U.S. patent application number 11/332158 was filed with the patent office on 2006-05-18 for sustained release pharmaceutical preparations and methods for producing the same.
This patent application is currently assigned to DAVA Pharmaceuticals, Inc.. Invention is credited to Davejibhai Kumbhani, Harish B. Pandya, Hiren Patel.
Application Number | 20060105037 11/332158 |
Document ID | / |
Family ID | 29214431 |
Filed Date | 2006-05-18 |
United States Patent
Application |
20060105037 |
Kind Code |
A1 |
Kumbhani; Davejibhai ; et
al. |
May 18, 2006 |
Sustained release pharmaceutical preparations and methods for
producing the same
Abstract
An extended release tablet comprising a core including albuterol
sulfate and extended release agent; and an extended release coating
on the core to provide for sustained release of the albuterol
sulfate.
Inventors: |
Kumbhani; Davejibhai;
(Parsippany, NJ) ; Pandya; Harish B.; (Piscataway,
NJ) ; Patel; Hiren; (Parsippany, NJ) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
DAVA Pharmaceuticals, Inc.
|
Family ID: |
29214431 |
Appl. No.: |
11/332158 |
Filed: |
January 17, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10120501 |
Apr 12, 2002 |
|
|
|
11332158 |
Jan 17, 2006 |
|
|
|
Current U.S.
Class: |
424/468 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/2866 20130101; A61K 9/2886 20130101; A61K 31/137 20130101;
A61P 11/06 20180101; A61P 11/08 20180101; A61P 11/00 20180101 |
Class at
Publication: |
424/468 |
International
Class: |
A61K 9/22 20060101
A61K009/22 |
Claims
1. An extended release tablet comprising: a core including
albuterol sulfate and extended release agent; and an extended
release coating associated with the core to provide for sustained
release of the albuterol sulfate.
2. The extended release tablet according to claim 1 wherein the
extended release agent comprises a hydophobic polymer.
3. The extended release tablet according to claim 2 wherein the
hydrophobic polymer comprises ethyl cellulose.
4. The extended release tablet according to claim 1 wherein the
extended release coating comprises hydrophobic polymer and
hydrophilic polymer.
5. The extended release tablet according to claim 4 wherein the
hydrophobic polymer comprises ethyl cellulose and the hydrophilic
polymer comprises methyl cellulose.
6. The extended release tablet according to claim 1 wherein the
extended release coating comprises ethyl cellulose and methyl
cellulose, and the extended release agent comprises ethyl
cellulose.
7. The extended release tablet according to claim 4 wherein the
hydrophobic polymer and hydrophilic polymer of said extended
release coating are present in a weight ratio of 55-65:45-35 of
said hydrophobic polymer to said hydrophilic polymer.
8. The extended release tablet according to claim 7 wherein the
hydrophobic polymer and hydrophilic polymer of said extended
release coating are present in a weight ratio of 53:47 of said
hydrophobic polymer to said hydrophilic polymer.
9. The extended release tablet according to claim 7 wherein the
hydrophobic polymer and hydrophilic polymer of said extended
release coating comprise ethyl cellulose and methyl cellulose,
respectively.
10. The extended release tablet according to claim 8 wherein the
hydrophobic polymer and hydrophilic polymer of said extended
release coating comprise ethyl cellulose and methyl cellulose,
respectively.
11. The extended release tablet according to claim 7 wherein the
extended release coating has a weight of about 5 to 25 mg.
12. The extended release tablet according to claim 11 wherein the
extended release coating has a weight of about 8 to 13 mg.
13. The extended release tablet according to claim 4 wherein
ethanol is utilized as a solvent for preparing the core and the
extended release coating.
14. The extended release tablet according to claim 1 wherein the
core includes an anhydrous sulfate.
15. The extended release tablet according to claim 1 wherein the
anhydrous sulfate comprises calcium sulfate.
16. The extended release tablet according to claim 1 wherein the
core includes lactose monohydrate.
17. The extended release tablet according to claim 1 comprising an
albuterol dissolution profile for a formulation containing 8 mg of
albuterol of: TABLE-US-00038 2.sup.nd Hour Not more than 30%
6.sup.th Hour 50-75% 10.sup.th Hour Not less than 75%.
18. The extended release tablet according to claim 1 comprising an
albuterol dissolution profile for a formulation containing 4 mg of
albuterol of: TABLE-US-00039 2.sup.nd Hour Not more than 20%
6.sup.th Hour 45-70% 10.sup.th Hour Not less than 75%.
19. The extended release tablet according to claim 1 having
bioequivalency to an albuterol sulfate osmotic device
formulation.
20. A diffusion controlled tablet for extended release of albuterol
sulfate comprising albuterol sulfate in a diffusion controlled
formulation structured and arranged to provide an albuterol
dissolution profile for a formulation containing 8 mg of albuterol
of: TABLE-US-00040 2.sup.nd Hour Not more than 30% 6.sup.th Hour
50-75% 10.sup.th Hour Not less than 75%.
21. A diffusion controlled tablet for extended release of albuterol
sulfate comprising albuterol sulfate in a diffusion controlled
formulation structured and arranged to provide an albuterol
dissolution profile for a formulation containing 4 mg of albuterol
of: TABLE-US-00041 2.sup.nd Hour Not more than 20% 6.sup.th Hour
45-70% 10.sup.th Hour Not less than 75%.
22. A diffusion controlled formulation for extended release of
albuterol sulfate comprising albuterol sulfate in a diffusion
controlled formulation structured and arranged to provide
bioequivalency to an albuterol sulfate osmotic device
formulation.
23. The diffusion controlled formulation according to claim
22-wherein bioequivalency is measured in a randomized, single dose,
2-way cross-over bioavailability study of healthy adult males under
fasting conditions, based upon 36 individuals and plasma albuterol
levels, for a formulation containing 4 mg of albuterol.
24. The diffusion controlled formulation according to claim 23
wherein ln AUC 0-t is within 80-125% of 53074 pg.h/mL, ln AUCinf is
within 80-125% of 55606 pg.h/mL, and ln Cmax is within 80-125% of
4383 pg/mL.
25. The diffusion controlled formulation according to claim 22
wherein bioequivalency is measured in a randomized, single dose,
3-way cross-over bioavailability study of healthy adult males under
fed and fasting conditions, based upon 16 individuals and plasma
albuterol levels, for a formulation containing 8 mg of
albuterol.
26. The diffusion controlled formulation according to claim 25
wherein, for fed adult males, ln AUC 0-t is within 80-125% of
106139 pg.h/mL, ln AUCinf is within 80-125% of 109692 pg.h/mL, and
ln Cmax is within 80-125% of 7149 pg/mL.
27. The diffusion controlled formulation according to claim 22
wherein bioequivalency is measured in a randomized, 2-way
cross-over steady state bioavailability study of healthy adult
males under fasting conditions, based upon 37 individuals and
plasma albuterol levels, for a formulation containing 8 mg of
albuterol.
28. The diffusion controlled formulation according to claim 27
wherein ln AUC 0-T is within 80-125% of 1125573 pg.h/mL and ln Cmax
is within 80-125% of 14522 pg/mL.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to sustained release
pharmaceutical preparations and methods for producing the same. In
particular, this invention relates to albuterol sulfate
pharmaceutical sustained release formulations and their
preparation.
[0003] 2. Discussion of Background Information
[0004] Albuterol sulfate is a bronchodilator which is believed to
be a beta-adrengenic agonist which stimulates beta-adrengeric
receptor, which leads to relaxation of bronchial smooth muscle and
inhibits hypersensitivity of mast cells. Albuterol sulfate is
indicated for the relief of bronchospasm for the management of
asthma and reversible obstructibe airway disease.
[0005] Albuterol sulfate is also known as, (.+-.) .varies.,
-[(tert-butylamino)methyl]-4-hydroxy-m-xylene-.varies.,.varies.'-diol
sulfate (2:1) salt, and has an empirical formula
(C.sub.13H.sub.21NO.sub.3).sub.2.H.sub.2SO.sub.4, a molecular
weight of 576.7, and has the following structural formula:
##STR1##
[0006] Albuterol sulfate extended release tablets are currently
available as Volmax.RTM. Tablets, which are available in two
strengths, 4 and 8 mg, and manufactured by Glaxo Wellcome Ltd. UK
England, Muro Pharmaceutical Inc., Tewksbury, Mass. The oral
administration of Volmax.RTM. tablets provides a duration of action
up to 12 hours, with the maximum concentration of drug in plasma
being reached within 6 hours, and the plasma half-life being about
9 hours. Volmax.RTM. releases the drug from polymeric coated
tablets through a laser drilled hole on one side of the tablet
(OROS.TM. technology). The tablets include a rate controlling
semi-permeable membrane, and a core of albuterol and osmotic agent.
An osmotic gradient caused by core components draws water only into
the tablet, where albuterol and osmotic agent dissolve, and
albuterol is released through the laser drilled hole.
[0007] As disclosed in U.S. Pat. No. 5,837,379, the disclosure of
which is incorporated by reference herein in its entirety, extended
release tablets containing osmotic tablets are known which have had
an osmotically active drug core surrounded by a semi-permeable
membrane. As disclosed therein, the core can be divided into two
layers, one containing the active drug and the other containing a
push layer of pharmacologically inactive ingredients which are
osmotically active in the presence of gastrointestinal fluids.
