CA1239652A - Sleep-aid composition containing an analgesic and diphenhydramine dihydrogencitrate, and method of use - Google Patents
Sleep-aid composition containing an analgesic and diphenhydramine dihydrogencitrate, and method of useInfo
- Publication number
- CA1239652A CA1239652A CA000380935A CA380935A CA1239652A CA 1239652 A CA1239652 A CA 1239652A CA 000380935 A CA000380935 A CA 000380935A CA 380935 A CA380935 A CA 380935A CA 1239652 A CA1239652 A CA 1239652A
- Authority
- CA
- Canada
- Prior art keywords
- asa
- diphenhydramine
- acetaminophen
- dihydrogencitrate
- tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
- A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
Abstract
ABSTRACT OF THE DISCLOSURE
An analgesic and sleep-aid composition containing an analgesic (e.g. ASA, APAP or combinations thereof) and diphenhydramine dihydrogencitrate. Discloses several dosage forms including a two layer tablet in which ASA is contained in one layer and APAP contained in the other layer; the preferred form being such that the diphenhydramine dihydrogencitrate is contained in the APAP layer.
An analgesic and sleep-aid composition containing an analgesic (e.g. ASA, APAP or combinations thereof) and diphenhydramine dihydrogencitrate. Discloses several dosage forms including a two layer tablet in which ASA is contained in one layer and APAP contained in the other layer; the preferred form being such that the diphenhydramine dihydrogencitrate is contained in the APAP layer.
Description
~3~iS2 SLEEP-AID COMPOSITION CONTAINING AN
ANALGESIC AND DIPHENHYDRAMINE DIHYDROGENCITRATE
_ ___ AND METHOD OF USE
This in~ention relates to an analgesic and sleep aid composltion containing an analgesic (e.g. acetyl-salicylic acid (ASA), acetaminophen (APAP) or combina-tions thereof) and diphenhydramine dihydrogencitrate.
It also concerns diphenhydramine dihydrogencitrate as a novel compound which may be expressed by the formula:
C6H5 ~CH3 ~ 2 H
(I) CHO - CH2CH2N . HO - C - COOH
It is known in the prior art to formulate so-called "nighttime analgesics" consisting of an ASA layer and an APAP layer; the latter also containing metha-pyrilene fumarate. A tablet of this character is described in the "Physicians Desk Reference" 28th Edition, 1974, page 640, column 3 (published by Medical Economics Company, a Litton Division, Oradell, New Jersey). In these tablets, the methapyrilene fumarate is believed to function as a sleep-aid; whereas, the ASA and APAP are thought to play their usual roles.
These tablets have proven to be effective in the past for their intended purposes. Recently, however, some negative opinion has developed with respect to the safety of methapyrilene fumarate. This led to a search for a drug which might replace it in these tablets.
In the course of this search, Applicants attempted to formulate tablets of the above described type which made use of a widely employed antihistamine i.e. diphen-hydramine hydrochloride. This is the hydrochloride ~3~5~
salt of 2-diphenylmethoxy-N,N-dimethylethylamine and has the structure:
C6~5~ / H3 (II) CHO -CH2CH2N . HCl It was found, however, that when this was used to prepare the aforesaid tablets, the resulting products did not have acceptable chemical and physical stability or tabletting characteristics. Thus, for example, at room tempera-ture and at elevated temperatures and at high humidity conditions, unacceptable discoloration and mottling of the APAP layer occurred. Similarly, at high temperature storage (125F), severe darkening also took place in the ASA layer. In addition, other tablet-ting problems were encountered when the diphenhydramine hydrochloride was employed. Lubrication and compression problems were run into during the tabletting process and the tab~ets were unduly soft.
Efforts were also made to use other diphenhydramine salts in formulating the aforesaid tablets. Particularly, the salicylate and fumarate salt were employed. However, it was found that with these salts also, the resulting tablets were unsatisfactory resulting in soft, mottled and generally physically and chemically unstable tablets.
It has now been discovered, unexpectedly, that when the dihydrogencitrate salt of diphenhydramine is employed in preparing the above described tablets containing ASA, APAP or combinations thereof, the stability of the resulting tablets was very significantly increased.
1~3~5;~ -This also has application to other dosage forms as, for example, when these materials are dispensed in the form of powders or granules contained in a capsule, packet, etc.
It is accordinyly an object of the present invention to provide a relatively stable analgesic sleep-aid compo-sition containing ASA, APAP or combinations thereof and diphenhydramine dihydrogencitrate and a process for preparing the same.
It is also an object of the present invention to provide the novel diphenhydramine dihydrogencitrate salt.
Other and more detailed objects of the present invention will be apparent from the following description and claims.
Thus, in one embodiment the present invention provides a process for preparing diphenhydramine dihydrogencitrate comprising the step of reacting diphenhydramine with citric acid.
As indicated above, the composition of the present invention will contain an analgesic component which may comprise ASA, APAP or a combination of the two. The quantity of the analgesic component that will be contained within a dosage unit (e.g. tablet, capsule, etc.) will be enough so that the required dosage of analgesic can be delivered by the administration of a reasonable number of dosage units. Generally, the quantity of analgesic in a dosage unit in accordance with the present invention may vary from about 80 milligrams to about 1000 milligrams.
This may be all ASA, all APAP or some proportion of each~
When the ASA and APAP are present in the compo-sition, the weight ratio of ASA to APAP can vary over a range (e.g. from about .2 to about 5). However, they will usually be used in about equal proportions by weight.
,~
~39~5,~ `
In the preferred aspects o~ the present invention, the quantity of analgesic which will be contained in the present composition will Eall in the range of from about 450 mg. to about 600 mg. of analgesic. It is also S preferred that both ASA and APAP be contained in the composition and that they be used in about roughly equal proportions by weight i.e. the ratio of ASA
to APAP is in the range o~ from about .90 to 1.10.
The diphenhydramine dihydrogencitrate may be con-tained in the compositions of this invention in varying proportions depending on the quantity and nature of the other ingredients in the composition. Generally, however, it will be present in these compositions at a level of from about 17 mg. to 77 mg. (and pre~erably at a level of about 38.5 mg. per unit dose).
In a preferred aspect of the present invention, the product is prepared as a two layer tablet which comprises an ASA layer and an APAP layer. In this instance too, the total analgesic contained in the tablet will generally be in the range of from about 80 mg. to about 1000 mg. with the preferred range being from about 450 mg.
to 600 mg. Here also weight ratio of ASA to APAP
can vary over a wide range (e.g. from about .2 to about 5) with the preferred ratio being in the range of from about .90 to about 1.10.
