U.S. patent application number 13/449284 was filed with the patent office on 2012-08-09 for pharmaceutical formulations for the treatment of overactive bladder.
This patent application is currently assigned to THERAVIDA, INC.. Invention is credited to Roger S. FLUGEL, Peter R.P. FREED, Mehdi PABORJI, Robert V. TUOHY, III.
Application Number | 20120201894 13/449284 |
Document ID | / |
Family ID | 42289923 |
Filed Date | 2012-08-09 |
United States Patent
Application |
20120201894 |
Kind Code |
A1 |
PABORJI; Mehdi ; et
al. |
August 9, 2012 |
PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT OF OVERACTIVE
BLADDER
Abstract
Disclosed herein are pharmaceutical compositions comprising a
plurality of first beads each comprising: a core; a first layer
comprising pilocarpine or a pharmaceutically acceptable salt
thereof; and a second layer comprising a first polymer. Also
disclosed are pharmaceutical compositions comprising a plurality of
second beads each comprising: a core; and a first layer comprising
tolterodine or a pharmaceutically acceptable salt thereof. Further
disclosed are pharmaceutical formulations comprising: a) a
plurality of the first beads; b) a plurality of the second beads;
or c) a plurality of the first beads and a plurality of the second
beads.
Inventors: |
PABORJI; Mehdi; (Cupertino,
CA) ; TUOHY, III; Robert V.; (Norristown, PA)
; FREED; Peter R.P.; (Norristown, PA) ; FLUGEL;
Roger S.; (Redwood City, CA) |
Assignee: |
THERAVIDA, INC.
San Mateo
CA
|
Family ID: |
42289923 |
Appl. No.: |
13/449284 |
Filed: |
April 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13078881 |
Apr 1, 2011 |
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13449284 |
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61320202 |
Apr 1, 2010 |
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Current U.S.
Class: |
424/495 ;
514/397 |
Current CPC
Class: |
A61K 31/4178 20130101;
A61K 9/5078 20130101; A61K 9/1676 20130101; A61K 9/5047 20130101;
A61K 9/5084 20130101; A61P 1/02 20180101; A61K 9/1617 20130101;
A61P 43/00 20180101; A61P 13/00 20180101; A61K 31/222 20130101;
A61K 9/1652 20130101; A61P 13/10 20180101 |
Class at
Publication: |
424/495 ;
514/397 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61P 13/10 20060101 A61P013/10; A61K 31/4178 20060101
A61K031/4178 |
Claims
1. A pharmaceutical composition comprising: a) a plurality of first
beads each comprising: a microcrystalline cellulose bead core, a
first layer comprising pilocarpine, or a pharmaceutically
acceptable salt thereof, and hydroxypropylmethylcellulose, and a
second layer comprising one or both of hydroxypropylcellulose and
ethylcellulose; and b) a plurality of second beads each comprising:
a microcrystalline cellulose bead core, a first layer comprising
tolterodine, or a pharmaceutically acceptable salt thereof,
hydroxypropylmethylcellulose, and polyethylene glycol, wherein the
plurality of first beads release less than 20% of the pilocarpine,
or a pharmaceutically acceptable salt thereof, when immersed for 20
minutes in 0.1 N HCl.
2. The pharmaceutical composition of claim 1, wherein the first
bead core comprises between about 10% to about 50% of the total
weight of the finally-formulated bead.
3. The pharmaceutical composition of claim 1, wherein the first
layer of the first bead comprises between about 5% to about 30% of
the total weight of the bead.
4. The pharmaceutical composition of claim 1, wherein the first
bead coated with the first layer comprises an amount of pilocarpine
that provides a dose of between 3 mg and 12 mg of pilocarpine per
pharmaceutical composition.
5. The pharmaceutical composition of claim 1, wherein the first
layer of the first bead comprises hydroxypropylmethylcellulose in
about between about 2% to about 40% of the total weight of the
bead.
6. The pharmaceutical composition of claim 1, wherein the second
layer comprises both hydroxypropylcellulose and ethylcellulose, and
the weight ratio of hydroxypropylcellulose to ethylcellulose is
between about 5:1 to about 1:5 by weight.
7. The pharmaceutical composition of claim 1, wherein the second
layer comprises hydroxypropylcellulose in about between about 5% to
about 40% of the total weight of the bead.
8. The pharmaceutical composition of claim 1, wherein the second
layer comprises ethylcellulose in about between about 5% to about
40% of the total weight of the bead.
9. The pharmaceutical composition of claim 1, wherein the second
bead core comprises between about 25% to about 85% of the total
weight of the finally-formulated bead.
10. The pharmaceutical composition of claim 1, wherein the first
layer of the second bead comprises between about 2% to about 25% of
the total weight of the bead.
11. The pharmaceutical composition of claim 1, wherein the second
bead coated with the first layer comprises an amount of tolterodine
tartrate that provides a dose of between 1 mg and 6 mg of
tolterodine per pharmaceutical composition.
12. The pharmaceutical composition of claim 1, wherein the second
bead coated with the first layer comprises
hydroxypropylmethylcellulose in between about 5% to about 15% of
the total weight of the bead.
13. The pharmaceutical composition of claim 1, wherein the second
bead further comprises a de-tackifier or a glidant.
14. The pharmaceutical composition of claim 1, wherein the addition
of the second layer to the first bead represents a weight gain
selected from the group consisting 75%, 100%, 125%, 150%, 175%,
200%, and 250%.
15. A pharmaceutical composition comprising a plurality of first
beads each comprising: a microcrystalline cellulose bead core,
wherein the bead core comprises between about 15% to about 40% of
the total weight of the finally-formulated bead; a first layer
comprising pilocarpine, or a pharmaceutically acceptable salt
thereof, and hydroxypropylmethylcellulose, wherein the first layer
comprises between about 5% to about 15% of the total weight of the
finally-formulated bead; a second layer comprising one or both of
hydroxypropylcellulose and ethylcellulose, wherein the weight of
the second layer is between about 75% to about 250% of the weight
of the bead prior to the application of the second layer; wherein
the plurality of first beads release less than 20% of the
pilocarpine, or a pharmaceutically acceptable salt thereof, when
immersed for 20 minutes in 0.1 N HCl.
16. The pharmaceutical composition of claim 15, wherein the
pilocarpine is pilocarpine hydrochloride.
17. The pharmaceutical composition of claim 15, wherein the second
layer comprises both hydroxypropylcellulose and ethylcellulose, and
the weight ratio of hydroxypropylcellulose to ethylcellulose is
between about 5:1 to about 1:5 by weight.
18. A pharmaceutical composition comprising a plurality of beads
each comprising: a microcrystalline cellulose bead core, wherein
the core comprises between about 40% to about 80% of the total
weight of the finally-formulated bead; a first layer comprising
tolterodine, or a pharmaceutically acceptable salt thereof,
hydroxypropylmethylcellulose, and polyethylene glycol, wherein the
first layer comprises between about 4% to about 25% of the total
weight of the finally-formulated bead.
