Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
WO 95/04528
PCT/EP94/02515
PHARMACEUTICAL COMPOSITION CONTAINING A DRUG/BETA-CYCLODEXTRIN COMPLEX IN
COMBINATION WITH AN ACID-BASE COUPLE
This invention relates to a pharmaceutical composition containing a drug
which is lipophilic and has poor water solubility in the fornl of a clathrate
complex, a
process for its preparation, and a palatable formulation thereof suitable for
oral
consumption. In particular, the invention relates to a composition containing
a non-
steroidal anti-inflammatory (NSAID) drug as a cyclodextrin clathrate complex
suitable for oral consumption in aqueous solution.
The group of non-steroidal antiinflammatory agents (NSAIDs) includes drugs
such as ibuprofen, naproxen and ketoprofen which have utility in providing
relief
from pain and inflammation associated with a wide range of disorders including
for
example chronic disease states such as arthritis. Ibuprofen is also widely
indicated for
the treatment of symptoms associated with the common cold and flu. Formulation
of
these and other poorly water-soluble drugs into preparations suitable for oral
administration, in particular into water-soluble forms suitable for liquid
dosing, is
often complicated by the physical characteristics of the drugs which include
poor
water solubility, irritating odour and unpleasant taste. It is an object of
the present
invention to provide a palatable pharmaceutical composition containing a
lipophilic,
poorly water-soluble drug, for example an NSA1D such as ibuprofen, naproxen or
ketoprofen, formulated for oral dosing as an aqueous solution.
The ability of drug-cyclodextrin complexes to enhance water solubility and to
mask unpleasant taste and odour has been known for many years. In this
respect,
NSA1D's such as ibuprofen have proved to be very suitable as candidates for
complexation with cyclodextrins.
Japanese patent publication, JP 56-46837 (Kowa Yakuhin Kogyo) discloses a
method for the preparation of an ibuprofen-Li-cyclodextrin clathrate complex
involving the combination of ibuprofen with (3-cyclodextrin in water at
elevated
temperature and isolation of the clathrate by spray-drying. This method is
reported to
yield a product containing a high percentage of ibuprofen with a molar ratio
of
ibuprofen to 13-cyclodextrin in excess of 0.7. The increase in water
solubility of the
drug is considerable, being raised more than 8-fold from 10.44mg per 100m1 to
89.38mg per 100m1 at 27°C.
The water solubility achieved by complexation with (3-cyclodextrin, although
significant, is not considered sufficient to permit formulation of ibuprofen
as a
soluble dosage form for oral administration in liquid form wherein ibuprofen
is
present at a therapeutic dosage level (200-600mg) in a suitable volume of
water (SO-
250m1).
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WO 95/04528 ~ ~ ~ PCT/EP94/02515
European patent publication 274 444 (Bristol Myers) describes the
preparation of ibuprofen-cyclodextrin complexes using a-cyclodextrin, 7-
cyclodextrin or a methylated (3-cyclodextrin in place of Li-cyclodextrin. The
water
solubility of the ibuprofen-cyclodextrin complex is further enhanced to levels
of
practical utility using these forms of cyclodextrin, but the high cost of
these
materials, reflected in the cost of medicinal products containing them, is
unlikely to
promote their widespread use in analgesic products, more particularly in
products
available for self medication for the treatment of minor aches and pains and
the
symptomatic relief of colds and flu.
United Kingdom patent publication GB 2,189,994 (Zambon) discloses an
effervescent water-soluble ibuprofen formulation comprising ibuprofen plus
arginine
or a mixture of arginine and lysine and an effervescent couple in the form of
sodium
or potassium bicarbonate and sodium bitarnate.
US Patent No 4,762,702 (Gergely) discloses a pharmaceutical preparation in
which ibuprofen particles are enveloped by a coating of a hydro-colloid and
fumaric
acid which is intended to reduce the irritant effects of orally ingested
ibuprofen. An
effervescent formulation incorporating citric acid and calcium carbonate into
the
preparation is also described.