In the two layered tablet, the diphenhydramine dihydrogencitrate may be distributed in the ASA
layer, or the APAP layer, or may be distributed in various proportions in both layers. Here again, the diphenhydramine dihydrogencitrate may be present in the two layered tablet at a level of from about 19 mg. to about 77 mg.
with the preferred quantity being about 3~.5 mg. In :~LX39~5~
a preferred aspect of the invention, essentially all of diphenhydramine dihydrogencitrate is containe~ in the APAP layer.
It is useful also to express the relative quantities of the active ingredients contained in the two layered tablets with respect to the total weight of the tablet.
Thus, the ASA may constitute between about 15% to about 90% by weight based on the total weight of the tablet, with the preferred percentage being about 40%
by weight. Similarl~, the APAP may be present in the two layered tablet at a le~el of from about ~5% to about 90% by weight based on the total weight of the tablet.
Here too, the preferred level is about 40% by weight based on the total weight of the table .
The diphenhydramine dihydrogencitrate will usually constitute between about 3% to about 12% by weight based on the total weight of the two layered tablet.
In this case, the preferred level of the diphenhydramine dihydrogencitrate will be about 6% on the same weight basis.
In the preferred procedure for preparing the ASA
layer in the two-layered tablet, ASA is compacted with starch, such that the ASA represents from 85% to 90% of the mixture, and the compact is reduced to granules of an appropriate size range for compression into tablets. A wetting agent such as sodium lauryl sulfate may be added, if desired, to further facilitate disintegration.
Usually, the starch will be present in the ASA
layer at a level of from 18 mg. to 150 mg. (preferably 25 mg.) and will constitute from about lO~ to about 15%
by weight of the ASA layer (preferably 10%).
~35~6~
The APAP layer of the two layered tablet may also contain a disintegrating agent. Several disintegrating agents are known in the prior art which would be suitable for this purpose. Corn starch has proven to be very acceptable. The quantity of disintegrating agent that may be incorporated in the APAP layer may also vary somewhat. For the most part, howe~er, this will be present in the range of from about 12 mg. to about 50 mg.
per tablet and constitute from about 2% to about 8%
by weight based on the total weight of the tablet.
In preparing the APAP layer, it is convenient to prepare a granulation of the active ingredients before compressing the ingredients to form the APAP layer.
For this purpose, as in the preparation of the ASA
layer, it is useful to employ a granulating agent.
Many granulating agents known to those skilled in this art can serve this purpose. ~owever, pregelatinized starch is the preferred granulating agent which usually will be present in an amount in the range of from 5 mg.
to 60 mg. per APAP layer and comprise about 1.5% to about 9% by weight of the finished APAP layer. Preferably, the level of pregelatinized starch will be about 15 mg.
per APAP layer constituting about 4~5~ by weight based on the weight of the APAP layer.
The APAP layer may be prepared in a variety of fashions. In one procedure, the diphenhydramine dihydrogen-citrate is blended with a small quantity of a disinte-grating agent (e.g. starch) which is then reduced to an appropriate particle size. This is then mixed with the APAP and pregelatinized starch and the mixture is granu-lated with water (or water solution containing the color-ing agents). After drying and screening the granulation, the balance of disintegrating agent ~e.g. starch) and the 5~
-- 7 ~
lubricating agent (e.g. hydrogenated castor oil powder) may be blended into the granulation and the mixture compressed to form the APAP layer.
Alternatively, a direct compression APAP product may be utilized. In this instance, the APAP has been preprocessed by the manufacturer to contain various ingredients such as starch, carboxymethyl starch, cellulose or other organic or inorganic materials to impart direct compression properties to it.
In addition, the tablets of the present invention may include the usual tablet additives e.g. lubricating agents, food grade coloring agents, etc. As an illus-tration of a lubricating agent that may be used herein, mention may be made of hydrogenated castor oil powder.
This may be used at a level of from about 0.3% to about 1.3% by weight based on the total weight of the tablet.
The two layered tablet is prepared by filling the die cavity at the first filling station of a two layer tablet press with the appropriate amount of ASA
granulation, adding an appropriate amount of the APAP-diphenhydramine dihydrogencitrate granulation at the second filling station, and compressing the whole into a two layered tablet. Tamping lightly after first layer fill may be included.
In using the compositions of the present invention, one or mc,re of the unit dosage forms described above would be taken by a subject who may be experiencing pain and difficulty in falling asleep. The number of unit dosage forms that will be taken will depend on the particular quantities of active ingredients contained in the dosage form and the dose of active ingredient that is recommended as being safe and effective. In the typical case, where ~3g~
the level of analgesic in a unit dosage form is about 500 mg. which consists of about equal parts by weight of ASA and acetaminophen and the level of diphen-hydramine dihydrogencitrate present is about 38.5 mg., two unit dosage forms (e.g. tablets) will be taken to obtain the desired effect.
The following Examples are given to further illus-trate the present invention. It is to be understood, however, that the invention is not limited thereto.
Preparation of Diphenhydramine Dihydrogencitxate 1. 3 gm. diphenhydramine HCl dissolved in 20 ml. water
ANALGESIC AND DIPHENHYDRAMINE DIHYDROGENCITRATE
_ ___ AND METHOD OF USE
This in~ention relates to an analgesic and sleep aid composltion containing an analgesic (e.g. acetyl-salicylic acid (ASA), acetaminophen (APAP) or combina-tions thereof) and diphenhydramine dihydrogencitrate.
It also concerns diphenhydramine dihydrogencitrate as a novel compound which may be expressed by the formula:
C6H5 ~CH3 ~ 2 H
(I) CHO - CH2CH2N . HO - C - COOH
It is known in the prior art to formulate so-called "nighttime analgesics" consisting of an ASA layer and an APAP layer; the latter also containing metha-pyrilene fumarate. A tablet of this character is described in the "Physicians Desk Reference" 28th Edition, 1974, page 640, column 3 (published by Medical Economics Company, a Litton Division, Oradell, New Jersey). In these tablets, the methapyrilene fumarate is believed to function as a sleep-aid; whereas, the ASA and APAP are thought to play their usual roles.
These tablets have proven to be effective in the past for their intended purposes. Recently, however, some negative opinion has developed with respect to the safety of methapyrilene fumarate. This led to a search for a drug which might replace it in these tablets.
In the course of this search, Applicants attempted to formulate tablets of the above described type which made use of a widely employed antihistamine i.e. diphen-hydramine hydrochloride. This is the hydrochloride ~3~5~
salt of 2-diphenylmethoxy-N,N-dimethylethylamine and has the structure:
C6~5~ / H3 (II) CHO -CH2CH2N . HCl It was found, however, that when this was used to prepare the aforesaid tablets, the resulting products did not have acceptable chemical and physical stability or tabletting characteristics. Thus, for example, at room tempera-ture and at elevated temperatures and at high humidity conditions, unacceptable discoloration and mottling of the APAP layer occurred. Similarly, at high temperature storage (125F), severe darkening also took place in the ASA layer. In addition, other tablet-ting problems were encountered when the diphenhydramine hydrochloride was employed. Lubrication and compression problems were run into during the tabletting process and the tab~ets were unduly soft.
