167-82) This invention relates in general to certain new and useful improvements in pharmaceutical preparations and, more particularly, to medicated granules which release the medication into the human system gradually over a sustained period of time and methods of making the same. This application is a continuation-in-part of my copending application Serial No. 461,354, filed October 11, 1954, now Pat. No. 2,736,682, which is, in turn, a continuation of an earlier application Serial No. 195,369, filed November 13, 1950, now abandoned.
It has been accepted practice in the compounding of pharmaceutical tablets to provide certain types of tablets with what has been commonly referred to as anenteric coating. The enteric coating is one which will resist the action of the gastric juices in the stomach and will not dissolve therein or be otherwise ailected thereby so that the drug which is incorporated in the tablet will pass through the stomach and into the intestine. The so-called enteric coating is of such a nature that it will be dissolved very readily in the intestinal fluids so that the drug which has been enclosed in the enteric coating will become eiiective in the intestinal tract rather than in the stomach. Such tablets, however, are merely de layed action tablets. In other words, by selecting an enteric coating of the proper type-and by using an appropriate amount, it is possible to delay the eiiective entry of the drug into the patients system for a number of hours. The so-called enteric coated tablet is also used when it is desirable to introduce the medicament into the patients intestinal tract without discharging any of the medicament into the stomach. These procedures are useful in certain applications, but the patient sooner or later receives the entire dosage in a single shot, so to speak.
Recently, efforts have been made to provide delayed dosage by surrounding an enteric coated core with a second layer or group of layers of medicament and then, largely for appearance, covering the resulting tablet, ellipsoid or sphere with a soluble sugar coating. The theory is that the sugar coating and outer layers dissolve in the stomach and almost immediately release the initial dosage which lasts the patient for several hours. Whereupon, the enteric coated core has reached the intestinal tract and dissolves therein very rapidly, releasing the second dosage. Even if this theory were borne out in practice, the net result would merely be a spaced interval two shot medication which is very little diiferent in pathological effect from the simple business of giving the patient two smaller tablets at the same intervals. As a matter of fact, however, the existing methods of forming enteric coatings are not particularly accurate and the enteric coatings now in use are not always completely reliable. The research of Maney and Kuever (J. Am. Pharm. Soc. 30, 1941, p. 276), and of Abbott and Seeport (Pharm. J. 151, 1943, p. 52), suggests that various known enteric materials yield varying results and some such coatings seem to resist disintegration for periods up to five or six hours. Actual tests, with various. types of atent G ice enteric coatings using the in vitro method of Maney and Kuever have shown that most available enteric coatings dissolved to an appreciable extent in the gastric juices of the stomach or at least are attacked by such gastric juices to such an extent as to lose physical or structural strength, a factor which has been hitherto overlooked. In the stomach, peristalic action is severe enough to disrupt the physically weakened enteric coating and the drug or medicament enters the system with a surge, as has been discovered by blood level studies. The important point, however, is that enteric coatings, however eflicient or inefficient they may be, merely withhold the medicament for some time-delay period and then release it to the patients system in the same surge dose as though the period of time delay had not occurred. In other words, the patient ultimately gets the surge.
However, recent pharmacological investigations have shown that with many drugs the patient responds far better to sustained min'utedncremental dosage, that is to say, very minute quantities administered at very short intervals continuously over sustained periods of time. This can be referred to, for want of a better term, as the trickle system. Such procedures have been recognized for quite some time with respect to liquid medications such as the trickle treatment with penicillin for syphillis. The use of conventional enteric coated tablets, however, for the reason heretofore set out will not achieve even an approximation of sustained minute-incremental dosage.
it is the primary object of the present invention, therefore, to provide a pharmaceutical preparation having a unique and novel composition and structure, which, as a result of a drug or medicament, can be administered in a persistent sustained incremental dosage.
It is also an object of the present invention to provide a pharmaceutical preparation which is capable of maintaining a desired level of medication within the patients system over prolonged periods of time.
