U.S. patent application number 16/015552 was filed with the patent office on 2018-10-18 for rapidly dispersible dosage form with high drug content.
This patent application is currently assigned to APRECIA PHARMACEUTICALS LLC. The applicant listed for this patent is APRECIA PHARMACEUTICALS LLC. Invention is credited to Kelly CAPUTO, Micael GUILLOT, Jules JACOB, Kenneth J. SULTZBAUGH, Thomas G. WEST.
Application Number | 20180296479 16/015552 |
Document ID | / |
Family ID | 51537567 |
Filed Date | 2018-10-18 |
United States Patent
Application |
20180296479 |
Kind Code |
A1 |
JACOB; Jules ; et
al. |
October 18, 2018 |
Rapidly Dispersible Dosage Form with High Drug Content
Abstract
A high dose orodispersible dosage form of oxcarbazepine is
provided. Drug-containing particles of oxcarbazepine are included
within a porous bound matrix. The dosage form disperses in saliva
or water in less than 15 sec and it has sufficient hardness to
withstand handling and storage. It can be used to treat diseases or
disorders that are therapeutically responsive to oxcarbazepine or a
derivative thereof.
Inventors: |
JACOB; Jules; (Yardley,
PA) ; CAPUTO; Kelly; (Langhorne, PA) ;
GUILLOT; Micael; (Lansdale, PA) ; SULTZBAUGH; Kenneth
J.; (Bridgewater, NJ) ; WEST; Thomas G.;
(Lawrenceville, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
APRECIA PHARMACEUTICALS LLC |
Blue Ash |
OH |
US |
|
|
Assignee: |
APRECIA PHARMACEUTICALS LLC
Blue Ash
OH
|
Family ID: |
51537567 |
Appl. No.: |
16/015552 |
Filed: |
June 22, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15437966 |
Feb 21, 2017 |
10028909 |
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16015552 |
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15045711 |
Feb 17, 2016 |
9616018 |
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15437966 |
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14837493 |
Aug 27, 2015 |
9314429 |
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15045711 |
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PCT/US2014/028125 |
Mar 14, 2014 |
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14837493 |
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61791726 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/1623 20130101;
A61K 9/2027 20130101; A61K 9/1611 20130101; A61K 9/7007 20130101;
A61K 9/1652 20130101; A61K 9/2009 20130101; A61K 9/2095 20130101;
A61K 9/1617 20130101; B29K 2105/0035 20130101; A61K 9/2077
20130101; A61K 9/2013 20130101; A61P 25/08 20180101; B29K 2105/251
20130101; B33Y 10/00 20141201; B33Y 70/00 20141201; A61K 9/1694
20130101; B29C 64/165 20170801; A61K 9/2054 20130101; B29K
2105/0058 20130101; B33Y 80/00 20141201; A61K 31/55 20130101; A61K
9/0056 20130101; A61K 9/2018 20130101; A61K 9/1635 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 9/20 20060101 A61K009/20; B33Y 70/00 20150101
B33Y070/00; B33Y 80/00 20150101 B33Y080/00; A61K 31/55 20060101
A61K031/55; A61K 9/70 20060101 A61K009/70; B33Y 10/00 20150101
B33Y010/00; A61K 9/16 20060101 A61K009/16; B29C 64/165 20170101
B29C064/165 |
Claims
1) A rapidly dispersible solid dosage form comprising a porous
non-compressed three-dimensionally printed bound matrix comprising:
drug-containing particles having an effective particle size and
comprising a first grade of oxcarbazepine (OXC) particles having a
first native particle size, a second grade of OXC particles having
a second native particle size, at least one disintegrant, at least
one surfactant, and at least one binder; at least one disintegrant;
and at least one binder; wherein the dosage form disperses in 15
sec or less when placed in 15 ml of aqueous fluid; and the ratio of
effective particle size to first native particle size is >1:1 to
5:1, and the ratio of effective particle size to second native
particle size is 20:1 to 50:1.
2) A rapidly dispersible three-dimensionally printed porous
non-compressed bound matrix comprising: a first grade of OXC
particles having a first native particle size, a second grade of
OXC particles having a second native particle size, at least one
sweetener, at least one binder, at least one disintegrant, at least
one surfactant, and at least one glidant; wherein the matrix
comprises particles bound by binder; the matrix disperses in less
than 15 sec in a volume of 15 ml of aqueous fluid; the OXC
particles are included in drug-containing particles having an
effective particle size and comprising the OXC particles and at
least one pharmaceutical excipient as carrier; the content of OXC
in the matrix ranges from 35-60% wt based upon the total weight of
the matrix; and the ratio of effective particle size to first
native particle size is >1:1 to 5:1, and the ratio of effective
particle size to second native particle size is 20:1 to 50:1.
3) The dosage form of claim 1, wherein: a) OXC particles possess a
bi-modal or multi-modal particle size distribution; b) the
drug-containing particles possess a mono-modal, bi-modal or
multi-modal particle size distribution; or c) a combination of one
or more of the above.
4) The dosage form of claim 1, wherein: a) the at least one
surfactant is present in an amount ranging from 0.5-7.0% wt based
upon the final weight of the dosage form; b) the at least one
sweetener is present in an amount ranging from 0.01-2.0% based upon
the final weight of the dosage form; c) the at least one binder is
present in an amount ranging from 5-15% based upon the final weight
of the dosage form; d) the at least one disintegrant is present in
an amount ranging from 10-30% based upon the final weight of the
dosage form; and/or e) the at least one glidant is present in an
amount ranging from 0-2% based upon the final weight of the dosage
form.
5) The dosage form of claim 1, wherein: a) the hardness of the
matrix ranges from about 1 to about 7 kiloponds (kp), about 1 to
about 3 kp; b) the matrix disperses in 10 sec or less when placed
in 15 ml of water or in saliva; c) binder is introduced into the
matrix by way of printing fluid used to form the matrix; d) binder
is introduced into the matrix by way of bulk powder used to form
the matrix; e) the matrix comprises about 150 mg to about 600 mg of
OXC; and/or f) the matrix comprises 10 to 40 three-dimensionally
printed incremental layers.
6) The dosage form of claim 1, wherein the drug-containing
particles further comprise sweetener and/or flavorant.
7) The dosage form of claim 1, wherein: a) the content of
drug-containing particles in the matrix generally ranges from
55-85% wt, 60-80% wt or 65-70% wt based upon the total weight of
matrix in the final dosage form; b) the content of native particles
of OXC in the drug-containing particles ranges from 55-85% wt,
60-80% wt or 65-70% wt, based upon the final weight of the
drug-containing particles; c) the content of disintegrant in the
drug-containing particles ranges from 0-30%, 1-15%, or 2-5% wt,
based upon the final weight of the drug-containing particles; d)
the content of binder in the drug-containing particles ranges from
0-10%, 1-7%, or 2-5% wt, based upon the final weight of the
drug-containing particles; e) the content of surfactant in the
drug-containing particles ranges from 0-10%, 1-5%, or 1.4-4.2% wt,
based upon the final weight of the drug-containing particles;
and/or f) the drug-containing particles are manufactured by wet
granulation.
8) The dosage form of claim 1, wherein the matrix comprises about
150 to about 1200 mg, about 150 mg, about 300 mg, about 450 mg,
about 600 mg, about 750 mg, about 900 mg, about 1050 mg or about
1200 of OXC.
9) The dosage form of claim 1, wherein the dosage form has been
prepared by a three-dimensional printing process employing printing
fluid, drug-containing particles and bulk powder of the following
compositions: TABLE-US-00013 Printing fluid Water (% wt) 80-95 or
80-90 Glycerin (% wt) 0.5-20 or 2-7 Alcohol (% wt) 0.1-20 or 1-10
Surfactant (% wt) 0.01-10 or 1-5 Sweetener (% wt) 0-10 or 1-5
Binder (% wt) 0-10
TABLE-US-00014 OXC Drug-containing particles: OXC (% wt) 55-75 or
60-70 Disintegrant (% wt) 15-45 or 30-40 Binder (% wt) 0-10 or 2-5
Surfactant (% wt) 0-10 or 1-5
TABLE-US-00015 Bulk powder: OXC containing particles (% wt) 55-65
or 55-65 Disintegrant (% wt) 2-15 or 3-12 Binder (% wt) 20-45 or
20-35 Glidant (% wt) 0.1-1.5 or 0.2-0.7.
10) The dosage form of claim 1, wherein the dosage form has the
following composition: TABLE-US-00016 Oxcarbazepine (% wt) 30-40
35-45 Disintegrant (% wt) 15-30 15-25 Binder (% wt) 30-55 30-50
Glidant (% wt) 0-5 >0-5 Glycerin (% wt) >0-20 >0-5
Surfactant (% wt) 0-5 >0-5 Sweetener (% wt) 0-5 >0-5
11) The dosage form of claim 1, wherein the dosage form is shaped
as a wafer, cylinder, ring, donut, tube, cube, spheroid, ellipsoid
or rectangular box.
12) The dosage form of claim 1, wherein: a) the binder is selected
from the group consisting of polyvinylpyrrolidone (povidone),
mannitol, hydroxypropylcellulose, and a combination thereof; b) the
disintegrant is selected from the group consisting of
microcrystalline cellulose, a combination of two grades of
microcrystalline cellulose, croscarmellose, and a combination
thereof; orb) a combination of the above.
13) A method of treating a disease, condition or disorder that is
therapeutically responsive to oxcarbazepine comprising
administering the dosage form of claim 1 one to three times daily
to a subject in need thereof throughout a treatment period.
14) The dosage form of claim 5, wherein the thickness (height) of
an incremental layer ranges from 0.006 to 0.014 inches or 0.008 to
0.012 inches.
15) A rapidly dispersible porous non-compressed three-dimensionally
printed bound matrix comprising: drug-containing particles
comprising at least one disintegrant, at least one binder, at least
one surfactant and native particles of drug, wherein the
drug-containing particles have an effective particle size and the
native particles of drug have a native particle size, and the ratio
of effective particle size to native particle size ranges from
greater than 1:1 to 200:1; at least one disintegrant; and at least
one binder; wherein the hardness of the matrix ranges from about 1
to about 7 kiloponds.
16) The matrix of claim 15, wherein the matrix disperses in 15 sec
or less when placed in 15 ml of aqueous fluid.
17) The matrix of any one of the above claims, wherein the average
native particle size is such that 90%-100% of the drug is <10
microns, and the ratio of effective particle size to native
particle size is in the range of 10:1 to 200:1.
18) The matrix of any one of the above claims, wherein the average
native particle size is such that not more than 20% of the drug is
<32 microns, 40-70% of the drug is <63 microns, 70-95% of the
drug is <125 microns, and 100% of the drug is <250 microns,
and the ratio of effective particle size to native particle size is
in the range of >1:1 to about 10:1.
19) The matrix of any one of the above claims, wherein the native
particles of drug have an average, mean or median native particle
size in the range of about 1 to about 90 microns, about 1 to about
75 microns, about 1 to about 50 microns, about 1 to about 30
microns, about 1 to about 15 microns, about 1 to about 10 microns,
about 2 to about 14 microns, about 10 to about 80 microns, about 20
to about 70 microns, about 20 to about 60 microns or about 30 to
about 50 microns.
20) The matrix of any one of the above claims, wherein the
drug-containing particles have an average, mean or median effective
particle size in the range of about 50 to about 400 microns, about
50 to about 300 microns, about 50 to about 250 microns, about 60 to
about 250 microns, about 60 to about 100 microns, or about 75 to
about 250 microns.
21) The matrix of any one of the above claims, wherein the drug is
a poorly water soluble.
22) The matrix of claim 21, wherein the drug is OXC.
23) The matrix of claim 15, comprising: drug-containing particles
comprising at least one disintegrant, at least one binder, at least
one surfactant, a first grade of native particles of drug and a
second grade of native particles of drug, wherein the
drug-containing particles have an effective particle size and the
first grade of native particles of drug have a first native
particle size and the second grade of native particles of drug have
a second native particle size, and the ratio of effective particle
size to first native particle size ranges from greater than 1:1 to
about 5:1, and the ratio of effective particle size to second
native particle size ranges from about 20:1 to about 50:1; at least
one disintegrant; and at least one binder; wherein the hardness of
the matrix ranges from about 1 to about 7 kiloponds.
24) The matrix of any one of the above claims, wherein: the
drug-containing particles further comprise at least one sweetener
and at least one glidant; the matrix comprises particles bound by
binder; the matrix disperses in less than 15 sec in a volume of 15
ml of aqueous fluid; and/or the content of drug in the matrix
ranges from 35-60% wt based upon the total weight of the
matrix.
25) The matrix of claim 24, wherein: a) the at least one surfactant
is present in an amount ranging from 0.5-7.0% wt based upon the
final weight of the dosage form; b) the at least one sweetener is
present in an amount ranging from 0.01-2.0% based upon the final
weight of the dosage form; c) the at least one binder is present in
an amount ranging from 5-15% based upon the final weight of the
dosage form; d) the at least one disintegrant is present in an
amount ranging from 10-30% based upon the final weight of the
dosage form; and/or e) the at least one glidant is present in an
amount ranging from 0-2% based upon the final weight of the dosage
form.
26) The matrix any one of the above claims, wherein: a) the native
particles of drug possess a bi-modal or multi-modal particle size
distribution; b) the drug-containing particles possess a
mono-modal, bi-modal or multi-modal particle size distribution; or
c) a combination of one or more of the above.
27) The matrix any one of the above claims, wherein: a) the
hardness ranges from about 1 to about 3 kp; b) the matrix disperses
in 10 sec or less when placed in 15 ml of water or in saliva; c)
the at least one binder is introduced into the matrix by way of
printing fluid used to form the matrix; d) the at least one binder
is introduced into the matrix by way of bulk powder used to form
the matrix; e) the matrix comprises about 150 mg to about 600 mg of
drug; and/or f) the matrix comprises 10 to 40 three-dimensionally
printed incremental layers.
28) The matrix any one of the above claims, wherein the
drug-containing particles further comprise sweetener and/or
flavorant.
29) The matrix any one of the above claims, wherein: a) the content
of drug-containing particles in the matrix generally ranges from
55-85% wt, 60-80% wt or 65-70% wt based upon the total weight of
matrix in the final dosage form; b) the content of native particles
of OXC in the drug-containing particles ranges from 55-85% wt,
60-80% wt or 65-70% wt, based upon the final weight of the
drug-containing particles; c) the content of disintegrant in the
drug-containing particles ranges from 0-30%, 1-15%, or 2-5 wt,
based upon the final weight of the drug-containing particles; d)
the content of binder in the drug-containing particles ranges from
0-10%, 1-7%, or 2-5% wt, based upon the final weight of the
drug-containing particles; e) the content of surfactant in the
drug-containing particles ranges from 0-10%, 1-5%, or 1.4-4.2% wt,
based upon the final weight of the drug-containing particles;
and/or f) the drug-containing particles are manufactured by wet
granulation.
30) The matrix any one of the above claims, wherein the matrix
comprises about 150 to about 1200 mg, about 150 mg, about 300 mg,
about 450 mg, about 600 mg, about 750 mg, about 900 mg, about 1050
mg or about 1200 of drug.
31) The matrix any one of the above claims, wherein the matrix has
been prepared by a three-dimensional printing process employing
printing fluid, drug-containing particles and bulk powder of the
following compositions: printing fluid comprising glycerin;
drug-containing particles comprising a first grade of drug native
particles, at least one first disintegrant, at least one first
binder and at least one first surfactant; and bulk powder
comprising the drug-containing particles, at least one second
disintegrant, at least one second binder and at least one
glidant.
32) The matrix of claim 31, wherein the printing fluid comprises
glycerin and alcohol or alcohol.
33) The matrix of claim 31, wherein the bulk powder comprises the
drug-containing particles, at least one second disintegrant, at
least one second binder and at least one glidant.
34) The matrix of claim 31, wherein: printing fluid comprises
water, glycerin, alcohol and surfactant; drug-containing particles
comprising a first grade of drug native particles, at least one
first disintegrant, at least one first binder and at least one
first surfactant; and bulk powder comprising the drug-containing
particles, at least one second disintegrant, at least one second
binder and at least one glidant.
35) The matrix of claim 31, wherein the matrix has been prepared by
a three-dimensional printing process employing printing fluid,
drug-containing particles and bulk powder of the following
compositions: TABLE-US-00017 Printing fluid Water (% wt) 80-95 or
80-90 Glycerin (% wt) 0.5-20 or 2-7 Alcohol (% wt) 0.1-20 or 1-10
Surfactant (% wt) 0.01-10 or 1-5 Sweetener (% wt) 0-10 or 1-5
Binder (% wt) 0-10
TABLE-US-00018 OXC Drug-containing particles: OXC (% wt) 55-75 or
60-70 Disintegrant (% wt) 15-45 or 30-40 Binder (% wt) 0-10 or 2-5
Surfactant (% wt) 0-10 or 1-5
TABLE-US-00019 Bulk powder: OXC containing particles (% wt) 55-65
or 55-65 Disintegrant (% wt) 2-15 or 3-12 Binder (% wt) 20-45 or
20-35 Glidant (% wt) 0.1-1.5 or 0.2-0.7.
36) The matrix of any one of the above claims, wherein the matrix
is shaped as a wafer, cylinder, ring, donut, tube, cube, spheroid,
ellipsoid or rectangular box.
