U.S. patent application number 11/165896 was filed with the patent office on 2005-12-01 for oral pharmaceutical compositions containing taxanes and methods of treatment employing the same.
This patent application is currently assigned to Baker Norton Pharmaceuticals, Inc.. Invention is credited to Cacace, Janice L., Gutierrez-Rocca, Jose C., Rutledge, J. Michael, Selim, Sami, Testman, Robert.
Application Number | 20050267201 11/165896 |
Document ID | / |
Family ID | 47631112 |
Filed Date | 2005-12-01 |
United States Patent
Application |
20050267201 |
Kind Code |
A1 |
Gutierrez-Rocca, Jose C. ;
et al. |
December 1, 2005 |
Oral pharmaceutical compositions containing taxanes and methods of
treatment employing the same
Abstract
Pharmaceutical compositions for oral administration to mammalian
subjects comprise a taxane or taxane derivative (e.g., paclitaxel
or docetaxel) as active ingredient and a vehicle comprising at
least 30% by weight of a carrier for the taxane, said carrier
having an HLB value of at least about 10. The compositions may also
comprise 0-70% of a viscosity-reducing co-solubilizer. The
compositions may be incorporated into conventional oral
pharmaceutical dosage forms, or can be in the form of a two-part
medicament wherein the first part includes the taxane in a
solubilizing vehicle and the second part comprises a carrier for
the taxane to promote oral absorption. Methods of treatment of
taxane-responsive disease conditions employing the novel
compositions are also disclosed, whereby the compositions can be
administered alone or in association with an oral bioavailability
enhancing agent.
Inventors: |
Gutierrez-Rocca, Jose C.;
(Miami, FL) ; Cacace, Janice L.; (Miami, FL)
; Selim, Sami; (Irvine, CA) ; Testman, Robert;
(Miami, FL) ; Rutledge, J. Michael; (Riverdale,
NY) |
Correspondence
Address: |
LERNER, DAVID, LITTENBERG,
KRUMHOLZ & MENTLIK
600 SOUTH AVENUE WEST
WESTFIELD
NJ
07090
US
|
Assignee: |
Baker Norton Pharmaceuticals,
Inc.
Miami
FL
|
Family ID: |
47631112 |
Appl. No.: |
11/165896 |
Filed: |
June 24, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11165896 |
Jun 24, 2005 |
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09055818 |
Apr 6, 1998 |
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09055818 |
Apr 6, 1998 |
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08863513 |
May 27, 1997 |
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08863513 |
May 27, 1997 |
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08733142 |
Oct 16, 1996 |
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6245805 |
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08733142 |
Oct 16, 1996 |
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08608776 |
Feb 29, 1996 |
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5968972 |
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60007071 |
Oct 26, 1995 |
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Current U.S.
Class: |
514/449 ;
424/464 |
Current CPC
Class: |
A61K 9/4866 20130101;
A61K 9/1075 20130101; A61K 47/22 20130101; Y02A 50/30 20180101;
A61P 13/08 20180101; A61P 35/00 20180101; Y02A 50/411 20180101;
A61K 47/10 20130101; A61K 45/06 20130101; A61K 47/40 20130101; A61P
1/18 20180101; A61P 33/06 20180101; A61K 31/335 20130101; A61P
13/12 20180101; A61K 9/4858 20130101; A61K 38/13 20130101; A61K
47/14 20130101; A61K 31/337 20130101; A61P 39/00 20180101; A61P
1/16 20180101; A61K 38/13 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/449 ;
424/464 |
International
Class: |
A61K 031/337; A61K
009/20 |
Claims
We claim:
1. A two-part medicament for oral administration to a mammalian
subject, the first part of said medicament comprising a taxane or
taxane derivative as active ingredient in a solubilizing vehicle
for said taxane, and the second part of said medicament comprising
at least 30% by weight of a carrier for the taxane, said carrier
having an HLB value at least about 10.
2. A two-part medicament according to claim 1 wherein the
solubilizing vehicle is capable of solubilizing at least about 25
mg/ml of the taxane at about 20-25.degree. C.
3. A two-part medicament according to claim 1 wherein the
solubilizing vehicle comprises water, ethanol or a polyoxyethylated
or hydrogenated castor oil.
4. A two-part medicament according to claim 1 wherein the
solubilizing vehicle comprises sweetening, flavoring or coloring
agents.
5. A two-part medicament according to claim 1 wherein the
solubilizing vehicle contains about 2-500 mg/ml or mg/g of the
taxane.
6. A two-part medicament according to claim 5 wherein the
solubilizing vehicle contains about 2-50 mg/ml or mg/g of the
taxane.
7. A two-part medicament according to claim 1 wherein the carrier
includes at least one non-ionic surfactant or emulsifier.
8. A two-part medicament according to claim 7 wherein the carrier
includes at least one surfactant or emulsifier selected from the
group consisting of Vitamin E TPGS, saturated polyglycolyzed
glycerides, modified castor oils, polyoxyethylated stearate esters,
polyoxyethylated sorbitan esters, polyoxyethylated fatty ethers,
modified almond and corn oil glycerides sorbitan diisostearate
esters, polyoxyethylated hydroxystearates, and
.beta.-cyclodextrin.
9. A two-part medicament according to claim 1 wherein the second
part of the medicament comprises about 30-240 ml of fluid.
10. A two-part medicament according to claim 1 wherein the taxane
is paclitaxel or docetaxel.
11. A two-part medicament according to claim 10 wherein the taxane
is paclitaxel.
12. A method of treating a mammalian subject suffering from a
taxane-responsive disease condition comprising the oral
administration to the subject of a two-derivative as active
ingredient in a solubilizing vehicle for said taxane and the second
part of said medicament comprising at least 30% by weight of a
carrier for the taxane, said carrier having an HLB value at least
about 10.
13. A method according to claim 12 wherein the solubilizing vehicle
is capable of solubilizing at least about 25 mg/ml of the taxane at
about 20-25.degree. C.
14. A method according to claim 12 wherein the solubilizing vehicle
comprises water, ethanol or a polyoxyethylated or hydrogenated
castor oil.
15. A method according to claim 12 wherein the solubilizing vehicle
comprises sweetening, flavoring or coloring agents.
16. A method according to claim 12 wherein the solubilizing vehicle
contains about 2-500 mg/ml or mg/g of the taxane.
17. A method according to claim 12 wherein the solubilizing vehicle
contains about 2-50 mg/ml or mg/g of the taxane.
18. A method according to claim 12 wherein the carrier includes at
least one non-ionic surfactant or emulsifier.
19. A method according to claim 12 wherein the carrier includes at
least one surfactant or emulsifier selected from the group
consisting of Vitamin E TPGS, saturated polyglycolyzed glycerides,
modified castor oils, polyoxyethylated stearate esters,
polyoxyethylated sorbitan esters, polyoxyethylated fatty ethers,
modified almond and corn oil glycerides sorbitan diisostearate
esters, polyoxyethylated hydroxystearates, and
.beta.-cyclodextrin.
20. A method according to claim 12 wherein the second part of the
composition comprises about 30-240 ml of fluid.
21. A method according to claim 12 wherein the taxane is paclitaxel
or docetaxel
22. A method according to claim 21 wherein the taxane is
paclitaxel.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending application
Ser. No. 09/055,818, which is a continuation-in-part of co-pending
application Ser. No. 08/863,513, abandoned, which is a
continuation-in-part of application Ser. No. 08/733,142, filed Oct.
