U.S. patent application number 10/626501 was filed with the patent office on 2005-01-27 for stabilized formulation.
This patent application is currently assigned to DABUR RESEARCH FOUNDATION. Invention is credited to Burman, Anand C., Khattar, Dhiraj, Khullar, Praveen, Kumar, Dinesh, Kumar, Mukesh, Mukherjee, Rama, Srinivasan, Perundurai S., Srivastava, Rajesh.
Application Number | 20050016926 10/626501 |
Document ID | / |
Family ID | 34080443 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050016926 |
Kind Code |
A1 |
Burman, Anand C. ; et
al. |
January 27, 2005 |
Stabilized formulation
Abstract
A stabilized pharmaceutical composition of anticancer drug and a
solvent like Polyethoxylated castor oil (cremophor) also containing
any other suitable solubilizer suitable for human administration
like dehydrated alcohol, is disclosed. Compositions prepared using
this purified polyethoxylated castor oil enhance the stability of
paclitaxel in such compositions.
Inventors: |
Burman, Anand C.;
(Ghaziabad, IN) ; Mukherjee, Rama; (Ghaziabad,
IN) ; Kumar, Dinesh; (Ghaziabad, IN) ;
Khattar, Dhiraj; (Ghaziabad, IN) ; Kumar, Mukesh;
(Ghaziabad, IN) ; Khullar, Praveen; (Ghaziabad,
IN) ; Srinivasan, Perundurai S.; (Ghaziabad, IN)
; Srivastava, Rajesh; (Ghaziabad, IN) |
Correspondence
Address: |
Ladas & Parry
26 West 61 Street
New York
NY
10023
US
|
Assignee: |
DABUR RESEARCH FOUNDATION
|
Family ID: |
34080443 |
Appl. No.: |
10/626501 |
Filed: |
July 24, 2003 |
Current U.S.
Class: |
210/656 ;
210/198.2 |
Current CPC
Class: |
A61K 47/44 20130101;
B01J 20/287 20130101; B01D 15/325 20130101; C07D 305/14
20130101 |
Class at
Publication: |
210/656 ;
210/198.2 |
International
Class: |
B01D 015/08 |
Claims
1. A process for purifying a non-ionic solvent comprising the steps
of: (a) forming a solution of said solvent in alcohol and water,
with or without aid of heating; (b) loading the solution on to a
chromatography column packed with reverse phase silica (c) running
the chromatography column using de-ionized water as the mobile
phase to purify the solvent; (d) running the chromatography column
using an eluent recovering the purified solvent; and (e)
evaporating the residual water and the eluent.
2. The process according to claim 1 wherein the solvent is
polyethoxylated castor oil or polyoxyl-35-castor oil.
3. The process according to claim 1 wherein the solvent is
Cremophor EL or Cremophor ELP.
4. The process according to claim 1 wherein the alcohol is selected
from the group consisting of methanol, ethanol, butanol or
isopropanol.
5. The process according to claim 1 wherein the alcohol is
ethanol.
6. The process according to claim 1 wherein the eluent is selected
from the group consisting of methanol, ethanol, isopropyl alcohol,
acetone, acetonitrile and tetrahydrofuran.
7. The process according to claim 1 wherein the eluent is
acetone.
8. The process according to claim 1 wherein the de-ionized water is
HPLC grade.
9. The process according to claim 1 wherein in step (a) said
solution is a solution of polyethoxylated castor oil, alcohol and
water.
10. The process according to claim 1 wherein said step of forming
said solution comprises mixing about polyethoxylated castor oil,
dehydrated ethanol and de-ionized water in a ratio of 10:1:33 w/v/v
with or without the aid of heat.
11. The process according to claim 1 wherein said step of forming
said solution comprises mixing about 300 gm of polyethoxylated
castor oil, 30 gm of dehydrated ethanol and one litre of HPLC grade
non ionic water with or without the aid of heat.