Efforts were also made to use other diphenhydramine salts in formulating the aforesaid tablets. Particularly, the salicylate and fumarate salt were employed. However, it was found that with these salts also, the resulting tablets were unsatisfactory resulting in soft, mottled and generally physically and chemically unstable tablets.
It has now been discovered, unexpectedly, that when the dihydrogencitrate salt of diphenhydramine is employed in preparing the above described tablets containing ASA, APAP or combinations thereof, the stability of the resulting tablets was very significantly increased.
1~3~5;~ -This also has application to other dosage forms as, for example, when these materials are dispensed in the form of powders or granules contained in a capsule, packet, etc.
It is accordinyly an object of the present invention to provide a relatively stable analgesic sleep-aid compo-sition containing ASA, APAP or combinations thereof and diphenhydramine dihydrogencitrate and a process for preparing the same.
It is also an object of the present invention to provide the novel diphenhydramine dihydrogencitrate salt.
Other and more detailed objects of the present invention will be apparent from the following description and claims.
Thus, in one embodiment the present invention provides a process for preparing diphenhydramine dihydrogencitrate comprising the step of reacting diphenhydramine with citric acid.
As indicated above, the composition of the present invention will contain an analgesic component which may comprise ASA, APAP or a combination of the two. The quantity of the analgesic component that will be contained within a dosage unit (e.g. tablet, capsule, etc.) will be enough so that the required dosage of analgesic can be delivered by the administration of a reasonable number of dosage units. Generally, the quantity of analgesic in a dosage unit in accordance with the present invention may vary from about 80 milligrams to about 1000 milligrams.
This may be all ASA, all APAP or some proportion of each~
When the ASA and APAP are present in the compo-sition, the weight ratio of ASA to APAP can vary over a range (e.g. from about .2 to about 5). However, they will usually be used in about equal proportions by weight.
,~
~39~5,~ `
In the preferred aspects o~ the present invention, the quantity of analgesic which will be contained in the present composition will Eall in the range of from about 450 mg. to about 600 mg. of analgesic. It is also S preferred that both ASA and APAP be contained in the composition and that they be used in about roughly equal proportions by weight i.e. the ratio of ASA
to APAP is in the range o~ from about .90 to 1.10.
The diphenhydramine dihydrogencitrate may be con-tained in the compositions of this invention in varying proportions depending on the quantity and nature of the other ingredients in the composition. Generally, however, it will be present in these compositions at a level of from about 17 mg. to 77 mg. (and pre~erably at a level of about 38.5 mg. per unit dose).
In a preferred aspect of the present invention, the product is prepared as a two layer tablet which comprises an ASA layer and an APAP layer. In this instance too, the total analgesic contained in the tablet will generally be in the range of from about 80 mg. to about 1000 mg. with the preferred range being from about 450 mg.
to 600 mg. Here also weight ratio of ASA to APAP
can vary over a wide range (e.g. from about .2 to about 5) with the preferred ratio being in the range of from about .90 to about 1.10.
In the two layered tablet, the diphenhydramine dihydrogencitrate may be distributed in the ASA
layer, or the APAP layer, or may be distributed in various proportions in both layers. Here again, the diphenhydramine dihydrogencitrate may be present in the two layered tablet at a level of from about 19 mg. to about 77 mg.
with the preferred quantity being about 3~.5 mg. In :~LX39~5~
a preferred aspect of the invention, essentially all of diphenhydramine dihydrogencitrate is containe~ in the APAP layer.
It is useful also to express the relative quantities of the active ingredients contained in the two layered tablets with respect to the total weight of the tablet.
Thus, the ASA may constitute between about 15% to about 90% by weight based on the total weight of the tablet, with the preferred percentage being about 40%
by weight. Similarl~, the APAP may be present in the two layered tablet at a le~el of from about ~5% to about 90% by weight based on the total weight of the tablet.
Here too, the preferred level is about 40% by weight based on the total weight of the table .
The diphenhydramine dihydrogencitrate will usually constitute between about 3% to about 12% by weight based on the total weight of the two layered tablet.
In this case, the preferred level of the diphenhydramine dihydrogencitrate will be about 6% on the same weight basis.
In the preferred procedure for preparing the ASA
layer in the two-layered tablet, ASA is compacted with starch, such that the ASA represents from 85% to 90% of the mixture, and the compact is reduced to granules of an appropriate size range for compression into tablets. A wetting agent such as sodium lauryl sulfate may be added, if desired, to further facilitate disintegration.
Usually, the starch will be present in the ASA
layer at a level of from 18 mg. to 150 mg. (preferably 25 mg.) and will constitute from about lO~ to about 15%
by weight of the ASA layer (preferably 10%).
~35~6~
The APAP layer of the two layered tablet may also contain a disintegrating agent. Several disintegrating agents are known in the prior art which would be suitable for this purpose. Corn starch has proven to be very acceptable. The quantity of disintegrating agent that may be incorporated in the APAP layer may also vary somewhat. For the most part, howe~er, this will be present in the range of from about 12 mg. to about 50 mg.
per tablet and constitute from about 2% to about 8%
by weight based on the total weight of the tablet.
In preparing the APAP layer, it is convenient to prepare a granulation of the active ingredients before compressing the ingredients to form the APAP layer.
For this purpose, as in the preparation of the ASA
layer, it is useful to employ a granulating agent.
Many granulating agents known to those skilled in this art can serve this purpose. ~owever, pregelatinized starch is the preferred granulating agent which usually will be present in an amount in the range of from 5 mg.
to 60 mg. per APAP layer and comprise about 1.5% to about 9% by weight of the finished APAP layer. Preferably, the level of pregelatinized starch will be about 15 mg.
per APAP layer constituting about 4~5~ by weight based on the weight of the APAP layer.
The APAP layer may be prepared in a variety of fashions. In one procedure, the diphenhydramine dihydrogen-citrate is blended with a small quantity of a disinte-grating agent (e.g. starch) which is then reduced to an appropriate particle size. This is then mixed with the APAP and pregelatinized starch and the mixture is granu-lated with water (or water solution containing the color-ing agents). After drying and screening the granulation, the balance of disintegrating agent ~e.g. starch) and the 5~
-- 7 ~
lubricating agent (e.g. hydrogenated castor oil powder) may be blended into the granulation and the mixture compressed to form the APAP layer.
Alternatively, a direct compression APAP product may be utilized. In this instance, the APAP has been preprocessed by the manufacturer to contain various ingredients such as starch, carboxymethyl starch, cellulose or other organic or inorganic materials to impart direct compression properties to it.