It is a further object of the present invention to provide a pharmaceutical preparation which has a unique and novel composition and structure, which is simple and precise in its action and which is economical to.
i produce.
It is also an object of the present invention to provide methods of making pharmaceutical preparations of the type stated.
With the above and other objects in view, my inven tion resides in the novel features of form, construction, arrangement, and combination of parts presently de scribed and pointed out in the claims.
Broadly speaking, the present invention resides in the discovery that a pharmaceutical preparation adapted for sustained minute-incremental dosage can be made by intimately mixing various enteric water insoluble excipients, such as shellac, with powdered drugs to form a somewhat pasty mass which is then spread on drying trays and dried to produce a rough granular material. This granular material is crushed and remixed with the excipieat to form a pasty mass which is then spread on trays and dried again to form a rough granular material. This procedure of crushing, mixing with excipient, and traydrying is repeated a number of times and finally the end product is screened to produce a granule of substantially uniform size. It has been found that the excipient and the medicament are intimately mixed or dispersed throughout the mass of each granule in the form of very minute particles. Visual examination of the granules under high-magnification shows that the surface thereof is not covered with a continuous film of the dried excipient or a continuous film of the medicament, but, rather, is dotted with minute particles of the dried excipient and minute particles of the medicament in a sort of heterogeneous arrangement. Furthermore, this general physical structure exists throughout the granule. By both in vitro t'sts and mead-level studies, it clearly appears that these granules, when in the human stomach and intestinal tract are neither soluble or insoluble in the strictest sense of these terms, but, instead, the medicament leaches out steadily in minute increments or doses, that is to say, is a sustained trickle.
This material, however, for many types of illnesses, may not release a sufficient amount of the drug or medicament initially to build up to the desired blood-level concentra'tion. Therefore, it is necessary to provide some means by which an initial surge does can be conveniently given. It has been found that this can be accomplished by forming a unique type of laminated tablet, that is to say, a tablet which in effect consists of two identically shaped cylindrical slugs adhered together in back-to-back relation. To make such a laminated tablet, a tableting machiire of conventional type is used having a series of die-cavities and reciprocating punches. The cams of the machine are set so that each punch will enter its companion die-cavity twice before the tablet is ejected. The machine should also be provided with two conventional feeding hoppers located at spaced positions along the path of movement of the die plate. Each die-cavity is initially filled with a suitable quantity of the granules prepared as above described and the punch driven into the die recess to compress the granules. The punch, upon being withdrawn, leaves the die-cavity about halffilled. Then a quantity of plain drug, i. e. not formed into slow-release granules, is charged into the unfilled portion of the die-cavity. The punch is again driven into the diecavity, compressing the second filling and the whole tablet into a firm two-ply or laminated tablet.
While this invention is not intended to be limited thereby, the following are examples of pharmaceutical preparations which can be made in accordance with the present invention:
Example I 3 lbs. of dicalcium phosphate and 1 lb. d-amphetamine sulfate is mixed in the dry. To this mixture, wax-free shellac (3 lb. cut-U. S. P. grade) is slowly added with agitation and in sufficient amount to produce a pasty mass which is spread out on cloth drying trays and air dried for 7-10 hours. The resulting product, when removed from the drying trays, forms a free flowing granular mass in which the granules have an average size of wheat grains. These granules are then crushed to about the size of coarse sugar and again mixed with enough shellac (of the type above) until a pasty mass results. This mass is again placed on cloth drying trays and the above procedure repeated for a total of eleven times, using a total of about 1 gallon of shellac. The first four mixing-drying steps are repeated over a time cycle which involves about 7 to 10 hour drying periods and all subsequent mixing-drying steps include about to 22 hour drying periods. These time periods can be speeded up by placing the drying trays in a hot room. The hot room should be maintained at about 100 to 120 F. with a relative humidity not in excess of and the material dried until the granules are hard and frangible, that is to say, will form fine-grained particles upon crushing. Final yield' is approximately 15 .lbs. of granules of heterogeneous and irregular shapes.
