GB2219585A - Cyclodextrin/ibuprofen complexes - Google Patents
Cyclodextrin/ibuprofen complexes Download PDFInfo
- Publication number
- GB2219585A GB2219585A GB8911938A GB8911938A GB2219585A GB 2219585 A GB2219585 A GB 2219585A GB 8911938 A GB8911938 A GB 8911938A GB 8911938 A GB8911938 A GB 8911938A GB 2219585 A GB2219585 A GB 2219585A
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- Prior art keywords
- ibuprofen
- complex
- cyclodextrin
- salt
- sodium
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
Abstract
Complexes of beta -cyclodextrin with various salts of ibuprofen are described in which the molar ratios of ibuprofen to beta - cyclodextrin are within the range of from 1:0.20 to 1:0.75. The ibuprofen salts are selected from the sodium, potassium, ammonium, magnesium, calcium, arginine, glycine or lysine salts of ibuprofen. The complexes have enhanced taste profile and bioavailability. Also disclosed are methods for preparing the complexes and also pharmaceutical compositions thereof.
Description
PHARMACEUTICAL COMPOSITION
This invention relates to cyclodextrin complexes and in particular to complexes with ibuprofen salts, their preparation and pharmaceutical compositions thereof.
Ibuprofen, whose chemical name is 2-(4-isobutylphenyl)propionic acid, is a well known compound having analgesic, antipyretic and antiinflammatory properties and having utility in the treatment of pain and inflammatory conditions. Ibuprofen is only poorly soluble in water, has poor wettability and suffers organoleptically because of its bitter taste which latter makes it unacceptable.
Attempts to increase its solubility by, for example, conversion to its sodium salt, whilst affording improved solubility causes an even more unacceptable taste profile.
On the other hand attempts to improve the taste profile by the use of insoluble salts, coatings, granulations or incorporation of flavourings have tended to be unsatisfactory and may even have an adverse effect on the bioavailability of the drug and time to peak plasma levels.
ss-Cyclodextrins and their derivatives have been used in pharmaceutical formulations to enhance solubility, dissolution rate and bioavailability of various drugs.
Japanese patent Kokai 46837/1981 (published 28 April 1981) reviews various previous attempts to prepare complexes of ss-cyclodextrin and ibuprofen. In one of the reviewed methods the molar ratio of ibuprofen to ss- cyclodextrin was 0.36:1.0 whilst in another which involved a seven step procedure the ratio was 0.82:1.0. The patent publication describes a procedure in which ibuprofen, - cyclodextrin and water are mixed at a temperature about that of the melting point of ibuprofen, eg 60 to 800C and the resultant dispersion is spray dried at a temperature above 750C. In the examples the molar ratios of ibuprofen to ss-cyclodextrin in the complexes obtained were 0.79:1.0, 0.73:1.0 and 0.81:1.0 respectively.
Chow and Karara, Int.J.Pharmac 28, 95-101 (1986) prepared and studied an ibuprofen - ss-clodextrin complex (2:3 molar ratio). They found that the dissolution rate of the ibuprofen was significantly enhanced by complexation and that after 20 minutes the percentage of drug released from the complex as compared with that from drug powder were 95 and 5 respectively. Bioavailability studies in rats showed that the extent of absorption was the same from free and complexed ibuprofen but that the time to reach peak plasma concentrations was 2.5 times faster with the complex.
Hitherto in the complexes between ss-cyclodextrin and ibuprofen the molar ratio of ibuprofen to ss-cyclodextrin has never been greater than 1:1 and in the prior art discussed above it has ranged between 0.81:1.0 and 0.66:1.0.
ss-Cyclodextrin tends to be an expensive commodity (10 per
Kilo).
We have now found it possible to prepare complexes incorporating ss-cyclodextrin and ib?rofen in which the molar proportion of ibuprofen is considerably greater than that of ss-cyclodextrin whilst retaining the increased water solubility, increased bioavailability and improved taste properties.
