U.S. patent application number 11/100681 was filed with the patent office on 2005-09-01 for pharmaceutical formulations comprising paclitaxel, derivatives and pharmaceutically acceptable salts thereof.
Invention is credited to Chen, Hongming.
Application Number | 20050191323 11/100681 |
Document ID | / |
Family ID | 26943439 |
Filed Date | 2005-09-01 |
United States Patent
Application |
20050191323 |
Kind Code |
A1 |
Chen, Hongming |
September 1, 2005 |
Pharmaceutical formulations comprising paclitaxel, derivatives and
pharmaceutically acceptable salts thereof
Abstract
The invention concerns paclitaxel solubilizers and formulations
thereof with a high propensity to dissolve paclitaxel. The
formulations of the invention reduce or obviate the need for the
disadvantageous excipient Cremophor.RTM. EL. The formulations of
the invention are useful for administering paclitaxel, its
derivatives, or pharmaceutically acceptable salts of such
derivatives to patients in need thereof. The formulations of the
invention are suitable for parenteral, oral, local, or transdermal
administration to mammals including humans, particularly for
intravenous delivery.
Inventors: |
Chen, Hongming; (Acton,
MA) |
Correspondence
Address: |
TRANSFORM PHARMACEUTICALS, INC.
29 HARTWELL AVENUE
LEXINGTON
MA
02421
US
|
Family ID: |
26943439 |
Appl. No.: |
11/100681 |
Filed: |
April 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11100681 |
Apr 7, 2005 |
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10343780 |
Feb 3, 2003 |
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6919370 |
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10343780 |
Feb 3, 2003 |
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PCT/US01/43306 |
Nov 20, 2001 |
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60253640 |
Nov 28, 2000 |
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60272117 |
Feb 28, 2001 |
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Current U.S.
Class: |
424/400 ;
424/649; 514/10.4; 514/283; 514/34; 514/449; 514/458; 514/49;
514/492; 514/651 |
Current CPC
Class: |
A61K 31/337 20130101;
A61P 43/00 20180101; A61K 47/10 20130101; A61K 47/14 20130101; A61K
9/0019 20130101; A61K 31/137 20130101; A61K 9/1075 20130101; A61K
47/26 20130101; A61P 35/00 20180101; A61K 31/4745 20130101; A61K
31/28 20130101; A61K 47/186 20130101 |
Class at
Publication: |
424/400 ;
514/016; 514/449; 514/458; 514/049; 514/034; 514/283; 514/651;
424/649; 514/492 |
International
Class: |
A61K 038/10; A61K
031/7072; A61K 031/704; A61K 031/4745; A61K 031/337 |
Claims
1. A pharmaceutical formulation for administration to a mammal
comprising: (a) paclitaxel, a derivative, or a pharmaceutically
acceptable salt thereof; and (b) one or more of a PEG-glyceryl
fatty ester, a quaternary ammonium salt or a PEG-fatty alcohol.
2. The pharmaceutical formulation of claim 1, wherein the
formulation is cremophor free.
3. The pharmaceutical formulation of claim 1, further comprising an
additional active.
4. The pharmaceutical formulation of claim 3, wherein the
additional active is cisplatin, carboplatin, tamoxifen, epirubicin,
leuprolide, bicalutamide, goserelin implant, irinotecan,
gemcitabine, or sargramostim or a pharmaceutically acceptable salt
thereof.
5. The pharmaceutical formulation of claim 1, wherein the
formulation is suitable for dissolution in an aqueous medium.
6. The pharmaceutical formulation of claim 1, wherein the
formulation is in a form of a solid, semisolid, gel, suspension, or
emulsion.
7. The pharmaceutical formulation of claim 1, wherein the
formulation is in liquid form.
8. The pharmaceutical formulation of claim 1, wherein the
formulation is in liquid-concentrate form.
9. The pharmaceutical formulation of claim 8, further comprising
ethanol.
10. The pharmaceutical formulation of claim 6, wherein the solid is
a lyophilized solid.
11. The pharmaceutical formulation of claim 1, further comprising
an aqueous medium.
12-153. (canceled)
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/253,640 filed Nov. 28, 2000, and U.S.
Provisional Application No. 60/272,117 filed Feb. 28, 2001, which
are incorporated by reference herein in their entirety.
1. FIELD OF THE INVENTION
[0002] The present invention is directed to excipients or
combinations thereof suitable for preparing a formulation
containing a pharmaceutical agent. More particularly, the invention
is directed to stable and efficacious pharmaceutical formulations
comprising paclitaxel, derivatives, and pharmaceutically acceptable
salts thereof.
2. BACKGROUND OF THE INVENTION
[0003] Pharmaceuticals are rarely distributed as pure compounds
because of problems with, among others, stability, solubility, and
bioavailability of the pharmaceutical itself (i.e., the active),
and in most cases, are administered in a pharmaceutical formulation
comprising the active, and other components, such as excipients,
binders, diluents, and other delivery vehicles or systems. It is
well documented that physical and chemical properties, such as
stability, solubility, dissolution, permeability, and partitioning
of most pharmaceuticals are directly related to the medium in which
they are administered. And, in turn, the physical and chemical
properties of drug-in-formulation mixtures affect the
pharmacological and pharmacokinetic properties, such as absorption,
bioavailability, metabolic profile, toxicity, and potency. Such
effects are caused by interactions between the formulation's
components and the pharmaceutical and/or interactions between the
components themselves. Other properties influenced by the
formulation in which a pharmaceutical is administered include
mechanical properties, such as compressibility, compactability, and
flow characteristics and sensory properties, such as taste, smell,
and color. Thus, discovery of pharmaceutical formulations that
optimize bioavailability and duration of action of the
pharmaceutical and minimize undesirable properties is an important
part of pharmaceutical development and research. For a general
review of the subject of formulations see Howard, Introduction to
Pharmaceutical Dosage Forms, Lea & Febiger, Philadelphia Pa.,
4.sup.th ed., 1985; Remington: the Science and Practice of
Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa.,
19th ed., 1995, Chapter 83.
[0004] Formulation development is normally a tedious process, where
many variables must be separately assessed. For example, if the
formulation contains a pharmaceutical characterized by poor
solubility, the solubility of the pharmaceutical in a range of salt
concentrations; pHs; excipients; and pharmaceutical concentrations
must be prepared and tested to find interactions between the
pharmaceutical and excipients or interactions between excipients
that affect the pharmaceutical's solubility. While some general
rules exist, the effect of excipients and combinations of
excipients on the physical and chemical properties of the
pharmaceutical are not easily predicted. Moreover, there are over
3,000 excipients to choose from when designing pharmaceutical
formulations, each having differing degrees and types of
interactions with each other and with the pharmaceutical. (For a
listing of generally regarded as safe (GRAS) excipients see the
Code of Federal Regulations (CPR) at 21 CFR 182 and 21 CFR 184).
Because of the many variables involved, industry does not have the
time or resources to identify, measure, or exploit interactions
between excipients and pharmaceuticals and thus cannot provide
optimized pharmaceutical formulations tailored to the particular
pharmaceutical. Such work would require testing hundreds to
thousands of formulations a day. Assuming three hundred substances
are to be tested for efficacy as excipients in a pharmaceutical
formulation, even with no variations in concentrations and no
physical or chemical property variations, the number of possible
combinations is enormous: when two of the substances are selected,
there are 45,150 possible combinations, for three components there
are 4,545,100 combinations, and for four components, there are
344,291,325 possible combinations. The complexity is increased when
the relative ratio of each component is considered. Unfortunately,
technologies that can make many pharmaceutical-excipient
combinations at the same time, then automatically feed each
combination into a system for identifying the combinations that
have optimized properties are not known. Today, since it is more
cost effective, most pharmaceuticals are distributed and
administered in the standard, un-optimized formulations, see e.g.,
Allen's Compounded Formulations: U.S. Pharmacists Collection 1995
to 1998, ed. Lloyd Allen.
[0005] Paclitaxel is presently available in the United States only
as a non-aqueous sub-optimal formulation concentrate for
intravenous injection. An intravenous dosage regimen of 135
mg/m.sup.2 paclitaxel is recommended for previously untreated
patients with carcinoma of the ovary, given every three weeks.
Similar dosage regimens are recommend for other carcinomas.
Paclitaxel is practically insoluble in water. The
commercially-available paclitaxel formulation (Bristol-Myers
Squibb) comprises 6 mg/ml of paclitaxel dissolved in Cremophor.RTM.
EL (PEG-35 castor oil, polyoxyethylated castor oil) and dehydrated
ethanol (50% v/v). Similar formulations are sold by other
manufacturers, for example, IVAX Co. Before intravenous injection,
the commercial dose must be diluted to a final concentration of 0.3
to 1.2 mg/ml prior to injection. Recommended diluents are 0.9%
aqueous sodium chloride, 5% aqueous dextrose, or 0.9% sodium
chloride 5% dextrose aqueous solution, or 5% dextrose in Ringer's
injection (The Physician's Desk Reference, 54th edition, 881-887,
Medical Economics Company (2000); Goldspiel 1994 Ann.
Pharmacotherapy 28:S23-26, both of which are incorporated herein by
reference).
[0006] In general, the amount of Cremophor.RTM. EL necessary to
deliver the required doses of paclitaxel is significantly higher
than that administered with other drugs currently formulated in
Cremophor.RTM. EL. This is a particular problem since several toxic
effects have been attributed to Cremophor.RTM. EL, including
vasodilation, dyspnea, and hypotension. This vehicle has also been
shown to cause serious hypersensitivity in laboratory animals and
humans (Weiss et al., 1990, J. Clin. Oncol. 8:1263-1268). In fact,
the maximum dose of paclitaxel that can be administered to mice by
i.v. bolus injection is dictated by the acute lethal toxicity of
the Cremophor.RTM. EL vehicle (Eiseman et al., 1994, Cancer
Chemother. Pharmacol. 34:465-471).
[0007] In addition, Cremophor.RTM. EL is known to leach phthalate
plasticizers such as di(2-ethylhexyl)phthalate (DEHP) from the
polyvinylchloride bags and intravenous administration tubing. DEHP
is known to cause hepatotoxicity in animals and is carcinogenic in
rodents. Upon dilution with infusion solutions, paclitaxel
Cremophor.RTM. EL formulations can result in particulate formation.
In addition, fibrous precipitates of unknown composition can form
in the concentrate during storage for extended periods of time. It
is generally believed that the precipitates are degradation
by-products of either components in the solvent or paclitaxel. In
such case, filtration of the diluted Cremophor.RTM.
EL/ethanol/paclitaxel formulation is necessary during
administration (Goldspiel 1994 Ann. Pharmacotherapy 28:S23-26).
[0008] It has further been reported, in U.S. Pat. No. 5,504,102,
that commercial grade Cremophor.RTM. EL with ethanol as a
co-solvent, although effective in dissolving paclitaxel, produces
injection formulations that exhibit instability over extended
periods of time. In particular, pharmaceutical formulations of
paclitaxel in a co-solvent of 50:50 by volume of dehydrated ethyl
alcohol and commercial grade Cremophor.RTM. EL exhibit a loss of
potency of greater than 60% after storage for 12 weeks at
50.degree. C. The loss of potency is attributed to the degradation
of paclitaxel during storage. Other disadvantages of Cremophor.RTM.
EL have been reported.
[0009] Some efforts have focused on limiting or eliminating
Cremophor.RTM. EL by preparing paclitaxel derivatives having
improved aqueous solubility over paclitaxel. Research in this area
includes preparation of 2'-succinate- and amino-acid-ester prodrugs
of paclitaxel (see e.g., Deutsch et al., 1989, J. Med. Chem.,
32:788-792; Matthew et al., 1992, J. Med. Chem. 35:145-151). In
other efforts, Greenwald et al. reported the synthesis of highly
water-soluble 2' and 7-polyethylene glycol esters of paclitaxel
(Greenwald et al., 1994, Bioorganic & Medicinal Chemistry
Letters 4:2465-2470), however, no data concerning the in-vivo
antitumor activity of these compounds were reported (Greenwald et
al., 1995, J. Org. Chem. 60:331-336). Others attempts to solve
paclitaxel's aqueous-solubility problems have involved
microencapsulation of paclitaxel in both liposomes and nanospheres
(Bartoni et al., 1990, J. Microencapsulation 7:191-197). The
liposome formulation was reported to be as effective as free
paclitaxel, however, only liposome formulations containing less
than 2% paclitaxel were physically stable (Sharma et al., 1994,
Pharm. Res. 11:889-896). There is a need, therefore, for
formulations comprising paclitaxel, derivatives, and
pharmaceutically acceptable salts thereof that can deliver
therapeutically effective amounts of paclitaxel and derivatives
thereof that overcome the disadvantages caused by paclitaxel's
insolubility and the disadvantages of Cremophor.RTM. EL.
