U.S. patent application number 09/745095 was filed with the patent office on 2002-02-07 for hydrogel-driven drug dosage form.
Invention is credited to Appel, Leah E., Beyerinck, Ronald A., Chidlaw, Mark B., Curatolo, William J., Friesen, Dwayne T., Smith, Kelly L., Thombre, Avinash G..
Application Number | 20020015731 09/745095 |
Document ID | / |
Family ID | 22625827 |
Filed Date | 2002-02-07 |
United States Patent
Application |
20020015731 |
Kind Code |
A1 |
Appel, Leah E. ; et
al. |
February 7, 2002 |
Hydrogel-Driven Drug Dosage Form
Abstract
A controlled release dosage form has a coated core with the core
comprising a drug-containing composition and a water-swellable
composition, each occupying separate regions within the core. The
drug-containing composition comprises a low-solubility drug and a
drug-entraining agent. The coating around the core is
water-permeable, water-insoluble and has at least one delivery port
therethrough. A variety of formulations having specific drug
release profiles are disclosed.
Inventors: |
Appel, Leah E.; (Bend,
OR) ; Beyerinck, Ronald A.; (Bend, OR) ;
Chidlaw, Mark B.; (Bend, OR) ; Curatolo, William
J.; (Niantic, CT) ; Friesen, Dwayne T.; (Bend,
OR) ; Smith, Kelly L.; (Bend, OR) ; Thombre,
Avinash G.; (East Lyme, CT) |
Correspondence
Address: |
Gregg C. Benson
Pfizer Inc. MS 4159
Eastern Point Road
Groton
CT
06340
US
|
Family ID: |
22625827 |
Appl. No.: |
09/745095 |
Filed: |
December 20, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60171968 |
Dec 23, 1999 |
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Current U.S.
Class: |
424/473 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 9/0004 20130101; A61P 15/10 20180101; A61P 25/24 20180101 |
Class at
Publication: |
424/473 |
International
Class: |
A61K 009/24 |
Claims
1. A controlled release drug dosage form comprising a core and a
coating around said core wherein: (a) said core comprises a
drug-containing composition and a water-swellable composition, each
occupying separate regions within said core; (b) said
drug-containing composition comprises a drug, a swelling agent, and
a drug-entraining agent; (c) said coating is water-permeable,
water-insoluble, and has at least one delivery port therethrough;
(d) said swelling agent has a swelling ratio of at least 3.5; and
(e) said drug-entraining agent comprises at least 15 wt % of said
drug-containing composition.
2. A controlled release drug dosage form comprising a core and a
coating around said core wherein: (a) said core comprises a
drug-containing composition and a water-swellable composition, each
occupying separate regions within said core; (b) said
drug-containing composition comprises a drug and a drug-entraining
agent; (c) said water-swellable composition comprises a swelling
agent and a tableting aid; (d) said coating is water-permeable,
water-insoluble, and has at least one delivery port therethrough;
(e) the mass ratio of said drug-containing composition to said
water-swellable composition has a value of at least 1.5; (f) said
water-swellable composition has a swelling ratio of at least 3.5;
and (g) said core has a strength following tableting of at least 3
Kp/cm.sup.2.
3. A controlled release drug dosage form comprising a core and a
coating around said core wherein: (a) said core comprises a
drug-containing composition and a water-swellable composition, each
occupying separate regions within said core; (b) said
drug-containing composition comprises a drug and a drug-entraining
agent; and (c) said coating is water-permeable, water-insoluble,
has at least one delivery port therethrough, has a water flux
(40/75) of at least 1.0.times.10.sup.-3 gm/cm.sup.2.multidot.hr,
and a durability of at least 1 Kp/cm.sup.2.
4. A controlled release dosage form comprising a core and a coating
around said core wherein: (a) said core comprises a drug-containing
composition and a water-swellable composition, each occupying
separate regions within said core; (b) said drug-containing
composition comprises a drug and a drug-entraining agent; and (c)
said coating is water-permeable, water-insoluble, has at least one
delivery port therethrough, is porous and is formed from a
substantially homogeneous solution comprising a solvent, a
cellulosic polymer, and a non-solvent.
5. A controlled release drug dosage form comprising a core and a
coating around said core wherein: (a) said core comprises a
drug-containing composition and a water-swellable composition, each
occupying separate regions within said core; (b) said
drug-containing composition comprises a drug, a drug-entraining
agent, and a fluidizing agent, said fluidizing agent having a
solubility of at least 30 mg/mL and comprising at least 10 wt % of
said drug-containing composition; and (c) said coating is
water-permeable, water-insoluble, and has at least one delivery
port therethrough, wherein at least about 70 wt % of said
low-solubility drug is released to a use environment within about
12 hours after introduction to said use environment.
6. A controlled release dosage form comprising a core and a coating
around said core wherein: (a) said core comprises a drug-containing
composition and a water-swellable composition, each occupying
separate regions within said core; (b) said drug-containing
composition comprises a drug, a solubilizer, and a drug-entraining
agent; and (c) said coating is water-permeable, water-insoluble,
and has at least one delivery port therethrough.
7. The dosage form of any one of claims 1-6 wherein said
drug-entraining agent is selected from the group consisting of
polyols, oligomers of polyethers, mixtures of polyfunctional
organic acids, cationic materials, polyethylene oxide, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
methyl cellulose, carboxyethylcellulose, gelatin, and xanthan
gum.
8. The dosage form of claim 7 wherein said drug-entraining agent is
selected from the group consisting of polyethylene oxide,
hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, methyl cellulose,
carboxyethylcellulose, gelatin, and xanthan gum.
9. The dosage form of claim 8 wherein said drug-entraining agent is
polyethylene oxide.
10. The dosage form of claim 1 wherein said swelling agent is an
ionic swelling agent.
11. The dosage form of claim 10 wherein said ionic swelling agent
is selected from the group consisting of sodium croscarmellose and
sodium starch glycolate.
12. The dosage form of any one of claims 2-6 wherein said
drug-containing composition further comprises a swelling agent.
13. The dosage form of claim 12 wherein said swelling agent of said
drug-containing composition is an ionic swelling agent.
14. The dosage form of claim 13 wherein said swelling agent of said
drug-containing composition is selected from the group consisting
of sodium croscarmellose and sodium starch glycolate.
15. The dosage form of claim 14 wherein said swelling agent of said
drug-containing composition comprises sodium croscarmellose.
16. The dosage form of claim 14 wherein said swelling agent of said
drug-containing composition comprises sodium starch glycolate.
17. The dosage form of any one of claims 1-5 wherein said core
includes a solubilizer.
18. The dosage form of claim 17 wherein said drug-containing
composition further includes a concentration-enhancing polymer.
19. The dosage form of claim 17 wherein said solubilizer is an
organic acid, and said drug has enhanced solubility in the presence
of said organic acid.
20. The dosage form of any one of claims 1-5 wherein said
drug-containing composition further comprises a solubilizer.
21. The dosage form of claim 20 wherein said solubilizer is an
organic acid, and said drug has enhanced solubility in the presence
of said organic acid.
22. The dosage form of any one of claims 1-6 wherein said
water-swellable composition includes a solubilizer.
23. The dosage form of claim 22 wherein said solubilizer is an
organic acid, and said low-solubility drug has enhanced solubility
in the presence of said organic acid.
24. The dosage form of claim 23 wherein said drug-containing
composition further comprises a concentration-enhancing
polymer.
25. The dosage form of any one of claims 1-4 and 6 wherein said
drug-containing composition further comprises a fluidizing
agent.
26. The dosage form of claim 25 wherein said fluidizing agent is
selected from the group consisting of an organic acid, a salt, a
sugar, an amino acid, a polyol, and a low-molecular weight oligomer
of a water-soluble polymer.
27. The dosage form of claim 26 wherein said fluidizing agent is
selected from the group consisting of a sugar and an organic
acid.
28. The dosage form of claim 27 wherein said sugar is selected from
the group consisting of glucose, sucrose, xylitol, fructose,
mannitol, sorbitol, lactose, and maltitol.
29. The dosage form of claim 28 wherein said sugar is xylitol.
30. The dosage form of claim 27 wherein said organic acid is
selected from the group consisting of citric acid, lactic acid,
ascorbic acid, tartaric acid, malic acid, fumaric acid, and
succinic acid.
31. The dosage form of claim 30 wherein said organic acid is citric
acid.
32. The dosage form of claim 31 wherein said organic acid is
tartaric acid.
33. The dosage form of claim 5 wherein said fluidizing agent is
selected from the group consisting of an organic acid, a salt, a
sugar, an amino acid, a polyol, and a low-molecular weight oligomer
of a water-soluble polymer.
34. The dosage form of claim 33 wherein said fluidizing agent is
chosen from the group consisting of a sugar and an organic
acid.
35. The dosage form of claim 34 wherein said sugar is selected from
the group consisting of glucose, sucrose, xylitol, fructose,
mannitol, sorbitol, lactose and maltitol.
36. The dosage form of claim 34 wherein said sugar is xylitol.
37. The dosage form of claim 34 wherein said organic acid is
selected from the group consisting of citric acid, lactic acid,
ascorbic acid, tartaric acid, malic acid, fumaric acid, and
succinic acid.
38. The dosage form of claim 37 wherein said organic acid is citric
acid.
39. The dosage form of claim 37 wherein said organic acid is
tartaric acid.
40. The dosage form of any one of claim 1, 3, 4, 5 or 6 wherein
said water-swellable composition comprises a swelling agent.
41. The dosage form of claim 40 wherein said swelling agent in said
water-swellable composition is selected from the group consisting
of polyethylene oxide, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, methyl cellulose,
carboxyethyl cellulose, gelatin, and xanthan gum.
42. The dosage form of claim 40 wherein said swelling agent of said
water-swellable composition is an ionic swelling agent.
43. The dosage form of claim 42 wherein said swelling agent of said
water-swellable composition is selected from the group consisting
of sodium starch glycolate and sodium croscarmellose.
44. The dosage form of claim 2 wherein said swelling agent of said
water-swellable composition is an ionic swelling agent.
45. The dosage form of claim 2 wherein said swelling agent of said
water-swellable composition is selected from the group consisting
of sodium starch glycolate and sodium croscarmellose.
46. The dosage form of any one of claim 1, 3, 4, 5 or 6 wherein
said water-swellable composition has a swelling ratio of at least
3.5.
47. The dosage form of claim 46 wherein said swelling ratio of said
water-swellable composition is at least 5.
48. The dosage form of claim 46 wherein said swelling ratio of said
water-swellable composition is at least 7.
49. The dosage form of claim 2 wherein said swelling ratio of said
water-swellable composition is at least 5.
50. The dosage form of claim 2 wherein said swelling ratio of said
water-swellable composition is at least 7.
51. The dosage form of claim 2 wherein said tableting aid is
selected from the group comprising microcrystalline cellulose,
hydroxypropylcellulose, methyl cellulose, and hydroxpropylmethyl
cellulose.
52. The dosage form of any of claim 40 wherein said water-swellable
composition further includes a tableting aid.
53. The dosage form of claim 52 wherein said tableting aid is
selected from the group comprising microcrystalline cellulose,
hydroxypropylcellulose, methyl cellulose, and hydroxpropylmethyl
cellulose.
54. The dosage form of any of claim 1, 3, 4, 5 or 6 wherein the
mass ratio of said drug-containing composition to said
water-swellable composition is at least 1.5
55. The dosage form of claim 54 wherein the mass ratio of said
drug-containing composition to said water-swellable composition is
at least 3.5.
56. The dosage form of claim 2 wherein the mass ratio of said
drug-containing composition to said water-swellable composition is
at least 3.5.
57. The dosage form of any one of claims 1-6 wherein said
low-solubility drug is selected from the group consisting of
sildenafil and pharmaceutically acceptable salts of sildenafil.
58. The dosage form of any one of claims 1-6 wherein said
low-solubility drug is selected from the group consisting of
sertraline and pharmaceutically acceptable salts of sertraline.
59. The dosage form of any one of claims 1-6 wherein said
low-solubility drug is the mesylate salt of the drug
4-[3-[4-(2-methylimidazol-1-yl) phenylthio]
phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide hemifumarate.
60. The dosage form of any one of claims 1-6 wherein said
low-solubility drug is 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-3-((3R,
4S)-dihydroxypyrrolidin-1-yl-)-(2R)-hydroxy-3-oxypropyl] amide.
61. The dosage form of any one of claims 1-6 wherein said
low-solubility drug is
5-(2-(4-(3-benzisothiazolyl)-piperazinyl)ethyl-6-chlorooxindole.
62. The dosage form of any one of claims 1-6 wherein said
low-solubility drug is carprofen.
63. The dosage form of any one of claims 1-6 wherein said drug has
a maximum solubility of 20 mg/mL in aqueous solution that has a pH
between 1 and 8.
64. The dosage form of any one of claims 1-6 wherein said drug is a
low-solubility drug.
65. The dosage form of any one of claims 1-6 wherein said drug is
substantially water insoluble.
66. The dosage form of any one of claims 1-6 wherein said drug is
sparingly water soluble.
67. The dosage form of any of claim 1, 2, 4, 5 or 6 wherein said
coating has a water flux (40/75) of at least 1.0.times.10.sup.-3
gm/cm.sup.2-hr.
68. The dosage form of claim 67 wherein said coating has a
durability of at least 1 Kp/cm.sup.2.
69. The dosage form of any one of claims 1-6 wherein said coating
comprises a hydrophilic cellulosic polymer.
70. The dosage form of claim 69 wherein said cellulosic polymer is
selected from cellulose esters, cellulose ethers and cellulose
esters/ethers.
71. The dosage form of claim 69 wherein said hydrophilic cellulosic
polymer is selected from the group consisting of cellulose acetate,
and mixtures of cellulose acetate and a second polymer.
72. The dosage form of claim 71 wherein said hydrophilic cellulosic
polymer has a degree of substitution equivalent to 25 to 42 wt %
acetyl groups.
73. The dosage form of claim 71 wherein said cellulose acetate has
an average molecular weight of at least 45,000.
74. The dosage form of any one of claims 1-6 wherein said coating
is formed from a solution having a weight ratio of cellulose
acetate to polyethylene glycol of from 9:1 to 6.5:3.5.
75. The dosage form of any one of claims 1-6 wherein said coating
is formed from a solution having a water concentration of greater
than 4 wt %.
76. The dosage form of claim 74 wherein said solution has a water
concentration of greater than 4 wt %.
77. The dosage form of any one of claims 1-6 wherein said coating
is formed from a solution having a water concentration of greater
than 15 wt %.
78. The dosage form of claim 74 wherein said solution has a water
concentration greater than 15 wt %.
79. The dosage form of any one of claims 1-6 wherein said coating
includes at least a pore former.
80. The dosage form of claim 79 wherein said pore former is
selected from the group consisting of polyethylene glycol,
polyvinyl pyrrolidone, polyethylene oxide, hydroxyethyl cellulose,
hydroxypropyl methyl cellulose, water-soluble acrylate esters,
water-soluble methacrylate esters, and polyacrylic acids.
81. The dosage form of claim 79 wherein said pore former is
polyethylene glycol.
82. The dosage form of claim 4 wherein said non-solvent is selected
from the group consisting of water, glycerol, C.sub.1 to C.sub.4
alcohols, ethylene glycerol and its oligomers and propylene glycol
and its oligomers.
83. The dosage form of claim 4 wherein said solvent is acetone.
84. The dosage form of claim 4 wherein said cellulosic polymer is
cellulose acetate.
85. The dosage form of claim 4 wherein said solvent is acetone,
said pore former is polyethylene glycol and said non-solvent is
water.
86. The dosage form any one of claims 82 and 84 wherein said
solution has a water concentration of greater than 4 wt %.
87. The dosage form of claim 86 wherein said solution has a water
concentration greater than 15 wt %.
88. The dosage form of any one of claims 1-3, and 5-6 wherein said
coating is porous and is formed from a homogeneous solution
comprising a solvent, a hydrophilic cellulosic polymer, and a
non-solvent.
89. The dosage form of claim 88 wherein said solution further
comprises a pore former.
90. The dosage form of claim 89 wherein said pore former is
polyethylene glycol.
91. The dosage form of claim 88 wherein said non-solvent is
water.
92. The dosage form of claim 88 wherein said solvent is
acetone.
93. The dosage form of claim 88 wherein said hydrophilic cellulosic
polymer is cellulose acetate.
94. The dosage form of claim 93 wherein said solvent is acetone,
said pore former is PEG, and said non-solvent is water.
95. The dosage form of any one of claim 1, 2, 3, 5 or 6 wherein
said coating is porous with a dry-state density of less than 0.9
times that of the same coating material in nonporous form.
96. The dosage form of claim 95 wherein said coating has a
dry-state density of less than 0.75 times that of the same coating
material in nonporous form.
97. The dosage form of claim 95 wherein said coating comprises a
polymeric asymmetric membrane comprising a thick, porous region and
a dense thin region.
98. The dosage form of claim 4 wherein said coating is porous with
a dry-state density of less than 0.9 times that of the same
nonporous coating material in nonporous form.
99. The dosage form of claim 98 wherein said coating has a
dry-state density of less than 0.75 times that of the same coating
material in nonporous form.
100. The dosage form of claim 98 wherein said coating comprises a
polymeric asymmetric membrane comprising a thick, porous region and
a dense thin region.
101. The dosage form of any one of claims 1-6 wherein said coating
has a mass of from 3 to 30 wt % of said core.
102. The dosage form of claim 99 wherein said coating has a mass of
from 8 to 25 wt % of said core.
103. The dosage form of any one of claims 1-6 wherein, following
introduction of said dosage form to a use environment, no more than
50 wt % of said drug is released to said use environment within 2
hours and at least 60 wt % to said use environment is released
within 12 hours.
104. The dosage form of any one of claim 1, 2, 3, 4 or 6 wherein,
following introduction of said dosage form to a use environment, at
least 60 wt % of said drug is released to said use environment
within 12 hours.
105. The dosage form of any one of claim 1, 2, 3, 4 or 6 wherein,
following introduction of said dosage form to a use environment, at
least about 70 wt % of said drug is released to said use
environment within about 12 hours.
106. The dosage form of any one of claims 1-6 wherein, following
introduction of said dosage form to a use environment, at least 80
wt % of said drug is released to said use environment within 24
hours.
107. The dosage form of any one of claims 1-6 wherein, following
introduction of said dosage form to a use environment, at least 90
wt % of said drug is released to said use environment within 24
hours.
108. The dosage form of any one of claims 1-6 wherein, following
introduction of said dosage form to a use environment, at least 95
wt % of said drug is released to said use environment within 24
hours.
109. The dosage form of claim 4 wherein said substantially
homogeneous solution further comprises a pore former.
110. The dosage form of claim 4 wherein said non-solvent is present
in said substantially homogeneous solution in an amount greater
than 20% of its concentration at the cloud point.
111. The dosage form of claim 4 wherein said coating has a
dry-state density of less than 90% of the density of a nonporous
coating of the same composition.
112. The dosage form of claim 4 wherein said at least one delivery
port is formed, at least in part, in the use environment.
113. A controlled release dosage form comprising a core and a
coating around said core wherein: (a) said core comprises a
drug-containing composition and a water-swellable composition, each
occupying separate regions within said core; (b) said
drug-containing composition comprises a low-solubility drug and a
drug-entraining agent; and (c) said coating is water-permeable,
water-insoluble, and has at least one delivery port therethrough;
and (d) wherein said low-solubility drug is in the form of an
amorphous dispersion.