Upon assay, the granules are precisely uniform in constituency. In other words, any given weight of granules will be found to contain the same dosage of amphetamine. Of course, each batch should be assayed and the actual amphetamine content by weight or percentage determined. It has been found that by following a standardized manufacturing procedure, successive batches of granules have closely similar assays well within admissible limits of pharmaceutical accuracy. However, this is not overly important since the granules thus formed are measured into capsules or tableted by conventional procedure for administration to the patient and any variations in con 4 tent can be taken into account in making up the capsule or tablet.
These slow-release granules are then formed into a two-ply or laminated tablet with plain or untreated amphetamine sulfate in the initial-dosage portion as above described.
Example II A dry mixture of 12 oz. d-amplretamin'e sulfate, 8 oz. secobarbital and 3 lbs. 8 oz'. dicalcium phosphate is taken up with shellac as per Example I employing approximately 1 gal. shellac in eleven successive mixing-drying steps. Yield approximately 16 lbs. of granules.
These slow-release granules are then formed into a two-ply or laminated tablet with plain or untreated amphetamine sulfate in the initial-dosage portion as above described.
Example III A dry mixture of 2 lbs. pentobarbituric acid, 1 lb. phenobarbital and 6 oz. d-amphetamine sulfate, 3 lbs. dicalcium phosphate is taken up in shellac as per Example I employing nine successive mixing drying steps.
These slow release granules are then formed into a two-ply or laminated tablet with a plain or untreated mixture of pentobarbituric acid, d-amphetamine sulfate, and dicalcium phosphate in the above named proportions in the initial-dosage portion, as above described.
The above described procedure has been employed in making granules with a Wide variety of drugs or medicinals, such as, for instance, scopolamine, methyl bromide, pentaerythritol tetranitrate, sodium nitrite, hexamethoniuni chloride, veratrum viride, reserpine, stilbesterol, methyl testosterone, phenobarbitol, pyralimine, digitoxin, and Caffeine. In each instance, the quantity of the drug is calculated by usual arithmetic methods well known in pharmaceutical manufacturing.
It has also been found that other liquid excipients, such as a mixture of castor oil, stearic acid, and confectioners glaze (i. e. shellac) can be employed in practicing the herein described invention. Similarly, by increasing the number of mixing-drying steps, it is possible to slow down the rate of entry of the drug into the patients system and, conversely, by lowering the number of successive mixingdrying steps, it is possible to speed up the rate of entry of the drug into the patients system. However, it has been found that a minimum of such steps is two and a practical maximum is fifteen, since additional mixing drying steps resulting in such a slow rate of drug absorption by the patient has been found to be impractical for presently known medical purposes.
It should be understood that changes and modifications in the form, construction, arrangement, and combination of the several parts of the pharmaceutical preparation may be made and substituted for those herein shown and described without departing from the nature and principle of my invention.
Having thus described my invention, what I claim and desire to secure by Letters Patent is:
l. The method or" making a laminated tablet having a layer containing an immediate release medicated preparation and a layer containing a delayed release medicated preparation having a slow but continuous and attenuated solubility in the gastro-intestinal tract, which method comprises intimately mixing a powdered drug and an enteric water insoluble excipient to produce a pasty mass, drying the mass slowly Without agitation in such a manner as to produce a rough granular material, breaking up the rough granular material by light crushing, whereby to reduce it to granular particles, said mixing, drying and crushing operations constituting one cycle, and remixing the granular particles with an additional quantity of the excipient to produce a pasty mass, redrying such pasty mass slowly and without agitation in such a manner as to produce a granular material, again breaking up the rough granular material by light crushing, whereby to reduce it again to granular particles, said second mixing,-drying and crushing operations constituting a second cycle, said process consisting of not less than three nor more than fifteen mixing, crushing and drying cycles repeated in successive order whereby to produce the delayed release medicated preparation, introducing one of said medicated preparations into a die cavity and compressing same to form a first solid layer, introducing the other of said preparations into the cavity on top of the compressed first preparation, and thereafter compressing said other preparation into a second solid layer which adheres firmly to said first solid layer.
