U.S. patent application number 13/901978 was filed with the patent office on 2013-11-28 for aprepitant injectable formulations.
This patent application is currently assigned to Innopharma, Inc.. The applicant listed for this patent is Innopharma, Inc.. Invention is credited to Tushar Hingorani, Satish Pejaver, Navneet Puri, Kumaresh Soppimath.
Application Number | 20130317016 13/901978 |
Document ID | / |
Family ID | 49622077 |
Filed Date | 2013-11-28 |
United States Patent
Application |
20130317016 |
Kind Code |
A1 |
Hingorani; Tushar ; et
al. |
November 28, 2013 |
Aprepitant Injectable Formulations
Abstract
An aqueous stable and ready-to-use formulation of aprepitant is
prepared. Especially preferred formulations comprise a synergistic
combination of a co-solvent and a surfactant and may further
include a secondary co-solvent. Among other advantages of
contemplated formulations, aprepitant is dissolved at high
concentrations and remains dissolved and stable, even over
prolonged periods of time.
Inventors: |
Hingorani; Tushar;
(Piscataway, NJ) ; Soppimath; Kumaresh; (Monmouth
Junction, NJ) ; Pejaver; Satish; (Bridgewater,
NJ) ; Puri; Navneet; (Bridgewater, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Innopharma, Inc. |
Piscataway |
NJ |
US |
|
|
Assignee: |
Innopharma, Inc.
Piscataway
NJ
|
Family ID: |
49622077 |
Appl. No.: |
13/901978 |
Filed: |
May 24, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61651501 |
May 24, 2012 |
|
|
|
61798276 |
Mar 15, 2013 |
|
|
|
Current U.S.
Class: |
514/230.8 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 47/24 20130101; A61P 1/08 20180101; A61K 31/5377 20130101;
A61K 47/44 20130101; A61K 9/0019 20130101; A61K 9/08 20130101; A61K
47/18 20130101; A61K 47/26 20130101 |
Class at
Publication: |
514/230.8 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377 |
Claims
1. A sterile liquid formulation of aprepitant for injection,
comprising: an aqueous single phase solvent system comprising
water, a primary co-solvent, a surfactant, and a secondary
co-solvent; wherein the primary co-solvent and the surfactant are
present in a synergistic ratio with respect to solubilization of
aprepitant; wherein the secondary co-solvent is present in an
amount of equal or less than 6 volume % of the water and the
primary co-solvent together; and aprepitant at a concentration of
at least 5 mg/ml.
2. The sterile liquid formulation of claim 1, wherein the primary
co-solvent is a short-chain alcohol.
3. The sterile liquid formulation of claim 2, wherein the
short-chain alcohol is ethanol.
4. The sterile liquid formulation of claim 1, wherein the
surfactant is a nonionic surfactant.
5. The sterile liquid formulation of claim 4, wherein the non-ionic
surfactant is a polysorbate.
6. The sterile liquid formulation of claim 1, wherein the secondary
co-solvent is a short-chain polyethylene glycol or
dimethylacetamide.
7. The sterile liquid formulation of claim 6, wherein the secondary
co-solvent is a short-chain polyethylene glycol and is present in
an amount of equal or less than 3 volume %.
8. The sterile liquid formulation of claim 6, wherein the secondary
co-solvent is dimethylacetamide and is present in an amount of
equal or less than 1 volume %.
9. The sterile liquid formulation of claim 1, wherein the primary
co-solvent is ethanol, the secondary co-solvent is a short-chain
polyethylene glycol or dimethylacetamide, and wherein the
surfactant is a polysorbate.
10. The sterile liquid formulation of claim 1, wherein the
secondary co-solvent is omitted from the sterile liquid
formulation.
11. A kit for preparation of a sterile liquid formulation of
aprepitant for injection, the kit comprising: (a) a first container
that includes a solvent system comprising a primary co-solvent, a
surfactant, and an optional secondary co-solvent; wherein the
primary co-solvent and the surfactant are present in a synergistic
ratio with respect to solubilization of aprepitant; wherein the
optional secondary co-solvent is present in an amount of equal or
less than 30 vol % of the primary co-solvent and the surfactant
together; aprepitant at a concentration of at least 9 mg/ml; (b) a
second container that includes a sterile aqueous diluent in an
amount sufficient to dilute the aprepitant to a concentration of at
least 5 mg/ml; and wherein the non-aqueous solvent system and the
sterile aqueous diluent are present in an amount such that the
aprepitant at the concentration of at least 5 mg/ml is completely
soluble and stable in the sterile liquid formulation.
12. The kit of claim 11 wherein the primary co-solvent is a
short-chain alcohol, and wherein the surfactant is a non-ionic
surfactant.
13. The kit of claim 11 wherein the secondary co-solvent is a
short-chain polyethylene glycol or dimethylacetamide.
14. The kit of claim 11 wherein the sterile aqueous diluent is
water.
15. A method of increasing solubility and stability of aprepitant
in an aqueous solution, the method comprising: preparing an aqueous
single phase solvent system comprising water, a primary co-solvent,
and a surfactant, wherein the primary co-solvent and the surfactant
are present in a synergistic ratio with respect to solubilization
of aprepitant; dissolving aprepitant in a secondary co-solvent to
form a concentrated aprepitant solution; combining the concentrated
aprepitant solution with the aqueous single phase solvent system to
thereby form an aprepitant formulation with increased solubility
and stability for aprepitant.
