U.S. patent application number 11/030537 was filed with the patent office on 2005-07-07 for pharmaceutical compositions based on diclofenac.
Invention is credited to Reiner, Alberto, Reiner, Giorgio.
Application Number | 20050147671 11/030537 |
Document ID | / |
Family ID | 34714064 |
Filed Date | 2005-07-07 |
United States Patent
Application |
20050147671 |
Kind Code |
A1 |
Reiner, Alberto ; et
al. |
July 7, 2005 |
Pharmaceutical compositions based on diclofenac
Abstract
New pharmaceutical compositions for oral use containing
Diclofenac together with alkali metal bicarbonates in amounts of
from 20 to 80 by weight with respect to Diclofenac are described.
These compositions are entirely palatable and free from any
unpleasant taste or other side effects; in particular, these
formulations permit to obtain in human patients higher C.sub.max of
the active principle and shorter T.sub.max together with a lower
coefficient of variation.
Inventors: |
Reiner, Alberto; (Como,
IT) ; Reiner, Giorgio; (Como, IT) |
Correspondence
Address: |
KING & SPALDING LLP
191 PEACHTREE STREET, N.E.
ATLANTA
GA
30303-1763
US
|
Family ID: |
34714064 |
Appl. No.: |
11/030537 |
Filed: |
January 5, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11030537 |
Jan 5, 2005 |
|
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|
09524747 |
Mar 14, 2000 |
|
|
|
09524747 |
Mar 14, 2000 |
|
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09192493 |
Nov 17, 1998 |
|
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Current U.S.
Class: |
424/464 ;
514/567 |
Current CPC
Class: |
A61K 9/2009 20130101;
A61K 8/44 20130101; A61K 31/197 20130101; A61K 47/02 20130101; A61Q
11/00 20130101; A61K 31/196 20130101 |
Class at
Publication: |
424/464 ;
514/567 |
International
Class: |
A61K 031/195; A61K
009/20 |
Foreign Application Data
Date |
Code |
Application Number |
May 17, 1996 |
IT |
MI96A000992 |
May 17, 1996 |
WO |
PCT/EP97/02709 |
Claims
1) A fast-release diclofenac composition, in the form of a unit
dose packet of powder for dissolving or suspending in water, or in
the form of a fast release layer in a two layered diclofenac tablet
that comprises a fast layer and a slow layer, wherein said
composition comprises diclofenac in acid and/or salt form.
2) The composition of claim 1 wherein said diclofenac is present as
diclofenac potassium.
3) The composition of claim 1 wherein said diclofenac is present in
an amount ranging from about 10 to about 60 mg.
4) The composition of claim 1 in the form of a unit dose packet of
powder wherein said diclofenac is present in an amount of about 50
mg.
5) The composition of claim 1 in the form of a unit dose packet of
powder wherein said diclofenac is present as diclofenac potassium
in an amount of about 50 mg.
6) The composition of claim 1 in the form of a unit dose packet of
powder, wherein said composition is capable of yielding an average
T.sub.max of diclofenac in a human patient between 5 and 30 minutes
after administration of said diclofenac to said patient, said
average T.sub.max having a coefficient of variation (CV %) less
than about 70%.
7) The composition of claim 1 in the form of a unit dose packet of
powder, wherein said composition is capable of yielding an average
T.sub.max of diclofenac in a human patient between 13 and 27
minutes after administration of said diclofenac to said patient,
said average T.sub.max having a coefficient of variation (CV %)
less than about 70%.
8) The composition of claim 1 in the form of a fast release layer
in a two layered diclofenac tablet.
9) The composition of claim 1 in the form of a fast release layer,
wherein said composition comprises about 15 mg. of diclofenac
potassium salt, and said slow release layer comprises about 70 mg.
of diclofenac potassium salt.
10) The composition of claim 1, further comprising means for
potentiating the bioavailability of said diclofenac.
11) The composition of claim 10 wherein said means decreases the
Tmax of said diclofenac.
12) The composition of claim 10 wherein said means increases the
Cmax of said diclofenac.
13) The composition of claim 10 wherein said means decreases the
coefficient of variation of the Cmax of said diclofenac.
14) The composition of claim 10 in the form of a unit dose packet
of powder wherein said diclofenac is present in an amount of from
about 10 to about 60 mg.
15) The composition of claim 10 in the form of a unit dose packet
of powder wherein said diclofenac is present in an amount of about
50 mg.
16) The composition of claim 10 wherein said means comprises one or
more alkali metal carbonates or bicarbonates.
17) The composition of claim 10 wherein said means comprises one or
more alkali metal carbonates or bicarbonates in an amount greater
than about 20 wt. % based on the weight of said diclofenac.
18) The composition of claim 10 in the form of a unit dose packet
of powder wherein said diclofenac is present in an amount of about
50 mg. and said means comprises one or more alkali metal carbonates
or bicarbonates in an amount greater than about 20% based on the
weight of said diclofenac.
