CA1105835A - Pharmaceutical tablet comprising anti-allergic drug - Google Patents
Pharmaceutical tablet comprising anti-allergic drugInfo
- Publication number
- CA1105835A CA1105835A CA278,833A CA278833A CA1105835A CA 1105835 A CA1105835 A CA 1105835A CA 278833 A CA278833 A CA 278833A CA 1105835 A CA1105835 A CA 1105835A
- Authority
- CA
- Canada
- Prior art keywords
- formulation according
- active ingredient
- tetrahydro
- oxo
- pyran
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT
There is described a pharmaceutical tablet formulation comprising an anti-allergic drug having sodium cromoglycate like activity, as active ingredient, in combination with a lubricant and a diluent (and preferably also a flow aid and a binder) the low aid, binder, lubricant and diluent containing no material capable of causing an adverse reaction in an allergic patient.
Unit dosage forms of 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid and 6,7,8,9-tetrahydro-S-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-ccarboxylic acid are also described.
The formulations and unit dosage forms are indicated for use in the treatment of allergies.
There is described a pharmaceutical tablet formulation comprising an anti-allergic drug having sodium cromoglycate like activity, as active ingredient, in combination with a lubricant and a diluent (and preferably also a flow aid and a binder) the low aid, binder, lubricant and diluent containing no material capable of causing an adverse reaction in an allergic patient.
Unit dosage forms of 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid and 6,7,8,9-tetrahydro-S-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-ccarboxylic acid are also described.
The formulations and unit dosage forms are indicated for use in the treatment of allergies.
Description
~1~35~35 This invention relates to a novel formulation.
It has for a number of years been known to formulate a variety OL anti-allergic drugs with various excipients in order to present the drugs in convenient pharmaceutically ac-S ceptable form. However a number of the excipients have beenfound to be, or contain, materials to which some patients are allergic. Thus the anomolous situation has arisen in which it has been proposed that a group of patients who may be particu-larly prone to allergies should be treated with an anti-allergic drug which has been formulated with a material capableof causing an adverse, e.g. allergic, reaction.
According to the invention we provide a pharmaceutical tablet formulation comprising an anti-allergic drug having so-dium cromoglycate like activity, as active ingredient, wherein the formulation is (a) a tablet formulation comprising the drug in combination with a lubricant and a diluent, the lubri-cant and diluent containing no material capable of causing an adverse reaction in an allergic patient, (b) a formulation comprising from 2 to 12 mg (determined as the free acid) of 20 6,7,8,9-tetrahydro-5 hydroxy-4-oxo-10-propyl-4H-naphtho[2,3,-b]pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof, in unit dosage form, or (c) a formulation comprising from 10 to 50 mg (determined as the free acid) of 6,7,8,9-tetrahydro-4-oxo-lO-propyl-4H-naphtho-[2,3,b]pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof, in unit dosage form.
The formulation preferably also contains a flow aid and/or a binder, the flow aid and/or binder containing no 5~335 -2a-material capable of causing an adverse reaction in an allergic patient.
The material capable of causing an adverse reaction in the patient may be a material, e.g. lactose, which can cause an adverse reaction through an enzyme deficiency in certain individuals or may be a material which contains residual traces of an anti-biotic such as penicillin or may be a material con-taining an actually or - -~ 3 ~ ~1~35835 potentially allergenic material.
Material which is not actually or potentially allergenic is material which will not result in increased hypersensitivity of the individual treated to the material. The material should not be capable of eliciting an immune response, either anti-body or cell mediated. The material should also not combine with protein to form a hapten carrier system and should not activate the complement pathways in formation of C5a or C3a~
We particularly prefer there to be no proteinaceous material in the formulation. Examples of materials which should be excluded from the formulation are gelatin, starch, starch derivatives (e.g. sodium starch glycollate) and acacia. Materials which contain traces of protein because of their originr e.g.
lactose; or method of manufacture, e.g. maltose-dextrose oombinations produced by enzyme treatment (and sold under the Trade Mark Emdex) should also be excluded from the formulation.
The formation of the tablet may comprise the steps of wet granulation, dry granulation, melting, moulding, enteric coating, film coating or formation into controlled release form. However we prefer to use a oomposition which can be compressed into a tablet directly without an intermediate, e.g. a wet or dry granulation, stage.
The flow aid may bel for example, purified talc or silicon dioxide and especially colloidal silicon dioxide having a mean particle size of about 12 nm.
_ 4 _ 3L~583S
The binder may be, for example, polyvinylpyrrolidone or methyl cellulose.
The lubricant may be, for example, stearic acid, a metallic stearate, a polyethylene glycol of molecular weight of 4,000 or more, or purified talc.
The diluent, which may also serve as disintegrant, may be microcrystalline cellulose, or a cellulose derivative, e.g. a cellulose ether such as methyl cellulose; or sodium ~icarbonate or dibasic calcium phosphate. The formulation may also comprise a disintegrant as anentity separate from the diluent. When the disintegrant is a separate entity it should contain no material capable of causing an adverse, e.g. allergic reaction, in an allergic patient.
The formulation may be made by dry mixing the active ingredient with the other ingredients, e.g. the flow aid, binder, lubricant and diluent/disintegrant, for example in a powder blending machine. The mixing may be carried out in two stages, the blend, or parts thereof, being sieved through an appropriate screen (e.g. 60 mesh, 250 micron) at the end of a first stage in order to disperse any persistant aggregates. The sieved powder may then be mixed further. The resulting mixture ma~ then be compressed in a tablet forming machine.