37) The matrix of any one of the above claims, wherein: a) the
binder is selected from the group consisting of
polyvinylpyrrolidone (povidone), mannitol, hydroxypropylcellulose,
and a combination thereof; b) the disintegrant is selected from the
group consisting of microcrystalline cellulose, a combination of
two grades of microcrystalline cellulose, croscarmellose, and a
combination thereof; or b) a combination of the above.
38) A method of treating a disease, condition or disorder that is
therapeutically responsive to the drug comprising administering the
matrix of any one of the above claims one or more times daily to a
subject in need thereof throughout a treatment period.
39) The matrix of any one of the above claims, wherein the
thickness (height) of an incremental layer ranges from 0.006 to
0.014 inches or 0.008 to 0.012 inches.
40) A three-dimensionally printed bound matrix comprising:
drug-containing particles comprising at least one first binder and
native particles of drug, wherein the drug-containing particles
have an effective particle size and the native particles of drug
have a native particle size, and the ratio of effective particle
size to native particle size ranges from greater than 1:1 to
200:1.
41) The matrix of claim 40, wherein: the drug-containing particles
comprise at least one first binder, a first grade of native
particles of drug and a second grade of native particles of drug,
wherein the first grade of native particles of drug have a first
native particle size and the second grade of native particles of
drug have a second native particle size, and the first native
particle size is smaller than the second native particle size.
42) The matrix of claim 41, wherein: the drug-containing particles
comprise at least one first binder, a first grade of native
particles of drug and a second grade of native particles of drug,
wherein the drug-containing particles have an effective particle
size and the first grade of native particles of drug have a first
native particle size and the second grade of native particles of
drug have a second native particle size, and the ratio of effective
particle size to first native particle size ranges from greater
than 1:1 to about 5:1, and the ratio of effective particle size to
second native particle size ranges from about 20:1 to about 200:1
or about 20:1 to about 50:1.
43) The matrix of claim 40, 41 or 42, wherein the bound matrix
further comprises at least one second binder that binds the
drug-containing particles to form the bound matrix.
44) The matrix of claim 40-42 or 43, wherein the drug-containing
particles further comprise at least one first disintegrant.
45) The matrix of claim 40-43 or 44, wherein the bound matrix
further comprises at least second disintegrant outside the
drug-containing particles.
46) The matrix of any one of the above claims, wherein the
drug-containing particles are prepared by wet granulation.
47) A rapidly dispersible porous non-compressed three-dimensionally
printed bound matrix comprising: drug-containing particles
comprising at least one first disintegrant, at least one first
binder, at least one surfactant and native particles of drug,
wherein the drug-containing particles have an average, mean or
median effective particle size and the native particles of drug
have an average, mean or median native particle size, and the ratio
of average, mean or median effective particle size to average, mean
or median, respectively, native particle size ranges from greater
than 1:1 to 200:1; at least one second disintegrant; and at least
one second binder; wherein the hardness of the matrix ranges from
about 1 to about 7 kiloponds.
48) The matrix of claim 47, wherein the matrix disperses in 15 sec
or less when placed in 15 ml of aqueous fluid.
49) The matrix of claim 47, wherein the average native particle
size is such that 90%-100% wt of the drug is <10 microns, and
the ratio of average effective particle size to average native
particle size is in the range of 10:1 to 200:1.
50) The matrix of claim 47, wherein the average native particle
size is such that not more than 20% wt of the drug is <32
microns, 40-70% wt of the drug is <63 microns, 70-95% wt of the
drug is <125 microns, and 100% wt of the drug is <250
microns, and the ratio of average effective particle size to
average native particle size is in the range of greater than 1:1 to
about 10:1.
51) The matrix of claim 47, wherein the native particles of drug
have an average, mean or median native particle size in the range
of about 1 to about 90 microns, about 1 to about 75 microns, about
1 to about 50 microns, about 1 to about 30 microns, about 1 to
about 15 microns, about 1 to about 10 microns, about 2 to about 14
microns, about 10 to about 80 microns, about 20 to about 70
microns, about 20 to about 60 microns or about 30 to about 50
microns.
52) The matrix of claim 47, wherein the drug-containing particles
have an average, mean or median effective particle size in the
range of about 50 to about 400 microns, about 50 to about 300
microns, about 50 to about 250 microns, about 60 to about 250
microns, about 60 to about 100 microns, or about 75 to about 250
microns.
53) The matrix of claim 47, wherein the drug is a poorly water
soluble.
54) The matrix of claim 47, comprising: drug-containing particles
comprising at least one first disintegrant, at least one first
binder, at least one surfactant, a first grade of native particles
of drug and a second grade of native particles of drug, wherein the
drug-containing particles have an average, mean or median effective
particle size and the first grade of native particles of drug have
an average, mean or median first native particle size and the
second grade of native particles of drug have an average, mean or
median second native particle size, and the ratio of average, mean
or median effective particle size to average, mean or median,
respectively, first native particle size ranges from greater than
1:1 to about 5:1, and the ratio of average, mean or median
effective particle size to average, mean or median, respectively,
second native particle size ranges from about 20:1 to about 50:1;
at least one second disintegrant; and at least one second binder;
wherein the hardness of the matrix ranges from about 1 to about 7
kiloponds.
55) The matrix of claim 54, wherein: the drug-containing particles
further comprise at least one sweetener and at least one glidant;
the matrix comprises particles bound by said second binder; the
matrix disperses in less than 15 sec in a volume of 15 ml of
aqueous fluid; and/or the content of drug in the matrix is 35-60%
wt based upon the total weight of the matrix.
56) The matrix of claim 55, wherein: a) the at least one surfactant
is present in an amount of 0.5-7.0% wt based upon the final weight
of the dosage form; b) the at least one sweetener is present in an
amount of 0.01-2.0% wt based upon the final weight of the dosage
form; c) the at least one first binder and the at least one second
binder are together present in an amount of 5-15% wt based upon the
final weight of the dosage form; d) the at least one first
disintegrant and the at least one second disintegrant are together
present in an amount of 10-30% wt based upon the final weight of
the dosage form; and/or e) the at least one glidant is present in
an amount of 0-2% wt based upon the final weight of the dosage
form.
57) The matrix of claim 47, wherein: a) the native particles of
drug possess a bi-modal or multi-modal particle size distribution;
b) the drug-containing particles possess a mono-modal, bi-modal or
multi-modal particle size distribution; or c) a combination of one
or more of the above.
58) The matrix of claim 47, wherein: a) the hardness ranges from
about 1 to about 3 kp; b) the matrix disperses in 10 sec or less
when placed in 15 ml of water or in saliva; c) the matrix comprises
about 150 mg to about 600 mg of drug; and/or d) the matrix
comprises 10 to 40 three-dimensionally printed incremental
layers.
59) The matrix of claim 47, wherein: a) the content of
drug-containing particles in the matrix is 55-85% wt, 60-80% wt or
65-70% wt based upon the total weight of matrix in the final dosage
form; b) the content of native particles of drug in the
drug-containing particles is 55-85% wt, 60-80% wt or 65-70% wt,
based upon the final weight of the drug-containing particles; c)
the content of first disintegrant in the drug-containing particles
ranges up to 30%, 1-15%, or 2-5% wt, based upon the final weight of
the drug-containing particles; d) the content of first binder in
the drug-containing particles ranges up to 10%, 1-7%, or 2-5% wt,
based upon the final weight of the drug-containing particles; e)
the content of surfactant in the drug-containing particles ranges
up to 10%, 1-5%, or 1.4-4.2% wt, based upon the final weight of the
drug-containing particles; and/or f) the drug-containing particles
are manufactured by wet granulation.
60) The matrix of claim 47, wherein the matrix comprises about 150
to about 1200 mg about 150 mg, about 300 mg, about 450 mg, about
600 mg, about 750 mg, about 900 mg, about 1050 mg or about 1200 of
drug.
61) The matrix of claim 47, wherein the matrix has been prepared by
a three-dimensional printing process employing printing fluid,
drug-containing particles and bulk powder of the following
compositions: printing fluid comprising glycerin; drug-containing
particles comprising a first grade of drug native particles, the at
least one first disintegrant, the at least one first binder and at
least one first surfactant; and bulk powder comprising the
drug-containing particles, the at least one second disintegrant,
the at least one second binder and at least one glidant.
62) The matrix of claim 61, wherein the printing fluid comprises:
a) glycerin and alcohol; or b) alcohol.
63) The matrix of claim 31, wherein: the printing fluid comprises
water, glycerin, alcohol and surfactant.
64) The matrix of claim 47, wherein the matrix is shaped as a
wafer, cylinder, ring, donut, tube, cube, spheroid, ellipsoid or
rectangular box.
65) The matrix of claim 47, wherein: a) the first binder and second
binder are independently selected at each occurrence from the group
consisting of polyvinylpyrrolidone, mannitol,
hydroxypropylcellulose, and a combination thereof; b) the first
disintegrant and the second disintegrant are independently selected
at each occurrence from the group consisting of microcrystalline
cellulose, a combination of two grades of microcrystalline
cellulose, croscarmellose, and a combination thereof; or c) a
combination of the above.
66) The matrix of claim 47, wherein: a) the drug-containing
particles comprise at least two first disintegrants and at least
one binder; b) the matrix comprises at least two second binders and
at least one second disintegrant; c) a combination of any of the
above.
67) The matrix of claim 47, wherein: a) at least one first binder
is different than the at least one second binder; b) at least one
first disintegrant is different than the at least one second
disintegrant; c) at least one first binder is the same as the at
least one second binder; d) at least one first disintegrant is the
same as the at least one second disintegrant; or e) a combination
of any of the above.
68) A method of preparing a rapidly dispersible porous
three-dimensionally printed bound matrix, the method comprising:
forming drug-containing particles comprising at least one first
disintegrant, at least one first binder, at least one surfactant
and native particles of drug, wherein the drug-containing particles
have an average, mean or median effective particle size and the
native particles of drug have an average, mean or median native
particle size, and the ratio of average, mean or median effective
particle size to average, mean or median, respectively, native
particle size ranges from greater than 1:1 to 200:1; combining at
least one second disintegrant and at least one second binder with
said drug-containing particles to form a bulk powder; and
three-dimensionally printing said bulk powder to form one or more
of said three-dimensionally printed bound matrix.
69) The method of claim 68, wherein the step of forming
drug-containing particles comprises granulating the at least one
first disintegrant, at least one first binder, at least one
surfactant and native particles of drug.
70) The method of claim 68 or 69, wherein the step of
three-dimensionally printing comprises forming plural stacked
incremental layers of said bulk powder and binding particles of
said bulk powder.
71) The method of claim 70, wherein the step of binding comprises
depositing printing fluid on one or more of said incremental layers
according to one or more predetermined patterns.
72) The method of claim 71 further comprising the step of removing
or reducing the amount of printing fluid in the matrix.
73) The method of any one of claims 68-72, wherein the average
native particle size is such that not more than 20% wt of the drug
is <32 microns, 40-70% wt of the drug is <63 microns, 70-95%
wt of the drug is <125 microns, and 100% wt of the drug is
<250 microns, and the ratio of average effective particle size
to average native particle size is in the range of greater than 1:1
to about 10:1.
74) The method of any one of claims 68-72, wherein the native
particles of drug have an average, mean or median native particle
size in the range of about 1 to about 90 microns, about 1 to about
75 microns, about 1 to about 50 microns, about 1 to about 30
microns, about 1 to about 15 microns, about 1 to about 10 microns,
about 2 to about 14 microns, about 10 to about 80 microns, about 20
to about 70 microns, about 20 to about 60 microns or about 30 to
about 50 microns.
75) The method of any one of claims 68-72, wherein the
drug-containing particles have an average, mean or median effective
particle size in the range of about 50 to about 400 microns, about
50 to about 300 microns, about 50 to about 250 microns, about 60 to
about 250 microns, about 60 to about 100 microns, or about 75 to
about 250 microns.
76) The method of any one of claim 68-75, wherein: the
drug-containing particles further comprise at least one sweetener
and at least one glidant; the matrix comprises particles bound by
said second binder; the matrix disperses in less than 15 sec in a
volume of 15 ml of aqueous fluid; and/or the content of drug in the
matrix is 35-60% wt based upon the total weight of the matrix.
77) The method of claim 76, wherein: a) at least one surfactant is
present in an amount of 0.5-7.0% wt based upon the final weight of
the matrix; b) the at least one sweetener is present in an amount
of 0.01-2.0% wt based upon the final weight of the matrix; c) the
at least one first binder and the at least one second binder are
together present in an amount of 5-15% wt based upon the final
weight of the matrix; d) the at least one first disintegrant and
the at least one second disintegrant are together present in an
amount of 10-30% wt based upon the final weight of the matrix;
and/or e) the at least one glidant is present in an amount of 0-2%
wt based upon the final weight of the matrix.
78) The method of any one of claims 68-77, wherein: a) the native
particles of drug possess a bi-modal or multi-modal particle size
distribution; b) the drug-containing particles possess a
mono-modal, bi-modal or multi-modal particle size distribution; c)
the ratio of average, mean or median effective particle size to
average, mean, or median, respectively, native particle size ranges
from 2:1 to 100:1 or 3:1 to 50:1; or d) a combination of one or
more of the above.
79) The method of any one of claims 68-78 further comprising the
step of including at least one second surfactant in the bulk
powder.
80) The method of claim 68, wherein the method comprises: forming
drug-containing particles comprising at least one first
disintegrant, at least one first binder, at least one surfactant, a
first grade of native particles of drug and a second grade of
native particles of drug, wherein the drug-containing particles
have an average, mean or median effective particle size and the
first grade of native particles of drug have an average, mean or
median first native particle size and the second grade of native
particles of drug have an average, mean or median second native
particle size, and the ratio of average, mean or median effective
particle size to average, mean or median, respectively, first
native particle size ranges from greater than 1:1 to about 5:1, and
the ratio of average, mean or median effective particle size to
average, mean or median, respectively, second native particle size
ranges from about 20:1 to about 50:1; combining at least one second
disintegrant and at least one second binder with said
drug-containing particles to form a bulk powder; and
three-dimensionally printing said bulk powder to form one or more
of said three-dimensionally printed bound matrix.
81) The method of claim 80, wherein the step of forming
drug-containing particles comprises granulating the at least one
first disintegrant, at least one first binder, at least one
surfactant and native particles of drug.
82) The method of claim 80 or 81, wherein the step of
three-dimensionally printing comprises forming plural stacked
incremental layers of said bulk powder and binding particles of
said bulk powder.
83) The method of claim 82, wherein the step of binding comprises
depositing printing fluid on one or more of said incremental layers
according to one or more predetermined patterns.
84) The method of claim 83 further comprising the step of removing
or reducing the amount of printing fluid in the matrix.
85) The method of any one of claims 80-84 further comprising the
step of including at least one second surfactant in the bulk
powder.
86) A method of preparing a rapidly dispersible porous
three-dimensionally printed bound matrix, the method comprising:
forming drug-containing particles comprising at least one first
disintegrant, at least one first binder, and native particles of
drug, wherein the drug-containing particles have an average, mean
or median effective particle size and the native particles of drug
have an average, mean or median native particle size, and the ratio
of average, mean or median effective particle size to average, mean
or median, respectively, native particle size ranges from greater
than 1:1 to 200:1; combining at least one surfactant, at least one
second disintegrant and at least one second binder with said
drug-containing particles to form a bulk powder; and
three-dimensionally printing said bulk powder to form one or more
of said three-dimensionally printed bound matrix.
87) The method of claim 86, wherein the step of forming
drug-containing particles comprises granulating the at least one
first disintegrant, at least one first binder, and native particles
of drug.
88) The method of claim 86 or 87, wherein the step of
three-dimensionally printing comprises forming plural stacked
incremental layers of said bulk powder and binding particles of
said bulk powder.
89) The method of claim 88, wherein the step of binding comprises
depositing printing fluid on one or more of said incremental layers
according to one or more predetermined patterns.
90) The method of claim 89 further comprising the step of removing
or reducing the amount of printing fluid in the matrix.
91) The method of any one of claims 86-90, wherein the average
native particle size is such that not more than 20% wt of the drug
is <32 microns, 40-70% wt of the drug is <63 microns, 70-95%
wt of the drug is <125 microns, and 100% wt of the drug is
<250 microns, and the ratio of average effective particle size
to average native particle size is in the range of greater than 1:1
to about 10:1.
92) The method of any one of claims 86-90, wherein the native
particles of drug have an average, mean or median native particle
size in the range of about 1 to about 90 microns, about 1 to about
75 microns, about 1 to about 50 microns, about 1 to about 30
microns, about 1 to about 15 microns, about 1 to about 10 microns,
about 2 to about 14 microns, about 10 to about 80 microns, about 20
to about 70 microns, about 20 to about 60 microns or about 30 to
about 50 microns.
93) The method of any one of claims 86-90, wherein the
drug-containing particles have an average, mean or median effective
particle size in the range of about 50 to about 400 microns, about
50 to about 300 microns, about 50 to about 250 microns, about 60 to
about 250 microns, about 60 to about 100 microns, or about 75 to
about 250 microns.