United Kingdom patent publication GB 2,219,585 (Reckitt & Colman)
discloses a complex of 13-cyclodextrin with the sodium, potassium, ammonium,
magnesium, calcium, arginine, glycine or lysine salt of ibuprofen, having a
molar
ratio of ibuprofen to 13-cyclodextrin in the range 1:0.2 to 1:0.75. The
complexes may
be formulated with a buffer system or an effervescent couple incorporating a
pharmaceutically acceptable acid salt to provide a pH in the range 6 to 8 on
reconstitution with water.
European patent publication 0 490 193 (Medics Chem-Pharm) discloses
complexes of the active enantiomer of ibuprofen and/or its physiologically
tolerated
salts with a cyclodextrin and /or a cyclodextrin derivative. Although there is
disclosed an ibuprofen effervescent tablet formulation, it is not soluble in
the volume
of water needed to form a therapeutically acceptable composition.
International Patent Application PCT/GB93/00702 (SmithKline Beecham)
overcomes the problem of poor solubility of ibuprofen by reconstituting an
ibuprofen/a-cyclodextrin complex in hot water to provide a pleasant tasting
soluble
liquid presentation. It was found that an approximately 30-fold increase in
solubility
could be achieved by dosing an ibuprofen-13-cyclodextrin complex in aqueous
solution at elevated temperatures and thereby achieve therapeutic dosage
levels of
ibuprofen in solution in a single-dose liquid formulation.
The present invention provides a further drug-cyclodextrin complex
formulation which is suitable for administration as an aqueous solution, and
which is
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WO 95/04528 PCT/EP94/02515
palatable and inexpensive to manufacture. The formulation according to the
present
invention provides a therapeutically active dose of the drug as a complex with
~i-
cyclodextrin. The formulation is suitable for reconstitution with cold water
and
provides a pleasant tasting solution at acid or neutral pH.
It has been found that when formulated in the presence of an acid-base
couple, preferably an effervescent acid-base couple, a drug/(3-cyclodextrin
complex,
which in isolation is soluble in water only at elevated temperatures, has
enhanced
solubility and dissolves in cold water to provide a therapeutic drug dose as a
single-
dose, liquid formulation.
According to the present invention there is provided a pharmaceutical
composition for oral consumption in aqueous solution comprising a drug/&
cyclodextrin complex, characterised in that the composition further comprises
a
pharmaceutically acceptable acid-base couple, preferably an effervescent acid-
base
couple, in a quantity sufficient to cause the drug/f3-cyclodextrin complex to
dissolve
when the composition is mixed with cold water and provide a solution with acid
or
neutral pH.
Suitable non-effervescent acid-base couples for use in the invention are those
commonly known in the art, for example a combination of a water soluble acid
and a
conjugate base in the form of a sodium or potassium salt. Suitable effervesent
couples
are also commonly known in the art, for example a combination of one or more
water
soluble acidic substances with one or more basic compounds which liberate
carbon
dioxide on neutralisation with acid.
Examples of suitable acids for use in the invention include, tartaric acid,
citric
acid, ascorbic acid and other edible organic acids. Suitable salts of organic
acids
include mono- di- and tri-basic salts, for example monosodium citrate,
trisodium
citrate, monosodium tarnate, trisodium tarnate and other salts of edible
organic acids.
Inorganic acidic substances such as monosodium phosphate are also suitable
components of acid-base couples. Examples of suitable bases for use in the
invention
include sodium carbonate, percarbonate and bicarbonate, and other alkali metal
and
alkali earth metal carbonates, percarbonates and bicarbonates, and mixed
carbonate
salts, such as sodium glycine carbonate and potasium glycine carbonate.
The preferred acid-base couple for this invention is an effervescent couple
which contains citric and/or tartaric acid and sodium bicarbonate and/or
carbonate.