3. SUMMARY OF THE INVENTION
[0010] In a preferred embodiment, the invention concerns paclitaxel
solubilizers and formulations thereof with a high propensity to
promote dissolution of paclitaxel or that stabilize aqueous
paclitaxel solutions. The formulations of the invention are useful
for administering paclitaxel, its derivatives, or pharmaceutically
acceptable salts of such derivatives to patients in need thereof.
The formulations of the invention are suitable for parenteral,
oral, local, or transdermal administration to mammals including
humans, particularly for intravenous delivery.
[0011] More generally, the paclitaxel solubilizers of the invention
or mixtures thereof can replace the disadvantageous excipient
Cremophor.RTM. EL as a solubilizing excipient in existing
pharmaceutical formulations comprising hydrophobic pharmaceuticals
or the need to use Cremophor.RTM. EL with such pharmaceuticals.
Thus, the formulations of the invention are suitable to administer
any drug for which Cremophor.RTM. EL is now used or would today be
the first choice as an aqueous solubilization excipient. The
formulations of the invention are particularly suitable to
administer paclitaxel and derivatives thereof.
[0012] In one embodiment, the invention concerns a pharmaceutical
formulation for administration to a mammal comprising:
[0013] (a) paclitaxel, a derivative, or a pharmaceutically
acceptable salt thereof; and
[0014] (b) one or more of a PEG-glyceryl fatty ester, a quaternary
ammonium salt or a PEG-fatty alcohol.
[0015] In this embodiment, preferably, the quaternary ammonium salt
is benzalkonium chloride, benzethonium chloride, or cetrimide; the
PEG-glyceryl fatty ester is PEG-glyceryl monooleate or PEG-glyceryl
monolaurate; and the PEG-fatty alcohol is an octoxynol, an oleth,
or a laureth.
[0016] In another embodiment, the invention concerns a
pharmaceutical formulation for administration to a mammal
comprising:
[0017] (a) paclitaxel, a derivative, or a pharmaceutically
acceptable salt thereof; and
[0018] (b) two or more of a PEG-vitamin E, a quaternary ammonium
salt, a PEG-monoacid fatty ester, a PEG-glyceryl fatty ester, a
polysorbate, or a PEG-fatty alcohol.
[0019] Preferably, the PEG-vitamin E is tocophersolan; the
quaternary ammonium salt is benzalkonium chloride, benzethonium
chloride, or cetrimide; the PEG-monoacid fatty ester is PEG-20
monooleate, PEG-20 monolaurate, PEG-20 monostearate; the
PEG-glyceryl fatty ester is PEG-20 glyceryl monooleate, PEG-20
glyceryl monostearate, or PEG-20 glyceryl monolaurate; the
polysorbate is polysorbate 20 or polysorbate 80; and the PEG-fatty
alcohol is an octoxynol, an oleth, or a laureth. A preferred
octoxynol is octoxynol-9 and preferred laureth is laureth-23.
[0020] In a separate embodiment, the formulations of the invention
do not contain a quaternary ammonium salt.
[0021] In one preferred aspect of this embodiment, the paclitaxel
solubilizers are a PEG-vitamin E and one or more of a PEG-monoacid
fatty ester, the PEG-glyceryl fatty ester, a polysorbate, or a
PEG-fatty alcohol.
[0022] In another preferred aspect of this embodiment, the
paclitaxel solubilizers are a quaternary ammonium salt and one or
both of a polysorbate or a PEG-fatty alcohol.
[0023] In still another preferred aspect of this embodiment, the
paclitaxel solubilizers are a PEG-monoacid fatty ester and one or
more of a PEG-vitamin E, the PEG-glyceryl fatty ester, a
polysorbate, or a PEG-fatty alcohol.
[0024] In another embodiment, the paclitaxel solubilizers are a
PEG-glyceryl fatty ester and one or more of the PEG-vitamin E, the
PEG-monoacid fatty ester, or the polysorbate.
[0025] In yet another preferred aspect of this embodiment, the
paclitaxel solubilizers are a polysorbate and one or more of a
quaternary ammonium salt, a PEG-monoacid fatty ester, a
PEG-glyceryl fatty ester, or a PEG-fatty alcohol.
[0026] In another preferred aspect of this embodiment, the
paclitaxel solubilizers are a PEG-fatty alcohol and one or more of
a PEG-vitamin E, a quaternary ammonium salt, a PEG-monoacid fatty
ester, or a polysorbate.
[0027] In another embodiment, the invention concerns a
pharmaceutical formulation for administration to a mammal
comprising:
[0028] (a) paclitaxel, a derivative, or a pharmaceutically
acceptable salt thereof; and
[0029] (b) PEG-400 and one or more of a PEG-vitamin E, a quaternary
ammonium salt, a PEG-monoacid fatty ester, a PEG-glyceryl fatty
ester, a polysorbate, or a PEG-fatty alcohol.
[0030] In a separate embodiment, the invention relates to a method
of treating cancer or other conditions treatable by paclitaxel in a
mammal comprising administering to said mammal a therapeutically
effective amount of a formulation of the invention.
[0031] In still another embodiment, the formulations of the
invention can be independent of paclitaxel, a derivative, or a salt
thereof. Such formulations are referred to herein as paclitaxel
free formulations of the invention and can be used to solubilize
and administer any pharmaceutical. Paclitaxel free formulations of
the invention are particularly useful as a replacement for
cremophor and similar excipients in pharmaceutical formulations
currently comprising them.
[0032] In another embodiment, the invention relates to a
pharmaceutical formulation suitable for administration to a human
consisting essentially of:
[0033] (a) paclitaxel, a derivative, or a pharmaceutically
acceptable salt thereof;
[0034] (b) one or more of a PEG-vitamin E, a quaternary ammonium
salt, a PEG-monoacid fatty ester, a PEG-glyceryl fatty ester, a
polysorbate, or a PEG-fatty alcohol; and
[0035] (c) ethanol,
[0036] wherein said formulation is free of cremophor and is
suitable for dissolution or reconstitution with an aqueous medium
into a particulate-free solution suitable for parenteral
administration.
[0037] In yet another embodiment, the invention relates to a
pharmaceutical formulation suitable for administration to a human
consisting essentially of:
[0038] (a) paclitaxel, a derivative, or a pharmaceutically
acceptable salt thereof;
[0039] (b) two or more of a PEG-vitamin E, a quaternary ammonium
salt, a PEG-monoacid fatty ester, a PEG-glyceryl fatty ester, a
polysorbate, or a PEG-fatty alcohol; and
[0040] (c) ethanol,
[0041] wherein said formulation is free of cremophor and is
suitable for dissolution or reconstitution with an aqueous medium
into a particulate-free solution suitable for parenteral
administration.
[0042] In another embodiment, the invention relates to arrays and
methods for high-throughput preparation of a large number of
excipient/active combinations (e.g., thousands to hundreds of
thousands), at varying concentrations, at the same time, and
high-throughput testing thereof. An example of such a process is
described in the Examples section herein. Such methods allow
detection or measurement of interactions between formulation
components (e.g., excipients) and actives; between multiple
formulation components; or between multiple actives. Once such
interactions or lack of interactions are identified, the active can
be "retrofitted" into an optimal formulation for pharmaceutical
administration.
[0043] The invention thus encompasses the high-throughput testing
of formulations comprising paclitaxel, a derivative, or a salt
thereof in order to determine the overall optimal formulations, or
to optimize any particular desired property or results, e.g.,
bioavailability, potency, release, stability, and the like; or
both. To applicant's knowledge, a systematic, high-throughput
method for formulation generation, screening, testing, and
analysis, has not been published prior to this invention.
[0044] In this regard, another embodiment of the invention concerns
an array of samples, each sample comprising paclitaxel, a
derivative, or a pharmaceutically acceptable salt thereof and at
least one formulation component, wherein each sample differs from
any other sample with respect to at least one of:
[0045] (i) the identity of the formulation component, or
[0046] (ii) the ratio of the paclitaxel, the derivative, or the
pharmaceutically acceptable salt thereof to the formulation
component.
[0047] In still another embodiment, the invention relates to a
method to find a pharmaceutical formulation suitable to administer
paclitaxel to mammal, comprising:
[0048] (a) preparing an array of samples, each sample comprising
paclitaxel, a derivative, or a pharmaceutically acceptable salt
thereof and a formulation component, wherein each sample differs
from any other sample with respect to at least one of:
[0049] (i) the identity of the formulation component,
[0050] (ii) the ratio of the paclitaxel, the derivative, or the
pharmaceutically acceptable salt thereof to the formulation
component; and
[0051] (b) testing each sample for a property.
[0052] In still another embodiment, the invention relates to a
particulate-free pharmaceutical formulation suitable for parenteral
administration to a mammal comprising about 0.2 mg/ml to about 3.0
mg/ml of paclitaxel in a non-cremophor aqueous-based solution,
where per mg of the paclitaxel in the formulation the amount of
water is about 4.5 ml to about 0.3 ml.
3.1 BRIEF DESCRIPTION OF THE DRAWINGS
[0053] FIG. 1 is a pK profile comparison of 1) commercially
available TAXOL.RTM. (Bristol-Myers Squibb Company), 2) Formulation
V, and 3) Formulation W, in each case, upon adminstration of a 5
mg/kg bolus dose in male Sprague-Dawley rats.
[0054] FIG. 2 is a pK profile comparison of 1) commercially
available TAXOL.RTM., 2) Formulation V, and 3) Formulation W, in
each case, upon adminstration of a 10 mg/kg bolus dose in male
Sprague-Dawley rats.
[0055] FIG. 3 is a pK profile comparison of 1) Formulation V upon
adminstration of a 5 mg/kg bolus dose, and 2) Formulation V upon
adminstration of a 10 mg/kg bolus dose, in male Sprague-Dawley
rats.
[0056] FIG. 4 is a pK profile comparison of 1) Formulation W upon
adminstration of a 5 mg/kg bolus dose, and 2) Formulation W upon
adminstration of a 10 mg/kg bolus dose, in male Sprague-Dawley.
3.2 DEFINITIONS
[0057] The term "mammal" as used herein, encompasses any mammal.
Preferably a mammal is in need of a formulation of the invention.
Examples of mammals include, but are not limited to, cows, horses,
sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys,
etc., more preferably, a human.
[0058] As referred to herein, derivatives and analogs of paclitaxel
include, but are not limited to, docetaxel and compounds having the
general formula I below and stereoisomers and pharmaceutically
acceptable salts thereof: 1
[0059] wherein, each occurrence of R is independently H,
(C.sub.1-C.sub.6)alkyl, aryl, C(O)(C.sub.1-C.sub.6)alkyl, or
C(O)aryl. Preferably, (C.sub.1-C.sub.6)alkyl is methyl and aryl is
phenyl. Such derivatives are well known in the art. For example,
paclitaxel derivatives encompassed by formula I are disclosed in
U.S. Pat. Nos. 5,399,726; 5,654,447; 6,066,747; 5,338,872;
6,107,332; 5,703,117; 5,714,512; 5,580,899; 6,118,011; 5,470,866;
5,319,112; and 6,136,961.