12. The process according to claim 1 wherein said solvent is
polyethoxylated castor oil and the step the chromatography column
comprises a column of 15.times.30 cms packed with reverse phase
silica of C-8 or C-18 type having a particle size of 30-60.
13. The process according to claim 1 wherein the step of running
the chromatograph to purify the solvent comprises the use of
de-ionized water as the mobile phase for 1 to 50 minutes.
14. The process according to claim 13 wherein the de-ionized water
is HPLC grade.
15. The process according to claim 1 wherein the aqueous fractions
are discarded.
16. A composition comprising combining the purified non-ionic
solvent prepared according to the process of claim 1 and
paclitaxel.
17. The composition according to claim 16 wherein the percent by
weight of degradation products of paclitaxel after being stored at
50.degree. C. for 10 days is less than or equal to 0.3% wherein
said degradation products are Baccatin ImI, Ethyl ester side chain
of Paclitaxel, 10-Deacetyl paclitaxel, 10-Deacetyl 7-epipaclitaxel
and 7-epipaclitaxel.
18. A process for purifying a polyoxyl 35 castor oil solution said
solution comprising polyoxyl 35 castor oil, water and an alcohol
said process comprising loading the solution on to a chromatography
column packed with reverse phase silica and running the
chromatograph using de-ionized water as the mobile phase followed
by eluting the purified polyoxyl 35 castor oil with methanol,
ethanol or acetone evaporating the residual alcohol, water and
methanol, ethanol or acetone to obtain purified polyoxyl 35 castor
oil adapted to produce, when combined with paclitaxel, a
pharmaceutical composition not showing more than 0.3% degradation
products of paclitaxel identified as Baccatin III, Ethyl ester side
chain of Paclitaxel, 10-Deacetyl paclitaxel, 10-Deacetyl
7-epipaclitaxel and 7-epipaclitaxel, after being stored at
50.degree. C. for 10 days.
19. A process for purifying a polyoxyl 35 castor oil solution said
solution comprising polyoxyl 35 castor oil, water and an alcohol
said process comprising loading the solution on to a chromatography
column packed with reverse phase silica of C-8 or C-18 type having
a particle size of 30 - 60 and running the chromatograph using
de-ionized water (HPLC grade) as the mobile phase followed by
eluting the purified polyoxyl 35 castor oil with methanol, ethanol
or acetone, evaporating the residual alcohol, water and methanol,
ethanol or acetone to obtain purified polyoxyl 35 castor oil
adapted to produce, when combined with paclitaxel, a pharmaceutical
composition not showing more than 0.3% degradation products of
paclitaxel identified as Baccatin II, Ethyl ester side chain of
Paclitaxel, 10-Deacetyl paclitaxel, 10-Deacetyl 7-epipaclitaxel and
7-epipaclitaxel, after being stored at 50.degree. C. for 10
days.
20. The process according to claim 19 wherein the eluent is
acetone.
21. A pharmaceutical composition comprising a solvent containing a
solvent purified according to the process of claim 1 wherein the
solvent is a polyethoxylated castor oil and a pharmaceutical
agent.
22. The composition according to claim 21 wherein the
pharmaceutical agent is an antineoplastic agent.
23. The composition according to claim 22 wherein the
pharmaceutical agent is paclitaxel.
24. The composition of claim 21 wherein said solvent further
comprises an alcohol.
25. A stabilized pharmaceutical composition comprising a solvent
containing a purified polyethoxylated castor oil according to claim
19 and paclitaxel, said composition showing not more than 0.3%
degradation products of paclitaxel identified as Baccatin III,
Ethyl ester side chain of Paclitaxel, 10-Deacetyl paclitaxel,
10-Deacetyl 7-epipaclitaxel and 7-epipaclitaxel, after being stored
at 50.degree. C. for 10 days.
26. A pharmaceutical composition comprising a solvent containing a
solvent purified according to the process of claim 2 wherein the
solvent is a polyethoxylated castor oil and a pharmaceutical
agent.
