Note: Descriptions are shown in the official language in which they were submitted.
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INHALATION CHEMOTHERAPY FOR PREVENTION AND TREATMENT OF
METASTATIC TUMORS IN THE LUNG
5
This application is a continuation-in-part of copending U.S. patent
application No. 09/165,864, which is a continuation in part of U.S. patent
application No. 09/000,775, filed December 30, 1997, which claims the
benefit of U.S. Provisional Application No. 60/033,789 filed on December 30,
10 1996.
FIELD OF THE INVENTION
The invention deals with methods useful for preventing metastasis and
treating metastatic neoplasms, particularly neoplasms that metastasize to the
15 respiratory tract (e.g. hemangiosarcoma), by treating the primary tumor by
known methods and using in addition methods for the pulmonary
administration of one or more antineoplastic drugs and concurrent systemic
administration of one or more antineoplastic drugs.
20 BACKGROUND OF THE INVENTION
Cancer is one of the leading causes of death worldwide. Lung cancer
in particular, is among the top 3 most prevalent cancers and has a very poor
survival rate (about 13% five-year survival rate). Despite the availability of
many cancer drugs it has been difficult and, in the case of some cancer types,
25 almost impossible to improve cure rates or survival. There are many reasons
for this lack of success but one reason is the inability to deliver adequate
amounts of the drugs to the tumor without causing debilitating and life-
threatening toxicities in the patient. Indeed, most chemotherapeutic drugs
used to treat cancer are highly toxic to both normal and tumor tissues.
3o it is customary in the treatment of cancer to administer the drugs by
the intravenous route, which exposes the entire body to the drug. Doses are
selected that destroy tumor cells, but these doses also destroy normal cells.
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As a result, the patient usually experiences severe toxic side effects. For
example, severe myelosuppression may result which compromises the ability
of the patient to resist infection and allows spread of the tumor. There are
other life-threatening effects such as hepatotoxicity, renal toxicity,
pulmonary
5 toxicity, cardiotoxicity, neurotoxicity, and gastrointestinal toxicity
caused by
anticancer drugs. The anticancer drugs also cause other effects such as
alopecia, stomatitis, and cystitis that may not be life threatening, but are
serious enough to affect a patient's quality of life. Moreover, it is
important-to
note that these toxicities are not associated to the same extent with all
10 anticancer drugs but are all due to systemic delivery of the drug.
Although myelosuppression is commonly associated with most
anticancer drugs, because of differences in the mechanisms by which the
various anticancer drugs act or in the ways they are distributed in the body,
metabolized and excreted from the body, each drug presents a somewhat
15 different toxicity profile, both quantitatively and qualitatively. For
example,
anthracyclines such as doxorubicin, epirubicin and idarubicin are known to
cause severe cardiotoxicity. l7oxorubicin, additionally, is known to cause
severe progressive necrosis of tissues when extravasated. Cisplatin therapy
is known to cause renal toxicity; vincristine causes neurotoxicity, bleomycin
20 and mitomycin cause pulmonary toxicity, cyclophosphamide causes cystitis;
and 5-fluorouracii causes cerebral disjunction (see Cancer Chemotherapy:
Principles and Practice, BA Shabner and J.M. Collings, eds. J.B. Lippincott
Co., Philadelphia, 1990).
The differences in mechanisms of action and pharmacokinetic
25 properties determine, in part, the efficacy of the various anticancer drugs
against different tumor types, which exhibit various biological behaviors.
Some attempts have been made to deliver anticancer drugs directly to
the tumor or to the region of the tumor to minimize exposure of normal
tissues to the drug. This regional therapy, for example has been used to treat
30 liver cancer by delivering drugs directly into the hepatic artery so that
the full
dose goes to the liver while reducing the amount that goes to the rest of the
body. For the treatment of urinary bladder cancer, anticancer drugs are
2
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instilled directly into the bladder through the urethra, allowed to remain in
contact with the tumor for a period of time and then voided. Other examples
of regional therapy include the delivery of anticancer drugs into the
peritoneal
cavity to treat cancer that has developed in or metastasized to this location.
5 Other methods of targeting anticancer drugs involve the attachment of the
drugs to antibodies that seek out and deliver the drug directly to the cancer
cells.
In 1968 Shevchenko, LT., (Neoplasma 15, 4, 1968) pp.419-426
reported on the treatment of advanced bronchial cancer using a combination
i0 of inhalation of chemotherapeutic agents, radiotherapy, and oxygen
inhalation. The reported chemotherapeutic agents were benzotaph,
thiophosphamid, cyclophosphan and endoxan that were applied as an aerosol
by means of an inhaler. For 58 treated patients the combination of three
treatments showed tumor disappearance in 8 cases while in 6 the size of the
15 tumor diminished considerably. The study did not include a control group.
In 1970, Sugawa, I. (Ochanoizu Med. J.; Vol. 18; No.3; (1970),
pp.103-114, reported on tests using mitomycin-C in the treatment of
metastatic lung cancer. One of four patients treated reportedly showed some
improvement. Inhalation of mitomycin-C also appeared to reduce tumor
20 growth in IV-inoculated tumors in rabbits; results appeared to be more
inconclusive in rats. Tests were conducted to determine the toxic effects to
the respiratory tract following intrabronchial infusions of several drugs. The
drugs were given to healthy animals and included: thiotepa (rats), Toyomycin
(chromomycin A3) (rats,), endoxan (cyclophosphamide) (rats and rabbits), 5-
25 fluorourcil (rats and rabbits), mitomycin-C (rats, rabbits, and dogs). The
results of these tests showed that: 5-FU and cyclophosphamide resulted in
only mild inflammation; thiotepa produced bronchial obstruction;
chromomycin A3 and mitomycin-C produced the most severe results. Toxic
effects of mitomycin-C and chromomycin A3 were studied in rabbits and dogs.
30 In 1983, Tatsumura et al (Jap. J. Cancer Cln., Vol. 29, pp. 765-770)
reported that the anticancer drug, fluorouracil (5-FU, MW=130) was effective
for the treatment of lung cancer in a small group of human patients when
3
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administered directly to the lung by aerosolization. They referred to this as
nebulization chemotherapy. It was also noted by Tatsamura et al (1993) (Br.
J. Cancer, Vol. 68(6): pp.1146-1149) that the 5-FU did not cause toxicity to
the lung. This finding was not totally unexpected because 5-FU has a very
5 low molecular weight and does not bind tightly to proteins. Therefore, it
passes through the lung rapidly lessening the opportunity to cause local
toxicity. Moreover 5-FU is considered to be one of the least toxic anticancer
drugs when applied directly to tissue. Indeed, 5-FU is used as a topical drug
for the treatment of actinic keratosis for which it is applied liberally,
twice
10 daily, to lesions on the face. This therapy may continue for up to four
weeks.
Also, because S-FU is poorly absorbed from the gastrointestinal tract, there
is
little concern about the amount of drug that may be inadvertently swallowed
and gain access to the blood stream from the gut. It is well known that a
large percentage of aerosolized drug intended for the lung is swallowed.
15 Another report includes the use of ~-cytosine arabinoside (Ara-C,
cytarabine, MW=243) administered via intratracheal delivery to the
respiratory system of rats. Liposome encapsulated and free Ara-C were
instilled intratracheally to the rats as a bolus. The encapsulated Ara-C
persisted for a long time in the lung while the free Ara-C which is not highly
20 protein bound was rapidly cleared from the lung. The free Ara-C rapidly
diffused across the lung mucosa and entered the systemic circulation. The
paper suggests that liposome encapsulation of drugs may be a way to
produce local pharmacologic effect within the lung without producing adverse
side effects in other tissues. However, bolus administration results in
25 muitifocal concentrated pockets of drug. See the articles by H.N.
MacCullough et al, JNCI, Vol. 63, No. 3, Sept., pp.727-731 (1979) and R.L.
Juliano et al, J. Ph. & Exp. Ther., Vol. 214, No.2, pp.381-387 (1980).
An additional report includes the use of cisplatin (MW=300) for
inhalation chemotherapy in mice that had been implanted with FM3A cells
30 (murine mammary tumor cells) in the air passages. The cisplatin exposed
inhalation group were reported to have statistically smaller lung tumor sizes
and survived longer than the untreated control group. See A. Kinoshita,
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"Investigation of Cisplatin Inhalation Chemotherapy Effects on Mice after Air
Passage Implantation of FM3A Cells", J. Jap. Soc. Cancer Ther. 28(4): pp.
705-715 (1993).
In US patent 5,531,219 to Rosenberg, the patent disclosure suggests
5 the use of doxorubicin, 5-FU, vinblastine sulfate, or methotrexate in
combination with pulmonary infused liquid fluorocarbons. The patient is
suggested to be positioned so that the tumor affected area is at a
gravitational low point so that liquid perfluorocarbon having relatively low
vapor pressure will pool selectively around the area with the drug then
10 pertused in the pool of liquid perfluorocarbon. The present invention
avoids
the problems with positioning of the patient and further does not require the
liquid fluorocarbons used by Rosenberg.
In US patent 5,439,686 to Desai et al there are disclosed compositions
where a pharmaceutically active agent is enclosed within a polymeric shell for
15 administration to a patient. One of the routes of administration listed as
possible for the compositions of the invention is inhalational. Among the
listed pharmaceutically active agents potentially useful in the invention are
anticancer agents such as paclitaxel and doxorubicin. No tests using the
inhalational rout of administration appear to have been made.
2o Although several antineoplastic drugs have been administered to
animals and to humans, for treatment of tumors in the lungs and respiratory
system, the differences in the mechanism of action, and toxicity profiles
among the broad classes of anticancer drugs, and the heretofore known
characterizations have made it impossible to predict whether a particular
25 anticancer drug will be efficacious or toxic based upon previous inhalation
results with a different drug of a different type. Further, previous reports
used very imprecise means of delivering drugs and were not consistent in
delivering measured doses of drugs in an evenly distributed manner to the
entire respiratory tract. The present invention provides means for predicting
30 and selecting drugs including the highly toxic chemotherapeutic compounds,
amenable for inhalation therapy of neoplastic disease and methods for
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actually distributing specific measured doses to pre-selected regions of tfie
respiratory tract.
It has now been demonstrated by the applicants that anticancer
cytotoxic drugs of multiple classes such as anthracyciines (doxorubicin),
5 antimicrotubule agents such as the vinca alkaloids {vincristine), and
taxanes
such as paclitaxel can be given directly by inhalation without causing severe
toxicity to the lung or other body organs. This finding is surprising, because
it
is well known among those who administer cytotoxins such as doxorubicin to
patients, that this drug causes severe ulceration of the skin and underlying
10 tissues if allowed to be delivered outside of a vein. After extravasation
the
drug continues to affect the tissues to such an extent that amputat;on of
limbs in which the extravasation has occurred has been required. So severe
is this toxicity that the prescribing information for doxorubicin (and some
other similar vesicating drugs) in the Physicians Desk Reference contains a
15 "Box Warning" regarding this danger. The present invention, therefore,
provides an effective way to administer chemotherapeutic agents, including
highly toxic agents such as doxorubicin, while minimizing the major side
effects described above.
20 BRIEF DESCRIPTION OF THE INVENTION
Broadly the present invention discloses methods for treating a patient
for a neoplasm and for preventing pulmonary metastasis from the neoplasm
to the lung including the steps of (a) treating the patient for the primary
neoplasm wherein the treatment is selected from the group consisting of
25 partial or complete surgical excision, radiation therapy, local-regional
chemotherapy, immunotherapy, gene therapy and combinations thereof;
{b) administering an antineopiastic drug by systemic chemotherapy; and
(c) administering an antineoplastic drug to the patient by inhalation.
Typically the patient is also administered one or more chemoprotective drugs.
30 In some embodiments the method typically involves administering an
effective amount of one or more antineoplastic drugs to the patient by
inhalation; and administering an effective amount of one or more of the same
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or different antineoplastic drug to the patient systemically. Typically the
patient is a mammal such as a human.
In some embodiments, the method includes drugs wherein when 0.2
ml of at least one of the drugs is injected intradermally to rats, at the
clinical
5 concentration for parenteraf use in humans: a lesion results which is
greater
than 20 mm2 in area fourteen days after the intradermal injection; and at
least 50% of the tested rats have these lesions.
All novel features and combination of features disclosed in the present
application are considered to be a part of the invention herein.
10
BRIEF DESCRIhTION OF THE DRAWINGS
Figure 1 shows the plasma drug concentration time profile for dog
#101 having doxorubicin administered intravenously (IV) (circles) and by the
pulmonary inhalation route (IH) (squares). The vertical Y scale is the
15 concentration of drug in the circulatory system in ng/ml and the horizontal
X
scale is time after treatment in hours.
Figure 2 shows the plasma drug concentration time profile for dog
#102 having doxorubicin administered intravenously (IV) (circles) and by the
pulmonary inhalation route (IH) (squares). The vertical Y scale is the
20 concentration of drug in the circulatory system in ng/ml and the horizontal
X
scale is time after treatment in hours.
Figure 3 shows the plasma drug concentration time profile for dog
#103 having doxorubicin administered intravenously (IV) (circles) and by the
pulmonary inhalation route (IH) (squares). The vertical Y scale is the
25 concentration of drug in the circulatory system in ng/ml and the horizontal
X
scale is time after treatment in hours.
Figure 4 shows a schematic of the pulmonary delivery apparatus
arrangement that was used to administer drug to dogs by inhalation for
Example 3.
