Note: Descriptions are shown in the official language in which they were submitted.
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SOFT ELASTIC CAPSULES COMPRISING RITONAVIR ANDIOR LOPINAVIR
Technical Field
The invention relates to a soft elastic capsule, fill and shell compositions
of the soft
elastic capsule, and pharmaceutical agents contained within the soft elastic
capsules. The
invention further relates to soft elastic capsules and HIV protease inhibiting
compounds
contained in the soft elastic capsule. The soft elastic capsule can be used
with a broad range
of pharmaceutical agents including antibiotics, anti-AIDS pharmaceutical
agents, and an
array of other medicinally active agents. Important pharmaceutical agents are
anti-HIV
agents.
Background
Inhibitors of human immunodeficiency virus (HIV) protease have been approved
for
use in the treatment of HIV infection for several years. A particularly
effective HIV protease
inhibitor is (2S, 3S, SS)-5-(N-((N-methyl-N-((2-isopropyl-4- thiazolyl)-
methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-
amino)-1,6
diphenyl-3-hydroxyhexane (ritonavir), which is marketed as NORVIR~. Ritonavir
is known
to have utility for the inhibition of HIV protease, the inhibition of HIV
infection, and the
enhancement of the pharmacokinetics of compounds which are metabolized by
cytochrome
P4so monooxygenase. Ritonavir is particularly effective for the inhibition of
HIV infection
when used alone or in a combination with one or more reverse transcriptase
inhibitors and/or
one or more other HIV protease inhibitors. Ritonavir and processes for its
preparation are
disclosed in U.S. Patent No. 5,541,206, issued July 30, 1996, the disclosure
of which is
herein incorporated by reference. Crystalline Form II of ritonavir and
processes for its
preparation are disclosed in International Patent Application WO00/04016,
published January
27, 2000, which is incorporated herein by reference.
A HIV protease inhibitor useful in combination with ritonavir is lopinavir
which has a
chemical name of (2S,3S,SS)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-
(2S-(I-
tetrahydropyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane.
Lopinavir is an
inhibitor of the HIV protease and prevents cleavage of the HIV Gag-Pol
protein, resulting in
the production of immature, non-infectious viral particles. The preparation of
lopinavir is
disclosed in U.S. Patent No. 5,914,332, issued June 22, 1999, the disclosure
of which is
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2
herein incorporated by reference. Ritonavir and Lopinavir are available as a
co-formulation
which is marl~eted under the name of KALETRA~.
Factors that affect the bioavailability of a pharmaceutical agent when
administered
orally include aqueous solubility, pharmaceutical agent absorption, dosage
strength and first
pass effect. Various salts or other derivatives of the pharmaceutical agent
can be prepared in
attempts to achieve maximum aqueous solubility. Various capsule dosage forms
can also be
formulated to maximize the bioavailability of the pharmaceutical agent.
A compound of formula I (ritonavir) has been found to have good solubility in
pharmaceutically acceptable organic solvents. The solubility in such solvents
is enhanced in
the presence of a pharmaceutically acceptable long chain fatty acid.
Pharmaceutical compositions comprising HIV protease inhibitors (especially,
ritonavir,
lopinavir and mixtures thereof) have been prepared as a solution in a complex
carrier medium
comprising several components; these compositions have been described in U.S.
Patent
Application No. 09/576,097 filed May 22, 2000 and U.S. Patent No. 6, 232, 333,
issued May
15, 2001, both herein incorporated by reference. The carrier medium may be
designed to
form an emulsion upon administration thereby facilitating absorption of the
HIV protease
inhibitor.
There is a need for improved formulations of soft elastic capsules containing
pharmaceutical agents and for procedures for manufacturing said soft elastic
capsules.
Summary of the Invention
The current invention provides soft elastic capsules that have a fill, which
includes
pharmaceutical agent(s), an alcohol, and fatty acid; and a shell, which
includes gelatin and
plasticizing agent(s). The pharmaceutical agents can be, and are preferably,
HIV protease-
inhibiting agents. The fill and the shell of the soft elastic capsules also
have an initial state,
which occurs prior to the diffusion and equilibrium of fill and shell
components, and an
equilibrium state. In the initial state, the shell is underplasticized and the
fll contains an
amount of alcohol sufficient to solubilize the pharmaceutical agents and to
plasticize the shell
upon equilibrium. In the equilibrium state the shell is sufficiently
plasticized to provide a
desired degree of hardness and the pharmaceutical agents remain solubilized.
In one embodiment of the invention, the initial fill composition includes an
increased
amount of alcohol (relative to the amount required to solubilize the
pharmaceutical agent(s)),
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preferably propylene glycol, HIV protease-inhibiting agent(s), a medium ox
long chain fatty
acid, and a surfactant. The initial shell composition includes gelatin, a
reduced amount of
plasticizing agent(s), and water. A portion of the propylene glycol of the
initial fill
composition diffuses into the shell, which is underplasticized in the initial
state, and
plasticizes the shell to an acceptable physical condition upon equilibrium.
The amount of
propylene glycol remaining in the fill composition at equilibrium is Buff
cient to solubilize
the HIV protease-inhibiting agent(s).
In another embodiment of the invention, a process for making soft elastic
capsules
that have a fill composition and a shell composition in which the fill
composition includes
pharmaceutical agent(s), is provided. In one step of the process, a fill
composition is
prepared that includes pharmaceutical agent(s), an increased amount of
alcohol, and fatty
acid. In another step, a shell composition is prepared that includes gelatin,
a reduced amount
of plasticizing agent(s), and water. The fill composition and the shell
composition are then
formed into a soft elastic capsule, in which the shell in the initial state is
underplasticized.
Next, the components of the fill composition and the shell composition
equilibrate and the
shell becomes plasticized and the pharmaceutical agents) remain dissolved.
Brief Description of the Drawing
Figure 1 shows a portion of a gel encapsulation machine and a process for
manufacturing capsules.
Detailed Description
As used herein 'pharmaceutical agent' refers to a compound with
pharmacological
activity.
As used herein, the term 'soft elastic capsule' refers to a dosage form that
includes a
soft shell, often partially composed of gelatin, said capsules containing a
liquid fill, the fill
containing a pharmaceutical agent or combination of pharmaceutical agents
suitable for
pharmaceutical delivery.
As used herein, the term 'fill' refers to the liquid composition of a soft
elastic capsule,
encapsulated by a shell, which contains a solubilized pharmaceutical agent or
combination of
pharmaceutical agents and compounds.
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4
As used herein, the term 'fill composition' refers to the components, or
material, in
the fill. The fill composition can also indicate the concentration of
materials in the fill.
During the manufacturing and storage of the soft elastic capsule, the
concentration of
materials in the fill can change.
As used herein, the term 'shell' refers to the casing of the soft elastic
capsule that
encloses the fill.
As used herein, the term 'shell composition' refers to the components, or
material, in
the shell. The shell composition can also indicate the concentration of
materials in the shell.
During the manufacturing and storage of the soft elastic capsule, the
concentration of
1.0 materials in the shell can change.
As used herein, the term 'initial state' refers to the physical and chemical
characteristics of the soft elastic capsule, the concentration of components
in the fill, and the
concentration of components in the shell, prior to the diffusion of components
from the fill to
the shell or from the shell to the fill. 'Initial shell composition' and
'initial fill composition'
refer to the concentration of components in the fill and the concentration of
components in
the shell, respectively, prior to the diffusion of components from the fill to
the shell or from
the shell to the fill.