27. A pharmaceutical composition comprising a solvent containing a
solvent purified according to the process of claim 3 wherein the
solvent is a polyethoxylated castor oil and a pharmaceutical
agent.
28. A pharmaceutical composition comprising a solvent containing a
solvent purified according to the process of claim 4 wherein the
solvent is a polyethoxylated castor oil and a pharmaceutical
agent.
29. A pharmaceutical composition comprising a solvent containing a
solvent purified according to the process of claim 10 wherein the
solvent is a polyethoxylated castor oil and a pharmaceutical
agent.
30. A pharmaceutical composition comprising a solvent containing a
solvent purified according to the process of claim 11 wherein the
solvent is a polyethoxylated castor oil and a pharmaceutical agent.
Description
[0001] The present invention relates to a stabilized pharmaceutical
composition in a solvent system and in particular a co-solvent
system suitable for preparing a stabilized injection composition
containing at least one pharmaceutical agent. More particularly,
the present invention relates to stabilized compositions of anti
cancer drugs.
[0002] Administration of pharmaceutical compounds, particularly by
injection, usually requires a suitable solvent or delivery system
to enable the composition to be administered to a patient.
[0003] An ideal solvent must typically have the following
properties:
[0004] 1. It must be capable of solubilizing a therapeutically
effective amount of the active agent to produce an effective
composition.
[0005] 2. It must be compatible with the active agent.
[0006] 3. It should be safe i.e. it should not cause any toxicity
to the patient.
[0007] 4. It should produce a composition having a good shelf
life.
[0008] Many solvents while possessing most of the above
advantageous qualities are not particularly efficient in
solubilizing the pharmaceutical agent to produce an effective
composition for administration.
[0009] On the other hand numerous pharmaceutical agents are not
sufficiently soluble in any one solvent to enable the resulting
composition to be effective. Therefore, mixtures of two or more
solvents are quite commonly used in pharmaceutical industry to
overcome the limitations of a single solvent to solubilize the
active agent. These co-solvent systems are suitable for
solubilizing many pharmaceutical agents, which cannot otherwise be
solubilized or dispersed in a single solvent.
[0010] One example of a co-solvent system is a mixture of a polar
solvent and a non-ionic solvent, such as a mixture of a
polyethylene glycol and Cremophor EL or ELP (polyethoxylated castor
oil). Cremophor EL or ELP is a condensation product of castor oil
and ethylene oxide sold by BASF.
[0011] Although these co-solvent systems can be effective in
solubilizing many compounds, they are not without their
disadvantages. A commonly used co-solvent system used for many
pharmaceutical agents is a 50:50 mixture of ethanol and Cremophor
ELP. A potential problem associated with such solvents is that
acids, salts or other ionic impurities, as well as residual water
in the solvent or solvent system, even if within the acceptable
limits, can catalyze the degradation of the pharmaceutical agent.
For example, co-solvents of ethanol and Cremophor are known to
result in particulates forming upon dilution with infusion
solutions. In addition, fibrous precipitates of unknown composition
form in some formulations during storage for extended periods of
time.
[0012] A solvent with sufficiently low levels of particularly
deleterious impurities will yield more stable pharmaceutical
compositions. The US FDA approved pharmaceutical composition of
Taxol marketed by Bristol Myers Squibb is paclitaxel in a
co-solvent of 50:50 by volume of dehydrated ethanol and commercial
grade Cremophor EL. These compositions exhibit a loss of potency of
greater than 60% after storage for 12 weeks at 500 C (U.S. Pat. No.
