US2951792A - Sustained release pharmaceutical tablets - Google Patents

Sustained release pharmaceutical tablets Download PDF

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US2951792A
US2951792A US853844A US85384459A US2951792A US 2951792 A US2951792 A US 2951792A US 853844 A US853844 A US 853844A US 85384459 A US85384459 A US 85384459A US 2951792 A US2951792 A US 2951792A
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release layer
sustained release
carbon atoms
medicament
tablet
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Joseph V Swintosky
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Smith Kline and French Laboratories Ltd
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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

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  • This invention relates to a pharmaceutical tablet and to such a tablet which provides an immediately released dosage to achieve a therapeutic level and a sustained release dosage to maintain a therapeutic level of the medicament over an extended period of time.
  • the tablet of this invention provides a substantially constant uniform release of medicament over an extended period of time even as the surface areas of the sustained release portion wear away.
  • a tablet which provides an initial dosage to promptly achieve a therapeutic level together with excellent substantially uniform sustained release of the medicament to sustain the therapeutic level over a period of in excess of four hours and up to twelve hours.
  • the tablet is advantageous in that it is easy to make and lends itself to mass production through the use of a tableting machine. Further, the production of the tablet is markedly less expensive than the production of the above discussed encapsulated pellets.
  • the tablet in accordance with this invention comprises a substantially flat faced tablet having a layer of medicament dispersed in a conventional filler such as, for example, terra alb a, milk of sugar, talc or stearic acid.
  • a conventional filler such as, for example, terra alb a, milk of sugar, talc or stearic acid.
  • a sustained release layer Contiguous with the first immediately released layer is a sustained release layer containing the same medicament dispersed in time delay material.
  • the total surface area of the sustained release layer including the side surface area and the surface area abutting the immediately released layer, will be from 2.5 to
  • a sustained release layer made in accordance with these limitations provides a substantially constant uniform release of medicament as against, for example, a similar composition in the form of a ball which would, as the surface area were away, provide an ever decreasing amount of medicament for a unit of time.
  • the immediately released layer may be conventionally formed by mixing the medicament with one or more fillers and granulating, using, for example, water, an acacia solution, starch paste or a gelatin solution and a screen of, for example, 8 to 30 mesh.
  • the thus formed granules are dried and then compressed into substantially fiat faced tablets.
  • the sustained release layer may also be prepared using the granulation technique.
  • the medicament may, for example, be dispersed in a melt of a suitable time delay material and the mix congealed.
  • the congealed mix may then be passed through a screen of, for example, 8 to 30 mesh. If an increased release rate is desired, the granulation can be mixed with a small amount of hydrophilic material.
  • the immediately released layer in tablet form is then placed in a tablet machine die and the granulation for the sustained release layer is added to the die and compressed by the tablet machine punch on to the tablet to form a contiguous two layer tablet.
  • the granulation for the immediately released layer and the granulation for the sustained release layer may be added to the die of a tableting machine one on top of the other and then compressed by the tablet machine punch.
  • the hydrophilic material for the immediate release layer may be, for example, starch, sugar, alginic acid or colloidal magnesium aluminum silicate.
  • the time delay material for the sustained release layer will be a solid lipid material such as, for example, an alcohol or ester, alone, or an admixture thereof.
  • the fatty alcohols may have from 12 to 31 carbon atoms and may be, for example, lauryl alcohol, cetyl, stearyl, myristyl, myricyl, arachyl, carnubyl or ceryl alcohol.
  • the esters may be mono, dior triglyceryl esters formed from fatty acids having from 10 to 22 carbon atoms, such as, for example, glyceryl distearate, glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate or gly
  • esters are esters of a fatty acid having from 12 to 31 carbon atoms and a fatty alcohol having from 12 to 31 carbon atoms, the ester having a carbon atom content of from 24 to 62, or a mixture thereof.
  • esters include myricyl palmitate, beeswax, cetyl palmitate, spermacetic wax, myricyl cerotate, carnauba wax, cetyl myristate, ceryl palmitate, ceryl cerotate, myricyl melissate, stearyl palmitate, stearyl myristate, lauryl laurate.
  • Figure 1 is a vertical section of a tablet in accordance with this invention.
  • Figure 2 is an alternate embodiment of a tablet in accordance with this invention.
  • a cylindrical tablet 2 has a sustained release layer 4 and an immediate release layer 6.