According to this invention there is provided a complex of ss-cyclodextrin with an ibuprofen salt selected from the sodium, potassium, ammonium, magnesium, calcium, arginine, glycine or lysine salts in which the molar ratio of ibuprofen to B-cyclodextrin is within the range of from 1:0.20 to 1:0.75.
A preferred complex is one with ibuprofen sodium salt.
In the preparation of the ss-cyclodextrin/ibuprofen sodium salt complex a mixture of ibuprofen, ss-cyclodextrin and water are mixed at a temperature in the range of 50 800C and preferably about 700C. The resultant dispersion is neutralised with sodium hydroxide solution to provide a clear solution which is then allowed to cool to 30 - 40 C and thereafter the solution is dried to remove the water by a technique such as spray granulation, spray drying, drum drying or freeze drying. A preferred technique is spray drying since it produces a free flowing granular solid.
The concentration of the solution prior to spray drying is preferably in the range 5 to 40% (w/w) and most preferably about 35%.
It has been found that a fluid bed spray drying (FSD) technique is particularly useful. A free flowing powder with a mean particle size of between 170 and 210 ym is readily produced by the technique. Suitable drying conditions are a main inlet temperature of between 170 and 2000C, preferably about 195 C, a fluid bed inlet temperature of between 90 and 11000, preferably about 1000C, an outlet temperature of about 760C and total air drying of 620 Kg/ hour.
The above described conditions afford a palatable free flowing powder which is soluble in water. In order to improve the tabletting properties of the powder it is convenient, prior to the removal of the water, to add a water soluble binder such as polyvinylpyrrolidone, polyethylene glycol, carboxyvinylpolymethylene or mixtures thereof to the solution of the ss-cyclodextrin/ibuprofen sodium salt complex. Conveniently the amount of water soluble binder relative to that of the complex is in the range 0.1 to 5% w/w and preferably 3 to 4%.
Complexes with ibuprofen salts such as the potassium, ammonium, arginine, glycine and lysine may be prepared in a similar procedure as for the sodium salt using in the neutralisation step potassium hydroxide, potassium carbonate, ammonium hydroxide, arginine, glycine or lysine.
Complexes with magnesium or calcium ibuprofen may be conveniently prepared by mixing an aqueous solution of the sodium salt complex with a suitable calcium or magnesium salt such as calcium chloride, magnesium chloride, calcium sulphate, magnesium sulphate, calcium gluconate, magnesium gluconate or calcium lactate.
The ss-cyclodextrin/ibuprofen salt complexes may be incorporated into pharmaceutical compositions suitable for oral administration.
In an aspect of the invention there are provided pharmaceutical compositions for oral administration comprising a ss-cyclodextrin/ibuprofen salt complex as herein defined together with a pharmaceutically acceptable diluent or carrier.
The compositions are preferably in the form of powders, granules or tablets. The compositions may be formulated with an effervescent couple, a buffer system, sweeteners, flavouring, colours etc. Preferred diluent or carriers are water soluble saccharides such as dextrose, lactose or sucrose.
It has been found that when the compositions are formulated in the absence of a buffer system or formulated to afford a pH of between 3 and 6 there is a tendency when the compositions are added to water for the complex to be precipitated. Such precipitation can be prevented by the incorporation of a buffer system or where the composition includes an effervescent couple the incorporation of a pharmaceutically acceptable acid salt such as sodium citrate. The amounts of acid salt or buffer system employed are chosen so that the pH of the composition in aqueous solution is between 6.0 and 8.0.
Pharmaceutically acceptable effervescent couples are well known to the art. Typically, effervescent couples comprise a solid organic acid, such as citric acid, adipic acid, malic acid or tartaric acid with a carbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate. The amount of effervescent couple used is selected so that the pH of the composition in aqueous solution is between 6.0 and 8.0.In the case of complexes in which the salt is the sodium salt it is prefera@le f@r compositions which are to De accec to water to h@ve an effervescent cou@le which will @rovide a pH of between @.3 and 7.0 so as to avoid precipitation of the active com@onent. The effervescent couple or either of the comco@ents may form the b@ffer system.
