Note: Descriptions are shown in the official language in which they were submitted.
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VASOPRESSIN ANTAGONIST FORMULATION AND PROCESS
This applications concerns new formulations for N-[4-(SH-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-
methylbenzamide, and pharmaceutically acceptable salts thereof, as well as
processes
for manufacturing the formulations. The invention particularly relates to
orally
administered formulations of these compounds.
Background of the Invention
The art describes many methods of producing liquid or semi-solid
encapsulated pharmaceutical formulations. In Bull. Tech./Gattefosse Rep.
(1996), 89,
27-38, authors Shah et al. describe hard gelatin capsule technology,
particularly for
use in enhancing the bioavailability of poorly soluble or poorly absorbed
drugs.
U.S. Patent No. 4,620,974 (Hersh et al.) teaches a hard gelatin capsule
comprising a telescoping two-piece cap with a lubricant comprising a
polyethylene
glycol of a molecular weight between about 200 and about 900 present in
admixture
with the composition at a concentration of from about 0.5 to about 25 weight
percent.
WO 96/40071 (Lamberti) discloses methods and devices for producing
minimal volume capsules. WO 96/41622 (Tanner et al.) teaches suspensions
suitable
for encapsulation in gelatin capsules, particularly including a solid phase of
solid
particles and a liquid phase capable of suspending the solid phase.
U.S. Patent No. 5,641,512 (Cimiluca) teaches soft gelatin encapsulated
analgesics in which the shell contains a xanthine derivative, such as
caffeine.
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U.S. Patent No. 4,578,391 (Kawata et al.) describes oily compositions for
antitumor agents comprising at least one sparingly oil soluble or water-
soluble
antitumor drug, at least one fat or oil, and at least one solubilizing
adjuvant in an oily
vehicle, selected from crown ether, lecithin, polyethylene glycol, propylene
glycol,
vitamin E, polyoxyehtylene alkylether, and sucrose esters of fatty acids.
EP 0 815 854 A1 discloses a substantially translucent, semi-solid fill
material
for a soft gelatin capsule, the semi-solid material being sufficiently viscous
that it
cannot be expelled from the capsule with a syringe at room temperature.
U.S. Patent No. 4,744,988 (Brox) teaches soft gelatin capsules comprising a
shell of gelatin, a softener and a filling of a polyethylene glycol and a low
polyhydric
alcohol and at least one active substance, characterized in that the shell
contains 4 to
40 percent sorbital or sorbitanes, at least half of the weight of polyethylene
glycol
used is a polyethylene glycol having a mean molecular weight of 600, and the
capsule
filling comprises up to 20% by weight of glycerol and/or 1,2-propylene glycol.
WO 95/19579 (Dhabhar) teaches a process for solubilizing difficulty soluble
pharmaceutical agents in a mixture of polyethylene glycol and propylene glycol
by
using a polyvinylpyrrolidone with a specific viscosity average molecular
weight of
from about 5,000 to about 25,000.
Summary of the Invention
This invention provides orally administerable formulations for N-[4-(SH-
pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-
methylbenzamide, also known as VPA-985, or the pharmaceutically acceptable
salts
thereof, which has the structure:
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c
VPA-985 is a V2 receptor antagonist (vasopressin antagonist) with the ability
to elicit the removal of water in mammals, without the excretion of necessary
electrolytes. The synthesis of this compound and its salts is disclosed in
U.S. Patent
No. 5,516,774 (Albright et al.), which is fully incorporated herein by
reference.
VPA-985 can be seen as Example 482 in U.S. Patent No. 5,516,774. This compound
is highly insoluble in both conventional, orally acceptable oils, such as
safflower or
sesame seed oils, and in aqueous systems. Therefore, its pharmaceutical
formulation
requires a novel approach.
