U.S. patent application number 09/875680 was filed with the patent office on 2001-11-08 for formulation and method for treating neoplasms by inhalation.
Invention is credited to Brooker, Michael J., Donovan, Maureen D., Flanagan, Douglas R. JR., Frye, John E., Imondi, Anthony R., Placke, Michael E., Shah, Praful K..
Application Number | 20010038827 09/875680 |
Document ID | / |
Family ID | 21872447 |
Filed Date | 2001-11-08 |
United States Patent
Application |
20010038827 |
Kind Code |
A1 |
Placke, Michael E. ; et
al. |
November 8, 2001 |
Formulation and method for treating neoplasms by inhalation
Abstract
A formulation, method, and apparatus for treating neoplasms such
as cancer by administering a pharmaceutically effective amount of
highly toxic composition by inhalation, wherein the composition is
a non-encapsulated antineoplastic drug.
Inventors: |
Placke, Michael E.;
(Columbus, OH) ; Imondi, Anthony R.; (Westerville,
OH) ; Brooker, Michael J.; (Westerville, OH) ;
Frye, John E.; (Groveport, OH) ; Shah, Praful K.;
(Hilliard, OH) ; Flanagan, Douglas R. JR.; (Iowa
City, IA) ; Donovan, Maureen D.; (Solon, IA) |
Correspondence
Address: |
BATTELLE MEMORIAL INSTITUTE
505 KING AVENUE
COLUMBUS
OH
43201-2693
US
|
Family ID: |
21872447 |
Appl. No.: |
09/875680 |
Filed: |
June 6, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09875680 |
Jun 6, 2001 |
|
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09000775 |
Dec 30, 1997 |
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60033789 |
Dec 30, 1996 |
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Current U.S.
Class: |
424/43 ; 424/649;
514/283; 514/34; 514/449 |
Current CPC
Class: |
A61K 31/00 20130101;
A61P 35/00 20180101; A61K 9/0073 20130101 |
Class at
Publication: |
424/43 ; 424/649;
514/34; 514/283; 514/449 |
International
Class: |
A61K 033/24; A61K
009/00 |
Claims
We claim:
1. A formulation for treating a patient for a neoplasm by
inhalation comprising: an effective amount of a vesicant and a
pharmaceutically acceptable carrier, wherein said vesicant does not
exhibit substantial pulmonary toxicity.
2. The formulation according to claim 11 wherein said vesicant
comprises a moderate vesicant.
3. The formulation according to claim 1, wherein said vesicant
comprises paclitaxel and carboplatin.
4. The formulation according to claim 1, wherein said moderate
vesicant comprises: a non-encapsulated anticancer drug, wherein
when 0.2 ml of said drug is injected intradermally to rats, at the
clinical concentration for parenteral use in humans: (a) a lesion
results that is at least 20 mm.sup.2 in area fourteen days after
said intradermal injection; and (b) at least 50% of the tested rats
have this size of lesion.
5. The formulation according to claim 1, wherein said vesicant
comprises a severe vesicant.
6. The formulation according to claim 1, wherein said vesicant
comprises a severe vesicant selected from the group comprising
doxorubicin, vincristine, and vinorelbine.
7. The formulation according to claim 1, wherein said neoplasm is a
pulmonary neoplasm, a neoplasm of the head and neck, or other
systemic neoplasm.
8. The formulation according to claim 1, wherein said drug is in
the form of a liquid, a powder, a liquid aerosol, or a powdered
aerosol.
9. The formulation according to claim 1, wherein said drug
comprises tubulin inhibitors.
10. The formulation according to claim 1, wherein said drug
comprises alkylating agents.
11. The formulation according to claim 1, wherein said drug
comprises an anthracycline.
12. The formulation according to claim 11, wherein said
anthracycline is selected from the group consisting of epirubicin,
daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyl
doxorubicin, doxorubicin, and idarubicin.
13. The formulation according to claim 12, wherein when doxorubicin
is selected said effective amount of said drug for animals is about
2 to 90 mg/m.sup.2 and the human dose is about 3 to 130 mg/m.sup.2,
wherein both doses are based on body surface area.
14. The formulation according to claim 1, wherein said drug is a
vinca alkaloid.
15. The formulation according to claim 14, wherein said vinca
alkaloid is selected from the group consisting of vincristine,
vinorelbine, vinorelbine, vindesine, and vinblastine.
16. The formulation according to claim 15, wherein when vincristine
is selected the animal dose is about 0.06 to 2 mg/m.sup.2 and the
human dose is about 0.1 to 3 mg/M.sup.2; and when vinorelbine is
selected animal dose is about 1.3 to about 60 mg/m.sup.2 and the
human dose is about 2 to 90 mg/m.sup.2, wherein all doses are based
on body surface area.
17. The formulation according to claim 1, wherein said drug is a
vesicant selected from the group consisting of mechlorethamine,
mithramycin, and dactinomycin.
18. The formulation according to claim 1, wherein said drug is
bisantrene.
19. The formulation according to claim 1, wherein said drug is
amsacrine.
20. The formulation according to claim 1, wherein said drug is a
taxane.
21. The formulation according to claim 1, wherein said drug is
paclitaxel.
22. The formulation according to claim 21, wherein the animal dose
is 6 to 90 mg/m.sup.2, and the human dose is 10 to 400 mg/m.sup.2,
wherein both doses are based on body surface area.
23. A formulation for treating a patient having a neoplasm by
inhalation comprising: (1) a safe and effective amount of a
non-encapsulated antineoplastic drug having a molecular weight
above 350, that does not exhibit substantial pulmonary toxicity;
and (2) an effective amount of a pharmaceutically acceptable
carrier.
24. The formulation according to claim 23, wherein said neoplasm is
a pulmonary neoplasm, a neoplasm of the head and neck, or a
systemic neoplasm.
25. The formulation according to claim 23, wherein said drug is in
the form of a liquid, a powder, a liquid aerosol, or a powdered
aerosol.
26. The formulation according to claim 23, wherein said drug has a
protein binding affinity of 25% or more.
27. The formulation according to claim 26, wherein said drug has a
protein binding affinity of 50% or more.
28. The formulation according to claim 23, wherein said drug has a
molecular weight above 400.
29. A formulation for treating a patient for a neoplasm by
inhalation comprising: a safe and effective amount of a taxane in
an effective amount of vehicle comprising polyethyleneglycol (PEG)
and an alcohol.
30. The formulation according to claim 29, further comprising an
acid, said acid present in amount effective to stabilize said
taxane.
31. The formulation according to claim 29, wherein said alcohol is
ethanol.
32. The formulation according to claim 29, wherein said acid is an
organic acid.
33. The formulation according to claim 29, wherein said acid is
citric acid.
34. The formulation according to claim 29, wherein said taxane
comprises paclitaxel.
35. The formulation according to claim 34, comprising about 8% to
40% polyethyleneglycol, about 90% to 60% alcohol, and about 0.01%
to 2% acid.
36. The formulation according to claim 35 wherein said safe and
effective amount provides an animal dose of about 6 to about 90
mg/m.sup.2 and a human dose of about 10 to 400 mg/m.sup.2, wherein
said dose is based on body surface area.
37. A formulation for treating a patient for a neoplasm by
inhalation comprising: a safe and effective amount of a drug
selected from the group consisting of carmustine, dacarbazine,
melphalan, mercaptopurine, mitoxantrone, esorubicin, teniposide,
aclacinomycin, plicamycin, streptozocin, and menogaril; and a safe
and effective amount of a pharmaceutically effective carrier,
wherein said drugs do not exhibit substantial pulmonary
toxicity.
38. A formulation for treating a patient for a neoplasm by
inhalation comprising: a safe and effective amount of a drug
selected from the group consisting of estramustine phosphate,
geldanamycin, bryostatin, suramin, carboxyamido-triazoles;
onconase, and SU101 and its active metabolite SU20; and a safe and
effective amount of a pharmaceutically effective carrier, wherein
said drugs do not exhibit substantial pulmonary toxicity.
39. A formulation for treating a patient for a neoplasm by
inhalation comprising: a safe and effective amount of etoposide and
a DMA carrier.
40. The formulation according to claim 39, wherein said formulation
provides an animal dose of about 4.6 to 200 mg/m.sup.2 and a human
dose of about 7 to 300 mg/m.sup.2, wherein said doses are base on
body surface area.
41. A formulation for treating a patient for a neoplasm by
inhalation comprising: a safe and effective amount of a
microsuspension of 9-aminocamptothecin in an aqueous carrier.
42. The formulation according to claim 39, wherein said formulation
provides an animal dose of about 2.6 to 10 mg/m.sup.2 and a human
dose of about 0.04 to 15 mg/m.sup.2, wherein said doses are base on
body surface area.
43. A formulation for treating a patient having a neoplasm
comprising: administering to said patient by inhalation, (1) an
effective amount of a highly toxic antineoplastic drug; and (2) an
effective amount of a chemoprotectant, wherein said chemoprotectant
reduces or eliminates toxic effects in said patient that are a
result of administering said highly toxic antineoplastic drug.
44. The formulation according to claim 43, wherein said
chemoprotectant reduces or eliminates systemic toxicity in said
patient.
45. The formulation according to claim 43, wherein said
chemoprotectant reduces or eliminates respiratory tract toxicity in
said patient.
46. The formulation according to claim 43, wherein said
chemoprotectant comprises dexrazoxane (ICRF-187), mesna (ORG-2766),
ethiofos (WR2721), or a mixture thereof.
47. The formulation according to claim 43, wherein said
chemoprotectant is administered before, after, or during said
administration of said antineoplastic drug.
48. The formulation according to claim 43, wherein said
antineoplastic drug comprises a nonvesicant.
49. The formulation according to claim 43, wherein said
antineoplastic drug comprises a moderate vesicant.
50. The formulation according to claim 43, wherein said
antineoplastic drug comprises a severe vesicant.
51. The formulation according to claim 43, wherein said
antineoplastic drug comprises bleomycin.
52. The formulation according to claim 43, wherein said
antineoplastic drug comprises doxorubicin.
53. The formulation according to claim 43, wherein said
antineoplastic drug comprises mitomycin-C.
54. A method for treating a patient having a neoplasm comprising:
administering to said patient by inhalation, (1) an effective
amount of a highly toxic antineoplastic drug; and (2) an effective
amount of a chemoprotectant, wherein said chemoprotectant reduces
or eliminates toxic effects in said patient that are a result of
administering said highly toxic antineoplastic drug.
55. The method according to claim 54, wherein said chemoprotectant
reduces or eliminates systemic toxicity in said patient.
56. The method according to claim 54, wherein said chemoprotectant
reduces or eliminates respiratory tract toxicity in said
patient.
57. The method according to claim 54, wherein said chemoprotectant
comprises dexrazoxane (ICRF-187), mesna (ORG-2766), ethiofos
(WR2721), or a mixture thereof.
58. The method according to claim 54, wherein said chemoprotectant
is administered before, after, or during said administration of
said antineoplastic drug.
59. The method according to claim 54, wherein said antineoplastic
drug comprises a nonvesicant.
60. The method according to claim 54, wherein said antineoplastic
drug comprises a moderate vesicant.
61. The method according to claim 54, wherein said antineoplastic
drug comprises a severe vesicant.
62. The method according to claim 54, wherein said antineoplastic
drug comprises bleomycin.
63. The method according to claim 54, wherein said antineoplastic
drug comprises doxorubicin.
64. The method according to claim 54, wherein said antineoplastic
drug comprises mitomycin-C.