30 Figure 5 shows a schematic of the pulmonary delivery apparatus
arrangement that was used to administer high doses and multiple doses of
drug to dogs by inhalation for Example 4.
7
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Figure 6 shows a schematic drawing of details of a mask useful for
administering drugs by inhalation to a mammal such as a dog.
Figure 7 shows a schematic drawing of a portable device for
administration of anticancer drugs according to the invention.
5 Figure 8 is a graph showing data derived from dogs treated for
hemangiosarcoma, where the Vertical Scale shows the percent of dogs that
are alive (Y-axis) and the horizontal scale (X-axis) shows the number of days
survival.
10 DETAILED DESCRIPTION OF THE INVENTION AND BEST MODE
The present application is related to U.S. application entitled
"Formulation and Method for Treating Neoplasms by Inhalation", having Serial
No. 09/000,775 and filed December 30, 1997, the full disclosure of which is
incorporated by reference as if fully rewritten herein.
15 The delivery of antineoplastic drugs by inhalation by the pulmonary
route is an attractive alternative to the administration of drugs by various
injectabie methods, particularly those drugs that are given on a chronic or
repeated administration schedule. A cause of concern is the toxic nature of
the drugs particularly those that are cytotoxic such as the classes
represented
20 by alkyfating agents, taxanes, vinca alkaloids, platinum complexes,
anthracyclines and others that are considered particularly toxic especially
when administered outside the circulatory system.
Broadly, the inventors have discovered that highly toxic, vesicant and
previously unknown nonvesicant antineoplastic drugs can be effectively
25 delivered to a patient in need of treatment for neoplasms or cancers by
inhalation. This route is particularly effective for treatment of neoplasms or
cancers of the pulmonary system because the highly toxic drugs are delivered
directly to the site where they are needed, providing regional doses much
higher than can be achieved by conventional IV delivery. As used herein the
30 respiratory tract includes the oral and nasal-pharyngeal, tracheo-
bronchial,
and pulmonary regions. The pulmonary region is defined to include the upper
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and lower bronchi, bronchioles, terminal bronchioles, respiratory bronchioles,
and alveoli.
An important benefit from inhalation therapy for neoplasms of the
head, neck and respiratory tract, is that exposure to the rest of the body is
5 controlled following administration of high doses of drug and consequently
is
spared much of the adverse side effects often associated with high doses of
systemically administered highly toxic antineoplastic drugs, yet significantly
increased doses are provided at the site of the tumor. These toxic effects
include for example: cardiotoxicity, myelosuppression, thrombocytopenia,
to renal toxicity, and hepatic toxicity that are often life threatening. The
toxic
effects are often so severe that it is not uncommon for patients to die from
the effects of the systemically administered drugs rather than from the
disease for which they are being treated.
Broadly, vesicants as used herein include chemotherapeutic agents that
15 are toxic and typically cause long lasting damage to surrounding tissue if
the
drug is extravasated. If inadvertently delivered outside of a vein, a vesicant
has the potential to cause pain, cellular damage including cellulitis, tissue
destruction (necrosis) with the formation of a long lasting sore or ulcer and
sloughing of tissues that may be extensive and require skin grafting. In
20 extreme cases extravasation of vesicants such as doxorubicin has required
surgical excision of the affected area or amputation of the affected limb.
Examples of antineoplastic chemotherapeutic agents that are generally
accepted vesicants include alkylating agents such as mechlorethamine,
dactinomycin, mithramycin; topoisomerase II inhibitors such as bisantrene,
25 doxorubicin (adriamycin), daunorubicin, dactinomycin, amsacrine,
epirubicin,
daunorubicin, and idarubicin; tubulin inhibitors such as vincristine,
vinblastine,
and vindesine; and estramustine. A partial list of vesicants is found in
Table 1.
In another embodiment, vesicants as more narrowly used herein
30 include drugs that produce a lesion in rats, where the average lesion size
is
greater than about 20 mmz in area, fourteen days after an intradermal
injection of 0.2 ml of the drug, and where 50% or more of the animals have
9
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this size of lesion. The drug concentration for the intradermal injection is
the
clinical concentration recommended by the manufacturer for use in humans,
the dose recommended in the Physicians Desk Reference, 1997 (or a more
current version of this reference), or another drug manual for health
5 specialists. If there is no recommendation by the manufacturer (for example
for because the drug is new) and there is no recommendation in the
Physicians Desk Reference or similar drug manual for health specialists then
other current medical literature may be used. If more than one clinical
concentration is recommended, the highest recommended clinical
10 concentration is used. Lesion as used herein means an open sore or ulcer or
sloughing off of skin with exposure of underlying tissue.
In a yet further embodiment of the invention, 0.2 ml of a highly toxic
anticancer drug (vesicant) at a dose recommended for humans (as discussed
above) is administered intradermally to rats at a concentration that causes
the
15 above mentioned lesion size for a more extended period of time. That is,
the
lesions remain above about 10 mmZ up to at feast 30 days in at least 50% or
more of the animals.
Nonvesicants typically are also irritating and can cause pain, but do not
usually result in long lasting sores or ulcers or sloughing off of tissues
except
20 in exceptional cases. Examples include alkylating agents such as
cyciophosphamide, bleomycin (blenoxane), carmustine, and dacarbazine; DNA
crosslinking agents such as thiotepa, cispiatin, melphalan (L-PAM);
antimetabolites such as cytarabine, fluorouracil (5-FU), methotrexate (MTX),
and mercaptopurine (6 MP); topoisomerase II inhibitors such as
25 mitoxantrone; epipodophyllotoxins such as etoposide (VP-16) and teniposide
(VM-26); hormonal agents such as estrogens, glucocorticosteroids,
progestins, and antiestrogens; and miscellaneous agents such as
asparaginase, and streptozocin.
A listing of materials usually accepted to be vesicants or nonvesicants
30 is provided below as Table 1- Vesicant/Nonvesicant Drug Activity.
10
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Table 1
Vesicant/Non-Vesicant Drug Activity
Classification Vesicant ~ ~ Non-Vesicant
r~~
Alkylating Agents Mechlorethamine'.'.a.'Cyclophosphamide
* C toxan)b
Mitorn cin-C'.'.'*Bleom cin (Blenoxane)b.'
Dactinom cin.'* Carmustine'.".
Mithramycin Mithramycin'."
(Plicam cin) (Plicam cin)
Dacarbazine'.b.'
DNA Crosslinkin A Thiote ab
ents
Cis latinb~'
Mel halan (L-PAM)
Antimetabolites C tarabine (ARA C)b
Fluorouracil (5 F bd'
Methotrexate (MTX)b
Merca to urine (6 MP)"
Topoisomerase Ii Bisantrene'.'* Mitoxantroneb.'
Inhibitors Anthracene) Anthracene)
Dactinom cin'.' Esorubicin'
Doxorubicin'.b.'..'*Etoposide (VP-16)',",'
(Anthrac cline (E i odo h Ilotoxin)
CyanomorpholinylTeniposide (VM-26)'.b.'
Doxorubicin'* (E i odo h llotoxin)
Amsacrine'.'.'*
E irubicin'.'*
Daunorubicin',.'*
Idarubicin'.'*
Li osomal anthraC clines'
Hormonal A ents Estro ens"
Glucocorticosteroidsb
Pro estinsb
Antiestro ensb
Tubulin Inhibitors Vinblastine'.'*
Vincristine',.'*
Vinorelbine'*
Vindesine','*
Paclitaxel'. Paclitaxel'.f
Miscellaneous As ara inaseb (Enz
me)
Aclacinom cin'
Stre tozocin'.b
Meno aril'
11
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a - According to US Patent 5,602,112
b - Dorr, R.T. et ai, Lack of Experimental Vesicant Activity for the
Anticancer Agents Cisplatin,
Melphalan, and Mitoxantrone, Cancer Chemother. Pharmacol., Vol. 16, 1986, pp.
91-94
c - According to Blcher, A, et al, Infusion Site Soft-Tissue Injury After
Paditaxel
5 Administration, Cancer, Vol. 76, No. 1, July 1, 1995, pp. 116-120
d - Rudolph, R, et ai; Etiology and Treatment of Chemotherapeutic Agent
Extravasation
Injuries: A Review; Journal ofClinlral Dnmlogy, Voi. 5; No. 7; July 1987; pp.
1116-1126
a - Bertelli, G., Prevention and Management of Extravasation of Cytotoxic
Drugs, Drug
Safety, 12 (4) 1995; pp. 245-255. The listed drugs have been reported in at
least one case,
10 either clinically or experimentally, to cause tissue necrosis after
accidental extravasation.
Symbol: * = vesicants, drugs with the highest potential for localized tissue
damage after
extravasation
f - Cancer, R.T., Communications, Author Reply, Cancer, pp. 226
15
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Typical embodiments of the invention use highly toxic antineoplastic
drugs that have similar or greater vesicating activity than those that have
been tested in animals by inhalation to date. One embodiment typically uses
severely vesicating toxic antineoplastic drugs having higher vesicating
activity
5 than those represented by 5-FU, ~i-cytosine arabinoside (Ara-C, cytarabine),
mitomycin C, and cisplatin. In respect to the latter, it is disclosed that a
highly toxic drug represented by the class anthracyclines (of which
doxorubicin is among the most toxic), has been administered by inhalation to
a patient in need of treatment for neoplasms. In a further embodiment of the
10 invention it is disclosed that vesicants other than doxorubicin can be
given to
patients by inhalation. In respect to the latter, highly toxic drugs
represented
by the classes vinca alkaloids, and taxanes, having similar high toxicities
have
been administered by inhalation to a patient in need of treatment for
neoplasms. In a yet further embodiment of the invention there is disclosed
15 that certain antineoplastic drugs that are nonvesicants can be administered
by
inhalation to a patient in need of treatment for neoplasms. In a further
embodiment of the invention there are disclosed formulations and methods
for applying the aforementioned highly toxic drugs to a patient in need of
treatment for pulmonary neopfasms by inhalation.
20
Example 1
This example illustrates and confirms toxicity and vesicant/nonvesicant
activity of several antineopiastic drugs. The vesicant activities of thirteen
anticancer drugs were investigated (see the listing in Table 2 below).
25 Doxorubicin has traditionally been considered a vesicant (see Table 1).
Paclitaxel has previously been considered a nonvesicant, but recent literature
has advocated its classification as a vesicant. Some of the remaining drugs
are traditionally considered to be vesicants and others nonvesicants (Table
1).
Day fourteen after injection was chosen as the time for comparison for
30 vesicant activity, because lesions caused by nonvesicants should have been
significantly reduced while lesions caused by vesicants should still be large.
13
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Sterile saline solution (0.9%) for injection USP, pH 4.5-7.0, or sterile water
for
injection, as appropriate, was used to reconstitute the drugs.
The drugs used for the vesicant activity tests are identified as follows:
doxorubicin (Adriamycin PFS), a red liquid in glass vials, no formulation was
5 necessary; cisplatin (Platinol-AQ~"'), a liquid in glass vials, no
formulation was
necessary; Paclitaxel (Taxoh"'), a liquid in glass vials, formulated with
saline
solution; ffuorouracil, a clear yellow liquid in glass vials, no formulation
was
necessary; cytarabine (Cytosar-UTM), a white powder in glass vials, formulated
with water; 9-aminocamptothecin (9-AC colloidal suspension), a yellow
10 powder in glass vials, formulated with water; cyclophosphamide
(Cytoxann"'),
a yellow powder in glass vials, formulated with a saline/water mixture;
carboplatin (Paraplatin'~"'), a white powder in injectable vials, formulated
with
saline solution; etoposide (VePesid~"'), a clear liquid in glass vials,
formulated
with saline solution; bleomycin (bleomycin sulfate, USP), a lyophilized powder
15 tablet in glass vials, formulated with saline solution; vincristine
(vincristine
sulfate), an injectable liquid in injection vials, no formulation necessary;
vinorelbine tartrate (NavelbineT"'), a clear liquid in glass vials, diluted
with
water per package instructions; and mitomycin (Mutamycin""), a gray
crystalline powder in glass amber bottles, formulated with water. All of these
20 drugs were reconstituted following standard and known methods
recommended by the manufacturers.
The tests for vesicant activity were conducted using Sprague Dawley
rats (7-8 weeks old having 150-200 g of body weight. Each received a single
intradermal injection of the test drug at the recommended clinical
25 concentration (listed below in Table 2) in the right dorsum. Approximately
24
hours prior to administration, the hair was removed from the dorsum using
clippers and a depilatory agent. Each 0.2 ml injection was given with a 1 ml
syringe and 27 gauge needle. All drug solutions were either isotonic or
slightly hypertonic.
14
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Table 2
Formulations administered for Vesicant Tests
Formulation
Test Formulation Concentration
1 Doxorubicin 2 m ml
2 Platinol 1 m ml
3 Paclitaxei 1.2 m ml
4 Fluorouracil 50 m ml
5 C rabine 100 m /ml
6 9-aminocam tothecin 100 wg/ml
7 C clo hos hamide 20 m ml
8 Carbo latin 10 m ml
9 Eto oside 0.4 m ml
10 Bleom cin 20 units/ml
11 Vincristine 1 m ml
12 Vinorelbine 3 m ml
13 Mitom cin-C 0.5 m /ml
5
Table 3 below is a tabulation of the resultant lesion sizes that
developed from intradermal injections of the above drugs. Lesion sizes were
10 measured as more fully discussed below.