As used herein, the term 'equilibrium state' refers to the physical and
chemical
characteristics of the soft elastic capsule, the concentration of components
in the fill, and the
concentration of components in the shell, after diffusion of components from
the fill to the
shell or from the shell to the fill Where the components have reached
equilibrium in the soft
elastic capsule.
As used herein, 'acceptable physical characteristics' of soft elastic capsules
refers to
the quality, hardness, disintegration time, and moisture content of the soft
elastic capsules
that are pharmaceutically suitable for maintaining and delivering a fill
composition
containing a pharmaceutical agent or combination of pharmaceutical agents.
As used herein, 'plasticized' refers to the relative hardness or softness of
the shell of
the soft elastic capsule as affected by the plasticizing agent.
'Underplasticized' refers to a
shell composition that results in a soft elastic capsule that is too hard or
brittle as a result of
an inadequate amount of plasticizing agent in the shell composition.
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Pharmaceutical agents
The pharmaceutical agents of the current invention include, but are not
limited to,
HIV protease inhibiting compounds.
A preferred HIV protease inhibiting compound of the current invention includes
a
compound of formula I:
HsC S ~ CHs S \\
H N
N ,O
HaC N
O
H3C
(I~
or a pharmaceutically acceptable salt thereof, disclosed in PCT Patent
Application No.
WO 94/14436, published July 7, 1994, and U.S. Patent No. 5,541,206, issued
July 30, 1996,
the disclosure of both of which are herein incorporated by reference.
A preferred compound of formula I is known as ritonavir. The compounds of
formula I are useful to inhibit HIV infections and, thus, are useful for the
treatment of AIDS.
A process for the preparation of ritonavir is disclosed in U.S. Patent No.
5,567,823, issued
October 22, 1996, the disclosure of which is herein incorporated by reference.
The process
disclosed in this patent also produces ritonavir as crystalline Form I. Other
processes for
preparing ritonavir are disclosed in U.S. Patent No. 5,491,253, issued
February 13,
1996; U.S. Patent No. 6,022,989, issued February 8, 2000; U.S. Patent No.
6,160,122, issued
December 12, 2000; and U.S. Patent No. 5,932,766, issued August 3, 1999, all
of which are
incorporated herein by reference.
Pharmaceutical compositions comprising ritonavir or a pharmaceutically
acceptable
salt thereof are disclosed in U.S. Patent Nos. 5,541,206, issued July 30,
1996; 5,484,801,
issued January 16, 1996; 5,725,878, issued March 10, 1998; and 5,559,158,
issued
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6
September 24, 1996; 6,232,333 issued May 15, 2000; and 5,948,436, issued
September 7,
1999, the disclosures of all of which are herein incorporated by reference.
The use of ritonavir to inhibit HIV infection is disclosed in U.S. Patent No.
5,541,206,
issued July 30, 1996. The use of ritonavir in combination with one or more
reverse
transcriptase inhibitors to inhibit an HIV infection is disclosed in U.S.
Patent No. 5,635,523,
issued June 3, 1997. The use of ritonavir in combination with one or more HIV
protease
inhibitors to inhibit an HIV infection is disclosed in U.S. Patent No.
5,674,882, issued
October 7, 1997. The use of ritonavir to enhance the pharmacokinetics of
compounds
metabolized by cytochrome P450 monooxygenase is disclosed in U.S. Patent No.
6,037,157,
issued March 14, 2000. The disclosures of all of these patents and patent
applications are
herein incorporated by reference.
Another preferred HIV protease inhibiting compound of the current invention
includes a compound of formula II:
CH3
H
~ /N N NH
O
CH3 IOI O
CH3
(II)
and related compounds as disclosed in U.S. Patent No. 5,914,332 issued June
22, 1999 the
disclosure of which is herein incorporated by reference. A preferred compound
of formula II
is known as lopinavir and has a chemical name of (2S,3S,SS)-2-(2,6-
dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-
methyl-
butanoyl)amino-1,6-diphenylhexane. The preparation of this compound is
disclosed in U.S.
Patent Application No. 5,914,332, issued June 22, 1999, the disclosure of
which is herein
incorporated by reference.
Additional HIV protease inhibiting compounds include: N-(2(R)-hydroxy-1
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7
(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-( 1-(4-(3-pyridylmethyl)-2(S)-N'-
(t-
butylcarboxamido)-piperazinyl))-pentaneamide (for example, indinavir) and
related
compounds, disclosed in European Patent Application No. EP 541168, published
May 12,
1993, and U.S. Patent No. 5,413,999, issued May 9, 1995, both of which are
herein
incorporated by reference; N-tent-butyl-decahydro-2-[2(R)-hydroxy- 4-phenyl-
3(S)-[[N-(2-
quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-
carboxamide (for
example, saquinavir) and related compounds disclosed in U.S. Patent No.
5,196,438, issued
March 23, 1993, which is incorporated herein by reference; 5(S)-Boc-amino-4(S)-
hydroxy-6-
phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and
related
compounds, disclosed in European Patent Application No. EP532466, published
March 17,
1993, which is incorporated herein by reference; 1 -Naphthoxyacetyl-beta-
methylthio-Ala-
(2S,3S)-3-amino-2-hydroxy-4-butanoyl 1,3-thiazolidine-4-t-butylamide (for
example, 1-
Naphthoxyacetyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBU), 5-isoquinolinoxyacetyl-beta-
methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-
butylamide, and
related compounds, disclosed in European Patent Application No. EP490667,
published
June 17, 1992 and Chem. Pharm. Bull. 40 (8) 2251 (1992), which are both
incorporated
herein by reference; [1 S-[1 R*-(R*-),2S*])-Nl [3-[[[(1,1-
dimethylethyl)amino]carbonyl](2-
methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-
quinolinylcarbonyl)amino]-
butanediamide (for example, SC-52151) and related compounds, disclosed in PCT
Patent
Application No. WO 92/08701, published May 29, 1992 and PCT Patent Application
No. WO
93/23368, published November 25, 1993, both of which are herein incorporated
by reference;
OH ~ NHS
H
O N N~
_ O \'O
Oi O
Ph/
(for example, VX-478) and related compounds, disclosed in PCT Patent
Application No.
WO 94/05639, published March 17, 1994, which is incorporated herein by
reference;
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0
HO ~ ~ N' 'N ~ OH
HO OH
S (for example, DMP-323) or
0
HzN ~ ~ N' 'N ~ NH
z
HO OH
(for example, DMP-4S0) and related compounds, disclosed in PCT Patent
Application No.
WO 93/07128, published April 1 S, 1993, which is incorporated herein by
reference;
Hiiioi
OH
~~H
H
N N
HO
O -
1 S PhS~ O N
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9
(for example, AG1343, (nelfmavir)), disclosed in PCT Patent Application No. WO
95/09843,
published April 13, 1995 and LJ.S. Patent No. 5,484,926, issued January 16,
1996, which are
both incorporated herein by reference;
OH OH
H
BccHN N
Ph/
(for example, BMS 186,318) disclosed in European Patent Application No.
EP580402,
published January 26, 1994, which is incorporated herein by reference;
0
H II H I
/N / N I
N
H
O
Phi
(for example, SC-55389a) and related compounds disclosed in PCT Patent
Application No.