94) The method of any one of claim 86-93, wherein: the
drug-containing particles further comprise at least one sweetener
and at least one glidant; the matrix comprises particles bound by
said second binder; the matrix disperses in less than 15 sec in a
volume of 15 ml of aqueous fluid; and/or the content of drug in the
matrix is 35-60% wt based upon the total weight of the matrix.
95) The method of claim 94, wherein: a) the at least one surfactant
is present in an amount of 0.5-7.0% wt based upon the final weight
of the matrix; b) the at least one sweetener is present in an
amount of 0.01-2.0% wt based upon the final weight of the matrix;
c) the at least one first binder and the at least one second binder
are together present in an amount of 5-15% wt based upon the final
weight of the matrix; d) the at least one first disintegrant and
the at least one second disintegrant are together present in an
amount of 10-30% wt based upon the final weight of the matrix;
and/or e) the at least one glidant is present in an amount of 0-2%
wt based upon the final weight of the matrix.
96) The method of any one of claims 86-95, wherein: a) the native
particles of drug possess a bi-modal or multi-modal particle size
distribution; b) the drug-containing particles possess a
mono-modal, bi-modal or multi-modal particle size distribution; c)
the ratio of average, mean or median effective particle size to
average, mean, or median, respectively, native particle size ranges
from 2:1 to 100:1 or 3:1 to 50:1; or d) a combination of one or
more of the above.
97) The method of claim 86, wherein the method comprises: forming
drug-containing particles comprising at least one first
disintegrant, at least one first binder, a first grade of native
particles of drug and a second grade of native particles of drug,
wherein the drug-containing particles have an average, mean or
median effective particle size and the first grade of native
particles of drug have an average, mean or median first native
particle size and the second grade of native particles of drug have
an average, mean or median second native particle size, and the
ratio of average, mean or median effective particle size to
average, mean or median, respectively, first native particle size
ranges from greater than 1:1 to about 5:1, and the ratio of
average, mean or median effective particle size to average, mean or
median, respectively, second native particle size ranges from about
20:1 to about 50:1; combining at least one surfactant, at least one
second disintegrant and at least one second binder with said
drug-containing particles to form a bulk powder; and
three-dimensionally printing said bulk powder to form one or more
of said three-dimensionally printed bound matrix.
98) The method of claim 97, wherein the step of forming
drug-containing particles comprises granulating the at least one
first disintegrant, at least one first binder, and native particles
of drug.
99) The method of claim 97 or 98, wherein the step of
three-dimensionally printing comprises forming plural stacked
incremental layers of said bulk powder and binding particles of
said bulk powder.
100) The method of claim 99, wherein the step of binding comprises
depositing printing fluid on one or more of said incremental layers
according to one or more predetermined patterns.
101) The method of claim 100 further comprising the step of
removing or reducing the amount of printing fluid in the moist
matrix.
102) The method of any one of claims 68-101, wherein the matrix has
been prepared by a three-dimensional printing process employing
printing fluid comprising alcohol, glycerin, water, at least one
surfactant or a combination thereof.
103) A method of preparing a rapidly dispersible porous
three-dimensionally printed bound matrix, the method comprising:
forming drug-containing particles comprising at least one first
disintegrant, at least one first binder, and native particles of
drug, wherein the drug-containing particles have an average, mean
or median effective particle size and the native particles of drug
have an average, mean or median native particle size, and the ratio
of average, mean or median effective particle size to average, mean
or median, respectively, native particle size ranges from greater
than 1:1 to 200:1; combining at least one second disintegrant and
at least one second binder with said drug-containing particles to
form a bulk powder; and depositing a printing fluid to said bulk
powder to form one or more of said three-dimensionally printed
bound matrix, wherein the printing fluid comprises at least one
surfactant.
104) The method of claim 103, wherein the step of forming
drug-containing particles comprises granulating the at least one
first disintegrant, at least one first binder, and native particles
of drug.
105) The method of claim 103 or 104, wherein the step of depositing
comprises depositing a printing fluid to said bulk powder to bind
particles of said bulk powder thereby forming plural stacked
incremental layers of said bulk powder which together form one or
more of said three-dimensionally printed bound matrix, wherein the
printing fluid comprises at least one surfactant.
106) The method of any one of claims 103-105, wherein the
depositing of printing fluid to said bulk powder is done according
to one or more predetermined patterns.
107) The method of any one of claims 103-106 further comprising the
step of removing or reducing the amount of printing fluid in the
matrix.
108) The method of any one of claims 103-107, wherein the average
native particle size is such that not more than 20% wt of the drug
is <32 microns, 40-70% wt of the drug is <63 microns, 70-95%
wt of the drug is <125 microns, and 100% wt of the drug is
<250 microns, and the ratio of average effective particle size
to average native particle size is in the range of greater than 1:1
to about 10:1.
109) The method of any one of claims 103-107, wherein the native
particles of drug have an average, mean or median native particle
size in the range of about 1 to about 90 microns, about 1 to about
75 microns, about 1 to about 50 microns, about 1 to about 30
microns, about 1 to about 15 microns, about 1 to about 10 microns,
about 2 to about 14 microns, about 10 to about 80 microns, about 20
to about 70 microns, about 20 to about 60 microns or about 30 to
about 50 microns.
110) The method of any one of claims 103-107, wherein the
drug-containing particles have an average, mean or median effective
particle size in the range of about 50 to about 400 microns, about
50 to about 300 microns, about 50 to about 250 microns, about 60 to
about 250 microns, about 60 to about 100 microns, or about 75 to
about 250 microns.
111) The method of any one of claims 103-110, wherein: the
drug-containing particles further comprise at least one sweetener
and at least one glidant; the matrix comprises particles bound by
said second binder; the matrix disperses in less than 15 sec in a
volume of 15 ml of aqueous fluid; and/or the content of drug in the
matrix is 35-60% wt based upon the total weight of the matrix.
112) The method of claim 111, wherein: a) the at least one
surfactant is present in an amount of 0.5-7.0% wt based upon the
final weight of the matrix; b) the at least one sweetener is
present in an amount of 0.01-2.0% wt based upon the final weight of
the matrix; c) the at least one first binder and the at least one
second binder are together present in an amount of 5-15% wt based
upon the final weight of the matrix; d) the at least one first
disintegrant and the at least one second disintegrant are together
present in an amount of 10-30% wt based upon the final weight of
the matrix; and/or e) the at least one glidant is present in an
amount of 0-2% wt based upon the final weight of the matrix.
113) The method of any one of claims 103-112, wherein: a) the
native particles of drug possess a bi-modal or multi-modal particle
size distribution; b) the drug-containing particles possess a
mono-modal, bi-modal or multi-modal particle size distribution; c)
the ratio of average, mean or median effective particle size to
average, mean, or median, respectively, native particle size ranges
from 2:1 to 100:1 or 3:1 to 50:1; or d) a combination of one or
more of the above.
114) The method of any one of claims 103-113 further comprising the
step of including at least one second surfactant in the bulk
powder.
115) The method of claim 103, wherein the method comprises: forming
drug-containing particles comprising at least one first
disintegrant, at least one first binder, a first grade of native
particles of drug and a second grade of native particles of drug,
wherein the drug-containing particles have an average, mean or
median effective particle size and the first grade of native
particles of drug have an average, mean or median first native
particle size and the second grade of native particles of drug have
an average, mean or median second native particle size, and the
ratio of average, mean or median effective particle size to
average, mean or median, respectively, first native particle size
ranges from greater than 1:1 to about 5:1, and the ratio of
average, mean or median effective particle size to average, mean or
median, respectively, second native particle size ranges from about
20:1 to about 50:1; combining at least one second disintegrant and
at least one second binder with said drug-containing particles to
form a bulk powder; and depositing a printing fluid to said bulk
powder to form one or more of said three-dimensionally printed
bound matrix, wherein the printing fluid comprises at least one
surfactant.
116) The method of claim 115, wherein the step of forming
drug-containing particles comprises granulating the at least one
first disintegrant, at least one first binder, and native particles
of drug.
117) The method of claim 115 or 116, wherein the step of depositing
comprises depositing a printing fluid to said bulk powder to bind
particles of said bulk powder thereby forming plural stacked
incremental layers of said bulk powder which together form one or
more of said three-dimensionally printed bound matrix, wherein the
printing fluid comprises at least one surfactant.
118) The method of any one of claims 115-117, wherein the
depositing of printing fluid to said bulk powder is done according
to one or more predetermined patterns.
119) The method of any one of claims 115-118 further comprising the
step of removing or reducing the amount of printing fluid in the
matrix.
120) The method of any one of claims 115-119 further comprising the
step of including at least one second surfactant in the bulk
powder.
121) The method of any one of claims 103-120, wherein the printing
fluid further comprises alcohol, glycerin, water, or a combination
thereof.
122) The method of any one of claims 68-121, wherein: a) the
hardness of the matrix ranges from about 1 to about 3 kp or about 1
to about 7 kp; b) the matrix disperses in 15 sec or less or 10 sec
or less when placed in 15 ml of water or in saliva; c) the matrix
comprises about 150 mg to about 600 mg of drug; and/or d) the
matrix comprises 10 to 40 three-dimensionally printed incremental
layers.
123) The method of any one of claims 68-122, wherein: a) the
content of drug-containing particles in the matrix is 55-85% wt,
60-80% wt or 65-70% wt based upon the total weight of matrix in the
final dosage form; b) the content of native particles of drug in
the drug-containing particles is 55-85% wt, 60-80% wt or 65-70% wt,
based upon the final weight of the drug-containing particles; c)
the content of first disintegrant in the drug-containing particles
ranges up to 30%, 1-15%, or 2-5% wt, based upon the final weight of
the drug-containing particles; d) the content of first binder in
the drug-containing particles ranges up to 10%, 1-7%, or 2-5% wt,
based upon the final weight of the drug-containing particles; e)
the content of surfactant in the bulk powder ranges up to 10%,
1-5%, or 1.4-4.2% wt, based upon the final weight of the bulk
powder; and/or f) the drug-containing particles are manufactured by
wet granulation.
124) The method of any one of claims 68-123, wherein the matrix
comprises about 150 to about 1200 mg, about 150 mg, about 300 mg,
about 450 mg, about 600 mg, about 750 mg, about 900 mg, about 1050
mg or about 1200 of drug.
125) The method of any one of claims 68-124, wherein: a) the first
binder and second binder are independently selected at each
occurrence from the group consisting of polyvinylpyrrolidone,
mannitol, hydroxypropylcellulose, and a combination thereof; b) the
first disintegrant and the second disintegrant are independently
selected at each occurrence from the group consisting of
microcrystalline cellulose, a combination of two grades of
microcrystalline cellulose, croscarmellose, and a combination
thereof; or c) a combination of the above.
126) The method of any one of claims 68-125, wherein: a) the
drug-containing particles comprise at least two first disintegrants
and at least one binder; b) the matrix comprises at least two
second binders and at least one second disintegrant; or c) a
combination of any of the above.
127) The method of any one of claims 68-126, wherein: a) at least
one first binder is different than the at least one second binder;
b) at least one first disintegrant is different than the at least
one second disintegrant; c) at least one first binder is the same
as the at least one second binder; d) at least one first
disintegrant is the same as the at least one second disintegrant;
or e) a combination of any of the above.
128) A rapidly dispersible porous non-compressed
three-dimensionally printed bound matrix comprising: 55-85 wt % of
drug-containing particles comprising at least one first
disintegrant, at least one first binder, and native particles of
drug; up to 10 wt % of surfactant based upon the final weight of
the matrix, wherein the surfactant is included in the
drug-containing particles, included in material excluding the
drug-containing particles, or include in both; 3-20 wt % of at
least one second disintegrant; 10 wt % to 45 wt % at least one
second binder; wherein: the hardness of the matrix ranges from
about 1 to about 7 kiloponds; the matrix comprises about 150 mg to
about 1200 mg of drug; and the weight percentages are based upon
the final weight of the matrix, thereby providing the rapidly
dispersible porous non-compressed three-dimensionally printed bound
matrix.
129) The matrix of claim 128, wherein the surfactant is present in
the material excluding the drug-containing the particles.
130) The matrix of claim 128 or 129, wherein the surfactant is
present in the drug-containing particles.
131) The matrix of any one of claim 128, 129, or 130, wherein the
drug-containing particles comprise 55 wt % to 85 wt % of drug based
upon the final weight of the drug-containing particles.
132) The matrix of any one of claim 128-130 or 131, wherein the
drug-containing particles comprise 15-35 wt % of disintegrant based
upon the final weight of the drug-containing particles.
133) The matrix of any one of claim 128-130 or 131, wherein the
drug-containing particles comprise up to 30 wt % of disintegrant
based upon the final weight of the drug-containing particles.
134) The matrix of any one of claim 128-132, or 133, wherein the
drug-containing particles comprise up to about 10 wt % of binder
based upon the final weight of the drug-containing particles.
135) The matrix of any one of claim 128-133, or 134, wherein the
drug-containing particles comprise up to about 10 wt % of
surfactant based upon the final weight of the drug-containing
particles.
136) The matrix of any one of claim 128-134, or 135, wherein the
content of drug in the matrix ranges from 35-60 wt % based upon the
final weight of the matrix.
137) The matrix of any one of claim 128-135, or 136, wherein the
content of binder in the matrix ranges from 5-15 wt % based upon
the final weight of the matrix.
138) The matrix of any one of claim 128-136, or 137, wherein the
content of disintegrant in the matrix ranges from 10-30 wt % based
upon the final weight of the matrix.
139) The matrix of any one of claim 128-137, or 138, wherein the
matrix comprises 0.5-7.0 wt % of surfactant based upon the final
weight of the matrix.
140) The matrix of any one of claim 128-138, or 139, wherein the
matrix comprises not more than 10 wt % of moisture based upon the
final weight of the matrix.
141) The matrix of claim 140, wherein the matrix comprises at least
0.1 wt % moisture based upon the final weight of the matrix.
142) The matrix of any one of claim 128-140, or 141, wherein the
matrix further comprises one or more of the following: a) at least
one glidant present in an amount of up to 2 wt % based upon the
final weight of the matrix; b) at least one sweetener present in an
amount in the of range 0.01-2.0 wt % based upon the final weight of
the matrix; c) flavorant present in an amount of up to 10 wt %
based upon the final weight of the matrix; d) glycerin present in
an amount of up to 2 wt % based upon the final weight of the
matrix; or e) a combination of two or more thereof.
143) The matrix of any one of claim 128-141, or 142, wherein: a)
the native particles of drug possess a bi-modal or multi-modal
particle size distribution; b) the drug-containing particles
possess a mono-modal, bi-modal or multi-modal particle size
distribution; or c) a combination of one or more of the above
144) The matrix of any one of claim 128-142, or 143, wherein the
drug-containing particles have an average, mean or median effective
particle size in the range of about 50 to about 400 microns.
145) The matrix of claim 144, wherein the native particles of drug
have an average, mean or median native particle size in the range
of about 1 to about 90 microns, or have a particle size
distribution characterized by a Dv90 of less than about 100
microns, have a Dv50 of less than about 75 microns, and a Dv10 of
less than about 30 microns.
146) The matrix of claim 145, wherein the drug-containing particles
have a ratio of effective particle size to native particle size of
up to about 200:1.
147) The matrix of claim 145, wherein the drug-containing particles
comprise a first population of particles having a ratio of
effective particle size to native particle size of greater than 1:1
up to about 5:1 and a second population of particles having a ratio
of effective particle size to native particle size of about 20:1 to
about 50:1.
148) The matrix of claim 144, wherein the native particles of drug
have an average native particle size is such that not more than 20
wt % of the drug is <32 microns, 40-70 wt % of the drug is
<63 microns, 70-95 wt % of the drug is <125 microns, and 100
wt % of the drug is <250 microns, and the ratio of average
effective particle size to average native particle size is in the
range of greater than 1:1 to about 10:1.
149) The matrix of any one of claim 128-147, or 148, wherein the
porosity of the matrix ranges from about 10% to about 90% of the
matrix volume.
150) The matrix of any one of claim 128-148, or 149, wherein the
bulk density of the matrix ranges from 150 mg/mL to about 1300
mg/mL.
151) The matrix of any one of claim 128-149, or 150, wherein the
matrix comprises the following types of incremental layers grouped
into respective sections of the dosage form: a) a first end
comprising plural layers of first solid print pattern; a middle
portion comprising plural layers of annular print pattern and
plural layers of combination annular and grayscale print pattern;
and a second end comprising plural layers of indicum print pattern;
b) a first end comprising plural layers of first solid print
pattern; a middle portion comprising plural layers of combination
annular and grayscale print pattern; and a second end comprising
plural layers of first solid print pattern and/or plural layers of
indicum print pattern; c) a first end comprising plural layers of
first solid print pattern; a middle portion comprising plural
layers of annular print pattern, plural layers of combination
annular and grayscale print pattern; and a second end comprising
plural layers of first solid print pattern and/or plural layers of
indicum print pattern; or d) a first end comprising plural layers
of first solid print pattern; a middle portion comprising
alternating groups of layers, wherein one group comprises plural
layers of annular print pattern, and another group comprises plural
layers of combination annular and grayscale print pattern; and a
second end comprising plural layers of first solid print pattern
and/or plural layers of indicum print pattern.
152) The matrix of claim 151, wherein the thickness the incremental
layers ranges from 0.005-0.015 inches or from 100-400 .mu.m.