  • Sustained release'layer '4 has faces 8 and 10 and a side 12.
  • Immediate release layer 6 has a face 14 and a side 16.
  • the total surface area of sustained release layer 4, including side 12, is about 9 times the surface areaof side 12.
  • Tablet 20- has a sustained release layer 22, an upper immediate release layer 24 and a lower immediate release layer 26.
  • Sustained release layer 22 has an upper face 28, a lower face 30 and a side 32.
  • Immediate release layer 24 has a face 34 and a side 36.
  • Immediate release layer 26 has a'face 38 and a side 40.
  • the surface area of sustained release layer 22 is about times the surface area of the sides of this layer.
  • Example A granulation is prepared from the following powders:
  • the powders are mixed well in the dry condition. Then cc. of gelatin in distilled water is added slowly, with mixing, to the powders. The wet mixture is then passed through a No. 10 screen and dried overnight at 110 F. The dried granules are then passed through a No. 14 screen. These dried granules are compressed into /z-inch cylindrical flat faced tablets, each weighing 1% grains and designated tablets (X).
  • Another granulation is prepared by melting 300 gms. hydrogenated castor oil and adding to this 300 gms. aminophylline. Thisproduct is mixed Well until congealed. The congealed product is put through a comminution mill utilizing a No. 10 screen. Then 65 gms. of this granulation are mixed with 5 gms. of starch and designated granulation (Y).
  • the final sustained drug release tablet is prepared from tablets (X) and granulation (Y) as follows:
  • a tablet (X) isplaced in the /2 inch die.
  • 7.0 grains of granulation (Y) are added to the die and compressed onto tablet (X) using a fiat head punch.
  • the final tablet provides uniform sustained release for about 8 hours and is useful in treating, for example, asthmatic conditions, congestive heart failure and in general where aminophylline has been used heretofore.
  • the medicament may be a sympathomimetic amine such as dextroamphetamine sulfate; a sedative-hypnotic such as, for example, a barbiturate such as phenobarbital or amobarbital; an antihistaminic such as, for example, chlorprophenpyridarnine maleate or thenylpyramine hydrochloride; an antispasmodic such as, for example, homatropine methylbromide, hyoscyamine sulfate, atropine sulfate or scopolamine hydrobromide.
  • a sympathomimetic amine such as dextroamphetamine sulfate
  • a sedative-hypnotic such as, for example, a barbiturate such as phenobarbital or amobarbital
  • an antihistaminic such as, for example, chlorprophenpyridarnine maleate or thenylpyramine hydrochloride
  • a substantially flat faced sustained release pharmaceutical tablet having an immediate release layer containing a medicament dispersed in a filler, said immediate release layer providing a therapeutic blood level of said .medicament, a sustained release layer contiguous with sustained release layer including the face abutting the immediate release layer being in the range of from 2.5 to 25 times the side surface area of said sustained release layer, said sustained release layer providing a substantially uniform release for a period of in excess of four hours, said immediate release layer being exterior of said sustained release layer.
  • a substantially flat faced sustained release pharmaceutical tablet having an immediate release layer'c'ont aining a medicament dispersed in a filler, said immediate release layer providing a therapeutic blood level of said medicament, a sustained release layer containing the same medicament dispersed within granules of a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, said granules being in admixture with a solid ingestible hydrophilic material, said sustained release layer being contiguous with said first mentioned layer, the total surface area of said sustained release layer including the face abutting the immediate release layer being in the range of from 2.5 to 25 times the side surface area of said sustained release layer and said sustained release layer providing a substantially uniform release for
  • a substantially flat faced sustained release pharmaceutical tablet having an exposed immediate release portion containing a medicament dispersed in a filler, said immediate release portion providing a therapeutic level of said medicament, a sustained release portion containing the same medicament dispersed within granules of a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, the total surface area of said sustained release portion being in the range of from 2.5 to 25 times the side surface area of said sustained release portion, said sustained release portion providing a substantially uniform release of the medicament for a period of in excess of four hours, said immediate release portion being exterior of said sustained release portion.
