Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL CARRIER FORMULATION
This application concerns new formulations for pharmaceutical carriers,
excipients or pharmaceutical media which are useful in formulating
pharmaceutical
compositions for biologically active compounds having poor oil and water
solubility
and/or poor biological absorption properties. 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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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°Io 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.
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.
WO 98/24430 (Gautier et al.) teaches an anhydrous solubilizing/stabilizing
system, emulsifiable or microemulsifiable in water, for solubilizing
hydrophobic N-
sulphonyl indolin derivatives of the structure:
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U.S. Patent No. 5,356,904 (Freidinger et al.) discloses methods of using
oxytocin antagonist compounds of the formulae:
o, i , _.
\ / (C H~n
A
R1
WO 95/03305 discloses nitrogenous aromatic 5-membered fused benzazepine
derivatives, having the structure below, which are pharmacologically useful as
arginine vasopressin antagonists.
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EP 0 514 667 B1 (Ogawa et al.) teaches benzazepine derivatives of the
structure below:
as vasopressin antagonists useful as vasodilators, hypotensive agents, water
diuretics
and platelet agglutination inhibitors.
U.S. Patent No. 5,525,614 (Blankley et al.) teaches substituted 1,2,3,4-
tetrahydroisoquinolines, having the general structure below:
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R1~
R/ \
2 R
4
R3 R5
as having angiotensin II receptor antagonist properties and as effective in
treating
disorders related to excessive vasopressin secretion.
U.5. Patent No. 5,516,774 (Albright et al.) teaches tricyclic vasopressin
compounds, including those having a pyrrolobenzodiazepine core. U.S. Patents
Nos.
5,700,796 and 5,719,278 provide other tricyclic benzazepine compounds useful
as
vasopressin antagonists. U.S. Patent No. 5,654,297 teaches vasopressin
antagonists
having bicyclic non-peptide cores and U.S. Patent No. 5,686,445 discloses
similarly
active compounds having pyridobenzoxazapine and pyridobenzothiazepine core
structures.
Summary of the Invention
This invention provides new pharmaceutical carrier or excipient systems
useful in the formulation of biologically active compounds and formulations
produced using the carrier system, as well as processes for producing the
carrier
systems and formulations. Of particular interest is the use of the novel
carrier
systems in the formulation of encapsulated oral pharmaceutical compositions
for
mammalian use, preferably for human use.
In general, the Garner systems of this invention comprise, by weight
percentage, a composition having the components:
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a) from about 1% to about 20%, preferably from about 5% to about 12%,
of a surfactant component, more preferably from about 9% to about 14% or from
about 10.5% to about 13% surfactant;
b) from about 55% to about 93%, preferably from about 60% to about
85%, of a component of one or more polyethylene glycols (PEG) with an average
molecular weight range of from about 190 to about 3450, preferably 400 to
1540; and
c) from about 1% to about 25%, preferably from about 5% to about 15%,
more preferably from about 9% to about 14% or from about 10% to about 13% of
one or more sucrose fatty acid esters or polyvinylpyrrolidone (PVP) with a K
value
between about 15 and about 90, preferably with a K value of from about 16 to
about
18, most preferably about 17, as defined in USP/NF, or a combination of one or
more
sucrose fatty acid esters or PVP.
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
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 1:1 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
polyethylene
glycol component may suitably be from about 32% to about 36% of PEG 1000 and
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from about 35% to about 46% PEG 400 or from about 33% to about 35% PEG 1000
and from about 37.5% to about 43% PEG 400.
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 salts defined by Martindale The Extra Pharmacopoeia
Thirtieth
Edition on pagel341-1342 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.
In addition to these components, other enhancing or protective
pharmaceutically acceptable antioxidants or preservatives may be added to the
compositions of this invention, preferably accounting for from about 0.1 % to
about
4% by weight of the composition, more preferably from about 0.1% to about 3%
of
the composition. Examples may include ascorbyl palmitate, 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%
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to about 0.15% (% w/w), preferably with a mixture of BHA and BHT within these
ranges. Preferred amounts of BHA are from about 0.5% to about 2.0% or from
about
0.75% to about 1.5%. Preferred amounts of BHT are from about 0.005% to about
0.02% or from about 0.075% to about 1.5%. Further embodiments are those
wherein
about 0.2% BHT is included.