The amount of couple required to solubilise the drug/f3-cyclodextrin complex
will depend on the amount and type of drug used. However a minimum level of
couple considered acceptable in a composition of the invention is an amount
such that
the weight of couple is greater than about 1 % of the weight of water in which
it is
designed to be reconstituted or is greater than 1 % of the weight of water in
which it is
to be dissolved, ie the final concentration of the couple on reconstitution in
water (not
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WO 95/04528 ~ ~ PCT/EP94/02515
allowing for loss of carbon dioxide for effervescent couples) should be
greater than
about 1 % by weight. Levels below this amount are generally considered
unsuitable
since, on reconstitution with water, incomplete dissolution of the drug/Li-
cyclodextrin
occurs. The maximum level of couple considered acceptable in a composition of
the
invention is 15% of the weight of water in which it is to be reconstituted.
For
effervescent compositions, levels in excess of this amount tend to lead to
excessive
effervescence, resulting in overflow of liquid from the glass or beaker and
loss of
some of the formulation. In addition high levels of acid-base couple tend to
impart a
salty taste to the palate. Compositions of the present invention are suitably
1o administered as pleasant tasting solutions in the pH range 4.0 to 7Ø
The constituents of acid-base couples suitable for use in compositions of the
invention and their relative amounts may be selected using principles well
known in
the art of pharmaceutical drug formulation. An acid-base couple for use in
compositions of the invention may be designed so that the final pH of the
formulation
15 following reconstitution with water is in the range of 4.0 - 7.0 and
preferably in the
range of 5.0 - 6.5. The pH of solutions resulting from reconstitution of the
couple in
water may be adjusted by altering the ratio of the alkali and acid components
of the
couple. If the couple is designed so that the final pH of the formulation
following
reconstitution with water falls below the specified range there may be a
tendency for
2o the drug/f3-cyclodextrin clathrate to precipitate, which detracts from the
appearance
and palatibility of the product. If the couple is designed to so that the
final pH
following reconstitution is above the specified range then the solution will
impart an
alkaline /soapy taste.
Preferred drugs for use in the compositions of the present invention include
25 lipophilic NSAID's, for example propionic acid derivatives such as
ibuprofen,
naproxen and ketoprofen.
Accordingly, drug/(3-cyclodextrin clathrates which are suitable for use in
this
invention include ibuprofen /13-cyclodextrin clathrates, naproxen / (3-
cyclodextrin
clathrates, ketoprofen /(3-cyclodextrin clathrates and clathlerates of (3-
cyclodextrin
30 with other propionic acid type NSAID's. In addition, the invention may use
clathrates
of f3-cyclodextrin with salts of ibuprofen, naproxen and other propionic acid
type
NSAID's, for example metal salts, such as sodium, potassium, magnesium, and
calcium, or amino-acid salts such as arginine, ornithine or lysine.
The drugs according to this invention may be as either the racemate or
35 enantiomers. Any reference to the drug is intended to cover all active
forms and may
be either in the R or S enantiomer or racemate form.
The molar ratio of 13-cyclodextrin to drug (or drug salt) may be in the range
0.8:1 to 10:1, suitably in the range 1:1 to 10:1, more suitably in the range
1:1 to 5:1
and preferably in the range l: l to 3:1. If the ratio falls below this range,
an
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WO 95/04528 PCT/EP94/02515
insufficient amount of the drug will be complexed which will lead to a
deterioration
in taste properties of the final product, and undissolved drug following
reconstitution
with water. If the amount of cyclodextrin is excessive then, for effervescent
formulations, there is a tendency for excessive foam formation on mixing the
formulation with water which may lead to loss of some of the formulation.
Furthermore, it is for economic reasons considered desirable to minimise the
amount
of cyclodextrin used in the composition.
The invention also provides a process for the preparation of a pharmacetical
composition of the invention which process comprises the admixture of a drug/B-
cyclodextrin clathrate complex and an acid-base couple.
A drug/B-cyclodextrin complex may be prepared by heating the drug and B-
cyclodextrin in water or in a buffered aqueous solution, suitably to a
temperature of
100°C, followed by crystallisation of the drug/B-cyclodextrin complex
from the
solution thus formed, suitably by maintaining the solution in the temperature
range -5
to 20°C. Alternatively a drug/B-cyclodextrin complex may be made by any
other
method known in the art, for example by a co-precipitation or kneading method
or by
spray-drying a solution of the drug and B-cyclodextrin.