[0060] As used herein, "paclitaxel solubilizer" means one or a
mixture of substances that has a high propensity to solubilize
paclitaxel in an aqueous medium. Preferably, a paclitaxel
solubilizer, when included in an aqueous paclitaxel medium, can
dissolve the paclitaxel at room temperature to a concentration of
at least about 1.2 mg/ml water. A "paclitaxel solubilizer of the
invention" refers to PEG-Vitamin Es, quaternary ammonium salts,
PEG-monoacid fatty esters, polysorbates, and PEG-fatty alcohols or
combinations thereof. It is to be understood that a "paclitaxel
solubilizer" can be used to solubilize, distribute, and administer
drugs generally, for example, the paclitaxel solubilizers of the
invention can be used to solubilize, distribute, and administer,
but not limited to, other cancer and cancer-related
pharmaceuticals, such as cisplatin, carboplatin, epirubicin,
leuprolide, bicalutamide, goserelin implant, irinotecan,
gemcitabine, and sargramostim; cardiovascular drugs; such as
amlodipine besylate, enalapril maleate, losartan potassium
lisinopril, irbesartan, nifedipine, diltiazem, clopidogrel,
digoxin, abciximab, furosemide, amiodarone, beraprost, and
tocopheryl; anti-infective agents, such as amoxicillin,
clavulanate, ciprofloxacin, azithromycin, itraconazole, acyclovir
fluconazole, terbinafine, erythromycin, and sulfisoxazole acetyl;
psychotherapeutic agents, such as fluoxetine, paroxetine,
sertaline, vanlafaxine, bupropion, olanzapine, alprazolam,
methylphenidate, fluvoxamine, and ergoloid; gastrointestinal
medicaments, such as omeprazole, lansoprazole, ranitidine,
famotidine, ondansetron, granisetron, sulfasalazine, and
infliximab; respiratory therapies, such as loratadine,
fexofenadine, cetirizine, fluticasone, salmeterol xinafoate, and
budesonide; cholesterol reducers, such as simvastatin, atorvastatin
calcium, pravastatin, lovastatin, bezafibrate, ciprofibrate, and
gemfibrozil; blood modifiers, such as epoetin alpha, enoxaparin,
and antihemophilic factor; antiarthritic agents, such as celecoxib,
diclofenac sodium, nabumetone, misoprostol, and rofecoxib; AIDS and
AIDS-related drugs, such as lamivudine, zidovudine, indinavir,
stavudine, and lamivudine; diabetes and diabetes-related therapies,
such as metformin, troglitazone, and acarbose; biologicals, such as
hepatitis vaccines; Hormones, such as estradiol; immunosuppressive
agents, such as cyclosporine, mycophenolate mofetil, and
methylprednisolone; analgesics, such as tramadol, fentanyl,
metamizole, ketoprofen, morphine, lysine acetylsalicylate,
ketoralac tromethamine, morphine, loxoprofen sodium, and ibuprofen;
dermatological products, such as isotretinoin and clindamycin;
anesthetics, such as propofol, midazolam, and lidocaine; migraine
therapies, such as sumatriptan succinate, zolmitriptan, and
rizatriptan; sedatives and hypnotics, such as, zolpidem, triazolam,
and hycosine butylbromide; multiple sclerosis agents, such as
interferon beta-1a, interferon beta-1a, and glatiramer;
osteoporosis agents, such as vitamin k.sub.2; cystic fibrosis
agents, such as dornase alpha and tobramycin; Alzheimer's disease
therapies, such as dolasetron and donepezil; and imaging agents,
such as iohexol, technetium Tc99m sestamibi, iomeprol, gadodiamide,
ioversol, and iopromide; or pharmaceutically acceptable salts
thereof.
[0061] The term "active" refers to a pharmaceutical, more
specifically to paclitaxel, derivatives, and pharmaceutically
acceptable salts thereof.
[0062] The term "cremophor" means PEG-35 caster oil (commercially
available from BASF, Wash., NJ, under the trade name Cremophor.RTM.
EL).
[0063] As used herein, the phrase "formulations of the invention"
refers to a specific composition or combination of ingredients
(i.e., one or more paclitaxel solubilizer(s) and any other
excipients, diluents, or carriers) useful for administering,
delivering, or distributing paclitaxel, a derivative, or salt
thereof. A "formulations of the invention" may or may not include
an active. Preferably, the formulations of the invention are
suitable for reconstitution or dissolution in an aqueous medium to
a particulate-free, injectable solution. It is also preferable that
formulations of the invention are sterile. A formulation of the
invention can be in the form of a solid, liquid, semisolid, gel,
suspension, emulsion, or a solution. A solution includes both
aqueous and organic solvent solutions and liquid concentrates
thereof.
[0064] As used herein, a "liquid concentrate" means a solution of
active and one or more paclitaxel solubilizers of the invention,
preferably in an organic solvent, such as ethanol, that is to be
diluted with an aqueous medium prior to administration. A liquid
concentrate can include various amounts of water but is preferably
substantially anhydrous.
[0065] Solids include any solid form, such as a powder, a
compressed pharmaceutical dosage form, or a lyophilized solid. In
one embodiment, formulations of the invention if solid or other
than liquid, are suitable for reconstitution into an injectable,
particulate-free, preferably sterile formulation, such as an
aqueous medium.
[0066] An "aqueous medium" will comprise at least water.
Preferably, an aqueous medium is sterile and suitable for use as a
carrier of an active for administration to a mammal. Examples of
preferred aqueous mediums include, but are not limited to, water;
saline solution; Ringer's solution; and solutions of water-miscible
substance, such as dextrose and other electrolytes. Other aqueous
mediums suitable for parenteral administration of actives are
listed in Remington: the Science and Practice of Pharmacy, Alfonso
R Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995,
Chapter 87; incorporated herein by reference. Preferably, the
aqueous medium does not affect the ability of the paclitaxel
solubilizer of the invention to solubilize paclitaxel, derivatives,
or salts thereof.
[0067] The phrase "pharmaceutically acceptable salt(s)", as used
herein, means those salts of paclitaxel derivatives that retain the
biological effectiveness and properties of the free acids or free
bases and that are not otherwise unacceptable for pharmaceutical
use. Pharmaceutically acceptable salts of paclitaxel derivatives
include salts of acidic or basic groups which may be present in the
paclitaxel derivatives. Derivatives of paclitaxel that are basic in
nature are capable of forming a wide variety of salts with various
inorganic and organic acids. The acids that may be used to prepare
pharmaceutically acceptable acid addition salts of such basic
compounds are those that form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions, such as
chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate,
acid phosphate, isonicotinate, acetate, lactate, salicylate,
citrate, acid citrate, tartrate, pantothenate, bitartrate,
ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Derivatives of
paclitaxel that include an amino moiety can also form
pharmaceutically acceptable salts with various amino acids, in
addition to the acids mentioned above. Derivatives of paclitaxel
that are acidic in nature are capable of forming a wide variety of
salts with various inorganic and organic bases. Suitable base salts
are formed from bases that donate cations to form on-toxic salts,
suitable cations include, but are not limited to, sodium, aluminum,
calcium, lithium, magnesium, potassium, zinc and diethanolamine
salts. For a review on pharmaceutically acceptable salts see Berge
et al., J. Pharm. Sci., 66, 1-19 (1977), incorporated herein by
reference.
[0068] As used herein, the term "excipient" means the substances
used to formulate actives into pharmaceutical formulations; in a
preferred embodiment, an excipient does not lower or interfere with
the primary therapeutic effect of the active. Preferably, an
excipient is therapeutically inert. The term "excipient"
encompasses carriers, diluents, vehicles, solubilizers,
stabilizers, and binders. Excipients can also be those substances
present in a pharmaceutical formulation as an indirect result of
the manufacturing process. Preferably, excipients are approved for
or considered to be safe for human and animal administration, i.e.,
GRAS substances (generally regarded as safe). GRAS substances are
listed by the Food and Drug administration in the Code of Federal
Regulations (CFR) at 21 CFR 182 and 21 CFR 184, incorporated herein
by reference.
[0069] As used herein, the phrase "array" means a plurality of
samples associated under a common experiment, wherein each of the
samples comprises at least paclitaxel, a derivative, or salt
thereof (i.e., an active) and a formulation component. The array is
designed to provide a data set, analysis of which allows detection
or measurement of interactions (including lack of interactions)
between the active and the formulation component. Samples in the
array differ from other samples in the array with respect to at
least one of:
[0070] (i) the identity of the formulation component, or
[0071] (ii) the ratio of the active to the formulation
component.
[0072] According to the invention, the ratio of the active to the
formulation component will differ between samples when such ratio
is intentionally varied to induce a measurable change in the
sample's properties.
[0073] As used herein, the term "property" means a physical or
chemical characteristic of a sample. Preferred properties are those
that relate to the efficacy, safety, stability, or utility of
formulations before or after administration. Properties include
physical properties, for example, but not limited to, rheology,
friability, stability, solubility, dissolution, and permeability,
preferably, solubility. The term "property" also includes
mechanical properties, for example, but not limited to,
compressibility, compactability, and flow characteristics.
[0074] An array can comprise 24, 36, 48, 96, or more samples,
preferably 1000 or more samples, more preferably, 10,000 or more
samples. An array is typically comprises one or more sub-arrays.
For example, a sub-array can be a 96-well plate of sample
wells.
[0075] As used herein, the term "sample" means a mixture of
paclitaxel, a derivative, or salt thereof (i.e., an active) and one
or more formulation components. The term "sample" encompasses
duplicates, triplicates, etc. of the same sample used as controls
in an array. In other words, multiples of the same sample in an
array, for control purposes, are considered one sample for the
purposes of the invention. Preferably a sample comprises 2 or more
formulation components, more preferably, 3 or more formulation
components. A sample can be present in any container or holder or
in or on any material or surface, the only requirement is that the
samples be located at separate sites. Preferably, samples are
contained in sample wells, for example, a 24, 36, 48, or 96 well
plates (or filter plates) of volume 250 ul available from
Millipore, Bedford, Mass.
[0076] As used herein, the phrase "formulation component" means any
substance in addition to the active in a sample. Preferably, a
formulation component is therapeutically inactive. Examples of
suitable formulation components include, but are not limited to,
excipients, solvents, diluents, stabilizers, and combinations
thereof.
[0077] As used herein, the term "alkyl group" means a saturated,
monovalent, unbranched or branched hydrocarbon chain. Examples of
alkyl groups include, but are not limited to,
(C.sub.1-C.sub.25)alkyl groups, such as methyl, ethyl, propyl,
isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,
3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,
2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,
2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,
2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,
isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, and longer
alkyl groups, such as heptyl, and octyl, nonyl, decyl, undecyl,
dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,
octadecyl, nonadecyl, icosanyl, heniconsanyl, docosanyl,
tricosanyl, tetracosanyl, and pentacosanyl. An alkyl group can be
unsubstituted or substituted with one or more suitable
substituents.
[0078] An "alkenyl group" means a monovalent, unbranched or
branched hydrocarbon chain having one or more double bonds therein.
The double bond of an alkenyl group can be unconjugated or
conjugated to another unsaturated group. Suitable alkenyl groups
include, but are not limited to (C.sub.2-C.sub.3)alkenyl groups,
such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl,
pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,
4-(2-methyl-3-butene)-pentenyl, nonenyl, decenyl, undecenyl,
dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl,
heptadecenyl, octadecenyl, nonadecenyl, icosanenyl, heniconsanenyl,
docosanenyl, tricosanenyl, tetracosanenyl, and pentacosanenyl. An
alkenyl group can be unsubstituted or substituted with one or more
suitable substituents.
[0079] An "alkynyl group" means monovalent, unbranched or branched
hydrocarbon chain having one or more triple bonds therein. The
triple bond of an alkynyl group can be unconjugated or conjugated
to another unsaturated group. Suitable alkynyl groups include, but
are not limited to, (C.sub.2-C.sub.25)alkynyl groups, such as
ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,
4-methyl-1-butynyl, 4-propyl-2-pentynyl, 4-butyl-2-hexynyl,
nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl,
pentadecynyl, hexadecenyl, heptadecynyl, octadecynyl, nonadecynyl,
icosanynyl, heniconsanynyl, docosanynyl, tricosanynyl,
tetracosanynyl, and pentacosanynyl. An alkynyl group can be
unsubstituted or substituted with one or more suitable
substituents.
[0080] An "aryl group" means a monocyclic or polycyclic-aromatic
ring comprising carbon and hydrogen atoms. Examples of suitable
aryl groups include, but are not limited to, phenyl, tolyl,
anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as
benzo-fused carbocyclic moieties such as
5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or
substituted with one or more suitable substituents. Preferably, the
aryl group is a monocyclic ring, wherein the ring comprises 6
carbon atoms, referred to herein as "(C.sub.6)aryl".
[0081] A "cycloalkyl group" means a monocyclic or polycyclic
saturated ring comprising carbon and hydrogen atoms and having no
carbon-carbon multiple bonds. Examples of cycloalkyl groups
include, but are not limited to, (C.sub.3-C.sub.7)cycloalkyl
groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and cycloheptyl, and saturated cyclic and bicyclic terpenes. A
cycloalkyl group can be unsubstituted or substituted by one or more
suitable substituents. Preferably, the cycloalkyl group is a
monocyclic ring or bicyclic ring.
