U.S. patent application number 10/114612 was filed with the patent office on 2003-03-20 for antifungal composition with enhanced bioavailability.
This patent application is currently assigned to SCHERING CORPORATION. Invention is credited to Harris, David, Mahashabde, Shashank, Sequeira, Joel, Sharpe, Stefan.
Application Number | 20030055067 10/114612 |
Document ID | / |
Family ID | 23076102 |
Filed Date | 2003-03-20 |
United States Patent
Application |
20030055067 |
Kind Code |
A1 |
Sharpe, Stefan ; et
al. |
March 20, 2003 |
Antifungal composition with enhanced bioavailability
Abstract
A liquid suspension comprising an antifungally effective amount
of the micronized compound represented by the chemical structural
formula I: 1 at least one thickening agent, a non-ionic surfactant,
and a pharmaceutically acceptable liquid carrier is disclosed.
Inventors: |
Sharpe, Stefan; (Jersey
City, NJ) ; Sequeira, Joel; (Edison, NJ) ;
Harris, David; (New Providence, NJ) ; Mahashabde,
Shashank; (Kendall Park, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
SCHERING CORPORATION
|
Family ID: |
23076102 |
Appl. No.: |
10/114612 |
Filed: |
April 1, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60281139 |
Apr 3, 2001 |
|
|
|
Current U.S.
Class: |
514/254.05 ;
424/484 |
Current CPC
Class: |
A61K 9/10 20130101; A61K
31/496 20130101; A61K 9/0095 20130101; A61P 31/10 20180101; A01N
43/653 20130101; A01N 43/653 20130101; A01N 25/30 20130101; A01N
25/10 20130101; A01N 25/04 20130101; A01N 43/653 20130101; A01N
2300/00 20130101 |
Class at
Publication: |
514/254.05 ;
424/484 |
International
Class: |
A61K 031/497; A61K
009/14 |
Claims
We claim:
1. A liquid suspension comprising an antifungally effective amount
of the micronized compound represented by the chemical structural
formula I comprising: 8at least one thickening agent, at least one
non-ionic surfactant, and a pharmaceutically acceptable liquid
carrier.
2. The liquid suspension of claim 1, wherein the at least one
non-ionic surfactant is a block copolymer of ethylene oxide and
propylene oxide, glycol or glyceryl esters of saturated or
unsaturated C.sub.8to C.sub.20 acids, polyoxyethylene esters of
saturated or unsaturated C.sub.8to C.sub.20 acids, polyoxyethylene
ethers of saturated or unsaturated C.sub.8to C.sub.20 acids,
polyvinylalcohols or sorbitan esters of saturated or unsaturated
C.sub.10 to C.sub.20 acids.
3. The liquid suspension of claim 1, wherein the at least one
non-ionic surfactant is a polyoxyethylene derivative of a sorbitan
ester of a saturated or unsaturated C.sub.10to C.sub.20 acid.
4. The liquid suspension of claim 1, wherein the at least one
thickening agent is selected from xanthan gum, liquid sugars,
starches, celluloses and mixtures thereof.
5. The liquid suspension of claim 1, wherein a combination of
xanthan gum and a liquid sugar are used as the at least one
thickening agent.
6. The liquid suspension of claim 1, wherein the micronized
compound of formula I has a mean particle size of about 1200 nm to
about 1600 nm.
7. A liquid suspension comprising: (a) an antifungally effective
amount of the micronized compound represented by the chemical
structural formula I: 9(b) an effective amount of at least one
thickening agent; (c) an amount of a buffer system effective to
maintain the pH of the system in the range of about 4.0 to about
6.0; (d) an effective amount of at least one non-ionic surfactant;
and (e) a pharmaceutically acceptable liquid carrier.
8. The liquid suspension of claim 7, wherein the at least one
non-ionic surfactant is a polyoxyethylene derivative of a sorbitan
ester of a saturated or unsaturated C.sub.10to C.sub.20 acid.
9. The liquid suspension of claim 7, wherein the sorbitan ester is
a fatty acid ester of sorbitan selected from sorbitan monolaurate,
sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate,
sorbitan monopalmitate, sorbitan monostearate and sorbitan
tristearate, or mixtures thereof.
10. The liquid suspension of claim 7, wherein the at least one
thickening agent is selected from gums, liquid sugars, starches,
cellulose and mixtures thereof.
11. The liquid suspension of claim 7, wherein a combination of a
xanthan gum and a liquid sugar is used as the at least one
thickening agent.
12. The liquid suspension of claim 7, wherein a combination of a
xanthan gum and a liquid glucose is used as the thickening
agent.
13. The liquid suspension of claim 7, wherein the buffer system
comprises sodium citrate and citric acid.
14. The liquid suspension of claim 7, wherein the pharmaceutically
acceptable liquid carrier is a combination of purified water,
glucose and glycerin.