The active ingredient may be any suitable anti-allergic drug, having sodium cromoglycate like activity. A drug having sodium cromoglycate like activity is able to inhibit the release of .
pharmaoological mediators which result from the in vivo combination of certain types of ~nti-body and specific antigen, for example the ccmbination of reaginic antibody and specific antigen (see Example 27 of British Patent Specification No 1,292,601 - the rat passive cutaneous anaphylaxis test).
The active ingredients may be characterised by the following biological tests and results thereof.
The compound is first tested in the rat passive cutaneous anaphylaxis test. If the oompound does not show significant inhibition of allergic manifestations at 20 mg/kg intraperitoneally (i.p) or intravenously (i.v) in this test, its activity is generally too low. Various other biological tests may be used to show that the compound exhibits its anti-allergy activity as an inhibitor of mediators of anaphylaxis rather than as, for example an end oryan antagonist, cholinergic or anti-cholinergic and adenyl cyclase stimulator. Therefore, tests to see if the compound inhibits the effect of histamine, serotonin, and slow reacting substance of anaphylaxis (SRSA), that is, that the compound is an end organ antagonist of the mediators, may be employed. Such tests are well known and include contraction of guinea pig ileum in the presence of methylsergide for serotonin activity. If activity is still observed in these systems, it is due to histamine action. A
further check on histamine is through the spectrafluorimetric assay descriked by Shore, Burkhalter and Cohn, Journal of Pharmacology and Experimental Therapeutics/ Vol 127 page 182. ~ctive ingredients . =~
6 ~ 8 3 5 according bo the invention are not end organ antagonists.
If the results frcm these tests show that the active ingredient is not an end organ antagonist further tests may be run to show that the co~pound is not exhibiting its activity through cholinergicity or anti-cholinergicity, e.g. by the reversal of acetylcholine induced guinea pig tracheal chain contraction. An active ingredient will not be a cholinergic or anti-cholinergic.
Specific groups of active ingredients are b~ be found among the chrcmone-2-carboxylic acids, and suitable derivatives thereof, e.g. those described in British Patent Specifications Nos 1,368,243;
1,144,905; 1,230,087 and West German Patent Specification No 2,553,688. Other active ingredients are to be found among the xanthones, e.g. of Belgian Patent Nos 759,292 and 787,843 and Dutch Patent Specification Nos 72,09622 and 73,06958; among the compounds of Belgian Patent No 8~9,935; among the nitroindanediones, e.g. of Belgian Patent No 792,867; among the phenanthrolines, e.g. of Belgium Patent No 773,200; among the azapurines, e.g. of Belgian Patent No 776,683; the oxazoles, e.g. of West German OLS 2,459,380;
and the flavones, e.g. of Belgian Patent No 823,875.
Partlcularly preferred are the chrcmones and chromone like oompounds of British Patent SpecificationsNos 1,144,905; and 1,230,087 and West German Patent Specification No 2,553,688. More specifically we prefer 1,3-bis(2-carboxychrcmon-5-yloxy)propan-2-ol or a pharmaceutically acceptable derivative, e.g. salt such as the disodium salt, ther~of; this latter is commonly kncwn as sodium ~5835 c~omoglycate or cromolyn sodium. As further preferred co~pounds there may be mentioned 6,7,~,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-bjpyran-2-carboxylic acid and pharmaceutically acceptable derivatives thereof (oollectively referred to herein as 'active ingredient B') and 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho~2,3-b]pyran-2-carboxylic acid and pharmaceutically acceptable derivatives thereof (oollectively referred to herein as 'active ingredient A'). When using the chromone and chromone like compounds described in this paragraph we prefer the oomposition not to oontain di- or tri- basic cations.
Pharmaceutically acceptable derivatives within the meaning of active ingredient A or B include pharmaceutically acceptable salts, esters and amides of the 2-carboxylic acid group. Suitable salts include ammonium, alkali metal (e.g. sodium, potassium and lithium) salts and salts with suitable organic bases, e.g. salts with hydroxylamine, lcwer alkylamines such as methylamine or ethylamine, with substituted lower alkylamines, e.g. hydroxy substituted alkylamines such as tris(hydroxymethyl)methylamine, or with simple monocyclic nitrogen heterocyclic ccmpounds, e.g.
piperidine or morpholine. Suitable esters include simple lcwer alkyl esters, e.g. the ethyl ester, esters derived from alcohols containing basic groups, e.g. di-lcwer alkyl amino substituted alkanols such as the ~-(diethoxyamino)-ethyl ester, and acyloxy alkyl esters, e.g. a lcwer acyl-lcwer alkyl ester such as the pivaloyloxymethyl ester, or a bis-ester derived from a dihydroxy - 8 - ~ ~ ~5~35 compound, e.g. a di(hydroxy-lcwer alkyl) ether, e.g. the bis-2-oxapropan-1,3-diyl ester. The pharmaceutically acceptable salts of the basic esters, e.g. the hydrochloride, may also be used.
We prefer to use as active ingredient A or B the free carboxylic acid or the scdium salt thereof. In particular we prefer to use the free carboxylic acid as it is more orally acceptable than the derivatives thereof.