65. A method for treating a patient having a neoplasm comprising:
administering a pharmaceutically effective amount of a
non-encapsulated antineoplastic drug to said patient by inhalation,
said drug selected from the group consisting of antineoplastic
drugs wherein when 0.2 ml of said drug is injected intradermally to
rats, at the clinical concentration for IV use in humans: (a) a
lesion results which is greater than 20 mm.sup.2 in area fourteen
days after said intradermal injection; and (b) at least 50% of the
tested rats have these lesions.
66. The method according to claim 65, wherein when said drug is
doxorubicin or vinblastine sulfate, said drug is inhaled in the
absence of perfluorocarbon.
67. The method according to claim 65, wherein said neoplasm is a
pulmonary neoplasm, a neoplasm of the head and neck, or other
systemic neoplasm.
68. The method according to claim 65, wherein said drug is inhaled
as a liquid aerosol or as a powdered aerosol.
69. The method according to claim 65, wherein said patient is a
mammal.
70. The method according to claim 65, wherein said patient is a
human.
71. The method according to claim 65, wherein said drug is an
anthracycline selected from the group consisting of doxorubicin,
daunorubicin, methoxymorpholinodoxorubicin, epirubicin,
cyanomorpholinyl doxorubicin, and idarubicin.
72. The method according to claim 65, wherein said drug is a vinca
alkaloid.
73. The method according to claim 65, wherein said drug is selected
from the group consisting of vincristine, vinorelbine, vindesine,
and vinblastine.
74. The method according to claim 65, wherein said drug is selected
from the group consisting of mechlorethamine, mithramycin and
dactinomycin.
75. The method according to claim 65, wherein said drug comprises
bisantrene.
76. The method according to claim 65, wherein said drug comprises
amsacrine.
77. The method according to claim 65, wherein said drug comprises a
taxane.
78. The method according to claim 77, wherein said taxane comprises
doxitaxel.
79. The method according to claim 77, wherein said drug comprises
paclitaxel.
80. A method for treating a patient having a neoplasm comprising:
administering an effective amount of a highly toxic
non-encapsulated antineoplastic drug to a patient by inhalation,
wherein the molecular weight of said drug is above 350, and said
drug has no substantial pulmonary toxicity.
81. The method according to claim 80, wherein said neoplasm is a
pulmonary neoplasm, a neoplasm of the head and neck, or a systemic
neoplasm.
82. The method according to claim 80, wherein said drug is inhaled
as a liquid aerosol or as a powdered aerosol.
83. The method according to claim 80, wherein said drug has a
protein binding affinity of 25% or more.
84. The method according to claim 83, wherein said drug has a
protein binding affinity of 50% or more.
85. The method according to claim 80, wherein said drug is selected
from the group comprising doxorubicin, epirubicin, daunorubicin,
methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, and
idarubicin.
86. The method according to claim 80, wherein said drug is a vinca
alkaloid administered without the presence of a
perfluorocarbon.
87. The method according to claim 80, wherein said drug is selected
from the group consisting of vincristine, vinorelbine, vindesine,
and vinblastine.
88. The method according to claim 80, wherein said drug is
mechlorethamine, mithramycin, or dactinomycin.
89. The method according to claim 80, wherein said drug is
bisantrene or amsacrine.
90. The method according to claim 80, wherein said drug is
doxytaxel or paclitaxel.
91. The method according to claim 80, wherein said patient is a
mammal.
92. The method according to claim 80, wherein said patient is a
human.
93. A method for treating a patient for a neoplasm comprising:
administering an effective amount of an antineoplastic drug to said
patient by inhalation; and administering a pharmaceutically
effective amount of the same and/or different antineoplastic drug
to said patient parenterally.
94. The method according to claim 93, wherein said patient also is
treated by radiotherapy.
95. The method according to claim 93, wherein said patient is also
treated with immunotherapy.
96. The method according to claim 93, wherein said patient is also
treated with gene therapy.
97. The method according to claim 93, wherein said patient is also
administered chemoprotective drugs.
98. The method according to claim 93 wherein said patient is also
administered chemopreventive drugs.
99. A method for treating a patient for a neoplasm comprising:
administering an effective amount of an antineoplastic drug to said
patient by inhalation; and administering an effective amount of the
same and/or different antineoplastic drug to said patient by
isolated organ perfusion.
100. The method according to claim 99, wherein said patient is a
mammal.
101. The method according to claim 99, wherein said patient is a
human.
102. The method according to claim 99, wherein said patient is also
treated by radiotherapy.
103. The method according to claim 99, wherein said patient is also
treated by immunotherapy.
104. The method according to claim 99, wherein said patient is also
treated by gene therapy.
105. The method according to claim 99, wherein said patient is also
administered chemoprotective drugs.
106. The method according to claim 99, wherein said patient is also
administered chemopreventive drugs.
107. A method for treating a patient for a pulmonary neoplasm
comprising: (1) selecting one or more antineoplastic drugs
efficacious in treating said neoplasm and having a residence time
in the pulmonary mucosa sufficient to be efficacious in the
treatment of said pulmonary neoplasm; and (2) administering said
drug(s) to said patient by inhalation in a non-encapsulated
form.
108. The method according to claim 107, wherein when 0.2 ml of said
or at least one of said drugs is injected intradermally to rats, at
the clinical concentration for parenteral use in humans: A. a
lesion results which is greater than 20 mm.sup.2 in area fourteen
days after said intradermal injection; and B. at least 50% of the
tested rats have these lesions.
109. The method according to claim 108, wherein said formulation
results in a lesion which is greater than about 10 mm.sup.2 in area
30 days after said intradermal injection; and at least about 50% of
the tested rats have these longer lasting lesions.
110. The method according to claim 107, wherein the molecular
weight of at least one of said selected drugs is above 350.
111. The method according to claim 107, wherein said patient is a
mammal.
112. The method according to claim 107, wherein said patient is a
human.
113. A method of use, comprising the administration of one or more
non-encapsulated highly toxic anticancer drugs to a mammal by
inhalation, wherein at least one of said drugs comprises a severe
vesicant.
114. An apparatus for treating a patient for a neoplasm by
inhalation comprising: in combination a nebulizer and a formulation
for treating a neoplasm comprising: (1) a non-encapsulated
anticancer drug, and (2) a pharmaceutically acceptable carrier;
wherein when 0.2 ml of said formulation is injected intradermally
to rats, at the clinical concentration for parenteral use in
humans: (a) a lesion results which is greater than about 20
mm.sup.2 in area fourteen days after said intradermal injection;
and (b) at least 50% of the tested rats have these lesions.
115. The apparatus according to claim 114, wherein said formulation
results in a lesion which is greater than about 10 mm in area 30
days after said intradermal injection; and at least about 50% of
the tested rats have these longer lasting lesions.
116. The apparatus according to claim 114, wherein said formulation
further comprises an anthracycline.
117. The apparatus according to claim 116, wherein said
anthracycline is selected from the group consisting of epirubicin,
daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyl
doxorubicin, doxorubicin, and idarubicin.
118. The apparatus according to claim 114, wherein said formulation
further comprises a vinca alkaloid.
119. The apparatus according to claim 118, wherein said vinca
alkaloid is selected from the group consisting of vincristine,
vinorelbine, vinorelbine, vindesine, and vinblastine.
120. The apparatus according to claim 114, wherein said formulation
comprises a vesicant selected from the group consisting of
mechlorethamine, mithramycin, and dactinomycin.
121. The apparatus according to claim 114, wherein said formulation
further comprises bisantrene or amsacrine.
122. The apparatus according to claim 114, wherein said formulation
further comprises a taxane.
123. The formulation according to claim 122, wherein said taxane is
paclitaxel or doxytaxel.
124. An inhalation mask for administering aerosols to an patient
comprising: a. means for enclosing the mouth and nose of said
patient, having an open end and a closed end, said open end adapted
for placing over the mouth and nose of said patient; b. upper and
lower holes in said closed end adapted for insertion of a nose
outlet tube and a mouth inhalation tube; c. said nose outlet tube
attached to said upper hole, adapted to accept exhaled breath from
the nose of said patient; d. a one way valve in said nose tube
adapted to allow exhalation but not inhalation; e. said mouth
inhalation tube having an outer and an inner end, partially
inserted through said lower hole, said inner end continuing to end
at the rear of said patients mouth, said inhalation tube end cut at
an angle so that the lower portion extends further into said
patients mouth than the upper portion and adapted to fit the
curvature of the rear of said patients mouth; and f. a y-adapter
attached to the outer end of said mouth inhalation tube.
125. The mask according to claim 124, further comprising a moderate
vesicant present in said inhalation tube.
126. The mask according to claim 124, further comprising a severe
vesicant present in said inhalation tube.
127. Any and all novel features or combination of features,
disclosed in the specification of this application.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/033,789 filed on Dec. 30, 1996.
FIELD OF THE INVENTION
[0002] The invention deals with formulations and methods useful for
treating neoplasms, particularly neoplasms of the respiratory tract
(e.g. lung cancer and cancers of the head and neck), by pulmonary
administration of highly toxic or vesicating anticancer drugs.
Additionally, several new formulations and methods for treating
neoplasms using antineoplastic drugs that are nonvesicants are also
disclosed.
BACKGROUND OF THE INVENTION
[0003] 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, 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.
[0004] 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. 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 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 anticancer drugs but are all due to
systemic delivery of the drug.
[0005] 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 different toxicity profile, both
quantitatively and qualitatively. For example, anthracyclines such
as doxorubicin, epirubicin and idarubicin are known to cause severe
cardiotoxicity. Doxorubicin, additionally, is known to cause severe
progressive necrosis of tissues when extravasated. Cisplatin
therapy is known to cause renal toxicity; vincristine causes
neurotoxicity, bleomycin and mitomycin cause pulmonary toxicity,
cyclophosphamide causes cystitis; and 5-fluorouracil causes
cerebral disjunction (see Cancer Chemotherapy: Principles and
Practice, B A Shabner and J. M. Collings, eds. J. B. Lippincott
Co., Philadelphia, 1990).
[0006] The differences in mechanisms of action and pharmacokinetic
properties determine, in part, the efficacy of the various
anticancer drugs against different tumor types, which exhibit
various biological behaviors.
[0007] 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 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
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. 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.
[0008] In 1968 Shevchenko, I. T., (Neoplasma 15, 4, 1968)
pp.419-426 reported on the treatment of advanced bronchial cancer
using a combination 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 tumor
diminished considerably. The study did not include a control
group.
[0009] 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 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-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.
[0010] 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 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 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 daily,
to lesions on the face. This therapy may continue for up to four
weeks. Also, because 5-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.
[0011] Another report includes the use of .beta.-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 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 multifocal concentrated pockets of drug.
See the articles by H. N. MacCullough et al, JNCI, Vol. 63, No. 3,
September, pp.727-731 (1979) and R. L. Juliano et al, J. Ph. &
Exp. Ther., Vol. 214, No.2, pp.381-387 (1980).
[0012] An additional report includes the use of cisplatin (MW=300)
for inhalation chemotherapy in mice that had been implanted with
FM3A cells (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, "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).
[0013] In U.S. Pat. No. 5,531,219 to Rosenberg, the patent
disclosure suggests 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 perfused
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.
[0014] In U.S. Pat. No. 5,439,686 to Desai et al there are
disclosed compositions where a pharmaceutically active agent is
enclosed within a polymeric shell for 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.
[0015] 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 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 and selecting drugs including the highly toxic
chemotherapeutic compounds, amenable for inhalation therapy of
neoplastic disease and methods for actually distributing specific
measured doses to pre-selected regions of the respiratory
tract.
[0016] It has now been demonstrated by the applicants that
anticancer cytotoxic drugs of multiple classes such as
anthracyclines (doxorubicin), 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 tissues if allowed to be delivered outside
of a vein. After extravasation the drug continues to affect the
tissues to such an extent that amputation 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 "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.
