U.S. patent application number 13/331324 was filed with the patent office on 2012-08-16 for moisture resistant container systems for rapidly bioavailable dosage forms.
This patent application is currently assigned to APR APPLIED PHARMA RESEARCH, S.A.. Invention is credited to Alberto Reiner, Giorgio Reiner.
Application Number | 20120208886 13/331324 |
Document ID | / |
Family ID | 38334344 |
Filed Date | 2012-08-16 |
United States Patent
Application |
20120208886 |
Kind Code |
A1 |
Reiner; Giorgio ; et
al. |
August 16, 2012 |
Moisture Resistant Container Systems for Rapidly Bioavailable
Dosage Forms
Abstract
Provided are rapidly bioavailable solid oral dosage forms of
acute pain medications, and moisture resistant packaging that
enables the formulation of such rapidly bioavailable dosage
forms.
Inventors: |
Reiner; Giorgio; (Como,
IT) ; Reiner; Alberto; (Como, IT) |
Assignee: |
APR APPLIED PHARMA RESEARCH,
S.A.
Balerna
CH
|
Family ID: |
38334344 |
Appl. No.: |
13/331324 |
Filed: |
December 20, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12555975 |
Sep 9, 2009 |
8097267 |
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13331324 |
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11349008 |
Feb 7, 2006 |
7700125 |
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12555975 |
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Current U.S.
Class: |
514/567 |
Current CPC
Class: |
A61K 9/1611 20130101;
A61P 19/02 20180101; A61K 9/2009 20130101; A61K 9/2059 20130101;
A61K 9/2054 20130101; B65B 1/04 20130101; A61K 9/2027 20130101;
A61K 9/1635 20130101; A61K 9/1652 20130101; A61K 9/1623 20130101;
A61K 9/2077 20130101; A61K 9/2866 20130101; A61P 29/00 20180101;
A61K 31/195 20130101; A61J 3/00 20130101 |
Class at
Publication: |
514/567 |
International
Class: |
A61K 31/195 20060101
A61K031/195 |
Claims
1-20. (canceled)
21. A method comprising: a) providing a moisture resistant package
that prevents the dosage form described in step (b) from absorbing
more than 4 wt. % moisture in three months when stored at
40.degree. C. and 75% relative humidity; b) providing a 10-60 mg.
diclofenac potassium solid oral tablet dosage form formulated for
rapid bioavailability, in a formulation comprising: i) at least 20
wt. % of one or more buffers and/or alkalizing agents, based on the
weight of diclofenac in its acid form; and ii) from about 30 to
about 80 wt % of a hygroscopic diluent based on the weight of the
tablet and said one or more freely soluble diluents at a weight
ratio of from about 1:20 to about 5:1, wherein said hygroscopic
diluent absorbs greater than about 0.5 wt. % water within a twenty
four hour period in a humidity chamber maintained at 60% relative
humidity ("RH") and 25.degree. C.; c) providing said dosage form in
said package; and d) administering said dosage form to a human in
need thereof.
22. The method of claim 21 wherein said rapid bioavailability has
been shown to comprise a time to maximum plasma concentrations
(t.sub.max) of from about 5 to about 30 minutes, and a maximum
plasma concentration (C.sub.max) of from about 1700 to about 2300
ng/ml.
23. The method of claim 21 wherein said rapid bioavailability has
been established to comprise a time to maximum plasma
concentrations (t.sub.max) of from about 13 to about 27 minutes,
and a maximum plasma concentration (C.sub.max) of from about 1500
to about 2500 ng/ml wherein said t.sub.max has exhibited an
inter-subject variability of less than about 49%.
24. The method of claim 21 wherein said dosage form has been shown
to yield one maximum plasma concentration (C.sub.max) peak when
orally ingested.
25. The method of claim 21 wherein said container comprises a foil
seal at the cap and one or more dessicant pouches inside said
container.
26. The method of claim 21 wherein said dosage form comprises from
about 7 to about 20 wt. % of an excipient that absorbs greater than
about 1 wt. % water within a twenty four hour period in a humidity
chamber maintained at 80% RH and 25.degree. C.
27. The method of claim 21 wherein said dosage form absorbs greater
than about 1 wt. % water within a twenty four hour period in a
humidity chamber maintained at 80% RH and 25.degree. C.
28. The method of claim 21 wherein said dosage form further
comprises at least 20 wt. % of mannitol, lactose, sucrose, or a
combination thereof.
29. The method of claim 21 wherein said dosage form further
comprises a surfactant.
30. The method of claim 21 wherein said dosage form further
comprises a surfactant having a hydrophilic lipophilic balance
("HLB") greater than 14.
31. The method of claim 21 wherein said dosage form further
comprises sodium lauryl sulfate.
32. The method of claim 21 wherein said dosage form further
comprises an excipient base that comprises an inverse relationship
between disintegration rate and moisture uptake.
33. A method comprising: a) providing a moisture resistant package
that prevents the dosage form described in step (b) from absorbing
more than 4 wt. % moisture in three months when stored at
40.degree. C. and 75% relative humidity; b) providing a 50 mg.
diclofenac potassium solid oral tablet dosage form formulated for
rapid bioavailability, in a formulation comprising: i) at least 20
wt. % of one or more buffers and/or alkalizing agents, based on the
weight of diclofenac in its acid form; and ii) from about 30 to
about 80 wt % of a hygroscopic diluent based on the weight of the
tablet and said one or more freely soluble diluents at a weight
ratio of from about 1:20 to about 5:1, wherein said hygroscopic
diluent absorbs greater than about 0.5 wt. % water within a twenty
four hour period in a humidity chamber maintained at 60% relative
humidity ("RH") and 25.degree. C.; c) providing said dosage form in
said package; and d) administering said dosage form to a human in
need thereof.
34. The method of claim 33 wherein said dosage form has been shown
to yield one maximum plasma concentration (C.sub.max) peak when
orally ingested.
35. The method of claim 33 wherein said dosage form comprises from
about 7 to about 20 wt. % of an excipient that absorbs greater than
about 1 wt. % water within a twenty four hour period in a humidity
chamber maintained at 80% RH and 25.degree. C.
36. The method of claim 33 wherein said dosage form absorbs greater
than about 1 wt. % water within a twenty four hour period in a
humidity chamber maintained at 80% RH and 25.degree. C.
37. The method of claim 33 wherein said hygroscopic excipient
comprises mannitol, lactose, sucrose, or a combination thereof.
38. The method of claim 33 wherein said dosage form further
comprises a surfactant.
39. The method of claim 33 wherein said dosage form further
comprises a surfactant having a hydrophilic lipophilic balance
("HLB") greater than 14.
40. The method of claim 33 wherein said dosage form further
comprises sodium lauryl sulfate.