114. The dosage form of claim 113 wherein said amorphous dispersion
is a solid dispersion of low-solubility drug in a
concentration-enhancing polymer.
115. The dosage form of claim 114 wherein said
concentration-enhancing polymer is selected from the group
consisting of (a) ionizable cellulosic polymers; (b) non-ionizable
cellulosic polymers; and (c) vinyl polymers and copolymers having
substituents selected from the group consisting of hydroxyl,
alkylacyloxy, and cyclicamido.
116. The dosage form of claim 115 wherein said
concentration-enhancing polymer is a cellulosic polymer selected
from the group consisting of cellulosic esters, cellulosic ethers,
and cellulosic esters/ethers.
117. The dosage form of claim 115 wherein said
concentration-enhancing polymer is selected from the group
consisting of polyvinyl pyrrolidone, polyvinyl alcohol, copolymers
of polyvinyl pyrrolidone and polyvinyl acetate and aqueous-soluble
cellulosic polymers.
118. The dosage form of any of claims 1 to 6 wherein said
low-solubility drug is in the form of an amorphous dispersion.
119. The dosage form of claim 118 wherein said amorphous dispersion
is a solid dispersion of low-solubility drug in a
concentration-enhancing polymer.
120. The dosage form of claim 119 wherein said
concentration-enhancing polymer is selected from the group
consisting of (a) ionizable cellulosic polymers; (b) non-ionizable
cellulosic polymers; and (c) vinyl polymers and copolymers having
substituents selected from the group consisting of hydroxyl,
alkylacyloxy, and cyclicamido.
121. The dosage form of claim 120 wherein said
concentration-enhancing polymer is a cellulosic polymer selected
from the group consisting of cellulosic esters, cellulosic ethers,
and cellulosic esters/ethers.
122. The dosage form of claim 120 wherein said
concentration-enhancing polymer is selected from the group
consisting of polyvinyl pyrrolidone, polyvinyl alcohol, copolymers
of polyvinyl pyrrolidone and polyvinyl acetate and aqueous-soluble
cellulosic polymers.
123. A method for treating a disorder, comprising administering to
a mammal in need of such treatment, including a human patient, a
therapeutically effective amount of drug in a dosage form as
defined in claim 1.
124. A method for treating a disorder, comprising administering to
a mammal in need of such treatment, including a human patient, a
therapeutically effective amount of drug in a dosage form as
defined in claim 2.
125. A method for treating a disorder, comprising administering to
a mammal in need of such treatment, including a human patient, a
therapeutically effective amount of drug in a dosage form as
defined in claim 3.
126. A method for treating a disorder, comprising administering to
a mammal in need of such treatment, including a human patient, a
therapeutically effective amount of drug in a dosage form as
defined in claim 4.
127. A method for treating a disorder, comprising administering to
a mammal in need of such treatment, including a human patient, a
therapeutically effective amount of drug in a dosage form as
defined in claim 5.
128. A method for treating a disorder, comprising administering to
a mammal in need of such treatment, including a human patient, a
therapeutically effective amount of drug in a dosage form as
defined in claim 6.
129. A method for treating a disorder, comprising administering to
a mammal in need of such treatment, including a human patient, a
therapeutically effective amount of drug in a dosage form as
defined in claim 113.
130. The dosage form of any one of claims 1-6 wherein said
drug-containing composition further includes a
concentration-enhancing polymer.
131. The dosage form of claim 130 wherein said
concentration-enhancing polymer is selected from the group
consisting of (a) ionizable cellulosic polymers; (b) non-ionizable
cellulosic polymers; and (c) vinyl polymers and copolymers having
substituents selected from the group consisting of hydroxyl,
alkylacyloxy, and cyclicamido.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to a dosage form that provides
a controlled release of a low-solubility beneficial agent, or drug,
to an environment of use.
[0002] Osmotic and hydrogel-driven drug delivery devices for the
release of a drug have been known in the art for some time.
Exemplary dosage forms have included a tablet comprising a
semipermeable wall surrounding a compartment containing the drug
and a layer of swellable hydrogel, with the drug being delivered
through a passageway in the semipermeable wall by swelling of the
hydrogel, as described in U.S. Pat. No. 4,327,725; another tablet
comprising a wall permeable to an exterior fluid but impermeable to
the drug, the wall surrounding a compartment containing two osmotic
agents, two expandable polymers and the drug, as described in U.S.
Pat. No. 4,612,008; drug dispersed in a swellable hydrogel matrix
core that releases the drug by diffusion into the environment of
use, as described in U.S. Pat. No. 4,624,848; a hydrogel reservoir
containing a multiplicity of tiny pills wherein each tiny pill
consists of a wall surrounding a drug core, as described in U.S.
Pat. No. 4,851,232; and a two-layered tablet wherein one layer is
drug mixed with a hydrogel and the other layer is a hydrogel, as
described in U.S. Pat. No. 5,516,527.
[0003] While the conventional dosage forms described above are
functional, nonetheless such dosage forms suffer from a variety of
drawbacks. A controlled release dosage form should ideally deliver
substantially all of the drug from the dosage form to the
environment of use. However, a common problem encountered by
osmotic and hydrogel-driven dosage forms, particularly when the
drug has low aqueous solubility, is that residual drug is left in
the tablet interior after the hydrogel or other swellable material
has completely swelled. This residual drug is not available for
absorption and, accordingly, such dosage forms require increased
amounts of drug to compensate for the failure of the system to
release all of the drug into the environment of use.
[0004] In addition, the controlled release dosage form must operate
within certain size constraints, and yet be capable of delivering
most or all of the drug to the environment of use. Dosage forms,
particulary for humans, are limited in size, and are usually less
than 1 gram, more preferably less than 700 mg in weight. However,
for some types of drugs, the dose amount may make up to half or
even more of the weight of the dosage form. The water-swellable
materials that provide the delivery of the drug must in instances
where the dose is high be capable of providing a highly efficient
delivery of the drug, since very little of the dosage form may be
available for the swellable material or other excipients.
[0005] In addition, it is often desired that the dosage form begin
extruding drug relatively quickly upon entering the use
environment. However, many delivery systems exhibit a time lag
before extruding drug. This is particularly a problem when the drug
has low aqueous solubility or is hydrophobic. Several techniques
have been proposed to reduce the time lag, but each has its own
drawback. One technique has been to provide high-permeabilitiy
coatings by utilizing thin coatings around the dosage form. While
this technique provides a quicker uptake of fluid, the thin coating
lacks strength and often bursts in use or provides insufficient
protection to the dosage form which becomes susceptible to damage
during handling. Yet another technique has involved providing pores
or one or more passageways that communicate with the
water-swellable materials, but this often leads to unacceptable
amounts of residual drug. Another technique involves coating the
dosage form with an immediate release drug formulation, but this
requires additional processing steps and provides a dosage form
with two different release rates, which may be undesirable.
[0006] Yet another problem encountered with conventional osmotic
and hydrogel-driven drug delivery systems is that such dosage forms
often require the presence of osmagents. Osmagents are selected
such that they generate an osmotic pressure gradient across the
barrier of the surrounding coating. The osmotic pressure gradient
drives the permeation of water into the tablet and the resulting
buildup of sufficient hydrostatic pressure, which forces the drug
through the delivery port. These osmagents increase the weight of
the dosage form, thus limiting the amount of drug which may be
contained in the dosage form. In addition, the presence of
additional ingredients in the dosage form, such as osmagents,
increases the costs of manufacture due to the need to insure
uniform concentrations of the ingredients throughout the dosage
form, and may have other drawbacks such as adverse effects on
compression properties and on drug stability.
[0007] Accordingly, there is still a need in the art for a
controlled release dosage form that results in a highly efficient
delivery of drug to an environment of use with very little residual
drug, that allows large drug loading so as to minimize the dosage
size, that begins releasing drug soon after entering the
environment of use, and that limits the number of necessary
ingredients. These needs and others which will become apparent to
one skilled in the art are met by the present invention, which is
summarized and described in detail below.
BRIEF SUMMARY OF THE INVENTION
[0008] The various aspects of the invention each provide a
controlled release drug dosage form having a core comprising a
drug-containing composition and a water-swellable composition. The
drug-containing composition and the water-swellable composition
occupy separate regions within the core. The drug-containing
composition comprises a low-solubility drug and a drug-entraining
agent. A coating around the core is water-permeable,
water-insoluble and has at least one delivery port
therethrough.
[0009] In a first aspect of the invention, the drug-containing
composition further includes a swelling agent having a swelling
ratio of at least 3.5, and the drug-entraining agent comprises at
least 15 wt % of the drug-containing composition.
[0010] In a second aspect of the invention, the mass ratio of the
drug-containing composition to the water-swellable composition has
a value of at least 1.5, and the water-swellable composition
comprises a water-swellable agent and a tableting aid, the
water-swellable composition having a swelling ratio of at least
3.5, and a strength of at least 3 Kp/cm.sup.2 (where Kp is
Kiloponds).
[0011] In a third aspect of the invention, the water-swellable
composition comprises a swelling agent. The coating around the core
has a minimum durability of 1 Kp/cm.sup.2, and a minimum water flux
(40/75) of at least 1.0.times.10.sup.-3 gm/cm.sup.2-hr.
[0012] In a fourth aspect of the invention, the coating is porous
and is formed from a substantially homogeneous solution comprising
a solvent, a hydrophilic cellulosic polymer, and a non-solvent.
[0013] In a fifth aspect of the invention, the drug-containing
composition further comprises a fluidizing agent. Following
introduction into an environment of use, the dosage form releases
at least about 70 wt % of the low-solubility drug to the use
environment within about 12 hours.
[0014] In a sixth aspect of the invention, the drug-containing
composition further comprises a solubilizer. When the drug is a
basic drug, the solubilizer may be an organic acid.
[0015] In a seventh aspect of the invention, the low-solubility
drug is in the form of an amorphous dispersion.
[0016] In an eighth aspect of the invention, a method is provided
for treating a patient in need of a drug by administering a
therapeutically effective amount of the drug in a dosage form of
the invention.
[0017] In one embodiment, the dosage form includes a
concentration-enhancing polymer.
[0018] The various aspects of the present invention have one or
more of the following advantages. The dosage forms of the present
invention are capable of delivering greater amounts of drug to the
desired environment of use with greater efficiency using smaller
amounts of swelling materials, and also result in lower amounts of
residual drug than do conventional compositions. The compositions
are also capable of higher drug loading compared with conventional
compositions. In addition, the compositions begin delivering drug
to the environment of use more quickly than do conventional osmotic
controlled release dosage forms. The dosage forms are capable of
rapidly delivering a low-solubility drug without the coating
failing due to rupture as a result of excessive pressure within the
core when the dosage form is introduced into an environment of use.
The dosage forms are also capable of delivering a low-solubility
drug in a solubilized form.
[0019] The foregoing and other objectives, features, and advantages
of the invention will be more readily understood upon consideration
of the following detailed description of the invention, taken in
conjunction with the accompanying drawing.
BRIEF DESCRIPTION OF THE DRAWING
[0020] FIG. 1 is a schematic drawing of a cross section of an
exemplary embodiment of a dosage form of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention provides a controlled release dosage
form that is specifically designed to provide controlled release of
a low-solubility drug primarily by imbibition of water and
extrusion of drug from the dosage form as opposed to primarily by
diffusion. FIG. 1 shows an exemplary dosage form 10 having a core
12 comprising a drug-containing composition 14 and a
water-swellable composition 16. The drug-containing composition and
the water-swellable composition occupy separate regions in the
core. By "separate regions" is meant that the two compositions
occupy separate volumes, such that the two are not substantially
mixed together. Of course, a small amount of intermixing of the
compositions may occur where the compositions come in contact with
each other, for example, at the interface between two layers. A
coating 18 surrounds the core 12 and is water-permeable,
water-insoluble and has one or more delivery ports 20 therethrough.
In use, the core 12 imbibes water through the coating 18 from the
environment of use such as the gastrointestinal ("GI") tract. The
imbibed water causes the water-swellable composition 16 to swell,
thereby increasing the pressure within the core 12. The imbibed
water also increases the fluidity of the drug-containing
composition. The pressure difference between the core 12 and the
environment of use drives the release of the fluidized
drug-containing composition 14. Because the coating 18 remains
intact, the drug-containing composition 14 is extruded out of the
core 12 through the delivery port(s) 20 into the environment of
use. Because the water-swellable composition 16 contains no drug,
almost all of the drug is extruded through the delivery port(s) 20,
leaving very little residual drug.
[0022] The dosage form of the present invention releases the drug
to an environment of use primarily by "extrusion" rather than by
diffusion. The term "extrusion" as used herein is intended to
convey an expulsion or forcing out of some or all of the drug
through one or more delivery ports or pores in the coating to the
exterior of the dosage form by hydrostatic forces, to be
distinguished from delivery by a diffusion mechanism or by erosion
of the mass of the device. The drug may be released primarily by
extrusion either in the form of a suspension of solids in aqueous
solution or the drug may be in solution, to the extent dissolution
has taken place in the core 12.
[0023] Reference to the "release" of drug as used herein means (1)
transport of drug from the interior of the dosage form to its
exterior such that it contacts the fluid within a mammal's GI tract
following delivery or (2) tran sport of drug from the interior of
the dosage form such that it contacts a test medium for evaluation
of the dosage form by an in vitro test as described below.
Reference to a "use environment" can thus be either to in vivo GI
fluids or to an in vitro test medium. "Introduction" to a use
environment includes either by ingestion or swallowing or use of
implants or suppositories, where the use environment is in vivo, or
being placed in a test medium where the use environment is in
vitro.
Release Characteristics
[0024] An important attribute of the dosage forms of the present
invention is the delivery of drug to a use environment in a
controlled manner. The dosage forms provide drug concentration
release profiles that meet the following criteria.
[0025] First, in some aspects of the present invention, the dosage
forms start releasing drug soon after introduction to the use
environment. When a rapid onset of delivery is desired, preferably
the dosage forms release at least 5 wt % of the drug, and more
preferably at least 10 wt % of the drug within 2 hours after
introduction to the use environment, where these percentages
correspond to the mass of drug released from the core relative to
the total mass of drug originally present in the core. By quickly
beginning the release of the drug, the dosage form shortens the
time required to achieve a maximum drug concentration in a use
environment and increases the total amount of time during which the
drug is in a use environment, resulting in increased absorption and
greater bioavailability.
[0026] Second, the dosage forms release the drug in a controlled
manner, preferably at a substantially constant rate. Thus, the
dosage forms release no more than about 60 wt % of the drug, and
preferably no more than about 50 wt % of the drug, into the use
environment within 2 hours after introduction to the use
environment.
[0027] Third, the rate of release of drug from the dosage form
should be sufficiently high to allow release of the drug within a
time frame that allows a substantial fraction of the drug delivered
to be absorbed into the blood stream. Specifically, the dosage
forms release at least 60 wt % of the drug, and preferably at least
70 wt % of the drug to the use environment within 16 hours after
introduction to the use environment. The inclusion of a fluidizing
agent in the drug-containing composition is particularly useful
when more rapid delivery of drug to the use environment is desired.
In particular, when it is desirable to deliver at least 70 wt % of
the drug to the use environment within 12 hours after introduction
thereto, the invention allows rapid drug release without rupture or
otherwise failure of the dosage form coating during operation.
[0028] Fourth, the dosage forms release a substantial amount of the
drug contained within the dosage form, leaving a relatively small
residual amount of drug after 24 hours. Obtaining low residual
amounts of drug is particularly difficult when it is desired to
deliver high doses of low-solubility drug. The dosage forms of the
present invention release at least 80 wt % of drug, preferably at
least 90 wt %, and more preferably at least 95 wt % of drug to the
use environment within 24 hours after introduction of the dosage
form to the use environment.
[0029] An in vitro test may be used to determine whether a dosage
form provides a release profile within the scope of the present
invention. In vitro tests are well known in the art. An example is
a "residual test," which is described below for sertraline HCl. The
dosage form is first placed into a stirred USP type 2 dissoette
flask containing 900 mL of a buffer solution simulating gastric
environment (10 mM HCl, 100 mM NaCl, pH 2.0, 261 mOsm/kg) at
37.degree. for 2 hours, then removed, rinsed with deionized water,
and transferred to a stirred USP type 2 dissoette flask containing
900 mL of a buffer solution simulating the contents of the small
intestine (6 mM KH.sub.2PO.sub.4, 64 mM KCl, 35 mM NaCl, pH 7.2,
210 mOsm/kg). In both flasks, the dosage form is placed in a wire
support to keep the dosage form off of the bottom of the flask, so
that all surfaces are exposed to the moving release solution and
the solutions are stirred using paddles that rotate at a rate of 50
rpm. At each time interval, a single dosage form is removed from
the solution, released material is removed from the surface, and
the dosage form cut in half and placed in 100 mL of a recovery
solution (1:1 wt/wt ethanol:water, pH adjusted to 3 with 0.1 N
HCl), and vigorously stirred overnight at ambient temperature to
dissolve the drug remaining in the dosage form. Samples of the
recovery solution containing the dissolved drug are filtered using
a Gelman Nylon.RTM. Acrodisc.RTM. 13, 0.45 .mu.m pore size filter,
and placed in a vial and capped. Residual drug is analyzed by HPLC.
Drug concentration is calculated by comparing UV absorbance of
samples to the absorbance of drug standards. The amount remaining
in the tablets is subtracted from the total drug to obtain the
amount released at each time interval.
[0030] An alternative in vitro test is a direct test, in which
samples of the dosage form are placed into a stirred USP type 2
dissoette flask containing 900 mL of a receptor solution such as
USP sodium acetate buffer (27 mM acetic acid and 36 mM sodium
acetate, pH 4.5) or 88 mM NaCl. Samples are taken at periodic
intervals using a VanKel VK8000 autosampling dissoette with
automatic receptor solution replacement. Tablets are placed in a
wire support as above, paddle height is adjusted, and the dissoette
flasks stirred at 50 rpm at 37.degree. C. The autosampler dissoette
device is programmed to periodically remove a sample of the
receptor solution, and the drug concentration is analyzed by HPLC
using the procedure outlined above. Since the drug is usually
extruded from the dosage form as a suspension in an entraining
polymer, there is often a time lag between when the drug is
released and when it is dissolved in the test medium, and thus,
measured in the direct test. This time lag depends on the
solubility of the drug, the test medium, and the ingredients of the
drug-containing composition, but typically is on the order of 30 to
90 minutes.
[0031] Alternatively, an in vivo test may be used to determine
whether a dosage form provides a drug release profile within the
scope of the present invention. However, due to the inherent
difficulties and complexity of the in vivo procedure, it is
preferred that in vitro procedures be used to evaluate dosage forms
even though the ultimate use environment is often the human GI
tract. Drug dosage forms are dosed to a group of humans or dogs and
drug release and drug absorption is monitored either by (1)
periodically withdrawing blood and measuring the serum or plasma
concentration of drug or (2) measuring the amount of drug remaining
in the dosage form following its exit from the anus (residual drug)
or (3) both (1) and (2). In the second method, residual drug is
measured by recovering the tablet upon exit from the anus of the
test subject and measuring the amount of drug remaining in the
dosage form using the same procedure described above for the in
vitro residual test. The difference between the amount of drug in
the original dosage form and the amount of residual drug is a
measure of the amount of drug released during the mouth-to-anus
transit time. This test has limited utility since it provides only
a single drug release time point but is useful in demonstrating the
correlation between in vitro and in vivo release.