16. The method of claim 15 wherein the primary co-solvent is a
short-chain alcohol.
17. The method of claim 15 wherein the surfactant is a nonionic
surfactant.
18. The method of claim 15 wherein the secondary co-solvent is a
short-chain polyethylene glycol or dimethylacetamide.
19. The method of claim 15 wherein aprepitant formulation contains
at least 5 mg/ml aprepitant.
20. The method of claim 15 wherein aprepitant in the aprepitant
formulation remains in solution for at least one month when stored
at 40.degree. C. and 75% relative humidity.
Description
[0001] This application claims priority to U.S. provisional
application having Ser. No. 61/651501, which was filed May 24,
2012, and to U.S. provisional application having Ser. No.
61/798276, which was filed Mar. 15, 2013, both incorporated by
reference herein.
FIELD OF THE INVENTION
[0002] The field of the invention is parenteral, and especially
injectable dosage forms for the administration of aprepitant to an
individual. In especially preferred dosage forms, aprepitant is in
a stable and dissolved form.
BACKGROUND
[0003] Aprepitant
(5-([(2R,3S)-2-((R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluoro-
-phenyl)morpholino]methyl)-1H-1,2,4-triazol-3(2H)-one) is an
antiemetic compound that belongs to the class of substance P
antagonists that mediate their effect by blocking the neurokinin
(NK1) receptor. Aprepitant is a selective, high-affinity antagonist
at human substance P NK-1 receptors and is manufactured by Merck
& Co. (available under the brand name, Emend.RTM.). It is
available as oral capsules for the prevention and control of acute
and delayed chemotherapy induced nausea and vomiting and for
prevention of postoperative nausea and vomiting.
[0004] Aprepitant is a white to off-white crystalline solid, with a
molecular weight of 534.43 with structure:
##STR00001##
[0005] Aprepitant is practically insoluble in water, sparingly
soluble in ethanol and isopropyl acetate, and slightly soluble in
acetonitrile. Typical solubility data of Aprepitant using ethanol
as a solvent (with the balance water) are shown in Table 1 below.
As can be seen from the table, pharmaceutically relevant
concentrations are typically only achieved at unacceptably high
ethanol concentrations.
TABLE-US-00001 TABLE 1 Ethanol Conc. (v/v) Aprepitant Conc. (mg/mL)
10 0.0001 30 0.0232 50 1.76 55 3.30 60 5.1 70 12.8 90 21.8
[0006] To overcome problems associated with poor solubility of
aprepitant in pharmaceutical compositions, oral formulations of
aprepitant can be prepared and are commercially available as a
nanoparticulate composition (EMEND.TM., Merck) with an average
particle size of less than about 1000 nm. However, the
bioavailability of the compound when given orally is only about
60-65%.
[0007] Several attempts were made to solubilize the aprepitant by
solid-state manipulation. For example, WO 2007/088483 describes the
preparation of amorphous aprepitant, while WO 2007/112457 discloses
a mixture of two crystalline forms, namely, Form I and Form II, and
pharmaceutical compositions thereof. US 2010/0151035 discloses a
pharmaceutical composition of aprepitant containing a polymer and
inert pellets, whereby the dissolution rate of the drug is
dependent on particle size of pellets. WO 2007/147160 describes
compositions of amorphous aprepitant in the form of a
co-precipitate with enhanced solubility of aprepitant, and US
2011/0009362 discloses a solubility enhanced form of aprepitant
that involves forming a co-precipitate between the drug and
cyclodextrin. However, the stability of such compositions in
solution is generally insufficient. These and all other extrinsic
materials discussed herein are incorporated herein by reference in
their entirety. Where a definition or use of a term in an
incorporated reference is inconsistent or contrary to the
definition of that term provided herein, the definition of that
term provided herein applies and the definition of that term in the
reference does not apply. However, notwithstanding numerous
attempts to increase the solubility of aprepitant, aprepitant per
se is available only in a formulation for oral administration.
[0008] Aprepitant is also available as a water soluble prodrug salt
form (e.g., EMEND.TM. for injection, Merck), fosaprepitant
dimeglumine, for intravenous (IV) administration since aprepitant
by itself has limited water solubility. Fosaprepitant is a
phosphorylated prodrug form of aprepitant and is rapidly converted
to aprepitant after IV administration. Prodrug formation of
aprepitant molecule involves phosphorylation of the aprepitant
molecule followed by salt formation with dimeglumine Fosaprepitant
has been reported to undergo rapid conversion to aprepitant in less
than 30 minutes of an IV infusion. Studies have shown the
non-inferiority and bioequivalency of fosaprepitant to aprepitant
with respect to the prevention and control of acute and delayed
chemotherapy induced nausea and vomiting. However, the additional
steps required for the synthesis of fosaprepitant add significant
complexity and cost to the drug. Furthermore, the commercial
formulation of the prodrug of aprepitant, Emend.RTM. is reported to
be stable only for 24 hours after reconstitution.
[0009] In view of the fact that fosaprepitant rapidly converts to
the active form in vivo, it would certainly be advantageous from a
manufacturing, use, and cost standpoint to formulate aprepitant in
a soluble and stable form for parenteral administration. However,
and to the best of the inventors' knowledge, no such soluble and
stable formulation of aprepitant has been reported. Thus, there is
a need for a stable liquid formulation of aprepitant for parenteral
delivery.