153) A rapidly dispersible three-dimensionally printed porous
non-compressed bound matrix comprising: 55-65 wt % of
drug-containing particles; 2-15 wt % of disintegrant; and 20-45 wt
% of binder; wherein: the drug-containing particles comprise: 55-75
wt % of drug; 15-45 wt % of disintegrant; up to 10 wt % of binder;
and up to 10 wt % of surfactant.
154) A rapidly dispersible three-dimensionally printed porous
non-compressed bound matrix comprising: 55-85 wt % of
drug-containing particles; 2-15 wt % of disintegrant; and 20-45 wt
% of binder; wherein: the drug-containing particles comprise: 55-85
wt % of drug; up to 30 wt % of disintegrant; up to 10 wt % of
binder; and up to 10 wt % of surfactant.
155) A rapidly dispersible three-dimensionally printed porous
non-compressed bound matrix comprising drug, binder, disintegrant,
and surfactant, wherein: the matrix comprises particles bound by
binder; the matrix disperses in less than 15 sec in a volume of 15
ml of aqueous fluid; the drug is included in drug-containing
particles comprising up to 30 wt % of disintegrant based upon the
weight of the drug-containing particles, up to 10 wt % of binder
based upon the weight of the drug-containing particles, and 55-85
wt % of native particles of the drug based upon the weight of the
drug-containing particles; the content of drug-containing particles
in the matrix ranges from 55-85 wt % based upon the final weight of
the matrix; the content of drug in the matrix ranges from 35-60 wt
% based upon the final weight of the matrix; the content of binder
ranges from 5-15 wt % based upon the final weight of the matrix;
the content of disintegrant ranges from 10-30 wt % based upon the
final weight of the matrix; and the content of surfactant ranges
from 0.5-7.0 wt % based upon the final weight of the matrix,
wherein the surfactant is included in the drug-containing
particles, in material excluding the drug-containing particles, or
in both.
156) A method of treating a disease, condition or disorder that is
therapeutically responsive to the comprising administering the
matrix of any one of claim 128-154, or 155 one to three times daily
to a subject in need thereof throughout a treatment period.
Description
CROSS-REFERENCE TO EARLIER FILED APPLICATIONS
[0001] The present application claims the benefit of and is a
continuation of Ser. No. 15/437,966 filed Feb. 21, 2017, which is a
continuation of Ser. No. 15/045,711 filed Feb. 17, 2016, now U.S.
Pat. No. 9,616,018 issued Apr. 11, 2017, which is a continuation of
Ser. No. 14/837,493 filed Aug. 27, 2015, now U.S. Pat. No.
9,314,429 issued Apr. 19, 2016, which is a continuation of
PCT/US2014/028125 filed Mar. 14, 2014, which claims the benefit of
provisional application 61/791,726 filed Mar. 15, 2013, the entire
disclosures of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention concerns a rapidly dispersing
(orodispersible) solid oral dosage form of oxcarbazepine. In
particular, the dosage form disperses within a period of less than
about ten seconds when placed in the mouth of a subject. The
invention also relates to methods of use of the dosage form for the
treatment of diseases, disorders or conditions that are
therapeutically responsive to oxcarbazepine or a derivative
thereof. A process for preparing the dosage form is also
provided.
BACKGROUND OF THE INVENTION
[0003] Solid oral dosage forms containing oxcarbazepine (OXC;
10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide; disclosed
in U.S. 2004-0044200A1, U.S. Pat. No. 3,642,775 and U.S. Pat. No.
3,716,640) are known (FDA Electronic Orange Book). OXC is
susceptible to hydrolysis under basic/alkaline conditions.
Oxcarbazepine is a prodrug that is quickly reduced to a
10-monohydroxy metabolite derivative (MHD) which is the active
metabolite.
[0004] OXC is an antiepileptic indicated for use as monotherapy or
adjunctive therapy in the treatment of partial seizures in adults
and as monotherapy in the treatment of partial seizures in children
aged 4 years and above with epilepsy, and as adjunctive therapy in
children aged 2 years and above with epilepsy.
[0005] OXC is hydrophobic and poorly water soluble and must be
present in very small particles sizes when administered as a solid
oral dosage form in order to provide sufficient absorption of drug.
U.S. Pat. No. 7,037,525 specifies oxcarbazepine having a particle
size such that the maximum residue on a 40 micron sieve is less
than or equal to 5% and the median particle size is approximately 2
to 12 microns, or 4 to 10 microns or 6 to 8 microns. EP 2,010,499
A1 discloses oxcarbazepine having a particle size distribution with
a D[v,0.5] value of between about 15 microns to about 30 microns
and a D[v,0.9] value of less than or equal to 90 microns. U.S. Pat.
No. 8,119,148 discloses OXC wherein the quantity of particles
larger than 40 micrometers (.mu.m) is limited to a maximum of 5% by
weight and the median particle size by Fraunhofer diffraction is
specified to be within 4-10 .mu.m. EP 2,077,822 discloses OXC with
a median particle size of 4-10 .mu.m. PCT Publication WO
2007-007182 discloses OXC with a median particle size in the range
of 15 to 30 .mu.m and wherein the composition contains no wetting
agent. PCT Publication WO 2006-046105 discloses OXC with a median
particle size in the range of 15 to 30 .mu.m and wherein the
composition contains no wetting agent. PCT Publication WO
2002-094774 discloses OXC with a median particle size of about 20
.mu.m to about 50 .mu.m with a maximum residue of about 10% on a 45
.mu.m to up to 100 .mu.m sieve and wherein a wetting agent is
present. Indian Application No. 1186/MUM/2004 discloses a
pharmaceutical composition containing oxcarbazepine particles and
meglumine, which aids in dissolution of the drug, wherein the
oxcarbazepine has a particle size of not less than 50 .mu.m or
about 80 to 140 .mu.m. EP 2,146,699 A1 discloses dosage forms
containing oxcarbazepine having a median particle size of about 2
.mu.m or less.
[0006] OXC is dosed orally according to a twice daily regimen (BID)
at doses of 300 to 2400 mg per day for the treatment of epilepsy.
When a unit dose includes 150 to 1200 mg of OXC, young and elderly
patients typically experience difficulty in swallowing solid oral
dosage forms containing such high doses, especially because of the
large amount of excipients included in known dosage forms.
Difficulty in swallowing leads to poor patient compliance. Attempts
to resolve this problem have led to the development of oral liquid
formulations. Stability, contamination and inaccurate dosing
problems, however, are still associated with such dosage forms.
[0007] Given the high doses of OXC required per tablet, it is
difficult to formulate rapidly dispersible solid oral dosage forms
with sufficient hardness and friability suitable for storage and
handling while at the same time providing a dosage form that is
small enough for easy swallowing.
[0008] Orodispersible dosage forms disperse or disintegrate in the
mouth in a minimal amount of saliva or water. Such dosage forms
provide ease of swallowing, accuracy of dosing, and rapid
therapeutic action. U.S. Pat. No. 7,749,533 to Fu et al. discloses
a dosage form containing granules containing a drug, porous plastic
substance, water penetration enhancer, binder and drug. The
granules must be compressed in order to create the dosage form.
U.S. Pat. No. 4,371,516 to Gregory et al. and U.S. Pat. No.
5,738,875 disclose freeze-dried dosage forms. U.S. Pat. No.
5,178,878 to Wehling et al. discloses a soft-compress
orodispersible dosage form. Effervescent dosage forms and quick
release coatings of insoluble microparticles are described in U.S.
Pat. Nos. 5,578,322 and 5,607,697. Freeze dried foams and liquids
are described in U.S. Pat. No. 4,642,903 and U.S. Pat. No.
5,631,023. Melt-spun dosage forms are described in U.S. Pat. Nos.
4,855,326, 5,380,473 and 5,518,730. U.S. 20070218129 discloses an
immediate release dispersible and orodispersible solid
pharmaceutical composition having the form of particles with a size
lower than 710 .mu.m upon dispersion into water, wherein the
formulation is made by wet granulation; however, the disintegration
times range from 53 to 60 sec.
[0009] U.S. Pat. No. 6,471,992, U.S. 2012-0207929 and U.S.
2003-0133975 disclose three-dimensionally printed rapidly
dispersing dosage forms. Even so, an orodispersible
three-dimensionally printed dosage form containing OXC has not been
suggested. It is not possible to predict a priori whether a
three-dimensionally printed dosage form containing substantial
amounts of OXC can be made to disperse in a minimal amount of
aqueous fluid in 10 sec or less or 5 sec or less while at the same
time possessing sufficient hardness to endure handling and
storage.
[0010] Very few orodispersible dosage forms containing OXC have
been disclosed or suggested. U.S. Pat. No. 8,127,516 and U.S.
20120110957 to Lee suggest a film-coated tablet or film-coated
powder fill. U.S. Pat. No. 8,012,505 and U.S. 20040228919 to
Houghton suggest a freeze-dried non-compressed fast-dispersing
solid dosage form. U.S. Pat. No. 6,709,669 and U.S. Pat. No.
6,509,040 to Murray and U.S. 20040076666 to Green suggest a
freeze-dried non-compressed fast-dispersing solid dosage form
having fish gelatin as carrier. U.S. 20080312168 to Pilgaonkar
discloses a dispersible compressed tablet that disperses in water
in three minutes. The tablet contains oxcarbazepine, Copovidone
(Kollidon VA 64), microcrystalline cellulose (Avicel PH 102),
Sodium starch glycolate (Primojel), Crospovidone (Kollidon CL),
Hydroxypropylmethylcellulose (Methocel K100 LV),
Hydroxyethylcellulose (Natrosol HHX), Aerosil, Talc and magnesium
stearate.
[0011] It would be beneficial to provide a rapidly-dispersing solid
oral dosage form containing a high concentration of OXC and
exhibiting low friability and sufficient hardness to withstand
storage and handling while at the same time exhibiting an extremely
rapid disintegration rate and acceptable taste; however, no such
suitable dosage form has been suggested in the art. In particular,
no such three-dimensionally printed dosage form has been
suggested.
SUMMARY OF THE INVENTION
[0012] The present invention seeks to overcome some or all of the
disadvantages inherent in the art. The present invention provides
an orodispersible solid dosage form, as described herein,
comprising oxcarbazepine as the primary or sole active ingredient,
wherein the dosage form comprises a bound matrix that disperses in
about 15 sec or less in a volume of about 10 ml or less of water or
saliva. The matrix disperses in the mouth of a subject to which it
is administered, thereby facilitating swallowing and
administration.
[0013] The inventors have discovered it is very difficult to
produce three-dimensionally printed rapidly-dispersing dosage forms
containing a high weight percentage or high amount of small
particle size OXC and exhibiting adequate hardness, acceptable
surface texture and extremely rapid dispersion/disintegration.
Dosage forms made from bulk powder comprising high amounts
(percentages) of small native particles of OXC perform poorly;
however, OXC must still be included in the dosage form in very
small particle size form (as discussed above) in order to ensure
adequate absorption in a subject to which it is administered.
[0014] In order to resolve this problem, the inventors have
discovered that the "effective particle size" of OXC in the bulk
powder must be increased without increasing the "actual particle
size" of the drug. Doing so permits administration of OXC with an
actual particle size suitable for absorption and an effective
particle size suitable for use in the bulk powder of a 3DP
orodispersible dosage form. The "effective particle size" is
increased by including small "native particles" of OXC in
"drug-containing particles" in the bulk powder, such that the
drug-containing particles are larger in size than the native
particles of OXC.
[0015] In some aspects, the invention provides a rapidly
dispersible, i.e. orodispersible, dosage form and administration
thereof for the treatment of diseases, conditions or disorders that
are therapeutically responsive to oxcarbazepine. The rapidly
dispersible solid dosage form comprises a porous
three-dimensionally printed bound orodispersible matrix comprising
drug-containing particles of OXC and bulk material comprising at
least one disintegrant, at least one surfactant, and at least one
binder. The bulk material may further comprise at least one
glidant, at least one sweetener and/or at least one flavorant.
[0016] The matrix is formed by deposition of a printing fluid to a
powder, whereby the particles of the powder become bound by binder.
The matrix is porous with a defined overall bulk density,
disintegration (dispersion) time in aqueous fluid, dissolution time
in aqueous fluid, and moisture content. The matrix provides a
balance of sufficient hardness, low friability and extremely rapid
dispersion time in a small volume of aqueous liquid.
[0017] In some embodiments, OXC is present in crystalline form. All
polymorphs thereof are contemplated. The crystallinity of OXC or
any other material can be determined by differential scanning
calorimetry (DSC) to determine the presence of amorphous material.
In some embodiments, OXC is present in amorphous form in the bulk
powder or in the matrix.
[0018] The invention also provides an orodispersible dosage form
comprising a three-dimensionally printed matrix comprising bound
sweetener, binder, disintegrant, surfactant, and drug-containing
particles of OXC, wherein the binder binds the matrix. The matrix
is generally not bound by OXC itself. The printing fluid does not
dissolve any substantial amount of OXC during a three-dimensional
printing process.
[0019] One aspect of the invention provides an orodispersible
three-dimensionally printed matrix comprising: OXC, at least one
sweetener, at least one binder, at least one disintegrant, at least
one surfactant, and at least one glidant; wherein the matrix
comprises particles bound by binder; the matrix is porous and
non-compressed; the matrix disperses in less than 15 sec in a
volume of 15 ml of aqueous fluid; OXC is included in
drug-containing particles comprising small particles of OXC and at
least one pharmaceutical excipient as carrier; and the content of
OXC in the matrix ranges from 35-60 wt based upon the total weight
of the matrix.
[0020] Some embodiments of the invention include those wherein: a)
the at least one surfactant is present in an amount ranging from
0.5-7.0% wt based upon the final weight of the dosage form; b) the
at least one sweetener is present in an amount range from 0.01-2.0%
based upon the final weight of the dosage form; c) the at least one
binder is present in an amount range from 5-15% based upon the
final weight of the dosage form; d) the at least one disintegrant
is present in an amount range from 10-30% based upon the final
weight of the dosage form; and/or e) the at least one glidant is
present in an amount range from 0-2% based upon the final weight of
the dosage form.
[0021] Some embodiments of the invention include those wherein: a)
the hardness of the matrix ranges from about 1 to about 7 kiloponds
(kp), about 1 to about 3 kp; b) the matrix disperses in 10 sec or
less when placed in 15 ml of water or in saliva; c) binder is
introduced into the matrix by way of printing fluid used to form
the matrix; d) binder is introduced into the matrix by way of bulk
powder used to form the matrix; e) the matrix comprises about 150
mg to about 600 mg of OXC; f) the matrix comprises 10 to 40 printed
incremental layers; g) the thickness (height) of an incremental
layer ranges from 0.006 to 0.014 inches or 0.008 to 0.012 inches;
h) the matrix is porous and non-compressed.
[0022] The drug-containing particles comprise OXC and at least one,
at least two, at least three, at least four, or at least five
pharmaceutical excipients. In some embodiments, the drug-containing
particles comprise OXC, at least one binder, at least one
surfactant, and at least one disintegrant. The drug-containing
particles may further comprise sweetener and/or flavorant. In some
embodiments, the drug-containing particles comprise OXC, at least
two binders, at least one surfactant, and at least one
disintegrant.
[0023] Some embodiments of the invention include those wherein: a)
content of drug-containing particles in the matrix generally ranges
from 55-85% wt, 60-80% wt or 65-70% wt based upon the total weight
of matrix in the final dosage form; b) the drug-containing
particles comprise disintegrant, binder, surfactant and native
particles of OXC; c) the content of native particles of OXC in the
drug-containing particles ranges from 55-85% wt, 60-80% wt or
65-70% wt, based upon the final weight of the drug-containing
particles; d) the content of disintegrant in the drug-containing
particles ranges from 0-30%, 1-15%, or 2-5% wt, based upon the
final weight of the drug-containing particles; e) the content of
binder in the drug-containing particles ranges from 0-10%, 1-7%, or
2-5% wt, based upon the final weight of the drug-containing
particles; f) the content of surfactant in the drug-containing
particles ranges from 0-10%, 1-5%, or 1.4-4.2% wt, based upon the
final weight of the drug-containing particles; g) the
drug-containing particles are manufactured by wet granulation.
[0024] The drug-containing particles have an average, mean or
median particle size in the range of about 50 to about 400 microns,
about 50 to about 300 microns, about 50 to about 250 microns, about
60 to about 250 microns, about 60 to about 100 microns, or about 75
to about 250 microns.