[0032] In one in vivo method of monitoring drug release and
absorption, the serum or plasma drug concentration is plotted along
the ordinate (y-axis) against the blood sample time along the
abscissa (x-axis). The data may then be analyzed to determine drug
release rates using any conventional analysis, such as the
Wagner-Nelson or Loo-Riegelman analysis. See also Welling,
"Pharmacokinetics: Processes and Mathematics" (ACS Monograph 185,
Amer. Chem. Soc., Washington, D.C., 1986). Treatment of the data in
this manner yields an apparent in vivo drug release profile.
Drug-containing Composition
[0033] Referring again to FIG. 1, The drug-containing composition
14 of the core 12 of the dosage form 10 includes at least a
low-solubility drug and an entraining agent, and preferably
additional excipients. The drug-containing composition occupies a
separate, substantially distinct region from the water-swellable
composition, and comprises about 50 to 90 wt % of the core,
preferably 60 to 85 wt % of the core, and more preferably greater
than 70 wt % of the core. Preferably, the drug-containing
composition 14 is in contact with the coating 18 which surrounds
the dosage form.
[0034] The drug may be virtually any beneficial therapeutic agent
and may comprise from 0.1 to 65 wt % of the drug-containing
composition 14. In cases where the dose to be delivered is high, it
is preferred that the drug comprise at least 35 wt % of the
drug-containing composition 14. The drug may be in any form, either
crystalline or amorphous. The drug may also be in the form of a
solid dispersion. The invention finds particular utility when the
drug is a "low-solubility drug." In this context, "low-solubility
drug" generally means that the solubility is sufficiently low that,
during operation within a use environment, at least a portion of
the drug remains undissolved and therefore is delivered as a
suspension. In the small volume of a coated tablet, the drug
solubility and dose-to-aqueous solubility ratio must be quite high
in order for all of the drug to dissolve and be delivered as a
solution. Specifically, by "low-solubility drug" we mean that the
drug is either "substantially water-insoluble" (which means that
the drug has a minimum aqueous solubility at physiologically
relevant pH (e.g., pH 1-8) of less than 0.01 mg/mL), or "sparingly
water soluble," that is, has a minimum aqueous solubility at
physiologically relevant pH up to about 1 to 2 mg/mL, or has even
low to moderate aqueous solubility, having a minimum aqueous
solubility at physiologically relevant pH as high as about 20 to 40
mg/mL. In general, it may be said that the drug has a
dose-to-aqueous solubility ratio greater than 10 mL, and more
typically greater than 100 mL, where the drug solubility is the
minimum value in mg/mL observed in any physiologically relevant
aqueous solution (e.g., those with pH values between 1 and 8)
including USP simulated gastric and intestinal buffers and the dose
is in mg. The drug may be employed in its neutral (e.g., free acid,
free base or zwitterion) form, or in the form of its
pharmaceutically acceptable salts as well as in anhydrous,
hydrated, or solvated forms, and pro drugs.
[0035] Preferred classes of drugs include, but are not limited to,
antihypertensives, antidepressants, antianxiety agents,
anticlotting agents, anticonvulsants, blood glucose-lowering
agents, decongestants, antihistamines, antitussives,
anti-inflammatories, antipsychotic agents, cognitive enhancers,
cholesterol-reducing agents, cholesterol ester transfer protein
inhibitors, high-density lipoprotein enhancers, antiobesity agents,
autoimmune disorders agents, anti-impotence agents, antibacterial
and antifungal agents, hypnotic agents, anti-Parkinsonism agents,
antibiotics, antiviral agents, anti-neoplastics, barbituates,
sedatives, nutritional agents, beta blockers, emetics,
anti-emetics, diuretics, anticoagulants, cardiotonics, androgens,
corticoids, anabolic agents, growth hormone secretagogues,
anti-infective agents, coronary vasodilators, carbonic anhydrase
inhibitors, antiprotozoals, gastrointestinal agents, serotonin
antagonists, anesthetics, hypoglycemic agents, dopaminergic agents,
anti-Alzheimer's Disease agents, anti-ulcer agents, platelet
inhibitors and glycogen phosphorylase inhibitors.
[0036] Specific examples of the above and other classes of drugs
and therapeutic agents deliverable by the invention are set forth
below, by way of example only. Specific examples of
antihypertensives include prazosin, nifedipine, trimazosin,
amlodipine, and doxazosin mesylate; a specific example of an
antianxiety agent is hydroxyzine; a specific example of a blood
glucose lowering agent is glipizide; a specific example of an
anti-impotence agent is sildenafil citrate; specific examples of
anti-neoplastics include chlorambucil, lomustine and echinomycin;
specific examples of anti-inflammatory agents include
betamethasone, prednisolone, piroxicam, aspirin, flurbiprofen and
(+)-N-{4-[3-(4fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea;
a specific example of a barbituate is phenobarbital; specific
examples of antivirals include acyclovir, nelfinavir, and virazole;
specific examples of vitamins/nutritional agents include retinol
and vitamin E; specific examples of a .beta.-blocker include
timolol and nadolol; a specific example of an emetic is
apomorphine; specific examples of a diuretic include chlorthalidone
and spironolactone; a specific example of an anticoagulant is
dicumarol; specific examples of cardiotonic include digoxin and
digitoxin; specific examples of an androgen include
17-methyltestosterone and testosterone; a specific example of a
mineral corticoid is desoxycorticosterone; a specific example of a
steroidal hypnotic/anesthetic is alfaxalone; specific examples of
an anabolic agent include fluoxymesterone and methanstenolone;
specific examples of antidepression agents include fluoxetine,
pyroxidine, venlafaxine, sertraline, paroxetine, sulpiride,
[3,6-dimethyl-2-(2,4,6-trimethyl-pheno-
xy)-pyridin-4-yl]-(lethylpropyl)-amine and
3,5-dimethyl-4-(3'-pentoxy)-2-(-
2',4',6'-trimethylphenoxy)pyridine; specific examples of an
antibiotic include ampicillin and penicillin G; specific examples
of an anti-infective include benzalkonium chloride and
chlorhexidine; specific examples of a coronary vasodilator include
nitroglycerin and mioflazine; a specific example of a hypnotic is
etomidate; specific examples of a carbonic anhydrase inhibitor
include acetazolamide and chlorzolamide; specific examples of an
antifungal include econazole, terconazole, fluconazole,
voriconazole and griseofulvin; a specific example of an
antiprotozoal is metronidazole; a specific example of an
imidazole-type anti-neoplastic is tubulazole; specific examples of
an anthelmintic agent include thiabendazole, oxfendazole and
morantel; specific examples of an antihistaminic include
astemizole, levocabastine, cetirizine, and cinnarizine; a specific
example of a decongestant is pseudoephedrine; specific examples of
antipsychotics include fluspirilene, penfluridole, risperidone and
ziprasidone; specific examples of a gastrointestinal agent include
loperamide and cisapride; specific examples of a serotonin
antagonist include ketanserin and mianserin; a specific example of
an anesthetic is lidocaine; a specific example of a hypoglycemic
agent is acetohexamide; a specific example of an anti-emetic is
dimenhydrinate; a specific example of an antibacterial is
cotrimoxazole; a specific example of a dopaminergic agent is
L-DOPA; specific examples of anti-Alzheimer agents are THA and
donepezil; a specific example of an anti-ulcer agent/H2 antagonist
is famotidine; specific examples of a sedative/hypnotic include
chlordiazepoxide and triazolam; a specific example of a vasodilator
is alprostadil; a specific example of a platelet inhibitor is
prostacyclin; specific examples of an ACE
inhibitor/antihypertensive include enalaprilic acid and lisinopril;
specific examples of a tetracycline antibiotic include
oxytetracycline and minocycline; specific examples of a macrolide
antibiotic include azithromycin, clarithromycin, erythromycin and
spiramycin; specific examples of glycogen phosphorylase inhibitors
include
[R-(R*S*)]-5-Chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylme-
thyl)-propyl]-1H-indole-2-carboxamide and
5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-(2R)-hydroxy-3((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-oxyp-
ropyl]amide.
[0037] Further examples of drugs deliverable by the invention are
the glucose-lowering drug chlorpropamide, the anti-fungal
fluconazole, the anti-hypercholesterodemic atorvastatin, the
antipsychotic thiothixene, the anxiolytics hydroxyzine and doxepin,
the anti-hypertensive amlodipine, the antiinflammatories piroxicam,
celicoxib, valdicoxib and carprofen, and the antibiotics
carbenicillin indanyl, bacampicillin, troleandomycin, and
doxycycline.
[0038] In an alternative embodiment, the drug is present in the
form of a solid, amorphous dispersion. By solid, amorphous
dispersion is meant that the drug is dispersed in a polymer so that
a major portion of the drug is in a substantially amorphous or
non-crystalline state, and its non-crystalline nature is
demonstrable by x-ray diffraction analysis or by differential
scanning calorimetry. The dispersion may contain from about 5 to 90
wt % drug, preferably 10 to 70 wt %. The polymer is aqueous-soluble
and inert, and is preferably concentration-enhancing. Suitable
polymers and methods for making solid amorphous dispersions are
disclosed in commonly assigned U.S. patent application Ser. Nos.
09/459,059 and 09/495,061, the relevant disclosures of which are
incorporated by reference. Suitable dispersion polymers include
ionizable and non-ionizable cellulosic polymers, such as cellulose
esters, cellulose ethers, and cellulose esters/ethers; and vinyl
polymers and copolymers having substituents selected from the group
consisting of hydroxyl, alkylacyloxy, and cyclicamido, such as
polyvinyl pyrrolidone, polyvinylalcohol, copolymers of polyvinyl
pyrrolidone and polyvinyl acetate. Particularly preferred polymers
include hydroxypropylmethyl cellulose acetate succinate (HPMCAS),
hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl
cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP),
cellulose acetate trimellitate (CAT), and polyvinyl pyrrolidone
(PVP). Most preferred are HPMCAS, HPMCP, CAP and CAT.
[0039] The drug-containing composition 14 must include an
entraining agent. The use of an entraining agent is necessitated by
the low-solubility drug, which due to its low-solubility does not
dissolve sufficiently within the core 12 to be extruded in the
absence of an entraining agent. The entraining agent suspends or
entrains the drug so as to aid in the delivery of the drug through
the delivery port(s) 20 to the environment of use. While not
wishing to be bound by any particular theory, it is believed that
upon imbibing water into the dosage form, the entraining agent
imparts sufficient viscosity to the drug-containing composition to
allow it to suspend or entrain the drug, while at the same time
remaining sufficiently fluid to allow the entraining agent to pass
through the delivery port(s) 20 along with the drug. It has been
found that there is a good correlation between the usefulness of a
material as an entraining agent and the viscosity of an aqueous
solution of the material. The entraining agent generally is a
material that has high water solubility and in operation forms
aqueous solutions with viscosities of at least 50 centipoise (cp)
and preferably aqueous solutions with viscosities of 200 cp or
greater.
[0040] The amount of the entraining agent present in the
drug-containing composition may range from about 20 wt % to about
98 wt % of the drug-containing composition. The entraining agent
may be a single material or a mixture of materials. Examples of
such materials include polyols, and oligomers of polyethers, such
as ethylene glycol oligomers or propylene glycol oligomers. In
addition, mixtures of polyfunctional organic acids and cationic
materials such as amino acids or multivalent salts, such as calcium
salts may be used. Of particular utility are polymers such as
polyethylene oxide (PEO), polyvinyl alcohol, PVP, cellulosics such
as hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC),
HPMC, methyl cellulose (MC), carboxy methyl cellulose (CMC),
carboxyethylcellulose (CEC), gelatin, xanthan gum or any other
water-soluble polymer that forms an aqueous solution with a
viscosity similar to that of the polymers listed above. An
especially preferred entraining agent is non-crosslinked PEO or
mixtures of PEO with the other materials listed above.
[0041] When the low-solubility drug and a polymeric entraining
agent make up about 80 wt % or more of the drug-containing
composition, then the entraining agent, should have a sufficiently
low molecular weight that it becomes sufficiently fluid so that
both the drug and entraining agent can be rapidly extruded from the
dosage form, instead of swelling and rupturing the water-permeable
coating that surrounds the dosage form. Thus, for example, when PEO
is the drug-entraining agent, it is generally preferred that it
have a molecular weight of from about 100,000 to about 300,000
daltons. (References to molecular weights of polymers herein and in
the claims are to average molecular weights.)
[0042] When the low-solubility drug and the entraining agent make
up less than about 80 wt % of the drug-containing composition, a
smaller portion of a more viscous entraining agent is preferred.
For example, when the entraining agent is PEO, a lower fraction of
a higher molecular weight of PEO from about 500,000 to 800,000
daltons may be used. Thus, there is an inverse relationship between
the preferred PEO molecular weight and the weight fraction of the
drug-containing composition that is drug and entraining agent.
Thus, as the weight fraction decreases from about 0.9 to about 0.8,
to about 0.7, to about 0.6, the preferred PEO molecular weight
increases from about 200,000 daltons to about 400,000 daltons, to
about 600,000 daltons, to about 800,000 daltons, respectively, and
the weight fraction of entraining agent correspondingly decreases
(the weight fraction of drug being relatively constant). It should
be noted that for a particular formulation, the optimum PEO
molecular weight for the entraining agent may vary higher or lower
than those values by 20% to 50%. Likewise, when selecting an
appropriate molecular weight of other polymeric entraining agents
such as HEC, HPC, HPMC, or MC, as the weight fraction of entraining
agent in the drug-containing composition is reduced, a higher
molecular weight for the entraining agent is generally
preferred.
[0043] In one embodiment of the invention, the drug-containing
composition comprises a swelling agent in addition to the
low-solubility drug and the drug-entraining agent. The swelling
agent is generally a water-swellable polymer that substantially
expands in the presence of water. Inclusion of even a small amount
of such a swellable polymer can significantly enhance the onset,
rate, and completeness of drug delivery. The degree of swelling of
a swelling agent can be assessed by compressing particles of the
swelling agent in a press to form a compact of the material having
a "strength" ranging from 3 to 16 Kp/cm.sup.2, where strength is
the hardness of the compact in Kp as measured with a Schleuniger
Tablet Hardness Tester, model 6D, divided by its maximum
cross-sectional area normal to the direction of force in cm.sup.2.
For example, about 500 mg of a swelling agent can be compressed in
a {fraction (13/32)}-inch die using an "f press." The swelling of a
compact is measured by placing it between two porous glass frits in
a glass cylinder and contacting it with a physiologically relevant
test medium, such as simulated gastric or intestinal buffer, or
water. The volume of the water-swollen compact after 16 to 24 hours
contact with the test medium divided by its initial volume is
termed the "swelling ratio" of the swelling agent. Generally,
swelling agents suitable for inclusion in the drug layer are those
water-swellable polymers that have swelling ratios, when water is
the test medium, of at least 3.5, preferably greater than 5.
[0044] A preferred class of swelling agents comprises ionic
polymers. Ionic polymers are generally polymers that have a
significant number of functional groups that are substantially
ionized in an aqueous solution over at least a portion of the
physiologically relevant pH range 1 to 8. Such ionizable functional
groups include carboxylic acids and their salts, sulfonic acids and
their salts, amines and their salts, and pyridine salts. To be
considered an ionic polymer, the polymer should have at least 0.5
milli-equivalents of ionizable functional groups per gram of
polymer. Such ionic polymer swelling agents include sodium starch
glycolate, sold under the trade name EXPLOTAB, and croscarmellose
sodium, sold under the trade name AC-DI-SOL.
[0045] In one embodiment of the invention in which the
drug-containing composition comprises a low-solubility drug, a
drug-entraining agent, and a swelling agent, the swelling agent is
present in an amount ranging from about 2 to about 20 wt % of the
drug-containing composition 14. In other embodiments of the
invention, the swelling agent is optionally present in an amount
ranging from 0 to about 20 wt %.
[0046] In another embodiment of the present invention, the
drug-containing composition further comprises a fluidizing agent.
As used herein, a "fluidizing agent" is a water-soluble compound
that allows the drug-containing composition to rapidly become fluid
upon imbibing water when the dosage form is introduced into a use
environment. Rapid fluidization of the drug-containing composition
allows the composition to be extruded from the dosage form without
a build-up of excessive pressure. This results in a relatively
short time lag. That is, the time between introduction of the
dosage form into the environment of use and the onset of drug
delivery is relatively short. In addition, the inclusion of a
fluidizing agent reduces the pressure within the core and thus
reduces the risk of failure of the coating that surrounds the core
of the dosage form. This is particularly important when a
relatively rapid rate of drug release is desired, necessitating the
use of a highly water-permeable coating that conventionally is
relatively thin and weak. (By a rapid rate of release is generally
meant that greater than 70 wt % of the low-solubility drug
originally present in the dosage form is released within 12 hours
of the time the dosage form is introduced into the use
environment.)
[0047] The fluidizing agent can be essentially any water-soluble
compound that rapidly increases the fluidity of the drug-containing
composition when water is imbibed into the core. Such compounds
generally have aqueous solubilities of at least 30 mg/mL and
generally have a relatively low molecular weight (less than 10,000
daltons) such that upon imbibing a given quantity of water, the
drug-containing composition rapidly becomes more fluid relative to
a similar drug-containing composition that does not include the
fluidizing agent. By more fluid is meant that the pressure required
to extrude the drug through the delivery port(s) is lower than a
similar composition without the fluidizing agent. This increased
fluidity can be temporary, meaning that the increased fluidity
occurs for only a short time after introduction of the dosage form
to a use environment (e.g., 2 hours), or the increased fluidity can
occur over the entire time the dosage form is in the use
environment. Exemplary fluidizing agents are sugars, organic acids,
amino acids, polyols, salts, and low-molecular weight oligomers of
water-soluble polymers. Exemplary sugars are glucose, sucrose,
xylitol, fructose, lactose, mannitol, sorbitol, maltitol, and the
like. Exemplary organic acids are citric acid, lactic acid,
ascorbic acid, tartaric acid, malic acid, fumaric, and succinic
acid. Exemplary amino acids are alanine and glycine. Exemplary
polyols are propylene glycol and sorbitol. Exemplary oligomers of
low-molecular weight polymers are polyethylene glycols with
molecular weights of 10,000 daltons or less. Particularly preferred
fluidizing agents are sugars and organic acids. Such fluidizing
agents are preferred as they often improve tableting and
compression properties of the drug-containing composition relative
to other fluidizing agents such as inorganic salts or low-molecular
weight polymers.