19) The composition of claim 10 in the form of a unit dose packet
of powder wherein said diclofenac is present as diclofenac
potassium in an amount of about 50 mg. and said means comprises
potassium bicarbonate in an amount greater than about 20% based on
the weight of said diclofenac.
20) The composition of claim 10 in the form of a unit dose packet
of powder wherein said diclofenac is present as diclofenac
potassium in an amount of about 50 mg. and said means comprises
potassium bicarbonate in an amount of from about 40 wt. % to about
80 wt. % based on the weight of said diclofenac.
21) A fast-release diclofenac composition, in the form of a unit
dose packet of powder for dissolving or suspending in water, or in
the form of a fast release layer in a two layered diclofenac tablet
comprising a fast layer and a slow layer, wherein the composition
comprises diclofenac in acid and/or salt form and means for
potentiating the bioavailability of said diclofenac.
22) The composition of claim 21 wherein said means comprises
greater than about 20 wt. % of one or more alkali metal carbonates
or bicarbonates based on the weight of said diclofenac.
23) A fast-releasing diclofenac composition, in the form of a unit
dose packet of powder for dissolving or suspending in water,
comprising about 50 mg. of diclofenac in acid and/or salt form.
24) The composition of claim 23 wherein said diclofenac is present
as diclofenac potassium.
25) The composition of claim 23 wherein said diclofenac is present
as diclofenac potassium, further comprising from about 40 to about
80 wt. % of potassium bicarbonate.
26) A fast-release diclofenac composition, in the form of a fast
release layer in a two layered diclofenac tablet comprising a fast
layer and a slow layer, comprising from about 10 to about 60 mg. of
diclofenac in acid and/or salt form.
27) The composition of claim 26 wherein said diclofenac is present
as diclofenac potassium.
Description
[0001] The present application is a continuation of U.S. Ser. No.
09/524,747, filed Mar. 14, 2000 (pending), which is a continuation
in part of U.S. Ser. No. 09/192,493, filed Nov. 17, 1998
(abandoned).
[0002] The present invention relates to new immediate release
pharmaceutical compositions containing
[(2,6-dichloro-anilino)-2-phenyl]-- 2-acetic acid (more commonly
known as Diclofenac) in acid and/or salt form.
[0003] Diclofenac is a non-steroidal drug which was invented at the
end of the sixties by A. Sallmann and R. Pfister (NL-6,604,752 and
U.S. Pat. No. 3,558,690 both to Ciba-Geigy) and whose structural
formula is indicated below. 1
[0004] Diclofenac is widely dispensed and used owing to its
well-known analgesic, anti-pyretic, anti-arthritic, anti-phlogistic
and anti-rheumatic properties and it is generally taken orally in
the form of normal tablets or tablets covered with coatings
resistant to gastric juices, or rectally, or by injection, or
topically.
[0005] The possibility of taking it in the form of sweets, tablets
dissolving in the mouth, drages, chewing gum or other similar
pharmaceutical forms or in formulations for the extemporary
preparation of Diclofenac-based aqueous solutions and/or
suspensions would represent a different mode of administration
which is definitely more suitable, especially for children and
elderly persons.
[0006] Owing to its poor solubility in water, Diclofenac is
normally used in salt form; the salts of Diclofenac customarily
used are those of sodium, potassium or other alkali and alkaline
earth metals, together with salts of organic nature, such as the
salts of basic amino acids, such as lysine, arginine and ornithine,
or other pharmacologically acceptable organic bases which have the
ability to render the resulting salt soluble in water.
[0007] The pharmaceutical compositions of the Diclofenac salts for
oral use are generally 25 accompanied by side effects of not
inconsiderable consequence: Diclofenac salts are in fact
characterised by a particularly unpleasant and bitter taste and by
the fact that they produce a sensation of strong astringency and
cause an especially intense form of irritation in the buccal
cavity, especially in the area of the larynx.
[0008] Although the first problem has been partly solved by using
flavourings which are able in some manner to mask the taste,
satisfactory solutions have still not been proposed for the two
remaining problems.
[0009] Therefore, the pharmaceutical compositions containing
Diclofenac salts still have a poor palatability which limits their
adoption and possible fields of application, despite the excellent
therapeutic effect with which they are associated.
[0010] A second problem connected to Diclofenac is that, when it is
orally administered by means of immediate release formulations, the
corresponding T.sub.max (the time to the maximum plasma
concentration) is usually located at about 1 hour since
administration, this being of course a not completely satisfactory
result when a prompt and strong analgesic/anti-pyretic effect is
sought for. Furthermore, the corresponding coefficient of variation
is normally in the range of 70-90%, which means that the T.sub.max
is strongly variable and dependent on the physical characteristics
of the patient (Physicians' Desk Reference, 52 edition, 1998, pag.
1831). Attempts are therefore still being made in order to enhance
the rate of absorption of Diclofenac and to provide an earlier
onset of the therapeutical effect (N. Davies, K Anderson; Clinical
Pharmacokinetic of Diclofenac, Clin. Pharmacokinet., 1997, Sep.
