CA1165242A - Compressed and formed alkaline component suitable for use in buffered acetylsalicylic acid product - Google Patents
Compressed and formed alkaline component suitable for use in buffered acetylsalicylic acid productInfo
- Publication number
- CA1165242A CA1165242A CA000383212A CA383212A CA1165242A CA 1165242 A CA1165242 A CA 1165242A CA 000383212 A CA000383212 A CA 000383212A CA 383212 A CA383212 A CA 383212A CA 1165242 A CA1165242 A CA 1165242A
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- Prior art keywords
- alkaline
- magnesium
- component
- compressed
- alkaline component
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/10—Carbonates; Bicarbonates
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
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- Medicinal Chemistry (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A compressed and formed alkaline component suitable for use in a buffered acetylsalicylic acid product. The alkaline component is made of alkaline materials selected from the group consisting of calcium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and mixtures thereof and having incorporated therein citric acid and monobasic sodium phosphate.
A compressed and formed alkaline component suitable for use in a buffered acetylsalicylic acid product. The alkaline component is made of alkaline materials selected from the group consisting of calcium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and mixtures thereof and having incorporated therein citric acid and monobasic sodium phosphate.
Description
116524~
COMPRESSED AND FORMED ALKALINE COMPONENT SUITABLE
FOR USE IN BUFFERED ACETYLSALICYLIC ACID PRODUCT
This invention relates to alkaline components for buffered acetylsalicylic acid (ASA) products. More particu-larly, it concerns alkaline components of the above type which are characterized by an improved rate of reaction with acid that is present in the stomach when such products are adminis-tered to a subject. The novel combined alkaline component-ASA products of this invention have utility as analgesics and/or antipyretics that are commonly ascribed to ASA products.
Buffered ASA products; that is, ASA products that are formulated so as to simultaneously deliver alkaline material and ASA to the stomach has been known for a long time. The alkaline materials are administered simul-taneously with ASA , among other reasons, in order to reduce the acidity of the stomach content during this administration and at the same time, react with ASA
to foxm a s~luble salt. In this fashion, it is hoped that the potential of ASA for gastric irritation and bleeding may be reduced.
The reduction of the acidity in the stomach brought about by the alkaline material is essentially due to the neutralization reaction that takes place between the alkaline material and the acid content of the stomach.
Any factor which would increase the rate of this reaction would tend to increase the beneficial effect of the alkaline material when administered with ASA.
It is customary in the simultaneous administration of alkaline material and ASA to separate the alkaline material from the ASA in the unit dosage form. This may take the form of a mu'ti-layexed tablet in which the B ~
., . ... . .. ~.. .. ~ . .. . . . . . . . . . .
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alkaline material is formed into one layer and the ASA in another layer. In another dosage form, the alkaline layer may be formed into a small tablet or pellet and the ASA may be delivered as a powder or granulation.
In this case, the small tablet might be loaded into a capsule followed by the powdered or granulated ASA
material. In each of the aforesaid cases, the alkaline material is usually prepared as a granulation and then compressed into a form. In the first case, the form takes the shape as a layer of a multi-layered tablet. In the second case, it takes the form of a discrete tablet or pellet.
It has now been found that the rate of reaction of the alkaline material in the aforesaid compressed forms with the acid content of the stomach can be increased if in shaping said alkaline forms, a combination of citric acid and monobasic sodium phosphate (NaH2PO4) is incorporated in the alkaline composition. The citric acid and the monobasic sodium phosphate will usually be added in the orm as a component of the granulating liquid or solution.
Moreover, best results are obtained with alXaline materials selected from the group consisting of magnesium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide and combinations thereof. Of special interest are the following combinations of alkaline materials (1) MgO and CaCO3;
~2) Mg~OH)2 and CaCO3; (3) MgO, MgCO3 and CaCO3; (4) Mg~OH)2, MgCO3 and CaCO3; ~5) MgCO3 and CaCO3; and (6) MgO and Mg(OH)2.
It is accordingly an object of the present invention to provide a compressed and shaped alkaline component for a buffered ASA product which increases the rate of .. . . .. . . . . ... .. .. .... . . .. . . . . .
1165Z4~
reaction of said alkaline component with the acid content of the stomach.
It is also an object of this invention to provide a process for alleviating pain and/or fever in a subject by administering to said subject the product of the fore-going object.
Other and more detailed objects of this invention will be apparent from the following description and claims.
Although the formed compressed alkaline component of the present invention may be used in conjunction with ASA in a variety of modes (e.g. as multi-layered tablets) for convenience of description, emphasis for the most part will be placed on those dosage forms in which the alkaline component is formed into at least one discrete tablet or pellet which is then loaded into a capsule along with a powdered or granulated ASA mix.
This mode of the present invention provides capsules containing analgesic compositions in which the active analgesic ingredient is normally unstable. ASA may be the sole active analgesic ingredient. However, other active analgesics in addition to ASA as well as, other pharmaceutically active ingredients with or without non- ASA analgesics may be contained in the capsule.
The small alkaline tablet which forms part of the analgesic product of this mode of the present invention will contain a combination of the alkaline materials mentioned above. In addition, it may also contain other ingredients which are compatible with the alkaline material in the tablet.
As used herein, the term "ASA mixture" refers to ,tq !... ..
., .
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that powder and/or granular portion of the composition that contains the ASA but may also contain other compatible powder or granular materials. The term "alkaline tablet" refers to the small tablet which con-tains the alkaline material but may also contain other compatible ingredients.
The term "magnesium oxy component" as used in the present specification means a material selected from the group consisting of magnesium oxide, magnesium hydroxide or a combination of magnesium oxide and magnesium hydroxide.
Unless otherwise specified, percent is given as percent by weight based on the total weight of the product contained in the dosage f~rm.
ALKALI~E TABLET
The alkaline tablet used in this mode of the inven-tion is a small tablet dimensioned so that it can be con-veniently dropped into the open end of a capsule which is of a suitable size for use in this invention e.g. #0, #1 and #2. The capsules can be either hard shell or soft shell gelatin capsules, with hard shell preferred. The alkaline tablets will usually comprise the combination of alkaline materials described above that are formed into a granulation by a wet granulation process to provide a material that is readily compressible to form a tablet.
The wet granulation process will usually involve preparing a granulating liquid comprising an aqueous vehicle having dissolved therein citric acid and monobasic sodium phosphate. The quantity of these ingredients con-tained in the granulating liquid may vary somewhat; usually, however, they will fall within the following percent ranges based on the total weight of the granul ating liquid:
' n ,D
.,: .. . . . . . . .. .. . . .. . .. ... . .. .. ... .... ............ . . . . ... .
,, 1~65Z4~
citric acid from about 1% to about 5%; monobasic sodium phosphate from about 1% to about 5%. Other ingredients commonly contained in a granulating liquid may also be contained in the granulating liquid employed in this S invention.
In preparing the alkaline granulation, the granu-lating liquid containing the citric acid and monobasic sodium phosphate is mixed with the alkaline mix described in more detail below. This is then passed through a screen having suitable size openings to form granules which are then dried. The granules 50 formed are then passed through an oscillating screen of suitable size to provide granules that can be compressed into an alkaline tablet.
The quantity of citric acid and monobasic soidum phos-phate that will be contained in the alkaline tablet or other similar formed and compressed alkaline component will var~ some-what. Usually, this will be within the following ranges based on the total weight of said alkaline component: citric acid from about 1% to about 5%; monobasic sodium phosDhate from about 1% to about 5%.
The total quantity of alkaline material as a com-bination of the alkaline ingredients mentioned above may vary somewhat as long as they can be formed into a suitable alkaline sized tablet. The total amount of alkaline material is usually related to the amount of ASA contained in the ASA component. Typically, the amount of alkaline material is present in the tablet at a level of from about 20% to about 150% by weight based on the weight of ASA contained in each capsule.
The quantity employed will depend on the acid consuming capacity ~ACC value) of the alkaline material.
To get the full benefit of the alkaline component insofar as it has an effect on the absorption rate of the ASA, it is important that the alkaline tablet have a l~
. . , , , ~ ............ . . ............. . . .
.
116s24~
fast disintegration rate. Good disintegration rates are obtained where the alkaline material consists of a combina-tion of magnesium carbonate, calcium carbonate and the magnesium oxy component as defined above.
The quantity of alkaline material contained in the compressed alkaline component of this invention may vary somewhat. As used herein, the term alkaline component refers to the formed and compressed alkaline section of the dosage forms. This includes the separate alkaline tablet or tablets that are to be included in a capsule along with ASA or it may be a layer of a multi-layered tablet.
The formed and compressed alkaline component ordinarily will contain other ingredients besides alkaline materials.
Usually, the quantity of alkaline matesial that will be contained within the alkaline component will comprise between about 35% to about 95% by weight based on the total weight of the compressed and formed alkaline component.
Most often, howe~er, alkaline material will constitute between about 75% to about 95% on the same weight basis.