41. The method of claim 21 wherein said dosage form further
comprises an excipient base that comprises an inverse relationship
between disintegration rate and moisture uptake.
42. The method of claim 21 where said one or more buffers and/or
alkalizing agents are freely soluble in water.
43. The method of claim 21 wherein said method comprising: a)
providing a moisture resistant package that prevents the dosage
form described in step (b) from absorbing more than 4 wt. %
moisture in three months when stored at 40.degree. C. and 75%
relative humidity; b) providing a 10-60 mg. diclofenac potassium
solid oral tablet dosage form formulated for rapid bioavailability,
in a formulation comprising: i) at least 20 wt. % of one or more
buffers, based on the weight of diclofenac in its acid form; and
ii) from about 30 to about 80 wt % of a hygroscopic diluent based
on the weight of the tablet and said one or more freely soluble
diluents at a weight ratio of from about 1:20 to about 5:1, wherein
said hygroscopic diluent absorbs greater than about 0.5 wt. % water
within a twenty four hour period in a humidity chamber maintained
at 60% relative humidity ("RH") and 25.degree. C.; c) providing
said dosage form in said package; and d) administering said dosage
form to a human in need thereof.
44. The method of claim 21 wherein said method comprising: a)
providing a moisture resistant package that prevents the dosage
form described in step (b) from absorbing more than 4 wt. %
moisture in three months when stored at 40.degree. C. and 75%
relative humidity; b) providing a 10-60 mg. diclofenac potassium
solid oral tablet dosage form formulated for rapid bioavailability,
in a formulation comprising: i) at least 20 wt. % of one or more
alkalizing agents, based on the weight of diclofenac in its acid
form; and ii) from about 30 to about 80 wt % of a hygroscopic
diluent based on the weight of the tablet and said one or more
freely soluble diluents at a weight ratio of from about 1:20 to
about 5:1, wherein said hygroscopic diluent absorbs greater than
about 0.5 wt. % water within a twenty four hour period in a
humidity chamber maintained at 60% relative humidity ("RH") and
25.degree. C.; c) providing said dosage form in said package; and
d) administering said dosage form to a human in need thereof.
45. The method of claim 33 where said one or more buffers and/or
alkalizing agents are freely soluble in water.
46. The method of claim 33 wherein said method comprising: a)
providing a moisture resistant package that prevents the dosage
form described in step (b) from absorbing more than 4 wt. %
moisture in three months when stored at 40.degree. C. and 75%
relative humidity; b) providing a 50 mg. diclofenac potassium solid
oral tablet dosage form formulated for rapid bioavailability, in a
formulation comprising: i) at least 20 wt. % of one or more
buffers, based on the weight of diclofenac in its acid form; and
ii) from about 30 to about 80 wt % of a hygroscopic diluent based
on the weight of the tablet and said one or more freely soluble
diluents at a weight ratio of from about 1:20 to about 5:1, wherein
said hygroscopic diluent absorbs greater than about 0.5 wt. % water
within a twenty four hour period in a humidity chamber maintained
at 60% relative humidity ("RH") and 25.degree. C.; c) providing
said dosage form in said package; and d) administering said dosage
form to a human in need thereof.
47. The method of claim 33 wherein said method comprising: a)
providing a moisture resistant package that prevents the dosage
form described in step (b) from absorbing more than 4 wt. %
moisture in three months when stored at 40.degree. C. and 75%
relative humidity; b) providing a 50 mg. diclofenac potassium solid
oral tablet dosage form formulated for rapid bioavailability, in a
formulation comprising: i) at least 20 wt. % of one or more
alkalizing agents, based on the weight of diclofenac in its acid
form; and ii) from about 30 to about 80 wt % of a hygroscopic
diluent based on the weight of the tablet and said one or more
freely soluble diluents at a weight ratio of from about 1:20 to
about 5:1, wherein said hygroscopic diluent absorbs greater than
about 0.5 wt. % water within a twenty four hour period in a
humidity chamber maintained at 60% relative humidity ("RH") and
25.degree. C.; c) providing said dosage form in said package; and
d) administering said dosage form to a human in need thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention concerns rapidly bioavailable solid
oral dosage forms and moisture resistant packaging that enables the
formulation of such dosage forms. The invention is particularly
concerned with packaging systems for acute pain medications.
BACKGROUND
[0002] The bioavailability of pharmaceutical products is a critical
concern in rational drug design. The pharmacokinetics of a drug,
which measure the time it takes a drug to become bioavailable and
its concentration profile in serum over time, can have a
significant effect on the effectiveness of a drug, as well as its
safety. Pharmacokinetics are of particular concern for drugs that
require an immediate onset of action, such as drugs used in the
treatment of acute pain.
[0003] Various factors can influence the time it takes for a drug
to become bioavailable in therapeutically effective concentrations.
For orally administered solid dosage forms, some of the most
important parameters include the disintegration/dissolution time of
the drug, the stability and solubility of the molecule in the
gastrointestinal tract, and first pass metabolism, to mention just
a few. For some drugs such as potassium diclofenac the pH of the
formulation can also affect its bioavailability. For example, it is
known that diclofenac potassium has a tendency to precipitate in an
acidic environment, thereby making it less bioavailable. This
problem is highlighted in bioavailability studies of Cataflam, a
commercially marketed form of diclofenac potassium, which exhibits
two concentration peaks in the bloodstream when orally
ingested.
[0004] When rapid bioavailability is desired, preferred modes of
administration include parenteral, inhalation, mucosal and buccal
administration. Tablets and capsules are generally available only
in immediate release, extended release, and delayed release
formats, and are not typically employed when rapid bioavailability
is desired because of the time it takes for the dosage form to
dissolve, and the resulting delay in gastrointestinal absorption. A
novel delivery system for orally delivering diclofenac in a rapidly
bioavailable tablet has been proposed in PCT/EP97/02709 (published
as WO 97/44023), but solid oral dosage forms based on this type of
platform are clearly the exception and not the rule.
OBJECTS OF THE INVENTION
[0005] It is an object of the present invention to increase the
rate of bioavailability of solid oral dosage forms, such as tablets
and capsules.
[0006] Another object of the present invention is to increase the
bioavailability of acute pain medications.
[0007] It is another object to provide packaging for rapidly
bioavailable solid oral dosage forms that preserves and enhances
their bioavailability, stability and physical handling
properties.
SUMMARY OF THE INVENTION
[0008] it has unexpectedly been discovered that diclofofenac
potassium tablets, particularly those formulated for rapid
disintegration and dissolution, can be made to disintegrate and
dissolve faster by limiting their moisture uptake during storage,
and allowing them to become harder over time. Whereas one would
normally expect a tablet to disintegrate faster as it softens, the
inventors have discovered that diclofenac potassium tablets
disintegrate slower when the tablet softens, and that the tablet
will not become softer if it is protected from moisture. In other
words, the inventors have discovered that one can make diclofenac
potassium tablets disintegrate faster, and hence be more rapidly
bioavailable, simply by preventing them from absorbing moisture
during storage. These results are counterintuitive and support the
patentability of the present invention.