[0025] In some embodiments, OXC native particles have an average,
mean or median particle size in the range of about 1 to about 90
microns, about 1 to about 75 microns, about 1 to about 50 microns,
about 1 to about 30 microns, about 1 to about 15 microns, about 1
to about 10 microns, about 2 to about 14 microns, about 10 to about
80 microns, about 20 to about 70 microns, about 20 to about 60
microns or about 30 to about 50 microns. In some embodiments, OXC
natives particles have a particle size distribution with a Dv90 of
less than about 100 microns, a Dv90 of less than about 90 microns,
a Dv90 of less than about 75 microns, a Dv90 of less than about 50
microns, and/or have a Dv50 of less than about 75 microns, a Dv50
of less than about 50 microns, a Dv50 of less than about 40
microns, a Dv50 of less than about 30 microns, a Dv50 of less than
about 20 microns, a Dv50 of less than about 10 microns, a Dv50 of
less than about 5 microns, a Dv50 of about 1 to about 40 microns, a
Dv50 of about 1 to about 30 microns, a Dv50 of about 1 to about 20
microns, a Dv50 of about 5 to about 15 microns and/or have a Dv10
of less than about 30 microns, a Dv10 of less than about 20
microns, a Dv10 of less than about 10 microns, a Dv10 of less than
about 5 microns, a Dv10 of less than about 1 microns. All
combinations of these Dv10, Dv50 and Dv90 values and ranges are
contemplated. The native particle size distribution and/or
effective particle size distribution can be mono-modal, bi-modal or
multi-modal. OXC can be present as a mixture of two or more
different native drug powders each having its own native particle
size distribution and/or method of preparation. The drug-containing
particles can be present as a mixture of two or more different
powders each having its own effective particle size distribution
and/or method of preparation. In some embodiments, the OXC
comprises a milled first form and a micronized second form. The
amount of first form can range from 0-25% wt, 10-15% wt or 13-15%
wt, and the amount of second form can range 100-75% wt, 90-85% wt,
or 97-85% wt, respectively.
[0026] Some embodiments of the invention include those wherein the
matrix comprises about 150 to about 1200 mg, about 150 mg, about
300 mg, about 450 mg, about 600 mg, about 750 mg, about 900 mg,
about 1050 mg or about 1200 of OXC.
[0027] The matrix rapidly disperses (disintegrates) in a small
amount of aqueous fluid. Some embodiments of the invention include
those wherein the matrix disperses in about 30 sec or less, about
20 sec or less, about 15 sec or less, about 10 sec or less, or
about 5 sec or less when placed in a small amount of aqueous fluid.
In some embodiments, the disintegration time is determined
according to USP <701>.
[0028] A method of treating a disease or disorder that is
therapeutically responsive to OXC is provided. The method comprises
daily administration of one, two or three dosage forms of the
invention to a subject in need thereof over a treatment period
lasting days, weeks or months thereby reducing or eliminating one
or more symptoms of the disease or disorder. In some embodiments, a
3DP dosage form comprising a dose of about 150 to about 1200 mg, or
about 150 to about 600 mg is administered twice daily for a
treatment period.
[0029] A method of preparing an orodispersible dosage form is also
provided. The method comprises forming a non-compressed porous
matrix as described herein by forming incremental layers of powders
and depositing printing fluid on each incremental layer to bind
disintegrant, binder, surfactant, glidant, sweetener and
drug-containing particles of OXC into a rapidly orodispersible
non-compressed porous matrix.
[0030] The invention includes all combinations of the aspects,
embodiments and sub-embodiments disclosed herein.
BRIEF DESCRIPTION OF THE FIGURES
[0031] The following figures form part of the present description
and describe exemplary embodiments of the claimed invention. The
skilled artisan will, in light of these figures and the description
herein, be able to practice the invention without undue
experimentation.
[0032] FIG. 1 depicts a sectional front elevation of an
orodispersible dosage form made from a three-dimensionally printed
matrix comprising sequentially-formed incremental layers of bound
bulk material.
[0033] FIG. 2 depicts a sectional front elevation of an alternate
embodiment of an orodispersible dosage form made from a
three-dimensionally printed matrix.
[0034] FIGS. 3A-3E depict various different printing patterns that
can be used to apply printing fluid to incremental layers of
powder.
[0035] FIG. 4A depicts a sectional front elevation of an alternate
embodiment of an orodispersible dosage form made from a
three-dimensionally printed matrix.
[0036] FIG. 4B depicts a perspective view of the dosage form of
FIG. 4A.
DETAILED DESCRIPTION OF THE INVENTION
[0037] As used herein and unless otherwise specified, the term
oxcarbazepine (OXC) refers to the drug in underivatized
(10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) or
derivatized form. Oxcarbazepine is available from Jubilant Life
Sciences (Nanjangug, Mysore, Karnataka, India), CTX Life Sciences
Pvt. Ltd. (Sachin, Surat, Gujarat, India), Trifarma S.p.A (Milano,
Italy) and Fabrica Italiana Sintetici S.p.A (Montecchio
Maggiore-Vicenza, Italy). OXC can be present in crystalline or
amorphous form. Polymorphs of oxcarbazepine have been recognized
recently (e.g., in J. Pharm Sci 99 (2) 2010:794-803) and are
considered to be within the scope of the term oxcarbazepine.
[0038] As used herein, "native particles" refers to particles of a
compound without any other added components, i.e. native particles
of OXC are particles containing OXC, wherein the particles do not
contain any added excipient(s). "Drug-containing particles" refers
to preformed particles comprising "native particles of OXC" and one
or more excipients. The drug-containing particles are necessarily
larger in size than the native particles. The drug containing
particles can be granules, beads, pellets, or other engineered
particles or agglomerates that otherwise incorporate the smaller,
primary drug particles themselves and can withstand conventional
powder handling for flow and transfer.
[0039] As used herein and unless otherwise specified, "particle
size" and "actual particle size" refer to the particle size of a
compound without any other added component(s), i.e. the particle
size of the native particles of OXC, or refers to the particle size
of the drug-containing particles.
[0040] The present invention provides a rapidly orodispersible
dosage form comprising drug-containing particles comprising OXC and
one or more pharmaceutical excipients. The dosage form comprises a
non-compressed matrix of particles bound by binder. The matrix
comprises the drug-containing particles, disintegrant, binder,
surfactant, glidant, sweetener and glycerin. The matrix is porous
and disperses within less than 20 sec when placed in a small amount
of water.
[0041] The impact of particle size of O.times.C upon
characteristics of a 3DP orodispersible dosage form was evaluated
by directly blending OXC with other excipients to form the powder
material used for printing. It was determined that lots with very
small particle size, e.g. mean particle size >10 microns,
produced dosage forms with unacceptably rough surfaces and poor
(unacceptably low) hardness. Lots with large mean particle size,
e.g. 40-50 microns, produced better surface texture and hardness;
however, those particles are substantially larger than desired for
oral administration.
[0042] Inventive drug-containing particles of OXC were prepared
using small particle size OXC, disintegrant, binder, and glidant.
The inventive particles were prepared by wet granulation according
to Example 1. Wet granulation can be conducted in a low shear
mixer, e.g. planetary mixer, or high shear mixer, e.g. GMX mixer.
Comparator drug-containing particles were prepared by dry
granulation with roller compaction.
[0043] The ratio of effective particle size to native drug particle
size will vary according to the respective mean, median, average or
D50 particle size distributions: the smaller the native particle
size and the larger the effective particle size, then the larger
the ratio, and vice versa. For example, if the average native
particle size is such that 90%-100% of the drug is <10 microns,
then the ratio of effective particle size to native particle size
might be in the range of 10:1 to 200:1. Likewise, if the average
native particle size is such that NMT 20% of the drug is <32
microns, 40-70% of the drug is <63 microns, 70-95% of the drug
is <125 microns, and 100% of the drug is <250 microns, then
the ratio of effective particle size to native particle size might
be in the range of >1:1 to about 10:1. Accordingly, the ratio
can be in the range of >1:1 to about 200:1, or 2:1 to 100:1, or
3:1 to 50:1. Use of more than one grade of native drug is
contemplated, which may comprise one or more native particle size
distributions. In some embodiments having more than one grade of
native drug, more than one ratio of effective particle size to
native drug particle size may be used to describe the relative
particle sizes. In some embodiments, there is a first ratio of
effective particle size to native particle size of >1:1 to 5:1
with respect to a first native API, and a second ratio of effective
particle size to native particle size of 20:1 to 50:1 with respect
to a second native API.
[0044] Then, three-dimensionally printed (3DP) dosage forms
comprising the various different drug-containing particles of OXC
were prepared according to Example 3. The resulting 3DP dosage
forms were evaluated for hardness, dispersion time and friability
to determine which of the drug-containing particles provided
suitable 3DP orodispersible dosage forms with very rapid dispersion
times, adequate hardness and minimal friability. It was determined
that only the drug-containing particles made by wet granulation,
preferably high shear wet granulation, provided 3DP dosage forms
meeting these stringent performance criteria. None of the
comparator formulations made by dry granulation provided 3DP dosage
forms meeting these stringent performance criteria. This finding is
quite unexpected, since the compositions of the comparator
drug-containing particles were the same as those of the inventive
drug-containing particles
[0045] The weight ratio of OXC to other excipients in the
drug-containing particles can be varied; however, doing so will
have an impact upon hardness, dispersion time, friability, dosage
form size and dose of drug in the dosage form. If the excipient
content in the drug-containing particles is too low, performance of
the dosage form is sacrificed. If excipient content in the
drug-containing particles is too high, the dosage form size has to
be increased substantially in order to include a suitable dose of
OXC therein, thereby making it extremely difficult to prepare
reasonably sized dosage forms containing high amounts of OXC.
[0046] Drug-containing particles, especially granules prepared by
wet granulation, can be used to prepare rapidly dispersible 3DP
matrices comprising OXC having a hardness in the range of 1-3 kP
and a dispersion time in water of 15 sec or less, or 10 sec or
less. Suitable drug-containing particles comprise 65-70% wt OXC,
21.5-23% wt diluent/disintegrant, e.g. microcrystalline cellulose,
3-5% wt superdisintegrant, e.g. croscarmellose, 1-4.5% wt
surfactant, e.g. sodium lauryl sulfate, and 2.5-5% binder, e.g.
hydroxypropylcellulose. Drug-containing particles produced by high
shear wet granulation had a Dv0.5 of about 60-100 microns.
[0047] It has been determined that inclusion of a surfactant in the
printing fluid, bulk powder and drug-containing particles aids in
ensuring rapid dispersion of the 3DP dosage form when placed in a
minimal amount of water. The surfactant serves to enhance wetting
of the particles. The surfactant need only be present in an amount
sufficient to enhance dispersion as compared to another 3DP dosage
form excluding the surfactant. If the surfactant is present in too
high of an amount, however, it will negatively impact mouth feel,
performance and/or physical properties of the dosage form. The
surfactant can be included in the drug-containing granule, bulk
powder and/or printing fluid. In some embodiments, the total amount
of surfactant present in the drug-containing particles ranges from
about 0-5%, >0-5%, 1-4.2%, 2-3% wt. based upon the weight to the
drug-containing particles. In some embodiments, the amount of
surfactant present in the bulk powder, excluding the
drug-containing particles, ranges from about 0-5%, >0-5%,
1-4.2%, 2-3% wt. based upon the weight to the bulk powder.
[0048] The rapidly dispersible dosage form can disperse
(disintegrate) in about 30 seconds or less, about 20 seconds or
less, about 15 seconds or less, about 10 seconds or less, about 5
sec or less, about 4 sec or less, or about 3.5 sec or less when
placed in a small volume of aqueous fluid, such as a saliva,
gastric fluid and/or a sip of water. In some embodiments, the
dispersion (disintegration) time is measured in a small volume of
20 ml or less, 15 ml or less, 10 ml or less, 5 ml or less, 3 ml or
less and at least 1 ml of an aqueous fluid. In some embodiments,
the disintegration time is determined according to USP
<701>.
[0049] The small volume of aqueous fluid can be a sip such as a
volume 50 ml or less, 40 ml or less, 30 ml or less, 20 ml or less,
10 ml or less, 5 ml or less, 2.5 ml or less or 1 ml or less. The
small volume can be at least 0.1 ml, at least 0.25 ml, at least 0.5
ml, at least 0.75 ml, at least 1 ml, at least 1.5 ml or at least 2
ml. All possible combinations of these volumes are contemplated.
Suitable ranges for the small volume include 0.1 to 50 ml, 0.1 to
40 ml, 0.1 to 30 ml, 0.1 to 20 ml, 0.1 to 10 ml, 0.2 to 10 ml, 0.3
to 10 ml, 0.5 to 10 ml, 1 to 10 ml, 5 to 10 ml, 1 to 7.5 ml, 1 to 5
ml, 0.5 to 3 ml, or other such ranges. Preferably, the sip is about
15 ml (one tablespoon) of water. Preferably a sip is about 2 to
about 30 ml, about 10 to about 15 ml (1 tablespoon) or about 13 ml
of water (fluid).
[0050] In some embodiments, the dosage form comprises not more than
10% wt., not more than 7.5% wt., not more than 5% wt., not more
than 4% wt., not more than 3% wt., not more than 2.5% wt., not more
than 2% wt. or not more than 1.5% wt. moisture as determined by
loss on drying (LOD) at 120.degree. C. In some embodiments, the
dosage form comprises at least 0.1% wt., at least 0.2% wt., at
least 0.5% wt., at least 0.75% wt., at least 1% wt., at least 1.5%
wt., at least 2% wt., at least 2.5% wt., at least 3% wt., at least
4% wt., or at least 5% wt. moisture as determined by loss on drying
at 120.degree. C. In some embodiments, the dosage form comprises
0.1 to 10% wt, 0.2 to 7.5% wt, 0.25 to 5% wt, 0.5 to 4% wt or
0.75-2% wt moisture. All combinations of these various limits are
within the scope of the invention.
[0051] In some embodiments, the overall hardness (as determined by
a tablet breaking force assay according to USP <127>) of the
matrix ranges from about 0.5 kiloponds (kp) to about 5 kp or from
about 1 kp to about 3 kP. In some embodiments, the overall hardness
is at least 1.0 kp, at least 1.5 kp or at least 2 kp. In some
embodiments, the overall hardness is no more than 5 kp, no more
than 4 kp or no more than 3 kp.
[0052] The term friability is the tendency of the matrix to lose
material from its outer edges and surfaces upon mechanical insult.
Friability is reduced by increasing the hardness. In some
embodiments, the dosage form possesses a friability of less than
about 25%, preferably less than about 10% as determined according
to USP <1216> and as further described below.
[0053] In some embodiments, the porosity of the matrix ranges from
about 10% to about 90% or from about 30% to about 70% of the dosage
form volume.
[0054] In some embodiments, the bulk density of the matrix (as
determined by measurement of weight and dimensions and calculation)
ranges from 150 (mg/mL) to about 1300 (mg/mL), 200-1000 (mg/ml), or
from about 300 (mg/mL) to about 700 (mg/mL).
[0055] The rapidly dispersible dosage form of the invention is made
by a three-dimensional printing (3DP) process. Suitable equipment
assemblies for three-dimensional printing of articles are
commercially available or are already in use: Massachusetts
Institute of Technology Three-Dimensional Printing Laboratory
(Cambridge, Mass.), Z Corporation's 3DP and HD3DP.TM. systems
(Burlington, Mass.), The Ex One Company, L.L.C. (Irwin, Pa.),
Soligen (Northridge, Calif.), Specific Surface Corporation
(Franklin, Mass.), TDK Corporation (Chiba-ken, Japan), Therics
L.L.C. (Akron, Ohio, now a part of Integra Lifesciences), Phoenix
Analysis & Design Technologies (Tempe, Ariz.), Stratasys,
Inc.'s Dimension.TM. system (Eden Prairie, Minn.), Objet Geometries
(Billerica, Mass. or Rehovot, Israel), Xpress3D (Minneapolis,
Minn.), and 3D Systems' Invision.TM. system (Valencia, Calif.).
Other suitable 3DP systems are disclosed in U.S. No. 20080281019,
No. 20080277823, No. 20080275181, No. 20080269940, No. 20080269939,
No. 20080259434, No. 20080241404, No. 20080231645, No. 20080229961,
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cylindrical (radial or polar) coordinate-based system due to its
construction. The entire disclosure of each of these references is
hereby incorporated herein.
[0056] The 3DP process described herein requires a powder layering
system that forms a layer of powder and printing system that
applies a printing fluid to the layer of powder according to a
predetermined pattern, thereby forming an incremental printed
layer. The printing fluid serves to form bound particles of powder,
i.e. particles that are adhered to one another by one or more
pharmaceutical excipients and/or one or more active ingredients.
Incremental printed layers are formed one on top of another to
vertically build the dosage form of the invention, thereby forming
a dosage form comprising plural incremental printed layers. The
process of spreading powder and depositing droplets is repeated
until the desired number of layers for the dosage form is complete.
The incremental layers adhere to one another due to bleeding of
printing fluid from one layer to an adjacent other layer such that
one or more excipients and/or one or more active ingredients adhere
to both adjacent layers. Following completion of the initial
three-dimensional structure, residual printing fluid is removed
from or reduced in the dosage form by drying. The evaporation of
solvent during the drying process leaves a matrix having a
three-dimensional architecture comprising the particles of bulk
material bound by solidified binder and/or other components
including one or more active ingredients and/or any optional
pharmaceutically acceptable excipients.
[0057] The three-dimensional printing process is normally conducted
at ambient temperatures. The process can utilize a variety of
printing fluids, including biologically compatible organic and
aqueous solvents. The process is additive, whereby microscopic
features are incorporated layer by layer, allowing a wide range of
possible architectures to be constructed precisely on a
sub-millimeter scale. Using three-dimensional printing to control
simultaneously both the microscopic features and the macroscopic
shape, the unique drug delivery systems of the present invention
are obtained.
[0058] A particularly suitable printing assembly for
three-dimensional printing of the instant dosage form is described
in U.S. application No. 61/696,839, filed Sep. 5, 2012, the
disclosure of which is hereby incorporated by reference in its
entirety. The assembly includes build modules each having an
incrementally height adjustable platform disposed within a cavity
of the build modules, a powder layering system, a printing system,
a printing fluid removal system and a dosage form handling
system.