[0048] In order for the fluidizing agent to rapidly increase the
fluidity of the drug-containing composition at low water levels in
the core 12 of the dosage form, the fluidizing agent must generally
be present in an amount such that it makes up at least about 10 wt
% of the drug-containing composition 14. To ensure that the
drug-containing composition 14 does not become so fluid such that
the drug-entraining agent cannot properly entrain or suspend the
drug, particularly long after (12 hours or longer) introduction of
the dosage form into the use environment, the amount of fluidizing
agent generally should not exceed about 60 wt % of the
drug-containing composition. In addition, as mentioned above, when
a fluidizing agent is included, a drug-entraining agent with a
higher molecular weight and correspondingly higher viscosity is
generally included in the drug-containing composition, but at a
lower level. Thus, for example, when the drug-containing
composition comprises about 20 to 30 wt % of the low-solubility
drug and about 30 wt % of a fluidizing agent such as a sugar, about
20 to 50 wt % of a high molecular weight polymer such as PEO with a
molecular weight of about 500,000 to 800,000 daltons is preferable
to a lower molecular weight PEO.
[0049] The drug-containing composition 14 may further include
solubility-enhancing agents that promote the aqueous solubility of
the drug, present in an amount ranging from about 0 to about 30 wt
% of the drug-containing composition 14. Examples of suitable
solubility-enhancing agents include surfactants; pH control agents
such as buffers, organic acids and organic acid salts and organic
and inorganic bases; glycerides; partial glycerides; glyceride
derivatives; polyhydric alcohol esters; PEG and PPG esters;
polyoxyethylene and polyoxypropylene ethers and their copolymers;
sorbitan esters; polyoxyethylene sorbitan esters; carbonate salts;
and cyclodextrins.
[0050] There are a variety of factors to consider when choosing an
appropriate solubilizing agent for a drug. The solubilizing agent
should not interact adversely with the drug. In addition, the
solubilizing agent should be highly efficient, requiring minimal
amounts to effect the improved solubility. It is also desired that
the solubilizing agent have a high solubility in the use
environment. For acidic, basic, and zwitterionic drugs, organic
acids, organic acid salts, and organic and inorganic bases and base
salts are known to be useful solubilizing agents. It is desired
that these compounds have a high number of equivalents of acid or
base per gram. The selection of solubilizing agent will therefore
be highly dependent on the properties of the drug.
[0051] A preferred class of solubilizers for basic drugs is organic
acids. Since basic drugs are solubilized by protonation, and since
the solubility of basic drugs in an aqueous environment of pH 5 or
higher is reduced and often may reach an extremely low value by pH
7.5 (as in the colon), it is believed that addition of an organic
acid to the dosage form for delivery to the use environment with
such drugs assists in solubilization and hence absorption of the
drug. An exemplary basic drug is sertraline, which has moderate
solubility at low pH, low solubility at pH values above 5 and
extremely low solubility at pH of about 7.5. Another example of a
basic drug that may benefit from an acidic solubilizer is
ziprasidone. Even a slight decrease in the pH of the aqueous
solution at high pH may result in dramatic increases in the
solubility of basic drugs. In addition to simply lowering the pH,
the presence of organic acids and their conjugate bases also raises
the solubility at a given pH if the conjugate base salt of the
basic drug has a higher solubility than the neutral form or the
chloride salt of the drug.
[0052] It has been found that a preferred subset of organic acids
meeting such criteria consists of citric, succinic, fumaric,
adipic, malic and tartaric acids. The table below gives properties
of these organic acids. Of these, fumaric and succinic are
especially preferred when a high ratio of equivalents of acid per
gram is desired. In addition, citric, malic, and tartaric acid have
the advantage of extremely high water solubility. Succinic acid
offers a combination of both moderate solubility and a high acid
equivalent per gram value. Thus, the use of a highly soluble
organic acid serves multiple purposes: it improves the solubility
of the basic drug, particularly when the use environment is at a pH
above about 5 to 6; it makes the drug-containing composition more
hydrophilic so that it readily wets; and it dissolves, lowering the
viscosity of the layer rapidly, thus acting as a fluidizing agent.
Thus, by accomplishing multiple functions with a single ingredient,
additional space is available for the low-solubility drug within
the drug-containing composition.
1 Properties of Organic Acid Solubilizing Agents Equivalents Water
Organic Value Solubility Acid (mEq/g) (mg/mL) Fumaric 17.2 11
Succinic 16.9 110 Citric 15.6 >2000 Malic 14.9 1750 Adipic 13.7
45 Tartaric 13.3 1560
[0053] For acidic drugs, solubility is increased as pH increases.
Exemplary classes of solubilizers for acidic drugs include
alkylating or buffering agents and organic bases. It is believed
that addition of an alkylating agent or organic base to the dosage
form assists in solubilization and hence absorption of the drug.
Examples of alkylating or buffering agents include potassium
citrate, sodium bicarbonate, sodium citrate, dibasic sodium
phosphate, and monobasic sodium phosphate. Examples of organic
bases include meglumine, eglumine, monoethanol amine, diethanol
amine, and triethanol amine.
[0054] The drug-containing composition 14 may optionally include a
concentration-enhancing polymer that enhances the concentration of
the drug in a use environment relative to control compositions that
are free from the concentration-enhancing polymer. The
concentration-enhancing polymer should be inert, in the sense that
it does not chemically react with the drug in an adverse manner,
and should have at least some solubility in aqueous solution at
physiologically relevant pHs (e.g. 1-8). Almost any neutral or
ionizable polymer that has an aqueous solubility of at least 0.1
mg/mL over at least a portion of the pH range of 1-8 may be
suitable. Especially useful polymers are those discussed above for
forming solid-amorphous dispersions of the drug with a polymer.
Preferred polymers include hydroxypropylmethyl cellulose acetate
succinate (HPMCAS), hydroxypropylmethyl cellulose (HPMC), hydroxy
propylmethyl cellulose phthalate (HPMCP), cellulose acetate
phthalate (CAP), cellulose acetate trimellitate (CAT), and
polyvinylpyrrolidone (PVP). More preferred polymers included
HPMCAS, HPMCP, CAP and CAT.
[0055] Without being bound by any particular theory or mechanism of
action, it is believed that the concentration-enhancing polymer
prevents or retards the rate at which a drug, delivered from the
dosage form and present in the use environment at a concentration
greater than its equilibrium value, approaches its equilibrium
concentration. Thus, when the dosage form is compared to a control
dosage form that is identical except for the absence of the
concentration-enhancing polymer, the concentration-enhancing
polymer-containing dosage form provides, at least for a short time
period, a greater concentration of dissolved drug in the use
environment. Appropriate drug forms and concentration-enhancing
polymers are discussed in commonly assigned pending patent
application "Pharmaceutical Compositions Providing Enhanced Drug
Concentrations" filed Dec. 23, 1999 concurrently herewith, U.S.
provisional patent application No. 60/171,841, the relevant
portions of which are herein incorporated by reference.
[0056] The drug-containing composition 14 may optionally include
excipients that promote drug stability. Examples of such stability
agents include pH control agents such as buffers, organic acids and
organic acid salts and organic and inorganic bases and base salts.
These excipients can be the same materials listed above for use as
solubilizers or fluidizing agents. Another class of stability
agents is antioxidants, such as butylated hydroxy toluene (BHT),
butylated hydroxyanisole (BHA), vitamin E, and ascorbyl palmitate.
The amount of stability agent used in the drug-containing
composition should be sufficient to stabilize the low-solubility
drug. For pH control agents such as organic acids, the stability
agent, when present, may range from 0.1 to 20 wt % of the
drug-containing composition. Note that in some formulations,
antioxidants such as BHT can lead to discoloration of the dosage
form. In these cases, the amount of antioxidant used should be
minimized so as to prevent discoloration. The amount of antioxidant
used in the drug-containing composition generally ranges from 0 to
1 wt % of the drug-containing composition.
[0057] Finally, the drug-containing composition 14 may also include
other conventional excipients, such as those that promote
performance, tableting or processing of the dosage form. Such
excipients include tableting aids, surfactants, water-soluble
polymers, pH modifiers, fillers, binders, pigments, osmagents,
disintegrants and lubricants. Exemplary excipients include
microcrystalline cellulose; metallic salts of acids such as
aluminum stearate, calcium stearate, magnesium stearate, sodium
stearate, and zinc stearate; fatty acids, hydrocarbons and fatty
alcohols such as stearic acid, palmitic acid, liquid paraffin,
stearyl alcohol, and palmitol; fatty acid esters such as glyceryl
(mono- and di-) stearates, triglycerides, glyceryl (palmitic
stearic) ester, sorbitan monostearate, saccharose monostearate,
saccharose monopalmitate, and sodium stearyl fumarate; alkyl
sulfates such as sodium lauryl sulfate and magnesium lauryl
sulfate; polymers such as polyethylene glycols, polyoxyethylene
glycols, and polytetrafluoroethylene; and inorganic materials such
as talc and dicalcium phosphate. In a preferred embodiment, the
drug-containing composition 14 contains a lubricant such as
magnesium stearate.
Water-swellable Composition
[0058] Referring again to FIG. 1, the dosage form further comprises
a water-swellable composition 16. The water-swellable composition
greatly expands as it imbibes water through the coating 18 from the
use environment. As it expands, the water-swellable composition
increases the pressure within the core 12, causing extrusion of the
fluidized drug-containing composition through the port(s) 20 into
the environment of use. To maximize the amount of drug present in
the dosage form and to ensure that the maximum amount of drug is
released from the dosage form so as to minimize residual drug, the
water-swellable composition should have a swelling ratio of at
least about 2, preferably 3.5, and more preferably 5.
[0059] The water-swellable composition 16 comprises a swelling
agent in an amount ranging from about 30 to 100 wt % of the
water-swellable composition 16. The swelling agent is generally a
water-swellable polymer that greatly expands in the presence of
water. As discussed above in connection with the swelling agent of
the drug-containing composition, the degree of swelling of a
swelling agent, or the water-swellable composition itself, can be
assessed by measuring its swelling ratio.
[0060] Suitable swelling agents for the water-swellable composition
are generally hydrophilic polymers that have swelling ratios of
about 2.0 or greater. Exemplary hydrophilic polymers include
polyoxomers such as PEO, cellulosics such as HPMC and HEC, and
ionic polymers. In general, the molecular weight of water swellable
polymers chosen for the swelling agent is higher than that of
similar polymers used as entraining agents such that, at a given
time during drug release, the water-swellable composition 16 after
imbibing water tends to be more viscous, less fluid, and more
elastic relative to the drug-containing composition 14. In some
cases the swelling agent may be even substantially or almost
entirely water insoluble such that when partially water swollen
during operation, it may constitute a mass of water-swollen elastic
particles. Generally, the swelling agent is chosen such that,
during operation, the water-swellable composition 16 generally does
not substantially intermix with the drug-containing composition 14,
at least prior to extruding a majority of the drug-containing
composition 14. Thus, for example, when PEO is the swelling agent
used in the water-swellable composition 16, a molecular weight of
about 800,000 daltons or more is preferred and more preferably a
molecular weight of 3,000,000 to 8,000,000 daltons.
[0061] A preferred class of swelling agents is ionic polymers,
described above for use in various embodiments of the
drug-containing composition 14. Exemplary ionic polymer swelling
agents include sodium starch glycolate, sold under the trade name
EXPLOTAB, croscarmellose sodium, sold under the trade name
AC-DI-SOL, polyacrylic acid, sold under the trade name CARBOBOL,
and sodium alginate sold under the trade name KELTONE.
[0062] The water-swellable composition may optionally further
comprise osmotically effective agents, often referred to as
"osmogens" or "osmagents." The amount of osmagent present in the
water-swellable composition may range from about 0 to about 40 wt %
of the water-swellable composition. Typical classes of suitable
osmagents are water-soluble salts and sugars that are capable of
imbibing water to thereby effect an osmotic pressure gradient
across the barrier of the surrounding coating. The osmotic pressure
of a material can be calculated using the van't Hoff equation.
(See, e.g., Thermodynamics, by Lewis and Randall). By "osmotically
effective agent" is meant the inclusion of a material with low
enough molecular weight, high enough solubility, and sufficient
mass in the water-swellable composition that upon imbibing water
from the use environment it forms an aqueous solution within the
interior of the tablet such that its osmotic pressure exceeds that
of the use environment, thereby providing an osmotic pressure
driving force for permeation of water from the use environment into
the tablet core. Typical useful osmagents include magnesium
sulfate, magnesium chloride, calcium chloride, sodium chloride,
lithium chloride, potassium sulfate, sodium carbonate, sodium
sulfite, lithium sulfate, potassium chloride, sodium sulfate,
d-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glucose,
fructose, lactose, and mixtures thereof.
[0063] In one embodiment of the invention, the water-swellable
composition 16 is substantially free from an osmotically effective
agent, meaning that there is either a sufficiently small amount of
osmagent or that any osmagent present has sufficiently low
solubility so as not to increase the osmotic pressure of the
water-swellable composition 16 substantially beyond that of the use
environment. In order for the dosage form to provide satisfactory
release of drug in the absence of an osmagent in the
water-swellable composition 16, and when the water-swellable
polymer is not an ionic polymer, the dosage form should have a
coating that is highly permeable to water. Such high-permeability
coatings are described below. When the water-swellable composition
16 is substantially free of an osmotically effective agent, the
water swellable composition preferably contains a substantial
quantity, typically at least 10 wt % and preferably at least 50 wt
%, of a highly swelling polymer such as sodium starch glycolate or
sodium croscarmellose. As described earlier, highly swelling
materials can be identified by measuring the "swelling ratio" of
the material formed into a compact using the method described
previously.
[0064] The release of a low-solubility drug relatively quickly
without the inclusion of an osmagent in the water-swellable
composition is a surprising result, since conventional wisdom in
the art has held that osmagents should be included in the
water-swellable composition to achieve good performance.
Circumventing the need for inclusion of an osmagent provides
several advantages. One advantage is that the space and weight
which would otherwise be occupied by osmagent may be devoted to
drug, thus permitting an increase in the amount of drug within the
dosage form. Alternatively, the overall size of the dosage form may
be decreased. In addition, eliminating the osmagent simplifies the
process for manufacture of the dosage form, since the
water-swellable composition 16 may omit the step of including an
osmagent.
[0065] In one embodiment of the invention, the water swellable
composition 16 comprises a swelling agent and a tableting aid. The
preferred swelling agents (e.g., those that are highly swelling)
are difficult to compress to a hardness suitable for use in the
dosage form. However, it has been found that adding a tableting aid
to the water-swellable composition in the amount of 5 to 50 wt % of
the water-swellable composition 16 results in a material that
compresses to a hardness suitable for use in the dosage form. At
the same time inclusion of a tableting aid can adversely affect the
swelling ratio of the water-swellable composition 16. Thus, the
quantity and type of tableting aid used must be carefully selected.
In general, hydrophilic materials with good compression properties
should be used. Exemplary tableting aids include sugars such as
lactose, in particular spray-dried versions sold under the trade
name FASTFLOW LACTOSE, or xylitol, polymers such as
microcrystalline cellulose, HPC, MC or HPMC. Preferred tableting
aids are microcrystalline cellulose, both standard grades sold
under the trade name AVICEL and silicified versions sold under the
trade name PROSOLV and HPC. The amount of tableting aid is chosen
to be sufficiently high so that the core 12 compresses well yet
sufficiently low so that the water-swellable composition 16 still
has a swelling ratio of at least 2, preferably 3.5, more preferably
greater than 5. Typically, the amount is at least 20 but less than
60 wt %.
[0066] It is further desired that the mixture of swelling agent and
tableting aid result in a material that has a "strength" of at
least 3 Kiloponds (Kp)/cm.sup.2, and preferably at least 5
Kp/cm.sup.2. Here, "strength" is the fracture force, also known as
the core "hardness," required to fracture a core 12 formed from the
material, divided by the maximum cross-sectional area of the core
12 normal to that force. In this test, the fracture force is
measured using a Schleuniger Tablet Hardness Tester, model 6D. Both
the compressed water-swellable composition 16 and resulting core 12
should have a strength of at least 3 Kp/cm.sup.2, and preferably at
least 5 Kp/cm.sup.2.
[0067] In a preferred embodiment, the water-swellable composition
16 comprises a mixture of swelling agents in addition to a
tableting aid. For example, the swelling agent croscarmellose
sodium can be compressed into a compact with higher strength than
the swelling agent sodium starch glycolate. However, the swelling
ratio of croscarmellose sodium is lower than that of sodium starch
glycolate. A water-swellable composition 16 with the desired
combination of high swelling ratio and high strength can be formed
using a mixture comprising 15 to 40 wt % sodium starch glycolate,
50 to 70 wt % croscarmellose sodium, and 5 to 20 wt % of the
tableting aid microcrystalline cellulose.
[0068] The water-swellable composition 16 may also include
solubility-enhancing agents or excipients that promote stability,
tableting or processing of the dosage form of the same types
mentioned above in connection with the drug-containing composition.
However, it is generally preferred that such excipients comprise a
minor portion of the water-swellable composition 16. In one
preferred embodiment, the water-swellable composition 16 contains a
lubricant such as magnesium stearate.
The Core
[0069] The core 12 may be any known tablet that can be formed by an
extrusion or compression process and be subsequently coated and
utilized for delivery of drug to a mammal. The tablet can generally
range in size from about 1 mm to about 10 cm for its longest
dimension. The maximum size of the tablet will be different for
different animal species. It can have essentially any shape such
that its aspect ratio, defined as the tablet's longest dimension
divided by the tablet's shortest dimension, ranges from about 1 to
about 5. It is generally preferred that the dimension of the tablet
in the direction that the center of mass of the drug-containing
layer 14 moves when in the process of being extruded from the
dosage form divided by the longest dimension normal to this
direction of motion be greater than about 0.5. In addition, the
dosage form may comprise two or more relatively small tablets
contained in a relatively large container such as a capsule.
[0070] Exemplary core 12 shapes are spheres, ellipsoids, cylinders,
capsule or caplet shapes and any other known shape. The core 12,
following coating, can comprise the entire or a portion of the
dosage form. The final dosage form can be for oral, rectal,
vaginal, subcutaneous, or other known method of delivery into the
environment of use. When the dosage form 10 is intended for oral
administration to a human, the core 12 generally has an aspect
ratio of about 3 or less, a longest dimension of about 2 cm or less
and a total weight of about 1.5 g or less and preferably a total
weight of about 1.0 g or less.
[0071] To form the dosage form, the ingredients comprising the
drug-containing composition 14 and the water-swellable composition
16 are first mixed or blended using processes known in the art. See
for example, Lachman, et al., "The Theory and Practice of
Industrial Pharmacy" (Lea & Febiger, 1986). For example, a
portion of the ingredients of the drug-containing composition 14
can first be blended, then wet granulated, dried, milled, and then
blended with additional excipients prior to tableting. Similar
processes can be used to form the water-swellable composition.
[0072] Once the materials are properly mixed, the core 12 is formed
using procedures known in the art, such as compression or
extrusion. For example, to form cores in the form of tablets, the
desired amount of drug-containing composition 14 is placed in a
tablet press and leveled by lightly tamping with the press. The
desired amount of water-swellable composition 16 is then added, and
the tablet formed by compression. Alternatively, the
water-swellable composition may be added to the tablet press first,
followed by the drug-containing composition. The amount of force
used to compress the tablet core will depend on the size of the
dosage form, as well as the compressibility and flow
characteristics of the compositions. Typically, a pressure is used
that results in a tablet with a strength of 3 to 20
Kp/cm.sup.2.
The Coating
[0073] Following formation of the core 12, coating 18 is applied.