WO 9506061, published March 2, 1995, which is incorporated herein by reference
and at the
2nd National Conference on Human Retroviruses and Related Infections,
(Washington, D.C.,
Jan. 29 - Feb. 2, 1995), Session 88; and
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N
Val -H N N
N
0 N
H
(for example, BILA 1096 BS) and related compounds disclosed in European Patent
Application No. EP560268, published September 15, 1993, which is incorporated
herein by
reference; and
~ CF3
Ph /
~J
N
p- v~
IO
(for example, U-140690 (tipranavir)) and related compounds disclosed in PCT
Patent
Application No. WO 9530670, published November 16, 1995, and U.S. Patent No.
5,852,195, issued December 22, 1998, the disclosures of both of which are
herein
incorporated by reference; and
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11
0
/ \
for example, BMS-232,623 (3S-(3R*, 8'R*, 9'R*, 12R*))-3,12-bis(1,1-
dimethylethyl)-8-
hydroxy-4,11-dioxo-9-(phenylmethyl)-6-((4-(2-pyridinyl)-phenylmethyl)-
2,5,6,10,13-
pentaazatetradecanedioic acid, dimethyl ester) and related compounds disclosed
in
International Patent Application No. W099/36404, published July 22, 1999 and
International
Patent Application No. W097/40029, published October 30, 1997, both herein
incorporated
by reference; or a pharmaceutically acceptable salt of any of the above.
Other pharmaceutical agents that can be used in the current invention include,
but are
not limited to, anti-viral compounds, cell growth inhibitors, antibiotics,
antihistamines,
analgesics, food supplements, nutrients, vitamins, steroids, and anesthetics..
The current
invention relates to any physiologically or pharmacologically active substance
that produces
a local or systemic effect.
Fill Composition
The fill composition for the soft elastic capsule of the invention can include
a
solubilized HIV protease inhibiting compound or a combination of solubilized
HIV protease
inhibiting compounds. Preferably, the HIV protease inhibiting compound is a
compound of
the formula I, formula II, saquinavir, nelfinavir, amprenavir, or indinavir.
More preferably
the compound is ritonavir, lopinavir, saquinavir, nelfmavir, amprenavir, or
indinavir. Most
preferably the compound is ritonavir or lopinavir. A combination of
solubilized HIV
protease inhibiting compounds can also be used. Preferably the combination is
ritonavir or
nelfinavir and another HIV protease inhibitor, for example, lopinavir,
saquinavir, indinavir,
amprenavir, or nelfmavir. More preferably, the combination is of ritonavir or
nelfinavir and
another HIV protease inhibitor, for example, lopinavir, saquinavir, indinavir,
amprenavir, or
H3C/ ~ \CH3
CH3
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12
nelfinavir. Most preferably the combination is ritonavir and lopinavir. A
preferred ratio of
the amount, as measured by weight, of ritonavir to lopinavir in the fill
composition is in the
range of 2:1 to 1:10; more preferably this ratio is in the range of l :l to
1:10; most preferably
this ratio is in the range of 1:3 to 1:5, and it is most highly preferred that
the ratio is about
1:4.
The HIV protease inhibiting compound or a combination of solubilized HIV
protease
inhibiting compounds can be present in the fill composition, as measured by
weight, in a
range of 10-35%. More preferably, the HIV protease inhibiting compound or
compounds are
present in the range of 12.5-22.5%. Most preferably, the HIV protease
inhibiting compound
or compounds are present in the range of 15- 20%.
This HIV protease inhibiting compound or a combination of HIV protease
inhibiting
compounds can be solubilized in a pharmaceutically acceptable organic solvent.
Preferably,
the pharmaceutically acceptable organic solvent comprises from about 75% to
about 90% by
weight of the fill composition. More preferably, the pharmaceutically
acceptable organic
solvent or mixture of pharmaceutically acceptable organic solvents comprises
from about
77.5% to about 87.5% by weight of the fill composition. This pharmaceutically
acceptable
organic solvent of the fill composition can include (1) a pharmaceutically
acceptable medium
and/or long chain fatty acid or mixtures thereof; (2) an alcohol, preferably
propylene glycol;
and (3) a pharmaceutically acceptable surfactant. Optionally, water can be
included in the fill
composition and can be present preferably in a percentage by weight that is
relatively low as
compared to the other components of the fill composition.
The fill composition can be prepared with a percentage by weight of organic
solvent
sufficient to solubilize the pharmaceutical agent or combination of
pharmaceutical agents, for
example, the HIV protease inhibitors, contained in the initial fill
composition. In one
embodiment of the invention, the initial fill composition contains an
increased percentage by
weight of alcohol, for example, propylene glycol, sufficient to solubilize the
pharmaceutical
agent or combination of pharmaceutical agents. The percentage of alcohol, for
example,
propylene glycol, is increased relative to the other components in the initial
fill composition.
The alcohol percentage is increased greater than the amount of alcohol
necessary to solubilize
the pharmaceutical agents, for example HIV protease inhibitors. In this
embodiment, the
propylene glycol is preferably increased by 100-200% of the minimal amount of
propylene
glycol necessary to solubilize the HIV protease inhibitors in the initial fill
composition.
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In the current invention, a portion of the amount of alcohol present in the
initial fill
composition will migrate into the shell of the soft elastic capsule upon
equilibrium of the fill
components with the shell components. A substantially smaller portion, if any,
of the
amounts of the other components of the fill composition, for example, the
pharmaceutical
agents, the fatty acid, and the surfactant, will migrate into the shell upon
equilibrium.
Therefore, the ranges by percentage weight in the fill composition of the
pharmaceutical
agents, the fatty acid, and the surfactant, as described herein, sufficiently
reflect the
concentration of these components of the fill composition in both the initial
state and the
equilibrium state.
Included in this embodiment, the increased amount of alcohol in the initial
fill
composition is also sufficient to retain the solubility of the pharmaceutical
agent or
combination of pharmaceutical agents upon equilibration of the fill
composition with the
shell composition. The initial fill composition is also formulated to include
an amount of
alcohol, for example, propylene glycol, sufficient to solubilize the
pharmaceutical agent or
pharmaceutical agents, for example, HIV protease inhibitors, without the
addition of heat.
Preferably, the initial fill composition is prepared at temperatures that
avoid the degradation
of a HIV protease inhibitor, for example, ritonavir.
Included in this embodiment, the increased amount of alcohol in the fill
composition
is also sufficient to properly plasticize the shell of the soft elastic
capsule upon equilibrium of
the fill composition and the shell composition. The amount of plasticizing
agent in the initial
shell composition is not sufficient to provide proper plasticity to the shell
if no additional
plasticizing agent(s), for example, alcohol, migrates into the shell during
equilibrium or is
otherwise added. For example, a initial shell composition formulated to be
underplasticized
will produce a soft elastic capsule having a shell that is too brittle if no
additional alcohol, for
example, polypropylene glycol, migrates into the shell. In the current
invention, the excess
alcohol contained in the initial fill composition can contribute to the
plasticity of the shell and
can become a plasticizing agent in the shell upon equilibrium.
The alcohol of the fill composition can be propylene glycol, another suitable
alcohol,
or mixtures thereof. Suitable alcohols include, for example, ethanol, 2-
2(ethoxyethoxy)ethanol, benzyl alcohol, glycerol, polyethylene glycol 200,
polyethylene
glycol 300, and polyethylene glycol 400. Preferably, propylene glycol, a
suitable alcohol, or
a mixture thereof, is present in the initial fill composition, as measured by
weight, in a range
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14
of 3-20%. More preferably, propylene glycol, a suitable alcohol, or a mixture
thereof, is
present in a range of 9-14%. Most preferably, propylene glycol, a suitable
alcohol, or a
mixture thereof, is present in the range of 10-13% in the initial fill
composition. Propylene
glycol can be obtained commercially from, for example Lyondell Chemie (Route
Du Quai -
Mineralier - Fos-S42-Mer France). Alternatively, other deriviatives of
propylene glycol are
available commercially and can be used in the initial fill composition, for
example propylene
glycol monocaprylate or propylene glycol monolaurate (Capryol~ PGMC or
Lauroglycol~
90, respectively, Gattefosse, Westwood, NJ).