We prefer the formulation to contain less than 50%, and preferably between about 0.5 and 18% by weight of active ingredient A or B. Unexpectedly even with very small proportions of active ingredient A or B we have found that a lubricant is highly desirable. We prefer the lubricant to oomprise up to 4.0%
and preferably 0.2 to 4.0%, by weight of the composition. We also prefer the composition to contain between about 0.1 and 5.0%, e.g.
about 0.5%, by weight of the flow aid. We prefer the binder to oomprise from about 0.5 to 5% by weight of the composition, and the diluent/disintegrant to comprise from about 80 to 99~ by weight of the oomposition.
We prefer tablet formulations containing an active ingredient A to contain frcm 3 to 15%, and more preferably from 4 to 10% by weight of water as such formulations have advantageous flow and oompression characteristics.
Aocording to a further feature of our invention we provide a pharmaceutical formulation oomprising from 2 to 12 mg (determined as the free acid) of an active ingredient A in unit dosage form.
"''~
~ ~ - 8 -~'`''~'' '" ' '' ' ' - 9 ~ 5835 In particular we prefer a unit dosage form comprising from 3 to 12 mg (determined as the free acid) and re preferably from 3 to 6 mg (determined as the free acid) of an active ingredient A.
Suitably unit dosage forms comprising 3, 6 or 12 mg (determined as the free acid) of the active ingredient A may be used.
We also provide a pharmaceutical formulation comprising from 10 to 50 mg (determined as the free acid) of an active ingredient in unit dosage form. In particular we prefer a unit dosage form comprising from 10 to 30 mg (determined as the free acid) of active ingredient B.
The unit dosages of this invention are advantageous in that they represent the dosage the patient is to take at any one t~me.
Thus the patient only has to take one unit dose (or posssibly two unit doses, depending on the patient's ability to swallcw the larger unit doses) at any one time, thereby leading to consistent and convenient therapy through the elimination of dosage errors.
Dosages above a single dose of 20 mg of active ingredient A
(determined as the free acid) or above 50 mg of active ingredient B
(determined as the free acid) at any one time have a tendency to cause some stomach irritation in some patients and doses below
It has for a number of years been known to formulate a variety OL anti-allergic drugs with various excipients in order to present the drugs in convenient pharmaceutically ac-S ceptable form. However a number of the excipients have beenfound to be, or contain, materials to which some patients are allergic. Thus the anomolous situation has arisen in which it has been proposed that a group of patients who may be particu-larly prone to allergies should be treated with an anti-allergic drug which has been formulated with a material capableof causing an adverse, e.g. allergic, reaction.
According to the invention we provide a pharmaceutical tablet formulation comprising an anti-allergic drug having so-dium cromoglycate like activity, as active ingredient, wherein the formulation is (a) a tablet formulation comprising the drug in combination with a lubricant and a diluent, the lubri-cant and diluent containing no material capable of causing an adverse reaction in an allergic patient, (b) a formulation comprising from 2 to 12 mg (determined as the free acid) of 20 6,7,8,9-tetrahydro-5 hydroxy-4-oxo-10-propyl-4H-naphtho[2,3,-b]pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof, in unit dosage form, or (c) a formulation comprising from 10 to 50 mg (determined as the free acid) of 6,7,8,9-tetrahydro-4-oxo-lO-propyl-4H-naphtho-[2,3,b]pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof, in unit dosage form.
The formulation preferably also contains a flow aid and/or a binder, the flow aid and/or binder containing no 5~335 -2a-material capable of causing an adverse reaction in an allergic patient.
The material capable of causing an adverse reaction in the patient may be a material, e.g. lactose, which can cause an adverse reaction through an enzyme deficiency in certain individuals or may be a material which contains residual traces of an anti-biotic such as penicillin or may be a material con-taining an actually or - -~ 3 ~ ~1~35835 potentially allergenic material.
Material which is not actually or potentially allergenic is material which will not result in increased hypersensitivity of the individual treated to the material. The material should not be capable of eliciting an immune response, either anti-body or cell mediated. The material should also not combine with protein to form a hapten carrier system and should not activate the complement pathways in formation of C5a or C3a~
We particularly prefer there to be no proteinaceous material in the formulation. Examples of materials which should be excluded from the formulation are gelatin, starch, starch derivatives (e.g. sodium starch glycollate) and acacia. Materials which contain traces of protein because of their originr e.g.
lactose; or method of manufacture, e.g. maltose-dextrose oombinations produced by enzyme treatment (and sold under the Trade Mark Emdex) should also be excluded from the formulation.
The formation of the tablet may comprise the steps of wet granulation, dry granulation, melting, moulding, enteric coating, film coating or formation into controlled release form. However we prefer to use a oomposition which can be compressed into a tablet directly without an intermediate, e.g. a wet or dry granulation, stage.
The flow aid may bel for example, purified talc or silicon dioxide and especially colloidal silicon dioxide having a mean particle size of about 12 nm.
_ 4 _ 3L~583S
The binder may be, for example, polyvinylpyrrolidone or methyl cellulose.
The lubricant may be, for example, stearic acid, a metallic stearate, a polyethylene glycol of molecular weight of 4,000 or more, or purified talc.
The diluent, which may also serve as disintegrant, may be microcrystalline cellulose, or a cellulose derivative, e.g. a cellulose ether such as methyl cellulose; or sodium ~icarbonate or dibasic calcium phosphate. The formulation may also comprise a disintegrant as anentity separate from the diluent. When the disintegrant is a separate entity it should contain no material capable of causing an adverse, e.g. allergic reaction, in an allergic patient.