5,504,102). The loss of potency is attributed to the decomposition
of paclitaxel during storage. It is believed that carboxylate
anions present in Cremophor EL can catalyze the decomposition of
paclitaxel, even at levels within the defined limits set forth in
the National Formulary. U.S. Pat. No. 5,504,102 (Agharkar et al)
incorporated herein by reference discloses removing the carboxylate
anions from polyethoxylated castor oils (cremophor) by acid
addition or alumina adsorption. U.S. Pat. No. 5,504,102 discloses
that paclitaxel reacts with ethanol during storage and that the
decomposition of paclitaxel is catalyzed by the carboxylate anions
in the solvent. They also disclose that lowering the carboxylate
concentration of the solvent produced a stabilizing effect on the
pharmaceutical composition. The composition in question being
Taxol, prepared as an injection concentrate containing 6 mg/ml
paclitaxel in 50:50 by volume ethanol and polyoxyethylated castor
oil.
[0013] As per their disclosure, the pharmaceutical agents of
interest are those having an ester linkage that can be cleaved by
an alcohol in the presence of carboxylate anions. In their
preferred embodiments, the solvent is a co-solvent mixture of at
least one solvent and a solubilizing agent. The preferred solvent
includes alcohol such as dehydrated ethanol. The solubilizing agent
in preferred embodiments is a polyoxyethylated castor oil such as
that sold under the tradename Cremophor EL or Cremophor ELP by
BASF.
[0014] In their preferred embodiments, the carboxylate anion
content of the solvent is lowered by a number of methods. In one
embodiment of the invention, the Cremophor EL or other solvent is
passed through a standard chromatography column of aluminum oxide
which adsorbs the carboxylate anions as well as other impurities to
reduce the carboxylate anion content of the solvent. In an
alternative embodiment, the solvent is treated by the addition of
an acid in a stabilizing amount to reduce the carboxylate anion
content to a sufficiently low level to substantially prevent
catalyzed degradation of the pharmaceutical compound.
[0015] Nikolayev et al in U.S. Pat. No. 5,925,776 disclose a method
of reducing the cation content in the polyethoxylated castor oil
(cremophor). This is achieved by pre-treating the polyethoxylated
castor oil with a strong cation exchange resin. The low cationic
content polyethoxylated castor oil of the invention is then
utilized to prepare formulations of various agents which are found
to be sensitive to the previously commercially available
polyethoxylated castor oil (cremophor EL). The stability of
paclitaxel formulated in a mixture of low cationic content
polyethoxylated castor oil of the invention and ethyl alcohol is
shown to be better as compared to a formulation using untreated
polyethoxylated castor oil of the invention and ethyl alcohol.
[0016] Anevski et al in U.S. Pat. No. 6,388,112 disclose a process
for purifying a non-ionic surfactant or solvent capable of
dispersing and solubilizing a pharmaceutical compound. In the
process, a solution of solvent and alcohol is brought in contact
with an activated carbon column and an ion exchange resin column.
The process is particularly adapted to the purification of
polyethoxylated castor oils. The purified solvent is useful in the
preparation of pharmaceutical compositions having enhanced shelf
life, such as for use with paclitaxel.
[0017] Carver et al in U.S. Pat. No. 6,306,894 disclose a
pharmaceutical formulation of paclitaxel and polyethoxylated castor
oil wherein the formulation is relatively acidified to a pH of less
than 8.1 and preferably within a pH range of 5 to 7, inclusively.
Ethanol is optionally included in the formulation. A formulation
method is also disclosed and includes the step of mixing an acid
with a carrier material, such as polyethoxylated castor oil, to
form a carrier solution after which paclitaxel is added in an
amount such that the resulting pH is less than 8.1 and preferably
in a pH range of 5 to 7. Ethanol may optionally be slurried with
the paclitaxel before mixing with the carrier solution.
[0018] A variety of acidifying agents, a preferred one being
anhydrous citric acid, are described. Acids in the form of powders,
for example citric acid, have been preferred over those which
contain water, for example sulfuric acid. The most preferred acid
for use in accordance with the invention disclosed in U.S. Pat. No.