16, 1996, now U.S. Pat. No. 6,245,805, which is a
continuation-in-part of application Ser. No. 08/608,776, filed Feb.
29, 1996, now U.S. Pat. No. 5,968,972, which claims the priority of
provisional application Ser. No. 60/007,071, filed Oct. 26,
1995.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to compositions for orally
administering paclitaxel and related taxanes to human patients, and
methods of treatment employing such compositions.
[0004] 2. Description of the Prior Art
[0005] Many valuable pharmacologically active compounds cannot be
effectively administered by the oral route to human patients
because of poor or inconsistent systemic absorption from the
gastrointestinal tract. These pharmaceutical agents are, therefore,
generally administered via intravenous routes, requiring
intervention by a physician or other health care professional,
entailing considerable discomfort and potential local trauma to the
patient and even requiring administration in a hospital setting
with surgical access in the case of certain IV infusions.
[0006] One of the important classes of cytotoxic agents which are
not normally bioavailable when administered orally to humans are
the taxanes, which include paclitaxel, its derivatives and analogs.
Paclitaxel (currently marketed as TAXOL.RTM. by Bristol-Myers
Squibb Oncology Division) is a natural diterpene product isolated
from the Pacific yew tree (Taxus brevifolia). It is a member of the
taxane family of terpenes. It was first isolated in 1971 by Wani et
al. (J. Am. Chem. Soc., 93:2325, 1971), who characterized its
structure by chemical and X-ray crystallographic methods. One
mechanism for its activity relates to paclitaxel's capacity to bind
tubulin, thereby inhibiting cancer cell growth. Schiff et al.,
Proc. Natl. Acad. Sci. USA, 77:1561-1565 (1980); Schiff et al.,
Nature, 277:665-667 (1979); Kumar, J. Biol. Chem., 256: 10435-10441
(1981).
[0007] Paclitaxel has been approved for clinical use in the
treatment of refractory ovarian cancer in the United States
(Markman et al., Yale Journal of Biology and Medicine, 64:583,
1991; McGuire et al., Ann. Intern. Med., 111:273, 1989). It is
effective for chemotherapy for several types of neoplasms including
breast (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991) and has
been approved for treatment of breast cancer as well. It is a
potential candidate for treatment of neoplasms in the skin (Einzig
et al., Proc. Am. Soc. Clin. Oncol., 20:46), lung cancer and head
and neck carcinomas (Forastire et al. Sem. Oncol., 20:56, 1990).
The compound also shows potential for the treatment of polycystic
kidney disease (Woo et al, Nature, 368:750, 1994) and malaria.
[0008] Paclitaxel is only slightly soluble in water and this has
created significant problems in developing suitable injectable and
infusion formulations useful for anticancer chemotherapy. Some
formulations of paclitaxel for IV infusion have been developed
utilizing CREMOPHOR EL.TM. (polyethoxylated castor oil) as the drug
carrier because of paclitaxel's aqueous insolubility. For example,
paclitaxel used in clinical testing under the aegis of the NCI has
been formulated in 50% CREMOPHOR EL.TM. and 50% dehydrated alcohol.
CREMOPHOR EL.TM. however, when administered intravenously, is
itself toxic and produces vasodilation, labored breathing,
lethargy, hypotension and death in dogs. It is also believed to be
at least partially responsible for the allergic-type reactions
observed during paclitaxel administration, although there is some
evidence that paclitaxel may itself provoke acute reactions even in
the absence of Cremophor.
[0009] In an attempt to increase paclitaxel's solubility and to
develop more safe clinical formulations, studies have been directed
to synthesizing paclitaxel analogs where the 2' and/or 7-position
is derivatized with groups that would enhance water solubility.
These efforts have yielded prodrug compounds that are more water
soluble than the parent compound and that display the cytotoxic
properties upon activation. One important group of such prodrugs
includes the 2'-onium salts of paclitaxel and docetaxel,
particularly the 2'-methylpyridinium mesylate (2'-MPM) salts.
[0010] Paclitaxel is very poorly absorbed when administered orally
(less than 1%); see Eiseman et al., Second NCI Workshop on Taxol
and Taxus (September 1992); Suffness et al. in Taxol Science and
Applications (CRC Press 1995). Eiseman et al. indicate that
paclitaxel has a bioavailability of 0% upon oral administration,
and Suffness et al. report that oral dosing with paclitaxel did not
seem possible since no evidence of antitumor activity was found on
oral administration up to 160 mg/kg/day. For this reason,
paclitaxel has not been administered orally to human patients in
the prior art, and certainly not in the course of treating
paclitaxel-responsive diseases.
[0011] Docetaxel (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl
paclitaxel) has become commercially available as TAXOTERE.RTM.
(Rhone-Poulenc-Rorer S.A.) in parenteral form for the treatment of
breast cancer. To date, no reference has been made in the
scientific literature to oral absorption of docetaxel in animals or
patients.
[0012] It has been speculated that, in some cases, the poor or
non-existent bioavailability of a drug such as paclitaxel after
oral administration is a result of the activity of a multidrug
transporter, a membrane-bound P-glycoprotein, which functions as an
energy-dependent transport or efflux pump to decrease intracellular
accumulation of drug by extruding xenobiotics from the cell. This
P-glycoprotein has been identified in normal tissues of secretory
endothelium, such as the biliary lining, brush border of the
proximal tubule in the kidney and luminal surface of the intestine,
and vascular endothelial cells lining the blood brain barrier,
placenta and testis.
[0013] It is believed that the P-glycoprotein efflux pump prevents
certain pharmaceutical compounds from transversing the mucosal
cells of the small intestine and, therefore, from being absorbed
into the systemic circulation. A number of known non-cytotoxic
pharmacological agents have been shown to inhibit P-glycoprotein,
including cyclosporin A (also known as cyclosporine), verapamil,
tamoxifen, quinidine and phenothiazines, among others. Many of
these studies were aimed at achieving greater accumulation of
intravenously administered cytotoxic drugs inside tumor cells. In
fact, clinical trials have been conducted to study the effects of
cyclosporine on the pharmacokinetics and toxicities of paclitaxel
(Fisher et al., Proc. Am. Soc. Clin. Oncol., 13: 143, 1994);
doxorubicin (Bartlett et al., J. Clin. Onc. 12:835-842, 1994); and
etoposide (Lum et al., J. Clin. Onc. 10:1635-42, 1992), all of
which are anti-cancer agents known to be subject to multidrug
resistance (MDR). These trials showed that patients receiving
intravenous cyclosporine prior to or together with the anti-cancer
drugs had higher blood levels of those drugs, presumably through
reduced body clearance, and exhibited the expected toxicity at
substantially lower dosage levels. These findings tended to
indicate that the concomitant administration of cyclosporine
suppressed the MDR action of P-glycoprotein, enabling larger
intracellular accumulations of the therapeutic agents. For a
general discussion of the pharmacologic implications for the
clinical use of P-glycoprotein inhibitors, see Lum et al., Drug
Resist. Clin. One. Hemat., 9: 319-336 (1995); Schinkel et al., Eur.