2. A method in accordance with claim 1 wherein the enteric water insoluble excipient is shellac.
3. A method in accordance with claim 1 wherein the enteric water insoluble excipient comprises a mixture of shellac and stearic acid.
4. A pharmaceutical preparation comprising a single tablet having two laminated layers attached integrally to each other, one layer containing a medicated preparation in readily assimilable form for immediate release into a patients system and the other layer containing a medicated preparation having a slow but continuous and attenuated solubility in the gastro-intestinal tract, said last-mentioned preparation containing a solid mass of dry discrete granules, each said granule being made by intimately mixing a powdered drug and an enteric water insoluble excipient to produce a pasty mass, drying the mass slowly without agitation in such a manner as to produce a rough granular material, breaking up the rough granular material by light crushing, whereby to reduce it to granular particles, said mixing, drying and crushing operations constituting one cycle, and remixing the granular particles with an additional quantity of the excipient to produce a pasty mass, redrying such pasty mass slowly and without agitation in such a manner as to produce a granular material, again breaking up the rough granular material by light crushing, whereby to reduce it again to granular particles, said second mixing, drying and crushing operations constituting a second cycle, said process consisting of not less than three nor more than fifteen mixing, crushing and drying cycles repeated in successive order.
5. A pharmaceutical preparation in accordance with claim 4 wherein the enteric water insoluble excipient is shellac.
6. A pharmaceutical preparation in accordance with claim 4 wherein the enteric water insoluble excipient comprises a mixture of shellac and stearic acid.
References Cited in the file of this patent UNITED STATES PATENTS 701,438 Whyte June 3, 1902 2,052,376 Zellers Aug. 25, 1936 2,736,682 Hermelin Feb. 28, 1956 OTHER REFERENCES Clarkson: Tablet Coating (New York, 1951), p. 61.
Claims (1)
1. THE METHOD OF MAKING A LAMINATED TABLET HAVING A LAYER CONTAINING AN IMMEDIATE RELEASE MEDICATED PREPARATION AND A LAYER CONTAINING A DELAYED RELEASE MEDICATED PREPARATION HAVING A SLOW BUT CONTINUOUS AND ATTENUATED SOLUBALITY IN THE GASTRO-INTESTINAL TRACT, WHICH METHOD COMPRISES INTIMATELY MIXING A POWDERED DRUG AND AN ENTERIC WATER INSOLUBLE EXCIPIENT TO PRODUCE A PASTY MASS, DRYING THE MASS SLOWLY WITHOUT AGITATION IN SUCH A MANNER AS TO PRODUCE A ROUGH GRANULAR MATERIAL, BREAKING UP THE ROUGH GRANULAR MATERIAL BY LIGHT CRUSHING , WHEREBY TO REDUCE IT TO GRANULAR PARTICLES, SAID MIXING, DRYING AND CRUSHING OPERATIONS CONSTITUTING ONE CYCLE, AND REMIXING THE GRANULAR PARTICLES WITH AN ADDITIONAL QUANTITY OF THE EXCIPIENT TO PRODUCE A PASTY MASS, REDRYING SUCH PASTY MASS SLOWLY AND WITHOUT AGITATION IN SUCH A MANNER AS TO PRODUCE A GRANULAR MATERIAL, AGAIN BREAKING UP THE ROUGH GRANULAR MATERIAL BY LIGHT CRUSHING, WHEREBY TO REDUCE IT AGAIN TO GRANULAR PARTICLES, SAID SECOND MIXING, DRYING AND CRUSHING OPERATION CONSTITUTING A SECOND CYCLE, SAID PROCESS CONSISTING OF NOT LESS THAN THREE NOR MORE THAN FIFTEEN MIXING, CRUSHING AND DRYING CYCLES REPEATED IN SUCCESSIVE ORDER WHEREBY TO PRODUCE THE DELAYED RELEASE MEDICATED PREPARATION, INTRODUCING ONE OF SAID MEDICATED PREPARATIONS INTO A DIE CAVITY AND COMPRESSING SAME TO FORM A FIRST SOLID LAYER, INTRODUCING THE OTHER OF SAID PREPARATIONS INTO THE CAVITY ON TOP OF THE COMPRESSED FIRST PREP ARATION, AND THEREAFTER COMPRESSING SAID OTHER PREPARATION INTO A SECOND SOLID LAYER WHICH ADHERES FIRMLY TO SAID