Also, as disclosed therein, an outer water permeable coating
provided with an aperture covers the tablet to allow the drug to be
pushed out of the tablet. Products of this type are disclosed in
U.S. Pat. Nos. 4,327,725, 4,612,008, 4,751,071, 4,765,989,
4,777,049. 4,783,337 and 4,851,229. The disclosures of which are
each incorporated by reference herein in their entireties.
[0008] U.S. Pat. No. 4,503,030, the disclosure of which is
incorporated by reference herein in its entirety, discloses an
osmotic device for delivering drugs to the stomach and the
intestine. The device disclosed therein includes a shaped wall
around a compartment described as a compartment which maintains its
physical and chemical integrity in the stomach but loses its
chemical and physical integrity in the intestine.
[0009] U.S. Pat. No. 4,587,117, the disclosure of which is
incorporated by reference herein in its entirety, discloses an oral
osmotic device which has a shaped wall which loses its integrity at
a pH of 3.5 to 8.0, a passageway from a compartment to the exterior
of the device.
[0010] U.S. Pat. No. 5,837,379, the disclosure of which is
incorporated by reference herein in its entirety, also discloses
the belief that its osmotic tablet operates by water passing
through the membrane on the surface of the tablet which causes the
core to swell and increase the pressure inside the tablet. This is
disclosed to cause a very slight expansion of the partially
hydrated core which is controlled by the use of a relatively small
amount of water swellable polymer. It is disclosed that the
expansion of the core will cause the membrane to open to relieve
the internal pressure, and that once the initial opening or
openings are formed, the swelling effect of the core components
will cause the contents of the core to extrude through the initial
opening without complete disintegration of the membrane. It is
further disclosed that the internal pressure which is exerted on
the membrane by the swelling and expanding osmotic core is relieved
by the passage of the first portions of the core contents through
the initial openings.
[0011] Moreover, sustained release tablets are known, such as
disclosed in U.S. Pat. Nos. 5,500,227, 6,024,982 and 6,210,714, the
disclosures of which are each incorporated by reference herein in
their entireties, wherein release of the drug is controlled by
means of the resistance of a coating layer or matrix against the
diffusion of the drug therethrough. The release of drugs from such
formulations is disclosed to be driven, e.g., by the gradient of
the drug concentration resulting from penetration of, e.g., gastric
fluid, by diffusion into the formulation.
[0012] Still further, U.S. Pat. No. 6,245,351, the disclosure of
which is incorporated by reference herein in its entirety,
discloses a drug-containing core coated with a coating composition
containing a water-insoluble substance and a swellable polymer
having no basis groups.
[0013] U.S. Pat. No. 5,254,347, the disclosure of which is
incorporated by reference herein in its entirety, discloses a
controlled release pharmaceutical preparation, comprising a core
containing a pharmaceutically active ingredient, and a porous film
of a hydrophobic polymeric substance or a hydrophobic polymeric
substance and a hydrophilic polymeric substance, the core being
coated with the porous film. It is further disclosed that the
hydrophobic polymeric substance may be ethyl cellulose and that the
hydrophilic polymer may be a water-soluble polymeric substance such
as methyl cellulose.
[0014] U.S. Pat. Nos. 5,674,895, 5,840,754, 5,912,268, 6,124,355
and 6,262,115, the disclosures of which are each incorporated by
reference herein in their entireties, disclose a dosage form for
delivering oxybutynin in a rate-controlled dose.
SUMMARY OF THE INVENTION
[0015] The present invention is directed to extended release
pharmaceutical preparations.
[0016] The present invention is also directed to methods for
producing extended release pharmaceutical preparations.
[0017] The present invention provides a stable formulation of
extended release tablets of albuterol in albuterol sulfate extended
release tablets which are bioequivalent to Volmax.RTM. tablets,
including the 4 and 8 mg tablets, manufactured by Glaxo Wellcome
Muro Pharmaceutical Inc.
[0018] The present invention provides a diffusion controlled
formulation that achieves bioequivalence to formulations utilizing
osmotic devices.
[0019] The present invention is also directed to controlled release
pharmaceutical preparations having desired dissolution rates that
can be obtained in a diffusion controlled tablet.
[0020] The present invention provides an extended release tablet
comprising a core including albuterol sulfate and extended release
agent; and an extended release coating associated with the core to
provide for sustained release of the albuterol sulfate.
[0021] The extended release agent can comprise a hydophobic
polymer. The hydrophobic polymer can comprise ethyl cellulose.
[0022] The extended release coating can comprise hydrophobic
polymer and hydrophilic polymer. The hydrophobic polymer can
comprise ethyl cellulose and the hydrophilic polymer can comprise
methyl cellulose.
[0023] The extended release coating can comprise ethyl cellulose
and methyl cellulose, and the extended release agent can comprise
ethyl cellulose.
[0024] The hydrophobic polymer and hydrophilic polymer of the
extended release coating can be present in a weight ratio of
55-65:45-35 of the hydrophobic polymer to the hydrophilic polymer,
preferably in a weight ratio of 53:47 of the hydrophobic polymer to
the hydrophilic polymer.
[0025] The hydrophobic polymer and hydrophilic polymer of the
extended release coating can comprise ethyl cellulose and methyl
cellulose, respectively.
[0026] The extended release coating can have a weight of about 5 to
25 mg, more preferably about 8 to 13 mg.
[0027] Ethanol is preferably utilized as a solvent for preparing
the core and the extended release coating.
[0028] The core can also include an anhydrous sulfate, such as
calcium sulfate and/or lactose monohydrate.
[0029] The extended release tablet can have an albuterol
dissolution profile for a formulation containing 8 mg of albuterol
of: TABLE-US-00001 2.sup.nd Hour Not more than 30% 6.sup.th Hour
50-75% 10.sup.th Hour Not less than 75%.
[0030] The extended release tablet can have an albuterol
dissolution profile for a formulation containing 4 mg of albuterol
of: TABLE-US-00002 2.sup.nd Hour Not more than 20% 6.sup.th Hour
45-70% 10.sup.th Hour Not less than 75%.
[0031] The extended release tablet can have bioequivalency to an
albuterol sulfate osmotic device formulation.
[0032] The present invention is also directed to a diffusion
controlled tablet for extended release of albuterol sulfate
comprising albuterol sulfate in a diffusion controlled formulation
structured and arranged to provide an albuterol dissolution profile
for a formulation containing 8 mg of albuterol of: TABLE-US-00003
2.sup.nd Hour Not more than 30% 6.sup.th Hour 50-75% 10.sup.th Hour
Not less than 75%.
[0033] The present invention is also directed to a diffusion
controlled tablet for extended release of albuterol sulfate
comprising albuterol sulfate in a diffusion controlled formulation
structured and arranged to provide an albuterol dissolution profile
for a formulation containing 4 mg of albuterol of: TABLE-US-00004
2.sup.nd Hour Not more than 20% 6.sup.th Hour 45-70% 10.sup.th Hour
Not less than 75%.
[0034] The present invention is also directed to a diffusion
controlled formulation for extended release of albuterol sulfate
comprising albuterol sulfate in a diffusion controlled formulation
structured and arranged to provide bioequivalency to an albuterol
sulfate osmotic device formulation.
[0035] The bioequivalency can be measured in a randomized, single
dose, 2-way cross-over plasma albuterol levels, for a formulation
containing 4 mg of albuterol, and ln AUC 0-t is within 80-125% of
53074 pg.h/mL, ln AUCinf is within 80-125% of 55606 pg.h/mL, and ln
Cmax is within 80-125% of 4383 pg/mL.
[0036] The bioequivalency can be measured in a randomized, single
dose, 3-way cross-over bioavailability study of healthy adult males
under fed and fasting conditions, based upon 16 individuals and
plasma albuterol levels, for a formulation containing 8 mg of
albuterol, and wherein, for fed adult males, ln AUC 0-t is within
80-125% of 106139 pg.h/mnL, ln AUCinf is within 80-125% of 109692
pg.h/mL, and ln Cmax is within 80-125% of 7149 pg/mL.
[0037] The bioequivalency can be measured in a randomized, 2-way
cross-over steady state bioavailability study of healthy adult
males under fasting conditions, based upon 37 individuals and
plasma albuterol levels, for a formulation containing 8 mg of
albuterol, and wherein ln AUC 0-T is within 80-125% of 1125573
pg.h/mL and ln Cmax is within 80-125% of 14522 pg/mL.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] The present invention is further described in the detailed
description which follows, in reference to the noted plurality of
non-limiting drawings, wherein:
[0039] FIG. 1 shows a semi-log plot of mean plasma albuterol
concentrations for plasma albuterol concentration vs. time for data
shown in Table 16;
[0040] FIG. 2 shows a linear plot of mean plasma albuterol
concentrations for plasma albuterol concentration vs. time for data
shown in Table 16;
[0041] FIG. 3 shows a semi-log plot of mean plasma albuterol
concentrations for plasma albuterol concentration vs. time for data
shown in Table 17;
[0042] FIG. 4 shows a linear plot of mean plasma albuterol
concentrations for plasma albuterol concentration vs. time for data
shown in Table 17;
[0043] FIG. 5 shows a semi-log plot of mean plasma albuterol
concentrations for plasma albuterol concentration vs. time for data
shown in Table 18; and
[0044] FIG. 6 shows a linear plot of mean plasma albuterol
concentrations for plasma albuterol concentration vs. time for data
shown in Table 18.