15
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
0 0~
,~'~ ~;N ~0pi J i i i ii i i i i i ii i Z i Z
h ~O V'1~ Md'
I -'~o0I ~ Ii ' i II i I ii i i i i '
N .-,
M M ~"V100O
~ ip ~ N ~N I II i i ii i i ' ' i i i I i
M 00V1 O O NT
N ~ et~OG i I sI i i ii i i i' i l ' i i i i
N .-.N
~'NN OvV1V1v1
NI ' ' nI ; s i i iI i i ii s I i i i
O~O N1N ~ ' , n
~
n ~~O O'00~
N ~ ~00 OGN ~ i ii ~ C I I ii i Ii i i I i
,
h e~~nc. -..v,000 ,~ ~ v o0
~ I , I ' I
N ~ ON ~CN VOv, ' _ .r00N' ' , , I i i I
D
'
N 00O ~OO V1~O V1
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16
CA 02346029 2001-04-02
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CA 02346029 2001-04-02
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18
CA 02346029 2001-04-02
WO 00/19991 PCT/US99112845
Results were as follows:
1. Abrasions of the dorsal body were observed in a majority of animals for all
drugs except cytarabine.
2. Alopecia of the dorsal body was seen for doxorubicin (3/7), paclitaxel
(7/7),
5 and fluorouracil (7/7), etoposide (7/7), bleomycin (7/7), vincristine (2/7),
vinorelbine (7/7), and mitomycin-C (mutamycin) (4/7).
3. Discoloration of the skin around the site of injection was seen for
doxorubicin, vincristine, vinorelbine, and mitomycin-C.
4. Rough coat was observed in fluorouracil (1/7), vincristine (4/7), and
10 vinorelbine (2/7).
5. Systemic effects were observed only for vincristine. Three animals had to
be removed from the tests because of their poor condition.
6. Slight edema was observed for all groups. Moderate edema was observed
in doxorubicin, vincristine, vinorelbine, and mitomycin-C treated animals.
15 Severe edema was observed only for animals treated with vinorelbine and
vincristine.
7. Severe erythema was seen for all drugs except for cisplatin {platinol) and
cytarabine.
8. Dermal lesions were observed for all drugs except for cytarabine. Most
20 lesions appeared befinreen days 6 and 10 and maximized in size during the
first seven days, and then gradually decreased in size. Doxorubicin,
vincristine, vinorelbine, and mitomycin-C were the only drugs that caused
lesions that lasted until the test termination at day 41. However, for
mitomycin-C only one animal of seven still had lesions to the end of the test.
25 One rat (#123) injected with paclitaxel (taxol) was determined to not have
received a proper intradermal injection and was not used in the results.
Dermal lesions at the site of injection were determined to be the best
and most objective measure and predictor of vesicant activity for a drug.
Lesion size was quantitated by micrometer measurements of the two largest
30 perpendicular diameters and the two values multiplied to yield a lesion
area in
mm2. Lesions were regularly evaluated and scored as shown in Table 3.
19
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WO 00/19991 PCT/US99/22845
A vesicant as determined by the methods used herein is defined as
causing a lesion of at least about 20 mm2 , in at least one half of the
animals,
two weeks after injection (day 15 in Table 3). Table 3 shows that
doxorubicin, paclitaxel, carboplatin, vincristine, vinorelbine, and mitomycin-
C
5 fulfill these criteria. Cisplatin, etoposide, bleomycin, cytarabine,
cyclophosphamide, fluorouracil, and 9-aminocamptothecin are thus
categorized as non-vesicants.
A moderate vesicant as determined by the methods used herein is -
defrned as causing a lesion of at least about 20 mmz , in at least one half of
10 the animals, two weeks after injection (day 15 in Table 3), but less than
half
of the animals will have lesions greater than about I0 mm2 30 days after
injection (day 3i in Table 3). The data from Table 3 shows that paciitaxel,
carboplatin, and mitomycin-C fulfill these criteria. Of these, mitomycin-C has
been determined to exhibit substantial pulmonary toxicity.
15 A severe vesicant as determined by the methods used herein is defined
as causing a lesion of at least about 20 mm2 , in at least one-half of the
animals, two weeks after injection (day 15 in Table 3), and at least one-half
of the animals will still have lesions greater than about 10 mm2, 30 days
after
injection (day 31 in Table 3). Table 3 shows that doxorubicin, vincristine,
20 and vinorelbine satisfy these criteria.
Surprisingly it has now been found that moderate to severe vesicants
can be used for inhalation therapy of cancer as revealed in the discussion and
examples below. Further, other highly toxic drugs, although not having the
severity of reaction of moderate to severe vesicants have also been found to
25 be useful in the treatment of cancer by inhalation as further discussed
below.
20
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Antineoplastic drugs that are highly toxic and useful in an embodiment
of the present invention include the anthracyclines { e.g. doxorubicin,
epirubicin, idarubicin, methoxy-morpholinodoxorubicin, daunorubicin, and the
like); vinca afkaloids ( e.g. vincristine, vinblastine, vindesine, and the
like);
alkylating agents (e.g. mechlorethamine and the like); carboplatin; nitn~gen
mustards (e.g. melphalan and the like), topoisomerase I inhibitors (e.g. 9-
aminocamptothecin, camptothecin, topotecan, irenotecan, 9-NO-
camptothecin, and the like); topoisomerase II inhibitors (e.g. etoposide, -
teniposide, and the like); and paclitaxel and the like. These and other useful
l0 compounds are further discussed below.
In yet a further embodiment of the invention, there are disclosed
formulations and methods for applying an appropriate selection of highly toxic
drugs that are efFcacious in treating the neoplasm or cancer, that are applied
by inhalation and that reside in the pulmonary system for a time sufficient to
15 increase the exposure of the neoplasm to the drug, yet allow a reduction
and/or controlled systemic exposure of the drug, and provide a more
efficacious treatment for pulmonary neoplasms.
In a further embodiment of the invention, it is disclosed that it is
possible to deliver antineoplastic drugs by the pulmonary route as a means to
20 provide systemic treatment of distant tumors. The inventors have shown that
for selected drugs inhalation can be used as a noninvasive route of delivery
without causing significant toxicity to the respiratory tract. This is in
contrast
with the prior art that used inhalation for treatment of disease in the
respiratory system.
25 As used herein the term patient includes a mammal including, but not
limited to, mice, rats, cats, horses, dogs, cattle, sheep, apes, monkeys,
goats,
camels, other domesticated animals, and of course humans.
Administration by inhalation as used herein includes the respiratory
administration of drugs as either liquid aerosols or powdered aerosols
30 suspended in a gas such as air or other nonreacctive carrier gas that is
inhaled
by a patient. Non-encapsulated drug as used herein means that the
antineoplastic drug is not enclosed within a liposome, or within a polymeric
21
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WO 00/19991 PCT/US99/22845
matrix, or within an enclosing shell. Where the term encapsulated drug is
used herein the term means that the antineoplastic drug is enclosed within a
liposome, within a polymeric matrix, or within an enclosing shell. However,
in some embodiments the antineoplastic drug may be coupled to various
5 molecules yet is still not enclosed in a liposome, matrix or shell as
further
discussed below.
In other embodiments of the invention the antineoplastic drugs
disclosed herein may be coupled with other molecules through ester bonds.
Enzymes present in the respiratory system later cleave the ester bonds. One
10 purpose of coupling the antineoplastic drugs through an ester bond is to
increase the residence time of the antineoplastic drug in the pulmonary
system. Increased residence time is achieved by: first, an increase in
molecular weight due to the attached molecule; second, by appropriate choice
of a coupled molecule; third, other factors such as for example charge,
i5 solubility, shape, particle size of the delivered aerosol, and protein
binding can
be modified and used to alter the diffusion of the drug. Molecules useful for
esterification with the drug include alpha-hydroxy acids and oligomers
thereof, vitamins such as vitamins A, C, E and retinoic acid, other retinoids,
ceramides, saturated or unsaturated fatty acids such as linoieic acid and
20 glycerin. Preferred molecules for esterification are those naturally
present in
the area of deposition of the active drug in the respiratory tract.
As a demonstration of the proof of concept, doxorubicin was used in a
series of tests. Doxorubicin was chosen as an initial test agent since it is
one
of most cytotoxic and potent vesicants of all anti-neoplastic agents
considered
25 in the broad embodiment (pulmonary delivery of anti-neoplastic drugs) of
the
present invention. Based on positive outcome of these proof of concept
studies, anticancer drugs from other major classes were simultaneously
tested. Results consistently showed that using the approach and methods
described in this invention the drug could be safely and effectively delivered
30 by inhalation. In Examples 2 and 3 below, doxorubicin was administered to
three dogs (beagles) by both the pulmonary and intravenous route of
22
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WO 00/19991 PCT/US99/22845
administration. The dogs were given a clinically effective dosage of the drug
and the amount of the drug appearing in the blood system was measured.
An anthracycline antineoplastic drug, a salt of doxorubicin, doxorubicin
HCI, available from Farmitalia Carlo Erba (now Pharmacia & Upjohn), Milan,
5 Italy, was used in some of the examples herein. The liquid formulation that
was administered to the dogs by inhalation of an aerosol was obtained by
mixing the doxorubicin hydrochloride with a mixture of ethanol/water at a
doxorubicin concentration of approximately 15 - 25 mg/ml. Typically
solutions of 5 - 75% ethanol are preferred. Water/ethanol ratios may be
i0 adjusted to select the desired concentration of doxorubicin and the desired
particle size of the aerosol.
Example 2
Three adult, male, beagle dogs were used in the tests. The dogs
15 (designated dog 101, 102, and i03) had body weights of 10.66, 10.24, and
10.02 kg respectively . As used herein "mZ " used alone with reference to
dose refers to square meters in terms of the body surface area of a treated
animal or patient, at other times it is qualified in terms of lung surface
area.
The dogs were given a slow IV infusion treatment of the anthracycline drug
20 doxorubicin HCI at the recommended initial clinical dose (for dogs) of 20
mg/m2 or 1 mg/kg of body weight. A 1 mg/ml drug solution was
administered at a rate of 2.0 ml/kg/hr for 30 minutes. The 30-minute
infusion interval simulated the time/dose exposure relationship of the
inhalation group in Example 3 below. A series of blood samples were taken to
25 characterize the IV pharmacokinetics at predose, 2, 5, 10, 30, 60, 90
minutes
and 2, 4, 6, 12, 18, and 36 hours post dosing. Additional blood samples were
collected for clinical pathology evaluations on days 3 and 7 of the IV
treatment. Changes in blood chemistry and hematology were as expected
with administration of doxorubicin HCI at these doses.
30
Example 3
23
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WO 00/19991 PCT/US99/22845
The three dogs used in Example 2 were allowed a one-week washout
period before being subjected to exposure to the anthracycline drug
doxorubicin HCI by inhalation. The dogs were acclimated to wearing masks
for administration of the aerosol prior to treatment. The dogs were exposed
5 to an aerosol concentration of drug sufficient to deposit a total dose of
about
10 mg (1 mg/kg). Based on aerosol dosimetry models, approximately one
half of this dose was deposited within the respiratory tract. The total dose
was about equal to the dosage administered by IV infusion. The dose was
calculated using the following equation:
10
Dose = Drug Conc. (mg/liter) x Mean minute Vol. (liter/min) x Exposure
Duration (min) x Total Deposition Fraction (%)~ = Body Weight (kg)
wherein
15 Mean Min. Vol. = Tidal volume x minute respiratory rate
Exposure Duration = 30 min
Mean Body Weight = weight in kg for each dog
Total Deposition Fraction = 60% (determined by particle size and
respiratory tract deposition models from the published literature such as
20 "Respiratory Tract Deposition of Inhaled Polydisperse Aerosols in Beagle
Dogs", R.G. Cuddihy et al, Aerosol Science, Vol 4, pp. 35-45 (1973) and
"Deposition and Retention Models for Internal Dosimetry of the Human
Respiratory Tract", Task Group on Lung Dynamics, Health Physics, Vol. 12,
pp. 173-207 (1966).
25 Pulmonary function measurements (respiratory rate, tidal volume, and
minute volume (calculated)) were monitored during a 30 minute inhalation
exposure session. These data provided an estimate of each animal's inspired
volume during exposure, and were used to calculate the mass of drug
deposited in the respiratory tract.
30 A series of blood samples were collected at the end of the exposure to
characterize the pharmacokinetics. Clinical pathology evaluations were
conducted on the third day. All three dogs were necropsied on the third day.
24
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WO 00/19991 PCT/US99/22845
Referring now to Figure 4, the drug formulation was administered to
the dogs of F~cample 3 with drug exposure system 400. The drug was
aerosolized with two Pari LC Jet PIusT"" nebulizers 401 . The nebulizer was
filled with a solution of 15 mg doxorubicin per ml of 50%water/50% ethanol.
5 The output of each nebulizer 40i was continuous and set to provide the
required concentration of aerosol in attached plenum 405. The nebulizers
401 were attached directly to plenum 405 that had a volume of approximately
90 liters . Plenum 405 was connected by four tubes 407 to four venturi 40g,
respectively, and subsequently connected to four Y-fittings 413 by additional
10 tubing 411. Typical venturi were used to measure the inhaled volume of drug
formulation. One end of each of the Y-fittings 411 interfaced with a dog
breathing mask 415 while the other end of Y-fitting 411 was connected to
tubing 417 leading to an exhaust pump 419. During the tests three dogs 418
were fitted with three of the breathing masks 415. A collection filter 421 was
15 placed in the remaining mask 415. A vacuum pump 423 that drew 1 titer per
minute of air for 3 minutes was used in the place of a dog to draw aerosol in
order to monitor and measure the amount of drug administered. The vacuum
pump was activated four times during the 30-minute administration of drug to
the dogs and the amount of drug trapped by the filter set forth in Table 5
20 below.
