U.S. patent application number 10/728277 was filed with the patent office on 2004-07-22 for treatment of mucositis.
Invention is credited to Etter, Jeffrey B., Rodell, Timothy C., Rosenthal, Gary J., Samaniego, Adrian, Schauer, Wren H..
Application Number | 20040141949 10/728277 |
Document ID | / |
Family ID | 24898290 |
Filed Date | 2004-07-22 |
United States Patent
Application |
20040141949 |
Kind Code |
A1 |
Rosenthal, Gary J. ; et
al. |
July 22, 2004 |
Treatment of mucositis
Abstract
This present invention provides a therapeutic composition for
use in the treatment of mucositis and a method for using such a
therapeutic composition. The therapeutic composition includes a
pharmaceutical substance effective for treating mucositis
formulated with a biocompatible polymer, such as a biocompatible
reverse-thermal gelation polymer.
Inventors: |
Rosenthal, Gary J.;
(Louisville, CO) ; Etter, Jeffrey B.; (Boulder,
CO) ; Rodell, Timothy C.; (Aspen, CO) ;
Schauer, Wren H.; (Boulder, CO) ; Samaniego,
Adrian; (Louisville, CO) |
Correspondence
Address: |
MARSH, FISCHMANN & BREYFOGLE LLP
3151 SOUTH VAUGHN WAY
SUITE 411
AURORA
CO
80014
US
|
Family ID: |
24898290 |
Appl. No.: |
10/728277 |
Filed: |
December 4, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10728277 |
Dec 4, 2003 |
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09993383 |
Nov 21, 2001 |
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6685917 |
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09993383 |
Nov 21, 2001 |
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09721516 |
Nov 22, 2000 |
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Current U.S.
Class: |
424/85.1 ;
514/1.2; 514/1.7; 514/12.2; 514/15.1; 514/21.9; 514/562 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 9/006 20130101; A61P 1/02 20180101; A61K 31/195 20130101; A61K
9/0014 20130101; A61P 13/10 20180101; A61K 31/198 20130101; A61K
9/06 20130101; A61P 27/16 20180101; A61K 47/34 20130101; A61P 1/00
20180101; A61P 11/06 20180101; A61P 29/00 20180101 |
Class at
Publication: |
424/085.1 ;
514/018; 514/562 |
International
Class: |
A61K 038/19; A61K
038/05; A61K 031/198 |
Claims
What is claimed is:
1. A therapeutic composition useful for treatment of a mucositis at
a mucosal site, the composition comprising: at least one
pharmaceutical substance, effective to provide therapeutic effect
for at least one of the prevention of the mucositis and treatment
of the mucositis; and at least one biocompatible polymer that is
different than the pharmaceutical substance.
2. The therapeutic composition of claim 1, comprising a carrier
liquid.
3. The therapeutic composition of claim 1, wherein the mucositis
comprises a disorder selected from the group consisting of oral
mucositis, esophagitis, cystitis, sinusitis, asthma, colitis, GERD,
proctitis, stomatitis, celiac disease, inflammatory bowel disease,
and Crohn's disease.
4. The therapeutic composition of claim 1, wherein the
pharmaceutical substance is selected from the group consisting of
an antibacterial, an anti-inflammatory, an antioxidant, an
anesthetic, an analgesic, a protein, a peptide and a cytokine.
5. The therapeutic composition of claim 1, wherein the
pharmaceutical substance comprises a thiol-containing compound.
6. The therapeutic composition of claim 5, wherein the
thiol-containing compound is selected from the group consisting of
N-acetylcysteine, and glutathione.
7. The therapeutic composition of claim 1, wherein the
pharmaceutical substance comprises a sulfur-containing
antioxidant.
8. The therapeutic composition of claim 7, wherein the
sulfur-containing antioxidant is selected from the group consisting
of S-carboxymethylcysteine and methylmethionine sulfonium
chloride.
9. The therapeutic composition of claim 7, wherein the
sulfur-containing antioxidant includes sulfur in at least one
functional group selected from the group consisting of thiol,
thioether, thioester, thiourea, thiocarbamate, disulfide, and
sulfonium salt.
10. The therapeutic composition of claim 1, wherein the
pharmaceutical substance comprises a precursor for glutathione
biosynthesis.
11. The therapeutic composition of claim 10, wherein the precursor
is selected from the group consisting of N-acetylcysteine,
procysteine, lipoic acid, s-allyl cysteine, and methylmethionine
sulfonium chloride.
12. The therapeutic composition of claim 1, wherein the
pharmaceutical substance is N-acetylcysteine.
13. The therapeutic composition of claim 1, wherein the therapeutic
effect comprises a decrease in the severity of at lease one of
inflammation, infection and ulceration from the mucositis at the
mucosal site experienced by the host relative to no treatment for
the mucositis.
14. The therapeutic composition of claim 13, wherein the
therapeutic effect comprises a decrease in the duration that the
host experiences at least one of inflammation, infection and
ulceration from the mucositis at the mucosal site relative to no
treatment for the mucositis.
15. The therapeutic composition of claim 1, wherein the
pharmaceutical substance comprises from about 0.001 percent by
weight to about 50 percent by weight of the composition.
16. The therapeutic composition of claim 1, wherein the therapeutic
composition exhibits reverse-thermal viscosity behavior over at
least some range of temperatures between 1.degree. C. and
37.degree. C.
17. The therapeutic composition of claim 1, wherein the therapeutic
composition exhibits reverse-thermal viscosity behavior over at
least some range of temperature between 1.degree. C. to 20.degree.
C.
18. The therapeutic composition of claim 1, wherein the
biocompatible polymer is a reverse-thermal gelation polymer.
19. The therapeutic composition of claim 18, wherein the
biocompatible polymer, as formulated in the therapeutic
composition, has a reverse-thermal liquid-gel transition
temperature within a range of from 1.degree. C. to 37.degree. C.,
so that the therapeutic composition gels as the temperature of the
therapeutic composition is increased from below to above the
reverse-thermal gel transition temperature.
20. The therapeutic composition of claim 18, wherein the
biocompatible polymer, as formulated in the composition, does not
impart reverse-thermal gelation properties to the composition.
21. The therapeutic composition of claim 18, wherein the
biocompatible polymer is a polyoxyalkylene block copolymer.
22. The therapeutic composition of claim 18, wherein the
biocompatible polymer comprises from 5 weight percent to 25 weight
percent of the composition.
23. The therapeutic composition of claim 1, wherein the
biocompatible polymer comprises from 1 weight percent to 70 weight
percent of the composition.
24. The therapeutic composition of claim 1, wherein the therapeutic
composition comprises a carrier liquid and the biocompatible
polymer is dissolved in the carrier liquid when the composition is
at a temperature of 5.degree. C.
25. The therapeutic composition of claim 1, wherein the
pharmaceutical substance is dissolved in the carrier liquid when
the composition is at a temperature of 5.degree. C.
26. The therapeutic composition of claim 1, comprising a
penetration enhancer.
27. The therapeutic composition of claim 26, wherein the
penetration enhancer is different than each of the pharmaceutical
substance and the biocompatible polymer.