BRIEF DESCRIPTION OF THE INVENTION
[0017] Broadly, one embodiment of the invention includes a
formulation for treating a patient for a neoplasm by inhalation
comprising: a safe and effective amount of a vesicant and a
pharmaceutically acceptable carrier, preferably the vesicant does
not exhibit substantial pulmonary toxicity. In one aspect of the
embodiment the vesicant is typically a moderate vesicant such as
paclitaxel or carboplatin. A description of such a moderate
vesicant would include a non-encapsulated anticancer drug, wherein
when 0.2 ml of the drug is injected intradermally to rats, at the
clinical concentration for parenteral use in humans: (a) a lesion
results that is at least 20 mm.sup.2 in area fourteen days after
the intradermal injection; and (b) at least 50% of the tested rats
have this size of lesion. Other aspects of this broad embodiment
typically include a vesicant that is a severe vesicant such as
doxorubicin, vincristine, and vinorelbine. The neoplasm to be
treated is typically a pulmonary neoplasm, a neoplasm of the head
and neck, or other systemic neoplasm. The drug may be in the form
of a liquid, a powder, a liquid aerosol, or a powdered aerosol.
Typically the patient is a mammal such as a domestic animal or a
human. In other aspects the embodiment includes formulations of
drugs such as etoposide and a carrier such as DMA. Typically the
severe vesicant is an anthracycline such as epirubicin,
daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyl
doxorubicin, doxorubicin, or idarubicin; or a vinca alkaloid such
as vincristine, vinorelbine, vinorelbine, vindesine, or
vinblastine. In other formulations the drug is typically
mechlorethamine, mithramycin, dactinomycin, bisantrene, or
amsacrine. Typically the formulation may include a taxane such as
paclitaxel, its derivatives and the like. Typical animal and human
doses are provided in the tables and text below.
[0018] A further broad embodiment of the invention includes a
formulation for treating a patient having a neoplasm by inhalation
comprising: a safe and effective amount of a non-encapsulated
antineoplastic drug having a molecular weight above 350, that does
not exhibit substantial pulmonary toxicity; and an effective amount
of a pharmaceutically acceptable carrier. The neoplasm treated with
the formulation is typically a pulmonary neoplasm, a neoplasm of
the head and neck, or a systemic neoplasm. The drug used in the
formulation is in the form of a liquid, a powder, a liquid aerosol,
or a powdered aerosol. Typically the drug has a protein binding
affinity of 25% or 50% or more. Further the drug can typically have
a higher molecular weights such as above 400, 450, or 500 daltons.
Typical animal and human doses are provided in the tables and text
below.
[0019] In a yet further embodiment of the invention, there is
disclosed a formulation for treating a patient for a neoplasm by
inhalation comprising: a safe and effective amount of a taxane in
an effective amount of vehicle comprising polyethyleneglycol (PEG)
and an alcohol. Typically the formulation will also contain an
acid, where the acid present in amount effective to stabilize the
taxane. Typically the alcohol is ethanol, and the acid is an
inorganic acid such as HCl, or an organic acid such as citric acid
and the like. In some typical formulations the taxane is paclitaxel
and the formulation contains about 8% to 40% polyethyleneglycol,
about 90% to 60% alcohol, and about 0.01% to 2% acid. Typical
animal and human doses are provided in the table and text
below.
[0020] Another embodiment provides for formulations for treating a
patient for a neoplasm by inhalation comprising: a safe and
effective amount of a drug selected from the group consisting of
carmustine, dacarbazine, melphalan, mercaptopurine, mitoxantrone,
esorubicin, teniposide, aclacinomycin, plicamycin, streptozocin,
and menogaril; and a safe and effective amount of a
pharmaceutically effective carrier, wherein the drugs do not
exhibit substantial pulmonary toxicity.
[0021] A yet further embodiment provides for a formulation for
treating a patient for a neoplasm by inhalation comprising: a safe
and effective amount of a drug selected from the group consisting
of estramustine phosphate, geldanamycin, bryostatin, suramin,
carboxyamido-triazoles; onconase, and SU101 and its active
metabolite SU20; and a safe and effective amount of a
pharmaceutically effective carrier, wherein the drugs do not
exhibit substantial pulmonary toxicity.
[0022] A still further embodiment provides for a formulation for
treating a patient for a neoplasm by inhalation comprising: a safe
and effective amount of etoposide and an effective amount of a DMA
carrier. Typical animal and human doses are provided in the tables
and text below.
[0023] Another embodiment includes a formulation for treating a
patient for a neoplasm by inhalation comprising: a safe and
effective amount of a microsuspension of 9-aminocamptothecin in an
aqueous carrier. Typical anima and human doses are provided in the
tables and text below.
[0024] A further broad embodiment of the invention includes a
formulation for treating a patient having a neoplasm comprising:
administering to the patient by inhalation, (1) an effective amount
of a highly toxic antineoplastic drug; and (2) an effective amount
of a chemoprotectant, wherein the chemoprotectant reduces or
eliminates toxic effects in the patient that are a result of
administering the highly toxic antineoplastic drug. Typically the
chemoprotectant reduces or eliminates systemic toxicity in the
patient, and/or reduces or eliminates respiratory tract toxicity in
the patient. Typically the formulation includes a chemoprotectant
such as dexrazoxane (ICRF-187), mesna (ORG-2766), ethiofos
(WR2721), or a mixture thereof. The chemoprotectant may be
administered before, after, or during the administration of the
antineoplastic drug. The antineoplastic drug used with the
chemoprotectant may be a nonvesicant, moderate vesicant, or a
severe vesicant. Typical among the drugs with which the
chemoprotectant is useful are bleomycin, doxorubicin, and
mitomycin-C.
[0025] The invention also typically includes a method for treating
a patient having a neoplasm comprising: administering to the
patient by inhalation, (1) an effective amount of a highly toxic
antineoplastic drug; and (2) an effective amount of a
chemoprotectant, wherein the chemoprotectant reduces or eliminates
toxic effects in the patient that are a result of administering the
highly toxic antineoplastic drug. Typically the chemoprotectant
reduces or eliminates systemic toxicity in the patient and/or
reduces or eliminates respiratory tract toxicity in the patient.
Chemoprotectants can typically be dexrazoxane (ICRF-187), mesna
(ORG-2766), ethiofos (WR2721), or a mixture thereof. The
chemoprotectant may be administered before, after, or during the
administration of the antineoplastic drug. Typically the
antineoplastic drug is a nonvesicant, a moderate vesicant, or a
severe vesicant. Typically the antineoplastic drug comprises
bleomycin, doxorubicin, or mitomycin-C.
[0026] An additional embodiment of the invention includes a method
for treating a patient having a neoplasm comprising: administering
a safe and effective amount of a non-encapsulated antineoplastic
drug to the patient by inhalation, the drug selected from the group
consisting of antineoplastic drugs wherein when 0.2 ml of the drug
is injected intradermally to rats, at the clinical concentration
for IV use in humans: (a) at least one lesion per rat results which
is greater than 20 mm.sup.2 in area fourteen days after the
intradermal injection; and (b) at least 50% of the tested rats have
these lesions. In some typical embodiments when the drug is
doxorubicin or vinblastine sulfate, the drug is inhaled in the
absence of perfluorocarbon. Typical diseases treated include a
neoplasm such as a pulmonary neoplasm, a neoplasm of the head and
neck, or other systemic neoplasm. The drug may typically be inhaled
as inhaled as a liquid aerosol or as a powdered aerosol. Mammal
animals and humans are typical patients treated with the method.
The drug may typically be selected from the group consisting of
doxorubicin, daunorubicin, methoxymorpholino-doxorubicin,
epirubicin, cyanomorpholinyl doxorubicin, and idarubicin. When the
drug is a vinca alkaloid it is typically selected from the group
consisting of vincristine, vinorelbine, vindesine, and vinblastine.
Other useful drugs typically include the alkylating agents
mechlorethamine, mithramycin and dactinomycin. Still additional
useful drugs typically include bisantrene and amsacrine. The drug
can typically be a taxane such as doxitaxel or paclitaxel.
[0027] Another embodiment of the invention includes a method for
treating a patient having a neoplasm comprising: administering an
effective amount of a highly toxic non-encapsulated antineoplastic
drug to a patient by inhalation, wherein the molecular weight of
the drug is above 350, and the drug has no substantial pulmonary
toxicity. Typically the neoplasm is a pulmonary neoplasm, a
neoplasm of the head and neck, or a systemic neoplasm. The drug may
be inhaled as a liquid aerosol or as a powdered aerosol. Typically
the drug has a protein binding affinity of 25%, 50% or more. In one
aspect the drug is typically selected from the group comprising
doxorubicin, epirubicin, daunorubicin, methoxymorpholinodoxoru-
bicin, cyanomorpholinyl doxorubicin, and idarubicin. If the drug is
doxorubicin or vinca alkaloid it may be typically be administered
without the presence of a perfluorocarbon. Typically the vinca
alkaloid is selected from the group consisting of vincristine,
vinorelbine, vindesine, and vinblastine. Typical alkylating agent
type drugs include mechlorethamine, mithramycin, dactinomycin.
Other topoisomerase II inhibitors include bisantrene or
amsacrine.
[0028] An additional embodiment includes a method for treating a
patient for a neoplasm by the steps of administering an effective
amount of an antineoplastic drug to the patient by inhalation; and
administering a pharmaceutically effective amount of the same
and/or different antineoplastic drug to the patient parenterally.
The patient may be treated with one or more adjunct therapies
including radiotherapy, immunotherapy, gene therapy,
chemoprotective drug therapy.
[0029] A further embodiment includes a method for treating a
patient for a neoplasm including the steps of administering an
effective amount of an antineoplastic drug to the patient by
inhalation; and administering an effective amount of the same
and/or different antineoplastic drug to the patient by isolated
organ perfusion. The patient may be treated by one or more adjunct
therapies including radiotherapy, immunotherapy, gene therapy, and
chemoprotective drug therapy.
[0030] An further embodiment includes a method for treating a
patient for a pulmonary neoplasm by the steps of (1) selecting one
or more antineoplastic drugs efficacious in treating the neoplasm
and having a residence time in the pulmonary mucosa sufficient to
be efficacious in the treatment of the pulmonary neoplasm; and (2)
administering the drug(s) to the patient by inhalation in a
non-encapsulated form. Typically when 0.2 ml of at least one of the
drugs is injected intradermally to rats, at the clinical
concentration for parenteral use in humans: a lesion results which
is greater than 20 mm.sup.2 in area fourteen days after the
intradermal injection; and B. at least 50% of the tested rats have
these lesions. Typically the molecular weight of at least one of
the selected drugs is above 350.
[0031] A still further embodiment includes a method of use
including the steps of administering one or more non-encapsulated
highly toxic anticancer drugs to a mammal by inhalation, wherein at
least one of the drugs comprises a severe vesicant.
[0032] Another embodiment is an apparatus for treating a patient
for a neoplasm by inhalation that is a combination of a nebulizer
and a formulation for treating a neoplasm, the formulation
including (1) a non-encapsulated anticancer drug, and (2) a
pharmaceutically acceptable carrier; wherein when 0.2 ml of the
formulation is injected intradermally to rats, at the clinical
concentration for parenteral use in humans: (a) a lesion results
which is greater than about 20 mm.sup.2 in area fourteen days after
the intradermal injection; and (b) at least 50% of the tested rats
have these lesions. A further embodiment includes a formulation
which when injected results in a lesion which is greater than about
10 mm.sup.2 in area 30 days after the intradermal injection; and at
least about 50% of the tested rats have these longer lasting
lesions. Typically the formulation includes an anthracycline.