33(3).
[0011] The object of the present invention is therefore that of
providing a fully palatable formulation of Diclofenac which is able
to generate a more rapid, uniform and foreseeable release of the
active principle if compared to the compositions known in the art
and presently available on the market. For the purposes of the
present invention T.sub.max means the time to the maximum plasma
concentration whereas C.sub.max is the maximum plasma concentration
of the active principle, namely Diclofenac. It has now been found
that, by adding alkali metal bicarbonates or mixtures thereof to
the Diclofenac in its acid and/or salt form, in amounts of from 20
to 80% by weight based on the acid-form of Diclofenac,
pharmaceutical compositions an be obtained which are substantially
free from the side effects mentioned above. The first object of the
present invention is therefore represented by a pharmaceutical
formulation for oral use containing Diclofenac in acid and/or salt
form together with alkali metal bicarbonates or mixtures thereof
and customary excipients and adjuvants, wherein said alkali metal
bicarbonates are present in amounts of from 20 to 80% by weight
based on the weight of Diclofenac.
[0012] It has in fact been surprisingly demonstrated that the use
of alkali metal bicarbonates in the above-mentioned ratio permits
to achieve constant, reproducible and foreseeable blood levels of
the active ingredient, with the consequent indisputable advantages
from the therapeutic point of view, furthermore, it has also been
found that the combined use of Diclofenac together with alkali
metal bicarbonates yields Diclofenac-based pharmaceutical
compositions in which the active ingredient is released more
rapidly compared with normal formulations, bringing about higher
blood levels and therefore a more immediate therapeutic effect;
finally the so-obtained immediate release formulations are
substantially palatable and free from aftertaste.
[0013] According to the preferred embodiment of the present
invention, the amount of alkali metal bicarbonates to be added is
comprised between 40 and 80% by weight, based on the weight of the
acid-form Diclofenac, whereas the alkali metal bicarbonates are
selected from sodium and/or potassium bicarbonates, Diclofenac
being normally present in the form of its sodium and/or potassium
salts.
[0014] It has also been found, and forms a second subject of the
present invention, that the addition of flavouring substances
selected from mint, aniseed, ammonium glycyrrhizinate and mixtures
thereof to the compositions containing the Diclofenac salts and
alkali metal bicarbonates produces a synergistic effect which
completely eliminates all the above-mentioned
palatability/astringency effects, providing pharmaceutical
compositions which are entirely palatable (and/or drinkable in the
case of those used for the preparation of solutions and/or
suspensions) and free from aftertaste.
[0015] The flavouring substances may be used as such or supported
on inert materials, for example maltodextrin, in order to obtain a
better distribution of the granulates and to facilitate excellent
dispersibility of the flavouring in solution. Preferably, they are
absorbed on maltodextrin with a power of 1 to 2000 and 1 to
1000.
[0016] The amount of flavouring substances in its pure form is also
preferably from 1/5 to 3 times the weight of the acid-form
Diclofenac.
[0017] These flavouring substances are used in the implementation
of the present invention without altering their organoleptic
properties and without depriving them of their intrinsic qualities
of flavourings which are liposoluble and generally oily in the pure
state.
[0018] As it will be clear from the examples, the immediate release
formulations for oral use of the present invention conning from 10
to 60 mg of Diclofenac in acid and/or salt form together with
alkali metal bicarbonates or mixtures thereof in amounts of from 20
to 80% by weight based on the weight of Diclofenac permit to
generate in human patients an average C.sub.max of Diclofenac
comprised between 400 and 2500 ng/ml independently on the age, sex
or weight of the patients themselves.
[0019] Secondly, the formulations according to the present
invention permit to obtain in humans an average T.sub.max of
Diclofenac after 5.div.30 minutes since administration, generally
13.div.27, independently on the amount of Diclofenac contained
therein and also independently on the age, sex, weight of the
patient.
[0020] Furthermore, the T.sub.max of the formulations of the
present invention show a coefficient of variation which is about
44-86% lower than the presently marketed formulations; this is
evidently an extremely important result from the clinical point of
view as it is now possible to have a therapeutical effect of
Diclofenac which is foreseable, reproducible and independent on the
sex, weight and health conditions of the patient.
[0021] Thus, the presently claimed Diclofenac-based formulations
permit to achieve a higher C.sub.max in a shorter T.sub.max and
with a lower corfficient of variation if compared to the
formulations available on the market, with therapeutical advantages
which do not need to be commented.
[0022] According to the best mode for carrying out the present
invention the pharmaceutical formulations will contain from 10 to
60 mg/dose of diclofenac in its potassium or sodium salt form
together with 40 to 80% by weight of potassium or sodium
bicarbonate based on the weight of Diclofenac in its acid form,
together with the usual excipients and adjuvants; even more
preferably they will packaged as:
[0023] a sachet or tablet formulation containing 50 mg of
Diclofenac potassium salt and 22 mg of potassium bicarbonate or 50
mg of Diclofenac sodium salt and 19 mg of sodium bicarbonate;
[0024] a sachet or tablet formulation containing 12.5 mg of
Diclofenac sodium salt and 5.5 mg of potassium bicarbonate or 25 mg
of Diclofenac sodium salt and 11 mg potassium bicarbonate.