One component of the organic solvent of the fill composition is a
pharmaceutically
acceptable medium and/or long chain fatty acid or mixtures thereof.
Preferably, the fatty
acids are present in the fill composition, as measured by weight, in a range
of 50-80%. More
preferably, the fatty acids are present in a range of 62.5- 75%. Most
preferably, the fatty
acids are present in the range of 64-70% in the fill composition. The
pharmaceutically
acceptable medium and/or long chain fatty acid or mixture of the fill
composition can be
saturated or unsaturated C8 to C24 fatty acids. These fatty acids can include,
for example,
Caprylic acid, Capric acid, Lauric acid, Myristic acid, Palmitic acid, Stearic
acid, Behenic
acid, and similar suitable medium and/or long chain fatty acid. Preferred
fatty acids are
mono-unsaturated C16-C2o fatty acids which are liquids at room temperature. A
most
preferred fatty acid is oleic acid, with or without additional medium and/or
long chain fatty
acids in the mixture. Fatty acids can be obtained commercially and one
suitable source of
said oleic acid is, for example, Henkel Corporation (Cincinnati, OH).
Another component of the organic solvent of the fill composition is a
pharmaceutically acceptably surfactant. Preferably, the surfactant is present
in the fill
composition, as measured by weight, in a range of 0-10%. More preferably, the
surfactant is
present in a range of 0-7.5%. Most preferably, the surfactant is present in
the range of 0-5%
in the fill composition. A pharmaceutically acceptable surfactant can be a
pharmaceutically
acceptable non-ionic surfactant such as polyoxyethylene castor oil
derivatives,. for example,
polyoxyethyleneglyceroltriricinoleate, polyoxyl ethylene 35 castor oil
(Cremophor~ EL,
BASF Corp.), polyoxyethyleneglycerol oxystearate (Cremophor~ RH 40 (glycerol
polyethyleneglycol oxystearate) or Cremophor~ RH 60 (polyethyleneglycol 60
hydrogenated
castor oil), BASF Corp., and the like), block copolymers of ethylene oxide and
propylene
oxide, also known as polyoxyethylene polyoxypropylene block copolymers or
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polyoxyethylenepolypropylene glycol, for example Poloxamer~ 124, Poloxamer~
188,
Poloxamer~ 237, Poloxamer~ 338, Poloxamer~ 407, and the like, (BASF Wyandotte
Corp.), a mono fatty acid ester of polyoxyethylene (20) sorbitan (for example,
polyoxyethylene (20) sorbitan monooleate (Tween~ 80), polyoxyethylene (20)
sorbitan
5 monostearate (Tween~ 60), polyoxyethylene (20) sorbitan monopalmitate
(Tween~ 40),
polyoxyethylene (20) sorbitan monolaurate (Tween~ 20)) and the like), or a
sorbitan fatty
acid ester (including sorbitan laurate, sorbitan oleate, sorbitan palmitate,
sorbitan stearate and
the like). A preferred pharmaceutically acceptable surfactant is polyoxyl 35
castor oil
(Cremophor~ EL, BASF Corp.), polyoxyethylene (20) sorbitan monolaurate (Tween~
20),
10 polyoxyethylene (20) sorbitan monooleate (Tween~ 80) or a sorbitan fatty
acid ester, for
example sorbitan oleate. A most preferred pharmaceutically acceptable
surfactant is polyoxyl
35 castor oil (Cremophor~ EL, BASF Corp.).
Optionally, the fill composition can include water. If water is included in
the fill
composition it is preferably present in a percentage by weight that is
relatively low as
15 compared to the other components of the fill composition. Preferably the
percentage of water
in the fill composition is no greater than 3% by weight and more preferably no
greater than
1.5% by weight of the fill composition.
In addition, the composition of the invention can comprise antioxidants (for
example,
ascorbic acid, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene),
vitamin E,
and the like) for chemical stability.
Solutions as described herein can include micellar solutions, which are
thermodynamically stable systems formed spontaneously in water above a
critical
temperature and concentration. Micellar solutions contain small colloidal
aggregates
(micelles), the molecules of which are in rapid thermodynamic equilibrium with
a measurable
concentration of monomers. Micellar solutions exhibit solubilization phenomena
and
thermodynamic stability.
Optionally, the fill composition can include a pharmaceutically acceptable
acid.
Pharmaceutically acceptable acid as used herein can include (i) an inorganic
acid such as
hydrochloric acid, hydrobromic acid, hydroiodic .acid and the like, (ii) an
organic mono-, di-
or tri- carboxylic acid (for example, formic acid, acetic acid, adipic acid,
alginic acid, citric
acid, ascorbic acid, aspartic acid, benzoic acid, butyric acid, camphoric
acid, gluconic acid,
glucuronic acid, galactaronic acid, glutamic acid, heptanoic acid, hexanoic
acid, fumaric acid,
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16
lactic acid, lactobionic acid, malonic acid, malefic acid, nicotinic acid,
oxalic acid, pamoic
acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid,
propionic acid, succinic
acid, tartaric acid, undecanoic acid and the like) or (iii) a sulfonic acid
(for example,
benzenesulfonic acid, sodium bisulfate, sulfuric acid, camphorsulfonic acid,
dodecylsulfonic
acid, ethanesulfonic acid, methanesulfonic acid, isethionic acid,
naphthalenesulfonic acid, p-
toluenesulfonic acid and the like).
The fill composition can also contain other pharmaceutical agents, for
example, anti-
viral compounds, cell growth inhibitors, antibiotics, antihistamines,
analgesics, food
supplements, nutrients, vitamins, steroids, or anesthetics. Other
pharmaceutical agents can be
co-administered with the HIV protease inhibitors, if compatible with the
inhibitors, or by
themselves.
Shell Composition
The shell composition of the current invention is suitable for encapsulating
fill
compositions including a pharmaceutically active compound or a mixture of
pharmaceutically active compounds, for example HIV protease inhibitors, as
described
herein. The formulation of the initial shell composition is particularly
suitable for
maintaining the solubility of the components of the fill composition after
equilibrium has
been established between components of the fill composition and the shell
composition. In
addition, the current invention provides components of the initial shell
composition and a
process utilizing these components for the manufacture of a soft elastic
capsule containing
pharmaceutically active compound(s), as described herein, wherein the shell of
the soft
elastic capsule acquires and retains desirable physical characteristics during
and after the
manufacturing of the soft elastic capsule.
In one embodiment of the current invention, the initial shell composition is
formulated to produce, in the absence of any later added or migrated
plasticizing agents, a
shell that contains a percentage by weight of a plasticizing agent or agents
that is too low to
provide appropriate hardness. In the composition of this invention, the
initial shell is
underplasticized and upon equilibrium of the shell composition with the fill
composition, as
described herein, the shell becomes plasticized to an acceptable physical
range. The
increased percentage by weight of alcohol, for example, propylene glycol, of
the initial fill
composition contributes to increasing the plasticity of the shell upon
equilibrium of the fill
and shell components. Upon reaching equilibrium, the alcohol of the fill
composition, for
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17
example, propylene glycol, which has migrated into the shell, acts as a
plasticizing agent.