The acid-base couple may be prepared by any method known in the art, for
example by dry mixing the components of the couple in a suitable mixer, or by
granulation using a rotary granulator, fluid-bed granulator or other suitable
granulator, followed by drying to remove residual moisture. If granulation is
the
chosen method of preparation, other components of the formulation may be
included
into the granulation step, for example part, or all of the drug/B-cyclodextrin
clathrate,
flavours, sweeteners and colours.
A composition of the invention may be formulated in any convenient form,
for example as a tablet for solution, or alternatively in powder or granular
form for
reconstitution with water or as a ready-to-drink preparation.
Compositions of the invention may be formulated with any appropriate carrier
or adjuvant appropriate to the chosen dosage form. Thus, compositions of the
invention may include for example preservatives, suspending agents, wetting
agents,
flavouring agents, bulking agents, binders, adhesives, lubricants,
disintegrants,
colouring agents, sweetening agents, adsorbents, thickeners and diluents,
appropriate
to their form.
Compositions of the invention containing a drug/B-cyclodextrin complex and
an acid-base couple may in addition include additional pharmaceutical agents
suitable
for administration therewith which are not complexed with B-cyclodextrin,
including
for example analgesics, antiinflammatories and antipyretics and also
expectorants,
antihistamines, decongestants and antitussive agents, such as for example
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WO 95/04528 ~ ~ PCTIEP94I02515
phenypropanolamine, phenylephrine, pseudoephedrine, dextromethorphan,
caffeine,
codeine and ascorbic acid.
The following Examples (1 to 18) are illustrative of the invention. Examples
(A to G) are outside the scope of the invention but are included to further
demonstrate aspects of the invention.
In the Examples, unless otherwise stated, the abbreviation BCD refers to B-
cyclodextrin undecahydrate (B-cyclodextrin. 11 H20).
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WO 95/04528 pCT/EP94/02515
Example 1
Preparation of I3CD/Ibuprofen Clathrate (1.1:1)
BCD (146.6g, 110mM) was dissolved in water (1000m1) at 100°C.
Ibuprofen
(20.68, 100mM) was added and the resulting solution was cooled to 1 °C
to give a
white crystalling precipitate which was washed with cold water and dried at
50°C for
4 hours in a convection oven. The product, a white solid, was sieved through a
500p.m screen to yield 125g of BCD/ibuprofen clathrate, containing about 14%
ibuprofen.
(400mg ibuprofen per 2857mg of clathrate).
Example 2
Preparation of an effervesent pharmaceutical composition containing
Ibuprofen/I3CD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a 500pm screen and mixed in a
suitable mixer for 5 minutes. A small aliquot of water was added and the
product was
mixed for a further 5 minutes and then placed on stainless steel trays and
dried for 2
hours at 60°C. The resulting granule was sieved through a SOOpm screen
mixed for 5
minutes with ingredient 1 and then filled into sachets, (target fill weight
10.85g) with
each sachet containing the equivalent of 400mg ibuprofen.
1. Ibuprofen/BCD clathrate from example 1 57.14g
2. Sodium bicarbonate lpp.ppg
3. Citric acid (anhydrous) 60.OOg
The powder from one of the sachets was added to 200m1 of cold water
(15°C)
to give an effervescent, pleasant tasting, clear solution, which contained
400mg
ibuprofen / 200 ml of water at a pH of approximately 6.3.
Example 3
Preparation of an effervesent pharmaceutical composition containing
Ibuprofen/fiCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a
suitable mixer for 5 minutes. A small aliquot of water was added and the
product was
mixed for a further 5 minutes and then placed on stainless steel trays and
dried for 2
hours at 60°C. The resulting granule was sieved through a SOOpm screen
mixed for 5
minutes with ingredients 1 and 4 and then filled into sachets, (target fill
weight
6.428g) with each sachet containing the equivalent of 200mg ibuprofen.