The formulations of this invention comprise (by °Io w/w):
a) from about 1% to about 20°Io of N-[4-(SH-pyrrolo[2,1-
c] [ 1,4]benzodiazepin-10( 11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-
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methylbenzamide, or a pharmaceutically acceptable salt thereof, preferably
from
about 1% to about 16% or from about 5% to about 16% or from about 5% to about
18% of this active ingredient;
b) from about 1% to about 18% of a surfactant component, preferably
from about 5% to about 18% or from about 5% to about 15% of the surfactant
component, more preferably from about 5% to about 10% of the surfactant
component;
c) from about 50% to about 80% of a component of one or more
polyethylene glycols (PEG), preferably from about 55% to about 70% of one or
more
different molecular weight grades of polyethylene glycols; and
d) from about 1% to about 20%, preferably from about 5% to about 15%
and more preferably between about 8% and about 12%, of a component of:
i) one or more sucrose fatty acid esters; or
ii) a polyvinylpyrrolidone (PVP) with a K value between about 15
and 90, preferably with a K value of from about 17 as defined in USP/NF; or
iii) a combination of one or more sucrose fatty acid esters and a
PVP, as defined above.
Suitable pharmaceutically acceptable salts of N-[4-(SH-pyrrolo[2,1-
c] [ 1,4]benzodiazepin-10( 11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-
methylbenzamide include those derived from organic and inorganic acids such as
lactic, citric, acetic, tartaric, succinic, malefic, malonic, hydrochloric,
hydrobromic,
phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable
acids.
The polyethylene glycol component may be comprised of one or more PEG
polymers, preferably commercially available PEG polymers between PEG 200 and
PEG 4,000, i.e. those PEG polymers having an average molecular weight between
about 190 and about 4800. More preferred are PEG polymers between average
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molecular weights of from about 190 to about 3450, most preferably between
about
400 and 1540. Among the preferred PEG polymers are PEG 400, having an average
molecular weight between about 380 and about 420, and PEG 1,000, having an
average molecular weight between about 950 and about 1050. The ratio of high
and
low molecular weight PEG species within the PEG component is preferably from
about 2.5:1 to about 1:2.5, more preferably about 1:1. As an example, a
preferred
blend of PEG polymers within this invention would include a 1:l blend of PEG
400
and PEG 1000. It may be preferable to choose a mixture of PEG components which
will have a melting point at or near the physiological temperature of the
mammal to
receive the formulation. Mixtures of final components which have a viscosity
range
of from about 140 to about 1500 centipoise at 37°C may be preferred,
more
preferably a range of from 300 to about 800 centipoise at 37°C.
The surfactants that may be used with the present formulations include, but
not limited to, polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate),
Polysorbate 60, Polysorbate 40, polysorbate 80, Span 80 Sorbitan Oleate, a
product of
ICI Americas, Wilmington, Delaware, polysorbate 81, polysorbate 85,
polysorbate
120, bile acids and their salts defined by Martindale The Extra Pharmacopoeia
Thirtieth Edition on page1341-1342 such as Sodium taurocholates, Sodium
deoxytaurocholates, Chenodeoxycholic acid, and ursodeoxycholic acid, and
pluronic
or poloxamers such as Pluronic F68, Pluronic L44, Pluronic L101, or
combinations of
one or more of the above. Polysorbate 80, by itself or in combination with one
or
more other surfactants, is preferred for use with this invention.
The sucrose fatty acid esters useful with this invention include those
commercially available and art recognized esters useful for orally
administered
pharmaceutical compositions, including monoesters, diesters and triesters of
sucrose,
or mixtures or blends thereof. Specific examples of esters useful with this
invention
are sucrose monolaurate, sucrose monomyristate, sucrose monopalminate, sucrose
monostearate, sucrose distearate, sucrose tristearate, sucrose trimyristate,
and sucrose
tripalmitate, or combinations thereof.
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In addition to these components, other enhancing or protective
pharmaceutically acceptable antioxidants or preservatives may be added to the
compositions of this invention to comprise up to about 4% of the composition,
by
weight, more preferably up to about 3%. Examples may include ascorbyl
palrnitate,
benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene
(BHT),
etc. Examples of these components in the present formulations would include
BHA
at a concentration from about 0.3% to about 2.5% (% w/w) and BHT at a
concentration from about 0.005% to about 0.15% (% w/w), preferably with a
mixture
of BHA and BHT within these ranges. Further embodiments include about 0.2%
BHT.
