U.S. patent application number 11/208209 was filed with the patent office on 2006-01-05 for vaginal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems for cancer therapy.
Invention is credited to Leslie Z. Benet, James H. Liu, Giovanni M. Pauletti, Wolfgang A. Ritschel.
Application Number | 20060002966 11/208209 |
Document ID | / |
Family ID | 23226449 |
Filed Date | 2006-01-05 |
United States Patent
Application |
20060002966 |
Kind Code |
A1 |
Pauletti; Giovanni M. ; et
al. |
January 5, 2006 |
Vaginal delivery of chemotherapeutic agents and inhibitors of
membrane efflux systems for cancer therapy
Abstract
Devices, methods, and compositions for cancer therapy by
administration of chemotherapeutic agents and/or inhibitors of
membrane efflux systems to the vagina for topical and systemic
tumor targets.
Inventors: |
Pauletti; Giovanni M.;
(Loveland, OH) ; Liu; James H.; (Cincinnati,
OH) ; Benet; Leslie Z.; (Belvedere, CA) ;
Ritschel; Wolfgang A.; (Cincinnati, OH) |
Correspondence
Address: |
Hana Verny;Peters, Verny, Jones, Schmitt & Aston LLP
Suite 230
425 Sherman Avenue
Palo Alto
CA
94306
US
|
Family ID: |
23226449 |
Appl. No.: |
11/208209 |
Filed: |
August 18, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10226667 |
Aug 21, 2002 |
|
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11208209 |
Aug 18, 2005 |
|
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60315877 |
Aug 29, 2001 |
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Current U.S.
Class: |
424/422 ;
514/19.3; 514/20.5; 514/283; 514/34 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 9/0034 20130101; A61K 9/0036 20130101 |
Class at
Publication: |
424/422 ;
514/011; 514/034; 514/283 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 31/704 20060101 A61K031/704; A61K 31/4745 20060101
A61K031/4745 |
Claims
1-33. (canceled)
34. A method for a vaginal delivery of chemotherapeutic agents to a
systemic circulation for treatment, control and maintenance of
cancer in a human female patient, wherein said agent is delivered
into the systemic circulation through a vaginal mucosa from a
mucoadhesive composition or from an intravaginal device
incorporated with said composition, said method comprising steps
of: a) providing the mucoadhesive vaginal composition consisting of
from about 1 to about 1000 mg/day of the chemotherapeutic agent
selected from the group consisting of daunorubicin, doxorubicin,
idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone,
etoposide, teniposide, vinblastine, vincristine, mitomycin C,
paclitaxel, docetaxel, actinomycin D, colchicine, topotecan,
irinotecan, gemcitabine and a mixture thereof; from about 30 to
about 95% of a lipophilic or hydrophilic carrier selected from the
group consisting of saturated mono-, di- or triglyceride of fatty
acids from 8 to 18 carbons, a mixture thereof, polyethylene glycol
of molecular weight between about 200 and 8000, a derivative
thereof and a mixture thereof; from about 5 to about 25% of a
mucoadhesive agent selected from the group consisting of a
cellulose derivative, natural gum, alginate and pectin; and from
about 5 to about 25% of a sorption promoter selected from the group
consisting of a non-ionizable glycol ester derivative, a glycol
derivative with a glycerol ester, a non-ionizable glycol ether
derivative and an interesterified stone oil; wherein said
composition is formulated as or incorporated into the device as a
suppository, cream, gel, foam, ointment, capsule containing
microparticles, microcapsules, microparticles, nanoparticles, or
liposome suspension; and b) delivering said composition to the
vaginal mucosa by administering said composition or inserting said
device incorporated with said composition into the vagina, wherein
said vaginal device is a vaginal tampon, vaginal ring, vaginal
strip, vaginal capsule, vaginal tablet, vaginal pessary, vaginal
cup or vaginal sponge.
35. The method of claim 34 wherein said chemotherapeutic agent is
colchicine administered in a range from about 4 to about 8 mg/day,
paclitaxel administered in a range from about 60 to about 100
mg/day, topotecan administered in a range from about 0.5 to about
1.5 mg/day, doxorubicin administered in a range from about 100 to
about 1000 mg/day, vincristine administered in a range from about
1-2 mg/week, verapamil administered in a range from about 10 to
about 125 mg/dose or cyclosporin administered in about 60
mg/dose.
36. The method of claim 35 wherein said mucoadhesive agent is
hydroxypropyl methylcellulose, wherein said lipophilic carrier is
the saturated mono-, di- or triglyceride of fatty acids of from 8
to 18 carbons, or the mixture thereof, and wherein said hydrophilic
carrier is a polyethylene glycol (PEG) 8000, PEG 6000, PEG 4000,
PEG 3000, PEG 2000, PEG 1500, PEG 400 or a mixture thereof and
wherein said sorption promoter is ethoxydiglycol.
37. A mucoadhesive vaginal composition for vaginal delivery of
chemotherapeutic agents to a systemic circulation for treatment,
control and maintenance of cancer in a human female patient, said
composition essentially consisting of: a) from about 1 to about
1000 mg of the chemotherapeutic agent selected from the group
consisting of daunorubicin, doxorubicin, idarubicin, amrubicin,
pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide,
vinblastine, vincristine, mitomycin C, paclitaxel, docetaxel,
actinomycin D, colchicine, topotecan, irinotecan, gemcitabine and a
mixture thereof; from about 30 to about 95% of a lipophilic or
hydrophilic carrier selected from the group consisting of saturated
mono-, di- or triglyceride of fatty acids from 8 to 18 carbons, a
mixture thereof, polyethylene glycol of molecular weight between
about 200 and 8000, a derivative thereof and a mixture thereof;
from about 5 to about 25% of a mucoadhesive agent selected from the
group consisting of a cellulose derivative, natural gum, alginate
and pectin; and from about 5 to about 25% of a sorption promoter
selected form the group consisting of a non-ionizable glycol ester
derivative, a glycol derivative with a glycerol ester, a
non-ionizable glycol ether derivative and an interesterified stone
oil; wherein said composition is formulated as a suppository,
cream, gel, foam, ointment, capsule containing microparticles,
microcapsules, microparticles, nanoparticles or a liposome
suspension.
38. The composition of claim 37 wherein said chemotherapeutic agent
is colchicin administered in a range from about 4 to about 8
mg/day, paclitaxel administered in a range from about 60 to about
100 mg/day, topotecan administered in a range from about 0.5 to
about 1.5 mg/day, doxorubicin administered in a range from about
100 to about 1000 mg/day, vincristine administered in a range from
about 1-2 mg/week, verapamil administered in a range from about 10
to about 125 mg/dose or cyclosporin administered in about 60
mg/dose.
39. The composition of claim 38 wherein said sorption promoter is
ethoxydiglycol present in from about 10 to about 15%, wherein said
mucoadhesive agent is a cellulose derivative hydroxypropyl
methylcellulose present in from about 10 to about 15%, wherein said
lipophilic carrier is the saturated mono-, di- or triglyceride of
fatty acids of from 8 to 18 carbons or the mixture thereof, and
wherein said hydrophilic carrier is a polyethylene glycol (PEG)
8000, PEG 6000, PEG 4000, PEG 3000, PEG 2000, PEG 1500, PEG 400 or
a mixture thereof.
40. The composition of claim 39 wherein said chemotherapeutic agent
is released from said composition or from the device incorporated
with said composition in a controlled release manner for a
continuous or pulsed release.
41. The composition of claim 40 additionally comprising a
penetration enhancer or a solubilizer.
42. The composition of claim 41 administered daily, bi-daily,
weekly, monthly or quarterly.
43. The composition of claim 42 incorporated into a vaginal
device.
44. The composition of claim 43 said device is a vaginal tampon,
vaginal ring, vaginal strip, vaginal capsule, vaginal tablet,
vaginal pessary, vaginal cup or vaginal sponge.
45. A vaginal device for delivery of chemotherapeutic agents to the
general circulation, wherein said device is a vaginal tampon,
vaginal ring, vaginal strip, vaginal capsule, vaginal tablet,
vaginal bioadhesive tablet, vaginal pessary, vaginal cup or vaginal
sponge incorporated with a mucoadhesive composition comprising from
about 1 to about 1000 mg of the chemotherapeutic agent selected
from the group consisting of daunorubicin, doxorubicin, idarubicin,
amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide,
teniposide, vinblastine, vincristine, mitomycin C, paclitaxel,
docetaxel, actinomycin D, colchicine, topotecan, irinotecan,
gemcitabine and a mixture thereof; from about 30 to about 95% of a
lipophilic or hydrophilic carrier selected from the group
consisting of saturated mono-, di- or triglyceride of fatty acids
from 8 to 18 carbons, a mixture thereof, polyethylene glycol of
molecular weight between about 200 and 8000, a derivative thereof
and a mixture thereof; from about 5 to about 25% of a mucoadhesive
agent selected from the group consisting of a cellulose derivative,
natural gum, alginate and pectin; and from about 5 to about 25% of
a sorption promoter selected form the group consisting of a
non-ionizable glycol ester derivative, a glycol derivative with a
glycerol ester, a non-ionizable glycol ether derivative and an
interesterified stone oil; wherein said composition is formulated
as a suppository, cream, gel, foam, ointment, capsule containing
microparticles, microcapsules, microparticles, nanoparticles or a
liposome suspension.
46. The device of claim 45 wherein said device is incorporated with
the composition comprising from about 4 to about 8 mg/day of
colchicin, from about 60 to about 100 mg/day of paclitaxel, from
about 0.5 to about 1.5 mg/day of topotecan, from about 100 to about
1000 mg/day of doxorubicin, from about 1-2 mg/week of doxorubicin,
from about 10 to about 125 mg/dose of verapamil or about 60 mg/dose
of cyclosporin, about 10% of hydroxypropyl methylcellulose, about
75% of saturated triglyceride of fatty acids for a hydrophilic drug
or PEG 6000/PEG 400 for a lipophilic drug and about 15% of
ethoxydiglycol.
47. The device of claim 46 wherein said device is the vaginal
tampon.
48. The device of claim 46 wherein said device is the vaginal
strip.
49. The device of claim 46 wherein said device is the vaginal
pessary.
50. The device of claim 46 wherein said device is the vaginal
sponge.
51. The device of claim 46 wherein said device is the vaginal
foam.
52. The device of claim 46 wherein said device is the vaginal
ring.
53. The device of claim 46 wherein said device is the vaginal
capsule, vaginal tablet, vaginal bioadhesive tablet or vaginal cup.
Description
[0001] This invention is a continuation of the patent application
Ser. No. 10/226,667, filed on Aug. 21, 2002, allowed, which is
based on and claims priority of the Provisional application
60/315,877 filed on Aug. 29, 2001.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
[0002] The present invention concerns vaginal delivery of
chemotherapeutic agents and/or inhibitors of membrane efflux
systems for cancer therapy and a method for treatment of cancer. In
particular, the invention concerns a method, composition and device
for a mucosal and transmucosal delivery of a chemotherapeutic agent
and/or inhibitor of membrane efflux systems to the vagina for
topical vaginal and/or systemic cancer therapy using a mucoadhesive
composition directly or incorporated into an intravaginal medicated
device.
