Note: Descriptions are shown in the official language in which they were submitted.
' CA 02281560 1999-08-16
1
Pharmaceutical composition for oral administration of heterocyclic
compounds in the form of quaternary ammonium
The present invention relates to novel pharmaceutical compositions in
which a heterocyclic compound in quaternary ammonium form is present as the
S active principle.
In particular, the invention relates to pharmaceutical compositions for oral
administration which contain, as the active principle, a compound of the
formula
Q
A~. ArrY(CH2)2-~-CH2-N-T-A-Z (I)
Ar
in which:
- A~ is a pharmaceutically acceptable anion;
- Am~ is:
i - either a group Am,~ of the formula
/W~
Arl-(CH2)x NO
in which:
- Arl is a phenyl which is unsubstituted or monosubstituted or polysubstituted
by a
substituent selected from a halogen atom, a hydroxyl, a (C,-C4)alkoxy, a (Cl-
C4)-
alkyl and a trifluoromethyl, said substituents being identical or different;
- x is zero or one; and
- W1 is a (C,-C6)alkyl or a benzyl group, the substituent Wl being either in
the
axial position or in the equatorial position;
ii - or a group Amz of the formula
/Wt
Are-(CH2)X NO
Ri
in which:
- Arl, x and W, are as defined above; and
- R~ is a hydroxyl, a (Ci-C.~)alkoxy, a formyloxy, a (C1-C3)alkylcarbonyloxy,
a
carboxyl, a (C1-C4)alkoxycarbonyl, a cyano, a (C,-C3)alkylcarbonylamino, a
CA 02281560 1999-08-16
2
mercapto or a (C1-C4)alkylthio;
iii - or a group Am3~ of the formula
/Wi
Arl-N N-
+~
R2
in which:
S - Ar, and W 1 are as defined above; and
- R2 is hydrogen, a (C~-C3)alkyl or a (C,-C3)alkylcarbonyl;
iv - or a group Am4~ of the formula
(CH2)P
Arl-(CH2)X N-
0+
in which:
- Arl and x are as defined above; and
- p is one or two;
v - or a group Ams~ of the formula
N-
Arl-(CH2)X O+
in which:
- Are and x are as defined above;
- Ar is a phenyl which is unsubstituted or monosubstituted or disubstituted by
a
substituent selected from a halogen atom, a (C1-C3)alkoxy, a (C,-C3)alkyl and
a
trifluoromethyl, said substituents being identical or different; a naphthyl;
an
indolyl;
- Q and Y have one of the following groups of meanings:
a) Q ~ and Y a
b) Q2 and Y2 when Am~ is a group Ami~, Am2 , Am4~ or Ams~;
c) Q3 and Y3 when Am~ is a group Am~~ or Am2 or a group Am4~ in which
Are is a phenyl and p is two; or
d) Q4 and Y4 when Am~ is a group Am,~, Am3~, Aln4~ or Am5~;
- Q1 is hydrogen;
- Y1 is hydrogen ; a (C,-C4)alkyl ; an ~-(C1-C4)alkoxy-(C2-C4)alkylene ; an w-
(C,-
CA 02281560 1999-08-16
3
C4)alkylcarbonyloxy-(C2-C4)alkylene ; an w-benzoyloxy-(C2-C4)alkylene, an w-
hydroxy-(C2-C4)alkylene ; an w-(C,-C4)alkylthio-(C2-C4)alkylene ; an w-(C,-C4)-
alkylcarbonyl-(C2-C4)alkylene ; an w-carboxy-(C2-C4)alkylene ; an w-(Cl-C4)-
alkoxycarbonyl-(C2-C4)alkylene ; an w-benzyloxy-(C2-C4)alkylene ; an w-formyl-
oxy-(Cz-C4)alkylene; an w-R3NHC00-(C2-C4)alkylene; an w-R4RSNC0-(C2-C4)-
alkylene; an w-R6CONR~-(C2-C4)alkylene; an w-RgOCONR~-(C2-C4)alkylene; an
w-R4RSNCONR~-(C2-C4)alkylene ; an w-R9S02NR~-(C2-C4)alkylene ; an w-
cyano-(C,-C3)alkylene;
- Q2 and YZ together form an ethylene, trimethylene or tetramethylene group;
- Q3 and Y3 together form a group
O
-(CH2)n-C- in which n is one, two or three ;
- Q4 and Y4 together form a radical selected from:
A 1 ) -O-CH2_
A2) -O-CO-
A3) -CH2-O-CO-
Aq,) -O-CH2-CO-
AS) -O-CH2-CH2_
A6) _N(R10)_CO_
A~) -N(R10)-CO-CO-
Ag) -N(R10)-CH2-CH2_
- T is either a group -CO- when Q and Y are the groups Q1 and Y~, the groups
QZ
and Y2 or the groups Q4 and Y4 in which Q4 and Y4 together form a radical A1),