The formulation may be made by dry mixing the active ingredient with the other ingredients, e.g. the flow aid, binder, lubricant and diluent/disintegrant, for example in a powder blending machine. The mixing may be carried out in two stages, the blend, or parts thereof, being sieved through an appropriate screen (e.g. 60 mesh, 250 micron) at the end of a first stage in order to disperse any persistant aggregates. The sieved powder may then be mixed further. The resulting mixture ma~ then be compressed in a tablet forming machine.
The active ingredient may be any suitable anti-allergic drug, having sodium cromoglycate like activity. A drug having sodium cromoglycate like activity is able to inhibit the release of .
pharmaoological mediators which result from the in vivo combination of certain types of ~nti-body and specific antigen, for example the ccmbination of reaginic antibody and specific antigen (see Example 27 of British Patent Specification No 1,292,601 - the rat passive cutaneous anaphylaxis test).
The active ingredients may be characterised by the following biological tests and results thereof.
The compound is first tested in the rat passive cutaneous anaphylaxis test. If the oompound does not show significant inhibition of allergic manifestations at 20 mg/kg intraperitoneally (i.p) or intravenously (i.v) in this test, its activity is generally too low. Various other biological tests may be used to show that the compound exhibits its anti-allergy activity as an inhibitor of mediators of anaphylaxis rather than as, for example an end oryan antagonist, cholinergic or anti-cholinergic and adenyl cyclase stimulator. Therefore, tests to see if the compound inhibits the effect of histamine, serotonin, and slow reacting substance of anaphylaxis (SRSA), that is, that the compound is an end organ antagonist of the mediators, may be employed. Such tests are well known and include contraction of guinea pig ileum in the presence of methylsergide for serotonin activity. If activity is still observed in these systems, it is due to histamine action. A
further check on histamine is through the spectrafluorimetric assay descriked by Shore, Burkhalter and Cohn, Journal of Pharmacology and Experimental Therapeutics/ Vol 127 page 182. ~ctive ingredients . =~
6 ~ 8 3 5 according bo the invention are not end organ antagonists.
If the results frcm these tests show that the active ingredient is not an end organ antagonist further tests may be run to show that the co~pound is not exhibiting its activity through cholinergicity or anti-cholinergicity, e.g. by the reversal of acetylcholine induced guinea pig tracheal chain contraction. An active ingredient will not be a cholinergic or anti-cholinergic.
Specific groups of active ingredients are b~ be found among the chrcmone-2-carboxylic acids, and suitable derivatives thereof, e.g. those described in British Patent Specifications Nos 1,368,243;
1,144,905; 1,230,087 and West German Patent Specification No 2,553,688. Other active ingredients are to be found among the xanthones, e.g. of Belgian Patent Nos 759,292 and 787,843 and Dutch Patent Specification Nos 72,09622 and 73,06958; among the compounds of Belgian Patent No 8~9,935; among the nitroindanediones, e.g. of Belgian Patent No 792,867; among the phenanthrolines, e.g. of Belgium Patent No 773,200; among the azapurines, e.g. of Belgian Patent No 776,683; the oxazoles, e.g. of West German OLS 2,459,380;
and the flavones, e.g. of Belgian Patent No 823,875.
Partlcularly preferred are the chrcmones and chromone like oompounds of British Patent SpecificationsNos 1,144,905; and 1,230,087 and West German Patent Specification No 2,553,688. More specifically we prefer 1,3-bis(2-carboxychrcmon-5-yloxy)propan-2-ol or a pharmaceutically acceptable derivative, e.g. salt such as the disodium salt, ther~of; this latter is commonly kncwn as sodium ~5835 c~omoglycate or cromolyn sodium. As further preferred co~pounds there may be mentioned 6,7,~,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-bjpyran-2-carboxylic acid and pharmaceutically acceptable derivatives thereof (oollectively referred to herein as 'active ingredient B') and 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho~2,3-b]pyran-2-carboxylic acid and pharmaceutically acceptable derivatives thereof (oollectively referred to herein as 'active ingredient A'). When using the chromone and chromone like compounds described in this paragraph we prefer the oomposition not to oontain di- or tri- basic cations.
Pharmaceutically acceptable derivatives within the meaning of active ingredient A or B include pharmaceutically acceptable salts, esters and amides of the 2-carboxylic acid group. Suitable salts include ammonium, alkali metal (e.g. sodium, potassium and lithium) salts and salts with suitable organic bases, e.g. salts with hydroxylamine, lcwer alkylamines such as methylamine or ethylamine, with substituted lower alkylamines, e.g. hydroxy substituted alkylamines such as tris(hydroxymethyl)methylamine, or with simple monocyclic nitrogen heterocyclic ccmpounds, e.g.
piperidine or morpholine. Suitable esters include simple lcwer alkyl esters, e.g. the ethyl ester, esters derived from alcohols containing basic groups, e.g. di-lcwer alkyl amino substituted alkanols such as the ~-(diethoxyamino)-ethyl ester, and acyloxy alkyl esters, e.g. a lcwer acyl-lcwer alkyl ester such as the pivaloyloxymethyl ester, or a bis-ester derived from a dihydroxy - 8 - ~ ~ ~5~35 compound, e.g. a di(hydroxy-lcwer alkyl) ether, e.g. the bis-2-oxapropan-1,3-diyl ester. The pharmaceutically acceptable salts of the basic esters, e.g. the hydrochloride, may also be used.