J. Cancer, 31A: 1295-1298 (1995).
[0014] In the aforedescribed studies relating to the use of
cyclosporine to increase the blood levels of pharmaceutical agents,
the active anti-tumor agents and the cyclosporine were administered
intravenously. No suggestion was made in these publications that
cyclosporine could be orally administered to substantially increase
the bioavailability of orally administered anti-cancer drugs and
other pharmaceutical agents which are themselves poorly absorbed
from the gut without producing highly toxic side effects. None of
the published studies provided any regimen for implementing the
effective oral administration to humans of poorly bioavailable
drugs such as paclitaxel, e.g., indicating the respective dosage
ranges and timing of administration for specific target drugs and
bioavailability-enhancing agents are best suited for promoting oral
absorption of each target drug or class of drugs.
[0015] In published PCT application WO 95/20980 (published Aug. 10,
1995) Benet et al. disclose a purported method for increasing the
bioavilability of orally administered hydrophobic pharmaceutical
compounds. This method comprises orally administering such
compounds to the patient concurrently with a bioenhancer comprising
an inhibitor of a cytochrome P450 3A enzyme or an inhibitor of
P-glycoprotein-mediated membrane transport. Benet et al., however,
provide virtually no means for identifying which bioavailability
enhancing agents will improve the availability of specific "target"
pharmaceutical compounds, nor do they indicate specific dosage
amounts, schedules or regimens for administration of the enhancing
or target agents. In fact, although the Benet et al. application
lists dozens of potential enhancers (P450 3A inhibitors) and target
drugs (P450 3A substrates), the only combination of enhancer and
target agent supported by any experimental evidence in the
application is ketoconazole as the enhancer and cyclosporin A as
the target drug.
[0016] When describing the general characteristics of compounds
which can be used as bioenhancers by reduction of P-glycoprotein
transport activity, Benet et al. indicate that these are
hydrophobic compounds which generally, but not necessarily,
comprise two co-planar aromatic rings, a positively charged
nitrogen group or a carbonyl group--a class that includes an
enormous number of compounds, most of which would not provide the
desired absorption enhancing activity in the case of specific
target agents. Moreover, the classes of target agents disclosed by
Benet et al. include the great majority of pharmaceutical agents
listed in the Physicians' Desk Reference. These inclusion criteria
are of no value to medical practitioners seeking safe, practical
and effective methods of orally administering specific
pharmaceutical agents.
[0017] In general, Benet et al. provides no teaching that could be
followed by persons skilled in the medical and pharmaceutical arts
to identify suitable bioenhancer/target drug combinations or to
design specific treatment regimens and schedules which would render
the target agents therapeutically effective upon oral
administration to human patients. Benet et al. also provides no
direction whatsoever regarding how paclitaxel and other taxanes
might be administered orally to humans with therapeutic efficacy
and acceptable toxicity.
[0018] In published PCT application WO 97/15269, which corresponds
to U.S. patent application Ser. No. 08/733,142 (the grandparent of
the present application) and which is commonly owned with this
application, it is disclosed that various therapeutically effective
pharmaceutical "target agents" which exhibit poor oral
bioavailability can be made bioavailable, providing therapeutic
blood levels of the active agent, by oral co-administration of
certain bioavailability enhancing agents. Preferred examples of
such target agents disclosed in WO 97/15269 include the
cyclosporins, e.g., cyclosporins A, D and G. Preferred examples of
target agents include the taxane class of antineoplastic agents,
particularly paclitaxel. Therapeutic regimens and dosage amounts
for co-administration for target agents and enhancing agents are
also disclosed. All of the disclosures of published application WO
97/15269 are incorporated herein by reference.
[0019] Neither commonly owned application WO 97/15269 nor any prior
art disclosure, however, describes classes of oral formulations or
compositions containing the active target agent, e.g., paclitaxel,
which are particularly adapted for co-administration with an oral
bioavailability enhancing agent to yield therapeutic blood levels
of target agents heretofore considered unsuitable for oral
administration.
SUMMARY OF THE INVENTION
[0020] The present invention relates to oral pharmaceutical
compositions containing taxane antitumor agents, for example
paclitaxel or docetaxel, which, when administered to a mammalian
patient, preferably with co-administration of an oral
bioavailability enhancing agent, enable sufficient absorption of
the taxane agent from the gastrointestinal tract into the
bloodstream to provide therapeutically significant blood levels of
the active drug.
[0021] The compositions of the invention comprise a vehicle
including a carrier in which the taxane agent is dissolved or
dispersed. The vehicle may also include a viscosity-reducing
co-solubilizer which renders the vehicle more flowable at body
temperature or at least reduces the melting point of the vehicle
below body temperature, and may also provide increased taxane
solubility.
[0022] The carrier used in the novel compositions is preferably a
non-ionic surface active agent (surfactant) or emusifier having a
hydrophilic-lipophilic balance (HLB) value at least about 10. The
viscosity-reducing co-solubilizer is selected from, e.g., organic
solvents suitable for oral administration, vegetable oils,
hydrogenated or polyoxyethylated castor oil, citrate esters and
saturated polyglycolized glycerides. Certain saturated
polyglycolized glycerides may also serve as carriers in the
compositions of the invention.
[0023] The novel pharmaceutical compositions contain about 2-500
mg/ml or mg/g of taxane, and preferably about 2-50 mg/ml or mg/g of
taxane. The therapeutically inactive vehicle comprises at least 30%
by weight of carrier and about 0-70% of co-solubilizer, and may
also contain conventional pharmaceutical additives and excipients
such as flavoring and coloring agents and the like.
[0024] Another aspect of the invention pertains to methods of
treatment of mammalian patients suffering from taxane-responsive
disease conditions by the administration to such patients of oral
pharmaceutical compositions in accordance with the invention,
preferably with co-administration of an oral bioavailability
enhancing agent.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The oral pharmaceutical compositions of the invention
contain at least two components: an active agent comprising a
taxane, preferably the antitumor agent paclitaxel or docetaxel, and
a therapeutically inactive vehicle comprising a pharmaceutically
acceptable carrier for said taxane.
[0026] In order to produce compositions for oral administration
that are liquid or at least flowable form at body temperature
(about 37.degree. C.), as generally required for oral
bioavailability, it is required in some instances to add an
additional component to the vehicle: a viscosity-reducing
co-solubilizer which decreases the viscosity and increases the
flowability of the vehicle at body temperature, and also may
increase the amount of the active agent that can be dissolved or
dispersed in the vehicle in comparison with the use of a carrier
alone.
[0027] The novel compositions may comprise more than one taxane as
active ingredient and more than one carrier and/or co-solubilizer
as inactive vehicle components. The vehicle comprises at least 30%
by weight of carrier, preferably 30-90% by weight. Preferred
carriers for use in the invention are non-ionic surfactants or
emulsifiers having HLB values at least about 10. It has been found
that such non-ionic surfactants or emulsifiers are not only
compatible carriers for the lipophilic taxanes (which are poorly
soluble in water) but also promote absorption of the active
ingredient from the gastrointestinal tract into the
bloodstream.