DETAILED DESCRIPTION OF THE INVENTION
[0045] The particulars shown herein are by way of example and for
purposes of illustrative discussion of the various embodiments of
the present invention only and are presented in the cause of
providing what is believed to be the most useful and readily
understood description of the principles and conceptual aspects of
the invention. In this regard, no attempt is made to show details
of the invention in more detail than is necessary for a fundamental
understanding of the invention, the description taken with the
drawings making apparent to those skilled in the art how the
several forms of the invention may be embodied in practice.
[0046] All percent measurements in this application, unless
otherwise stated, are measured by weight based upon 100% of a given
sample weight. Thus, for example, 30% represents 30 weight parts
out of every 100 weight parts of the sample.
[0047] Unless otherwise stated, a reference to a compound or
component, includes the compound or component by itself, as well as
in combination with other compounds or components, such as mixtures
of compounds.
[0048] Before further discussion, a definition of the following
terms will aid in the understanding of the present invention.
[0049] Osmotic formulation device or osmotic tablet device is
utilized herein to refer to formulations or tablets wherein one or
more osmotic agents are configured and arranged to provide osmotic
pressure or force associated with the formulation or tablet so as
to cause active ingredient to be released from the formulation or
tablet primarily due to the osmotic pressure or force, such as, but
not limited to, pressure causing the active ingredient to be
released by being pushed by pressure through an aperture in the
formulation or tablet, or by causing pressure to expand a tablet
layer.
[0050] Diffusion controlled is utilized herein to refer to
formulations or tablets wherein the active ingredient is not
released due to pressure or force, but is primarily released by
diffusion according to Fick's laws.
[0051] Without being wished to be bound by theory, diffusion
includes processes wherein molecules intermingle as a result of
their kinetic energy of random motion. In contrast, osmosis is a
selective diffusion process driven, e.g., forced, by the internal
energy of the solvent molecules.
[0052] When referring to dissolution and dissolution profiles in
the present specification and claims, the dissolution is performed
utilizing the dissolution procedure set forth in, the Examples, or
a dissolution technique that is equivalent thereto.
[0053] As an overview, the present invention relates to extended
(sustained) release pharmaceutical preparations. These preparations
are especially useful for the extended release of albuterol
sulfate. In particular, the present invention is directed to a
tablet formulation including a core containing albuterol sulfate
and an extended release agent; an extended release coating
combining a hydrophilic agent and a hydrophobic agent; and can have
one or coatings. The core and extended release coating are
formulated with respect to each other in order to provide a
pharmaceutically acceptable in vitro dissolution profile, and
particularly a dissolution profile and characteristics that are
bioequivalent to that of albuterol obtainable with osmotic
devices.
[0054] The tablet according to the present invention achieves
desired dissolution in vitro profiles and bioequivalence to FDA
approved albuterol tablet formulations, i.e., Volmax.RTM. tablets,
in a tablet that is diffusion controlled as compared to being
osmotically operated, such as Volmax.RTM. tablets.
[0055] In accordance with the present invention, the preferred
percent of labeled amount of albuterol released at each specified
time interval utilizing the dissolution test set forth in the
Examples, for 8 mg albuterol tablets, is: TABLE-US-00005 2.sup.nd
Hour Not more than 30% 6.sup.th Hour 50-75% 10.sup.th Hour Not less
than 75%
[0056] Moreover, in accordance with the present invention, the
preferred percent of labeled amount of albuterol released at each
specified time interval utilizing the dissolution test set forth in
the Examples, for 4 mg albuterol tablets, is: TABLE-US-00006
2.sup.nd Hour Not more than 20% 6.sup.th Hour 45-70% 10.sup.th Hour
Not less than 75%
[0057] The moisture content of the tablet is preferably not more
than 0.5 wt %. Moreover, residual alcohol content of alcohols
utilized in preparing the formulation is preferably less than 0.5
wt %.
[0058] According to the present invention, the core includes the
active pharmaceutical ingredient and an extended release agent. The
active pharmaceutical ingredient preferably comprises albuterol
sulfate.
[0059] The core according to the present invention preferably is
prepared by a granulation process, with the granules containing the
active pharmaceutical ingredient and the extended release agent.
These granules preferably have an average particle diameter of
about 125.mu. to 1700.mu., more preferably about 180.mu. to
1000.mu., and most preferably about 250.mu. to 600.mu..
[0060] The active pharmaceutical ingredient content of the core is
preferably about 4 to 8 mg based upon active ingredient. For
example, for albuterol sulfate, the content is the core would
preferably be about 4.8 to 9.6 mg.
[0061] The core is preferably constructed to provide overall
dosages of 4 or 8 mg of albuterol. The core is preferably
formulated with 4.8 mg of albuterol sulfate to provide an overall
dosage of 4 mg of albuterol, and the core is preferably formulated
with 9.6 mg of albuterol sulfate to provide an overall dosage of 8
mg of albuterol. Thus, the tablet of the present invention can be
described by either the amount of active ingredient contained
therein, e.g., albuterol, or by pharmaceutically acceptable salts
thereof, preferably albuterol sulfate.
[0062] The albuterol sulfate utilized in the formulation preferably
has a particle size distribution, determined using a Malvern
Mastersizer (Malvern 2600c with PS64 dry powder feeder, lens 100 mm
obscuration 0.1 to 0.4) using particle in air method. Preferably,
at least 50% of the particles of albuterol sulfate that are to be
added to the core is not more than (NMT) 25 .mu.m, and at least 90%
is not more than 55 .mu.m. Without wishing to be bound by theory,
it is believed that particles within these parameters provide a
good combination of dissolution and core hardness. Specific batches
of albuterol sulfate tested had the following particle size
distribution denoted in Table 1 below. TABLE-US-00007 TABLE 1
Particle Size Distribution of Albuterol Sulfate Sample 1 Sample 2
Sample 3 Sample 4 50%, NMT 25 .mu.m 9% 8% 11% 11% 90%, NMT 55 .mu.m
24% 22% 31% 32%
[0063] The extended release agent can comprise one or more
ingredients which in combination with the extended release coating
control the release of the active pharmaceutical ingredient,
especially albuterol sulfate, from the core in order to achieve a
desired dissolution profile, and, in particular, bioequivalency
with FDA approved formulations of albuterol sulfate. The extended
release agent can comprise various water-insoluble materials,
Examples of such water insoluble materials include hydrophobic
polymers including, but are not limited to, one or more of ethyl
cellulose, butyl cellulose, cellulose acetate, cellulose
propionate, polyvinyl acetate, polyvinyl butyrate, ethyl
acrylate-methyl methacrylate-ethyl ammonium trimethyl chloride
methacrylate copolymer and N-vinyl-2-pyrrolidonecellulose ether,
cellulose ester, polyvinyl ester, acrylic acid type polymer having
a quaternary ammonium-alkyl group, and Plasdone.RTM. K-90,
Povidone, homopolymer of N-vinyl-2-pyrrolidone. Preferably, the
extended release agent comprises one or more of ethyl cellulose,
butyl cellulose, cellulose acetate, cellulose propionate, polyvinyl
acetate, polyvinyl butyrate, ethyl acrylate-methyl
methacrylate-ethyl ammonium trimethyl chloride methacrylate
copolymer and N-vinyl-2-pyrrolidone. Most preferably, the extended
release agent comprises ethyl cellulose, such as Ethocel N-10 which
is obtainable from Dow Chemical, Midland, Mich.
[0064] The core can be prepared in any manner, such as by utilizing
any conventional manufacturing technique. Thus, the core can be
produced by combining the active pharmaceutical ingredient and at
least one agent capable of restricting release of the active
ingredient with each other, and other ingredients. For example, the
core may contain a wide variety of excipients, such as those
ingredients that are conventionally included in the core of
tablets, including diluents, glidents, binders, granulating
solvent, granulating agents, anti-aggregating agents, buffers,
lubricants.
[0065] For example, diluents can include, but are not limited to,
one or more of sugars such as sucrose, lactose, mannitol, glucose;
starch; microcrystalline cellulose; sorbitol, maltodextrin, whey,
calcium phosphate; calcium sulfate; sodium sulfate or similar
anhydrous sulfate; calcium lactate; lactose anhydrous; and lactose
monohydrate. Preferably, the diluents comprise calcium sulfate
and/or lactose monohydrate. Preferably, lactose anhydrous is not
included in the core, because of its ability to absorb water from
solvents, such as ethanol, thereby contributing to undesirable
weight gain.
[0066] Examples of binders include, but are not limited to, one or
more of polyvinyl alcohol, polyacrylic acid, polymethacryic acid,
polyvinyl pyrrolidone, sucrose, sorbitol, hydroxyethyl cellulose,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose,
polyethylene glycols, gum arabic, gelatin, agar, starch, etc.
[0067] Lubricants and anti-aggregating agents include, but are not
limited to, one or more of talc, magnesium stearate, calcium
stearate, colloidal silica, stearic acid, waxes, hydrogenated
vegetable oil, polyethylene glycols, sodium benzoate, sodium
laurylsulfate, magnesium laurylsulfate and dl-leucine. Preferably,
the lubricants include stearic acid and/or magnesium stearate.
[0068] Solvents include, but are not limited to, one or more of
acetone, ethanol, isopropyl alcohol (IPA) and/or methylene
chloride. Preferably, the solvent for the core comprises ethanol.