A flow of air was supplied to each of the nebulizers 401 from a supply
of air 425 via lines 427. Additional air for providing a bias flow of air
through
the system and for the breathing requirements of the dogs was provided from
air supply 425 by supply lines 429 connected to one way valves 431. The one
25 way valves 431 were connected to the upper portion of the nebulizers 401.
This additional supply of air provided a continuous flow of air through the
system 400 from the air supply 425 to the exhaust pump 417. Alternatively
one could eliminate the extra supply of air from supply lines 429 to one way
valves 431 and let ambient room air enter the one way valves from the
30 suction action of the nebulizers 401. A Hepa filter 441 mounted to the top
of
plenum 405 allowed room air to flow in and out of plenum 405 and assured
that there was always ambient pressure in the plenum. There was a
25
CA 02346029 2001-04-02
WO 00/19991 PCTNS99/22845
continuous flow of air containing the aerosol past the masks of the dogs and
the dogs were able to breathe air containing the aerosol on demand. An
inner tube 621 located within dog breathing mask 415 extended into the
mouth of the dogs and was provided with an extension 633 at its lower
5 portion that served to depress the tongue of the dogs to provide an open
airway for breathing. See the discussion of Fgure 6 below.
Each of the four venturi 409 were connected by line 441 to a pressure
transducer 443 ( the one shown is typical for the four venturi) that was used
to measure pressure differences across the venturi. The pressure transducers
10 443 were connected by line 445 to an analog amplifier 447 to increase the
output signal and prepare the signal sent via line 449 to computer system
451. Computer system 451 is a desk model PC of typical design in the
industry and can be used in conjunction with a BUXCO or PO-NE-MAH
software program to calculate the uptake of air containing aerosol and thus
15 the drug dosage by each of the dogs.
Table 4 below summarizes the exposure data for doxorubicin
administration to dogs from Example 3. The total mass for each dog was
determined. The total inhaled volume of air for the 30 minute drug
administration was measured in liters. The aerosol concentration in mg of
20 drug/liter of air (mg/I) was determined from calibration tests done
earlier. A
total deposition fraction of 60% was calculated (As calculated 30% for the
inhaled dose was deposited in the conducting upper airways and peripheral
lung while and additional 30% was deposited in the oral-pharyngeal region)
based on the measured doxorubicin aerosol particle size and the published
25 literature (see references cited above).
Thus about 25%-30% of the administered doxorubicin was deposited
and available to the pulmonary region. Since the drug was administered in its
salt form, a correction for the chlorine portion of the molecule was made. As
shown in the Table 4 this resulted in an applied dose of 0.51, 0.60, and 0.57
30 mg/kg to the pulmonary region of dogs 101, 102, and 103 respectively
Filter data obtained from analysis of drug deposited on a filter 421
placed in a fourth mask 415 are shown in Table 5 for four different
26
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
measurements . The drug mass collected on the filter was corrected for the
chlorine portion of the doxorubicin salt. Fnally, the doxorubicin
concentration
in the three liters of air drawn into each mask was determined in mg/I. The
four figures were averaged to obtain a mean doxorubicin aerosol
5 concentration of 0.218 mg/I.
Table 6 shows data and calculations that verify the figures of Table 4.
The dog weight and breath volumes measured for Table 4 are used.
However, the mean doxorubicin concentration that was obtained from the
filter data shown in Table 5 was used to calculate doxorubicin concentrations.
10 Making calculations with the data as in Table 4, the inhaled dose for each
dog
was calculated. The inhaled dose was reduced by 40% as before to obtain
the total dose deposited, and reduced by 50% again to obtain the total
deposited pulmonary dose. The pulmonary doses obtained by this method of
0.47, 0.56, and 0.53 mg/kg for dogs 101, 102, and 103 respectively compare
15 well with the earlier calculated figures in Table 4.
27
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/Z2845
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28
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
Surprisingly it was found that free non-encapsulated doxorubicin
administered by the pulmonary route was not rapidly cleared from the lung.
Figures 1, 2 and 3 show examples of the type of results achieved when
cytotoxic anticancer drugs were given by inhalation. High efficiency
5 nebulization systems as shown in Figures 4 and 5 were used to deliver a
large
percentage of aerosolized drug to the pulmonary region of the respiratory
tract. Doses equal to or greater than those that cause toxicity when given IV,
were only moderately absorbed into the blood following pulmonary delivery -
and caused little to no direct or systemic toxicity after a single exposure at
10 this dose.
As can be seen from Figures 1, 2 and 3, the pulmonary route
administered doxorubicin achieved a consistently lower level of doxorubicin in
systemic blood, with peak blood levels being over an order of magnitude
lower following inhalation exposure. The initial concentration of doxorubicin
15 at 2 minutes was about 1.5 orders of magnitude larger when administered N
than by the pulmonary route. Later, after about 4 hours, the systemic
doxorubicin level was about six times higher for the IV administered drug.
This suggests that free doxorubicin remained in the lung for an extended
period of time and slowly passed through the mucosa into systemic
20 circulation. This reduces the systemic toxic effects of the drug and allows
its
concentration in the lung for more effective treatment of respiratory tract
associated neoplasms while reducing overall systemic toxic effects. It is
believed that the toxic effects of doxorubicin to tissues outside the lung are
as
a result of the aforementioned high levels of systemic drug concentration
25 following N treatment.
Another surprising finding was that doxorubicin administered by the
pulmonary route did not produce the severe toxic effects on the respiratory
tract (including the oral and nasal-pharyngeal, tracheo-bronchial, and
pulmonary regions). As was noted earlier, doxorubicin belongs to the
30 anthracycline class of drugs that are typically very toxic. In particular
doxorubicin is one of the most toxic drugs in the class, yet when the dogs in
the test were necropsied, no damage to the respiratory tract was observed.
29
CA 02346029 2001-04-02
wo oon9m rc~rius99nzsas
It is surprising that the doxorubicin was not toxic to the lung when given by
inhalation at clinically relevant doses such as 20 to 60 mg/m2. Unlike 5-FU
and Ara-C, and cisplatin, doxorubicin is well known to generate the production
of free radicals (Myers et al, 1977) which are notorious for causing pulmonary
5 toxicity (Knight, 1995). It is this property, in fact, which is held
responsible
for the cardiotoxicity caused by doxorubicin given by the intravenous route
(Myers et al, 1977).
In some typical embodiments, to obtain additional benefits of the
disclosed invention for treating pulmonary neoplasms and reducing systemic
10 toxicity, it is important that antineoplastic drugs administered in non-
encapsulated form by the pulmonary route be absorbed into and remain in
the tumor tissue for an extended period of time and diffuse across the lung
mucosa in a relatively slow manner. In general, although solubility, charge
and shape have an influence, slow diffusion is obtained by drugs having
15 higher molecular weights while faster diffusion is obtained by those having
relatively lower molecular weights. Thus drugs such as doxorubicin having a
molecular weight of 543.5, have relatively slow rates of diffusion, drugs such
as vincristine {MW=825), vinblastine (MW=811), paclitaxel (MW=854),
etoposide (MW=589), having higher molecular weights also diffuse slowly.
20 Other drugs having somewhat lower molecular weights such as 9-
aminocamptothecin, while diffusing more slowly are still included within the
invention. It has been demonstrated that significantly higher tissue
concentrations can be achieved in the lung by pulmonary delivery compared
to conventional parenteral or oral administration. Further, systemic coverage
25 of micrometasteses can be provided under these conditions, with the benefit
of significantly greater doses of drug delivered to the respiratory tract
tumor
sites and controlled systemic exposure.
Thus in one embodiment of the invention drugs having a molecular
weight above 350 are used. In this regard mitomycin-C (MW of about 334) is
30 thus excluded from this embodiment. While molecular weight is not the sole
determinant controlling diffusion through the lung it is one of the important
factors for selecting compounds useful in the present invention. This lower
30
CA 02346029 2001-04-02
WO 00/19991 PCTNS99/22845
molecular weight limit is about 64% that of doxorubicin. This will help assure
that the limited systemic availability of the drug discussed above is
maintained. In further embodiments of the invention the molecular weight of
the drugs administered is above 400, 450, and 500 respectively.
5 In conjunction with the above discussed molecular weights, protein
binding of the antineoplastic agents to be delivered by pulmonary
administration should also be considered with respect to diffusion through the
lung. Higher rates of protein binding will further slow diffusion through the
lung mucosa. In this respect 5-FU and Ara-C in addition to having low
10 molecular weights also have relatively low protein binding affinity of 7%
and
13% respectively. That is, when placed into a protein-containing solution,
only 7% and 13% of these drugs bind to the protein while the remainder is
free in solution. In this respect, cisplatin does not bind to tissues, rather
at a
later stage it is the platinum in the cisplatin that binds to tissues, thus
15 allowing cisplatin to enter systemic circulation as further discussed
below. In
comparison doxorubicin, vincristine, vinblastine, paclitaxel, etoposide, and 9-
amino-camptothecin have rates of protein binding above 50%. Typically
protein-binding affinity above 25% is preferred, more preferred is binding
above 50%, with protein binding above 75% being most preferred when lung
2o retention is the objective.
In a preferred formulation and method for treating neoplasms of the
pulmonary system by inhalation, the diffusion characteristics of the
particular
drug formulation through the pulmonary tissues are chosen to obtain an
efFcacious concentration and an efficacious residence time in the tissue to be
25 treated. Doses may be escalated or reduced or given more or less frequently
to achieve selected blood levels. Additionally the timing of administration
and
amount of the formulation is preferably controlled to optimize the therapeutic
effects of the administered formulation on the tissue to be treated and/or
titrate to a specific blood level.
30 Diffusion through the pulmonary tissues can additionally be modified
by various excipients that can be added to the formulation to slow or
accelerate the absorption of drugs into the pulmonary tissues. For example,
31
CA 02346029 2001-04-02
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the drug may be combined with surfactants such as the phospholipids,
dimyristoylphosphatidyl choline, and dimyristoylphosphatidyl glycerol. The
drugs may also be used in conjunction with bronchodilators that can relax the
bronchial airways and allow easier entry of the antineoplastic drug to the
lung. Albuterol is an example of the latter with many others known in the art.
Further, the drug may complexed with biocompatible polymers, micelle
forming structures or cyclodextrins
Particle size for the aerosolized drug used in the present examples was
measured at about 2.0-2.5 ~m with a geometric standard deviation (GSD) of
10 about 1.9-2Ø Typically the particles should have a particle size of from
about 1.0-5.0 wm with a GSD less than about 2.0 for deposition within the
central and peripheral compartments of the lung. As noted elsewhere herein
particle sizes are selected depending on the site of desired deposition of the
drug particles within the respiratory tract.
15 Aerosols useful in the invention include aqueous vehicles such as water
or saline with or without ethanol and may contain preservatives or
antimicrobial agents such as benzalkonium chloride, paraben, and the like,
and/or stabilizing agents such as polyethyleneglycol.
Powders useful in the invention include formulations of the neat drug
20 or formulations of the drug combined with excipients or carriers such as
mannitol, lactose, or other sugars. The powders used herein are effectively
suspended in a carrier gas for administration. Alternatively, the powder may
be dispersed in a chamber containing a gas or gas mixture which is then
inhaled by the patient.
25 Further, the invention includes controlling deposition patterns and total
dose through careful control of patient inspiratory flow and volume. This may
be accomplished using the pulmonary devices described herein and similar
devices. The inventors have shown by gamma scintigraphy measurements
that drug aerosol deposition is maximized and evenly distributed in the
30 peripheral lung when the patient inhales using slow flow rates and inhales
to
maximum lung volumes followed by brief breath holds. Central lung
deposition is favored when faster inspiratory flow rates and lower inspiratory
32
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
volumes are used. Further, total deposited and regionally deposited doses
are significantly changed as a patient's inspiratory patterns change.
Therefore, the method of treatment and the use of the delivery devices
described herein can be modified to target different regions of the
respiratory
5 tract and adjusted too deliver different doses of drug. It is the
integration of
drug molecular weight, protein binding affinity, formulation, aerosol
generation condition, particle sized distribution, interface of aerosol
delivery to
the patient via the device and the control of the patient's inspiratory
patterns
that permit targeted and controlled delivery of highly toxic anti-cancer drugs
10 to the respiratory tract with the option to minimize or provide controlled
systemic availability of drug.
Example 4
The tests far administration of doxorubicin by inhalation referred to in
15 Example 3 were substantially repeated at different dosages using a
different
drug administration system 500 described below. In the present examples
eight dogs were used. The dogs were divided into two dose groups. A first
group was the low dose group given a total daily dose of 60 mg/mz for three
days or a total dose of 180 mg/m2. This resulted in a pulmonary deposition of
20 about 90 mg/mz.
A high dose group was administered a dose of 180 mg/m2 daily for
three days or a total dose of 540 mg/m2. This resulted in a pulmonary
deposition of about 270 mg/mZ.
One half of the animals were necropsied after three days of exposure
25 and the remaining dogs necropsied after a three day recovery period.
The purpose of the tests was to identify the maximum tolerated dose
of inhaled drug.