We prefer to use as active ingredient A or B the free carboxylic acid or the scdium salt thereof. In particular we prefer to use the free carboxylic acid as it is more orally acceptable than the derivatives thereof.
We prefer the formulation to contain less than 50%, and preferably between about 0.5 and 18% by weight of active ingredient A or B. Unexpectedly even with very small proportions of active ingredient A or B we have found that a lubricant is highly desirable. We prefer the lubricant to oomprise up to 4.0%
and preferably 0.2 to 4.0%, by weight of the composition. We also prefer the composition to contain between about 0.1 and 5.0%, e.g.
about 0.5%, by weight of the flow aid. We prefer the binder to oomprise from about 0.5 to 5% by weight of the composition, and the diluent/disintegrant to comprise from about 80 to 99~ by weight of the oomposition.
We prefer tablet formulations containing an active ingredient A to contain frcm 3 to 15%, and more preferably from 4 to 10% by weight of water as such formulations have advantageous flow and oompression characteristics.
Aocording to a further feature of our invention we provide a pharmaceutical formulation oomprising from 2 to 12 mg (determined as the free acid) of an active ingredient A in unit dosage form.
"''~
~ ~ - 8 -~'`''~'' '" ' '' ' ' - 9 ~ 5835 In particular we prefer a unit dosage form comprising from 3 to 12 mg (determined as the free acid) and re preferably from 3 to 6 mg (determined as the free acid) of an active ingredient A.
Suitably unit dosage forms comprising 3, 6 or 12 mg (determined as the free acid) of the active ingredient A may be used.
We also provide a pharmaceutical formulation comprising from 10 to 50 mg (determined as the free acid) of an active ingredient in unit dosage form. In particular we prefer a unit dosage form comprising from 10 to 30 mg (determined as the free acid) of active ingredient B.
The unit dosages of this invention are advantageous in that they represent the dosage the patient is to take at any one t~me.
Thus the patient only has to take one unit dose (or posssibly two unit doses, depending on the patient's ability to swallcw the larger unit doses) at any one time, thereby leading to consistent and convenient therapy through the elimination of dosage errors.
Dosages above a single dose of 20 mg of active ingredient A
(determined as the free acid) or above 50 mg of active ingredient B
(determined as the free acid) at any one time have a tendency to cause some stomach irritation in some patients and doses below
2 mg of active ingredient A (determined as the free acid) or belcw 10 mg of active ingredient B (determined as the free acid) tend to produce an increasing failure of the patient to respond therapeutically.
In addition to the active ingredient A or B the unit dosages ,~
, ~ , .
, .
' ' ' ~
- 10 - ~ 5835 may also contain (preferably a major proportion of) a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets and dragées; microcrystalline cellulose, lactose, starch, talc or stearic acid; for capsules, tartaric acid, starch, stearic acid or lactose. The unit dosages may also be formulated in controlled release form.
We also provide a process for the production of unit dosage forms according to the invention, which comprises forming an active ingredient A or B, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, into discreet and separate units each of which oomprises the required unit dosage. The forming into discreet units will normally be effected by filling an appropriate volume (or weight) of the finely divided or granulated active ingredient, optionally in ~ combination with an adjuvant, diluent or carrier into a defined ; space, e.g. a capsule, or the die of a tabletting machine.
According to our invention we also provide a pharmaceutical tablet ccrposition ccmprising an active ingredient A or B, in combination with a lubricant and a diluent, and also, preferably, a flow aid, a binder and a disintegrant.
We prefer that none of the ingredients oontain actually or potentially allergenic material and in particular no proteinaceous material. Thus we prefer tablet formulations as described above and containing an active ingredient A or B.
~ ``;'i ' ' 583~
Tablets according to the invention preferably have a diametral crushing strength of at least 1.5, and preferably from 3 to 7, kp Schleuniger (Dr K Schleuniger and Co, Zurich, Switzerland). We also prefer that the tablets are such that when tested using the S disintegration test apparatus of the United States Pharmacopoeia XIX, using water as the medium, they disintegrate in less than 30 minutes. We also prefer that the tablets have a lcw friability.
In particular we prefer that, when 20 pre-dusted and weighed tablets are rotated in a Roche Friabilator drum (Shafer EGE, Wollish EG
and Engel OE Journal of the American Pharmaceutical Association (1956) Vol 45 pages 114-116) at 25 rpm for 8 minutes, and are then re-dusted, the tablet weight 106s shàll be less than 3%, and more preferably less than 1%.
The unit dosages and other compositions of this invention, and in particular compositions containing sodium cromoglycatè or an active ingredient A or B, are indicated for use in the treatment of ~ allergic conditions, e.g. asthma, (notably allergic asthma) and ; conditions of the gastrointestinal tract such as Crohn's disease, ulcerative oolitis and proctitis. The unit dosages and other compositions are also indicated for use in the treatment of so-called 'intrinsic' asthma (in which no sensitivity to extrinsic antigen can be demonstrated). The unit dosages and other compositions - are also indicated for use in the treatment of hay fever, urticaria and eczema.
We particularly prefer formulations containing 1,3-bis(2-. ~ :
. .
: '' '- ' , ~ . ' carboxy-chromon-5-yloxy)propan-2-ol or 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid, oe a pharmaceutically acceptable derivative of either thereof.
The invention is illustrated, but in no way limited by the following Examples.