[0028] Preferred carriers for use in the invention include, for
example, Vitamin E TPGS (d- -tocopheryl polyethylene glycol 1000
succinate, Eastman Chemical Co., Kingsport Tenn.); saturated
polyglycolyzed glycerides such as GELUCIRE.TM. and LABRASOL.TM.
products (Gattefoss Corp., Westwood, N.J.) which include glycerides
of C.sub.8-C.sub.18 fatty acids; CREMOPHOR.TM. EL or RH40 modified
castor oils (BASF, Mt. Olive, N.J.); MYRJ.TM. polyoxyethylated
stearate esters (ICI Americas, Charlotte, N.C.); TWEEN.TM. (ICI
Americas) and CRILLET.TM. (Croda Inc., Parsippany, N.J.)
polyoxyethylated sorbitan esters; BRIJ.TM. polyoxyethylated fatty
ethers (ICI Americas); CROVOL.TM. modified (polyethylene glycol)
almond and corn oil glycerides (Croda Inc.); EMSORB.TM. sorbitan
diisostearate esters (Henkel Corp., Ambler, Pa.); SOLUTOL.TM.
polyoxyethylated hydroxystearates (BASF); and -cyclodextrin. Only
those members of these surfactant families which have HLB values of
about 10 or greater may be used as carriers in the subject
compositions.
[0029] Preferred viscosity-reducing co-solubilizers include, e.g.,
PHARMASOLVE.TM. (N-methyl-2-pyrrolidone, International Specialty
Products, Wayne, N.J.); MIGLYOL.TM. glycerol or propylene glycol
esters of caprylic and capric acids (Huls AG, Marl, Germany);
polyoxyethylated hydroxystearates (e.g., SOLUTOL.TM. HS 15);
TWEEN.TM. polyoxyethylated sorbitan esters; SOFTIGEN.TM.
polyethylene glycol esters of caprylic and capric acids (Huls AG);
modified castor oils (such as CREMOPHOR.TM. EL or RH 40); vegetable
oils such as olive oil, polyoxyethylated fatty ethers or modified
castor oils; certain saturated polyglycolyzed glycerides (such as a
LABRASOL.TM.) citrate esters such as tributyl citrate, triethyl
citrate and acetyl triethyl citrate; propylene glycol, alone or in
combination with PHARMASOLVE.TM.; ethanol; water; and lower
molecular weight polyethylene glycols such as PEG 200 and 400.
[0030] The vehicle contains about 0-70% by weight of the
co-solubilizer, and preferably about 10-50% by weight. It will be
noted that several of the materials identified as carriers have
also been found to be effective co-solubilizers, either alone or in
combination with other viscosity-reducing agents, for certain other
carriers. In general, any solvent in which paclitaxel or other
taxanes are at least moderately soluble at body temperature or with
gentle heating can be used as a co-solubilizer in the vehicle of
the novel compositions. Preferred co-solubilizers are those in
which at least 25 mg/ml of paclitaxel or other taxane can be
solubilized at about 20-25.degree. C.
[0031] The concentration of the active taxane ingredient or
ingredients in the composition may vary based on the solubility of
the active agent in the carrier(s) or carrier(s)/co-solubilizer(s)
system and on the desired total dose of taxane to be administered
orally to the patient. The concentration of taxane may range from
about 2 to about 500 mg/ml or mg/g of vehicle, and preferably from
about 2 to about 50 mg/ml or mg/g.
[0032] The compositions of the invention may be prepared by any
conventional method known to individuals of skill in the
pharmaceutical arts for preparing liquid or other fluid oral
formulations containing surfactant carriers and lipophilic active
ingredients. Since the majority of the preferred carriers are very
viscous at room temperature, and in some cases retain a relatively
high viscosity even upon the addition of a minor proportion of
co-solubilizer, it is generally preferred in preparing the novel
compositions to mix the carriers and co-solubilizers to be used,
add the taxane active ingredient, and heat the resulting mixture
while stirring, for example to about 40.degree. C. This method
enables the preparation of clear solutions. Certain
co-solubilizers, however, particularly PHARMASOLVE.TM., lower the
carrier viscosity and enhance taxane solubility to such a degree
that the composition can be prepared by stirring at room
temperature with no heating.
[0033] It is desirable that the viscosity of the finished
composition not be higher than 40,000 cps at body temperature
(approximately 37.degree. C.).
[0034] The oral compositions of the invention may be in the form of
true solutions, emulsions or even suspensions, but solutions of the
active taxane ingredient in the carrier or carrier/co-solubilizer
system are preferred.
[0035] The present invention also comprehends methods of treating
human patients afflicted with cancers, tumors, Kaposi's sarcoma,
malignancies, uncontrolled tissue or cellular proliferation
secondary to tissue injury, and any other disease conditions
responsive to taxanes such as paclitaxel and docetaxel, and/or
prodrugs and derivatives of the foregoing, with the novel orally
administered pharmaceutical compositions. Among the types of
carcinoma which may be treated particularly effectively with oral
paclitaxel, docetaxel, other taxanes, and their prodrugs and
derivatives, are hepatocellular carcinoma and liver metastases,
cancers of the gastrointestinal tract, pancreas, prostate and lung,
and Kaposi's sarcoma. Examples of non-cancerous disease conditions
which may be effectively treated with these active agents
administered orally in accordance with the present invention are
uncontrolled tissue or cellular proliferation secondary to tissue
injury, polycystic kidney disease, inflammatory diseases (e.g.,
arthritis) and malaria, including chloroquine- and
pyrimethamine-resistant malaria parasites (Pouvelle et al., J.
Clin. Invest., 44: 413-417, 1994).
[0036] Although some of the oral pharmaceutical compositions of the
invention may provide therapeutic blood levels of the taxane active
ingredient when administered alone, the preferred method of the
invention for treating mammalian patients (particularly human
patients) suffering from taxane-responsive disease conditions is to
administer the oral compositions containing the taxane target agent
concomitantly with the administration of at least one dose of an
oral bioavailability enhancing agent.
[0037] The preferred embodiment of the method of the invention for
oral administration to humans of paclitaxel, its derivatives,
analogs and prodrugs, and other taxanes comprises the oral
administration of an oral absorption or bioavailability enhancing
agent to a human patient simultaneously with, or prior to, or both
simultaneously with and prior to the oral administration to
increase the quantity of absorption of the intact target agent into
the bloodstream. The orally administered enhancing agents which may
be used in practicing the preferred embodiment of the invention
include, but are not limited to, the following:
[0038] Cyclosporins, including cyclosporins A through Z but
particularly cyclosporin A (cyclosporine), cyclosporin F,
cyclosporin D, dihydro cyclosporin A, dihydro cyclosporin C, acetyl
cyclosporin A, PSC-833, SDZ-NIM 811.sup.1 (both from Sandoz
Pharmaceutical Corp). The structures of cyclosporins A-Z are
described in Table 1 below. SDZ-NIM 811 is (Me-Ile-4)-cyclosporin,
an antiviral, non-immunosuppressive cyclosporin.