[0003] The composition of the invention or intravaginal device
medicated with the mucosal composition of the invention delivers
the chemotherapeutic agent and/or inhibitor of membrane efflux
system into the vagina, provides a continuous contact with the
vaginal mucosa, releases the agent from the formulation and
delivers it transmucosally into the systemic circulation. The
composition permits delivery of the therapeutic agent
transmucosally through a vaginal wall to the systemic circulation
or topically to the vaginal mucosa. The method avoids intravenous
administration, permits extended continuous or pulsed delivery of
the chemotherapeutic agents and/or inhibitors of membrane efflux
systems and achieves delivery of higher concentrations of such
agents to a site of neoplasias in the female.
[0004] The mucoadhesive composition comprises at least a
therapeutic agent, a mucoadhesive agent, a sorption promoter and a
carrier and optionally a penetration enhancer.
[0005] The mucoadhesive composition or medicated intravaginal
device of the invention permits administration of lower
concentrations of the drug than those needed for systemic
administration, prevents leaking of the drug out of the vagina,
results in greater systemic bioavailability than after oral
administration and enhances transmucosal absorption of
chemotherapeutic agents.
BACKGROUND AND RELATED DISCLOSURES
[0006] Treatment of cancer or a cellular malignancy where there is
a loss of normal control over cell growth, which results in
unregulated growth, lack of differentiation and ability to invade
local tissues and metastasize, poses a great challenge for the
whole medical community. Because of the cancer's great
aggressiveness, the available treatments, such as radiation and
chemotherapy utilizing cytotoxic agents, are typically also very
aggressive. As a result, the treatments of cancer result in many
adverse reactions and toxicity.
[0007] Successful cancer therapy must be diverted to the primary
tumors and to metastases, typically requiring a systemic, mainly
intravenous, drug administration. Because of their aggressivity and
toxicity, such intravenous administration often leads to phlebitis
or collapse of the veins. Moreover, for intravenous injections it
requires delivery of the treatment in the hospital or doctor's
office as well as periods of following observation. To date,
alternative treatments which would enable home administration of
these drugs are limited.
[0008] Thus, it would be advantageous to have available alternative
routes of administration of the chemotherapeutic agents and/or
inhibitors of membrane efflux systems which would permit
self-administration or, through extension, on-going monitoring.
[0009] It has been estimated that in the United States half of the
one million new cancer cases annually will be treated with systemic
chemotherapy. Although the oral route would be the most preferred
from a patient's perspective, absorption from the gastrointestinal
tract is generally low due to various protein systems expressed in
the intestinal mucosa. This includes metabolically active enzymes,
such as cytochrome P450 superfamily, that degrade the therapeutic
agent before it can reach the systemic distribution system. In
addition, the intestinal mucosa contains a high level of
specialized transport proteins that remove structurally unrelated
drug molecules before reaching the systemic circulation. Examples
of such membrane efflux systems that belong to the ABC transporter
superfamily are P-glycoprotein (P-gp) and multidrug-resistance
associated protein (MRP). It is also known that drug metabolizing
enzymes and membrane efflux systems in the gastrointestinal mucosa
act in concert, which results in low oral bioavailability of drugs
that are substrates for both systems.
[0010] Biochemically, efflux systems in the gastrointestinal tract
are related to the proteins that cause failure of chemotherapy in
cancer patients as a result of multidrug resistance (MDR), as
described in Ann. Rev. Cell Biol., 8:67 (1992). It is well
documented that overexpression of membrane efflux systems such as
P-gp and MRP in tumor cells confer MDR by actively decreasing net
intracellular accumulation of diverse cytotoxic drugs (J. Biol.
Chem., 263:12163 (1998); PNAS (USA), 85:3680 (1988); Semin. Cancer
Biol., 2:213 (1991); and J. Biol. Chem., 270:16167 (1995)).
[0011] A new treatment of drug-resistant tumor cells includes
administration of inhibitors of membrane efflux systems. The
treatment with these inhibitors significantly increase accumulation
of chemotherapeutic agents in drug-resistant tumor cells and,
hence, provide a more effective tumor therapy at lower doses of the
chemotherapeutic agents. However, since P-gp and MRP are also
expressed in the gastrointestinal mucosa, where they serve as an
important physiological defense barrier to environmental toxins,
oral administration of inhibitors of membrane efflux systems may
have only limited efficacy and also cause severe toxic side
effects. As a consequence, administration of inhibitors of membrane
efflux systems in cancer therapy is currently limited to the
parenteral route using injections or short-term infusions.
[0012] Thus, it would be advantageous to have available alternative
treatment which would overcome these intestinal membrane efflux
systems and provide a continuous and predictable delivery of the
chemotherapeutic drugs and/or inhibitors of membrane efflux systems
to the tumor. To lessen toxicity of these drugs, such delivery
should be preferably via absorption through other mucosal tissues
than alimentary tract and should deliver the drug transmucosally to
the general blood circulation to avoid a necessity to administer
the drug intravenously.
[0013] Transvaginal delivery systems according to the invention
could thus offer an alternative effective means of delivering
therapeutic quantities of chemotherapeutic drugs for the treatment
of neoplastic growth in the female because, in contrast to the
gastrointestinal mucosa, the expression level of membrane efflux
systems in the vaginal mucosa is significantly reduced.
[0014] Transvaginal delivery of anti-inflammatory and other drugs
via a vaginal device has been discovered by inventors and is
disclosed in the U.S. Pat. Nos. 6,086,909, 6,197,327 and 6,416,779
B1, incorporated herein by reference.
[0015] It is therefore a primary objective of this invention to
provide a device, composition and a method for administration of
chemotherapeutic agents and/or inhibitors of membrane efflux
systems by transmucosal or topical vaginal delivery. The method of
the invention provides a novel route of delivery of
chemotherapeutic agents for treatment, control or maintenance of
cancer which eliminates the need for parenteral administration,
permits extended continuous or pulsed delivery of the drug to the
vaginal mucosa locally and topically and transvaginal delivery of
the drug to the general circulation. Additionally, the vaginal
delivery of inhibitors of membrane efflux systems reduces the risk
of toxic side effects following administration to cancer patients
diagnosed with drug-resistant tumors. The method for treatment,
control and maintenance of cancer comprises administering the
chemotherapeutic agents and inhibitors of membrane efflux system
intravaginally to the mucosa or transmucosally to the systemic
circulation.
[0016] All references, patents and patent applications cited herein
are hereby incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
[0017] One aspect of the present invention is a method, composition
and a device for vaginal delivery of effective doses of a
chemotherapeutic agent and/or inhibitor of membrane efflux systems
to the vaginal mucosa or transmucosally to the general blood
circulation.
[0018] Another aspect of this invention is a method for treatment,
management and control of cancer, said method comprising steps of
contacting vaginal mucosa with a mucoadhesive composition or with
an intravaginal device incorporated with said mucoadhesive
composition comprising an antineoplastic agent selected from the
group consisting of antiestrogens, androgen inhibitors, antibiotic
derivatives, antimetabolites, cytotoxic agents, hormones, nitrogen
mustard derivatives and steroids, each alone or in combination with
an inhibitor of membrane efflux systems or further in combination
with other pharmaceutical agents or pharmaceutically acceptable
excipients and maintaining said composition or device in contact
with said vaginal, mucosa for a period of time permitting a
continuous or pulsed delivery of the agent to or through vaginal
mucosa, said composition further comprising at least a mucoadhesive
agent, carrier and sorption promoter.
[0019] Still another aspect of this invention is a method for
treating a human female suffering from cancer, said method
comprising steps of contacting vaginal mucosa with a mucoadhesive
composition or with an intravaginal device incorporated with said
composition, the mucoadhesive composition comprising a
chemotherapeutic agent and/or inhibitor of membrane efflux systems
selected from but not limited to the group of compounds consisting
of daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin,
epirubicin, mitoxantrone, etoposide, teniposide, vinblastine,
vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D,
colchicine, topotecan, irinotecan, gemcitabine cyclosporin,
verapamil, valspodor, probenecid, MK571, GF120918, LY335979,
biricodar, terfenadine, quinidine, pervilleine A, and XR9576, alone
or in combination with another pharmaceutical agent or a
pharmaceutically acceptable excipient, said composition further
comprising at least a mucoadhesive agent, a lipophilic or
hydrophilic carrier and a sorption promoter.
[0020] Still another aspect of this invention is a mucosal
composition comprising a chemotherapeutic agent and/or inhibitor of
membrane efflux systems alone or in admixture with another
pharmaceutical agent or a pharmaceutically acceptable excipient,
said composition suitable for administration to the vagina or for
incorporation into an intravaginal device for the vaginal or
transmucosal vaginal delivery of the drug through the vaginal
mucosa into the general circulation, said agent present in an
amount sufficient to assert its therapeutic effect.
[0021] Still yet another aspect of this invention is a mucoadhesive
composition comprising, in dosage unit form, from 0.001 to 3000 mg,
preferably from 1 to 1000 mg, of a chemotherapeutic agent selected
from the group consisting of but not limited to the group of
daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin,
epirubicin, mitoxantrone, etoposide, teniposide, vinblastine,
vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D,
colchicine, topotecan, irinotecan, gemcitabine cyclosporin,
verapamil, valspodor, probenecid, MK571, GF120918, LY335979,
biricodar, terfenadine, quinidine, pervilleine A, and XR9576, alone
or in combination, or in combination with other pharmaceutical
agents or pharmaceutically acceptable excipients suitable for
intravaginal or transvaginal delivery of said agent to a human
female, said composition consisting essentially of a combination of
an effective amount of said chemotherapeutic agent and/or inhibitor
of membrane efflux systems with at least a mucoadhesive agent
promoting adhesion of the composition to the vaginal mucosa for
delivery of the drug to the vaginal mucosa or with at least a
mucoadhesive agent, a sorption promoter and a lipophilic or
hydrophilic carrier for transmucosal delivery of the agent through
the vaginal mucosa to the systemic circulation.
[0022] Yet another aspect of this invention is an intravaginal
composition for vaginal or transmucosal vaginal delivery of a
chemotherapeutic agent and/or inhibitor of membrane efflux systems,
said composition administered directly or incorporated into a
device selected from the group consisting of an intravaginal
tampon, intravaginal ring, intravaginal pessary, intravaginal
sponge, intravaginal tablet or intravaginal strip incorporated with
a composition comprising a chemotherapeutic agent and/or inhibitor
of membrane efflux systems from the group consisting of
antiestrogens, androgen inhibitors, antibiotic derivatives,
antimetabolites, cytotoxic agents, hormones, nitrogen mustard
derivatives and steroids, formulated as a cream, lotion, foam,
ointment, suppository, liposomal suspension, microemulsion,
bioadhesive microparticle, bioadhesive nanoparticle, solution or
gel.
[0023] Another aspect of this invention is a medicated device
incorporated with a mucosal composition comprising at least a
chemotherapeutic agent and/or inhibitor of membrane efflux systems
in combination with a mucoadhesive agent, a sorption promoter and a
lipophilic or hydrophilic carrier, suitable for treatment,
management and control of cancer.