[0009] Therefore, in one embodiment the invention provides a method
of packaging a rapidly bioavailable diclofenac potassium tablet
comprising: (a) formulating a potassium diclofenac tablet for rapid
bioavailability; and (b) packaging said tablet in a moisture
resistant bottle that prevents said tablet from absorbing more than
2.0 wt. % moisture in three months when stored at 40.degree. C. and
75% relative humidity. In another embodiment, the invention
provides a method for treating a patient suffering from acute pain
by administering the tablets packaged according to the present
invention. Tablets are formulated for rapid bioavailability in the
sense that they are specially formulated to quickly disintegrate or
dissolve rapidly when ingested in the stomach, for example in less
than ten or even five minutes.
[0010] Additional advantages of the invention will be set forth in
part in the description which follows, and in part will be obvious
from the description, or may be learned by practice of the
invention. The advantages of the invention will be realized and
attained by means of the elements and combinations particularly
pointed out in the appended claims. It is to be understood that
both the foregoing general description and the following detailed
description are exemplary and explanatory only and are not
restrictive of the invention, as claimed.
DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is a graphical comparison of the dissolution profile
of the formulation of Example 3A with a commercial diclofenac
formulation.
[0012] FIG. 2 is a graphical comparison of the dissolution profile
of the formulation of Example 3B with a commercial diclofenac
formulation.
[0013] FIG. 3 is a graphical depiction of the mean plasma
concentration time profile in subjects after oral administration of
T.sub.1 formulation.
[0014] FIG. 4 is a graphical depiction of the mean plasma
concentration time profile in subjects after oral administration of
T.sub.2 formulation.
[0015] FIG. 5 is a graphical depiction of the mean plasma
concentration time profile in subjects after oral administration of
a commercial formulation.
[0016] FIG. 6 is a graphical overlay of the mean plasma
concentration time profiles profile in subjects after oral
administration of T.sub.1, T.sub.2 and a commercial
formulation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions
[0017] As used in the specification and claims, the singular forms
a, an and the include plural references unless the context clearly
dictates otherwise. For example, the term a pharmaceutical
excipient may refer to one or more pharmaceutical excipients for
use in the presently disclosed formulations and methods.
[0018] USP means the United States Pharmacopeia and National
Formulary (USP 23-NF 23). Rockville, Md.: United States
Pharmacopeia Convention; 2004, unless stated to the contrary. USP
28 <701> refers to physical test 701, disintegration,
contained on pages 2411-2412 of the USP. USP 28 <711> refers
to physical test 711, dissolution, contained on pages 2412-2414 of
the USP.
[0019] A dosage form, as used herein, refers to a formulation that
is ready for administration to a subject. As used herein, it
specifically refers to solid dosage forms, including, but not
limited to, tablets, capsules and powders. Tablets are most
preferably employed, though it will be understood that other solid
oral dosage forms can also benefit from the teachings of the
present invention. An "intact" dosage form refers to a dosage form
which is ingested in the form it is provided. Intact dosage forms
are therefore to be distinguished from orally disintegrating
tablets which disintegrate in the mouth before being ingested, or
effervescent tablets which are dissolved in water before being
ingested. In preferred embodiments of this invention, the dosage
form is a tablet, and the tablets are ingested in an intact
form.
[0020] C.sub.max refers to the maximum plasma concentration of a
drug following oral administration of the solid oral dosage form to
patients. Normalized C.sub.max refers to the value obtained by
dividing C.sub.max into the dosage strength of the solid oral
dosage form.
[0021] AUC refers to the area under the curve that tracks the
plasma concentration (ng/ml) of a drug over a given time following
the oral administration of the solid oral dosage form to patients.
AUC can be measured from 0 to 12 hours or from 0 to 24 hrs
following the administration and in these cases are referred to as
AUC ((0-12)) or AUC ((0-24)), respectively.
[0022] Normalized AUC is obtained by dividing the AUC into the
dosage strength of the solid oral dosage form of the drug. For
example, if the AUC ((0-12)) is 160 hrng/ml following the oral
administration of a solid oral dosage form containing 200 mg of
active ingredient, the normalized AUC ((0-12)) is 0.8
hrng/ml/mg.
[0023] An excipient is considered "freely soluble" in the context
of this application if the excipient meets the requirements for
either "freely soluble" or "very soluble" excipients set forth in
the United States Pharmacopeia. Therefore, an excipient that is
"freely soluble" in water is an excipient for which 10 or fewer
parts of water are required to dissolve one part of the excipient
material at 20.degree. C.
[0024] Diclofenac is chemically described as
[(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid, and is represented
by the following chemical structure:
##STR00001##
When used herein, the term diclofenac means the acetic acid form of
diclofenac, and any of its pharmaceutically acceptable sails.
Therefore, when a weight ratio is given, it will be understood that
the ratio refers to the relative weight of diclofenac acid in the
ratio, and the relative weight of diclofenac potassium (or other
salt) in the ratio.
[0025] Acute pain conditions include pain that is temporary or
passing, in contrast to chronic pain that is recurring or constant.
Acute pain conditions thus include pain deriving from soft tissue
disorders such as sprains and strains, soft tissue lascerations,
migraine attacks, and other painful conditions such as renal colic,
acute gout, dysmenorrhoea, and following invasive surgical
procedures. While the invention is particularly useful in the
treatment of acute pain, it will also be understood that the
compositions of the present invention are also useful in chronic
pain conditions. Examples of chronic pain conditions include
rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis;
and periarticular disorders such as bursitis and tendonitis.
Reducing Moisture Uptake to Improved Bioavailability
[0026] As discussed above, the invention relates to moisture
resistant packaging, and the use of moisture resistant packaging to
decrease the disintegration/dissolution time of diclofenac
potassium dosage forms. In one embodiment the invention provides a
method of packaging a rapidly bioavailable diclofenac potassium
tablet comprising: (a) formulating a solid oral potassium
diclofenac dosage form (preferably a tablet) for rapid
bioavailability; and (b) packaging said dosage form in a moisture
resistant bottle that prevents said dosage form from absorbing more
than 4.0 3.0, 2.0 or even 1.0 wt. % moisture in three months when
stored at 40.degree. C. and 75% relative humidity. In another
embodiment the invention relates to methods of using rapidly
bioavailable diclofenac potassium dosage forms that are packaged in
moisture resistant bottles, and provides a method of treating acute
pain comprising: (a) providing a rapidly bioavailable solid oral
potassium diclofenac dosage form (preferably a tablet) in a
moisture resistant bottle that prevents said dosage form from
absorbing more than 2.0 wt. % moisture in three months when stored
at 40.degree. C. and 75% relative humidity; and (h) administering
said diclofenac potassium dosage form to a patient suffering from
acute pain.