The use of chlorinated solvents, such as methylene chloride is
preferably avoided. Therefore, the tablets preferably do not
contain a chlorinated solvent, such as methylene chloride. The
amount of solvent can be adjusted to provide a sufficient amount to
achieve the formation of granules while not being of such a high
amount as to turn the mixture into a large mass instead of granular
in nature. Moreover, it is preferred to control the solvent
addition time to effect adequate granulation. It is preferred that
the temperature of granulating solution is preferably not be more
than 26.degree. C. at the time of addition to avoid lumping.
[0069] The ingredients can be combined and/or granulated in one or
more procedures utilizing any appropriate techniques, such as by
granulating in a low shear granulator, fluidized bed granulation,
high shear granulator.
[0070] It is noted that during development of granulation,
formulations were prepared with and without the use of calcium
sulfate to study its impact on dissolution profile of the product.
Based on a fast drug release of albuterol sulfate from tablets
without calcium sulfate, it is preferred that calcium sulfate be
incorporated in the core to control drug release from the
tablets.
[0071] Following production of the granules for the core, the
granules are dried under sufficient conditions to provide granules
preferably having not more than 0.5 wt % alcohol, and preferably
not more than 0.5 wt % water. Therefore, for commercial batches, it
is preferred that the batches be dried at a preferred temperature
of at about 50.degree. C. preferably for at least 16 hours to
ensure solvent removal, such as ethanol and/or water.
[0072] The cores are compressed into tablets to a hardness of
preferably between about 2 and 6 kP, with a preferred value being
about 4 kP.
[0073] The extended release coating is deposited on the tablets in
a location that is external to the core, and is preferably layered
directly onto the core. The extended release coating is formulated
to provide in conjunction with the extended release agent in the
core a desired dissolution profile, and bioequivalency to
commercially available albuterol sulfate tablet formulations, such
as Volmax.RTM. tablets.
[0074] The extended release coating comprises a film preferably a
combination of hydrophobic and hydrophilic polymers. Preferably,
the active pharmaceutical ingredient, which is preferably albuterol
sulfate, is not present in the extended release coating. In this
regard, preferably the active pharmaceutical ingredient, which is
preferably albuterol sulfate, is only present in the core.
[0075] The hydrophobic polymer constituting the film is not
particularly limited, provided that it has film forming ability,
and is insoluble in water, but soluble in a water-miscible organic
solvent. Examples of hydrophobic polymers include, but are not
limited to, one or more of ethyl cellulose, butyl cellulose,
cellulose acetate, cellulose propionate, polyvinyl acetate,
polyvinyl butyrate, ethyl acrylate-methyl methacrylate-ethyl
ammonium trimethyl chloride methacrylate copolymer and
N-vinyl-2-pyrrolidonecellulose ether, cellulose ester, polyvinyl
ester, acrylic acid type polymer having a quatemary ammonium-alkyl
group, and Plasdone.RTM. K-90, Povidone, homopolymer of
N-vinyl-2-pyrrolidone. Preferably, there may be included, for
example, ethyl cellulose, butyl cellulose, cellulose acetate,
cellulose propionate, polyvinyl acetate, polyvinyl butyrate, ethyl
acrylate-methyl methacrylate-ethyl ammonium trimethyl chloride
methacrylate copolymer and N-vinyl-2-pyrrolidone. Most preferably,
the hydrophobic polymeric substance comprises ethyl cellulose, such
as Ethocel N-10, which is obtainable from Dow Chemical, Midland,
Mich.
[0076] The hydrophilic polymer may be a water-soluble polymeric
substance, including, but are not limited to, one or more of methyl
cellulose, polysaccharides optionally having a sulfuric acid group
such as pullulan, dextrin, alkali metal alginate, etc.;
polysaccharides having a hydroxy-alkyl group or a carboxyalkyl
group such as hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, carboxymethyl cellulose sodium, etc.; methyl cellulose,
polyvinyl pyrrolidone, polyvinyl alcohol or polyethylene glycol,
etc. may be included. Preferably, the hydrophilic polymeric
substance comprises methyl cellulose, such as Methocel E-15, which
is obtainable from Dow Chemical, Midland, Mich.
[0077] Changing the weight ratio of hydrophobic polymer to
hydrophilic polymer in the extended release coating affects the
dissolution of the albuterol from the tablet. Therefore, the weight
ratio of hydrophobic polymer to hydrophilic polymer can be varied
for each specific formulation to obtain desired dissolution
profiles for the formulation. Preferable weight ratios for the
hydrophobic polymer to hydrophilic polymer include weight ratios of
55-65:45-35, with one preferred weight ratio of hydrophobic polymer
to hydrophilic polymer being 57:43.
[0078] The solvent for the extended release coating can comprise
various solvents including, but are not limited to, acetone,
ethanol, isopropyl alcohol (IPA) and/or methylene chloride.
Preferably, the solvent for the extended release coating comprises
ethanol. The use of chlorinated solvents, such as methylene
chloride is preferably avoided. Various combinations of solvents
can be used, such as, but not limited to, ethanol and isopropyl
alcohol, and combinations of isopropyl alcohol:water, denatured
alcohol:water and ethyl alcohol:water.
[0079] Tablets prepared using isopropyl alcohol were found to have
a drug release that is slower than when ethanol is used as coating
solvent. In addition, when isopropyl alcohol is used for both,
granulation and coating, the drug release is found to be slower
compared to that of the product made using ethanol for granulation
and coating. Accordingly, ethanol is a preferred solvent for both
granulation and coating.
[0080] To obtain a product that is bioequivalent to Volmax.RTM.,
the hydrophobic polymer and the hydrophilic polymer are blended
with each other to provide an extended release coating that has
desired dissolution profiles and/or bioequivalence properties in
conjunction with the extended release agent and active ingredient
included in the core. For example, using the preferred formulations
as disclosed herein, a weight ratio of 57 parts by weight of
Ethocel N-10 to 43 parts by weight of Methocel E-15, a coating
weight gain of about 5-25 mg per tablet is preferred. Preferably, a
coating weight gain of 20 mg per tablet, for 4 mg and 8 mg tablets,
using R&D equipment provides a drug release profile similar to
that of Volmax.RTM. tablets. Commercial tablets preferably have a
weight gain of 8.7 and 12.4 mg, respectively, for 4 mg and 8 mg
albuterol sulfate tablets. A preferred weight gain for the extended
release coating is about 5 to 25 mg, more preferably about 8 to 13
mg.
[0081] Coating of the extended release coating can be performed
using various techniques, such as conventional coating techniques
such as perforated pan, or using fluidized bed technique. These
methods are commonly understood by individuals who are practicing
the art tablet manufacture. The angle of spray guns utilized in
spayed on the coating can be varied, such as, but not limited to
between 30.degree. and 75.degree., with one preferred angle being
65.degree..
[0082] Without being wished to be bound by theory, it is believed
that the hydrophilic polymer provides a porous layer for diffusion
of the active ingredient from the core. In this regard, the
hydrophilic polymer is believed to be dissolved to leave pores
through which diffusion takes place.
[0083] In the formulation of the present invention, by adequately
controlling the weight of the extended release coating, and the
ratio of hydrophobic polymer to hydrophilic polymer as well as the
extended release agent in the core, it is possible to make a tablet
having a desired in vitro dissolution rate. For example, and
without wishing to be bound by theory, when the pharmaceutically
active ingredient contained in the core is a drug which is desired
to exhibit a pharmaceutical effect within a short period of time
after administration, it is preferred to make the film thinner and
the porosity thereof greater upon dissolving of the hydrophilic
polymeric substance, while in the case of a drug which is desired
to be released persistently for a prolonged period of time, it is
preferred to make the film thicker and the porosity thereof smaller
upon dissolving of the hydrophilic polymeric substance.
[0084] For a set composition for the extended release coating, a
difference in dissolution rate of the active pharmaceutical
ingredient can be obtained by varying the weight of the coating.
Thus, a higher coating weight of the extended release coating
provides for a greater time to dissolve an equivalent concentration
of active pharmaceutical ingredient as compared to a lower weight
of the extended release coating. Therefore, the weight of the
extended release coating is preferably accurately monitored during
production of the tablet to ensure a desired dissolution rate for
an extend release coating composition. For example, the weight of
the extended release coating can be monitored by determining core
weight prior to applying the extended release coating, and then
determining the total weight of the core and extended release
coating. The difference between these two values would be the
weight gain due to the extended release coating. For example, a
weight gain of 10 mg would provide a slower dissolution rate than a
weight gain of 9 mg.
[0085] The tablet can include optional coatings, such as coatings
to provide cosmetic elegance and/or to facilitate packaging of the
product. For example, an optional coating can comprise a color
coating including, but not limited to, Opadry Green. Another
optional coating can include, for example, a clear solution, such
as, but not limited to, Opadry Clear. These optional coatings can
be utilized in combination, such as a clear coat being applied over
a color coating.
[0086] The active pharmaceutical ingredient according to the
present invention preferably comprises albuterol sulfate, but can
comprise other active ingredients. However, the present invention
is particularly suited to albuterol sulfate as the active
pharmaceutical ingredient. In this regard, as noted above, the
present invention provides for the extended release of albuterol
sulfate having similar dissolution profiles to that of
pharmaceutical tablets operating on osmotic principles and provides
bioequivalency thereto.
[0087] The present invention will be further illustrated by way of
the following Examples. These Examples are non-limiting and do not
restrict the scope of the invention.
[0088] Unless stated otherwise, all percentages, parts, etc.
presented in the examples are by weight.