15. The liquid suspension of claim 7, wherein the micronized
compound of formula I has a mean particle size of about 1200 nm to
about 1600 nm.
16. A liquid suspension comprising: (a) an antifungally effective
amount of the micronized compound comprising chemical structural
formula I: 10 wherein the micronized compound of formula I has a
mean particle size in the range of about 1200 nm to about 1600 nm,
(b) an effective amount of a polyoxyethylene derivative of sorbitan
esters of saturated or unsaturated C.sub.12 to C.sub.18 acids; (c)
an effective amount of a buffer system sufficient to maintain a pH
in the range of about 4.0 to about 6.0; (d) an effective amount of
a combination of two thickening agents, wherein one is a liquid
sugar; and (e) a pharmaceutically acceptable liquid carrier.
17. A method of treating and/or preventing a fungal infection in a
patient comprising administering to a patient in need of such
treating and/or preventing an antifungally effective amount of
micronized particles of of the compound of formula I in the form of
an oral suspension I: 11
18. A suspension comprising an antifungally effective amount of the
micron ized particles of the compound comprising chemical
structural formula I: 12at least one thickening agent and a
non-ionic surfactant in a pharmaceutically acceptable liquid
carrier.
19. A composition of matter comprising micronized particles of the
compound represented by structural formula I 13and at least one
non-ionic surfactant.
20. A composition of matter comprising micronized particles of the
compound represented by chemical structural formula I: 14in
suspension.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to stable, liquid suspensions
containing an antifungally effective amount of the micronized
compound represented by the chemical structural formula I: 2
[0002] at least one thickening agent, a non-ionic surfactant, and a
pharmaceutically acceptable liquid carrier, and methods of using
the suspensions to treat or prevent fungal infections
[0003] U.S. Pat. No. 5,661,151 discloses the compound of formula I
and its potent antifungal activity against a broad range of fungi
such as Aspergillis, Candida, Cryptococcus, Fusarium, and other
opportunistic fungi.
[0004] U.S. Pat. Nos. 5,834,472 and 5,846,971, disclose oral
pharmaceutical capsule compositions of the compound of structural
formula I coated onto inert beads together with a binder. However,
the compound of structural formula I is highly lipophilic, and has
an extremely low water solubility. Thus, aqueous compositions of
the compound of structural formula I were found to have reduced
anti-fungal activity and/or bioavailability, presumably due to the
extremely low water solubility of the compound. Accordingly, a need
exists for an oral pharmaceutical composition of the compound of
structural formula I that has enhanced bioavailability and improved
stability characteristics
SUMMARY OF THE INVENTION
[0005] We have found pharmaceutical compositions, in the form of
liquid suspension, suitable for oral administration comprising
micronized particles of posaconazole, the compound having the
chemical structural formula I 3
[0006] at least one thickening agent, a non-ionic surfactant, and a
pharmaceutically acceptable liquid carrier that provides
significant advantages over the prior art.
[0007] Advantages of the liquid suspensions of the present
invention include improved homogeneity of the suspension and ease
of dispersibility of the suspension. The solids that settle in the
liquid suspension of the present invention do not form a solid cake
that is difficult to re-disperse. There is virtually no
sedimentation of the solids in the unreconstituted liquid
suspension of this invention for a period of at least three days.
This surprising feature ensures that a patient having a fungal
infection taking the liquid suspensions of the present invention
will receive an antifungally effective amount of posaconazole. The
liquid suspensions of the present invention have a longer shelf
life. Additionally, the liquid suspension, upon reconstitution,
provide substantially the same antifungally effective amount
posaconazole as the initially prepared suspension. These features
of the liquid suspensions of the present invention provide benefits
to pharmacies, pharmacists, doctors and patients having fungal
infections.
[0008] Accordingly, the present invention provides a liquid
suspension comprising micronized posaconazole, having the chemical
structural formula I: 4
[0009] at least one thickening agent, a non-ionic surfactant, and a
pharmaceutically acceptable liquid carrier.
[0010] This invention also provides a liquid suspension comprising
an antifungally effective amount of micronized posaconazole having
the chemical structural formula I: 5
[0011] an effective amount of at least one thickening agent, an
amount of a buffer system effective to maintain the pH of the
system in the range of about 4.0 to about 6.0, an effective amount
of a non-ionic surfactant, and a pharmaceutically acceptable liquid
carrier.
[0012] This invention further provides a liquid suspension
comprising an antifungally effective amount of micronized
posaconazole having the chemical structural formula I: 6
[0013] wherein the micronized compound has a mean particle size in
the range of about 1200 nm to about 1600 nm, an effective amount of
polyoxyethylene derivatives of sorbitan esters of saturated or
unsaturated C.sub.12 to C.sub.18 acids, an effective amount of a
buffer system sufficient to maintain a pH in the range of about 4.0
to about 6.0, an effective amount of a combination of two
thickening agents, wherein one is a liquid sugar, and a
pharmaceutically acceptable liquid carrier.
