NZ189255A - Pharmaceutical compositions containing 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxy propane - Google Patents
Pharmaceutical compositions containing 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxy propaneInfo
- Publication number
- NZ189255A NZ189255A NZ189255A NZ18925578A NZ189255A NZ 189255 A NZ189255 A NZ 189255A NZ 189255 A NZ189255 A NZ 189255A NZ 18925578 A NZ18925578 A NZ 18925578A NZ 189255 A NZ189255 A NZ 189255A
- Authority
- NZ
- New Zealand
- Prior art keywords
- composition according
- bis
- weight
- bicarbonate
- tablet
- Prior art date
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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number 1 89255
189255
y . fff7(^7?y. 77. [:
CC'jTl".^2 SpSCtttCGUcn F.l- -
• ■ • ■ •
Ci is*:: Wlfa;. .WM'/Hf.. • . n...... 31 MAY 198A
".ZV) a «. i Vi i • i i ■■•••••• ■
- ■ -f! /<?£?.
m-n /ffgx cut-, ir^ «®i ft?"*??15! ^
pns ^ ■; \ < -; i. ■. •■ . • '. . * jU'2
|&vj W # »>1P
No.:
Date:
COMPLETE SPECIFICATION "FORMULATION"
yWe, FXSONS LIMITED a British company of Fison House, 9 Grosvenor Street, London, England hereby declare the invention for which k/ we pray that a patent may be granted to riOC/us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
1 followed by page la
- **-
-e±/e/64
1 8925
53825/77-—
This invention concerns pharmaceutical compositions.
The confound disodium cromoglycate (the disodium salt o£ 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane) has been 5 known for some time as a treatment for asthma by inhalation of a powder containing it. It has recently been demonstrated that this compound is also useful in the treatment of various conditions of the gastro-intestinal tract in which allergic or immune reactions play a contributory part. However, when 10 administered orally to a patient in any of the conventional formulations for other drugs it is found that the conditions in various regions of the gastro-intestinal tract tend to convert the disodium salt tb the acid itself, which is insoluble. As a result, a thick gum-like surface coating, impervious to water, is 15 formed over the outside of the formulation, thereby preventing it from dissolving or dispersing further and thus effectively reducing the availability of the active ingredient. Even when a powder is administered, e.g. in a gelatin capsule, it is found that it forms a plug having such a coating, with much of the medicament 20 trapped within the coating and hence unavailable. We have now found a formulation which avoids or at least 'mitigates this problem.
Accordingly, in one aspect, this invention provides a pharmaceutical composition in the form of a tablet able to be swallowed and disintegrable in the presence of gastro-intestinal 25 fluids and comprising from 5 to 801 by weight of 1,3-bis(2-carboxy-
-
02/C/G4—
189255
chromon-5-yloxy)-2-hydroxypropane or a pharmaceutically-acceptable salt thereof, in association with from 20 to 95% by weight of a mixture of an alkali-metal or alkaline earth metal carbonate or bicarbonate and citric acid, the tablet having an equilibrated 5 relative humidity of less than 25%.
Pharaiaceutically-acceptable salts of the bis-chromone
«
include the alkali-metal salts, for example the di-sodium and di-potassium salts, and the alkaline earth metal salts, for example the calcium and magnesium salts. The disodium salt is especially 10 preferred.
The tablet preferably contains from 30 to 75%, especially from 35 to 65% by weight of the bis-chromone.
The carbonate or bicarbonate may, for example, be sodium or potassium carbonate or bicarbonate, sodium bicarbonate being 15 especially preferred, and is desirably present in an amount of from 25 to 50%, especially from 25 to 35%, by weight of the tablet.
The citric acid is desirably present in an amount of from 15 to 55% by weight of the tablet.
By the term 'equilibrated relative humidity' as used herein is 20 meant the relative humidity of air which causes no or substantially no net transfer of moisture between it and the composition when contacted therewith.
The equilibrated relative humidity may for example be determined by a SINA equi-hygroscope eZFBA (from Nova-Sina Limited, Zurich). It 25 is preferably less than 20%. Where water is employed as the granulating
Q3/C/61-
18 92 5
solvent the equilibrated relative humidity is preferably greater than 15%, although it may be lower if non-aqueous granulating solvents, e.g. isopropyl alcohol, are employed. In such a case it may desirably be from 9 to 20%.