28. The therapeutic composition of claim 26, wherein the
penetration enhancer is selected from the group consisting of a
chitosan; a chitosan derivative; a fatty acid; citric acid; a
salicylate; a caprylic/capric glyceride; sodium caprylate; sodium
caprate; sodium laurate; sodium glycyrrhetinate; dipotassium
glycyrrhizinate; glycyrrhetinic acid hydrogen succinate, disodium
salt; an acylcarnitine; a bile salt; and a phospholipid.
29. The therapeutic composition of claim 26, wherein the
penetration enhancer is a chitosan or a chitosan derivative.
30. The therapeutic composition of claim 26, wherein the
penetration enhancer comprises from about 0.01 percent by weight to
about 10 percent by weight of the therapeutic composition.
31. The therapeutic composition of claim 1, comprising a
bioadhesive agent that is different than the pharmaceutical
substance and the biocompatible polymer.
32. The therapeutic composition of claim 31, wherein the
bioadhesive agent is a polymer that aids in adhering the
therapeutic composition to a mucosal surface at the mucosal site
and holding the pharmaceutical substance adjacent the mucosal
surface.
33. The therapeutic composition of claim 31, wherein the
bioadhesive agent is selected from the group consisting of
poloxamers, mucin glycoproteins, trefoil peptides, cellulose
derivatives and carbomers.
34. The therapeutic composition of claim 31, wherein the
bioadhesive agent is a carbophil polymer.
35. The therapeutic composition of claim 1, comprising at least one
taste masking component.
36. The therapeutic composition of claim 35, wherein the taste
masking component is selected from the group consisting of fruit
flavorings, mint flavorings, chocolate flavorings, salt and
sugars.
37. The therapeutic composition of claim 35, wherein the flavor the
taste-masking component imparts a lemon flavor to the
composition.
38. The therapeutic composition of claim 1, comprising at least one
preservative component.
39. The therapeutic composition of claim 38, wherein the
preservative component is selected from the group consisting of
antioxidants, antifungals and antimicrobials.
40. The therapeutic composition of claim 38, wherein the
preservative component is sodium benzoate.
41. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form selected from the group consisting of an
oral solution, a bladder irrigation solution, a mouthwash, a gel,
drops, a spray, a suppository, a slurry, a tablet, a lozenge, a
patch, a film and a lollipop design.
42. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of an oral solution.
43. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a mouthwash.
44. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of drops.
45. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a spray.
46. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a suppository.
47. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a slurry.
48. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a tablet.
49. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a film.
50. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a lollipop.
51. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a gel.
52. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a lozenge.
53. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a patch.
54. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a bladder irrigation solution.
55. The therapeutic composition of claim 1, wherein the mucosal
site is selected from the group consisting of rectal, vaginal,
bladder, ocular, oral, sublingual, esophageal, nasal,
gastrointestinal, pulmonary and aural mucosal sites.
56. The therapeutic composition of claim 1, wherein the mucosal
site is in the rectum and the therapeutic composition is in the
form of a gel that is administrable rectally as a suppository to
contact the mucosal site.
57. The therapeutic composition of claim 1, wherein the mucosal
site is in the vagina and the therapeutic composition is in the
form of a gel that is administrable vaginally as a suppository to
contact the mucosal site.
58. The therapeutic composition of claim 1, wherein the mucosal
site is in the bladder and the therapeutic composition is in the
form of a bladder irrigation solution administrable to the bladder
by catheter to contact the mucosal site.
59. The therapeutic composition of claim 1, wherein the mucosal
site is an occular site and the therapeutic composition is
administrable to the eye in the form of drops to the eye to contact
the mucosal site.
60. The therapeutic composition of claim 1, wherein the mucosal
site is in the oral cavity and the therapeutic composition is in
the form of a mouthwash administrable orally to contact the mucosal
site.
61. The therapeutic composition of claim 1, wherein the therapeutic
composition is in the form of a lozenge administrable orally.
62. The therapeutic composition of claim 1, wherein the mucosal
site is sublingual and the therapeutic composition is in the form
of a tablet, patch or film that can be sublingually placed to
contact the mucosal site.
63. The therapeutic composition of claim 1, wherein the mucosal
site is in the nasal cavity and the therapeutic composition is
sprayable into the nasal cavity to contact the mucosal site.
64. The therapeutic composition of claim 1, wherein the therapeutic
composition is in a swallowable form that is swallowable to contact
the mucosal site.
65. The therapeutic composition of claim 64, wherein the mucosal
site is located in the esophagus and at least a portion of the
biocompatible polymer and pharmaceutical substance adhere to
mucosal surfaces in the esophagus when the therapeutic composition
is swallowed.
66. The therapeutic composition of claim 64, wherein the mucosal
site is located in the gastrointestinal tract and at least a
portion of the biocompatible polymer and the pharmaceutical
substance adhere to mucosal surfaces in the gastrointestinal tract
wherein the therapeutic composition is swallowed.
67. The therapeutic composition of claim 1, wherein the mucosal
site is in the lungs and the therapeutic composition is inhalable
in the form of an aerosol to contact the mucosal site.
68. The therapeutic composition of claim 1, wherein the mucosal
site is in the ear and the therapeutic composition is administrable
into the ear in the form of drops.
69. The therapeutic composition of claim 1, wherein the host is a
mammal.
70. The therapeutic composition of claim 69, wherein the mammal is
a human patient.
71. A therapeutic composition useful for treatment of mucositis at
a mucosal site, the composition comprising a sulfur-containing
antioxidant.
72. The therapeutic composition of claim 71, wherein the
sulfur-containing antioxidant includes sulfur in at least one
functional group selected from the group consisting of thiol,
thioether, thioester, thiourea, thiocarbamate, disulfide and
sulfonium salt.
73. The therapeutic composition of claim 71, wherein the
sulfur-containing antioxidant is a thiol.
74. The therapeutic composition of claim 73, wherein the thiol is
N-acetylcytseine.
75. The therapeutic composition of claim 71, wherein the
sulfur-containing antioxidant is procysteine.
76. The therapeutic composition of claim 71, wherein the
sulfur-containing antioxidant is lipoic acid.
77. The therapeutic composition of claim 71, wherein the
sulfur-containing antioxidant is s-allyl cysteine.
78. The therapeutic composition of claim 71, wherein the
therapeutic composition further comprises a biocompatible
polymer.
79. The therapeutic composition of claim 78, wherein the
biocompatible polymer is a reverse-thermal gelation polymer.
80. The therapeutic composition of claim 71, wherein the
therapeutic composition further comprises a bioadhesive agent.
81. The therapeutic composition of claim 80, wherein the
bioadhesive agent is a carbophil polymer.
82. The therapeutic composition of claim 71, wherein the
therapeutic composition exhibits reverse-thermal viscosity behavior
over at least some range of temperatures between 1.degree. C. and
37.degree. C.