BRIEF DESCRIPTION OF THE FIGURES
[0014] FIGS. I & 2 graphically display the mean plasma
concentration time profiles of posaconazole tablets and of the
liquid suspension of Example 1 of the present invention. FIG. 1 is
a linear:linear graphic profile of the plasma concentration
(ng/ml)of the compound of formula I versus time (hours) after
administration of the following four Treatments A- D: a single of
2.times.100 mg of the compound of formula I in the tablet
co-precipitate formulation of U.S. Pat. No. 5,834,472 with a
standardized high-fat breakfast- Treatment D and. symbol -.cndot.-;
a 200 mg of the compound of formula I in the oral suspension of
this invention (5 ml) following a 10-hr. fast -Treatment A and.
symbol -O-;a 200 mg of the compound of formula I in the oral
suspension of this invention (5 ml) with a standardized high-fat
breakfast-Treatment B and. symbol -.DELTA.-;and a 200 mg of the
compound of formula I in the oral suspension of this invention (5
ml) with a standardized non-fat breakfast-Treatment C and.
symbol-.quadrature.-.
[0015] FIG. 2 is a log linear graphic profile of the plasma
concentration (ng/ml)of the compound of formula I versus time in
hours for the data presented in FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention provides a stable suspension of
micronized particles of the antifungal compound posaconazole in a
pharmaceutically acceptable liquid carrier. The suspension of the
present invention is stable to settling without sedimentation when
stored undisturbed for more than three days at 25.degree. C. (See
Table 1 below).
[0017] Table 2 below shows that the liquid suspension formulations
of this invention are stable in that the concentration of
posaconazole in the suspension is substantially the same (.+-.2%)
compared to the initial concentration (as measured by HPLC) for
periods of up to 12 months.
[0018] We have also found that the stable suspension of the present
invention has a remarkably higher (23-36% increase) bioavailability
compared to an optimized oral tablet of micronized particles of
posaconazole when each is administered to subjects concurrently
with a high fat breakfast. See Tables 3 and 4 and FIGS. 1 &
2
[0019] One aspect of the present invention is to provide a
pharmaceutical composition that contains micronized particles of
posaconazole in combination with a non-ionic surfactant, such as a
sorbitan ester and at least one thickening agent, preferably a
combination of xanthan gum and a liquid sugar, that are easily
dispersible in a pharmaceutically acceptable liquid carrier such as
purified water. The pharmaceutical composition provides a
stabilized suspension that does not settle for at least three days,
thus ensuring that patients will get an effective dose of
posaconazole. Another feature of the stabilized suspension of the
present invention is that it is useful in treating patients with
HIV-1 infections with oral thrush without posaconazole
precipitating out of solution. Another aspect of the present
invention is that the suspension of the present invention avoids
formation of solid cakes which are difficult to disperse.
[0020] The compound of formula I used in the suspensions of the
present invention is available from Schering Corporation,
Kenilworth, N.J., and has been prepared according to Examples 24
and 32 of U.S. Pat. No. 5,661,151 and WO 95/17407.
[0021] Micron-sized particles of posaconazole preferably have a
mean particle size range of about 1000 nanometers (nm) to about
1800 nm, preferably about 1200 nm to about 1600 nm, and most
preferably about 1400 nm. This particle size can be obtained either
by the final step during the manufacture of the antifungal compound
of formula I or by the use of conventional micronizing techniques
after the conventional crystallization procedure(s).
[0022] The preferred micronizing technique that is employed to
micronize the posaconazole to the desired mean particle size range
is microfluidization. Microfluidization is an alternative to
traditional homogenization that utilizes the collision of two
product streams at high pressures to produce a much more uniform
particle size distribution (according to Microfluidics
International Co.) and smaller average particle size of about 1200
nm to 1600 nm. The process and equipment used in microfluidization
are described in U.S. Pat. No. 4,533,254.
[0023] The micronized posaconazole of the present invention may
also be present in crystalline form. It is preferably substantially
chemically and optically pure, and it contains less than about 10%
of its optical isomers, enantiomers or other diastereomers. It may
be 99% of the optically pure the levorotatory or dextrarotatory
isomer. This optically pure compound of chemical structure I should
avoid many of the untoward side effects of a mixture of other
optical isomers.
[0024] Posaconazole liquid suspension is employed in the
composition in antifungally amounts effective to control the fungi
of interest. Such antifungally effective amounts can range from
about 10 mg/ml to about 100 mg/ml concentration of the liquid
suspension formulations of the present invention, more preferably
from about 20 mg/ml to about 60 mg/ml, and most preferably about 40
mg/ml of the compound of formula I.