[0024] Yet another aspect of this invention is an intravaginal
device for vaginal or transmucosal vaginal delivery of a
chemotherapeutic agent and/or inhibitor of membrane efflux systems,
said device selected from the group consisting of an intravaginal
tampon, intravaginal ring, intravaginal pessary, intravaginal
sponge, intravaginal tablet or intravaginal strip incorporated with
a composition comprising a chemotherapeutic agent and/or inhibitor
of membrane efflux systems from the group consisting of
antiestrogens, androgen inhibitors, antibiotic derivatives,
antimetabolites, cytotoxic agents, hormones, nitrogen mustard
derivatives and steroids, formulated as a cream, lotion, foam,
ointment, suppository, liposomal suspension, microemulsion,
bioadhesive microparticle, bioadhesive nanoparticle, capsule,
capsule containing microparticles, solution or gel, incorporated
within said device.
[0025] Still yet another aspect of this invention is a medicated
intravaginal device incorporated with a mucosal composition
comprising, in dosage unit form, a chemotherapeutic agent selected
from the group consisting of but not limited to the group of
daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin,
epirubicin, mitoxantrone, etoposide, teniposide, vinblastine,
vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D,
colchicine, topotecan, irinotecan, gemcitabine cyclosporin,
verapamil, valspodor, probenecid, MK571, GF120918, LY335979,
biricodar, terfenadine, quinidine, pervilleine A, and XR9576, alone
or in combination, or in combination with other pharmaceutical
agents or pharmaceutically acceptable excipients for intravaginal
or transvaginal delivery to a human female, said composition
consisting essentially of a combination of an effective amount of
said chemotherapeutic agent and/or inhibitor of membrane efflux
systems with at least a mucoadhesive agent promoting adhesion of
the composition to the vaginal mucosa for delivery of the drug to
the vaginal mucosa or with a mucoadhesive agent, sorption promoter
and a lipophilic or hydrophilic carrier for transmucosal delivery
of the agent through the vaginal mucosa to the systemic
circulation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 is a graph showing concentration-time profiles of the
P-glycoprotein substrate verapamil in plasma of white New Zealand
rabbits following intravenous and vaginal administration of a
single dose of the drug.
[0027] FIG. 2 is a graph illustrating absolute bioavailability of
the P-glycoprotein substrate verapamil following intravenous and
vaginal administration of the drug to the female white New Zealand
rabbits.
[0028] FIG. 3 is a representation of the female reproductive
organs. FIG. 3A is cross-sectional representation of a portion of
the female reproductive organs including the systemic circulation
and vagina in the upright orientation. FIG. 3B is a cross-sectional
side view representation of a portion of the female reproductive
organs including the uterus and vagina.
[0029] FIG. 4 shows placement of a vaginal device of a drug
delivery system according to the present invention. FIG. 4A is a
front view and FIG. 4B is a cross-sectional side view
representation of the vaginal area adjacent the cervix showing
placement of a tampon device incorporating an annular delivery
composition.
[0030] FIG. 5 is the representation of FIG. 3B showing placement of
a tampon device according to the present invention.
[0031] FIG. 6 is the representation of FIG. 3B showing placement of
a tampon device incorporating a distal porous foam section.
[0032] FIG. 7 is the representation of FIG. 3B showing placement of
a tampon device incorporating a distal porous foam cup. FIG. 7A is
a cross-sectional view of the embodiment shown in FIG. 7, taken in
the direction indicated by the arrows labeled 7A in FIG. 7.
[0033] FIG. 8 is an alternate arrangement to the one shown in FIG.
7 in which medication is contained in the entire porous foam
cup.
[0034] FIG. 9 is the representation of FIG. 3B showing placement of
a tampon device incorporating a distal suppository or gel capsule.
FIG. 9A is a cross-sectional view of the embodiment shown in FIG.
9, taken in the direction indicated by the arrows labeled 9A in
FIG. 9.
[0035] FIG. 10 is the representation of FIG. 3B showing placement
of a tampon device incorporating a distal foam cup having
"fingers." FIG. 10A is a side view of the distal porous foam
cup.
[0036] FIG. 11 is the representation of FIG. 3B showing placement
of a tampon device incorporating a scoop-shaped distal porous foam
section.
[0037] FIG. 12 is a side view of the embodiment shown in FIG.
11.
[0038] FIG. 13 is a front view of the embodiment shown in FIG.
11.
[0039] FIG. 14 is the representation of FIG. 3B showing placement
of a tampon-like device incorporating distal fibers containing
concentrated medication.
[0040] FIG. 15 is the representation of FIG. 3B showing placement
of a tampon-like device incorporating non-absorbent tubing having a
distal opening.
[0041] FIG. 16 is the tampon drug delivery system of FIG. 15 in a
dehydrated and sheathed state.
[0042] FIG. 17 is the tampon drug delivery system of FIG. 16
showing deployment of the tampon.
DEFINITIONS
[0043] As used herein:
[0044] "Anti-cancer agent" means a chemotherapeutic agent or an
inhibitor of membrane efflux systems P-glycoprotein and MRP.
[0045] "Drug" or "agent" means a therapeutically effective compound
suitable for treatment, management or control of cancer or another
condition.
[0046] "Pharmaceutical agent" or "therapeutical agent" means a
chemotherapeutic agent, an inhibitor of membrane efflux system, a
mixture of both, or any other pharmaceutically acceptable and
therapeutically active agent.
[0047] "Chemotherapeutic" means an agent involved in treatment of
disease, typically malignancy, by means of chemical substance or
drug that exhibits cytostatic and/or cytotoxic effects on tumor
cells.
[0048] "Inhibitor of membrane efflux systems" means a chemical
compound, which is suitable to partially or completely block the
functional activity of membrane efflux systems. Such inhibitor is
typically a substrate for an enzyme, such as P-glycoprotein and
MRP, involved in the efflux system.
[0049] "MRP" means multidrug-resistance associated protein.
[0050] "MDR" means multidrug resistance.
[0051] "Continuous delivery" means continuous and uninterrupted
release of the drug from the formulation or device and delivering
such drug in continuous manner.
[0052] "Pulsed delivery" means a release and delivery of the drug
in intermittent intervals. Such pulsed delivery may be provided,
for example, by formulating the drug in individual layers
interspaced with inactive layer of dissolvable coatings or by using
different formulating agents.
[0053] "Intersterified stone oil" means a vegetable oil ethoxylated
by replacing part of glycerol of the glycerides contained in
vegetable oil by polyoxyethylene-glycols. Such replacement results
in hydrophilic properties. Example of the interesterified stone oil
is LABRAFIL.RTM., particularly LABRAFIL.RTM. M 1944 CS,
commercially available from Gattefosse.
[0054] "Mucosal" or "mucoadhesive" means a composition which is
suitable for administration to the mucosal tissue and adhere to
such mucosal tissue.
[0055] "Sorption promoter" means a compound which promotes
penetration and permeation of tissue, that is getting into tissue
as well as going through the tissue.
DETAILED DESCRIPTION OF THE INVENTION
[0056] This invention concerns a method, composition and a device
for topical mucosal and transmucosal vaginal delivery of
chemotherapeutic agents and inhibitors of membrane efflux systems
for cancer therapy. The cancer therapy according to the invention
is achieved by contacting vaginal mucosa with a mucosal composition
or with a device incorporated with a mucosal composition comprising
a chemotherapeutic agent or inhibitor of membrane efflux system or
a combination thereof.
[0057] A device, composition and a method for administration of
chemotherapeutic agents and/or inhibitors of membrane efflux
systems are suitable for both the transmucosal delivery to the
systemic circulation and a topical delivery to the vaginal
mucosa.
[0058] The method of the invention provides a novel route of
delivery of chemotherapeutic agents for treatment, control or
maintenance of cancer which eliminates the need for parenteral
administration, permits extended continuous or pulsed delivery of
the drug to the vaginal mucosa locally and topically and
transmucosal delivery of the drug to the general circulation.
Additionally, the vaginal delivery of inhibitors of membrane efflux
systems reduces the risk of toxic side effects following
administration to cancer patients diagnosed with drug-resistant
tumors.
[0059] I. Mucosal and Transmucosal Vaginal Delivery
[0060] A method for transmucosal and topical mucosal vaginal
delivery comprises intravaginal administration of the mucoadhesive
vaginal composition or the intravaginal device of the invention
incorporated with such composition. The composition or the device
delivers a chemotherapeutic agent and/or inhibitor of membrane
efflux systems to and through the vaginal mucosa into the general
circulation. Such delivery occurs without intravenous
administration and thus eliminates serious adverse reactions
typically connected with intravenously administered
chemotherapeutic agents or inhibitors of membrane efflux
systems.
[0061] A. Advantages of Vaginal Delivery
[0062] Existing systemic cancer therapy is almost exclusively
limited to parenteral administration due to the barrier properties
of the intestinal mucosa. Oral administration of chemotherapeutic
agents prevents these agents to reach the systemic circulation in
therapeutically relevant concentrations. Furthermore, oral
administration of chemotherapeutic agents and inhibitors of
membrane efflux systems, when attempted, often leads to significant
gastrointestinal side effects such as acute nausea and vomiting,
stomatitis, esophagitis, ulceration of stomach and colon, or
increases risk of infections and/or toxic reactions as a result of
reduced activity of membrane efflux systems in the alimentary and
gastrointestinal mucosa. Extended or repeated parenteral
administration of chemotherapeutic agents, as discussed above, has
a potential to cause vascular collapse, vascular damage,
phlebosclerosis, vascular hypersensitivities and other
complications.
[0063] The vaginal route of delivery permits extended, continuous
or pulsed delivery and administration of the drugs without need to
visit the doctor's office or hospital. Using the mucosal
composition and intravaginal device of the invention, the length of
the drug delivery can be extended and the delivered dose may be
lowered as the vaginal delivery by-passes the gastrointestinal
tract and eliminates the intravenous administration with all its
adverse effects and requirements.
[0064] The invention thus concerns discovery of an improved
delivery of chemotherapeutic agents and inhibitors of the membrane
efflux systems that overcomes the side effects and limitations
observed during the parenteral and oral administration of
chemotherapeutic agents and inhibitors of membrane efflux systems
in the female by focusing the delivery of drug therapy directly to
the vaginal mucosa and using a specifically formulated mucosal
composition or an intravaginal device incorporated with such
specifically formulated composition containing an appropriate
amount of a therapeutical agent. Such composition promotes adhesion
of the composition, including the drug released from the device, to
the vaginal mucosa and further promotes a transmucosal delivery of
the drug through vaginal mucosa to the general circulation.
[0065] The therapy according to the invention is suitable for
treatment of all cancers via transmucosal delivery and also for
treatment of ovarian, cervical or uterine cancers using a topical
vaginal or transmucosal delivery, or both. Contacting the vaginal
mucosa with chemotherapeutic drugs and/or inhibitors of membrane
efflux systems incorporated into the composition according to this
invention greatly increases concentrations of the drugs in the
localized area of tumor and circumvents the gastrointestinal tract
and intravenous delivery.
[0066] The newly developed vaginal delivery of the chemotherapeutic
agents or inhibitors of membrane efflux system according to the
invention thus represents an important improvement in the delivery
of the chemotherapeutic agents and important advancement in cancer
therapy.