19. The pharmaceutical composition of claim 18, wherein the
tolterodine is tolterodine tartrate.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/078,881, filed Apr. 1, 2011, by Mehdi Paborji, and entitled
"PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT OF OVERACTIVE
BLADDER," which in turn claims priority to U.S. Provisional
Application No. 61/320,202, filed Apr. 1, 2010, by Mehdi Paborji,
and entitled "PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT OF
OVERACTIVE BLADDER," both of which are incorporated herein by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention is in the field of pharmaceutical
formulations, and in particular formulations comprising pilocarpine
or cevimeline, formulations comprising a muscarinic antagonist, and
formulations comprising a combination of pilocarpine or cevimeline
and a muscarinic antagonist.
BACKGROUND OF THE DISCLOSURE
[0003] Muscarinic receptor antagonists, such as tolterodine, are
known for the treatment of overactive bladder. However, an adverse
side effect of these treatments is severe dry mouth. This side
effect causes significant patient discomfort and reduces compliance
greatly. Previous work has shown that the combination of
tolterodine or oxybutynin with pilocarpine, a muscarinic receptor
agonist that increases saliva formation, can significantly reduce
the incidents of dry mouth while not affecting the efficacy of the
muscarinic receptor antagonist. See, for example, U.S. Pat. Nos.
7,666,894, 7,678,821, and 7,781,472, and U.S. Application
Publication Nos. 2009/0275629 and 2010/0152263, all of which are
incorporated herein by reference in their entirety.
[0004] As discussed in the aforementioned publications, one cannot
simply take a muscarinic antagonist and pilocarpine or cevimeline
and expect to obtain the desired clinical efficacy. The timing of
the administration of the muscarinic agonist vis-a-vis the
administration of the muscarinic antagonist has to be adjusted
properly so that the maximum increase in saliva formation due to
the administration of the muscarinic agonist is reached at the same
time as the maximum dry mouth experienced due to the administration
of the muscarinic antagonist. Taking two tablets at two different
times, where the time difference between the two administrations
has to be exact, is inconvenient, cumbersome, and reduces patient
compliance. Therefore, a single pharmaceutical formulation is
needed where the desired time delay and release profile are
incorporated.
SUMMARY OF THE INVENTION
[0005] Disclosed herein are pharmaceutical compositions comprising
a plurality of first beads each comprising: a core; a first layer
comprising pilocarpine, cevimeline, or a pharmaceutically
acceptable salt thereof; and a second layer comprising a first
polymer. Also disclosed are pharmaceutical compositions comprising
a plurality of second beads each comprising: a core; and a first
layer comprising a muscarinic antagonist or a pharmaceutically
acceptable salt thereof. Further disclosed are pharmaceutical
formulations comprising: a) a plurality of the first beads; b) a
plurality of the second beads; or c) a plurality of the first beads
and a plurality of the second beads.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0006] Aspects of the present disclosure include pharmaceutical
formulations comprising a muscarinic antagonist in an immediate
release formulation. Once ingested by a subject, the muscarinic
antagonist in these formulations begins to release into the gut to
be systemically absorbed into the blood stream. Other aspects of
the present disclosure include pharmaceutical formulations
comprising pilocarpine or cevimeline, both of which are muscarinic
agonists. The muscarinic agonist of the pharmaceutical formulations
is present in a delayed immediate release formulation. Once
ingested, the muscarinic agonist is not released for some time. But
once the muscarinic agonist begins to be released, it is released
immediately.
[0007] In some embodiments, the muscarinic antagonist of the
formulations disclosed herein is a compound that is used for the
treatment of overactive bladder. In certain embodiments, the
muscarinic antagonist is selected from the group consisting of
tolterodine, 5-hydroxymethyl tolterodine, fesoterodine, oxybutynin,
solifenacin, darifenacin, trospium, imidafenacin, propiverine, and
dicyclomine.
[0008] In the context of the present disclosure, "immediate
release" or "released immediately" means that at least about 70% of
the ingested active pharmaceutical ingredient in the dosage form is
released from the pharmaceutical formulation within about 30-60
minutes of the ingestion of the dosage form. By "not released" or
"delayed released" it is meant that less than 20% of the ingested
active pharmaceutical ingredient in the dosage form is released
from the pharmaceutical formulation by the time the delay is
concluded and the release becomes immediate.
[0009] Throughout the present disclosure the term "about" a certain
value means that a range of value .+-.10%, and preferably a range
of value .+-.5%, is contemplated. Thus, for example, having about
70% of the active pharmaceutical ingredient (API) includes API
being present between 63% and 87%, and preferably between 66.5% and
73.5%; or by way of another example, "about 45 minutes" means that
the contemplated value is between 40.5 minutes and 49.5 minutes,
and preferably between 42.75 minutes and 47.25 minutes.
[0010] Disclosed herein are beads, or multiparticulate systems,
comprising a muscarinic agonist, i.e., pilocarpine or cemiveline,
and other beads comprising a muscarinic antagonist. Contemplated
within the scope of the present disclosure are pharmaceutical
compositions comprising muscarinic agonist beads only, muscarinic
antagonist beads only, or compositions comprising both muscarinic
agonist and muscarinic antagonist beads. The muscarinic
agonist-only or muscarinic antagonist-only beads can be
administered individually or in combination with beads or other
pharmaceutical formulations comprising other active
ingredients.
Muscarinic Agonist Beads
[0011] Thus, in one aspect, disclosed herein are pharmaceutical
compositions comprising a plurality of first beads each
comprising:
[0012] a core;
[0013] a first layer comprising a muscarinic agonist, i.e.,
pilocarpine or cemiveline, or a pharmaceutically acceptable salt
thereof; and
[0014] a second layer comprising a first polymer.
[0015] In some embodiments, the core comprises a polymer. In
certain embodiments, the core polymer is a cellulose polymer. In
some of these embodiments, the cellulose polymer is
microcrystalline cellulose. In other embodiments, the core
comprises a sugar. In certain embodiments, the sugar is selected
from the group consisting of glucose, sucrose, lactose, mannitol,
maltodextrine, xylitol, and sorbitol. In further embodiments, the
core comprises silicon dioxide.
[0016] In some embodiments, the core is obtained commercially. An
example of commercially available beads to be used as core for the
beads disclosed herein includes, but is not limited to, sugar
spheres (for example, Paular spheres), Cellets.RTM. cores, such as
Cellets.RTM. 100, Cellets.RTM. 200, Cellets.RTM. 350, Cellets.RTM.
500, Cellets.RTM. 700, or Cellets.RTM. 1000 (Glatt Air Techniques
Inc., Ramsey N.J.). In other embodiments, the core is prepared de
novo, for example by preparing a polymer mixture, extruding the
mixture, and spheronizing the extruded mixture to form spherical or
semi-spherical beads. In some embodiments, the beads are swellable
such that their exposure to aqueous media causes them to swell and
release the active ingredient rapidly and efficiently.