SUMMARY OF THE INVENTION
[0010] The inventive subject matter is drawn to compositions,
methods, and formulations of aprepitant in which aprepitant is
present in a stable liquid formulation that is either ready-to-use
or a concentrate ready for dilution in a suitable diluent,
preferably for injection using an intravenous, an intramuscular, or
a subcutaneous route. The formulations presented herein have a
relatively high water content and exhibit remarkable storage
stability.
[0011] In one embodiment of the inventive subject matter, a sterile
liquid formulation of aprepitant for injection comprises an aqueous
single phase solvent system that comprises water, a primary
co-solvent (an in selected embodiments the primary co-solvent
without water), a surfactant, and a secondary co-solvent, wherein
the primary co-solvent and the surfactant are present in a
synergistic ratio with respect to the solubilization of aprepitant,
wherein the secondary co-solvent is present in an amount of equal
or less than 6 volume % of the water and the primary co-solvent
together, and wherein aprepitant is present in the sterile liquid
formulation at a concentration of at least 2 mg/ml, and more
typically at least 5 mg/ml.
[0012] In the sterile liquid formulation of aprepitant, the primary
co-solvent is a short-chain alcohol, for example ethanol, while the
surfactants are nonionic surfactants, a polysorbate, etc. . . . The
secondary co-solvent is a short-chain polyethylene glycol
(typically present at equal or less than 3 volume %), or
dimethylacetamide (typically present at equal or less than 1 vol
%). In an embodiment, the formulation comprises ethanol as the
primary co-solvent, a short-chain polyethylene glycol or
dimethylacetamide as the secondary co-solvent, and a polysorbate
(e.g., polysorbate 80) as the surfactant. In an embodiment, the
secondary co-solvent may be omitted from the sterile liquid
formulation.
[0013] In yet another embodiment of the inventive subject matter,
disclosed herein is a kit for the preparation of a sterile liquid
formulation of aprepitant for injection. In an embodiment, the kit
will comprise (a) a first container that includes a non-aqueous
solvent system comprising a primary co-solvent, a surfactant, and
an optional secondary co-solvent, wherein the primary co-solvent
and the surfactant are present in a synergistic ratio with respect
to solubilization of aprepitant, wherein the optional secondary
co-solvent is present in an amount equal or less than 30 volume %
of the primary co-solvent and the surfactant together, and wherein
aprepitant is present at a concentration of at least 9 mg/ml; and
(b) a second container that includes a sterile aqueous diluent in
an amount sufficient to dilute the aprepitant to a concentration of
at least 5 mg/ml, wherein the non-aqueous solvent system and the
sterile aqueous diluent are present in an amount such that the
aprepitant at a concentration of at least 2 mg/ml, and more
typically at least 5 mg/ml, is completely soluble and stable in the
sterile liquid formulation.
[0014] In an embodiment, the primary co-solvent is a short-chain
alcohol, the surfactant is a non-ionic surfactant, and/or the
secondary co-solvent is a short-chain polyethylene glycol or
dimethylacetamide. In an embodiment the sterile aqueous diluent is
water. Such kits will allow for the formulation of an aqueous,
ready-to-use formulation of aprepitant in which the aprepitant
remains in solution upon dilution with an aqueous diluent.
Moreover, it should be noted that aprepitant in the formulations
presented herein has significant stability, even upon prolonged
storage in liquid form.
[0015] Therefore, and viewed from a different perspective,
disclosed herein is a method of increasing solubility and stability
of aprepitant in an aqueous solution. In an embodiment the
formulation step comprises preparation of an aqueous single phase
solvent system comprising water, a primary co-solvent, and a
surfactant, wherein the primary co-solvent and the surfactant are
present in a synergistic ratio with respect to solubilization of
aprepitant. In an embodiment, aprepitant is dissolved in a
secondary co-solvent to form a concentrated aprepitant solution,
and in yet another embodiment, the concentrated aprepitant solution
is combined with the aqueous single phase solvent system to form an
aprepitant formulation that provides increased solubility and
stability for aprepitant.
[0016] In an embodiment, the primary co-solvent is a short-chain
alcohol, and/or the surfactant is a nonionic surfactant, and/or the
secondary co-solvent is a short-chain polyethylene glycol or
dimethylacetamide. In another embodiment, the aprepitant
formulation contains at least 5 mg/ml aprepitant, and the
aprepitant in the formulation is chemically stable and remains in
solution for at least one month when stored at 40.degree. C. and
75% relative humidity.
[0017] Various objects, features, aspects and advantages of the
inventive subject matter will become more apparent from the
following detailed description of preferred embodiments.
DETAILED DESCRIPTION
[0018] The inventors have discovered that liquid aprepitant
formulations can be prepared in an entirely solubilized and stable
form suitable for injection. The sterile liquid formulation of
aprepitant disclosed herein have a relatively high water content
and exhibit remarkable storage stability. Contemplated solutions
can be prepared as concentrates that are diluted with a suitable
diluent prior to use, for example, within 24 hours of use, or can
be prepared as a ready-to-use sterile solution that can be used for
injection without dilution.
[0019] In one especially preferred aspect of the inventive subject
matter, the inventors have discovered that aprepitant solutions can
be prepared in which aprepitant is not only soluble at
pharmaceutically useful concentration, but also stable (i.e.,
remains chemically unchanged) over significant periods of time.
Moreover, the solvents used in the compositions and methods
according to the inventive subject matter are suitable for
injection.