One embodiment of a pharmaceutically useful carrier or excipient system of
this invention comprises, as compared by % weighdweight:
a) from about 32% to about 36% of PEG 1000;
b) from about 35% to about 46% polyethylene glycol
400 (PEG 400).
c) from about 9% to about 14% of povidone;
d) from about 9% to about 14% Polysorbate 80;
e) from about 0.005% to about 0.02% butylated hydroxytoluene
(BHT);
and
f) from about 0.5% to about 2.0% Butylated Hydroxyanisole (BHA).
In instances where a greater amount of antioxidant or preservative activity is
desired, the percentages of the BHT and BHA in components e) and f) can
understandably be increased relative to each other to create an
antioxidant/preservative component of up to about 4%.
It will be understood that the percentages of the compounds in each of the
formulations of these carrier or excipient systems will equal 100%, without
taking
into account an active pharmacological agent or other pharmacological
components,
such as coloring agents, fillers, pharmaceutically acceptable adjuvants,
encapsulating
or coating components, etc. In a preferred embodiment of this invention, the
carrier
system above is combined with a pharmacologically active agent and then
encapsulated, such as with a hard or soft gelatin capsule.
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Another preferred embodiment of this invention includes a Garner or excipient
system useful for pharmaceutical compositions comprising on a weight per
weight
percentage basis:
a) from about 33% to about 35% of PEG 1000;
b) from about 37.5% to about 43% polyethylene glycol 400 (PEG 400);
c) from about 10.5% to about 13% Polysorbate 80;
d) from about 0.075% to about 0.015% butylated hydroxytoluene (BHT);
e) from about 0.75% to about 1.5% Butylated Hydroxyanisole (BHA);
and
f) from about 10.0% to about 13% of povidone.
The Garner or excipient systems of this invention may be used to formulate
pharmaceutical compositions for numerous classes of compounds. These include
those chemical compounds produced around various bicyclic and tricyclic core
molecules, including bi- and tricyclic heterocycles. Examples of the compounds
in
question include those disclosed in U.S. Patents Nos. 5,516,774; 5,654,297;
5,686,445; 5,700,796; and 5,719,278, each of which is fully included herein by
reference. Also incorporated herein by reference for use with the present
Garner
systems are the compounds disclosed in WO 98/24430 (Gautier et al.), U.S.
Patent
No. 5,356,904 (Freidinger et al.), WO 95/03305, EP 0 514 667 B1 (Ogawa et
al.),
and U.S. Patent No. 5,525,614 (Blankley et al.), each mentioned above in the
Background of the Invention.
Of specific interest as an active pharmaceutical ingredient or agent for use
with the present invention is for N-[4-(5H-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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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 incorporated herein by reference.
Also among the most preferred compounds for use as an active ingredient
with the Garner or excipient formulations of this invention is [2-Chloro-4-(3-
methyl-
pyrazol-1-yl)-phenyl-(SH, 11H)-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-
methanone,
or pharmaceutically acceptable salts thereof, having the structure:
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C
CH3
Formulations using this compound are useful in methods for treating in
humans or other mammals diseases, conditions or disorders in which vasopressin
agonist activity is desired. These methods of treatment include those for
diseases,
conditions or disorders which make it desirable to release factor VIII and von
Willebrand factor into the circulatory system, release tissue-type plasminogen
activator (t-PA) in the blood circulation, or affect the renal conservation of
water and
urine concentration. Such methods of treatment include, but are not limited
to,
treatments for diabetes insipidus, nocturnal enuresis, nocturia, urinary
incontinence,
or bleeding and coagulation disorders in humans or other mammals, including
hemophilia. The methods herein for which the formulations may be used also
include facilitation in humans or other mammals of temporary delay of
urination,
which may also be described as controlling or treating the inability to
temporarily
delay urination, whenever desirable. This method is understood to include
treatments
facilitating the temporary delay of urination which are separate from and not
included
in the treatment of the conditions known as nocturnal enuresis and nocturia.
This compound has been synthesized by the steps described below.