Sweeteners, either nutritive or non-nutritive may also be included in the compositions. Examples of nutritive sweeteners are sucrose, glucose, dextrose, ladctose anc sorbitol. Examples of non-nutritive sweeteners are saccharin, aspartame and cyclamate. Preferably the sweetener is sodium saccharin.
It will be aporeciated that the compositions should be protected from atmospheri@ moisture. Anhydrous sodi@@ carbonate may be included to prevent the advarse effects of moisture.
or purposes of convenience and accuracy of dosing the compositions are in unit dosage form containin- the aquivalent of 50 to 500 mg of ibuprofan and preferably 2@@ to 430 mg.
The invention is illustrated by the following
Examples. Examples 1 to g describe the praparation of complexes between ss-cyclodextrin and various ibuprofen salts whilst Examples 10 to 15 describe the preparation of pharmaceutical compositions incorporating complexes.
Examples A and B are comparative Examples describing the preparation of complexes falling outside the scope of the invention.
EXAMPLE 1
Preparation of a complex containing the sodium salt of ibuprofen and 8-cyclodextrin in molar proportions of 1:0.347.
The complex was manufactured from the following ingredients:
Kg
Ibuprofen BP 3.53
B-Cyclodextrin 7.48
Sodium hydroxide BP 0.68
Water (deionised) 14.94
The ss-cyclodextrin was dispersed in 12.21 kg of deionised water, the ibuprofen was added and the mixture was stirred and heated to 700C for one hour, after which, the mixture was cooled to 380C. The sodium hydroxide dissolved in 2.73 kg of deionised water was then added and the mixture was stirred for half an hour, producing a straw coloured solution. The solution was then spray dried at an inlet temperature of 185 C, an outlet temperature of 115 C, an atomizer pressure of 4 kg/cm and a feed rate of 30 ml/min.
The product, so obtained, was a white powder with a mean particle size of 10 pm.
EXAMPLE 2
Preparation of a complex containing the calcium salt of ibuprofen and 8-cyclodextrin in molar proportions of 1:0.347. The complex was manufactured from the following ingredients: g Ibuprofen complex of Example 1 61.50
Calcium chloride dihydrate 7.35
Water (deionised) 200
The ibuprofen complex was dissolved in the deionised water and stirred for about fifteen minutes and thereafter the calcium chloride dihydrate was added and the mixture was stirred for one hour. A thick white precipitate was produced. The precipitate was collected by filtration and carefully washed with water. The product, which was a complex of calcium ibuprofen and B-cyclodextrin was dried in a vacuum oven at 600C for eight hours.
EXAMPLE 3
Preparation of a complex containing the magnesium salt of ibuprofen and ss-cyclodextrin in molar proportions of 1:0.347. The complex was manufactured from the following ingredients: g Ibuprofen complex of Example 1 30
Magnesium chloride hexahydrate 9.9
Water (deionised) 200
The ibuprofen complex was dissolved in deionised water (175 ml) and the magnesium chloride hexahydrate dissolved in deionised water (25 ml) was added with stirring, stirring being continued for one hour. A thick white precipitate was produced. The precipitate was collected by filtration and carefully washed with water. The product, which was a complex of magnesium ibuprofen and 8-cyclodextrin was dried in a vacuum oven at 500C for eight hours.
EXAMPLE 4
Preparation of a complex containing the sodium salt of ibuprofen and B-cyclodextrin in molar proportions of 1:0.347 together with polyvinylpyrrolidone.