In addition, the tablets of the present invention may include the usual tablet additives e.g. lubricating agents, food grade coloring agents, etc. As an illus-tration of a lubricating agent that may be used herein, mention may be made of hydrogenated castor oil powder.
This may be used at a level of from about 0.3% to about 1.3% by weight based on the total weight of the tablet.
The two layered tablet is prepared by filling the die cavity at the first filling station of a two layer tablet press with the appropriate amount of ASA
granulation, adding an appropriate amount of the APAP-diphenhydramine dihydrogencitrate granulation at the second filling station, and compressing the whole into a two layered tablet. Tamping lightly after first layer fill may be included.
In using the compositions of the present invention, one or mc,re of the unit dosage forms described above would be taken by a subject who may be experiencing pain and difficulty in falling asleep. The number of unit dosage forms that will be taken will depend on the particular quantities of active ingredients contained in the dosage form and the dose of active ingredient that is recommended as being safe and effective. In the typical case, where ~3g~
the level of analgesic in a unit dosage form is about 500 mg. which consists of about equal parts by weight of ASA and acetaminophen and the level of diphen-hydramine dihydrogencitrate present is about 38.5 mg., two unit dosage forms (e.g. tablets) will be taken to obtain the desired effect.
The following Examples are given to further illus-trate the present invention. It is to be understood, however, that the invention is not limited thereto.
Preparation of Diphenhydramine Dihydrogencitxate 1. 3 gm. diphenhydramine HCl dissolved in 20 ml. water
2. Add 10N NaOH to pH 12, extract with 2 x 25 ml. ether
3. Add and mix 2 gm. citric acid in 200 ml. ether to the ether extract of step 2; crystallize overnight in refrigerator
4. Filter, wash with ether and air dry 2G (M.P. 146.5-148C)
5. Recrystallize from boiling anhydrous ethanol;
filter, wash with anhydrous ethanol, and air dry (M.P. 147.5-148.5C) ^
s~
Preparation of Two-Layered Tablet _gredientsmg/tablet % w/w LAYER I
1. ASA -Starch Gran.
Blue 277.77845.5237 LAYER II
2. Acetaminophen, spec. powd.250.000 40.9713 3. Diphenhydramine dihydrogen-citrate 38.335 6.2825 4. Starch, corn 15.000 2.4583 5. Starch, pregelatinized 15.000 2.4583
filter, wash with anhydrous ethanol, and air dry (M.P. 147.5-148.5C) ^
s~
Preparation of Two-Layered Tablet _gredientsmg/tablet % w/w LAYER I
1. ASA -Starch Gran.
Blue 277.77845.5237 LAYER II
2. Acetaminophen, spec. powd.250.000 40.9713 3. Diphenhydramine dihydrogen-citrate 38.335 6.2825 4. Starch, corn 15.000 2.4583 5. Starch, pregelatinized 15.000 2.4583
6. Color, FD&C Blue #10.065 0.0107
7. Color, D&C Yellow #10 0.005 0.0008
8. Starch, corn 10.000 1.6389
9. Castor oil, hydrog., powd. 4.000 0.6555 Water, deionized q.s.
332.405 100.0000 610.1~3 LAYER I
A. Blend 9 parts ASA with 1 part starch, previously colored blue with FD&C Blue #1.*
B. Compact the mixture in a Chilsonator or other suitable compacting equipment.
C. Pass the compact through a siæe reduction apparatus (such as a Fitzmill or a Tornado mill) using a screen of proper mesh to give an appropriate size range of granules suitable for tabletting.
*Trademark ;~ ~; r, ' ~2~9~i2 LAYER II
A. Preblend 3 and 4, pass through 30 mesh screen to reduce agglomerates.
s. Mix preblend A with 2 and 5, and granulate with a solution of 6 and 7 in cool water (approx.
500 ml/10,000 tablets).
C. Pass wet granulation through Tornado, 5/16"
screen.
D. Dry in Fluid Bed Dryer using cool (R.T.) air to approx. 1% moisture (Ohaus).
E. Pass dry granulation through Oscillator, 0.078" opening screen.
F. Blend in 8 and 9, and this mixture is ready for compression as second layer.
The ASA granulation prepared as described in Layer I above is fed into a die cavity at a first filling station. This material may be tamped down lightly and the die cavity containing this granulation is passed on to a second filling station where the appropriate amount of APAP granulation prepared as des-cribed aboYe under Layer II is fed into the die. The die cavity containing the ASA layer and APAP layer is then passed to a compression station where the two layers are compressed together with a tablet punch to form a two layered tablet.
To compare the relative merits of two layered tablets containing diphenhydramine dihydrogencitrate and diphen-hydramine hydrochloride respectively, two compositions were prepared according to the procedure of Example 2 above. In the one case, the tablets had the composition shown in Example 2 containing the diphenhydramine dihydrogen-citrate and this was identified by the code CK 1566-50.
~ lZ;3~5Z
In the second case, the composition was the same as that shown in Example 2 excepting that an equimolar amount of diphenhydramine hydrochloride (25 mg.) replaced the diphenhydramine dihydrogencitrate and 25 mg. micro-crystalline cellulose replaced the 15 mg. starch as item 4. This product was coded CK 1566-52.
Each of these products was evalua~ed as to problems in tabletting, hardness, disintegration rate, and appearance after aginy under various conditions. The results of these tests are summarized in Table I below:
/
1;~396~;~
~, o o o ~
.~ o U~ .,, o U~ ~ .,, ~ 0 ~ ~ ~ , o I o ,, ~ e ~ ~ ,, , O :~
S~ e ~ ~ ~ O
o O ~ ~ o O ~ C ~ O O ~ ~
s~ ~ 1 o ~ ~ rl ~ a~ o ~ ~ a) ~ e ~
s . .~ ~
O I ~
~ f~
.C ~
Y
O ~ ~
.,~ tQ ~ X
a) ~ ~ D~ ~ O
-~~ ~ 0 ~ I o O ~ I
o v ~ oe e ~ o ~ o ~ 0 0 rl ~1 H U~ ~1 ~ 0 Y
c:_~ Q.O ~ O ~ \t ~ ~ ~ O u~ O
,a v ,1 ,¢
0 t) S~
~ S~
O O _ ~
I ~ ~ ~ ~ ~ ~ ~ ~
a~ o ~q O O O O . O O
In O~ ~ . o ~ .o~ .o~
s~~1 0 ~ 1 0 ~ ~ O -o~ 3 3 3 3 ~ o 3 3 3 e 3 3 3 Z H ~ r H ~1 ~r el~ ~ ~1 ~ ~r ~r O ~oC-) ~ 0 ~1~ ~
~ .~ s~ a~ ~ o .~u, a~ ~ .Y
a~ h ~ 0 S~ h ~~ .q ~ m a) S~h a) u~ ~:4 0 E~~ ~ .~ ~
~L~9652 Formula #1164 Using the procedure given in Example 2, a two layered tablet was prepared having the following compo-sition:
Ingredients mg/tablet % w/w LAYER I
1. ASA -Starch Gran. Blue270.000 44.4517 I~YER II
2. Acetaminophen, spec. powdO 243.000 40.0065 3. Diphenhydramine dihydrogen-citrate 38.335 6.3113 4. Starch, corn 15.000 2.4695 5. Starch, pregelatinized 15.000 2.4695 6. Color, FD&C Blue #10.060 0.0100 7. Color, FD&C Yellow #50.006 0.0010 8. Starch, corn 20.000 3.2927 9. Castor oil, hydrog., powd. 6.000 0.9878