[0020] More specifically, the inventors have discovered that the
solubility and stability of aprepitant in an aqueous solution can
be significantly increased over heretofore known formulations by
preparing an aqueous single phase solvent system that includes
water, a primary co-solvent, and a surfactant. The inventors
unexpectedly found that the primary co-solvent and the surfactant
can be combined to provide a synergistic mixture for solubilization
of aprepitant, i.e., the solvent mixture solubilizes aprepitant in
a quantity that is higher than the solubilization of aprepitant in
the primary co-solvent and surfactant alone. Solubility of
aprepitant in the final product can be even further increased by
pre-dissolution of aprepitant in a secondary co-solvent to form a
concentrated aprepitant solution, which is then combined with the
aqueous single phase solvent system. Aprepitant can be solubilized
in the final product to a concentration of at least 2 mg/ml, more
typically at a concentration of at least 3-4 mg/ml, and even more
typically at a concentration of at least 5 mg/ml. While such high
concentrations are typically only achieved by using unacceptably
high quantities of a primary co-solvent (e.g., 60 volume %
ethanol), or a surfactant (e.g., 30 w/v % polysorbate 80), the
compositions of the sterile liquid formulation of aprepitant will
typically have a significantly lower concentrations of primary
co-solvent (e.g., about 30 vol % ethanol) and surfactant (e.g.,
about 1.5 w/v % polysorbate 80). In an embodiment, the aprepitant
in the sterile liquid formulation of aprepitant remain dissolved
and stable over several weeks, and even months at storage at
40.degree. C. and 75% relative humidity. Such finding is
particularly remarkable as many of the formulations presented
herein have substantial quantities of water (either with water in
the original formulation or after dilution with aqueous
diluent).
[0021] In particularly preferred aspects, the primary co-solvent is
a short-chain alcohol (i.e., less than 6 carbon atoms), and
especially ethanol. However, it should be appreciated that numerous
other solvents are also contemplated herein, and exemplary
alternative solvents include pharmaceutically acceptable
non-aqueous solvents, which may be polar or non-polar, protic or
aprotic. For example, and among other solvents, contemplated
solvents include linear and branched hydrocarbons, dioxane, ethyl
acetate, propylene carbonate, dimethyl sulfoxide, short-chain
alcohols, acetic acid, etc. Moreover, it should be noted that the
primary co-solvent may be combined with one or more other
co-solvents to so form a solvent mixture. In especially preferred
aspects, the primary co-solvent is in admixture with water or
saline to so form an aqueous solvent system. While not limiting to
the inventive subject matter, it is generally preferred that the
water and primary co-solvent (and secondary co-solvent and/or
surfactant) form a single phase solvent system. However, in certain
alternative aspects, emulsions and other multi-phase solvent
systems are also deemed suitable for use herein. Most typically,
the primary co-solvent and water will form the predominant fraction
of the final formulation and will, for example, make up between
51-60 vol %, between 61-70 vol %, between 61-70 vol %, between
71-80 vol %, between 81-90 vol %, and in certain cases between
91-99 vol % (and even higher).
[0022] Particularly preferred surfactants include pharmaceutically
acceptable surfactants, and all surfactants are generally
contemplated herein. However, it is particularly preferred that the
surfactant is a nonionic or zwitterionic (neutrally charged at
physiological pH) surfactant. Therefore, especially preferred
surfactants include polyoxyethylene glycol alkyl ethers,
polyoxypropylene glycol alkyl ethers, glucoside alkyl ethers,
polyoxyethylene glycol octylphenol ethers, polyethylene glycol
ethers, polyethylene glycol esters, glycerol alkyl esters,
polyoxyethylene glycol sorbitan alkyl esters, sorbitan alkyl
esters, cocamide MEA, cocamide DEA, poloxamers, etc.
[0023] In less preferred aspects, the surfactant may be cationic
and comprise a quaternary ammonium group (e.g.
cetyltrimethylammonium bromide) or form an amine salt (e.g.
octadecylamine hydrochloride), or the surfactant may be anionic
(e.g., sodium/potassium stearate, sodium dioctylsulphosuccinate,
sodium dodecylbenzenesulphonate, sodium lauryl sulphate, etc.).
Alternatively, naturally occurring surface active agents may be
used and include various phospholipids, e.g. diacylphosphatidyl
glycerols, diaceylphosphatidyl cholines, and diaceylphosphatidic
acids, the precursors and derivatives thereof, such as for example
soybean lecithin and egg yolk, etc.
[0024] It is particularly preferred that the surfactant will be
able to form with the primary co-solvent in water a synergistic
combination with respect to solubilization of aprepitant, typically
in a synergistic ratio in which the primary co-solvent is present
in a quantity that is larger than the surfactant. Therefore,
contemplated synergistic ratios of primary co-solvent to
surfactants will be between 2:1 and 5:1, between 5:1 and 10:1,
between 10:1 and 20:1, between 20:1 and 40:1, or between 40:1 and
100:1. For example where the primary co-solvent is ethanol and the
surfactant is polysorbate 80, suitable ratios will be between 4:1
and 15:1, between 15:1 and 25:1, or between 25:1 and 60:1.
Consequently, it should be appreciated that the surfactant will
present a minor component of the final composition, typically in
quantities of between about 0.1-1.0 w/v %, or between about 1.0-3.0
w/v %, or between about 3-5 w/v % (and in some cases even
higher).