The relative amounts of calcium carbonate, magnesium carbonate and magnesium oxy component that will be con-tained in the compressed and formed alkaline component may also vary. This will largely be determined by the acid consuming capacity requirement for the particular dosage form. Generally, calcium carbonate, when present, will comprise up to 95% by weight of the compressed and formed alkaline component but most often this will not exceed 75%
on the same weight basis. Similarly, when magnesium carbonate i5 utilized, this will ordinarily not exceed 95% by weight of said alkaline component. Again, usually this will not exceed 35% on the same weight basis.
The magnesium oxy component in the form of magnesium oxide, magnesium hydroxide or combinations of magnesium oxide `','~
,... j , , 116524'~
- 6a -and magnesium as indicated above may constitute the sole alkaline material contained in the alkaline component or may be employed in conjunction with the other alkaline materials. When it constitutes all or a part of said alkaline component, it may be used at a level up to and including about 95~ by weight based on the weight of said alkaline component. However, this will ordinarily not exceed about 75% by weight on the same weight basis.
In the preferred form of this invention, all three types of alkaline materials i.e. calcium carbonate, magnesium carbonate and magnesium oxy component are used simultaneously. In this case, the percent ranges for the respective alkaline materials based on the total weight of the compressed and formed alkaline component are as follows:
calcium carbonate from about 20~ to about 75 magnesium carbonate from about 5% to about 35%
magnesium oxy component from about 10~ to about 75%
The magnesium oxy component may be added to the pre-granulation alkaline mix as magnesium oxide, magnesium hydroxide or as a combination of magnesium oxide and magnesium hydroxide. Since the granulation step involves wetting the pre-granulation mix with an aqueous granulating liquid when magnesium oxide is used, some part or all of the magnesium oxide may be converted into magnesium hydroxide.
It is also advantageous to incorporate a disintegrant in the alkaline tablet of the present product to increase the rate at which it disintegrates in the stomach. A variety of materials are known in the tabletting art which will accomplish this function. These include such materials as i ~
, ... . ..
.
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- 6b -corn starch, potato starch, wheat starch, modified starch (e.g. Sta-Rex) and sodium carboxymethyl starch (e.g.
Primoje~). Ordinarily, such materials are present in the alkaline tablet at a level in the range of from about 5% to about 25% by weight based on the total weight of the alkaline tablet.
/
,, B * Trademarks.
116524;~
Other ingredients may be added to the alkaline tablet to improve its physical or oryanoleptic character-istics or to facilitate the manufacture of the alkaline tablet. A lubricant such as magnesium stearate, stearic - 5 acid or silicone fluid may be added to facilitate the tabletting of the alkaline granulation.
The alkaline tablet is dimensioned so that it will contain a maximum amount of weight of material in a minimum Yolume so it can be readily dropped into a gelatin capsule e.g. #0 gelatin capsule. This is accomplished by forming the alkaline tablet as a spheroid or near-spheroid having a diagonal dimension of no greater than the diameter of the open end of the capsule. Usually, the diameter of the tablet at its greatest dimension will be in the range of from about 0.225" to about 0.255"
for #O gelatin capsule. For different sized capsules, the appropriate diameter tablet will be used.
Because of the difficulty in compressing a granu-lation into a true spheroidal tablet in the preferred practice of this inventionJ a modified deep ball punch is employed. This gives a modified spheroidal tablet having the form of a solid cylinder provided with an upper and lower dome. In this case, the important dimension is the diameter of the tablet in longitudinal cross section that extends from the top of one ~ertical side to the bottom of the other ~ertical. A suitable diameter is in the range of from about 0.210" to about 0.255" for #0 gelatin capsule. The punch size will be changed for different gelatin capsule size 80 that the weight of the tablet and the diameter of the tablet Wi'L be reduced proportion-ally to satisfy the ACC meq. alkalinity to the q.s.
ASA used.
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ASA MIXTURE
The principal ingredient on a weight basis in the ASA mixture will usually be ASA. This will ordin-arily take the form of a powder or dry granulation that may vary widely in particle size. In the typical cases, this will usually fall within the range of from about 100~ which pass through a 12 mesh screen to about 100%
which pass through a 80 mesh screen. "~icronized" ASA
well known to those skilled in this art may also be used.
The lower limit of ASA which will be contained in the capsule of this invention will be about 81 mg.
for pediatric use. For adults, this will usually be about 325 mg. The upper limit is limited only by the feasibility of swallowing the size of the capsule that is required to contain this material. As a practical matter, this will rarely exceed about 650 mg. of ASA per capsule. For the usual adult use, between 325 mg. to 500 mg of ASA will be contained in each capsule.
In the preferred embodiment, the ASA level will be about 500 mg~capsule. The ordinary single dose will be one or two capsules for adults.
The ASA mixture may also contain conventional excipients which are compatible with ASA and which are well known to those skilled in the pharmaceutical arts such as, for example, starch, modified starch (e.g.
product sold under the trade mark "Sta-Rx"), micro-crystalline cellulose (Avicel or Elcema), sodium carboxy-methyl starch (Explota~, Primojel).
The quantity of excipient in each capsule can vary depending upon the quantity of ASA contained therein and the size of the capsule. Typically, the quant_ty of excipient in each capsule is within the range of from about * Trademarks - , - - - ,- .
116524A~
g 0% to about 50% by weight based on the weight of the ASA contained in the mixture.
The ASA mixture may also contain a lubricant which serves to facilitate the flow of powder or granular materials during filling and processing. There are a number of lubricants well known to those skilled in this art that may be employed. For example, mention may be made of the Silicone Fluids (i.e. polydimethylsiloxane), fumed silicone dioxide (e.g. Cab-O-Sil* M-5 or Aerosil* 200), light mineral oil, and polyethylene glycol (Carbowax*
400), etc.
The quantity of lubricant in the ASA mixture is related to the quantity of ASA present. Typically, the quantity of lubricant in each capsule is within the range of from about 0.1% to about 5% by weight based on the weight of the ASA contained in the mixture.
In addition to ASA other pharmaceutically active ingredients may be contained in the ASA mixture.
These may be other analgesics, analgesic potentiators, antihistamines, decongestants, and antitussive agents.
By way of illustration of such other pharmaceutically active ingredients, mention may be made of acetaminophen, cafeine, chlorpheniramine maleate, phenylpropanolamine HCl, dextromethorphan, codeine, doxylamine succinate, phenindamine tartate and other salts thereof and surfactants such as sodium lauryl sulfate, polyvinyl-pyrrolidone, polyoxyethylene(20)sorbitan monooleate (Tween*80), etc.
After the alkaline tablets are formed, they are fed to a filling station where each is inserted into the ; body of a capsule and the capsule containing the alkaline tablet is passed on to a second station where it receives * Trademarks.
f D
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the powdered ASA mixture. After receiving the powdered ASA mlxture, the capsule is capped with the upper half of the capsule and the product is completed.
The capsules that are employed in the present inven-tion may be conventional gelatin capsules that are well known to those skilled in this art. These may vary some-what in size but usually they will be #0, ~l, #2 and #3.
Since a fast rate of absorption of ASA into the blood-stream is a desirable feature, it is advantageous to employ a capsule which in itself is fast dissolving.
With this in mind, it is useful to include in the gelatin material that constitutes the capsule about 10% by weight of calcium carbonate based on the total weight of the capsule mentioned.
As indicated above, the formed alkaline component of this invention may form part of a multi-layered tablet also containing ASA. A typical case of this character is a two-layered tablet in which the alkaline granulation described above in preparing the "alkaline tablet" may be used in forming one layer of the tablet and the "ASA
mixture" also described above i9 used to form the ASA
layer of ~uch a two-layered tablet. The technique for making the two-laysred tablets is well known to those skilled in this art. In general, this involves feeding a measured quantity of the ASA ~ranulation into a tablet punch, optionally tamping the ASA granulation down to form a first layer, feeding a measured quantity of the alkaline granulation into said tablet punch to cover said ASA layer and to form a second layer and then compressing the layers together.
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.
'' i~
,. - .. , . . - . . - ~ .
116~24~
For ula RF #2034 (Ca~sule?
Dosage unit Amount Item Gms/10,000 mg/tablet No. Ingredients Tablets PART I: A) Alkaline Granulation 38.24 1 Magnesium oxide U.S.P. heavy 382.4 23.90 2 Magnesium carbonate U.S.P. 239.0 95.60 3 Calcium carbonate U.S.P. heavy ** 956.0
COMPRESSED AND FORMED ALKALINE COMPONENT SUITABLE
FOR USE IN BUFFERED ACETYLSALICYLIC ACID PRODUCT
This invention relates to alkaline components for buffered acetylsalicylic acid (ASA) products. More particu-larly, it concerns alkaline components of the above type which are characterized by an improved rate of reaction with acid that is present in the stomach when such products are adminis-tered to a subject. The novel combined alkaline component-ASA products of this invention have utility as analgesics and/or antipyretics that are commonly ascribed to ASA products.