Upon reaching equilibrium the shell has acceptable physical properties, for
example,
hardness, and the fill composition maintains the solubility of the
pharmaceutical agent or
pharmaceutical agents, for example HIV protease inhibitors, within the fill.
The components of the initial shell composition (i.e., prior to capsule
formation or
encapsulation of the fill composition) of the current invention include
gelatin, a plasticizing
agent, preferably AnidrisorbTM, or optionally glycerin, and water. Optionally,
the shell
composition can also include a pigment, for example titanium dioxide, and
optionally a dye,
for example FD&C yellow number 6.
During the preparation of the soft elastic capsule the initial shell
composition is
prepared as a gelatin solution that contains water. During the preparation the
soft elastic
capsule the gelatin solution is heated and typically looses an amount of
water. The
formulations of the initial shell composition of the current invention include
water; however,
it is understood that water is lost during the manufacturing and drying
processes. These losses
will change the amount of water in the shell as the soft elastic capsule
reaches an equilibrium
state. Additionally, components in the initial fill composition will migrate
into the shell
composition thereby also changing the composition of the shell as the soft
elastic capsule
reaches an equilibrium state. The formulations listed herein refer to an
initial shell
composition, prior to loss of water or migration of fill components into the
shell, unless
otherwise noted.
Gelatin can be obtained from skin and bone of bovine and porcine sources. Acid
or
basic preparations of gelatin can be used as an ingredient in the initial
shell composition.
Depending on the source and the process of preparing the gelatin, different
levels of gelatin
strength can be used in the initial shell composition. Preparation of bovine
gelatin, for
example, 195B acid, can be used in the shell composition. Bovine gelatin can
be obtained
commercially from, for example, SKW Biosystems (Cedex, France). Gelatin can be
present
in the shell composition, by weight, preferably in the range of 30-60%, more
preferably in
the range of 35-55%, and most preferably in the range of 40-50%.
The plasticizing agent of the initial shell composition can be sorbitol,
sorbitan,
glycerol, xylitol, polyglycerol, propylene glycol, glucose, fructose, glucose,
polyols, for
example, macrogol 400, 600, 1200, 1500, 2000, or 4000, macrogols between 400
and 4000
(available from, for example, Union Carbide (Noorderlaan, 147 2030 Anversa
Belgio) or
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Poloxaxners. Preferably, a mixture of sorbitol, sorbitans, mannitol, and
hydrogenated
saccharides, which is available as a composition commercially available under
the trade name
of AnidrisorbTM, is used as the plasticizing agent. AnidrisorbTM can be
obtained
commercially from Roquette Freres (Letrem, France). The shell composition can
also have a
combination of more than one plasticizing agent. For example, AnidrisorbTM can
be used in
combination with other plasticizing agents, for example, glycerol. A preferred
combination
of plasticizing agents contains any of the following reagents: AnidrisorbTM,
glycerol, and
macrogols.
In the present invention, the initial shell composition has a relatively low
percentage
of plasticizing agent or combination of plasticizing agents, for example, not
more than 18%,
by weight. Preferably the plasticizing agent or agents is present in a range
of 4-18% in the
initial shell composition, more preferably in the range of 8-17%, and most
preferably in the
range of 10-16%.
In a preferred embodiment of the current invention, either AnidrisorbTM or a
combination of AnidrisorbTM and glycerin is used as the plasticizing agent in
the initial shell
composition. If a combination of AnidrisorbTM and glycerin are used, the ratio
of
AnidrisorbTM to glycerin is preferably in the range of 12:1 to 2:1.
The initial shell composition also includes water as a component. It is
understood that
water is used in the formulation of the initial shell composition and that
water is eliminated
from the shell during the manufacturing process of the soft elastic capsule.
Water can be
present in the shell composition, by weight, in a range of 20-55%, more
preferably in the
range of 25-50%, and most preferably in the range of 30-45%.
The initial shell composition of the current invention can also be defined by
the ratio
of gelatin to plasticizing agent. Preferably the ratio of gelatin to
plasticizing agent in the
initial shell composition is in the range of 2:1 to 10:1, more preferably in
the range of 2.3:1 to
7:1, and most preferably in the range of 2.5:1 to 5:1.
In one embodiment of the invention, the initial shell composition includes
gelatin, by
weight, in the range of 25-60%, a plasticizing agent, or combination of
plasticizing agents in
the range of 4-18%, and water in a range of 20-55%. More preferably, the
initial shell
composition includes gelatin, by weight, in the range of 30-55%, a
plasticizing agent, or
combination of plasticizing agents in the range of 8-17%, and water in a range
of 25-50%.
Most preferably, the initial shell composition includes gelatin, by weight, in
the range of 35-
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50%, a plasticizing agent, or combination of plasticizing agents in the range
of 10-16%, and
water in a range of 30-45%.
The soft elastic gelatin capsule material can also comprise additives such as,
opacifiers, dyes or excipients, for example, flavors, sweeteners, and
preservatives.
The current invention provides a soft elastic capsule that, after equilibrium
of the fill
composition and shell composition, has acceptable physical properties and
maintains the
active ingredients, for example, HIV protease inhibitor(s), in a soluble
state. One aspect of
the soft elastic capsule in the equilibrium state is the ratio of gelatin to
plasticizing agent,
which can affect the physical characteristics of the soft elastic capsule. In
a preferred
embodiment of the invention, the gelatin to plasticizing agent ratio is in the
range of 2:1 to
4:1 when the shell and fill composition are in the equilibrium states. This
range of gelatin to
plasticizing agent can provide the soft elastic capsule with acceptable
physical properties.
An alcohol partition coefficient can be determined after the soft elastic
capsule has
reached an equilibrium state. The alcohol partition coefficient, for example,
the propylene
glycol partition coefficient, is a ratio reflecting the amount of propylene
glycol in the shell at
equilibrium compared to the amount of propylene glycol in the fill in the
initial state,
respectively. In one embodiment of the invention, the propylene glycol
partition coefficient
between the shell at equilibrium and the fill in the initial state is
preferably in the range of 1:2
- 1:2.5, respectively, and more preferably in the range of 1:2.2 - 1:2.4,
respectively.
Various manufacturing processes that are well known in the art can be used to
form
soft elastic capsules from the fill and shell compositions described herein.
Descriptions of
these processes can be found in various references, for example, Principles
and Practices of
Pharmaceutics, The Pharmaceutical Codex, Twelfth Edition.; Ed.: Walter Lund,
The
Pharmaceutical Press, London, 1994, p23-24 or Oral Solid Dosage Forms,
Remihgtoh's
Pharmaceutical Sciences, 17th Edition; Ed.: Gennaro, A.R., Mack Publishing
Co., Easton,
Pennsylvania, 1985, p. 1629-1631. These various processes include, for
example, a seamless
capsule method, microencapsulation, and soft gelatin coating of tablets.
Various
manufacturing machines can be used for manufacturing the capsules, for
example, a Norton~
Capsule Machine, Accogel~ Capsule Machine, or a Liner~ machine.
A preferred process for manufacturing soft elastic capsules from fill and
shell
compositions, as described herein, is performed according to the Rotary Die
Process.
Generally, two continuous gelatin ribbons, which are formed by the capsule-
forming
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machine, are brought together between a pair of revolving dyes and an
injection wedge.