1TABLE 1 Cyclosporins A-Z Cyclosporin Aminoacids Cy- 1 2 3 4 5 6 7
8 9 10 11 CyA Mebmt Abu Sar MeLeu Val MeLeu Ala D-Ala MeLeu MeLeu
MeVal CyB Mebmt Ala Sar MeLeu Val MeLeu Ala D-Ala MeLeu MeLeu MeVal
CyC Mebmt Thr Sar MeLeu Val MeLeu Ala D-Ala MeLeu MeLeu MeVal CyD
Mebmt Val Sar MeLeu Val MeLeu Ala D-Ala MeLeu MeLeu MeVal CyE Mebmt
Abu Sar MeLeu Val MeLeu Ala D-Ala MeLeu MeLeu Val CyF Desoxy- Abu
Sar MeLeu Val MeLeu Ala D-Ala MeLeu MeLeu MeVal Mebmt CyG Mebmt Nva
Sar MeLeu Val MeLeu Ala D-Ala MeLeu MeLeu MeVal CyH Mebmt Abu Sar
MeLeu Val MeLeu Ala D-Ala MeLeu MeLeu D-Mev CyI Mebmt Val Sar MeLeu
Val MeLeu Ala D-Ala MeLeu Leu MeVal CyK Desoxy- Val Sar MeLeu Val
MeLeu Ala D-Ala MeLeu MeLeu MeVal Mebmt CyL Bmt Abu Sar MeLeu Val
MeLeu Ala D-Ala MeLeu MeLeu MeVal CyM Mebmt Nva Sar MeLeu Val MeLeu
Ala D-Ala MeLeu MeLeu MeVal CyN Mebmt Nva Sar MeLeu Val MeLeu Ala
D-Ala MeLeu Leu MeVal CyO MeLeu Nva Sar MeLeu Val MeLeu Ala D-Ala
MeLeu MeLeu MeVal CyP Bmt Thr Sar MeLeu Val MeLeu Ala D-Ala MeLeu
MeLeu MeVal CyQ Mebmt Abu Sar Val Val MeLeu Ala D-Ala MeLeu MeLeu
MeVal CyR Mebmt Abu Sar MeLeu Val Leu Ala D-Ala MeLeu Leu MeVal CyS
Mebmt Thr Sar Val Val MeLeu Ala D-Ala MeLeu MeLeu MeVal CyT Mebmt
Abu Sar MeLeu Val MeLeu Ala D-Ala MeLeu Leu MeVal CyU Mebmt Abu Sar
MeLeu Val Leu Ala D-Ala MeLeu MeLeu MeVal CyV Mebmt Abu Sar MeLeu
Val MeLeu Ala D-Ala MeLeu MeLeu MeVal CyW Mebmt Thr Sar MeLeu Val
MeLeu Ala D-Ala MeLeu MeLeu Val CyX Mebmt Nva Sar MeLeu Val MeLeu
Ala D-Ala Leu MeLeu MeVal CyY Mebmt Nva Sar MeLeu Val Leu Ala D-Ala
MeLeu MeLeu MeVal CyZ MeAmino Abu Sar MeLeu Val MeLeu Ala D-Ala
MeLeu MeLeu MeVal octyl acid
[0039] Cyclosporins are a group of nonpolar cyclic oligopeptides
(some of which have immunosuppressant activity) produced by the
genus, Tolypocladium, including, e.g., Tolypocladium inflatum Gams
(formerly designated as Trichoderma Polysporum), Tolypocladium
terricola and other fungi imperfecti. The major component,
cyclosporin A (cyclosporine or CsA), has been identified along with
several other lesser metabolites, for example, cyclosporins B
through Z, some of which exhibit substantially less
immunosuppressive activity than cyclosporin A. A number of
synthetic and semi-synthetic analogs have also been prepared. See
generally Jergorov et al., Phytochemistry, 38: 403-407 (1995). The
present invention comprehends natural, semi-synthetic and synthetic
analogs of cyclosporins.
[0040] Cyclosporins are neutral, lipophilic, cyclic undecapeptides
with molecular weights of about 1200. They are used intravenously
or orally as immunosuppressants, primarily for organ
transplantation and certain other conditions. Cyclosporins,
particularly cyclosporine (cyclosporin A), are known inhibitors of
the P-glycoprotein efflux pump and other transporter pumps as well
as of certain P450 degradative enzymes, but to date no effective
regimens for applying this property clinically have been developed
to the point of clinical and commercial feasibility or regulatory
approval.
[0041] The dosage range of the enhancing agent to be
co-administered with the target agent in accordance with the
invention is about 0.1 to about 20 mg/kg of patient body weight.
"Co-administration" of the enhancing agent comprehends
administration substantially simultaneously with the target agent
(either less than 0.5 hr. before, less than 0.5 hr. after or
together), from about 0.5 to about 72 hr. before the administration
of the target agent, or both, i.e., with one or more doses of the
same or different enhancing agents given at least 0.5 hr. before
and one dose given substantially simultaneously with (either
together with or immediately before of after) the target agent.
Additionally, "co-administration" comprehends administering more
than one dose of target agent within 72 hr. after a dose of
enhancing agent, in other words, the enhancing agent(s) need not be
administered again before or with every administration of target
agent, but may be administered intermittently during the course of
treatment.
[0042] The dosage range of orally administered taxane target agents
will vary from compound to compound based on its therapeutic index,
the requirements of the condition being treated, the status of the
subject and so forth. The method of the invention makes it possible
to administer paclitaxel and other taxanes orally ranging from
about 20 mg/m.sup.2 to about 1000 mg/m.sup.2 (based on patient body
surface area) or about 0.5-30 mg/kg (based on patient body weight)
as single or divided (2-3) daily doses, and maintain the plasma
levels of paclitaxel in humans in the range of 50-500 ng/ml for
extended periods of time (e.g., 8-12 hours) after each oral dose.
These levels are at least comparable to those achieved with 96-hour
IV infusion paclitaxel therapy (which causes the patient great
inconvenience, discomfort, loss of quality time, infection
potential, etc.). Moreover, such plasma levels of paclitaxel are
more than sufficient to provide the desired pharmacological
activities of the target drug, e.g., inhibition of tubulin
disassembly (which occurs at levels of about 0.1 .quadrature.M, or
about 85 ng/ml) and inhibition of protein isoprenylation (which
occurs at levels of about 0.03 .quadrature.M, or about 25 ng/ml)
which are directly related to its antitumor effects by inhibiting
oncogene functions and other signal-transducing proteins that play
a pivotal role in cell growth regulation.
[0043] Two or more different enhancing agents and/or two or more
different taxane target agents may be administered together,
alternately or intermittently in all of the various aspects of the
method of the invention.
[0044] As indicated above, oral paclitaxel administered alone
(e.g., in a solid dosage form or even in a liquid vehicle not
containing an oral absorption promoting carrier) exhibits near zero
bioavailability. To be considered an orally bioavailable
pharmaceutical composition containing paclitaxel or other taxanes
for purposes of the present invention, the composition must meet
the following criterion: when the composition is administered
orally to a mammalian subject (e.g., a laboratory rat or a human
patient), i.e., is ingested by the subject, one hour after
administration of an effective oral dose of an oral bioavailability
enhancing agent, the amount of the active ingredient absorbed into
the bloodstream is at least 15% of the amount absorbed when the
same dose of paclitaxel is administered to the subject
intravenously in a standard intravenous vehicle, for example a
CREMOPHOR.TM. EL/ethanol vehicle. The relative percentage of
absorption is determined by comparing the respective AUC (area
under the curve) values of the taxane blood level vs. time curve
generated upon oral administration and the corresponding curve
generated upon intravenous administration.
[0045] The preferred bioavailability enhancing agent for use in
making the experimental determination of whether a particular oral
composition meets the 15% of IV absorption criterion is cyclsoporin
A, for example a single oral dose of 5 mg/kg of CsA.