[0025] It will be by the way evident to any skilled in this art
that the present formulations can also be used as immediate release
layers of multilayered release pharmaceutical formulations
containing Diclofenac as one of the active ingredients; said
formulations are therefore a further object of the present
invention.
[0026] The following Examples are given purely by way of
non-limiting illustration.
EXAMPLE 1
Composition Dissolving Instantly in Water
[0027]
1 Active ingredients 1) Diclofenac potassium salt*: 50 mg 2)
Potassium bicarbonate: 22 mg 3) Mint flavouring on
maltodextrin(1:2000)**: 60 mg 4) Aniseed flavouring on maltodextrin
(1:1000)***: 104 mg Excipients and adjuvants 5) Saccharin: 4 mg 6)
Aspartame: 10 mg 7) Mannitol: 50 mg 8) Saccharose****q.s.: 2 g *If
it is desired to prepare compositions based on Diclofenac sodium
salt, it is advantageous to use sodium bicarbonate in a quantity of
approximately 38% by weight based on the weight of the Diclofenac
sodium salt present. Sodium carbonate may also be added to the
sodium bicarbonate, maintaining the following optimum proportions:
27% of sodium bicarbonate and 4-5% of # sodium carbonate, always
based on the amount by weight of Diclofenac sodium salt present.
**The title of the pure mint essence, as obtained according to the
Dean-Stark method, is of 18% by weight; the related amount is
therefore in this case of 10.8 mg. ***The title of the pure anise
essence, as obtained according to the Dean-Stark method, is of
14.5% by weight, the related amount is therefore in this case of 16
mg. ****The presence of saccharose is not strictly necessary; in
its absence, a composition having a very limited granulate content
is obtained which is perfectly soluble in contact with water. In
that case, nothing is changed from the point of view of
tolerability in contact with the mucosa and from the point of view
of the palatability of the drinkable solution.
[0028] Preparation
[0029] Components 1, 2, 5, 6 and 7 are mixed in a suitable mixer,
and the mixture so obtained is wetted with 95% ethanol. Granulation
is carried out with a 66 mm mesh and the granulate is preferably
dried in a current of air.
[0030] Components 3, 4 and 8, which have already been granulated
using a mesh of the same granulometry, are then added and the whole
is mixed.
[0031] The mixture is then introduced into a metering machine
filling packets or similar containers.
EXAMPLE 2
Tablet for Dissolving in the Mouth
[0032]
2 Active ingredients 1) Diclofenac potassium salt*: 50 mg 2)
Potassium bicarbonate: 35 mg 3) Mint flavouring on maltodextrin**
50 mg (1:2000) + gum arabic (E 414): 4) Aniseed flavouring (1:1000)
120 mg on maltodextrin*** + silicon dioxide (E 551): Excipients and
adjuvants 5) Saccharin: 50 mg 6) Aspartame: 12 mg 7) Mannitol: 20
mg 8) Saccharose****: 300 mg * to **** see Example 1
EXAMPLE 3
Gum Tablet
[0033]
3 Active ingredients 1) Diclofenac potassium salt*: 50 mg 2)
Potassium bicarbonate: 35 mg 3) Mint flavouring on maltodextrin**:
30 mg 4) Aniseed flavouring on maltodextrin***: 80 mg Excipients
and adjuvants 5) Mannitol: 30 mg 6) Menthol: 0.01 mg 7) Gum base:
600 mg 8) Sorbitol: 700 mg 9) Saccharin: 3 mg 10)
Hydroxypropylmethylcellulose: 33 mg 11) Colouring agent: 7 mg * to
*** see Example 1
EXAMPLE 4
Comparative Test
[0034] The packaged composition containing 50 mg of Diclofenac
potassium of Example 1 (formulation C) was subjected to a
pharmacokinetic test for comparison with a similar composition not
containing alkali metal carbonates and bicarbonates (formulation
B), and with a second composition in tablet form (formulation A)
produced by Ciba-Geigy (Voltaren Rapid.RTM.), also in this case not
containing alkali metal carbonates and bicarbonates, both
formulations A and B containing 50 mg of Diclofenac potassium.
[0035] This comparative evaluation was carried out on the same 6
healthy volunteers in accordance with the experimental plan
described hereinafter.
[0036] Experimental scheme: Single-dose study using three methods
in randomised cross-over with a wash-out of three days.
[0037] Sampling times: 0 h (before administration), 5 min, 10 min.
30 mm, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, after each
administration.
[0038] Blood sample treatment: 8 MI in heparinised test tubes,
centrifugation for 15 min at 1500 rev/min, subdivided into two
factions and subsequently frozen at -20.degree. C.