  • a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon
  • a substantially flat faced sustained release pharmaceutical tablet having a single immediate release layer containing a medicament dispersed in a filler, said immediate release layer providing a therapeutic blood level of said medicament, a single sustained release layer contiguous with said first mentioned layer and containing the same medicament dispersed within granules of a solid ingestible lipid time delay-material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, the total surface area of said sustainedrelease layer including the face abutting the immediate release layer being in the range of from 2.5 to 25 times the side surface area of said sustained release layer, said sustained release layer providing a substantially uniform release for a period of in excess of four 5 hours, said immediate release layer being exterior of said sustained release layer.
  • a substantially flat faced sustained release pharmaceutical tablet having a pair of immediate release layers each containing a medicament dipsersed in a filler, said immediate release layers providing a therapeutic blood level of said medicament, a sustained release layer between said immediate release layers and containing the same medicament dispersed within granules of a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, the total surface area of said sustained release layer including the faces abutting the immediate release layers being in the range of from 2.5 to 25 times the side surface area of said sustained release layer, said sustained release layer providing a substantially uniform release for a period of in excess of four hours, said immediate release layers being exterior of said sustained release layer.

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Description

p 1960 J. v. SWINTOSKY 2,951,792
SUSTAINED RELEASE PHARMACEUTICAL TABLETS Original Filed Aug. 16, 1954 a 4 l2 f I I2 2 i\ |6 n; L L L l4 IO 6 Fl 6. I
as L 218 faz 32x 22 20 4o /V -40 L 30 2s 3s F I G. 2.
INVENTOR.
JOSEPH V. SWlNTOSKY BYBW ATTORNEYS United States Patent SUSTAJNED RELEASE PHARMACEUTICAL TABLETS Joseph V. Swintosky, Perkiomenville, Pa., assignor to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania Continuation of application Ser. No. 449,880, Aug. 16, 1954. This application Nov. 18, 1959, Ser. No. 853,844
Claims. (Cl. 167-82) This invention relates to a pharmaceutical tablet and to such a tablet which provides an immediately released dosage to achieve a therapeutic level and a sustained release dosage to maintain a therapeutic level of the medicament over an extended period of time. The tablet of this invention provides a substantially constant uniform release of medicament over an extended period of time even as the surface areas of the sustained release portion wear away.
In order to achieve efficient results from a very large number of drugs, it has been found advantageous to provide a uniform sustained release of such drugs over an extended period of time. The problem is further complicated in that it has been found in such cases that an initial immediately released dosage is usually necessary to bring the medicament up to the desired therapeutic level promptly in conjunction with means for gradually releasing uniform amounts of the medicament to sustain .the therapeutic level.
The best known solution of this uniform sustained release problem has been the use of large numbers of small pellets contained in a capsule, a percentage of the pellets providing an initial dosage of a medicament to promptly achieve the desired therapeutic level and the remaining percentage being variously coated with time delay material to provide gradual release of the medicament to sustain the therapeutic level. Although providing a thoroughly acceptable product from the point of view of its efficacy, this sustained release product is very difficult to make and, further, is of necessity an expensive product not easily adaptable to mass production techniques.
Now in accordance with this invention there is provided a tablet which provides an initial dosage to promptly achieve a therapeutic level together with excellent substantially uniform sustained release of the medicament to sustain the therapeutic level over a period of in excess of four hours and up to twelve hours. The tablet is advantageous in that it is easy to make and lends itself to mass production through the use of a tableting machine. Further, the production of the tablet is markedly less expensive than the production of the above discussed encapsulated pellets.
The tablet in accordance with this invention comprises a substantially flat faced tablet having a layer of medicament dispersed in a conventional filler such as, for example, terra alb a, milk of sugar, talc or stearic acid. This layer, on reaching the gastro-intestinal tract is quickly dissolved or distintegrated in the body fluids and thus rapidly provides a therapeutic blood level of the medicament.
Contiguous with the first immediately released layer is a sustained release layer containing the same medicament dispersed in time delay material.
The total surface area of the sustained release layer, including the side surface area and the surface area abutting the immediately released layer, will be from 2.5 to
.25 times the side surface area of the sustained release layer. A sustained release layer made in accordance with these limitations provides a substantially constant uniform release of medicament as against, for example, a similar composition in the form of a ball which would, as the surface area were away, provide an ever decreasing amount of medicament for a unit of time.
More specifically, the immediately released layer may be conventionally formed by mixing the medicament with one or more fillers and granulating, using, for example, water, an acacia solution, starch paste or a gelatin solution and a screen of, for example, 8 to 30 mesh. The thus formed granules are dried and then compressed into substantially fiat faced tablets.