Insertion of the fill composition under pressure and sealing of the capsule
shell occur
simultaneously and the two processes are precisely coordinated. The process of
sealing also
separates the formed capsules. The Rotary Die machine can also consist of
multiple injection
5 pumps allowing multiple capsules to be prepared at once. Accuracy of
injection of the proper
amount of fill solution and capsule weight are periodically determined by
analytical balances
associated with the machine.
According to Fig. 1, the mechanical workings of a Rotary Die machine are
shown.
Gel ribbons la and 1b are fed onto rotary cylinders 2a and 2b, respectively,
where, as shown
10 in Fig. 1, rotary cylinder 2a rotates clockwise and rotary cylinder 2b
rotates
counterclockwise. Both rotary cylinders contain sprocket portions 8 and divit
portions 9. Gel
ribbons la and 1b are drawn between rotary cylinders 2a and 2b and injection
wedge 3 by the
rotary motion of the cylinders. Injection pump 6 of injection wedge 3 pumps a
predetermined
amount of a fill composition 7 between gel ribbons la and 1b while cylinders
rotate. Capsule
15 4 is formed by opposing divit portions 9 of rotary cylinders 2a and 2b as
fill composition 7 is
injected between gel ribbons la and 1b. Consecutive capsules 4 emerge from the
rotary
cylinders ~a and 2b separated by a gelatin spacer 5.
Typically, soft elastic capsules are dried following their formation. Drying
processes
caxi include tumble drying, or successive tumble drying, and sheet or tray
drying. Capsules
20 can be tumble dried for various lengths of time, for example, from 0 to 6
hours and at various
temperatures, for example, from 20-25°C. Preferably, the capsules of
the current invention
are tumble dried for a total of 0.5 to 3 hours and at a temperature in the
range of 20-25°C.
Physical and chemical characteristics of soft elastic capsule following
manufacture
The fill composition and shell composition of the present invention allow a
soft
elastic capsule containing a pharmaceutical agent or combination of
pharmaceutical agents to
be manufactured that has acceptable physical and chemical characteristics. The
soft elastic
capsule can be manufactured to have acceptable physical and chemical
characteristics or
these characteristics can be acquired as the soft gel capsule reaches an
equilibrium state. The
equilibrium state can be achieved, at least partially, by the diffusion of an
alcohol, for
example, propylene glycol, into the shell. Following manufacture, acceptable
physical
characteristics include capsules having a shell that has acceptable plasticity
(as measured by
hardness), a shell that has an acceptable disintegration time, and a fill that
has an acceptable
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21
moisture content. Desirable chemical characteristics include capsules having a
fill that has an
acceptable alcohol, for example, propylene glycol, and water content; the
alcohol, for
example, propylene glycol, content is important in the solubility of the
pharmaceutical agent
or combination of pharmaceutical agents in the fill composition.
The physical characteristics of the shell can change during the manufacturing
process.
Particularly, during the steps of drying of the soft elastic capsule, the
propylene glycol of the
fill migrates into the shell and increases the plasticity of the shell. The
current invention
provides fill compositions and shell compositions that can be used to produce
a soft elastic
capsule that has an acceptable level of plasticity following manufacturing and
drying.
Plasticity of the shell of the manufactured capsule can be measured by its
hardness
initially after manufacturing and over a longer period of time, for example,
over a period of
months or years. Hardness of the shell capsule can be measured in Newtons,
using a
hardness tester, for example a BareissTM U73 hardness tester (Oberdischingen,
Germany) can
be used to test the capsules according to manufacturer's instructions and
accepted standards.
Upon initial manufacture, the capsules preferably have a hardness in the range
from
about 6 to about 12 Newtons, more preferably in the range from about 7 to
about 11
Newtons, and most preferably in the range from about 7.25 to about 10.75
Newtons. After
drying, and over a period of time, the hardness of the soft elastic capsule
slowly decreases
and then stabilizes and the propylene glycol concentration in the fill and in
the shell reach an
equilibrium state. Preferably, over a period of two weeks to three years the
hardness of the
gel capsule is maintained in a range from about 4.5 to about 12 Newtons, more
preferably in
a range from about 4.75 to about 12 Newtons, and most preferably in a range
from about 5 to
about 10 Newtons.
Upon initial manufacture, and over a longer period of time and after the
equilibrium
state is reached, for example, over a period of months or years, the soft
elastic capsule can be
physically examined wherein the total weight, the fill weight, and shell
weight can be
determined. Such physical examinations can be conducted according to accepted
standards.
Shell weight can be determined by emptying capsules of the fill and washing
the shell with an
organic solvent to remove residual fill. Suitable organic solvents for capsule
washing
include, for example, methylene chloride and chloroform. The weight of the
fill is calculated
by the difference between the weight of the shell and the total weight of the
capsule.
Preferably, over a period of two weeks to three years the total weight of the
gel capsule
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deviates not more than 5% from the initial total weight of the gel capsule,
more preferably
not more than 2.5% and most preferably not more than 1 %. Preferably, over a
period of two
weeks to three years the total weight of the fill of the gel capsule deviates
not more than 15%
from the original fill weight of the capsule, more preferably not more than
10% and most
preferably not more than 7.5%.
Moisture in the fill of the gel capsule can be determined using a suitable
apparatus, for
example, a titrator. A suitable titrator is a Karl Fischer titrator apparatus,
used according to
the manufacturer's directions and by accepted standards.
Preferably, over a period of two weeks to three years the total moisture of
the fill of
the gel capsule is not more than 2% of the fill weight of the gel capsule,
more preferably not
more than 1.5% and most preferably not more than 1%.
Disintegration time of the capsule can be measured by accepted standards
using, for
example, a disintegration tester. Preferably, over a period of two weeks to
three years the
disintegration time of the gel capsule remains not more than 30 minutes
according to this
procedure.
Propylene glycol content in the fill can be measured by accepted standards
using, for
example, a gas chromatography technique.
After equilibration the fill can have a propylene glycol concentration at
5°C of
approximately 40-50 mg per gram of fill. This concentration of propylene
glycol is sufficient
to maintain the solubility of the pharmaceutical agent or pharmaceutical agent
mixture.
Preferably, over a period of two weeks to three years the propylene glycol
concentration of
the fill of the gel capsule is at least 40 mg per gram of fill, more
preferably at least 45 mg per
gram of fill and most preferably at least 50 mg per gram of fill.
Example 1
Soft Elastic Capsule Containing
Ritonavir/L,opinavir Mixture
Fill compositions were prepared in a Pilot ~ Mixing Vessel 30L Code 730
(Pharmagel, Lodi, Italy). The mixer was operated at about 1400 R.P.M. during
working
conditions unless otherwise noted. During working conditions the pressure
inside the vessel
was maintained at 1 bar (ambient conditions).
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Materials for the fill composition were obtained as follows: oleic acid
(Medinique)
was obtained from Henkel Corporation (Cincinnati, OH); propylene glycol (EP)
was obtained
from Hulls (Lyondell chemie, Route Du Quai, Mineralier, Fos -S42 - Mer
France); and
Cremophor~ EL (polyoxyl 35 castor oil), a surfactant, was obtained from BASF
Corp.
(Worcester, Massachusetts, USA). The synthesis of ritonavir is disclosed in
U.S. Patent No.
5,541,206, issued July 30, 1996, the disclosure of which is herein
incorporated by reference.
The synthesis of ritonavir crystal form II is disclosed in International
Patent Application No.
W000/04016, published January 27, 2000, the disclosure of which is herein
incorporated by
reference. The synthesis of lopinavir is disclosed in U.S. Patent Application
No. 5,914,332,
issued June 22, 1999, the disclosure of which is herein incorporated by
reference.