For comparison with the results of Examples 2 and 3, one can convert
the data from mg/kg to mg/m2 (m2 of body area) by multiplying by 20
30 (conversion factor for the dog). Thus the exposure of the dogs in Examples
2
and 3 which were the equivalent of a clinical dose (for dogs) was about 20
mg/mz. When one compares these dosages to those of Example 4 (180
33
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
mg/m2 and 540 mg/m2) it is apparent that a significantly higher dose of non-
encapsulated drug can be delivered to the lung compared to the known art .
Although dogs receiving the lower total dose ranges showed few toxic effects,
while dogs receiving the higher total doses had pulmonary toxicity, these
5 doses were 9-27 times higher than those generally given clinically to dogs.
While the present examples used active drug doses of doxorubicin of
about 20 mg/m2, 180 mg/mZ, and 270 mg/m2, effective amounts of the active
anticancer drugs can be from very small amounts to those where toxicity to
normal tissue becomes a problem. As used herein, effective amounts and
10 pharmaceutically effective amounts of antineoplastic drug deposited or
applied to areas needing treatment are dosages that reduce a neoplasm or
tumor mass, stop its growth or eliminate it altogether.
Referring now to Figure 5, the liquid formulation was administered to
the dogs by aerosolizing with a nebulizer exposure system 500 comprising a
15 Pari LC Jet PIusT"" nebulizer 501. The nebulizer was filled with the
solution of
drug with which the dogs were to be treated. The output of the nebulizer 501
was pulsed in a series of bursts over time (one pulse every ten seconds). The
nebulizer 501 was attached directly to a 460 cc volume plenum 503 and the
plenum 503 was connected to a canine mouth only exposure mask 415 via a
20 short piece of anesthesia tubing 505 and Y-fitting 507. The mask 4i5 was
tapered to approximately fit the shape of the dog's snout. There was no bias
airflow through the exposure system 500. The test atmosphere was pulled
through the exposure system 500 by the inhalation of the dog 511. A one
way breathing valve 513 on the top of the nebulizer 501 allowed the dog 511
25 to draw in room air and pull the air through the system 500. The air
entrained and transported the aerosolized drug through the plenum 503,
tubing 505, Y-fitting 507, and mask 415 to the dog 511. A one way valve 515
connected to the Y-fitting 507 allowed the dog 511 to exhale and the exhaled
air exited the system. An air supply 520 provided a flow of air to controller
30 530 via line 521. Air flow to the nebulizer was controlled by controller
530
and supplied to the nebulizer via line 53I.
34
CA 02346029 2001-04-02
WO 00/19991 PCT/US99122845
Referring now to Figure 6, details of mask 415 are shown. Means for
enclosing the mouth and nose are of flexible material and are preferably held
on by straps such as VelcroT"" straps or belts. Means for enclosing 601 has
one end 603 for inserting the nose and mouth of the dog while the other end
5 605 has two openings 607,609 for attachment of nose outlet tube 611. Nose
outlet tube 611 has a one way valve 613 that allows the dog to exhale but not
inhale through the its nose. Mouth tube 621 is inserted and attached to
opening 609 and lies within the means for enclosing 601. An optional Y-
connector 623 may be attached and used with mouth tube 621 for providing
10 and receiving inhaled and exhaled gases. Air is generally inhaled through
leg
625 of the Y-connector 623. The air passes through the mouth tube 621 and
out the inner opening 631 into the respiratory system of the dog. Inner
opening 631 is cut at an angle with its lower portion 633 extending further
into the mouth of the dog than the upper portion 635. Lower portion 633
15 functions to depress the tongue of the dog and allow more efficient flow of
air
and aerosol into the dog. When the dog is wearing mask 415 it can only
breathe in through its mouth using the mouth tube 621. Means for enclosing
601 effectively seals the dog's mouth and nose from outside air. The use of a
nose outlet tube 611 has been found to greatly ease the dogs wearing of the
20 mask. Air exhaled through the mouth exits mouth tube 621 and passes into
optionally attached Y-connector or to another tube not shown. Air exits Y
connector 623 via outlet tube 627. If desired the Y-connector 623 or other
outer tube (e.g. straight tubing) may be made of one piece and simply pass
into the enclosing means 601 or may be of separate pieces that fit together.
25 In either case an adapter 637 may be used to hold the mouth tube 621 and
or other tubing to which it is connected.
A general device for administering aerosols to a patient includes an
inhalation mask for administering aerosols to the including means for
enclosing the mouth and nose of the patient, having an open end and a
30 closed end, the open end adapted for placing over the mouth and nose of the
patient; upper and lower holes in the closed end adapted for insertion of a
nose outlet tube and a mouth inhalation tube; the nose outlet tube attached
35
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
to the upper hole, adapted to accept exhaled breath from the nose of the
patient; a one way valve in the nose tube adapted to allow exhalation but not
inhalation; the mouth inhalation tube having an outer and an inner end,
partially inserted through the lower hole, the inner end continuing to end at
the rear of the patients mouth, the inhalation tube end cut at an angle so
that
the lower portion extends further into the patients mouth than the upper
portion and adapted to fit the curvature of the rear of the mouth; and a y-
adapter attached to the outer end of the mouth inhalation tube. _
Pulmonary administration by inhalation may be accomplished by means
10 of producing liquid or powdered aerosols, for example, by the devices
disclosed herein or by using any of various devices known in the art. (see
e.g. Newman, S.P., 1984, in Aerosols and the Lung, Ciarke and Davia (Eds.),
Butterworths, London, England, pp. 197-224; PCT Publication No. WO
92/16192 dated October 1, 1992; PCT Publication No. WO 91/08760 dated
15 June 27, 1991; NTIS Patent Application 7-504-047 filed April 3, 1990 by
Roosdorp and Crystal) including but not limited to nebulizers, metered dose
inhalers, and powder inhalers. Various delivery devices are commercially
available and can be employed, e.g. Uitravent nebulizer (Mailinckrodt, Inc,
St.
Louis, MO); Acorn II nebulizer (Marquest Medical Products, Engiewood, CO);
20 Ventolin metered dose inhalers (Glaxo Inc., Research Triangle Park, North
Carolina); Spinhaler powder inhaler (Fisons Corp., Bedford, MA) or Turbohaler
(Astray. Such devices typically entail the use of formulations suitable for
dispensing from such a device, in which a propellant material may be present.
Ultrasonic nebulizers may also be used.
25 Nebulizer devices such as those in Greenspan et al US patents
5,511,726 and 5,115,971 are useful in the invention. These devices use
electrohydrodynamic forces to produce a finely divided aerosol having
uniformly sized droplets by electrical atomization. White the Greenspan
devices use piezoelectric materials to generate electrical power any power
30 source is acceptable to produce the electrohydrodynamic forces for
nebulization.
36
CA 02346029 2001-04-02
WO 00/19991 PC'f/US99/22845
A nebulizer may be used to produce aerosol particles, or any of various
physiologically inert gases may be used as an aerosolizing agent. Other
components such as physiologically acceptable surfactants (e.g. glycerides),
excipients (e.g. lactose), carriers (e.g. water, alcohol), and diluents may
also
5 be included.
As will be understood by those skilled in the art of delivering
pharmaceuticals by the pulmonary route, a major criteria for the selection of
a
particular device for producing an aerosol is the size of the resultant
aerosol -
paracles. Smaller particles are needed if the drug particles are mainly or
only
10 intended to be delivered to the peripheral lung, i.e. the alveoli (e.g. 0.1-
3
Vim), while larger drug particles are needed (e.g. 3-10 Vim) if delivery is
only
or mainly to the central pulmonary system such as the upper bronchi. Impact
of particle sizes on the site of deposition within the respiratory tract is
generally known to those skilled in the art. See for example the discussions
15 and figures in the articles by Cuddihy et al (Aerosol Science; Vol. 4;
1973, pp
35-45) (Fig. 6, 7, and 8 of the article) and The Task Group on Lung Dynamics
(Fig. 11 and 14 of the article). As a result primary cancers in the naso-
pharyngial or oral-pharyngeal regions and upper tracheo-bronchial regions,
often referred to as cancers of the head and neck, are treatable with the
20 present invention. The major metastatic sites (lung and upper respiratory
tract) are also readily treated with this invention simultaneously, unlike
current methods of treatment.
Referring now to Figure 7, there is disclosed a nebulizer apparatus 700
that is preferably portable for administration of drug to a patient in need of
25 therapy. The nebulizer apparatus 700 is used in combination with the highly
toxic drugs of the present invention and with drugs having properties adapted
for optimum treatment of neoplasms as discussed elsewhere herein. Figure 7
is a schematic of a nebulizer combination according to the present invention.
Nebulizer 701 may be any nebulizer as described earlier herein that is able to
30 produce the particle sizes needed for treatment. In combination with
nebulizer 701 there is provided a highly toxic drug formulation 703 for
treatment of neoplasms as disclosed herein. An air supply 705 is provided
37
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
either as a tank of compressed gas or as a motorized pump or fan for moving
air from the room. An optional mouthpiece 707 may be used where it is
necessary to provide sealed contact between the nebulizer and the patient.
Optionally the mouthpiece 707 may be molded as part of nebulizer 701.
5 Power for use of the nebulizer apparatus 700 may come from the compressed
gas from hand manipulation by the user or administrator or by batteries or
electrical power not shown but well known by those skilled in the art.
To control environmental contamination resulting from use of a
nebulizer, the patient may be placed in a well-ventilated area with exhaust
air
l0 filtered to remove antineoplastic drug that escapes from the device.
Examples 5 to 11
Examples 5F to 11F show inhalation feasibility and proof of concept
tests and Examples 5R to lOR show dose escalation range tests with: vesicant
15 antineopiastic drugs including doxorubicin, paclitaxel, vincristine,
vinorelbine;
nonvesicant drugs including etoposide, and 9-aminocampothecin (9-AC) and
carboplatin. The drugs were delivered to the pulmonary system via aerosol at
a particle size of about 2 to about 3 um. The drugs were delivered in water
or other vehicles appropriate for the drug as is known in the art and as
20 exemplified herein.
Table 7 illustrates the dosage schedule for the range-finding studies. A
minimum of 7-14 days separated each escalating dose. No range finding
tests, only feasibility tests, were performed for mitomycin-C and 9-AC. No
feasibility tests, only dose range-finding tests, were performed for
vinorelbine.
25 It is important to note that the doses listed in Table 7 are the pulmonary
deposited doses not the total doses administered.
The results of the feasibility and dose escalation studies are
summarized in Tables 7 to 11.
38
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/Z2845
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39
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
Animals used in F~campfes 5 to il were adult beagle dogs. For the
feasibility studies, the dogs were initially given a single intravenous {N)
dose
of antineoplastic drug. This dose was given to allow a comparison of how
much drug was absorbed into the blood after inhalation compared to IV
5 delivery. The IV dose given was typically the usual human clinical dose that
had been scaled down for the dogs based on differences in body mass, or the
maximum tolerated dose in the dog, whichever is greater. An average human
having a weight of 70kg is considered to have a weight to body surface ratio
of 37 kg/m2 and a lung surface area of 70 - 100 m2 of lung surface area. The
10 average dog used in the tests was considered to have a weight of l0kg
corresponding and a weight to body surface ratio of 20 kg/m2 and a lung
surface area of 40 - 50 m2 lung surface area (CRC Handbook of Toxicology,
1995, CRC Press Inc.). The single IV dose was used to quantify the plasma
kinetics. With most of the cytotoxic agents treated, the single IV dose
15 resulted in a predictable mild decrease in white blood cell counts, with no
other measurable toxicities.
After the initial IV and before the inhalation feasibility tests, the dogs
were allowed a washout period of at least seven days (until the dogs returned
to normal conditions) before they were treated with inhaled antineoplastic
20 drugs. In the inhalation feasibility tests the dogs were generally exposed
to a
dose of inhaled antineoplastic drug in aerosol form once per day for three
consecutive days (except as noted in Tables 8 to 11) and necropsied one day
following the last dose with the plasma kinetics characterized after the first
and third exposures. With the exception of cisplatin and the high dose of
25 doxorubicin, which caused toxicity to the respiratory tract, the drugs did
not
exhibit any significant pulmonary toxicity in these repeated exposure
inhalation feasibility studies. In the feasibility tests the dogs used the
same
mask and apparatus used for the earlier examples. In the dose range-finding
tests, in order to control the deposited dose, the dogs were fitted with an
30 endo-tracheal tube and the drug administered as an aerosol directly from
the
endo-tracheal tube. This latter procedure made it easier to control the
pulmonary deposited dose since the aerosol was released directly into the
40
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
pulmonary air passages assuring deep deposition of the drug in the lung.
Also use of the endo-tracheal tube made it possible to do the tests in a
shorter time since the dogs needed a four to six week training period to
properly acclimate to and use the masks. The calculated deposited doses
5 ob~ined herein were verified experimentally by pulmonary scintigraphy tests
in dogs.
F~camples 5F and 5R
Referring now to Table 8, this table shows the details of the feasibility
l0 test of paclitaxel. Initially the dogs were administered 120 mg/mz of
paclitaxel by IV. After the washout period the dogs were administered a total
deposited dose of 120 mg/m2 of paclitaxel, by inhalation, three times for a
total deposited dose of 360mg/m2. This administered dose resulted in a
pulmonary deposited dose of about 27 mg each time or a total pulmonary
15 dose of about 8i mg. This represents a total pulmonary deposited dose of
about 2.1 mg/mz of lung surface area. The dosages were calculated as
follows: the dose of 120 mg/mZ was divided by 20 kg/m2 to yield a 6 mg/kg
dose that was multiplied by 10 kg for the average dog to yield about 60 mg of
drug. Since the dogs were using the masks for drug administration, one half
20 or about 30 mg of drug was considered deposited in the deep lung. Since the
drug was administered three times the total drug exposure was about 90 mg.