Anthracyclines may be selected from the group consisting of
epirubicin, daunorubicin, methoxymorpholinodoxorubicin,
cyanomorpholinyl doxorubicin, doxorubicin, and idarubicin. The
formulation also typically and contain a vinca alkaloid. Vinca
alkaloids may be selected from the group consisting of vincristine,
vinorelbine, vinorelbine, vindesine, and vinblastine. Alternately,
the formulation may contain vesicant selected from the group
consisting of mechlorethamine, mithramycin, and dactinomycin; or
bisantrene or amsacrine. Typically the formulation can also contain
a taxane which is typically a paclitaxel or doxytaxel.
[0033] Another embodiment of the invention includes an inhalation
mask for administering aerosols to an patient comprising: means for
enclosing the mouth and nose of the patient, having an open end and
a 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 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 patients mouth; and a y-adapter
attached to the outer end of the mouth inhalation tube. The mask
typically will have a moderate vesicant or a severe vesicant
present in the inhalation tube.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 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 concentration of drug in the circulatory
system in ng/ml and the horizontal X scale is time after treatment
in hours.
[0035] FIG. 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 concentration of drug in the circulatory
system in ng/ml and the horizontal X scale is time after treatment
in hours.
[0036] FIG. 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 concentration of drug in the circulatory
system in ng/ml and the horizontal X scale is time after treatment
in hours.
[0037] FIG. 4 shows a schematic of the pulmonary delivery apparatus
arrangement that was used to administer drug to dogs by inhalation
for Example 3.
[0038] FIG. 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.
[0039] FIG. 6 shows a schematic drawing of details of a mask useful
for administering drugs by inhalation to a mammal such as a
dog.
[0040] FIG. 7 shows a schematic drawing of a portable device for
administration of anticancer drugs according to the invention.
DETAILED DESCRIPTION OF THE INVENTION AND BEST MODE
[0041] The delivery of antineoplastic drugs by inhalation by the
pulmonary route is an attractive alternative to the administration
of drugs by various injectable 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 by
alkylating agents, taxanes, vinca alkaloids, platinum complexes,
anthracyclines and others that are considered particularly toxic
especially when administered outside the circulatory system.
[0042] Broadly, the inventors have discovered that highly toxic,
vesicant and previously unknown nonvesicant antineoplastic drugs
can be effectively 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 respiratory tract includes the oral and nasal-pharyngeal,
tracheo-bronchial, and pulmonary regions. The pulmonary region is
defined to include the upper and lower bronchi, bronchioles,
terminal bronchioles, respiratory bronchioles, and alveoli.
[0043] 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 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, 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.
[0044] Broadly, vesicants as used herein include chemotherapeutic
agents that 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 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,
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.
[0045] In another embodiment, vesicants as more narrowly used
herein include drugs that produce a lesion in rats, where the
average lesion size is greater than about 20 mm.sup.2 in area,
fourteen days after an intradermal injection of 0.2 ml of the drug,
and where 50% or more of the animals have 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 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 concentration is
used. Lesion as used herein means an open sore or ulcer or
sloughing off of skin with exposure of underlying tissue.
[0046] 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 above mentioned lesion size for
a more extended period of time. That is, the lesions remain above
about 10 mm.sup.2 up to at least 30 days in at least 50% or more of
the animals.
[0047] 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 in exceptional cases. Examples
include alkylating agents such as cyclophosphamide, bleomycin
(blenoxane), carmustine, and dacarbazine; DNA crosslinking agents
such as thiotepa, cisplatin, melphalan (L-PAM); antimetabolites
such as cytarabine, fluorouracil (5-FU), methotrexate (MTX), and
mercaptopurine (6 MP); topoisomerase II inhibitors such as
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.
[0048] A listing of materials usually accepted to be vesicants or
nonvesicants is provided below as Table 1--Vesicant/Nonvesicant
Drug Activity.
1TABLE 1 Vesicant/Non-Vesicant Drug Activity Classification
Vesicant Non-Vesicant Alkylating Agents Mechloreth-
Cyclophosphamide amine.sup.a,c,d,e* (Cytoxan).sup.b
Mitomycin-C.sup.a,c,e* Bleomycin (Blenoxane).sup.b,e
Dactinomycin.sup.d,e* Carmustine.sup.a,b,d Mithramycin.sup.d
Mithramycin.sup.a,b (Plicamycin) (Plicamycin) Dacarbazine.sup.a,b,e
DNA Crosslinking Thiotepa.sup.b Agents Cisplatin.sup.b,e Melphalan
(L-PAM).sup.b Antimetabolites Cytarabine (ARA C).sup.b Fluorouracil
(5 FU).sup.b,d,e Methotrexate (MTX).sup.b Mercaptopurine (6
MP).sup.b Topoisomerase II Bisantrene.sup.c,e* Mitoxantrone.sup.b,e
Inhibitors (Anthracene) (Anthracene) Dactinomycin.sup.a,c
Esorubicin.sup.e Doxorubicin.sup.a,b,c,d,e* Etoposide
(VP-16).sup.a,b,e (Anthracycline) (Epipodophyllotoxin)
Cyanomorpholinyl Teniposide (VM-26).sup.a,b,e Doxorubicin.sup.e*
(Epipodophyllotoxin) Amsacrine.sup.a,c,e* Epirubicin.sup.c,e*
Daunorubicin.sup.a,d,e* Idarubicin.sup.a,e* Liposomal
anthracyclines.sup.e Hormonal Agents Estrogens.sup.b
Glucocorticosteroids.sup.b Progestins.sup.b Antiestrogens.sup.b
Tubulin Inhibitors Vinblastine.sup.a,d,e* Vincristine.sup.a,d,e*
Vinorelbine.sup.e* Vindesine.sup.a,e* Paclitaxel.sup.c,
Paclitaxel.sup.e,f Miscellaneous Asparaginase.sup.b (Enzyme)
Aclacinomycin.sup.e Streptozocin.sup.a,b Menogaril.sup.e
.sup.aAccording to U.S. Pat. No. 5,602,112 .sup.bDorr, R.T. et al,
Lack of Experimental Vesicant Activity for the Anticancer Agents
Cisplatin, Meiphalan, and Mitoxantrone, Cancer Chemother.
Pharmacol., Vol. 16, 1986, pp. 91-94 .sup.cAccording to Bicher, A.
et al, Infusion Site Soft-Tissue Injury After Paclitaxel
Administration, Cancer, Vol. 76, No. 1, July 1, 1995, pp. 116-120
.sup.dRudolph, R. et al; Etiology and Treatment of Chemotherapeutic
Agent Extravasation Injuries: A Review; Journal of Clinical
Oncology, Vol. 5; No. 7; July 1987; PP. 1116-1126 .sup.eBertelli,
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, either clinically or experimentally,
to cause tissue necrosis after accidental extravasation. Symbol: *
= vesicants, drugs with the highest potential for localized tissue
damage after extravasation .sup.fCancer, R.T., Communications,
Author Reply, Cancer, pp. 226
[0049] 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 than those
represented by 5-FU, .beta.-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 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 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
neoplasms by inhalation.
EXAMPLE 1
[0050] This example illustrates and confirms toxicity and
vesicant/nonvesicant activity of several antineoplastic drugs. The
vesicant activities of thirteen anticancer drugs were investigated
(see the listing in Table 2 below). 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 vesicant activity, because lesions caused by
nonvesicants should have been significantly reduced while lesions
caused by vesicants should still be large. 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.
[0051] The drugs used for the vesicant activity tests are
identified as follows: doxorubicin (Adriamycin PFS), a red liquid
in glass vials, no formulation was necessary; cisplatin
(Platinol-AQ.TM.), a liquid in glass vials, no formulation was
necessary; Paclitaxel (Taxol.TM.), a liquid in glass vials,
formulated with saline solution; fluorouracil, a clear yellow
liquid in glass vials, no formulation was necessary; cytarabine
(Cytosar-U.TM.), a white powder in glass vials, formulated with
water; 9-aminocamptothecin (9-AC colloidal suspension), a yellow
powder in glass vials, formulated with water; cyclophosphamide
(Cytoxan.TM.), a yellow powder in glass vials, formulated with a
saline/water mixture; carboplatin (Paraplatin.TM.), a white powder
in injectable vials, formulated with saline solution; etoposide
(VePesid.TM.), a clear liquid in glass vials, formulated with
saline solution; bleomycin (bleomycin sulfate, USP), a lyophilized
powder tablet in glass vials, formulated with saline solution;
vincristine (vincristine sulfate), an injectable liquid in
injection vials, no formulation necessary; vinorelbine tartrate
(Navelbine.TM.), a clear liquid in glass vials, diluted with water
per package instructions; and mitomycin (Mutamycin.TM.), a gray
crystalline powder in glass amber bottles, formulated with water.
All of these drugs were reconstituted following standard and known
methods recommended by the manufacturers.
[0052] 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 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.
2TABLE 2 Formulations administered for Vesicant Tests Formulation
Test Formulation Concentration 1 Doxorubicin 2 mg/ml 2 Platinol 1
mg/ml 3 Paclitaxel 1.2 mg/ml 4 Fluorouracil 50 mg/ml 5 Cytarabine
100 .mu.g/ml 6 9-aminocamptothecin 100 mg/ml 7 Cyclophosphamide 20
mg/ml 8 Carboplatin 10 mg/ml 9 Etoposide 0.4 mg/ml 10 Bleomycin 20
units/ml 11 Vincristine 1 mg/ml 12 Vinorelbine 3 mg/ml 13
Mitomycin-C 0.5 mg/ml
[0053] Table 3 below is a tabulation of the resultant lesion sizes
that developed from intradermal injections of the above drugs.
Lesion sizes were measured as more fully discussed below.