Buffered ASA products; that is, ASA products that are formulated so as to simultaneously deliver alkaline material and ASA to the stomach has been known for a long time. The alkaline materials are administered simul-taneously with ASA , among other reasons, in order to reduce the acidity of the stomach content during this administration and at the same time, react with ASA
to foxm a s~luble salt. In this fashion, it is hoped that the potential of ASA for gastric irritation and bleeding may be reduced.
The reduction of the acidity in the stomach brought about by the alkaline material is essentially due to the neutralization reaction that takes place between the alkaline material and the acid content of the stomach.
Any factor which would increase the rate of this reaction would tend to increase the beneficial effect of the alkaline material when administered with ASA.
It is customary in the simultaneous administration of alkaline material and ASA to separate the alkaline material from the ASA in the unit dosage form. This may take the form of a mu'ti-layexed tablet in which the B ~
., . ... . .. ~.. .. ~ . .. . . . . . . . . . .
1165Z4;~
alkaline material is formed into one layer and the ASA in another layer. In another dosage form, the alkaline layer may be formed into a small tablet or pellet and the ASA may be delivered as a powder or granulation.
In this case, the small tablet might be loaded into a capsule followed by the powdered or granulated ASA
material. In each of the aforesaid cases, the alkaline material is usually prepared as a granulation and then compressed into a form. In the first case, the form takes the shape as a layer of a multi-layered tablet. In the second case, it takes the form of a discrete tablet or pellet.
It has now been found that the rate of reaction of the alkaline material in the aforesaid compressed forms with the acid content of the stomach can be increased if in shaping said alkaline forms, a combination of citric acid and monobasic sodium phosphate (NaH2PO4) is incorporated in the alkaline composition. The citric acid and the monobasic sodium phosphate will usually be added in the orm as a component of the granulating liquid or solution.
Moreover, best results are obtained with alXaline materials selected from the group consisting of magnesium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide and combinations thereof. Of special interest are the following combinations of alkaline materials (1) MgO and CaCO3;
~2) Mg~OH)2 and CaCO3; (3) MgO, MgCO3 and CaCO3; (4) Mg~OH)2, MgCO3 and CaCO3; ~5) MgCO3 and CaCO3; and (6) MgO and Mg(OH)2.
It is accordingly an object of the present invention to provide a compressed and shaped alkaline component for a buffered ASA product which increases the rate of .. . . .. . . . . ... .. .. .... . . .. . . . . .
1165Z4~
reaction of said alkaline component with the acid content of the stomach.
It is also an object of this invention to provide a process for alleviating pain and/or fever in a subject by administering to said subject the product of the fore-going object.
Other and more detailed objects of this invention will be apparent from the following description and claims.
Although the formed compressed alkaline component of the present invention may be used in conjunction with ASA in a variety of modes (e.g. as multi-layered tablets) for convenience of description, emphasis for the most part will be placed on those dosage forms in which the alkaline component is formed into at least one discrete tablet or pellet which is then loaded into a capsule along with a powdered or granulated ASA mix.
This mode of the present invention provides capsules containing analgesic compositions in which the active analgesic ingredient is normally unstable. ASA may be the sole active analgesic ingredient. However, other active analgesics in addition to ASA as well as, other pharmaceutically active ingredients with or without non- ASA analgesics may be contained in the capsule.
The small alkaline tablet which forms part of the analgesic product of this mode of the present invention will contain a combination of the alkaline materials mentioned above. In addition, it may also contain other ingredients which are compatible with the alkaline material in the tablet.
As used herein, the term "ASA mixture" refers to ,tq !... ..
., .
116524;~
that powder and/or granular portion of the composition that contains the ASA but may also contain other compatible powder or granular materials. The term "alkaline tablet" refers to the small tablet which con-tains the alkaline material but may also contain other compatible ingredients.
The term "magnesium oxy component" as used in the present specification means a material selected from the group consisting of magnesium oxide, magnesium hydroxide or a combination of magnesium oxide and magnesium hydroxide.
Unless otherwise specified, percent is given as percent by weight based on the total weight of the product contained in the dosage f~rm.
ALKALI~E TABLET
The alkaline tablet used in this mode of the inven-tion is a small tablet dimensioned so that it can be con-veniently dropped into the open end of a capsule which is of a suitable size for use in this invention e.g. #0, #1 and #2. The capsules can be either hard shell or soft shell gelatin capsules, with hard shell preferred. The alkaline tablets will usually comprise the combination of alkaline materials described above that are formed into a granulation by a wet granulation process to provide a material that is readily compressible to form a tablet.
The wet granulation process will usually involve preparing a granulating liquid comprising an aqueous vehicle having dissolved therein citric acid and monobasic sodium phosphate. The quantity of these ingredients con-tained in the granulating liquid may vary somewhat; usually, however, they will fall within the following percent ranges based on the total weight of the granul ating liquid:
' n ,D
.,: .. . . . . . . .. .. . . .. . .. ... . .. .. ... .... ............ . . . . ... .
,, 1~65Z4~
citric acid from about 1% to about 5%; monobasic sodium phosphate from about 1% to about 5%. Other ingredients commonly contained in a granulating liquid may also be contained in the granulating liquid employed in this S invention.
In preparing the alkaline granulation, the granu-lating liquid containing the citric acid and monobasic sodium phosphate is mixed with the alkaline mix described in more detail below. This is then passed through a screen having suitable size openings to form granules which are then dried. The granules 50 formed are then passed through an oscillating screen of suitable size to provide granules that can be compressed into an alkaline tablet.
The quantity of citric acid and monobasic soidum phos-phate that will be contained in the alkaline tablet or other similar formed and compressed alkaline component will var~ some-what. Usually, this will be within the following ranges based on the total weight of said alkaline component: citric acid from about 1% to about 5%; monobasic sodium phosDhate from about 1% to about 5%.
The total quantity of alkaline material as a com-bination of the alkaline ingredients mentioned above may vary somewhat as long as they can be formed into a suitable alkaline sized tablet. The total amount of alkaline material is usually related to the amount of ASA contained in the ASA component. Typically, the amount of alkaline material is present in the tablet at a level of from about 20% to about 150% by weight based on the weight of ASA contained in each capsule.
The quantity employed will depend on the acid consuming capacity ~ACC value) of the alkaline material.
To get the full benefit of the alkaline component insofar as it has an effect on the absorption rate of the ASA, it is important that the alkaline tablet have a l~
. . , , , ~ ............ . . ............. . . .
.
116s24~
fast disintegration rate. Good disintegration rates are obtained where the alkaline material consists of a combina-tion of magnesium carbonate, calcium carbonate and the magnesium oxy component as defined above.
The quantity of alkaline material contained in the compressed alkaline component of this invention may vary somewhat. As used herein, the term alkaline component refers to the formed and compressed alkaline section of the dosage forms. This includes the separate alkaline tablet or tablets that are to be included in a capsule along with ASA or it may be a layer of a multi-layered tablet.
The formed and compressed alkaline component ordinarily will contain other ingredients besides alkaline materials.
Usually, the quantity of alkaline matesial that will be contained within the alkaline component will comprise between about 35% to about 95% by weight based on the total weight of the compressed and formed alkaline component.
Most often, howe~er, alkaline material will constitute between about 75% to about 95% on the same weight basis.
The relative amounts of calcium carbonate, magnesium carbonate and magnesium oxy component that will be con-tained in the compressed and formed alkaline component may also vary. This will largely be determined by the acid consuming capacity requirement for the particular dosage form. Generally, calcium carbonate, when present, will comprise up to 95% by weight of the compressed and formed alkaline component but most often this will not exceed 75%
on the same weight basis. Similarly, when magnesium carbonate i5 utilized, this will ordinarily not exceed 95% by weight of said alkaline component. Again, usually this will not exceed 35% on the same weight basis.
The magnesium oxy component in the form of magnesium oxide, magnesium hydroxide or combinations of magnesium oxide `','~
,... j , , 116524'~
- 6a -and magnesium as indicated above may constitute the sole alkaline material contained in the alkaline component or may be employed in conjunction with the other alkaline materials. When it constitutes all or a part of said alkaline component, it may be used at a level up to and including about 95~ by weight based on the weight of said alkaline component. However, this will ordinarily not exceed about 75% by weight on the same weight basis.
In the preferred form of this invention, all three types of alkaline materials i.e. calcium carbonate, magnesium carbonate and magnesium oxy component are used simultaneously. In this case, the percent ranges for the respective alkaline materials based on the total weight of the compressed and formed alkaline component are as follows:
calcium carbonate from about 20~ to about 75 magnesium carbonate from about 5% to about 35%
magnesium oxy component from about 10~ to about 75%
The magnesium oxy component may be added to the pre-granulation alkaline mix as magnesium oxide, magnesium hydroxide or as a combination of magnesium oxide and magnesium hydroxide. Since the granulation step involves wetting the pre-granulation mix with an aqueous granulating liquid when magnesium oxide is used, some part or all of the magnesium oxide may be converted into magnesium hydroxide.
It is also advantageous to incorporate a disintegrant in the alkaline tablet of the present product to increase the rate at which it disintegrates in the stomach. A variety of materials are known in the tabletting art which will accomplish this function. These include such materials as i ~
, ... . ..