AS) or Ag); or a group -CH2- when Q and Y are the groups Q3 and Y3 or the
groups Q4 and Y4 in which Q4 and Y4 together form a radical A2), A3), A4), A6)
or A~);
- A is either a direct bond or a methylene group when T is -CO-, or a direct
bond
when T is -CH2-;
- Z is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a
substituent selected from a halogen atom; a trifluoromethyl; a cyano; a
hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or
polysubstituted by a (C,-C4)alkyl; a benzylamino; a carboxyl; a (Ci-Clo)alkyl;
a
(C3-C~)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted
by a methyl; a (C,-C,o)alkoxy; a (C3-C~)cycloalkoxy which is unsubstituted or
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4
monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-
C,o)alkylthio; a (Ci-C6)alkylcarbonyloxy; a (C1-C6)alkylcarbonylamino; a
benzoylamino; a (C1-C4)alkoxycarbonyl; a (C3-C~)cycloalkylcarbonyl; a
carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-
C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted
in
the 3-position by a (C,-C4)alkyl or a (C3-C~)cycloalkyl; and a (pyrrolidin-1-
yl)carbonylamino, said substituents being identical or different;
- a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a
halogen, a trifluoromethyl, a (C,-C4)alkyl, a hydroxyl or a (Ci-C4)alkoxy;
- a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl;
- R3 is a (Ci-C~)alkyl or a phenyl;
- R4 and RS are each independently a hydrogen or a (C1-C~)alkyl; RS can also
be a
(C3-C~)cycloalkyl, a (C3-C~)cycloalkylmethyl, a phenyl or a benzyl; or R4 and
R5,
together with the nitrogen atom to which they are bonded, form a heterocycle
selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine,
perhydroazepine and piperazine which is unsubstituted or substituted in the 4-
position by a (C~-C4)alkyl;
- R6 is a hydrogen, a (Ci-C~)alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or
a (C3-
C~)cycloalkyl which is unsubstituted or substituted by one or more methyls;
- R~ is a hydrogen or a (Ci-C~)alkyl;
- R8 is a (C~-C~)alkyl or a phenyl;
- R9 is a (C,-C~)alkyl; an amino which is unsubstituted or substituted by one
or
two (C~-C~)alkyls; a phenyl which is unsubstituted or monosubstituted or poly-
substituted by a substituent selected from a halogen atom, a (C,-C~)alkyl, a
trifluoromethyl, a hydroxyl, a (C~-C~)alkoxy, a carboxyl, a (C1-
C~)alkoxycarbonyl, a (C~-C~)alkylcarbonyloxy, a cyano, a nitro and an amino
which is unsubstituted or substituted by one or two (C~-C~)alkyls, said
substituents being identical or different;
- Rlo is hydrogen or a (C1-C4)alkyl,
and its optional salts with mineral or organic acids, and their optional
solvates.
The compounds of formula (I) which are useful for the invention include
both the racemates and the optically pure isomers, as well as the axial and
equatorial isomers when Am~ in the compound of formula (I) is a group Ami~, a
group Am2~ or a group Am3~.
The compounds of formula (I) are described in patent applications
CA 02281560 1999-08-16
EP-A-0 512 901, EP-A-0 515 240, EP-A-0 559 538, EP-A-0 591 040,
WO 95/26 339, EP-A-0 700 382, EP-A-0 723 959 and WO 96/23 787.
Among the compounds of formula (I), those of the formula
(CH2)P~
A . Arl-(CHz)x N-O(CH2)2 N-CO-CHZ-Z (I )
Ar'
in which:
- Are, x, p and AD are as defined for a compound of formula (I);
- Ar' is a 3,4-dichlorophenyl or a 3,4-difluorophenyl; and
- Z' is a phenyl substituted in the 3-position by a halogen or a (C1-
Cio)alkoxy,
are preferred for the invention.