Kg
Ibuprofen BP 0.500
B-Cyclodextrin 1.060
Sodium hydroxide BP 0.097
Water (deionised) 2.30
Polyvinylpyrrolidone 0.060
(Povidone K30, BASF)
The ss-cyclodextrin was dispersed in 2.0 kg of deionised water, the ibuprofen was added and the mixture was then stirred and heated to 700C for one hour, after which it was cooled to 350C. The sodium hydroxide dissolved in 0.3 kg of deionised water was then added and stirring was continued for half an hour, and thereafter the polyvinylpyrrolidone was added with stirring.
The resultant clear solution was then spray dried at an inlet temperature of 175 C, an outlet temperature of 110 C, an atomizer pressure of 4 kg/cm and a feed rate of 30 ml/min.
The product so obtained, was a white powder.
EXAMPLE 5
Preparation of a complex containing the sodium salt of ibuprofen and B-cyclodextrin in molar proportions of 1:0.202. The complex was manufactured from the following ingredients.
Kg
Ibuprofen BP 1.0 ss-Cyclodextrin 1.0
Sodium hydroxide BP 0.194
Water (deionised) 2.775
The B-cyclodextrin was dispersed in 2.0 kg of deionised water, the ibuprofen was added and the mixture was stirred and heated to 66 C for one hour, after which, it was cooled to 32 C. The sodium hydroxide dissolved in 0.775 kg of deionised water was then added and the mixture was stirred for half an hour producing a straw coloured solution.
This solution was then spray dried at an inlet temperature of 175 C, an outlet temperature of 125 C, an atomizer pressure of 2.6 kg/cm and a feed rate of 30 ml/min.
EXAMPLES 6-9 and COMPARATIVE EXAMPLES A and B
Preparation of complexes containing the sodium salt of ibuprofen and ss-cyclodextrin in molar proportions of 1 :x where x is as shown below. The complexes were manufactured using the method of Example 1 from the ingredients shown below.
Weiqht/g Eg x , Ibuprofenl B- | Sodium ' Water No I BP 1 Cyclodextrin I Hydroxide ' (De- BP |ioised) 6 0.239 1 266.73 1 400.2 1 51.66 , 1200 7 0.25 500.00 755.8 96.95 1950 8 0.27 750.00 1236.8 145.41 3200 9 0.648 625.00 2500.0 121.00 10000 Example 6-9 (cont)
A 0.081 350.1 700.2 135.67 1700 B 0.169 1000 1000 194.00 2775 The organoleptic profiles of the complexes of Examples 1-9 when dissolved in water were judged to be superior to that of sodium ibuprofen in terms of both taste and odour.
EXAMPLE 10
A non-effervescent powder composition was prepared from the following ingredients: g Ibuprofen complex of Example 1 30.0C
Trisodium citrate 14.37
Citric acid anhydrous 2.33
Sodium bicarbonate 4.12
Sodium saccharin 1.02
Lime flavour 0.15
All ingredients were sieved through a 500 pm screen and blended in a tumble mixer. The resultant powder composition was packed into water impervious sachets each containing 1.04 g of the powder which is equivalent to 200 mg of ibuprofen.
One unit dose of the formulation was dissolved in 50 ml of water and tasted. The formulation was judged -to be acceptable and could be readily consumed.
EXAMPLE 11
Tablets containing the equivalent of 200 mg of ibuprofen were prepared from the following ingredients:
Parts by weiqht
Example 11 (cont)
Ibuprofen complex of Example 1 600
Citric acid (anhydrous) 760
Trisodium citrate 200
Sodium bicarbonate 1000
Sodium saccharin 25
Mannitol 150
Sodium lauryl sulphate 4.5
Sodium carbonate 100
Flavouring (Fantasy Lime) 2.5
Magnesium stearate 1.2
All ingredients were sieved through a 780 jim screen. The citric acid, trisodium citrate, sodium bicarbonate, sodium saccharin and mannitol were tumbled together and then granulated with deionised water. The wet granules were dried using a fluidised bed drier. The dry granules were passed through a 780 jim screen.