.
1165Z4~
- 6b -corn starch, potato starch, wheat starch, modified starch (e.g. Sta-Rex) and sodium carboxymethyl starch (e.g.
Primoje~). Ordinarily, such materials are present in the alkaline tablet at a level in the range of from about 5% to about 25% by weight based on the total weight of the alkaline tablet.
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,, B * Trademarks.
116524;~
Other ingredients may be added to the alkaline tablet to improve its physical or oryanoleptic character-istics or to facilitate the manufacture of the alkaline tablet. A lubricant such as magnesium stearate, stearic - 5 acid or silicone fluid may be added to facilitate the tabletting of the alkaline granulation.
The alkaline tablet is dimensioned so that it will contain a maximum amount of weight of material in a minimum Yolume so it can be readily dropped into a gelatin capsule e.g. #0 gelatin capsule. This is accomplished by forming the alkaline tablet as a spheroid or near-spheroid having a diagonal dimension of no greater than the diameter of the open end of the capsule. Usually, the diameter of the tablet at its greatest dimension will be in the range of from about 0.225" to about 0.255"
for #O gelatin capsule. For different sized capsules, the appropriate diameter tablet will be used.
Because of the difficulty in compressing a granu-lation into a true spheroidal tablet in the preferred practice of this inventionJ a modified deep ball punch is employed. This gives a modified spheroidal tablet having the form of a solid cylinder provided with an upper and lower dome. In this case, the important dimension is the diameter of the tablet in longitudinal cross section that extends from the top of one ~ertical side to the bottom of the other ~ertical. A suitable diameter is in the range of from about 0.210" to about 0.255" for #0 gelatin capsule. The punch size will be changed for different gelatin capsule size 80 that the weight of the tablet and the diameter of the tablet Wi'L be reduced proportion-ally to satisfy the ACC meq. alkalinity to the q.s.
ASA used.
l~.,", ~165Z4;~
ASA MIXTURE
The principal ingredient on a weight basis in the ASA mixture will usually be ASA. This will ordin-arily take the form of a powder or dry granulation that may vary widely in particle size. In the typical cases, this will usually fall within the range of from about 100~ which pass through a 12 mesh screen to about 100%
which pass through a 80 mesh screen. "~icronized" ASA
well known to those skilled in this art may also be used.
The lower limit of ASA which will be contained in the capsule of this invention will be about 81 mg.
for pediatric use. For adults, this will usually be about 325 mg. The upper limit is limited only by the feasibility of swallowing the size of the capsule that is required to contain this material. As a practical matter, this will rarely exceed about 650 mg. of ASA per capsule. For the usual adult use, between 325 mg. to 500 mg of ASA will be contained in each capsule.
In the preferred embodiment, the ASA level will be about 500 mg~capsule. The ordinary single dose will be one or two capsules for adults.
The ASA mixture may also contain conventional excipients which are compatible with ASA and which are well known to those skilled in the pharmaceutical arts such as, for example, starch, modified starch (e.g.
product sold under the trade mark "Sta-Rx"), micro-crystalline cellulose (Avicel or Elcema), sodium carboxy-methyl starch (Explota~, Primojel).
The quantity of excipient in each capsule can vary depending upon the quantity of ASA contained therein and the size of the capsule. Typically, the quant_ty of excipient in each capsule is within the range of from about * Trademarks - , - - - ,- .
116524A~
g 0% to about 50% by weight based on the weight of the ASA contained in the mixture.
The ASA mixture may also contain a lubricant which serves to facilitate the flow of powder or granular materials during filling and processing. There are a number of lubricants well known to those skilled in this art that may be employed. For example, mention may be made of the Silicone Fluids (i.e. polydimethylsiloxane), fumed silicone dioxide (e.g. Cab-O-Sil* M-5 or Aerosil* 200), light mineral oil, and polyethylene glycol (Carbowax*
400), etc.
The quantity of lubricant in the ASA mixture is related to the quantity of ASA present. Typically, the quantity of lubricant in each capsule is within the range of from about 0.1% to about 5% by weight based on the weight of the ASA contained in the mixture.
In addition to ASA other pharmaceutically active ingredients may be contained in the ASA mixture.
These may be other analgesics, analgesic potentiators, antihistamines, decongestants, and antitussive agents.
By way of illustration of such other pharmaceutically active ingredients, mention may be made of acetaminophen, cafeine, chlorpheniramine maleate, phenylpropanolamine HCl, dextromethorphan, codeine, doxylamine succinate, phenindamine tartate and other salts thereof and surfactants such as sodium lauryl sulfate, polyvinyl-pyrrolidone, polyoxyethylene(20)sorbitan monooleate (Tween*80), etc.
After the alkaline tablets are formed, they are fed to a filling station where each is inserted into the ; body of a capsule and the capsule containing the alkaline tablet is passed on to a second station where it receives * Trademarks.
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1165Z4~
the powdered ASA mixture. After receiving the powdered ASA mlxture, the capsule is capped with the upper half of the capsule and the product is completed.
The capsules that are employed in the present inven-tion may be conventional gelatin capsules that are well known to those skilled in this art. These may vary some-what in size but usually they will be #0, ~l, #2 and #3.
Since a fast rate of absorption of ASA into the blood-stream is a desirable feature, it is advantageous to employ a capsule which in itself is fast dissolving.
With this in mind, it is useful to include in the gelatin material that constitutes the capsule about 10% by weight of calcium carbonate based on the total weight of the capsule mentioned.
As indicated above, the formed alkaline component of this invention may form part of a multi-layered tablet also containing ASA. A typical case of this character is a two-layered tablet in which the alkaline granulation described above in preparing the "alkaline tablet" may be used in forming one layer of the tablet and the "ASA
mixture" also described above i9 used to form the ASA
layer of ~uch a two-layered tablet. The technique for making the two-laysred tablets is well known to those skilled in this art. In general, this involves feeding a measured quantity of the ASA ~ranulation into a tablet punch, optionally tamping the ASA granulation down to form a first layer, feeding a measured quantity of the alkaline granulation into said tablet punch to cover said ASA layer and to form a second layer and then compressing the layers together.
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.
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116~24~
For ula RF #2034 (Ca~sule?
Dosage unit Amount Item Gms/10,000 mg/tablet No. Ingredients Tablets PART I: A) Alkaline Granulation 38.24 1 Magnesium oxide U.S.P. heavy 382.4 23.90 2 Magnesium carbonate U.S.P. 239.0 95.60 3 Calcium carbonate U.S.P. heavy ** 956.0
2.39 4 Citric Acid, anhy. powder 23.9 2.39 5 Monosodium phosphate, anhy. (NaH2PO4) 23.9 q.s. to q.s. to dissolve dissolve 4 & 5 6 Water, deionized 4 & 5 2.87 7 Starch, corn 28.7 q. 9 . to 8 Water, deionizedq.s. to suspend 7 suspend 7 16.25 9 Starch, corn 162.5 181.64 1816.4 B) Alkaline Tablet 181.64 10 (A) Alkaline Granulationi816.4 Range 0.36-0.72++ 11 Magnesium stearate, U.S.P.3.6 182.00 1820.0 Procedure:
A) Alkaline Granulation -a. rn ribbon blender charge 1, 2 and 3. Mix for 5 minutes.
11~5~4'~
b. Dissolve 4 and 5 in 6 at 100C.
c. Suspend 7 in 8 and add to (b) while agitating (1 minute).
d. Add hydrolyzed starch (b,c) to (a) and mix for 3-5 minutes.
e. Add 9 to (a) mix another 1-2 minutes.
f. Pass (e) through Tornado Mill with a 3/4"
screen.
g. Dry in Fluid Bed Dryer (inlet temp. 8-90C) outlet temp. 35-36C) to a moisture of 1-2% maximum.
h. Pass (g) through oscillator with a 10 mesh screen.
B) Alkaline Tablet a. In a V-blender mix 10 & 11 for 15 minutes.
b. Compress to the specifications below:
Appearance: White spherical tablet Taste,odor: Alkaline taste Moisture: Part A - 1-2% max.
ACC meq. 4.3 per tablet Punch: 7/32" special spherical punch Weight: 182 mg.
Thickness++: .210"-.230" (cup depth 0.050"-0.057") Disintegration: USP Basket App., Water 37C - 10-30 sec.
Diagonal Measurement .260"
Tablet Wt.: 182 mg + 5%
116524;~
Dosage Unit Prepared for Amount Item 200,000 capsules mg/capsule No._gredients Gms/4,440 PART II: A) Excipient and Lubricant 5 21.20 1Modified starch 15004,000 (Before Range Sta-Rx 1500* drying 4,240) 2.00 2Dimethylpolysiloxane Range Fluid 360 Medical 2-5 Type/350 centistokes 400 0.20 3Polyoxyethylene(20) sorbitan monooleate (Tween 80)* 40 23.40 4,440 B) ASA Mixture 500.00 4 ASA 80 mesh 100,000 22.20 5(A) Excipient & lubricant 4,440 522.20 104.440 ., Procedure A) Excipient and Lubricant -a. Place 1 in a mixer and add 2 and 3 ~previously mixed). Mix for 5 minutes.
b. Dry (a) in a Fluid Bed Dryer (inlet temp. 80C - outlet temp. 55-60C) approx. 15 minutes.