[0027] Various methods can be used to ensure that the tablets do
not absorb more moisture than is called for by the present
invention. A hermetic seal on the bottle is perhaps most important,
which could constitute nothing more than a foil or other laminar
seal at the opening to the bottle. A dessicant pouch, such as a
silica gel pouch, may also be used for absorbing any moisture that
does enter the bottle.
[0028] The dosage forms are rapidly bioavailable in the sense that
they are specially formulated to disintegrate/dissolve quickly when
ingested into the stomach. Numerous means are available for
promoting the disintegration or dissolution of diclofenac tablets
or capsules, including, for example, the shell used for the
capsule, formulation excipients such as disintegrants, pH buffers,
effervescing agents, freely soluble excipients, hygroscopic
excipients, surfactants that promote the disintegration and
dissolution of the dosage form and the active molecule, and
counterions of the drug molecule. The dosage forms of the present
invention are typically characterized by an inverse relationship
between disintegration rate and moisture uptake. The hardness of
the tablets is typically greater than about 4.1 kp, and more
typically greater than about 6.0 or 8.0 kp.
[0029] Disintegration times for the dosage foams of the present
invention, when tested according to USP 28 <701>, are
preferably less than about 20 minutes, 15 minutes, 10 minutes, 5
minutes, or even 4 minutes, and greater than about 1, 2 or 3
minutes, most preferably from about 3 to about 5 minutes.
Dissolution times for the dosage forms of the present invention,
when tested according to USP 28 <711>, based on the time it
takes to dissolve 90 or 95 wt. % of the drug substance, are
preferably less than about 20 minutes, 15 minutes, 10 minutes, 5
minutes, or even 3 minutes, and greater than about 1 or 2 minutes.
In a preferred embodiment, the dissolution profile for the dosage
forms of the present invention is in accordance with the following
specification: not less than 85, 90 or 95% dissolved after 15
minutes in simulated intestinal fluid (e.g. water) at pH=6.8
[0030] Mean t.sub.max attained by the dosage forms of the present
invention is preferably less than about 40 minutes, 35 minutes, 30
minutes, 25 minutes or 20 minutes, and greater than about 5
minutes, 10 minutes or 15 minutes. Mean t.sub.max is preferably
from about from about 5 to about 30 minutes, from about 10 to about
30 minutes, or from about 13 to about 27 minutes. The corresponding
coefficient of variation for most diclofenac tablets 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)).
In contrast, the inter-subject coefficient of variability for said
t.sub.max for dosage forms of the present invention is preferably
less than about 80, 75, 60, 50, 49, 46, 40, 35, 30% or 25%.
[0031] Mean C.sub.max attained by the formulations of the present
invention, for a 50 mg. formulation, is preferably greater than
about 1400 ng/ml (0.028 liter.sup.-1), 1500 ng/ml (0.03
liter.sup.-1), 1600 ng/ml (0.032 liter.sup.-1) or 1700 ng/ml (0.034
liter.sup.-1), and less than about 2500 ng/ml (0.05 liter.sup.-1)
or 2300 ng/ml (0.046 liter.sup.-1). A preferred range is 1500-2500,
1700-2500, or 1700-2300 ng/ml for a 50 mg. formulation. The
inter-subject coefficient of variability for said C.sub.max
preferably is less than about 70, 60, 50, 45 or 40%. in contrast to
other commercially marketed diclofenac formulations, the
formulations of the present invention preferably display only one
meaningful peak blood concentration after ingestion. Compare FIGS.
3 and 4.
[0032] Preferred C.sub.max and t.sub.max ranges for various dosage
forms of the invention are set forth below in Table A:
TABLE-US-00001 TABLE A Mean C.sub.max (ng/ml) Mean t.sub.max (min)
50 mg. 1500-2100; 1750-2000; 5-35; 10-30; 12-25; diclofenac tablet
1600-1900 15-20 or capsule 25 mg. 700-1150; 750-950; 800-900; 5-35;
10-30; 15-30; diclofenac tablet 850-1050; 900-1000 15-25 or capsule
12.5 mg. 350-650; 400-600; 450-550 5-35; 10-30; 15-25 diclofenac
tablet or capsule
[0033] In one embodiment the rapid bioavailability is achieved by
incorporating in the dosage form means for generating a gaseous and
alkaline environment when orally ingested into the stomach.
Suitable means for generating a gaseous and alkaline environment
that is not harmful to the gastrointestinal mucosa include, but are
not limited to, sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, calcium carbonate, magnesium
carbonate, sodium glycine carbonate, disodium hydrogen phosphate,
sodium dihydrogen phosphate, and mixtures thereof. Suitable gas
generating means are not limited to those which are based upon a
reaction which forms carbon dioxide. Reactants which evolve oxygen
or other gases and which are safe for human consumption are also
considered within the scope of the present invention.
[0034] The dosage form also preferably includes a hygroscopic
excipient which may double as the means for generating an alkaline
and gaseous environment. Products that at relative humidity of 80%
(RH=80%) and 25.degree. C. demonstrate low water absorption ability
(lower than 1% during 24 hrs) have a hygroscopic point below 80%
(j<80% RH) and are not considered hygroscopic within the meaning
of this invention. A hygroscopic excipient could thus have the
ability to absorb greater than about 1 wt. %, 3 wt. %, 5 wt. % or 7
wt. % moisture within a twenty four hour period in a humidity
chamber maintained at 80% RH and 25.degree. C. Alternatively, a
hygroscopic excipient could be defined as an excipient that is able
to absorb greater than about 0.75 wt %, 1 wt. %, 2 wt. %, 3 wt. %
or 4 wt. % moisture within a twenty four hour period in a humidity
chamber maintained at 60% RH and 25.degree. C. Various hygroscopic
excipients could be used in practicing the present invention,
including various water-soluble hygroscopic polyhydroxy compounds
or esters thereof such as glycerol and its mono- and diesters
derived from low molecular weight carboxylic; acids, e.g.,
monoacetin and diacetin (respectively, glyceryl monoacetate and
glyceryl diacetate), ethylene glycol, diethylene glycol,
triethylene glycol, 1,3-propanediol, trimethylolethane,
trimethylolpropane, pentaerythritol, sorbitol, and the like. Other
examples of hygroscopic water-swellable materials include
pharmaceutically acceptable disintegrants such as crosslinked
polyvinylpyrrolidone, starch NF, and hygroscopic. In a preferred
embodiment the hygroscopic excipient is potassium bicarbonate or
sodium bicarbonate.