[0025] The present invention also provides for a method of treating
and/or preventing fungal infection in a mammal comprising
administering to the mammal an amount of the liquid suspension
containing the micronized posaconazole in an amount effective for
treating and/or preventing such fungal infection. Antifungally
effective amounts of liquid suspensions of present invention
containing 40 mg/ml of the compound of formula I is administered
orally in the doses of 5 ml--containing 200 mg of formula I--three
times a day (TID) or four times a day (QID)--or 10 ml--containing
400 mg of the compound of formula 1--twice a day (BID). Of course,
the attending clinician may change the dose and dosing regimen in
view of the age, health, and sex of the patient as well as the
severity of the fungal infection.
[0026] The following terms are used to describe the present
pharmaceutical compositions, ingredients that may be employed in
its formulation and methods for assessing the compound's
bioactivity or bioavailability.
[0027] Non-ionic surfactant refers to a surfactant which lacks a
net ionic charge and does not dissociate to an appreciable extent
in aqueous media. The properties of non-ionic surfactants are
largely dependent upon the proportions of the hydrophilic and
hydrophobic groups in the molecule. Hydrophilic groups include the
oxyethylene group (--OCH.sub.2CH.sub.2--) and the hydroxy group. By
varying the number of these groups in a hydrophobic molecule, such
as an ester of a fatty acid, substances are obtained which range
from strongly hydrophobic and water insoluble compounds, such as
glyceryl monostearate, to strongly hydrophilic and water-soluble
compounds, such as the macrogols. Between these two extremes types
include those in which the proportions of the hydrophilic and
hydrophobic groups are more evenly balanced, such as the macrogol
esters and ethers and sorbitan derivatives. Suitable non-ionic
surfactants may be found in Martindale, The Extra Pharmacopoeia,
28th Edition, 1982, The Pharmaceutical Press, London, Great
Britain, pp. 370 to 379.
[0028] Such suitable non-ionic surfactants include block copolymers
of ethylene oxide and propylene oxide, glycol or glyceryl esters of
saturated or unsaturated C.sub.8 to C.sub.20 acids, preferably,
polyoxyethylene esters of saturated or unsaturated C.sub.8 to
C.sub.20 acids, polyoxyethylene ethers of saturated or unsaturated
C.sub.8to C.sub.20 acids, and polyvinylalcohols or sorbitan esters
of saturated or unsaturated C.sub.10to C.sub.20 acids. Preferably,
the non-ionic surfactant is a sorbitan ester of a saturated or
unsaturated C.sub.10 to C.sub.20 acid, and more preferably the
sorbitan ester is a fatty acid ester of sorbitan selected from
sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate,
sorbitan trioleate, sorbitan monopalmitate, sorbitan monostearate
and sorbitan tristearate, or mixtures thereof.
[0029] Suitable sorbitan esters include, e.g. Polysorbate 20,
Polysorbate 40, Polysorbate 60, Polysorbate 65, Polysorbate 80,
Polysorbate 85, Sorbitan Monolaurate, Sorbitan Mono-oleate,
Sorbitan Monopalmitate, Sorbitan Monostearate, Sorbitan
Sesquioleate, Sorbitan Trioleate and Sorbitan Tristearate. The most
preferred non-ionic surfactant is Polysorbate 80, available from
ICI Americas under the tradename Tween 80 which is a mixture of
oleate esters of sorbitol and sorbitol anhydrides, consisting
predominantly of the monoester, condensed with approximately 20
moles of ethylene oxide.
[0030] Suitable block copolymers of ethylene oxide and propylene
oxide generically called "Poloxamers" and include those represented
by the following chemical structure I: 7
[0031] wherein a is an integer ranging from about 10 to about 110,
preferably from about 12 to 101; more preferably from about 12 to
80; and
[0032] b is an integer ranging from about 20 to about 60, more
preferably from about 20 to about 56; also from about 20 to 27.
[0033] Suitable glycol and glyceryl esters of fatty acids include
glyceryl monooleate and similar water soluble derivatives;
[0034] Suitable polyoxyethylene esters of fatty acids (macrogol
esters) include polyoxyethylene castor oil and hydrogenated castor
oil derivatives;
[0035] Suitable polyoxyethylene ethers of fatty acids (macrogol
ethers) include Cetomacrogel 1000, Lauromacrogols (a series of
lauryl ethers of macrogols of differing chain lengths), e.g.
Laureth 4, Laureth 9 and Lauromacrogol 400.
[0036] The effective amount of non-ionic surfactant in the
composition can range from about 5 mg/ml to about 50 mg/ml
concentration of the formulation, more preferably from about 5
mg/ml to about 25 mg/ml, and most preferably 10 mg/ml.
[0037] Thickening agents found suitable in the present invention
include any commercially available agent useful for such purpose.