3TABLE 3 Individual Lesion Size Measurements (mm.sup.2) (part 1 of
3) (see text for explanation of measurements) Animal Day of Test
(post injection) Number Test Drug 6 8 10 13 15 17 20 22 24 27 29 31
34 36 38 41 101 Doxorubicin -- 21.4 33.9 57.0 42.9 34.0 35.4 27.2
32.2 31.7 31.7 17.1 8.3 6.3 6.7 4.5 102 Doxorubicin -- 18.8 23.5
10.9 12.9 9.7 10.2 9.9 11.8 10.5 9.9 10.2 2.8 -- -- -- 103
Doxonibicin -- 36.5 58.0 82.9 45.5 37.7 28.1 26.9 21.0 23.9 18.6
16.2 12.5 10.3 7.6 6.1 104 Doxorubicin -- 44.6 27.3 33.6 17.7 21.7
28.1 19.5 16.6 16.1 18.9 13.9 9.0 5.1 4.5 4.0 105 Doxorubicin --
33.9 35.2 33.3 35.1 29.4 30.2 29.7 25.0 24.4 24.8 23.5 24.0 24.5
21.6 22.0 106 Doxorubicin -- 30.6 43.2 32.2 35.2 34.4 29.2 30.2
15.5 16.0 15.4 14.5 16.2 14.8 14.3 5.2 107 Doxorubicin -- 26.1 39.7
38.6 33.8 31.3 25.0 22.0 21.6 19.8 22.4 21.5 20.9 21.0 18.4 18.9
111 Platinol 26.9 18.7 18.0 11.8 21.2 17.1 6.9 1.5 1.0 -- -- -- --
-- -- -- 112 Platinol 35.5 20.3 20.8 15.5 16.1 16.2 16.5 4.1 -- --
-- -- -- -- -- -- 113 Platinol 15.3 15.8 14.6 10.1 9.1 9.0 8.3 2.9
2.6 1.7 -- -- -- -- -- -- 114 Platinol 17.2 11.3 13.2 9.7 9.2 10.3
10.5 9.1 -- -- -- -- -- -- -- -- 115 Platinol 26.8 25.0 14.8 21.8
18.0 15.0 16.0 16.0 2.1 1.7 1.4 -- -- -- -- -- 116 Platinol 21.8
20.7 12.2 11.8 12.9 12.6 8.4 10.8 8.5 8.4 -- -- -- -- -- -- 117
Platinol 24.9 21.3 16.7 15.1 16.4 14.8 14.3 12.2 12.5 2.8 -- -- --
-- -- -- 121 Taxol 23.7 21.6 21.2 18.9 3.5 -- -- -- -- -- -- -- --
-- -- -- 122 Taxol 37.3 30.1 26.1 25.2 21.8 21.7 5.6 2.1 1.8 -- --
-- -- -- -- -- 123 Taxol 7.9 5.9 4.3 1.1 1.2 -- -- -- -- -- -- --
-- -- -- -- 124 Taxol 43.2 36.9 32.9 30.6 29.0 28.5 -- -- -- -- --
-- -- -- -- -- 125 Taxol 38.4 34.6 28.6 22.1 5.9 -- -- -- -- -- --
-- -- -- -- -- 126 Taxol 69.5 59.5 53.3 53.3 42.9 5.2 -- -- -- --
-- -- -- -- -- -- 127 Taxol 45.9 23.1 16.1 14.3 8.4 5.0 -- -- -- --
-- -- -- -- -- -- 131 Fluorouracil 29.0 19.9 13.5 11.2 14.3 11.6
8.3 2.0 -- -- -- -- -- -- -- -- 132 Fluorouracil 17.1 16.2 11.8 3.0
-- -- -- -- -- -- -- -- -- -- -- -- 133 Fluorouracil 27.0 23.8 17.4
17.6 17.9 0.5 -- -- -- -- -- -- -- -- -- -- 134 Fluorouracil 21.9
18.9 17.0 6.7 -- -- -- -- -- -- -- -- -- -- -- -- 135 Fluorouracil
20.5 27.5 21.4 4.5 -- -- -- -- -- -- -- -- -- -- -- -- 136
Fluorouracil 23.5 14.0 10.1 9.5 8.0 7.8 1.8 -- -- -- -- -- -- -- --
-- 137 Fluorouracil 20.5 7.0 6.2 4.8 4.6 3.8 -- -- -- -- -- -- --
-- -- -- 151 9-aminocamptothecin 21.8 15.8 16.0 14.5 9.0 19.9 -- --
-- -- -- -- -- -- -- -- 152 9-aminocamptothecin 8.6 4.4 5.4 3.7 4.0
3.6 -- -- -- -- -- -- -- -- -- -- 153 9-aminocamptothecin 4.4 2.6
2.9 1.3 1.1 -- -- -- -- -- -- -- -- -- -- -- 154
9-aminocamptothecin 23.8 21.9 20.9 19.8 15.5 18.6 -- -- -- -- -- --
-- -- -- -- 155 9-aminocamptothecin 12.5 7.9 10.0 9.6 9.9 0.6 -- --
-- -- -- -- -- -- -- -- 156 9-aminocamptothecin 12.6 10.4 5.8 4.6
3.1 -- -- -- -- -- -- -- -- -- -- -- 157 9-aminocamptothecin 12.5
7.8 5.2 3.7 -- -- -- -- -- -- -- -- -- -- -- -- 161
Cyclophosphamide 16.4 13.6 11.3 9.4 8.3 8.6 -- -- -- -- -- -- -- --
-- -- 162 Cyclophosphamide 35.1 33.8 23.2 3.5 1.4 -- -- -- -- -- --
-- -- -- -- -- 163 Cyclophosphamide 25.8 18.9 21.0 19.3 17.2 17.2
12.1 12.5 14.0 7.8 2.4 -- -- -- -- -- 165 Cyclophosphamide 19.4
18.2 17.9 17.4 16.6 15.9 13.2 12.2 12.7 7.5 1.8 1.5 -- -- -- -- 166
Cyclophosphamide 31.8 33.8 25.4 23.9 11.9 2.2 -- -- -- -- -- -- --
-- -- -- 167 Cyclophosphamide 25.2 19.7 19.1 19.3 18.9 18.9 17.4
14.6 15.6 4.1 2.0 -- -- -- -- -- 171 Carboplatin 16.2 17.3 12.2
10.9 10.4 8.1 4.6 0.8 -- -- -- -- -- -- -- -- 172 Carboplatin 9.0
5.1 21.9 17.5 7.6 4.1 5.2 6.2 5.9 5.2 3.2 2.6 -- -- -- -- 173
Carboplatin 24.8 23.4 17.7 20.5 18.5 16.0 8.6 3.4 0.8 0.6 -- -- --
-- -- -- 174 Carboplatin 31.9 23.1 18.2 24.2 27.0 19.4 15.5 13.1
11.2 4.0 1.5 -- -- -- -- -- 175 Carboplatin 20.5 24.5 22.1 13.4
20.4 16.8 5.4 4.9 1.8 1.2 -- -- -- -- -- -- 177 Carboplatin 42.9
39.1 30.1 31.7 32.7 32.6 35.4 34.7 34.6 23.9 25.2 25.7 19.2 0.6 --
-- 181 Etoposide 21.1 15.0 11.2 9.2 9.8 9.0 2.9 -- -- -- -- -- --
-- -- -- 182 Etoposide -- -- 3.8 2.4 2.0 1.7 1.1 -- -- -- -- -- --
-- -- -- 183 Etoposide 1.3 4.6 3.1 2.9 3.8 1.2 -- -- -- -- -- -- --
-- -- -- 184 Etoposide -- 9.6 4.7 -- -- -- -- -- -- -- -- -- -- --
-- -- 185 Etoposide 5.9 6.0 6.0 2.6 2.1 2.0 -- -- -- -- -- -- -- --
-- -- 186 Etoposide 10.6 14.1 7.7 6.6 8.4 3.8 1.7 -- -- -- -- -- --
-- -- -- 187 Etoposide 6.5 10.0 9.3 5.3 5.4 5.1 3.5 -- -- -- -- --
-- -- -- -- 191 Bleomycin 8.2 5.1 8.8 2.2 1.6 -- -- -- -- -- -- --
-- -- -- -- 192 Bleomycin 21.1 15.3 10.8 16.3 3.8 1.3 -- -- -- --
-- -- -- -- -- -- 193 Bleomycin 23.5 18.9 15.4 13.8 5.5 1.3 -- --
-- -- -- -- -- -- -- -- 194 Bleomycin 5.0 3.2 1.0 2.3 -- -- -- --
-- -- -- -- -- -- -- -- 195 Bleomycin 7.7 6.5 6.7 6.5 7.0 3.2 1.3
-- -- -- -- -- -- -- -- -- 196 Bleomycin 13.4 7.8 6.8 7.2 6.6 0.7
-- -- -- -- -- -- -- -- -- -- 197 Bleomycin 27.0 27.0 26.0 25.2
26.0 24.0 1.0 0.6 -- 0.4 -- -- -- -- -- -- 202 Vincristine -- --
469.0 307.7 227.7 160.5 109.2 93.3 93.6 83.6 67.2 57.9 47.5 40.3
40.2 34.0 203 Vincristine -- -- -- 165.3 158.5 67.0 29.7 28.6 24.7
21.1 22.0 22.8 27.5 30.6 21.2 13.8 205 Vincristine -- -- -- 130.4
136.2 111.6 76.1 61.5 58.0 42.0 26.5 18.1 12.6 5.3 4.2 1.3 206
Vincristine -- -- 145.6 96.9 81.6 96.1 66.7 59.2 51.3 13.0 7.2 --
-- -- -- -- 211 Vinorelbine -- 16.8 421.7 315.2 289.7 274.6 250.8
200.8 170.8 159.1 237.2 243.6 243.1 219.4 180.6 149.0 212
Vinorelbine -- 436.7 422.1 426.5 408.5 347.6 316.8 298.8 292.4
282.0 251.0 81.3 82.0 83.8 45.8 17.2 213 Vinorelbine -- 402.2 429.0
352.6 323.4 372.9 366.3 311.6 312.1 299.2 302.3 294.0 102.7 137.7
212.1 192.1 214 Vinorelbine -- 322.1 261.6 283.6 293.9 241.7 227.0
221.9 227.2 105.0 86.1 72.5 65.3 71.4 52.5 62.0 215 Vinorelbine --
297.0 277.8 269.7 225.3 204.2 82.5 69.8 67.8 40.0 28.4 31.9 17.4
19.2 14.0 14.5 216 Vinorelbine -- 348.3 325.1 308.1 288.9 297.0
278.7 255.9 269.3 255.8 134.9 103.7 61.2 95.7 123.2 108.2 217
Vinorelbine -- 275.1 309.6 272.1 249.0 217.1 208.1 209.3 190.7
175.5 173.2 172.0 173.4 157.3 187.7 155.5 221 Mutamycin 45.0 46.8
47.5 77.0 48.2 38.8 45.4 41.6 40.3 28.6 9.6 6.4 4.1 0.7 -- -- 222
Mutamycin 50.4 50.4 49.6 41.9 45.1 34.8 42.0 46.2 9.9 9.3 7.5 -- --
-- -- -- 223 Mutamycin 98.3 73.0 79.1 79.8 71.0 64.6 66.0 28.5 17.6
24.3 28.2 1.1 -- -- -- -- 224 Mutamycin 58.2 82.4 62.6 78.8 73.3
66.1 53.9 36.9 32.9 31.2 19.8 16.8 15.5 16.8 21.0 25.6 225
Mutamycin 28.1 24.2 28.0 19.8 29.8 23.0 12.8 13.2 11.9 8.5 6.6 7.2
2.0 1.5 -- -- 226 Mutamycin 61.3 53.3 59.9 49.7 48.9 38.0 39.5 42.1
40.6 23.0 5.6 4.8 4.6 4.6 1.2 -- 227 Mutamycin 36.0 35.8 37.8 37.8
39.7 33.8 31.1 13.9 10.9 7.9 8.1 2.9 -- -- -- --
[0054] Results were as follows:
[0055] 1. Abrasions of the dorsal body were observed in a majority
of animals for all drugs except cytarabine.
[0056] 2. Alopecia of the dorsal body was seen for doxorubicin
(3/7), paclitaxel (7/7), and fluorouracil (7/7), etoposide (7/7),
bleomycin (7/7), vincristine (2/7), vinorelbine (7/7), and
mitomycin-C (mutamycin) (4/7).
[0057] 3. Discoloration of the skin around the site of injection
was seen for doxorubicin, vincristine, vinorelbine, and
mitomycin-C.
[0058] 4. Rough coat was observed in fluorouracil (1/7),
vincristine (4/7), and vinorelbine (2/7).
[0059] 5. Systemic effects were observed only for vincristine.
Three animals had to be removed from the tests because of their
poor condition.
[0060] 6. Slight edema was observed for all groups. Moderate edema
was observed in doxorubicin, vincristine, vinorelbine, and
mitomycin-C treated animals. Severe edema was observed only for
animals treated with vinorelbine and vincristine.
[0061] 7. Severe erythema was seen for all drugs except for
cisplatin (platinol) and cytarabine.
[0062] 8. Dermal lesions were observed for all drugs except for
cytarabine. Most lesions appeared between 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. One
rat (#123) injected with paclitaxel (taxol) was determined to not
have received a proper intradermal injection and was not used in
the results.
[0063] 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 perpendicular diameters and the two
values multiplied to yield a lesion area in mm.sup.2. Lesions were
regularly evaluated and scored as shown in Table 3.
[0064] A vesicant as determined by the methods used herein is
defined as causing a lesion of at least about 20 mm.sup.2, 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 fulfill these criteria.