[0082] The term "alkoxy group" means an --O-alkyl group, wherein
alkyl is as defined above. An alkoxy group can be unsubstituted or
substituted with one or more suitable substituents. Preferably, the
alkyl chain of an alkoxy group is from 1 to 25 carbon atoms in
length, referred to herein as "--(C.sub.1-C.sub.25)alkoxy".
[0083] The term "aryloxy group" means an --O-aryl group, wherein
aryl is as defined above. An aryloxy group can be unsubstituted or
substituted with one or more suitable substituents. Preferably, the
aryl ring of an aryloxy group is a monocyclic ring, wherein the
ring comprises 6 carbon atoms, referred to herein as
"(C.sub.6)aryloxy".
[0084] The term "benzyl" means --CH.sub.2-phenyl.
[0085] The term "phenyl" means --C.sub.6H.sub.5. A phenyl group can
be unsubstituted or substituted with one or more suitable
substituents.
[0086] A "carbonyl" group is a divalent group of the formula
--C(O)--.
[0087] An "alkoxycarbonyl" group means a monovalent group of the
formula --C(O)-alkoxy. Preferably, the hydrocarbon chain of an
alkoxycarbonyl group is from 1 to 25 carbon atoms in length.
[0088] As used herein, "halogen" means fluorine, chlorine, bromine,
or iodine. Correspondingly, the meaning of the terms "halo" and
"Hal" encompass fluoro, chloro, bromo, and iodo.
[0089] As used herein, a "suitable substituent" means a group that
does not nullify the synthetic or pharmaceutical utility of the
active or the paclitaxel solubilizer of the invention. Examples of
suitable substituents include, but are not limited to:
(C.sub.1-C.sub.8)alkyl; (C.sub.1-C.sub.8)alkenyl;
(C.sub.1-C.sub.8)alkynyl; (C.sub.6)aryl;
(C.sub.2-C.sub.5)heteroaryl; (C.sub.3-C.sub.7)cycloalkyl;
(C.sub.1-C.sub.8)alkoxy; (C.sub.6)aryloxy; CN; OH; oxo; halo,
CO.sub.2H; NH.sub.2; NH((C.sub.1-C.sub.8)alkyl);
N((C.sub.1-C.sub.8)alkyl).sub.2; NH((C.sub.6)aryl);
N((C.sub.6)aryl).sub.2; CHO; CO((C.sub.1-C.sub.8)alkyl- );
CO((C.sub.6)aryl); CO.sub.2((C.sub.1-C.sub.8)alkyl); and
CO.sub.2((C.sub.6)aryl). One of skill in art can readily choose a
suitable substituent based on the stability and pharmacological and
synthetic activity of the paclitaxel solubilizer of the
invention.
[0090] As used herein, a "PEG-vitamin E" means a compound of the
formula: 2
[0091] wherein the variable x is 0 or 1 and the variable n is about
1 to about 20,000, preferably, from about 3 to about 1000.
Preferably, the PEG-vitamin E is .alpha.-tocopheryl polyethylene
glycol 1000 succinate, referred to herein as tocophersolan (sold by
Eastman Chemical Co. under the trade name vitamin E TPGS NE). In
tocophersolan, x is 1 and n has an average value of 22. Other
preferred PEG-vitamin Es, include tocophereth-5, tocophereth-10,
tocophereth-12, tocophereth-18, and tocophereth-50. In such
tocophereths, x is 0 and the average ethoxylation value is 5, 10,
12, 18, and 50 respectively. PEG-vitamin Es are available
commercially, for example, from Eastman Chemical Co., Kingsport,
Tenn. and Pacific Corporation, Seoul, Korea.
[0092] As used herein, a quaternary ammonium salt means a compound
of the general formula: 3
[0093] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 are independently
selected from the group consisting of (C.sub.1-C.sub.25)alkyl,
aryl, (C.sub.1-C.sub.25)alkylaryl, (C.sub.2-C.sub.25)alkenyl,
(C.sub.2-C.sub.25)alkynyl, (C.sub.2-C.sub.25)alkenylaryl,
(C.sub.2-C.sub.25)alkynylaryl, phenyl, and benzyl.
[0094] The group X is a suitable anion, for example, but not
limited to, halide, acetate, benzenesulfonate, benzoate,
bicarbonate, bitartrate, calcium edetate, camsylate, carbonate,
citrate, edetate, edisylate, estolate, esylate, fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydroxynaphthoate,
isethionate, lactate, lactobionate, malate, maleate, mandelate,
mesylate, methylbromide, methylnitrate, methylsulfate, muscate,
napsylate, nitrate, pamoate (embonate), panthothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
subacetate, succinate, sulfate, tannate, tartrate, teoclate, and
triethiodide. Preferred quaternary ammonium salts include, but are
not limited to, benzethonium chloride, benzalkonium chloride, and
cetrimde.
[0095] As used herein, the term "polyethylene glycol of a fatty
alcohol (PEG-fatty alcohol)" means a compound of the formula:
C.sub.8H.sub.17-A-B--(OCH.sub.2CH.sub.2).sub.n--OH
[0096] wherein n has an average value of about 1 to about 75; the
variable "A" represents the optional presence of one or more
carbon-carbon double bonds and the variable "B" represents
(C.sub.1-C.sub.15)alkyl. Preferred PEG-fatty alcohols are
octoxynols, oleths, and laureths. As used herein, an "octoxynol" is
a compound of the formula:
C.sub.8H.sub.17--C.sub.6H.sub.4--(OCH.sub.2CH.sub.2).sub.n--OH
[0097] wherein n is an integer having an average value of about 1
to about 75, preferably, n has an average value of 1, 3, 5, 7, 8,
9, 10, 11, 12, 13, 16, 20, 25, 30, 33, 40, or 70, more preferably,
n has an average value of about 7 to 12, more preferably about 9.
Preferred octoxynols include octoxynol-9 (Triton.RTM. X-100).
Octoxynols are commercially available, for example, from
Rhne-Poulenc, Shelton, Conn. under the trade name TRITON.
[0098] As used herein, an "oleth" is a compound of the formula:
4
[0099] wherein n is an integer having an average value of about 1
to about 55, preferably, n has an average value of 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 15, 16, 20, 25, 40, 44, or 50, more
preferably, n has an average value of about 7 to 12, more
preferably about 9. Oleths are commercially available, for example,
from ICI Surfactants, Wilmington, Del. under the trade name BRIJ or
from Heterene, Inc., Paterson, N.J. under the trade name
HETOXOL.
[0100] As used herein, a "laureth" is a compound of the
formula:
C.sub.8H.sub.17--C.sub.4H.sub.8--(OCH.sub.2CH.sub.2).sub.n--OH
[0101] wherein n is an integer having an average value of about 1
to about 55, preferably, n has an average value of 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 15, 16, 20, 23, 25, 30, or 40 more
preferably, n has an average value of about 7 to 12, more
preferably about 23 (i.e., laureth-23 also known as BRIJ 35, ICI
Surfactants). Laureths are commercially available, for example,
from ICI Surfactants, Wilmington, Del. under the trade name BRU or
from Rhne-Poulenc, Shelton, Conn. under the trade name
RHODASURF.
[0102] As used herein, the term "polysorbate" means a compound of
the general formula: 5
[0103] wherein the sum of W+X+Y+Z is an integer having an average
value of about 5, 4, or 20; R.sup.5, R.sup.6, and R.sup.7 are
independently H, 6
[0104] and n is an integer ranging from 8 to 20. Preferred
polysorbates are polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85,
more preferably polysorbate 20 or polysorbate 80. Polysorbates are
available commercially under the trade name TWEEN from
Rhne-Poulenc, Shelton, Conn.
[0105] As used herein, the term "polyethyleneglycol monoacid fatty
ester" (PEG-monoacid fatty ester) means a compound of the general
formula: 7
[0106] where R.sup.8 is (C.sub.1-C.sub.25)alkyl,
(C.sub.2-C.sub.25)alkenyl- , or (C.sub.2-C.sub.25)alkynyl, in
substantially pure form. As used herein, "substantially pure form"
means that at least about 85% of polyethyleneglycol monoacid fatty
ester is a single polyethyleneglycol monoacid fatty ester,
preferably about 95%. The variable m is an integer having an
average value of from 2 to 200, preferably, 6 to 150, more
preferably, 10 to 50. Preferably, R.sup.8 is (C.sub.8C.sub.20) or
(C.sub.8-C.sub.20)alkenyl. Preferably, R.sup.8(CO)O is laurate,
oleate, or stearate. Preferred PEG-monoacid fatty esters include,
but are not limited to, PEG-20 monolaurate, PEG-20 monooleate, and
PEG-20 monostearate.
[0107] As used herein, the term "polyethyleneglycol-glyceryl fatty
ester" (PEG-glyceryl fatty ester) means a compound of the general
formula:
[0108] where R.sup.9 is independently OH, OCOR.sup.8,
(OCH.sub.2CH.sub.2).sub.mOH, or
(OCH.sub.2CH.sub.2).sub.mOCOR.sup.8, wherein: 8
[0109] (a) at least one of R.sup.9 is OCOR.sup.8 and one of R.sup.9
is (OCH.sub.2CH).sub.mOH; or
[0110] (b) at least one of R.sup.9 is
(OCH.sub.2CH.sub.2).sub.mOCOR.sup.8.
[0111] R.sup.8 is (C.sub.1-C.sub.25)alkyl,
(C.sub.2-C.sub.25)alkenyl, or (C.sub.2-C.sub.25)alkynyl. And The
variable m is an integer having an average value of from 2 to 200,
preferably, 6 to 150, more preferably, 10 to 50. Preferably,
R.sup.8 is (C.sub.8-C.sub.20) or (C.sub.8-C.sub.20)alkenyl.
Preferably R.sup.8(CO)O is laurate, oleate, or stearate.
[0112] A subclass of PEG-glyceryl fatty esters has the formula:
9
[0113] where R.sup.8 is (C.sub.1-C.sub.25)alkyl,
(C.sub.2-C.sub.25)alkenyl- , or (C.sub.2-C.sub.25)alkynyl. And
R.sup.9 is independently OH, OCOR.sup.8,
(OCH.sub.2CH.sub.2).sub.mOH, or (OCH.sub.2CH.sub.2).sub.mOCOR-
.sup.8, wherein at least one of R.sup.9 is
(OCH.sub.2CH.sub.2).sub.mOH or (OCH.sub.2CH.sub.2).sub.mOCOR.sup.8.
The variable m is an integer having an average value of from 2 to
200, preferably, 6 to 150, more preferably, 10 to 50. Preferably,
R.sup.8 is (C.sub.8-C.sub.20) or (C.sub.8-C.sub.20)alkenyl.
Preferably R.sup.8(CO)O is laurate, oleate, or stearate.
[0114] A further subclass of PEG-glyceryl fatty esters has the
formula: 10
[0115] Wherein R.sup.8 is defined as above. Preferred PEG-glyceryl
fatty esters include, but are not limited to, PEG-20 glyceryl
monooleate, PEG-20 glyceryl monostearate, and PEG-20 glyceryl
monolaurate.
4. DETAILED DESCRIPTION OF THE INVENTION
[0116] The invention encompasses cremophor-free formulations
comprising paclitaxel, derivatives, or pharmaceutically acceptable
salts thereof and one or more paclitaxel solubilizers that are
useful for use in mammals, particularly humans. Paclitaxel
solubilizers of the invention include compounds falling within the
classes of PEG-Vitamin Es; quaternary ammonium salts; PEG-monoacid
fatty esters; PEG-glyceryl fatty esters; polysorbates; PEG-fatty
alcohols. These formulations are advantageous in that they do not
contain cremophor and thus avoid or reduce the toxicities and other
disadvantages of cremophor formulations. The formulations of the
invention also solubilize paclitaxel in aqueous medium and thus are
particularly advantageous because paclitaxel is practically
insoluble in water.