[0067] B. Confirmation of Transmucosal Delivery
[0068] Mucosal or preferably transmucosal delivery according to the
invention is suitable for delivery of chemotherapeutic agents as
well as inhibitors of membrane efflux systems that belong to the
ABC transporter superfamily. Examples of such inhibitors are
P-glycoprotein (P-gp) and multidrug-resistance associated protein
(MRP).
[0069] Biochemically, efflux systems in the gastrointestinal tract
are related to the proteins that cause failure of chemotherapy in
cancer patients as a result of multidrug resistance (MDR).
Overexpression of membrane efflux systems such as P-gp and MRP in
tumor cells result in multidrug resistance (MDR) by actively
decreasing intracellular accumulation of cytotoxic drugs.
Inhibitors of membrane efflux systems are therefore valuable
anti-cancer agents that permit a significant increase in
accumulation of chemotherapeutic agents in drug-resistant tumor
cells. These inhibitors provide a more effective tumor therapy at
lower doses of the chemotherapeutic agents.
[0070] To confirm that transmucosal delivery of the inhibitors,
studies using verapamil, a membrane efflux system inhibitor for
p-glycoprotein were performed. As discussed above, the
p-glycoprotein is overexpressed in the gastrointestinal mucosa,
however, its expression in the vaginal mucosa is significantly
reduced. Consequently, transvaginal delivery systems of the
invention, if experimentally confirmed, would prove to be an
effective means of delivering therapeutic quantities of
chemotherapeutic drugs for the treatment of neoplasms in the
female.
[0071] The objective of this study was to determine whether vaginal
delivery of verapamil leads to significantly improved
bioavailability of verapamil. Studies were designed to compare
bioavailability of verapamil administered orally, i.v., or
transmucosally through vagina into systemic circulation.
[0072] Plasma pharmacokinetic of verapamil was determined in
anesthetized female white New Zealand rabbits after intravenous and
vaginal administration of verapamil at dose between 0.15-0.19
mg/kg. For analytical purpose, each dose was supplemented with a
trace amount of [.sup.3H] verapamil. Pharmacokinetic parameters
were obtained by non-compartmental analysis using WinNonlin.
Results are shown in FIGS. 1 and 2 and in Table 1.
[0073] FIG. 1 is a graph showing concentration-time profiles of the
P-glycoprotein substrate verapamil in plasma of female white New
Zealand rabbits following intravenous and vaginal administration of
a single dose (0.15-0.19 mg/kg). Results are represented as
mean.+-.S.E.M (n=2-3).
[0074] Results seen in FIG. 1 show that following i.v.
administration of a verapamil solution, verapamil rapidly
disappeared from the vascular system, followed by a slower
elimination phase with a mean terminal half-life of 9.5 hours. When
delivered vaginally in form of a suppository formulated with 15%
(w/w) of the sorption promoter transcutol, verapamil concentrations
in plasma slowly increased to a maximum of 21.3.+-.2.3 ng/ml
measure after 5.5 hours.
[0075] Comparison of the dose-normalized areas under the curve
(AUCs) for verapamil following vaginal and intravenous
administration revealed an absolute bioavailability of
62.3.+-.25.1%. Results are seen in FIG. 2.
[0076] FIG. 2 is a graph showing an absolute bioavailability of
P-glycoprotein substrate verapamil following intravenous and
vaginal administration to female white New Zealand rabbits
(0.15-0.19 mg/kg, n=2-3). In comparison to the oral bioavailability
of this drug in humans (J. Clin. Pharmacol., 40: 219-230 (2000)),
vaginal bioavailability in the rabbit model is significantly
greater (p<0.001).
[0077] Table 1 lists individual pharmacokinetic parameters of
verapamil following intravenous and vaginal administration in
female white New Zealand rabbits. TABLE-US-00001 TABLE 1
Pharmacokinetic Parameters of Verapamil Following Intravenous and
Vaginal Administration in Female New Zealand Rabbits Parameter
Intravenous Vaginal Dose [mg .times. kg.sup.-1] 0.15 0.15-0.19
.sup.c.sub.max[ng .times. ml.sup.-1] 39.9 .+-. 4.9 21.3 .+-. 2.3
.sup.t.sub.max[hr] 0 5.5 .+-. 1.2 AUC[ng .times. hr .times.
mL.sup.-1] 1139.3 .+-. 408.1 709.9 .+-. 285.6 .sup.t.sub.1/2[hr]
9.5 .+-. 5.7 7.6 .+-. 1.2
[0078] Pharmacokinetic parameters were calculated from plasma
verapamil drug concentration using the model-independent analysis
module of WinNonlin.
[0079] The calculated terminal half-lives of verapamil, seen in
Table 1, show that absorption across the vaginal mucosa after
release of verapamil from the suppository is not rate-limiting.
[0080] The findings seen in FIGS. 1 and 2 and Table 1 confirm that
verapamil, as a P-glycoprotein substrate, readily permeates the
vaginal mucosal barrier. In contrast, oral absorption of verapamil
is significantly reduced as demonstrated by a low oral
bioavailability of 20-25%. These results show that vaginal delivery
of substrates for membrane efflux systems, such as P-glycoprotein,
increases the systemically available fraction of these therapeutic
agents when compared to oral administration. Consequently, vaginal
delivery of substrates for membrane efflux systems improves the
therapeutic benefit of drugs used in the treatment of cancer.
[0081] C. Method for Delivery of the Cancer Therapy
[0082] A method of the invention is developed and particularly
suitable for non-parenteral delivery of effective doses of a
chemotherapeutic agent and/or inhibitor of membrane efflux systems
topically to the vaginal mucosa or transmucosally to the general
blood circulation.
[0083] The method, useful for treatment, management and control of
cancer, comprises steps of contacting vaginal mucosa with a
mucoadhesive composition or with an intravaginal device
incorporated with such composition. Said composition comprises at
least one chemotherapeutic agent or one inhibitor of membrane
efflux systems selected from the group consisting of antiestrogens,
androgen inhibitors, antibiotic derivatives, antimetabolites,
cytotoxic agents, hormones, nitrogen mustard derivatives and
steroids, alone, in combination with another chemotherapeutic agent
or said inhibitor of membrane efflux systems, or in combination
with another pharmaceutical agent or a pharmaceutically acceptable
excipient, and maintaining said composition or device in contact
with said vaginal mucosa for a period of time permitting a
continuous or pulsed delivery of the agent to or through vaginal
mucosa and necessary to deliver a therapeutic amount of the
chemotherapeutic agent. Such time is typically one to several
hours.
[0084] The delivery route utilizes the transmucosal composition
directly or incorporated into an intravaginal device for
transmucosal delivery and comprises delivery of a combination of
the chemotherapeutic drug and/or inhibitors of membrane efflux
systems with mucoadhesive agents, solubilizing agents, carriers
and, optionally, penetration enhancing agents and solubilizers for
transvaginal delivery.
[0085] Additionally, more than one drug may be present in the
composition and the combination of a chemotherapeutic or any other
pharmacologically active drug in tumor therapy, including
inhibitors of membrane efflux systems, is intended to be within the
scope of the invention.
[0086] The method thus includes a delivery of anti-cancer drugs in
a combination with drugs which may enhance immune system, fight
bacterial or viral infections, have analgesic effect and such other
therapeutically and/or pharmaceutically active agents.
[0087] Specifically, the anti-cancer compounds suitable for
delivery according to the method are selected from but are not
limited to the group consisting of daunorubicin, doxorubicin,
idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone,
etoposide, teniposide, vinblastine, vincristine, mitomycin C,
paclitaxel, docetaxel, actinomycin D, colchicine, topotecan,
irinotecan, gemcitabine cyclosporin, verapamil, valspodor,
probenecid, MK571, GF120918, LY335979, biricodar, terfenadine,
quinidine, pervilleine A, and XR9576. Compounds may be administered
alone or in combination with another pharmaceutical agent or a
pharmaceutically acceptable excipient.
[0088] The method may be practiced either by administering the
mucoadhesive composition directly to the vagina as a cream, lotion,
foam, ointment, suppository, liposomal suspension, microemulsion,
capsule, capsule containing microparticles, bioadhesive
microparticle, bioadhesive nanoparticle, fluid or gel or by
inserting the intravaginal device medicated with the above
described mucosadhesive composition comprising a chemotherapeutic
agent and/or inhibitor of membrane efflux systems incorporated
therein. The device suitable for these purposes is selected from
the group consisting of an intravaginal tampon, intravaginal ring,
intravaginal pessary, intravaginal sponge, intravaginal tablet,
intravaginal capsule, intravaginal cup and intravaginal strip.
[0089] Cancer therapy according to the invention comprises
contacting the vaginal mucosa directly with a composition of the
invention comprising the chemotherapeutic agent and/or inhibitor of
membrane efflux systems. Such direct contact permits an immediate,
extended continuous or pulsed delivery and efficacious treatment.
Such direct treatment also permits use of only such a dosage of the
chemotherapeutic agent and/or inhibitor of membrane efflux system
as is therapeutically required for topical and/or systemic
treatment of the affected tissue.
[0090] The method of the invention, suitable for cancer therapy,
comprises providing a specifically formulated mucosal composition
comprising the chemotherapeutic agent and/or inhibitor of membrane
efflux systems or an intravaginal device incorporated with said
composition, inserting said composition or device into the vagina
and maintaining said composition or device in the vagina for a
period of time required for a therapeutic effect of said mucosal
composition. The composition is formulated to deliver the
chemotherapeutic agent and/or inhibitor of membrane efflux systems
to the target organ for treatment of cancer. For each of the
treatments, the drug is formulated differently.
[0091] The method for cancer therapy using transmucosal delivery of
the drug to systemic circulation involves adding to the composition
of the invention components promoting absorption and/or transport
and penetration of the drug through the vaginal mucosa. Such
components are added in amounts sufficient to facilitate
transmucosal delivery to the general circulation.
[0092] Transmucosal treatment is based on the concept that the
upper vagina and the uterus have specific blood flow
characteristics, either by a portal type circulation or by venous
and lymphatic channels, permitting preferential transport and
delivery of the pharmacological agents from the vagina directly to
the blood circulation thereby by-passing the gastrointestinal tract
absorption and liver detoxification.
[0093] The most specific demonstration of the transvaginal concept
has been achieved by inventors with several types of drugs, as
described in U.S. Pat. Nos. 6,086,909, and 6,197,327 and 6,416,779
B1, incorporated by reference. Chemotherapeutic agents or
inhibitors of membrane efflux systems, when properly formulated,
are transported through the vaginal wall in the same manner as
described in the above patents.
[0094] The composition is a stand alone treatment or it is
incorporated into a suitable intravaginal delivery device which
assures the contact with the vaginal mucosa.
[0095] The composition or the medicated device according to the
method is applied, that is, inserted intravaginally for from about
ten minutes, preferably half an hour, to several hours once, twice
or several times a day or week, as needed, or according to a
treatment regimen. The device is typically provided in dry or wet
form or may be wetted prior to insertion.
[0096] The method of the invention, as described herein and
confirmed experimentally, provides several advantages over oral or
intravenous administration of chemotherapeutic drugs and/or
inhibitors of membrane efflux systems.