Cisplatin, etoposide, bleomycin, cytarabine, cyclophosphamide,
fluorouracil, and 9-aminocamptothecin are thus categorized as
non-vesicants.
[0065] A moderate vesicant as determined by the methods used herein
is defined as causing a lesion of at least about 20 mm.sup.2, in at
least one half of the animals, two weeks after injection (day 15 in
Table 3), but less than half of the animals will have lesions
greater than about 10 mm.sup.2 30 days after injection (day 31 in
Table 3). The data from Table 3 shows that paclitaxel, carboplatin,
and mitomycin-C fulfill these criteria. Of these, mitomycin-C has
been determined to exhibit substantial pulmonary toxicity.
[0066] A severe vesicant as determined by the methods used herein
is defined as causing a lesion of at least about 20 mm.sup.2, 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 mm.sup.2, 30 days after injection
(day 31 in Table 3). Table 3 shows that doxorubicin, vincristine,
and vinorelbine satisfy these criteria.
[0067] 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 be useful in the treatment
of cancer by inhalation as further discussed below.
[0068] 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
alkaloids (e.g. vincristine, vinblastine, vindesine, and the like);
alkylating agents (e.g. mechlorethamine and the like); carboplatin;
nitrogen 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 compounds are
further discussed below.
[0069] 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 efficacious in treating
the neoplasm or cancer, that are applied by inhalation and that
reside in the pulmonary system for a time sufficient to 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.
[0070] 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 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.
[0071] 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.
[0072] Administration by inhalation as used herein includes the
respiratory administration of drugs as either liquid aerosols or
powdered aerosols suspended in a gas such as air or other
nonreactive 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
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 molecules yet is still not enclosed
in a liposome, matrix or shell as further discussed below.
[0073] 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 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,
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 linoleic acid and
glycerin. Preferred molecules for esterification are those
naturally present in the area of deposition of the active drug in
the respiratory tract.
[0074] 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 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 by inhalation. In Examples 2 and 3
below, doxorubicin was administered to three dogs (beagles) by both
the pulmonary and intravenous route of 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.
[0075] An anthracycline antineoplastic drug, a salt of doxorubicin,
doxorubicin HCl, available from Farmitalia Carlo Erba (now
Pharmacia & Upjohn), Milan, 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 adjusted to select the desired concentration of doxorubicin and
the desired particle size of the aerosol.
EXAMPLE 2
[0076] Three adult, male, beagle dogs were used in the tests. The
dogs (designated dog 101, 102, and 103) had body weights of 10.66,
10.24, and 10.02 kg respectively. As used herein "m.sup.2" 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
doxorubicin HCl at the recommended initial clinical dose (for dogs)
of 20 mg/m.sup.2 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 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 HCl at these doses.
EXAMPLE 3
[0077] The three dogs used in Example 2 were allowed a one-week
washout period before being subjected to exposure to the
anthracycline drug doxorubicin HCl by inhalation. The dogs were
acclimated to wearing masks for administration of the aerosol prior
to treatment. The dogs were exposed 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:
Dose={Drug Conc. (mg/liter).times.Mean minute Vol.
(liter/min).times.Expos- ure Duration (min).times.Total Deposition
Fraction (%)}.div.Body Weight (kg)
[0078] wherein
[0079] Mean Min. Vol.=Tidal volume.times.minute respiratory
rate
[0080] Exposure Duration=30 min
[0081] Mean Body Weight=weight in kg for each dog
[0082] Total Deposition Fraction=60% (determined by particle size
and respiratory tract deposition models from the published
literature such as "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).
[0083] 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.
[0084] 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.
[0085] Referring now to FIG. 4, the drug formulation was
administered to the dogs of Example 3 with drug exposure system
400. The drug was aerosolized with two Pari LC Jet Plus.TM.
nebulizers 401. The nebulizer was filled with a solution of 15 mg
doxorubicin per ml of 50%water/50% ethanol. The output of each
nebulizer 401 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 409, respectively, and subsequently connected to
four Y-fittings 413 by additional 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 placed in the remaining mask 415. A vacuum pump 423
that drew 1 liter 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
below.
[0086] 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 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 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
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 portion that served to depress the
tongue of the dogs to provide an open airway for breathing. See the
discussion of FIG. 6 below.
[0087] 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 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
the drug dosage by each of the dogs.
[0088] 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 drug/liter of air (mg/l) 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 literature (see references cited above).
[0089] 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 mg/kg to the
pulmonary region of dogs 101, 102, and 103 respectively
[0090] 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 measurements. The drug mass collected on the filter
was corrected for the chlorine portion of the doxorubicin salt.
Finally, the doxorubicin concentration in the three liters of air
drawn into each mask was determined in mg/l. The four figures were
averaged to obtain a mean doxorubicin aerosol concentration of
0.218 mg/l.
[0091] 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. 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 well with the earlier calculated figures in
Table 4.
4TABLE 4 TOTAL MASS DATA Total Inhaled Vol. Inhaled Air Inhaled
Deposited Pulmonary Dog Weight (I) Aerosol Deposition Test Art.
Dose Dose Dose Dog No. (kg) For 30 Min. Conc. (mg/l) Fraction
Fraction (mg/kg) (mg/kg) (mg/kg) 101 10.66 77.5 0.250 0.60 0.937
1.70 1.02 0.51 102 10.24 86.8 0.250 0.60 0.937 1.99 1.19 0.60 103
10.02 80.8 0.250 0.60 0.937 1.89 1.13 0.57 A B C D E
[0092]
5TABLE 5 FILTER DATA Sample Weight Total Dox. Ratio Sample Vol.
Gain Doxorubicin Conc. Conc. Dox/ No. (liter) (mg) mass (mg) (mg/l)
(mg/l) Total 1 3 0.78 .times. .937 0.70 0.260 0.233 0.897 2 3 0.72
.times. .937 0.61 0.240 0.203 0.847 3 3 0.73 .times. .937 0.62
0.243 0.207 0.849 4 3 0.77 .times. .937 0.68 0.257 0.227 0.883 Mean
0.250 0.218 0.869 A B C D
[0093]
6TABLE 6 ANALYTICAL DATA Total Dog Inhaled Aerosol Inhaled
Deposited Pulmonary Dog Weight Vol. Conc. Dose Dose Dose No. (kg)
(l) (mg/l) (mg/kg) (mg/kg) (mg/kg) 101 10.66 77.5 0.218 1.58 0.95
0.47 102 10.24 86.8 0.218 1.85 1.11 0.56 103 10.02 80.8 0.218 1.76
1.06 0.53 A B C
[0094] Surprisingly it was found that free non-encapsulated
doxorubicin administered by the pulmonary route was not rapidly
cleared from the lung. FIGS. 1, 2 and 3 show examples of the type
of results achieved when cytotoxic anticancer drugs were given by
inhalation. High efficiency nebulization systems as shown in FIGS.
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 this dose.
[0095] As can be seen from FIGS. 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 at 2 minutes was about 1.5 orders of
magnitude larger when administered IV 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
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
following IV treatment.
[0096] 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 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. 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/m.sup.2. 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 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).
[0097] In some typical embodiments, to obtain additional benefits
of the disclosed invention for treating pulmonary neoplasms and
reducing systemic 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 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. 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 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.
[0098] 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 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 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.
[0099] 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 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 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 retention is the
objective.
[0100] 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 efficacious concentration
and an efficacious residence time in the tissue to be 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.
[0101] 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, 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
[0102] Particle size for the aerosolized drug used in the present
examples was measured at about 2.0-2.5 .mu.m with a geometric
standard deviation (GSD) of about 1.9-2.0. Typically the particles
should have a particle size of from about 1.0-5.0 .mu.m 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.
[0103] 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.
[0104] Powders useful in the invention include formulations of the
neat drug 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.
[0105] 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
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 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
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 to the respiratory tract with the option to minimize or
provide controlled systemic availability of drug.
EXAMPLE 4
[0106] The tests for administration of doxorubicin by inhalation
referred to in 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/m.sup.2 for three days or a total
dose of 180 mg/m.sup.2. This resulted in a pulmonary deposition of
about 90 mg/m.sup.2.
[0107] A high dose group was administered a dose of 180 mg/m.sup.2
daily for three days or a total dose of 540 mg/M.sup.2. This
resulted in a pulmonary deposition of about 270 mg/m.sup.2.
[0108] One half of the animals were necropsied after three days of
exposure and the remaining dogs necropsied after a three day
recovery period.
[0109] The purpose of the tests was to identify the maximum
tolerated dose of inhaled drug.
[0110] For comparison with the results of Examples 2 and 3, one can
convert the data from mg/kg to mg/m.sup.2 (m.sup.2 of body area) by
multiplying by 20 (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/m.sup.2. When one
compares these dosages to those of Example 4 (180 mg/m.sup.2 and
540 mg/m.sup.2) 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 doses were 9-27 times higher
than those generally given clinically to dogs.
[0111] While the present examples used active drug doses of
doxorubicin of about 20 mg/m.sup.2, 180 mg/m.sup.2, and 270
mg/m.sup.2, 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
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.
[0112] Referring now to FIG. 5, the liquid formulation was
administered to the dogs by aerosolizing with a nebulizer exposure
system 500 comprising a Pari LC Jet Plus.TM. 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 short piece of anesthesia tubing 505 and Y-fitting
507. The mask 415 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 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 530 via line 521. Air flow to the
nebulizer was controlled by controller 530 and supplied to the
nebulizer via line 531.
[0113] Referring now to FIG. 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 Velcro.TM. straps or
belts. Means for enclosing 601 has one end 603 for inserting the
nose and mouth of the dog while the other end 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 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 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 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. In either case an
adapter 637 may be used to hold the mouth tube 621 and or other
tubing to which it is connected.
[0114] 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 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 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.
[0115] Pulmonary administration by inhalation may be accomplished
by means 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, Clarke 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 Jun. 27, 1991; NTIS Patent
Application 7-504-047 filed Apr. 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. Ultravent nebulizer
(Mallinckrodt, Inc, St. Louis, Mo.); Acorn II nebulizer (Marquest
Medical Products, Englewood, Colo.); Ventolin metered dose inhalers
(Glaxo Inc., Research Triangle Park, N.C.); Spinhaler powder
inhaler (Fisons Corp., Bedford, Mass.) or Turbohaler (Astra). 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.
[0116] Nebulizer devices such as those in Greenspan et al U.S. Pat.
Nos. 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.
While the Greenspan devices use piezoelectric materials to generate
electrical power any power source is acceptable to produce the
electrohydrodynamic forces for nebulization.
[0117] 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 be
included.
[0118] 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 particles. Smaller particles
are needed if the drug particles are mainly or only intended to be
delivered to the peripheral lung, i.e. the alveoli (e.g. 0.1-3
.mu.m), while larger drug particles are needed (e.g. 3-10 .mu.m) 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 and figures in
the articles by Cuddihy et al (Aerosol Science; Vol. 4; 1973, pp
35-45) (FIGS. 6, 7, and 8 of the article) and The Task Group on
Lung Dynamics (FIGS. 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 present invention. The major
metastatic sites (lung and upper respiratory tract) are also
readily treated with this invention simultaneously, unlike current
methods of treatment.
[0119] Referring now to FIG. 7, there is disclosed a nebulizer
apparatus 700 that is preferably portable for administration of
drug to a patient in need of 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. FIG. 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 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 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. 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.
[0120] To control environmental contamination resulting from use of
a nebulizer, the patient may be placed in a well-ventilated area
with exhaust air filtered to remove antineoplastic drug that
escapes from the device.