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S (2-Chloro-4-fluorophenyl)-(SH,11H-pyrrolof2,1-clfl,4lbenzodiazepin-10-yl)-
methanone _
Oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4-
fluorobenzoic acid (3.44 g) in dichloromethane (50 ml). Two drops of
dimethylformamide were added and the mixture was stirred for 18 hours at room
temperature. The resultant solution was evaporated to give the crude 2-chloro-
4-
fluorobenzoyl chloride as a viscous oil (3.72 g).
The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25
ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-
SH-
pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and
dichloromethane (50 ml). After 18 hours at room temperature, the reaction
mixture
was washed with water and saturated aqueous sodium bicarbonate. The
dichloromethane solution was dried with anhydrous sodium sulfate and filtered
through a short column of hydrous sodium magnesium silicate and further eluted
with
several volumes of dichloromethane. The combined organic phase was
concentrated
on a hot plate with the gradual addition of hexane until crystallization
occurred. After
cooling, the crystals were collected by filtration to yield the title compound
(3.85 g),
m.p. 110-112 °C.
f 2-Chloro-4-(3-methyl-pyrazol-1-yl)-phenyll-(SH,11H)-pyrrolof 2,1-
clf 1,41benzodiazepin-10-yl)-methanone (Isomer A) and f2-Chloro-4-(5-methyl-
~yrazol-1-~phenyll-(SH,11H)-pyrrolof 2,1-cl f 1,41benzodiazepin-10-yl)-
methanone
Isomer B
Method 1 To 60% sodium hydride in oil (0.3 g, degreased with hexane)
in dimethylformamide (25 ml) was added 3-methylpyrazole (0.55 g). When the
hydrogen evolution subsided, (2-chloro-4-fluorophenyl)-(SH,11H-pyrrolo[2,1-
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c][1,4]benzodiazepin-10-yl)-methanone (1.70 g) was added. The reaction mixture
was heated for 18 hours in a sand bath (internal temperature 125 °C).
The reaction
mixture was then poured onto ice and further diluted with a saturated saline
solution.
The precipitated solid was recovered by filtration. The crude product was
dissolved
in dichloromethane, dried over anhydrous sodium sulfate, and then filtered
through a
short column of hydrous sodium magnesium silicate and further eluted with
several
volumes of dichloromethane. The combined eluate was refluxed on a hot plate
with
the gradual addition of hexane until an opaque solution was observed. On
cooling an
amorphous solid was obtained. On subjecting this material to a second column
of
hydrous sodium magnesium silicate and evaporation of the solvent in vacuo gave
a
mixture of regioisomers 9A and 9B in approximately a 9:1 ratio as an amorphous
glass ( 1.11 g), MS, m/z: 403.2 (M+H)+.
Method 2: To a pre-cooled, stirred suspension of hexane-washed 60%
sodium hydride (3.00 g) in dry dimethylformamide (250 ml) was added dropwise
under nitrogen 3-methylpyrazole (5.50 g) at 0°C. The mixture was warmed
to room
temperature. After gas evolution ceased, 2-chloro-4-fluorophenyl)-(SH,11H-
pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (17.0 g) was added as a
solid,
and the mixture heated to 130°C for one hour. The reaction mixture was
poured into
ice water, a precipitate collected by filtration, and air-dried. The
precipitate was
dissolved in dichloromethane, dried over anhydrous sodium sulfate, and
filtered
through a short column of silica gel, eluting with ethyl acetate. The combined
filtrate
was evaporated in vacuo to a residual foam (18.5 g). Purification and
separation of
regioisomers by low pressure column chromatography on silica gel eluting with
a
gradient mixture of ethyl acetate-hexane (10:90 to 25:75), yielded two
purified
regioisomers:
Isomer A, [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(SH,11H)-pyrrolo-
[2,1-c][1,4]benzodiazepin-10-yl)-methanone (13.5 g), as a colorless amorphous
solid;
MS (EI), m/z: 402 (M)+. A sample (0.5 g) was crystallized from diethyl ether,
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followed by recrystallization from ethanol to yield regioisomer A (0.275 g) as
a
colorless, crystalline solid, m.p. 141-143°C;
Isomer B, [2-chloro-4-(5-methyl-pyrazol-1-yl)-phenyl]-(SH,11H)-pyrrolo[2,1-
c][1,4]benzodiazepin-10-yl)-methanone (1.93 g) as a colorless amorphous solid.