83. A method of delivering to a mucosal site within a host a
pharmaceutical substance for treatment of mucositis at the mucosal
site, the method comprising: introducing a therapeutic composition
into the host, the therapeutic composition comprising the
pharmaceutical substance and a biocompatible polymer, the
pharmaceutical substance being effective for treating mucositis at
the mucosal site; wherein, after the introducing, at least a
portion of the biocompatible polymer and the pharmaceutical
substance adhere to a mucosal surface at the mucosal site.
84. The method of claim 83, wherein the introducing comprises
introducing the therapeutic composition into at least one of the
rectum, vagina, bladder, orbita, oral cavity, nasal cavity,
esophagus, gastrointestinal tract of the host, lungs and ear of the
host.
85. The method of claim 83, wherein the pharmaceutical substance is
selected from the group consisting of an antibacterial, an
anti-inflammatory, an antioxidant, an anesthetic, an analgesic, a
protein, a peptide and a cytokine.
86. The method of claim 83, wherein the pharmaceutical substance
comprises a thiol-containing compound.
87. The method of claim 86, wherein the thiol-containing compound
is selected from the group consisting of N-acetylcysteine, and
glutathione.
88. The method of claim 83, wherein the pharmaceutical substance
comprises a sulfur-containing antioxidant.
89. The method of claim 83, wherein the pharmaceutical substance
comprises a sulfur-containing antioxidant is selected from the
group consisting of S-carboxymethylcysteine and methylmethionine
sulfonium chloride.
90. The method of claim 89, wherein the sulfur-containing
antioxidant includes sulfur in at least one functional group
selected from the group consisting of thiol, thioether, thioester,
thiourea, thiocarbamate, disulfide, and sulfonium salt.
91. The method of claim 83, wherein the pharmaceutical substance
comprises a precursor for glutathione biosynthesis.
92. The method of claim 91, wherein the precursor is selected from
the group consisting of N-acetylcysteine, procysteine, lipoic acid,
s-allyl cysteine, and methylmethionine sulfonium chloride.
93. The method of claim 83, wherein the pharmaceutical substance is
N-acetylcysteine.
94. The method of claim 83, wherein the therapeutic composition
exhibits reverse-thermal viscosity behavior over at least some
range of temperatures between 1.degree. C. and the physiological
temperature of the host.
95. The method of claim 94, wherein when the therapeutic
composition is introduced into the host the therapeutic composition
is at a temperature at which the viscosity of the therapeutic
composition is smaller than 60 cP.
96. The method of claim 94, wherein when the therapeutic
composition is introduced into the host the therapeutic composition
is at a temperature at which the viscosity of the therapeutic
composition is smaller than 50 cP.
97. The method of claim 94, wherein the therapeutic composition
exhibits an increase in viscosity from smaller than 50 cP to larger
than 70 cP with increasing temperature over the range of
temperatures.
98. The method of claim 83, wherein the therapeutic composition has
reverse-thermal gelation properties and a reverse-thermal
liquid-gel transition temperature in a range of from 1.degree. C.
to the physiological temperature of the host.
99. The method of claim 98, wherein when introduced into the host,
the therapeutic composition is at a temperature below the
reverse-thermal gel transition temperature where the viscosity of
the therapeutic composition is no larger than 50 cP.
100. The method of claim 83, wherein the therapeutic composition
comprises a bioadhesive agent.
101. The method of claim 83, wherein the therapeutic composition
comprises a penetration enhancer.
102. The method of claim 83, wherein the mucosal site is a rectal
mucosal site and the introducing comprises introducing the
therapeutic composition into the rectum of the host.
103. The method of claim 85, wherein the therapeutic composition
has reverse-thermal gelation properties, and when introduced into
the rectum the therapeutic composition is at a temperature below a
reverse-thermal gel transition temperature of the therapeutic
composition.
104. The method of claim 103, wherein the reverse-thermal gel
transition temperature is no higher than the physiological
temperature of the host.
105. The method of claim 83, wherein the mucosal site is a vaginal
mucosal site and the introducing comprises introducing the
therapeutic composition into the vagina of the host.
106. The method of claim 105, wherein the therapeutic composition
has reverse-thermal gelation properties, and when introduced into
the vagina the therapeutic composition is at a temperature below a
reverse-thermal gel transition temperature of the therapeutic
composition.
107. The method of claim 106, wherein the reverse-thermal gel
transition temperature is no higher than the physiological
temperature of the host.
108. The method of claim 83, wherein the mucosal site is a mucosal
site within the bladder and the introducing comprises introducing
the therapeutic composition into the bladder of the host.
109. The method of claim 83, wherein the mucosal site is an ocular
mucosal site and the introducing comprises applying at least one
drop of the therapeutic composition to at an eye of the host.
110. The method of claim 109, wherein the biocompatible polymer is
a reverse-thermal gelation polymer not present in the therapeutic
composition in sufficient quantity to impart reverse-thermal
gelation properties to the therapeutic composition.
111. The method of claim 83, wherein the mucosal site is within the
oral cavity and the introducing comprises introducing the
therapeutic composition into the oral cavity of the host.
112. The method of claim 111 comprising, after the introducing,
swishing the therapeutic composition in the mouth and thereafter
ejecting from the mouth at least a portion of remaining of the
therapeutic composition.
113. The method of claim 111, wherein the mucosal site is
sublingual and the introducing comprises sublingual placement of
the therapeutic composition.
114. The method of claim 111, wherein the therapeutic composition
exhibits reverse-thermal viscosity behavior over at least some
range of temperatures between 1.degree. C. and the physiological
temperature of the host; and when introduced into the oral cavity
of the host, the therapeutic composition is at a temperature at
which the viscosity of the therapeutic composition is smaller than
60 cP.
115. The method of claim 83, wherein the mucosal site is an
esophageal mucosal site and the introducing comprises introducing
the therapeutic composition into the esophagus of the host.
116. The method of claim 115, wherein the therapeutic composition
has reverse-thermal gelation properties and a reverse-thermal gel
transition temperature no higher than the physiological temperature
of the host.
117. The method of claim 115, wherein the introducing comprises
introducing the therapeutic composition into the mouth of the host
when the therapeutic composition is at a temperature where the
therapeutic composition has a viscosity of at least 70 cP.
118. The method of claim 115, wherein the therapeutic composition
comprises a bioadhesive agent.
119. The method of claim 118, wherein the bioadhesive agent is
selected from the group consisting of poloxamers, mucin
glycoproteins, trefoil peptides, cellulose derivatives and
carbomers.
120. The method of claim 118, wherein the bioadhesive agent
comprises a carbophil polymer.
121. The method of claim 83, wherein the mucosal site is a nasal
mucosal site and the introducing comprises introducing the
therapeutic composition into the nasal cavity of the host.
122. The method of claim 121, wherein the introducing comprises
introducing a spray of the therapeutic composition into the nasal
cavity.
123. The method of claim 121, wherein the therapeutic composition
has reverse-thermal gelation properties and a reverse-thermal gel
transition temperature that is no higher than the physiological
temperature of the host; and the method comprises forming the spray
when the therapeutic composition is at a temperature that is lower
than the reverse-thermal gel transition temperature.