EXAMPLES
[0089] The following procedures are utilized in connection with the
present invention:
A. Dissolution Procedure--For Determining Dissolution Rates and
Profiles in Accordance with the Present Invention:
[0090] The dissolution procedure utilized in connection with the
present invention includes the following:
[0091] The dissolution apparatus is a Van Kel Model VK-7000
utilized according to USP 24, Method <724>. The dissolution
units have paddle shafts or equivalent dissolution unit to meet USP
24 Method<711> criteria on six samples, and using an HPLC
system equipped with UV detector. The following reagents and
standards are used in the dissolution procedure:
[0092] Reagents and Standards: TABLE-US-00008 Water Purifi water
Sodium Chloride ACS reagent 1-Octane sulfonic acid sodium salt
Reagent Grade Ammonium acetate ACS reagent 2-Propanol HPLC grade
Methanol HPLC grade Glacial Acetic Acid ACS reagent Albuterol
Sulfate Standard with known purity or USP RS
Preparation of Dissolution Medium:
[0093] Dissolve 9.0 grams of sodium chloride in 1000 mL of water,
heat to 37.degree. C..+-.0.5.degree. C., filter and degas, to
thereby form 0.9% sodium chloride solution.
Preparation of Mobile Phase:
[0094] Dissolve 600 mg of 1-Octane sulfonic acid sodium salt, and
20.0 g of ammonium acetate into 920 mL of water. Add 30 mL of
2-propanol, 10 mL of methanol, and 40 mL of glacial acetic acid,
mix well.
[0095] Filter with vacuum and degas by sonication for 5 minutes.
Helium sparging is also suitable.
Preparation of Standard Solution:
[0096] A. Stock Standard Solution:
[0097] Accurately weigh about 24 mg of albuterol sulfate, and
transfer quantitatively into 100 mL volumetric flask with the aid
of about 50 mL dissolution medium. Dissolve the standard by
sonication, dilute with dissolution medium to volume, and mix.
[0098] B. Working Standard Solution:
[0099] Pipet 4.0 mL of stock standard solution into a volumetric
flask, a 200 ml volumetric flask for 4 mg tablet, and a 100 mL
volumetric flask for 8 mg tablet.
[0100] Dilute with dissolution medium to volume and mix. Filter a
portion of the solution through nylon disk filter of 0.45 .mu.m
porosity SRI (Scientific Resources, Inc. catalog: #44525-NC) or
equivalent, discarding a first few mL. Fill 1 mL HPLC glass vials
with the filtered material.
Chromatographic System for Dissolution Measurement:
[0101] Prepare a liquid chromatographic system according to Table 2
below: TABLE-US-00009 TABLE 2 Chromatographic System for
Dissolution Measurement: Equipment and Conditions: Column Symmetry
C18, 5 .mu.m, 3.9 .times. 150 mm, Waters catalog # WAT 046980,
which represents USP packing L1 type or equivalent Column
Thermostatically controlled at 30.degree. C. Temperature Flow Rate
1.0 mL per minute using a Waters 600 series pump or equivalent
Detector UV at 276 nm using a Waters 486 or equivalent Integrator
Waters Millennium System or equivalent Injector Volume 50 .mu.L
with a Waters Model 717 or an equivalent autosampler Retention Time
About 5 minutes Run Time 8 minutes
[0102] The dissolution tests are performed using 900 mL of
dissolution medium (0.9% sodium chloride solution) and a paddle
rotational speed of 50 rpm, and sampling is conducted in accordance
with USP 24 Method <711>. For each withdrawal of 10 mL of
sample for testing, 10 mL of dissolution medium preheated to
37.degree. C..+-.0.5.degree. C. is added to the dissolution vessel
thereby replacing the withdrawn dissolution solution.
[0103] Analysis of the samples is performed using standard HPLC
techniques to conform the average value of the following parameters
to: [0104] The relative standard deviation (RSD) of albuterol peak
area response for replicate injections should not be more than
3.0%. [0105] The tailing factor for albuterol peak area should not
be more than 2.0.
[0106] The number of theoretical plates per column for albuterol
peak should not be less than 2000.
[0107] Particle size and powder fineness can be. determined using
sieve analysis according to USP-23 NF 18, such as by using an ATM
Sonic Sifter Model L3P.
Examples 1-7
[0108] The following Tables 3 and 4 illustrate formulations of 4
and 8 mg tablets according to the present invention which were used
in the Examples which follow. TABLE-US-00010 TABLE 3 ALBUTEROL
SULFATE ER TABLETS, 4 MG AND 8 MG Strength 8 mg 4 mg 4 mg 8 mg 8 mg
8 mg 8 mg 4 mg 4 mg Example # Example-I Example-I Example-II
Example-III Example-IV Example-V Example-V Example-VI Example-VI
Ingredients (in mg) A B C I CORE Albuterol Sulfate USP 9.60 4.80
4.80 9.60 9.60 9.60 9.60 4.80 4.80 Lactose monohydrate 66.00 70.80
70.80 74.40 66.00 66.00 66.00 70.80 70.80 NF powder Calcium Sulfate
8.40 8.40 8.40 -- 8.40 11.40 15.07 8.40 8.40 powder USP Ethocel
N-10 premium 12.50 12.50 13.00 12.50 -- 9.17 5.83 13.00 13.00
Ethocel N-10 premium 2.00 2.00 1.50 2.00 -- 2.00 2.00 1.50 1.50 PVP
K-90 -- -- -- -- 14.50 -- -- -- -- Isopropyl alcohol USP 15.00* --
-- -- -- -- -- Ethyl alcohol, 95% USP *15.00 *15.00 n/a *20.0 *20.0
*20.0 *20.0 -- 15.00* Denatured Alcohol -- -- -- -- -- -- -- 15.00*
-- (SDA-3A) Stearic Acid NF 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
1.00 Magnesium Stearate NF 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50
0.50 Total (Solids in mg) 100.00 100.00 100.00 100.00 100.00 99.67
100.00 100.00 100.00 II ER Coating solution Methocel E-15 premium
8.325 8.325 2.14 4.20 4.20 4.00 4.00 2.14 2.14 Ethocel N-10 premium
11.25 11.25 2.88 4.20 4.20 5.40 5.40 2.88 2.88 Triacetin USP 2.50
2.50 0.64 1.00 1.00 1.20 1.20 0.64 0.64 Purified water USP 32.50*
32.50* *8.40 *13.33 *13.33 *15.0 *15.0 *8.40 *8.40 Ethyl alcohol
USP 292.50* 292.50* *74.67 *113.33 *113.33 *134.0 *134.0 *74.67
*74.67 Total (Solids in mg) 22.075 22.075 5.66 9.40 9.40 10.60
10.60 5.66 5.66 III White F/C suspension and clear solution Opadry
white YS-1-7003 ***1.67 ***1.67 1.65 1.67 1.67 2.00 2.00 1.65 1.65
Purified water USP 16.67* 16.67* 16.67* *16.67 *16.67 *20.00 *20.00
16.67* 16.67* Opadry clear YS-1-7006 0.167 0.167 0.17 0.167 0.167
0.20 0.20 0.17 0.17 Propylene Glycol USP 0.167 0.167 0.17 0.167
0.167 0.20 0.20 0.17 0.17 Purified water USP 8.33* 8.33* 8.33*
*8.33 *8.33 *10.0 *10.0 8.33* 8.33* Carnauba wax 0.167 0.167 0.1
0.167 0.167 0.20 0.20 0.1 0.1 Powder NF Total (Solids in mg) 2.171
2.171 2.11** 2.171 2.171 2.60 2.60 2.11** 2.11**
[0109] TABLE-US-00011 TABLE 4 ALBUTEROL SULFATE ER TABLETS, 4 MG 4
mg Control# Example-VII Ingredients (in mg) I CORE Albuterol
Sulfate USP 4.80 Lactose monohydrate NF powder 70.80 Calcium
Sulfate powder USP 8.40 Ethocel N-10 premium 12.50 Ethocel N-10
premium 2.00 Isopropyl alcohol USP Ethyl alcohol, 95% USP *15.00
Stearic Acid NF 1.00 Magnesium Stearate NF 0.50 Total (Solids in
mg) 100.00 A B C D II ER Coating solution Methocel E-15 premium
1.56 3.12 4.68 5.475 Ethocel N-10 premium 14.08 12.52 10.96 10.165
Triacetin USP 2.00 2.00 2.00 2.00 Purified water USP 26.00* 26.00*
26.00* 26.00* Ethyl alcohol USP 234.00* 234.00* 234.00* 234.00*
Total (Solids in mg) 17.64 17.64 17.64 17.64 III White F/C
suspension and clear solution Opadry green 1.67 1.67 1.67 1.67
Purified water USP *16.67 *16.67 *16.67 *16.67 Opadry clear
YS-1-7006 0.167 0.167 0.167 0.167 Propylene Glycol USP 0.167 0.167
0.167 0.167 Purified water USP *8.33 *8.33 *8.33 *8.33 Carnauba wax
Powder NF 0.167 0.167 0.167 0.167 Purified water USP Total (Solids
in mg) 2.171 2.171 2.171 2.171 *= Ingredient will be removed **=
Blue and Yellow dye were mixed in formula ***= opadry green instead
of Opadry white
[0110] The following procedure is utilized to produce tablets
according to the present invention unless otherwise stated:
Core Preparation
[0111] Screen ingredients including lactose monohydrate, albuterol
sulfate and calcium sulfate through #18 mesh and the extended
release agent (Ethocel N-10) through #12 mesh. The ingredients are
mixed in a twin shell blender without I-bar to a uniform blend. The
contents are emptied into an AMF mixer and set at 45.+-.5 RPM.