Xanthan gum, liquid sugars, starches, celluloses and mixtures
thereof are preferred thickening agents. More preferred is a
combination of xanthan gum and a liquid sugar and, most preferred
is a combination of xanthan gum, NF and glucose, NF. Preferably,
the xanthan gum is present in an amount of about 1 mg/ml to about 5
mg/ml, and more preferably the xanthan gum is present in an amount
of about 3 mg/ml. Preferably, the glucose NF is present in an
amount of about 200 to about 500 mg/ml, and more preferably about
350 mg/ml. The effective amount of thickening agent of the present
invention may be about 1 to about 500 mg/ml, more preferably about
200 to about 500 mg/ml, most preferably about 353 mg/ml. The
thickening agents of the present invention facilitate suspension of
the formulation after constitution with minimum agitation and
prevent rapid settling and caking of the suspension over time.
[0038] Pharmaceutically acceptable carriers include those well
known in the art, including purified water USP, liquid glucose, NF,
and anhydrous glycerol. Most preferred is purified water USP and
liquid glucose, NF. The pharmaceutically acceptable carrier may be
present in an amount of about 10 to about 500 mg/ml, more
preferably about 200 mg/ml to about 400 mg/ml, most preferably
about 350 mg/ml.
[0039] The buffer systems suitable for the formulations of the
present invention are those which maintain the pH of the liquid
suspension in the range of about 4 to about 6, preferably in the
4.5 to 5.0, and most preferably about 4.5. The use of a buffer
system of sodium citrate, USP and citric acid, USP, is preferred.
Other suitable buffer systems may be used to maintain the desired
pH range of 4 to 6. The buffering agents may be present in a
concentration of about 0.4 to about 1.5 mg/ml, more preferably
about 0.7 to about 1.5 mg/ml, most preferably about 1.1 mg/ml.
[0040] Anti-foaming agents found suitable in the present invention
include any commercially available agent useful for such purpose
including the methylated linear siloxsane polymers end blocked with
trimethylsiloxyl units such as dimethicone and simethicone, as well
as mixtures of dimethicone with an average chain length of 200 to
250 dimethylsiloxane units and silica gel. The effective amount of
anti-foaming agents is an amount sufficient to provide a
concentration of about 2 mg/ml to about 4 mg/ml, preferably about 3
mg/ml.
[0041] The water soluble preservatives found useful in present
invention include sodium benzoate, sodium citrate and benzalkonium
chloride as well as other pharmaceutically acceptable water soluble
preservatives. Use of sodium benzoate as a preservative is
preferred. The effective amount of the water soluble preservative
is an amount sufficient to provide a concentration of about 0.5
mg/ml to about 3 mg/ml, most preferably about 2 mg/ml.
[0042] The opacifier agents found suitable in the present invention
include pharmaceutically acceptable metal oxides, especially
titanium dioxide. The effective amount of the opacifier agent is an
amount sufficient to provide a concentration of about 2 mg/ml to
about 6 mg/ml, most preferably about 4 mg/ml.
[0043] Typical flavoring agents are those that are approved by FDA
for use in sweetened pharmaceuticals, foods, candies, beverages and
the like; these materials impart flavors such as grape, cherry,
citrus, peach, strawberry, bubble gum, peppermint and many others.
The effective amount of the flavoring agents is an amount
sufficient to provide a concentration of about 0.01 mg/ml to about
6 mg/ml, more preferably about 5 mg/ml.
[0044] The following examples describe compositions of the present
invention containing posaconazole, but they are not to be
interpreted as limiting the scope of the claims.
1 Concentration Range Ingredient (mg/ml) Posaconazole (micronized)
10-100 Polysorbate 80 5-50 Sodium Citrate, USP, 0.4-0.8 Monohydrate
Citric Acid, USP, Monohydrate 0.36-0.6 Simethicone, USP 2-4 Xanthan
Gum, NF 1-5 Sodium Benzoate, NF 0.5-3 Liquid Glucose, NF 200-500
Glycerin, USP 50-150 Artificial Cherry Flavor 2-10 Titanium Dioxide
2-6 Purified Water, USP q.s. ad --
[0045] The above ranges of ingredients may be varied as is evident
to one skilled in the art.
[0046] Specific examples of a composition within the scope of the
invention is set forth below.