[0017] In some embodiments, the core comprises between about 10% to
about 50% of the total weight of the finally-formulated bead. In
some embodiments, the core comprises between about 15% to about 40%
of the total weight of the finally-formulated bead. In some
embodiments, the core comprises between about 20% to about 30% of
the total weight of the finally-formulated bead. In some
embodiments, the core comprises about 20% of the total weight of
the finally-formulated bead. In some embodiments, the core
comprises about 25% of the total weight of the finally-formulated
bead.
[0018] In some embodiments, a solution of the muscarinic agonist, a
free base thereof or a pharmaceutically acceptable salt thereof, is
prepared and then sprayed onto the core and then dried. The act of
spraying and drying causes a layer (the first layer) of the API
(i.e., pilocarpine or cevimeline) to form over the bead. In some
embodiments, the solution comprises a polymer that causes the API
to more efficiently adhere to the core. The amount of the API
present in the dosage form can be controlled by controlling the
thickness of the first layer and/or by the concentration of the
solution comprising the API. The thicker the first layer, or the
more concentrated the API solution, the more API is present in the
dosage form. Once the first layer is exposed to aqueous media, for
example gastric or intestinal juice, the pilocarpine contained
therein immediately dissolves into the aqueous medium. Methods of
applying the first layer uniformly onto the core are well-known in
the art.
[0019] In some embodiments, the first layer comprises between about
1% to about 50% of the total weight of the bead. In some
embodiments, the first layer comprises between about 2% to about
40% of the total weight of the bead. In some embodiments, the first
layer comprises between about 5% to about 30% of the total weight
of the bead. In some embodiments, the first layer comprises between
about 7% to about 25% of the total weight of the bead. In some
embodiments, the first layer comprises between about 8% to about
15% of the total weight of the bead. In some embodiments, the first
layer comprises about 8% of the total weight of the bead. In some
embodiments, the first layer comprises about 10% of the total
weight of the bead. In some embodiments, the first layer comprises
about 12% of the total weight of the bead. In some embodiments, the
first layer comprises about 15% of the total weight of the
bead.
[0020] In some embodiments, pilocarpine or cevimeline is present as
the free base. In other embodiments, pilocarpine or cevimeline is
present as a pharmaceutically acceptable salt. The term
"pharmaceutically acceptable salt" refers to a formulation of a
compound that does not abrogate the biological activity and
properties of the compound. Pharmaceutical salts can be obtained by
reacting a compound of the invention with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical
salts can be obtained by reacting a compound of the invention with
inorganic acids such as tartric acid, oxolic acid, "carbonic acid"
to form the bicarbonate or carbonate salt of the compound, acetic
acid, formic acid, benzoic acid, and the like. Pharmaceutical salts
can also be obtained by reacting a compound of the invention with a
base to form a salt such as an ammonium salt, an alkali metal salt,
such as a sodium or a potassium salt, an alkaline earth metal salt,
such as a calcium or a magnesium salt, a salt of organic bases such
as dicyclohexylamine, N-methyl-D-glucamine,
tris(hydroxymethyl)methylamine, and salts with amino acids such as
arginine, lysine, and the like. In some embodiments, the
pilocarpine is pilocarpine HCl or pilocarpine nitrate.
[0021] Once the API (pilocarpine, cevimeline, or a salt thereof) is
coated onto the bead, the bead is coated with a second layer. The
second layer delays the exposure of the first layer to the aqueous
media. The second layer comprises at least one polymer, the first
polymer.
[0022] In some embodiments, the first polymer comprises a soluble
film-forming polymer. By "soluble" it is meant that the polymer is
soluble in aqueous media, which means that at least about 50% of
the polymer has dissolved within one hour after exposure to the
aqueous media. It is understood that some polymers disperse in
aqueous solutions. This dispersion is not the same as dissolving.
For a compound or polymer to be soluble, there needs to be a
concentration of the compound or polymer in the solvent having
solute-solvent interactions, as understood in the chemical
arts.
[0023] In some embodiments, the first polymer is a sugar or a
polysaccharide. In some of these embodiments, the sugar or
polysaccharide is selected from the group consisting of cellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, maltodextrin,
sucrose, modified starch, a salt of alginic acid, soluble gums, and
carageenan. In other embodiments, the first polymer is
polyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone (PVPP).
[0024] In some embodiments, the soluble-forming polymer is a
mixture of two or more polymers. In some embodiments, the mixture
comprises hydroxypropylmethylcellulose (HPMC) and
hydroxypropylcellulose (HPC).
[0025] In some embodiments, hydroxypropylmethylcellulose is present
in between about 1% to about 50% of the total weight of the bead.
In some embodiments, hydroxypropylmethylcellulose is present in
between about 2% to about 40% of the total weight of the bead. In
some embodiments, hydroxypropylmethylcellulose is present in
between about 5% to about 30% of the total weight of the bead. In
some embodiments, hydroxypropylmethylcellulose is present in
between about 7% to about 25% of the total weight of the bead. In
some embodiments, hydroxypropylmethylcellulose is present in
between about 8% to about 15% of the total weight of the bead. In
some embodiments, hydroxypropylmethylcellulose is present in about
8% of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 10% of the total
weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 12% of the total
weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 15% of the total
weight of the bead.
[0026] In some embodiments, hydroxypropylcellulose is present in
between about 1% to about 90% of the total weight of the bead. In
some embodiments, hydroxypropylcellulose is present in between
about 5% to about 40% of the total weight of the bead. In some
embodiments, hydroxypropylcellulose is present in between about 10%
to about 30% of the total weight of the bead. In some embodiments,
hydroxypropylcellulose is present in between about 15% to about 25%
of the total weight of the bead. In some embodiments,
hydroxypropylcellulose is present in between about 20% to about 25%
of the total weight of the bead. In some embodiments,
hydroxypropylcellulose is present in about 21.50% of the total
weight of the bead. In some embodiments, hydroxypropylcellulose is
present in about 22.25% of the total weight of the bead. In some
embodiments, hydroxypropylcellulose is present in about 22.75% of
the total weight of the bead. In some embodiments,
hydroxypropylcellulose is present in about 24.50% of the total
weight of the bead.
[0027] In some embodiments, the second layer further comprises an
insoluble film-forming polymer. By "insoluble" it is meant that the
polymer is insoluble in aqueous media, which means that at most
about 10% of the polymer has dissolved within one hour after
exposure to the aqueous media. The presence of the insoluble
film-forming polymer in the second layer causes greater delay in
the exposure of the first layer to the aqueous media. The insoluble
film-forming polymer and the soluble film-forming polymer form a
matrix where upon exposure to the aqueous media the soluble polymer
dissolves leaving pores in a network of insoluble polymer through
which pores the API in the first layer leaches out into the aqueous
media.
[0028] In some embodiments, the insoluble film-forming polymer is a
polysaccharide. In some of these embodiments, the polysaccharide is
selected from the group consisting of ethylcellulose, cellulose
acetate phthalate, hydroxypropylmethylcellulose phthalate, and
insoluble gums. In other embodiments, the insoluble film-forming
polymer is selected from the group consisting of a
polymethacrylate, a polyvinyl alcohol, shellac, and polyvinyl
acetate phthalate.