1. Ibuprofen/BCD clathrate from example 1 71.4g
2. Sodium bicarbonate 116.Og
3. Citric acid (anhydrous) 109.Og
4. Sodium carbonate (anhydrous) 25.Og
WO 95/04528 ~ ~ ~ PCT/EP94/02515
The powder from one of the sachets was added to 150m1 cold water
(16°C) to i
give an effervescent, pleasant tasting, clear solution, which contained 200mg
ibuprofen / 150 ml of water at a pH of approximately 6Ø
Example 4
Preparation of 13CD/Naproxen Clathrate (1.8:1)
Li-cyclodextrin (120.3g, 90mM) was dissolved in water (500m1) at
100°C.
Naproxen (11.5 g SOmM) was added and the resulting solution was cooled to
1°C to
give a white precipitate, which was dried at 60°C in a convection oven
for 16 hours.
1o The product, a white solid, was sieved through a SOOpm screen to yield 110g
of
(3CD/naproxen clathrate, containing about 9.4% naproxen.
Example 5
Preparation of (iCD/Naproxen Clathrate (1.1:1)
a-cyclodextrin (2948, 220mM) was dissolved in water (1500m1) at 100°C.
Naproxen (46g 200mM) was added and the resulting mixture was stirred for 1
hour at
95°C and then cooled, with stirring, to 1°C to give a white
precipitate, which was
dried at 60°C in a convection oven for 16 hours. The product, a white
solid, was
sieved through a 250pM screen, to yield 250g of 13CD/naproxen clathrate,
containing
about 15.3% naproxen.
Example 6
Preparation of an effervescent pharmaceutical composition containing
Naproxen/lZCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a 500pm screen and mixed in a
suitable mixer for 5 minutes. A small aliquot of water was added and the
product was
mixed for a further 5 minutes and then placed on stainless steel ways and
dried for 2
hours at 60°C. The resulting granule was sieved through a 500pm screen,
mixed for 5
minutes with ingredients 1 and 4, and then filled into sachets, (target fill
weight
7.38g) with each sachet containing the equivalent of 200mg naproxen
1. Naproxen/LiCD clathrate from example 4 106.Og
2. Sodium bicarbonate 116.Og
3. Citric acid (anhydrous) 109.Og
4. Sodium carbonate (anhydrous) 25.Og
The powder from one of the sachets was added to 150m1s cold water
(15°C) _
to give an effervescent, pleasant tasting, clear solution, which contained
200mg
naproxen/ 150 ml of water at a pH of approximately 6Ø
_g_
WO 95/04528 PCT/EP94/02515
l~xample 7
Preparation of an effervescent pharmaceutical composition containing
Naproxen/(3CD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a 500pm screen and mixed in a
suitable mixer for 5 minutes. A small aliquot of water was added and the
product was
mixed for a further 5 minutes and then placed on stainless steel trays and
dried for 2
hours at 60°C. The resulting granule was sieved through a SOOpm screen,
mixed for 5
minutes with ingredients 1 and 4, and then filled into sachets, (target fill
weight
6.307g) with each sachet containing the equivalent of 200mg naproxen.
1. Naproxen/LiCD clathrate from example 5 65.Sg
2. Sodium bicarbonate 116.Og
3. Citric acid (anhydrous) 109.Og
4. Sodium carbonate (anhydrous) 25.Og
The powder from one of the sachets was added to 150m1s cold water
(15°C)
to give an effervescent, pleasant tasting, clear solution, which contained
200mg
naproxen/ 150 ml of water at a pH of approximately 6Ø
Example 8 '
Preparation of an effervescent pharmaceutical composition containing
Naproxen/13CD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a
suitable mixer for 5 minutes. A small aliquot of water was added and the
product was
mixed for a further 5 minutes and then placed on stainless steel trays and
dried for 2
hours at 60°C. The resulting granule was sieved through a SOOpm screen,
mixed for 5
minutes with ingredients 1 and 4, and then filled into sachets, (target fill
weight
7.614g) with each sachet containing the equivalent of 400mg naproxen.