The 90 mg of drug was divided by 40 to yield a total dose to the lung of
about 2.25 mg/m2 lung surface area.
The clinical condition of the dogs was normal. Clinical pathology
25 profiles were normal with only mildly reduced white blood cell counts. The
histopathology showed bone marrow and lymphoid depletion, GI villous
atrophy and congestion and laryngeal inflammation. These changes indicated
that some significant fraction of the deposited drug was absorbed
systemically. There was no respiratory tract toxicity found. Bioavailability
of
30 the paclitaxel was found to be low to moderate based,on plasma kinetic
evaluations. The low to moderate bioavailability indicates that most of the
pacfitaxel remained in the lungs and did not rapidly enter systemic
circulation
41
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
in large amounts. Therefore, given the lack of significant direct respiratory
tact toxicity, the probable dose limiting toxicity is considered to be
myelosuppression and/or GI toxicity. Thus factors extrinsic to the lung are
expected to limit dosages provided by the pulmonary route.
5 Referring again to Tables 7 and 8, in the range-finding tests 60 to 120
mg/m2 of paclitaxel were administered at weekly intervals for five weeks. The
amount of pulmonary deposited dose ranged from about 30 to about 60 mg.
This range corresponded to about 0.75 to about 1.50 mg/m2 lung surtace
area. The clinical conditions of these dogs were normal, with clinical
l0 pathology changes limited to moderate white blood cell count reduction. The
histopathology showed thoracic and mesenteric lymphoid depletion along with
GI inflammation and ulceration. The histopathology reflects that normally
found in iV administration of paciitaxel particularly GI inflammation and
ulceration which is probably associated with systemically administered
15 paclitaxel. Respiratory tract toxicity indicated minimal pulmonary
interstitial
inflammation. Systemic bioavailability was proportional to dose. The
probable dose limiting toxicity is myelosuppression and GI toxicity, and not
pulmonary toxicity.
42
CA 02346029 2001-04-02
WO 00/19991 PCTNS99/Z2845
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SUBS77TUTE SHEEP (RULE 26)
CA 02346029 2001-04-02
WO 00/19991 PCT/US99l22845
Examples 6F and 6R
Referring now to Table 9, 20 mg of doxorubicin were initially
5 administered by IV. After the washout period three sets of inhalation
feasibility tests were made. In the first, a single dose of 20 mg/m2 of
doxorubicin was administered that gave about a 10 mg body dose, a
pulmonary deposited dose of about 5 mg or about 0.125 mg/m2 lung surface
area. No changes were noted in the animal from this dose. A second set of
10 moderate inhalation dosages of about 40 mg/m2 of doxorubicin (about 10 mg
deposited within the lung) was administered three times a day for three
consecutive days. Total cumulative dose administered was 120 mg/m2
corresponding to a about a 60 mg body dose, and a total pulmonary
deposited dose of about 30 mg (or about 0.75 mg/m2 of lung surface area}.
15 A third set of high inhalation dosages of 120 mg/mZ of doxorubicin was
administered three times per day over a three day period for a total dose of
360 mg/mz corresponding to a 180 mg body dose, a total pulmonary
deposited dose of about 90 mg or about 2.25 mg/mz of lung surface area.
One half of the low dose group dogs was necropsied the day after the final
20 exposure and the remaining half was necropsied four days later. All high
dose dogs were necropsied the day after the final exposure.
Exposure to these extremely high doses resulted in the death of
one high dose group dog after three days of exposure with the remaining
three dogs euthanized in moderately debilitated to moribund conditions. This
25 dose intensive treatment caused pulmonary edema, a sequels of
microscopically recognizable degeneration, necrosis and inflammation of
epithelial surfaces lining the bronchials and larynx and the mucosal surfaces
of the nose and lips. These lesions were life threatening and more severe in
the high dose group, but were considered survivable at the lower dose, based
30 on the clinical condition of the animals. Despite these higher doses, there
were no clinical pathology changes indicative of doxorubicin induced
myelosuppression. There was microscopic evidence of lymphoid depletion in
44
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
the regional lymph nodes of the respiratory and gastrointestinal tracts
suggestive of regional drainage of free doxorubicin to the draining lymph
nodes of the thoracic and GI systems. WBC values actually increased in the
high dose group, a change associated with the inflammatory response
5 observed in the respiratory tract. There were no other clinical pathology
changes of note other than increased serum alkaline phosphatase in the high
dose group, a nonspecific change, due likely to respiratory tract tissue
damage.
Generally, changes noted at the moderate and high dosages were
l0 edema, increased white blood cell count and increased respiratory rate.
Histopathology revealed thoracic and GI lymphoid depletion for the moderate
and higher doses, respectively. Respiratory tract toxicity including airway
epithelial degeneration and moderate to severe inflammation was noted at
the increased dosages. Bioavailability was low to moderate indicating an
15 absorption rate limiting process in movement of the drug into the systemic
circulation. The probable dose limiting toxicity of doxorubicin is expected to
be respiratory tract toxicity rather than a systemic toxicity.
In addition, a dose escalation study was conducted on a weekly
exposure schedule. Initial doses of 12 mg deposited were delivered via
20 endotracheal tube to the lungs, with a 5~" weekly dose of 18 mg deposited
within the lungs. This provided a total body dose of 24 to 36 mg/m2. The
results of this repeated dose trial were similar in character (but not in
severity) to the higher dose tests. Animals survived this treatment regimen
with minimal clinical evidence of toxicity and no evidence of systemic
25 changes. Histologically, there was no evidence of respiratory tract
epithelial
degeneration and inflammation.
45
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
~o
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46
SUBSTITUTE SHEET (RULE 26y
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
Plasma levels of doxorubicin were dose dependent and exhibited clear
evidence of drug accumulation, including daily increases in Cmax (maximum
concentration in blood) and steady state-like profiles, suggesting there was a
rate limited absorption from the lung into the blood with significant
5 accumulation of doxorubicin in the lungs following each additional exposure
given at a frequency of daily intervals. This accumulation was considered
likely responsible for the tissue damage observed.
Referring again to Tables 7 and 9, an inhalation dose range of 20-40-
mg/m2 was administered in five weekly doses that resulted in a body
i0 exposure of about 10 mg to about 20 mg, a pulmonary deposited dose range
of about 10 to about 20 mg or a range of about 0.25 mg/m2 to about 0.5
mg/m2 lung surface area. The clinical condition included increased respiratory
rate and mild transient pulmonary edema. A decrease in white blood cell
count was noted for the higher dosages. Histopathology revealed mild to
15 moderate thoracic and mesenteric lymphoid depletion. Respiratory tract
toxicity noted was mild to moderate degeneration of airway epithelium. A
mild to moderate to marked interstitial inflammation was noted with some
limited fibrosis. Bioavailability was noted to be low to moderate with
absorption being rate limited. The probable dose limiting toxicity appears
20 again to be respiratory tract toxicity.
Example 7F and 7R
Referring now to Table 10, 1.4 mg of vincristine was initially
administered by IV. After the washout period one inhalation feasibility test
25 was made. The vincristine was formulated in a 50% water/ 50% ethanol
vehicle. A single dose of 2.8 mg/m2 of vincristine was administered that gave
about a 1.8 mg body dose, a pulmonary deposited dose of about 0.9 mg or
about 2.25 mg/m2 lung surface area. No changes were noted in the animal
from this dose.
47
CA 02346029 2001-04-02
WO 00/19991 PCTNS99/22845
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48
h
SUBSTITUTE SHEET (RULE 26)
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
Referring now to Tables 7 and 10, range finding tests of inhaled
vincristine were made in the range of 0.5 to 1.5 mg of pulmonary deposited
vincristine administered in six weekly doses. Therefore the amount of
5 pulmonary deposited dose ranged from about 12.5 - 37.5 ~g/m2 lung surface
area. This corresponded to a total body dose of 50-150 ~g/kg or 1.0-3.0
mg/m2 of body surface area. This dose range is near and generally above
typical dose ranges for vincristine given IV. But in the examples given here;
the entire dose was administered to the lungs. Vincristine is a potent drug
10 and causes significant myelosuppression and neurotoxicity at doses above
1.0
mg/mZ given systemically. The results of the pilot inhalation studies showed
the drug was well tolerated at all doses delivered by pulmonary administration
with little to no evidence of respiratory tract toxicity with mild lymphoid
depletion/myelosuppression only occurring at the highest doses given (2.0-3.0
15 mg/mz).
Example 8R
Vinorelbine, which is also a vinca alkaloid was evaluated in a repeated
exposure pilot tests. Compared to vincristine, vinorelbine was approximately
20 5-10 times less potent in producing toxicity, but produced similar types of
changes. Vinorefbine delivered by pulmonary administration directly into the
lungs of dogs by endotracheal tube, on a weekly basis (for 5 weeks) at
escalating doses was well tolerated. A dose of 6 mg deposited in the lung
was initially selected and escalated to 15 mg deposited within the lung. This
25 represented a lung surface exposure of N0.15-0.375 mg/m2 of lung surface
area and total body doses of 12-30 mg/m2. This treatment regimen produced
very minimal effects within the respiratory tract, characterized principally
by
slight inflammation. At the higher dose levels, inhaled vinorelbine produced
sufficient blood levels to cause mild to moderate myelosuppression and
30 lymphoid depletion, both of which were reversible and of a severity, which
was not life-threatening.
49
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
Examples 9F and 9R
An additional proof of concept, pilot inhalation tests involved etoposide.
Etoposide is a cytotoxic drug, representative of a class of drugs known as
topoisomerase II inhibitors. Given orally or IV, etoposide causes typical .
5 cytotoxic systemic toxicity, including myelosuppression, severe GI toxicity
and
alopecia. Etoposide is a highly insoluble drug and therefore difficult to
formulate. The vehicle used clinically also causes adverse effects,
predominantly anaphylactic type reactions.
In this invention, etoposide was reformulated in a novel vehicle,
10 dimethylacetamide (DMA) which does not cause anaphylactic reactions. While
DMA cannot be used for IV administration due to systemic toxicity, it was
shown to be a safe delivery vehicle for the pulmonary route of delivery. The
etoposide was delivered in a 100% DMA vehicle. This formulation allowed
the formation of the appropriate particle sizes. In these tests, escalating
15 doses of etoposide were given to dogs on a weekly schedule. The initial
dose
used was 25 mg of etoposide deposited in the pulmonary region with a 6~'
and final dose delivered of 80 mg deposited within the pulmonary region.
This equated to a dose range of 50-160 mg/m2 of body surface area. This
treatment regimen caused no systemic toxicity and only minimal inflammation
20 of the lung and no overt damage of the respiratory tract. In addition,
there
was good evidence of lymphoid depletion of the thoracic lymph nodes, in the
absence of systemic changes, indicating that the drug was draining directly
through the regional lymph system. This would provide additional regional
therapeutic effectiveness in dealing with metastatic cells.
25 An additional pharmacokinetic test of inhaled etoposide showed the
drug had moderately good bioavailability. A single inhaled total deposited
dose of 260 mg/m2 (about 65 mg of drug deposited in the pulmonary region)
produced blood levels of etoposide similar to an IV dose of 50 mg/m2 (see
Figures 1-3). In other words, to reach similar blood concentrations
30 approximately 5X more drug was given by inhalation, a dose which caused
neither respiratory tract nor systemic toxicity.
50
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
Example lOF
Additional proof of concept inhalation studies involved the cytotoxic
drug 9-aminocamptothecin (9-AC) which is within tfie drug class known as
5 camptothecins. Like etoposide, 9-AC is insoluble and difFcult to formulate.
Supporting the concept and claims of this invention, the inventors generated
aerosols of 9-AC formulated as a microsuspension in an aqueous vehicle
(100% water).
These aerosols were delivered to dogs at daily doses of 40 mg/m2
10 body surface area (10 mg of drug deposited within the pulmonary region) for
3 consecutive days. Inhalation treatment produced lower drug plasma levels
than an IV dose of 10 mg/m2. The daily inhalation dose was 4 times greater
than the IV dose and the total cumulative 3 day inhalation dose was 12 times
greater than the single N dose given (which causes mild systemic toxicity).
15 Despite the significantly greater doses given by inhalation, there were no
measurable toxic effects (neither local effects within the respiratory tract
nor
systemic changes). Results from these tests supported the concept of
improved overall safety and dose-intensification within the respiratory tract
and also demonstrated the concept with aerosolized microsuspensions of
20 chemotherapeutic drugs.
Example 11F
In addition, this feasibility trial was extended to examine another
platinum-containing chemotherapeutic, carboplatin. The usual clinical
25 formulation using water was used. Carboplatin is generally considered less
toxic than cisplatin at comparable doses, and this appeared consistent with
the results seen when the two agents were delivered by inhalation. Inhaled
doses of up to 30 mg carboplatin deposited via endotracheal tube into the
lungs of dogs (60 mg/m2 total body dose) caused no evidence of either direct
30 respiratory tract or systemic toxicity.
51
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
c ,~ .~ p
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52
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/Z2845
Examples 12 to 20
These examples illustrate results of clinical treatment of dogs having
end stage lung cancer where other treatments have failed. For treatment, the
dogs were anaesthetized and the inhalation treatment was through an
5 endotracheal tube.