[0029] In some embodiments, ethylcellulose is present in between
about 1% to about 90% of the total weight of the bead. In some
embodiments, ethylcellulose is present in between about 5% to about
40% of the total weight of the bead. In some embodiments,
ethylcellulose is present in between about 10% to about 30% of the
total weight of the bead. In some embodiments, ethylcellulose is
present in between about 15% to about 25% of the total weight of
the bead. In some embodiments, ethylcellulose is present in between
about 20% to about 25% of the total weight of the bead. In some
embodiments, ethylcellulose is present in about 21.50% of the total
weight of the bead. In some embodiments, ethylcellulose is present
in about 22.25% of the total weight of the bead. In some
embodiments, ethylcellulose is present in about 22.75% of the total
weight of the bead. In some embodiments, ethylcellulose is present
in about 24.50% of the total weight of the bead.
[0030] In some embodiments, the second layer comprises
hydroxypropylcellulose and ethylcellulose. In some embodiments, the
ratio of hydroxypropylcellulose to ethylcellulose is between about
5:1 to about 1:5 by weight. In some embodiments, the ratio of
hydroxypropylcellulose to ethylcellulose is between about 4:1 to
about 1:4 by weight. In some embodiments, the ratio of
hydroxypropylcellulose to ethylcellulose is between about 3:1 to
about 1:3 by weight. In some embodiments, the ratio of
hydroxypropylcellulose to ethylcellulose is between about 2:1 to
about 1:2 by weight. In some embodiments, the ratio of
hydroxypropylcellulose to ethylcellulose is about 1:1 by
weight.
[0031] In some embodiments, the first bead further comprises a
de-tackifier or a glidant. In some embodiments, the de-tackifier or
glidant is an inert mineral. An inert mineral is a mineral, i.e.,
an inorganic compound or salt, that is pharmaceutically acceptable
and does not interfere with the pharmacological action of the
therapeutic compound. In some embodiments, the inert mineral is a
mineral of magnesium. In other embodiments, the mineral of
magnesium is magnesium silicate. In certain embodiments, the
de-tackifier or glidant is selected from the group consisting of
talc, a monoglyceride, a diglyceride, glyceryl monostearate,
calcium stearate, and magnesium stearate.
[0032] In some embodiments, the de-tackifier or glidant is present
in between about 1% to about 50% of the total weight of the bead.
In some embodiments, the de-tackifier or glidant is present in
between about 2% to about 40% of the total weight of the bead. In
some embodiments, the de-tackifier or glidant is present in between
about 3% to about 20% of the total weight of the bead. In some
embodiments, the de-tackifier or glidant is present in between
about 4% to about 10% of the total weight of the bead. In some
embodiments, the de-tackifier or glidant is present in about 4% of
the total weight of the bead. In some embodiments, the de-tackifier
or glidant is present in about 4.5% of the total weight of the
bead. In some embodiments, the de-tackifier or glidant is present
in about 5% of the total weight of the bead. In some embodiments,
the de-tackifier or glidant is present in about 5.5% of the total
weight of the bead. In some embodiments, the de-tackifier or
glidant is present in about 6% of the total weight of the bead. In
some embodiments, the de-tackifier or glidant is present in about
6.5% of the total weight of the bead.
[0033] In some embodiments, the first polymer is, or comprises, a
lipid excipient. The lipid excipient can be selected from the group
consisting of glyceryl behenate, glycerol esters of fatty acids,
glyceryl dibehenate, behenoyl macrogoglycerides, glyceryl
distearate, glycerol distearate, glyceryl palmitostearate, lauroyl
macrogoglycerides, stearoyl macrogoglycerides, abitec products,
glyceryl mono-oleate, medium chain mono- & diglycerides,
glyceryl monocaprylate, glyceryl tricaprylate/caprate/stearate,
hydrogenated vegetable oil, hydrogenated cottonseed oil,
hydrogenated soybean oil, hydrogenated soybean oil and castor wax,
polyoxyethylene 8 caprylic/capric glycerides, polyoxyethylene 6
caprylic/capric glycerides, polyoxyethylene 32 lauric glycerides,
polyoxyethylene 6 prop. Glycol esters, polyoxyethylene 7 coconut
glycerides, polyoxyethylene 30 coconut glycerides, polyoxyethylene
80 coconut glycerides, polyoxypropylene 15 stearyl ether,
polyoxyethylene 26 glyceryl ether, polyoxyethylene 35 soybean
glycerides, polyoxyethylene 20 sorbitol, polyoxypropylene 3
myristyl ether, polyoxypropylene 10 cetostearyl ether, palm
kernelamide diethanolamide, triglycerol mono-oleate, sasol
products, hydrogenated coco-glycerides, cetyl palmitate,
trimyristin, tripalmitin, tristearin, hydrogenated palm oil,
glyceryl monostearate, glyceryl stearate, cetearyl alcohol, cetyl
alcohol, capric triglyceride, acetylated glycerides, glyceryl
cocoate, and polyethylene glycol.
[0034] In some embodiments, the first bead further comprises a
plasticizer. In some embodiments, the plasticizer is selected from
the group consisting of a phthalate-based plasticizer, a
trimellitate, an adipate-based plasticizer, a sebacate-based
plasticizer, an organophosphate, a maleate, a sulfonamide, a
glycols or polyether, an acetylated monoglyceride, and an alkyl
citrate.
[0035] In some embodiments, the phthalate-based plasticizer is
selected from the group consisting of bis(2-ethylhexyl)phthalate
(DEHP), diisononyl phthalate (DINP), bis(n-butyl)phthalate (DnBP,
DBP), butyl benzyl phthalate (BBzP), diisodecyl phthalate (DIDP),
di-n-octyl phthalate (DOP or DnOP), diisooctyl phthalate (DIOP),
diethyl phthalate (DEP), diisobutyl phthalate (DIBP), and
di-n-hexyl phthalate. In some embodiments, the trimellitate is
selected from the group consisting of trimethyl trimellitate
(TMTM), tri-(2-ethylhexyl)trimellitate (TEHTM-MG),
tri-(n-octyl,n-decyl)trimellitate (ATM),
tri-(heptyl,nonyl)trimellitate (LTM), and n-octyl trimellitate
(OTM). In some embodiments, the adipate-based plasticizer is
selected from the group consisting of bis(2-ethylhexyl)adipate
(DEHA), dimethyl adipate (DMAD), monomethyl adipate (MMAD), and
dioctyl adipate (DOA). In some embodiments, the sebacate-based
plasticiser is dibutyl sebacate (DBS). In some embodiments, the
maleate is dibutyl maleate (DBM) or diisobutyl maleate (DIBM). In
some embodiments, the sulfonamide is selected from the group
consisting of ortho or para N-ethyl toluene sulfonamide (ETSA),
N-(2-hydroxypropyl)benzene sulfonamide (HP BSA), and
N-(n-butyl)benzene sulfonamide (BBSA-NBBS). In some embodiments,
the organophosphate is tricresyl phosphate (TCP) or tributyl
phosphate (TBP). In some embodiments, the glycol or polyether is
selected from the group consisting of triethylene glycol
dihexanoate (3G6, 3 GH), tetraethylene glycol diheptanoate (4G7),
and polyethylene glycol. In some embodiments, the alkyl citrate is
selected from the group consisting of Triethyl citrate (TEC),
acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl
tributyl citrate (ATBC), trioctyl citrate (TOC), acetyl trioctyl
citrate (ATOC), trihexyl citrate (THC), acetyl trihexyl citrate
(ATHC), butyryl trihexyl citrate (BTHC, trihexyl o-butyryl
citrate), and trimethyl citrate (TMC). In some embodiments, the
plasticizer is selected from the group consisting of dibutyl
sebacate, polyethylene glycol, glycerin, triacetin, diethyl
phthalate, propylene glycol, triethyl citrate, mineral oil, an
acetylated monoglyceride, and oleic acid.