More particularly, the invention relates to pharmaceutical compositions for
the oral administration of (S)-1-{2-[3-(3,4-dichlorophenyl)-1-(3-
isopropoxyphenyl-
acetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane, or SR
140333,
of the formula
1
N-(CH2)2 (S) N-CO-CH2
O CH,
-O\ , s
CH
Cl CH3
Cl
in which A~ is a pharmaceutically acceptable anion.
The benzenesulfonate of SR 140333, hereafter called compound A, is very
particularly preferred. The international non-proprietary name of compound A
is
nolpitantium besilate.
The compounds of formula (I) have been described as antagonists of
substance P, which is the natural agonist of the NK1 receptors. For oral
administration, such compounds must have a good absorption, which entails both
a
good solubility in aqueous media and a good capacity to pass through the
intestinal
membrane (M. Rowland and T.N. Tozer in Clinical pharmacokinetics, concepts
and applications, published by Lea and Fehiger, 1989, 2nd edition, pp. 113 -
130).
CA 02281560 1999-08-16
6
The solubility of the compounds of formula (I) has been studied in different
media: their solubility in water is generally below 5 mg/ml, but they are
soluble in
hydrophilic solvents such as alcohols or glycols.
Being quaternary ammonium compounds, the compounds of formula (I)
remain in ionized form irrespective of the pH of the medium in which they are
present, especially at neutral pH, which is the pH of the intestinal medium.
It is known that ionic compounds, especially quaternary ammonium
compounds, cannot easily pass through the epithelial membranes (J.P. Labaune
in
Pharmacocinetique, Principes fondamentaux, published by Masson, 1988, 2nd
edition, pp. 7 - 33).
The cell line Caco-2 has the particular characteristic of exhibiting
differentiation in vitro to form an epithelial monolayer. This line is
conventionally
used for evaluating the ability of compounds to permeate the epithelium (Crit.
Rev.
Ther. Drug Carrier System, 1991, 8 (4), 105 - 330).
1 S In this model, the permeability to compound A is 3.4.10'' cm/s.
Furthermore, correlations made between the in vitro results and the in vivo
results
have shown that a coefficient of permeability of this order corresponds to an
absorption of less than 5% for totally solubilized molecules. In the present
case,
studies performed on the rat with a 0.6% aqueous solution of compound A in
methyl cellulose have shown that its estimated absorption is less than 1 %.
Thus, to develop an oral galenic formulation for the compounds of formula
(I), it is necessary to overcome both their very low solubility in aqueous
media and
their poor passage through the intestinal epithelium.
To modify the particular cationic character due to the quaternary
ammonium form of the compounds according to the invention, it is possible to
transform them by adding a stoichiometric amount of an anionic surfactant to
give
an ion pair of overall neutral charge. However, the ion pair formed between
the
cationic part of the compound of formula (I) and the anionic part of the
surfactant
has a higher molecular weight than the compound (I), so its hydrophobic
character
increases and this ion pair is practically insoluble in water.
It has been found that the intestinal absorption of the ion pair formed by a
compound of formula (I) and an anionic surfactant decreases relative to that
of a
compound of formula (I) in ammonium form.
Non-ionic surfactants and absorption promoters have also been tested in
order to find out their effect on the ability of a compound of formula (I) to
CA 02281560 1999-08-16
permeate membranes. These products have not shown any positive effects.
Derivatives are known which are in semi-solid form at ordinary temperature
and which, by possessing both lipidic character and amphiphilic character, can
be
used to solubilize lipophilic active principles and facilitate their
intestinal
absorption (Bull. Techn. Gattefosse, 1994, 87 49 - 54). Such compounds are
selected from saturated polyglycosylated glycerides consisting of a mixture of
glycerol monoesters, diesters and triesters of fatty acids with Cg-C1g
hydrocarbon
chains, and polyethylene glycol monoesters and diesters of fatty acids with Cg-
C,8
hydrocarbon chains. The most valuable of these are:
- lauroyl macrogoglyceride with a melting point of 44°C and a
hydrophilic/
lipophilic balance (HLB) of 14;
- stearoyl macrogoglyceride with a melting point of 50°C and a
hydrophilic/
lipophilic balance of 13; and
- caprylocaproyl macrogoglyceride, an oily liquid with a hydrophilic/
lipophilic balance of 14.
These compounds are marketed by Gattefosse under the trade marks
Gelucire° 44-14, Gelucire~ 50-13 and Labrasol°
respectively.