A formulation of this invention utilizing one or more of these antioxidants or
preservatives comprises:
a) from about 1% to about 20% of N-[4-(5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-
methylbenzamide, or a pharmaceutically acceptable salt thereof, preferably
from
about 1% to about 16% or from about 5% to about 16% or from about 5% to about
18% of this active ingredient;
b) from about 1% to about 18% of a surfactant component, preferably
from about 5% to about 18% or from about 5% to about 15% of the surfactant
component, more preferably from about 5% to about 10% of the surfactant
component;
c) from about 50% to about 80% of a component of one or more different
molecular weight grades of polyethylene glycols (PEG), preferably from about
55%
to about 70% of one or more polyethylene glycols;
d) from about 1% to about 20%, preferably about 5% to about 15%, of
one or more sucrose fatty acid esters or polyvinylpyrrolidone (PVP) with a K
value
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between about 15 and 90, preferably with a K value of from about 17 as defined
in
USP/NF; and
e) from about 0.1% to about 4%, preferably from about 0.1 to about 3%,
of one or more preservatives or antioxidants, for example from about 0.3% to
about
2.5% (% w/w) BHA and/or from about 0.005% to about 0.15% (% w/w) BHT.
One preferred embodiment of this invention provides a pharmaceutical
formulation comprising:
a) from about 5% to about 16% of N-[4-(5H-pyrrolo[2,1-
c] [ 1,4]benzodiazepin-10( 11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-
methylbenzamide, or a pharmaceutically acceptable salt thereof;
b) from about 5% to about 10% of a surfactant component;
c) a component of from about 55% to about 70% of one or more different
molecular weight grades of polyethylene glycols;
d) from about 5% to about 15% of polyvinylpyrrolidone (PVP) with a K
value between about 15 and 90, preferably with a K value of from about 17 as
defined
in USP/NF; and
e) from about 0.3% to about 2.5% (% w/w) BHA and from about 0.005%
to about 0.15% (% w/w) BHT.
Preferably, the formulations of this invention are enclosed in a sealed
enclosure after manufacture, such as soft or hard gelatin capsules. The
formulations
of this invention may be created as a liquid or semi-liquid formulation and
introduced
into a capsule. Similarly, using an acceptable range of components and/or
temperatures, the formulation may be made as a gel or solid prior to
encapsulation.
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Detailed Description of the Invention
This invention also includes a method for producing the formulations
disclosed herein. The process comprises the steps of:
a) combining, preferably with mixing or stirnng, the PEG and surfactant
components to create a first carrier mixture;
b) raising the temperature of the first carrier mixture to a range of from
about 75°C to about 95°C, preferably from about 80°C to
about 90°C;
c) adding the active pharmacological agent (VPA-985) or a
pharmaceutically acceptable salt thereof to create a first pharmaceutical
composition
mixture;
d) stirring the first pharmaceutical composition mixture, preferably with
heating, until the first pharmaceutical composition mixture is clear,
preferably at a
temperature from about 115°C to about 170°C, preferably from
about 130°C to about
170°C, more preferably at a temperature from about 135°C to
about 150°C or from
about 135°C to about 145°C.
e) cooling the first pharmaceutical composition, if necessary, to a
temperature of from about 60°C to about 110°C, preferably from
about 80°C to about
90°C;
f) adding the amount of sucrose fatty acid esters) and/or povidone to
create a final pharmaceutical composition mixture, preferably with stirnng
until the
final pharmaceutical composition mixture is clear.
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In cases wherein optional antioxidants or preservatives are used, such as BHA,
BHT, etc., the following steps may be employed:
a) combining, preferably with mixing or stirring, the PEG component
(such as a mixture of PEG 400 and PEG 1000) and the surfactant component (such
as
Polysorbate 80) to create a first carrier mixture;
b) raising the temperature of the first carrier mixture to a range of from
about 75°C to about 95°C, preferably from about 80°C to
about 90°C;
c) adding to the first carrier mixture optional antioxidant or preservative
components to create a second carrier mixture, which is then stirred or
otherwise
mixed until the second carrier mixture is a clear solution;
d) adding the active pharmacological agent or drug component (VPA-
985) or a pharmaceutically acceptable salt thereof to create a first
pharmaceutical
composition mixture;
e) stirring the first pharmaceutical composition mixture, preferably with
heating, until the first pharmaceutical composition mixture is clear,
preferably at a
temperature from about 130°C to about 150°C, more preferably at
a temperature from
about 135°C to about 145°C;
f) optionally cooling the first pharmaceutical composition to a
temperature of from about 75°C to about 95°C, preferably from
about 80°C to about
90°C;
g) adding the amount of sucrose fatty acid esters) andlor povidone to
create a final pharmaceutical composition mixture, preferably with stirring
until the
final pharmaceutical composition mixture is clear.