[0059] In general, at least two components are used in the
three-dimensional printing process used to prepare the matrix of
the rapidly dispersing dosage forms. The first component is the
powder material to be included in the incremental powder layers.
The second component is the printing fluid (in some cases the fluid
may also contain a binder) that is dispensed by a printhead onto
the powder layer. In some embodiments, the powder material is
comprised of bulk powder comprising plural excipients and of
drug-containing particles comprising OXC and plural excipients. The
excipients in the bulk powder can be the same as or different than
the excipients in the drug-containing particles. In some
embodiments, one or more excipients in the bulk powder is different
that one or more excipients in the drug-containing particles.
[0060] At least one component of the matrix must serve as a
"binding agent" that binds particles of bulk powder together in the
completed three-dimensional matrix. The binding agent produces
adhesion between particles of the bulk powder and drug-containing
particles. It is this adhesion that enables the dosage form to
maintain a fixed shaped (geometry) and maintain its characteristics
of hardness and friability adequate to permit handling and storage.
The strength and extent of the binding depends on the proportion of
the binding agent either in the powder layer or dissolved in the
solvent, and is a function of the amount of fluid deposited. The
term adhesion means the bonding or binding of particles of the bulk
material to each other or to particles of another material present.
There are various ways in which a binding agent can be included in
the matrix. The invention contemplates a combination of one or of
two or more of these different ways.
[0061] In some embodiments of the method of preparation of the
matrix, binding agent is present in the bulk powder, the
drug-containing particles, the printing fluid, or a combination or
two or three thereof. A binding agent in the printing fluid can be
the same as or different than a binding agent in the bulk powder
and/or drug-containing particles.
[0062] The binding agent can be a pharmaceutically acceptable
binder. Including a pharmaceutical "binder" as the binding agent in
the printing fluid will result in a different internal
microstructure of the dosage forms, particularly the pore size,
than the internal microstructure of an otherwise same dosage form
excluding binder in the binding solution. Upon printing, as the
solvent evaporates, binder remains as a solid residue, which
occupies void space in between powder particles, e.g. particles of
disintegrant or drug. The resulting structure will have higher
density compared to tablets fabricated without binder in the
printing fluid.
[0063] The invention provides a process for the preparation of a
rapidly dispersing solid dosage form comprising a
three-dimensionally printed solid porous matrix comprising a bulk
powder, binder and drug-containing particles of OXC, the process
comprising: (a) providing a powdered mixture of one or more
disintegrants, one or more binders, one or more sweeteners, one or
more humectants, one or more glidants and drug-containing particles
(comprising OXC and one or more excipients), together with any
optional pharmaceutically acceptable excipients; (b) forming an
incremental layer of the powdered mixture; (c) applying to the
incremental layer droplets of printing fluid according to a
predetermined pattern to form a printed incremental layer; (d)
repeating (b) and (c) a predetermined number of times, thereby
providing a three-dimensionally printed moist matrix; and (e)
removing or reducing the amount of printing fluid in the moist
matrix, thereby providing three-dimensionally printed solid porous
matrix having a composition, moisture content, porosity, overall
bulk density, hardness, matrix dispersion time, in vitro drug
dissolution time, in vitro dispersion behavior, in vivo
pharmacokinetic behavior, structure, incremental layer thickness,
drug particle size, drug-containing particle size, disintegrant
particle size, drug content, and/or friability within the ranges
specified herein.
[0064] The dosage form of the present invention may be further
shaped as desired to facilitate placement thereof in the buccal
cavity of a subject. One such embodiment may be a wafer-like shape,
donut, ring, tube, cube, spheroid, ellipsoid or rectangular
box.
[0065] FIG. 1 depicts a sectional front elevation of an
orodispersible dosage form (1) made from a three-dimensionally
printed matrix comprising sequentially-formed incremental layers of
bound bulk material (2-3). The exterior surfaces (3) envelope a
middle portion (2). The exterior surfaces have a greater hardness
than the interior portion. This dosage form is made by
three-dimensionally printed plural incremental layers. The bottom
incremental layer, which defines the lower surface, and the upper
incremental layer, which defines the upper surface, and the
circumferential surfaces (left and right of the middle portion) are
harder than the interior portion. The increased hardness is
achieved by using a higher saturation level, higher content of
binder or as otherwise described herein. The increased hardness at
the periphery of the incremental layers of the middle portion is
achieved by increasing the saturation level and/or content of
binder at the periphery, but not the center (non-peripheral
portion) of the respective incremental layers.
[0066] FIG. 2 depicts a sectional front elevation of an alternate
embodiment of an orodispersible dosage form (5) made from a
three-dimensionally printed matrix. The bottom incremental layer,
which defines the lower surface (8), and the upper incremental
layer, which defines the upper surface (7) are harder than the
interior portion (6) comprising plural incremental layers. The
dosage forms (1) and (5) differ primarily in the process used to
print the middle incremental layers, the layers of (6) not having a
periphery with increased hardness.
[0067] FIGS. 3A-3E depict the top plan view of three different
print patterns that can be used to prepare the printed incremental
layers of a 3DP orodispersible matrix of the invention. Even though
each print pattern is depicted as being circular, substantially any
geometry can be used, e.g. circle, oval, square, rectangle, oblong
circle, etc. FIG. 3A depicts a first solid print pattern wherein
substantially the same full, heavy or higher saturation level is
used throughout the entire print area. FIG. 3B depicts a second
solid print pattern wherein substantially the same medium, low,
light or lower saturation level is used throughout the entire print
area. This second solid pattern is referred to as a grayscale
pattern since it has a reduced saturation level. FIG. 3C depicts an
annular (hollow) print pattern wherein printing fluid is applied to
the periphery of the print area but not toward the center of the
print area. FIG. 3D depicts a combination annular and grayscale
print pattern wherein printing fluid is applied to the periphery of
the print area at a higher saturation level and toward the center
of the print area at a grayscale (reduced) saturation level. FIG.
3E depicts an indicum print pattern wherein substantially the same
saturation level is used throughout the entire print area except in
the indicum region(s) wherein no printing fluid is applied thereby
forming a debossed indicum in the surface of the final dosage
form.
[0068] In some embodiments, the dosage form comprises (consists
essentially of or consists of) the following types of printed
incremental layers: a) plural layers of first solid print pattern,
and plural layers of combination annular and grayscale print
pattern; b) plural layers of first solid print pattern, plural
layers of annular print pattern, and plural layers of combination
annular and grayscale print pattern; c) plural layers of first
solid print pattern, plural layers of annular print pattern, plural
layers of combination annular and grayscale print pattern, and
plural layers of indicum print pattern; d) plural layers of first
solid print pattern, plural layers of annular print pattern, plural
layers of combination annular and grayscale print pattern, plural
layers of first solid print pattern, and plural layers of indicum
print pattern; e) plural layers of first solid print pattern,
plural layers of grayscale print pattern, and plural layers of
first solid print pattern; f) plural layers of grayscale print
pattern; g) plural layers of combination annular and grayscale
print pattern; h) plural layers of first solid print pattern; i)
plural layers of first solid print pattern and plural layers of
annular print pattern; or j) plural layers of first solid print
pattern, plural layers of combination annular and grayscale print
pattern, and plural layers of indicum print pattern.
[0069] In some embodiments, the dosage form comprises (consists
essentially of or consists of) the following types of incremental
layers grouped into respective sections of the dosage form: a) a
first end comprising plural layers of first solid print pattern; a
middle portion comprising plural layers of annular print pattern
and plural layers of combination annular and grayscale print
pattern; and a second end comprising plural layers of indicum print
pattern; b) a first end comprising plural layers of first solid
print pattern; a middle portion comprising plural layers of
combination annular and grayscale print pattern; and a second end
comprising plural layers of first solid print pattern and/or plural
layers of indicum print pattern; c) a first end comprising plural
layers of first solid print pattern; a middle portion comprising
plural layers of annular print pattern, plural layers of
combination annular and grayscale print pattern; and a second end
comprising plural layers of first solid print pattern and/or plural
layers of indicum print pattern; or d) a first end comprising
plural layers of first solid print pattern; a middle portion
comprising alternating groups of layers, wherein one group
comprises plural layers of annular print pattern, and another group
comprises plural layers of combination annular and grayscale print
pattern; and a second end comprising plural layers of first solid
print pattern and/or plural layers of indicum print pattern.
[0070] The dosage form can also be shaped as a donut, ring or tube.
FIG. 4A depicts an exemplary dosage form wherein the core of the
dosage form about the vertical axis of the cylindrical shape has
been left out or removed during manufacture of the dosage form. The
diameter of the bore or hole can be in the range of 3-10 mm. In
some embodiments, the hole is created via an unprinted zone within
the dosage form and reaching at least one exterior surface such
that unbound powder empties out. FIG. 4B depicts a perspective view
of the dosage form of FIG. 4A.
[0071] The physical properties of the dosage form can be controlled
by varying incremental powder layer thickness, powder composition,
printing fluid composition, printing fluid saturation level (print
density) on a layer, and identity and amount of the excipients
included within the dosage form, e.g. identity and amount of
disintegrant, binder, sweetener, surfactant. These variables
exhibit different levels of effect upon dosage form hardness, bulk
density, disintegration time, dissolution time, bioavailability,
moisture content, taste, and friability. It was determined that the
result effective variables include, at least, the amount of drug,
amount of disintegrant, amount of binder, layer thickness, identity
of some components, and composition of the drug-containing
particles.
[0072] Three-dimensional printing can have spatial descriptors in
each of three different, typically orthogonal directions. In
three-dimensional printing, fluid may be deposited in drops or in
fluid units resembling drops. Drops may be deposited in a
succession that forms a line corresponding to the motion of the
printhead. The spacing between those drops is the drop-to-drop
spacing. After completion of one line, another line may be
deposited adjacent to the earlier-deposited line and separated from
the earlier-deposited line by a distance that is a line-to-line
spacing. After completion of printing on a layer of powder, another
powder layer may be deposited, with each powder layer having a
layer thickness. The powder layer thickness is the third
descriptor.
[0073] In some instances, the spacing of droplets may be described
in terms of the resolution of the printing system, often expressed
as dots per inch (dpi), which is the reciprocal of droplet spacing.
For example, resolutions of 300 and 600 dpi correspond to droplet
spacing's of about 84.7 microns and about 42.3 microns,
respectively. The drop-to-drop spacing (within a line), or the line
spacing (spacing of droplets from one line to the next), or any
other spacing of droplets may be described in terms of resolution
expressed in dpi. In some instances, layer-by-layer instructions
for making the dosage forms may consist of a series of pixelated
images characterized by a resolution in dots-per-inch in each of
two orthogonal linear directions. In some instances, these
pixelated images are 1-bit monochrome images, alternately referred
to as binary or bi-level images in which each pixel contains one
bit of information (0 or 1) that may be represented as either black
or white onscreen.
[0074] In some instances, the relative amount of binding in
localized regions of the dosage form is achieved by "grayscaling"
(i.e., use of a grayscale print pattern) in the dosage form design.
In the case of 1-bit monochrome images used for machine
instructions, grayscaling is achieved by changing the number of
"black" pixels relative to "white" pixels in a chosen region of a
dosage form, or in a chosen layer of a dosage form, or throughout a
dosage form. Any other regions that may be "solid" by using all
black pixels. In some embodiments, the dosage form design includes
a "solid" exterior and a "grayscaled" interior. In some
embodiments, grayscaling may be achieved with equally spaced black
pixels amongst white pixels to reach an overall ratio of black to
white pixels in the grayscaled region. In other embodiments,
grayscaling may be achieved with randomly placed black pixels
amongst white pixels to achieve an overall ratio of black to white
pixels in the grayscaled region. In still other embodiments,
grayscaling may be achieved with a chosen pattern (e.g., parallel
lines, hashed pattern, dot pattern) of black pixels amongst white
pixels to achieve an overall ratio of black to white pixels in the
grayscaled region.
[0075] In three-dimensional printing, a voxel or unit volume may be
defined by one drop-to-drop spacing in the fast axis direction of
motion, by one line-to-line spacing in the slow axis direction of
motion, and by one layer thickness in the vertical direction. Some
of this unit volume is occupied by powder particles, and the
remainder of the unit volume is empty space that collectively has a
volume that is the void volume.
[0076] The saturation level (print density) describes how much of
the void space in this unit volume is occupied by liquid which is
dispensed in a drop or fluid unit which is dedicated to that
particular voxel. The saturation level is the ratio of the
dispensed fluid volume to the volume of empty space in the voxel.
In general, in three-dimensional printing, saturation levels may be
chosen to be slightly less than, or somewhere approximately equal
to, 1.0, also expressed as 100%. Excessively low saturation levels
tend to result in poor structural integrity. Excessively high
saturations levels tend to result in excessive bleeding of liquid
beyond where the liquid was deposited. In the present dosage form,
the saturation level during the step of applying printing fluid to
a powder layer ranges from about 85% to about 120%, about 10% to
about 110%, about 15% to about 80%, about 20% to about 50% or about
15% to about 35% in aggregate across the dosage form, or otherwise
in selected regions of the dosage form.
[0077] Suitable printing devices include those having a continuous
jet printhead or those having a drop-on-demand printhead. A
continuous jet printhead provides a continuous jet (spray) of
droplets while depositing printing fluid onto a powder layer. A
drop-on-demand printhead only deposits droplets of printing fluid
onto the powder layer if it receives an instruction (demand,
operational command) to do so. A printhead scans (applies fluid to)
the surface of powder layer from left to right at a predetermined
rate, e.g. a scan rate, to form a line of droplets. A high scan
rate will result in a lower saturation level, and a low scan rate
with result in a higher saturation level when comparing printing
fluid deposition at a constant volume per unit time. When
considering the situation where binder is present in the binding
solution, an increase in the print speed from 1.0 m/s to 2.0 m/s
reduces the total volume of binder solution deposited in the
tablets by half. As the print speed increases, the bulk density
(theoretical, calculated from the weight and dimensions of the
tablet) decreases. A simultaneous decrease in the dimensions and
weight of the tablets is also seen. This decrease is attributed to
the fact that a decrease in the total volume of binder droplets
deposited onto the powder results in a decrease in the extent of
binder solution spreading in the powder. As expected, increasing
the print speed also decreases the flash time and the hardness and
increases the friability of the tablets. This result is obtained
because the proportion of binder decreases in the tablets as the
print speed increases. An increase in the print speed also
increases the void volume inside the tablets, as illustrated by an
increase in the percent volume of the tablets penetrated by mercury
at 30 psi (% intrusion).
[0078] When using a continuous jet printhead, the printhead scans
at a rate of about 0.5 to 3.0 m/sec, and most preferably at about
1.75 m/sec. When using a drop-on-demand jet printhead, the
printhead scans at a rate of 0.1 to 1 m/sec, most preferably at
about 0.5 m/sec.
[0079] The volume of individual droplets can be varied as desired.
Increasing the volume of the droplet increases the saturation level
and decreasing the volume of a droplet decreases the saturation
level when comparing printing fluid deposition at a constant scan
rate. When using a continuous jet printhead, the size of the fluid
droplets delivered by the printhead preferably ranges from about 15
.mu.m to about 150 .mu.m in diameter. When using a drop-on-demand
printhead, the size of the fluid droplets delivered by the
printhead preferably ranges from about 50 .mu.m to about 500 .mu.m
in diameter.
[0080] The flow rate of the fluid delivered by the printhead can be
varied as desired. Increasing the flow rate will increases the
saturation level and decreasing the flow rate decreases the
saturation level when comparing printing fluid deposition at a
constant scan rate. As discussed herein, the printhead deposits
droplets of printing fluid to form parallel lines thereof in the
powder layer. When using a continuous jet printhead, the line
spacing ranges from about 20 to about 1000 .mu.m, about 50 to about
500 .mu.m, or and preferably about 100 to 200 .mu.m. When using a
drop-on-demand jet printhead, the line spacing ranges from about
100 to about 1500 .mu.m, about 250 to about 1000 .mu.m, or
preferably are about 500 to 750 .mu.m.
[0081] The powder layering system and the height adjustable
platform cooperate to form thin incremental layers of powder in the
build modules. The total thickness (height) of the dosage form will
be a function of the number and thickness of the incremental
layers. The number of printed incremental layers typically ranges
from 5 to 50. A matrix will typically comprise (consist essentially
of or consist of) 20 to 50, 20 to 40, 30 to 40 or 30 to 35 printed
incremental layers. The "end" section of a dosage form will
typically comprise 1 to 10, 1 to 7, 2 to 7, or 4 to 6 printed
incremental layers. An end section with an indicum will typically
comprise 2 to 10, 2 to 7, or 4 to 7 printed incremental layers. The
balance of the printed incremental layers will comprise the middle
portion, with respect to the vertical height, of the dosage form.
The middle portion will typically comprise 5 to 40, 10 to 30, 10 to
20, or 20 to 30 printed incremental layers.