Although the tablet may be composed entirely of the bis-chromone,
the carbonate or bicarbonate and the citric acid, other diluents, carriers, binders or adjuvants may be incorporated into the tablet if desired. As an example, it is usually preferred to incorporate up to 1% by weight, for example 0.25-1% by weight, of a 10 pharmaceutically-acceptable lubricating agent, for example magnesium lauryl sulphate or magnesium stearate, in order to facilitate manufacture of the tablets. Desirably, however, at least 901, and more preferably at least 95%, by weight of the tablet is composed of the bis-chromone, the carbonate or bicarbonate and the citric acid. 15 The molar ratio of the carbonate or bicarbonate to the acid is preferably such as to allow substantially complete reaction between them, i.e. they are preferably present in stoichiometric amounts. Preferred weight ratios of sodium or potassium bicarbonate to citric acid are thus preferably from 1.2:1 to 1.7:1. 20 For the tablet to be able to be swallowed, it should desirably weigh not more than 1 gram, and more preferably weigh not more than 500 mg. A preferred weight range is from 200 to 500 mg.
The tablets are disintegrate in the presence of gastrointestinal fluids, e.g. in the stomach, to give either a solution 25 of the bis-chromone if water-soluble or a finely-dispersed suspension
—04/C/64—
1 89255
of the bis-chromone if water-insoluble. To be disintegrable and yet avoid undue disintegration of the tablet before reaching the stomach, it is preferred that it should have a disintegration time as measured by the British Pharmacopoeia (1973) disintegration test in the range 5 1 to 15 minutes, especially in the range 3 to 10 minutes.
The tablets of the invention may be produced by a process in which one or more of the ingredients are, if necessary, granulated to an appropriate granule size in the presence of a suitable granulating medium, any remaining ingredients are blended with the 10 thus granulated material, and the mixture is compressed into tablets, all operations being conducted under appropriate conditions to give tablets of the desired equilibrated relative humidity.
The granulating medium may if desired be water, but in such a case the carbonate or bicarbonate should not be admixed with the 15 citric acid prior to granulation. Alternatively, an alkanol, e.g. isopropyl alcohol may be employed, in which case the ingredients may be admixed before granulation.
The conditions necessary to give the desired equilibrated relative humidity are readily assessable by one skilled in the art 20 from a knowledge of the moisture content of the ingredients employed.
The tablets of the present invention are of use in the treatment in man of conditions of the stomach or gastro-intestinal tract after the stomach, in which conditions allergy or immune reactions play a contributory part. Conditions vjhich may be treated 25 include Crohn's disease (a condition of the small, and sometimes
^DS/C764
1 8925
also of the large, intestine), atrophic gastritis (a condition of the stomach), ulcerative colitis (a condition of the rectum), proctitis (a condition of the rectum and lower large intestine), coeliac disease (a condition of the small intestine), regional 5 ileitis (a regional inflammatory condition of the terminal ileum) , peptic ulceration (a condition of the stomach and duodenum), gastro-intestinal allergy (e.g. gluten or other food allergy), and irritable bowel syndrome.
The dosage to be administered will of course depend upon 10 the condition to be treated and its severity. However, in general, a total daily dosage of from 100 to 4,000 mg of the bis-chromone, and more preferably from 400 to 2,000 mg thereof, administered in smaller doses 2 to 4 times per day is found to be satisfactory. An individual tablet may conveniently contain 15 from 50 to 450 mg, especially 100 to 250 mg of the bis-chromone.
Preferably administration takes place a short time, for example about 30 minutes, before the patient takes food.
The following Examples are now given, though only by way of illustration.
Example 1
The following ingredients were formulated into tablets of the invention by the method described hereinafter:
*06/ew
189255
mg per tablet
1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane, disodium salt
Sodium bicarbonate BP
Citric acid (granular) BP
Magnesium stearate Water
An excess of the disodium salt was sieved through a 36 mesh 10 screen and its moisture content was determined. The appropriate quantity to give 200 mg/tablet was then calculated and mixed with the appropriate quantity of granular sodium bicarbonate. Water was then sprayed into the mixer to give a moisture content of 20% by weight. The temperature was maintained at below 35°C, and 15 the wet mass was passed through an 8 mesh screen on an oscillating granulator. The granules were then part-dried in a fluid bed drier at 100°C, passed through a 20 mesh screen, and further dried to a moisture content below 20% equilibrated relative ' humidity, and were then blended with the citric acid and the 20 magnesium stearate in a drum roller. The mix was then compressed to give tablets having an equilibrated relative humidity of 15% and a BP (1973) disintegration time of about 7 minutes, which were stored at less than 30% relative humidity at 20°C and strip-packed individually.
A further sample of the mix was compressed to give tablets of
200 120 91.2 1.03 Approx 12
424.23
07/6/64-
189255
twice the weight, that is containing 400 mg of the chromone salt in a total tablet weight of 848.46 mg.