[0117] The formulations of the invention are useful for treating
mammalian cancers and other medical conditions treatable by
paclitaxel. By "treating" it is meant that the formulations are
administered to inhibit or reduce the rate of cancer-cell
proliferation in an effort to induce partial or total remission,
for example, inhibiting cell division by promoting microtubule
formation. For instance, the formulations of the invention are
useful for treating solid tumors and blood-born tumors. Examples of
cancers treatable or preventable by formulations of the invention
include, but are not limited to, cancers of the lymph node; breast;
cervix; uterus; gastrointestinal tract; lung; ovary; prostate;
mouth; brain; head; neck; throat; testes; kidney; pancreas; bone;
spleen; liver; bladder; skin; larynx; nasal passages; AIDS-related
cancers, and cancers of the blood. The formulations can be used
alone or in combination with other chemotherapeutics. The mode,
dosage, and schedule of administration of paclitaxel, derivatives,
and pharmaceutically acceptable salts thereof in human cancer
patients have been extensively studied, see, e.g. 1989 Ann. Int.
Med., 111:273-279, incorporated herein by reference.
[0118] The invention encompasses single-unit dosage forms and
multi-unit dosage forms of paclitaxel, derivatives, and
pharmaceutically acceptable salts thereof in solid, liquid,
semisolid, gel, suspension, emulsion, or solution form. In one
embodiment, the invention relates to single-unit dosage and
multi-unit dosage forms. In another embodiment, the invention
relates to single-unit dosage and multi-unit dosage forms of
liquid-concentrates, solids, semi-solids, and gels in concentrated
form for further formulation (e.g., lyophilized solids and liquid
concentrates for reconstitution prior to parenteral
administration). Formulations of the invention in
liquid-concentrate form are, preferably, in an organic solvent,
such as ethanol or aqueous ethanol, that is to be diluted with an
aqueous medium prior to administration. Preferably, the
formulations are easy to handle, stable for storage and shipment,
and inexpensive to manufacture compared to previous paclitaxel
formulations. Preferably, the formulations of the invention are
sterile.
[0119] The formulations of the invention can be prepared by
combining the actives, solubilizers of the invention, and other
components using well-known pharmaceutical-formulation methods.
Formulation of liquid dosage forms, such as for intravenous
administration is described in Remington: the Science and Practice
of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton,
Pa., 19th ed., 1995, Chapters 87 and 88; incorporated herein by
reference. A comprehensive discussion on formulating solid forms,
such as powders, tablets, pills, and capsules is presented in
Remington: the Science and Practice of Pharmacy, Alfonso R. Gennaro
ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, Chapters 91
and 92, incorporated herein by reference. A comprehensive
discussion on formulating solutions, emulsions, and suspensions is
presented in Remington: the Science and Practice of Pharmacy,
Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed.,
1995, Chapter 86, incorporated herein by reference. Formulations of
the invention in the form of gels and semisolids containing the
active can be prepared according to well known methods. For
instance, by mixing the active with the paclitaxel solubilizers of
the invention, and any additional components or excipients in a
standard V-blender. Preferably, for reconstitution, solids (e.g.,
lyophilized solids), liquid concentrates, semisolids, gels,
suspensions, and emulsions, contain about 25 milligrams to about
2500 milligrams of active, more preferably, about 50 milligrams to
about 500 milligrams.
[0120] The paclitaxel solubilizers of the invention are used in
formulations of the invention in amounts that enhance the
solubility of paclitaxel, derivatives, and pharmaceutically
acceptable salts thereof in an aqueous medium. Armed with the
present disclosure that specifies specific paclitaxel solubilizers
and combinations thereof that enhance the aqueous solubility of
paclitaxel, derivatives, and pharmaceutically acceptable salts
thereof, one of skill in the art can readily determine suitable
paclitaxel-solubilizer amounts by simple solubility experiments.
For example, by mixing the paclitaxel solubilizer and the active,
contacting the resulting mixture with an aqueous medium, filtering,
and measuring the amount of dissolved active, for example, by
spectrophotometry.
[0121] In one embodiment, the amount(s) of paclitaxel solubilizer
in formulations of the invention can be expressed as a ratio
relative to the amount of active. This is particularly useful when
formulating a formulation of the invention in other than liquid
form, e.g. solid, semisolid, gel, suspension, or emulsion, for
example, a lyophilized solid. Preferred ratios of paclitaxel
solubilizers to paclitaxel, derivatives, and pharmaceutically
acceptable salts thereof are as follows:
1 Preferred ratio of More preferred ratio of paclitaxel solubilizer
paclitaxel solubilizer expressed as unit weight expressed as unit
weight per unit weight of per unit weight of paclitaxel,
derivative, paclitaxel, derivative, Excipient Class or salt thereof
or salt thereof PEG-Vitamin Es about 5 to about 200 about 10 to
about 100 Quaternary about 0.01 to about 1 about 0.016 to about 0.3
ammonium salts PEG-monoacid about 5 to about 200 about 10 to about
100 fatty esters PEG-glyceryl about 5 to about 200 about 10 to
about 100 fatty esters Polysorbates about 5 to about 200 about 10
to about 100 PEG-fatty alcohols about 5 to about 200 about 10 to
about 100
[0122] In another embodiment, the formulations of the invention
comprise an aqueous medium. Preferably, such a formulation is
suitable for parenteral administration. In this embodiment, the
preferred concentration of paclitaxel, a derivative, or a salt
thereof is from about 0.2 mg/ml to about 3 mg/ml, more preferably,
about 0.3 mg/ml to about 1.2 mg/ml. Preferred concentrations of
paclitaxel solubilizers for use with aqueous paclitaxel solutions
of the invention are as follows:
2 Preferred More preferred concentrations of concentrations of
paclitaxel solubilizers paclitaxel solubilizers in in an aqueous
medium an aqueous medium Excipient Class (mg/ml) (mg/ml)
PEG-Vitamin Es about 3 to about 120 about 15 to about 100
Quaternary about 0.0048 to about 0.35 about 0.001 to about 0.2
ammonium salts PEG-monoacid about 3 to about 120 about 15 to about
100 fatty esters PEG-glyceryl about 3 to about 120 about 15 to
about 100 fatty esters Polysorbates about 3 to about 120 about 15
to about 80 PEG-fatty about 3 to about 120 about 15 to about 110
alcohols
[0123] In another embodiment, the formulations of the invention are
in liquid-concentrate form. Liquid concentrate meaning that the
formulations are to be diluted prior to parenteral administration,
preferably, diluted with an aqueous medium. Preferably, liquid
concentrates of the invention have less than about 5% by weight
water, more preferably, less than about 1%, even more preferably,
liquid concentrates are substantially anhydrous. Preferably, the
concentration of paclitaxel in liquid concentrates of the invention
is from about 3 mg/ml to about 10 mg/ml, more preferably, about 6
mg/ml. Paclitaxel solubilizers of the invention can comprise about
0.1% to about 99% by weight of liquid-concentrate formulations of
the invention. Preferably, liquid concentrates of the invention
comprise about 20% to about 99% total solubilizer weight, e.g.,
about 20% to about 99% total weight of one or more of a PEG-vitamin
E, a PEG-monoacid fatty ester, a PEG-glyceryl fatty ester, a
polysorbate, or a PEG-fatty alcohol. Thus, preferably, in a
liquid-concentrate formulations, when one paclitaxel solubilizer of
the invention is used in combination with one or more other
paclitaxel solubilizers of the invention, the total
paclitaxel-solubilizer weight percent is from about 20% to about
99%. Preferably, when combinations of paclitaxel solubilizers are
used in liquid-concentrate formulations, each individual paclitaxel
solubilizer (excluding the class of quaternary ammonium salts)
represents at least about 5% by weight of the total
paclitaxel-solubilizer weight. When a quaternary ammonium salt is
included in a liquid-concentrate formulation of the invention, the
preferred concentration is about 0.005 mg/ml to about 5 mg/ml.
[0124] A few preferred liquid concentrate formulations of the
invention (i.e., formulations 1-13) are shown below.
3 Formulation 1 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% *PEG-400 0.1% to 99% 2.5% to 92.5%
*Polysorbate 80 0.1% to 99% 2.5% to 92.5% Ethanol 0% to 49% 5% to
59% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01%
to 1% 0.01% to 1% *The combination of PEG-400 and Polysorbate 80
comprises at least about 40% by weight of the formulation.
[0125]
4 Formulation 2 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 2% to
93% monooleate Ethanol 0% to 59% 5% to 69% *Polysorbate 80 0.1% to
99% 2% to 93% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric
acid 0.01% to 1% 0.01% to 1% *The combination of PEG-20 glyceryl
monooleate and Polysorbate 80 comprises at least about 30% by
weight of the formulation.
[0126]
5 Formulation 3 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 1% to
94% monooleate Ethanol 0% to 79% 5% to 79% *Vitamin E TPGS 0.1% to
99% 1% to 94% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric
acid 0.01% to 1% 0.01% to 1% *The combination of PEG-20 glyceryl
monooleate and Vitamin E TPGS comprises at least about 20% by
weight of the formulation.
[0127]
6 Formulation 4 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 2% to
93% monooleate Ethanol 0% to 59% 5% to 69% *PEG-20 monolaurate 0.1%
to 99% 2% to 93% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric
acid 0.01% to 1% 0.01% to 1% *The combination of PEG-20 glyceryl
monooleate and PEG-20 monolaurate comprises at least about 30% by
weight of the formulation.
[0128]
7 Formulation 5 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 2% to
93% monooleate Ethanol 0% to 59% 5% to 69% *Polysorbate 20 0.1% to
99% 2% to 93% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric
acid 0.01% to 1% 0.01% to 1% *The combination of PEG-20 glyceryl
monooleate and Polysorbate 20 comprises at least about 30% by
weight of the formulation.
[0129]
8 Formulation 6 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 2% to
93% monooleate Ethanol 0% to 59% 5% to 69% *PEG-20 monooleate 0.1%
to 99% 2% to 93% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric
acid 0.01% to 1% 0.01% to 1% *The combination of PEG-20 glyceryl
monooleate and PEG-20 monooleate comprises at least about 30% by
weight of the formulation.
[0130]
9 Formulation 7 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 79% 5% to 79%
Vitamin E TPGS 20% to 99% 20% to 94% Benzethonium chloride 0% to
0.2% 0% to 0.2% Citric acid 0.01% to 1% 0.01% to 1%
[0131]
10 Formulation 8 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80%
*Vitamin E TPGS 0.1% to 99% 1% to 94% *PEG-400 0.1% to 99% 1% to
94% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01%
to 1% 0.01% to 1% *The combination of Vitamin E TPGS and PEG-400
comprises at least about 20% by weight of the formulation.
[0132]
11 Formulation 9 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80%
*Vitamin E TPGS 0.1% to 99% 1% to 94% *PEG-20 monooleate 0.1% to
99% 1% to 94% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric
acid 0.01% to 1% 0.01% to 1% *The combination of Vitamin E TPGS and
PEG-20 monooleate comprises at least about 20% by weight of the
formulation.
[0133]
12 Formulation 10 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80%
*Vitamin E TPGS 0.1% to 99% 1% to 94% *Polysorbate 80 0.1% to 99%
1% to 94% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid
0.01% to 1% 0.01% to 1% *The combination of Vitamin E TPGS and
Polysorbate 80 comprises at least about 20% by weight of the
formulation.
[0134]
13 Formulation 11 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80%
*Vitamin E TPGS 0.1% to 99% 1% to 94% *Polysorbate 20 0.1% to 99%
1% to 94% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid
0.01% to 1% 0.01% to 1% *The combination of Vitamin E TPGS and
Polysorbate 20 comprises at least about 20% by weight of the
formulation.
[0135]
14 Formulation 12 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80%
*Vitamin E TPGS 0.1% to 99% 1% to 94% *PEG-20 monolaurate 0.1% to
99% 1% to 94% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric
acid 0.01% to 1% 0.01% to 1% *The combination of Vitamin E TPGS and
PEG-20 monolaurate comprises at least about 20% by weight of the
formulation.
[0136]
15 Formulation 13 Preferred weight % Component Weight % range range
Paclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 70% 5% to 70%
*Polysorbate 80 0.1% to 99% 1% to 94% *PEG-20 monooleate 0.1% to
99% 1% to 94% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric
acid 0.01% to 1% 0.01% to 1% *The combination of Polysorbate 80 and
PEG-20 monooleate comprises at least about 30% by weight of the
formulation.
[0137] The formulations of the invention can include additional
pharmaceutically acceptable excipients. Preferred additional
excipients do not affect the ability of the paclitaxel solubilizers
of the invention to solubilize paclitaxel. Preferred additional
excipients for intravenous administration are water, aqueous
vehicles such as saline, Ringer's solution, or dextrose solution.