[0082] The incremental layers are of a predetermined height
(vertical thickness), which typically varies from 0.005 to 0.015
inches, 0.008 to 0.012 inches, 0.009 to 0.011 inches, 100-300
.mu.m, 100-500 .mu.m, about 200 .mu.m, about 250 .mu.m inches. As
thicker incremental layers are used, an increasing amount of
printing fluid must be deposited on that layer to ensure adequate
binding both within the plane of the layer and layer-to-layer.
Conversely, for a thinner incremental layer a lesser amount of
printing fluid must be deposited to obtain the same extent of
binding. For a given amount of printing fluid deposited per layer,
using a larger layer thickness will reduce (worsen) dosage form
handleability and reduce (improve) dispersion time. If too thick of
a layer is used for a given amount of fluid, laminar defects may
form that cause the dosage form to easily fracture along the plane
of the layers (delamination), or the dosage form itself may not
have adequate strength to handle at all. In some embodiments, the
thickness of the incremental layers ranges from 100-400 microns,
150-300 microns, or 200-250 microns. In one preferred embodiment,
the layer thickness is 200 microns. In another preferred
embodiment, the layer thickness is 250 microns.
[0083] Dosage forms produced by the 3DP process described herein
vary in size according to the content of OXC and the respective
drug-containing particles. In order to minimize dosage form size,
the content of drug-containing particles should be maximized and
the content of OXC in the drug-containing particles should be
maximized; however, as described herein, the resulting dosage form
must possess sufficient hardness and a very rapid dispersion time.
When the content of OXC in the drug-containing particles is in the
range of 65-70% wt, and the content of drug-containing particles in
the matrix is about 60%, a matrix having a 150 mg dose of OXC can
weigh about 380-390 mg, a matrix having a 300 mg dose of OXC can
weigh about 770-780 mg, and a matrix having a 600 mg dose can weigh
about 1540-1560 mg. Accordingly, if the matrix comprises a higher
percentage of drug-containing particles or if drug-containing
particles having a higher percentage of OXC are employed, the
dosage form weight can be decreased correspondingly and vice
versa.
[0084] One or more pharmaceutically acceptable excipients can be
included in bulk powder material and/or the printing fluid. Each
excipient may be independently selected upon each occurrence from a
water soluble, aqueous fluid soluble, partially water soluble,
partially aqueous fluid soluble, water insoluble or aqueous fluid
insoluble excipient as needed to provide the required
particle-to-particle binding in a printed matrix.
[0085] Most pharmaceutically acceptable excipients, both small
molecules and polymers, can be employed, which allow a
pharmaceutically active ingredient to be loosely encased in a
porous structure (a matrix of bound particles) that is subject to
rapid dispersion in the presence of an appropriate aqueous fluid,
e.g., saliva. Some of these excipients, suitable for use in the
three-dimensional printing process of the invention, are listed in
the Handbook of Pharmaceutical Excipients (Eds. A. Wade and P. J.
Weller, Second edition, American Pharmaceutical Association, The
Pharmaceutical Press, London, 1994).
[0086] Suitable types of excipients for the dosage form include
binder, disintegrant, dispersant, sweetener, glidant, flavorant,
surfactant, humectant, preservative and diluent. Although
conventional pharmaceutical excipients may be used, they may not
always function in precisely the same manner as with traditional
pharmaceutical processing
[0087] One or more binders can be included in the printed matrix.
The binder may be included in either the bulk powder,
drug-containing particles and/or in the printing fluid dispensed
through the printhead. The binder is independently selected upon
each occurrence. Adhesion of the particles to and/or by the binder
occurs either when the binder is contacted by the printing fluid
from the printhead or when it is present (i.e., soluble) in the
printing fluid. The binder is preferably water soluble, aqueous
fluid soluble, partially water soluble or partially aqueous fluid
soluble. In some embodiments, the printing fluid comprises 0-10% wt
of binder. In some embodiments, the bulk powder comprises >0 to
50% wt, 10% to 45%, 20% to 45%, 25-40%, 25-35% wt of binder. In
some embodiments, the drug-containing particles comprise >0 to
10%, 2 to 10%, 2 to 7%, or 2 to 5% wt of binder. In some
embodiments, the printed matrix comprises >0 to 50% wt, 10% to
45%, 20% to 45%, 25-40% wt of binder. In some embodiments, binder
is absent from the printing fluid or absent from the bulk
material.
[0088] Suitable binders include water-soluble synthetic polymer,
carboxymethylcellulose, hydroxypropylcellulose,
polyvinlypyrrolidone, hydroxypropyl-methylcellulose, sorbitol,
mannitiol, xylitol, lactitol, erythritol, pregelatinized starch,
modified starch, arabinogalactan. Preferred binders include
polyvinylpyrrolidone (povidone), mannitol, hydroxypropylcellulose,
or a combination thereof.
[0089] The following materials are considered binders, even though
they exhibit low strength binding: spray dried lactose, fructose,
sucrose, dextrose, sorbitol, mannitol, xylitol,
[0090] One or more disintegrants can be included in the printed
matrix. The disintegrant can be present in the bulk powder and/or
drug-containing particles. The disintegrant is independently
selected upon each occurrence. In some embodiments, the bulk powder
comprises 3-20% wt, 3-15% wt, 4-12% wt or 10-16% wt of
disintegrant. In some embodiments, the drug-containing particles
comprise 15-35% wt, 20-30% or 25-30%% wt of disintegrant.
[0091] Suitable disintegrants include microcrystalline cellulose
(MCC), croscarmellose (cross-linked carboxymethylcellulose),
powdered cellulose or a combination thereof. Preferred
disintegrants include microcrystalline cellulose, e.g. AVICEL.RTM.
PH 101, a combination of two grades of microcrystalline cellulose,
and croscarmellose. Suitable grades of AVICEL.RTM. are summarized
in the table below. The dosage form can comprise one or a
combination of the specified grades. All such embodiments
containing single grades or a combination of grades are
contemplated.
TABLE-US-00001 Nominal Particle LooseBulk Product Grades Size,
.mu.m Moisture, % Density, g/cc AVICEL DG 45 NMT 5.0 0.25-0.40
AVICEL PH-101 50 3.0 to 5.0 0.26-0.31 AVICEL PH-102 100 3.0 to 5.0
0.28-0.33 AVICEL HFE*-102 100 NMT 5.0 0.28-0.33 AVICEL PH-102 SCG**
150 3.0 to 5.0 0.28-0.34 AVICEL PH-105 20 NMT 5.0 0.20-0.30 AVICEL
PH-102 SCG 150 3.0 to 5.0 0.28-0.34 AVICEL PH-200 180 2.0 to 5.0
0.29-0.36 AVICEL PH-301 50 3.0 to 5.0 0.34-0.45 AVICEL PH-302 100
3.0 to 5.0 0.35-0.46 AVICEL PH-103 50 NMT 3 0.26-0.31 AVICEL PH-113
50 NMT 2 0.27-0.34 AVICEL PH-112 100 NMT 1.5 0.28-0.34 AVICEL
PH-200 LM 180 NMT 1.5 0.30-0.38 AVICEL CE-15 75 NMT 8 N/A NMT means
"not more than".
[0092] The binder and disintegrant are key ingredients for
controlling the hardness, friability and dispersion time of the
matrix. The greater the amount of binder, the higher the hardness,
the lower the friability and the slower the dispersion time. On the
other hand, increasing the amount of disintegrant provides lower
hardness, increased friability and a faster dispersion time.
Accordingly, the matrix of the invention comprises a balanced
amount of binder and disintegrant.
[0093] One or more sweeteners can be included in the printed
matrix. The sweetener can be present in the bulk powder,
drug-containing particles and/or the printing fluid. Better
taste-masking is observed when at least one sweetener is present in
at least the printing fluid. The sweetener is independently
selected upon each occurrence. The printing fluid, drug-containing
particles and/or the bulk powder can have at least one sweetener in
common. In some embodiments, the bulk powder comprises >0 to 5%
wt, or >0 to 2% wt, or >0 to 1.5% wt of sweetener. In some
embodiments, the printing fluid comprises >0 to 5% wt, >0 to
4% wt, >0 to 3% wt, >0 to 2% wt., 0.1 to 5% wt, 0.1 to 4% wt,
0.1 to 3% wt, 0.1 to 2% wt, 0.5 to 3% wt, or 1 to 3% wt sweetener.
In some embodiments, the drug-containing particles comprise 0-5% wt
of sweetener.
[0094] Suitable sweeteners are selected from the group consisting
of glycyrrhizinic acid derivative, e.g. magnasweet (monoammonium
glycyrrhizinate), sucralose and a combination thereof. The
preferred sweetener in the printing fluid is sucralose. Sweetener
is present in at least the printing fluid but may also be present
in the bulk powder.
[0095] One or more flavorants can be included in the matrix. The
flavorant can be present in the bulk powder, drug-containing
particles, and/or the printing fluid. The flavorant is preferably
water soluble, aqueous fluid soluble, partially water soluble or
partially aqueous fluid soluble. If present in the bulk powder, the
flavorant is preferably present in a form applied to a carrier
powder before preparation of the bulk powder. Suitable carrier
powders may include starches, modified starches, celluloses, and
other powder capable of absorbing, adsorbing, encasing, or
encapsulating the flavorant. In some embodiments, the printing
fluid comprises 0-5% % wt, 0.01-1.0% wt or 0.05-0.5% wt of
flavorant. In some embodiments, the bulk powder comprises 0.1 to
10% wt, or 1 to 10% wt, 2 to 8% wt, 3-7% wt of
flavorant-incorporated carrier powder. In some embodiments, the
printed matrix comprises 0-10% wt, 0.01-10% wt of flavorant. In
some embodiments, the flavorant is absent from the printing fluid
or absent from the bulk material. Suitable flavorants include
peppermint, spearmint, mint, vanilla, orange, lemon, citrus, lime,
grape, cherry, strawberry, chocolate, coffee or a combination
thereof.
[0096] One or more surfactants can be included in the printing
fluid, drug-containing particles or bulk powder. In some
embodiments, the printing fluid comprises 0 to about 10%, >0 to
about 7%, or about 1 to about 5% wt of surfactant. In some
embodiments, the drug-containing particles comprise 0 to about 10%,
>0 to about 7%, or about 1 to about 5% wt of surfactant. In some
embodiments, the bulk powder comprises 0 to about 10%, >0 to
about 7%, about 1 to about 5% wt of surfactant. Suitable
surfactants include sodium lauryl sulfate, polysorbate (PEG-ylated
sorbitan (a derivative of sorbitol) esterified with fatty acid) or
a combination thereof. Suitable polysorbates include polysorbate 20
(Polyoxyethylene (20) sorbitan monolaurate), polysorbate 40
(Polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60
(Polyoxyethylene (20) sorbitan monostearate), polysorbate 80
(Polyoxyethylene (20) sorbitan monooleate), sodium lauryl sulfate,
poloxamer (comprising a central (poly(propylene oxide)) flanked by
two chains of (poly(ethylene oxide), e.g. LUTROL), low molecular
weight polyethylene glycol (e.g. PEG 400)
[0097] Even though the dosage form can be preservative-free, one or
more preservatives may optionally be included in the printing fluid
or powder blend. Suitable preservatives include antifungal or
antimicrobial preservatives such as methylparaben and
proprylparaben. In some embodiments, the printing fluid comprises
0.001 to 0.2% preservative.
[0098] One or more glidants can be included in the bulk powder
and/or drug-containing particles. In some embodiments, the bulk
powder comprises 0-5% or >0-2% wt of glidant. In some
embodiments, the drug-containing particles comprise 0-5% or
>0-2% wt of glidant. Suitable glidants include fumed silica
(colloidal silicon dioxide).
[0099] The matrix may also comprise glycerin (glycerol) introduced
therein either by way of the bulk powder or the printing fluid.
Glycerin can exhibit characteristics of a humectant, sweetener,
preservative, lubricant, saponifier or solvent. The present
inventors have discovered that glycerin unexpectedly behaves
contrary to other excipients when included in a three-dimensionally
printed dosage form. As noted above, increasing the amount of other
excipients disclosed generally results in increased hardness with
concomitantly increased disintegration time; however, increasing
the amount of glycerin results in increased hardness but
unexpectedly reduced disintegration time. The ability of glycerin
to behave in this manner is particularly advantageous and has not
been observed with any other material incorporated into a
three-dimensionally printed orodispersible dosage form.
[0100] In some embodiments, glycerin is included in the printing
fluid. Accordingly, the invention provides a printing fluid for use
in three-dimensional printing wherein the printing fluid comprises
glycerin, water, surfactant and at least one organic solvent. The
invention also provides a three-dimensional printing method
comprising: a) depositing a printing fluid comprising glycerin,
water and at least one organic solvent onto at least one layer of
powder; and b) reducing the content of water and solvent in the at
least one layer, thereby forming a three-dimensionally printed
porous matrix. The invention also provides a three-dimensional
printing system comprising: a) a layer-forming system that forms
layers of powder; and b) a printing fluid deposition system that
deposits printing fluid onto the layers of powder, wherein the
printing fluid comprises glycerin, water and at least one organic
solvent.
[0101] In some embodiments, the printing fluid comprises 0 to about
20% wt, >0 to about 15%, >0 to about 10% or >0 to about 5%
wt of glycerin. In some embodiments, the matrix comprises 0 to
about 2% or >0 to about 1% wt of glycerin
[0102] In some embodiments, the process of the invention employs a
printing fluid comprising at least one or combination of
pharmaceutically acceptable solvent for at least one material in
the bulk powder and/or in the printing fluid itself. The printing
fluid may comprise: a) a solvent for a material in the bulk powder;
b) a solvent for a material in the printing fluid; or c) a
combination thereof.
[0103] Embodiments of the process of the invention include those
wherein the printing fluid comprises a solvent for: a) a binder in
the bulk powder; b) a binder in the printing fluid; or c) a
combination thereof.
[0104] The printing fluid can comprise about 75% to about 95%, or
about 80% to about 90% % wt of water.
[0105] The printing fluid can comprise 0 to about 20%, >0 to
about 20%, >0 to about 15%, >0 to about 10%, >0 to about
5% wt of at least one organic solvent. A suitable organic solvent
is alcohol. Suitable alcohols include ethanol, methanol, propanol,
isopropanol or a combination thereof. In some embodiments, the
alcohol is ethanol or isopropanol.
[0106] It should be understood that compounds used in the art of
pharmaceutics generally serve a variety of functions or purposes.
Thus, if a compound named herein is mentioned only once or is used
to define more than one term herein, its purpose or function should
not be construed as being limited solely to that named purpose(s)
or function(s).
[0107] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with tissues of human beings and
animals and without excessive toxicity, irritation, allergic
response, or any other problem or complication, commensurate with a
reasonable benefit/risk ratio.
[0108] As used herein a "derivative" is: a) a chemical substance
that is related structurally to a first chemical substance and
theoretically derivable from it; b) a compound that is formed from
a similar first compound or a compound that can be imagined to
arise from another first compound, if one atom of the first
compound is replaced with another atom or group of atoms; c) a
compound derived or obtained from a parent compound and containing
essential elements of the parent compound; or d) a chemical
compound that may be produced from first compound of similar
structure in one or more steps.
[0109] One or more of the components of the formulation can be
present in its free base or pharmaceutically or analytically
acceptable salt form. As used herein, "pharmaceutically or
analytically acceptable salt" refers to a compound that has been
modified by reacting it with an acid as needed to form an ionically
bound pair. Examples of acceptable salts include conventional
non-toxic salts formed, for example, from non-toxic inorganic or
organic acids. Suitable non-toxic salts include those derived from
inorganic acids such as hydrochloric, hydrobromic, sulfuric,
sulfonic, sulfamic, phosphoric, nitric and others known to those of
ordinary skill in the art. The salts prepared from organic acids
such as amino acids, acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and others
known to those of ordinary skill in the art. Lists of other
suitable salts are found in Remington's Pharmaceutical Sciences,
17th. ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
relevant disclosure of which is hereby incorporated by
reference.
[0110] The invention also provides a method of administering
oxcarbazepine to a subject in need thereof. The method comprises:
(a) providing a rapidly dispersing, non-compressed matrix dosage
form as described herein, and (b) inserting the dosage form into a
moisture-containing body cavity, such as the mouth, of a subject in
need thereof, the moisture being capable of dissolving the binder
and dispersing the dosage form within a time period ranging from
about one to about twenty seconds, thereby dispersing the dosage
form in the body cavity. In some embodiments, the method further
comprises the step of administering the dosage form to the subject,
optionally with a sip (small volume) of fluid after the dosage form
is placed in the mouth.
[0111] The invention also provides a method of treating a disease,
disorder or condition that is therapeutically responsive to
oxcarbazepine, the method comprising: a) administering to a subject
in need thereof a three-dimensionally printed orodispersible matrix
as described herein or as made by the process described herein. The
matrix comprises oxcarbazepine (in drug-containing particles), a
bulk powder, and binder, and the matrix is dispersible in a small
volume of fluid. The dosage and administration regimens detailed in
the package inserts for FDA approved products containing
oxcarbazepine, e.g. TRILEPTAL.RTM., can be followed for
administering the instant dosage form.
[0112] In view of the above description and the examples below, one
of ordinary skill in the art will be able to practice the invention
as claimed without undue experimentation. The foregoing will be
better understood with reference to the following examples that
detail certain procedures for the preparation of embodiments of the
present invention. All references made to these examples are for
the purposes of illustration. The following examples should not be
considered exhaustive, but merely illustrative of only a few of the
many embodiments contemplated by the present invention.