[0039] Times: wash-out of two days between treatments.
[0040] Determination method: HPLC, with internal standard,
sensitivity 10 ng/ml.
[0041] Analysis Method
[0042] Column: Nova Pak C18, 3.9.times.150 mm, 4 .mu.m Waters
S.p.A.--Vimodrone, Italy.
[0043] Eluant: NaH2PO4 0.01 M+0.1% TEA, pH 3.0
(H3P04)/acetonitrile, 60/40.
[0044] Flow: 1.2 ml/min
[0045] Detection: TV/275 nin
[0046] Temperature: 30.degree. C.
[0047] Injection: 50 al
[0048] Analysis time: 16 min.
[0049] Sample Preparation
[0050] 10 al of the internal standard methanolic solution, and
flufenamic acid (corresponding to 1320 ng) are added to 1 ml of
defrosted plasma in 10 ml glass test tubes. The tubes are agitated
in a Vortex mixer for 1 minute. 0.5 ml of a 0.5N HCl/1N NaCl
solution is added. The whole is agitated in a Vortex mixer for 1
minute. 6 ml of a 95/5 n-hexane/isopropanol solution are added
[0051] The mixture is then agitated in the Vortex mixer for a
further 15 minutes. Centrifugation is carried out at 3000 rev/min
for 15 minutes and the organic phase is transferred to fresh 10 ml
glass test tubes and evaporated to dryness in a centrifugal
evaporator under vacuum at ambient temperature. The whole is taken
up in 200 al of a 70/30 acetonitrile/water solution, and the
precipitate is dissolved under ultrasound for 2 minutes.
[0052] FIGS. 1, 2 and 3 show the concentrations of Diclofenac in
the blood of the six volunteers as regards formulations A, B
(Ciba-Geigy comparative formulations) and C (formulation
corresponding to the composition of Example 1), respectively. As
will be appreciated the blood concentration of the formulation of
the present invention has, compared with the comparative
formulations, a more constant and uniform pattern. This
characteristic is also found in FIGS. 4, 5 and 6 which show the
average values corresponding to the blood levels of the six
volunteers together with the corresponding standard deviation.
[0053] The result is clear and surprising: compared with the sample
compositions, the compositions of the present invention permit
constant, reproducible and foreseeable blood levels of the active
ingredient, irrespective of the characteristics of the volunteer
(weight, age, etc), with the consequent indisputable advantages
from the therapeutic point of view.
[0054] Finally, FIG. 7 shows, by comparison, the graphs relating to
the average values of the six volunteers (that is to say, the
preceding FIGS. 4, 5 and 6); as will be noted, the formulation of
the present invention permits, in addition to the advantages
already mentioned, the attainment of a blood peak higher than that
of the other formulations.
EXAMPLE 5
Two Layered Tablet (Fast and Slow Release)
[0055]
4 Fast release layer 1) Diclofenac potassium salt: 15 mg 2)
Potassium bicarbonate: 30 mg 3) Lactose: 13.2 mg 4) Maize starch
(intragranular): 6 mg 5) Methyl cellulose: 0.12 mg 6) Sodium
laurylsulfate: 0.06 mg 7) Maize starch (extragranular): 9 mg 8)
Crospovidone: 0.6 mg 9) Sodium carboxtmethylstarch: 1.5 mg 10)
Magnesium stearate: 2.7 mg 11) Colloidal silicon dioxide: 0.6 mg
Slow release layer 1) Diclofenac potassium salt: 70 mg 2) Potassium
bicarbonate: 30.8 mg 3) Lactose: 32.2 mg 4) Polyvinylpyrrolidone:
1.16 mg 5) Hydrpxypropylmethylcellulose: 70 mg 6) Magnesium
stearate: 0.84 mg 7) Colloidal silicon dioxide: 0.21 mg 8) Talc:
3.92 mg 9) Polyethylene glycol: 0.56 mg
EXAMPLE 6
Drops
[0056]
5 1) Diclofenac potassium salt: 75 g 2) Methyl p-oxybenzoate: 2.7 g
3) Propyl p-oxybenzoate: 0.3 g 4) Aspartame: 37.5 g 5) Potassium
bicarbonate: 37.5 g 6) Glycerol: 300 g 7) Ethyl alcool: 450 g 8)
Water q.s.: 1500 g Possible modifications: a) Addition of sodium
metabisulfite (0.06%) b) Addition of sodium metabisulfite (0.06%)
Mint flavouring (1.25%) Strawberry flavouring (0.75%)
EXAMPLE 7