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US541031A US2809917A (en) | 1955-10-17 | 1955-10-17 | Sustained release pharmaceutical tablets |
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Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2998350A (en) * | 1959-04-02 | 1961-08-29 | American Cyanamid Co | Article of manufacture for the treatment of alcoholism |
US3039933A (en) * | 1957-10-07 | 1962-06-19 | Premo Pharmaceutical Lab Inc | Ethyl cellulose-polyethylene glycol tablet matrix |
US3048526A (en) * | 1958-08-04 | 1962-08-07 | Wander Company | Medicinal tablet |
US3096248A (en) * | 1959-04-06 | 1963-07-02 | Rexall Drug & Chemical Company | Method of making an encapsulated tablet |
US3098703A (en) * | 1959-08-04 | 1963-07-23 | Gilbert G Reuter Company | Apparatus and method for insect control |
US3134719A (en) * | 1962-04-05 | 1964-05-26 | American Cyanamid Co | Calcium phosphates in tablet compressing |
US3317394A (en) * | 1955-12-22 | 1967-05-02 | Haessle Ab | Medicinal tablet and a method for its preparation |
US3336200A (en) * | 1963-05-28 | 1967-08-15 | Warner Lambert Pharmaceutical | Tablet structure |
US4454108A (en) * | 1981-09-04 | 1984-06-12 | Chugai Seiyaku Kabushiki Kaisha | Prolonged-action multiple-layer tablets |
US4503031A (en) * | 1982-12-17 | 1985-03-05 | Glassman Jacob A | Super-fast-starting-sustained release tablet |
US4609542A (en) * | 1978-12-22 | 1986-09-02 | Elan Corporation, P.L.C. | New pharmaceutical forms for administration of medicaments by oral route, with programmed release |
US4704284A (en) * | 1982-08-12 | 1987-11-03 | Pfizer Inc. | Long-acting matrix tablet formulations |
US4720387A (en) * | 1983-06-22 | 1988-01-19 | Shionogi & Co., Ltd. | Sustained-release preparation of pinacidil |
US4880830A (en) * | 1986-02-13 | 1989-11-14 | Ethical Pharmaceuticals Limited | Slow release formulation |
US5849330A (en) * | 1991-09-17 | 1998-12-15 | Orion-Yhtyma Oy | Controlled release pharmaceutical |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US701438A (en) * | 1902-02-10 | 1902-06-03 | Schieffelin And Company | Compressed tablet. |
US2052376A (en) * | 1933-05-18 | 1936-08-25 | Edgar G Zellers | Insoluble pill or tablet for internal medicinal uses |
US2736682A (en) * | 1954-10-11 | 1956-02-28 | Victor M Hermelin | Method of making a prolonged action medicinal tablet |
-
1955
- 1955-10-17 US US541031A patent/US2809917A/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US701438A (en) * | 1902-02-10 | 1902-06-03 | Schieffelin And Company | Compressed tablet. |
US2052376A (en) * | 1933-05-18 | 1936-08-25 | Edgar G Zellers | Insoluble pill or tablet for internal medicinal uses |
US2736682A (en) * | 1954-10-11 | 1956-02-28 | Victor M Hermelin | Method of making a prolonged action medicinal tablet |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3317394A (en) * | 1955-12-22 | 1967-05-02 | Haessle Ab | Medicinal tablet and a method for its preparation |
US3039933A (en) * | 1957-10-07 | 1962-06-19 | Premo Pharmaceutical Lab Inc | Ethyl cellulose-polyethylene glycol tablet matrix |
US3048526A (en) * | 1958-08-04 | 1962-08-07 | Wander Company | Medicinal tablet |
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