[0097] First, there is a continuous concentration of drug delivered
to the vaginal mucosa and to the blood. This provides for higher
bioavailability of the drug. Second, there is prevention of
first-pass elimination of the drug in the intestinal mucosa and the
liver by avoiding the gastrointestinal system. Third, the device of
the invention provides a continuous drug depot which allows
continuous and uninterrupted delivery of drug to the vaginal mucosa
over a long period of time. Fourth, and very important, is the
reduction of side effects due to avoidance of repeated intravenous
administration of the drug or inhibition of gastrointestinal efflux
systems that act as crucial physiological barriers to protect the
interior milieu of the body from environmental toxins.
[0098] II. Mucoadhesive Compositions
[0099] A mucoadhesive composition of the invention for transmucosal
delivery consists typically of four essential components. These
components are a therapeutically active agent, a mucoadhesive
agent, a lipophhilic or hydrophillic carrier and a sorption
promoter. For topical delivery to the vaginal mucosa, the
composition consists at least of two components, a therapeutically
active agent and a mucoadhesive agent. The therapeutically active
agents is either a chemotherapeutic agent and/or inhibitor of
membrane efflux systems. These agents are formulated either alone
or in admixture with another pharmaceutical agent or a
pharmaceutically acceptable excipient. All the above mentioned
components of the composition must be suitable for administration
to the vagina or for incorporation into an intravaginal device for
the vaginal or transmucosal vaginal delivery of the drug through
the vaginal mucosa into the general circulation. The
therapeutically active compound is present in an amount sufficient
to assert its therapeutic effect, typically from about 0.001 to
about 3000 mg, preferably from 1 to 1000 mg, most preferably from
100 to about 500 mg.
[0100] The mucoadhesive composition is typically formulated in
dosage unit form, and contains a chemotherapeutic agent or an
inhibitor of membrane efflux systems selected generally from
antiestrogens, androgen inhibitors, antibiotic derivatives,
antimetabolites, cytotoxic agents, hormones, nitrogen mustard
derivatives and steroids, alone, in combination, or in combination
with other pharmaceutical agents or pharmaceutically acceptable
component and excipients for intravaginal or transvaginal delivery
to a human female.
[0101] The composition typically contains from 0.001 to about 3000
mg, preferably from 1 to 1000 mg, of a chemotherapeutic agent
and/or inhibitor of membrane efflux systems with at least a 5-25%
of mucoadhesive agent promoting adhesion of the composition to the
vaginal mucosa, from about 5 to about 25% of sorption promoter
assuring the penetration of the drug through the mucosa and from
about 40 to about 95% of a lipophilic or hydrophilic carrier
serving as a vehicle for the drug, and optionally, from about 0 to
about 30%, preferably about 1 to 5% of a permeation enhancer or
solubilizer for transmucosal delivery of the agent through the
vaginal mucosa to the systemic circulation.
[0102] Specific therapeutical anti-cancer drug suitable for
delivery according to this invention using the above composition
are daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin,
epirubicin, mitoxantrone, etoposide, teniposide, vinblastine,
vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D,
colchicine, topotecan, irinotecan, gemcitabine, cyclosporin,
verapamil, valspodor, probenecid, MK571, GF120918, LY335979,
biricodar, terfenadine, quinidine, pervilleine A, and XR9576,
alone, or in combination.
[0103] The composition is formulated as a cream, lotion, foam,
ointment, suppository, liposomal suspension, microemulsion,
bioadhesive microparticle, bioadhesive nanoparticle, capsule,
capsule containing microparticles, solution or gel, and can be
delivered as stand alone or incorporated within an intravaginal
device.
[0104] Alternatively, the composition can be incorporated into an
intravaginal device or a coating of such device, for example, a
tampon or tampon-like device coating, or incorporated into a
sponge, foam, strip, pessary, or other material. Absorbent material
or matrix of such devices may be impregnated with a drug containing
liquid solution, suspension lotion, cream, microemulsions or
suspension of liposomes, bioadhesive nanoparticles, or bioadhesive
microparticles. The devices of the invention are described in
greater detail below in section III.
[0105] Any form of drug delivery system which will effectively
deliver the anti-cancer agent to the vaginal mucosa or
transmucosally through the vaginal mucosa into the systemic
circulation is intended to be included within the scope of this
invention.
[0106] A. Anti-Cancer Therapeutical Agents
[0107] The anti-cancer therapeutical agents are chemotherapeutic
agents or inhibitors of membrane efflux system generally selected
from the following groups and types of compounds: antiestrogens,
androgen inhibitors, antibiotic derivatives, antimetabolites,
cytotoxic agents, hormones, nitrogen mustard derivatives or
steroids.
[0108] Specific chemotherapeutic compounds are selected from but
not limited to the group of compounds including daunorubicin,
doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin,
mitoxantrone, etoposide, teniposide, vinblastine, vincristine,
mitomycin C, paclitaxel, docetaxel, actinomycin D, colchicine,
topotecan, irinotecan, gemcitabine and any other compound know now
or which will become known in future to have similar
chemotherapeutic properties. All these compounds are intended to be
covered by this invention.
[0109] Specific inhibitors of membrane efflux system are generally
compounds which are substrates and/or inhibitors for the membrane
efflux systems, such as P-glycoprotein or MDR. The inhibitors a
P-glycoprotein are selected from but not limited to the group of
compounds represented by cyclosporin, verapamil, valspodor,
biricodar, quinidine, terfenadine, pervilleine A, and
investigational drugs currently known under their coded names
GF120918, LY335979, OC144-093 (Ontogen) and XR9576. The MRP2
inhibitors are probenecid and the Merck investigational compound
known under its coded name MK571. Any other compound know now or
which will become known in future to have similar inhibitory
properties is intended to be covered by this invention.
[0110] The compounds of the invention are administered in from
about 0.001 to about 3000 mg/day, preferably in about 1 to about
1000 mg/day dosages. The individual chemotherapeutic agents and
inhibitors are administered in different dosages and ranges
depending on their activity. Exemplary dosage for colchicin are,
for example in a range from about 4 to about 8 mg/day, paclitaxel
from about 60 to about 100 mg/m.sup.2, topotecan from about 0.5 to
about 1.5 mg/m.sup.2, doxorubicin from about 100 to about 1000
mg/day, vincristine about 1-2 mg/dose, verapamil from about 10 to
about 125 mg/dose and cyclosporin in about 60 mg/dose.
[0111] The chemotherapeutic agents or inhibitors of membrane efflux
systems are formulated in said composition alone, in admixture of
two or more or in admixture of the chemotherapeutic agent and
inhibitor and/or in combination with another pharmaceutical agent
or a pharmaceutically acceptable component or excipient.
[0112] B. Pharmaceutical Compositions and Formulations
[0113] In order to achieve desirable drug release at a site where
it can act either directly on the vaginal mucosa or to be
transported transmucosally through the vaginal wall to the systemic
circulation, the chemotherapeutic drug and/or inhibitor of membrane
efflux systems is formulated in conjunction with other components
which permit its adhesion to the vaginal mucosa and absorption
through the vaginal mucosa to the systemic circulation. A resulting
composition typically contains at least a mucoadhesive agent, a
sorption promoter and a non-toxic lipophilic or hydrophilic
carrier, and optionally, a permeation enhancer and/or a
solubilizing agent and/or another pharmaceutically acceptable
excipient suitable for vaginal delivery, such as a buffer, filler,
stabilizer, emulsifier, and any such other excipient as is known in
the art to be useful for these purposes.
[0114] Any component and/or excipient used in formulations of this
invention needs to be approved for human use and acceptable for use
in the vagina with understanding that not all excipients approved
for oral use may be approved and/or suitable for vaginal use.
[0115] 1. Individual Components
[0116] For vaginal transmucosal delivery, the formulation of the
invention comprises the following components.
[0117] a. Anti-Cancer Agent
[0118] The anti-cancer agent is selected from the drugs described
above and is typically present in from about 0.01 to about 10%, by
weight. The agent is typically either lipophilic or hydrophillic
and, depending on its affinity, it requires different formulation
protocol.
[0119] b. Mucoadhesive Agent
[0120] For vaginal transmucosal delivery, the composition
comprises, as an essential component, a mucoadhesive agent. The
mucoadhesive agent permits a close and extended contact of the
composition, or the drug released from said composition, with
mucosal surface by promoting adherence of said composition or drug
to the mucosa. The mucoadhesive agent is preferably a polymeric
compound, such as preferably, a cellulose derivative but it may be
also a natural gum, alginate, pectin, or such similar polymer. The
most preferred cellulose derivative is hydroxypropyl
methylcellulose available under the trade name METHOCEL.RTM.,
commercially available from Dow Chemical Co.
[0121] The mucoadhesive agent is present in from about 5 to about
25%, by weight, preferably in from about 10 to about 15% and most
preferably about 10%.
[0122] c. Sorption Promoters
[0123] The mucoadhesive composition additionally includes a
sorption promoter present in from about 2 to about 30%, by weight.
Sorption promoter assures a permeation and penetration, that is
moving through the tissue and entering systemic blood circulation
of the drug through the vaginal mucosa. Sorption promoters include
non-ionizable glycol ester derivatives, such as polyethylene glycol
caprylic/capric glycerides known as LABRASOL.RTM. from Gattefosse,
glycol derivatives with glycerol esters, such as oleic acid esters
of propylene glycol and glycerol known as. ARLACEL.RTM. 186 from
Imperial Chemical Industries. Particularly preferred are
non-ionizable glycol ether derivatives, such as, most preferably,
ethoxydiglycol known under its trade name TRANSCUTOL.RTM. and
commercially available from Gattefosse, or interesterified stone
oil, for example LABRAFIL M 1944CS, commercially available from
Gattefosse. The interesterified stone oil is a vegetable oil
ethoxylated by replacing part of glycerol of the glycerides
contained in vegetable oil by polyoxyethylene-glycols.
[0124] d. Lipophilic and Hydrophilic Carriers
[0125] Depending on the drug affinity, the composition of the
invention additionally comprises either the lipophilic or the
hydrophilic carrier that is appropriate for the pharmaceutical
agent. Such carrier is typically present from about 30 to about
95%, by weight.
[0126] The carrier is selected from such compounds for which the
drug has low affinity. Thus the lipophilic carrier is appropriate
for formulation of the hydrophilic drug and the hydrophilic carrier
is appropriate for formulation of the lipophilic drug.
[0127] i. Lipophilic Carriers
[0128] Preferred lipophilic carriers for use with hydrophilic drugs
include any medium chain triglycerides and/or a saturated mono-,
di- or triglyceride of fatty acids, particularly those having
carbon chain of from 8 to 18 carbons, or a mixture thereof.
Examples of the lipophilic carrier are saturated glycerides known
and available under the trade name SUPPOCIRE.RTM. AS2 or CS2, and
related compounds commercially available, for example, from
Gattefosse, Westwood, N.J.
[0129] ii. Hydrophillic Carriers
[0130] Preferred hydrophilic carriers include polyethylene glycols
of molecular weight between about 200 and 8000, OR derivatives or
mixtures thereof, such as PEG 6000/PEG 1500, or PEG 6000/PEG
1500/PEG 400, or PEG 6000/PEG 400, or PEG 8000/PEG 1500,
commercially available from, for example, Sigma/Aldrich, St. Louis,
Mo.