B) ASA Mixture -a. In a Ribbon blender, charge 4 and 5. Mix for 15 minutes.
b. Pass (a) through oscillator with an 8 mesh screen.
OR -1) a. Dry Sta-Rx in o~en at 40-50C to 4~ maximum moisture.
b. In Ribbon blender~ mix Sta-Rx and ASA
for 5 minutes. Then add premixed silicone ~ * Trademarks.
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fluid and Tween 80, mix another 5 min.
Pass through #8 mesh screen.
2) a. Buy dry Sta-Rx 4% maximum moisture.
b. Same as (1 b) Appearance: White oily powder Taste,Odor: Slight Tween*odor Moisture A) Excipient & Lubricant 4% max. (Range 1-4%) Capsule Filling Procedure:
Alkaline tablets prepared in accordance with the procedure described above in Part I (A) and (B) are inserted into ca~sules tcapsule size #0) with an automatic filler.
The ASA mixture prepared in accordance with the pro-cedure described above in Part II (A) and (B) is fed to a hopper and is used to load the capsule in accordance with the following specifications:
Ingredients mg/capsule Excipient 22.20 + 5%
Alkaline Tablet 182.00 Empty caps. 100.00 804.20 Range: 764 mg - 844 mg ~ Trademarks.
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1165Z4'~
Formula 1565-73 (Capsule) Alkaline Tablet -Ingredients mg/tablet gms/batch Magnesium oxide 40 1600 Magnesium carbonate25 1000 Calcium carbonate 100 4000 Starch 2~ 800 Citric Acid 2.5 100 2 4 2.5 100 .
190.0 7600 : Moisture less than 1%
Add Magnesium stearate 0.38 190.38 Disintegration: 10-20 seconds Thickness: .215" - .220"
ACC value = 4.5 meq ASA Mix -Ingredients mg/tablet ASA ~80 mesh) 450.
ASA (micronized) 50.
Sta-Rx (starch) 20.
Silicone fluid 2.
Tween 80 30 2S 522.30 * Trademarks.
..... ,; ...... ... .... .
:, ' 11652~;~
Using automatic or semi-automatic filling equipment #0 gelatin capsules were filled with one alkaline tablet each and the specified amount of ASA mix. Each capsule had the following specifications:
Alkaline tablet 190.38 mg.
ASA mix 522.30 mg Total composition 712.68 mq + 3%
,:
Empty caps. 100.00 mg.
Total Product Weight 812.68 mg.
Formula 1565-82 (Capsule) Alkaline Tablet -Ingredients mg/tablet Magnesium hydroxide 65 Magnesium carbonate 25 Calcium carbonate 78 Sturcal*H
Citric acid 2.5 N H2 4 2.5 Starch 3 Starch 17 Moisture: 1.5%
Alkaline granulation: 193 Magnesium stearate: 0.386 193.386 Weight: 0.193.38 ~hickness: 0.235"
Diagonal: 0.250" + .005 Disintegration time: 10-30 sec.
* Trademark.
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Alkaline tablets made in accordance with the above formula and specifications may be loaded into #0 gelatin capsule, one tablet for each capsule. The aspirin mix described in Example 2 may then be l~aded into each capsule in the measured quantity also specified in Example 2 and then the capsule is capped.
ExAMæLE 4 Formula CL 1565-85 (Capsule) (A) ASA Mix Ingredients mg/capsule ASA 80 crystals 325.
Sta-Rx*(dry) 14.
Silicone Fluid 360 1.4 Tween 80* 0.15 340.55 (B) Alkaline Tablet Same as alkaline tablet of Example 1.
Two alkaline tablets, as described in Example 1, each weighing about 183 mg were prepared from the alkaline mix and placed in an empty #0 gelatin capsule. The aspirin mix is then added to specifications and the cap of the capsule is applied.
*Trademarks.
. . .. . . . . .
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Formula CL 1565-84A (Two-Layered Tablet) (A) ASA Layer Ingredients mg/tablet ASA 12/50 362.
(granulation containing 10~ Starch) ., (B) Alkaline Layer Alkaline mixture of Example 1 before compression into tablet (Formula RF# 2034) 300.
662.
This tablet had a thickness of within .205-.210 and an ACC value of 7.0 meq.
Formula CL_1565-84B (Two-layered Tablet) ~A) ASA Layer Ingredients mg/tablet (granulation containing 10% Starch) 362.
(B) Alkaline Layer Alkaline mixture of Example 1 before compression into tablet (Formula RF #2034) 360.
722.
This tablet had a thickness of from .45" - .220"
and an ACC value of 8.5 meq.
1~3 ' ; ' ' .' ' ~
1~65Z4;~
Formula CL 1565-84C (Two-layered tablet) The same as Example 6, except that tablet had a thickness of .230".
ExAMæLE 8 Formula CL 1565-84D (Two-layered tablet) The same as Example 6, except that tablet had a thickness of .235" - .240".
EX~PLE 9 10Formula CL 1565-84E (Two-layered tablet) The same as Example 6, except that tablet had a thickness of .245".
Formula CD 1854-23 (Two-layered tablet 15capsule shape) LAYER I
Ingredients mg/tablet ASA 12/50 555.5 ~granulation containing 10% starch) LAYER II
Magnesium oxide 63.87 Magnesium carbonate 39.92 Calcium carbonate 159.68 Citric acid 3.99 Monosodium phosphate 3.99 Corn Starch, Part I 4.79 Corn Starch, Part ~ 27.15 Magnesium stearate 0.61 304.00 859.5 ACC value: 7.18 meq.
Compressed on Stokes Rotary press equipped with capsule shaped punches.
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Formula 1595-183 (Two-layered tablet) LAYER I
Ingredients mg/tablet ASA starch granulation 12/50 (ASA 7 1/2 gr) 541.7 LAYER II
Magnesium oxide 88.96 Magnesium carbonate 55.60 Calcium carbonate 222.40 Citric acid 5.56 Monosodium phosphate 5.56 Corn Starch, Part I 6.67 Corn Starch, Part II 37.81 Magnesium stearate 0.84 423.4 965.1 ACC value: 10 meq.
" . ~. , . ~, ~ , .. , . , " .. .. .. ..........
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Formula 1595-182 (Two-layered tablet) LAYE~ I
Ingredients mg/tablet ASA starch granulation 12/50 (ASA 7 1/2 gr) 541.7 LAYER II
Magnesium oxide 63.87 Magnesium carbonate 39.92 Calcium carbonate 159.68 Citric acid 3.99 Monosodium phosphate 3.99 Corn Starch, Part I 4.79 Corn Starch, Part II 27.15 Magnesium stearate 0.61 304.00 .
845.7 ACC value: 7.2 meq.
To compare the relative speed of reaction of the formed alkaline component of the present invention containing the citric acid and monobasic sodium phosphate with one in which these components are absent, the following in vitro experiments were carried out. Alkaline tablets having the formulas set out below were prepared:
116524;~
Formula CL 1565-83A
Alkaline Tablet:
Ingredients mg/tablet Magnesium carbonate 23.90 Calcium carbonate (Sturcal H) 95.60 Magnesium oxide 38.24 Starch 19.12 176.86 Magnesium stearate 0.35 177.21 Formula CL 1565-83B
The same as 1565-83A, except that the CaCO3 was sourced from Pfizer.
Formula CL 1565-73 See Example 2, Alkaline tablet.
Formula CL 1565-82 -See Example 3, Alkaline tablet.
The acid consuming capacity (ACC value) for each of the a~oresaid alkaline tablets were as follows:
CL 1565-82 4.1 meq CL 1565-73 4.3 meq CL 1565-83A 3.75 meq CL 1565-83B 4.1 meq Procedure:
A Radiometer pH stat, Model 79752 was used for this work. The alkaline material is added to the sample cup along with 40 ml of O.OlN HCl. The apparatus is set to maintain the pH at 2. The instrument will automatically add acid ~0.2N) to keep the pH constant at 2. As the antacid reacts it will attempt to raise the solution pH. A strip --` 116524;~
chart recorder plots the addition of acid versus time.
An antacid which reacts rapidly will cause the acid to be added rapidly, resulting i.n a steep slope for the recorder plot.
Tests:
To determine the rate of reaction o~ the respective alkaline tablets with acid, two measurements were made.