[0046] The novel pharmaceutical compositions may be administered in
any known pharmaceutical dosage form. For example, the compositions
may be encapsulated in a soft or hard gelatin capsule or may be
administered in the form of a liquid preparation. Each dosage form
may include, apart from the essential components of the composition
(at least one carrier and one taxane active ingredient, and in some
instances at least one co-solubilizer), conventional pharmaceutical
excipients, diluents, sweeteners, flavoring agents, coloring agents
and any other inert ingredients regularly included in dosage forms
intended for oral administration (see, e.g., Remington's
Pharmaceutical Sciences, 17th Ed., 1985).
[0047] Precise amounts of each of the target drugs included in the
oral dosage forms will vary depending on the age, weight, disease
and condition of the patient. For example, paclitaxel or other
taxane dosage forms may contain sufficient quantities of the target
agent to provide a daily dosage of about 20-1000 mg/m.sup.2 (based
on mammalian subject or patient body surface area) or about 0.5-30
mg/kg (based on mammalian subject or patient body weight) as single
or divided (2-3) daily doses. Preferred dosage amounts are about
50-200 mg/m.sup.2 or about 2-6 mg/kg.
[0048] Dosing schedules for the treatment method of the present
invention, for example, the treatment of paclitaxel-responsive
diseases with oral paclitaxel dosage forms co-administered with
enhancing agents, can likewise be adjusted to account for the
patient's characteristics and disease status. Preferred dosing
schedules for administration of oral paclitaxel are (a) the daily
administration to a patient in need thereof of 1-3 equally divided
doses providing about 20-1000 mg/m.sup.2 (based on body surface
area), and preferably about 50-200 mg/m.sup.2, with said daily
administration being continued for 1-4 consecutive days each 2-3
weeks, or (b) administration for about one day each week. The
former schedule is comparable to use of a 96-hour paclitaxel
infusion every 2-3 weeks, which is considered by some a preferred
IV treatment regimen.
[0049] Oral administration of taxanes in accordance with the
invention may actually decrease toxic side effects in many cases as
compared with currently utilized IV therapy. Rather than producing
a sudden and rapid high concentration in blood levels as is usually
the case with an IV infusion, absorption of the active agent
through the gut wall (promoted by the enhancing agents), provides a
more gradual appearance in the blood levels and a stable,
steady-state maintenance of those levels at or close to the ideal
range for a long period of time.
[0050] In a further embodiment of the present invention, the oral
compositions of the invention may be administered in a two-part
medicament system. Thus, for example, there may be certain carriers
coming within the scope of the invention which are desirable for
use in vehicles for certain taxane agents because of their ability
to solubilize the taxane and promote its oral absorption, but the
carrier may be chemically or physically incompatible with desired
adjunctive ingredients such as flavoring or coloring agents. In
such cases, the active ingredient can be administered to the
patient as the first part of the medicament in a relatively small
volume of any suitable liquid solubilizing vehicle (such as water,
CREMOPHOR.TM. or ethanol), which may be sweetened, flavored or
colored as desired to mask the unpleasant taste of the vehicle and
render it more palatable. The administration of the active
ingredient can be followed by administration of the second part of
the medicament: a larger volume of fluid, for example 1 to 8 fluid
ounces (30-240 ml), containing at least one carrier or a
carrier/co-solubilizer system in accordance with the invention. It
has been discovered that administration of the second, "chaser"
formulation a short time after the taxane active ingredient can
retard precipitation of the taxane which might otherwise occur upon
entry into the gastric fluid and promote oral absorption to a
degree comparable to that observed when the taxane is intermixed
with the carrier and administered simultaneously. Illustrative
examples of "chaser" formulations which may be used in a two-part
oral taxane medicament include:
[0051] a) 2-20% (by weight) Vitamin E TPGS+water q.s.;
[0052] b) 2-25% Vitamin E TPGS+2-25% PHARMASOLVE.TM.+water
q.s.;
[0053] c) 2-20% Vitamin E TPGS+2-25% propylene glycol+water
q.s.
[0054] Pursuant to yet another aspect of the invention, the oral
compositions of the invention can contain not only one or more
taxane active ingredients but also one or more bioavailability
enhancing agents in a combination dosage form. For example, such
combination dosage form may contain from about 0.1 to about 20
mg/kg (based on average patient body weight) of one or more of
cyclosporins A, D, C, F and G, dihydro CsA, dihydro CsC and acetyl
CsA together with about 20 to about 1000 mg/m.sup.2 (based on
average patient body surface area), and preferably about 50-200
mg/m.sup.2, of paclitaxel, docetaxel, other taxanes or paclitaxel
or docetaxel derivatives.
[0055] The compositions and methods of the present invention
provide many advantages in comparison with prior art intravenous
compositions containing paclitaxel and other taxanes and prior art
intravenous administration regimens. Apart from the issues of
decreased toxicity, patient convenience and comfort, ease of
administration and lowered expense, discussed previously, the
invention makes it possible to administer powerful taxane antitumor
agents to patients with greatly reduced likelihood of allergic
hypersensitivity reactions which are common with IV administration.
Thus, the need for pre-medication regimens of H-1 and H-2 blockers
plus steroids can be eliminated.
[0056] The present invention also makes it possible to give
taxanes, e.g., paclitaxel, in comparatively infrequent daily doses
(e.g., about twice/day) and according to schedules that would
otherwise not be possible or practical with the intravenous route.
The use of the bioavailability enhancer (e.g., cyclosporin A)
promotes oral absorption of paclitaxel for the first dose and if a
second paclitaxel dose is to be given later in the day, the use of
additional cyclosporin A may not even be needed. Thus, paclitaxel
could be given intermittently as single dose on a fixed schedule
(weekly, biweekly, etc.) or chronically, over a period of
consecutive days (e.g., 4 days) every 2-4 weeks with the goal of
keeping the levels within a safe and effective "window".
[0057] The following examples illustrate various aspects of the
invention. These examples are not intended, however, to limit the
invention in any way or to set forth specific active ingredients,
carriers, co-solubilizers, enhancing agents, dosage ranges, testing
procedures or other parameters which must be used exclusively to
practice the invention.
EXAMPLE 1
Animal Screening Model
[0058] Groups of three male rats each were fasted for 16-18 hours
prior to dosing with .sup.3H-radiolabeled paclitaxel. Each group of
animals received one oral dose of cyclosporin A (5 mg/kg) prior to
dosing with experimental oral paclitaxel formulation. One hour
subsequent to cyclosporin dosing, each group received approximately
9 mg/kg of paclitaxel orally in the form of a composition according
to the invention. Each group received a different oral
formulation.
[0059] Blood samples were collected from each animal at 0.5, 1, 2,
3, 4, 6, 8, 12 and 24 hours post-dose of paclitaxel. The blood
samples were combusted and assayed for total radioactivity.
[0060] The total blood radioactivity levels (corresponding to
concentration in the blood of .sup.3H-paclitaxel) were plotted on a
graph vs. time post-dose. Data for each group of rats were compiled
in the form of mean AUC, C.sub.max and T.sub.max.
[0061] The percentage of absorption of .sup.3H-paclitaxel for each
group of animals was calculated by comparing the mean AUC value for
the group to the corresponding mean AUC of a reference group of
rats administered .sup.3H-paclitaxel (9 mg/kg) intravenously in the
form of PAXENE.TM. (Baker Norton Pharmaceuticals, Miami Fla.) which
includes CREMOPHOR.TM. EL, ethanol and citric acid.