[0112] Prepare a solution of the extended release agent (Ethocel
N-10, 2 kg.) in of warm (50.degree. C..+-.5.degree. C.) solvent
(Ethyl Alcohol). Stir the solution until clear, such as for a
minimum time of one hour. Then, cool the solution to not more than
26.degree. C. Start the mixer and pump the Ethocel N-10 solution to
granulate ingredients, such as by delivering the solution over a
period of three minutes. Mix to achieve adequate granulation, such
as for about 6 to 9 minutes. Dry by spreading, such as on a
stainless steel tray at 50.degree. C..+-.5.degree. C. for not more
than 16 hours and until the average loss on drying at 75.degree. C.
is less than 0.5%.
[0113] Mill the dried granulation in a Fitzmill having screwfeeder,
perforated Stainless Steel plate #0065, set for medium speed,
knives-forward and feeder at 3.5.+-.0.5 kg.
[0114] Screen remaining ingredients of the stearic acid and
magnesium stearate through #18 mesh and collect in a suitable
container. Transfer milled granulation, screened ingredients
through twin shell without I-bar blender, and blend until uniform,
preferably about 5 minutes.
[0115] Set the tablet press for 1/4'' round, deep concave, plain
tooling, and compress the blend at a nominal value of at 100
mg.+-.7 mg. Compress at 4 kp (range 2-6 kp) hardness. The cores in
these examples are at a thickness and 0.130''-0.155'', and have a
friability less than 1%.
Preparation of Extended Release Coating Solution
[0116] Prepare Extended Release (ER) coating solution by dissolving
Methocel E-15 and Ethocel N-10 in a mixture of ethyl alcohol and
purified water, mixing until clear, such as for a minimum of 5
hours. Add Triacetin and stir for preferably 15 more minutes to
equally distribute. Store this solution for minimum time of 10
hours before application, such as 15 to 16 hours.
Preparation of Film Coating Solutions
[0117] Prepare film coating colored solution using Opadry Green and
purified water, stirring the suspension until dispersed, such as
for 2 hours.
[0118] Prepare film coating clear solution using Opadry Clear and
purified water, stirring the suspension until dispersed and clear,
such as for 2 hours.
[0119] Add Propylene Glycol into the solution and stir for 15 more
minutes.
Coating Core with Extended Release Coating Solution
[0120] Transfer the core tablets into a 48'' perforated pan. Set
spray guns at 65.degree. angle, and adjust the atomizing air
pressure at 25 PSI atomizing air pressure. Set the pump for
extended release coating solution to provide solution at 130
ml/min/gun (RANGE: 100-130 ml/min/gun). Set the air temperature at
75.degree. C. or less to warm the core tablets. Turn the coating
pan at 6 RPM pan speed (range 4-8 RPM). Dry the extended release
solution coated tablets for 30 minutes at 70.degree.
C..+-.5.degree. C. inlet air temperature. Determine the coating
weight gain.
Coating with Film Coating Solutions
[0121] Apply coatings as above, except liquid rate is at 90.+-.15
ml/min/gun. Dry the tablets for 10 minutes at 70.degree.
C..+-.5.degree. C. Determine the coating weight gain.
Example 1
[0122] Example 1 is directed to an 8 mg tablet produced utilizing
the ingredients and processes indicated above and in Table 3.
Dissolution testing was performed using the dissolution procedure
as discussed above. The coating weight ratio of Ethocel E-10 to
Methocel E-15 was 57:43 in this example. The results are
illustrated in Table 5 below. In particular, the release of
albuterol sulfate in the tablet according to the present invention
was found to be comparable to that of the commercial product.
[0123] Table 3 also shows an example of a formulation of a 4 mg
tablet according to the present invention. TABLE-US-00012 TABLE 5
Time, Hrs 1 2 4 6 8 10 Invention, 8 mg 0 11 54 74 87 94 Volmax, 8
mg 10 22 47 70 86 93
Example 2
[0124] Example 2 is directed to a 4 mg tablet produced utilizing
the ingredients and processes indicated above and in Table 3.
Dissolution testing was performed using the dissolution procedure
as discussed above. In particular, this example is similar to that
of Example 1 with isopropyl alcohol being used instead of ethyl
alcohol in granulation and coating, and a 4 mg formulation being
utilized. The results are illustrated in Table 6 below. The release
of albuterol sulfate in the tablet according to the present
invention was found to be slower than the commercial product.
TABLE-US-00013 TABLE 6 Time, Hrs 1 2 4 6 8 10 Invention, 4 mg 1 5
38 62 79 89 Volmax, 4 mg 8 22 47 69 87 92
Example 3
[0125] Example 3 is directed to an 8 mg tablet produced utilizing
the ingredients and processes indicated above and in Table 3.
Dissolution testing was performed using the dissolution procedure
as discussed above. In particular, this example is similar to that
of Example 1 with CaSO.sub.4 being omitted, and the amount of
lactose monohydrate being correspondingly increased to bring the
core to 100 mg. The results are illustrated in Table 7 below. The
coating weight ratio of Ethocel E-10 to Methocel E-15 was 50:50 in
this example. The release of albuterol sulfate in the tablet
according to the present invention was found to be faster than the
commercial product. TABLE-US-00014 TABLE 7 Time, Hrs 1 2 4 6 8 10
Invention, 8 mg 28 51 80 96 100 101 Volmax, 8 mg 10 22 47 70 86
93
Example 4
[0126] Example 4 is directed to an 8 mg tablet produced utilizing
the ingredients and processes indicated above and in Table 3.
Dissolution testing was performed using the dissolution procedure
as discussed above. In particular, this example is similar to that
of Example 1 with PVP K-90 replacing Ethocel N-10 as binder. The
coating weight ratio of Ethocel E-10 to Methocel E-15 was 50:50 in
this example. For tablets having the same thickness of Exampe 1,
the hardness was found to be 12 Kp. The results are illustrated in
Table 8 below. The release of albuterol sulfate in the tablet
according to the present invention was found to be faster than the
commercial product. TABLE-US-00015 TABLE 8 Time, Hrs 1 2 4 6 8 10
Sidmak, 8 mg 4 25 65 87 98 100 Volmax, 8 mg 10 22 47 70 86 93
Example 5
[0127] Example 5 is directed to an 8 mg tablet produced utilizing
the ingredients and processes indicated above and in Table 3.
Dissolution testing was performed using the dissolution procedure
as discussed above. In particular, this example is similar to that
of Example 1 with a portion of Ethocel N-10 in granulation being
replaced with CaSO.sub.4. The results are illustrated in Table 9
below. The release of albuterol sulfate in the tablet according to
the present invention was found to be faster than the commercial
product. TABLE-US-00016 TABLE 9 Time, Hrs 1 2 4 6 8 10 Invention, 8
mg 10 40 72 91 98 100 Volmax, 8 mg 10 22 47 70 86 93
Example 6
[0128] Example 6 is directed to a 4 mg tablet produced utilizing
the ingredients and processes indicated above and in Table 3.
Dissolution testing was performed using the dissolution procedure
as discussed above. In particular, this example is similar to that
of Example 1 with core tablets being manufactured using denatured
alcohol (100 parts by weight of ethyl alcohol, 95% USP and 5 parts
by weight of methyl alcohol, USP) instead of ethyl alcohol. The
results are illustrated in Table 10 below. The release of albuterol
sulfate in the tablet according to the present invention was found
to be comparable to that using ethyl alcohol. TABLE-US-00017 TABLE
10 Time, Hrs 1 2 4 6 8 10 Invention, Denatured alcohol, 4 mg 29 53
84 96 97 97 Invention, ethyl alcohol, 4 mg 31 57 87 97 99 99
Example 7
[0129] Example 7 is directed to 4 mg tablets produced utilizing the
ingredients and processes indicated above and in Table 4.
Dissolution testing was performed using the dissolution procedure
as discussed above. In particular, this example is similar to that
of Example 1 with core tablets being coated with varying weight
ratios of Ethocel N-10 and Methocel E-15, as indicated in Table 4
and indicated below, as follows:
[0130] Tablets were coated with extended release coating suspension
having
[0131] Methocel: Ethocel weight ratio of: TABLE-US-00018 A 10:90 B
20:80 C 30:70 D 35:65
[0132] The extended release coating for all four ratios was applied
to same weight gain, except for D where 50% coating suspension
applied sample was studied for dissolution.
[0133] The results are illustrated in Table 11 below. The release
of albuterol sulfate in the tablet according to the present
invention was found to be too slow for comparison. TABLE-US-00019
TABLE 11 Time, Hrs 1 2 4 6 8 10 A(10:90) 0 0 0 0 0 0 B(20:80) 0 0 0
0 0 0 C(30:70) 0 0 0 0 0 1 D(35:65), 50% 1 4 34 59 76 87 Volmax
.RTM., 4 mg 8 22 47 69 87 92
Example 8
Dissolution Profiles of Volmax.RTM. Tablets
[0134] 4 and 8 mg Volmax.RTM. tablets were subjected to dissolution
testing according to the dissolution procedure set forth herein,
with the exception that 12 tablets were tested for the 4 mg tablet
whereas 6 tablets were tested for the 8 mg tablets. Solutions of
different pH were prepared according to USP 25. The data for the
tests using 0.90% NaCl were obtained from outside data. The
dissolution results are shown in Tables 12 and 13 below.