Drops
[0057]
6 1) Diclofenac potassium salt: 37.5 g 2) Methyl p-oxybenzoate: 2.7
g 3) Propyl p-oxybenzoate: 0.3 g 4) Aspartame: 37.5 g 5) Potassium
bicarbonate: 18.75 g 6) Saccharin: 6.0 g 7) Glycerol: 300 g 8)
Ethyl alcool: 450 g 9) Water q.s.: 1500 g Possible modifications:
a) Addition of sodium metabisulfite (0.03%) b) Addition of sodium
metabisulfite (0.03%) Mint flavouring (1.25%) Strawberry flavouring
(0.75%)
EXAMPLE 8
Mouthwash
[0058]
7 1) Diclofenac potassium salt: 0.75 g 2) Glycerol: 50 g 3)
Sorbitol: 12 g 4) Saccharin: 0.5 g 5) Aspartame: 1.0 g 6) Methyl
p-oxybenzoate: 0.5 g 7) Propyl p-oxybenzoate: 0.1 g 8) Mint
flavouring: 1.0 g 9) Ethyl alcool: 100 g 10) Potassium bicarbonate:
0.33 g 11) Water q.s.: 500 ml
EXAMPLE 9
Gum-Paste
[0059]
8 1) Diclofenac potassium salt: 5.0 g 2) Glycerol: 630 g 3) Sodium
benzoate: 5.0 g 4) Silica (Wessalon S .RTM. - Degussa): 120 g 5)
Silica (Siddent 9 .RTM. - Degussa): 80 g 6) Cellulose gum: 3.0 g 7)
Polyethylenglycol 600: 30 g 8) Sodium lauroyl sarcosinate 60 g (or
sodium lauryl sulfate): 9) Mint flavouring: 10 g 10) Sodium
saccharin: 1.0 g 11) Aspartame: 3.0 g 12) Potassium bicarbonate:
2.2 g 13) Water q.s.: 1 kg
EXAMPLE 10
Tooth-Paste
[0060]
9 1) Diclofenac potassium salt: 5.0 g 2) Glycerol: 630 g 3) Sodium
benzoate: 5.0 g 4) Silica (Wessalon S .RTM. - Degussa): 20 g 5)
Silica (Siddent 9 .RTM. - Degussa): 80 g 6) Cellulose gum: 3.0 g 7)
Polyethylenglycol 600: 30 g 8) Sodium lauroyl sarcosinate 60 g (or
sodium lauryl sulfate): 9) Mint flavouring: 10 g 10) Sodium
saccharin: 1.0 g 11) Aspartame: 3.0 g 12) NaF: 1.0 g 13)
Na.sub.2FPO.sub.3: 4.0 g 14) Potassium bicarbonate: 2.2 g 15) Water
q.s.: 1 kg
EXAMPLE 11
Tablet
[0061]
10 1) Diclofenac potassium salt: 50 mg 2) Mannitol: 50 mg 3)
Potassium bicarbonate: 22 mg 4) Maize starch (intragranular): 10 mg
5) Methyl cellulose: 0.2 mg 6) Sodium laurylsulfate: 0.1 mg 7)
Maize starch (extragranular): 15 mg 8) Crospovidone: 1.0 mg 9)
Sodium carboxymethylstarch: 2.5 mg 10) Magnesium stearate: 4.5 mg
11) Colloidal silicon dioxide: 10 mg
EXAMPLE 12
Comparative Test
[0062] In the present experiment a sachet formulation containing 50
mg of Diclofenac potassium was compared to a bioequivalent sugar
coated fast release tablet also containing 50 mg of Diclofenac
potassium, produced and marketed in Italy by Novartis as
Cataflam.RTM..
[0063] The sachet formulation according to the present invention
had the following Composition:
11 1) Diclofenac potassium salt: 50 mg 2) Potassium bicarbonate: 22
mg 3) Mint flavour: 50 mg 4) Anice flavour 100 mg 5) Saccharin
sodium: 4 mg 6) Aspartame: 10 mg 7) Mannitol: 50 mg 8) Sucrose
sugar crystals: 1714 g
[0064] The above test formulation and the Cataflam.RTM. formulation
were administered as a single dose to 24 healty volunteers of both
sexes. The pharmacokinetic parameters obtained with the two
different formulations are reported in table 1 and in FIG. 5. As it
will be easily appreciated, the rate of absorption was considerably
faster with the sachet formulation of the present invention than
with Cataflam.RTM., the sachet formulation having a higher average
C.sub.max (2213 vs 1071 ng/ml) and a shorter average T.sub.max
(0.228 vs 0.885 hours); furthermore, the T.sub.max of the sachet
formulation shows a coefficient of variation lower than the
reference formulation (16% vs 97%), this being an extremely
important result from the clinical point of view regarding the
healing of the pain in terms of quick time and repeteability
inter-subjects in order to reach the C.sub.max.
EXAMPLE 13
Comparative Test
[0065] Following to the excellent results obtained in example 12,
two tablet formulations containing 12.5 or 25 mg of Diclofenac
sodium salt and potassium bicarbonate (in the same weight ratio)
have been prepared.