The sustained release layer may also be prepared using the granulation technique. The medicament may, for example, be dispersed in a melt of a suitable time delay material and the mix congealed. The congealed mix may then be passed through a screen of, for example, 8 to 30 mesh. If an increased release rate is desired, the granulation can be mixed with a small amount of hydrophilic material.
The immediately released layer in tablet form is then placed in a tablet machine die and the granulation for the sustained release layer is added to the die and compressed by the tablet machine punch on to the tablet to form a contiguous two layer tablet.
Alternatively, the granulation for the immediately released layer and the granulation for the sustained release layer may be added to the die of a tableting machine one on top of the other and then compressed by the tablet machine punch.
The hydrophilic material for the immediate release layer, if desired, may be, for example, starch, sugar, alginic acid or colloidal magnesium aluminum silicate.
The time delay material for the sustained release layer will be a solid lipid material such as, for example, an alcohol or ester, alone, or an admixture thereof. The fatty alcohols may have from 12 to 31 carbon atoms and may be, for example, lauryl alcohol, cetyl, stearyl, myristyl, myricyl, arachyl, carnubyl or ceryl alcohol.
The esters may be mono, dior triglyceryl esters formed from fatty acids having from 10 to 22 carbon atoms, such as, for example, glyceryl distearate, glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate or glyceryl tridecenoate, hydrogenated castor oil, hydrogenated peanut oil and hydrogenated coconut oil.
Further exemplary of esters are esters of a fatty acid having from 12 to 31 carbon atoms and a fatty alcohol having from 12 to 31 carbon atoms, the ester having a carbon atom content of from 24 to 62, or a mixture thereof. Exemplary are myricyl palmitate, beeswax, cetyl palmitate, spermacetic wax, myricyl cerotate, carnauba wax, cetyl myristate, ceryl palmitate, ceryl cerotate, myricyl melissate, stearyl palmitate, stearyl myristate, lauryl laurate.
The invention will be further clarified by a study of the following description in conjunction with the drawing, in which:
Figure 1 is a vertical section of a tablet in accordance with this invention.
Figure 2 is an alternate embodiment of a tablet in accordance with this invention.
As shown in Figure 1, a cylindrical tablet 2 has a sustained release layer 4 and an immediate release layer 6. Sustained release'layer '4 has faces 8 and 10 and a side 12. Immediate release layer 6 has a face 14 and a side 16. The total surface area of sustained release layer 4, including side 12, is about 9 times the surface areaof side 12.
In Figure 2 an alternative tablet 20 is disclosed. Tablet 20- has a sustained release layer 22, an upper immediate release layer 24 and a lower immediate release layer 26. Sustained release layer 22 has an upper face 28, a lower face 30 and a side 32. Immediate release layer 24 has a face 34 and a side 36. Immediate release layer 26 has a'face 38 and a side 40. In the case of tablet 20, the surface area of sustained release layer 22 is about times the surface area of the sides of this layer.
The tablet in accordance with this invention and a method for its preparation will be further illustrated by the following specific example:
Example A granulation is prepared from the following powders:
Gm. Stearic acid 16.0 Talc 16.0 Aminophylline 64.0
The powders are mixed well in the dry condition. Then cc. of gelatin in distilled water is added slowly, with mixing, to the powders. The wet mixture is then passed through a No. 10 screen and dried overnight at 110 F. The dried granules are then passed through a No. 14 screen. These dried granules are compressed into /z-inch cylindrical flat faced tablets, each weighing 1% grains and designated tablets (X).
Another granulation is prepared by melting 300 gms. hydrogenated castor oil and adding to this 300 gms. aminophylline. Thisproduct is mixed Well until congealed. The congealed product is put through a comminution mill utilizing a No. 10 screen. Then 65 gms. of this granulation are mixed with 5 gms. of starch and designated granulation (Y).
The final sustained drug release tablet is prepared from tablets (X) and granulation (Y) as follows:
A tablet (X) isplaced in the /2 inch die. 7.0 grains of granulation (Y) are added to the die and compressed onto tablet (X) using a fiat head punch. The final tablet provides uniform sustained release for about 8 hours and is useful in treating, for example, asthmatic conditions, congestive heart failure and in general where aminophylline has been used heretofore.