1. Naproxen/BCD clathrate from example 5 130.7g
2. Sodium bicarbonate 116.Og
3. Citric acid (anhydrous) 109.Og
4. Sodium carbonate (anhydrous) 25.Og
The powder from one of the sachets was added to 200m1s cold water
(15°C)
to give an effervescent, pleasant tasting, clear solution, which contained
400mg
naproxen/ 200 ml of water at a pH of approximately 6Ø
Example 9
Preparation of BCD/Naproxen sodium Clathrate (1.1:1)
13-cyclodextrin (147g, 110mM) was dissolved in water (SOOmI) at 100°C.
Naproxen sodium (25.2 g 100mM) was added and the resulting solution was
stirred
for 1 hour at 95°C and then poured onto trays and evaporated to dryness
in a
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WO 95/04528 ~ ~ ~ ~ PCT/EP94/02515
convection oven at 60°C. The product, a white amorphous solid, was
sieved through
a 250um screen, to yield 1238 of aCD/naproxen clathrate, containing about
15.156
naproxen.
Example 10
Preparation of an effervescent pharmaceutical composition containing
Naproxen sodium/IiCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a
suitable mixer for 5 minutes. A small aliquot of water was added and the
product was
mixed for a further 5 minutes and then placed on stainless steel trays and
dried for 2
hours at 60°C. The resulting granule was sieved through a 500pm screen,
mixed for 5
minutes with ingredients 1 and 4, and then filled into sachets, (target fill
weight
6.325g) with each sachet containing the equivalent of 200mg naproxen
1. Naproxen sodium/f3CD clathrate from example 9 66.38
2. Sodium bicarbonate 116.Og
3. Citric acid (anhydrous) 109.Og
4. Sodium carbonate (anhydrous) 25.Og
The powder from one of the sachets was added to 150m1s cold water
(15°C)
to give an effervescent, pleasant tasting, clear solution, which contained
200mg
naproxen/ 150 ml of water at a pH of approximately 6Ø
Example 11
Preparation of a non-effervescent pharmaceutical composition containing
Naproxen/(3CD clathrate for reconstitution with cold water
Ingredients 2 and 3 were mixed together in a suitable mixer for 5 minutes and
the resulting powder was filled into sachets, (target weight 5510mg), with
each sachet
containing the equivalent of 200mg naproxen.
1. Naproxen/(3CD clathrate l3.lg
2. Tri-sodium citrate 40.Og
3. Citric acid (anhydrous) 2.Og
The powder from one of the sachets was added to 250m1 of cold water (
15°C)
and stirred for 1 minute to give a non-effervescent, clear solution, which
contained
200mg naproxen/ 150m1 water at a pH of approximately 6.2.
Example 12
Preparation of IZCD / Ketoprofen Clathrate (5:1)
Li-cyclodextrin (53.3g, 40mM) was dissolved in water (200m1) at 100°C.
Ketoprofen
(2.05g, 8mM) was added and the resulting mixture was stirred for 1 hour at
95°C and
then cooled, with stirring, to 1°C to give a white precipitate, which
was dried at 60°C
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WO 95/04528 PCT/EP94/02515
in a convection oven for 16 hours. The product, a white solid, was sieved
through a
250uM screen to yield 50.4g of f3CD / ketoprofen clathrate, containing about
3.8%
ketoprofen.