The compounds (I) of hydrophilic character are not soluble in such
derivatives; in particular, they are not soluble in the products Gelucire~ 44-
14,
Gelucire° 50-13 and Labrasol~.
According to the present invention, it has now been found that a compound
of formula (I) can be solubilized in a saturated polyglycosylated glyceride
provided
that at least one of the following constituents:
- a hydrophilic solvent
- an anionic surfactant
is added.
The resulting formulation makes it possible to improve the bioavailability
of the active principle.
It is also advantageous to solubilize a compound of formula (I) in a
saturated polyglycosylated glyceride by adding both a hydrophilic solvent and
an
anionic surfactant.
Surprisingly, it has been found that the addition of one particular
polysorbate, namely polysorbate 80, to a solution of compound A in the cell
culture
medium improves the transepithelial passage in the Caco-2 model.
It can thus be advantageous to add a small proportion of polysorbate 80 to
CA 02281560 1999-08-16
8
the formulation determined above.
Thus, according to one of its aspects, the present invention relates to a
pharmaceutical composition for the oral administration of a compound of
formula
(I) which contains:
- active principle 0.1% to 15% by weight
- hydrophilic solvent 0% to 60% by weight
- anionic surfactant 0 to S% by weight
- polysorbate 80 0 to 5% by weight
- macrogoglyceride in sufficient amount (QS) for 100% by weight,
with the proviso that at least one constituent selected from the hydrophilic
solvent
and the anionic surfactant is present. Preferably, in the absence of anionic
surfactant, the concentration of active principle is less than or equal to 30%
by
weight of the concentration of hydrophilic solvent.
According to the present invention, macrogoglyceride is understood as
meaning the products Gelucire° 44-14, Gelucire° 50-13 and
Labrasol° as
described above, the product Gelucire ° 44-14 being preferred.
The hydrophilic solvent used can be an alcohol such as ethanol or a glycol
derivative such as propylene glycol or the product Transcutol°, which
is a
monoethyl ether of diethylene glycol. Propylene glycol is the preferred
hydrophilic
solvent.
The anionic surfactant used can be a bile salt such as sodium taurocholate
or a sodium alkylsulfate such as sodium octylsulfate or, preferably, sodium
lauryl-
sulfate, the latter being a preferred anionic surfactant according to the
invention.
The pharmaceutical compositions according to the invention can be
presented in different forms intended for oral administration, examples being
gelatin capsules, sachets, drops, vials to be taken orally, or bottles.
Advantageously the present invention relates to a pharmaceutical com-
position which contains:
- active principle 0.1% to 15% by weight
- hydrophilic solvent 1% to 60% by weight
- anionic surfactant 0.03% to 5% by weight
- polysorbate 80 0 to 5% by weight
- macrogoglyceride QS for 100% by weight.
In particular, the present invention relates to a pharmaceutical composition
for the oral administration of a compound of formula (I) which contains:
CA 02281560 1999-08-16
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- active principle 0.1 to 15% by weight
- hydrophilic solvent 5 to 60% by weight
- polysorbate 80 0 to 5% by weight
- macrogoglyceride QS for 100% by weight,
with the proviso that the concentration of active principle is less than or
equal to
30% by weight of the concentration of hydrophilic solvent.
In particular also, the present invention relates to a pharmaceutical
composition for the oral administration of a compound of formula (I) which
contains:
- active principle 0.1 to 15% by weight
- hydrophilic solvent 0 to 30% by weight
- anionic surfactant 0.03 to 5% by weight
- polysorbate 80 0 to 5% by weight
- macrogoglyceride QS for 100% by weight.
According to the invention, the anionic surfactant is preferably in a
stoichiometric amount relative to the active principle. As the anionic
surfactant is
introduced in concentrated aqueous solution, the above pharmaceutical
composition contains from 0.1 to 12% of water.
When preparing gelatin capsules of the soft or hard type, the proportion of
hydrophilic solvent in the pharmaceutical composition must be compatible with
gelatin. Thus the present invention relates more particularly to
pharmaceutical
compositions for the preparation of gelatin capsules which contain:
- active principle 0.1 to 9% by weight
- hydrophilic solvent 0 to 30% by weight
- anionic surfactant 0 to 3% by weight
- polysorbate 80 0 to 5% by weight
macrogoglyceride QS for 100% by weight,
with the proviso that at least one constituent selected from the hydrophilic
solvent
and the anionic surfactant is present.