[0025] With respect to suitable secondary co-solvents it is
generally contemplated that the secondary co-solvent is miscible
with the water and primary co-solvent without formation of a
distinct phase in the quantities used, and/or that the secondary
co-solvent will be able to completely dissolve aprepitant at
relatively high concentrations (e.g., at least at 1 mg/ml, in an
embodiment at least 10 mg/ml, in another embodiment at least 50
mg/ml, and in yet another embodiment at least 100 mg/ml).
Therefore, especially suitable secondary co-solvents include
tetraglycol, dimethylacetamide, short-chain polyethylene glycol
(typically having an average molecular weight of less than 2,000,
in an embodiment less than 1,000, and in yet another embodiment
less than 500), NMP (N-methylpyrrolidone), propylene glycol,
vitamin E TPGS, benzyl alcohol, ethanol, etc. The secondary
co-solvent will form a minor fraction of the final formulation and
will, for example, make up between 49-40 vol %, between 39-30 vol
%, between 29-20 vol %, between 19-10 vol %, between 9-1 vol %, and
in certain cases between 1-0.09 vol % (and even less). Therefore,
in an example of the formulations, the secondary co-solvent may be
present in an amount of equal or less than 30 vol %, equal or less
than 10 vol %, in an embodiment equal or less than 6 volume %, in
another embodiment equal or less than 3 volume %, and in yet
another embodiment equal or less than 1 volume % of the water and
the primary co-solvent together. In an embodiment of the
formulations, the secondary co-solvent may also be entirely omitted
from the sterile liquid formulation.
[0026] Liquid aprepitant-containing formulation disclosed herein
may further include various other excipients to maintain or
increase drug stability. Such excipients may include buffer(s),
antioxidant(s), chelating agent(s), etc. If required, the
composition may also contain crystal growth inhibitors. Examples of
crystal growth inhibitors include vinyl polymers such as
polyvinylpyrrolidone, cellulosic polymers such as hydroxypropyl
cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose,
etc.
[0027] In especially preferred aspects of the inventive subject
matter, aprepitant-containing formulations are sterile formulations
(e.g., prepared via filtration, irradiation, gassing, etc.) and
will be bottled into suitable containers, typically for single or
multiple independent administrations. Therefore, aprepitant may be
present in the container in an amount of 100-200 mg (and most
preferably 130 mg), 200-400 mg, 400-600 mg, 600-1000 mg, and even
more.
[0028] Depending on the particular end user, the aprepitant
formulations may be provided as a ready-to-use formulation, i.e., a
formulation ready to be administered to the patient without further
processing, or as a concentrate that is diluted with a suitable
diluent, typically sterile water or other aqueous solvent, e.g.,
saline. In such case, a kit is provided that includes at least two
components, (a) a first container that includes a non-aqueous
solvent system comprising a primary co-solvent, a surfactant, and
an optional secondary co-solvent, and aprepitant (typically at a
concentration of at least 5 mg/ml, more typically at least 9 mg/ml,
and most typically 15 mg/ml), and (b) a second container that
includes a sterile aqueous diluent in an amount sufficient to
dilute the aprepitant to a concentration of at least 5 mg/ml in the
final formulation that is ready for administration.
[0029] In such concentrates, and as also noted above it is
generally preferred that the primary co-solvent and the surfactant
are selected such as to form a synergistic mixture with respect to
solubilization of aprepitant or present in a synergistic ratio with
respect to solubilization of aprepitant. Most typically and where
included, the optional secondary co-solvent is present in an amount
of equal or less than 30 vol % of the primary co-solvent and the
surfactant together.
[0030] In further contemplated aspects of the inventive subject
matter, formulations can also use or even be exclusively based on
complexing agents such as cyclodextrins, and/or by pH adjustment.
Suitable complexing agents will thus include any molecule that has
capability of forming a complex with aprepitant to thereby render
the aprepitant complexing agent soluble in a suitable solvent. For
example, preferred complexing agents include cyclodextrins (e.g.,
one or more of .beta.-cyclodextrins, HP.beta.-cyclodextrins,
sulfobutylether.beta.-cyclodextrins etc). The cyclodextrins can be
used in a molar ratio of 0.05:1 to 10:1, preferably in a molar
ratio of 1:30 of cyclodextrin to aprepitant and more preferable in
a molar ratio of 1:10 of cyclodextrin to aprepitant.
[0031] Most typically, the process of forming complex between
aprepitant and a complexing agent involves adding the aprepitant in
solid form to a (typically aqueous) solution of the complexing
agent, or adding drug and complexing agent together in solid form
in aqueous media, or adding a solution of drug prepared using a
suitable solvent to the aqueous solution of complexing agent, or
adding a solution of drug and complexing agent prepared in a
suitable solvent to the aqueous media. Most preferably, a solution
of drug is first prepared in a suitable solvent, which is then
added to the aqueous solution of complexing agent. The process may
further include adjusting the pH of solution using a suitable pH
adjusting agent.