The remaining components of the formulation were added to the dry granules and tumble mixed. The bulk mixture was then tabletted to afford tablets of weight 2.84 g.
EXAMPLE 12
A slightly effervescent powder composition was prepared from the following ingredients:
Parts by weight
Ibuprofen complex of Example 1 600
Trisodium citrate 500
Citric acid 80
Sodium bicarbonate 120
Example 12 (cont)
Sodium saccharin 25
Flavouring (Fantasy Lime) 4
Dextrose, anhydrous 2672
All ingredients were sieved through a 500 jim screen and blended in a tumble mixer. The resultant powder composition was packed into water impervious sachets each containing 4 g of the powder which is the equivalent of 200 mg of ibuprofen.
The packed sachets were subjected to a storage test at 240C, 240C high humidity, 350C and 45 C and were found to be satisfactory and stable after a period of twelve weeks.
EXAMPLE 13
A slightly effervescent powder composition was prepared from the following ingredients:
Parts by weight
Ibuprofen complex of Example 1 600
Trisodium citrate 500
Citric acid 80
Sodium bicarbonate 120
Sodium saccharin 22
Flavouring (Orange) 147
Colour (1% CWS, B-carotene) 58
Dextrose, anhydrous 2473
All ingredients were sieved through a 500 jim screen and blended in a tumble mixer. The resultant powder composition was packed into water impervious sachets each containing 4 g of the powder which is the equivalent of 22 mg cf louprofen.
EXAMPLE 14 @ @en-effervescescant powder composition was pre@ared from the following ingredients: Parts by wei@@t I@uprefen complex of Example 1 @@@ Trisodiu- citrate itric acid 47
odium bicarbonate 38
Sodium saccharin 1
Flavouring (natural aniseed) 0.5
All ingredients were sieved through a 5@@ m screen and blenced in a tumble mixer. The resultant powder composition was packed into uater impervious sachets each containing 1 @ of the powder which is the equivalent of 2@@ @@ -9 of Ibuprofen.
EXAMPLE 15
A effervescent powder composition was prepare rom tne following ingredients:
Parts by weicht
Ibuprofen complex of Example 1 7.50
Citric acid 1.23
Sodium bicarbonate 1 .60
odium saccharin 0.19 rlavouring (peppermint and vanilla) G.16 All ingredients were sieved through a 500 jim screen and blended in a tumble mixer.The resultant powder composition was packed into water impervious sachets each containing 0.3-, 1.3 c 2.7 g of the pouder which is te aquivalent of 1@@, @@@ or @@@ @@ of ibuprofan respectively.
In an organolaptio test six subjects tested 20 ml of each of the formuletions of Example 1, Examples n an @omparative Examples @ and @ in paired compariso@s apain@t 20 ml of a stancard solution of sodium ibucrofen in daionised water. All the solutions contained ha aquivalent of 200 mg ibuprofen per 100 ml. Each subject scored the odour, overall taste, aftertaste and youth feed of the standard and test solutions on a visual analocue scale ranging from accaptable (0) to not accaptable (100).
An overall rating of the acceptability of the test products was also obtained (ie ecceptable/unacceptable).
For each paired comparison an analysis was carried out on tne difference between the visual analocue scores of the test solution and the standard solution. The analysis tested the extent to which the differences in score influenced by the ibuprofen: ss-cyclodextrin ratio in the test solution and by variation between subjects in tha assessments and in the score given to the standard solution.
This last item is included because the score of the standard solution influences the size of the difference in visual analogue score which can be obtained.
The results of the test are given in Table 1.