[0035] The means for generating a gaseous and alkaline environment
and/or hygroscopic excipients are typically employed in a weight
ratio relative to the diclofenac of greater than about 1:5, 2:5,
2:1, 3:1 or 5:1. If desired, an upper limit on the
buffer:diclofenac ratio can be placed at about 20:1, 10:1, 5:1,
1:1, 4:5 or 3:5. Ranges can be selected from any two of the
foregoing values that are mathematically possible. In a preferred
embodiment, the buffer:diclofenac weight ratio ranges from about
1:5 to about 4:5. As a total percentage of the dosage form, the
means for generating a gaseous and alkaline environment preferably
makes up greater than about 5, 7 or 9 wt. % of the dosage form
formulation, and less than about 25, 20 or 15 wt. % of the
formulation. The means preferably yields a pH greater than about
7.0, 7.5, 7.8 or 8.0, and less than about 9.2, 9.0, 8.8 or 8.5 when
the dosage form is mixed with 50 ml of water at 25 degrees Celsius.
Alternatively, the means preferably yields a pH greater than about
6.8, 7.0, 7.2, or 7.5, and less than about 8.8, 8.5, 8.3 or 8.0
when the dosage form is mixed with 200 ml of water at 25 degrees
Celsius.
[0036] Alternatively, the dosage form itself can be characterized
by its hygroscopicity. In the present invention, dosage forms that
at relative humidity of 80% (RH=80%) demonstrate low water
absorption ability (lower than 1% during 24 hrs) have a hygroscopic
point below 80% (j<80% RH) and are not hygroscopic at normal
conditions. A hygroscopic dosage form could thus have the ability
to absorb greater than about 1 wt. %, 1.25 wt. %, 1.5 wt. % or 2
wt. % moisture within a twenty four hour period in a humidity
chamber maintained at 80% RH and 25.degree. C. Alternatively, a
hygroscopic dosage form could be defined as a dosage form that is
able to absorb greater than about 0.50 wt. %, 0.75 wt. %, 1 wt. %,
1.25 wt. %, or 1.5 wt. % moisture within a twenty four hour period
in a humidity chamber maintained at 60% RH and 25.degree. C.
[0037] Tests performed on 50 mg, diclofenac potassium tablets of
the present invention maintained at 25.degree. C. and 60% RH over
twenty four hours showed an increase in KF (% water) from 1.995%
(at time zero) to 3.456% (after 24 hours). Tests performed on 50
mg, diclofenac potassium capsules of the present invention
maintained at 25.degree. C. and 60% RH over twenty four hours
showed an increase in KF (% water) from 1.905% (at time zero) to
2.93% (after 24 hrs.). The final dosage form will not typically
contain greater than about 5 wt. % water, initially or after 1, 2
or 3 years of storage.
[0038] The dosage form can also be formulated to be rapidly
bioavailable by incorporating at least 20 wt. %, 30 wt %, 40 wt. %,
50 wt. %, or 60 wt. % of excipients that are freely soluble in
water. An excipient is considered freely soluble in the context of
this application if 1 part of excipient is soluble in 1-10 parts of
water at 20.degree. C. Examples of freely soluble excipients
include mannitol, dextrates (i.e. a purified mixture of saccharides
resulting from the controlled enzymatic hydrolysis of starch),
dextrin, dextrose, fructose, lactilol, lactose anhydrous, sorbitol,
sucrose, and compressible sugar. Of these, mannitol and lactilol
are particularly preferred due to their beneficial non-hygroscopic
properties, which improves their processability and handling during
the manufacturing process. In a preferred embodiment the dosage
form will comprise from about 30 to about 80 wt. % of the combined
hygroscopic diluent and freely soluble diluent, from about 35 to
about 75 wt. % of the combined hygroscopic diluent and freely
soluble diluent, or from about from about 40 to about 70 wt. % of
the combined hygroscopic diluent and freely soluble diluent. In
addition, the hygroscopic diluent and freely soluble excipient will
preferably be present in a weight ratio of from about 1:20 to about
5:1, from about 1:10 to about 3:1, from about 1:8 to about 1:1,
from about 1:8 to about 1:2, or from about 1:4 to about 1:1.
[0039] Yet another way to render the dosage forms rapidly
bioavailable is to incorporate a surfactant that aids in the
solubility of the dosage form, such as sodium lauryl sulfate.
Preferred surfactants will have an HLB value of at least 10 or 12,
and preferably at least about 14 or 15. An upper bound can also be
placed on the HLB of the surfactant, preferably of 60, 50 or 40. In
certain preferred embodiments, the HLB value of the surfactant is
from about 15 to 60, and in further embodiments the HLB is most
preferably from about 20 to about 50. Suitable
pharmaceutically-acceptable anionic surfactants include, for
example, those containing carboxylate, sulfonate, and sulfate ions.
The most common cations associated with these surfactants are
sodium, potassium, ammonium and triethanolamine. The chain length
of the fatty acids typically range from 12 to 18. Although a large
number of alkyl sulfates are available as surfactants, one
particularly preferred surfactant is sodium lauryl sulfate, which
has an HLB value of about 40. Other suitable wetting agents include
glyceryl monooleate, sorbitan ester, docusate sodium, and
cetrimide.
[0040] A preferred class of acute pain medications for use in the
present invention are non-steroidal anti-inflammatory drugs
including, among others, fenamic acid derivatives, indene
derivatives, and ibufenac derivatives. Csaky and Barnes in
"Cutting's Handbook of Pharmacology," Appleton-Century-Crofts,
Norwalk, Conn. (1984). Fenamic acid derivatives are broadly
classified as o.about.anilino derivatives of benzoic, phenylacetic,
and nicotinic acids and are defined by Csaky and Barnes as
including flufenemic acid, mefenamic acid, meclofenamic acid,
clonixeril, clonixin, flunixin, and diclofenac, including the
pharmaceutically acceptable salts thereof. Indene derivatives
generally are acetic acid, propionic acid, and benzoic acid
derivatives containing a pyrrole (or a pyrazole, pyrroline or
pyrrolidine) ring and are defined by Csaky and Barnes as including
indomethacin, carprofen, etodolac, fendosal, indoprofen, prodolic
acid, sermetacin, zidometacin, and zomeprirac, including the
pharmaceutically acceptable salts thereof. Compounds not so
classified by Csaky and Barnes but related in being acetic acid,
propionic acid, or benzoic acid, derivatives and here so classified
include tolmetin, sulinac, cicloprofen, and cinchophen, including
the pharmaceutically acceptable salts thereof. Ibufenac derivatives
are acetic and propionic acid derivatives bearing a substituted
aromatic hydrocarbon ring, such as phenyl or naphthyl, and are
defined by Csaky and Barnes as including ifiunisal, fenoprofen,
ibuprofen, naproxen, alclofenac, amfenac, cliprofen, fenclofenac,
fenclorac, suprofen, ketoprofen, naproxol, fenbufen, and ibufenac;
including the pharmaceutically acceptable salts thereof.