Although the invention is specifically exemplified using aminophylline, it will be appreciated that it is useful with any medicament which it is desired to provide in sustained release form. Thus, for example, the medicament may be a sympathomimetic amine such as dextroamphetamine sulfate; a sedative-hypnotic such as, for example, a barbiturate such as phenobarbital or amobarbital; an antihistaminic such as, for example, chlorprophenpyridarnine maleate or thenylpyramine hydrochloride; an antispasmodic such as, for example, homatropine methylbromide, hyoscyamine sulfate, atropine sulfate or scopolamine hydrobromide.
This is a continuing application based on my copending patent application, Serial No. 449,880, filed August 16, 1954, now abandoned.
What is claimed is:
1. A substantially flat faced sustained release pharmaceutical tablet having an immediate release layer containing a medicament dispersed in a filler, said immediate release layer providing a therapeutic blood level of said .medicament, a sustained release layer contiguous with sustained release layer including the face abutting the immediate release layer being in the range of from 2.5 to 25 times the side surface area of said sustained release layer, said sustained release layer providing a substantially uniform release for a period of in excess of four hours, said immediate release layer being exterior of said sustained release layer.
2. A substantially flat faced sustained release pharmaceutical tablet having an immediate release layer'c'ont aining a medicament dispersed in a filler, said immediate release layer providing a therapeutic blood level of said medicament, a sustained release layer containing the same medicament dispersed within granules of a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, said granules being in admixture with a solid ingestible hydrophilic material, said sustained release layer being contiguous with said first mentioned layer, the total surface area of said sustained release layer including the face abutting the immediate release layer being in the range of from 2.5 to 25 times the side surface area of said sustained release layer and said sustained release layer providing a substantially uniform release for a period of in excess of four hours, said immediate release layer being exterior of said sustained release layer.
3. A substantially flat faced sustained release pharmaceutical tablet having an exposed immediate release portion containing a medicament dispersed in a filler, said immediate release portion providing a therapeutic level of said medicament, a sustained release portion containing the same medicament dispersed within granules of a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, the total surface area of said sustained release portion being in the range of from 2.5 to 25 times the side surface area of said sustained release portion, said sustained release portion providing a substantially uniform release of the medicament for a period of in excess of four hours, said immediate release portion being exterior of said sustained release portion.
4. A substantially flat faced sustained release pharmaceutical tablet having a single immediate release layer containing a medicament dispersed in a filler, said immediate release layer providing a therapeutic blood level of said medicament, a single sustained release layer contiguous with said first mentioned layer and containing the same medicament dispersed within granules of a solid ingestible lipid time delay-material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, the total surface area of said sustainedrelease layer including the face abutting the immediate release layer being in the range of from 2.5 to 25 times the side surface area of said sustained release layer, said sustained release layer providing a substantially uniform release for a period of in excess of four 5 hours, said immediate release layer being exterior of said sustained release layer.
5. A substantially flat faced sustained release pharmaceutical tablet having a pair of immediate release layers each containing a medicament dipsersed in a filler, said immediate release layers providing a therapeutic blood level of said medicament, a sustained release layer between said immediate release layers and containing the same medicament dispersed within granules of a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, the total surface area of said sustained release layer including the faces abutting the immediate release layers being in the range of from 2.5 to 25 times the side surface area of said sustained release layer, said sustained release layer providing a substantially uniform release for a period of in excess of four hours, said immediate release layers being exterior of said sustained release layer.