6,306,894 is citric acid, but a wide range of acids may be used
including:
[0019] Citric acid-monohydrous, Citric acid-anhydrous, Citric
acid-hydrous, Acetic acid, Formic acid, Ascorbic acid, Aspartic
acid, Benzene sulphonic acid, Benzoic acid, Hydrochloric acid,
Sulphuric acid, Phosphoric acid, Nitric acid, Tartaric acid,
Diatrizoic acid, Glutamic acid, Lactic acid, Maleic acid, and
Succinic acid.
[0020] Owens et al in U.S. Pat. No. 6,071,952 disclose a
pharmaceutical composition with long term storage stability
comprising a taxane or taxoid by incorporating an effective amount
of an antioxidant.
[0021] Previous efforts to develop a shelf stable composition of
some pharmaceutical compositions in various co-solvent systems have
not been entirely successful. Thus, there is a continuing need in
the art for a solvent or co-solvent system capable of being used
for preparing stabilized compositions and, in particular,
stabilized injection compositions containing a pharmaceutical
agent.
[0022] The disadvantages and limitations of the previous injection
composition and solvent systems are overcome by the present
invention while providing a convenient and efficient method of
producing a solvent and a method of stabilizing pharmaceutical
compositions including compositions suitable for injection. The
present invention is primarily directed to a solvent suitable for
producing a stabilized pharmaceutical composition and to a method
of producing and stabilizing a pharmaceutical composition.
[0023] The invention is directed to a solvent suitable for
preparing stabilized injection compositions containing at least one
pharmaceutical agent. Accordingly, it is a primary aspect of the
invention to provide a method of preparing a treated solvent which
when used in a composition has a stabilizing effect on the
composition and a method of preparing stabilized pharmaceutical
compositions using the treated solvent.
[0024] The stabilized pharmaceutical compositions produced using
the treated solvent of the invention have been shown to have a
shelf life greater than the compositions produced from untreated
solvent. The solvent system of the invention is particularly
suitable for use with pharmaceutical compounds that exhibit
decomposition, which is catalyzed by the presence of ionic,
metallic and oxidizing impurities. The advantages of the invention
are also attained by producing a stabilized pharmaceutical
composition comprising at least one antineoplastic compound and a
solvent system capable of solubilising the antineoplastic compound,
the solvent system comprising a solubilizing amount of an alcohol
such as absolute alcohol and a solubilizer such as polyoxyethylated
castor oil having been purified to have an impurities content
sufficiently low to substantially minimize degradation of the
antineoplastic compound.
[0025] Of particular interest are the antineoplastic agents such as
paclitaxel, teniposide, camptothecin and derivatives thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The solvent system of the invention essentially comprises a
purified non-ionic solvent The solubilizing agent can be a
condensation product of an alkylene oxide and a lipid or fatty
acid. The preferred solubilizing agent includes a polyoxyethylated
castor oil such as that sold by M/s BASF under the tradename
Cremophor EL or Cremophor ELP and an alcohol. The polyoxyethylated
castor oil is purified by a process of chromatography to reduce the
water soluble ionic, metallic and oxidizing impurities to a
sufficiently low concentration to minimize the decomposition of the
pharmaceutical agent that is catalyzed by the presence of these
impurities. The content of impurities in the polyoxyethylated
castor oil is lowered by reverse-phase chromatography using
suitable mobile and stationary phases.
[0027] Further advantages of the invention are attained by
providing a method of stabilizing a pharmaceutical composition
containing a pharmaceutical agent such as paclitaxel, teniposide,
camptothecin and derivatives thereof, and a solvent containing
absolute ethanol and a purified solubilizing agent as described
above.
[0028] The invention provides a pharmaceutical stable formulation
of paclitaxel made using a purified solvent. The process involves
purification of a non-ionic solvent such as polyethoxylated castor
oil, preferably polyoxy-35-castor oil, more preferably cremophor
such as Cremophor EL or Cremophor ELP using reverse-phase
chromatography such that the content of ionic, metallic and
oxidizing impurities of the cremophor is lowered.