[0036] In some embodiments, the plasticizer is present in between
about 1% to about 50% of the total weight of the bead. In some
embodiments, the plasticizer is present in between about 2% to
about 40% of the total weight of the bead. In some embodiments, the
plasticizer is present in between about 3% to about 20% of the
total weight of the bead. In some embodiments, the plasticizer is
present in between about 4% to about 10% of the total weight of the
bead. In some embodiments, the plasticizer is present in about 4%
of the total weight of the bead. In some embodiments, the
plasticizer is present in about 4.5% of the total weight of the
bead. In some embodiments, the plasticizer is present in about 5%
of the total weight of the bead. In some embodiments, the
plasticizer is present in about 5.5% of the total weight of the
bead. In some embodiments, the plasticizer is present in about 6%
of the total weight of the bead. In some embodiments, the
plasticizer is present in about 6.5% of the total weight of the
bead.
[0037] In some embodiments, the weight of the second layer is
between about 50% to about 300% of the weight of the bead prior to
the application of the second layer. In some embodiments, the
weight of the second layer is between about 75% to about 250% of
the weight of the bead prior to the application of the second
layer. In some embodiments, the weight of the second layer is about
75% of the weight of the bead prior to the application of the
second layer. In some embodiments, the weight of the second layer
is about 100% of the weight of the bead prior to the application of
the second layer. In some embodiments, the weight of the second
layer is about 125% of the weight of the bead prior to the
application of the second layer. In some embodiments, the weight of
the second layer is about 150% of the weight of the bead prior to
the application of the second layer. In some embodiments, the
weight of the second layer is about 175% of the weight of the bead
prior to the application of the second layer. In some embodiments,
the weight of the second layer is about 200% of the weight of the
bead prior to the application of the second layer. In some
embodiments, the weight of the second layer is about 225% of the
weight of the bead prior to the application of the second layer. In
some embodiments, the weight of the second layer is about 250% of
the weight of the bead prior to the application of the second
layer.
Muscarinic Antagonist Beads
[0038] In another aspect, disclosed herein are pharmaceutical
compositions comprising a plurality of second beads each
comprising: [0039] a core; and [0040] a first layer comprising a
muscarinic antagonist or a pharmaceutically acceptable salt
thereof.
[0041] In some embodiments, the muscarinic antagonist is present as
the free base. In other embodiments, the muscarinic antagonist is
present as a pharmaceutically acceptable salt. Pharmaceutically
acceptable salts are defined above. In some embodiments, the
muscarinic antagonist is selected from the group consisting of
tolterodine, 5-hydroxymethyl tolterodine, fesoterodine, oxybutynin,
solifenacin, darifenacin, trospium, imidafenacin, propiverine, and
dicyclomine. In some embodiments, the tolterodine is tolterodine
tartrate. In other embodiments, the oxybutynin is oxybutynin
chloride.
[0042] In some embodiments, the core of the plurality of the second
beads is comprised of the same material as the core of the
plurality of the first beads, discussed above.
[0043] In some embodiments, the core comprises between about 10% to
about 90% of the total weight of the finally-formulated bead. In
some embodiments, the core comprises between about 25% to about 85%
of the total weight of the finally-formulated bead. In some
embodiments, the core comprises between about 40% to about 80% of
the total weight of the finally-formulated bead. In some
embodiments, the core comprises about 80% of the total weight of
the finally-formulated bead. In some embodiments, the core
comprises about 75% of the total weight of the finally-formulated
bead. In some embodiments, the core comprises about 85% of the
total weight of the finally-formulated bead.
[0044] In some embodiments, a solution of the API (i.e., the
muscarinic antagonist), or a pharmaceutically acceptable salt
thereof, is prepared and then sprayed onto the core and then dried.
The act of spraying and drying causes a layer (the first layer) of
the API to form over the bead. In some embodiments, the solution
comprises a polymer that causes the API to more efficiently adhere
to the core. The amount of the API present in the dosage form can
be controlled by controlling the thickness of the first layer. The
thicker the first layer the more API is present in the dosage form.
Once the first layer is exposed to aqueous media, for example
gastric or intestinal juice, the tolterodine contained therein
immediately dissolves into the aqueous medium. Methods of applying
the first layer uniformly onto the core are well-known in the
art.
[0045] In some embodiments, the first layer comprises between about
1% to about 50% of the total weight of the bead. In some
embodiments, the first layer comprises between about 2% to about
40% of the total weight of the bead. In some embodiments, the first
layer comprises between about 4% to about 25% of the total weight
of the bead. In some embodiments, the first layer comprises between
about 5% to about 15% of the total weight of the bead. In some
embodiments, the first layer comprises between about 5.5% to about
10% of the total weight of the bead. In some embodiments, the first
layer comprises about 6% of the total weight of the bead. In some
embodiments, the first layer comprises about 6.5% of the total
weight of the bead. In some embodiments, the first layer comprises
about 7% of the total weight of the bead. In some embodiments, the
first layer comprises about 8% of the total weight of the bead.
[0046] In some embodiments, the first layer comprises a soluble
film-forming polymer, as defined above.
[0047] In some embodiments, hydroxypropylmethylcellulose is present
in between about 1% to about 50% of the total weight of the bead.
In some embodiments, hydroxypropylmethylcellulose is present in
between about 2% to about 40% of the total weight of the bead. In
some embodiments, hydroxypropylmethylcellulose is present in
between about 5% to about 30% of the total weight of the bead. In
some embodiments, hydroxypropylmethylcellulose is present in
between about 7% to about 25% of the total weight of the bead. In
some embodiments, hydroxypropylmethylcellulose is present in
between about 8% to about 15% of the total weight of the bead. In
some embodiments, hydroxypropylmethylcellulose is present in about
8% of the total weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 10% of the total
weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 12% of the total
weight of the bead. In some embodiments,
hydroxypropylmethylcellulose is present in about 15% of the total
weight of the bead.