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One skilled in the art will understand the viscosity and form of the final
formulation may be manipulated with components within the scope of this
invention
and temperature ranges during processing. For instance, a fluid or semi-solid
composition may be produced with the more fluid PEG, surfactant and PVP
species
within the scope of this invention. More gel-like, viscous or semi-solid
compositions
may be produced with combinations of higher molecular weight PEG components
and PVP components having higher K values. Moreover, the components may be
cooled below their melting point if milling or other processing of the final
composition is desired. To create a more pelletized initial composition, a
fluid
composition of this invention may be sprayed onto a cooled Teflon-coated
surface
to form small solid spheres, which may be individually coated or collected for
further
processing.
Specific non-limiting examples of formulations within the scope of this
invention are provided below.
Example 1
50 mg/capsule~ VPA-985 Oral Formulation at 10 % Drug Loading
In place of the polysorbate 80 in this formulation of Example 1, other
polysorbate series such as Tween 20, 40 and 60 can also be used, alone or in
combination with each other and/or polysorbate 80.
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(% w/w) per capsule 20,000
(mg) capsule batch
(g)
Active Ingredient:
VPA-985 @ 100 % 10.42 50.00 1000.00
Inactive Ingredients:
PEG 1000, NF 30.96 148.61 2,972.16
Povidone USP K-17 10.00 48.00 960.00
Polysorbate 80, NF 10.00 48.00 960.00
B~~ ~ 0.09 0.42 8.32
B~, ~ 0.87 4.16 83.2
PEG 400, NFZ Q.S. to Q.S. to Q.S. to 9,600
100 480.00
1. Weigh the Polysorbate 80, PEG 400, and PEG 1000 into a suitable
mixing vessel, stir using a top mounted mixer, and warm to 85 ~ 5 °C.
2. Add BHT and BHA to the mixing vessel, very slowly to prevent
formation of lumps. Continue stirnng at 85 ~ 5 °C, until a clear
solution was
formed.
3. Add VPA-985 to the vessel at 85 ~ 5 °C , very slowly to prevent
formation of lumps. Slowly raise the temperature to 125 ~ 5 °C, and
stir until VPA-
985 dissolves completely.
4. Cool the solution in step 4. to 60 ~ 5 °C.
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5. Add Povidone, USP, K-17 (Plasdone C-15, ISP) slowly to step 5, to
prevent the formation of lumps.
Let the solution warm up to 85 ~ 5 °C. Stir until the solution becomes
clear.
6. Encapsulate 480 mg of the finished solution (in step 10) into size 1
capsules at 38 ~ 5 °C using either soft or hard gelatin capsule filler.
During
encapsulation cool the body of capsule using cool Nitrogen to prevent leaking.
7. Band seal the capsules with gelatin solution (optional).
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Example 2
50 m capsule: VPA-985 Oral Formulation at 10 % Drug Loading
In place of surfactant used in this formulation (poloxamer 188), other
polymers in the series such as Pluronic L44, Pluronic L101 can also be used.
(% w/w) per capsule 20,000
(mg) capsule batch
(g)
Active Ingredient:
VPA-985 @ 100 % 10.42 50.00 1000.00
Inactive Ingredients:
Povidone USP K-17 10.00 48.00 960.00
(Plasdone C-15,ISP)
Poloxamer 188, NF 12.00 57.60 1152.00
g~' ~' 0.09 0.42 8.32
0.87 4.16 83.20
PEG 400 NF Q. S. to Q.S. to 480.00Q.S. to
100 9600 g
This formulation is manufactured the same as that of the formula of Example
1 (50 mg/capsule) with the exception that 12 % of poloxamer was used in place
of the
polysorbate 80 in this formulation. The encapsulation weight is 480 mg.