EXAMPLE 1
[0047]
2 Concentration Ingredient (mg/ml) Posaconazole (micronized) 40
Polysorbate 80 10 Sodium Citrate, USP, 0.6 Monohydrate Citric Acid,
USP, Monohydrate 0.48 Simethicone, USP 3 Xanthan Gum, NF 3 Sodium
Benzoate, NF 2 Liquid Glucose, NF 350 Glycerin, USP 100 Artificial
Cherry Flavor 5 Titanium Dioxide 4 Purified Water, USP q.s. ad 1
ml
[0048] This example is prepared as follows: charge approximately 5%
of the final batch volume of purified water at 20.+-.3.degree. C.
to a suitable vessel equipped with a mixer propeller. Add 40% of
the polysorbate 80 to the purified water in step 1 and mix until
dissolved. Add 40% of the simethicone and mix until it is
dispersed. Recirculate the mixture in step 3 through a
Microfluidizer, operating at about 30,000 .+-.5000 psi for
approximately 5 passes. Add approximately 7% of the final batch
volume of purified water at about 20.+-.3.degree. C., and mix for
approximately five minutes. Add the Posaconazole to the vessel in
step 5 with constant mixing. Continue mixing until it is fully
dispersed. Recirculate the suspension portion from step 6 through a
Microfluidizer, operating at a pressure of about 30,000.+-.5,000
psi. Process the concentrate until the median of the particles
shows a particle size of about 1.4.+-.0.2 .mu.m, when measured via
laser diffraction techniques that are known in the art.
[0049] When the particle size has been achieved, pass the
suspension through the microfluidizer and collect in a suitable
sized vessel. Add approximately 8-10% of the final batch volume of
purified water (at 20.+-.3.degree. C.) to the feed vessel, and pass
through the microfluidizer operating at approximately 30,000 psi.
Collect the rinse in the vessel containing the concentrate. Add
approximately 22% of the final batch volume of purified water
(20.+-.3.degree. C.) to the vessel with the concentrate, and mix
for approximately five (5) minutes. Add the remainder of the
polysorbate 80 and simethicone, and mix for approximately five (5)
minutes.
[0050] Add the sodium benzoate, sodium citrate and citric acid and
mix for approximately five (5) minutes. Add the xanthan gum slowly
with constant mixing. Continue to mix after addition of the xanthan
gum. Allow the xanthan gum to hydrate without mixing for 30
minutes. Add the glycerin with constant mixing. Add the liquid
glucose slowly with constant mixing. Mix for five minutes or until
it is dissolved. Add the titanium dioxide and mix using a suitable
homogenizer until that ingredient is fully dispersed. Add the
artificial cherry flavor, and mix for approximately five minutes.
Add purified water at 20.+-.3.degree. C., and qs up to a final
volume, and mix until a uniform suspension is attained. Collect
approximately 20 ml sample for pH measurement and physical
observation of the suspension. The pH of the suspension of Example
1 was 5.0.
EXAMPLE 2
[0051] Example 2 is another example of a formulation within the
scope of the present invention prepared using the procedure of
Example 1 and has a pH of 4.5.
3 Concentration Ingredient (mg/ml) Posaconazole (micronized) 40
Polysorbate 80 10 Sodium Citrate, USP, 0.6 Monohydrate Citric Acid,
USP, Monohydrate 1.5 Simethicone, USP 3 Xanthan Gum, NF 3 Sodium
Benzoate, NF 2 Liquid Glucose, NF 350 Glycerin, USP 100 Artificial
Cherry Flavor 5 Titanium Dioxide 4 Purified Water, USP q.s. ad 1
ml
[0052] The rate of sedimentation of the liquid suspension of the
present invention was determined as set forth below.
4TABLE 1 Posaconazole Oral Suspension 40 mg/ml Rate of
Sedimentation Sodium Bottle Posaconazole % Label Benzoate % Label
Number Time mg/ml Strength mg/ml Strength 1 0 min 39.9 99.8 2.00
100 1 5 min 40.0 100 1.99 99.5 1 10 min 40.0 100 2.00 100 1 30 min
40.0 100 2.00 100 1 60 min 40.2 101 2.01 101 1 3 days 40.2 101 2.02
101 2 0 min 39.8 99.5 2.01 101 2 5 min 39.9 99.8 2.00 100 2 10 min
40.2 101 2.01 101 2 30 min 39.8 99.5 1.99 99.5 2 60 min 40.2 101
2.02 101 2 3 days 40.1 100 2.01 101
[0053] Two bottles containing the suspension of the present
invention were shaken and left to rest. The bottles were then
sampled immediately (time zero), then after 5 minutes, 10 minutes,
30 minutes, 60 minutes and after 72 hours (three days) post
shaking. The levels of posaconazole and of the preservative (Sodium
Benzoate) in these samples were assayed by HPLC. HPLC methods of
detection are well-known to one of skill in the art.
[0054] The results of the assay of the preservative and of the
posaconazole remained consistent and did not change. These ranged
from 39.8 to 40.2 mg/ml (99.5 to 101%) for the active and 1.99 to
2.02 mg/m: (99.5 to 101%) for the preservative, respectively. The
results of this experiment are shown in Table 1 above.
[0055] The sodium benzoate was not expected to sediment.