[0131] e. Penetration Enhancers
[0132] Penetration enhancers are compounds which assist in
improving penetration properties of the drug or their mixtures by
changing the surface properties of the drugs or their mixtures, or
drug containing solutions or suspensions. These compounds thus, in
a way act as solubilizers. Examples of the penetration enhancers
are non-ionic surfactants.
[0133] f. The Solubilizing Agents
[0134] The composition optionally includes also a solubilizing
agent, such as complex-forming solubilizer citric acid,
ethylenediamine-tetraacetate, sodium meta-phosphate, succinic acid,
urea, cyclodextrin, polyvinylpyrrolidone,
diethylammonium-ortho-benzoate, or micell-forming solubilizers such
as tweens and spans, for example Tween 80. Other solubilizer useful
for the compositions of this invention are polyoxyethylene sorbitan
fatty acid ester, polyoxyethylene n-alkyl ethers, n-alkyl amine
n-oxides, poloxamers, organic solvents, phospholipids and
cyclodextrines.
[0135] f. Additional Excipients
[0136] The composition of the invention may additionally contain
other excipients, such as, fillers, emulsifiers, stabilizers,
buffers, and others as appropriate. Examples of these excipients
are isostearylstearate, isopropyl myristate, glycerin, mineral oil,
polycarbophil, carbomer 934P or 940, hydrogenated palm oil,
glyceride, sodium hydroxide, sorbic acid, and purified water.
[0137] 2. Preferred Formulations
[0138] All and every formulation which contains components of the
invention in ranges given above are intended to be within the scope
of this invention. Few compositions presented here as preferred
formulation are only exemplary and are not intended to limit the
scope of the invention in any way.
[0139] Preferred formulations for hydrophilic drugs comprise
between about 0.01-10%, by weight, of the drug, about 60-90%, by
weight, lipophilic carrier, between about 5-25%, by weight,
mucoadhesive agent, between about 1-25%, by weight, sorption
promoter and optionally a penetration enhancer or solubilizing
agent, usually present in 1-30%, by weight.
[0140] Preferred formulations for the lipophilic drugs comprise
between about 0.01-10%, by weight, of the drug, about 30-90%, by
weight of hydrophilic carrier, between about 1-25%, by weight, of
mucoadhesive agent, between 1 and 25% of sorption promoter and
optionally between about 1-30%, by weight, solubilizing agent
and/or permeation enhancer.
[0141] In another preferred embodiment of the invention, 0.01-10%
of the drug is formulated with other components such as between
about 60 to 90% by weight lipophilic carrier, between about 5 to
20% mucoadhesive agent, between about 10-20% of sorption promoter,
between 0 to 30% solubilizing agent, and between about 1 to 30%
permeation enhancer and.
[0142] In another preferred embodiment of the invention, 0.01-10%
drug is formulated in admixture with about 60 to 90%, by weight, of
hydrophilic carrier, between about 5 and about 20% of mucoadhesive
agent, between about 10 and 15% of sorption promoter and optionally
between 0-30% of solubilizing agent and/or between about 1 and 30%
of permeation enhancer.
[0143] In another preferred embodiment of the invention, the drug
is formulated as a vaginal suppository which includes 0.01-10% of a
hydrophilic drug, 75% of a lipophilic carrier SUPPOCIRE.RTM. AS2,
2% hydroxypropyl methylcellulose, and 15% of ethoxydiglycol
(TRANSCUTOL.RTM.). The suppository may be a stand-alone device or
be incorporated into a tampon or tampon-like device.
[0144] In another preferred embodiment of the invention, the drug
is formulated as a vaginal suppository which includes 0.01-10% of a
lipophilic drug, 75% of a hydrophilic carrier PEG 6000/PEG 1500, 2%
hydroxypropyl methylcellulose, and 15% of ethoxydiglycol
(TRANSCUTOL.RTM.). The suppository may be a stand-alone device or
be incorporated into a tampon or tampon-like device.
[0145] 3. Process for Formulating Hydrophilic or Lipophilic
Drugs
[0146] The lipophilic or hydrophilic chemotherapeutic agents or
inhibitors of membrane efflux system are formulated using the
following process.
[0147] In a general method for preparing a formulation for a
hydrophilic drug, the lipophilic carrier is melted at 45-50.degree.
C. in a heated vessel. The mucoadhesive agent is added to the
carrier with stirring. The preferred hydrophilic drug is dissolved
in the sorption promoter combined with the penetration enhancer and
solubilizing agent. This mixture is added to the
carrier/mucoadhesive agent suspension. The final formulation is
poured into molds of the desired size and shape or incorporated
into a device of the invention. The molds which are stored in a
refrigerator at 4-6.degree. C.
[0148] In a general method for preparing a formulation including a
lipophilic drug, the hydrophilic carrier is melted in a heated
vessel at an appropriate temperature recommended by manufacturer.
The mucoadhesive agent is added to the carrier with stirring. The
preferred lipophilic drug is dissolved in the sorption promoter,
and penetration enhancer combined with the solubilizing agent are
optionally added. This mixture is admixed with the
carrier/mucoadhesive agent suspension. The final formulation is
poured into molds of the desired size and shape or incorporated
into a device of the invention. The final formulation is then
placed in a refrigerator at 4-6.degree. C.
[0149] 4. Sustained Release
[0150] In one embodiment, the composition can be formulated as a
sustained and controlled release drug system.
[0151] The drug which is formulated for controlled and sustained
release is formulated either for continuous release or for pulsed
delivery.
[0152] Continuous release or delivery means continuous and
uninterrupted release of the drug from the formulation or device
wherein the drug is formulated either in the matrix, microparticle,
bioadhesive particle, liposomal suspension or any another system
typically used for such release.
[0153] Pulsed release or delivery is a delivery of the drug in
intermittent intervals. Such pulsed delivery may be provided, for
example, by formulating the drug in the matrix, microparticle,
bioadhesive particle, liposomal suspension or any another system,
as described for continuous delivery, in individual layers
interspaced with inactive layer of inactive, for example,
dissolvable coatings or by using different formulating agents.
Methods and formulating agents for sustained delivery are known in
the art.
[0154] The controlled release, a drug delivery system must be
capable of controlled release of a drug into the vaginal mucosa
over several hours or more. This is achieved by the addition of
time release additives such as hydrogel-forming polymers,
non-errodible matrices, etc., known in the art.
[0155] Additionally, during the menstrual cycle when the pH of the
vagina changes, the drug delivery systems additionally may contain
buffers to stabilize pH to enhance absorption.
[0156] The sustained release composition of the invention is
typically in a form of a cream, lotion, foam, suppository, tablet,
microparticle, nanoparticle, capsule containing microparticles,
liposomal suspension fluid, bioadhesive systems and
microemulsions.
[0157] 5. Bioadhesive Systems and Microemulsions
[0158] Bioadhesive systems and microemulsions are formulations
particularly suitable for vaginal transmucosal delivery.
[0159] The microemulsion may contain pharmaceutically acceptable
surfactants, for example, LABRASOL.RTM., PLUROL.RTM. isostearate
(Gattefosse), co-solvents such as isopropanol or ethanol, and
water. Microemulsions containing one or more of the above
components have been shown to improve bioavailability of
chemotherapeutic drugs.
[0160] Bioadhesive microparticles or bioadhesive nanoparticles
constitute still another intravaginal drug delivery system suitable
for use in the present invention.
[0161] The bioadhesive systems use derivatives of cellulose such as
hydroxypropyl cellulose and polyacrylic acid. They release the
cytotoxic or chemotherapeutic drugs for up to five days once they
are placed in the appropriate formulation. This system represents a
multi-phase liquid or semi-solid preparation which does not seep
from the vagina as do most current suppository formulations. The
microparticles or nanoparticles cling to the wall of the vagina and
release the drug over a several hour period of time. Many of these
systems were designed for nasal use, as described in U.S. Pat. Nos.
4,756,907, and 6,200,590 incorporated herein by reference, but can
be easily modified for use in the vagina. The bioadhesive system
may comprise microparticles or nanoparticles filled with the
chemotherapeutic agent and/or inhibitor of membrane efflux systems
and may contain a surfactant for enhancing solubility and/or uptake
of the drug. The microparticles have a diameter of 1-100 .mu.m,
whereas nanoparticles have a diameter of 10-1000 nm. Microparticles
and nanoparticles can be prepared from starch, gelatin, albumin,
collagen, or dextran according to methods known in the art.
[0162] Bioadhesive tablets are another drug delivery system
suitable for transmucosal delivery. These bioadhesive systems use
hydroxypropyl cellulose and polyacrylic acid. They release drugs
for up to five days once they are placed in the appropriate
formulation. The tablet of the invention has the shape of a
suppository or a tampon so that the maximum contact is achieved
between the vaginal wall and the tablet surface or such a shape as
is suitable for incorporation into the device.
[0163] Bioadhesive microparticles or nanoparticles, described
above, constitute still another drug delivery system suitable for
use in the present invention. This system is a multi-phase liquid
or semi-solid preparation which does not seep from the vagina as do
most current suppository formulations. The substances cling to the
wall of the vagina and release the drug over a several hour period
of time or are released from the device.
[0164] The drug can also be incorporated into creams, lotions,
foams, paste, ointments, microemulsions, liposomal suspensions, and
gels which can be applied to the vagina using an applicator.
Processes for preparing pharmaceuticals in these vehicles can be
found throughout the literature.
[0165] Suitable nontoxic pharmaceutically acceptable excipients for
use in the compositions of the present invention will be apparent
to those skilled in the art of pharmaceutical formulations and
examples are described in REMINGTON: The Science and Practice of
Pharmacy, 20.sup.th Edition, A. R. Gennaro, ed., (2000). The choice
of suitable carriers will depend on the exact nature of the
particular vaginal dosage form desired, e.g., whether the
chemotherapeutic agent and/or inhibitor of membrane efflux systems
is/are to be formulated into a cream, lotion, foam, ointment,
paste, solution, microemulsions, liposomal suspension,
microparticles, nanoparticles or gel, as well as on the
physicochemical properties of the active ingredient(s).
[0166] Although the compositions described above typically contain
only one pharmaceutically active ingredient from the group of
chemotherapeutic agents or inhibitors of membrane efflux systems
for treatment of cancer and neoplastic growth, such compositions
may additionally contain other pharmaceutical agents or a
combination thereof, such as, for example, pain killers,
antivirals, antipruritics, corticosteroids and other agents which
may enhance the therapeutic effect of the primary drug.
[0167] All bioadhesive systems described above may be administered
directly or via an intravaginal device.
[0168] III. Device and/or System for Transvaginal Drug Delivery
[0169] The composition of the invention for transmucosal delivery
is administered either directly to the vagina or is incorporated
into the intravaginal device.
[0170] The intravaginal device of the invention is typically a
tampon, tampon-like device, ring, pessary, strip, cup or foam which
has a solid structure into which the formulation is incorporated
and from which it is released in a timely fashion over a period of
time. The time period is typically limited to from several minutes
to 24 hours, preferably 4-8 hours, which is a hygienically
acceptable time to leave the device in place.
[0171] Advantages of the medicated intravaginal device include
continuous delivery of a predictable amount of the drug. The device
may also have a washable and reusable design, such as, vaginal ring
or pessary.