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Example 3
50 m,~/capsule
Example 3 provides a formulation with a combination of two or more
surfactants.
(°7o wlw) per capsule (mg) 20,000
capsule batch
(g)
Active Ingredient:
VPA-985 @ 100 % 10.64 51.07 1,021.44
Inactive Ingredient:
PEG 1000, NF 28.60 137.28 2,745.60
Povidone USP K-17 10.00 48.00 960.00
(Plasdone C-15, ISP)
Polysorbate 40, NF 5.00 24.00 480.00
Poloxamer 188, NF 10.00 48.00
0.09 0.43 8.64
BHA, NF 0.87 4.18 83.52
PEG 400, NF Q.S. to Q.S. to 480.00Q.S.
100 to
9600.00
The formulation of Example 3 is manufactured the same as that of Example 1
(50 mg/capsule) with the exception that two surfactants, polysorbate 40 and
poloxamer 188 were added in step 1 along with PEG 400 and PEG 1000. The
encapsulation weight is 480 mg.
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Example 4
25 mg/capsule~ VPA-985 Oral Formulation at 5 % Drug Loading
(% w/w) per capsule 20,000
(mg) capsule
batch (g)
Active Ingredient:
VPA-985 @ 100 % 5.49 25.00 500.00
Inactive Ingredient:
PEG 1000, NF 32.66 148.61 2,972.16
Povidone, USP K-17 10.55 48.00 960.00
(Plasdone C-15,ISP)
Polysorbate 80, NF 10.55 48.00 960.00
0.09 0.42 8.32
0.91 4.16 83.2
PEG 400, NFz Q.S. to 100 Q.S. to Q.S.
to
455.00 9,100
g
The formulation of Example 4 is produced in the same manner as that of 50
mg/capsule, above, with the exception that the heating temperature to
solubilize VPA-
985 in step 3 is 115 ~ 5 °C, instead of 120 ~ 5 °C. The
encapsulation weight is 455
mg.
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Example 5
100 m~/capsule: VPA-985 Oral Formulation at 15 % Drug Loading
(°7o w/w) per capsule 20,000 capsule
(mg) batch (g)
Active Ingredient:
VPA-985 @ 100 °70 15.38 100.00 2,000.00
Inactive Ingredient:
PEG 1000, NF 28.98 188.35 3,767.05
Povidone USP K-17 10.00 65.00 1,300.00
(Plasdone C-15, ISP)3
Polysorbate 80, NF 9.45 61.39 1,227.91
0.08 0.53 10.64
0.82 5.32 106.42
PEG 400, NF Q.S. to Q.S. to Q.S. to 13,000.00
100 650.00
This formulation is produced with the same steps as the 50 mg/capsule, above,
with the exception that the heating temperature to solubilize VPA-985 in step
3 is 145
~ 5 °C, instead of 120 ~ 5 °C. The encapsulation weight is 650
mg in size 0 hard
gelatin capsule.
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Example 6
VPA-985: 150 mg in Size 00 Capsule
(% w/w) per capsule 20,000
(mg) capsule batch
(g)
Active Ingredient:
VPA-985 C 100 % 16.48 149.97 2,999.36
Inactive Ingredients:
PEG 1000, NF 26.3 239.33 4,786.60
Povidone USP K-17 15 136.50 2,730.00
(Plasdone C-15,ISP)
Polysorbate 80, NF 9.32 84.81 1,696.24
B~, ~ 0.08 0.73 14.56
B~, ~ 0.81 7.37 147.42
PEG 400, NF Q.S. to 100 Q.S. Q.S. to
to
910.00 18,200.00
This formulation of Example 6 is produced with the same steps as that of 50
mg/capsule with the exception of the heating temperature to solubilize VPA-985
in
step 3 is 150 ~ 5 °C, instead of 145 ~ 5 °C. The encapsulation
weight is 910 mg in
size 00 hard gelatin capsule.