Coating 18 should have both a sufficiently high water permeability
that the drug can be delivered within the desired time frame, and
high strength, while at the same time be easily manufactured. A
water permeability is chosen to control the rate at which water
enters the core, thus controlling the rate at which drug is
delivered to the use environment. Where a high dose of a
low-solubility drug is required, the low solubility and high dose
combine to make it necessary to use a high permeability coating to
achieve the desired drug release profile while keeping the tablet
acceptably small. High strength is required to ensure the coating
does not burst when the core swells as it imbibes water, leading to
an uncontrolled delivery of the core contents to the use
environment. The coating must be easily applied to the dosage form
with high reproducibility and yield. Furthermore, the coating must
be non-dissolving and non-eroding during release of the
drug-containing composition, generally meaning that it be
sufficiently water-insoluble that drug is substantially entirely
delivered through the delivery port(s) 20, in contrast to delivery
via permeation through coating 18.
[0074] As described above, the coating 18 is highly water-permeable
to allow rapid imbibition of water into core 12 and as a result a
rapid release of the drug-containing composition 14. A relative
measure of the water permeability of the coating can be made by
conducting the following experiment. Finished dosage forms are
placed in an open container which is in turn placed in an
environmental chamber held at a constant temperature of 40.degree.
C. and a constant relative humidity of 75%. The initial rate of
weight gain of the dry dosage forms, determined by plotting the
weight of the dosage form versus time, divided by the surface area
of the dosage form yields a value termed "water flux (40/75)." The
water flux (40/75) for a dosage form has been found to be a useful
relative measure of the water permeabilities of coatings. For the
dosage forms of one embodiment of the present invention, in
particular when a rapid release of the drug is desired, the coating
should have a water flux (40/75) value of at least
1.0.times.10.sup.-3 gm/hr.multidot.cm.sup.2, and preferably at
least 1.3.times.10.sup.-3 gm/hr.multidot.cm.sup.2.
[0075] As mentioned, the coating should also have a high strength
to ensure the coating 18 does not burst when the core swells due to
imbibition of water from the use environment. A relative measure of
coating strength can be made by conducting the following experiment
that measures the "durability" of the coating. Finished tablets are
placed into an aqueous medium for 10 to 24 hours, allowing the core
to imbibe water, swell, and release drug to the media. The swollen
dosage form can then be tested in a hardness tester, such as a
Model 6D Tablet Tester manufactured by Schleuniger Pharmatron, Inc.
The dosage form is placed into the tester so that its delivery
port(s) (20) faces one side of the compression plates. The force,
in Kp, required to rupture the coating is then measured. The
durability of the coating is then calculated by dividing the
measured rupture force by the maximum cross-sectional area of the
dosage form normal to the applied force. In one embodiment of the
present invention, the coating should have a durability of at least
1 Kp/cm.sup.2, preferably at least 2 Kp/cm.sup.2, and most
preferably at least 3 Kp/cm.sup.2. Coatings with this or greater
durability ensure virtually no burst tablets when the dosage forms
are tested in vivo.
[0076] Coatings with these characteristics can be obtained using
hydrophilic polymers such as plasticized and unplasticized
cellulose esters, ethers, and ester-ethers. Particularly suitable
polymers include cellulose acetate ("CA"), cellulose acetate
butyrate, and ethyl cellulose. A particularly preferred set of
polymers are cellulose acetates having acetyl contents of 25 to
42%. A preferred polymer is CA having an acetyl content of 39.8%,
and specifically, CA 398-10 manufactured by Eastman of Kingsport,
Tenn., having an average molecular weight of about 40,000 daltons.
Another preferred CA having an acetyl content of 39.8% is high
molecular weight CA having an average molecular weight greater than
about 45,000, and specifically, CA 398-30 (Eastman) reported to
have an average molecular weight of 50,000 daltons. The high
molecular weight CA provides superior coating strength, which
allows thinner coatings and thus higher permeability.
[0077] Coating is conducted in conventional fashion by first
forming a coating solution and then coating by dipping, fluidized
bed coating, or preferably by pan coating. To accomplish this, a
coating solution is formed comprising the coating polymer and a
solvent. Typical solvents useful with the cellulosic polymers noted
above include acetone, methyl acetate, ethyl acetate, isopropyl
acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl
ketone, ethylene glycol monoethyl ether, ethylene glycol monoethyl
acetate, methylene dichloride, ethylene dichloride, propylene
dichloride, nitroethane, nitropropane, tetrachloroethane,
1,4-dioxane, tetrahydrofuran, diglyme, and mixtures thereof. A
particularly preferred solvent is acetone. The coating solution
typically will contain 3 to 15 wt % of the polymer, preferably 5 to
10 wt %, most preferably 7 to 10 wt %.
[0078] The coating solution may also comprise pore-formers,
non-solvents, or plasticizers in any amount so long as the polymer
remains substantially soluble at the conditions used to form the
coating and so long as the coating remains water-permeable and has
sufficient strength. Pore-formers and their use in fabricating
coatings are described in U.S. Pat. Nos. 5,612,059 and 5,698,220,
the pertinent disclosures of which are incorporated herein. The
term "pore former," as used herein, refers to a material added to
the coating solution that has low or no volatility relative to the
solvent such that it remains as part of the coating following the
coating process but that is sufficiently water swellable or water
soluble such that, in the aqueous use environment it provides a
water-filled or water-swollen channel or "pore" to allow the
passage of water thereby enhancing the water permeability of the
coating. Suitable pore-formers include polyethylene glycol (PEG),
PVP, PEO, HEC, HPMC and other aqueous-soluble cellulosics,
water-soluble acrylate or methacrylate esters, polyacrylic acid and
various copolymers and mixtures of these water soluble or water
swellable polymers. Enteric polymers such as cellulose acetate
phthalate (CAP) and HPMCAS are included in this class of polymers.
A particularly preferred pore former is PEG having an average
molecular weight from 1000 to 8000 daltons. A particularly
preferred PEG is one having a molecular weight of 3350 daltons. The
inventors have found that to obtain a combination of high water
permeability and high strength when PEG is used as a pore former,
the weight ratio of CA:PEG should range from about 6.5:3.5 to about
9:1.
[0079] The addition of a non-solvent to the coating solution
results in exceptional performance. By "non-solvent" is meant any
material added to the coating solution that substantially dissolves
in the coating solution and reduces the solubility of the coating
polymer or polymers in the solvent. In general, the function of the
non-solvent is to impart porosity to the resulting coating. As
described below, porous coatings have higher water permeability
than an equivalent weight of a coating of the same composition that
is not porous and this porosity, when the pores are gas filled, as
is typical when the non-solvent is volatile, is indicated by a
reduction in the density of the coating (mass/volume). Although not
wishing to be bound by any particular mechanism of pore formation,
it is generally believed that addition of a non-solvent imparts
porosity to the coating during evaporation of solvent by causing
the coating solution to undergo liquid-liquid phase separation
prior to solidification. As described below for the case of using
water as the non-solvent in an acetone solution of cellulose
acetate, the suitability and amount of a particular candidate
material can be evaluated for use as a non-solvent by progressively
adding the candidate non-solvent to the coating solution until it
becomes cloudy. If this does not occur at any addition level up to
about 50 wt % of the coating solution, it generally is not
appropriate for use as a non-solvent. When clouding is observed,
termed the "cloud point," an appropriate level of non-solvent for
maximum porosity is the amount just below the cloud point. When
lower porosities are desired, the amount of non-solvent can be
reduced as low as desired. It has been found that suitable coatings
can be obtained when the concentration of non-solvent in the
coating solution is greater than about 20% of the non-solvent
concentration that results in the cloud point.
[0080] Suitable non-solvents are any materials that have
appreciable solubility in the solvent and that lower the coating
polymer solubility in the solvent. The preferred non-solvent
depends on the solvent and the coating polymer chosen. In the case
of using a volatile polar coating solvent such as acetone or methyl
ethyl ketone, suitable non-solvents include water, glycerol,
ethylene glycol and its low molecular-weight oligomers (e.g., less
than about 1,000 daltons), propylene glycol and its low molecular
weight oligomers (e.g., less than about 1,000 daltons), C.sub.1 to
C.sub.4 alcohols such as methanol or ethanol, ethylacetate,
acetonitrile and the like.
[0081] In general, to maximize its effect, (e.g., formation of
pores), the non-solvent should have similar or less volatility than
the coating solution solvent such that, during initial evaporation
of the solvent during the coating process, sufficient non-solvent
remains to cause phase separation to occur. In many cases, where a
coating solution solvent such as acetone is used, water is a
suitable non-solvent. For acetone solutions comprising 7 wt % CA
and 3 wt % PEG, the cloud point at room temperature is at about 23
wt % water. Thus the porosity and in turn the water permeability
(which increases with increasing porosity) can be controlled by
varying the water concentration up to near the cloud point. For
acetone solutions comprising CA and PEG with a total concentration
of about 10 wt %, it is desired that the coating solution contain
at least 4 wt % water to obtain a suitable coating. When a higher
porosity, and thus a higher water permeability is desired (to
obtain a faster release rate), the coating solution should contain
at least about 15 wt % water.
[0082] In one embodiment of the invention, the coating solution is
homogeneous, in that when the polymer, solvent, and any pore
formers or non-solvents are mixed, the solution comprises a single
phase. Typically, a homogenous solution will be clear, and not be
cloudy as discussed above.
[0083] When using CA 398-10, exemplary coating solution weight
ratios of CA:PEG 3350:water are 7:3:5, 8:2:5, and 9:1:5, with the
remainder of the solution comprising a solvent such as acetone.
Thus, for example, in a solution having a weight ratio of CA:PEG
3350:water of 7:3:5, CA comprises 7 wt % of the solution, PEG 3350
comprises 3 wt % of the solution, water comprises 5 wt % of the
solution, and acetone comprises the remaining 85 wt %.
[0084] Preferred coatings are generally porous even in the dry
state (prior to delivery to the aqueous use environment). By
"porous" is meant that the coating has a dry-state density less
than the density of the nonporous coating material. By "nonporous
coating material" is meant a coating material formed by using a
coating solution containing no non-solvent, or the minimum amount
of non-solvent required to produce a homogeneous coating solution.
The coating in the dry state has a density that is less than 0.9
times, and more preferably less than 0.75 times that of the
nonporous coating material. The dry-state density of the coating
can be calculated by dividing the coating weight (determined from
the weight gain of the tablets before and after coating) by the
coating volume (calculated by multiplying the coating thickness, as
determined by optical or scanning electron microscopy, by the
tablet surface area). The porous nature of the coating is one of
the factors that leads to the combination of high water
permeability and high strength of the coating.
[0085] The coatings may also be asymmetric, meaning that there is a
gradient of density throughout the coating thickness. Generally,
the outside surface of the coating will have a higher density than
the coating nearest the core.
[0086] The coating can optionally include a plasticizer. A
plasticizer generally swells the coating polymer such that the
polymer's glass transition temperature is lowered, its flexibility
and toughness increased and its permeability altered. When the
plasticizer is hydrophilic, such as polyethylene glycol, the water
permeability of the coating is generally increased. When the
plasticizer is hydrophobic, such as diethyl phthalate or dibutyl
sebacate, the water permeability of the coating is generally
decreased.
[0087] It should be noted that additives can function in more than
one way when added to the coating solution. For example, PEG can
function as a plasticizer at low levels while at higher levels it
can form a separate phase and act as a pore former. In addition,
when a non-solvent is added, PEG can also facilitate pore formation
by partitioning into the non-solvent-rich phase once liquid-liquid
phase separation occurs.
[0088] The weight of the coating around the core depends on the
composition and porosity of the coating, the surface to volume
ratio of the dosage form, and the desired drug release rate, but
generally should be present in an amount ranging from about 3 to 30
wt %, preferably from 8 to 25 wt %, based on the weight of the
uncoated core. However, a coating weight of at least about 8 wt %
is generally preferred so as to assure sufficient strength for
reliable performance, and more preferably a coating greater than
about 13 wt %.
[0089] While porous coatings based on CA, PEG, and water yield
excellent results, other pharmaceutically acceptable materials may
be used so long as the coating has the requisite combination of
high water permeability, high strength, and ease of manufacture.
Further, such coatings may be dense, or asymmetric, having one or
more dense layers and one or more porous layers, as described in
U.S. Pat. Nos. 5,612,059 and 5,698,220.
[0090] The coating 18 must also contain at least one delivery port
20 in communication with the interior and exterior of the coating
to allow for release of the drug-containing composition to the
exterior of the dosage form. The delivery port can range in size
from about the size of the drug particles, and thus could be as
small as 1 to 100 microns in diameter and may be termed pores, up
to about 5000 microns in diameter. The shape of the port may be
substantially circular, in the form of a slit, or other convenient
shape to ease manufacturing and processing. The port(s) may be
formed by post-coating mechanical or thermal means or with a beam
of light (e.g., a laser), a beam of particles, or other high-energy
source, or may be formed in situ by rupture of a small portion of
the coating. Such rupture may be controlled by intentionally
incorporating a relatively small weak portion into the coating.
Delivery ports may also be formed in situ by erosion of a plug of
water-soluble material or by rupture of a thinner portion of the
coating over an indentation in the core. Delivery ports may be
formed by coating the core such that one or more small regions
remains uncoated. In addition, the delivery port can be a large
number of holes or pores that may be formed during coating, as in
the case of asymmetric membrane coatings of the type disclosed in
U.S. Pat. Nos. 5,612,059 and 5,698,220, the disclosures of which
are incorporated by reference. When the delivery pathways are pores
there can be a multitude of such pores that range in size from 1
.mu.m to greater than 100 .mu.m. During operation, one or more of
such pores may enlarge under the influence of the hydrostatic
pressure generated during operation. The number of delivery ports
20 may vary from 1 to 10 or more. At least one delivery port should
be formed on the side of the coating that is adjacent to the
drug-containing composition, so that the drug-containing
composition will be extruded out of the delivery port by the
swelling action of the water-swellable composition. It is
recognized that some processes for forming delivery ports may also
form holes or pores in the coating adjacent to the water-swellable
composition. In aggregate, the total surface area of core exposed
by delivery ports is less than 5%, and more typically less than
1%.
[0091] Other features and embodiments of the invention will become
apparent from the following examples which are given for
illustration of the invention rather than for limiting its intended
scope.
EXAMPLE 1
[0092] Exemplary dosage forms of the present invention were made
with a bi-layer core geometry of the type depicted in FIG. 1. The
bi-layer core consisted of a drug-containing composition and a
water-swellable composition.
[0093] To form the drug-containing composition the following
materials were blended (see Table A): 35 wt % of the citrate salt
of
1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyri-
midin-5-yl)phenylsulphony]-4-methylpiperazine for treatment of
penile erectile disfunction, also known as sildenafil citrate
(hereinafter referred to as Drug 1) having a solubility of about 20
.mu.g/mL at pH 6, 30 wt % xylitol (trade name XYLITAB 200), 29 wt %
PEO with an average molecular weight of 600,000, 5 wt % sodium
starch glycolate (trade name EXPLOTAB), and 1 wt % magnesium
stearate. The drug-containing composition ingredients were first
combined without the magnesium stearate and blended for 20 minutes
in a TURBULA mixer. This blend was pushed through a screen (screen
size of 0.065 inch), then blended again for 20 minutes in the same
mixer. Next, magnesium stearate was added and the drug-containing
composition was blended again for 4 minutes in the same mixer. To
form the water-swellable composition, the following materials were
blended: 74.5 wt % EXPLOTAB, 25 wt % of the tableting aid
silicified microcrystalline cellulose (trade name PROSOLV 90), and
0.5 wt % magnesium stearate. The water-swellable composition was
formulated in the same manner as the drug-containing
composition.
[0094] Tablet cores were formed by placing 400 mg of
drug-containing composition in a standard {fraction (13/32)} inch
die and gently leveling with the press. Then, 100 mg
water-swellable composition was placed in the die on top of the
drug-containing composition. The tablet core was then compressed to
a hardness of about 11 Kp. The resulting bi-layer tablet core had a
total weight of 500 mg and contained a total of 28 wt % Drug 1 (140
mg), 24 wt % XYLITAB 200, 23 wt % PEO 600,000, 18.9 wt % EXPLOTAB,
5 wt % PROSOLV 90, and 1.1 wt % magnesium stearate.
[0095] Coatings were applied by a Vector LDCS-20 pan coater. The
coating solution contained CA (CA 398-10 from Eastman Fine
Chemical, Kingsport, Tennessee), polyethylene glycol (PEG 3350,
Union Carbide), water, and acetone in a weight ratio of 7/3/5/85
(wt %). The flow rate of the inlet heated drying air of the pan
coater was set at 40 ft.sup.3/min with the outlet temperature set
at 25.degree. C. Nitrogen at 20 psi was used to atomize the coating
solution from the spray nozzle, with a nozzle-to-bed distance of 2
inches. The pan rotation was set to 20 rpm. The so-coated tablets
were dried at 50.degree. C. in a convection oven. The final dry
coating weight amounted to 40.5 mg or 8.1 wt % of the tablet core.
Five 900 .mu.m diameter holes were then mechanically drilled in the
coating on the drug-containing composition side of the tablet to
provide 5 delivery ports per tablet. Table C summarizes the
characteristics of the dosage form.
[0096] To simulate in vivo drug dissolution, tablets were placed in
900 mL of a simulated gastric solution (10 mM HCl, 100 mM NaCl, pH
2.0, 261 mOsm/kg) for 2 hours, then transferred to 900 mL of a
simulated intestinal environment solution (6 mM KH.sub.2PO.sub.4,
64 mM KCl, 35 mM NaCl, pH 7.2, 210 mOsm/kg), both solutions being
stirred at 50 rpm. A residual dissolution test was performed as
described in the Detailed Description section. Residual drug was
analyzed by HPLC using a Waters Symmetry C.sub.18 column. The
mobile phase consisted of 0.05 M triethanolamine (pH
3)/methanol/acetonitrile in a volume ratio of 58/25/17. Drug
concentration was calculated by comparing UV absorbance at 290 nm
to the absorbance of Drug 1 standards. The amount of drug remaining
in the tablets was subtracted from the total initial amount of drug
in the tablet to obtain the amount released at each time interval.
Results are shown in Table 1 and summarized in Table D.
2 TABLE 1 Time Drug (hours) (wt % released) 0 0 2 25 4 46 8 74 14
94 20 98
[0097] The data show that 25 wt % of the drug was released within 2
hours, 74 wt % within 8 hours, and 98 wt % of the drug was released
within 20 hours. Thus, the present invention provided a rapid
release of over 70 wt % within 8 hours and very low residual value
at 20 hours of a relatively high dose (140 mg) of a low-solubility
drug in a relatively low mass (540 mg) dosage form.
EXAMPLE 2
[0098] This example demonstrates the inventive delivery of a high
dose of Drug 1 from bi-layer tablets by increasing the amount of
drug in the drug-containing composition. For the tablets of Example
2, the drug-containing composition consisted of 56 wt % Drug 1, 20
wt % XYLITAB 200, 19 wt % PEO with an average molecular weight of
600,000, 4 wt % EXPLOTAB, and 1 wt % magnesium stearate. The
water-swellable composition consisted of 74.5 wt % EXPLOTAB, 25 wt
% PROSOLV 90, and 0.5 wt % magnesium stearate. These tablets were
made as in Example 1, except that 500 mg of the drug-containing
composition was used to make the tablet. See Table C for further
details of the make-up of the tablets. The drug-containing
composition and water-swellable composition for this example were
combined in a ratio of 83.3 wt % drug-containing composition to
16.7 wt % water-swellable composition. Dissolution tests were
performed as described in Example 1. Results are shown in Table 2
and summarized in Table D.