This preliminary trial was performed to determine whether the
inhalation chemotherapy treatment could be successfully used in animals with
lung tumors. Initially, nine dogs with neoplastic lung disease were studied. -
Three different drugs were used- doxorubicin, vincristine, cyclophosphamide,
10 cisplatin, and paclitaxel at the doses and schedules summarized in Table
12.
One 16 year old mixed breed dog had no evidence of tumor in the lung
following excision of a primary lung tumor, but did have evidence of
metastases in the hilar lymph nodes, a sign that metastases would soon
appear in the lung. However, the results showed that no metastases
15 developed in the lung for four months during which time the dog received
four treatments of inhaled doxorubicin. In six other dogs, there were
metastases in the lung and in each of these, the inhaled chemotherapy
stopped the growth of the metastases, i.e. there was stable disease (or SD).
In two dogs inhalational chemotherapy was not effective and tfiere was
20 progressive disease (or PD). Since no chemotherapy was given to these dogs
by the intravenous route, tumors outside of the lung progressed even while
the lung tumors were stabilized. Thus, the results demonstrated that
inhalational chemotherapy was effective in the local treatment of lung cancer
in the dog.
53
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
c~
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54
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
Examples 21 to 33
Additionally, tests were conducted in dogs using a defined protocol. In
these tests, dogs with either gross metastatic disease, micrometastatic
hemangiosarcoma or micrometastatic primary lung cancer were randomized
5 to receive either doxorubicin, paclitaxef or both by inhalation via an
endotracheal tube in a crossover design. Aerosol particle size was 2 - 3 Nm
as in the previous tests. The apparatus used was basically that shown in
Figure 5 and as described above. Formulations for administration of the -
drugs were as follows: 16 mg/ml doxorubicin in 70%ethanol/30%water; 75
10 mg paclitaxel in about 30% PEG/70%ethanol. Preferably the paclitaxel is
administered with 0.2% of citric acid to prevent degradation of the drug
unless it is immediately used after preparation. The treatments were
administered once every two weeks, and if a diagnosis of progressive disease
was made on two consecutive intervals the dog was crossed over to the
15 alternate drug. At each treatment session, blood was sampled for
hematology and biochemical analyses and urine was collected for analysis.
The status of the tumors was monitored radiographically.
The results are summarized in Table 13. Pulmonary deposited doses
listed in the table are based on scintigraphy studies that relate inhaled
doses
20 to deposited doses. Among the 10 dogs that had gross metastatic disease
(Examples 21-28), which is regarded as a terminal condition with a very short
life expectancy, 4 dogs (in Examples 21, 22, 24, and 27) showed stable
disease in the lung indicating that the drug was having a positive effect. In
the remaining 6 dogs (see Examples 23, 25, 26, and 28), the lung disease
25 progressed. In two of the dogs with metastatic osteosarcoma (Examples 24
and 25) and in the dog with metastatic melanoma (Example 28), there were
partial responses, i.e. there were tumors that decreased in size by more than
50%.
Four dogs had splenic hemangiosarcoma (Examples 29 and 30), a
30 disease that invariably metastasizes to the lung and is fatal within two to
four
months. These dogs were given doxorubicin by inhalation in addition to
intravenous chemotherapy to control systemic disease. The results in Table
55
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
13 show that each of the four dogs was alive (at least two months at the time
of this writing) and that there was no evidence of disease in the lung.
The last group of dogs (Examples 31 - 33) are those that had primary
lung tumors which were removed surgically. These dogs had metastases in
5 their thoracic lymph nodes and have a life expectancy measured in weeks.
As shown in Table 13, two dogs (Examples 31 and 32) received doxorubicin
by inhalation (1.5 mg) and two dogs (Example 33) received paciitaxel (20
mg). The dog that received five treatments of doxorubicin was alive with no
evidence of disease 81 days later suggesting that the treatment is having a
10 positive effect. One dog (Example 32) received two doses of doxorubicin and
died from metastases outside of the lung. The other two dogs (Example 33)
have no evidence of disease but not enough time has passed to determine
how effective the treatment will be.
The result of these tests, therefore, confirm those of the preliminary
15 tests that inhalational chemotherapy is effective in the treatment of lung
cancer.
56
CA 02346029 2001-04-02
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Table 13
Efficacy of Inhalational Chemotherapy in Dogs with t_ung Cancer
No. Inhalation
Ex. Diagnosis of Treatment* Results
D
s
21 Lung carcinoma1 DOX 5 mg (5x) SD
then
aclitaxel 60
m 2x
22 Metastatic i DOX 5 mg (2x) SD -
23 hemangiosarcomai DOX 5 mg (ix) PD
24 Metastatic i DOX 5 mg (Sx) SD (PR after 3r
+ DOX
osteosarcoma paclitaxel 60 treatment)
mg (2x)
25 " 3 DOX Smg (2x) PD.{PR in one dog)
+
aclitaxel 60
m ix
26 Metastatic 1 DOX 5 mg (2x) PD
fibrosarcoma
27 Metastatic 1 DOX 5 mg (4x) SD
+
li osarcoma aclitaxel 60
m ix
28 Metastatic 1 paclitaxel 60 PD (PR noted in
mg (2x) nodules
melanoma + < 2 cm)
DOX 5 m ix
29 Splenic 2 DOX 5mg (4x) Alive and NED
+
hemangiosarcoma systemic
chemotherapy
30 " 2 DOX 1.5 mg(3x) Alive and NED
+
systemic
chemothera
31 Primary lung 1 DOX 1.5 mg (5x) Alive and NED
tumor
32 excised- 1 DOX 1.5 mg (2x) Dead from extrapleural
micrometastatic metastases
33 disease 2 aclitaxel 20 Alive and NED
m ix
* - Deposited pulmonary doses
5 DOX = doxorubicin; ( x) = number of treatments received; SD = stable
disease; PD = progressive disease; NED = no evidence of disease;
PR = partial response (50% decrease in tumor size)
57
SUBST(ME SHEET (RULE 26)
CA 02346029 2001-04-02
WO 00/19991 PCT/US99/22845
The safe and effective range of doses of the inhalant antineoplastic
drugs in humans and animals (e.g. dogs and similar small animals) are shown
in Table 14 below. Larger animal dosages can be calculated by using
multiples of the small animal based dose based on the known relationship of
5 (body weight in kg/m2 of body surface area. The exact doses will vary
depending upon such factors as the type and location of the tumor, the age
and size of the patient, the physical condition of the patient and concomitant
therapies that the patient may require. The dosages shown are for doses for
one course of therapy, that is, for an individual treatment session. A course
10 of therapy may be given, monthly, weekly, biweekly, triweekly or daily
depending on the drug, patient, type of disease, stage of the disease and so
on. Exemplary safe and effective amounts of carrier for each product have
been published by the respective manufacturer and are summarized in the
Physicians Desk Reference, although, some may not be amenable to
15 inhalation therapy.
Table 14
Drug Animal Dose*Human
m mz Dose* m
m2
Doxorubicin 2 to 90 3 to 130
Paclitaxel 6 to 270 10 to 250
Vincristine 0.06 to 2 0.1 to 3
Vinorelbine 1.3 to 60 2 to 90
Cisplatin 4.6 to 200 7 to 300
Etoposide 4.6 to 200 7 to 300
Carboplatin 15 to 400 20-600
9-Aminocampothecin 2.6 to 10 0.04 to
15
* - m' body surface area
20 Based on the results of the inhalation tests herein with doxorubicin,
inhalation treatments with anthracyciines in addition to doxorubicin are also
expected to be well tolerated and efficacious when administered by the
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pulmonary route. Based on the inhalation tests herein with vincristine and
vinorelbine, other vinca alkaloids are expected to be well tolerated and
efficacious when administered by the pulmonary route. Based on the
inhalation tests herein for the vesicants doxorubicin, vincristine,
vinorelbine,
5 and paciitaxel, all of which are capable of serious vesicating injuries,
other
vesicating drugs (e.g. mechlorethamine, dactinomycin, mithramycin,
bisantrene, amsacrine, epirubicin, daunorubicin, idarubicin, vinblastine,
vindesine, and so on) are expected to be well tolerated and efficacious when
administered by the pulmonary route. The exception, of course, would be
10 vesicant drugs that are known to exhibit significant pulmonary toxicity
when
administered by N (e.g. mitomycin-C). In this regard, a safe and effective
amount of a particular drug or agent is that amount which based on its
potency and toxicity, provides the appropriate effcacy/risk balance when
administered via pulmonary means in the treatment of neoplasms. Similarly a
15 safe and effective amount of a vehicle or carrier is that amount based on
its
solubility characteristics, stability, and aerosol forming characteristics,
that
provides the required amount of a drug to the appropriate site in the
pulmonary system for treatment of the neoplasm.
For the nonvesicant antineoplastic drugs, based on the inhalation tests
20 herein for the vesicating and nonvesicating drugs it is expected that all
the
nonvesicating drugs that do not exhibit direct pulmonary toxicity when
administered intravenously are expected be well tolerated and exhibit
efficacy. Bleomycin and mitomycin-C, for example, exhibit sufficient
pulmonary toxicity to be excluded except when a chemoprotectant is used. In
25 this regard typically carmustine, dacarbazine, melphalan, methotrexate,
mercaptopurine, mitoxantrone, esorubicin, teniposide, aclacinomycin,
plicamycin, streptozocin, menogaril are expected to be well tolerated and
exhibit efficacy. Similarly, drugs of presently unknown classification such as
geldanamycin, bryostatin, suramin, carboxyamido-triazoles such as those in
30 US patent 5,565,478, onconase, and SU101 and its active metabolite SU20
are likewise expected to be well tolerated and exhibit efficacy subject to the
limitation on pulmonary toxicity. These drugs would be administered by the
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same methods disclosed for the tested antineoplastic drugs. They would be
formulated with a safe and effective amount of a vehicle and administered in
amounts and in a dosing schedule safe and effective for treating the
neoplastic disease.
5 Pulmonary toxicity of compounds to be administered by inhalation is an
important consideration. As mentioned above one of the major
considerations is whether the drug exhibits significant pulmonary toxicity
when injected by IV. While almost all antineoplastic drugs are toxic to the -
body and thus arguably exhibit pulmonary toxicity if given in a large enough
10 dose, the test for pulmonary toxicity as used herein requires significant
pulmonary toxicity at the highest manufacturers recommended dose that is to
be administered to a patient. The determination of whether a drug exhibits
sufficient pulmonary toxicity by IV so as to exclude it from the group of
drugs
useful for pulmonary administration can be made from the drug
IS manufacturers recommendations as published in the Physicians Desk
Reference (see "Physicians Desk Reference" 1997, (Medical Economics Co.),
or later editions thereof), in other drug manuals published for health care
providers, publicly available filings of the manufacturer with the FDA, or in
literature distributed directly by the manufacturers to physicians, hospitals,
20 and the like. For example in the "Physicians Desk Manual" 1997:
~ Doxorubicin {Astray pp. 531-533 - vesicant, there is no indication of
pulmonary toxicity while cardiac toxicity, hematologic toxicity particularly
leukopenia and myelosuppression; extravasation injuries are also noted;
~ Idarubicin (Pharmacia & Upjohn) pp 2096-2099 - vesicant, primary
25 toxicity appears to be myelosuppression no mention is made of pulmonary
toxicity making the drug useful in the present invention;
Etoposide (Astray pp539-541 - no indication of pulmonary toxicity, but
dose limiting hematologic toxicity is important;
~ Paclitaxel (Bristol-Meyers Squibb) pp. 723-727 - vesicant, pulmonary
30 toxicity is not listed for paclitaxel, but dose limiting bone marrow
suppression (primarily neutropenia) is important;
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~ Bleomycin (Blenoxane~ Bristol-Meyers Squibb) pp. 697-699 , pulmonary
toxicities occur in about 10% of treated patients by IV administered drug,
this makes bleomycin unacceptable for pulmonary administration for the
present invention;
5 ~ Mitomycin C (Mutamycin~ Bristol-Meyers Squibb) - vesicant, infrequent
but severe life threatening pulmonary toxicity has occurred by IV
administration, this although infrequent severe life threatening pulmonary
toxicity shows that the drug exhibits substantial pulmonary toxicity;
~ Methotrexate (Immunex) pp. 1322-1327 - MW=454, primary toxicity
10 appears to be hepatic and hematologic, signs of pulmonary toxicity should
be closely monitored for signs of lesions;
~ Dactinomycin (Merck & Co.) - vesicant, primary toxicity appears to be oral,
gastrointestinal, hematologic, and dermologic; no mention is made of
pulmonary toxicity making the drug acceptable in the present invention;
15 ~ mechlorethamine (Merck & Co.) - vesicant, primary toxicity appears to be
renal, hepatic and bone marrow, no mention is made of pulmonary toxicity
making the drug acceptable in the present invention;
~ Irinotecan (Camptosar~ Pharmacia & Upjohn) - a derivative of
camptothecin, primary toxicity appears to be severe diarrhea and
20 neutropenia, no mention is made of pulmonary toxicity making the drug
useful in the present invention;
~ Vincristine (Oncovin~ Lilly) pp. 1521-1523 - extremely toxic with high
vesicant activity found in the tests herein, but no pulmonary toxicity
noted;
25 ~ Vinblastine (Velban~ Lilly) pp.1537-1540 - extremely toxic with high
vesicant activity found in the tests herein, but no pulmonary toxicity noted.