Other examples of suitable excipients, such as binders and fillers
are listed in Remington: the Science and Practice of Pharmacy, 18th
Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, Pa., 1995
and Handbook of Pharmaceutical Excipients, 3rd Edition, ed. Arthur
H. Kibbe, American Pharmaceutical Association, Washington D.C.
2000. Whatever excipient is incorporated into the present
formulations, preferably, that excipient is sterile when added, or
sterilized during the same process that sterilizes the
formulation.
[0138] Administration of formulations of the invention can be
systemic or local. In most instances, administration to a mammal
will result in systemic release of the active (i.e., into the
bloodstream). Methods of administration include enteral routes,
such as oral administration; topical routes, such as local,
transdermal and intradermal administration; and parenteral routes,
such as intravenous injection. Preferably, the formulations of the
invention are administered intravenously.
[0139] Typically, formulation of the invention for parenteral
administration are solutions in sterile isotonic aqueous vehicles,
such as water, saline, Ringer's solution, or dextrose solution.
Formulations for intravenous administration may optionally include
a local anesthetic such as lignocaine to ease pain at the site of
the injection. For parenteral administration, the formulations of
the invention can be supplied as a sterile, dry lyophilized powder
or a water-free liquid concentrate in a hermetically sealed
container, such as an ampoule or an i.v. bag, the container
indicating the quantity of active. Such a powder or concentrate is
then diluted with an appropriate aqueous medium prior to
administration. An ampoule of sterile water, saline solution, or
other appropriate aqueous medium can be provided with the powder or
concentrate in a separate container to dilute the active prior to
administration. Alternatively, the formulations can be supplied in
pre-mixed form, ready for administration.
[0140] A further embodiment of the present invention includes a
sterilization step. The sterilization may be carried out in several
ways, e.g., by using a bacteriological filter, by incorporating
sterilizing agents into the composition, by irradiation, or by
heating. Sterilization may be effected, for example, by filtration
through a 0.2 .mu.m pore size filter. Other methods of sterilizing
well known to those skilled in the art can also be employed.
[0141] To formulate aqueous parenteral dosage forms, an aqueous
medium, e.g., physiological saline or purified water, paclitaxel
solubilizers, and any additional components are mixed in sanitized
equipment, filtered, and packaged according to well known methods
in the art (for a discussion see e.g., Remington: the Science and
Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co.
Easton, Pa., 19th ed., 1995, Chapter 87). For parenteral
administration the dosage will, of course, vary with the potency of
the particular active based on potency, the patient weight, and the
nature of the patient's condition. The preferred dosage for
intravenous administration is that listed in The Physician's Desk
Reference, 54th edition, 881-887, Medical Economics Company (2000).
Dosages typically fall in the range of about 135 mg/m.sup.2 to 400
mg/m.sup.2, preferably 175 mg/m.sup.2, more preferably, 200
mg/m.sup.2. An oncologist skilled in the art of cancer treatment
will be able to ascertain appropriate protocols for effective
administration of the formulations of the invention by referring to
the earlier studies of paclitaxel, derivatives, and
pharmaceutically acceptable salts thereof or the dosages listed in
medical reference books.
[0142] Formulations of the invention for oral delivery are
preferably in the form of capsules, tablets, pills, soft-gel
capsules, emulsions, solutions, or suspensions. Oral compositions
can include standard vehicles, excipients, and diluents. Orally
administered formulations of the invention can optionally include
one or more sweetening agents and one or more flavoring agents to
provide a pharmaceutically palatable preparation. A therapeutically
effective oral dosage for formulations of the invention is
determined by standard clinical techniques according to the
judgment of a medical practitioner. For example, in addition to
information provided in medical reference books and pharmaceutical
literature, well-known in vitro or in vivo assays can be used to
help identify optimal dosages.
[0143] To formulate and administer transdermal dosage forms, well
known transdermal delivery devices such as patches can be used
(Ghosh, T. K; Pfister, W. R.; Yum, S. I. Transdermal and Topical
Drug Delivery Systems, Interpharm Press, Inc. p. 249-297,
incorporated herein by reference). For example, a reservoir type
patch design can comprise a backing film coated with an adhesive,
and a reservoir compartment comprising a formulation of the
invention, that is separated from the skin by a semipermeable
membrane (e.g., U.S. Pat. No. 4,615,699, incorporated herein by
reference). The adhesive coated backing layer extends around the
reservoir's boundaries to provide a concentric seal with the skin
and hold the reservoir adjacent to the skin.
[0144] To formulate and administer local dosage forms, well known
mediums such as lotions, creams, and ointments can be used.
[0145] The present formulations can include additional actives and
thus can serve as base formulation for combination therapy. Such
additional actives can be included and distributed in the
formulation itself (e.g., pre-diluted or in a form for
reconstitution) or added to the formulation prior to
administration. For example, the formulations of the invention and
other actives can be combined in an i.v. bag prior to
administration. Additional actives can be any pharmaceutical
conventionally administered with paclitaxel, for example, other
chemotherapeutics, such as, but not limited to, cisplatin,
carboplatin, tamoxifen, epirubicin, leuprolide, bicalutamide,
goserelin implant, irinotecan, gemcitabine, and sargramostim or
pharmaceutically acceptable salts thereof, preferably cisplatin.
Thus, the formulations of the invention encompass formulations
comprising active, the paclitaxel solubilizers of the invention,
and other actives suitable for co-administration with
paclitaxel.
[0146] The formulations of the invention can be packaged and
distributed as a non-aqueous liquid-solution concentrates for
dilution in an aqueous medium prior to administration. For example,
the present formulations in liquid-concentrate form or in the form
of a lyophilized solid can be added to an i.v. bag and diluted with
an aqueous medium prior to intravenous infusion. Preferably, such
concentrates comprise a non-aqueous solvent, the active, and one or
more of the paclitaxel solubilizers of the invention. Preferably,
the non-aqueous solvent is an organic solvent, such as ethanol.
Thus, the formulations of the invention in liquid-concentrate form
can be packaged as ethanol solutions, for example, packaged in a
multi-unit-dose vial containing 30 mg paclitaxel, the paclitaxel
solubilizers, and about 0.2 ml to about 3 ml ethanol or a
multi-unit-dose vial containing 100 mg paclitaxel, the paclitaxel
solubilizers, and about 0.6 ml to 10 ml of ethanol.
[0147] The formulations of the invention, can be distributed in
containers that allow rapid dissolution of the formulation upon
reconstitution with appropriate sterile diluents, in situ, giving
an appropriate sterile solution of desired active concentration for
administration. As used herein, the term "suitable containers"
means a container capable of maintaining a sterile environment,
such as a vial, package, or bottle, capable of delivering a vacuum
dried product hermetically sealed by a stopper means. Additionally,
suitable containers implies appropriateness of size, considering
the volume of solution to be held upon reconstitution of the vacuum
dried composition; and appropriateness of container material,
generally Type I glass. The stopper means employed, e.g., sterile
rubber closures or an equivalent, should be understood to be that
which provides the aforementioned seal, but which also allows entry
for the purpose of introduction of diluent, e.g., sterile Water for
Injection, USP, Normal Saline, USP, or 5% Dextrose in Water, USP,
for the reconstitution of the desired active solution. These and
other aspects of the suitability of containers for pharmaceutical
products such as those of the invention are well known to those
skilled in the practice of pharmaceutical arts.
[0148] The present invention will be further understood by
reference to the following non-limiting examples. The following
examples are provided for illustrative purposes only and are not to
be construed as limiting the invention scope of the invention in
any manner.
5. EXAMPLES
Example 1
Preparation and Identification of Aqueous Paclitaxel Formulations
with Enhanced Solubility
[0149] A plurality of aqueous formulations, each containing
paclitaxel and various combinations and concentrations of the
excipients listed in Table 1 below were prepared and systematically
analyzed for their ability to dissolve paclitaxel.
[0150] The GRAS ("generally regarded as safe") excipients listed in
Table 1 are all obtainable from Sigma-Aldrich Fine Chemicals, BASF,
or other commercial suppliers.
16TABLE 1 Excipients Used in the Examples 1 .gamma.-Cyclodextrin 2
.beta.-Cyclodextrin 3 Diethanolamine 4 Propyleneglycol 5 Glycerin 6
Poloxomer .RTM. 188 7 Poloxomer .RTM. 237 8 Poloxomer .RTM. 338 9
Poloxomer .RTM. 407 10 Polyethyleneglycol 300 (PEG-300) 11
Polyethyleneglycol 600 (PEG-600) 12 Polyethyleneglycol 1000 (PEG-
1000) 13 Polyethyleneglycol 4000 (PEG- 4000) 14 Polysorbate 20 15
Polysorbate 80 16 Polyethyleneglycol-20 monostearate (PEG-20
monostearate) 17 Polyethyleneglycol-40 monostearate (PEG-40
monostearate) 18 Polyethyleneglycol-50 monostearate (PEG-50
monostearate) 19 Choline chloride Polyethyleneglycol-20 glyceryl
monooleate (PEG-20 glyceryl monooleate) 20 Sodium caprylate 21
Polyethyleneglycol-100 monostearate (PEG-100 monostearate) 22
Povidone 23 Deoxycholoate 24 Laureth-23 25 Isosorbide dimethyl
ether 26 Polyethyleneglycol-20 monooleate (PEG-20 monooleate) 27
Polyethyleneglycol-20 monolaurate (PEG- 20monolaurate) 28
Polyethyleneglycol-tetrahydrofurfuryl ether (PEG-
tetrahydrofurfuryl) 29 octoxynol-9 30 2-pyrrolidone 31 Benzethonium
chloride 32 Benzalkonium chloride 33 cetrimide 34
Polyethyleneglycol-1,2-diacyl-sn-glycerol-3-
phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]
(PEG-DSPE) 35 Polyvinyl alcohol 36 tocophersolan 37 Sodium lauryl
sulfate (SDS) 38 Protamine sulfate 39 Laureth-23 40
Polyethyleneglycol-20 glyceryl monolaurate(PEG-20 glyceryl
monolaurate)
[0151] Preparation of Formulations with Improved Solubilities
[0152] A stock solution comprising about 10 milligrams paclitaxel
per milliliter ethanol was prepared. Then a plurality of excipients
were selected from Table 1 and each selected excipient was prepared
as an aqueous solution, at various concentrations, for example, as
three physiological-saline stock solutions each at one of three set
concentrations, e.g. about 120 milligrams/milliliter, about 60
milligrams/milliliter, and about 30 milligrams/milliliter. Then all
permutations of formulations that each comprise about 12 .mu.l of
the paclitaxel/ethanol solution (about 120 .mu.g of paclitaxel per
sample well) and about 90 .mu.l of one to three of the excipient
stock solutions were prepared.
[0153] All permutations of excipients stock solutions and
paclitaxel were generated using the MATLAB program formulating
software (commercially available from Mathworks, Natick, Mass.).
The permutations so generated were downloaded into a Microsoft
EXCEL spread sheet and from this spread sheet, a worklist was
constructed according to standard programming methods well known to
those skilled in the art. The work-list is then used to direct the
Genesis liquid-handling device to prepare the various permutations
of excipients and paclitaxel generated by MATLAB. The worklist
combines the formulation output of the MATLAB program with
Genesis-appropriate commands (as found in the Genesis operating
manual) in a file format that is directly readable by the Genesis
device. For example, the number of possible unique combinations
with 120 excipient stock solutions is: 1 ( 120 + 3 - 1 ) ! 3 ! (
120 - 1 ) ! = 295 , 240
[0154] giving a grand total of 295,240 unique formulations. The
formulations were prepared in DYNEX 96 sample well polystyrene
plates (available from Thermo Labsystems Oy, Helsinki, Finland).
Each sample well has a volume of 250 .mu.l. Each sample formulation
generated by the MATLAB program was prepared in triplicate by
adding about 12 .mu.l of the paclitaxel/ethanol solution and about
30 .mu.l of three of the excipient stock solution to each sample
well. The stock solutions were added using a Genesis
liquid-handling device (Tecan-US, RTP, NC). The force provided by
adding the excipient via the Genesis liquid-handling device was
sufficient to adequately mix the components. The plates were sealed
with aluminum sealing tapes and incubated at 25.degree. C. for 48
hours before they were measured on a UV plate reader at 500 nm
(SpectraMax Plus, Molecular Devices, Sunnyvale, Calif.).