Whyte June 3, 1902 Svedres May 28, 1957

Claims (1)

1. A SUBSTANTIALLY FLAT FACED SUSTAINED RELEASE PHARMACEUTICAL TABLET HAVING AN IMMEDIATE RELEASE LAYER CONTAINING A MEDICAMENT DISPERSED IN A FILLER, SAID IMMEDIATE RELEASE LAYER PROVIDING A THERAPEUTIC BLOOD LEVEL OF SAID MEDICAMENT, A SUSTAINED RELEASE LAYER CONTIGUOUS WITH SAID FIRST MENTIONED LAYER AND CONTAINING AND SAME MEDICAMENT DISPERSED WITHIN GRANULES OF A SOLID INGESTIBLE LIPID TIME DELAY MATERIAL SELECTED FROM THE GROUP CONSISTING OF FATTY ALCOHOLS HAVING FROM 12 TO 31 CARBON ATOMS, GLYCERYL ESTERS FORMED FROM FATTY ACIDS HAVING FROM 10 TO 22 CARBON ATOMS AND ESTERS HAVING FROM 24 TO 62 CARBON ATOMS FORMED FROM FATTY ACIDS HAVING FROM 12 TO 31 CARBON ATOMS AND FATTY ALCOHOLS HAVING FROM 12 TO 31 CARBON ATOMS, THE TOTAL SURFACE AREA OF SAID SUSTAINED RELEASE LAYER INCLUDING THE FACE ABUTTING THE IMMEDIATE RELEASE LAYER BEING IN THE RANGE OF FROM 2.5 TO 25 TIMES THE SIDE SURFACE AREA OF SAID SUSTAINED RELEASE LAYER, SAID SUSTAINED RELEASE LAYER PROVIDING A SUBSTANTIALLY UNIFORM RELEASE FOR A PERIOD OF IN EXCESS OF FOUR HOURS, SAID IMMEDIATE RELEASE LAYER BEING EXTERIOR OF SAID SUSTAINED RELEASE LAYER.
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Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3048526A (en) * 1958-08-04 1962-08-07 Wander Company Medicinal tablet
US3056724A (en) * 1956-11-05 1962-10-02 Commw Scient Ind Res Org Therapeutic pellets for ruminants
US3096241A (en) * 1959-07-13 1963-07-02 Wallace & Tiernan Inc Synergistic antihistamine mixture
US3108046A (en) * 1960-11-25 1963-10-22 Smith Kline French Lab Method of preparing high dosage sustained release tablet and product of this method
US3121044A (en) * 1960-10-06 1964-02-11 Beecham Res Lab Three-layer compressed penicillin tablet
US3133863A (en) * 1961-03-10 1964-05-19 Strong Cobb Arner Inc Sustained release therapeutic tablet compositions comprising organic solvent-gelled gums
US3136695A (en) * 1961-03-10 1964-06-09 Strong Cobb Arner Inc Anhydrous thixotropic gel sustained release therapeutic compositions and method of preparation
US3146167A (en) * 1961-10-05 1964-08-25 Smith Kline French Lab Method of preparing sustained release pellets and products thereof
US3147187A (en) * 1962-09-10 1964-09-01 Don Hall Lab Sustained release pharmaceutical
US3336200A (en) * 1963-05-28 1967-08-15 Warner Lambert Pharmaceutical Tablet structure
US3400197A (en) * 1965-01-26 1968-09-03 Robins Co Inc A H Compressible sustained release pharmaceutical tablet lipid-colloidal silica gel matrix fragment granules
US3402240A (en) * 1957-06-25 1968-09-17 Pfizer & Co C Medicinal tablet and process of making same
US4308251A (en) * 1980-01-11 1981-12-29 Boots Pharmaceuticals, Inc. Controlled release formulations of orally-active medicaments
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
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
US4764380A (en) * 1982-03-22 1988-08-16 Alza Corporation Drug delivery system comprising a volume increasing matrix containing a plurality of tiny pills
US4794001A (en) * 1986-03-04 1988-12-27 American Home Products Corporation Formulations providing three distinct releases
US4851232A (en) * 1987-02-13 1989-07-25 Alza Corporation Drug delivery system with means for obtaining desirable in vivo release rate pattern
US4853229A (en) * 1987-10-26 1989-08-01 Alza Corporation Method for adminstering tiny pills
US4898733A (en) * 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
US4904476A (en) * 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
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
US4961932A (en) * 1987-10-26 1990-10-09 Alza Corporation Plurality of tiny pills in liquid dosage form
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
US5030454A (en) * 1987-10-26 1991-07-09 Alza Corporation Method for delivering drug in tiny pills in liquid carrier
US5032406A (en) * 1989-02-21 1991-07-16 Norwich Eaton Pharmaceuticals, Inc. Dual-action tablet