[0066] The tablet formulations had the following composition (in
mg):
12 Cores Diclofenac sodium 12.5 25 Mannitol 25 50 Lactose
monohydrate 23.75 47.5 Potassium bicarbonate 5.5 11 Maize starch
22.5 45 Methylcellulose 0.075 0.15 Sodium laurylsulphate 0.125 0.25
Crospovidone 3 6 Ultramyl 5 10 Coloidal silica 0.55 1.1 Cellulose
microcrystalline 0.5 1 Magnesium stearate 1.5 3 Purified water q.s.
100 200 Coating Opadry OY-35009 red 2 4 Macrogol 400 0.25 0.5
[0067] A four-way comparative bioavailability study was carried out
on 18 healty volunteers of both sexes in order to evaluate the in
vivo results of the pharmaokinetic profiles of the present
formulations if compared to those of bioequivalent fast release
formulations such as Cataflam.RTM. (25 mg of Diclofenac potassium)
and Voltarol.RTM. (50 mg of Diclofenac sodium), both by Novartis.
The results, which are summarized in FIG. 6, indicate that
T.sub.max is prompter with the present formulations (T=26 min,
T2=24.6 min vs R1=71.4 min and R2=40.8 min) and that C.sub.max is
higher (T1=847 ng/ml and T2=861 ng/ml vs R1=452 ng/ml and R2=703
ng/ml); furthermore, the T.sub.max of both present formulations
shows a coefficient of variation lower than reference formulations
(T1=46% and T2=49% vs R1=87% and R2=96%).
EXAMPLE 14
Comparative Test
[0068] A further comparative test was carried out on immediate
release formulations according to the present invention, containing
50 mg of Diclofenac potassium and 22 mg of potassium bicarbonate,
manufactured with different that is, respectively: T1=wet
granulation using alcohol, T2=dry granulation by direct
compression. The composition in mg of the two formulations is
herebelow reported:
13 Diclofenac potassium 50 50 Potassium bicarbonate 22 22
Mannitol/pearlitol 400 DC 119.9 Mannitol EP cf 50 Maize starch 25
Methocel A4C 0.2 Sodium laurylsulphate 0.1 0.1 Polyplasdone XL 6 1
Ultramyl 2.5 Magnesium stearate 2 4.5 Silicium aerosil 1 Core mass
200 156.3
[0069] A comparative bioavailability study was carried out on 6
healty volunteers of both sexes in order to evaluate the in vivo
results of the pharmaokinetic profiles of the present formulations
if compared to those of a bioequivalent fast release formulation
such Voltarene Rapid.RTM. (50 mg of Diclofenac potassium), both by
Novartis. The results, which are reported in FIGS. 7-10 are also in
this case excellent: the T.sub.max is in fact prompter with the
present formulations (T1=18.6 min, T2=16.8 min vs R1=40.8 min) and
the C.sub.max is higher (T1=1878.3 ng/ml and T2=1744.8 ng/ml vs
R1=1307 ng/ml); furthermore, also in this case the T.sub.max of
both present formulations shows a coefficient of variation lower
than reference formulation (T1=12.9% and T2=25% vs R1=95.6%).
14TABLE 1 Pharmacokinetic parameters for two different diclofenac
formulations: test (Diclofenac potassium salt sachets) and
reference (Diclofenac potassium salt sugar coated tablets)
t.sub.max C.sub.max t.sub.1/2 AUC (h) (ng/mL) (h) (ng .multidot.
mL.sup.-1 .multidot. h) Vol. no. Test Ref. Test Ref. Test Ref. Test
Ref. Vol. 1 0.250 0.500 1573.000 1186.211 1.505 0.939 1024.511
885.549 Vol. 2 0.250 4.000 2382.368 965.100 0.875 1.358 1653.124
2092.036 Vol. 3 0.184 1.000 2614.655 1352.400 0.796 1.610 1687.529
1763.484 Vol. 4 0.250 3.000 2404.848 735.454 0.996 1.132 1881.944
1834.958 Vol. 5 0.250 0.500 2971.457 1405.000 1.667 1.903 1819.756
1687.075 Vol. 6 0.250 0.750 2158.700 1351.500 0.843 0.650 1197.716
1091.996 Vol. 7 0.250 0.750 1739.200 1741.717 0.596 0.658 1448.713
1301.887 Vol. 8 0.250 0.500 1715.350 534.300 0.818 1.111 991.864
1126.414 Vol. 9 0.250 0.750 444.112 747.800 0.787 1.188 669.084
886.300 Vol. 10 0.267 0.750 2350.100 1110.400 0.960 1.070 1327.808
1020.286 Vol. 11 0.167 0.500 1867.200 1465.502 1.141 0.762 1337.821
892.870 Vol. 12 0.167 0.500 4273.026 1432.200 1.052 0.697 1703.655
1139.003 Vol. 13 0.250 0.500 2097.089 1155.371 1.313 1.198 1486.526
1233.531 Vol. 14 0.167 0.250 2242.684 967.795 0.997 0.837 987.522
927.726 Vol. 15 0.184 0.500 2040.247 1129.957 0.724 0.804 1213.725
1040.424 Vol. 16 0.250 0.750 2143.692 818.200 0.560 1.199 1186.603
1250.221 Vol. 17 0.250 1.500 1527.845 480.900 2.752 1.309 958.821
978.797 Vol. 18 0.250 1.000 1859.608 666.500 1.630 1.383 1131.413
933.008 Vol. 19 0.250 0.750 1537.508 770.100 1.726 1.137 980.348
906.275 Vol. 20 0.250 0.250 1956.004 655.100 0.853 0.883 1309.289
1036.836 Vol. 21 0.250 0.500 3551.360 2421.060 1.322 1.233 2147.217
1639.619 Vol. 22 0.167 0.500 2464.978 1274.648 0.611 0.624 1038.817
816.924 Vol. 23 0.167 0.750 2304.351 453.500 2.066 0.862 1161.414
1049.327 Vol. 24 0.250 0.500 2901.504 894.337 0.970 1.279 1645.384
1086.512 Mean 0.228 0.885 2213.370 1071.461 1.148 1.076 1332.942
1192.544 SD 0.037 0.860 743.099 450.780 0.523 0.320 358.048 350.116
CV % 16.300 97.091 33.573 42.072 45.557 29.700 26.862 29.359 Min.