332.405 100.0000 610.1~3 LAYER I
A. Blend 9 parts ASA with 1 part starch, previously colored blue with FD&C Blue #1.*
B. Compact the mixture in a Chilsonator or other suitable compacting equipment.
C. Pass the compact through a siæe reduction apparatus (such as a Fitzmill or a Tornado mill) using a screen of proper mesh to give an appropriate size range of granules suitable for tabletting.
*Trademark ;~ ~; r, ' ~2~9~i2 LAYER II
A. Preblend 3 and 4, pass through 30 mesh screen to reduce agglomerates.
s. Mix preblend A with 2 and 5, and granulate with a solution of 6 and 7 in cool water (approx.
500 ml/10,000 tablets).
C. Pass wet granulation through Tornado, 5/16"
screen.
D. Dry in Fluid Bed Dryer using cool (R.T.) air to approx. 1% moisture (Ohaus).
E. Pass dry granulation through Oscillator, 0.078" opening screen.
F. Blend in 8 and 9, and this mixture is ready for compression as second layer.
The ASA granulation prepared as described in Layer I above is fed into a die cavity at a first filling station. This material may be tamped down lightly and the die cavity containing this granulation is passed on to a second filling station where the appropriate amount of APAP granulation prepared as des-cribed aboYe under Layer II is fed into the die. The die cavity containing the ASA layer and APAP layer is then passed to a compression station where the two layers are compressed together with a tablet punch to form a two layered tablet.
To compare the relative merits of two layered tablets containing diphenhydramine dihydrogencitrate and diphen-hydramine hydrochloride respectively, two compositions were prepared according to the procedure of Example 2 above. In the one case, the tablets had the composition shown in Example 2 containing the diphenhydramine dihydrogen-citrate and this was identified by the code CK 1566-50.
~ lZ;3~5Z
In the second case, the composition was the same as that shown in Example 2 excepting that an equimolar amount of diphenhydramine hydrochloride (25 mg.) replaced the diphenhydramine dihydrogencitrate and 25 mg. micro-crystalline cellulose replaced the 15 mg. starch as item 4. This product was coded CK 1566-52.
Each of these products was evalua~ed as to problems in tabletting, hardness, disintegration rate, and appearance after aginy under various conditions. The results of these tests are summarized in Table I below:
/
1;~396~;~
~, o o o ~
.~ o U~ .,, o U~ ~ .,, ~ 0 ~ ~ ~ , o I o ,, ~ e ~ ~ ,, , O :~
S~ e ~ ~ ~ O
o O ~ ~ o O ~ C ~ O O ~ ~
s~ ~ 1 o ~ ~ rl ~ a~ o ~ ~ a) ~ e ~
s . .~ ~
O I ~
~ f~
.C ~
Y
O ~ ~
.,~ tQ ~ X
a) ~ ~ D~ ~ O
-~~ ~ 0 ~ I o O ~ I
o v ~ oe e ~ o ~ o ~ 0 0 rl ~1 H U~ ~1 ~ 0 Y
c:_~ Q.O ~ O ~ \t ~ ~ ~ O u~ O
,a v ,1 ,¢
0 t) S~
~ S~
O O _ ~
I ~ ~ ~ ~ ~ ~ ~ ~
a~ o ~q O O O O . O O
In O~ ~ . o ~ .o~ .o~
s~~1 0 ~ 1 0 ~ ~ O -o~ 3 3 3 3 ~ o 3 3 3 e 3 3 3 Z H ~ r H ~1 ~r el~ ~ ~1 ~ ~r ~r O ~oC-) ~ 0 ~1~ ~
~ .~ s~ a~ ~ o .~u, a~ ~ .Y
a~ h ~ 0 S~ h ~~ .q ~ m a) S~h a) u~ ~:4 0 E~~ ~ .~ ~
~L~9652 Formula #1164 Using the procedure given in Example 2, a two layered tablet was prepared having the following compo-sition:
Ingredients mg/tablet % w/w LAYER I
1. ASA -Starch Gran. Blue270.000 44.4517 I~YER II
2. Acetaminophen, spec. powdO 243.000 40.0065 3. Diphenhydramine dihydrogen-citrate 38.335 6.3113 4. Starch, corn 15.000 2.4695 5. Starch, pregelatinized 15.000 2.4695 6. Color, FD&C Blue #10.060 0.0100 7. Color, FD&C Yellow #50.006 0.0010 8. Starch, corn 20.000 3.2927 9. Castor oil, hydrog., powd. 6.000 0.9878
10. Water, deionized q.s.
337.401 100.0000 607.401 Formula #1701 Using the procedure given in Example 2, a two layered tablet is prepared having the following composition:
~39~
mg/tablet % w/w LAYER I
1. ASA -Starch Gran. Blue 277.778 44.7134 LAYER II
2. Acetaminophen, spec. powd. 250.000 40.2420 3. Diphenhydramine dihydrogen-citrate 38.335 6.1707 4. Starch, pregelatinized 15.000 2.4145 5. Povidone K-29-32 3.000 0.4829 6. Color, FDC Blue #10.120 0.0193 7. Color, FDC Yellow #10 0.008 0.0013 8. Cellulose, microcrystalline35.000 5.6339 9. Stearic acid, powd.2.000 0.3220 343.463 100. 000 *Trademark 621.241 Using the procedure given in Example 2, the following two layered tablet is prepared:
Ingredients mg/tablet % w/w LAYER I
1. ASA -Starch Gran. Blue277.77844.7149 L~YER II
2. Acetaminophen, Direct Compression, 90~277.778 44.7149 3. Starch, corn 25.000 4.0243 4. Diphenhydramine dihydrogen-citrate 38.335 6.1709 5. Color, FDC Blue #10.300 0.0483 6. Color, FDC Yellow #10 0.030 0.0048 7. Stearic acid, powd.2.000 0.3219 343.4~3 621.221 100.0000 ~ J,:?, ~ A~.