124. The method of claim 83, wherein the mucosal site is within the
gastrointestinal tract and the introducing comprises introducing
the therapeutic composition into the gastrointestinal tract of the
host.
125. The method of claim 83, wherein the mucosal site is a
pulmonary mucosal site and the introducing comprises introducing
the therapeutic composition into at least one lung of the host.
126. The method of claim 125, wherein the introducing comprises
inhaling the therapeutic composition in aerosol form.
127. The method of claim 125, wherein the therapeutic composition
has reverse-thermal gelation properties and a reverse-thermal gel
transition temperature that is no higher than the physiological
temperature of the host; and the method comprises forming the
aerosol form when the therapeutic composition is at a temperature
that is lower than the reverse-thermal liquid-gel transition
temperature.
128. The method of claim 83, wherein the mucosal site is an aural
mucosal site and the introducing comprises introducing the
therapeutic composition into an ear of the host.
129. Use of the therapeutic composition of claim 1 for prevention
or treatment of mucositis.
130. Use of the therapeutic composition of claim 1, for prevention
or treatment of oral mucositis.
131. Use of the therapeutic composition of claim 1, for prevention
or treatment of esophagitis.
132. Use of the therapeutic composition of claim 71 for prevention
or treatment of mucositis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/993,383 filed Nov. 21, 2001, which is a
continuation-in-part of U.S. patent application Ser. No. 09/721,516
filed Nov. 22, 2000, the entire contents of both applications are
incorporated herein by reference as if set forth herein in
full.
FIELD OF THE INVENTION
[0002] This invention relates to a therapeutic composition useful
for treatment of mucositis and methods for using the therapeutic
composition.
BACKGROUND OF THE INVENTION
[0003] Mucositis is a serious and often very painful disorder
involving inflammation of the mucous membrane, with the
inflammation often accompanied by infection and/or ulceration.
Mucositis can occur at any of the different mucosal sites in the
body. A nonlimiting list of examples of locations where mucositis
can occur include mucosal sites in the oral cavity, esophagus,
gastrointestinal tract, bladder, vagina, rectum, lung, nasal
cavity, ear and orbita. Mucositis often develops as a side effect
of cancer therapy, and especially as a side effect of chemotherapy
and radiation therapy for the treatment of cancer. While cancerous
cells are the primary targets of cancer therapies, other cell types
can be damaged as well. Exposure to radiation and/or
chemotherapeutics often results in significant disruption of
cellular integrity in mucosal epithelium, leading to inflammation,
infection and/or ulceration at mucosal sites.
[0004] As one example, oral mucositis (OM) is a painful and costly
complication of some cancer therapies. The oral cavity is lined
with mucosal epithelium, and exposure to radiation and/or
chemotherapeutics results in the disruption of cellular integrity
leading to the development of ulcerative lesions commonly referred
to as oral mucositis. Oral mucositis is most prevalent in patient
populations with head and neck malignancies being treated with
radiation therapy. Oral mucositis usually occurs after the second
week of radiation therapy, with severe symptoms usually resolving
within six weeks following completion of therapy. It has been
reported that this condition also affects approximately forty
percent of patients undergoing chemotherapy, bone marrow
transplantation or combinations thereof. Chemotherapeutic agents
likely to cause oral mucositis include bleomycin, dactinomycin,
doxorubicin, etoposide, floxuridine, 5-fluorouracil, hydroxyurea,
methotrexate, mitomycin, vinblastine, vincristine, and vinorelbine.
The risk of developing mucositis is markedly exacerbated when
chemotherapeutic agents that typically produce mucosal toxicity are
given in high doses, in frequent repetitive schedules, or in
combination with ionizing irradiation (e.g., conditioning regimens
prior to bone marrow transplant). The lesions induced by
chemotherapeutic agents are clinically significant by about a week
after treatment and the severity progresses to about day ten
through twelve and begins to subside by day fourteen.
[0005] Oral mucositis appears to be a four-phase process: the
primary phase is inflammatory/vascular in nature resulting in a
cytokine release from the epithelium brought on by damage caused by
radiation and/or chemotherapy. The second phase, referred to as the
epithelial phase, is signaled by atrophy and ulceration of the
mucosal epithelium. The third phase is defined as the
ulcerative/bacterial phase represented by ulcerative lesions that
are prone to bacterial infection further compromising the patients'
immune system. These painful lesions often limit a patient's
ability to eat and drink and in some cases require hospitalization.
The presence of these lesions can also interrupt scheduled
chemotherapy and/or radiation treatments. The last phase, the
healing phase, is characterized by a proliferation and
differentiation of epithelium as well as bacterial control.
[0006] Routine oral hygiene is extremely important in reducing the
incidence and severity of mucositis. Oral hygiene methods include
rinsing/irrigation and mechanical plaque removal. Although not
entirely supported by controlled clinical trials, allopurinol
mouthwash and vitamin E have been cited as agents that may decrease
the severity of mucositis. Prophylaxis against fungal infections is
commonly employed in an effort to treat oral mucositis and includes
use of topical antifungal agents such as nystatin-containing
mouthwashes and clotrimazole troches. Although topical antifungal
prophylaxis and treatment may clear superficial oropharyngeal
infections, topical agents tend not to be well absorbed and have
not been demonstrated to be effective against more deeply invasive
fungal infections, which typically involve the esophagus and lower
gastrointestinal tract. For this reason, systemic agents are
indicated for treating all except superficial fungal infections in
the oral cavity.
[0007] Many different compounds have been evaluated for use as a
prophylaxis and treatment of oral mucositis. Current therapies
include cryotherapy (ice chips) to reduce pain and inflammation,
analgesics to manage pain, and antibiotic therapy to control the
opportunistic infection. Analgesics such as lidocaine mouthwashes
are effective for short periods of time but within hours the pain
and discomfort usually returns.
[0008] Chlorhexidine is a broad spectrum antimicrobial with
activity against gram-positive and gram-negative organisms, yeast,
and other fungal organisms. It also has the desirable properties of
sustained binding to oral surfaces and minimal gastrointestinal
(GI) absorption, thereby limiting adverse systemic effects. Its use
in the prophylaxis of oral infections shows promise in reducing
inflammation and ulceration, as well as in reducing oral
microorganisms in high-risk patient groups. Other agents, such as
allopurinol, leucovorin, vitamins, and growth factors, have been
tried for the prevention of chemotherapy-induced mucositis. Use of
a capsaicin-containing candy has also been advocated to desensitize
pain receptors in the mouth. Also, studies utilizing nonsteroidal
agents and coating agents, such as sucralfate (Carafate), have had
conflicting results. Finally, claims that chlorhexidine (Peridex)
reduces mucositis in both irradiated patients and leukemia patients
receiving bone marrow transplants have not been verified. To date,
none of these approaches has shown a significant impact.
[0009] Occurrence of mucositis at mucosal sites other than in the
oral cavity in association with chemotherapy or radiation therapy
are mechanistically similar to the occurrence of oral mucositis.