US5368861A (en) * 1989-10-26 1994-11-29 Nippon Shinyaku Co., Ltd. Gastric preparation with sustained release
WO1995001781A1 (en) * 1993-07-09 1995-01-19 Apr Applied Pharma Research Sa Multilayered controlled-release oral solid pharmaceutical forms
JP2646851B2 (en) 1989-10-26 1997-08-27 日本新薬株式会社 Gastric retention formulation
US5690959A (en) * 1993-05-29 1997-11-25 Smithkline Beecham Corporation Pharmaceutical thermal infusion process
US5714167A (en) * 1992-06-15 1998-02-03 Emisphere Technologies, Inc. Active agent transport systems
US5827537A (en) * 1995-05-04 1998-10-27 Smithkline Beecham Corporation Pharmaceutical thermal infusion process
US20040024018A1 (en) * 2000-06-26 2004-02-05 Venkata-Rangarao Kanikanti Sustained-release preparations of quinolone antibiotics and method for preparation thereof
US20040180089A1 (en) * 2002-12-26 2004-09-16 Pozen Inc. Multilayer dosage forms containing NSAIDs and triptans
US20070202167A1 (en) * 2004-06-30 2007-08-30 Sovereign Pharmaceuticals, Inc. Hyoscyamine dosage form
US20090238873A1 (en) * 2008-03-21 2009-09-24 Mylan Pharmaceuticals, Inc. Extended release formulation containing a wax
US8022095B2 (en) 1996-08-16 2011-09-20 Pozen, Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
WO2016020901A1 (en) 2014-08-07 2016-02-11 Acerta Pharma B.V. Methods of treating cancers, immune and autoimmune diseases, and inflammatory diseases based on btk occupancy and btk resynthesis rate
US11278506B2 (en) 2015-10-09 2022-03-22 Rb Health (Us) Llc Pharmaceutical formulation
US12370189B2 (en) 2014-10-21 2025-07-29 Rb Health (Us) Llc Pharmaceutical formulation

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Cited By (54)

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US3056724A (en) * 1956-11-05 1962-10-02 Commw Scient Ind Res Org Therapeutic pellets for ruminants
US3402240A (en) * 1957-06-25 1968-09-17 Pfizer & Co C Medicinal tablet and process of making same
US3048526A (en) * 1958-08-04 1962-08-07 Wander Company Medicinal tablet
US3096241A (en) * 1959-07-13 1963-07-02 Wallace & Tiernan Inc Synergistic antihistamine mixture
US3121044A (en) * 1960-10-06 1964-02-11 Beecham Res Lab Three-layer compressed penicillin tablet
US3108046A (en) * 1960-11-25 1963-10-22 Smith Kline French Lab Method of preparing high dosage sustained release tablet and product of this method
US3133863A (en) * 1961-03-10 1964-05-19 Strong Cobb Arner Inc Sustained release therapeutic tablet compositions comprising organic solvent-gelled gums
US3136695A (en) * 1961-03-10 1964-06-09 Strong Cobb Arner Inc Anhydrous thixotropic gel sustained release therapeutic compositions and method of preparation
US3146167A (en) * 1961-10-05 1964-08-25 Smith Kline French Lab Method of preparing sustained release pellets and products thereof
US3147187A (en) * 1962-09-10 1964-09-01 Don Hall Lab Sustained release pharmaceutical
US3336200A (en) * 1963-05-28 1967-08-15 Warner Lambert Pharmaceutical Tablet structure
US3400197A (en) * 1965-01-26 1968-09-03 Robins Co Inc A H Compressible sustained release pharmaceutical tablet lipid-colloidal silica gel matrix fragment granules
US4308251A (en) * 1980-01-11 1981-12-29 Boots Pharmaceuticals, Inc. Controlled release formulations of orally-active medicaments
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
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
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
US4454108A (en) * 1981-09-04 1984-06-12 Chugai Seiyaku Kabushiki Kaisha Prolonged-action multiple-layer tablets
US4764380A (en) * 1982-03-22 1988-08-16 Alza Corporation Drug delivery system comprising a volume increasing matrix containing a plurality of tiny pills
US4704284A (en) * 1982-08-12 1987-11-03 Pfizer Inc. Long-acting matrix tablet formulations
US4503031A (en) * 1982-12-17 1985-03-05 Glassman Jacob A Super-fast-starting-sustained release tablet