[0155] Results
[0156] The screening results, measured as turbidity at 500 nm for
all of the samples were imported into a data analysis and
visualization program Spotfire (Spotfire, Cambridge, Mass.) and
samples that reproducibly (% standard deviation <5%)
demonstrated an absorbance below 0.045 were selected as hits. An
absorbance below 0.045 indicates that the paclitaxel was completely
dissolved, i.e., the paclitaxel concentration was 1.2 mg/ml, and
stayed dissolved for 48 hours. The selected formulations along with
concentrations of the paclitaxel solubilizers are listed in Table 2
below. Each of these examples can readily be used to formulate
paclitaxel into a suitable injectable dosage form.
[0157] The chemical stability of the paclitaxel formulations in
Table 2 was analyzed using a Waters Alliance 2790 HPLC equipped
with a Waters 996 Photo Diode Array Detector. The separation was
carried out on a Phenomenex Curosil Pentafluorphenyl column
(150.times.3.2 mm, 3 m) with a mobile phase of 55% water and 45%
acetonitrile, held isocratic at a flow rate of 0.5 ml/min. A
control solution of paclitaxel (0.1 mg/ml) for comparison was
prepared from a stock solution of 1 mg/ml in ethanol by
sub-dilution into acetonitrile. Each of the formulations of
paclitaxel were diluted in acetonitrile to a concentration of
approximately 0.1 mg/ml before HPLC analysis and absorbance was
measured at 229 nm. The chromatograph for each formulation was
compared with the control solution. No degradation of Paclitaxel
was observed for the selected formulations, even after 48 hours
incubation at RT in physiological saline, establishing chemical
stability of the formulations of the invention. Using this general
procedure with the 40 excipients listed in Table 1, the
formulations listed in Table 2 were selected as stable and capable
of dissolving paclitaxel in an aqueous medium to a concentration of
1.2 mg/ml.
17TABLE 2 Selected Formulations Conc. Conc. Conc. Abs Excipient
mg/ml Excipient mg/ml Excipient mg/ml 0.039 polysorbate 80 18
octoxynol-9 18 benzalkonium chloride 18 0.039 polysarbate 80 18
octoxynol-9 18 cetrimide 18 0.039 polysorbate 80 36 octoxynol-9 36
PEG-20 monolaurate 36 0.039 polysorbate 80 36 octoxynol-9 36 PEG-20
monooleate 36 0.040 polysorbate 80 36 octoxynol-9 72 0.039
polysorbate 20 36 octoxynol-9 36 PEG-20 monolaurate 36 0.039
polysorbate 20 36 octoxynol-9 72 0.039 polysorbate 20 18 Sodium
caprylate 18 cetrimide 18 0.040 polysorbate 80 72 PEG-20 monooleate
36 0.040 polysorbate 80 36 PEG-20 monooleate 72 0.040 polysorbate
20 36 PEG-20 monooleate 72 0.040 polysorbate 80 72 PEG-20
monolaurate 36 0.040 polysorbate 80 36 PEG-20 monolaurate 72 0.040
polysorbate 20 36 PEG-20 monolaurate 72 0.039 polysorbate 80 18
benzethonium chloride 18 PEG 1000 18 0.039 polysorbate 20 36
2-pyrrolidone 36 octoxynol-9 36 0.039 octoxynol-9 36 benzalkonium
chloride 18 0.039 octoxynol-9 36 PEG-20 monolaurate 36 PEG-20
monooleate 36 0.038 octoxynol-9 72 PEG-20 monolaurate 36 0.040
octoxynol-9 36 PEG-20 monolaurate 72 0.040 octoxynol-9 72 PEG-20
monooleate 36 0.038 octoxynol-9 108 0.040 Isosorbide dimethyl ether
36 octoxynol-9 36 PEG-20 monolaurate 36 0.039 Isosorbide dimethyl
ether 36 octoxynol-9 72 0.039 benzethonium chloride 36 octoxynol-9
18 0.039 PEG-tetrahydrofurfuryl ether 36 octoxynol-9 36 PEG-20
monolaurate 36 0.039 benzethonium chloride 18 octoxynol-9 36 0.039
Sodium caprylate 18 octoxynol-9 18 benzalkonium chloride 18 0.038
benzethonium chloride 18 octoxynol-9 18 cetrimide 18 0.038 SDS 36
octoxynol-9 18 0.039 Povidone 18 SDS 18 .beta.-cyclodextrin 4.5
0.038 Sodium caprylate 18 SDS 36 0.039 benzethonium chloride 36
propylene glycol 18 0.038 SDS 36 propylene glycol 18 0.039
benzethonium chloride 36 cetrimide 18 0.040 benzethonium chloride
36 benzalkonium chloride 18 0.038 cetrimide 36 benzalkonium
chloride 18 0.040 PEG-20 monooleate 108 0.039 benzethonium chloride
54 0.038 SDS 54 0.040 tocophersolan 60 protamine sulfate 3.06 0.040
tocophersolan 48 protamine sulfate 1.836 0.040 tocophersolan 60
PEG-20 monostearate 30 0.040 tocophersolan 60 PEG-20 monostearate
18 0.042 tocophersolan 30 PEG-20 monostearate 60 0.039
tocophersolan 48 PEG-20 monostearate 30 0.040 tocophersolan 30
PEG-20 monostearate 48 0.040 tocophersolan 48 PEG-20 monostearate
18 0.039 tocophersolan 36 PEG-20 monostearate 30 0.040
tocophersolan 60 PEG 300 102 0.040 tocophersolan 60 PEG 300 61.2
0.040 tocophersolan 48 PEG 300 61.2 0.040 tocophersolan 90 0.040
tocophersolan 78 0.040 tocophersolan 66 0.040 tocophersolan 54
0.040 polysorbate 80 30 tocophersolan 60 0.041 polysorbate 80 48
tocophersolan 30 0.040 polysorbate 80 18 tocophersolan 60 0.041
polysorbate 80 36 tocophersolan 30 0.040 polysorbate 80 36
tocophersolan 18 0.041 polysorbate 80 30 tocophersolan 30 PEG-20
monostearate 18 0.040 polysorbate 80 30 tocophersolan 18 PEG-20
monostearate 30 0.041 polysorbate 80 18 tocophersolan 30 PEG-20
monostearate 30 0.043 polysorbate 80 18 tocophersolan 30 protamine
sulfate 3.06 0.040 polysorbate 20 30 tocophersolan 60 0.040
polysorbate 20 18 tocophersolan 60 0.039 polysorbate 20 36
tocophersolan 30 0.039 PEG-20 monooleate 30 tocophersolan 60 0.039
PEG-20 monooleate 30 tocophersolan 48 0.040 PEG-20 monooleate 18
tocophersolan 60 0.039 PEG-20 monooleate 30 tocophersolan 30 PEG-20
monostearate 30 0.039 PEG-20 monolaurate 30 tocophersolan 60 0.040
choline chloride 48 tocophersolan 30 0.040 choline chloride 30
tocophersolan 48 0.040 choline chloride 18 tocophersolan 60 0.040
choline chloride 18 tocophersolan 48 0.039 laureth-23 30
tocophersolan 60 0.039 laureth-23 30 tocophersolan 48 0.041
laureth-23 18 tocophersolan 48 0.040 laureth-23 18 tocophersolan 30
PEG-20 monostearate 18 0.039 polysorbate 80 18 PEG-20 monooleate 18
tocophersolan 30 0.040 polysorbate 80 18 choline chloride 30
tocophersolan 30 0.040 polysorbate 80 30 PEG-20 monooleate 60 0.042
PEG-20 monostearate 66 0.040 PEG-20 monooleate 30 PEG-20
monostearate 60 0.040 PEG-20 monooleate 90 0.039 laureth-23 18
PEG-20 monooleate 18 tocophersolan 30 0.038 PEG-20 glyceryl
monooleate 100 polysorbate 80 40 0.039 PEG-20 glyceryl monooleate
100 polysorbate 80 60 0.039 PEG-20 glyceryl monooleate 100
polysorbate 80 80 0.040 PEG-20 glyceryl monooleate 100 PEG-20
monooleate 60 0.039 PEG-20 glyceryl monooleate 100 PEG-20
monooleate 80 0.039 PEG-20 glyceryl monooleate 100 PEG-20
monolaurate 60 0.040 PEG-20 glyceryl monooleate 100 PEG-20
monolaurate 80 0.039 PEG-20 glyceryl monooleate 100 PEG-20
monolaurate 40 0.040 PEG-20 glyceryl monooleate 100 PEG-20
monolaurate 20 0.038 PEG-20 glyceryl monooleate 100 polysorbate 20
40 0.039 PEG-20 glyceryl monooleate 100 polysorbate 20 60 0.039
PEG-20 glyceryl monooleate 100 polysorbate 20 80 0.038 PEG-20
glyceryl monooleate 100 tocophersolan 20 0.038 PEG-20 glyceryl
monooleate 100 tocophersolan 40 0.038 PEG-20 glyceryl monooleate
100 tocophersolan 60 0.039 PEG-20 glyceryl monooleate 100
tocophersolan 80 0.039 PEG-20 glyceryl monooleate 80 tocophersolan
100 0.039 PEG-20 glyceryl monooleate 60 tocophersolan 100 0.040
PEG-20 glyceryl monooleate 40 tocophersolan 100 0.039 PEG-20
glyceryl monooleate 20 tocophersolan 100 0.040 tocophersolan 100
0.038 PEG-20 glyceryl monolaurate 100 tocophersolan 60 0.039 PEG-20
glyceryl monolaurate 100 tocophersolan 80 0.039 PEG-20 glyceryl
monolaurate 80 tocophersolan 100 0.039 PEG-20 glyceryl monolaurate
60 tocophersolan 100 0.040 PEG-20 glyceryl monolaurate 40
tocophersolan 100 0.039 PEG-20 glyceryl monolaurate 20
tocophersolan 100
[0158] Excipients classes that were present in at least 10
formulations listed in Table 2 above and gave stable paclitaxel
solutions were selected as paclitaxel solubilizers of the invention
(i.e., PEG-vitamin Es, quaternary ammonium salts, PEG-monoacid
fatty esters, PEG-glyceryl fatty esters, polysorbates, and
PEG-fatty alcohols) first, because they were present in
formulations that dissolved paclitaxel to a concentration of about
1.2 mg/ml and, second, by appearing at high frequency, indicated
that they interacted with paclitaxel or the other components to
facilitate dissolution of paclitaxel in an aqueous medium.
18TABLE 3 Paclitaxel Solubilizers of the Invention Excipient Class
Hits PEG-Vitamin Es 59 Quaternary ammonium salts 14 PEG-monoacid
fatty esters 44 PEG-glyceryl fatty esters 20 Polysorbates 38
PEG-fatty alcohols 27
[0159] Preferred paclitaxel solubilizers are PEG-Vitamin Es, such
as tocophersolan; polysorbates, such as polysorbates 80 and 20;
PEG-monoacid fatty esters, such as PEG-20 monooleate, PEG-20
monolaurate, and PEG-20 monostearate; PEG-glyceryl fatty esters,
such as PEG-20 glyceryl monooleate, PEG-20 glyceryl monostearate,
and PEG-20 glyceryl monolaurate; and PEG-fatty alcohols, such as
octoxynols (e.g., octoxynol-9), oleths, and laureths (e.g.,
laureth-23).
[0160] The data in Table 2 was further analyzed with respect to the
paclitaxel solubilizers of the invention (Table 3) to determine
combinations of excipients useful for solubilizing and
administering paclitaxel, derivatives, and salts thereof.
[0161] Table 4 below lists excipients along with the excipient
class, that appeared as a component with a PEG-vitamin E in the
selected formulations of Table 2 at a high frequency (i.e., at
least 4 times).
19TABLE 4 Excipient Classes That in Combination with a PEG-vitamin
E provide Formulations with a High Propensity to Dissolve
Paclitaxel Class Excipient Excipient hits Class hits PEG-monoacid
fatty PEG-20 monooleate 6 19 esters PEG-20 monostearate 12 PEG-20
monolaurate 1 PEG-glyceryl fatty PEG-20 glyceryl 8 14 esters
monooleate PEG-20 glyceryl 6 monolaurate Polysorbates polysorbate
20 3 14 polysorbate 80 11 PEG-fatty alcohols octoxynol-9 0 5
laureth-23 5
[0162] The data in Table 4 above demonstrates that PEG-vitamin Es
in combination with excipient classes PEG-monoacid fatty esters,
PEG-glyceryl fatty esters, polysorbates, or PEG-fatty alcohols
interact to provide formulations useful for solubilizing
paclitaxel.