The first measurement was the initial slope of the curve that is generated by plotting the ~olume of test acid added to the reaction beaker over time to maintain the constant pH (pH 2). The other measurement is the time in minutes that it takes to consume 50% of the acid consuming capacity of the test alkaline tablet. Five runs were made with each of the test alkaline tablets. The results of these runs are reported in Table I below:
TABLE I
190 mg w/citro-193 mg w/citro-177 mg without without citric phospha-t-e phosp-h-ate_citrophosphate acid T ~in T min T min T min slope S0% meq slope 50% meq slope 50% me~slope 50% meq 21.4 0.~ 23.3 0.5 10.1 1.9 9.1 2.0 20.5 0.6 24.7 0.6 11.1 1.7 8.8 2.0 22.1 0.5 20.3 0.6 7.9 2.1 9.7 2.1 22.8 0.6 23.1 0.6 10.2 1.8 8.1 2.0 20.0 0.6 21.7 0.6 9.2 2.0 8.0 2.1 M = 21.4 0.6 + 0 22.6 0.6 9.7 1.9 8.7 2.0 + 1.7 + 0 + 1.2+ 1.2 + 0.7+ 0.1 CR=0.9CR=2.2 CR=2.5 30The "CR" value reported in Table I is the comparison ratio and is obtained from the following formula:
CR - comparison ratio = Slope (M) standard Slope (M) ~ample 116S24;~
where the mean slope value (M) for CL 1565-73 is taken as the standard. This is introduced to minimize the variation in results that may be due to variations in stirring.
An examination of this Table will show that by all the criteria, the reaction rate of the alkaline tablets containing the citric acid and monobasic sodium phosphate i.e. Formulas CL 1565-73 and CL 1565-~2 was greater when compared with those alkaline compositions that did not con-tain these materials.
A) Alkaline Granulation -a. rn ribbon blender charge 1, 2 and 3. Mix for 5 minutes.
11~5~4'~
b. Dissolve 4 and 5 in 6 at 100C.
c. Suspend 7 in 8 and add to (b) while agitating (1 minute).
d. Add hydrolyzed starch (b,c) to (a) and mix for 3-5 minutes.
e. Add 9 to (a) mix another 1-2 minutes.
f. Pass (e) through Tornado Mill with a 3/4"
screen.
g. Dry in Fluid Bed Dryer (inlet temp. 8-90C) outlet temp. 35-36C) to a moisture of 1-2% maximum.
h. Pass (g) through oscillator with a 10 mesh screen.
B) Alkaline Tablet a. In a V-blender mix 10 & 11 for 15 minutes.
b. Compress to the specifications below:
Appearance: White spherical tablet Taste,odor: Alkaline taste Moisture: Part A - 1-2% max.
ACC meq. 4.3 per tablet Punch: 7/32" special spherical punch Weight: 182 mg.
Thickness++: .210"-.230" (cup depth 0.050"-0.057") Disintegration: USP Basket App., Water 37C - 10-30 sec.
Diagonal Measurement .260"
Tablet Wt.: 182 mg + 5%
116524;~
Dosage Unit Prepared for Amount Item 200,000 capsules mg/capsule No._gredients Gms/4,440 PART II: A) Excipient and Lubricant 5 21.20 1Modified starch 15004,000 (Before Range Sta-Rx 1500* drying 4,240) 2.00 2Dimethylpolysiloxane Range Fluid 360 Medical 2-5 Type/350 centistokes 400 0.20 3Polyoxyethylene(20) sorbitan monooleate (Tween 80)* 40 23.40 4,440 B) ASA Mixture 500.00 4 ASA 80 mesh 100,000 22.20 5(A) Excipient & lubricant 4,440 522.20 104.440 ., Procedure A) Excipient and Lubricant -a. Place 1 in a mixer and add 2 and 3 ~previously mixed). Mix for 5 minutes.
b. Dry (a) in a Fluid Bed Dryer (inlet temp. 80C - outlet temp. 55-60C) approx. 15 minutes.
B) ASA Mixture -a. In a Ribbon blender, charge 4 and 5. Mix for 15 minutes.
b. Pass (a) through oscillator with an 8 mesh screen.
OR -1) a. Dry Sta-Rx in o~en at 40-50C to 4~ maximum moisture.
b. In Ribbon blender~ mix Sta-Rx and ASA
for 5 minutes. Then add premixed silicone ~ * Trademarks.
~ ,,j ,1 ,~
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6S24'~
fluid and Tween 80, mix another 5 min.
Pass through #8 mesh screen.
2) a. Buy dry Sta-Rx 4% maximum moisture.
b. Same as (1 b) Appearance: White oily powder Taste,Odor: Slight Tween*odor Moisture A) Excipient & Lubricant 4% max. (Range 1-4%) Capsule Filling Procedure:
Alkaline tablets prepared in accordance with the procedure described above in Part I (A) and (B) are inserted into ca~sules tcapsule size #0) with an automatic filler.
The ASA mixture prepared in accordance with the pro-cedure described above in Part II (A) and (B) is fed to a hopper and is used to load the capsule in accordance with the following specifications:
Ingredients mg/capsule Excipient 22.20 + 5%
Alkaline Tablet 182.00 Empty caps. 100.00 804.20 Range: 764 mg - 844 mg ~ Trademarks.
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1165Z4'~
Formula 1565-73 (Capsule) Alkaline Tablet -Ingredients mg/tablet gms/batch Magnesium oxide 40 1600 Magnesium carbonate25 1000 Calcium carbonate 100 4000 Starch 2~ 800 Citric Acid 2.5 100 2 4 2.5 100 .
190.0 7600 : Moisture less than 1%
Add Magnesium stearate 0.38 190.38 Disintegration: 10-20 seconds Thickness: .215" - .220"
ACC value = 4.5 meq ASA Mix -Ingredients mg/tablet ASA ~80 mesh) 450.
ASA (micronized) 50.
Sta-Rx (starch) 20.
Silicone fluid 2.
Tween 80 30 2S 522.30 * Trademarks.
..... ,; ...... ... .... .
:, ' 11652~;~
Using automatic or semi-automatic filling equipment #0 gelatin capsules were filled with one alkaline tablet each and the specified amount of ASA mix. Each capsule had the following specifications:
Alkaline tablet 190.38 mg.
ASA mix 522.30 mg Total composition 712.68 mq + 3%
,:
Empty caps. 100.00 mg.
Total Product Weight 812.68 mg.
Formula 1565-82 (Capsule) Alkaline Tablet -Ingredients mg/tablet Magnesium hydroxide 65 Magnesium carbonate 25 Calcium carbonate 78 Sturcal*H
Citric acid 2.5 N H2 4 2.5 Starch 3 Starch 17 Moisture: 1.5%
Alkaline granulation: 193 Magnesium stearate: 0.386 193.386 Weight: 0.193.38 ~hickness: 0.235"
Diagonal: 0.250" + .005 Disintegration time: 10-30 sec.
* Trademark.
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Alkaline tablets made in accordance with the above formula and specifications may be loaded into #0 gelatin capsule, one tablet for each capsule. The aspirin mix described in Example 2 may then be l~aded into each capsule in the measured quantity also specified in Example 2 and then the capsule is capped.
ExAMæLE 4 Formula CL 1565-85 (Capsule) (A) ASA Mix Ingredients mg/capsule ASA 80 crystals 325.
Sta-Rx*(dry) 14.
Silicone Fluid 360 1.4 Tween 80* 0.15 340.55 (B) Alkaline Tablet Same as alkaline tablet of Example 1.
Two alkaline tablets, as described in Example 1, each weighing about 183 mg were prepared from the alkaline mix and placed in an empty #0 gelatin capsule. The aspirin mix is then added to specifications and the cap of the capsule is applied.
*Trademarks.
. . .. . . . . .
``` 1~65Z4~
Formula CL 1565-84A (Two-Layered Tablet) (A) ASA Layer Ingredients mg/tablet ASA 12/50 362.
(granulation containing 10~ Starch) ., (B) Alkaline Layer Alkaline mixture of Example 1 before compression into tablet (Formula RF# 2034) 300.
662.
This tablet had a thickness of within .205-.210 and an ACC value of 7.0 meq.
Formula CL_1565-84B (Two-layered Tablet) ~A) ASA Layer Ingredients mg/tablet (granulation containing 10% Starch) 362.
(B) Alkaline Layer Alkaline mixture of Example 1 before compression into tablet (Formula RF #2034) 360.
722.
This tablet had a thickness of from .45" - .220"
and an ACC value of 8.5 meq.
1~3 ' ; ' ' .' ' ~
1~65Z4;~
Formula CL 1565-84C (Two-layered tablet) The same as Example 6, except that tablet had a thickness of .230".
ExAMæLE 8 Formula CL 1565-84D (Two-layered tablet) The same as Example 6, except that tablet had a thickness of .235" - .240".
EX~PLE 9 10Formula CL 1565-84E (Two-layered tablet) The same as Example 6, except that tablet had a thickness of .245".
Formula CD 1854-23 (Two-layered tablet 15capsule shape) LAYER I
Ingredients mg/tablet ASA 12/50 555.5 ~granulation containing 10% starch) LAYER II
Magnesium oxide 63.87 Magnesium carbonate 39.92 Calcium carbonate 159.68 Citric acid 3.99 Monosodium phosphate 3.99 Corn Starch, Part I 4.79 Corn Starch, Part ~ 27.15 Magnesium stearate 0.61 304.00 859.5 ACC value: 7.18 meq.