Surprisingly, the posaconazole was not sedimented after 3 days.
[0056] Thus, the compositions of the present invention have both
ease of dispersibility and homogeneity as is evidenced by the
stability of the samples in Table 1.
[0057] Next, accelerated homogeneity testing was performed on the
liquid suspension of the present invention.
5TABLE 2 Posaconazole Oral Suspension 40 mg/ml Homogeneity
Accelerated Posaconazole Sodium Benzoate Condition Time point %
Label Strength % Label Strength Initial Initial 103; 102; 104 105;
102; 103 30 H (30.degree. C./60% 3 Months 103; 105; 104 103; 107;
105 RH) RH4 (40.degree. C./75% 3 Months 102; 104; 103 104; 106; 106
RH) 30 H 6 Months 102; 101; 102 103; 101; 102 RH4 6 Months 102;
102; 102 101; 101; 102 25 H 12 Months 104; 104; 104 101; 100; 100
25 H 24 Months 104; 104; 104 101; 101; 101 * Shaking and receiving
the dose as per patient instruction.
[0058] These data (sedimentation rate experiment) were in agreement
with the real time stability data (up to 6 months at 40.degree.
C./75% RH and up to 24 months at 25.degree. C./60% RH) that are
shown in Table 2. The assay homogeneity results, surprisingly,
remained consistently homogenous and practically unchanged.
[0059] After 6 months at 40.degree. C./75% RH the homogeneity
results ranged from 40.7 to 40.8 mg/ml (101%) for the active and
2.01 to 2.03 mg/ml (101 to 102%) for preservative, respectively.
These results were obtained regardless of the portion of the bottle
assayed, i.e., top, or bottom of the bottle. Therefore, it can be
concluded that the suspension was homogenous throughout the bottle
even after relatively long exposure to accelerated stability
conditions.
[0060] After 24 months at 25.degree. C./60% RH the homogeneity
results ranged from 41.5 to 41.6 mg/ml (104%) for the active and
2.01 mg/ml (101%) for the preservative, respectively. These results
were obtained regardless of the portion of the bottle assayed,
i.e., top or bottom of the bottle. Therefore, it can be concluded
that the suspension was homogenous throughout the bottle even after
long term (24 months) exposure to 25.degree. C./60% RH.
[0061] Bioavailability is defined as the rate and extent to that
the active drug ingredient or therapeutic moiety is absorbed into
the systemic circulation from an administered dosage form as
compared to a standard or control.
[0062] C.sub.max value is defined as the maximum concentration of
the antifungal compound measured (i.e. "peak") in the plasma
serum.
[0063] Formulations of the present invention have the advantage
that they have an increased bioavailability and lower variability
than previous formulations.
[0064] The relative bioavailability of the posaconazole oral
suspension was compared to a solid dosage form of posaconazole in
healthy subjects.
[0065] The first objective was to determine the relative
bioavailability of posaconazole given as an oral suspension
compared to an oral solid formulation when administered with a
high-fat breakfast. The second objective was to determine the
effect of high-fat and non-fat food relative to fasting conditions
on the oral bioavailability of the compound of formula I when given
as an oral suspension.
[0066] Twenty healthy subjects completed this randomized,
open-label, 4-way crossover, single-dose bioavailability and food
effect study of posaconazole. Subjects received each of the
following four treatments separated by at least a 7 day washout
period:
6 Treatment A: 200 mg of the compound of formula I in the oral
suspension of this invention (5 ml) following a 10-hr. fast
Treatment B: 200 mg of the compound of formula I in the oral
suspension of this invention (5 ml) with a standardized high-fat
breakfast Treatment C: 200 mg of the compound of formula I in the
oral suspension of this invention (5 ml) with a standardized
non-fat breakfast Treatment D: 2 .times. 100 mg of the compound of
formula I in the tablets (co-precipitate formulation of U.S. Pat.
No. 5,834,472 with a standardized high-fat breakfast
[0067] Subjects were randomized to either remain fasted (Treatment
A), to receive a standardized high fat breakfast (Treatment B or D)
or a standardized non-fat breakfast (Treatment C). Meals were
consumed in a 20-minute period prior to the morning drug
administration and subjects received the appropriate treatment
within 5 minute of completing the breakfast.
[0068] Blood samples (6 ml) were collected into heparinized tubes
for each treatment immediately prior to dosing (0 hour) and at 0.5,
1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours after
dosing. Blood was centrifuged at 4.degree. C. and plasma stored at
or below -20.degree. C. until assayed. Plasma concentrations of
posaconazole were assayed using a validated high performance liquid
chromatographic assay with a LOQ of ng/ml.