Example 1 Tablet mg/tablet Micronised or milled 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-prop~1-4H-naphtho[2,3-b]
pyran-2-carboxylic acid 3.0 Colloidal silicon dioxide 'Aerosil 200' (Aerosil is a Trade Mark~ 0.5 Polyvinylpyrrolidone 'Plasdone' K29-32 (Plasdone is a Trade Mark) 2.0 Stearic acid 60 mesh O.S
Microcrystalline cellulose IAvicel PH 101' (Avicel is a Trade M~rk) 94.0 Approximately 100.0 The micronised or milled 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid was mixed with the oolloidal silicon dioxide, polyvinylpyrrolidone, stearic acid and the microcrystalline oe llulose in a high speed powder blender.
The walls of the blender and its impeller blade were scraped down with a spatula after about 5 minutes mixing and the mixing was then continued until a suitable degree of mixing had been achieved.
To improve the flow and compression properties and to improve tablet stability on storage (with respect to crushing strength and , .
disintegration time) the moisture content of the blend was oontrolled within the range 3-15% w/w, and preferably within the range 4-10~ w/w.
The final mixture was then compressed in a tablet forming 5 machine to a diametral crushing strength of 5 kp Schleuniger.
ExamPle 2 Tablet mg/tablet Sodium Cromoglycate B.P. 200 Sodium Bicarbonate B.P. 150 Purified Talc 16 Total weight dry 366 The sodium cromoglycate and sodium bicarbonate were dry mixed together in a planetary mixer, then moistened with purified water, approximately 20 parts of water being added to 100 parts by weight solids. The moistened material was passed through a 16 mesh screen then dried in a fluid bed drier. The purifier talc was blended into the dry granules and the tablets compressed on 10 mm punches on a rotary tablet machine to a diametral crushing strength of 6-8 kp Schleuniger.
; - 13 -... . . .
- .:
.
- 14 ~~ ~q~5835 ExamPle 3 Tablet mg/tablet 6,7,8,9-Tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid micronised or milled 25.0 Sodium bicarbonate B.P. 75.0 Microcrystalline cellulose 'Avicel PH 101' 50.0 Methyl oe llulose 20 B.P.C. (added as 5~
aqueous solution) 1.5 Stearic acid 60 mesh 3.0 154.5 The 6,7,8,9-tetrahydro-4-oxo-10-propyl-4EI-naphtho[2,3-b]-pyran-2-carboxylic acid, half the microcrystalline cellulose and the sodium bicarbonate were dry mixed together and moistened witll a 5~ aqueous solution of the methyl oe llulose, adding appropriately 20 parts of solution to 100 parts by weight of powder. The moistened powder was granulated through a 16 mesh (1,000 micron) screen and fluid bed dried using an inlet air temperature of 60C.
The dried granules were passed through a 16 mesh (1,000 micron) screen and mixed with the remaining microcrystalline cellulose and the stearic acid. The blend was compressed on a tablet forming machine to a diametral crushing strength of 4-7 kp Schleuniger.
In addition to the active ingredient A or B the unit dosages ,~
, ~ , .
, .
' ' ' ~
- 10 - ~ 5835 may also contain (preferably a major proportion of) a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets and dragées; microcrystalline cellulose, lactose, starch, talc or stearic acid; for capsules, tartaric acid, starch, stearic acid or lactose. The unit dosages may also be formulated in controlled release form.
We also provide a process for the production of unit dosage forms according to the invention, which comprises forming an active ingredient A or B, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, into discreet and separate units each of which oomprises the required unit dosage. The forming into discreet units will normally be effected by filling an appropriate volume (or weight) of the finely divided or granulated active ingredient, optionally in ~ combination with an adjuvant, diluent or carrier into a defined ; space, e.g. a capsule, or the die of a tabletting machine.
According to our invention we also provide a pharmaceutical tablet ccrposition ccmprising an active ingredient A or B, in combination with a lubricant and a diluent, and also, preferably, a flow aid, a binder and a disintegrant.
We prefer that none of the ingredients oontain actually or potentially allergenic material and in particular no proteinaceous material. Thus we prefer tablet formulations as described above and containing an active ingredient A or B.
~ ``;'i ' ' 583~
Tablets according to the invention preferably have a diametral crushing strength of at least 1.5, and preferably from 3 to 7, kp Schleuniger (Dr K Schleuniger and Co, Zurich, Switzerland). We also prefer that the tablets are such that when tested using the S disintegration test apparatus of the United States Pharmacopoeia XIX, using water as the medium, they disintegrate in less than 30 minutes. We also prefer that the tablets have a lcw friability.
In particular we prefer that, when 20 pre-dusted and weighed tablets are rotated in a Roche Friabilator drum (Shafer EGE, Wollish EG
and Engel OE Journal of the American Pharmaceutical Association (1956) Vol 45 pages 114-116) at 25 rpm for 8 minutes, and are then re-dusted, the tablet weight 106s shàll be less than 3%, and more preferably less than 1%.
The unit dosages and other compositions of this invention, and in particular compositions containing sodium cromoglycatè or an active ingredient A or B, are indicated for use in the treatment of ~ allergic conditions, e.g. asthma, (notably allergic asthma) and ; conditions of the gastrointestinal tract such as Crohn's disease, ulcerative oolitis and proctitis. The unit dosages and other compositions are also indicated for use in the treatment of so-called 'intrinsic' asthma (in which no sensitivity to extrinsic antigen can be demonstrated). The unit dosages and other compositions - are also indicated for use in the treatment of hay fever, urticaria and eczema.