Pharmaceutical compositions for the preparation of gelatin capsules which
contain:
- active principle 0.1 to 7% by weight
- hydrophilic solvent 5 to 20% by weight
- polysorbate 80 0 to 5% by weight
- macrogoglyceride QS for 100% by weight,
CA 02281560 1999-08-16
with the proviso that the concentration of active principle is less than or
equal to
about 30% by weight of the concentration of hydrophilic solvent, are very
particularly preferred.
Pharmaceutical compositions for the preparation of gelatin capsules which
5 contain:
- active principle 0.1 to 7% by weight
- hydrophilic solvent 0 to 15% by weight
- anionic surfactant 0.03 to 2% by weight
- polysorbate 80 0 to 5% by weight
10 - macrogoglyceride QS for 100% by weight
are also preferred.
The anionic surfactant is preferably in a stoichiometric amount relative to
the active principle.
The pharmaceutical composition according to the invention preferably
contains an amount greater than or equal to 1 % by weight of hydrophilic
solvent
and particularly preferably contains an amount greater than or equal to 1 % by
weight of propylene glycol.
It is also possible to prepare enteric formulations for pharmaceutical
compositions in the form of gelatin capsules.
Such formulations are used to protect the active principle from the strong
acidity in the stomach. They are prepared by coating the gelatin capsule with
a
polymer film which is insoluble in an acid environment and soluble in a basic
environment. Examples of coating films which may be mentioned are cellulose
acetophthalate, polyvinyl acetophthalate, hydroxypropyl methyl cellulose
phthalate
or methacrylic acid copolymers.
Examples of methacrylic acid copolymers which may be mentioned are the
type C methacrylic acid copolymer marketed under the trade mark
EUDRAGIT°
L30 D-SS by ROHM, or the ethyl acrylate/methacrylic acid copolymer marketed
under the trade mark KOLLICOAT~ MAE 30D by BASF.
The elasticity of the coating film can be increased by adding plasticizers
such as a polyethylene glycol, 1,2-propylene glycol, dibutyl phthalate or a
citrate.
In certain cases, in particular when preparing enteric formulations with
gelatin capsules, it may be preferable to cover the gelatin capsule with a
film
coating consisting of a precoating before the enteric coating. The precoating
can
be made, for example, of hydroxypropyl cellulose, povidone or a methacrylic
acid
CA 02281560 1999-08-16
11
copolymer in association with appropriate excipients.
In one particular embodiment, the present invention relates to a pharma-
ceutical composition for the oral administration of compound A which contains:
compound A 0.1 to 9% by weight
propylene glycol 1 to 30% by weight
sodium laurylsulfate 0 to 3% by weight
Gelucire° 44-14 QS for 100% by weight.
More particularly, the present invention relates to a pharmaceutical
composition of the following formulation:
compound A 0.1 to 7% by weight
propylene glycol 5 to 20% by weight
Gelucire~ 44-14 QS for 100% by weight,
with the proviso that the concentration of compound A is less than or equal to
about 30% by weight of the concentration of propylene glycol.
The present invention further relates to a pharmaceutical composition of the
following formulation:
compound A 0.1 to 7% by weight
propylene glycol 1 to 15% by weight
sodium laurylsulfate 0.03 to 2% by weight
Gelucire~ 44-14 QS for 100% by weight,
the sodium laurylsulfate preferably being in a stoichiometric amount relative
to the
compound A.
In one particular embodiment, the present invention relates to a pharma-
ceutical composition for the preparation of gelatin capsules which contains:
compound A 3.6% by weight
propylene glycol 15.9% by weight
Gelucire~ 44-14 80.5% by weight.
In another particular embodiment, the present invention relates to a pharma-
ceutical composition for the preparation of gelatin capsules which contains:
compound A 3.4% by weight
propylene glycol 15.3% by weight
sodium laurylsulfate 1.5% by weight
water 2.7% by weight
Gelucire ° 44-14 77.1 % by weight.
A pharmaceutical composition as described above can be prepared by the
CA 02281560 1999-08-16
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following procedure when there is no anionic surfactant in the composition:
the
active principle is suspended in the hydrophilic solvent and the suspension is
heated, with stirnng, to a temperature of between 60°C and 80°C,
depending on the
concentration of active principle introduced into the hydrophilic solvent. 90%
of
the macrogoglyceride, molten at 60°C, is added, optionally followed by
the
polysorbate 80. Finally the appropriate amount of macrogoglyceride is added to
make up to 100%.