Compressed on Stokes Rotary press equipped with capsule shaped punches.
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1~6524;~
Formula 1595-183 (Two-layered tablet) LAYER I
Ingredients mg/tablet ASA starch granulation 12/50 (ASA 7 1/2 gr) 541.7 LAYER II
Magnesium oxide 88.96 Magnesium carbonate 55.60 Calcium carbonate 222.40 Citric acid 5.56 Monosodium phosphate 5.56 Corn Starch, Part I 6.67 Corn Starch, Part II 37.81 Magnesium stearate 0.84 423.4 965.1 ACC value: 10 meq.
" . ~. , . ~, ~ , .. , . , " .. .. .. ..........
1~6SZ4'~
Formula 1595-182 (Two-layered tablet) LAYE~ I
Ingredients mg/tablet ASA starch granulation 12/50 (ASA 7 1/2 gr) 541.7 LAYER II
Magnesium oxide 63.87 Magnesium carbonate 39.92 Calcium carbonate 159.68 Citric acid 3.99 Monosodium phosphate 3.99 Corn Starch, Part I 4.79 Corn Starch, Part II 27.15 Magnesium stearate 0.61 304.00 .
845.7 ACC value: 7.2 meq.
To compare the relative speed of reaction of the formed alkaline component of the present invention containing the citric acid and monobasic sodium phosphate with one in which these components are absent, the following in vitro experiments were carried out. Alkaline tablets having the formulas set out below were prepared:
116524;~
Formula CL 1565-83A
Alkaline Tablet:
Ingredients mg/tablet Magnesium carbonate 23.90 Calcium carbonate (Sturcal H) 95.60 Magnesium oxide 38.24 Starch 19.12 176.86 Magnesium stearate 0.35 177.21 Formula CL 1565-83B
The same as 1565-83A, except that the CaCO3 was sourced from Pfizer.
Formula CL 1565-73 See Example 2, Alkaline tablet.
Formula CL 1565-82 -See Example 3, Alkaline tablet.
The acid consuming capacity (ACC value) for each of the a~oresaid alkaline tablets were as follows:
CL 1565-82 4.1 meq CL 1565-73 4.3 meq CL 1565-83A 3.75 meq CL 1565-83B 4.1 meq Procedure:
A Radiometer pH stat, Model 79752 was used for this work. The alkaline material is added to the sample cup along with 40 ml of O.OlN HCl. The apparatus is set to maintain the pH at 2. The instrument will automatically add acid ~0.2N) to keep the pH constant at 2. As the antacid reacts it will attempt to raise the solution pH. A strip --` 116524;~
chart recorder plots the addition of acid versus time.
An antacid which reacts rapidly will cause the acid to be added rapidly, resulting i.n a steep slope for the recorder plot.
Tests:
To determine the rate of reaction o~ the respective alkaline tablets with acid, two measurements were made.
The first measurement was the initial slope of the curve that is generated by plotting the ~olume of test acid added to the reaction beaker over time to maintain the constant pH (pH 2). The other measurement is the time in minutes that it takes to consume 50% of the acid consuming capacity of the test alkaline tablet. Five runs were made with each of the test alkaline tablets. The results of these runs are reported in Table I below:
TABLE I
190 mg w/citro-193 mg w/citro-177 mg without without citric phospha-t-e phosp-h-ate_citrophosphate acid T ~in T min T min T min slope S0% meq slope 50% meq slope 50% me~slope 50% meq 21.4 0.~ 23.3 0.5 10.1 1.9 9.1 2.0 20.5 0.6 24.7 0.6 11.1 1.7 8.8 2.0 22.1 0.5 20.3 0.6 7.9 2.1 9.7 2.1 22.8 0.6 23.1 0.6 10.2 1.8 8.1 2.0 20.0 0.6 21.7 0.6 9.2 2.0 8.0 2.1 M = 21.4 0.6 + 0 22.6 0.6 9.7 1.9 8.7 2.0 + 1.7 + 0 + 1.2+ 1.2 + 0.7+ 0.1 CR=0.9CR=2.2 CR=2.5 30The "CR" value reported in Table I is the comparison ratio and is obtained from the following formula:
CR - comparison ratio = Slope (M) standard Slope (M) ~ample 116S24;~
where the mean slope value (M) for CL 1565-73 is taken as the standard. This is introduced to minimize the variation in results that may be due to variations in stirring.
An examination of this Table will show that by all the criteria, the reaction rate of the alkaline tablets containing the citric acid and monobasic sodium phosphate i.e. Formulas CL 1565-73 and CL 1565-~2 was greater when compared with those alkaline compositions that did not con-tain these materials.
Claims (19)
1. A compressed and formed alkaline component adapted for use in conjunction with an acetylsalicylic acid (ASA) containing composition so as to provide a buffered ASA product;
said compressed alkaline component comprising an effective buffering amount of an alkaline material selected from the group consisting of calcium carbonate, magnesium carbonate, a magnesium oxy component and mixtures; said magnesium oxy component being selected from the group consisting of magnesium oxide, magnesium hydroxide and a combination of magnesium oxide and magnesium hydroxide; said compressed alkaline component also having incorporated therein citric acid and monobasic sodium phosphate in sufficient quantities to enhance the acid neutralizing reaction rate of said alkaline component.
said compressed alkaline component comprising an effective buffering amount of an alkaline material selected from the group consisting of calcium carbonate, magnesium carbonate, a magnesium oxy component and mixtures; said magnesium oxy component being selected from the group consisting of magnesium oxide, magnesium hydroxide and a combination of magnesium oxide and magnesium hydroxide; said compressed alkaline component also having incorporated therein citric acid and monobasic sodium phosphate in sufficient quantities to enhance the acid neutralizing reaction rate of said alkaline component.
2. A compressed and formed alkaline component according to Claim 1 in which the total alkaline material in said alkaline component is in the range of from about 35% to about 95% by weight based on the total weight of said alkaline component.
3. A compressed and formed alkaline component according to Claim 2 in which the alkaline material in said component is in the range of from about 75% to about 95% by weight based on the total weight of said alkaline component.
4. A compressed and formed alkaline component according to Claim 1 containing at least one of said alkaline materials and in which the various ingredients are present in said compressed alkaline component within the following ranges based on the total weight of said compressed alkaline component:
calcium carbonate from about 0% to about 95%
magnesium carbonate from about 0% to about 95%
magnesium oxy component from about 0% to about 95%
citric acid from about 1% to about 5%
monobasic sodium from about 1% to about 5%
phosphate
calcium carbonate from about 0% to about 95%
magnesium carbonate from about 0% to about 95%
magnesium oxy component from about 0% to about 95%
citric acid from about 1% to about 5%
monobasic sodium from about 1% to about 5%
phosphate
5. A compressed and formed alkaline component accor-ding to Claim 1 containing at least two of said alkaline materials and in which the various ingredients are present in said compressed alkaline component within the following ranges based on the total weight of said compressed alkaline component:
calcium carbonate from about 0% to about 75%
magnesium carbonate from about 0% to about 35%
magnesium oxy component from about 0% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
calcium carbonate from about 0% to about 75%
magnesium carbonate from about 0% to about 35%
magnesium oxy component from about 0% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
6. A compressed and formed alkaline component accor-ding to Claim 1 containing at least three of said alkaline materials in which the various ingredients are present in said compressed alkaline component within the following ranges based on the total weight of said compressed alkaline component:
calcium carbonate from about 20% to about 75%
magnesium carbonate from about 5% to about 35%
magnesium oxy component from about 10% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
calcium carbonate from about 20% to about 75%
magnesium carbonate from about 5% to about 35%
magnesium oxy component from about 10% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
7. A unit dosage form comprising a compressed and formed alkaline component and an ASA containing composition;
said compressed alkaline component comprising an effective buffering amount of an alkaline material selected from the group consisting of calcium carbonate, magnesium carbonate, a magnesium oxy component and mixtures thereof; said magnesium oxy component being selected from the group consist-ing of magnesium oxide, magnesium hydroxide and a combination of magnesium oxide and magnesium hydroxide; said compressed alkaline component also having incorporated therein citric acid and monobasic sodium phosphate in sufficient quantities to enhance the acid neutralizing reaction rate of said alkaline component; said ASA being present in said dosage form in therapeutically effective amounts.
said compressed alkaline component comprising an effective buffering amount of an alkaline material selected from the group consisting of calcium carbonate, magnesium carbonate, a magnesium oxy component and mixtures thereof; said magnesium oxy component being selected from the group consist-ing of magnesium oxide, magnesium hydroxide and a combination of magnesium oxide and magnesium hydroxide; said compressed alkaline component also having incorporated therein citric acid and monobasic sodium phosphate in sufficient quantities to enhance the acid neutralizing reaction rate of said alkaline component; said ASA being present in said dosage form in therapeutically effective amounts.
8. A unit dosage form according to Claim 7 in the form of a capsule containing the compressed alkaline component in the form of at least one tablet or pellet and the ASA in the form of a powder or granulation.