US4720387A (en) * 1983-06-22 1988-01-19 Shionogi & Co., Ltd. Sustained-release preparation of pinacidil
US4898733A (en) * 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
US4904476A (en) * 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
US4794001A (en) * 1986-03-04 1988-12-27 American Home Products Corporation Formulations providing three distinct releases
US4851232A (en) * 1987-02-13 1989-07-25 Alza Corporation Drug delivery system with means for obtaining desirable in vivo release rate pattern
US4961932A (en) * 1987-10-26 1990-10-09 Alza Corporation Plurality of tiny pills in liquid dosage form
US4853229A (en) * 1987-10-26 1989-08-01 Alza Corporation Method for adminstering tiny pills
US5030454A (en) * 1987-10-26 1991-07-09 Alza Corporation Method for delivering drug in tiny pills in liquid carrier
US5032406A (en) * 1989-02-21 1991-07-16 Norwich Eaton Pharmaceuticals, Inc. Dual-action tablet
US5368861A (en) * 1989-10-26 1994-11-29 Nippon Shinyaku Co., Ltd. Gastric preparation with sustained release
JP2646851B2 (en) 1989-10-26 1997-08-27 日本新薬株式会社 Gastric retention formulation
US5714167A (en) * 1992-06-15 1998-02-03 Emisphere Technologies, Inc. Active agent transport systems
US5824344A (en) * 1993-05-29 1998-10-20 Smithkline Beecham Corporation Pharmaceutical thermal infusion granules
US5690959A (en) * 1993-05-29 1997-11-25 Smithkline Beecham Corporation Pharmaceutical thermal infusion process
US5681583A (en) * 1993-07-09 1997-10-28 Apr Applied Pharma Research Sa Multilayered controlled-release oral solid pharmaceutical forms
WO1995001781A1 (en) * 1993-07-09 1995-01-19 Apr Applied Pharma Research Sa Multilayered controlled-release oral solid pharmaceutical forms
US5827537A (en) * 1995-05-04 1998-10-27 Smithkline Beecham Corporation Pharmaceutical thermal infusion process
US8022095B2 (en) 1996-08-16 2011-09-20 Pozen, Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
US7709022B2 (en) 2000-06-26 2010-05-04 Bayer Schering Pharma Ag Sustained-release preparations of quinolone antibiotics and method for preparation thereof
US20040024018A1 (en) * 2000-06-26 2004-02-05 Venkata-Rangarao Kanikanti Sustained-release preparations of quinolone antibiotics and method for preparation thereof
US8187632B2 (en) 2000-06-26 2012-05-29 Bayer Schering Pharma Ag Sustained-release preparations of quinolone antibiotics
US20070237824A1 (en) * 2000-06-26 2007-10-11 Bayer Healthcare Aktiengesellschaft Sustained-Release Preparations Of Quinolone Antibiotics
US7780986B2 (en) 2000-06-26 2010-08-24 Bayer Schering Pharma Ag Method of preparing sustained-release preparations of quinolone antibiotics
US20040180089A1 (en) * 2002-12-26 2004-09-16 Pozen Inc. Multilayer dosage forms containing NSAIDs and triptans
US7332183B2 (en) * 2002-12-26 2008-02-19 Pozen Inc. Multilayer dosage forms containing NSAIDs and triptans
US20070202167A1 (en) * 2004-06-30 2007-08-30 Sovereign Pharmaceuticals, Inc. Hyoscyamine dosage form
US9308164B2 (en) * 2004-06-30 2016-04-12 Sovereign Pharmaceuticals, Llc Hyoscyamine dosage form
US9844538B2 (en) * 2004-06-30 2017-12-19 Sovereign Pharmaceuticals, Llc Hyoscyamine dosage form
US20090238873A1 (en) * 2008-03-21 2009-09-24 Mylan Pharmaceuticals, Inc. Extended release formulation containing a wax
WO2016020901A1 (en) 2014-08-07 2016-02-11 Acerta Pharma B.V. Methods of treating cancers, immune and autoimmune diseases, and inflammatory diseases based on btk occupancy and btk resynthesis rate
WO2017025814A1 (en) 2014-08-07 2017-02-16 Acerta Pharma B.V. Methods of treating cancers, immune and autoimmune diseases, and inflammatory diseases based on btk occupancy and btk resynthesis rate
US12370189B2 (en) 2014-10-21 2025-07-29 Rb Health (Us) Llc Pharmaceutical formulation
US11278506B2 (en) 2015-10-09 2022-03-22 Rb Health (Us) Llc Pharmaceutical formulation
US12257218B2 (en) 2015-10-09 2025-03-25 Rb Health (Us) Llc Pharmaceutical formulation

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