For example, patients undergoing radiation therapy treatment for
non-small cell lung cancer frequently develop esophagitis as a side
effect of treatment. Esophagitis in this patient population can
impede the progress of cancer treatment.
[0010] Given that a large number of patients suffer mucositis
annually and patients undergoing cancer therapy often receive
multiple cycles of chemotherapy and/or radiation therapy, there is
a significant need for improved treatment of mucositis. The present
invention is directed to this need.
SUMMARY OF THE INVENTION
[0011] In one aspect, the present invention provides a therapeutic
composition for the treatment of mucositis. By treatment of
mucositis, it is meant that the therapeutic composition is
effective to prevent or reduce the incidence, severity and/or
duration of the disease. The therapeutic composition comprises at
least one pharmaceutical substance that, as formulated in the
therapeutic composition, presents therapeutic effect in mammalian
hosts, typically human hosts, for the treatment of mucositis,
together with at least one biocompatible polymer that aids delivery
of the pharmaceutical substance to the targeted mucosal site. One
preferred embodiment of the therapeutic composition includes
N-acetylcysteine as the pharmaceutical substance and a
polyoxyalkylene block copolymer as the biocompatible polymer.
[0012] The therapeutic composition can be made with or without
reverse-thermal viscosity behavior. For many applications,
reverse-thermal viscosity behavior is beneficial to permit
administration in a lower viscosity fluid form that tends to
convert to a higher viscosity form following administration as the
temperature of the therapeutic composition increases in the body.
This also facilitates administration at a refrigerated temperature,
which is soothing and refreshing to the host in a number of
situations, such as for the treatment of mucosal surfaces in the
oral cavity or esophagus. The biocompatible polymer will often be a
reverse-thermal gelation polymer capable of imparting the desired
reverse-thermal viscosity behavior to the therapeutic composition.
Also, the therapeutic composition can be made in a variety of
product forms, with different product forms being more desirable
for targeting treatment to different mucosal sites. Also, in some
applications it is desirable that the reverse-thermal viscosity
behavior can include reverse-thermal gelation, in which case the
therapeutic composition converts to a gel form as the temperature
of the composition is increased from below to above a
reverse-thermal gel transition temperature. When the therapeutic
composition has reverse-thermal gelation properties, the
therapeutic composition will preferably have a reverse-thermal gel
transition temperature that is no higher than, and even more
preferably lower than, the physiological temperature of the host.
Depending upon the specific application, the therapeutic
composition could be administered to the host at a cold temperature
at which the therapeutic composition is in the form of a flowable
medium, or at a temperature at which the therapeutic composition is
in the form of a gel. When administered in the form of a gel, the
therapeutic composition will often have a thick, pudding-like
texture. Inside the body, the gel tends to break down as biological
fluids dilute the therapeutic composition. But even with breakdown
of the gel, significant amounts of the biocompatible polymer and
pharmaceutical substance tend to adhere to mucosal surfaces to
promote effective delivery of the pharmaceutical substance to treat
the targeted mucosal site.
[0013] When treating for oral mucositis, the therapeutic
composition is preferably administered in the form of a flowable
medium with sufficient fluidity for use as a mouthwash that can be
swished in the oral cavity to promote adhesion of the biocompatible
polymer, and therefore also the pharmaceutical substance, to
mucosal surfaces in the oral cavity. The therapeutic composition
will typically include a carrier liquid (also referred to herein as
a liquid vehicle), such as water, and the pharmaceutical substance
and the biocompatible polymer are each dissolved or suspended in
the carrier liquid when the therapeutic composition is in the
flowable medium form for introduction into the oral cavity.
[0014] When treating for esophagitis, the composition will
preferably have a very high viscosity as it is swallowed to promote
a long residence time in the esophagus and effective coating of
mucosal surfaces in the esophagus. In one embodiment, the
therapeutic composition is in a thick, pudding-like form, typically
a gel form, that can spooned into the mouth and swallowed. In
another preferred embodiment, the therapeutic composition is
introduced into the oral cavity as a flowable medium that undergoes
a viscosity increase as it warms and is swallowed. For esophageal
applications, when the therapeutic composition is administered as a
cold flowable medium, the therapeutic composition preferably has
reverse-thermal gelation properties.
[0015] For targeting mucosal surfaces in the stomach, the
therapeutic composition will preferably be in a form so that it can
be readily swallowed to coat the mucosal surfaces in the stomach.
Preferred embodiments include those noted for treatment of
esophagitis.
[0016] For application to nasal mucosal surfaces, it is preferred
that the therapeutic composition be sufficiently fluid so as to be
nebulizable or otherwise sprayable to generate a nasal spray of the
therapeutic composition that can be introduced into the nasal
cavity. Preferably, the therapeutic composition is at a
refrigerated temperature when sprayed and exhibits reverse-thermal
viscosity behavior, so that it undergoes an increase in viscosity
as it warms in the nasal cavity, thereby promoting adhesion to
mucosal surfaces. For nasal applications, it is preferred that the
therapeutic composition have reverse-thermal gelation
properties.
[0017] For application to ocular mucosal surfaces, it is preferred
that the therapeutic composition be sufficiently fluid to be
administratable in the form of eye-drops, but the therapeutic
composition should preferably not gel following administration of
the eye drops.
[0018] For application to rectal or vaginal mucosal surfaces, the
therapeutic composition is preferably in the form of a viscous gel
when at physiological temperature. The therapeutic composition can
be formulated to exhibit reverse-thermal viscosity behavior so that
it is administrable in a refrigerated form at a lower viscosity and
converts to a higher viscosity form, preferably a gel form, as the
therapeutic composition warms following administration.
[0019] For application to pulmonary mucosal surfaces, the
therapeutic composition should be sufficiently fluid immediately
prior to administration to permit the therapeutic composition to be
aerosolized, such as by a nebulizer, for administration by
inhalation of the therapeutic composition in aerosol form.
[0020] For enhanced performance of the therapeutic composition, it
is important that one or more of the components of the therapeutic
composition are sufficiently bioadhesive to promote ready adhesion
to mucosal surfaces, thereby promoting retention of the
pharmaceutical substance adjacent the mucosal surface for effective
delivery to the targeted mucosal site. In one preferred embodiment,
the biocompatible polymer is bioadhesive, so that when the
therapeutic composition is contacted with a mucosal surface, at
least a portion of the biocompatible polymer readily adheres to the
surface. Preferably, the biocompatible polymer and the
pharmaceutical substance are closely associated with each other in
the therapeutic composition such that when the biocompatible
polymer adheres to a surface inside the oral cavity, the
pharmaceutical substance also adheres to the surface along with the
biocompatible polymer. This will often be the case when the carrier
liquid is water and the biocompatible polymer has surfactant
properties. In a preferred embodiment the surfactant properties of
the biocompatible polymer enhance solubility of the pharmaceutical
substance in the carrier liquid. In one embodiment, the therapeutic
composition includes, in addition to the biocompatible polymer, a
separate bioadhesive agent that enhances the bioadhesive properties
of the therapeutic composition. The bioadhesive agent is frequently
a second polymer having even greater bioadhesive properties.