T A B L E 1
ADJUSTED MEAN DIFFERENCES ACCEPTABILITY
(Test - Standerd)
Example Ibuprofen: Odour Overall After Mouth Split No ss-Cyclodextrin Taste Taste Feel Acceptable/ Ratio Unacceptable 1 0.347 -37.2 -40.2 -38.1 -19.5 5/0 6 0.239 -35.3 -35.7 -42.8 -18.9 6/0 7 0.25 -36.1 -41.9 -41.4 -17.9 4/2 8 0.27 -28.7 -37.2 -42.8 -16.7 4/2 9 0.648 -33.1 -45.1 -43.8 -19.9 5/0 A 0.081 -1.8 -0.6 1.9 -0.2 0/6 B 0.169 -11.7 -18.5 -19.0 -9.6 1/4 Significant differences were found between the results for Examples 1 and 6-9 and the results for Comparative
Examples A and B.
For overall taste, odour and aftertaste, Comparative
Example A was considerably less acceptable than all the other formulations except that of Example B and was indeed not significantly more acceptable than the standara ibuprofen solution. There were smaller differences between the test solutions and the ibuprofen standard in the results for mouth feel but in this test also,
Comparative Examples A and B were less acceptable than the rest.
The overall assessment of acceptability is also given in Table 1. From the results it can be seen that the formulations of Example 1 and Examples 6-9 were generally judged to be acceptable whilst the formulations of
Comparative Examples A and B were considered to be unacceptable. Calculations show that the probability of obtaining these results by chance is low.
From these results it can be seen that the ibuprofen/ss-cyclodextrin complexes of the invention have an organoleptic profile significantly superior to that of sodium ibuprofen and also superior to those of complexes outside the scope of the invention containing lesser amounts of 13-cyclodextrin.
Claims (17)
1. A complex or ss-cyclodextrin with an ibucrofen salt selected from the sodium, potassium, ammonium, magnesium, calcium, arginine, glycine or lysine salts in which the molar ratio of ibuprofen to ss-cyclodextrin is within the range of from 1 :0.20 to 1:0.5
2. A complex as claimed in Claim 1 wherein the complex is with ibuprofen sodium salt.
3. A complex as claimed in Claim 1 substantially as described in any one of Examples 1 to 9.
4. A process for the preparation of the complex as claimed in Claim 2 wherein a mixture of ibuprofen, ss-cyclodextrin and water are mixed at a temperature -in the range of 50 S00 and preferably about 70 C, thereafter the resultant dispersion is neutralised with sodium hydroxide solution to provide a clear solution which is then allowed to cool to 30 - 400C and thereafter the solution is dried to remove the water by a technique such as spray granulation, spray drying, rum drying or freeze drying.
5. A process as claimed in Claim 4 wherein the drying technique is spray drying and the concentration of the solution prior to spray drying is preferably in the range 5 to 40% (w/w) and most preferably about 35%.
6. A process as claimed in Claim 5 wherein the drying is fluid bed spray drying using a main inlet temperature of between 170 and 200 C, preferably about 195 C, a fluid bed inlet temperature of between 90 2nd 11.. C, preferably about 100 C, an outlet temperature of about 76 C and total air drying of 620 Kg/ hour.
7. A process as claimed in any one of Claims 4 to 5 wherein prior to the removal of the water there is added to the solution of the ss-cyclodextrin ibuprofen sodium salt complex a water soluble binder such as polyvinylpyrrolidine, polyethylene glycol, carboxyvinylpolymethylene or mixtures thereof.
5. A process as claimed in Claim 7 wherein the weight of water soluble binder relative to that of the complex is in the range of 0.1 to 5 and preferably 3 to 4di.
9. A process for the preparation of a complex as claimed in Claim 1 wherein the ibuprofen salt is selected from the potassium, ammonium, arginine, glycine or lysine salts and the process is analogous to that employed for the sodium salt as claimed in any one of Claims 4 to 8 using in the neutralisation step potassium hydroxide, potassium carbonate, ammonium hydroxide, arginine, glycine or lysine.
10. A process for the preparation of a complex as claimed in Claim 1 wherein the ibuprofen salt is selected from the magnesium or calcium salts and wherein an aqueous solution of the sodium salt complex is mixed with a suitable calcium or magnesium salt such as calcium chloride, magnesium chloride, calcium sulphate, magnesium sulphate, calcium gluconate, magnesium gluconate or calcium lactate.