TABLE-US-00020 TABLE 12 Dissolution Profile of Volmax .RTM. tablet,
4 mg in Various Media. Method: USP 23, 2 (paddle) at 50 RPM, 900 M,
37.degree. C. (12 Tablets) %, Dissolved 2 4 6 8 10 Medium 1 hour
hours hours hours hours hours Recovery PH 1.2 buffer 11 26 56 81 92
96 98 PH 4.5 buffer 12 29 59 83 92 95 97 PH 6.4 buffer 12 28 58 82
92 95 98 PH 7.4 buffer 11 26 53 77 90 94 97 0.90% NaCl 11 25 53 76
91 95 99
[0135] TABLE-US-00021 TABLE 13 Dissolution Profile of Volmax .RTM.
tablet, 8 mg in Various Media. Method: USP 23, 2 (paddle) at 50
RPM, 900 M, 37.degree. C. (6 Tablets) %, Dissolved 2 4 6 8 10
Medium 1 hour hours hours hours hours hours Recovery PH 1.2 buffer
12 25 52 78 92 96 99 PH 4.5 buffer 12 27 56 80 92 94 96 PH 6.4
buffer 13 30 60 86 93 95 98 PH 7.4 buffer 12 27 53 78 92 95 97
0.90% NaCl 11 25 52 78 93 98 101
Example 9
[0136] 4 and 8 tablets according to Exampl 1 wre subjected to
controlled accelerated conditions of 40.degree. C. and 75% Relative
Humidity for indication of the stability of tablets according to
the present invention. The results are shown in Tables 14 and 15.
TABLE-US-00022 TABLE 14 Stability data of Albuterol Sulfate ER
tablets, 8 mg Condition: 40.degree. C./75% RH Drug Release, 100's
500's % Initial 1 month 2 month 3 month 1 month 2 month 3 month
1.sup.st hour 3 2 3 2 2 2 2 2.sup.nd hour 19 20 22 18 21 21 19
4.sup.th hour 50 48 48 46 49 48 47 6.sup.th hour 69 68 67 65 69 67
66 8.sup.th hour 83 81 85 78 83 80 81 10.sup.th 92 87 87 88 90 89
87 hour Assay, 98.2 98.0 98.3 97.0 98.2 98.0 97.5 % Mois- 3.6 3.8
3.7 3.8 3.7 3.8 3.6 ture, %
[0137] TABLE-US-00023 TABLE 15 Stability data of Albuterol Sulfate
ER tablets, 4 mg Condition: 40.degree. C./75% RH Drug Release,
100's 500's % Initial 1 month 2 month 3 month 1 month 2 month 3
month 2.sup.nd hour 9 7 7 3 7 6 7 4.sup.th hour 45 43 41 39 43 40
43 6.sup.th hour 65 65 61 61 65 61 64 8.sup.th hour 79 80 77 76 79
76 78 10.sup.th 88 89 86 86 88 86 88 hour Assay, 98.9 98.7 97.2
98.2 98.8 97.6 98.6 % Mois- 3.4 3.3 3.4 3.4 3.4 3.4 3.3 ture, %
Example 10
[0138] This example is directed to bioequivalence study of both 4
& 8 mg products under fed and fasting conditions in healthy
subjects.
[0139] The objective of the clinical study was to compare the
relative steady state bioavailability of Sidmak products with
Reference products. The study design was comparative randomized 2
way crossover steady state studies of Sidmak and Muro (Volmax) 4
and 8 mg Albuterol Sulfate Extended Release tablets in healthy
adult males under fed and fasting conditions. Clinical supplies for
the test product according to the present invention were according
to Example 1, and Reference Product, Volmax manufactured by Glaxo
Wellcome were Lot No: 10460727 for 8 mg tablets and Lot No. D008194
for 4 mg tablets.
[0140] Blood samples were collected during each study period before
the initial drug administration and up to 12 hours post dose at
appropriate times. Overall, data for the number of subjects
indicated in the tables were analyzed in accordance with FDA
guidance "Bioavailability and Bioequivalence Studies for Orally
administered Drug Products--General Considerations.
[0141] Albuterol ion plasma was analyzed using a validated LC/MS/MS
method developed at MDS Pharma Services, Inc. The following
Pharmacokinetic parameters for plasma Albuterol were calculated.
TABLE-US-00024 AUC 0-t The area under the plasma concentration
versus time curve, from time 0 to the last measurable
concentration, as calculated by the linear trapezoidal method.
AUCinf The area under the plasma concentration versus time curve
from time 0 to infinity. AUCinf was calculated as the sum of the
AUC O-t plus the ratio of the last measurable plasma concentration
to the elimination rate constant. AUC/AUCinf The ratio of AUC O-t
to AUCinf. Cmax Maximum measured plasma concentration over the time
span Specified. tmax Time of the maximum measured plasma
concentration. If the maximum value occurred at more than one time
point, tmax was defined as the 1st time point with this value. kel:
Apparent first-order terminal elimination rate constant calculated
from a semi-log plot of the plasma concentration versus time curve.
The parameter was calculated by linear least-squares regression
analysis using the last three (or more) non-zero plasma
concentrations. T1/2 The apparent first-order terminal elimination
half-life is calculated as 0.693/kel
[0142] Statistical analysis was performed using ANOVA on the
transformed AUC 0-t; AUC inf, and Cmax pharmacokinetic parameters.
TABLE-US-00025 Albuterol Parameter Sidmak Fed Vs Fasting Sidmak Fed
Vs. Muro Fed AUC 0-t 97.6% 97.3% AUC inf 97.7% 97.1% Cmax 78.5%
98.8%
[0143] Whereas, the following data was obtained under steady state
fasting conditions TABLE-US-00026 Parameter Albuterol ln AUC 0-t
99.1% (95-103.3%) ln Cmax 104.8% (98.2-111.8%)
[0144] The ratios of LSM, least square means, and 90% confidence
intervals for the ln-transformed parameters AUC and Cmax were
within the 80-125% FDA acceptance range
[0145] Based on these results, the present invention and Muro 4 and
8 mg albuterol sulfate extended release tablets are bioequivalent
under fed as well as steady state fasting conditions.
[0146] Table 16 and FIGS. 1 and 2, and Table 17 and FIGS. 3 and 4
identify the data under each study for 8 mg product.
[0147] Similar studies were conducted using 4 mg of the invention
product and compared with Muro 4 mg Albuterol sulfate extended
release products. Table 18 and FIGS. 5 and 6 identify the data
under each study for 4 mg product. TABLE-US-00027 TABLE Summary of
Results - Albuterol in Plasma Pharmacokinetic Parameters (N = 17)
In AUC 0-t* In AUCinf* In Cmax* tmax Half-life kel (pg h/mL) (pg
h/mL) (pg/mL) (h) (h) (1/h) Sidmak (fast) (A) Mean 105616.66
109041.13 9075.487 4.556 11.958 0.06393 CV 23.5 23.8 29.5 33.5 32.0
32.2 n 17 17 17 17 17 17 Sidmak (fed) (B) Mean 102950.39 106529.81
7081.606 6.691 11.839 0.06759 CV 28.9 28.8 35.0 34.6 42.9 35.1 n 17
17 17 17 17 17 Huro (fed) (C) Mean 106138.68 109692.47 7149.817
7.526 11.420 0.07171 CV 16.4 16.8 17.7 20.7 51.6 36.4 n 16 16 16 16
16 16 Least-Squares Means Sidmak (fast) (A) 105313.16 108875.04
9001.416 Sidmak (fed) (B) 102747.86 106368.82 7066.553 Huro (fed)
(C) 105608.89 109554.92 7155.965 Ratio of Least-Squares Means
(B/A)% 97.6 97.7 78.5 (B/C)% 97.3 97.1 98.8 *For In-transformed
parameters, the antilog of the mean (i.e. the geometric mean) is
reported. Subject No. 13 did not complete period 3, Formulation C
PhAST STAB 2.3-000 DEFAULT
[0148] TABLE-US-00028 TABLE Summary of Results - Albuterol in
Plasma Pharmacokinetic Parameters (N = 36) In AUC 0-.tau.* In Cmax*
Cssav Cmin tmax Flux1 Flux2 (pg h/mL) (pg/mL) (pg/mL) (pg/mL) (h)
(%) (%) Sidmak (A) Mean 123488.78 15201.994 10539.18 7462.51 4.276
78.16 113.95 CV 22.9 21.6 21.5 25.7 20.7 23.3 31.3 n 36 36 36 36 36
36 36 Huro (B) Mean 125572.85 14521.762 10693.54 7508.92 4.576
70.77 103.02 CV 21.7 21.4 20.6 22.3 26.1 25.6 31.4 n 35 36 35 35 36
35 35 Least-Squares Means Sidmak (A) 126622.28 15431.180 Huro (B)
127783.42 14726.983 Ratio of 99.1 104.8 Least-Squares Means (A/B) %
90% Confidence Intervals (A/B) % lower limit: 95.0% 98.2% upper
limit: 103.3% 111.8% p-Value (ANOVA) A vs B 0.7149 0.2319
Intrasubject CV % 10.2 16.1 *For In-transformed parameters, the
antilog of the mean (i.e. the geometric mean) is reported. For
Subject No. 37, period 2, formulation 8, parameters AUC 0-.tau.,
Cssav, Cmin, Flux 1 and Flux 2 could not be calculated PhAST STAB
2.3-000 DEFAULT
[0149] TABLE-US-00029 TABLE Summary of Results - Albuterol in
Plasma Pharmacokinetic Parameters (N = 36) In AUC 0-t* In ACUinf*
In Cmax* tmax Half-life kel (pg h/mL) (pg h/mL) (pg/mL) (h) (h)
(l/h) Sidmak (A) Mean 51116.63 54777.81 4237.615 4.458 14.297
0.05633 CV 20.7 22.8 32.0 27.4 41.0 37.6 n 36 36 36 36 36 36 Huro
(B) Mean 53073.89 55606.14 4383.472 4.660 12.614 0.06426 CV 20.3
21.1 26.5 20.3 42.8 38.0 n 36 36 36 36 36 36 Least-Squares Means
Sidmak (A) 51116.63 54777.81 4237.615 Huro (B) 53073.89 55606.14
4383.472 Ratio of 96.3 98.5 96.7 Least-Squares Means (A/B)% 90%
Confidence Intervals (A/B)% Lower limit: 92.0% 94.1% 87.7% Upper
limit: 100.0% 103.1% 106.6% p-Value (ANOVA) A vs B 0.1715 0.5816
0.5613 Period 0.0267 0.0262 0.5056 Sequence 0.0356 0.0702 0.4380
Intrasubject CV % 11.6 11.5 24.8 *For In-transformed parameters,
the antilog of the mean (i.e. the geometric mean) is reported. See
Section 3 of Report for details on calculation of parameters PhAST
STAB 2.3-000 DEFAULT
Example 11
Dissolution Examples at Differing pH
[0150] 4 mg and 8 mg albuterol sulfate extended release tablets
were prepared according Example 1. These tablets according to the
invention, and Volmax.RTM. 4 and 8 mg tablets were studied using
the dissolution procedure set forth above for 12 tablets. The
tablets were dissolved in (900 ml) deionized water, 0.1 N HCl, pH
buffer 4.5 and pH Buffer 6.8 prepared according to USP 25. Samples
were taken at 1, 2, 4, 6 8 and 10 hours. The results are shown in
Tables 19-22 for 4 mg tablets, and Tables 23-26 for 8 mg tablets.