[0069] Individual plasma concentration-time data were used for
pharmacokinetic analysis using model-independent methods. The
maximum concentration (Cmax) and time of maximum concentration
(Tmax) were the observed values. The area under the plasma
concentration-time curve from time zero to the final quantifiable
sampling time [AUC(tf)] was calculated using the linear trapezoidal
method and extrapolated to infinity (I) as follows: 1 A U C ( l ) =
A U C ( tf ) C ( tf ) K
[0070] where C(tf) is the estimated concentration determined from
linear regression at time, tf.
[0071] Total body clearance was calculated by the following:
CL=Dose/AUC(I)
[0072] The apparent volume of distribution (Vdarea/F) was
calculated from the ratio of the total body clearance to the
terminal phase rate constant (K).
[0073] Summary statistics were calculated for the plasma suspension
formulation of the present invention compared to a prior art tablet
formulation concentration-time data at each time point and the
derived pharmacokinetic parameters. The original scale and
log-transformed Cmax and AUC values were analyzed using an analysis
of variance (ANOVA). The effects due to subject, phase and
treatment were extracted.
[0074] The plasma concentration-time data and pharmacokinetic
parameters for the compound of formula I are tabulated in Tables 3
& 4 and depicted graphically in FIGS. 1 & 2.
[0075] All subjects had 0-hour concentrations on Day 1 reported as
below the LOQ (5 ng/ml) except for Subject 20 in Phases 3 and 4 who
had quantifiable levels of posaconazole at 0-hour for Treatments B
and A of 8.5 and 22.5 ng/ml, respectively. These levels are most
likely due to a carry-over effect from accumulation from previous
doses.
[0076] A summary of the mean pharmacokinetic parameters are
provided in the table below:
7 TABLE 3 Tablet Suspension High Fat D 10 hr Fast A High Fat B
Non-Fat C Parameter Unit Mean % CV Mean % CV Mean % CV Mean % CV
Cmax ng/ml 413 33 132 50 512 34 378 43 Tmax Hr 5.5 32 5.01 49 4.8 9
4.1 21 AUC(tf) ng-hr/ml 10304 41 3553 36 13885 41 9511 38 AUC(l)
ng-hr/ml 11832 39 4179 31 15059 26 10753 35 t1/2 hr 21.0 15 23.5 25
23.0 19 22.2 18 a: Balanced means, n = 20 except for AUC(l) and
t1/2, n = 15.
[0077] Posaconazole was slowly absorbed; the mean Tmax values
ranged from 4.1 to 5.5 hr. Posaconazole was slowly eliminated with
a mean terminal t1/2 of about 22 hour which was independent of
treatment. This study was conducted to evaluate the bioavailability
of posaconazole oral suspension (Treatment B) compared to a tablet
formulation (Treatment D), both given with a high-fat food. The
results, based on log-transformed data, are shown below:
8TABLE 4 Treatments Given After Relative 90% High Fat Geometric
Bioavailability Confidence Parameter Breakfast Mean (%).sup.b
Interval Cmax Suspension 485 ng/ml 123.3 104-146 Tablet 394 ng/ml
AUC(tf).sup.a Suspension 13141 ng.hr/ml 136.5 119-156 Tablet 9624
ng.hr/ml .sup.aAUC(tf) was used for statistical comparisons because
it could be calculated for all treatments for all subjects.
.sup.bSuspension relative to tablet.
[0078] On average, the suspension formulation of the present
invention resulted in a 23% increase in Cmax and a 36% increase in
AUC(tf) compared to the tablet of the prior art.
[0079] The secondary objective of the study was to evaluate the
effect of high fat food (Treatment B) and non-fat food (Treatment
C) compared to fasting (Treatment A) on the oral bioavailability of
posaconazole administered as an oral suspension. The results, based
on log-transformed data, are shown below:
9TABLE 5 Relative 90% Suspension Geometric Bioavailability
Confidence Parameter Treatments Mean (%).sup.a Interval Cmax
High-Fat 485 417 352-493 (ng/ml) Non-Fat 345 296 250-350 Fast 116
-- -- AUC(tf) High-Fat 13141 392 343-448 (ng.hr/ml Non-Fat 8857 264
231-302 Fast 3352 -- -- .sup.aExpressed as a percent of Treatment A
- Suspension/Fast.
[0080] A high fat breakfast produced a 4-fold increase in the
bioavailability of posaconazole given in a suspension. This was
consistent with results from a previous study where food
significantly increased the bioavailability of posaconazole by
3-5-fold for both tablet and capsule formulations. The effect of a
non-fat breakfast (Treatment C) compared to fasting (Treatment A)
was less, with a 2.5-3-fold increase in bioavailability.
[0081] Many modifications and variations of this invention can be
made without departing from its spirit and scope, as will be
apparent to one skilled in the art. The specific embodiments
described herein are offered by way of example only, and the
invention is to be limited only by the terms of the appended claims
along with the full scope of equivalents to which such claims are
entitled.
* * * * *