Example 13
' Preparation of an effervescent pharmaceutical composition containing
Ketoprofen/~3CD clathrate for reconstitution with cold water
Ingredients 2 and 3 were sieved through a SOOpm screen and mixed in a suitable
mixer for 5 minutes. A small aliquot of water was added and the product was
mixed
for a further S minutes and then placed on stainless steel trays and dried for
2 hours at
60°C. The resulting granule was sieved through a 500pm screen, mixed
for 5 minutes
with ingredients 1 and 4, and then filled into sachets, (target fill weight
6.316g) with
each sachet containing the equivalent of SOmg ketoprofen
t5 1. Ketoprofen/~3CD clathrate from example 12 26.3g
2. Sodium bicarbonate 116.Og
3. Citric acid (anhydrous) 109.Og
4. Sodium carbonate (anhydrous) ~ 25.Og
The powder from one of the sachets was added to 150m1s cold water
(15°C) to give
an effervescent, pleasant tasting, clear solution, which contained SOmg
ketoprofen/
150 ml of water at a pH of approximately 6Ø
Example 14
Preparation of a ready made effervescent pharmaceutical composition
containing ~i-cyclodextrin / naproxen clathrate (1.1:1)
1. (3-cyclodextrin / naproxen clathrate 13.3g
2. Trisodium citrate 29.Og
3. Sodium carbonate 3.Og
4. Methyl paraben sodium 3.Og
5. Deionised water to 200 ml
Ingredients 1, 2, 3 and 4 were dissolved in item 5. 20 ml volumes of the
solution
were dispensed into 250m1 bottles containing 130 ml carbonated water, mixed
and
then fitted with air tight closures. Each bottle contained the equivalent to
approximately 200mg naproxen in a solution of pH approximately 6Ø
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Example 15
Preparation of (3CD / Naproxen Clathrate (0.9:1)
~-cyclodextrin (48.Og, 36 mmoles) and naproxen (9.2g, 40 mmoles) were added to
300 ml deionised water. The mixture was stirred for 1 hour at 95-100°C
and then
cooled to 1 °C to give a white precipitate, which was dried at
60°C in a convection
oven for 16 hours. The product, a white solid, was sieved through a 500 ltm
screen,
to yield 37.6g of (3CD / naproxen clathrate, containing about 19% naproxen.
Example 16
Preparation of a ready made effervescent pharmaceutical composition
containing (3-cyclodextrin / naproxen clathrate (0.9:1)
1. ~i-cyclodextrin / naproxen clathrate 10.52g
2. Trisodium citrate 29.Og
3. Sodium carbonate 3.Og
4. Methyl paraben sodium 3.Og
5. Deionised water to 200 ml
Ingredients 1, 2 ,3 and 4 were dissolved in item 5.20 ml volumes of the
solution were
dispensed into 250 ml bottles containing 130 ml carbonated water, mixed
and_then
fitted with air tight closures. Each bottle contained the equivalent
to_approximately
200 mg naproxen in a solution of pH approximately 6Ø
Example 17
Preparation of an effervescent pharmaceutical composition containing (3
cyclodextrin / naproxen clathrate (1.1:1) without precomplexation
1. (3-cyclodextrin 12.8g
2. Naproxen 2.Og
3. Trisodium citrate 29.Og
4. Sodium carbonate 3.Og
5. Methyl paraben sodium 3.Og
6. Deionised water to 200
ml
Ingredients 1, 2, 3, 4 and 5 were dissolved in item 6.20 ml volumes of the
solution
were dispensed into 250 ml bottles containing 130 ml carbonated water, mixed
and
then fitted with air tight closures. Each bottle contained the equivalent to
approximately 200 mg naproxen in a solution of pH approximately 6Ø
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~~ ~~~ ~9
WO 95/04528 PCT/EP94/02515
~xamp~e tai
Preparation of a ready made effervescent pharmaceutical composition
containing ~i-cyclodextrin / naproxen clathrate (0.9:1) without
precomplexation
1. (3-cyclodextrin 10.4g
' 2. Naproxen 2.Og
3. Trisodium citrate 29.Og
4. Sodium carbonate 3.Og
5. Methyl paraben sodium 3.Og
6. Deionised water to 200 ml
Ingredients 1, 2, 3, 4 and 5 were dissolved in item 6.20 ml volumes of the
solution
were dispersed into 250 ml bottles containing 130 ml carbonated water, mixed
and
then fitted with air tight closures. Each bottle contained the equivalent to
approximately 200 mg naproxen in a solution of pH approximately 6Ø
Example A
Reconstitution in water of a commercially available Ibuprofen tablet
A Nurofen Soluble (trade mark) tablet containing ibuprofen (200mg) was
added to 150m1 of cold water. The tablet failed to completely dissolve,
resulting in a
white suspension.
Example B
Reconstitution in water of a commercially available dispersible Naproxen
powder
The contents of a Naproxsyn (trade mark) sachet containing naproxen
(500mg) was added to 150m1 of cold water. The powder failed to completely
dissolve, resulting in a white suspension.