[0048] In some embodiments, the second bead further comprises a
de-tackifier or a glidant, as defined above. In some embodiments,
the de-tackifier or glidant is present in between about 1% to about
50% of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in between about 2% to about 40%
of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in between about 3% to about 20%
of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in between about 4% to about 10%
of the total weight of the bead. In some embodiments, the
de-tackifier or glidant is present in about 3% of the total weight
of the bead. In some embodiments, the de-tackifier or glidant is
present in about 3.5% of the total weight of the bead. In some
embodiments, the de-tackifier or glidant is present in about 4% of
the total weight of the bead. In some embodiments, the de-tackifier
or glidant is present in about 4.5% of the total weight of the
bead. In some embodiments, the de-tackifier or glidant is present
in about 5% of the total weight of the bead. In some embodiments,
the de-tackifier or glidant is present in about 5.5% of the total
weight of the bead.
[0049] In some embodiments, the first layer further comprises a
lipid excipient. The lipid excipient can be selected from the group
consisting of glyceryl behenate, glycerol esters of fatty acids,
glyceryl dibehenate, behenoyl macrogoglycerides, glyceryl
distearate, glycerol distearate, glyceryl palmitostearate, lauroyl
macrogoglycerides, stearoyl macrogoglycerides, abitec products,
glyceryl mono-oleate, medium chain mono- & diglycerides,
glyceryl monocaprylate, glyceryl tricaprylate/caprate/stearate,
hydrogenated vegetable oil, hydrogenated cottonseed oil,
hydrogenated soybean oil, hydrogenated soybean oil and castor wax,
polyoxyethylene 8 caprylic/capric glycerides, polyoxyethylene 6
caprylic/capric glycerides, polyoxyethylene 32 lauric glycerides,
polyoxyethylene 6 prop. glycol esters, polyoxyethylene 7 coconut
glycerides, polyoxyethylene 30 coconut glycerides, polyoxyethylene
80 coconut glycerides, polyoxypropylene 15 stearyl ether,
polyoxyethylene 26 glyceryl ether, polyoxyethylene 35 soybean
glycerides, polyoxyethylene 20 sorbitol, polyoxypropylene 3
myristyl ether, polyoxypropylene 10 cetostearyl ether, palm
kernelamide diethanolamide, triglycerol mono-oleate, sasol
products, hydrogenated coco-glycerides, cetyl palmitate,
trimyristin, tripalmitin, tristearin, hydrogenated palm oil,
glyceryl monostearate, glyceryl stearate, cetearyl alcohol, cetyl
alcohol, capric triglyceride, acetylated glycerides, glyceryl
cocoate, and polyethylene glycol.
[0050] In some embodiments, the second bead further comprises a
plasticizer, as defined above. In some embodiments, the plasticizer
is polyethylene glycol. In certain embodiments, the polyethylene
glycol is PEG 400.
[0051] In some embodiments, the plasticizer is present in between
about 0.1% to about 50% of the total weight of the bead. In some
embodiments, the plasticizer is present in between about 0.1% to
about 40% of the total weight of the bead. In some embodiments, the
plasticizer is present in between about 0.1% to about 5% of the
total weight of the bead. In some embodiments, the plasticizer is
present in between about 0.2% to about 2% of the total weight of
the bead. In some embodiments, the plasticizer is present in about
0.1% of the total weight of the bead. In some embodiments, the
plasticizer is present in about 0.15% of the total weight of the
bead. In some embodiments, the plasticizer is present in about 0.2%
of the total weight of the bead. In some embodiments, the
plasticizer is present in about 0.25% of the total weight of the
bead. In some embodiments, the plasticizer is present in about 0.3%
of the total weight of the bead. In some embodiments, the
plasticizer is present in about 0.35% of the total weight of the
bead. In some embodiments, the plasticizer is present in about 0.4%
of the total weight of the bead.
[0052] In some embodiments, the second beads further comprise a
second layer. In some embodiments, the second layer comprises
ingredients similar to the first layer, discussed above, except
that the second layer does not have any API. In some embodiments,
the first layer and the second layer have identical set of
ingredients, whereas in other embodiments, the first and second
layers have different combination of ingredients.
Pharmaceutical Formulations
[0053] In another aspect, disclosed herein are pharmaceutical
formulations comprising one of the following combinations of the
above beads: a) a plurality of the first beads; b) a plurality of
the second beads; or c) a plurality of the first beads and a
plurality of the second beads.
[0054] The disclosed pharmaceutical formulations contain sufficient
number of beads to provide a single administrable dose to a
subject. In some embodiments, a single administrative dose for the
muscarinic agonist is between 0.5-50 mg. In certain embodiments, a
single administrable dose of pilocarpine is selected from the group
consisting of 3 mg, 4 mg, 5 mg, 6 mg, 10 mg, 11 mg, and 12 mg. In
other embodiments, a single administrable dose of cevimeline is
selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, 25
mg, 30 mg, 40 mg, 50 mg, and 60 mg. In certain embodiments, a
single administrable dose for the muscarinic antagonist is between
0.1-100 mg. In certain embodiments, a single administrative dose is
selected from the group consisting of 0.1 mg, 0.2 mg, 0.4 mg, 0.5
mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 10 mg,
12 mg, 15 mg, 30 mg, and 60 mg.
[0055] In some embodiments, the pharmaceutical formulations are in
the form of capsules. The capsules may include push-fit capsules
made of gelatin, push-fit capsules, for example those made of
hydroxypropylmethylcellulose, banded push-fit capsules, as well as
soft, sealed capsules made of gelatin and a plasticizer, such as
glycerol or sorbitol.
[0056] In some embodiments, the pharmaceutical formulations are in
the form of dose sipping straws. In some embodiments, the beads are
filled into a straw and a patient then drinks liquid through the
straw, and through the process of drinking, the liquid pulled
through the straw brings the beads into the mouth along with the
liquid.
[0057] In some embodiments, the pharmaceutical formulations are in
the form of dry sachets. In some embodiments, the beads are
sprinkled onto food or mixed into a drink from dry sachet, and
taken orally. For the dosage to be effective, the disclosed beads
are filled into a sachet pouch, along with additional excipients
needed to form a readily dispersible suspension. When the pouch is
opened and the contents are poured over food or into a drink, the
beads and additional excipients are mixed with the food or the
drink, and form a palatable dispersion that is ingested by the
subject. Excipients, such as salivants and glidants, are added for
the contents to be easily swallowed with a minimum of chewing so
that the coatings are not broken in the mouth.
[0058] In some embodiments, the pharmaceutical formulations are in
the form of ready-to-use sachets. In some embodiments, the beads
are premixed with an edible, high viscosity food substance (for
example, yogurt, or energy gel), and the entire contents of the
package is taken orally. Excipients, such as salivants and
glidants, are added for the contents to be easily swallowed with a
minimum of chewing so that the coatings are not broken in the
mouth.
[0059] In some embodiments, the pharmaceutical formulations are in
the form of suspensions. In some embodiments, the suspensions
comprise ingredients such as glycerin, microcrystalline cellulose,
carboxymethyl cellulose sodium, sorbitol solution, xanthan gum, and
the like, and various colorings and flavorings to make the
suspension palatable for pediatric or geriatric use.
[0060] In some embodiments, the first beads disclosed above, having
pilocarpine or a pharmaceutically acceptable salt thereof, and the
first and second layers, are coated with a third layer comprising
tolterodine, or a pharmaceutically acceptable salt thereof. The
third layer is the same as, or similar to, the first layer of the
second beads discussed above. In certain embodiments, the
tolterodine-coated first bead is further coated with a fourth
layer, which is the same as, or similar to, the second layer of the
second beads discussed above.