3 TABLE 2 Time Drug (hours) (wt % released) 0 0 2 16 4 34 8 57 14
76 20 86
[0099] The above data show that 16 wt % of the drug was released
within 2 hours and 86 wt % within 20 hours. Thus, the dosage forms
of the present invention performed well, even with a high drug
loading in the drug-containing composition.
EXAMPLES 3A-3B
[0100] These examples demonstrate the inventive delivery of various
drugs from bi-layer tablets. For the tablets of Example 3A, the
drug-containing composition consisted of 35% sertraline HCl (Drug
2) having a solubility of 0.2 mg/mL at pH 7, 30 wt % XYLITAB 200,
28.75 wt % PEO with an average molecular weight of 600,000, 5 wt %
EXPLOTAB, and 1.25 wt % magnesium stearate. The water-swellable
composition consisted of 74.5 wt % EXPLOTAB, 25 wt % PROSOLV 90,
and 0.5 wt % magnesium stearate. These tablets were made as in
Example 1. Dissolution tests were performed on these tablets in the
same manner as Example 1 except the residual drug was analyzed by
HPLC using a Phenomenex Ultracarb 5 ODS 20 column. The mobile phase
consisted of 35 vol % TEA-acetate buffer (3.48 mL triethanolamine
and 2.86 mL glacial acetic acid in 1 L HPLC H.sub.2O) in
acetonitrile. Drug concentration was calculated by comparing UV
absorbance at 230 nm to the absorbance of sertraline standards. The
results are presented in Table 3 and summarized in Table D.
[0101] For the tablets of Example 3B, the drug-containing
composition consisted of 32.4 wt % of mesylate salt of the drug
4-[3-[4-(2-methylimidazol-1-yl)
phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-- pyran-4-carboxamide
hemifumarate a 5-lipoxygenase inhibitor for the treatment of
chronic inflammatory conditions such as asthma (Drug 3) having a
solubility of 3.7 mgA/mL at pH 4, 31.2 wt % XYLITAB 200, 29.9 wt %
PEO with an average molecular weight of 600,000, 5.2 wt % EXPLOTAB,
and 1.3 wt % magnesium stearate (see Table A). The water-swellable
composition consisted of 74.5 wt % EXPLOTAB, 24.5 wt % PROSOLV 90,
and 1 wt % magnesium stearate. These tablets were made as in
Example 1. Dissolution tests were performed on these tablets in
accordance with Example 1 with the following exceptions: residual
drug was analyzed by dissolving tablets in 0.1 N HCl and measuring
UV absorbance at 258 nm. Results are shown in Table 3 and
summarized in Table D.
4TABLE 3 Time Drug Example (hours) (% released) 3A 0 0 2 22 4 45 8
79 14 92 20 94 3B 0 0 2 18 4 38 8 68 12 85 18 89 24 91
[0102] Examples 3A and 3B show low residual drug after 24 hours
with virtually no lag time. Along with Example 1, these examples
show that different low-solubility drugs can be successfully
delivered from dosage forms of this invention.
EXAMPLE 4
[0103] This example demonstrates the inventive delivery of Drug 2
from bi-layer tablets without an ionic swelling agent in the
water-swellable composition. For the tablets of Example 4, the
drug-containing composition consisted of 35% Drug 2, 30 wt %
XYLITAB 200, 29 wt % PEO with an average molecular weight of
600,000, 5 wt % EXPLOTAB, and 1 wt % magnesium stearate (see Table
A). The water-swellable composition consisted of 65 wt % PEO with
an average molecular weight of 5,000,000, 29.4 wt % NaCl, 5% of the
tableting aid hydroxymethylcellulose (METHOCEL), and 0.6 wt %
magnesium stearate (see Table B). These tablets were made as in
Example 1, except that 490 mg of the drug-containing composition
and 245 mg of the water-swellable composition were used to make the
tablet (see Table C). Dissolution tests were performed on these
tablets as described in Example 3A. Results are shown in Table 4
and summarized in Table D.
5 TABLE 4 Time Drug (hours) (wt % released) 0 0 1 1 2 15 4 47 8 80
12 90 18 95 24 87
[0104] The data show that 15 wt % of the drug was released within 2
hours and 87 wt % was released within 24 hours when there was no
ionic swelling agent in the water-swellable composition.
EXAMPLES 5A-5C
[0105] These examples demonstrate that various amounts of ionic
swelling agent and tableting aid can be used to form dosage forms
with the desired release profile.
[0106] For the tablets of Examples 5A, 5B, and 5C, the
drug-containing composition consisted of 35 wt % Drug 1, 30 wt %
XYLITAB 200, 29 wt % PEO with an average molecular weight of
600,000, 5 wt % EXPLOTAB, and 1 wt % magnesium stearate. The
drug-containing composition was wet-granulated using deionized
water and dried overnight in a 40.degree. C. oven. For tablets of
Example 5A, the water-swellable composition consisted of 74.35 wt %
EXPLOTAB, 24.85 wt % PROSOLV 90, 0.3 wt % Red Lake #40, and 0.3 wt
% magnesium stearate. The water-swellable composition was formed by
wet-granulating the EXPLOTAB and PROSOLV 90 using water as solvent,
drying this mixture, and then blending with the other
ingredients.
[0107] For tablets of Example 5B, the water-swellable composition
consisted of 49.4 wt % EXPLOTAB, 49.4 wt % PROSOLV 90, 0.2 wt % Red
Lake #40, and 1 wt % magnesium stearate. The water-swellable
composition was wet-granulated as in Example 5A.
[0108] For tablets of Example 5C, the water-swellable composition
consisted of 59.35 wt % EXPLOTAB, 39.4 wt % PROSOLV 90, 0.25 wt %
Red Lake #40, and 1 wt % magnesium stearate. The water-swellable
composition was wet-granulated as in Example 5A.
[0109] Tablets were formed by placing 400 mg of drug-containing
composition in a standard {fraction (13/32)} inch die and tamping
lightly. Then, 100 mg water-swellable composition was placed in the
die on top of the drug-containing composition. The tablet was then
compressed to a hardness of about 12 Kp. All cores were coated in
the same manner as in Example 1, except the final dry coating
weights for each example were 40.5 mg (8.1 wt %) for 5A, 46.5 mg
(9.3 wt %) for 5B, and 43.5 mg (8.7 wt %) for 5C respectively.
[0110] Dissolution tests were performed on these tablets as
described in Example 1. Results are shown in Table 5 and summarized
in Table D.
6 TABLE 5 Time Drug Example (hours) (wt % released) 5A 0 0
EXPLOTAB/ 2 15 PROSOLV 90 = 4 43 75/25* 8 69 14 94 20 97 5B 0 0
EXPLOTAB/ 2 15 PROSOLV 90 = 4 40 50/50* 8 67 14 89 20 96 5C 0 0
EXPLOTAB/ 2 16 PROSOLV 90 = 4 40 60/40* 8 69 14 89 20 96
*approximate
[0111] The data show that the weight ratio of EXPLOTAB to PROSOLV
90 can be varied from about 75/25 to about 50/50 without any
adverse effect on the desired drug release profile.
EXAMPLE 6
[0112] This example demonstrates that low residual drug values may
be obtained with the dosage forms of the invention even with high
drug loading. For the tablets of Example 6, the drug-containing
composition and the water-swellable composition were the same as in
Example 2, and were made as in Example 2, except that 200 mg of the
water-swellable composition was used to make the tablets (71.4%
drug-containing composition/28.6% water-swellable composition) and
the tablets had a 77.7 mg (11.1 wt %) coating. Dissolution tests
were performed as described in Example 1. Results are shown in
Table 6.
7 TABLE 6 Time Drug (hours) (wt % released) 0 0 2 16 4 39 8 65 14
89 20 94
[0113] A comparison of these data with those of Example 2 show that
the initial rate of drug release was the same, releasing 16 wt % of
the drug within 2 hours. Compared to Example 2, the data also show
that increasing the amount of water-swellable composition in the
core (Example 6) resulted in a higher percentage (94% vs. 86%) of
the drug being released after 20 hours, thereby leaving a lower
amount of residual drug.
EXAMPLES 7A-7D
[0114] These examples demonstrate the relationship between the drug
release profile and the water permeability of the coating. For the
tablets of Examples 7A, 7B, 7C, and 7D, the drug-containing
composition consisted of 35 wt % Drug 1, 30 wt % XYLITAB 200, 29 wt
% PEO with an average molecular weight of 600,000, 5 wt % EXPLOTAB,
and 1 wt % magnesium stearate. The water-swellable composition
consisted of 74.35 wt % EXPLOTAB, 24.85 wt % PROSOLV 90, 0.3 wt %
Red Lake #40, and 0.3 wt % magnesium stearate.
[0115] These tablets were made as in Example 1, except that the
tablets had different amounts of coating (see Table C). For the
tablets of Example 7A, the coating had a final dry weight of 29 mg
(5.8 wt %). For the tablets of Example 7B, the coating had a final
dry weight of 56.5 mg (11.3 wt %). For the tablets of Example 7C,
the coating had a final dry weight of 89.5 mg (17.9 wt %). For the
tablets of Example 7D, the coating had a final dry weight of 124.5
mg (24.9 wt %). Generally, the thicker the coating, the lower the
expected water permeability. Dissolution tests were performed on
these tablets as described in Example 1. Results are shown in Table
7 and are summarized in Table D.
8TABLE 7 Time Drug Example (hours) (wt % released) 7A 0 0 2 30 4 57
8 88 14 98 20 97 7B 0 0 2 19 4 45 8 69 14 94 20 98 7C 0 0 2 8 4 27
8 60 14 82 20 94 7D 0 0 2 0 4 17 8 48 14 68 20 88
[0116] Examples 7A-7D show that as the water permeability
decreased, i.e., as the coating weight increased, the rate of drug
release decreased. The data show that as the coating thickness
increased, the fraction of drug delivered between 0 and 2 hours
decreased, while the fraction of drug delivered from 8 to 20 hours
increased.
EXAMPLE 8
[0117] This example demonstrates the delivery of an amorphous
dispersion of Drug 2 in a concentration-enhancing polymer from a
dosage form of the invention. Amorphous solid dispersions of Drug 2
in HPMCP were prepared by spray-drying a solution containing 0.65
wt % sertraline free base, 0.65 wt % hydroxy propylmethyl cellulose
phthalate (HPMCP 55), 49.35 wt % methanol, and 49.35 wt % acetone.
The drug was dissolved in the methanol, and the polymer was
dissolved in the acetone, before combining the solutions. The
solution was spray-dried using a two-fluid external mix spray
nozzle at 1.8 bar at a feed rate of 187 to 211 g/min into the
stainless steel chamber of a Niro spray-dryer, maintained at a
temperature of 230.degree. C. at the inlet and 72.degree. C. at the
outlet.
[0118] To form the drug-containing composition, the following
materials were blended: 41.15 wt % sertraline dispersion (1:1
sertraline free base:HPMCP), 26.75 wt % PEO having an average
molecular weight of 600,000, 26.75 wt % XYLITAB 200, 4.33 wt %
EXPLOTAB, and 1.02 wt % magnesium stearate. The drug-containing
composition ingredients were combined and precompressed, then
milled in a co-mill at 1100 rpm with a screen size having
0.075-inch openings.
[0119] To form the water-swellable composition, the following
materials were blended: 74.66 wt % EXPLOTAB, 24.73 wt % PROSOLV 90,
0.47 wt % magnesium stearate, and 0.14 wt % Red Lake #40. The
water-swellable composition ingredients were combined without the
magnesium stearate, blended 20 minutes in a Turbula mixer, then
blended again for 4 minutes with magnesium stearate. Assays of
these tablets confirmed 112 mg of active sertraline (mgA).
[0120] Release of the sertraline dispersion from the bi-layer
tablets into simulated intestinal buffer was measured by HPLC as
described in Example 3A. Results are shown in Table 8 and
summarized in Table D.
9 TABLE 8 Time Drug (hours) (wt % released) 0 0 1 7 2 17 4 40 8 68
12 86 18 91 24 86
[0121] The data demonstrate satisfactory delivery of a sertraline
dispersion from dosage forms of this invention.
EXAMPLE 9
[0122] This example illustrates the delivery of another drug
dispersion from a bi-layer tablet. The drug was in the form of a
solid amorphous dispersion comprising 50 wt % of
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3R,
4S)-dihydroxypyrrolidin-1-yl-)-(2R)-hydroxy-3-oxypro- pyl] amide (a
glycogen phosphorylase inhibitor) (Drug 4) having a water
solubility of 80 .mu.g/mL and 50% hydroxy proplymethyl cellulose
acetate succinate (HPMCAS MF grade). The solid dispersion was
prepared in essentially the same way as Example 8 except as
follows: the solution comprised 7.5 wt % Drug 4, 7.5 wt % polymer
and 85 wt % 95:5 acetone:H.sub.2O (wt:wt) This solution was
spray-dried using an external mix 2-fluid atomizer with feed rates
of 460 g/min atomizing gas and 200 g/min solution feed with an
inlet temperature of 195.degree. C. and an outlet temperature of
70.degree. C.
[0123] The resulting solid particles had an average diameter of
approximately 50 .mu.m. The drug-containing composition consisted
of 44.4 wt % solid dispersion, 26.1 wt % XYLITAB 200, 25.2 wt % PEO
with an average molecular weight of 600,000, 3.5 wt % EXPLOTAB, and
0.8 wt % magnesium stearate. The water-swellable composition
consisted of 74.8 wt % EXPLOTAB, 24.8 wt % PROSOLV 90, and 0.4 wt %
magnesium stearate (see Table B).
[0124] The drug-containing composition ingredients were
mechanically mixed until substantially homogeneous, compressed into
a weak tablet, then the resulting tablets were ground to particles
less than 16 mesh in size. The water-swellable composition
ingredients were then mixed until substantially homogeneous.
Tablets were formed by first placing 450 mg of ground
drug-containing composition in an f-press in a standard {fraction
(15/32)}-inch die and tamping lightly. Then, 150 mg of the
water-swellable composition mixture was placed in the die on top of
the drug-containing composition. The tablet was then compressed to
a hardness of 15 Kp.
[0125] The resulting bi-layer tablet core had a total weight of 600
mg and contained 199.8 mg of solid dispersion, 99.9 mg of which was
Drug 4. This core was then coated as in Example 1 to obtain a
coating weight of 8.9%, and five 900 .mu.m holes were drilled on
the drug face only of the tablet.
[0126] The dissolution of drug was studied by placing the bi-layer
tablets in intestinal buffer and stirring at 50 rpm. Tablets were
dissolved in 75/25 methanol/water for residual analysis. Drug
concentration over time was determined using a Zorbax SB C18
column, with a mobile phase of 35 vol % acetonitrile in water, and
UV absorbance measured at 297 nm. The results are shown in Table 9
and are summarized in Table D.
[0127] The data shows satisfactory release of a dispersion of Drug
4 from the bi-layer tablet.
10 TABLE 9 Time Drug (hours) (wt % released) 0 0 1 1 2 4 4 28 8 63
12 81 18 96 24 97
EXAMPLE 10
[0128] This example illustrates the delivery of
5-(2-(4-(3-benzisothiazoly- l)-piperazinyl)ethyl-6-chlorooxindole
(Drug 5) from a bi-layer tablet. The drug was in the from of a
solid dispersion comprising 10 wt % of Drug 5 having a solubility
of 3 .mu.g/mL in model fasted duodenal solution and 90 wt % HPMCAS,
HF grade. The solid dispersion was prepared in essentially the same
way as Example 8 except as follows: the solution comprised 0.3 wt %
Drug 5, 2.7 wt % HPMCAS and 97 wt % MeOH. This solution was spray
dried at 19 psi and a 140 g/min feed rate with an inlet temperature
of 264.degree. C. and an outlet temperature of 62.degree. C.
[0129] The drug-containing composition consisted of 45.1 wt % solid
dispersion, 25 wt % XYLITAB 200, 25 wt % PEO with an average
molecular weight of 600,000, 3.9 wt % EXPLOTAB, and 1% magnesium
stearate. The water-swellable composition consisted of 74.8 wt %
EXPLOTAB, 24.7 wt % PROSOLV 90, and 0.5 wt % magnesium stearate.
Tablets were formed by first mechanically mixing the above
drug-containing composition ingredients until homogeneous,
compressing into a tablet of 10-20 Kp, and grinding resulting
tablets to particles. The above water-swellable composition
ingredients were mixed until homogeneous. Bi-layer tablets were
prepared from the drug-containing composition particles and
water-swellable composition, as described in Example 9.
[0130] The resulting bi-layer core had a total weight of 700 mg and
contained 247.8 mg of solid dispersion, 22.84 mg of which was Drug
5. The bi-layer core was then coated as in Example 1 to obtain a
coating weight of 11.3%, and five 2 mM holes were drilled.
[0131] The dissolution of drug was studied by placing the bi-layer
tablets in intestinal buffer and stirring at 50 rpm. Tablets were
dissolved in 75/25 methanol/water (w/w) for analysis for residual
drug content. Drug concentration was determined using HPLC, with a
mobile phase of 60 vol % 0.02 M KH.sub.2PO.sub.4, pH 3.0 in ACN,
and diode array detection at 254 nm. The results are shown in Table
10 and summarized in Table D.
11 TABLE 10 Time Drug (hours) (wt % released) 0 0 1 5 2 13 4 26 8
46 12 73 18 76 24 74
[0132] The data shows satisfactory release of a dispersion of Drug
5 from the bi-layer tablet.
EXAMPLE 11
[0133] This example demonstrates the inventive delivery of Drug 2
from bi-layer tablets without a swelling agent in the
drug-containing composition. For the tablets of Example 11, the
drug-containing composition consisted of 22.8% Drug 2, 71.7 wt %
PEO with an average molecular weight of 200,000, 5 wt % Methocel,
and 0.5 wt % magnesium stearate. The water-swellable composition
consisted of 74.5 wt % EXPLOTAB, 25.0 wt % PROSOLV 90, and 0.5 wt %
magnesium stearate. These tablets were made as in Example 1, except
that 490 mg of the drug-containing composition and 245 mg of the
water-swellable composition were used to make the tablet.
Dissolution tests were performed on these tablets as described in
Example 1. Results are shown in Table 11 and summarized in Table
D.
12 TABLE 11 Time Drug (hours) (wt % released) 0 0 1 3 2 17 4 49 8
70 12 84 20 88 24 92
[0134] The data show that satisfactory drug delivery was obtained
with dosage forms of the invention without a swelling agent in the
drug-containing composition.
EXAMPLE 12
[0135] This example describes the results of tests to determine the
swelling volume of swelling agents that may be used in the
formulation of the water-swellable composition.