TABLE-US-00030 TABLE 19 % OF LABEL CLAIM RELEASED AT SPECIFIED TIME
INTERVAL IN DEIONIZED WATER 4 mg Tablet of Invention 4 mg Volmax
.RTM. Tablet Unit Unit Weight 1 2 4 6 8 10 Weight 1 2 4 6 8 10 Unit
# (mg) Hour Hours Hours Hours Hours Hours (mg) Hour Hours Hours
Hours Hours Hours Min. 111.2 2 20 52 70 82 91 86.4 11 23 46 66 87
91 Max. 117.9 3 30 62 78 89 96 90.5 15 33 65 92 96 96 Avg. 115.0 2
24 56 74 86 92 88.8 13 27 55 81 91 94 % RSD 2.0 27.2 13.4 5.1 3.2
2.3 1.4 1.4 12.4 10.7 10.1 8.2 2.6 1.7
[0151] TABLE-US-00031 TABLE 20 % OF LABEL CLAIM RELEASED AT
SPECIFIED TIME INTERVAL IN 0.1N HC 4 mg Tablet of Invention 4 mg
Volmax .RTM. Tablet Unit Unit Weight 1 2 4 6 8 10 Weight 1 2 4 6 8
10 Unit # (mg) Hour Hours Hours Hours Hours Hours (mg) Hour Hours
Hours Hours Hours Hours Min. 113.3 2 9 53 72 84 90 89.2 8 21 43 62
84 92 Max 117.5 4 28 60 78 89 96 93.5 13 27 53 81 94 98 Avg. 115.1
3 19 56 75 87 93 91.3 11 24 49 72 90 95 % RSD 1.2 19.8 30.2 3.8 2.3
1.7 2.2 1.6 15.0 7.6 6.5 7.3 3.2 2.1
[0152] TABLE-US-00032 TABLE 21 % OF LABEL CLAIM RELEASED AT
SPECIFIED TIME INTERVAL IN pH 4.5 BUFFER 4 mg Tablet of Invention 4
mg Volmax .RTM. Tablet Unit Unit Weight 1 2 4 6 8 10 Weight 1 2 4 6
8 10 Unit # (mg) Hour Hours Hours Hours Hours Hours (mg) Hour Hours
Hours Hours Hours Hours Min. 114.0 1 5 44 66 79 87 85.9 10 22 44 63
86 90 Max 119.6 2 21 52 71 83 91 91.9 14 32 64 89 98 99 Avg. 116.5
2 15 49 68 81 89 89.7 12 26 52 77 91 94 % RSD 1.2 28.3 34.8 4.5 2.4
1.5 1.4 2.2 8.6 10.8 10.7 11.2 4.2 2.5
[0153] TABLE-US-00033 TABLE 22 % OF LABEL CLAIM RELEASED AT
SPECIFIED TIME INTERVAL IN pH 6.8 BUFFER 4 mg Tablet of Invention 4
mg Volmax .RTM. Tablet Unit Unit Weight 1 2 4 6 8 10 Weight 1 2 4 6
8 10 Unit # (mg) Hour Hours Hours Hours Hours Hours (mg) Hour Hours
Hours Hours Hours Hours Min. 113.2 1 3 37 58 72 81 87.5 9 20 39 57
75 87 Max 120.6 1 12 46 65 78 87 92.6 12 26 52 81 92 96 Avg. 115.6
1 6 42 62 75 85 90.3 11 23 46 68 87 92 % RSD 1.9 25.6 56.0 6.0 3.6
2.6 2.3 1.8 8.7 8.7 9.2 11.4 5.7 2.7
[0154] TABLE-US-00034 TABLE 23 % OF LABEL CLAIM RELEASED AT
SPECIFIED TIME INTERVAL IN DEIONIZED WATER 4 mg Tablet of Invention
4 mg Volmax .RTM. Tablet Unit Unit Weight 1 2 4 6 8 10 Weight 1 2 4
6 8 10 Unit # (mg) Hour Hours Hours Hours Hours Hours (mg) Hour
Hours Hours Hours Hours Hours Min. 108.8 3 29 58 77 88 94 162.0 12
28 56 77 84 82 Max 113.6 13 36 66 85 95 99 175.3 15 37 72 94 99 99
Avg. 111.4 9 32 62 80 91 96 172.2 13 33 62 85 93 95 % RSD 1.3 32.2
6.3 3.6 2.8 2.2 1.7 2.2 8.6 9.9 8.1 6.1 4.2 4.9
[0155] TABLE-US-00035 TABLE 24 % OF LABEL CLAIM RELEASED AT
SPECIFIED TIME INTERVAL IN 0.1N HCl 8 mg Tablet of Invention 8 mg
Volmax .RTM. Tablet Unit Unit Weight 1 2 4 6 8 10 Weight 1 2 4 6 8
10 Unit # (mg) Hour Hours Hours Hours Hours Hours (mg) Hour Hours
Hours Hours Hours Hours Min. 110.0 3 28 58 76 87 94 168.4 8 22 45
66 79 76 Max 115.2 11 37 66 84 94 99 182.8 14 30 61 87 96 99 Avg.
112.1 7 32 63 81 91 97 174.8 11 26 54 78 91 95 % RSD 1.2 38.8 7.5
4.2 3.0 2.2 1.6 2.2 16.2 11.1 8.5 7.2 5.0 6.6
[0156] TABLE-US-00036 TABLE 25 % OF LABEL CLAIM RELEASED AT
SPECIFIED TIME INTERVAL IN pH 4.5 BUFFER 8 mg Tablet of Invention 8
mg Volmax .RTM. Tablet Unit Unit Weight 1 2 4 6 8 10 Weight 1 2 4 6
8 10 Unit # (mg) Hour Hours Hours Hours Hours Hours (mg) Hour Hours
Hours Hours Hours Hours Min. 107.6 2 24 52 70 84 91 166.9 11 22 46
67 88 91 Max 113.8 9 30 59 78 91 97 178.7 15 35 70 91 98 99 Avg.
111.1 5 27 55 74 86 94 173.5 13 30 59 82 92 95 % RSD 1.8 55.2 8.1
4.1 3.1 2.3 1.7 1.7 12.9 12.6 10.9 8.2 3.1 2.3
[0157] TABLE-US-00037 TABLE 26 % OF LABEL CLAIM RELEASED AT
SPECIFIED TIME INTERVAL IN pH 6.8 BUFFER 8 mg Tablet of Invention 8
mg Volmax .RTM. Tablet Unit Unit Weight 1 2 4 6 8 10 Weight 1 2 4 6
8 10 Unit # (mg) Hour Hours Hours Hours Hours Hours (mg) Hour Hours
Hours Hours Hours Hours Min. 107.8 1 17 43 61 74 84 162.2 10 21 45
68 87 91 Max 116.0 6 27 53 71 83 91 181.9 15 34 68 89 96 100 Avg.
111.0 2 22 49 67 80 88 173.4 12 27 57 80 92 96 % RSD 2.1 54.6 11.9
5.2 3.9 3.2 2.3 3.0 12.8 12.3 9.5 6.3 2.7 2.8
[0158] While the invention has been described in connection with
certain preferred embodiments so that aspects thereof may be more
fully understood and appreciated, it is not intended to limit the
invention to these particular embodiments. On the contrary, it is
intended to cover all alternatives, modifications and equivalents
as may be included within the scope of the invention as defined by
the appended claims.
* * * * *