When the pharmaceutical composition contains an anionic surfactant, it can
be prepared by the following procedure: the active principle is mixed with 90%
of
the macrogoglyceride heated to 60°C. The anionic surfactant, dissolved
hot in the
minimum amount of water, is added to the suspension formed, followed, if
appropriate, by the hydrophilic solvent and the polysorbate 80. Finally the
appropriate amount of macrogoglyceride is added to make up to 100%.
Very particularly, when preparing enteric formulations, the film coating of a
gelatin capsule according to the invention can contain a precoating film and a
coating film of the following compositions:
Precoating:
type C methacrylic acid copolymer 46.6% by weight
glycerol 4.6% by weight
polysorbate 80 in 33% aqueous solution 4.6% by weight
water 44.2% by weight.
Coating:
type C methacrylic acid copolymer 54.8% by weight
glycerol 3.3% by weight
polysorbate 80 in 33% solution 0.7% by weight
water 41.2% by weight.
The characteristics and advantages of the compositions according to the
invention will become apparent from the following description based on the
compositions given as Examples. In these Examples, the percentages are
expressed by weight.
TESTS
1. Testing of the solubility of compound A
1.1. Solubility in water
The solubility was measured at the saturation point, after 24 hours, at room
temperature; the measurements were made by UV spectrometry at ~, = 275 nm
after
CA 02281560 1999-08-16
13
calibration in an ethanolic solution.
H 1 3 S 7 9
Concentration of compound0.31 0.31 0.31 0.29 0.31
A
m /ml
1.2. Solubility in different solvents
The instantaneous solubility is evaluated, at room temperature, by
successive additions of the studied solvent to compound A in a hemolysis tube
until limpidity is observed.
Taking the density differences into account, the solubilities are determined
by weight/weight.
water 0.33 mg/g
ethanol 36.5 mg/g
methanol 365.0 mg/g
benzyl alcohol > 450.0 mg/g
Transcutol~ 5.0 mg/g
polyethylene glycol 400 0.45 mg/g
propylene glycol 12 mg/g
glycerol oleate 0.64 mg/g
groundnut oil < 0.2 mg/g
Gelucire 44-14 < 0.2 mg/g
Compound A is also soluble ide (DMSO) in an
in dimethyl sulfox amount
of 168 mg/ml.
1.3. Variation in the solubilityin propyleneglycol as a function
of
temperature
Solubility of compound A in propylene glycol
TC 23C 60C 80C
Concentration of 12 155 350
com ound A in m
/
1.4. Study of the solubility in glycerides
Solubility of compound A in Gelucire~ 44-14
CA 02281560 1999-08-16
14
TC 23C 60C
Concentration < 0.2 0.4
of
com ound A in
m /
1.5. Solubility of compound A in water in the presence of a stoichiometric
amount of sodium laurylsulfate: below 0.1 ~g/ml.
2. Evaluation of the intestinal transepithelial passage of compound A
Caco-2 cells are inoculated onto microporous polycarbonate filters covered
with collagen. The cellular monolayer formed on the filter then makes it
possible
to separate an apical compartment (imitating the intestinal lumen) from a
basal
compartment (imitating the blood circulation).
The composition containing the compound to be studied is then placed on
the apical side and the passage of this compound, dispersed or solubilized in
Hank's medium, through this cellular barner is evaluated by measuring the
kinetics
of its appearance on the basal side. This aqueous medium, of pH 6.5, has the
following composition: NaCI = 8.0 g/1; KCl = 0.4 g/1; CaCl2 = 0.19 g/1; MgCl2
=
0.1 g/l; MgS04 = 0.1 g/1; Na2HP04 = 0.09 g/l; KH2P04 = 0.06 g/l; NaHC03 = 0.35
g/1; glucose = 1 g/l; phenol red = 0.01 g/1.
The coefficient of permeability P, in cm/s, which characterizes the rate of
passage of the molecule through the membrane, is then determined, namely:
P = (da/dt).(1/A.Co)
where:
da/dt = variation of the amount of test compound passing through the
cellular monolayer as a function of time (molls)
A = surface area of the monolayer (cm2)
Co = initial concentration of the tested compound (mol/1)
2.1. Coefficient of permeability to compound A, introduced in Hank's
medium, in solution in DMSO
P = 3.4.10-~ cm/s
The permeability to compound A measured in this way in solution (in
DMSO) indicates an intrinsic characteristic of this compound. This result
confirms
the very poor ability of compound A to pass through the epithelium.