0.167 0.250 444.112 453.500 0.560 0.624 669.084 816.924 Max. 0.267
4.000 4273.026 2421.060 2.752 1.903 2147.217 2092.036 Geom. Mean
0.225 0.692 2070.719 987.180 1.056 1.032 1287.195 1150.713 Median
0.250 0.625 2151.196 1039.098 0.983 1.122 1261.507 1067.920 AUC AUC
C.sub.max/AUC extrapolated (ng .multidot. mL.sup.-1 .multidot. h)
C46 (h.sup.-1) (%) Vol. no. Test Ref. Test Ref. Test Ref. Test Ref.
Vol. 1 1050.137 910.868 11.800 18.700 1.498 1.302 2.37 0.00 Vol. 2
1693.172 2092.036 31.700 13.500 1.407 0.461 1.82 1.38 Vol. 3
1718.755 1788.111 27.200 10.600 1.521 0.756 0.83 1.15 Vol. 4
1897.754 1856.346 11.000 13.100 1.267 0.396 1.39 1.88 Vol. 5
1845.486 1719.478 10.700 11.800 1.610 0.817 1.56 1.90 Vol. 6
1216.693 1113.146 15.600 22.500 1.774 1.214 2.50 1.79 Vol. 7
1485.867 1325.661 43.200 25.000 1.170 1.314 1.46 1.78 Vol. 8
1006.522 1146.775 12.400 12.700 1.704 0.466 3.08 2.75 Vol. 9
690.354 911.329 18.700 14.600 0.643 0.821 1.74 1.80 Vol. 10
1351.357 1038.971 17.000 12.100 1.739 1.069 3.01 3.01 Vol. 11
1379.311 920.579 25.200 25.200 1.354 1.592 1.62 2.03 Vol. 12
1731.709 1162.638 18.500 23.500 2.468 1.232 1.26 1.56 Vol. 13
1505.454 1253.088 10.000 11.300 1.393 0.922 2.58 2.26 Vol. 14
1013.665 949.163 18.200 17.700 2.212 1.020 1.91 2.86 Vol. 15
1237.399 1071.029 22.700 26.400 1.649 1.055 1.33 1.58 Vol. 16
1202.653 1270.280 19.900 11.600 1.782 0.644 4.16 2.80 Vol. 17
1000.433 1006.986 10.500 14.900 1.527 0.478 5.51 2.26 Vol. 18
1197.411 954.597 28.100 10.800 1.553 0.698 2.57 2.11 Vol. 19
1006.229 925.835 10.400 11.900 1.528 0.832 2.03 2.02 Vol. 20
1336.472 1058.242 22.400 16.800 1.464 0.619 1.19 1.07 Vol. 21
2173.030 1657.372 13.500 10.000 1.634 1.461 1.75 1.68 Vol. 22
1057.293 830.908 21.000 15.500 2.331 1.534 3.13 1.80 Vol. 23
1198.950 1068.588 12.600 15.500 1.922 0.424 2.19 1.94 Vol. 24
1682.290 1108.024 26.400 11.700 1.725 0.807 2.10 1.78 Mean 1361.600
1214.169 19.113 15.725 1.620 0.914 2.213 1.883 SD 358.359 348.108
8.244 5.160 0.377 0.365 1.035 0.641 CV % 26.319 28.671 43.134
32.812 23.277 39.991 46.795 34.056 Min. 690.354 830.908 10.000
10.000 0.643 0.396 0.833 0.000 Max. 2173.030 2092.036 43.200 26.400
2.468 1.592 5.512 3.010 Geom. Mean 1316.580 1173.325 17.609 15.011
1.573 0.841 2.023 // Median 1286.936 1089.527 18.350 14.050 1.582
0.827 1.974 1.843
* * * * *