[0029] The process for purifying a non-ionic solvent comprising the
steps of:
[0030] (a) forming a solution of the non-ionic solvent in alcohol
and water, with or without the aid of heating;
[0031] (b) loading this solution on to a chromatography column
packed with reverse phase silica
[0032] (c) running the chromatograph using de-ionized water as the
mobile phase to purify the solvent;
[0033] (d) running the chromatograph using an eluent to recover the
purified solvent; and
[0034] (e) evaporating the residual water and the eluent.
[0035] Preferably the de-ionized water is HPLC grade.
[0036] The aqueous fractions obtained from running the
chromatograph using de-ionized water are not used and may be set
aside or discarded.
[0037] Preferably, the solvent is selected from polyethoxylated
castor oil, polyoxy-35-castor oil, Cremophor EL or Cremophor
ELP.
[0038] Preferably, the alcohol is selected from methanol, ethanol,
butanol, iso-propanol etc; more preferably ethanol and more
preferably dehydrated ethanol.
[0039] The eluents may be selected from methanol, ethanol,
isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran and other
such solvents of similar polarities. The preferred eluent is
acetone. Combinations of eluents may be used.
[0040] In one embodiment of the invention the mobile phase is run
for 1 to 50 minutes; preferably for 20 minutes.
[0041] In one of the preferred embodiments of the invention, the
polyethoxylated castor oil is purified by loading it on a
chromatography column packed with reverse-phase silica, preferably
C-8 or C-18 and chromatographed using de-ionized water to remove or
lower the concentration of water soluble impurities - both organic
and inorganic. The purified polyethoxylated castor oil is then
recovered by eluting the column using an eluent, preferably
acetone. Preferably the de-ionized water is HPLC grade.
[0042] In a preferred embodiment the weight ratio of
polyethoxylated castor oil to alcohol is 10:1. In another
embodiment of the invention the ratio of polyethoxylated castor oil
to alcohol to water is 10:1:33 w/v/v.
[0043] The solvent purified by this method can be combined with
antineoplastic compound to form a composition. Optionally the
compositions of this invention include an alcohol which may be
added to the solvent before combining with the antineoplastic
agent,t when the solvent is combined with the antineoplastic agent
or after the solvent is combined with the antineoplastic agent. The
alcohol may be a dehydrated alcohol. Compositions suitable for
parenteral administration such as injection or infusion may be
prepared by diluting the compositions with a suitable parenteral
fluid prior to parenteral administration, injection or
infusion.
[0044] The following non-limiting example is intended to
demonstrate the preferred embodiment of the invention. One skilled
in the art will readily recognize that numerous embodiments of the
invention can be practiced to achieve the stabilizing effect.
EXAMPLE-1
[0045] This example was carried out to demonstrate the effect of
purification of cremophor using reverse phase chromatography on the
stability of Paclitaxel formulation.
[0046] 300 gm of Cremophor ELP (of M/s BASF) was diluted with about
30 ml of absolute ethanol and the mixture was then dissolved in one
litre of HPLC grade de-ionized water pre-heated to 60.degree. C.
with stirring to make uniform solution.
[0047] This cremophor solution was then loaded on to a
chromatography column (15 cm.times.30 cm) packed with reverse-phase
silica, preferably C-8 or C-18, having an average particle size of
30 to 60 .mu.. The system was eluted using de-ionized HPLC grade
water as the mobile phase for about 20 minutes to remove or reduce
the water-soluble impurities in the cremophor. The eluted aqueous
fractions were discarded. The column was then eluted with 100%
acetone to recover the purified cremophor. Acetone was completely
removed by evaporation under vacuum using rotavapor at 40.degree.
C. The so obtained cremophor was further dried under vacuum at
elevated temperature of about 55.degree. C. to remove the residual
water to obtain purified cremophor.