[0172] The intravaginal device for vaginal or transmucosal vaginal
delivery of a chemotherapeutic agent and/or inhibitor of membrane
efflux systems is an intravaginal tampon, intravaginal ring,
intravaginal pessary, intravaginal sponge, intravaginal tablet or
intravaginal strip incorporated with a composition comprising a
chemotherapeutic agent and/or inhibitor of membrane efflux systems
formulated as a cream, lotion, foam, ointment, suppository,
liposomal suspension, microemulsion, bioadhesive microparticle,
bioadhesive nanoparticle, solution or gel.
[0173] The device may be configured for controlled release of the
chemotherapeutic drugs or inhibitors of membrane efflux system
where the drug incorporated into the device is formulated as a
sustained release system, as described above.
[0174] In one embodiment, the invention provides a tampon device
for delivering a chemotherapeutic agent and/or inhibitor of
membrane efflux systems across the vaginal mucosa comprising an
absorbent vaginal tampon having a proximal end and a distal end. A
cup-shaped porous foam portion at the distal end fits around the
cervix of the systemic circulation and contains a pharmaceutical
agent for delivery to the cervix. The device may also include a
nonabsorbing axial tube having a distal opening and extending
through the porous foam cup into the tampon for conducting blood
flow to the absorbent material. Optionally, a retrieval string or
tape connected to the tampon device is also included. The absorbent
vaginal tampon contains any of the above-mentioned drugs or be
coated with the drug and be used as a medicated tampon for
individual drug or drug combination delivery.
[0175] In another embodiment of a tampon device, the distal porous
foam cup has a rim which encircles the cervix. The rim has high
concentrations of medication and is positioned away from the direct
flow of blood which exudes from the cervix during menstruation.
[0176] In another embodiment of a tampon device, the distal porous
foam cup has a rim which encircles the cervix. The rim has fingers
extending into the fornix areas around the cervix and the tips of
the fingers have high concentrations of medication and are
positioned away from the direct flow of menstrual blood.
[0177] In another embodiment of a tampon device, a distal porous
foam section is in the shape of a scoop, which only partially
encircles the cervix. The porous foam scoop has a nib-like shape
which is designed to wedge itself into the posterior fornix. The
porous foam scoop is designed to deliver medication to the vaginal
wall along the entire length of the porous foam scoop.
[0178] In another embodiment, a tampon device is sheathed in a
thin, supple, non-porous material such as a plastic film or a
coated gauze that surrounds the absorbent tampon material like a
skirt and opens like an umbrella when it comes in contact with the
vaginal environment. A drug incorporated into a strip, ideally
suspended in a wax-like carrier that melts at body temperature,
encircles the sheathed tampon. Contact with vaginal fluids or
menstrual flow causes the tampon to swell, forcing the skirt to
open like an umbrella and to press tightly against the vaginal
wall, putting the drug in contact with the vaginal mucosa while
effectively preventing the drug from being absorbed into the
tampon.
[0179] In another embodiment of a tampon device, distal fibers of
the tampon which contact the cervix have high concentrations of
pharmaceutical agent for delivery of the agent to the cervical
tissue.
[0180] In another embodiment of a tampon device, the tampon device
has an outer tubing having perforations, the outer tubing is
concentric around an axial tube. The device has a distal porous
foam section which in its dehydrated state is tight around the
outer tubing. A bladder is located proximally to the porous foam
and filled with liquid pharmaceutical agent. The bladder is
connected to the outer tubing. An outer sheath covers the tampon.
The sheath has an annular constriction distal to the bladder such
that deployment of the tampon through the distal end of the sheath
causes the liquid in the bladder to be forced out distally through
the perforated outer tubing and into the porous foam.
[0181] In another embodiment of a tampon device, the tampon device
has an annular delivery composition around the distal end. The
composition contacts the vaginal mucosa for delivery of the
chemotherapeutic agent and/or inhibitor of membrane efflux systems.
A non-absorbing axial tube opens distally and extends into the
tampon for conducting blood flow to the absorbent material proximal
to the porous foam. The annular composition can be a suppository,
cream, ointment, foam, microparticles, paste, or gel.
[0182] Embodiments of the invention may include tampon devices of a
standard length, or may be longer or shorter than standard tampons
to facilitate positioning the tampon device closer to or in contact
with the vaginal wall or with the cervix, depending on the location
of tumor.
[0183] For purposes of simplifying the description of the invention
and not by way of limitation, tampon or tampon-like devices, such
as a suppository, for drug delivery will be described hereinafter,
it being understood that all effective delivery systems are
intended to be included within the scope of this invention.
[0184] Particular device embodiments of the invention are described
in greater detail in FIGS. 3-17. FIGS. 3A and 3B show anatomical
arrangement of the vagina, systemic circulation and other organs.
FIGS. 3-17 show various devices inserted into the vagina.
[0185] FIG. 3A is a cross-sectional representation of a portion of
the female reproductive organs, including the uterus 2 and the
vagina 8 in the upright orientation.
[0186] FIG. 3B is a cross-sectional side view representation
thereof. The systemic circulation 2 is a muscular organ enclosing
the womb 4, and opening at the cervix 5 via the cervical canal or
cervical os 6. The vagina 8 is defined by a muscular tube 10
leading from the labia minora 12 and labia majora 14 to the cervix
5.
[0187] FIG. 4A is a cross-sectional representation of FIG. 3A
showing placement of a drug delivery system 16 in the vagina 8
which drugs are introduced intravaginally to the vaginal wall 10 or
transmucosally to the systemic circulation 2 by way of the vaginal
blood vascular and lymphatic systems. FIG. 4B is a cross-sectional
representation of the vaginal area, adjacent the cervix 5, with a
first embodiment of a tampon drug delivery system according to the
invention. The tampon device 22 comprises an absorbent cylindrical
tampon 24 comprised of fibrous material, for example cotton, having
around its distal end 26 an annular delivery composition 28. The
tampon device 22 places the annular delivery composition 28,
supported around the distal end 26 of the tampon device 22, against
the upper mucosa 18 of the vagina 8 and posterior fornix 20 for
delivery through the vaginal surfaces in which the annular
composition 28 is in contact. The annular composition 28 can be an
annular suppository, foam, paste, gel, or any other formulation as
described above, composed of suitable delivery components. The
uterine discharge is absorbed by the tampon 24 and is prevented
from carrying away the treatment composition.
[0188] FIGS. 5-12 depict various embodiments of devices of the
invention which can be used to deliver a chemotherapeutic agent
and/or inhibitor of membrane efflux systems for treatment of
reproductive organ cancers according to the invention.
[0189] The device is incorporated with a mucosal composition of the
invention. Numerous methods exist by which a drug can be
incorporated into the device. For example, the drug can be
incorporated into a gel-like bioadhesive reservoir in the tip of
the device. Alternatively, the drug can be in the form of a
powdered material positioned at the tip of the tampon. The drug can
also be absorbed into fibers at the tip of the tampon or other
device, for example, by dissolving the drug in a pharmaceutically
acceptable carrier and absorbing the drug solution into the tampon
fibers. The drug can also be dissolved in a coating material which
is applied to the tip of the tampon. This arrangement permits
simultaneous drug delivery from the upper part of the device and
absorption of the discharge or menstrual blood in the lower porous
part of the tampon or tampon-like device. Alternatively, the drug
can be incorporated into an insertable suppository, tablet,
capsule, etc., which is placed in association with the tip of the
tampon.
[0190] The tampon-like device can be constructed so as to improve
drug delivery. For example, the tampon can be shaped to fit in the
area of the posterior fornix and pubic symphysis and constructed so
as to open up to have maximum surface area of contact for drug
delivery. If the drug is in a reservoir on the surface of the
device, the shape of the device should be such that it can maintain
the reservoir towards a vaginal mucosal orientation for best
predictable drug release characteristics.
[0191] The tampon device can also be constructed so as to have a
variable absorption profile. For example, the drug area at the tip
of the tampon device could be different from that of the more
proximal area in order to force the drug to diffuse out into
tissue, as opposed to down into the absorbent part of the tampon.
Alternatively, there could be a non-absorbing channel around the
cervix for the first centimeter or so in order to minimize
menstrual flow from washing away the drug composition.
[0192] The release of drug from the tampon device should be timed
to provide proper systemic concentration of the drug over a typical
length of use of a tampon device, usually 1-8 hours.
[0193] FIG. 5 is a cross-sectional representation of the vaginal
area adjacent the cervix 5 with a second embodiment of a tampon
drug delivery system according to the invention. In this
embodiment, tampon device 32 includes a non-porous tube 34 which
communicates with the cervical os 6 for delivery of the menstrual
discharge from the cervical os to an absorbent cylindrical tampon
36 comprised of fibers, for example cotton, for absorbing the
discharge. The tube 34 prevents contact of the discharge with an
annular drug delivery composition 38.
[0194] FIG. 6 is a cross-sectional representation of the vaginal
area adjacent the cervix 5 with a third embodiment of a tampon drug
delivery system according to the invention. In FIG. 6, the tampon
device 42 includes a distal porous foam section 43 which is in the
shape of a cup in the expanded state. In the center of the porous
foam section 43 is a non-porous tube 44 which will conduct blood
flow to absorbent tampon 45 proximal to the porous foam section 43.
The porous foam is preferably a soft, light weight, physiologically
inert foam material of polyurethane, polyester, polyether, such as
described in U.S. Pat. No. 4,309,997, or other material such as
collagen as described in U.S. Pat. No. 5,201,326, both incorporated
herein by reference. The axial tube is preferably a non-absorptive
physiologically inert material, such as rubber or plastic, and can
be coated on its inner surface with an anticoagulant. The proximal
end 46 of the tube 44 has a plastic loop 47 to which a string 48
may be tied for removal of the tampon device 42. The cup-shaped
porous foam section 43 fits around the cervix 5 of the systemic
circulation 2 and contains antineoplastic drug which may be
delivered to the cervical tissue.
[0195] FIG. 7 is a cross-sectional representation of the vaginal
area adjacent the cervix 5 with a fourth embodiment of a tampon
drug delivery system according to the invention. In FIG. 7, the
tampon device 52 includes a distal porous foam cup 54 and a
proximal absorbent tampon 56. The porous foam cup 54 has a rim 58
which encircles the cervix 5, and which contains high
concentrations of chemotherapeutic agent and/or inhibitor of
membrane efflux systems. The rim 58 area of the porous foam cup 54
is away from the direct flow of blood. The tampon device 52
includes a string 59 for removal of the tampon device 52. FIG. 7A
is a cross-sectional view of the embodiment shown in FIG. 7, taken
in the direction indicated by the arrows labeled 7A in FIG. 7. As
illustrated in FIG. 7A, the rim 58 area forms a ring which contains
a high concentration of medication. Alternatively, as illustrated
in FIG. 8, the entire porous foam cup 55 may contain medication,
not just in the ringed tip area 59 near the cervix 5.