[0062] Table 2 lists all carriers and carrier/co-solubilizer
combinations which were formulated into oral compositions
containing paclitaxel in accordance with the invention, were tested
in rats in accordance with the foregoing procedure and were found
to yield percentage absorption values in the experimental animals
of 15% or greater in comparison with IV paclitaxel.
2TABLE 2 Carriers and carrier/co-solubilizer combinations which
achieved greater than 15% paclitaxel absorption Carriers
Co-solubilizers TPGS Pharmasolve Propylene Mygliols Softigen PEG
200 & Propylene PEG 200 & glycol 400 glycol/ 400/
Pharmasolve Pharmasolve Gelucire 44/14 Pharmasolve Mygliols Olive
oil/ Olive Olive oil/ Cremophor EL Cremophor Brij 97 oil/ TPGS RH
40 Cremophor RH 40 Gelucire 44/14 Labrasol TPGS/ Tween 80 PEG 400
Solutol HS 15 Gelucire 50/13 Tween 80 PEG 400 Cremophor EL
Cremophor EL Pharmasolve Citrate Ethanol/water Ethanol esters
Cremophor RH 40 Ethanol/water Myrj 49 Pharmasolve Myrj 52
Pharmasolve Propylene glycol Myrj 53 Pharmasolve Tween 40* Tween
60* Tween 80* Ethanol Citrate Olive oil PEG 400 Water esters
Crillet 6* Emsorb 2726 Pharmasolve Solutol HS 15* Brij 76
Pharmasolve Brij 78 Pharmasolve Brij 98 Pharmasolve Crovol A-40*
Crovol M-40* .-Cyclodextrin Water *Have been demonstrated to work
as both solubilizer and carrier Note: All carriers listed above can
solubilize paclitaxel greater than 25 mg/ml at 37.quadrature.
C.
EXAMPLE 2
Polyoxyethylated (POE) Sorbitan Fatty Acid Esters as Carriers
[0063] Table 3 lists vehicle formulations including certain POE
sorbitan fatty acid esters as carriers for oral paclitaxel, alone
or in combination with a co-solubilizer. In formulations where more
than one component is present in the vehicle, the respective weight
ratios of the components is given. Each of these formulations was
tested in the animal model described in Example 1 and found to
yield a percentage absorption of paclitaxel upon oral
administration greater (in some cases far greater) than 15% of a
roughly comparable dose of paclitaxel administered intravenously.
The table sets forth the total dose of paclitaxel incorporated into
each vehicle as actually administered to the experimental animals,
the concentration of paclitaxel in the composition, the HLB value
of the carrier, the mean AUC value for the group of rats receiving
the formulation and the percentage of paclitaxel absorption in
comparison with rats receiving IV administration.
3TABLE 3 Absorption Results of Polyoxyethylated (POE) Sorbitan
Fatty Acid Esters Surfactants as Carriers AUC Dose Conc.
.quadrature.g .multidot. [mg/ [mg/ eq .times. hr/ % FORMULATIONS
kg] ml] HLB ml ABS* POE 20 sorbitan 10.2 18 16.7 17.2 54.6
monolaurate (Tween 20) POE 20 sorbitan 10.2 18 15.6 17.6 55.9
monopalmitate (Tween 40) POE 20 sorbitan 8.9 25 14.9 17.1 62.3
monostearate (Tween 60) POE 20 sorbitan 9.4 25 10.5 6.15 21.1
tristearate (Tween 65) POE 20 sorbitan 9.0 18 15.0 11.4 40.9
monooleate (Tween 80) POE 20 sorbitan 9.3 20 14.9 13.6 47.5
monoisostearate (Crillet 6) POE 40 sorbitan 10.2 25 15.0* 7.76 24.6
diisostearate/Pharmasolve (3:1) [Emsorb 2726] *Percent absorption
versus paclitaxel IV AUC (same for Tables 4-11)
EXAMPLE 3
POE Alkyl Ethers as Carriers
[0064] Table 4 pertains to vehicle formulations containing POE
alkyl ethers as carriers. The data set forth correspond to the data
described in the preceding example with respect to Table 3.
4TABLE 4 Absorption Results of Polyoxyethylated (POE) Alkyl Ethers
Surfactants as Carriers AUC Dose Conc. .quadrature.g .multidot. eq
.times. % FORMULATIONS [mg/kg] [mg/ml] HLB hr/ml ABS POE 10 stearyl
10.2 18 12.4* 9.54 30.3 ether/Pharmasolve (3:1) [Brij 76] POE 20
stearyl 9.5 18 15.3* 11.4 38.7 ether/Pharmasolve (3:1) [Brij 78]
POE 20 oleyl 9.6 25 15.3* 5.89 20.9 ether/Pharmasolve (3:1) [Brij
98] *Not an actual HLB value of mixture. Numbers represent HLB
values of pure surfactants.
EXAMPLE 4
POE Stearates as Carriers
[0065] Table 5 pertains to vehicle formulations containing POE
stearates as carriers. The data set forth correspond to the data
described in Example 2 with respect to Table 3.
5TABLE 5 Absorption Results of Polyoxyethylated (POE) Stearates as
Carriers AUC Dose Conc. .quadrature.g .multidot. eq .times. %
FORMULATIONS [mg/kg] [mg/ml] HLB hr/ml ABS POE 20 stearate 9.2 25
15.0* 10.3 36.4 ester/Pharmasolve (3:1) [Myrj 49] POE 40 stearate
9.4 18 16.9* 16.2 57.3 ester/Pharmasolve (3:1) [Myrj 52] POE 50
stearate 10.0 25 17.9* 7.01 22.3 ester/Pharmasolve (3:1) [Myrj 53]
*Not an actual HLB value of mixture. Numbers represent HLB values
of pure surfactants.
EXAMPLE 5
Ethoxylated Modified Triglycerides as Carriers
[0066] Table 6 pertains to vehicle formulations containing
ethoxylated-modified triglycerides as carriers. The data set forth
correspond to the data described in Example 2 with respect to Table
3.
6TABLE 6 Absorption Results of Ethoxylated Modified Triglycerides
as Carriers AUC Dose Conc. .quadrature.g .multidot. eq .times. %
FORMULATIONS [mg/kg] [mg/ml] HLB hr/ml ABS PEG-20 Almond 9.5 20 10
8.06 27.6 Glycerides (Crovol A-40) PEG-20 Corn 9.6 20 10 7.46 25.3
Glycerides (Crovol M-40)
EXAMPLE 6
POE 660 Hydroxystearates as Carriers
[0067] Table 7 pertains to vehicle formulations containing POE 660
hydroxystearates as carriers. The data set forth correspond to the
data described in Example 2 with respect to Table 3.
7TABLE 7 Absorption Results of Polyoxyethylated (POE) 660
Hydroxystearate as Carrier AUC Dose Conc. .quadrature.g .multidot.
eq .times. % FORMULATIONS [mg/kg] [mg/ml] HLB hr/ml ABS POE 660
hydroxystearate 9.1 25 .about.14 10.8 38.4 (Solutol HS 15) Gelucire
44/14 + Solutol 9.3 25 .about.14 6.54 22.8 HS + TPGS (2:1:1)
EXAMPLE 7
Saturated Polyglycolized Glycerides as Carriers
[0068] Table 8 pertains to vehicle formulations containing
saturated polyglycolyzed glycerides as carriers. The data set forth
correspond to the data described in Example 2 with respect to Table
3.