3~16~2 The following is an example of a one layer tablet containing only APAP as the analgesic:
Ingredients mg/tablet % w/w 1. Acetaminophen, spec. powd.500.000 79.8607 2. Diphenhydramine dihydrogen-citrate 38.335 6.1229 3. Micxocrystalline cellulose50.000 7.9861 4. Starch, corn 20.000 3.1944 5. Starch, pregelatinized 10.000 1.5972 6. Povidone K-29-32 5~000 0.7986 7. Color, FDC Blue #10.051 0.0082 8. Color, FDC Yellow #100.0040.0006 9. Methylparaben 0.500 0.0799 10. Propylparaben 0.200 0.0319
337.401 100.0000 607.401 Formula #1701 Using the procedure given in Example 2, a two layered tablet is prepared having the following composition:
~39~
mg/tablet % w/w LAYER I
1. ASA -Starch Gran. Blue 277.778 44.7134 LAYER II
2. Acetaminophen, spec. powd. 250.000 40.2420 3. Diphenhydramine dihydrogen-citrate 38.335 6.1707 4. Starch, pregelatinized 15.000 2.4145 5. Povidone K-29-32 3.000 0.4829 6. Color, FDC Blue #10.120 0.0193 7. Color, FDC Yellow #10 0.008 0.0013 8. Cellulose, microcrystalline35.000 5.6339 9. Stearic acid, powd.2.000 0.3220 343.463 100. 000 *Trademark 621.241 Using the procedure given in Example 2, the following two layered tablet is prepared:
Ingredients mg/tablet % w/w LAYER I
1. ASA -Starch Gran. Blue277.77844.7149 L~YER II
2. Acetaminophen, Direct Compression, 90~277.778 44.7149 3. Starch, corn 25.000 4.0243 4. Diphenhydramine dihydrogen-citrate 38.335 6.1709 5. Color, FDC Blue #10.300 0.0483 6. Color, FDC Yellow #10 0.030 0.0048 7. Stearic acid, powd.2.000 0.3219 343.4~3 621.221 100.0000 ~ J,:?, ~ A~.
3~16~2 The following is an example of a one layer tablet containing only APAP as the analgesic:
Ingredients mg/tablet % w/w 1. Acetaminophen, spec. powd.500.000 79.8607 2. Diphenhydramine dihydrogen-citrate 38.335 6.1229 3. Micxocrystalline cellulose50.000 7.9861 4. Starch, corn 20.000 3.1944 5. Starch, pregelatinized 10.000 1.5972 6. Povidone K-29-32 5~000 0.7986 7. Color, FDC Blue #10.051 0.0082 8. Color, FDC Yellow #100.0040.0006 9. Methylparaben 0.500 0.0799 10. Propylparaben 0.200 0.0319
11. Stearic acid, powd.2.000 0.3195 626.090 100.0000 The following is an example of a single layer tablet containing only ASA as the analgesic:
Ingredients mg/tablet % w/w 1. ASA - 10% starch granulation 555.555 93.231 252. Diphenhydramine dihydrogen-citrate 38.335 6.433 3. Stearic acid 2.000 0.336 595.890 100.000 Blend well and compress :~23~
The following is an example of a single layer tablet containing APAP as the analgesic:
Ingredients mg/tablet % w/w 1. Acetaminophen, direct compression, 95%526.316 82.670 2. Diphenhydramine dihydrogen-citrate 38.335 6.021 3. Cellulose, microcrystalline50.000 7.854 4. Starch, corn 20.000 3.141 5. Stearic acid 2.000 0.314 636.651 100.000 Blend well and compress The following is an example of a single layer tablet in which the analgesic is a mixture of ASA and APAP:
Ingredients mg/tablet ~ w/w 1. ASA, 10~ starch granulation 277.778 46.198 2. Acetaminophen, direct 2Q compression, 95~263.158 43.767 3. Diphenhydramine dihydrogen-citrate 38.335 6.376 4. Starch, corn 20.000 3.326 5. Stearic acid 2.000 0.333 6-01.271 100.000 Blend well and compress To compare the chemical stability of aspirin/APAP
compositions containing diphenhydramine dihydrogencitrate with ASA /APAP compositions containing diphenhydramine hydrochloride, the following formulas were prepared:
~g~52 TABLE II
Formula #
Active Agent CK 1566-52 CK 1566-50 ASA 250 mg 250 mg Acetaminophen 250 mg 2S0 mg Diphenhydramine hydrochloride 25 mg --Diphenhydramine dihydrogen- *
citrate -- 38.335 mg * 38.335 mg of diphenhydramine dihydrogencitrate is the molar equivalent of 25 mg of diphenhydramine hydro-chloride The important measure of chemical stability in any product in which ASA is combined with an amine salt is the rate of production of free salicylic acid produced by the degradation of ASA. The higher the level of free salicylic acid, the more ASA has degraded.
Formulas CK 1566-50 and CK 1566-52 were stored at various temperatures for various periods of time. At specified time intervals, samples of each formula were analyzed for free salicylic acid (FS~). The greater the amount of free salicylic acid found, the less stable the product. The results of this study are summarized in Table III below:
TABLE III
25Product #Condition of Storage Time mg FSA
CK 1566-50 60C/60% RH 90 hrs. 2.27 -52 " " " " 4.85 CK 1566-50 40C/80% RH 1 month 0.38 -52 " " " " 1.45 30CK 1566-50 50C 1 month 0.66 -52 " " 3.0-4.6 CK 1566-50 R.T. 11 months 0.33 -52 1l " O . 95 ~2;~9~5~
Additionally, tablet CK 1566-50 containing diphen-hydramine dihydrogencitrate exhibited a more rapid dissolution rate than tablet CK 1566-52 containing diphenhydramine hydrochloride, as may be seen from the following Table (2 tablets, 250 ml. water at 37C, 50 RPM stirrer):
TABLE IV
Dissolution Rates of Diphenhydramine Salts from Tablets Minutes (dihydrogencitrate~ 4.1 5.7 8.3 15(hyd,rochloride) 10.4 13.1 18.1 Although the invention has been described with reference to specific forms thereof, it will be understood that many changes and modifications may be made without departing from the spirit of this invention.