A
sample was crystallized from diethyl ether, followed by recrystallization from
methanol to yield regioisomer B as colorless, needles (1.4 g), m.p. 160-163
°C; MS
(EI), mlz: 402 (M)+, MS (+FAB), mlz: 403 (M+H)' .
In order to obtain consistency of administration, it is preferred that a
composition of the invention is in the form of a unit dose. Suitable unit dose
forms
preferably include tablets or capsules, though one skilled in the art will
understand
semi-solids or gels of this invention are also readily made and useful. Such
unit dose
25
forms may contain from 0.1 to 1000 mg of an active ingredient compound of the
invention and preferably from 2 to 50 mg. Still further preferred unit dosage
forms
contain 5 to 25 mg of a pharmaceutically active compound of the present
invention.
The formulations of the present invention can be administered orally at a dose
range
of about 0.01 to 100 mg/kg of active ingredient or preferably at a dose range
of 0.1 to
10 mg/kg of active ingredient. Such compositions may be administered from 1 to
6
times a day, more usually from 1 to 4 times a day.
The compositions of the invention may be formulated with other conventional
carriers or excipients such as fillers, disintegrating agents, adjuvants,
binders,
lubricants, flavoring agents and the like.
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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The carrier system of this invention may also be used in pharmaceutical
compositions containing as active pharmaceutical agents or ingredients other
poorly
soluble compounds including, but not limited to, the compounds disclosed in EP
0709386 (Yamanouchi Pharmaceutical Company, Ltd), including the compound N-
[ 1,1'-biphenyl]-2-yl-4-[(4,5-dihydro-2-mehtylimidazo [4,5-d] [ 1 ]benzazepin-
6( 1H)-
yl)carbonyl]-benzamide (CAS Reg. No. 179528-39-3 YM 087), or pharmaceutically
acceptable salts thereof.
Processes for Preparing Pharmaceutical Formulations
This invention also includes methods for producing the formulations using the
biologically and pharmacologically active ingredients of the type described
herein. A
process of this invention comprises the steps of:
a) combining, preferably with mixing or stirring, 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 ingredient or agent 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 , more preferably at
a temperature
from about 130°C to about 150°C, most preferably at a
temperature from about
135°C to about 145°C;
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e) cooling the first pharmaceutical composition, if necessary, to a
temperature of from about 75°C to about 95°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 stirring
until the
final pharmaceutical composition mixture is clear.
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 Garner mixture, which is then stirred or
otherwise
mixed until the second carrier mixture is a clear solution;
d) adding the active ingredient to create a first pharmaceutical
composition rruxture;
e) stirring the first pharmaceutical composition mixture, preferably with
heating, until the first pharmaceutical composition mixture is clear,
preferably at a
temperature of from about 115°C to about 170°C, more preferably
at a temperature
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from about 130°C to about 150°C, most 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) and/or povidone to
create a final pharmaceutical composition mixture, preferably with stirring
until the
final pharmaceutical composition mixture is clear.
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, using the compound of N-[4-(SH-pyrrolo[2,1
c] [ 1,4]benzodiazepin-10( 11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methyl
benzamide (VPA-985) as a non-limiting illustrative example. It is understood
that
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comparable formulations may be produced using other active ingredients, or
combinations thereof.
Example 1
50 mg/capsule: Oral Formulation at 10 % Drug Loading
In place of the polysorbate 80 in this formulation of Example l, 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.
(% w/w) per capsule 20,000
(mg) capsule batch (g)
active ingredient 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
BITI', NF 0.09 0.42 8.32
BHA, NF 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 stirring at 85 ~ 5 °C, until a clear
solution was
formed.
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3. Add active ingredient 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 the active ingredient dissolves completely.
4. Cool the solution in step 4. to 60 ~ 5 °C.
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, such as by using a Hoglinger and Karg (H&K) 800L
encapsulator machine. During encapsulation cool the body of capsule using cool
Nitrogen, which was passed through dry ice.