The following specific Examples 7 through 11 shown in Table l, below, were
formulated as described above to create formulations of 10% N-[4-(SH-
pyrrolo[2,1
c] [ 1,4]benzodiazepin-10( 11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methyl
benzamide (VPA-985) with varying concentrations of PEG 400, PEG 1000, two PVP
components with respective K values of 15 and 90, and a combination of BHA and
BHT as an adjuvant component.
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Table 1
Example PEG PEG PVP PVP BHT BHA NATC VPA-
No. 400 1000 K15 K90 985
C%) C%) (%) (%) (%) (%) (%) (%)
7 55.40 20.00 10.00 0.00 0.20 2.002.40 10.00
8 40.40 35.00 10.00 0.00 0.20 2.002.40 10.00
9 75.40 0.00 5.00 5.00 0.20 2.002.40 10.00
65.40 10.00 0.00 10.00 0.20 2.002.40 10.00
11 40.40 35.00 5.00 5.00 0.20 2.002.40 10.00
Similarly, the following Examples 12 through 32 were formulated by the
methods herein using PEG 400, PEG 1000, PVP with a K value of 17, VPA-985,
BHA and BHT as antioxidants or preservatives and the additional components
listed
10 as "other".
Table 2
Ex. PEG PEG PVP VPA- BHA BHT Other Other
No. 400 1000 K-17 985
12 40.40 35.00 10.00 10.00 2.00Sodium -
0.20
Taurocholate
2.40
13 75.40 - 5.00 10.21 2.00 0.20Sodium PVP
Taurocholate K-90
2.40 5.00
14 42.59 35.00 10.00 10.21 2.00 0.20 - -
34.35 28.23 10.00 10.21 2.00 0.20 Poloxamer 188 -
15.00
16 42.59 20.00 10.00 10.21 2.00 0.20 Poloxamer 188 -
15.00
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17 37.10 30.49 10.00 10.21 2.00 0.20 Poloxamer 188
10.00
18 35.72 29.3610.00 2.000.20 Poloxamer 188 -
10.21
12.50
19 34.35 28.2310.00 2.000.20 Poloxamer 188 -
10.21
15.00
20 37.10 30.4910.00 2.000.20 Poloxamer 188 -
10.21
10.00
21 34.35 28.2310.00 2.000.20 Poloxamer 188 -
10.21
15.00
22 35.72 29.3610.00 2.000.20 Poloxamer 188 -
10.21
12.50
23 36.86 30.3010.00 2.000.20 Pluronic L44 -
10.64
10.00
24 36.86 30.3010.00 2.000.20 Pluronic L101 -
10.64
10.00
25 39.61 32.5510.00 2.000.20 Tween 40 -
10.64
5.00
26 41.25 33.9110.00 2.000.20 Tween 40 -
10.64
2.00
27 39.61 32.5510.00 2.000.20 Tween 20 -
10.64
5.00
28 41.25 33.9110.00 2.000.20 Tween 20 -
10.64
2.00
29 34.12 28.0410.00 2.000.20 Tween 40 Poloxamer 188
10.64
5.00 10.00
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30 36.86 30.30 10.00 10.64 2.00 0.20 Tween 40
10.00
31 36.86 30.30 10.00 10.64 2.00 0.20 Tween 80 -
10.00
32 34.12 28.04 10.00 10.64 2.00 0.20 Tween 80 Poloxamer 188
5.00 10.00
Example 33
25 mg/capsule in Size #3 capsule: Oral formulation at 10 % Drug Loading
In place of the polysorbate 80, other polysorbate series such as Tween 20, 40
and 60 can also be used.
(% w/w) per capsule20,000
(mg) capsule batch
(g)
Active Ingredient:
VPA-985 @ 100% 10.42 25 500.00
Inactive Ingredients:
PEG 1000, NF 30.96 74.31 1,486.08
Povidone USP K-17 10.00 24.00 480.00
Polysorbate 80, NF 10.00 24.00 480.00
B~, ~ 0.09 0.21 4.16
BHA, NF 0.87 2.08 41.6
PEG 400, NF' Q.S. to 100 Q.S. to Q.S. to 4800
240