Table 1 indicates the amounts of compounds of the fill composition as measured
in
milligrams per gram of the fill composition. Two different preparation of fill
composition,
PS-A and PS-B, are shown for this example.
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Table 1. Composition of Fill
Batch: PS-A Batch:
PS-B
Fill (mg/g)Capsules Fill (mg/g)Capsules
(mg/cap) (mg/cap)
Formulation
Oleic Acid 685.11 602.9 662.53 602.9
Propylene Glycol (PG)101.25 89.1 130.88 119.1
Cremophor~ EL 24.32 21.4 23.52 21.4
Ritonavir 37.84 33.3 36.59 33.3
Lopinavir 151.48 133.3 146.48 133.3
General
Fill Weight 880 910
FiII Volume (~,L) 938 967
For this preparation, 4.5 Kg of fill PS-A and 4.6, Kg PS-B were prepared.
For batch PS-A, 3.083 Kg of oleic acid, 455.6 g of Propylene Glycol, 109.4 g
of
Cremophor~ EL, 170.3 g of Ritonavir, and 681.7 g of Lopinavir were used.
For batch PS-B, 3.048 Kg of oleic acid, 602 g of propylene glycol, 108.2 g of
Cremophor~ EL, 168.3 g of ritonavir, and 673.8 g of lopinavir were used.
First, the oleic acid was added to the tank. Propylene glycol was then added
to the
tank and mixed for five minutes. Next, ritonavir was added and mixed until
completely
dissolved. Next, lopinavir was added and mixed until completely dissolved.
Finally,
CremophorTM EL was added to the clear solution which was mixed for 10 minutes.
The
product was kept under a nitrogen atmosphere.
Gelatin compositions were prepared in a Pilot~ Melter 100L Code 0204 Code
(Pharmagel, Lodi, Italy). The stirring speed was maintained in a range of 25 -
35 R.P.M.
during working conditions unless otherwise noted. During working conditions
the pressure
inside the vessel was at 1 bar (ambient conditions).
AnidrisorbTM 85/70 (CAS n°: 50-70-4/12441-09-7 EINECS:200-061-5/235-
671-O)
was obtained from Roquette Freres (Letrem, France); Gelatin 195 Bloom Acid was
obtained
from SKW Biosystem (84808 Isle Sur La Sourge, Cedex, France); titanium dioxide
E171 was
obtained from Anstead International (Radford Way, Billericay, Essex CM12 ODE,
England);
Dye Yellow F.D.& C. No. 6 was obtained from F.1 1i Fiorio-Colori S.P.A. (Via
Italia, 28-
20060 Gessate (MI)).
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Table 2 indicates the percentage weight of compounds of the shell composition
prior
to heating the shell composition. During the preparation of the shell and the
manufacturing
of the soft elastic capsules water was eliminated.
5 Table 2. Composition of Gelatin Base (shell)
Shell Composition Batch: BA
Anidrisorb 10
Gelatin 50
Titanium Dioxide 0.26
Dye Yellow 6 0.14
Water 39.6
For this preparation (shell composition BA), the batch size of the shell
composition
was 40 Kg.
10 20.84 Kg water (includes 5.0 Kg excess to account for water loss during
heating) and
3.9 Kg of AnidrisorbTM 85/70 was loaded into the melter. The solution was then
heated to
80°C with mixing (heating to 80°C took approximately 30
minutes). Next, 104 g of titanium
dioxide and 56 g of yellow dye FD&C No. 6 was mixed with approximately 100 g
of
AnidrisorbTM 85/70 using a Silverson L4R to obtain a homogenous dispersion.
When the
15 solution reached 80°C, 20 Kg of gelatin was added and mixing was
maintained under a
vacuum. The temperature was maintained at 80°C, the vacuum at less than
0.1 bax, and the
mixing rate at 22 and 44 R.P.M. (using two mixing blades, respectively,
rotating in opposite
directions) until 5.0 Kg of water was removed from the mixing chamber.
Encapsulation was carried out using a MK3LDS Encapsulation Line (Pharmagel,
20 Lodi, Italy) which includes: Encapsulation Machine, Code 320; Complete Set
of Die Roll,
Code 950, Capsule Conveyor, Code 322; Electrical Control Panel, Code 335; and
Tumble
Drier, Code 323. For preparation of soft elastic capsules the following
manufacturing
conditions were used unless otherwise noted: the transfer line temperature was
set at 60°C;
the spread box temperature was set in the range of 54-58°C; the machine
speed was set at 3
25 R.P.M. (die roll speed), the drum temperature was set in the range of 14-
16°C; the injection
segment (wedge) temperature was set at 42-44°C; and the gelatin
thickness was set in the
range of 37 - 39 thousandths of an inch. The die roll was 15 oblong S. The
lubrication used
was Migliol 812TM (Dyna-France)/migliol 812 and lethicin. The encapsulation
procedure is
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carried out at room temperature, or approximately 20-25°C, and in a
relative humidity of
approximately 15%.
The portable tank of the encapsulation machine was preheated to 60°C
and maintained
at 60°C for the entire encapsulation process. After the portable tank
reached 60°C, the shell
composition (gelatin base), following preparation, was transferred from the
melter to the
portable tank of the encapsulation machine. The gelatin base transfer tank was
then
connected to the encapsulation line through the gelatin cleanline pump. Next,
the machine
temperature and speed was set. The fill solution was then placed in the
encapsulation
machine hopper and the encapsulation thickness set. Encapsulation of the fill
solution was
then started.
Tumble drying of the soft elastic capsules emerging from the encapsulation
machine
took place in tumble driers #1, #2, and #3, successively, each for 30 minutes
each with drying
at 20-25°C. All three tumble driers were connected in series. Following
tumble drying the
capsules were then spread on trays and placed on a trolley. The trolley was
placed in a dry
tunnel at 20-25°C for approximately 48 hours. The tray drying time for
different batches of
capsules may vary in the range of 36 to 72 hours depending on the physical
condition of the
capsules.
Capsules were stored at either 2-8°C (no humidity control) or at
25°C (with 60%
relative humidity control) for physical stability assays.
A representative sample of soft elastic capsules was physically examined to
determine
the total weight, the fill weight, and the shell weight. Total weight was
determined weighing
the individual capsules with a standard analytical scale. Shell weight was
determined by
emptying capsules of the fill and washing the shell with chloroform to remove
residual fill.
The weight of the fill was calculated with a standard analytical scale by the
difference
between the weight of the shell and the total weight of the same capsule. The
sealing axea was
verified with a microscope observed at SOX magnification and was calculated by
dividing the
thickness of the shell in the sealing area divided by the thickness of the
shell in an area of the
shell away from the sealing area. The value of the sealing area is typically
shown as a
percentage.
The moisture content of the fill of the soft elastic capsules was determined
using a
Mettler Toledo DL-38 Karl Fischer Titrator according to manufacturer's
instructions. In the
titration flask sufficient methanol was added to immerse the double platinum
electrode and
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27
titration was performed to the end point. Standardization was performed using
water. Using a
mL disposable syringe and needle, the fill content of 10 capsules was
withdrawn.
Approximately one third of the fill volume withdrawn from the capsules was
transferred to
the titration vessel and titration was performed to the end point and the
volume added was
5 recorded. The percentage moisture was calculated by dividing the titrating
reagent per
sample by the sample weight (mg) and multiplying by the water equivalent and
100.