[0032] In further contemplated processes, aprepitant may also be
solubilized in water by pH adjustment. The pH adjustment can be
achieved by adding suitable acids such as hydrochloric acid,
sulfuric acid, nitric acid, acetic acid, tartaric acid etc. and
suitable bases such as sodium hydroxide, potassium hydroxide,
ammonium hydroxide etc. Most preferably, the pH is adjusted by
addition of acetic acid or tartaric acid and sodium hydroxide. The
pH can be adjusted to the desired pH range in order to maintain
chemical stability of the drug, preferably in the range of 3 to 8
pH units. Most preferably, the drug is solubilized in an acidic
media, for example, acetic acid or tartaric acid followed by
addition of a base such as sodium hydroxide. The drug solution thus
obtained is then adjusted to final weight or volume by adding
water. The final pH can be adjusted in a range from 3 to 8,
preferably in a pH range of 4 to 7. Of course, use of a complexing
agent may also be enhanced by pH control.
[0033] In still further contemplated aspects of the inventive
subject matter, pharmaceutical composition of aprepitant can also
be prepared as an emulsion, preferably a microemulsion, and most
preferably a nanoemulsion. In a particularly preferred embodiment
as shown in more detail below, the nanoemulsion is made by
dissolving the drug in a suitable oil phase, which can be a
pharmaceutically acceptable oil or an organic solvent. The oil
phase containing drug is then dispersed in the aqueous external
phase mainly composed of water and containing suitable dispersing
agents. The emulsion thus obtained can be further homogenized or
microfluidized to obtain the desired particle size.
EXAMPLES
[0034] The following examples do not limit the scope of applicant's
invention but serve as an explanatory tool of applicant's
invention. The inventors have tested various methods of
solubilizing aprepitant, and these methods may be conceptually
grouped into different classes.
[0035] Solubilization of Aprepitant by pH
[0036] Aprepitant has a pka of 9.7 and does not have sufficient pH
dependent solubility in aqueous solutions in physiologically usable
pH ranges. Indeed, to be soluble in aqueous solution, a pH of
greater than 11.7 is required. However, a formulation with such a
high pH is not suitable for injection. Moreover, the instant such a
formulation is diluted in blood, the pH will change to about pH
7.4, which will lead to rapid precipitation of the drug. On the
other end of the pH spectrum, aprepitant was also found to be
soluble in concentrated formic acid, but precipitated almost
immediately on twofold dilution with aqueous medium. Similar
problems were also encountered where aprepitant is dissolved in a
water/ethanol solvent mixture where ethanol is at about 50 volume %
concentration. Here, dilution that would occur at the injection
site would lead to precipitation of the drug and so might lead to
chemo-embolism.
[0037] Solubilization of Aprepitant by Co-Solvents/Complexing
Agent
[0038] Example 1
[0039] 2.9 g of SBE-.beta.-cyclodextrin was dissolved in 5 mL of
water. The pH of cyclodextrin solution was adjusted to between 3 to
4. 100 mg of aprepitant was dissolved separately in 3 mL of
tetraglycol. Drug solution was gradually added to cyclodextrin
solution under constant stirring resulting in a soluble
drug-cyclodextrin complex.
Example 2
[0040] 20 mL of propylene glycol was mixed with 20 mL water
followed by addition of 15 mL of glacial acetic acid, 1.0 g of
tartaric acid and 5 mL of 2 N hydrochloric acid. 25 mg drug was
dissolved separately in 0.5 mL of tetraglycol. The drug solution is
added to the mixture of propylene glycol and acids gradually with
constant stiffing. pH of solution was adjusted with 10 N NaOH
gradually to pH 3 to 4 resulting in a clear, colorless, particulate
free drug solution.
Example 3
[0041] 3.0 mL of propylene glycol was added to 20 mL water followed
by addition of 3.0 g of tartaric acid. 25 mg of drug was dissolved
in 0.5 mL of tetraglycol separately. This drug solution was added
to the mixture of propylene glycol, tartaric acid and water. pH of
this solution was 1.5. The solution was made alkaline by quick
addition of 3 mL of 10 N NaOH. The resulting solution had pH of 10
and was clear and colorless with an approximate concentration of 1
mg/mL of aprepitant.
[0042] Thus, while the above approaches using complexing agents
and/or co-solvents led to a soluble form of aprepitant in at least
some instances, concentration of aprepitant is relatively low, and
aprepitant tends to precipitate out upon further dilution. As is
already known in the art, solubility of aprepitant increases
exponentially with increasing concentration of ethanol as shown in
Table 1 in the background section. Moreover, maximum allowed
concentrations of ethanol in a drug formulation are typically at or
below 49 volume %. However, the solubility of aprepitant is still
relatively low at or below the allowed concentrations, and only
significantly increase when ethanol concentration is .gtoreq.50%
v/v. Moreover, and as already noted above, an ethanol/water solvent
system is not suitable for injection as aprepitant will rapidly
precipitate upon dilution at the injection site.
[0043] Solubilization of aprepitant using surfactants: Solubility
of aprepitant was tested using different surfactants, and the
inventors found that aprepitant solubility was the highest using
Polysorbate 80. However, in a typical injectable formulation at
Polysorbate 80 concentration of 10% w/v, it would require 7 grams
of surfactant, and at Polysorbate 80 concentration of 30% w/v, it
would require 9 grams of surfactant to solubilize the aprepitant.
Unfortunately, such high quantities of surfactant are entirely
unsuitable for injectable formulations (e.g., due to
hypersensitivity issues related to polysorbate, foam formation
during mixing, etc.). Table 2 below illustrates typical solubility
data for aprepitant using water alone as solvent.