11. A process as claimed in any one of Claims 4 to 10 substantially as described in any one of Examples 1 to c.
12. A complex of a-zyclodxtrin with an ibuprofen salt when prepared by a process as claimed in any one cf Clans A to 11
13. A pharmaceutical composition for oral administration comprising a ss-cyclodextrin/ibuprofen salt complex as claimed in any one of Claims 1 to 3 or 12 together with a pharmaceutically acceptable diluent or carrier.
14. A composition as claimed in Claim 13 in the form of powder, granules or tablets.
15. A composition as claimed in Claim 14 which further includes an amount of a pharmaceutically acceptable acid salt such as sodium citrate or a buffer system such that when the composition is added to water the pH of the resultant solution is between 6.0 and 8.0.
16. A composition as claimed in any one of Claims 13 to 15 in un t dosage form containing the equivalent of 50 to 500 mg of ibuprofen and preferably 200 to 400 mg.
17. A pharmaceutical composition as claimed in Claim 13 substantially as described in any one of Examples 10 to 14.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888813682A GB8813682D0 (en) | 1988-06-09 | 1988-06-09 | Pharmaceutical compositions |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8911938D0 GB8911938D0 (en) | 1989-07-12 |
| GB2219585A true GB2219585A (en) | 1989-12-13 |
| GB2219585B GB2219585B (en) | 1991-11-06 |
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| GB888813682A Pending GB8813682D0 (en) | 1988-06-09 | 1988-06-09 | Pharmaceutical compositions |
| GB8911938A Expired - Lifetime GB2219585B (en) | 1988-06-09 | 1989-05-24 | Pharmaceutical composition |
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| GB888813682A Pending GB8813682D0 (en) | 1988-06-09 | 1988-06-09 | Pharmaceutical compositions |
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|---|---|
| US (1) | US5019563A (en) |
| EP (1) | EP0346006B1 (en) |
| JP (1) | JPH02243649A (en) |
| KR (1) | KR910000138A (en) |
| AT (1) | ATE83924T1 (en) |
| AU (1) | AU609988B2 (en) |
| CA (1) | CA1320192C (en) |
| DE (1) | DE68904121T2 (en) |
| DK (1) | DK280789A (en) |
| ES (1) | ES2052914T3 (en) |
| FI (1) | FI93692C (en) |
| GB (2) | GB8813682D0 (en) |
| GR (1) | GR3006729T3 (en) |
| IE (1) | IE61616B1 (en) |
| NO (1) | NO175039B (en) |
| NZ (1) | NZ229204A (en) |
| PT (1) | PT90760B (en) |
| ZA (1) | ZA893913B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006312119B2 (en) * | 2005-11-02 | 2010-04-29 | Teikoku Pharma Usa, Inc. | Organoleptically acceptable ibuprofen oral dosage formulations, methods of making and using the same |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3827974A1 (en) * | 1988-08-18 | 1990-02-22 | Boehringer Mannheim Gmbh | COMBINATION PREPARATIONS OF PROTEINKINASE-C INHIBITORS WITH LIPIDS, LIPID ANALOGS, CYTOSTATICA OR INHIBITORS OF PHOSPHOLIPASES |
| MY106598A (en) * | 1988-08-31 | 1995-06-30 | Australian Commercial Res & Development Ltd | Compositions and methods for drug delivery and chromatography. |
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|---|---|---|---|---|