EXAMPLES 5 TO 11
[0121] Examples 5F to 11F show inhalation feasibility and proof of
concept tests and Examples 5R to 10R show dose escalation range
tests with: vesicant antineoplastic 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 .mu.m. The drugs were delivered in water
or other vehicles appropriate for the drug as is known in the art
and as exemplified herein.
[0122] 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. It is
important to note that the doses listed in Table 7 are the
pulmonary deposited doses not the total doses administered.
[0123] The results of the feasibility and dose escalation studies
are summarized in Tables 7 to 11.
7TABLE 7 Escalating Dose Regimen for Range-Finding Studies Mean
Pulmonary Deposited Dose Example 1.sup.st Dose 2.sup.nd Dose
3.sup.rd Dose 4.sup.th Dose 5.sup.th Dose 6.sup.th Dose No. Test
Drug (mg) (mg) (mg) (mg) (mg) (mg) 5R Paclitaxel 30 35 40 40 60 --
6R Doxorubicin 12 15 15 15 18 -- 7R Vincristine 0.55 0.55 0.70 070
1.1 1.5 8R Vinorelbine 6 10 10 15 15 -- 9R Etoposide 25 30 45 55 40
80 10R 9-AC -- -- -- -- -- -- hR Carboplatin 30 -- -- -- -- --
Notes: A minimum of 7-14 days separated each escalating dose.
Animals necropsied after last dosing
[0124] Animals used in Examples 5 to 11 were adult beagle dogs. For
the feasibility studies, the dogs were initially given a single
intravenous (IV) 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 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/m.sup.2 and a lung surface area of 70-100
m.sup.2 of lung surface area. The average dog used in the tests was
considered to have a weight of 10kg corresponding and a weight to
body surface ratio of 20 kg/m.sup.2 and a lung surface area of
40-50 m.sup.2 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 resulted in a predictable mild decrease in white blood cell
counts, with no other measurable toxicities.
[0125] 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 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 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 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
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 obtained herein were verified
experimentally by pulmonary scintigraphy tests in dogs.
EXAMPLES 5F AND 5R
[0126] Referring now to Table 8, this table shows the details of
the feasibility test of paclitaxel. Initially the dogs were
administered 120 mg/m.sup.2 of paclitaxel by IV. After the washout
period the dogs were administered a total deposited dose of 120
mg/m.sup.2 of paclitaxel, by inhalation, three times for a total
deposited dose of 360mg/m.sup.2. This administered dose resulted in
a pulmonary deposited dose of about 27 mg each time or a total
pulmonary dose of about 81 mg. This represents a total pulmonary
deposited dose of about 2.1 mg/m.sup.2 of lung surface area. The
dosages were calculated as follows: the dose of 120 mg/m.sup.2 was
divided by 20 kg/m.sup.2 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 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/m.sup.2 lung
surface area.
[0127] The clinical condition of the dogs was normal. Clinical
pathology 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 the
paclitaxel was found to be low to moderate based on plasma kinetic
evaluations. The low to moderate bioavailability indicates that
most of the paclitaxel remained in the lungs and did not rapidly
enter systemic circulation 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.
[0128] Referring again to Tables 7 and 8, in the range-finding
tests 60 to 120 mg/m.sup.2 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/m.sup.2 lung surface area. The
clinical conditions of these dogs were normal, with clinical
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
paclitaxel particularly GI inflammation and ulceration which is
probably associated with systemically administered 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.
8TABLE 8 Paclitaxel Summary Results of Dog Feasibility and Dose
Range-Finding Studies Probable Pulmonary Respiratory Dose- IV
Inhalation Deposited Clinical Clinical Tract Limiting Chemotherapy
dose Dose Dose Condition Pathology Histopathology Toxicity
Bioavailability Toxicity Example 5F 120 120 30 mg .times. 3 Normal
.dwnarw. WBC Bone marrow None Low-moderate Myelo- mg/m.sup.2
mg/m.sup.2 .times. 3 doses & lymphoid suppression Paclitaxel
(360 depletion GI Feasibility mg/m.sup.2 toxicity total) GI villous
Atrophy & congestion Laryngeal inflammation Example 5R NA
60-120 30-60 mg Normal .dwnarw..dwnarw. WBC Thoracic and Minimal
Proportional Myelo- mg/m.sup.2 (5 per dose mesenteric pulmonary to
dose suppression Paclitaxel wkly Rx) lymphoid interstitial GI Dose
Range- depletion inflamma- toxicity Finding tion GI inflammation
and ulceration *- Divide the pulmonary deposi ted dose in mg by 40
to get the pulmonary deposited dose in mg/m.sup.2 of lung surface
area. WBC-white blood cell count
EXAMPLES 6F AND 6R
[0129] Referring now to Table 9, 20 mg of doxorubicin were
initially administered by IV. After the washout period three sets
of inhalation feasibility tests were made. In the first, a single
dose of 20 mg/m.sup.2 of doxorubicin was administered that gave
about a 10 mg body dose, a pulmonary deposited dose of about S mg
or about 0.125 mg/M.sup.2 lung surface area. No changes were noted
in the animal from this dose. A second set of moderate inhalation
dosages of about 40 mg/m.sup.2 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/m.sup.2 corresponding to a about a 60 mg body dose, and a total
pulmonary deposited dose of about 30 mg (or about 0.75 mg/m.sup.2
of lunq surface area). A third set of high inhalation dosages of
120 mg/m.sup.2 of doxorubicin was administered three times per day
over a three day period for a total dose of 360 mg/m.sup.2
corresponding to a 180 mg body dose, a total pulmonary deposited
dose of about 90 mg or about 2.25 mg/m.sup.2 of lung surface area.
One half of the low dose group dogs was necropsied the day after
the final exposure and the remaining half was necropsied four days
later. All high dose dogs were necropsied the day after the final
exposure.
[0130] 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 dose intensive treatment caused pulmonary
edema, a sequela 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 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 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
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.
[0131] Generally, changes noted at the moderate and high dosages
were 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
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.
[0132] In addition, a dose escalation study was conducted on a
weekly exposure schedule. Initial doses of 12 mg deposited were
delivered via endotracheal tube to the lungs, with a 5.sup.th
weekly dose of 18 mg deposited within the lungs. This provided a
total body dose of 24 to 36 mg/m.sup.2. 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 changes. Histologically, there was no evidence of
respiratory tract epithelial degeneration and inflammation.
9TABLE 9 Doxorubicin Summary Results of Dog Feasibility and Dose
Range-Finding Studies Probable Pulmonary Respiratory Dose-
Inhalation Deposited Clinical Clinical Tract Limiting Chemotherapy
IV dose Dose Dose* Condition Pathology Histopathology Toxicity
Bioavailability Toxicity Example 6F 20 20 mg/m.sup.2 .times. 5 mg
No change No change No change No change Low-moderate Respiratory
mg/m.sup.2 1 (absorption tract toxicity Doxorubicin 40 mg/m.sup.2
.times. 10 mg .times. 3 Mild- .Arrow-up bold. WBC Airway rate
limited) Feasibility 3 doses doses moderate Thoracic & GI
epithelial (120 pulmonary Lymphoid degenera- mg/m.sup.2 edema
depletion tion total .Arrow-up bold.IRR 120 mg/m.sup.2 .times. 30
mg .times. 3 Marked .Arrow-up bold..Arrow-up bold. WBC Thoracic
& GI Moderate- 3 doses doses edema Lymphoid severe (360
.Arrow-up bold..Arrow-up bold.IRR depletion inflamma- mg/m.sup.2
tion Example 6R N/A 24-36 12-18 mg .Arrow-up bold.RR .dwnarw. WBC
Mild-moderate Mild- Low-moderate Respiratory mg/m.sup.2 per dose
thoracic and moderate tract toxicity Doxorubicin (5 wkly Rx) Mild
mesenteric degenera- Dose Range- transient lymphoid tion of Finding
pulmonary depletion airway edema epithelium Mild- moderate
interstitial inflam. .Arrow-up bold. - Increase .dwnarw. - Decrease
IRR - increased respiratory rate WBC - white blood cells *Divide
the pulmonary deposited dose in mg by 40 to get the pulmonary
deposited dose in mg/m.sup.2 of lung surface area.
[0133] 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 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.
[0134] Referring again to Tables 7 and 9, an inhalation dose range
of 20-40 mg/m.sup.2 was administered in five weekly doses that
resulted in a body 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/m.sup.2 to about 0.5 mg/m.sup.2 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 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 again to be respiratory
tract toxicity.
EXAMPLE 7F AND 7R
[0135] Referring now to Table 10, 1.4 mg of vincristine was
initially administered by IV. After the washout period one
inhalation feasibility test was made. The vincristine was
formulated in a 50% water/ 50% ethanol vehicle. A single dose of
2.8 mg/m.sup.2 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/m.sup.2 lung surface area. No changes were noted in
the animal from this dose.
10TABLE 10 Vincristine & Vinorelbine Summary Results of Dog
Feasibility and Dose Range-Finding Studies Probable Pulmonary
Respiratory Dose- Inhalation Deposited Clinical Clinical Tract
Limiting Chemotherapy IV dose Dose Dose* Condition Pathology
Histopathology Toxicity Bioavailability Toxicity Example 7F 1.4 2.8
mg/m.sup.2 .times. 0.7 mg Normal Normal No change No change
Undetermined Undeter- mg/m.sup.2 1 mined Vincristine Feasibility
Example 7R N/A 1.1-3.0 0.55-1.5 Normal .dwnarw. WBC Minimal-mild
Minimal Undetermined Myelosup- mg/m.sup.2 (6 mg/dose bone marrow
interstitial pression Vincristine wkly Rx) and lymphoid inflamma-
Dose Range- depletion tion Finding Example 7R N/A 12-30 6-15 mg
Normal .dwnarw. WBC Bone marrow Minimal Undetermined Myelo-
mg/m.sup.2 (5 per dose and lymphoid pulmonary suppression
Vinorelbine wkly Rx) depletion and airway Dose Range- inflam.
Finding .Arrow-up bold. - increased .dwnarw. - decrease IRR -
increased respiratory rate WBC - white blood cell *Divide the
pulmonary deposited dose in ing by 40 to get the pulmonary
deposited dose in mg/m.sup.2 of lung surface area.
[0136] 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 pulmonary deposited dose ranged from about
12.5-37.5 .mu.g/m.sup.2 lung surface area. This corresponded to a
total body dose of 50-150 jig/kg or 1.0-3.0 mg/m.sup.2 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 and causes significant myelosuppression and
neurotoxicity at doses above 1.0 mg/m.sup.2 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 mg/m.sup.2).
EXAMPLE 8R
[0137] Vinorelbine, which is also a vinca alkaloid was evaluated in
a repeated exposure pilot tests. Compared to vincristine,
vinorelbine was approximately 5-10 times less potent in producing
toxicity, but produced similar types of changes. Vinorelbine
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 represented a lung surface exposure of
.about.0.15-0.375 mg/m.sup.2 of lung surface area and total body
doses of 12-30 mg/m.sup.2. 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 lymphoid depletion, both of which
were reversible and of a severity, which was not
life-threatening.
EXAMPLES 9F AND 9R
[0138] 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 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.
[0139] In this invention, etoposide was reformulated in a novel
vehicle, 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 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.sup.th and final dose delivered of 80 mg deposited within the
pulmonary region. This equated to a dose range of 50-160 mg/m.sup.2
of body surface area. This treatment regimen caused no systemic
toxicity and only minimal inflammation 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.
[0140] An additional pharmacokinetic test of inhaled etoposide
showed the drug had moderately good bioavailability. A single
inhaled total deposited dose of 260 mg/m.sup.2 (about 65 mg of drug
deposited in the pulmonary region) produced blood levels of
etoposide similar to an IV dose of 50 mg/m.sup.2 (see FIGS. 1-3).