TABLE-US-00002 TABLE 2 Concentration Aprepitant Conc. Surfactant (%
w/v) (mg/mL) Cremophor RH 40 10 1.24 30 3.51 Cremophor RH 60 10
1.24 Poloxamer 188 10 ND 30 1.24 Polysorbate 80 10 1.85 30 4.42
[0044] As is readily apparent from Table 2, significant quantities
of surfactant are required to achieve moderate concentrations of
aprepitant in the water solution.
[0045] Solubilization of aprepitant using co-solvents and
surfactants: The inventors further tested whether co-solvents
(i.e., solvents in addition to water) in combination with
surfactants would improve solubility of aprepitant. While numerous
co-solvents failed to significantly increase solubility of
aprepitant (data not shown), the inventors unexpectedly found that
sort-chain (i.e., less than 6 carbon atoms) alcohols, and
especially ethanol, synergistically formed with nonionic
surfactants, and especially polysorbate 80, a solvent system that
substantially improved solubility of aprepitant as compared to
solubility of aprepitant in either component alone. In most
preferred aspects, a relatively low concentration of nonionic
surfactant was chosen in a co-solvent mixture of ethanol and water,
and Tables 3-5 below exemplarily illustrate the results of such
combination.
[0046] More specifically, Table 3 depicts solubility results of
aprepitant in water without ethanol at surfactant concentrations
noted in the table.
TABLE-US-00003 TABLE 3 Polysorbate 80 Conc. (mg/mL) Aprepitant
Conc. (mg/mL) 11 0.179 22 0.308 44 0.505
[0047] Likewise, Table 4 depicts solubility results of aprepitant
in an ethanol/water mixture of (30 vol % EtOH, 70 vol % H2O) at
surfactant concentrations noted in the table, and Table 5 depicts
solubility results of aprepitant in an ethanol/water mixture of (55
volume % EtOH, 45 vol % H2O) at surfactant concentrations noted in
the table.
TABLE-US-00004 TABLE 4 Polysorbate 80 Conc. (mg/mL) Aprepitant
Conc. (mg/mL) -- 0.0232 11 0.560 44 0.793
TABLE-US-00005 TABLE 5 Polysorbate 80 Conc. (mg/mL) Aprepitant
Conc. (mg/mL) -- 3.3 11 1.936 22 3.309 44 4.182
[0048] Pre-solubilization of aprepitant using secondary co-solvent:
The inventors also tested whether solubility of aprepitant in
aqueous polysorbate 80 solutions could be improved when aprepitant
was pre-solubilized in a secondary solvent (e.g., dimethylacetamide
(DMAC)). For example, when 100 mg aprepitant was solubilized by
addition of 200 .mu.L of DMAC, followed by addition of 10 mL of
various surfactant solutions, the inventors noted that higher drug
solubility was achieved at significantly lower surfactant
concentrations as can be seen from Table 6 below. Remarkably, when
the inventors directly added 200 .mu.L of DMAC solubilized in 10 mL
of water to 100 mg aprepitant (i.e., without surfactant),
aprepitant was not detected in the solution phase.
TABLE-US-00006 TABLE 6 Conc. of Polysorbate 80 Aprepitant Conc.
Surfactant (% w/v) (mg/mL) Directly Added 10 1.85 30 4.42 Prior
Solubilization 5 0.85 in DMAC 10 2.03 15 3.13 20 4.35 30 4.80
[0049] Thus, it should be appreciated that the secondary co-solvent
in combination with the nonionic surfactant provided for an
increased stabilization of dissolved aprepitant that in turn
prompted the inventors to investigate various solvent systems, and
especially solvent systems that formed an aqueous single phase
solvent system from water, a primary co-solvent, a surfactant, and
a (optional) secondary co-solvent, wherein the primary co-solvent
and the surfactant are present in a synergistic ratio with respect
to solubilization of aprepitant, and wherein the secondary
co-solvent is present in an amount of equal or less than 6 volume %
of the water and the primary co-solvent together. Moreover, the
aprepitant concentration in such systems was typically at least 5
mg/ml. Based on the above results and further considerations (data
not shown), the inventors tested various formulations (concentrate
and ready-to-use).
[0050] Concentrate: Aprepitant concentrate for injection
formulations were prepared by dissolving required quantity of
aprepitant in suitable amount of ethanol, and polysorbate 80 were
added to the drug and ethanol solution. Typical results and
compositions are provided in Table 7 below. Formulations I and II
were found to precipitate immediately after dilution with diluent,
whereas formulations III, IV, V, VI, and VII were stable (no
formation of precipitate) for 24 hours after dilution with diluent.
When the water in Formulation I was replaced by PEG 300, a
hydrophilic solvent, it was found that it helped inhibit
precipitation of aprepitant from the formulation. For commercial
use of the concentrate, it is therefore envisioned that the
aprepitant solution will be packaged in one vial and that the
diluent (e.g., water for injection) is provided in another vial,
most typically together as a kit. The aprepitant solution will then
be mixed with the diluent and administered within 24 hr of
dilution.
TABLE-US-00007 TABLE 7 Formulation I II III IV V VI VII Concentrate
in vial I Aprepitant 130 mg 130 mg .sup. 130 mg 130 mg 130 mg.sup.