[0196] FIG. 9 is a cross-sectional representation of the vaginal
area adjacent the cervix 5 with a fifth embodiment of a tampon drug
delivery system according to the invention. In FIG. 9, the tampon
device 62 includes a proximal absorbent tampon 64 and a distal
section 66 which includes a dissolvable suppository or gel capsule
67 filled with liquid medication. The device, prior to the
medication dissolution or release has a "doughnut" shape to allow
for blood to pass through the center of the tampon 64. The tampon
device 62 includes a string 68 attached to the tampon 64 for
removal of the tampon device 62. FIG. 9A is a cross-sectional view
of the of the embodiment shown in FIG. 9, taken in the direction
indicated by the arrows labeled 9A in FIG. 9, and illustrates the
doughnut shape of the medication filled suppository or gel capsule
67.
[0197] FIG. 10 is a cross-sectional representation of the vaginal
area adjacent the cervix 5 with a sixth embodiment of a tampon drug
delivery system according to the invention. In FIG. 10, the tampon
device 72 includes a porous foam distal section 74 which is in the
shape of a cup with "fingers" 76 which extend into the fornix areas
20 around the cervix 5. The tips of the fingers 76 contain high
concentrations of medication which may be delivered to areas away
from the direct flow of blood or discharge as the blood or
discharge moves into absorbent tampon 78 proximal to the cup-shaped
porous foam distal section 74. The tampon device 72 includes a
string 79 for removal of the tampon device 72. FIG. 10A is a side
view of the porous foam cup 74 and illustrates the fingers 76 which
extend into the fornix areas 20 around the cervix 5 (FIG. 10).
[0198] It will be readily apparent to a person skilled in the art
that the characterization of the drug delivery device as having an
annular shape is only an approximate description of the shape
formed by fluid or semisolid drug delivery devices positioned
around a cylinder and in contact with adjacent vaginal wall mucosa,
and all shapes which conform to the vaginal mucosa and external
cervical surfaces are intended to be included within and indicated
by the term "annular". Moreover, use of the term "annular" does not
restrict the invention to the use of such devices which encircle
the entire cervix (i.e. 360.degree.). Devices which span an angle
of less than 360.degree., but which make sufficient contact with
the vaginal mucosa to deliver sufficient quantity of the drug are
within the scope of the invention.
[0199] The annular drug delivery composition (FIG. 4 or 5) can be
an absorbent material which expands in the presence of fluid or
body heat to completely fill the space between the tampon 22, 32
and the vaginal mucosa 18.
[0200] FIG. 11 illustrates such a drug delivery device having an
annular shape which does not completely encircle the entire cervix.
FIG. 11 is the representation of FIG. 2 showing placement of a
seventh embodiment of a tampon device 80 incorporating a
scoop-shaped porous foam section 85. FIG. 12 is a side view of the
tampon device 80 and FIG. 13 is a front view of the tampon device
80. The scoop-shaped porous foam section 85 is annular in shape,
but does not completely encircle the cervix 5. Instead, the
scoop-shaped porous foam section has a nib-shaped tip 81 which is
designed to wedge itself into the posterior fornix 20. The
scoop-shaped porous foam section 85 is designed to deliver
medication to the vaginal wall along the entire length of the
scoop-shaped porous foam section 85.
[0201] FIG. 14 is a cross-sectional representation of the vaginal
area adjacent the cervix 5 with an eighth embodiment of a tampon
drug delivery system according to the invention. In FIG. 14, the
tampon device 82 comprises an absorbent tampon 84. The section 86
of the tampon 84 which rests against the cervix 5 contains high
concentrations of medication. As the fibers absorb fluid, the
tampon 84 expands around the cervix 5 and delivers medication to
the tissue. The blood will be drawn to proximal sections of the
tampon 84 as fibers become more absorbent in this area. The tampon
device 82 includes a string 88 for removal of the tampon device
82.
[0202] Suitable cylindrical cartridge containers or inserter tubes
which assist in the insertion and storage of the tampon systems of
the present invention will be apparent to those skilled in the art
of tampon construction. Examples are described in U.S. Pat. Nos.
4,3178,447; 3,884,233; and 3,902,493, incorporated herein by
reference.
[0203] In general practice, a drug delivery device as described
herein is placed into the vagina and the inserter tube is removed.
The device, such as a tampon, contacts the inner wall of the vagina
where the mucoadhesive agents facilitate adhesion of the drug
released from the device to the vaginal wall where it is
therapeutically effective.
[0204] FIG. 15 is a cross-sectional representation of the vaginal
area adjacent the cervix 5 with another embodiment of a tampon drug
delivery system according to the invention. In FIG. 15, the tampon
device 92 includes a distal porous foam section 93 which, in its
dehydrated, sheathed state (FIG. 16), is tight around a perforated
outer tube 94. The perforated outer tube 94 is connected to a
bladder 96 located proximally which is filled, for example, with
liquid medication. Within the perforated outer tube 94 is a
concentric inner tube 95 which provides a pathway for blood to flow
into an absorbent tampon 97 which is proximal to the porous foam
section 93. Prior to insertion, the tampon device 92 is enveloped
in a sheath 98 which is necked down at site 99 between the porous
foam section 93 and the bladder 96 so that, when the tampon device
92 is deployed and the sheath 98 moves over the bladder 96, the
medication is forced out seen as 101, through the perforated outer
tube 94 into the porous foam section 93 (FIG. 17). The tampon
device 92 includes a string 102 for removal of the tampon device
92.
[0205] Another example of a suitable controlled release drug
delivery system for the present invention is the vaginal ring.
Vaginal rings usually consist of an inert elastomer ring coated by
another layer of elastomer containing the drug to be delivered. The
rings can be easily inserted, left in place for the desired period
of time, up to 7 days, then removed by the user. The ring may be
solid or hollow containing the chemotherapeutic drug and/or
inhibitor of membrane efflux systems or it may be a porous material
releasing the drug therefrom. The ring can optionally include a
third, outer, rate-controlling elastomer layer which contains no
drug. Optionally, the third ring can contain a second drug for a
dual release ring. The drug can be incorporated into polyethylene
glycol throughout the silicone elastomer ring to act as a reservoir
for drug to be delivered.
[0206] Pessaries, cups, strips, tablets and suppositories are other
examples of drug delivery systems which can be used in the present
invention. These systems have been used for delivery of vaginal
contraceptives, and have been described extensively in the
literature.
[0207] Another example of a delivery system is the vaginal sponge
and foams. The desired pharmaceutical agent can be incorporated
into a silicone matrix which is coated onto a cylindrical drug-free
polyurethane vaginal sponge, as described in the literature.
[0208] In practice, the drug delivery systems that is a composition
or a device of the invention are applied upon diagnosis of cancer.
Typically, the treatment is continued for as long as needed to
treat the cancer, to maintain remission state or prevent further
growth.
EXAMPLE 1
Preparation of Drug Containing Vaginal Tampon-Like Device for
Treatment of Cancer
[0209] This example describes a process for preparation of a
formulation as a suppository for transvaginal delivery of
doxorubicin.
[0210] Doxorubicin hydrochloride was obtained from Meiji Seika
Kaisha, LTD, Japan. Vaginal suppositories were formulated and
prepared 24 hours prior to administration. The three basic
ingredients for the doxorubicin formulation were the lipophilic
carrier SUPPOCIRE CS2 obtained from Gattefosse, Westwood, N.J. (75%
wt); a mucoadhesive hydroxypropyl methylcellulose (e.g., METHOCEL
K, HPMC K15M obtained from Dow Chemical, Midland, Mich. (8%/wt);
and a permeation enhancing polyoxyethylene alkyl ether (e.g.,
TRANSCUTOL.RTM. obtained from Gattefosse (17%/wt). These
ingredients were mixed in percent amounts as shown. To make eight
suppositories, 4.5 grams of SUPPOCIRE CS2, 480 mg of HPMC, 1020 mg
of TRANSCUTOL, and the calculated dose of drug (5 mg doxorubicin
base equivalent/suppository) were weighed out.
[0211] The lipophilic carrier was melted in a 100 mL glass beaker
maintained in a water bath at 65.degree. C. until the carrier was
completely liquified. The weighed amount of TRANSCUTOL was
quantitatively transferred to a preweighed small mortar and pestle.
The drug was added and homogeneously distributed to the Transcutol
by stirring with the pestle. Then HPMC was added under continuous
stirring until a homogeneous suspension was obtained which then was
added to the melt under stirring.
[0212] The mixture was quickly poured into TYGON tubing molds
(available from Fisher Scientific, Pittsburgh, Pa., 2.times.0.5 cm
dimensions), followed by cooling in the upright position on an
ice-cold glass slab.
[0213] Suppositories were kept refrigerated until administration.
The suppository was weighed prior to each experiment to determine
the actual drug dose.
[0214] The prepared suppository was then used directly or
incorporated into a tampon-like vaginal device according to the
invention in such a way that the drug was released from the surface
of the device in a sustained time-release manner.
[0215] In an alternative arrangement, the tampon-like vaginal
device was soaked with the formulation containing doxorubicin
hydrochloride, dried and protected by a cardboard applicator until
used.
EXAMPLE 2
Preparation of Vaginal Tampon-Like Device for Inhibitors
[0216] This example describes a process for preparation of a
tampon-like device for transvaginal delivery of verapamil, an
inhibitor of the membrane efflux system P-glycoprotein.
[0217] Verapamil hydrochloride obtained from Sigma-Aldrich, St.
Louis, Mont. was mixed with radioactively labeled [.sup.3H]
verapamil (5-8 .mu.Ci). Vaginal suppositories were formulated and
prepared 24 hours prior to administration. The three basic
ingredients for the verapamil formulation were the lipophilic
carrier SUPPOCIRE AS2 obtained from Gattefosse, Westwood, N.J.
(80%/wt); a mucoadhesive hydroxypropyl methylcellulose (e.g.,
METHOCEL K, HPMC K15M obtained from Dow Chemical, Midland, Mich.
(10%/wt); and a permeation enhancing polyoxyethylene alkyl ether
(e.g. TRANSCUTOL obtained from Gattefosse (10%/wt). These
ingredients were mixed in percent amounts as shown. To make eight
suppositories, 4.8 grams of SUPPOCIRE AS2, 600 mg of HPMC, 600 mg
of TRANSCUTOL, and the calculated dose of drug (0.75 mg verapamil
base equivalent/suppository) were weighed out. The lipophilic
carrier was melted in a 100 mL disposable polypropylene beaker in a
water bath at 50.degree. C. until the carrier was completely
liquefied. The weighed amount of TRANSCUTOL was quantitatively
transferred to a small, pre-weighed mortar and pestle. Both hot and
cold VERAPAMIL were added under stirring until a clear liquid was
obtained, to which HPMC was added. Stirring was continued until a
homogenous suspension was obtained. The mixture was quickly poured
into TYGON tubing molds (available from Fisher Scientific,
Pittsburgh, Pa., 2.times.0.5cm dimensions), followed by cooling in
the upright position on an ice-cold glass slab.
[0218] Suppositories were kept refrigerated until administration.
The suppository was weighed prior to each experiment to determine
the actual drug dose.
[0219] The prepared suppository was then used directly or
incorporated into a vaginal device according to the invention in
such a way that the drug was released from the surface of the
device in a sustained time-release manner.
[0220] In an alternative arrangement, the tampon-like vaginal
device was soaked with a formulation containing verapamil
hydrochloride, dried and protected by a cardboard applicator until
used.
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