[0021] In a further enhancement, the therapeutic composition may
include a penetration enhancer, which aids rapid transport of the
pharmaceutical substance across the mucosal epithelium. The
therapeutic composition can also include other components that are
compatible with the pharmaceutical substance and the biocompatible
polymer.
[0022] In another aspect, the invention involves a therapeutic
composition useful for treatment of mucositis at a mucosal site,
with the composition comprising a sulfur-containing antioxidant.
Such sulfur-containing anti-oxidants include those in which the
sulfur is preferably present in a thiol, thioether, thioester,
thiourea, thiocarbamate, disulfide, or sulfonium group. A
particularly preferred sulfur-containing antioxidant is
N-acetylcysteine.
[0023] In another aspect, the present invention involves use of the
therapeutic composition, in any form and with any formulation, for
treatment of mucositis.
[0024] In another aspect, a method is provided for delivering to a
mucosal site a pharmaceutical substance for treatment of mucositis
at a mucosal site, involving introduction into a host of a
therapeutic composition of the invention. In one embodiment, the
method involves introducing a therapeutic composition into the
host, with the therapeutic composition comprising the
pharmaceutical substance and a biocompatible polymer. After the
therapeutic composition is introduced into the host, at least a
portion of the biocompatible polymer and the pharmaceutical
substance adhere to a mucosal surface at the mucosal site.
[0025] Both the foregoing general description and the following
detailed description are exemplary and explanatory and are intended
to provide explanation of the invention as claimed. Other objects,
advantages and novel features will be readily apparent to those
skilled in the art from the following detailed description of the
invention.
BRIEF DESCRIPTION OF THE DRAWING
[0026] FIG. 1 is a plot of the clinical mucositis scores in the
hamster buccal pouch following acute radiation and application of
antioxidant-containing formulations. The various formulations
(described in Table 1) were applied topically to the buccal pouch
of Golden Syrian hamsters for 30 days. One day after beginning the
application the buccal pouch was irradiated with one acute dose of
radiation. The pouch was examined for mucositis by visually
inspecting the pouch and scored for clinical mucositis.
DETAILED DESCRIPTION OF THE INVENTION
[0027] As used herein, "NAC" means N-acetylcysteine.
[0028] As used herein, "biocompatible" means not having toxic or
injurious effects on biological function in humans.
[0029] As used herein, "bioadhesive" means having the ability to
adhere to a biological surface such as mucous membranes or other
tissues for an extended period of time.
[0030] As used herein, "transition temperature" or "gel transition
temperature" refers to a temperature at which a material, such as
the biocompatible polymer or the therapeutic composition as the
case may be, changes physical form from a liquid to a gel, or vice
versa.
[0031] As used herein, "reverse-thermal gel transition temperature"
refers to a temperature at which a material, such as the
biocompatible polymer or the therapeutic composition as the case
may be, changes physical form from a liquid to a gel as the
temperature is increased from below to above the temperature, and
changes physical form from a gel to a liquid as the temperature is
decreased from above to below the temperature.
[0032] As used herein, "thermal gelation property" refers to a
property of a material, such as the biocompatible polymer or the
therapeutic composition, as the case may be, to change physical
form from a liquid to a gel, or vice versa, due to a change in
temperature.
[0033] As used herein, "reverse-thermal gelation property" refers
to a property of a material, such as the biocompatible polymer or
the therapeutic composition, as the case may be, to change physical
form from a liquid to a gel with increasing temperature.
[0034] In one aspect, the present invention provides a therapeutic
composition for delivery of mucositis therapeutics to humans,
especially for use when bioadhesion and permeability of the oral
mucositis therapeutic(s) are desired. The composition comprises at
least one, and optionally more than one, mucositis therapeutic and
a biocompatible polymer. Each mucositis therapeutic is a
pharmaceutical substance that provides a therapeutic effect for at
least one of prevention of mucositis and treatment of mucositis,
either alone or in combination with other materials. In that
regard, the therapeutic effect may be due to the direct action of
the pharmaceutical substance of the composition, or may be due to
one or more other materials activated by the pharmaceutical
substance or for which the pharmaceutical substance is a
precursor.
[0035] Nonlimiting examples of mucositis therapeutics useful in the
present invention include antioxidants, antibacterials,
antiinflammatories, anesthetics, analgesics, proteins, peptides,
and cytokines, with antioxidants being particularly preferred.
Optionally, the composition can also comprise a permeability
enhancer and/or an active agent in addition to the oral mucositis
agent(s). The composition can also include other components to the
extent that the presence of the other components is not
inconsistent with performance objectives of the composition.
[0036] The amount of mucositis therapeutic in the therapeutic
composition of the present invention varies depending on the nature
and potency of the therapeutic. In most situations, however, the
amount of oral mucositis therapeutic in the composition will be
less than about 20% w/w relative to the total weight of the
therapeutic composition.
[0037] The therapeutic composition of the present invention
provides a delivery system for bioadhesion, permeation, or
prolonged and sustained action, of the oral mucositis therapeutic,
thereby improving the efficacy of the oral mucositis therapeutic
upon topical application to mucosal surfaces, a route that may
otherwise be an ineffective means of therapy. Furthermore, the
delivery system may reduce the frequency and duration of
administration of the mucositis therapeutic as part of a
treatment.
[0038] Not to be bound by theory but to aid in the understanding of
the invention, it is believed that the therapeutic composition of
the present invention improves bioadhesion onto and permeation into
the mucosa, thus allowing this therapeutic agent to exert its
actions more efficaciously at the target mucosal site. In addition,
it is believed that the therapeutic composition may reduce or
eliminate degradation of the therapeutic agent, again increasing
the effectiveness of the therapeutic agent. Stabilizing agents can
be incorporated into the composition of the present invention
thereby further minimizing the degradation of the mucositis
therapeutic, which directly impacts the effectiveness of the agent
for treating mucositis and the ability to store or transport the
composition.
[0039] The therapeutic composition can be in any convenient
physical form, but is often preferably in the form of a flowable
fluid medium at the time of administration. For example, when
treating for oral mucositis, the therapeutic composition is
preferably sufficiently fluid in character that it can be accepted
in the oral cavity and swished in the manner of a mouthwash. In
this situation, the therapeutic composition will typically include
as its largest constituent a carrier liquid to impart the flowable
fluid properties to the therapeutic composition. In most instances
the carrier liquid will be water. The biocompatible polymer and
mucositis therapeutic are each dissolved in the carrier liquid or
suspended in the carrier liquid as a disperse phase. For example,
the therapeutic composition can comprise an aqueous solution of the
biocompatible polymer, with the mucositis therapeutic also
dissolved in the solution and/or suspended as a precipitate in the
solution. Preferably, both of the biocompatible polymer and the
mucositis therapeutic are dissolved in the carrier liquid, at least
at a temperature at which the therapeutic composition is to be
administered to patients. Having the biocompatible polymer and the
mucositis therapeutic codissolved in the carrier liquid ensures
intimate mixing of the two materials, which promotes adhesion of
the mucositis therapeutic to surfaces of the oral cavity along with
the biocompatible polymer, thereby effectively using the
therapeutic.