The above listing is exemplary only and is not intended to limit the scope of
the invention.
An additional embodiment of the invention includes methods and
30 formulations that contain chemoprotectants and are administered by
inhalation for preventing toxicity and particularly pulmonary toxicity that
may
be elicited by antineoplastic drugs. The method would allow the use by
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inhalation of antineoplastic drugs that exhibit pulmonary toxicity or would
reduce the likelihood of pulmonary toxicity. One method would include
treating a patient having a neoplasm, via inhalation administration, a
pharmaceutically effective amount of a highly toxic antineoplastic drug and a
5 pharmaceutically effective amount of a chemoprotectant, wherein the
chemoprotectant reduces or eliminates toxic effects in the patient that are a
result of inhaling the highly toxic antineoplastic drug. More narrowly,
another
embodiment includes a combination of inhaled chemoprotectant and
antineoplastic drug that reduces or eliminates respiratory tract or pulmonary
10 tract toxicity in the patient. The chemoprotectant can be coadministered
with
the antineoplastic drug by inhalation, or both by inhalation and by IV, or the
chemoprotectant can be administered alone.
It is known, for example, that dexrazoxane (ICRF-187) when given by
intraperitoneal injection to mice is protective against pulmonary damage
15 induced by bleomycin given by subcutaneous injections. See for example
Herman, Eugene et al, ~~Morphologic and morphometric evaluation of the
effect of ICRF-187 on bleomycin-induced pulmonary toxicity", Toxicology 98,
(1995) pp: 163-175, the text of which is incorporated by reference as if fully
rewritten herein. The mice pretreated with intraperitoneal injections of
20 dexrazoxane prior to having bleomycin injected subcutaneously showed
reduced pulmonary alterations particularly fibrosis compared to another group
of mice that was not pretreated.
The following examples illustrate the use of a chemoprotectant by inhalation
in conjunction with an antineoplastic drug.
25
Example 34
Dexrazoxane (ICRF-187) is dissolved in a pharmaceutically acceptable
liquid formulation and administered to a patient as an aerosol using the
apparatus and methods described herein, at a dose ranging from 10 mg to
30 1000 mg over a period of from one minute to one day prior to giving a
chemotherapeutic drug such as doxorubicin by inhalation. The doxorubicin is
given in a dose from 1 mg to 50 mg.
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Example 35
Dexrazoxane (ICRF-187) is administered as described in Example 34 at
the same time or up to two hours before giving bleomycin by intravenous
5 injection. The dose of dexrazoxane ranges form about 2 times to about 30
times the dose of bleomycin. The dose of bleomycin by N ranges from about
5 to 40 units/mz.
Example 36
i0 Dexrazoxane (ICRF-187) is administered as described in Example 34 at the
same time or up to two hours before administering bleomycin by inhalation.
The dose of dexrazoxane ranges from about 2 times to about 30 times the
dose of bleomycin. The dose of bleomycin by inhalation ranges from 5 to 40
units/m2 at intervals of from 1 week to 4 weeks.
15
Examples 37 and 38
Chemoprotectants such as mesna (ORG-2766), and ethiofos {WR2721) may
be used in a manner similar to that described in Examples 34 to 36, above.
20 Combination Therapy
Another embodiment of the invention contemplates drug
coadministration by the pulmonary route, and by (1) other local routes,
and/or (2) systemically by IV. Results from the clinical tests on dogs
indicates
that, although the pulmonary route of administration will indeed control
25 neoplastic cells arising in or metastatic to the pulmonary tract,
neoplastic cells
elsewhere in the body may continue to proliferate. This embodiment provides
for effective doses of drug in the lung delivered via the lung and additional
drug delivered via (1) other local sites (e.g. liver tumors may also be
treated
via hepatic artery instillation, ovarian cancer by intxaperitoneal
administration)
30 and/or additional drugs) may be provided systemically by IV via the general
circulatory system. Administration can be at the same time, or administration
followed closely in time by one or more of the other therapeutic routes.
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Benefits are that much higher dosages can be supplied to affected tissues and
effective control of neoplasms can be maintained at multiple critical sites
compared to using a single mode of administration.
Also contemplated within the scope of the invention is the combination
5 of drugs for combination chemotherapy treatment. Benefits are those wel!
known in the treatment of cancer using combination chemotherapy by other
routes of administration. For example, combining drugs with different
mechanisms of action such as an alkylating agent plus a mitotic poison plus a
topoisomerase inhibitor. Such combinations increase the likelihood of
10 destroying tumors that are comprised of cells with many different drug
sensitivities. For example, some are easily killed by alkylating agents while
mitotic poisons kill others more easily.
Also included in the invention are embodiments comprising the method
for inhalation therapy disclosed herein and the application of radiotherapy,
15 gene therapy, and/or immunotherapy. Other embodiments include the
immediately above method combined with chemotherapy applied by IV and/or
local therapy.
Also included within the invention are formulations for paclitaxel. In
these formulations 100% to 40% ethanol is useful. However, to obtain better
20 control of particle size and stable aerosol generation the addition of
polyethylene glycol (PEG) is preferred. Although 1-60% PEG can be used
about 8-40% PEG is more preferred, and 10-30% PEG was found to be
optimal. A further embodiment also includes the addition of 0.01 to 2% of an
organic or inorganic acid, preferably an organic acid such as citric acid and
the
25 like. The acid being added to stabilize the formulation. With regard to
clinical
use in inhalation, citric acid in water has been found to cause tussive and
bronchioconstrictive effects. PEG may ameliorate this effect. The formulation
contains a safe and effective amount of paclitaxel useful for the treatment of
neoplasms.
30
Prevention of Metastasis
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Applicants have surprisingly discovered that metastasis of cancer cells
to the lung can be effectively prevented by a combined chemotherapeutic
regimen. While the tests herein have demonstrated that neoplasms can
effectively be treated via pulmonary administration by the methods and
formulations described herein, additional tests described below demonstrate
that a combined chemotherapeutic regimen can effectively prevent pulmonary
metastasis rather than merely slow the growth of metastatic tumors or
ameliorate the effects thereof.
Splenic hemangiosarcoma is recognized as disease that almost
10 invariably results in metastatic disease with a very high incidence of
metastases in the lung. For the tests herein dogs with micrometastatic
splenic hemangiosarcoma underwent surgery (splenectomy) to remove the
primary tumor followed by inhalation chemotherapy with concomitant or
concurrent systemic chemotherapy. Dogs selected for the tests were selected
15 to have no signs of metastasis to the lung or gross abdominal metastasis as
determined by radiographic techniques. Each dog was exposed to inhalation
to an aerosol concentration of an antineoplastic drug that would deposit drug
in the pulmonary region (based on a 65 percent deposition fraction).
The dogs underwent surgical excision of the primary tumors
20 (splenectomy). About two weeks following surgery, they were scheduled to
receive four cycles of standard systemic chemotherapy (30 mg/mz IV and
cyclophosphamide 150 mg/m2 IV) at about three week intervals. Concurrent
with systemic therapy, they were scheduled to receive four treatments of
doxorubicin inhalation therapy. Follow up thoracic radiographs and abdominal
25 ultrasounds were performed prior to the last treatment and every two months
thereafter. Important points such as percentage of dogs with lung tumors
and median survival time in days were compared with historical controls
receiving only surgical excision and systemic doxorubicin/cylcophosphamide
therapy as published in Clinical Cancer Research, David M. Vail et al, Vo1 1:
30 pp. 1165-1170 (Oct., 1995).
Referring to Table 15, details of the aforementioned treatments are
listed. The eight dogs tested were dogs that had spontaneously arising
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cancers. The dogs are designated A through M with the letters M or F after
this designation referring to male or female respectively, N stands for
neutered, and the last number is the age in years. The dogs were mostly
older dogs the youngest being 4 years old and the oldest 14 years (average
5 and median ages were both 10). The dogs were a variety of breeds with the
weight ranging from 2 to 49 kg. The actual method of treatment for the tests
of Table 15 were as follows: (a) the primary tumor was treated by surgical
excision; (b) following surgical excision (two weeks after surgery) the dogs
are scheduled to receive four cycles of standard systemic chemotherapy
10 (doxorubicin 30 mg/m2 IV and cyclophosphamide 150 mg/mZ IV) at three
week intervals (Note: one dog was treated on the day of surgery with
doxorubicin by inhalation with the remainder of the dogs being treated about
two weeks later); (c) concurrent with systemic therapy, the dogs receive four
treatments of doxorubicin inhalation therapy. It is noted Those skilled in the
15 art will appreciate that the methods presented herein, although only tested
on
dogs, will have general applicability to humans and other animals. It is noted
that the original calculated dose actually delivered to the dog appeared to be
about 10 mg doxorubicin. Recent tests however, indicate that the actual dose
was about 1 mg/mZ based on body surface area, per treatment.
20 Generally the method for treating a patient for a neoplasm and
preventing pulmonary metastasis includes the steps of (a) treating the patient
for the neoplasm wherein the treatment is selected from the group consisting
of partial or complete surgical excision, radiation therapy, local-regional
chemotherapy, immunotherapy, gene therapy and combinations thereof;
25 (b) administering an effective amount of systemic chemotherapy; and (c)
concurrently administering an effective amount of chemotherapy by
inhalation. Concurrently means that the two treatment regimes are given
close enough in time that the effect of the two treatments is greater than
that
of either alone or when given in greatly spaced apart treatments. That is the
30 two treatments synergistically interact to increase the efficacy of
treatment.
The present tests show that surgical excision is an effective part of the
treatment process, however the other treatment modalities listed above are
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CA 02346029 2001-04-02
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also considered to be efficacious in the present method. Local-regional
chemotherapy as used above includes for example local treatments such as
injections of antineoplastic drugs into the tumor, the organ (e.g. prostate)
or
spine , infusions into the bladder, and the like. Systemic chemotherapy
5 includes parenteral administration wherein the administered drug enters the
general circulation. The best example of systemic chemotherapy is of course
intravenous injection of antineoplastic drugs, however, other methods of
parenteral administration can result in effective systemic distribution of the
drugs. An efFective amount of systemic chemotherapy and an effective
10 amount of chemotherapy by inhalation is considered to be the level of
antineoplastic drug administered by each mode that results in elimination of
metastasis or at least reduced incidence of metastasis.
As will be appreciated by those skilled in the art, the elimination or
reduction of the incidence of metastatic cancers arising in the lung increases
15 survival time because the lung is an organ that if compromised results in
death fairly quickly. The present invention greatly increases the percentage
of animals that are free of cancers arising from metastasis to the lung. In
addition survival time is increased even though the animals succumbed to
disease outside the lung.
20 Referring now to Figure 8 and Table 15 it is apparent that there is a
fairly large decrease in the percentage of dogs having metastatic cancers in
the lung when compared to the data in Vail et al. One dog in the present test
that had been thought to have evidence of metastasis on necropsy, dog A,
was found on reevaluation not to have evidence of metastasis. However, dog
25 F as further discussed below did have microscopic evidence of metastasis.
Of the fourteen dogs entered in the tests shown in Table 15, ten have
completed therapy (one dog - F) received three of four scheduled treatments
due to the development of pneumonia which resolved), and four dogs are
presently receiving inhalation treatments. Of the fourteen dogs, six have died
30 of disease (survival was 149, 115, 310, 440, 123 and 156 days), one died of
an unrelated cause at 76 days, and seven are alive and free of disease at 615,
441, 94, 87, 47, 46, and 39 days.
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points for dogs treated with surgery and concomitant intravenous therapy and
inhalation chemotherapy (IV and IC) are shown as squares. The results so
far reveal that the median survival time for surgery and IV treatment is 148
days. in comparison, the median survival time for surgery and concomitant
5 IV and inhalation therapy is 233 days. The calculated statistical
significance
of this data is P = 0.22. The data for the two groups as shown in Figure 8
effectively reveals the significant increase in survival time for the dogs
receiving surgery and concomitant IV and inhalation therapy treatments. It is
further important to note that of the six dogs that died of metastasis to
other
10 sites in the body, evidence (microscopic only) of pulmonary involvement was
found at necropsy in only one dog, dog F, that had treatment delays due to
pneumonia. This rate of 16 % compares favorably with historical controls
such as that by Vail
Concomitant or concurrent chemotherapy by systemic and inhalation
15 modes of administration contemplates administration such that the two
modes of administration have a synergistic effect when used together
compared to either being used alone. This is usually obtained by
administration of the antineoplastic drugs close in time. Thus a preferred
method of administration is to have the drugs administered by inhalation and
20 systemically at the same time or approximately the same time. Thus
chemotherapy by inhalation could be administered shortly before, during, or
after systemic chemotherapy. Preferably the drugs are administered by each
mode within one week of each other and most preferably within a few days or
the same day. Those skilled in the art will appreciate that the exact timing
of
25 administration will be determined in part by the particular disease
response
and mode of action of antineoplastic drug.
The dosages for IV administration when used in combination with
inhalation therapy as described herein are typically those usually used for
current treatment by IV alone. Dosages for IV administration for particular
30 drugs may be determined from the Physicians Desk Reference cited above.
While the forms of the invention herein disclosed constitute presently
preferred embodiments, many others are possible. It is not intended herein
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to mention all of the possible equivalent forms or ramifications of the
invention. It is to be understood that the terms used herein are merely
descriptive, rather than limiting, and that various changes may be made
without departing from the spirit of the scope of the invention.
69
CA 02346029 2001-04-02
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