[0041] Diclofenac acid and its pharmaceutically acceptable salts
are a particularly preferred acute pain medication, especially
diclofenac potassium. Other pharmaceutically acceptable salts
include those of sodium and other alkali and alkaline earth metals,
or salts of organic nature, such as the salts of basic amino acids,
such as lysine, arginine and ornithine. In a preferred embodiment,
10-60 mg. or 50 mg. of diclofenac potassium is used in the final
dosage form, although other amounts could be used including 12.5,
25, 37.5, 75 or 100 mg. The diclofenac preferably has a loss on
drying of not less than 0.5%, and an average particle size of
greater than 100 microns, and less than 400 microns.
EXAMPLES
Example 1
Tablet Core Formulations
[0042] Uncoated diclofenac tablets containing 50 mg, of diclofenac
potassium were prepared based on the formulations given in Table I
below. Formulations were prepared using alcoholic granulation
(Tablet C) and direct compression (Tablet B).
TABLE-US-00002 TABLE 1 Tablet C Tablet B (alcoholic (direct Names
of ingredients granulation) compression) Function Standard Active
ingredients Diclofenac potassium 50 mg.* 50 mg Active ingredient
Eur. Ph. Tablet cores excipients Potassium hydrogen carbonate 22 22
Buffering agent Eur. Ph. Mannitol 50 119.9 Diluent and Eur. Ph.
disintegrating agent Maize starch 25 / Binder diluent Eur. Ph.
Methocel A4C 0.2 / Thichener Eur. Ph. Crospovidone 1.0 6.0 Binder
Eur. Ph. Sodium lauryl sulphate 0.1 0.1 Solubilizing agent Eur. Ph.
Magnesium stearate 4.5 2.0 Lubricant agent Eur. Ph. Ultramyl 2.5 /
Lubricant agent Eur. Ph. Aerosil 1.0 / Lubricant agent Eur. Ph.
Total weight 156.3 200.0 mg *Units are in milligrams unless
otherwise specified.
Example 2
Stability Testing
[0043] Stability tests were conducted in various blister packaging
materials on the tablet cores (Tablet B and Tablet C), and on
Tablet B tablets coated with an aqueous polymer coating, suspension
(Tablet BA) and an alcoholic polymer coating solution (Tablet BB).
Stability testing was restricted to three different blister types.
The properties of the forming and lidding films used in the three
blister materials tested are as follows: [0044] PVDC--coated PVC
and hard aluminum (25 .mu.m, coated on the underside with a vinyl
lacquer) are the materials of the forming film and the lidding part
of the tested blister 1, respectively. The thickness of the PVDC
coat is 40 .mu.m while that of the PVC film is 250 .mu.m. [0045]
PVDC--coated PVC and hard aluminum (25 .mu.m, coated on the
underside with a vinyl lacquer) are the materials of the forming
film and the lidding part of the tested blister 2, respectively.
The thickness of the PVDC coat is 80 .mu.m while that of the PVC
film is 250 .mu.m. [0046] OPA/Al/PVC and hard aluminum (25 .mu.m,
coated on the underside with a vinyl lacquer) are the materials of
the forming film and the lidding part of the tested blister 3,
respectively. Nylon (Oriented Polyamide)-Aluminum-PVC (OPA/Al/PVC)
is a laminate, which consists of 25 .mu.m OPA/45 .mu.m aluminum/60
.mu.m PVC.
[0047] An appropriate quantity of tablet cores (Tablets B and C)
and coated tablets (Tablets BA and BB), in original packaging
(blisters 1-3) was stored in Weiss-Enet climatic chambers for six
months under the following conditions of temperature and relative
humidity:
TABLE-US-00003 Temperature (.degree. C.) Relative humidity (.+-.1%)
25 60 30 60 40 75
[0048] Samples were withdrawn at suitable intervals and subjected
to testing for Diameter, Thickness, Hardness, Weight,
Disintegration time in water (37.degree. C.), Water content,
Dissolution buffered pH 7.5 medium, and Assay. The measurements
were performed on six tablet cores or coated tablets taken at
random in all instances, and the average values were recorded. The
results are given in Tables 2-7 below,
TABLE-US-00004 TABLE 2 Influence of packaging material (blisters 1,
2 and 3) on the stability of Tablets B and C stored at 25.degree.
C. (RH = 60%).sup.a Tablet Tablet B Tablet B Tablet B Tablet Tablet
C Tablet C Tablet C B.sup.b Blister 1.sup.c Blister 2 Blister 3
C.sup.d Blister 1.sup.c,e Blister 2.sup.e Blister 3.sup.e Time 3 6
3 6 3 6 Time 3 6 3 6 3 6 Tests zero months months months months
months months zero months months months months months months
Diameter.sup.f 7.0 7.0 / 7.1 7.1 7.0 7.1 7.0 7.0 / 7.0 / 7.0 / (mm)
Thickness.sup.f 4.4 4.4 / 4.4 4.5 4.4 4.4 3.5 3.6 / 3.5 / 3.5 /
(mm) Hardness.sup.f 71 65 / 65 63 71 74 31 24 / 25 / 32 / (N)
Weight 198 201 / 200 199 199 198 154 157 / 155 / 155 / (mg) Water
2.4 3.2 / 2.8 2.7 2.6 2.5 3.5 3.5 / 5.0 / 4.2 / content.sup.g (%)
Disintegration 2:50 6:12 / 3:43 3:56 2:33 2:33 3:05 2:28 / 2:23 /
2:12 / time.sup.h (min.:sec.) Dissolution.sup.i 93 96 / 98 96 95 99
95 96 / 98 / 97 / after 20 min. (%) Assay.sup.j 96.6 95.6 / 96.0
96.2 99.8 99.0 97.0 96.4 / 97.8 / 99.2 / (%) .sup.aAll values are
average values determined on six units taken at random.
.sup.bMatrix tablets produced by direct compression of the mixture
F11 with a rotary tablet machine. .sup.cStability in blister 1 was
interrupted after 3 months. .sup.dMatrix tablets produced from the
mixture F3 (alcoholic granulation) with a rotary tablet machine.
.sup.eStability of batch no. 990310C was interrupted after 3
months. .sup.fErweka TBH 30 HD apparatus. .sup.gDetermined
according to Eur. Ph. (Karl Fischer semi-micro water
determination). .sup.hDetermined in water (37.degree. C.) according
to Eur. Ph.. .sup.iDetermined in buffered pH 7.5 medium according
to Eur. Ph.. .sup.jDetermined by high performance liquid
chromatography (HPLC).
TABLE-US-00005 TABLE 3 Influence of packaging material (blisters 1,
2 and 3) on the stability of Tablets B and C stored at 30.degree.