[0040] Proper selection of the biocompatible polymer is important
to enhanced performance of therapeutic composition. In one
important embodiment, the biocompatible polymer is selected so that
when the biocompatible polymer is incorporated into the therapeutic
composition, the rheology of the therapeutic composition is such
that the viscosity of the therapeutic composition increases with
increasing temperature in the vicinity of physiological
temperature, which is typically about 37.degree. C. In this way,
the therapeutic composition can be administered as a lower
viscosity flowable fluid medium at a cool temperature, and the
viscosity of the therapeutic composition will increase as the
therapeutic composition is warmed to physiological temperature. In
one preferred embodiment for many applications when it is desirable
for the therapeutic composition to exhibit reverse-thermal
viscosity behavior, the therapeutic composition exhibits
reverse-thermal viscosity behavior over at least some range of
temperatures between 1.degree. C. and the physiological temperature
of the host (e.g., 37.degree. C. for a human host), and preferably
over some range of temperatures between 1.degree. C. and 20.degree.
C. The therapeutic composition can then be administered to the host
in a lower viscosity form at a reduced temperature, typically lower
than 20.degree. C. and more typically form 1.degree. C. to
20.degree. C. Often a refrigerated temperature of from 1.degree. C.
to 10.degree. C. and more often a refrigerated temperature of from
2.degree. C. to 8.degree. C. will be used. For example, the
therapeutic composition may be introduced into the oral cavity at a
temperature of from about 1.degree. C. to about 20.degree. C., and
more preferably a temperature of from about 1.degree. C. to about
10.degree. C.
[0041] Nonlimiting examples of biocompatible polymers that can be
used to make therapeutic composition of the present invention
include polyethers (preferably polyoxyalkylene block copolymers,
with more preferred polyoxyalkylene block copolymers including
polyoxyethylene-polyoxypropyle- ne block copolymers, referred to
herein as POE-POP block copolymers, such as Pluronic.RTM. F68,
Pluronic.RTM. F127, Pluronic.RTM. L121, and Pluronic.RTM. L101, and
Tetronic.RTM. T1501); cellulosic polymers (including
hydroxypropylmethyl cellulose, hydroxymethyl cellulose,
hydroxypropyl cellulose, methyl cellulose and ethylhydroxyethyl
cellulose); gelatin; polyethylene glycol; polyacrylic acid (such as
Carbopol.RTM. gel); polyoxyl-35-castor oil (Cremophor.RTM. EL); and
glycerol (glycerin). Pluronic.RTM., Tetronic.RTM. and
Cremophor.RTM. are trademarks of BASF Corporation. Carbopol.RTM. is
a trademark of B. F. Goodrich. Furthermore, more than one of these
exemplary biocompatible polymers may be included in the composition
to provide the desired characteristics and other biocompatible
polymers or other additives may also be included in the composition
to the extent the inclusion is not inconsistent with performance
requirements of the composition.
[0042] Particularly preferred biocompatible polymers, when the
composition is to be administered with the biocompatible polymer in
solution form dissolved in a solvent, include cellulosic polymers,
glycerin, polyethylene glycol and polyoxyalkylene block
copolymers.
[0043] Reverse-thermal gelation polymers are especially useful for
imparting desirable rheological properties to the therapeutic
composition. These biocompatible reverse-thermal gelation polymers
can be incorporated into the therapeutic composition at
concentrations so that the therapeutic composition has
reverse-thermal gelation properties, or can be incorporated into
the therapeutic composition at a concentration that does not impart
reverse-thermal gelation properties to the therapeutic composition,
but otherwise provides desired viscosity behavior for a particular
application.
[0044] As used herein, the terms "reverse-thermal viscosity
property" and "reverse-thermal viscosity behavior" each refer to a
property of a component or components, and in particular a
biocompatible polymer/water combination, to undergo a viscosity
increase with increasing temperature across at least some
temperature range. A reverse-thermal gelation property is a one
type of reverse-thermal viscosity behavior in which a component or
components, and in particular a biocompatible polymer/water
combination in the therapeutic composition, change from a liquid
form to a gel form as the temperature is raised from below to above
a reverse-thermal gel transition temperature. "Reverse-thermal
gelation polymer" refers to a polymer capable of interacting with a
liquid vehicle, and particularly water, so that the polymer/liquid
vehicle combination exhibits a reverse-thermal gelation property
when the polymer and liquid vehicle are combined in at least some
proportion. It should be appreciated that, if desired, a
reverse-thermal gelation polymer and water can be incorporated into
the therapeutic composition in such proportions that the
therapeutic composition does not have a reverse-thermal gelation
property, or does not even exhibit any reverse-thermal viscosity
behavior. For most situations, however, the presence of
reverse-thermal viscosity behavior is preferred.
[0045] With reverse-thermal viscosity behavior (which may or may
not involve reverse-thermal gelation), the therapeutic composition
can be administered to a patient at a cool temperature, as noted
above, which provides a beneficial `cold` feeling upon tissue, such
as in the oral cavity or esophagus, of the host following
administration. Also the therapeutic composition tends to become
more viscous, and possibly even gelatinous depending upon the
concentration of biocompatible polymer used, as the therapeutic
composition warms to physiological temperature, depending upon the
rapidity with which the therapeutic composition is diluted by
biological fluids. Such reverse-thermal viscosity behavior does
tend to promote greater bioadhesion of the biocompatible polymer
and the pharmaceutical substance onto mucosal surfaces, leading to
longer contact time of the pharmaceutical substance at the targeted
mucosal site.
[0046] Furthermore, the biocompatible polymer and other components
of the therapeutic composition may aid in the permeation of a
mucosal therapeutic into the mucosa. For example, permeation into
the oral mucosa or across oral mucosal cell membranes may aid in
placing the therapeutic agent at additional target sites as well as
provide for sustained action of the therapeutic agent within the
oral mucosa.
[0047] Non-limiting examples of some biocompatible reverse-thermal
gelation polymers include certain polyethers (preferably
polyoxyalkylene block copolymers with more preferred
polyoxyalkylene block copolymers including
polyoxyethylene-polyoxypropylene block copolymers referred to
herein as POE-POP block copolymers, such as Pluronic.TM. F68,
Pluronic.TM. F127, Pluronic.TM. L121, and Pluronic.TM. L101, and
Tetronic.TM. T1501); certain cellulosic polymers, such as
ethylhydroxyethyl cellulose; and certain poly(ether-ester) block
copolymers (such as those disclosed in U.S. Pat. No. 5,702,717, the
entire contents of which are incorporated by reference herein as if
set forth herein in full). Pluronic.TM. and Tetronic.TM. are
trademarks of BASF Corporation. Furthermore, more than one of these
and/or other biocompatible polymers may be included in the
therapeutic composition. Also, other polymers and/or other
additives may also be included in the therapeutic composition to
the extent the inclusion is not inconsistent with the desired
characteristics of the therapeutic composition. Furthermore, these
polymers may be mixed with other polymers or other additives, such
as sugars, to vary the transition temperature, typically in aqueous
solutions, at which reverse-thermal gelation occurs.