Ingredients mg/tablet % w/w 1. ASA - 10% starch granulation 555.555 93.231 252. Diphenhydramine dihydrogen-citrate 38.335 6.433 3. Stearic acid 2.000 0.336 595.890 100.000 Blend well and compress :~23~
The following is an example of a single layer tablet containing APAP as the analgesic:
Ingredients mg/tablet % w/w 1. Acetaminophen, direct compression, 95%526.316 82.670 2. Diphenhydramine dihydrogen-citrate 38.335 6.021 3. Cellulose, microcrystalline50.000 7.854 4. Starch, corn 20.000 3.141 5. Stearic acid 2.000 0.314 636.651 100.000 Blend well and compress The following is an example of a single layer tablet in which the analgesic is a mixture of ASA and APAP:
Ingredients mg/tablet ~ w/w 1. ASA, 10~ starch granulation 277.778 46.198 2. Acetaminophen, direct 2Q compression, 95~263.158 43.767 3. Diphenhydramine dihydrogen-citrate 38.335 6.376 4. Starch, corn 20.000 3.326 5. Stearic acid 2.000 0.333 6-01.271 100.000 Blend well and compress To compare the chemical stability of aspirin/APAP
compositions containing diphenhydramine dihydrogencitrate with ASA /APAP compositions containing diphenhydramine hydrochloride, the following formulas were prepared:
~g~52 TABLE II
Formula #
Active Agent CK 1566-52 CK 1566-50 ASA 250 mg 250 mg Acetaminophen 250 mg 2S0 mg Diphenhydramine hydrochloride 25 mg --Diphenhydramine dihydrogen- *
citrate -- 38.335 mg * 38.335 mg of diphenhydramine dihydrogencitrate is the molar equivalent of 25 mg of diphenhydramine hydro-chloride The important measure of chemical stability in any product in which ASA is combined with an amine salt is the rate of production of free salicylic acid produced by the degradation of ASA. The higher the level of free salicylic acid, the more ASA has degraded.
Formulas CK 1566-50 and CK 1566-52 were stored at various temperatures for various periods of time. At specified time intervals, samples of each formula were analyzed for free salicylic acid (FS~). The greater the amount of free salicylic acid found, the less stable the product. The results of this study are summarized in Table III below:
TABLE III
25Product #Condition of Storage Time mg FSA
CK 1566-50 60C/60% RH 90 hrs. 2.27 -52 " " " " 4.85 CK 1566-50 40C/80% RH 1 month 0.38 -52 " " " " 1.45 30CK 1566-50 50C 1 month 0.66 -52 " " 3.0-4.6 CK 1566-50 R.T. 11 months 0.33 -52 1l " O . 95 ~2;~9~5~
Additionally, tablet CK 1566-50 containing diphen-hydramine dihydrogencitrate exhibited a more rapid dissolution rate than tablet CK 1566-52 containing diphenhydramine hydrochloride, as may be seen from the following Table (2 tablets, 250 ml. water at 37C, 50 RPM stirrer):
TABLE IV
Dissolution Rates of Diphenhydramine Salts from Tablets Minutes (dihydrogencitrate~ 4.1 5.7 8.3 15(hyd,rochloride) 10.4 13.1 18.1 Although the invention has been described with reference to specific forms thereof, it will be understood that many changes and modifications may be made without departing from the spirit of this invention.
Claims (24)
1. A process for the preparation of diphenhydramine dihydrogencitrate comprising reacting diphenhydramine with citric acid.
2. A process as in claim 1 wherein the reaction is carried out in an organic solvent.
3. A process as in claim 2 wherein the organic solvent is ether.
4. Diphenhydramine dihydrogencitrate, whenever pre-pared by the process of claim 1, 2 or 3 or by an obvious chemical equivalent thereof.
5. An analgesic and sleep-aid composition contain-ing an analgesic component comprising acetylsalicylic acid (ASA), acetaminophen or a combination of the two; said composition also containing a pharmacologically effective amount of diphenhydramine dihydrogencitrate, said ASA, acetominophen or combination of the two being present in analgesically effective amounts.
6. A composition according to claim 5 in which said analgesic component comprises ASA.
7. A composition according to claim 5 in which said analgesic component comprises acetaminophen.
8. A composition according to claim 5 in which said analgesic component comprises a combination of ASA and acetaminophen.
9. A composition according to claim 8 in the form of a two layered tablet in which essentially all the ASA
is contained in one layer and essentially all the acetaminophen is contained in the other layer.
is contained in one layer and essentially all the acetaminophen is contained in the other layer.
10. A composition according to Claim 9 in which the diphenhydramine dihydrogencitrate is contained in the acetaminophen layer.
11. A composition according to Claim 5 in the form of a unit dosage form in which:
(a) said analgesic component is present in said unit dosage form in the amount of from about 80 mg. to about 1000 mg.; and (b) said diphenhydramine dihydrogencitrate is present in said unit dosage form in the range of from about 19 mg. to about 77 mg.
(a) said analgesic component is present in said unit dosage form in the amount of from about 80 mg. to about 1000 mg.; and (b) said diphenhydramine dihydrogencitrate is present in said unit dosage form in the range of from about 19 mg. to about 77 mg.
12. A composition according to Claim 11 in which said analgesic component comprises ASA.
13. A composition according to Claim 11 in which said analgesic component comprises acetaminophen.
14. A composition according to Claim 11 in which said analgesic component comprises a combination of ASA and acetaminophen.
15. A composition according to Claim 14 wherein the ratio of ASA to acetaminophen on a weight basis is in the range of from about .2 to about 5.
16. A composition according to Claim 15 in which the analgesic component present in said unit dosage form is present in the range of from about 450 mg. to 600 mg.
17. A composition according to Claim 16 in which the ratio of ASA to acetaminophen on a weight basis is in the range of from about .90 to about 1.10.
18. A composition according to Claim 18 in which said diphenhydramine dihydrogencitrate is present in said unit dosage form at a level of about 38.5 mg.
19. A two layered analgesic and sleep-aid tablet comprising an ASA layer and an acetaminophen layer, said tablet containing a pharmacologically effective amount of diphenhydramine dihydrogencitrate; the combina-tion of ASA and acetaminophen in said tablet amounting to from about 80 mg. to about 1000 mg. and the weight ratio of ASA to acetaminophen being in the range of from about .2 to about 5; said diphenhydramine dihydrogen-citrate being present in said tablet in the amount of from about 19 mg. to about 77 mg.
20. A tablet according to Claim 19 in which the diphenhydramine dihydrogencitrate is contained in the acetaminophen layer.
21. A tablet according to Claim 20 in which the amount of the combination of ASA and acetaminophen in said tablet is in the range of from about 450 mg. to about 600 mg.
22. A tablet according to Claim 21 in which the ratio of ASA to acetaminophen on a weight basis is in the range of from about .90 to about 1.10.
23. A tablet according to Claim 22 in which the diphenhydramine dihydrogencitrate is present at a level of about 38.5 mg.