Example C
Preparation of an effervescent pharmaceutical composition containing
Ibuprofen/(iCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a
suitable mixer for 5 minutes. A small aliquot of water was added and the
product
was mixed for a further 5 minutes and then placed on stainless steel trays and
dried
for 2 hours at 60°C. The resulting granule was sieved through a SOOpm
screen mixed
for 5 minutes with ingredients 1 and 4 and then filled into sachets, (target
fill weight
1.928g) with each sachet containing the equivalent of 200mg ibuprofen.
1. Ibuprofen/~iCD clathrate from example 1 171.4g
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WO 95/04528 ~ PCT/EP94/02515
2. Sodium bicarbonate 11.68
3. Citric acid (anhydrous) 10.9g
4. Sodium carbonate (anhydrous) 2.Sg
The powder from one of the sachets was added to 150m1 cold water (
16°C) to
give a suspension in which some of the ibuprofen/(3-cyclodextrin clathrate
remained
undissolved.
Example D
Preparation of an effervescent pharmaceutical composition containing
Naproxen/13CD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a
suitable mixer for 5 minutes. A small aliquot of water was added and the
product
was mixed for a further 5 minutes and then placed on stainless steel trays and
dried
for 2 hours at 60°C. The resulting granule was sieved through a SOOpm
screen, mixed
for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target
fill weight
2.62g) with each sachet containing the equivalent of 200mg naproxen
1. Naproxen/13CD clathrate from example 4 106.Og
2. Sodium bicarbonate 11.6g
3. Citric acid (anhydrous) 10.9g
4. Sodium carbonate (anhydrous) 2.Sg
The powder from one of the sachets was added to 150m1 cold water
(16°C) to
give a suspension in which some of the naproxen/f3-cyclodextrin clathrate
remained
undissolved.
Example E
The granulation and blending process described in Example 8 was repeated,
except that the naproxen 13-cyclodextrin was replaced with an equimolal
quantity of
naproxen sodium ( 10.95g). The resulting powder was filled into sachets
(target
weight 5.219g), with each sachet containing naproxen.(200mg). The powder from
one of the sachets was added to 150m1s cold water (16°C) to give a
suspension in
which some of the drug remained undissolved.
Example F
The granulation and blending process described in Example 8 was repeated,
except that the ibuprofen 13-cyclodextrin was replaced with an equimolal
quantity of
ibuprofen sodium (ll.lg). The resulting powder was filled into sachets (target
weight 5.221g), with each sachet containing ibuprofen (200mg).
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WO 95/04528 PCT/EP94/02515
The powder from one of the sachets was added to 150m1 cold water
(16°C) to
give a solution which initially had oily droplets floating on the surface. On
standing,
the droplets formed a white vitreous solid, containing undissolved ibuprofen.
Example G
Preparation of an effervescent pharmaceutical composition containing
Ibuprofen/(3CD clathrate for reconstitution with cold water
Ibuprofen sodium B-cyclodextrin complex (1: 0.37) was prepared as described
ih GB 2,219,585 (Reckitt & Colman) Example 1. Ingredients 2 and 3 were seived
through a SOOp.m screen and mixed in a suitable mixer for 5 minutes. A small
aliquot
of water was added and the product was mixed for a further 5 minutes and then
placed on stainless steel trays and dried for 2 hours at 60°C. The
resulting granule
was seived through a 500p.m screen, mixed for 5 minutes with ingredients 1 and
4
and then filled into sachets (target fill weight 5.6g) with each sachet
containing the
equivalent of 200mg ibuprofen.
1. Ibuprofen/BCD clathrate ( 1:0.347) 30.Og
2. Sodium bicarbonate 116.Og
3. Citric acid (anhydrous) 109.Og
4. Sodium carbonate (anhydrous) 25.Og
The powder from one of the sachets was added to 150m1 cold water (
16°C) to
give a solution which initially had oily droplets floating on the surface. On
standing,
the droplets formed a white viscous solid containing undissolved ibuprofen.
The pH
of the mixture was approximately 6.1.
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