[0048] The purified cremophor so obtained was tested for various
impurities including anions and cations. The cation and anion
content was measured in the cremophor before and after purification
and the results are as below
[0049] Cation Content:
1 Identity Zinc Magnesium Sodium Potassium Aluminum Tin Calcium
Cremophor 2.93 7.86 28.67 3.00 0.78 1.28 32.62 ELP (BASF) ELP-Prep
1 2.10 5.99 31.39 3.36 0.33 0.78 22.25 ELP-Prep 2 1.89 4.60 31.52
3.48 0.37 0.32 17.83 ELP-Prep 3 1.58 4.60 32.12 3.39 0.13 0.33
18.89 All values are in ppm
[0050] As is evident from the above table there is substantial
decrease in the concentrations of most of the cations listed above
except sodium and potassium. All the above tabulated cations are
known to promote degradation of paclitaxel.
[0051] Anion Content:
2 Identity Chloride Bromide Sulphate Cremophor 23.211 0.657 6.747
ELP (BASF) ELP-Prep 1 4.625 ND 2.545 ELP-Prep 2 14.673 ND 6.014
ELP-Prep 3 15.386 ND 2.352 All values are in ppm; ND = Not
detectable
[0052] As is evident from the above table there is a decrease in
the concentrations of the inorganic anions, as compared to the
untreated Cremophor ELP from M's BASF. These purified cremophor
samples were then used to make formulations of paclitaxel and
subjected to stress temperature studies to see the effect on
formation of degradation products of paclitaxel.
[0053] Samples 1 to 3 were prepared by dissolving 6 mg/ml of
paclitaxel in 50:50 v/v mixture of purified cremophor ELP and
absolute ethanol. The Cremophor ELP of the samples 1 to 3 was
purified as discussed above. Sample 4 was prepared as a control
sample from unprocessed Cremophor ELP in a 50:50 v/v mixture of
unprocessed Cremophor ELP and ethanol with paclitaxel in the amount
of 6 mg/ml.
[0054] The samples were then subjected to a stress temperature
study at 50.degree. C. The results obtained are summarized as
below:
3 TABLE 1 Paclitaxel Degradation Products % at 50.degree. C. PH
Total (including other (1:10 dilution in water) degradation
products) Cremophor Formulation 3 Days 10 Days 30 Days Sample 1
5.02 5.04 0.07 0.14 0.24 Sample 2 5.03 5.08 0.09 0.16 0.28 Sample 3
5.10 5.12 0.09 0.13 0.23 Sample 4 5.70 5.71 0.62 1.29 1.79
[0055] The degradation products of paclitaxel include: Baccatin
III, Ethyl Ester Side Chain of Paclitaxel, 10-Deacetyl Paclitaxel,
10-Deacetyl-7-Epi-paclitaxel, and 7 Epi-paclitaxel.
[0056] As is evident from the above results, purification of
cremophor results in reduction of the pH of cremophor from about
5.70 to around 5.10. As shown in Table 1--Samples 1 to 3 prepared
with purified cremophor are much more stable in terms of
degradation products of paclitaxel as compared to sample--4. Thus,
cremophor ELP purified using the process of the invention improves
the stability of paclitaxel formulation significantly as compared
to the formulation made using untreated Cremophor ELP.
[0057] The foregoing description of the preferred embodiment of the
invention has been presented for purpose of illustration and
description. It is not intended to be exhaustive or to limit the
invention to precise parameters disclosed. Obvious modifications or
variations are possible in light of the above teachings. The
embodiment has been chosen and described to provide the best
illustration of the principles of the invention and its practical
applications to thereby enable one of the ordinary skill in the art
to utilize the invention in various embodiments and with various
modifications like using various size chromatographic columns,
different types of reverse-phase chromatographic materials, column
packing materials of different particle size, and/or different
chromatographic temperatures etc. All such modifications and
variations are within the scope of the invention as determined by
the appended claims.
* * * * *