We particularly prefer formulations containing 1,3-bis(2-. ~ :
. .
: '' '- ' , ~ . ' carboxy-chromon-5-yloxy)propan-2-ol or 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid, oe a pharmaceutically acceptable derivative of either thereof.
The invention is illustrated, but in no way limited by the following Examples.
Example 1 Tablet mg/tablet Micronised or milled 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-prop~1-4H-naphtho[2,3-b]
pyran-2-carboxylic acid 3.0 Colloidal silicon dioxide 'Aerosil 200' (Aerosil is a Trade Mark~ 0.5 Polyvinylpyrrolidone 'Plasdone' K29-32 (Plasdone is a Trade Mark) 2.0 Stearic acid 60 mesh O.S
Microcrystalline cellulose IAvicel PH 101' (Avicel is a Trade M~rk) 94.0 Approximately 100.0 The micronised or milled 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid was mixed with the oolloidal silicon dioxide, polyvinylpyrrolidone, stearic acid and the microcrystalline oe llulose in a high speed powder blender.
The walls of the blender and its impeller blade were scraped down with a spatula after about 5 minutes mixing and the mixing was then continued until a suitable degree of mixing had been achieved.
To improve the flow and compression properties and to improve tablet stability on storage (with respect to crushing strength and , .
disintegration time) the moisture content of the blend was oontrolled within the range 3-15% w/w, and preferably within the range 4-10~ w/w.
The final mixture was then compressed in a tablet forming 5 machine to a diametral crushing strength of 5 kp Schleuniger.
ExamPle 2 Tablet mg/tablet Sodium Cromoglycate B.P. 200 Sodium Bicarbonate B.P. 150 Purified Talc 16 Total weight dry 366 The sodium cromoglycate and sodium bicarbonate were dry mixed together in a planetary mixer, then moistened with purified water, approximately 20 parts of water being added to 100 parts by weight solids. The moistened material was passed through a 16 mesh screen then dried in a fluid bed drier. The purifier talc was blended into the dry granules and the tablets compressed on 10 mm punches on a rotary tablet machine to a diametral crushing strength of 6-8 kp Schleuniger.
; - 13 -... . . .
- .:
.
- 14 ~~ ~q~5835 ExamPle 3 Tablet mg/tablet 6,7,8,9-Tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid micronised or milled 25.0 Sodium bicarbonate B.P. 75.0 Microcrystalline cellulose 'Avicel PH 101' 50.0 Methyl oe llulose 20 B.P.C. (added as 5~
aqueous solution) 1.5 Stearic acid 60 mesh 3.0 154.5 The 6,7,8,9-tetrahydro-4-oxo-10-propyl-4EI-naphtho[2,3-b]-pyran-2-carboxylic acid, half the microcrystalline cellulose and the sodium bicarbonate were dry mixed together and moistened witll a 5~ aqueous solution of the methyl oe llulose, adding appropriately 20 parts of solution to 100 parts by weight of powder. The moistened powder was granulated through a 16 mesh (1,000 micron) screen and fluid bed dried using an inlet air temperature of 60C.
The dried granules were passed through a 16 mesh (1,000 micron) screen and mixed with the remaining microcrystalline cellulose and the stearic acid. The blend was compressed on a tablet forming machine to a diametral crushing strength of 4-7 kp Schleuniger.
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical formulation comprising an anti-allergic drug having sodium cromoglycate like activity, as active ingredient, wherein the formulation is a tablet formulation comprising the drug in combination with a lubricant and a diluent, the lubricant and diluent containing no material capable of causing an adverse reaction in an allergic patient.
2. A formulation according to Claim 1, comprising a flow aid and a binder, the flow aid and the binder containing no material capable of causing an adverse reaction in an allergic patient.
3. A formulation according to Claim 1, wherein the diluent also serves as a disintegrant.
4. A formulation according to Claim 1, 2 or 3 containing no proteinaceous material.
5. A formulation according to Claim 2 or Claim 3, comprising purified talc or silicon dioxide as flow aid, polyvinylpyrrolidone or methyl cellulose as binder and wherein the diluent is micro-crystalline cellulose, a cellulose ether, sodium bicarbonate or dibasic calcium phosphate.
6. A formulation according to any one of Claims 1,2 or 3, wherein the active ingredient is 1,3-bis(2-carboxychromon-5-yloxy) propan-2-ol or a pharmaceutically acceptable derivative thereof.
7. A formulation according to any one of Claims 1,2 or 3, wherein the active ingredient is 6, 7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof.
8. A formulation according to any one of Claims 1, 2 or 3, wherein the active ingredient is 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof.
9. A formulation according to any one of Claims 1, 2 or 3 containing less than 50% by weight of active ingredient.
10. A formulation according to any one of Claims 1, 2 or 3 containing from 0.5 to 18% by weight of active ingredient, from 0.1 to 5.0% by weight of flow aid, from 0.5 to 5% by weight of binder, from 80 to 99% by weight of diluent, and from 0.2 to 4.0% by weight of lubricant.
11. A formulation according to any one of Claims 1, 2 or 3 containing6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naaphtho[2,3-b]
pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof, and from 3 to 15% by weight of water.
pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof, and from 3 to 15% by weight of water.