C. (RH = 60%).sup.a Tablet Tablet B Tablet B Tablet B Tablet Tablet
C Tablet C Tablet C B.sup.b Blister 1.sup.c Blister 2 Blister 3
C.sup.d Blister 1.sup.c,e Blister 2.sup.e Blister 3.sup.e Time 3 6
3 6 3 6 Time 3 6 3 6 3 6 Tests zero months months months months
months months zero months months months months months months
Diameter.sup.f 7.0 7.1 / 7.1 7.1 7.1 7.1 7.0 7.1 / 7.0 / 7.0 / (mm)
Thickness.sup.f 4.4 4.5 / 4.5 4.5 4.4 4.5 3.5 3.6 / 3.6 / 3.4 /
(mm) Hardness.sup.f 71 66 / 60 64 72 71 31 24 / 27 / 31 / (N)
Weight 198 202 / 200 202 199 199 154 158 / 157 / 154 / (mg) Water
2.4 6.4 / 3.6 3.1 2.2 2.5 3.5 6.4 / 5.7 / 4.0 / content.sup.g (%)
Disintegration 2:50 5:32 / 5:09 5:49 2:40 2:30 3:05 2:17 / 2:09 /
2:35 / time.sup.h (min.:sec.) Dissolution.sup.i 93 95 / 94 95 93 96
95 97 / 96 / 98 / after 20 min. (%) Assay.sup.j 96.6 94.2 / 95.4
96.0 96.0 96.4 97.0 97.2 / 97.2 / 100.0 / (%)
TABLE-US-00006 TABLE 4 Influence of packaging material (blisters 1,
2 and 3) on the stability of Tablets B and C stored at 40.degree.
C. (RH = 75%).sup.a Tablet Tablet B Tablet B Tablet B Tablet Tablet
C Tablet C Tablet C B.sup.b Blister 1.sup.c Blister 2 Blister 3
C.sup.d Blister 1.sup.c,e Blister 2.sup.e Blister 3.sup.e Time 3 6
3 6 3 6 Time 3 6 3 6 3 6 Tests zero Months months months months
months months zero months months months months months months
Diameter.sup.f 7.0 7.2 / 7.1 7.1 7.0 7.1 7.0 7.1 / 7.0 / 7.0 / (mm)
Thickness.sup.f 4.4 4.5 / 4.5 4.6 4.6 4.4 3.5 3.7 / 3.6 / 3.5 /
(mm) Hardness.sup.f 71 64 / 67 62 71 70 31 23 / 27 / 30 / (N)
Weight 198 205 / 201 205 198 200 154 161 / 158 / 154 / (mg) Water
2.4 5.3 / 3.6 5.2 2.1 2.2 3.5 7.3 / 6.2 / 4.0 / content.sup.g (%)
Disintegration 2:50 7:20 / 6:16 6:12 3:17 3:31 3:05 2:27 / 2:28 /
2:23 / time.sup.h (min.:sec.) Dissolution.sup.i 93 92 / 95 96 94 95
95 92 / 95 / 94 / after 20 min. (%) Assay.sup.j 96.6 92.6 / 92.6
92.2 96.0 96.3 97.0 97.2 / 96.4 / 99.4 / (%)
TABLE-US-00007 TABLE 5 Influence of packaging material (blisters 1,
2 and 3) on the stability of film-coated Tablets BA and BB stored
at 25.degree. C. (RH = 60%).sup.a Tablet Tablet BA Tablet BA Tablet
BA Tablet Tablet BB Tablet BB Tablet BB BA.sup.b Blister 1.sup.c
Blister 2 Blister 3 BB.sup.d Blister 1.sup.c Blister 2 Blister 3
Time 3 6 3 6 3 6 Time 3 6 3 6 3 6 Tests zero months months months
months months months zero months months months months months months
Diameter.sup.f 7.1 7.1 / 7.1 7.1 7.1 7.2 7.1 7.1 / 7.1 7.2 7.1 7.2
(mm) Thickness.sup.f 4.6 4.6 / 4.5 4.6 4.5 4.5 4.5 4.6 / 4.5 4.7
4.5 4.5 (mm) Hardness.sup.f 128 116 / 108 103 127 130 114 108 / 112
95 114 116 (N) Weight 204 206 / 204 205 204 204 203 207 / 204 211
203 204 (mg) Water 2.5 4.4 / 2.9 3.0 2.1 3.2 2.3 3.5 / 2.8 3.1 2.3
3.0 content.sup.g (%) Disintegration 3:23 6:15 / 4:28 4:42 3:24
4:28 3:26 7:00 / 4:09 9:02 3:13 4:12 time.sup.h (min.:sec.)
Dissolution.sup.i 93 95 / 96 98 94 95 96 93 / 94 94 97 96 after 20
min. (%) Assay.sup.j 95.8 95.0 / 96.0 96.3 98.4 98.7 95.6 93.4 /
94.4 94.0 96.4 96.8 (%)
TABLE-US-00008 TABLE 6 Influence of packaging material (blisters 1,
2 and 3) on the stability of film-coated Tablets BA and BB stored
at 30.degree. C. (RH = 60%).sup.a Tablet Tablet BA Tablet BA Tablet
BA Tablet Tablet BB Tablet BB Tablet BB BA.sup.b Blister 1.sup.c
Blister 2 Blister 3 BB.sup.d Blister 1.sup.c Blister 2 Blister 3
Time 3 6 3 6 3 6 Time 3 6 3 6 3 6 Tests zero months months months
months months months zero months months months months months months
Diameter.sup.f 7.1 7.1 / 7.1 7.1 7.1 7.1 7.1 7.1 / 7.1 7.1 7.1 7.1
(mm) Thickness.sup.f 4.6 4.6 / 4.5 4.6 4.5 4.5 4.5 4.6 / 4.5 4.6
4.3 4.6 (mm) Hardness.sup.f 128 103 / 110 110 130 128 114 99 / 104
100 112 114 (N) Weight 204 206 / 205 206 204 203 203 207 / 206 206
203 203 (mg) Water 2.5 5.5 / 3.1 3.6 2.2 3.0 2.3 4.1 / 3.2 3.8 3.3
2.6 content.sup.g (%) Disintegration 3:23 5:59 / 4:33 6.11 3:39
3:51 3:26 5:54 / 6:29 5:22 3:40 4:00 time.sup.h (min.:sec.)