In other words, to reach similar blood concentrations approximately
5.times. more drug was given by inhalation, a dose which caused
neither respiratory tract nor systemic toxicity.
EXAMPLE 10F
[0141] Additional proof of concept inhalation studies involved the
cytotoxic drug 9-aminocamptothecin (9-AC) which is within the drug
class known as camptothecins. Like etoposide, 9-AC is insoluble and
difficult 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).
[0142] These aerosols were delivered to dogs at daily doses of 40
mg/m.sup.2 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/m.sup.2.
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 IV dose given (which causes mild systemic
toxicity). 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
chemotherapeutic drugs.
EXAMPLE 11F
[0143] In addition, this feasibility trial was extended to examine
another platinum-containing chemotherapeutic, carboplatin. The
usual clinical 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/m.sup.2 total body dose) caused no evidence of either direct
respiratory tract or systemic toxicity.
11TABLE 11 Etoposide, & 9-Aminocampothecin (9-AC) Summary
Results of Dog Feasibility and Dose Range-Finding Studies Probable
Pulmonary Respiratory Dose- Inhalation Deposited Clinical Clinical
Tract Limiting Chemotherapy IV dose Dose Dose* Condition Pathology
Histopathology Toxicity Bioavailability Toxicity Example 9F 50 260
mg/m.sup.2 65 mg .times. 3 Normal No change Mild thoracic None
Moderate Undeter- mg/m.sup.2 .times. 3 (780 doses lymphoid mined
Etoposide mg/m.sup.2 depletion Feasibility total dose) Example 9R
N/A 50-160 25-80 mg Normal No change Mid-moderate Mild Moderate
Undeter- mg/m.sup.2 (6 dose thoracic interstitial mined Etoposide
Dose wkly Rx) lymphoid inflamma- Range-Finding depletion tion
Example 10F 10 40 mg/m.sup.2 .times. 10 mg .times. 3 Normal No
change Minimal Minimal Moderate-high Undeter- mg/m.sup.2 3 (120
doses lymphoid interstitial mined 9-AC mg/m.sup.2 depletion
inflamma- Feasibility total) tion *Divide the pulmonary deposited
dose in mg by 40 to get the pulmonary deposited dose in mg/m.sup.2
of lung surface area.
EXAMPLES 12 TO 20
[0144] 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 endotracheal tube.
[0145] 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, cisplatin, and paclitaxel at the
doses and schedules summarized in Table 12.
[0146] 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 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 there was
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.
12TABLE 12 Summary of Preliminary Clinical Results in Dogs Time of
Ex. Dog Type and Age Diagnosis Inhalation Treatment* Trial Results
12 Afghan Advanced lung carcinoma Dox 5 mg, .times. 1 1 week PD
extrapulmonary 10 years old 13 Cocker Spaniel Lung metastasis from
Dox 5 mg, .times. 2 2 mo. SD lung, died 10-12 years old excised
melanoma Vincristine 0.5 mg, once PD extrapulmonary, died 14 Beagle
Thyroid carcinoma with Dox 5 mg, .times. 4 4 mo. SD lung 7 years
old lung metastasis PD thyroid & extrapulmonary, died 15
Labrador Thyroid carcinoma with Dox 5 mg, .times. 2 2 mo. SD lung 8
years old lung metastasis PD thyroid & brain metastasis, died
16 Mixed Breed Excised lung primary, Dox S mg, .times. 4 4 mo. No
lung metastasis 16 years old positive hilar lymph nodes Death (CNS
metastasis) 17 Rottweiler Excised distal Dox 7 mg, .times. 2 1 mo.
PD lung 3 years old osteosarcoma, lung Cisplatin 15 mg, .times. 1
Further Rx declined nodule 18 Mixed Breed Lung metastasis (Dox 5 mg
+ CTX 25 2-1/2 mo. SD lung 14 years old (carcinoma) mg), .times. 3
PD visceral & Extrapulmonary, died Dox 5 mg, .times. 1 19
Flat-coated Retriever Excised salivary adeno- Paclitaxel 22.5 mg,
QW .times. 2-1/2 mo. SD (4 weeks) lung 8 years old carcinoma, lung
4 PD lung, Rx discontinued metastasis 20 Husky Advanced mammary
Paclitaxel 22.5 mg, .times. 2 2 mo. SD lung 16 years old
adenocarcinoma, lung (Paclitaxel 22.5 mg + metastasis Dox 5 mg),
.times. 2 *Calculate target dose. Abbreviations: PD = progressive
disease, SD = stable disease; Dox = Doxorubicin; CTX =
cyclophosphamide; QW = every week;
EXAMPLES 21 TO 33
[0147] 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 to receive either doxorubicin,
paclitaxel or both by inhalation via an endotracheal tube in a
crossover design. Aerosol particle size was 2-3 .mu.m as in the
previous tests. The apparatus used was basically that shown in FIG.
5 and as described above. Formulations for administration of the
drugs were as follows: 16 mg/ml doxorubicin in 70%ethanol/30%water;
75 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 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.
[0148] The results are summarized in Table 13. Pulmonary deposited
doses listed in the table are based on scintigraphy studies that
relate inhaled doses 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 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%.
[0149] Four dogs had splenic hemangiosarcoma (Examples 29 and 30),
a 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 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.
[0150] The last group of dogs (Examples 31-33) are those that had
primary lung tumors which were removed surgically. These dogs had
metastases in 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 paclitaxel (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
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.
[0151] The result of these tests, therefore, confirm those of the
preliminary tests that inhalational chemotherapy is effective in
the treatment of lung cancer.
13TABLE 13 Efficacy of Inhalational Chemotherapy in Dogs with Lung
Cancer No. of Inhalation* Ex. Diagnosis Dogs Treatment Results 21
Lung carcinoma 1 DOX 5 mg (5.times.) then SD paclitaxel 60 mg
(2.times.) 22 Metastatic 1 DOX 5 mg (2.times.) SD 23
hemangiosarcoma 1 DOX 5 mg (1.times.) PD 24 Metastatic 1 DOX 5 mg
(5.times.) + SD (PR after 3.sup.rd DOX osteosarcoma paclitaxel 60
mg (2.times.) treatment) 25 " 3 DOX 5 mg (2.times.) + PD (PR in one
dog) paclitaxel 60 mg (1.times.) 26 Metastatic 1 DOX 5 mg
(2.times.) PD fibrosarcoma 27 Metastatic 1 DOX 5 mg (4.times.) + SD
liposarcoma paclitaxel 60 mg (1.times.) 28 Metastatic 1 paclitaxel
60 mg (2.times.) + PD (PR noted in melanoma DOX 5 mg (1.times.)
nodules < 2 cm) 29 Splenic 2 DOX 5 mg (4.times.) + Alive and NED
hemangiosarcoma systemic chemotherapy 30 " 2 DOX 1.5 mg (3.times.)
+ Alive and NED systemic chemotherapy 31 Primary lung 1 DOX 1.5 mg
(5.times.) Alive and NED tumor 32 excised- 1 DOX 1.5 mg (2.times.)
Dead from extrapleural micrometastatic metastases 33 disease 2
paclitaxel 20 mg (1.times.) Alive and NED *Deposited pulmonary
doses DOX = doxorubicin; (.times.) = number of treatments received;
SD = stable disease; PD = progressive disease; NED = no evidence of
disease; PR = partial response (50% decrease in tumor size)
[0152] 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 (body weight in kg/m.sup.2 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. A course 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 are given for each
product have been published by the respective manufacturer and are
summarized in the Physicians Desk Reference.
14TABLE 14 Animal Dose* Human Drug mg/m.sup.2 Dose* mg/m.sup.2
Doxorubicin 2 to 90 3 to 130 Paclitaxel 6 to 270 10 to 400
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
9-Aminocampothecin 2.6 to 10 0.04 to 15 *m.sup.2 body surface
area
[0153] Based on the results of the inhalation tests herein with
doxorubicin, inhalation treatments with anthracyclines in addition
to doxorubicin are also expected to be well tolerated and
efficacious when administered by the 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, and paclitaxel, 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 vesicant
drugs that are known to exhibit significant pulmonary toxicity when
administered by IV (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
efficacy/risk balance when administered via pulmonary means in the
treatment of neoplasms. Similarly a 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.
[0154] For the nonvesicant antineoplastic drugs, based on the
inhalation tests 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 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 U.S. Pat. No.
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 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.
[0155] 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 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 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, and the like. For example in the "Physicians
Desk Manual" 1997:
[0156] Doxorubicin (Astra) 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;
[0157] Idarubicin (Pharmacia & Upjohn) pp 2096-2099--vesicant,
primary toxicity appears to be myelosuppression no mention is made
of pulmonary toxicity making the drug useful in the present
invention;
[0158] Etoposide (Astra) pp539-541--no indication of pulmonary
toxicity, but dose limiting hematologic toxicity is important;
[0159] Paclitaxel (Bristol-Meyers Squibb) pp. 723-727--vesicant,
pulmonary toxicity is not listed for paclitaxel, but dose limiting
bone marrow suppression (primarily neutropenia) is important;
[0160] Bleomycin (Blenoxane.RTM. 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;
[0161] Mitomycin C (Mutamycin.RTM. 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;
[0162] Methotrexate (Immunex) pp. 1322-1327--MW=454, primary
toxicity appears to be hepatic and hematologic, signs of pulmonary
toxicity should be closely monitored for signs of lesions;
[0163] 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;
[0164] 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;
[0165] Irinotecan (Camptosar.RTM. Pharmacia & Upjohn)--a
derivative of camptothecin, primary toxicity appears to be severe
diarrhea and neutropenia, no mention is made of pulmonary toxicity
making the drug useful in the present invention;
[0166] Vincristine (Oncovin.RTM. Lilly) pp. 1521-1523--extremely
toxic with high vesicant activity found in the tests herein, but no
pulmonary toxicity noted;
[0167] Vinblastine (Velban.RTM. Lilly) pp.1537-1540--extremely
toxic with high vesicant activity found in the tests herein, but no
pulmonary toxicity noted.
[0168] The above listing is exemplary only and is not intended to
limit the scope of the invention.
[0169] An additional embodiment of the invention includes methods
and 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 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 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 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.
[0170] It is known, for example, that dexrazoxane (ICRF-187) when
given by intraperitoneal injection to mice is protective against
pulmonary damage 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 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.
EXAMPLE 34
[0171] 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 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.
EXAMPLE 35
[0172] Dexrazoxane (ICRF-187) is administered as described in
Example 34 at the same time or up to two hours before giving
bleomycin by intravenous injection. The dose of dexrazoxane ranges
form about 2 times to about 30 times the dose of bleomycin. The
dose of bleomycin by IV ranges from about 5 to 40
units/m.sup.2.
EXAMPLE 36
[0173] 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/m.sup.2 at
intervals of from 1 week to 4 weeks.
EXAMPLES 37 AND 38
[0174] 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.
[0175] Combination Therapy
[0176] 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 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 intraperitoneal administration) and/or additional drug(s)
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. 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.
[0177] Also contemplated within the scope of the invention is the
combination of drugs for combination chemotherapy treatment.
Benefits are those well 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 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.
[0178] Also included in the invention are embodiments comprising
the method for inhalation therapy disclosed herein and the
application of radiotherapy, gene therapy, and/or immunotherapy.
Other embodiments include the immediately above method combined
with chemotherapy applied by IV and/or local therapy.
[0179] Also included within the invention are formulations for
paclitaxel. In these formulations 100% to 40% ethanol is useful.
However, to obtain better 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 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.
[0180] While the forms of the invention herein disclosed constitute
presently preferred embodiments, many others are possible. It is
not intended herein 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.
* * * * *