[0136] The following experiment was used to determine the swelling
ratio of materials. The materials were first blended and then 500
mg of the material was compressed into a tablet using a {fraction
(13/32)}-inch die, the tablet having a strength ranging from 3 to
16 Kp/cm.sup.2. This compressed material was then placed into a
glass cylinder of approximately the same inside diameter as the
tablet. The height of the tablet was then measured. Using this
height and the diameter of the tablet, the volume of the dry
material was determined. Next, the glass cylinder was filled with
test media of either deionized water, simulated intestinal buffer,
or simulated gastric buffer. The glass cylinder and test media were
all equilibrated at a constant temperature of 37.degree. C. As the
materials in the tablet absorbed water, the height of the tablet
increased. At each time interval, the height of the tablet was
measured, from which the volume of the swollen tablet was
determined. The ratio of the volume of the tablet after reaching a
constant height to that of the volume of the dry tablet is the
swelling ratio of the material. The results of these tests are
shown in Table 12.
13TABLE 12 Water-Swellable Composition Swelling Swelling Ratio
(v/v) Tableting Agent/ In- Swelling Aid/ Tableting Gastric testinal
Agent Additive Aid (w/w) Buffer Buffer Water PEO 5,000,000 NONE
100/0 2.4 2.4 2.4 PEO 5,000,000 Microcrystal- 85/15 2.2 2.1 2.4
line cellulose.sup.1 PEO 5,000,000 Microcrystal- 70/30 2.0 2.1 2.4
line cellulose PEO 5,000,000 Microcrystal- 50/50 2.0 1.9 1.9 line
cellulose PEO 5,000,000 NaCl 70/30 2.6 2.6 2.8 PEO 2,000,000
Microcrystal- 85/15 2.8 2.8 3.0 line cellulose Polyacrylic
Silicified 70/30 1.9 1.5 acid.sup.2 microcrystal- line
cellulose.sup.3 Polyacrylic Microcrystal- 50/50 1.8 1.7 acid line
cellulose Sodium cros- None 100/0 7.0 5.4 7.1 carmelose.sup.4
Sodium cros- Microcrystal- 85/15 7.1 5.9 7.2 carmellose line
cellulose Sodium cros- Microcrystal- 70/30 5.5 6.3 5.5 carmellose
line cellulose Sodium cros- Microcrystal- 50/50 4.6 5.3 5.7
carmellose line cellulose Sodium starch Microcrystal- 50/50 7.1 7.7
25.2 glycolate.sup.5 line cellulose Sodium starch Microcrystal-
70/30 9.0 9.6 26.8 glycolate line cellulose Sodium starch
Microcrystal- 85/15 10.9 11.9 34.7 glycolate line cellulose Sodium
starch Silicified 50/50 7.9 8.7 glycolate Microcrystal- line
cellulose Sodium starch Silicified 75/25 7.4 9.1 14.4 glycolate
Microcrystal- line cellulose Sodium starch Silicified 70/30 10.6
11.2 glycolate Microcrystal- line cellulose Sodium starch
Hydroxypropyl 98/2 -- 17.2 glycolate cellulose.sup.6 Sodium starch
Hydroxypropyl 95/5 5.6 8.4 glycolate cellulose Sodium starch
Hydroxypropyl 90/10 7.2 6.9 glycolate cellulose Sodium starch
Hydroxypropyl 85/15 -- 3.8 3.8 glycolate cellulose Sodium starch
Hydroxypropyl 70/30 3.7 3.9 3.3 glycolate cellulose Sodium starch
Hydroxypropyl 50/50 2.4 2.5 2.4 glycolate cellulose Sodium
Silicified 50/50 2.7 2.9 alginate.sup.7 microcrystal- line
cellulose Hydroxyethyl NONE 100/0 2.8 2.8 2.7 cellulose.sup.8
Hydroxyethyl Microcrystal- 50/50 2.4 2.1 2.5 cellulose line
cellulose .sup.1= AVICEL .sup.2= CARBOPOL 974PNF .sup.3= PROSOLV 90
.sup.4= AC-DI-SOL .sup.5= EXPLOTAB .sup.6= Klucel .sup.7= Keltone
LVCR .sup.8= Natrosol
EXAMPLE 13
[0137] Exemplary dosage forms of the present invention were made
with a bi-layer core geometry of the type depicted in FIG. 1. This
example illustrates dosage forms of this invention which release
drug over a short duration, utilizing a durable, high permeability
coating. The drug-containing composition comprised the following
materials: 22.8 wt % Drug 2, 71.7 wt % PEO with an average
molecular weight of 200,000 (Polyox WSR N80), 5.0 wt % METHOCEL K3
LV Prem (a tablet binder), and 0.5 wt % of the lubricant, magnesium
stearate.
[0138] To form the drug-containing composition, the ingredients
(without the magnesium stearate) were blended for 20 minutes in a
Turbula mixer. This blend was screened through a 0.065-inch screen,
then blended again for 20 minutes. Next, magnesium stearate was
added and the materials were blended again for 4 minutes. The
water-swellable composition comprised the following materials: 65.0
wt % PEO with an average molecular weight of 5,000,000 (Polyox WSR
Coagulant), 29.3 wt % sodium chloride, 5.1 wt % METHOCEL K3 LV
Prem., and 0.6 wt % magnesium stearate.
[0139] To form the water-swellable composition, the ingredients
(without the magnesium stearate) were blended 20 minutes in a
Turbula mixer, then blended again for 4 minutes with magnesium
stearate.
[0140] The drug-containing composition and the water-swellable
composition were tableted together using direct compression. A
portion of the drug-containing composition (490 mg) was placed in
an f-press with a standard round concave {fraction (15/32)}-inch
die, then gently leveled with the upper punch. A 245 mg portion of
the water-swellable composition was placed on top of this and the
tablet compressed. The compression distance between the upper and
lower punches on the f-press was adjusted until the hardness of the
resulting tablets measured 15 Kp. The resulting bi-layer tablet
contained a total of 15.2 wt % Sertraline HCl, 47.8 wt % PEO
200,000, 5.0 wt % METHOCEL, 0.5 wt % magnesium stearate, 21.7 wt %
PEO 5,000,000, and 9.8 wt % sodium chloride. Assays of these
tablets confirmed 112 mg of Sertraline HCl, or 100 mg of active
Sertraline (mgA).
[0141] The tablets were coated with a high water permeability
coating in a Vector LDCS-20 pan coater as described in Example 1.
The coating solution contained cellulose acetate (CA 398-10),
polyethylene glycol (PEG 3350), water, and acetone in a weight
ratio of 7/3/5/85. Heated drying air (40 cfm) was adjusted to
maintain the pan coater outlet temperature at 25.degree. C.
Nitrogen at 20 psi was used to atomize the coating solution from
the spray nozzle, with a nozzle-to-bed distance of 2 inches. The
pan tumbled at 20 rpm. The final dry coating weight amounted to
12.9 wt % of the weight of the tablet core. One 900-.mu.m hole was
hand-drilled on the face of the tablet. The total weight of the
coated tablet was 830 mg.
[0142] An in vitro residual test was performed as described in
Example 3A. Results are shown in Table 13 and are summarized in
Table D. The data show that 19% of the drug was released within 2
hours, and that 98% of the drug was released within 8 hours.
Observations of the tablets during the release test indicated that
the coating was able to withstand the swelling of the PEO-based
core and remained intact for the duration of the test.
14 TABLE 13 Time Drug (hours) (wt % released) 0 0 1 2 2 19 4 51 8
98 12 99 18 99 24 99
EXAMPLE 14
[0143] This example demonstrates the inventive delivery of Drug 2
from a tablet of the present invention, while increasing the
percentage of drug in the drug-containing composition to 35 wt %.
Tablets for Example 14 were made as in Example 13, with ingredients
indicated in Tables A, B, and C. Dissolution tests were performed
as described in Example 3A. Results are shown in Table 14 and
summarized in Table D.
15 TABLE 14 Time Drug (hours) (wt % released) 0 0 1 7 2 25 4 65 8
97 12 98 18 98 24 98
[0144] The data show that even with a high percentage of drug in
the drug-containing composition, the rate of drug release remained
high, showing a release of 25% after 2 hours. Furthermore, 97% of
the drug had been released within 8 hours. This example shows that
successful delivery of drug from dosage forms of this invention can
be obtained, even for delivery of large amounts of drug as a
percentage of the drug-containing composition. Such high drug
loadings are desirable when delivery of a high dose of drug is
desired while keeping tablet size acceptably small.
EXAMPLES 15A-C
[0145] These examples show the effects of the formulation of the
coating material on the water permeability of the coating by
measuring the water flux (40/75), a relative measure of the water
permeability of coatings useful in comparing coatings. Tablets were
made as in Example 13, with the exceptions noted in Tables A, B,
and C. The tablets were made using {fraction (15/32)}-inch tooling,
with compression at 13.4 Kp. Each tablet had a surface area of
approximately 4.35 cm.sup.2.
[0146] Coatings were applied to these tablets as in Example 1.
Table 15.1 reports the composition of the coating solutions used.
Acetone was used as the solvent in all cases.
16 TABLE 15.1 Coating Solution Coating weight Formulation (wt %)
per Tablet Example CA 398-10 PEG Water mg wt % 15A 7 3 5 82 11.2
15B 8 2 5 84 11.4 15C 9 1 5 86 11.7
[0147] To determine water flux (40/75) values, five tablets from
each example were placed in a weigh boat in an environmental
chamber having a constant temperature of 40.degree. C. and a
constant relative humidity of 75%. Periodically, the tablets were
removed and weighed. Table 15.2 gives the data from this
experiment.
17TABLE 15.2 Weight of 5 Tablets (g) Time(Hours) Example 15A
Example 15B Example 15C 0 4.0241 4.0383 4.0703 0.5 4.0491 4.0590
4.0867 1 4.0611 4.0676 4.0948 3 4.0882 4.0901 4.1158 4 4.0943
4.0966 4.1213 5 4.1025 4.1031 4.1281 6 4.1082 4.1076 4.1338 7
4.1119 4.1110 4.1370 22 4.1338 4.1303 4.1593 23 4.1374 4.1341
4.1627 24 4.1406 4.1356 4.1649
[0148] The water flux (40/75) values of the coatings were
determined by dividing the initial slope obtained by plotting
weight versus time by the tablet surface area for 5 tablets. Table
15.3 reports the results of these calculations (using a linear
regression fit of the first three data points to determine the
initial slope. The data show that the water flux (40/75) values
increased as the amount of PEG included in the coating solution was
increased relative to the amount of CA.
18TABLE 15.3 CA/PEG Ratio Water Flux (40/75) Example (by weight)
(g/hr .multidot. cm.sup.2) 15A 7:3 1.7 .times. 10.sup.-3 15B 8:2
1.4 .times. 10.sup.-3 15C 9:1 1.1 .times. 10.sup.-3
EXAMPLES 16A-16U
[0149] These examples measure the "durability" of the coating, a
relative measure of the strength of the coatings found to be a
useful measure for comparing coatings. For Examples 16A-16G,
tablets were made as in Example 1, with the exceptions noted in
Tables A and B. As indicated in Table C, two different types of
coatings and various coating weights were used to coat these
tablets. The tablets were made using {fraction (13/32)}-inch
tooling, yielding tablets with a maximum cross-sectional area of
0.84 cm.sup.2. For Examples 16H-16U, tablets were made as in
Example 14, with the exceptions noted in Tables A and B. These
tablets were coated with various coating weights, as indicated in
Table C. The tablets were made using {fraction (7/16)}-inch
tooling, yielding tablets with a maximum cross-sectional area of
0.97 cm.sup.2. Table 16.1 lists the compositions and coating
weights for the tablets of Example 16. Acetone was used as the
solvent in all cases.
[0150] To determine the coating durability, the tablets were placed
in deionized water at 37.degree. C. for 16 to 24 hours. The tablets
were then removed, rinsed in deionized water, and tested for
hardness on a Schleuniger tablet hardness tester, Model 6D. Tablets
were placed in the tester so that the delivery port was blocked
against the tester plate when force was applied. The durability for
each tablet, defined as the tablet hardness (in Kp) divided by the
maximum cross-sectional surface area (in cm.sup.2), was calculated
from these tests, and is set forth in Table 16.2.
19TABLE 16.1 Coating Coating-Solution Weight per Formulation (wt %)
Tablet Example CA 398-10 PEG Water Wt % 16A 4 1 2.5 11.7 16B 4 1
2.5 11.2 16C 8 2 5 6.9 16D 7 3 5 8.1 16E 7 3 5 8.3 16F 7 3 5 12.0
16G 7 3 5 12.8 16H 7 3 5 12.4 16I 7 3 5 11.1 16J 7 3 5 10.3 16K 7 3
5 7.9 16L 7 3 5 11.7 16M 7 3 5 22.8 16N 7 3 5 13.4 16O 7 3 5 18.0
16P 7 3 5 21.6 16Q 7 3 5 26.8 16R 7 3 5 13.6 16S 7 3 5 18.2 16T 7 3
5 21.4 16U 7 3 5 25.2
[0151]
20 TABLE 16.2 Durability Example (Kp/cm.sup.2) 16A 30.3 16B 20.5
16C 4.3 16D 10.3 16E 7.6 16F 13.4 16G 12.7 16H 8.5 16I 7.7 16J 7.6
16K 4.0 16L 6.0 16M 22.6 16N 13.8 16O 18.7 16P 22.8 16Q 30.6 16R
13.7 16S 17.3 16T 23.0 16U 29.8
[0152] These data show that the durabilities of the high
permeability coatings of the present invention are high, and that
the coating durability increases as the amount of coating applied
to the tablet increases. The data also show that for the same
amount of coating, coatings made with a high CA/PEG ratio (Examples
16A to 16C) have a higher durability than those made with a low
CA/PEG ratio (Examples 16D to 16U). These results, combined with
the results of Example 15, show that the coatings of the present
invention have high water permeability and high strength.
EXAMPLES 17A-17C
[0153] Including solubilizing acids in the drug-containing
composition may increase the bioavailability of the drug. These
examples demonstrate the utility of the present invention to
release an organic acid with Drug 2, sertraline. Here, it is
desirable that the solubilizing acid is released along with the
sertraline, so as to increase the solubility of sertraline in the
use environment, which in turn increases bioavailability.
[0154] In Examples 17A-17C, dosage forms of the present invention
were made wherein the drug-containing composition or the
water-swellable composition included a solubilizing acid selected
from citric acid and fumaric acid. These tablets were made as in
Example 3A, with the exceptions noted in Tables A, B, and C. In
Example 17A, the drug-containing composition contained 15 wt %
citric acid. In Example 17B, the drug-containing composition
contained 7 wt % fumaric acid. In Example 17C, both the
drug-containing composition and the water-swellable composition
contained 15 wt % citric acid.
[0155] The tablets were dissolution-tested in USP sodium acetate
buffer, using the direct test. The results for Examples 17A-C are
shown in Tables 17.1 and 17.2 and are summarized in Table D.
21TABLE 17.1 Time Drug Example (hours) (wt % released) 17A 0 0 1 0
2 3 4 23 6 47 8 69 10 88 12 91 16 82 20 92 24 92 17B 0 0 1 0 2 9 4
31 6 57 8 79 10 92 12 96 16 96 20 96
[0156]
22 TABLE 17.2 Time (wt % released) Example (hours) Drug Citric Acid
17C 0 0 0 1 0 0 2 6 9 4 24 28 6 46 47 8 65 62 10 81 76 12 94 84 16
96 89 20 96 93
[0157] The results of Examples 17A and 17B show that high rates of
sertraline release (91% and 96% within 12 hours, respectively) may
be obtained when including the solubilizing acid in the dosage
form. Comparison with dosage forms that do not contain the
solubilizing acid (e.g., Example 14) shows that solubilizing acids
did not affect the release profile for the drug.
[0158] The results of Example 17C show that the citric acid was
released at about the same rate as the sertraline (84% citric acid
and 94% sertraline within 12 hours). In addition, citric acid was
released at all times when sertraline was released. During the
release tests of Examples 17A-C, the receptor solution in the
vicinity of the tablets had a pH of about 3, indicating that
including organic acids in the dosage form leads to a locally low
pH. This test demonstrates that one may expect that the use
environment will contain sufficient solubilizing acid in the
vicinity of where the drug is released to result in a locally lower
pH, in turn causing higher concentration of dissolved drug and,
hence, increased bioavailability.
EXAMPLE 18
[0159] This example demonstrates the in vivo release of carprofen
(Drug 6) from bi-layer tablets. The solubility of Drug 6 is
approximately 0.015 mg/mL at pH 5.9. For the tablets of Example 18,
the drug-containing composition was composed of 12.6 wt % Drug 6,
52.4 wt % XYLITAB 200, 28.8 wt % PEO with an average molecular
weight of 600,000, 5.0 wt % Explotab, and 1.2 wt % magnesium
stearate; and the water-swellable composition was composed of 74.4
wt % EXPLOTAB, 24.6 wt % microcrystalline cellulose (AVICEL pH
200), and 1.0 wt % magnesium stearate. These tablets were made by a
direct blend-and-compress method using a single-station Manesty
f-press with {fraction (13/32)} inch standard round concave
tooling. For these tablets, the drug-containing composition made up
400 mg while the water-swellable composition made up 100 mg.
Tablets contained 50 mg of active drug. The bi-layer core was then
coated with a coating solution consisting of 7 wt % cellulose
acetate, 3 wt % PEG 3350, 5 wt % water, and 85 wt % acetone to
obtain a coating weight of 11 wt % (wt/wt core), and four 1 mM
slits were made on the tablet edge. In vivo residual tests were
performed in 5 dogs as follows: one tablet was orally administered
to each dog followed by a 50 mL gavage. The bowel movements were
screened for tablets and the recovery times noted. The residual
undelivered drug was determined by a residual test, and the drug
release was calculated by subtracting the residual amount from the
known initial amount of drug present in the tablets. Results are
shown in Table 18.1.
23 TABLE 18.1 Time Drug (hours) (wt % released) 9 48, 57, 58 20 84,
92
[0160] These tablets were also tested in vitro using a residual
dissolution test. These tests were performed in a USP type 2
dissoette using the following conditions: 37.degree. C., 100 rpm,
0.05 M phosphate buffer at pH 7.5. Results are shown in Table
18.2.
24 TABLE 18.2 Time Drug (hours) (wt % released) 0 0 2 12 4 37 8 66
12 78 20 95 24 98
[0161] The data show satisfactory in vivo drug delivery with dosage
forms of the invention. Good correlation is observed between in
vitro and in vivo data.
EXAMPLE 19
[0162] This example demonstrates the in vivo delivery of Tenidap
(Drug 7) from bi-layer tablets. The solubility of Drug 7 is 0.2
mg/mL at pH 7.4 and 0.002 mg/mL at pH 3.7. For the tablets of
Example 19, the drug-containing composition consisted of 12.5% Drug
7, 37.5 wt % XYLITAB 200, 36.15 wt % PEO with an average molecular
weight of 600,000, 12.5 wt % EXPLOTAB, and 1.25 wt % magnesium
stearate; and the water-swellable composition consisted of 74.0 wt
% EXPLOTAB, 24.5 wt % microcrystalline cellulose (AVICEL pH 200),
0.5 wt % FD&C Red, and 1.0 wt % magnesium stearate. These
tablets were made using a direct blend-and-compress manufacturing
process on a single-station Manesty f-press. For these tablets, the
drug-containing composition made up 400 mg and the water-swellable
composition made up 100 mg. Tablets contained 50 mg active Drug 7.