Example 2
The following ingredients were formulated into tablets of the 5 invention as follows:
mg/tablet
1,3-bis(2-carboxychromon-5-yloxy)-2-
hydroxypropane, disodium salt 200
Sodium bicarbonate BP 120
Citric Acid BP 91.2
Magnesium Lauryl Sulphate 2.06
Water Approx 8
421.26
The chromone salt is dried to a moisture content of less than 5% by weight, and the other ingredients are dried to a moisture 15 content of less than 0.5% by weight. All the ingredients except the magnesium lauryl sulphate were dry mixed in a suitable blender and were granulated with isopropyl alcohol (moisture content less than 0.251), approximately 500 ml of the alcohol being employed per kg of the powder mixture. The mass was then passed through an 20 8 mesh screen on a rotary granulator, dried on a fluid bed drier, and passed through a 20 mesh screen. The magnesium lauryl sulphate was then blended in and the mixture was compressed into tablets ( > 8 kp Schleuniger) of equilibrated relative humidity of about 15% and a BP/1973 disintegration time of about 6 minutes. Throughout, 25 all operations were effected in flame-proof equipment in an
Claims (24)
1. A pharmaceutical composition in the form of a tablet able to be swallowed and disintegrate in the presence of gastro-intestinal fluids and comprising from 5 to 80% by weight of 1,3-bis(2-carboxy-chromon-5-yloxy)-2-hydroxypropane or a pharmaceutically-acceptable . salt thereof, in association with from 20 to 95% by weight of a mixture of an alkali-metal or alkaline earth metal carbonate or bicarbonate and citric acid, the tablet having an equilibrated relative humidity of less than 25%.
2. A composition according to claim 1 wherein the bis-chromone is employed in the form of the disodium salt thereof.
3. A composition according to claim 1 or claim 2 wherein the tablet contains from 30 to 75% by weight of the bis-chromone.
4. A composition according to claim 3 wherein the tablet contains from 35 to 65% by weight of the bis-chromone.
5. A composition according to any of claims 1 to 4 wherein the carbonate or bicarbonate is sodium or potassium carbonate or bicarbonate.
6. A composition according to any of claims 1 to 5 wherein the carbonate or bicarbonate is present in an amount of from 25 to 50% by weighty WeJ Oft UvgJC ©f It* /-WaUfc- ,
7. A composition according to claim 6, wherein the carbonate or A ^ Used oa •«-? of t<U feUet bicarbonate is present in an amount of from 25 to 35% by weight^
8. A composition according to any of claims 1 to 7, wherein the citric acid is present in an amount of from 15 to 55% by weight - 9 - - 10 - 189255 of the tablet.
9. A composition according to any of claims 1 to 8, wherein the carbonate or bicarbonate and the citric acid are present in substantially stoichiometric amounts. 5
10. A composition according to any of claims 1 to 9, wherein at least 901 by weight of the tablet is composed of the bis-chromone, the carbonate or bicarbonate and the citric acid.
11. A composition according to claim 10 wherein at least 951 by weight of the tablet is composed of the bis-chromone, the carbonate 10 or bicarbonate and the citric acid.
12. A composition according to any of claims 1 to 11 which weighs not more than 1 gram.
13. A composition according to claim 12 which weighs not more than 500 mg. 15
14. A composition according to claim 13 which weighs from 200 to 500 mg.
15. A composition according to any of claims 1 to 14 which has a disintegration time as measured in the British Pharmocopoeia (1973) disintegration test in the range 1-15 minutes. 20
16. A composition according to claim 15 which has a disintegration time in the range 3-10 minutes.
17. A composition according to any of claims 1 to 16 the equilibrated relative humidity of which is from 9 to 20%.
18. A composition according to claim 17 the equilibrated relative 25 humidity of which is greater than 15%. - 10 - 1- # - 11 - 18 9255
19. A composition according to any of claims 1 to 18 which contains from 50 to 450 mg of the bis-chromone.
20. A composition according to claim 19 which contains from 100 to 250 mg of the bis-chromone. 5
21. A composition according to any of claims 1 to 20 and substantially as described herein with reference to the Examples.
22. A process for the preparation of a composition according to any of claims 1 to 21, in which one or more of the ingredients are, if necessary, granulated to an appropriate granule size in 10 the presence of a suitable granulating medium, any remaining ingredients are blended with the granulated material, and the mixture is compressed into tablets, all operations being conducted under appropriate conditions to give tablets of the desired equilibrated relative humidity. 15