| JPS5646837A (en) * | 1979-09-27 | 1981-04-28 | Kowa Yakuhin Kogyo Kk | Preparation of ibuprofen clathrate compound |
| DE3346123A1 (en) * | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF |
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| CA1298290C (en) * | 1987-01-09 | 1992-03-31 | Herand M. Markarian | Solution ibuprofen complexes, compositions and processes for preparing the same |
-
1988
- 1988-06-09 GB GB888813682A patent/GB8813682D0/en active Pending
-
1989
- 1989-05-18 AU AU34927/89A patent/AU609988B2/en not_active Ceased
- 1989-05-19 NZ NZ229204A patent/NZ229204A/en unknown
- 1989-05-24 ZA ZA893913A patent/ZA893913B/en unknown
- 1989-05-24 GB GB8911938A patent/GB2219585B/en not_active Expired - Lifetime
- 1989-05-25 US US07/356,691 patent/US5019563A/en not_active Expired - Lifetime
- 1989-05-29 CA CA000600940A patent/CA1320192C/en not_active Expired - Fee Related
- 1989-06-01 DE DE8989305535T patent/DE68904121T2/en not_active Expired - Fee Related
- 1989-06-01 AT AT89305535T patent/ATE83924T1/en not_active IP Right Cessation
- 1989-06-01 EP EP89305535A patent/EP0346006B1/en not_active Expired - Lifetime
- 1989-06-01 ES ES89305535T patent/ES2052914T3/en not_active Expired - Lifetime
- 1989-06-06 PT PT90760A patent/PT90760B/en not_active IP Right Cessation
- 1989-06-06 JP JP1143961A patent/JPH02243649A/en active Pending
- 1989-06-07 NO NO892340A patent/NO175039B/en unknown
- 1989-06-07 FI FI892780A patent/FI93692C/en not_active IP Right Cessation
- 1989-06-08 DK DK280789A patent/DK280789A/en not_active Application Discontinuation
- 1989-06-08 KR KR1019890007835A patent/KR910000138A/en not_active Application Discontinuation
- 1989-06-12 IE IE175789A patent/IE61616B1/en not_active IP Right Cessation
-
1992
- 1992-12-31 GR GR920403100T patent/GR3006729T3/el unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006312119B2 (en) * | 2005-11-02 | 2010-04-29 | Teikoku Pharma Usa, Inc. | Organoleptically acceptable ibuprofen oral dosage formulations, methods of making and using the same |
Also Published As
| Publication number | Publication date |
|---|---|
| PT90760B (en) | 1994-10-31 |
| EP0346006A1 (en) | 1989-12-13 |
| NO175039C (en) | 1994-08-24 |
| US5019563A (en) | 1991-05-28 |
| FI93692C (en) | 1995-05-26 |
| ES2052914T3 (en) | 1994-07-16 |
| AU609988B2 (en) | 1991-05-09 |
| DK280789A (en) | 1989-12-12 |
| AU3492789A (en) | 1989-12-14 |
| GB8911938D0 (en) | 1989-07-12 |
| GR3006729T3 (en) | 1993-06-30 |
| NO175039B (en) | 1994-05-16 |
| EP0346006B1 (en) | 1992-12-30 |
| KR910000138A (en) | 1991-01-29 |
| NZ229204A (en) | 1992-03-26 |
| IE891757L (en) | 1989-12-09 |
| ATE83924T1 (en) | 1993-01-15 |
| GB2219585B (en) | 1991-11-06 |
| GB8813682D0 (en) | 1988-07-13 |
| FI93692B (en) | 1995-02-15 |
| FI892780A0 (en) | 1989-06-07 |
| DE68904121T2 (en) | 1993-05-06 |
| JPH02243649A (en) | 1990-09-27 |
| DK280789D0 (en) | 1989-06-08 |
| IE61616B1 (en) | 1994-11-16 |
| NO892340L (en) | 1989-12-11 |
| CA1320192C (en) | 1993-07-13 |
| DE68904121D1 (en) | 1993-02-11 |
| NO892340D0 (en) | 1989-06-07 |
| ZA893913B (en) | 1990-02-28 |
| PT90760A (en) | 1989-12-29 |
| FI892780A (en) | 1989-12-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20040524 |