7. Band seal the capsules with gelatin solution.
Example 2
50 mg/capsule: Oral Formulation at 10 °7o 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.
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(% w/w) per capsule 20,000
(mg) capsule batch
(g)
active ingredient 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
BHT NF 0.09 0.42 8.32
BHA NF 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.
Example 3
50 mg/ca~sule
Example 4 provides a formulation with a combination of two or more
surfactants.
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(°Io w/w) per capsule (mg) 20,000 capsule
batch (g)
active ingredient 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
BHT, NF 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~psule: Oral Formulation at 5 % Drug Loading
(°Io w/w) per capsule 20,000
(mg) capsule
batch (g)
active ingredient 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
BHT, NF 0.09 0.42 8.32
BHA, NF 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 the
active ingredient 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 mg/capsule: Oral Formulation at 15 % Drug Loading
(% w/w) per capsule 20,000 capsule
(mg) batch (g)
active ingredient 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
BHT, NF 0.08 0.53 10.64
BHA, NF 0.82 5.32 106.42
PEG 400, NF Q.S. to Q.S. to 650.00Q.S.
100 to
13,000.00
This formulation is produced with the same steps as the 50 mg/capsule, above,
with the exception that the heating temperature to solubilize the active
ingredient 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
150 mg in Size 00 Capsule _
(°1o w/w) per capsule 20,000
(mg) capsule batch
(g)
active ingredient 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
BHT, NF 0.08 0.73 14.56
BHA, NF 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 the
active
ingredient 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 1, below, can
be formulated as described above to create formulations of 10% active
ingredient
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 Active
No. 400 1000 K15 K90 Ingred.
(%) (%) (%) (%) (%) (%) (%) (%)
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
Simlarly, the following Examples 12 through 32 may be formulated by the
10 methods herein using PEG 400, PEG 1000, PVP with a K value of 17, active
ingredient, BHA and BHT as antioxidants or preservatives and the additional
components listed as "other".
Table 2
Ex. PEG PEG PVP Active BHA BHT Other Other
No. 400 1000 K-17 Ingred.
12 40.40 35.00 10.00 2.00 0.20 Sodium
10.00
Taurocholate
2.40
13 75.40 - 5.00 10.21 2.00 0.20 Sodium PVP
Taurocholate K-90
2.40 5.00
14 42.59 35.00 10.00 10.21 2.00 0.20
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15 34.35 10.0010.21 2.00 0.20 Poloxamer 188 -
28.23
15.00
16 42.59 10.0010.21 2.00 0.20 Poloxamer 188 -
20.00
15.00
17 37.10 10.0010.21 2.00 0.20 Poloxamer 188 -
30.49
10.00
18 35.72 10.0010.21 2.00 0.20 Poloxamer 188 -
29.36
12.50
19 34.35 10.0010.21 2.00 0.20 Poloxamer 188 -
28.23
15.00
20 37.10 10.0010.21 2.00 0.20 Poloxamer 188 -
30.49
10.00
21 34.35 10.0010.21 2.00 0.20 Poloxamer 188 -
28.23
15.00
22 35.72 10.0010.21 2.00 0.20 Poloxamer 188 -
29.36
12.50
23 36.86 10.0010.64 2.00 0.20 Pluronic L44 -
30.30
10.00
24 36.86 10.0010.64 2.00 0.20 Pluronic L101 -
30.30
10.00
25 39.61 10.0010.64 2.00 0.20 Tween 40 -
32.55
5.00
26 41.25 10.0010.64 2.00 0.20 Tween 40 -
33.91
2.00
27 39.61 10.0010.64 2.00 0.20 Tween 20 -
32.55
5.00
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28 41.25 33.91 10.64 2.00 0.20 Tween 20 -
10.00
2.00
29 34.12 28.04 10.64 2.00 0.20 Tween 40 Poloxamer
10.00 188
5.00 10.00
30 36.86 30.30 10.64 2.00 0.20 Tween 40 -
10.00
10.00
31 36.86 30.30 10.64 2.00 0.20 Tween 80 -
10.00
10.00
32 34.12 28.04 10.64 2.00 0.20 Tween 80 Poloxamer
10.00 188
5.00 10.00