23. A process according to claim 22 wherein the granulating medium employed is water or an alkanol.
24. A process according to claim 23 or claim 2.2 and substantially as described in Example 1 or Example 2. 20 DATED THIs2-OfU DAY OF^GJCCU-^ 19
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB53825/77A GB1595220A (en) | 1977-12-23 | 1977-12-23 | Tablets containing 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ189255A true NZ189255A (en) | 1984-05-31 |
Family
ID=10469110
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ189255A NZ189255A (en) | 1977-12-23 | 1978-12-20 | Pharmaceutical compositions containing 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxy propane |
Country Status (18)
Country | Link |
---|---|
JP (1) | JPS5489016A (en) |
AU (1) | AU523616B2 (en) |
BE (1) | BE872918A (en) |
CA (1) | CA1108992A (en) |
CH (1) | CH641349A5 (en) |
DE (1) | DE2855001A1 (en) |
DK (1) | DK568278A (en) |
FI (1) | FI783897A (en) |
FR (1) | FR2412310A1 (en) |
GB (1) | GB1595220A (en) |
IE (1) | IE47539B1 (en) |
IL (1) | IL56239A (en) |
IT (1) | IT7831068A0 (en) |
LU (1) | LU80721A1 (en) |
NL (1) | NL7812344A (en) |
NZ (1) | NZ189255A (en) |
SE (1) | SE7813062L (en) |
ZA (1) | ZA787155B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH07116017B2 (en) * | 1986-05-17 | 1995-12-13 | アース製薬株式会社 | Bath additive |
GB9824604D0 (en) * | 1998-11-11 | 1999-01-06 | Hewlett Healthcare Limited | Treatment of allergic conditions |
JP2004514732A (en) * | 2000-12-06 | 2004-05-20 | ファルマシア・コーポレーション | Rapidly dispersing pharmaceutical composition |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2132521A1 (en) * | 1971-04-06 | 1972-11-24 | Sofrader Sa | Effervescent tablets prdn - by controlled drying in effervescent granule formation |
GB1423985A (en) * | 1972-02-15 | 1976-02-04 | Fisons Ltd | Pharmaceutical compositions containing bischromonyloxy compounds |
GB1517153A (en) * | 1974-11-30 | 1978-07-12 | Fisons Ltd | Naphthopyran-and benzodipyran-2-carboxylic acids and derivatives thereof |
GB1570993A (en) * | 1976-05-21 | 1980-07-09 | Fisons Ltd | Pharmaceutical tablet formulation |
GB1557082A (en) * | 1977-01-25 | 1979-12-05 | Fisons Ltd | Pharmaceutical mixture containing an antiinflammatory |
-
1977
- 1977-12-23 GB GB53825/77A patent/GB1595220A/en not_active Expired
-
1978
- 1978-12-18 DK DK568278A patent/DK568278A/en not_active Application Discontinuation
- 1978-12-18 IL IL56239A patent/IL56239A/en unknown
- 1978-12-18 AU AU42654/78A patent/AU523616B2/en not_active Expired
- 1978-12-19 CH CH1290478A patent/CH641349A5/en not_active IP Right Cessation
- 1978-12-19 SE SE7813062A patent/SE7813062L/en unknown
- 1978-12-19 FI FI783897A patent/FI783897A/en unknown
- 1978-12-20 NZ NZ189255A patent/NZ189255A/en unknown
- 1978-12-20 DE DE19782855001 patent/DE2855001A1/en not_active Withdrawn
- 1978-12-20 IT IT7831068A patent/IT7831068A0/en unknown
- 1978-12-20 NL NL7812344A patent/NL7812344A/en not_active Application Discontinuation
- 1978-12-20 BE BE192444A patent/BE872918A/en not_active IP Right Cessation
- 1978-12-20 ZA ZA00787155A patent/ZA787155B/en unknown
- 1978-12-21 CA CA318,406A patent/CA1108992A/en not_active Expired
- 1978-12-21 JP JP15697478A patent/JPS5489016A/en active Pending
- 1978-12-21 IE IE2540/78A patent/IE47539B1/en unknown
- 1978-12-22 LU LU80721A patent/LU80721A1/en unknown
- 1978-12-22 FR FR7836221A patent/FR2412310A1/en active Granted
Also Published As
Publication number | Publication date |
---|---|
AU523616B2 (en) | 1982-08-05 |
BE872918A (en) | 1979-06-20 |
DE2855001A1 (en) | 1979-07-05 |
AU4265478A (en) | 1979-06-28 |
CA1108992A (en) | 1981-09-15 |
IE782540L (en) | 1979-06-23 |
GB1595220A (en) | 1981-08-12 |
FR2412310A1 (en) | 1979-07-20 |
JPS5489016A (en) | 1979-07-14 |
NL7812344A (en) | 1979-06-26 |
FR2412310B1 (en) | 1982-12-31 |
FI783897A (en) | 1979-06-24 |
IL56239A (en) | 1983-02-23 |
CH641349A5 (en) | 1984-02-29 |
DK568278A (en) | 1979-06-24 |
IE47539B1 (en) | 1984-04-18 |
ZA787155B (en) | 1979-12-27 |
IL56239A0 (en) | 1979-03-12 |
SE7813062L (en) | 1979-06-24 |
IT7831068A0 (en) | 1978-12-20 |
LU80721A1 (en) | 1979-09-07 |
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