Hardness of the capsule shell was measured in Newtons using a BAREISS hardness
tester model G7394A (Priifgeratebau GmbH, D - 89610 Oberdischingen, Germany)
according to manufacturer's instructions.
10 Disintegration time for capsules were tested in water at 37 ~ 1 °C
using an EP/USP
disintegration tester DT3 (Sotax, Basel, Switzerland) consisting of a basket-
rack assembly, a
1000 ml low-form beaker for the immersion fluid, and a thermostatic
arrangement for heating
the fluid to the temperature designated. The disintegration tester was
operated according to
manufacturer's instructions.
Propylene glycol content was determined using capillary gas chromatography.
The
contents of ten capsules were emptied into a glass container and weighed..
About 2 g of the
capsule contents were placed into a 100 mL volumetric flask and 5.0 mL of an
internal
standard solution (butanol diluted with methanol) was added, and then
additionally diluted
with methanol and mixed. 1 mL of each sample was injected using an injection
device into a
fused silica wall coated open tubular capillary column (DB-Wax, J& W
Scientific) using
helium as a carrier gas. The injector temperature was 185°C and the
detector temperature
was 220°C. The helium had a flow rate of approximately 4.5 mL/min. A
gas chromatograph
equipped with split injector and flame ionization detector was used for
detection and the run
time was approximately 34 minutes.
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15
_Table 3. Physical data for the soft elastic capsules made from fill batch PS-
A and shell batch
BA.
Sample descriptionCapsules weightShell weightFill weightHardness
(mg) (mg) (mg)
Initial (in process)1528 650 878 nt
24 hours in tray 1312 439 873 10
dryer
48 hours in tray 1290 435 855 11
dryer
nt = not tested
_Table 4. Physical data for the soft elastic capsules made from fill batch PS-
B and shell batch
BA.
Sample descriptionCapsules weightShell weightFill weightHardness
(mg) (mg) (mg)
Initial (in process)1543 646 897 nt
24 hours in tray 1319 455 864 9
dryer
48 hours in tray 1260 386 874 10
dryer
Table 5: Physical data (stablility) for the soft elastic capsules made from
fill batch PS-A and
shell batch BA.
Test Initial 4 Wks
5C
Total Weight (mg) 1289 1287
Shell Weight (mg) 412 415
Fill Weight (mg) 877 872
Hardness (Newton) 11.3 Nt
Fill Moisture (mg/g) 11.4 10.4
PG assay (mg/g) 52.3 46.0
Disintegration Time 10 11
(min)
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Table 6: Physical data (stablility) for the soft elastic capsules made from
fill batch PS-B and
shell batch BA.
Test Initial 4 Wks 5C
Total Weight (mg) 1292 1295
Shell Weight (mg) 427 433
Fill Weight (mg) 864 862
Hardness (Newton) 9.8 Nt
Fill Moisture (mg/g)11.5 10.8
PG assay (mg/g) 60.2 48.7
Disintegration Time 10 11
(min)
Example 2
Soft Elastic Capsule Containing
Ritonavir/Lopinavir Mixture
The fill composition was prepared using the same equipment and conditions as
described in Example 1. Materials for the fill composition were the same as
described in
Example 1. The percentage of each component by weight was similar to that of
Batch PS-B
as described in Example 1.
Table 7. Composition of Fill
Fill (mg/g)Capsules (mg/cap)
Formulation
Oleic Acid 662.53 602.9
Propylene Glycol (PG) 130.88 119.1
Cremophor EL 23.52 21.4
Ritonavir 36.59 33.3
Lopinavir 146.48 13 3 .3
General
Fill Weight 910
Gelatin compositions were prepared using the same equipment and conditions as
described in Example 1
Materials for the shell composition were the same as described in Example 1
with the
exception of the addition of glycerin to shell formulations BE, BF, and BG.
Table 2 indicates
the percentage weight of compounds of the shell composition prior to heating
the shell
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composition. It is understood that during the preparation of the shell and the
manufacturing
of the soft elastic capsules water is eliminated.
Table 8: Compositions of Gelatin Base (shell)
Batches:
Gelatin base Composition BB BC BD BE BF BG*
Anidrisorb 12 14 16 12 12 12
Glycerin 0 0 0 2 4 2
Gelatin 47.5 47.5 47.5 47.5 47.5 47.5
Titanium Dioxide 0.26 0.26 0.26 0.26 0.26 0.26
Dye Yellow 6 0.14 0.14 0.14 0.14 0.14 0.14
Water 40.1 38.1 36.1 38.1 36.1 38.1
*Formulation BG contains 50% bloom gelatin 165 and 50% bloom gelatin 195.
Shell compositions were prepared using the same equipment and conditions as
described in Example 1.
10 Manufacturing and drying of the soft elastic capsules was carried out using
the same
equipment and conditions as described in Example 1. Physical and chemical
testing of the
soft elastic capsules, including the fill and the shell were the same as
described in Example 1
with the exception that the testing was conducted over a 52 week time period.
15 Table 9: 26 weeks stability data for batch BB (lot 60276N6)
Test Initial26 Wks 5C
Total Weight (mg) 1269 1280
Shell Weight (mg) 374 394
Fill Weight (mg) 896 886
Hardness (Newton) 9.5 6.6
Fill Moisture (mg/g)5.2 6.8
PG assay (mg/g) 59.5 54.8
Disintegration Time 9 11
(min)
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Table 10: 52 weeks stability data for batch BC (lot 60277N6)
Test Initial 26 Wks 52 Wks SC
5C
Total Weight (mg)1274 1276 1277
Shell Weight (mg)393 410 409
Fill Weight (mg) 881 865 868
Hardness (Newton)10 6.1 6.9
Fill Moisture 5.5 6.8 6.8
(mg/g)
PG assay (mg/g) 58.3 56.1 58.9
Disintegration 8 11 11
Time
(min)
Table 11: 26 weeks stability data for batch BD (lot 60728N6)
Test Initial 26 Wks 5C
Total Weight (mg) 1267 1280
Shell Weight (mg) 409 431
Fill Weight (mg) 858 849
Hardness (Newton) 9.2 5.9
Fill Moisture (mg/g)4.9 5.9
PG assay (mg/g) 54.4 52.6
Disintegration Time 9 ~ 11
(min) I
Table 12: 26 weeks stability data for batch BE (lot 60279N6)
Test Initial 26 Wks 5C
Total Weight (mg) 1259 1266
Shell Weight (mg) 397 413
Fill Weight (mg) 862 852
Hardness (Newton) 7.8 5.1
Fill Moisture (mg/g) 5.1 4.5
PG assay (mg/g) 54.0 51.5
Disintegration Time 9 9
(min) I
20
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Table 13: 26 weelcs stability data for batch BF (lot 60280N6)
Test Initial 26 Wks
5C
Total Weight (mg) 1249 1262
Shell Weight (mg) 3 84 407
Fill Weight (mg) 864 854
Hardness (Newton) 9.1 7.I
Fill Moisture (mg/g) 5.2 4.7
PG assay (mg/g) 56.0 54.1
Disintegration Time 11 ~ 10
(min) ~
Table 14: 52 weeks stability data for batch BG (lot 60281N6)
Test Initial 26 Wks 52 Wks 5C
5C
Total Weight (mg) 1233 1244 1229
Shell Weight (mg) 368 387 366
Fill Weight (mg) 866 857 864
Hardness (Newton) 8.9 6.3 7.4
Fill Moisture (mg/g) 4.9 5.8 5.9
PG assay (mg/g) 59.2 58.7 55.6
Disintegration Time 10 ~ 10 11
(min)