EXAMPLES
Example 1
Materials Used in the Bead Manufacturing Process
[0061] The raw materials listed in Table 1 were used in the
production of the pilocarpine and tolterodine beads.
TABLE-US-00001 TABLE 1 Components Used for Bead Production Generic
Name Trade Name Supplier Pilocarpine Hydrochloride Pilocarpine HCl
Boehringer Ingelheim Tolterodine Tartrate Tolterodine tartrate
Medichem Ethylcellulose Ethylcellulose N10 Hercules Ethylcellulose
Ethylcellulose N7 Hercules Hydroxypropyl Pharmacoat 606 Shin Etsu
Methylcellulose Hydroxypropyl Cellulose Klucel EF Hercules
Polyethylene Glycol 400 Carbowax 400 Dow Dibutyl Sebacate Dibutyl
Sebacate Vertellus Talc Luzenac Talc Minerals and Pigments
Dehydrated Alcohol, 200 Ethanol Spectrum proof Microcrystalline
Cellulose Cellets 700 Glatt Beads GMS Emulsion Plasacryl Emerson
Microcrystalline Cellulose Avicel PH 101 FMC Milled Lactose
Pharmatose 200M DMV Croscarmellose Sodium Ac-Di-Sol FMC
Crospovidone Polyplasdone XL-10 ISP Gelatin Capsules Conisnaps,
size 2 Capsugel Sterile water for Irrigation Water Hospira
Deionized water Deionized water N/A
[0062] The equipment listed in Table 2 was used for the preparation
of the beads.
TABLE-US-00002 TABLE 2 Equipment Used for Bead Production Equipment
Manufacturer Location FLM-1 fluid bed Vector Corporation Marion, IA
FLM-3 fluid bed Vector Corporation Marion, IA DG-L1 Extruder LCI
Charlotte, NC QJ-230 Spheronizer LCI Charlotte, NC Blend Master
V-blender Patterson Kelly East Stroudsburg, PA In Cap Automatic
Dott. Bonapace & C. Milan, Italy Encapsulator ProFill 100
Manual Capsugel Greenwood, SC Encapsulator Portable Dehumidifier
DRI-EAZ Burlington, WA
Example 2
Dissolution Rate Determination
[0063] This method describes the procedure for the determination of
the dissolution rate of the pilocarpine HCl and tolterodine
tartrate combination formulations by using a reverse-phase,
gradient, high-pressure liquid chromatography (HPLC) method, using
techniques well-known in the art.
[0064] Stock solutions of pilocarpine HCl and tolterodine tartrate
were prepared as working standards. Beads containing pilocarpine
HCl and tolterodine tartrate are separately mixed with a fixed
volume of 0.1 N HCl. At fixed time points after the mixing has
begun, aliquots of the dissolution mixtures are injected into HPLC
followed by several aliquots of the working standards. The amounts
of released (dissolved) tolterodine and pilocarpine entities of
formulations were calculated using the corresponding peak areas of
tolterodine and pilocarpine.
[0065] A USP 2 Paddles method with the following conditions was
employed to determine dissolution of various formulations.
[0066] Dissolution media: 0.1 N HCl
[0067] Agitation Rate: 50 RPM
[0068] Vessel Temp: 37.degree. C..+-.0.5.degree. C.
[0069] Sample Volume: 1.0 mL
[0070] Disso Volume: 500 mL
Example 3
Bead Formation
[0071] Beads were produced by drug layering microcrystalline
cellulose beads with aqueous, cellulosic coating systems containing
pilocarpine HCl or tolterodine tartrate. The beads were formulated
into single dose units. The coating formulations are displayed in
Tables 3 and 4 below:
TABLE-US-00003 TABLE 3 Sample A: Tolterodine Tartrate Drug
Layering: Component mg/unit % w/w Microcrystalline Cellulose Beads
25.0 79.4 Tolterodine Tartrate 2.0 6.3 HPMC 3.1 9.8 Talc 1.1 3.5
PEG 400 0.3 1.0 Total 31.5 100.0
TABLE-US-00004 TABLE 4 Sample B: Pilocarpine HCl drug layering:
Component mg/unit % w/w Microcrystalline Cellulose Beads 27.5 50.0
Pilocarpine HCl 11.0 20.0 HPMC 11.0 20.0 Talc 5.5 10.0 Total 55.0
100.0
[0072] Both coating solutions were applied to the Microcrystalline
Cellulose (MCC) Pellets using a Vector FLM-1 fluid bed with a
Wurster coating configuration. Beads were hand-filled into size 2
gelatin capsules and tested for dissolution using the procedure of
Example 2. The dissolution data of the drug layered beads are shown
in Tables 5 and 6:
TABLE-US-00005 TABLE 5 Sample A: Tolterodine Tartrate Release Data
% Dissolved at Time Point (min) Vessel # 0 5 12 20 30 45 60 V1 0 77
109 113 113 114 114 V2 0 71 100 104 106 108 108 V3 0 45 96 106 111
113 113 V4 0 43 100 109 112 113 113 V5 0 61 100 105 108 110 110 V6
0 43 92 107 111 113 113 Mean 0 56 99 107 110 111 112 SD 0 15.1 5.7
3.2 2.5 2.4 2.3 % RSD 0.00% 26.73% 5.74% 2.96% 2.29% 2.17%
2.04%
TABLE-US-00006 TABLE 6 Sample B: Pilocarpine HCl Release Data %
Dissolved at Time Point (min) Vessel # 0 10 20 30 45 60 V1 0 100
104 105 105 105 V2 0 99 106 106 106 106 V3 0 102 106 107 106 106 V4
0 101 106 106 107 107 V5 0 105 108 108 108 108 V6 0 93 109 109 109
109 Mean 0 100 107 107 107 107 SD 0 4.0 1.8 1.5 1.5 1.5 % RSD 4.0%
1.7% 1.4% 1.4% 1.4%
[0073] Both types of drug layered beads were top-coated. The
tolterodine beads were coated with a thin, immediate release HPMC
based coating system to ensure no tolterodine tartrate was lost
from erosion. The topcoat for the pilocarpine HCl beads was
developed in rounds 2-5 of development.