12. A formulation according to anyone of Claims 1, 2 or 3 comprising from 2 to 12 mg (determined as the free acid) of 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-ccarboxylic acid, or a pharmaceutically acceptable derivative thereof.
13. A formulation according to Claim 12, comprising from 3 to 6 mg (determined as the free acid) of 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof.
14. A formulation according to any one of Claims 1, 2 or 3 comprising from 10 to 50 mg (determined as the free acid) of 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphthoL[2,3-b]pyran-2-carboxylic acid, or a pharmaceutically acceptable derivative thereof.
15. A formulation according to any one of Claims 1, 2 or 3 in the form of a tablet having a diametral crushing strength of at least 1.5 kp Schleuniger.
16. A formulation according to any one of Claims 1, 2 or 3, in the form of a tablet which, when tested using the disintegration test apparatus of the United States Pharmacopoeia XIX, using water as the medium, disintegrates in less than 30 minutes.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB20984/76 | 1976-05-21 | ||
| GB20984/76A GB1570993A (en) | 1976-05-21 | 1976-05-21 | Pharmaceutical tablet formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105835A true CA1105835A (en) | 1981-07-28 |
Family
ID=10155196
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA278,833A Expired CA1105835A (en) | 1976-05-21 | 1977-05-19 | Pharmaceutical tablet comprising anti-allergic drug |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS52143220A (en) |
| AU (1) | AU511269B2 (en) |
| BE (1) | BE854690A (en) |
| CA (1) | CA1105835A (en) |
| DE (1) | DE2722917A1 (en) |
| DK (1) | DK218777A (en) |
| FI (1) | FI771587A (en) |
| FR (1) | FR2426460A1 (en) |
| GB (1) | GB1570993A (en) |
| IE (1) | IE45282B1 (en) |
| IL (1) | IL52102A0 (en) |
| LU (1) | LU77369A1 (en) |
| NL (1) | NL7705560A (en) |
| NO (1) | NO771765L (en) |
| NZ (1) | NZ184141A (en) |
| SE (1) | SE7705850L (en) |
| ZA (1) | ZA772989B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1595220A (en) * | 1977-12-23 | 1981-08-12 | Fisons Ltd | Tablets containing 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane |
| US5447728A (en) * | 1992-06-15 | 1995-09-05 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
| PT1383482E (en) * | 2001-05-01 | 2007-09-20 | Pfizer Prod Inc | Method for manufacturing a low dose pharmaceutical composition |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA753210B (en) * | 1974-06-14 | 1976-04-28 | Upjohn Co | Novel dosing regimen for intal biologues |
| IL48360A (en) * | 1974-11-09 | 1978-12-17 | Fisons Ltd | Pharmaceutical compositions for the treatment of aphthous stomatitis comprising 1,3-bis-(2-carboxychromon-5-yloxy)-2-carboxychromon-5-yloxy)-2-hydroxypropane |
| FR2292468A1 (en) * | 1974-11-30 | 1976-06-25 | Fisons Ltd | MONOCHROMES |
-
1976
- 1976-05-21 GB GB20984/76A patent/GB1570993A/en not_active Expired
-
1977
- 1977-05-16 FR FR7714858A patent/FR2426460A1/en active Granted
- 1977-05-16 IL IL52102A patent/IL52102A0/en unknown
- 1977-05-16 BE BE177619A patent/BE854690A/en unknown
- 1977-05-17 AU AU25214/77A patent/AU511269B2/en not_active Expired
- 1977-05-17 SE SE7705850A patent/SE7705850L/en unknown
- 1977-05-18 NZ NZ184141A patent/NZ184141A/en unknown
- 1977-05-18 LU LU77369A patent/LU77369A1/xx unknown
- 1977-05-18 DK DK218777A patent/DK218777A/en not_active Application Discontinuation
- 1977-05-18 ZA ZA00772989A patent/ZA772989B/en unknown
- 1977-05-19 JP JP5712777A patent/JPS52143220A/en active Pending
- 1977-05-19 FI FI771587A patent/FI771587A/fi not_active Application Discontinuation
- 1977-05-19 CA CA278,833A patent/CA1105835A/en not_active Expired
- 1977-05-20 NL NL7705560A patent/NL7705560A/en not_active Application Discontinuation
- 1977-05-20 IE IE1038/77A patent/IE45282B1/en unknown
- 1977-05-20 DE DE19772722917 patent/DE2722917A1/en not_active Ceased
- 1977-05-20 NO NO771765A patent/NO771765L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE45282B1 (en) | 1982-07-28 |
| FI771587A (en) | 1977-11-22 |
| ZA772989B (en) | 1978-04-26 |
| IE45282L (en) | 1977-11-21 |
| FR2426460A1 (en) | 1979-12-21 |
| NO771765L (en) | 1977-11-22 |
| DK218777A (en) | 1977-11-22 |
| FR2426460B1 (en) | 1983-04-29 |
| AU511269B2 (en) | 1980-08-07 |
| BE854690A (en) | 1977-11-16 |
| JPS52143220A (en) | 1977-11-29 |
| LU77369A1 (en) | 1977-12-13 |
| AU2521477A (en) | 1978-11-23 |
| NL7705560A (en) | 1977-11-23 |
| IL52102A0 (en) | 1977-07-31 |
| DE2722917A1 (en) | 1977-12-01 |
| GB1570993A (en) | 1980-07-09 |
| NZ184141A (en) | 1979-06-19 |
| SE7705850L (en) | 1977-11-22 |
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