The bi-layer core was then coated in a Freund HCT-30 EP coating pan
using a spray solution consisting of 7 wt % cellulose acetate, 3 wt
% PEG, 5 wt % water, and 85 wt % acetone to obtain a coating weight
of 10% (wt/wt core). Instead of drilling a delivery port, four
slits in the coating were made on the edge of each tablet.
[0163] In vivo residual tests were performed in dogs as follows:
Each of five dogs were dosed with tablets (so that they could be
later identified) over a six-hour period (i.e., one tablet every
two hours) with oral gavage of 50 mL water. The bowel movement was
screened for tablets and the recovery time noted. All tablets were
recovered intact, i.e., there were no splits in the coatings. The
amount of undelivered drug was determined by extracting the
unreleased drug from the tablets and the drug released was
determined by subtracting the unreleased amount from the known
initial amount of drug present in the tablets. Results are shown in
Table 19.1.
25 TABLE 19.1 Time Drug (hours) (wt % released) 4 25.8 (n = 2) 6
43.9 (n = 2) 8 59.7 (n = 1) 20 74.9 (n = 3) 21.5 83.3 (n = 1) 22.0
80.2 (n = 2) 23.5 87.7 (n = 1) 24.0 83.6 (n = 2) 25.5 87.0 (n =
1)
[0164] In addition to the in vivo test above, residual recovery
from a pharmacokinetic (PK) study in dogs was performed as follows:
dogs were dosed with one tablet each and blood samples withdrawn
periodically at selected times. The bowel movements were screened
for tablets and the recovery times noted. The residual undelivered
drug was determined by extraction and the drug released calculated
as described previously. The results from the residual PK study
agree with the results above; they are shown in Table 19.2.
26 TABLE 19.2 Time Drug (hours) (wt % released) 8 57.8 (n = 2)
16-25 83.4 (n = 2)
[0165] These tablets were also tested in vitro using a residual
dissolution. The dissolution of tablets with one slit on the tablet
face is shown for comparison. These tests were performed using a
USP type 2 dissoette under the following conditions: 900 mL pH 7.5
phosphate buffer, 100 rpm, 37.degree. C. Results are shown in Table
19.3.
27TABLE 19.3 Drug Drug Time (wt % released) (wt % released) (hours)
4 slits on edge 1 slit on face 0 0 0 2 16 6 4 43 24 8 75 61 12 84
80 20 91 94 24 94 94
[0166] The data show satisfactory in vivo drug delivery with dosage
forms of the invention. Good correlation is observed between in
vitro and in vivo data.
EXAMPLE 20
[0167] This example shows the utility of including a
concentration-enhancing polymer, a solubilizer, and a fluidizing
agent in the drug-containing composition. The drug-containing
composition comprised the following materials: 20 wt % Drug 2, 15
wt % tartaric acid (a solubilizer), 20 wt % HPMCAS (HPMCAS-LG
grade) (a concentration-enhancing polymer), 29 wt % PEO with an
average molecular weight of 600,000 (Polyox WSR-205) (a polymeric
entraining agent), 15 wt % xylitol (Xylitab 200) (a fluidizing
agent), and 1 wt % of the lubricant, magnesium stearate. To form
the drug-containing composition, the ingredients (without the
magnesium stearate) were blended for 10 minutes in a Turbula mixer.
This blend was wet-granulated using a mortar and pestle with a
mixture of isopropyl alcohol and water in a volume ratio of 85:15.
The wet-granulated material was dried in a 40.degree. C. oven
overnight. The dried granulation was passed through a Fitzpatrick
hammer mill, model L1A, at 3000 rpm, and screened through a
0.065-inch screen. This material was blended again in the Turbula
mixer for 10 minutes. Next, magnesium stearate was added and the
materials were blended for 4 additional minutes.
[0168] The water-swellable composition comprised the following
materials: 64.4 wt % PEO with an average molecular weight of 5
million (Polyox WSR Coagulant), 30 wt % sodium chloride, 5 wt %
HPMC (Methocel E5 LV Prem., a tablet binder), 0.1 wt % of a
colorant (Red Lake #40), and 0.5 wt % magnesium stearate. To form
the water-swellable composition, the ingredients (without the
colorant or magnesium stearate) were blended 20 minutes in a
twinshell mixer, then milled using a hammer mill and passed through
a 0.098-inch screen. This material was blended again for 20 minutes
in a twinshell mixer. The colorant and magnesium stearate were
mixed for 1 minute, and then added to the blend. These ingredients
were blended for 4 additional minutes.
[0169] The drug-containing composition and the water-swellable
composition were tableted together using direct compression to form
the core. A portion of the drug-containing composition (441.5 mg)
was placed in an f-press with a standard round concave {fraction
(7/16)}-inch die, then gently leveled with the upper punch. A
portion of the water-swellable composition (227.5 mg) was placed on
top of the layer of drug-containing composition and compressed. The
compression distance between the upper and lower punches on the
f-press was adjusted until the hardness of the resulting core
measured 11.4 Kp. The resulting bi-layer core weighed 669 mg and
contained a total of 13.2 wt % sertraline HCl, 9.9 wt % tartaric
acid, 13.2 wt % HPMCAS-LG, 19.1 wt % PEO 600,000, 9.9 wt % xylitol,
0.9 wt % magnesium stearate, 21.9 wt % PEO 5,000,000, 10.2 wt %
sodium chloride, 1.7 wt % HPMC, and 0.03 wt % colorant. Assays of
these tablets showed 82 mg of Sertraline HCl, or 73 mgA of active
sertraline.
[0170] The tablets were coated with a high water permeability
coating in a Vector LDCS-20 pan coater. The coating solution
contained CA 398-10, polyethylene glycol (PEG 3350), water, and
acetone in a weight ratio of 7/3/5/85. Heated drying air (40 cfm)
was adjusted to maintain the pan coater outlet temperature at
25.degree. C. Nitrogen at 20 psi was used to atomize the coating
solution from the spray nozzle, with a nozzle-to-bed distance of 2
inches. The pan tumbled at 20 rpm. The final dry coating weight
amounted to 20.4 wt % of the weight of the tablet core. One 2 mM
port was laser-drilled on the face of the tablet. The total weight
of the coated tablet was 805 mg.
[0171] An in vitro residual drug release test was performed.
Tablets were placed in a stirred USP type 2 dissoette flask
containing a solution of gastric buffer (10 mM HCl, 100 mM NaCl, pH
2.0, 261 mOsm/kg) for 2 hours, and then transferred to a solution
of intestinal buffer (6 mM KH.sub.2PO.sub.4, 64 mM KCl, 35 mM NaCl,
pH 7.2, 210 mOsm/kg). In both flasks, the dosage form was placed in
a wire support to keep the tablet off of the bottom of the flask so
that all surfaces were exposed to the solution, and the solutions
were stirred using paddles rotating at 50 revolutions per minute.
At spaced-apart time intervals, a single tablet was removed and
placed in recovery solution (50/50 wt/wt ethanol/water, pH 3) to
dissolve the drug remaining in the tablet. Residual drug was
analyzed by HPLC using a Phenomenex Ultracarb 5 ODS 20 column. The
mobile phase consisted of 35 vol % TEA-acetate buffer (3.48 mL
triethanolamine and 2.86 mL glacial acetic acid in 1 L HPLC-grade
H.sub.2O) in acetonitrile. Drug concentration was calculated by
comparing UV absorbance at 230 nm to the absorbance of known drug
standards. The amount remaining in the tablets was subtracted from
the initial amount of drug in the tablets (73 mgA) to obtain the
amount released at each time interval. Results are shown in Table
20 and are summarized in Table D.
28 TABLE 20 Time Drug (hours) (wt % A released) 0 0 1 3 2 4 4 32 8
74 12 78 16 86 20 89
[0172] The data show that 4 wt %A of the drug was released within 2
hours, and that 74 wt %A of the drug was released within 8 hours.
After 20 hours, 89% of the drug contained in the tablet had been
released. Observations of the tablets during the release test
indicated that the coating remained intact for the duration of the
test.
[0173] For comparison, identical tablets were prepared but without
the fluidizing agent xylitol. During dissolution tests of these
tablets, it was observed that the coating on one out of every 4
tablets split. Thus, including a fluidizing agent in the
formulation (as in Example 20) reduced the pressure at which the
drug-containing composition was delivered through the delivery
ports.
29TABLE A Summary of Drug-Containing Composition for All Examples
[Mg [Drug] [Explotab] [Xylitab Stearate] Other Conc. Example Drug
wt % [PEO] Type [PEO] wt % wt % 200] wt % wt % Ingredients wt %
Processing Method 1 1 35 600K 29 5.0 30.0 1.0 Dry Blended 2 1 56
600K 19 4.0 20.0 1.0 Dry Blended 3A 2 35.0 600K 28.75 5.0 30.0 1.25
Dry Blended 3B 3 32.4 600K 29.9 5.2 31.2 1.3 Dry Blended 4 2 35.0
600K 29.0 5.0 30.0 1.0 Dry Blended 5A 1 35.0 600K 29 5 30 1.0 Wet
granulated 5B 1 35.0 600K 29 5 30 1.0 Wet granulated 5C 1 35.0 600K
29 5 30 1.0 Wet granulated 6 1 56.0 600K 19.0 4.0 20.0 1.0 Dry
Blended 7A 1 35 600K 29.0 5.0 30.0 1.0 Dry Blended 7B 1 35 600K
29.0 5.0 30.0 1.0 Dry Blended 7C 1 35 600K 29.0 5.0 30.0 1.0 Dry
Blended 7D 1 35 600K 29.0 5.0 30.0 1.0 Dry Blended 8 2 20.57 600K
26.75 4.33 26.75 1.0 HPMCP 20.57 Precompressed, comilled 9 4 22.2
600K 25.2 3.5 26.1 0.8 HPMCAS-MF 22.2 Dry Blended 10 5 4.16 600K 25
3.9 25 1.0 HPMCAS-HF 40.94 Dry Blended 11 2 22.8 200K 71.7 0 0 0.5
Methocel 5.0 Dry Blended K3LV 13 2 22.8 200K 71.7 0 0 0.5 Methocel
5.0 Dry Blended K3LV 14 2 35 200K 59.6 0 0 0.5 Methocel 5.0 Dry
Blended K3LV 15A 2 22.8 200K 71.7 0 0 0.5 Methocel 5.0 Dry Blended
K3LV 15B 2 22.8 200K 71.7 0 0 0.5 Methocel 5.0 Dry Blended K3LV 15C
2 22.8 200K 71.7 0 0 0.5 Methocel 5.0 Dry Blended K3LV 16A--16G 1
35 600K 29 5.0 30.0 1.0 Dry Blended 16H--16U 2 35 200K 59.6 0 0 0.5
Methocel 5.0 Dry Blended K3LV 17A 2 30 200K 49.5 0 0 1.5 Klucel EF
4.5 Dry Blended Citric acid 15.0 17B 2 37.8 200K 48.8 0 0 1.0
Klucel EF 4.9 Dry Blended Fumaric acid 7.0 17C 2 29.9 200K 49.2 0 0
1.5 Klucel EF 4.5 Dry Blended Citric acid 14.9 18 6 12.6 600K 28.8
5.0 52.4 1.2 Dry Blended 19 7 12.5 600K 36.15 12.5 37.5 1.25 Dry
Blended 20 2 20 600K 29 0 15 1.0 Tartaric acid 15 Blended,
wet-granulated w/ HPMCAS 20 IPA/H2O (85/15),dried, milled,
blended
[0174]
30TABLE B Summary of Water-Swellable Composition for All Examples
[Prosolv 90] [Mg Stearate] Other Example [Explolab] wt % wt % wt %
Ingredients Conc. wt % Processing Method 1 74.5 25 0.5 Dry Blended
2 74.5 25 0.5 Dry Blended 3A 74.5 25 0.5 Dry Blended 3B 74.5 24.5
1.0 Dry Blended 4 0 0 0.6 Methocel K3LV 5.0 Dry Blended PEO 5
million 65.0 NaCl 29.4 5A 74.35 24.85 0.3 Red Lake #40 0.3 Wet
granulated 5B 49.4 49.4 1.0 Red Lake #40 0.25 Wet granulated 5C
59.35 39.4 1.0 Red Lake #40 0.25 Wet granulated 6 74.3 25.2 0.5 Dry
Blended 7A 74.35 24.85 0.3 Red Lake #40 0.3 Dry Blended 7B 74.35
24.85 0.3 Red Lake #40 0.3 Dry Blended 7C 74.35 24.85 0.3 Red Lake
#40 0.3 Dry Blended 7D 74.35 24.85 0.3 Red Lake #40 0.3 Dry Blended
8 74.66 24.73 0.47 Red Lake #40 0.14 Dry Blended 9 74.8 24.8 0.4
Dry Blended 10 74.8 24.7 0.5 Dry Blended 11 74.5 25.0 0.5 Dry
Blended 13 0 0 0.6 Methocel K3LV 5.1 Dry Blended PEO 5 million 65.0
NaCl 29.3 14 0 0 0.6 Methocel K3LV 5.1 Dry Blended PEO 5 million
65.0 NaCl 29.3 15A 0 0 0.6 Methocel K3LV 5.1 Dry Blended PEO 5
million 65.0 NaCl 29.3 15B 0 0 0.6 Methocel K3LV 5.1 Dry Blended
PEO 5 million 65.0 NaCl 29.3 15C 0 0 0.6 Methocel K3LV 5.1 Dry
Blended PEO 5 million 65.0 NaCl 29.3 16A-16G 74.5 25 0.5 Dry
Blended 16H-16U 0 0 0.6 Methocel K3LV 5.1 Dry Blended PEO 5 million
65.0 NaCl 29.3 17A 0 0 0.6 Methocel K3LV 5.9 Dry Blended PEO 5
million 64.3 NaCl 29.2 17B 0 0 0.5 Methocel K3LV 5.1 Dry Blended
PEO 5 million 64.4 NaCl 29.9 Red Lake #40 0.1 17C 0 0 0.6 Methocel
K3LV 5.9 Dry Blended PEO 5 million 64.3 NaCl 14.6 Citric acid 14.6
18 74.4 0 1.0 Avicel 24.6 Dry Blended 19 74.0 0 1.0 Avicel 24.5 Dry
Blended Red Lake #40 0.5 20 0 0 0.5 Methocel K3LV 5.0 Dry Blended
PEO 5 million 64.4 NaCl 30.0 Red Lake #40 0.1
[0175]
31TABLE C Summary of Details of Tablet Formulations for All
Examples Core Ratio of Drug to Coating Amount Number Weight Sweller
Layer [PEG] [H2O] wt % of uncoated of Port size Example (mg) Drug
Layer Sweller Layer (w/w) [CA] wt % wt % wt % tablet Ports (.mu.rr)
1 500 400 100 4.0 7 3 5 8.1 5 900 2 600 500 100 5.0 7 3 5 10.6 5
900 3A 500 400 100 4.0 7 3 5 9.6 5 900 3B 500 400 100 4.0 7 3 5
10.2 5 900 4 735 490 245 2.0 7 3 5 13.0 1 900 5A 500 400 100 4.0 7
3 5 8.1 5 900 5B 500 400 100 4.0 7 3 5 9.3 5 900 5C 500 400 100 4.0
7 3 5 8.7 5 900 6 700 500 200 2.5 7 3 5 11.1 5 900 7A 500 400 100
4.0 7 3 5 5.8 5 900 7B 500 400 100 4.0 7 3 5 11.3 5 900 7C 500 400
100 4.0 7 3 5 17.9 5 900 7D 500 400 100 4.0 7 3 5 24.9 5 900 8 700
550 150 3.7 7 3 5 9.7 5 2000 9 600 450 150 3.0 7 3 5 8.9 5 900 10
700 550 150 3.7 7 3 5 11.3 5 900 11 735 490 245 2.0 7 3 5 12.6 1
900 13 735 490 245 2.0 7 3 5 12.9 1 900 14 735 490 245 2.0 7 3 5
13.0 1 900 15A 735 490 245 2.0 7 3 5 11.2 1 900 15B 735 490 245 2.0
8 2 5 11.4 1 900 15C 735 490 245 2.0 9 1 5 11.7 1 900 16A 500 400
100 4.0 4 1 2.5 11.7 5 900 16B 500 400 100 4.0 4 1 2.5 11.2 5 900
16C 500 400 100 4.0 8 2 5 6.9 5 900 16D 500 400 100 4.0 7 3 5 8.1 5
900 16E 500 400 100 4.0 7 3 5 8.3 5 900 16F 500 400 100 4.0 7 3 5
12.0 5 900 16G 500 400 100 4.0 7 3 5 12.8 5 900 16H 735 490 245 2.0
7 3 5 12.4 1 900 16I 735 490 245 2.0 7 3 5 11.1 1 900 16J 735 490
245 2.0 7 3 5 10.3 1 900 16K 735 490 245 2.0 7 3 5 7.9 1 900 16L
735 490 245 2.0 7 3 5 11.7 1 900 16M 735 490 245 2.0 7 3 5 22.8 1
900 16N 735 490 245 2.0 7 3 5 13.4 1 900 16O 735 490 245 2.0 7 3 5
18.0 1 900 16P 735 490 245 2.0 7 3 5 21.6 1 900 16Q 735 490 245 2.0
7 3 5 26.8 1 900 16R 735 490 245 2.0 7 3 5 13.6 1 900 16S 735 490
245 2.0 7 3 5 18.2 1 900 16T 735 490 245 2.0 7 3 5 21.4 1 900 16U
735 490 245 2.0 7 3 5 25.2 1 900 17A 887 591 296 2.0 7 3 5 21.9 1
700 17B 700 469 231 2.0 7 3 5 20.0 1 700 17C 887 591 296 2.0 7 3 5
21.9 1 700 18 500 400 100 4.0 7 3 5 11 4 1000 (slits) 19 500 400
100 4.0 7 3 5 10 4 1000 (slits) 20 669 441.5 227.5 1.9 7 3 5 20.4 1
2000
[0176]
32TABLE D Summary of Release Rates in wt % for All Examples*
Example 2-hr release (%) 8-hr release (%) 12-hr release (%) 16-hr
release (%) 20-hr release 24-hr release (%) 1 25 74 87 95 98 2 16
57 70 78 86 3A 22 79 88 93 94 3B 18 68 85 88 91 4 15 80 90 93 87 5A
15 69 86 95 97 5B 15 67 82 91 96 5C 16 69 82 91 96 6 16 65 81 91 94
7A 30 88 95 98 (14-hr) 97 7B 19 69 86 95 98 7C 8 60 75 85 94 7D 0
48 61 75 88 8 17 68 86 89 86 9 4 63 81 91 97 10 13 46 73 75 74 11
17 70 84 86 92 13 19 98 99 99 99 14 25 97 98 98 98 17A 3 69 91 82
92 17B 9 79 96 96 96 17C (drug) 6 65 94 96 96 17C (citric acid) 9
62 84 89 93 18 12 66 78 87 98 19 (in vivo) 12.9 59.7 64.8 69.8 83.6
20 4 74 78 86 89 *some values are interpolated from concentrations
obtained at other time points
[0177] The terms and expressions which have been employed in the
foregoing specification are used therein as terms of description
and not of limitation, and there is no intention, in the use of
such terms and expressions, of excluding equivalents of the
features shown and described or portions thereof, it being
recognized that the scope of the invention is defined and limited
only by the claims which follow.
* * * * *