24. Diphenhydramine dihydrogencitrate.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US254,036 | 1981-04-14 | ||
US06/254,036 US4401665A (en) | 1981-04-14 | 1981-04-14 | Sleep-aid composition containing an analgesic and diphenhydramine dihydrogencitrate, and method of use |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1239652A true CA1239652A (en) | 1988-07-26 |
Family
ID=22962690
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000380935A Expired CA1239652A (en) | 1981-04-14 | 1981-06-30 | Sleep-aid composition containing an analgesic and diphenhydramine dihydrogencitrate, and method of use |
Country Status (2)
Country | Link |
---|---|
US (1) | US4401665A (en) |
CA (1) | CA1239652A (en) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1582884A (en) * | 1977-05-19 | 1981-01-14 | Beecham Group Ltd | Clavulanic acid derivatives their preparation and use |
DK330880A (en) * | 1979-08-03 | 1981-02-04 | Beecham Group Ltd | PROCEDURE FOR THE PREPARATION OF CLAVULANIC ACID DERIVATIVES |
NZ199061A (en) * | 1980-12-09 | 1984-10-19 | Beecham Group Ltd | 9-(n-tetrazolyl)-deoxyclavulanic acids,salts,esters,and pharmaceutical compositions |
US4562182A (en) * | 1980-12-23 | 1985-12-31 | Beecham Group P.L.C. | Compounds containing beta-lactams |
DE3346571A1 (en) * | 1983-12-23 | 1985-07-04 | Bayer Ag, 5090 Leverkusen | ORAL RETARDED ACETYLSALICYL ACID FORMULATIONS |
US4757060A (en) * | 1986-03-04 | 1988-07-12 | Bristol-Myers Company | Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 and H2, receptor blockers |
US4894236A (en) * | 1988-01-12 | 1990-01-16 | Choong-Gook Jang | Direct compression tablet binders for acetaminophen |
US5071842A (en) * | 1988-10-14 | 1991-12-10 | Bristol-Myers Squibb Company | Aspirin-containing composition including diphenhydramine and an alkalizing agent to reduce gastrointestinal injury potential |
US6264983B1 (en) | 1999-09-16 | 2001-07-24 | Rhodia, Inc. | Directly compressible, ultra fine acetaminophen compositions and process for producing same |
US20020177626A1 (en) * | 2001-01-19 | 2002-11-28 | Cook Graham D. | Treatment of sleep disturbances |
US20050261278A1 (en) * | 2004-05-21 | 2005-11-24 | Weiner David M | Selective serotonin receptor inverse agonists as therapeutics for disease |
US9592197B2 (en) * | 2004-12-16 | 2017-03-14 | Sovereign Pharmaceuticals, Llc | Dosage form containing diphenhydramine and another drug |
US20070003622A1 (en) * | 2004-12-16 | 2007-01-04 | Sovereign Pharmaceuticals, Ltd. | Diphenhydramine containing dosage form |
US7529255B2 (en) * | 2005-04-21 | 2009-05-05 | Microsoft Corporation | Peer-to-peer multicasting using multiple transport protocols |
US8653135B1 (en) | 2007-02-07 | 2014-02-18 | Sovereign Pharmaceuticals, Llc | Alternating sympathomimetic therapy for the treatment of respiratory aliments |
CN102229537B (en) * | 2011-05-06 | 2013-09-25 | 西南大学 | Method for synthesizing citric acid diphenhydramine |
EA201990684A1 (en) | 2013-12-24 | 2020-12-30 | Вирджиния Коммонвелт Юниверсити | METHODS OF APPLICATION OF OXYGENATED CHOLESTEROL SULPHATES (OCS) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3703519A (en) * | 1970-07-15 | 1972-11-21 | Edward Henderson | Piperazinium mono(acetylsalicylate) |
US4044125A (en) * | 1975-07-18 | 1977-08-23 | Eli Lilly And Company | Method of stabilizing acetylsalicylic acid in the presence of d-propoxyphene hydrochloride and compositions thereof |
US4025624A (en) * | 1975-11-18 | 1977-05-24 | A. H. Robins Company, Incorporated | Phenylalkylamines and phenylalkylureas in combinations to suppress gastric bleeding in aspirin therapy |
US4083950A (en) * | 1976-03-08 | 1978-04-11 | Miles Laboratories, Inc. | Stable acetylsalicylic acid and phenylpropanolamine salt composition |
-
1981
- 1981-04-14 US US06/254,036 patent/US4401665A/en not_active Expired - Lifetime
- 1981-06-30 CA CA000380935A patent/CA1239652A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
US4401665A (en) | 1983-08-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1239652A (en) | Sleep-aid composition containing an analgesic and diphenhydramine dihydrogencitrate, and method of use | |
CA1273873A (en) | Slow release solid preparation | |
JP3037757B2 (en) | Paroxetine tablets and their production | |
PL144347B1 (en) | Method of obtaining therapeutically active constant unit dosis exibiting regular and prolonged releasing system with admnistering | |
US20130142841A1 (en) | Calcium Carbonate Granulation | |
US20110177168A1 (en) | Composition | |
US3362880A (en) | Compressed drug tablets of ethyl cellulose, glyceryl monostearate, karaya gum, tragacanth, talc, and magnesium stearate | |
JPH0660102B2 (en) | Direct compression cyclophosphamide tablets | |
JPS5839618A (en) | Long-acting laminated tablet | |
BG65011B1 (en) | Improved fast disintegrating tablet | |
US4591592A (en) | Acid stabilized compositions of thieno-pyridine derived compounds | |
JPH10501537A (en) | Solid pharmaceutical composition comprising (S) -2- (4-isobutylphenyl) propionic acid as an active ingredient and microcrystalline cellulose and colloidal silica as excipients | |
CA1283857C (en) | Calcium supplement compressed tablets | |
PL179080B1 (en) | Paracetamol and domperidone containing antimigraine tablets and method of making same | |
EP0045238B1 (en) | Acid stabilized compositions of thieno-pyridine derived compounds and process for preventing degradation of such compounds | |
JP2012144560A (en) | Novel pharmaceutical composition and preparation method of the same | |
IL106743A (en) | Tablets with improved bioavailability of the active material clodronic acid | |
US4505862A (en) | Diphenydramine dihydrogencitrate | |
JPS6019715A (en) | Stable isocarbostyril pharmaceutical preparation | |
DE3517820A1 (en) | PHARMACEUTICAL PREPARATIONS WITH ANTI-HYPERTENSIVE AND CARDIOPROTECTIVE EFFECT | |
JP2512302B2 (en) | Method for producing nicorandil-stabilized preparation | |
DE60104442T2 (en) | NEW GALENIC DISPERSIBLE AND SOLUBLE PARACETAMOL PREPARATION, METHOD FOR ITS PREPARATION AND ITS APPLICATIONS | |
US4083950A (en) | Stable acetylsalicylic acid and phenylpropanolamine salt composition | |
CA1228817A (en) | Analgesic preparations | |
US4017614A (en) | Compositions for the relief of migraine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEX | Expiry |