8TABLE 8 Absorption Results of Saturated Polyglycolized Glycerides
as Carriers AUC Dose Conc. .quadrature.g .multidot. eq .times.
FORMULATIONS [mg/kg] [mg/ml] hr/ml % ABS Gelucire 44/14 + PEG 400
10.3 25 11.9 37.4 (6:1) Gelucire 44/14 + Labrasol 9.3 25 12.1 42.1
(6:1) Gelucire 44/14 + Mygliol 8.7 25 4.75 17.6 810 (6:1) Gelucire
44/14 + Mygliol 10.3 25 8.45 26.6 818 (6:1) Gelucire 44/14 +
Mygliol 9.5 25 6.48 22.0 840 (6:1) Gelucire 44/14 + Cremophore 9.5
25 10.7 36.6 RH 40 (6:1) Gelucire 44/14 + Cremophor 9.8 25 11.5
38.1 EL (6:1) Gelucire 44/14 + Solutol 9.3 25 6.54 22.8 HS + TPGS
(2:1:1) Gelucire 44/14 + Olive 9.6 20 11.9 39.9 Oil + Tween 80
(2:1:1) Gelucire 44/14 + Olive 9.6 20 9.83 33.2 Oil + TPGS (2:1:1)
Gelucire 44/14 + Olive 9.6 20 9.07 30.6 Oil + POE 10 Oleyl (2:1:1)
Gelucire 44/14 + Olive 9.1 20 7.73 27.5 Oil + Cremophor RH 40
(2:1:1) Gelucire 44/14 + Tween 9.7 25 10.05 33.5 80 (6:1) Gelucire
50/13 + Tween 9.4 25 8.21 28.4 80 (5:2) Gelucire 50/13 + PEG 400
9.3 25 6.46 22.5 (6:1) Gelucire 50/13 + Cremophor 9.1 25 8.11 28.9
EL (6:1) Labrasol: Saturated polyglycolyzed C8-C10 glycerides (HLB
= 14) Mygliols: Neutral oils (saturated coconut and palmkernel
fatty acids) mainly C8-C10 fatty acids Cremophor EL: Polyoxyl 35
castor oil (HLB 12-14) Cremophor RH 40: Polyoxyl 40 Hydrogenated
castor oil (HLB 14-16)
EXAMPLE 8
Vitamin E TPGS Systems as Carriers
[0069] Table 9 pertains to vehicle formulations containing Vitamin
E TPGS systems as carriers. The data set forth correspond to the
data described in Example 2 with respect to Table 3.
9TABLE 9 Absorption Results of TPGS Systems as Carriers AUC Dose
Conc. .quadrature.g .multidot. eq .times. FORMULATIONS [mg/kg]
[mg/ml] hr/ml % ABS* TPGS + Pharmasolve 8.2 25 8.93 35.2 (1.5:1)
TPGS + Pharmasolve 9.5 25 8.72 29.8 (1:1) TPGS + Pharmasolve 9.1 25
8.83 31.4 (2:1) TPGS + Propylene 8.5 20 9.65 36.9 glycol (1:1) TPGS
+ Pharmasolve + 9.0 25 8.31 29.8 PEG 200 (2:1:1) TPGS + Pharmasolve
+ 8.2 25 6.62 26.3 PEG 400 (2:1:1) TPGS + Pharmasolve + 8.9 25 8.07
29.3 PG (2:1:1) TPGS + Mygliol 810 9.1 25 5.65 20.0 (1:1) TPGS +
Softigen 767 10.2 25 8.66 27.5 (1:1) TPGS + PEG 200 (1:1) 8.3 25
7.75 30.4 TPGS + PEG 400 (1:1) 9.6 25 7.32 24.6 Softigen 767:
PEG-6-Caprylic/Capric Glycerides
EXAMPLE 9
POE and Hydrogenated Castor Oil Derivatives as Carriers
[0070] Table 10 pertains to vehicle formulations containing POE and
hydrogenated castor oil derivatives as carriers. The data set forth
correspond to the data described in Example 2 with respect to Table
3.
10TABLE 10 Absorption Results of Polyoxyethylated Castor Oil
(Cremophor) Derivatives Systems as Carriers Dose Conc. AUC [mg/
[mg/ .quadrature.g .multidot. eq .times. FORMULATIONS kg] ml] hr/ml
% ABS IV Paxene 10.0 6 11.15 37.2 Cremophor EL + Ethanol + 9.2 1.3
6.07 21.5 Water (1:1:8) IV Paxene + Water (1:1) 8.9 3 8.70 31.8 IV
Paxene + Water (1:5) 9.1 1 10.76 38.5 Cremophor EL + Pharmasolve
8.6 20 6.74 25.3 (1:1) Cremophor EL + TBC (1:1) 9.0 20 9.35 31.9
Cremophor EL + Gelucire 9.8 25 11.5 38.1 44/14 (1:6) Cremophor EL +
Gelucire 9.1 25 8.11 28.9 50/13 (1:6) Cremophor RH 40 + Ethanol +
9.0 3 7.14 25.7 Water (1:1:2) Cremophor RH 40 + Gelucire 9.5 25
10.7 36.6 44/14 (1:6) Cremophor RH 40 + Gelucire 9.1 20 7.73 27.5
44/14 + Olive Oil (1:2:1)
EXAMPLE 10
Polysorbate 80 Carriers
[0071] Table 11 pertains to vehicle formulations containing
polysorbate 80 as at least one of the carriers. The data set forth
correspond to the data described in Example 2 with respect to Table
3.
11TABLE 11 Absorption Results of Polysorbate 80 (Tween 80) Systems
as Carrierts Dose Conc. AUC [mg/ [mg/ .quadrature.g .multidot. eq
.times. % FORMULATIONS kg] ml] hr/ml ABS Polysorbate 80 9.0 18 11.4
40.9 Polysorbate 80 + Ethanol + Water 8.0 1.2 7.92 31.2 (1:1:8)
Polysorbate 80 + Ethanol (3:1) 8.9 18 9.97 36.3 Polysorbate 80 +
Water (3:1) 8.2 18 7.15 28.3 Polysorbate 80 + TBC (1:1) 9.5 20 9.12
31.2 Polysorbate 80 + ATEC (1:1) 9.1 20 8.50 30.3 Polysorbate 80 +
Olive oil (3:1) 9.0 20 13.3 43.7 Polysorbate 80 + PEG 400 (1:1) 9.7
20 9.41 31.5 Polysorbate 80 + Gelucire 44/14 + 9.6 20 11.9 39.9
Olive Oil (1:2:1) Polysorbate 80 + Gelucire 44/14 9.7 25 10.05 33.5
(1:6) TBC = Tributyl citrate (citrate ester) ATEC = Acetyl triethyl
citrate (citrate ester)
[0072] It has thus been shown that there are provided compositions
and methods which achieve the various objects of the invention and
which are well adapted to meet the conditions of practical use.
[0073] As various possible embodiments might be made of the above
invention, and as various changes might be made in the embodiments
set forth above, it is to be understood that all matters herein
described are to be interpreted as illustrative and not in a
limiting sense.
[0074] What is claimed as new and desired to be protected by
Letters Patent is set forth in the following claims.
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