Dissolution.sup.i 93 95 / 96 95 94 97 96 94 / 96 93 93 96 after 20
min. (%) Assay.sup.j 95.8 94.8 / 94.4 96.8 96.8 98.2 95.6 94.6 /
94.0 98.5 97.8 97.0 (%)
TABLE-US-00009 TABLE 7 Influence of packaging material (blisters 1,
2 and 3) on the stability of film-coated Tablets BA and BB stored
at 40.degree. C. (RH = 75%).sup.a Tablet Tablet BA Tablet BA Tablet
BA Tablet Tablet BB Tablet BB Tablet BB BA.sup.b Blister 1.sup.c
Blister 2 Blister 3 BB.sup.d Blister 1.sup.c Blister 2 Blister 3
Time 3 6 3 6 3 6 Time 3 6 3 6 3 6 Tests zero months months months
months months months zero months months months months months months
Diameter.sup.f 7.1 7.1 / 7.2 7.2 7.1 7.1 7.1 7.2 / 7.1 7.1 7.1 7.1
(mm) Thickness.sup.f 4.6 4.6 / 4.6 4.7 4.5 4.6 4.5 4.6 / 4.6 4.6
4.5 4.6 (mm) Hardness.sup.f 128 102 / 110 104 130 125 114 93 / 102
99 115 111 (N) Weight 204 209 / 207 210 204 204 203 210 / 208 204
204 203 (mg) Water 2.5 5.3 / 4.2 5.0 2.2 2.7 2.3 5.2 / 4.2 5.6 3.1
3.6 content.sup.g (%) Disintegration 3:23 7:18 / 6:51 6:48 3:50
3:30 3:26 9:16 / 6:45 4:18 4:15 3:16 time.sup.h (min.:sec.)
Dissolution.sup.i 93 93 / 94 96 95 96 96 94 / 95 96 97 96 after 20
min. (%) Assay.sup.j 95.8 95.0 / 95.4 98.1 98.2 96.3 95.6 94.0 /
95.6 96.7 98.0 95.2 (%)
Example 3
Diclofenac K Tablet Dissolution Profile Comparison
[0049] Using the dissolution test procedure described in the
European Pharmacopeia, the dissolution profiles for two tablets
(Ex. 3a and 3b) having the composition set forth in Table 8 were
generated. The only difference between the two tablets was the
source of the diclofenac potassium. Dissolution profiles of 50 mg.
diclofenac potassium tablets marketed as Voltaren Rapid and
Voltfast were also generated, and graphs of the contrasting
dissolution profiles were superimposed, to produce FIGS. 1 and 2
hereto.
TABLE-US-00010 TABLE 8 Composition of Test Formulations Reference
to Names of Ingredients Unit (mg.) Function Standards Drug
Substance Diclofenac Potassium 50.0 Anti-inflammatory agent Eur.
Ph. Matrix Tablet Excipients Potassium Bicarbonate 22.0 Buffering
Agent Eur. Ph. Mannitol 116.4 Diluent and Disintegrant Eur. Ph.
Agent Sodium Lauryl Sulfate 0.1 Solubilizing Agent Eur. Ph.
Macrogols (as Macrogol 6000) 1.5 Lubricant Agent Eur. Ph.
Crospovidone 6.0 Binder Eur. Ph. Magnesium Stearate 4.0 Lubricant
Agent Eur. Ph. Film-Coating Excipients Clear Opadry 4.0 Coating
Agent In House Specifications Total Weight 204.0
Example 4
Diclofenac K Tablet Pharmacokinetic Profile Comparison
[0050] A further comparative test was carried out on immediate
release formulations T1 and T2, as reported below in Table 9, A
comparative bioavailability study was carried out on 6 healthy
volunteers of both sexes in order to evaluate the in vivo results
of the pharmacokinetic profiles of the present formulations if
compared to those of a bioequivalent fast release formulation such
as Voltaren Rapid.RTM. (50 mg of diclofenac potassium), by
Novartis. The results, which are reported in FIGS. 3-6 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 mM 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%).
TABLE-US-00011 TABLE 9 Formulation of Comparison Tablets Reference,
K salt, 50 mg, T1, K salt, 50 mg, tablets T2, K salt, 50 mg,
tablets Voltaren .RTM. Rapid tablets Description Diclofenac
potassium Diclofenac potassium Diclofenac potassium 50 mg
film-coated tablets 50 mg film-coated tablets 50 mg film-coated
tablets (by alcoholic granulation) (by direct compression) Active
Diclofenac potassium mg 50 Diclofenac potassium mg 50 Diclofenac
potassium mg 50 ingredient Excipients Potassium bicarbonate mg 22
Potassium bicarbonate mg 22 Calcium phosphate Mannitol mg 50
Mannitol 400 mg 119.9 Saccharose Maize starch mg 25 Sodium
laurylsulfate mg 0.1 Maize starch Hydroxypropylmethylcellulose mg
Polyvinylpyrrolidone mg 6 Talc 0.2 Magnesium stearate mg 2 Sodium
Sodium laurylsulfate mg 0.1 Film Coating Opadry Clear
carboxymethylcellulose Polyvinylpyrrolidone mg 1 (HPMC 2910,
Colloidal anhydrous silicium Sodium starch glycollate mg 2.5
polyethyleneglycol 400) mg 4 Polyvinylpyrrolidone Magnesium
stearate mg 4.5 Microcrystalline cellulose Silicium aerosil FK 160
mg 1 Magnesium stearate Coating Opadry Clear (HPMC
Polyethylenglycole 2910 and polyethyleneglycol 400) Titanidioxide
(E171) mg 4 Iron oxide red (E172) Total weight 160.3 mg 204 mg
TABLE-US-00012 TABLE 10 Pharmacokinetics of Comparison Tablets. PK
results Test 1 (K, Test 2 (K, Reference (K, tablets 50 mg) tablets
50 mg) tablets 50 mg) C.sub.max Mean 1873.30 1744.8 1307.0 SD
553.80 572.3 558.4 CV % 29.5 32.8 42.7 Min 1228.9 1057.4 581.8 Max
2516.5 2468.9 1935.5 AUC Mean 1219 1237 1168 SD 246 276 282 CV %
20.2 22.3 24.1 Min 874 848 913 Max 1615 1668 1642 t.sub.max Mean
0.31 h (18.6 min) 0.28 h (16.8 min) 0.68 h (40.8 min) SD 0.04 0.07
0.65 CV % 12.9 25.0 95.6 Min 0.25 h (15 min) 0.17 h (10.2 min) 0.25
h (15 min) Max 0.33 h (19.8 min) 0.33 h (19.8 min) 2.00 h (120
min)
[0051] Throughout this application, various publications are
referenced. The disclosures of these publications in their
entireties are hereby incorporated by reference into this
application in order to more fully describe the state of the art to
which this invention pertain. It will be apparent to those skilled
in the art that various modifications and variations can be made in
the present invention without departing from the scope or spirit of
the invention. Other embodiments of the invention will be apparent
to those skilled in the art from consideration of the specification
and practice of the invention disclosed herein. It is intended that
the specification and examples be considered as exemplary only,
with a true scope and spirit of the invention being indicated by
the following claims.
* * * * *