Example 4
Bead Formation
[0074] The development in this example focused on the use of
several types and grades of cellulosic polymers in order to form a
semi-permeable barrier that would delay release. All coatings
applied were at relatively low weight gains, no higher than 50%. It
was determined that the application of high weight gains produced
the desired delayed release profile. The formulations and release
profiles are summarized in Table 7 below:
TABLE-US-00007 TABLE 7 Formulations Reference Film Component % w/w
A HPMC 606 40 EC N10 40 Talc 20 C HPC EF 24 EC N7 56 Talc 20 D HPC
EF 32 EC N7 48 Talc 20 E HPC EF 24 EC N10 56 Talc 20 F HPC EF 87
Plasacryl 13 G EC N7 90.9 Dibutyl Sebacate 9.1 H EC N10 90.9
Dibutyl Sebacate 9.1
[0075] The dissolution data of the beads of Samples F and G,
obtained using the procedure of Example 2, are shown in Tables 8
and 9:
TABLE-US-00008 TABLE 8 Sample F Dissolution Data % Dissolved at
Time Point (min) Vessel# 0 10 20 30 45 60 75 90 120 Infinity V1 0 9
48 71 84 89 96 99 101 101 V2 0 9 50 77 92 95 96 97 97 97 Mean 0 9
49 74 88 92 96 98 99 99 SD 0 0.0 1.4 4.2 5.7 4.2 0.0 1.4 2.8 2.8 %
RSD 0.0% 2.9% 5.7% 6.4% 4.6% 0.0% 1.4% 2.9% 2.9%
TABLE-US-00009 TABLE 9 Sample G Dissolution Data % Dissolved at
Time Point (min) Vessel # 0 10 20 30 45 60 75 90 120 Infinity V1
(1%)* 0 53 73 84 92 96 99 100 102 102 V2 (1%)* 0 55 73 84 93 99 102
103 104 104 Mean 0 54 73 84 93 98 101 102 103 103 SD 0 1.4 0.0 0.0
0.7 2.1 2.1 2.1 1.4 1.4 % RSD 2.6% 0.0% 0.0% 0.8% 2.2% 2.1% 2.1%
1.4% 1.4% V3 (4%)* 0 2 8 21 42 59 71 81 92 96 V4 (4%)* 0 2 9 22 43
59 71 82 91 95 Mean 0 2 9 22 43 59 71 82 92 96 SD 0 0.0 0.7 0.7 0.7
0.0 0.0 0.7 0.7 0.7 % RSD 0.0% 8.3% 3.3% 1.7% 0.0% 0.0% 0.9% 0.8%
0.7% V5 (8%)* 0 1 4 7 14 22 32 41 57 65 V6 (8%)* 0 1 3 5 11 19 28
36 52 61 Mean 0 1 4 6 13 21 30 39 55 63 SD 0 0.0 0.7 1.4 2.1 2.1
2.8 3.5 3.5 2.8 % RSD 0.0% 20.2% 23.6% 17.0% 10.3% 9.4% 9.2% 6.5%
4.5% *The percentages refer to different film thicknesses.
Example 5
Bead Formation
[0076] In this example, swellable beads containing pilocarpine HCl
were produced. First, placebo beads were produced in order to
compare two common super-disintegrants. The criterion for
super-disintegrant selection was volume increase as the beads were
placed in 0.1 N HCl. The formulations and results are below in
Table 9:
TABLE-US-00010 TABLE 9 Placebo bead formulations Experiment
Reference Bead Component % w/w I Microcrystalline Cellulose 45
Lactose 45 Croscarmellose Sodium 10 J Microcrystalline Cellulose 45
Lactose 45 Crospovidone 10
[0077] Two swellable pilocarpine HCl bead formulations were
produced, with differing quantities of pilocarpine. These beads
were then each coated with the same ethylcellulose based coating
system and tested for dissolution. The formulations and results are
set forth below in Table 10.
TABLE-US-00011 TABLE 10 Pilocarpine HCl swellable bead formulations
Experiment Reference Component % w/w K bead Microcrystalline
Cellulose 40.6 Lactose 40.6 Croscarmellose Sodium 8.8 Pilocarpine
HCl 10.0 L bead Microcrystalline Cellulose 43.1 Lactose 43.1
Crospovidone 8.8 Pilocarpine HCl 5.0 K and L coating Ethylcellulose
N7 90.9 formulation Dibutyl Sebacate 9.1
[0078] As shown in the dissolution data in Table 11, the
formulations had the desired delayed release, obtained using the
procedure of Example 2.
TABLE-US-00012 TABLE 11 Samples K and L Dissolution Data %
Dissolved at Time Point (min) Vessel # 0 10 20 30 45 60 Infinity
K-1 (4%) 0 1 4 17 44 61 72 K-2 (8%) 0 0 0 1 3 7 12 K-3 (12%) 0 0 0
0 1 2 3 L-1 (4%) 0 1 4 12 29 42 53 L-2 (8%) 0 0 0 1 2 5 10 L-3
(12%) 0 0 0 1 1 3 4
Example 6
Bead Formation
[0079] This example focused on coating drug-layered
microcrystalline cellulose cores with cellulosic polymers to high
weight gains (up to 200%). The first coating formulation consisted
of a soluble polymer, hydroxypropylcellulose (HPC), which forms a
hydrogel that delays release. The second formulation consisted of a
1:1 ratio of HPC and ethylcellulose. The thickness of both types of
films directly correlated to the delay in release of pilocarpine
HCl. The formulations for each prototype are shown below in Table
12.
TABLE-US-00013 TABLE 12 High weight gain cellulosic coatings
Experiment Reference Film Component % w/w M, N HPC EF 45.45 EC N10
45.45 Talc 9.10 O HPC EF 87 Plasacryl 13
[0080] Beads having the following weight gains were produced: 75%,
100%, 125%, 150%, 175%, and 200%. This set of beads exhibited a
wide range of lag times, followed by immediate release. The delay
in release is controlled by the thickness of the film. The
dissolution data, obtained using the procedure of Example 2, are
shown in Tables 13 and 14.
TABLE-US-00014 TABLE 13 Samples M and N Dissolution Data %
Dissolved at Time Point (min) Sample Description 0 5 12 20 30 45 60
75 Infinity M-1 (75%) 0 0 0 12 76 94 96 98 98 M-2 (100%) 0 0 0 1 33
90 95 96 96 N-1 (125%) 0 0 0 0 2 74 98 100 100 N-2 (150%) 0 0 1 0 0
27 89 98 99 N-3 (175%) 0 0 0 0 0 6 68 96 99 N-4 (200%) 0 0 0 1 0 1
28 83 93
TABLE-US-00015 TABLE 14 Sample O Dissolution Data % Dissolved at
Time Point (min) Sample Description 0 5 12 20 30 45 60 75 Infinity
O-1 (80%) 0 0 5 25 48 67 76 80 82 O-2 (100%) 0 0 2 15 40 62 72 78
83 O-3 (120%) 0 0 0 3 23 53 70 79 86 O-4 (140%) 0 0 1 3 15 46 65 76
83 O-5 (150%) 0 0 0 2 14 48 66 76 83
Example 7
Cevimeline Bead Formation
[0081] Cevimeline beads are produced in substantially the same
manner as pilocarpine beads, as described above, except that
cevimeline is used instead of pilocarpine.
Example 8
Muscarinic Antagonist Bead Formation
[0082] Beads containing a muscarinic antagonist selected from the
group consisting of the muscarinic antagonist is selected from the
group consisting of 5-hydroxymethyl tolterodine, fesoterodine,
oxybutynin, solifenacin, darifenacin, trospium, imidafenacin,
propiverine, and dicyclomine are prepared in substantially the same
manner as tolterodine beads, as described above, except that the
specific muscarinic antagonist is used instead of tolterodine.
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