[0163] Table 5 below lists excipients, along with the excipient
class, that appeared as a component with a quaternary ammonium salt
in the selected formulations of Table 2 at a high frequency.
20TABLE 5 Excipient Classes That in Combination with a Quaternary
Ammonium Salt Provide Formulations with a High Propensity to
Dissolve Paclitaxel Class Excipient Excipient hits Class hits
Polysorbates polysorbate 20 1 4 polysorbate 80 3 PEG-fatty alcohols
octoxynol-9 8 8 laureth-23 0
[0164] The data in Table 5 above demonstrates that quaternary
ammonium salts in combination with excipient classes polysorbates
or PEG-fatty alcohols interact to provide formulations useful for
solubilizing paclitaxel.
[0165] Table 6 below lists excipients, along with the excipient
class, that appeared as a component with a PEG-monoacid fatty
esters in the selected formulations of Table 2 at a high
frequency.
21TABLE 6 Excipient Classes That in Combination with a PEG-monoacid
Fatty Ester Provide Formulations with a High Propensity to Dissolve
Paclitaxel Class Excipient Excipient hits Class hits PEG-Vitamin Es
tocophersolan 18 18 Polysorbates polysorbate 20 2 11 polysorbate 80
9 PEG-fatty alcohols octoxynol-9 4 6 laureth-23 2 PEG-glyceryl
fatty PEG-20 glyceryl 6 6 esters monooleate PEG-20 glyceryl 0
monolaurate
[0166] The data in Table 6 above demonstrates that PEG-monoacid
fatty esters in combination with excipient classes PEG-vitamin Es,
polysorbates, PEG-fatty alcohols, or PEG-glyceryl fatty esters
interact to provide formulations useful for solubilizing
paclitaxel.
[0167] Table 7 below lists excipients, along with the excipient
class, that appeared as a component with a polysorbate in the
selected formulations of Table 2 at a high frequency.
22TABLE 7 Excipient Classes That in Combination with a PEG-Glyceryl
fatty esters Provide Formulations with a High Propensity to
Dissolve Paclitaxel Class Excipient Excipient hits Class hits
PEG-Vitamin Es tocophersolan 14 14 Polysorbates polysorbate 20 3 6
polysorbate 80 3 PEG-monoacid PEG-20 monooleate 2 6 fatty esters
PEG-20 monostearate 0 PEG-20 monolaurate 4
[0168] The data in Table 7 above demonstrates that PEG-glyceryl
fatty esters in combination with excipient classes PEG-vitamin Es,
polysorbates, or PEG-monoacid fatty esters interact to provide
formulations useful for solubilizing paclitaxel.
[0169] Table 8 below lists excipients, along with the excipient
class, that appeared as a component with a polysorbate in the
selected formulations of Table 2 at a high frequency.
23TABLE 8 Excipient Classes That in Combination with a Polysorbate
Provide Formulations with a High Propensity to Dissolve Paclitaxel
Excipient Class Class Excipient hits hits PEG-Vitamin Es
tocophersolan 14 14 Quaternary benzalkonium chloride 1 4 ammonium
salts benzethonium chloride 1 cetrimide 2 PEG-monoacid PEG-20
monooleate 5 13 fatty esters PEG-20 monostearate 3 PEG-20
monolaurate 5 PEG-glyceryl PEG-20 glyceryl monooleate 6 6 fatty
esters PEG-20 glyceryl monolaurate 0 PEG-fatty octoxynol-9 8 8
alcohols laureth-23 0
[0170] The data in Table 8 above demonstrates that polysorbates in
combination with excipient classes PEG-vitamin Es, quaternary
ammonium salts, PEG-monoacid fatty esters, PEG-glyceryl fatty
esters, or PEG-fatty alcohols, interact to provide formulations
useful for solubilizing paclitaxel.
[0171] Table 9 below lists excipients, along with the excipient
class, that appeared as a component with a PEG-fatty alcohol in the
formulations of Table 2 at a high frequency.
24TABLE 9 Excipient Classes That in Combination with a PEG-fatty
Alcohol Provide Formulations with a High Propensity to Dissolve
Paclitaxel Class Excipient Excipient hits Class hits PEG-Vitamin Es
tocophersolan 5 5 Quaternary benzalkonium chloride 3 8 ammonium
salts benzethonium chloride 3 cetrimide 2 PEG-monoacid PEG-20
monooleate 4 12 fatty esters PEG-20 monostearate 1 PEG-20
monolaurate 7 Polysorbates polysorbate 20 3 8 polysorbate 80 5
[0172] The data in Table 9 above demonstrates that PEG-fatty
alcohols in combination with excipient classes PEG-vitamin Es,
quaternary ammonium salts, PEG-monoacid fatty esters, or
polysorbates interact to provide formulations useful for
solubilizing paclitaxel.
Example 2
Preparation of Liquid-Concentrate Paclitaxel Formulations with
Enhanced Aqueous Solubility
[0173] The following liquid-concentrate paclitaxel formulations
were prepared by mixing paclitaxel, the paclitaxel solubilizers,
and additional components using standard pharmaceutical-formulation
procedures.
25 Formulation A Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-400 294 mg 29.2% Polysorbate 80 485 mg 48.1% Ethanol 221 mg
21.9% Citric acid 2 mg 0.2%
[0174]
26 Formulation B Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 500 mg 49.6% Ethanol 300 mg 29.8%
Polysorbate 80 200 mg 19.8% Citric acid 2 mg 0.2%
[0175]
27 Formulation C Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 500 mg 49.6% Ethanol 400 mg 39.7%
Vitamin E TPGS 100 mg 9.9% Citric acid 2 mg 0.2%
[0176]
28 Formulation D Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 500 mg 49.6 Ethanol 300 mg 29.8 PEG-20
monolaurate 200 mg 19.8 Citric acid 2 mg 0.2%
[0177]
29 Formulation E Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 500 mg 49.6% Ethanol 300 mg 29.8%
Polysorbate 20 200 mg 19.8% Citric acid 2 mg 0.2%
[0178]
30 Formulation F Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 500 mg 49.6% Ethanol 200 mg 19.8% PEG-20
monooleate 300 mg 29.8% Citric acid 2 mg 0.2%
[0179]
31 Formulation G Component Weight % weight Paclitaxel 6 mg 0.6%
Ethanol 500 mg 49.6% Vitamin E TPGS 500 mg 49.6% Citric acid 2 mg
0.2%
[0180]
32 Formulation H Component Weight % weight Paclitaxel 6 mg 0.6%
Ethanol 400 mg 39.7% Vitamin E TPGS 500 mg 49.6% PEG-400 100 mg
9.9% Citric acid 2 mg 0.2%
[0181]
33 Formulation I Component Weight % weight Paclitaxel 6 mg 0.6%
Ethanol 400 mg 39.7% Vitamin E TPGS 500 mg 49.6% PEG-20 monooleate
100 mg 9.9% Citric acid 2 mg 0.2%
[0182]
34 Formulation J Component Weight % weight Paclitaxel 6 mg 0.6%
Ethanol 400 mg 39.7% Vitamin E TPGS 500 mg 49.6% Polysorbate 80 100
mg 9.9% Citric acid 2 mg 0.2%
[0183]
35 Formulation K Component Weight % weight Paclitaxel 6 mg 0.6%
Ethanol 400 mg 39.7% Vitamin E TPGS 500 mg 49.6% Polysorbate 20 100
mg 9.9% Citric acid 2 mg 0.2%
[0184]
36 Formulation L Component Weight % weight Paclitaxel 6 mg 0.6%
Ethanol 400 mg 39.7% Vitamin E TPGS 500 mg 49.6% PEG-20 monolaurate
100 mg 9.9% Citric acid 2 mg 0.2%
[0185]
37 Formulation M Component Weight % weight Paclitaxel 6 mg 0.6%
Ethanol 559 mg 55.4% Polysorbate 80 294 mg 29.2% PEG-20 monooleate
147 mg 14.6% Citric acid 2 mg 0.2%
[0186]
38 Formulation N Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-400 500 mg 49.6% Polysorbate 80 300 mg 29.8% Ethanol 200 mg
19.9% Citric acid 2 mg 0.2%
[0187]
39 Formulation O Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-400 500 mg 49.6% Ethanol 150 mg 14.9% Polysorbate 80 350 mg
34.7% Citric acid 2 mg 0.2%
[0188]
40 Formulation P Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 400 mg 39.7% Ethanol 400 mg 39.7%
Polysorbate 80 200 mg 19.9% Citric acid 2 mg 0.2%
[0189]
41 Formulation Q Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 300 mg 29.8% Ethanol 500 mg 49.6%
Polysorbate 80 200 mg 19.9% Citric acid 2 mg 0.2%
[0190]
42 Formulation R Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 500 mg 49.6% Ethanol 400 mg 39.7%
Polysorbate 80 100 mg 9.9% Citric acid 2 mg 0.2%
[0191]
43 Formulation S Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 600 mg 59.5% Ethanol 400 mg 39.7% Citric
acid 2 mg 0.2%
[0192]
44 Formulation T Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 550 mg 54.5% Ethanol 450 mg 44.6% Citric
acid 2 mg 0.2%
[0193]
45 Formulation U Component Weight % weight Paclitaxel 6 mg 0.6%
PEG-20 glyceryl monooleate 500 mg 49.6% Ethanol 500 mg 49.6% Citric
acid 2 mg 0.2%
[0194]
46 Formulation V Component Weight % weight Paclitaxel 6 mg 0.6%
Polyethylene Glycol 400 294 mg 29.2% Polysorbate 80 529 mg 52.5%
Ethanol 176 mg 17.5% Citric Acid 2 mg 0.2%
[0195]
47 Formulation W Component Weight % weight Paclitaxel 6 mg 0.6%
Polyethylene Glycol 400 294 mg 29.2% Polysorbate 80 485 mg 48.1%
Ethanol 221 mg 21.9% Citric Acid 2 mg 0.2%
Example 3
Animal pK Study of Paclitaxel Formulations
[0196] Two formulations of the present invention with the following
compositions were prepared and used for PK studies in rats:
[0197] Sample V (formulation V): 6 mg/mL paclitaxel dissolved in
29.4% Polyethylene Glycol 400, 52.9% Polysorbate 80, 17.6% Ethanol
and 2.0 mg/mL citric acid.
[0198] Sample W (Formulation W): 6 mg/mL paclitaxel dissolved in
29.4% Polyethylene Glycol 400, 48.5% Polysorbate 80, 22.1% Ethanol
and 2.0 mg/mL citric acid.
[0199] Both samples and the control (commercially available
Taxol.RTM.) were diluted into sterile saline to a final
concentration of 1 mg/mL before dosing. Six male Sprague-Dawley
rats (7 weeks old, averaged 270 g each) from Charles River Japan
were used per experimental group. Two single intravenous bolus
doses (5 mg/kg and 10 mg/kg) were evaluated at an infusion rate of
1.5 mL/min. Plasma samples were collected at 0.083, 0.5, 1.0, 2.0,
3.0, 4.0, 8.0, and 24.0 hours post-dosing and stored at -20.degree.
C. until assayed with HPLC.
[0200] The pK profiles for each of the samples and the control were
prepared, and are illustrated in FIGS. 1-4.
[0201] The results indicate that Samples V and W have very similar
PK profiles in rats. The two formulations have lower AUC compared
to the control, presumably due to the well-established non-linear
pharmacokinetic interactions between paclitaxel and
CREMOPHOR.RTM..
[0202] All of the rats died in the control group (Taxol.RTM.) at
the 10 mg/kg dose. In comparison, all of the animals dosed with
formulations V and W tolerated them well, even at the high dose of
10 mg/kg. These results suggest that Formulations V and W have
improved safety in rats compared to TAXOL.RTM..
[0203] The foregoing has demonstrated the pertinent and important
features of the present invention. One of skill in the art will be
appreciate that numerous modifications and embodiments may be
devised. Therefore, it is intended that the appended claims cover
all such modifications and embodiments.
* * * * *