2.2. Relative rate of intestinal transepithelial passage of compound A
Different formulations were prepared with compound A so as to measure
CA 02281560 1999-08-16
their rate of passage and compare it with that of compound A in solution in
DMSO
Formulation 1:
- compound A 4.4%
- propylene glycol 15.9%
5 - Gelucire~ 44-14 79.7%
Formulation 2:
- compound A 4.2%
- Gelucire 44-14 76.3%
- propylene glycol 15.3%
10 - sodium laurylsulfate 1.4%
- H20 2.8%
Formulation 3:
- compound A 4.3%
- Gelucire 44-14 91.23%
15 - sodium laurylsulfate 1.52%
- H20 2.95%
Formulation 4:
- compound A 4.31
- Gelucire~ 44-14 91.19%
- sodium octylsulfate 1.53%
- H20 2.97%
Formulation 5:
- compound A 7.4%
- propylene glycol 28.7%
- Gelucire~ 44-14 63.9%
Formulation 6:
- compound A 8%
- propylene glycol 46%
- Gelucire 44-14 46%
Formulation 7:
- compound A 6%
- propylene glycol 34%
- Labrasol~ 60%
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FormulationSolution1 2 3 4 5 6 7
DMSO
Relative 1 12 15 7 7 10 8 10
rate
Each of these formulations causes a notable improvement in the
transepithelial passage of compound A and none of these formulations caused a
deterioration of the epithelial monolayer.
All these formulations were observed under the optical microscope. Total
solubilization of compound A was found, except in the case of formulations 3
and
4, where compound A is partially in crystalline form.
The best result is obtained with formulation 2, which combines the
formation of the ion pair with sodium laurylsulfate and the use of a mixture
of
Gelucire~ 44-14 and propylene glycol.
EXAMPLE 1: Gelatin capsule
compound A 4.4%
propylene glycol 15.9%
Gelucire° 44-14 79,7%
for a size 1 white-opaque gelatin capsule.
The active principle is solubilized in the propylene glycol at
70°C, the
solution obtained is then incorporated into the Gelucire° 44-14 at
60°C, with
mechanical stirring, and finally the gelatin capsule is filled at 40°C.
EXAMPLE 2: Gelatin capsule
compound A 4.2%
propylene glycol 15.3%
sodium laurylsulfate in 34%
aqueous solution 1.4%
water 2.8%
Gelucire~ 44-14 76.3%
for a size 1 white-opaque gelatin capsule.
The active principle is mixed with 90% of the Gelucire~ 44-14 heated to
60°C. The aqueous sodium laurylsulfate solution is added and the
remaining
Gelucire° 44-14 is then added to make up to 100%. The mixture is
incorporated
into the gelatin capsule after cooling to 40°C.
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EXAMPLE 3: Liquid form for
bottles
compound A 6.0%
propylene glycol 34.0%
Labrasol~ 60.0%
EXAMPLE 4: Vial to be taken
orally
compound A g,0%
propylene glycol 46.0%
Gelucire 44-14 46.0%
EXAMPLE 5: Gelatin capsule
compound A 4.5%
propylene glycol 15.0%
Gelucire~ 44-14 80.5%
EXAMPLE 6: Gelatin capsule
compound A 4.4%
propylene glycol 13.0%
sodium laurylsulfate 1.5%
water 3.0%
Gelucire 44-14 78.1%
EXAMPLE 7: Liquid for bottles
compound A g,0%
propylene glycol 27.5%
polysorbate 80 2.0%
Labrasol 62.5%
EXAMPLE 8: Liquid for bottles
compound A 7.5%
propylene glycol 20.5%
polysorbate 80 2.0%
sodium laurylsulfate 2.6%
water 4.9%
Labrasol 62.5%
EXAMPLE 9: Enteric gelatin
capsule
A gelatin capsule is prepared
according to Example l and
a film coating is
applied in 2 layers, one a
precoating layer and the other
a coating layer.
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Precoating:
Eudragit~ L30 D-55 46.6%
glycerol 4.6%
polysorbate 80 in 33% aqueous solution4.6%
water 44.2%
Coating:
Eudragit~ L30 D-55 54.8%
glycerol 3.3%
polysorbate 80 in 33% aqueous solution0.7%
water 41.2%