9. A unit dosage form according to Claim 7 in the form of a multi-layered tablet, said compressed alkaline component comprising one layer of said tablet and said ASA being contained in another layer of said tablet.
10. A unit dosage form according to Claims 7, 8 or 9 in which said alkaline material is present in said dosage form at a level of from about 20% to about 150% by weight based on the weight of the ASA in said unit dosage form.
11. A unit dosage form according to Claims 7, 8, or 9 in which the compressed alkaline component contains at least one of said alkaline materials and in which the various ingredients are present in said compressed alkaline component within the following ranges based on the total weight of said compressed alkaline component:
calcium carbonate from about 0% to about 95%
magnesium carbonate from about 0% to about 95%
magnesium oxy component from about 0% to about 95%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
calcium carbonate from about 0% to about 95%
magnesium carbonate from about 0% to about 95%
magnesium oxy component from about 0% to about 95%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
12. A unit dosage form according to Claims 7, 8, or 9 in which the compressed alkaline component contains at least two of said alkaline materials and in which the various ingredients are present in said compressed alkaline component within the following ranges based on the total weight of said compressed alkaline component:
calcium carbonate from about 0% to about 75%
magnesium carbonate from about 0% to about 35%
magnesium oxy component from about 0% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
calcium carbonate from about 0% to about 75%
magnesium carbonate from about 0% to about 35%
magnesium oxy component from about 0% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
13. A unit dosage form according to Claims 7, 8, or 9 in which the compressed alkaline component contains at least three of said alkaline materials and in which the various ingredients are present in said compressed alkaline component within the following ranges based on the total weight of said compressed alkaline component:
calcium carbonate from about 20% to about 75%
magnesium carbonate from about 5% to about 35%
magnesium oxy component from about 10% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
calcium carbonate from about 20% to about 75%
magnesium carbonate from about 5% to about 35%
magnesium oxy component from about 10% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
14. A unit dosage form comprising a capsule con-taining an alkaline component in the form of one or more tablets and an ASA mixture in powder or granular form;
said alkaline component comprising a mixture containing calcium carbonate, magnesium carbonate and a magnesium oxy component selected from the group consisting of magnesium oxide, magnesium hydroxide and a mixture of magnesium oxide and magnesium hydroxide and also having incorporated therein citric acid and monobasic sodium phosphate; said alkaline component being present in said capsule at a level of from about 150 mg to about 400 mg per capsule and the ASA being present in said capsule at a level of from about 81 mg to about 650 mg, the relative proportions of the ingredients in said alkaline component based on the total weight of said alkaline component being as follows:
calcium carbonate from about 20% to about 75%
magnesium carbonate from about 5% to about 35%
magnesium oxy component from about 10% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
said alkaline component comprising a mixture containing calcium carbonate, magnesium carbonate and a magnesium oxy component selected from the group consisting of magnesium oxide, magnesium hydroxide and a mixture of magnesium oxide and magnesium hydroxide and also having incorporated therein citric acid and monobasic sodium phosphate; said alkaline component being present in said capsule at a level of from about 150 mg to about 400 mg per capsule and the ASA being present in said capsule at a level of from about 81 mg to about 650 mg, the relative proportions of the ingredients in said alkaline component based on the total weight of said alkaline component being as follows:
calcium carbonate from about 20% to about 75%
magnesium carbonate from about 5% to about 35%
magnesium oxy component from about 10% to about 75%
citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
15. A unit dosage form according to Claim 14 in which the ASA is present in said capsule at a level from about 325 to about 650 mg. per capsule.
16. A unit dosage form comprising a multi-layered tablet containing an alkaline layer and an ASA layer;
said alkaline layer comprising a mixture containing calcium carbonate, magnesium carbonate and a magnesium oxy component selected from the group consisting of magnesium oxide, magnesium hydroxide and a mixture of magnesium oxide and magnesium hydroxide and also having incorporated therein citric acid and monobasic sodium phosphate, said alkaline material being present in said alkaline layer at a level of from about 150 mg to about 400 mg per unit dosage form and the ASA being present in said capsule at a level of from about 81 mg to about 650 mg per unit dosage form, the relative portions of the ingredients in said alkaline layer based on the total weight of said alkaline layer being as follows:
calcium carbonate from about 20% to about 75%
magnesium carbonate from about 5% to about 35 magnesium oxy component from about 10% to about 75 citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
said alkaline layer comprising a mixture containing calcium carbonate, magnesium carbonate and a magnesium oxy component selected from the group consisting of magnesium oxide, magnesium hydroxide and a mixture of magnesium oxide and magnesium hydroxide and also having incorporated therein citric acid and monobasic sodium phosphate, said alkaline material being present in said alkaline layer at a level of from about 150 mg to about 400 mg per unit dosage form and the ASA being present in said capsule at a level of from about 81 mg to about 650 mg per unit dosage form, the relative portions of the ingredients in said alkaline layer based on the total weight of said alkaline layer being as follows:
calcium carbonate from about 20% to about 75%
magnesium carbonate from about 5% to about 35 magnesium oxy component from about 10% to about 75 citric acid from about 1% to about 5%
monobasic sodium phosphate from about 1% to about 5%
17. A unit dosage form according to Claim 16 in which the ASA is present in said unit dosage form at a level of from about 325 mg to about 650 mg per unit dosage form.
18. A process for forming a compressed alkaline component which comprises forming a dry mix comprising calcium carbonate, magnesium carbonate and a magnesium oxy component selected from the group consisting of magnesium oxide, magnesium hydroxide and a combination of magnesium oxide and magnesium hydroxide, wetting said mixture with a granulating liquid containing citric acid and monobasic sodium phosphate, granulating said wetted mixture and then compressing said granulated material to form a compressed alkaline component.
19. A process according to Claim 18 in which said citric acid is present in said granulating liquid at a level in the range of from about 1% to about 5% by weight based on the total weight of the granulating liquid and said monobasic sodium phosphate is present in said granulating liquid at a level in the range of from about 1% to about 5% by weight based on the total weight of granulating liquid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US27801181A | 1981-07-01 | 1981-07-01 | |
| US278,011 | 1981-07-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1165242A true CA1165242A (en) | 1984-04-10 |
Family
ID=23063318
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000383212A Expired CA1165242A (en) | 1981-07-01 | 1981-08-05 | Compressed and formed alkaline component suitable for use in buffered acetylsalicylic acid product |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS588020A (en) |
| KR (1) | KR880001933B1 (en) |
| AU (1) | AU551510B2 (en) |
| BE (1) | BE893729A (en) |
| CA (1) | CA1165242A (en) |
| GR (1) | GR75990B (en) |
| NZ (1) | NZ200695A (en) |
| PH (1) | PH18787A (en) |
| PT (1) | PT75168B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7030162B2 (en) | 1996-11-12 | 2006-04-18 | Pozen Inc. | Treatment of migraine headache |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4102629A1 (en) * | 1991-01-30 | 1992-08-06 | Bayer Ag | PHARMACEUTICAL RUBBER WITH ACETYL SALICYLIC ACID |
| FR2708853A1 (en) * | 1993-06-30 | 1995-02-17 | Salsarulo Gilles | Acetylsalicylic acid composition with improved bioavailability and process for producing it |
| US5498426A (en) * | 1994-10-03 | 1996-03-12 | The Procter & Gamble Company | Liquid antacid compositions |
| UA95093C2 (en) | 2005-12-07 | 2011-07-11 | Нікомед Фарма Ас | Method for the preparation of calcium-containing compound |
| JP5663238B2 (en) * | 2009-08-31 | 2015-02-04 | ライオン株式会社 | Oral solid preparation and method for producing the same |
-
1981
- 1981-08-05 CA CA000383212A patent/CA1165242A/en not_active Expired
-
1982
- 1982-05-20 NZ NZ200695A patent/NZ200695A/en unknown
- 1982-05-24 AU AU84109/82A patent/AU551510B2/en not_active Ceased
- 1982-05-26 GR GR68265A patent/GR75990B/el unknown
- 1982-06-28 PH PH27503A patent/PH18787A/en unknown
- 1982-06-30 PT PT75168A patent/PT75168B/en not_active IP Right Cessation
- 1982-06-30 JP JP57111859A patent/JPS588020A/en active Granted
- 1982-07-01 KR KR8202953A patent/KR880001933B1/en active
- 1982-07-01 BE BE0/208511A patent/BE893729A/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7030162B2 (en) | 1996-11-12 | 2006-04-18 | Pozen Inc. | Treatment of migraine headache |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ200695A (en) | 1985-02-28 |
| JPS588020A (en) | 1983-01-18 |
| AU8410982A (en) | 1983-01-06 |
| PH18787A (en) | 1985-09-25 |
| GR75990B (en) | 1984-08-03 |
| AU551510B2 (en) | 1986-05-01 |
| PT75168A (en) | 1982-07-01 |
| KR840000239A (en) | 1984-02-18 |
| PT75168B (en) | 1985-06-28 |
| KR880001933B1 (en) | 1988-10-04 |
| JPH0244286B2 (en) | 1990-10-03 |
| BE893729A (en) | 1983-01-03 |
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