130 mg 130 mg.sup. Polysorbate 80 0.25 g 0.5 g 0.5 g.sup. 0.25 g
0.25 g 0.3 g.sup. 0.3 g .sup. Ethanol .sup. 10 ml .sup. 10 ml 12.5
mL 12.5 ml 10 ml 11 ml 11 ml PEG 300 -- -- -- .sup. -- 2 ml 2 ml 3
ml Water for Injection in vial II Diluent Water for Injection 12.5
ml 12.5 ml .sup. 10 mL .sup. 10 ml 8 ml 10 ml 9 ml
[0051] Ready-to-use aprepitant solutions for injection: Exemplary
ready-to-use aprepitant solutions for injection were prepared by
dissolving a required quantity of aprepitant in some examples with
dimethylacetamide, or in suitable amount of ethanol. Subsequently
added were polysorbate 80 and PEG as indicated, followed by
addition of water for injection. The results are presented in
Tables 8-9 below. Notably, PEG 300 used at lower concentration was
able to solubilize aprepitant, but led to drug precipitation at
higher concentrations.
TABLE-US-00008 TABLE 8 Formulation VIII IX X XI XII Aprepitant (mg)
130 130 130 130 130 Polysorbate 80 3 2 1.5 1 0.5 (g) Ethanol (ml)
12.57 12.57 12.57 12.57 12.57 DMAc (.mu.L) 200 200 200 200 200 PEG
300 (ml) -- -- -- -- 8 Water qs (mL) 30 25 30 23 50 Stability 40
Deg/ Stable Unstable Unstable Stable Unstable 75% RH
TABLE-US-00009 TABLE 9 Formulation XIII XIV XV XVI XVII XVIII
Aprepitant (mg) 130 130 130 130 130 130 Polysorbate 80 (g) 0.75 0.5
0.5 0.5 0.5 0.25 Ethanol (ml) 12.57 12.57 12.57 12.57 12.57 12.57
DMAc (.mu.L) 200 200 -- -- -- 200 PEG 300 (ml) -- -- 1 2 5 -- Water
qs (mL) 23 23 23 23 23 23 Stability 40 Deg/75% RH Stable 1 Month 2
Months 1 Month Unstable 10 Hours
[0052] Table 10 below shows exemplary stability data for exemplary
formulations XV and Xv tested under conditions as noted in the
table. As will be readily appreciated, aprepitant remained
dissolved and remained chemically stable in solution for extended
periods of time.
TABLE-US-00010 TABLE 10 Formulation Temperature Time Assay XVI 25
Deg/60% RH Initial 98.6 1 Week 98.0 2 Week 97.8 1 Month 97.9 40
Deg/75% RH 1 Week 98.5 2 Weeks 98.1 1 Month 98.2 XV 25 Deg/60% RH
Initial NT 1 Week 97.9 3 Weeks 98.6 25 Deg/60% RH 1 Week 97.9 3
Weeks 97.2 (NT: Not tested)
[0053] Therefore, it is contemplated that the formulations of the
present invention will be in a container in a volume suitable for
at least one administration (typically at a dose of 130 mg
aprepitant per administration). However, it should also be
appreciated that the container may include sufficient quantities of
aprepitant suitable for multiple independent administrations, for
example, 2, 3, 4, 5, and even more independent administrations.
[0054] Emulsion Formulations: As is well established, aprepitant is
substantially insoluble in both oil and water. However, the
inventors discovered that various emulsion formulations could be
prepared from which aprepitant did not precipitate.
[0055] Formulation I: Glycerin was weighed in the compounding
vessel. Water (80 mL) was added to the vessel and heated to
70.degree. C. Soybean oil (13 mL) was also heated to 70.degree. C.
Aprepitant (130 mg) was solubilized in 200 .mu.L of
N,N'-Dimethylacetamide and added to the oil phase. The aqueous
phase was added to the oil phase and a crude emulsion was formed
using a high speed homogenizer, and the crude emulsion was then
passed through a high pressure homogenizer to form the final
emulsion as shown in Table 11.
TABLE-US-00011 TABLE 11 Compound Quantity Aprepitant 130 mg DMAC
200 .mu.L Soybean oil 13 mL Lipoid E80 1.56 grams Glycerin 2.86
grams Water q.s 130 mL
[0056] Formulation II: Glycerin was weighed in the compounding
vessel. Water (80 mL) was added to the vessel and heated to
70.degree. C. Soybean oil (13 mL) was also heated to 70.degree. C.
Aprepitant (130 mg) was dispersed in the oil phase. The aqueous
phase was added to the oil phase and a crude emulsion was formed
using a high speed homogenizer, and the crude emulsion was then
passed through a high pressure homogenizer to form the final
emulsion as shown in Table 12.
TABLE-US-00012 TABLE 12 Compound Quantity Aprepitant 130 mg Soybean
oil 13 mL Lipoid E80 1.56 grams Glycerin 2.86 grams Water q.s 130
mL
[0057] It should be apparent to those skilled in the art that many
more modifications besides those already described are possible
without departing from the inventive concepts herein. The inventive
subject matter, therefore, is not to be restricted except in the
spirit of the appended claims. Moreover, in interpreting both the
specification and the claims, all terms should be interpreted in
the broadest possible manner consistent with the context. In
particular, the terms "comprises" and "comprising" should be
interpreted as referring to elements, components, or steps in a
non-exclusive manner, indicating that the referenced elements,
components, or steps may be present, or utilized, or combined with
other elements, components, or steps that are not expressly
referenced. Where the specification claims refers to at least one
of something selected from the group consisting of A, B, C . . .
and N, the text should be interpreted as requiring only one element
from the group, not A plus N, or B plus N, etc.
* * * * *