Example 1
Preparation of Drug-Containing Particles
[0113] The following process is used to make drug-containing
particles of oxcarbazepine. The following ingredients in the
amounts indicated are used.
TABLE-US-00002 AMT AMT AMT AMT AMT AMT (% WT.) (% WT.) (% WT.) (%
WT.) (% WT.) (% WT.) INGREDIENT 1 2 3 4 5 6 Oxcarbazpine 67.5 67.8
65-70 65-70 66.7 65.2 Microcrystalline 22.5 22.6 21-24 21.7-23.3
22.2 21.7 cellulose Hydroxypropyl- 3.8 3.8 2.5-5.sup. 2.6-5.sup.
2.6 4.8 cellulose Sodium lauryl 2.8 1.4 1-5 1.4-4.2 4.1 4 sulfate
Crosscarmellose 3.4 4.4 2.4-5.sup. 2.4-4.5 4.3 4.2 sodium
TABLE-US-00003 AMT AMT AMT AMT AMT AMT (% WT.) (% WT.) (% WT.) (%
WT.) (% WT.) (% WT.) INGREDIENT 7 8 9 10 11 12 Oxcarbazpine 70 68.6
66.4 68 67 68.3 Microcrystalline 23.3 22.9 22.2 22.7 22.3 22.8
cellulose Hydroxypropyl- 2.7 2.7 4.9 2.6 4.9 5 cellulose Sodium
lauryl 1.5 1.4 4.1 4.2 1.4 1.4 sulfate Crosscarmellose 2.5 4.5 2.4
2.4 1.4 2.4 sodium
TABLE-US-00004 Material % (w/w) Amount per batch (g) Oxcarbazepine
67.5% 2295.0 Microcrystalline cellulose (Avicel 22.5% 765.0 PH101,
FMC) Croscarmellose sodium (Ac-Di-Sol 3.4% 115.6 SD-711, FMC)
Sodium Lauryl Sulfate 2.8% 95.2 Hydroxypropyl cellulose (HPC-SL
3.8% 129.2 fine, Nisso)
[0114] The drug-containing particles are made by wet granulation at
a scale of 4 L to 200 L. The following equipment and operating
parameters were used.
TABLE-US-00005 Equipment Manufacturer Location Parameters High
Shear Collette Wommelgem, Bowl size = 25 L Granulator Belgium Mixer
and chopper on (GRAL 25) low speed Binder (water) flow rate 95
mL/min Fluid Bed Vector Marion, IA 50 C. inlet temperature
Processor ~40 cfm air flow (FLM.3) Dry to LOD 1-2% Comil Quadro
Waterloo, 3000 rpm (197S) Ontario, Multiple passes (050G, Canada
016C, 018R)
[0115] All powders were weighed and added to the bowl of the high
shear granulator. The dry powder was mixed at low speed for 1
minute. With the mixer and chopper on low speed, water was added at
a rate of 95 mL/min for a total of 1164 g water (25.5% of final wet
weight). The granulator was stopped once during the process to
scrape the bowl. The wet granulation was dried in a fluid bed drier
at 50.degree. C. to an LOD of 1-2%. Using a Comil at 3000 rpm, the
dried material was milled through a series of screens to reduce the
particle size to an acceptable range for 3DP. The milling began
through a 050G screen and ended through a 018R screen. For most
batches, a pass was made through an intermediate screen (016C) to
prevent blinding.
Example 2
Determination of Crystallinity
[0116] A differential scanning calorimeter is used to determine the
level of crystallinity of materials before and after inclusion in
coated particles. The following process for the temperature ramping
profile was used.
[0117] 1. Equilibrate at -10.degree. C.;
[0118] 2. Ramp 10.degree. C./min to 70.degree. C.;
[0119] 3. Isothermal for 5 min;
[0120] 4. Ramp 10.degree. C./min to -20.degree. C.;
[0121] 5. Equilibrate at -20.degree. C.;
[0122] 6. Modulate .+-.0.8.degree. C. every 60s;
[0123] 7. Isothermal for 2 min;
[0124] 8. Ramp 5.degree. C./min to 250.degree. C.;
[0125] 9. Ramp 5.degree. C./min to -10.degree. C.
Example 3
Preparation of a Three-Dimensionally Printed Orodispersible Dosage
Form
[0126] The following process is used to prepare a taste-masked
three-dimensionally printed orodispersible dosage form comprising a
matrix comprising bound drug-containing particles of oxcarbazepine.
The ingredients for the printing fluid and the bulk powder are used
in the amounts indicated below:
TABLE-US-00006 Printing fluid I-A Water (% wt) 85 Glycerin (% wt) 5
Ethanol (% wt) 5 Tween 20 (% wt) 1 Sucralose (% wt) 2
TABLE-US-00007 Bulk powder: II-A II-B II-C II-D II-E OXC containing
particles (% wt) 55 60 65 75 80 Avicel PH101 (% wt) 4.5 4.5 4.5 4.5
4.5 Mannitol (% wt) 33 28 23 13 8 Polyvinypyrrolidone (% wt) 7 7 7
7 7 Silica (% wt) 0.5 0.5 0.5 0.5 0.5 HPC SL (% wt)
(hydroxypropylcellulose) II-F II-G II-H OXC containing particles (%
wt) 70 70 60 Avicel PH101 (% wt) 19.5 9.5 9.5 Mannitol (% wt) 0 10
20 Polyvinypyrrolidone (% wt) 10 10 10 Silica (% wt) 0.5 0.5 0.5
II-L II-M II-N II-O II-P OXC containing particles (% wt) 70 70 70
60 60 Avicel PH101 (% wt) 9.5 0 0 4.5 4.5 Mannitol (% wt) 13 19.5
22.5 28 28 Polyvinypyrrolidone (% wt) 7 10 7 7 0 Silica (% wt) 0.5
0.5 0.5 0.5 0.5 HPC SL (% wt) 0 0 0 0 7 (hydroxypropylcellulose)
II-Q II-R II-S II-T OXC containing particles (% wt) 63.5 63.5 63.5
63.5 Avicel PH101 (% wt) 0 21 11.1 21 Mannitol (% wt) 36 15 24.9 9
Polyvinypyrrolidone (% wt) 0 0 0 0 Silica (% wt) 0.5 0.5 0.5 0.5
HPC SL (% wt) 0 0 0 6 (hydroxypropylcellulose)
[0127] Any three dimensional printer equipment assembly, known or
mentioned herein, can be used. An incremental layer of bulk powder
of predetermined thickness is spread onto a prior layer of powder,
and printing fluid is applied to the incremental layer as droplets
according to a predetermined saturation level, line spacing and
printing fluid flowrate to bind the particles therein. This two
step process is completed until a matrix comprising the target
amount of printed incremental layers.
[0128] The following printing parameters are used on a Z-Corp lab
scale printer (Model Z310). The printer is equipped with a HP-10
printhead and is operated at a scan rate of droplet size of 30-60
.mu.m and line spacing of 450-600 .mu.m. A solid print pattern is
used throughout the dosage form. The specified combination of
printing fluid formulation and bulk powder formulation is used. A
layer thickness of 0.008 to 0.011 inches is used. A saturation of
90 to 116% is used. The printing fluid I-A is used. Many different
combinations of the drug-containing particles Nos. 1-12 and bulk
powder formulations IIA through II-T are used.
[0129] The printed matrix is separated from loose unprinted powder
and the printed matrix is dried by any suitable means to reduce the
amount of solvent and moisture to a desired level, thereby
producing the final 3DP orodispersible dosage form.
[0130] The dispersion time, surface texture (smoothness) and
hardness of the dosage form are then determined.
Example 4
Preparation of a Taste-Masked Three-Dimensionally Printed
Orodispersible Dosage Forms with Varying Architecture Among
Incremental Layers
[0131] The 3DP process described above is followed; however, it can
be conducted in several different ways to prepare dosage forms of
different architecture varying in hardness and composition of
incremental layers. The following processes provide a dosage form
having greater hardness in the upper and lower surfaces as compared
to the hardness of the interior portion of the dosage form. This
tactic helps create sections within a dosage form with different
mechanical properties. This approach is used to design dosage forms
in which the composition of the top and bottom layers is different
from the middle layers. This design allows the dosage forms to have
stronger top and bottom layers, thereby increasing hardness and
reducing friability, and a large middle portion with lower
hardness, which enables the dosage form to disperse rapidly.
Method A:
[0132] In this process, the amount of binder deposited in different
incremental layers or within different predefined regions within
the same incremental layers is varied. The process of Example 3 is
followed to prepare these dosage forms, except that the amount of
binder, by way of the printing fluid, deposited onto the powder is
varied among the incremental powder layers by using printing fluids
differing in concentration of binder.
Method B:
[0133] The process of Example 3 is followed to prepare these dosage
forms, except that the amount of printing fluid deposited onto the
powder is varied among the incremental powder layers. The upper and
lower incremental layers receive a higher amount of printing fluid
and the incremental layers of the middle portion receive a lower
amount of printing fluid.
Method C:
[0134] In this process, the printing pattern, employed for the
upper and lower incremental layers of the dosage form, is a solid
pattern (FIG. 3A). The printing pattern for the middle portion of
incremental layers is a gray scale (FIG. 3 B).
Method D:
[0135] In this process, the printing pattern, employed for the
upper and lower incremental layers of the dosage form, is a solid
pattern (FIG. 3A). The printing pattern for the middle portion of
incremental layers is an annular/hollow high saturation printing
with no printing in the area surrounded by the annulus (FIG.
3C).
Method E:
[0136] In this process, the printing pattern, employed for the
upper and lower incremental layers of the dosage form, is a solid
pattern (FIG. 3A). The printing pattern for the middle portion of
incremental layers is a combination of interior gray scale printing
surrounded by an exterior high saturation printing (FIG. 3D).
Example 5
Characterization of Dosage Forms
[0137] The following procedures were used to characterize the
three-dimensionally printed solid porous orodispersible
matrices.
Friability
[0138] The matrices are analyzed for their resistance to breaking
using the tablet friability test (USP protocol <1216>). The
test employs a VanKel friabilator (model 45-2000, Varian, USA)
equipped with a drum having the dimensions of 285 mm in diameter
and 39 mm deep, which is rotated at 25 rpm for 100 revolutions. A
minimum number of 10 dosage forms are tumbled at each revolution by
a curved projection that extends from the middle of the drum to the
outer wall. Thus, at each turn the tablets are caused to roll or
slide and fall about 130 mm onto the drum or each other. All loose
powder is removed from the tablets and they are weighted
collectively before and after the 100 revolutions.
Surface Texture
[0139] The matrices are inspected visually with or without the aid
of a microscope. The surface texture analyzed to determine if it is
rough or smooth and whether the edges of indicia on the upper
surface and the edges of the perimeter of the dosage form are clean
and sharp or rough and jagged.
[0140] The matrices exhibited smooth surfaces with clean and sharp
edges.
Hardness
[0141] The matrices are analyzed for overall hardness as determined
by a tablet breaking force assay according to USP <127>
(31.sup.st edition) using a VK 200 tablet hardness tester (Varian,
US). The strength or hardness of the dosage forms is measured by a
fracture test. A dosage form is centered between the jaws of the
tester and force is applied until the dosage form fractures. The
load at fracture is returned in kiloponds (kp). A kilopond is a
metric unit of force measurement with 1 kp being equivalent to
9.807 Newtons. A minimum number of 6 dosage forms are tested.
[0142] The hardness of the dosage forms ranges from about 0.5 to
about 5 kP or about 1 to about 3 kP.
Dispersion Time
[0143] The matrices are analyzed for dispersion time in aqueous
fluid as follows using a Texture Analyzer (TA HP, Texture
Technologies, US) equipped with a 5 Kg load cell and a 1.0 inch
diameter acrylic probe (Stable Micro Systems). The dosage form is
attached to the probe with double-sided adhesive tape. Under a
constant 50 g force (Dor et al. in Pharm. Dev. Technol. (2000),
5(4), 575-577; and El-Arini et al. in Pharm. Dev. Technol. (2002),
7(3), 361-371), the dosage form is immersed in 3 ml of water at
room temperature in a flat bottom aluminum weigh boat. The
dispersion time test was conducted using the following parameters.
A minimum of 5 dosage forms was tested.
TABLE-US-00008 Test mode Compression Pre-test speed (mm/sec) 5 Test
speed (mm/sec) 8 Post-test speed (mm/sec) 10 Target mode Force
Force (g) 50 Hold time (sec) 15 Trigger type Auto (force) Trigger
force (g) 5 Water volume (ml) 3
[0144] The dispersion time observed for the dosage forms is about
10 sec or less or about 5 sec or less.
Bulk Density
[0145] The bulk density of the matrix is determined by measuring
the weight of a dosage form and dividing that value by the
calculated volume of the dosage form. The volume of a dosage form
is calculated by measuring its dimensions and using the proper
mathematical formula according to the shape of the dosage form. For
example, for a cylindrical dosage form, the volume of which is
calculated using the form .pi.*r.sup.2*H, wherein r is the radius
of the water and H is its height. A dosage form weighing 0.5 g,
having a height of 0.6 cm and a diameter of 1.1 cm, has a volume of
about 0.57 cm.sup.3, and a bulk density of about 0.877 g/cm.sup.3,
which is equivalent to about 877 mg/ml.
Dissolution of OXC
[0146] Dissolution testing is conducted according to the Guidance
for Industry (Section 3.3.2; Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate-Release Solid Oral Dosage
Forms Based on a Biopharmaceutics Classification System. August
2000. Section IIIc, p 7). The method of USP <711> was
followed. Dissolution is performed using a USP Apparatus II
(paddle) at 50 rpm using 900 mL of the following deaerated
dissolution media: (1) 0.1N HCl; (2) 0.05 M sodium acetate, pH 4.5
buffer and (3) 0.05M KH.sub.2PO.sub.4, pH 6.8 buffer at 37.degree.
C.
Example 6
In Vivo Evaluation of Three-Dimensionally Printed Orodispersible
Dosage Forms
[0147] This method is used to establish efficacy of the dosage
form. Single dosage forms comprising oxcarbazepine are administered
twice daily to a subject at 12-hour intervals. Administration is
done by placing the dosage form in the mouth of the subject and
optionally administering a sip (5-20 ml) of fluid to the subject.
Within a short period of time, the dosage form disperses in the
subject's mouth. Alternatively, the dosage form is dispersed in a
minimal amount of fluid and then administered to the subject
orally. The total daily dose of oxcarbazepine will typically range
from about 300 to 1200 mg. The subject's pharmacokinetic profile is
determined using known methods in the art. The subject level of
therapeutic response to the dosage form is determined using known
methods in the art.
Example 7
Preparation of Three-Dimensionally Printed Rapidly Dispersible
Dosage Forms
[0148] The 3DP process described above is used to prepare a
three-dimensionally printed rapidly dispersible dosage form
comprising a matrix comprising bound drug-containing particles of
oxcarbazepine. The ingredients for the printing fluid and the bulk
powder are used in the amounts indicated below.
TABLE-US-00009 Printing fluid III-A III-B Water (% wt) 80-95 80-90
Glycerin (% wt) 0.5-20 2-7 Alcohol (% wt) 0.1-20 1-10 Tween 20 (%
wt) 0.01-10 1-5 Sucralose (% wt) 0-10 1-5 Binder (% wt) 0-10
TABLE-US-00010 Drug-containing particles: IV-A IV-B OXC (% wt)
55-75 60-70 Avicel PH101 (% wt) 15-35 20-30 HPC (% wt) 0-10 2-5
Surfactant (% wt) 0-10 1-5 Croscarmellose (% wt) 0-10 >0-5
TABLE-US-00011 Bulk powder: V-A V-B OXC containing particles (% wt)
55-65 55-65 Avicel PH101 (% wt) 2-15 3-12 HPC (% wt) 0-10 0-10
Mannitol (% wt) 15-40 20-35 Polyvinypyrrolidone (% wt) 0-10 5-10
Silica (% wt) 0.1-1.5 0.2-0.7
[0149] The printing fluid is applied to incremental layers of bulk
powder by way of a 3DP process to prepare a three-dimensionally
printed orodispersible dosage form comprising a matrix comprising
bound drug-containing particles of OXC.
TABLE-US-00012 Final composition VII-A VII-B Oxcarbazepine (% wt)
30-40 35-45 Microcrystalline cellulose (% wt) 15-30 15-25
Croscarmellose (% wt) 1-5 1-3 Mannitol (% wt) 10-30 15-30 PVP(% wt)
0-10 0-10 HPC (% wt) 0-12 0-10 Colloidal silicon dioxide (% wt) 0-2
0-2 Glycerin (% wt) >0-20 >0-5 Surfactant (% wt) 0-5 >0-5
Sweetener (% wt) 0-5 >0-5
[0150] As used herein, the term "about" or "approximately" are
taken to mean.+-.10%, .+-.5%, .+-.2.5% or .+-.1% of a specified
valued. As used herein, the term "substantially" is taken to mean
"to a large degree" or "at least a majority of" or "more than 50%
of".
[0151] The above is a detailed description of particular
embodiments of the invention. It will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without departing from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims. All of the embodiments disclosed and claimed herein can be
made and executed without undue experimentation in light of the
present disclosure.
* * * * *