[0048] As will be appreciated, any number of biocompatible polymers
may now or hereafter exist that are capable of being used in the
therapeutic composition, and such polymers are specifically
intended to be within the scope of the present invention when
incorporated into the therapeutic composition.
[0049] Polyoxyalkylene block copolymers are particularly preferred
as biocompatible polymers for use in the therapeutic composition. A
polyoxyalkylene block copolymer is a polymer including at least one
block (i.e. polymer segment) of a first polyoxyalkylene and at
least one block of a second polyoxyalkylene, although other blocks
may be present as well. POE-POP block copolymers are one class of
preferred polyoxyalkylene block copolymers for use as the
biocompatible reverse-thermal gelation polymer in the formulated
biocompatible polymer. POE-POP block copolymers include at least
one block of a polyoxyethylene and at least one block of a
polyoxypropylene, although other blocks may be present as well. The
polyoxyethylene block may generally be represented by the formula
(C.sub.2H.sub.4O).sub.b when b is an integer. The polyoxypropylene
block may generally be represented by the formula
(C.sub.3H.sub.6O).sub.a when a is an integer. The polyoxypropylene
block could be for example (CH.sub.2CH.sub.2CH.sub.2O).sub.a, or
could be 1
[0050] Several POE-POP block copolymers are known to exhibit
reverse-thermal gelation properties, and these polymers are
particularly preferred for imparting reverse-thermal viscosity
and/or reverse-thermal gelation properties to the therapeutic
composition. Examples of POE-POP block copolymers include
Pluronic.TM. F68, Pluronic.TM. F127, Pluronic.TM. L121,
Pluronic.TM. L101, and Tetronic.TM. T1501. Tetronic.TM. T1501 is
one example of a POE-POP block copolymer having at least one
polymer segment in addition to the polyoxyethylene and
polyoxypropylene segments. Tetronic.TM. T1501 is reported by BASF
Corporation to be a block copolymer including polymer segments, or
blocks, of ethylene oxide, propylene oxide and ethylene
diamine.
[0051] Some preferred POE-POP block copolymers have the
formula:
HO(C.sub.2H.sub.4O).sub.b(C.sub.3H.sub.6O).sub.a(C.sub.2H.sub.4O).sub.bH
I
[0052] which, in the preferred embodiment, has the property of
being liquid at ambient or lower temperatures and existing as a
semi-solid gel at mammalian body temperatures wherein a and b are
integers in the range of 15 to 80 and 50 to 150, respectively. A
particularly preferred POE-POP block copolymer for use with the
present invention has the following formula:
HO(CH.sub.2CH.sub.2O).sub.b(CH.sub.2(CH.sub.3)CHO).sub.a(CH.sub.2CH.sub.2O-
).sub.bH II
[0053] wherein a and b are integers such that the hydrophobe base
represented by (CH.sub.2(CH.sub.3)CHO).sub.a has a molecular weight
of about 4,000, as determined by hydroxyl number; the
polyoxyethylene chain constituting about 70 percent of the total
number of monomeric units in the molecule and where the copolymer
has an average molecular weight of about 12,600. Pluronic.TM.
F-127, also known as Poloxamer 407, is such a material. In
addition, a structurally similar Pluronic.TM. F-68 may also be
used.
[0054] The procedures used to prepare aqueous solutions which form
gels or viscous solutions of polyoxyalkylene block copolymer are
well known and are disclosed in U.S. Pat. No. 5,861,174, which is
incorporated herein by reference in its entirety. When the
therapeutic composition exhibits reverse-thermal gelation
properties, the amount of biocompatible polymer and the amount of
oral mucositis therapeutic agent are typically selected such that
the resulting composition has a reverse-thermal gel transition
temperature that is not higher than the physiological temperature
of the host (e.g., 37.degree. C. for human hosts). In most
situations, the reverse-thermal gel transition temperature will be
in a range having a lower limit of about 1.degree., more typically
about 10.degree. C., sometimes about 20.degree. C. and sometimes
even 25.degree. C., and having an upper limit typically of about
40.degree. C., more typically about 37.degree. C. and even more
typically about 25.degree. C. Particularly preferred when the
therapeutic composition has reverse-thermal gelation properties is
for the reverse-thermal gel transition temperature to be in a range
of from about 10.degree. C. to about 25.degree. C. In this
situation, the reverse-thermal polymer/liquid vehicle combination
will be in a liquid form when stored at normal refrigeration
storage temperatures of 2.degree. C. to 8.degree. C.
[0055] As noted previously, in a preferred embodiment, at least the
biocompatible polymer is dissolved in the carrier liquid in the
therapeutic composition when the therapeutic composition is in a
flowable medium form. With many of the biocompatible polymers
useful with the present invention, however, at least some of the
polymer will often come out of solution as the therapeutic
composition is warmed in the after introduction into the host. This
is often, but not always, the case, for example, when the
therapeutic composition exhibits a reverse-thermal gel transition
temperature at physiological temperature or lower. In some
instances, the therapeutic composition is diluted by saliva in the
oral cavity, or other by other biological fluids at other mucosal
sites, at such a fast rate and to such an extent so as to entirely
prevent gelling from occurring. However, even when gelling does not
occur, some of the biocompatible polymer and mucosal therapeutic
polymer will adhere to mucosal surfaces. When the therapeutic
composition has the property of increasing viscosity with
increasing temperature, as discussed above, the increasing
viscosity may be accompanied, to some degree, by reduced solubility
of the biocompatible polymer in the carrier liquid, which further
promotes good adhesion to mucosal surfaces. In most situations, the
biocompatible polymer will be substantially entirely dissolved in
the carrier liquid when the temperature of the composition is at a
temperature of about 5.degree. C. There are, however, some
situations where it may be desirable to have the therapeutic
composition be in a gel form even at such low temperatures.
[0056] The concentration of the biocompatible polymer in the
composition will vary depending upon the specific biocompatible
polymer and the specific situation. In most situations, however,
the biocompatible polymer will comprise from about 1% by weight to
about 70% by weight, and more typically from about 5% by weight to
about 20% by weight of the therapeutic composition. For example,
particularly preferred for use of Pluronic.RTM. F-127 in many
applications is a range of from about 10% by weight to about 20% by
weight of the therapeutic composition.
[0057] The therapeutic composition of the present invention can
also comprise other additives, including polymer or therapeutic
agent stabilizers including sucrose, salts, and pH adjusting
agents; preservatives including antioxidants such as butylated
hydroxytoluene, antifungals, and antibacterials; and taste masking
components. Inclusion of taste masking components is particularly
desirable when administration is in the oral cavity, such as for
treatment of oral mucositis or esophagitis. Nonlimiting examples of
taste masking components include fruit flavorings (and particularly
citrus flavorings), mint flavorings, salt, or sugars. In one
preferred embodiment, the taste masking component imparts a citrus
flavor, and preferably lemon flavor to the composition, such as
when the taste masking component comprises lemon juice or a lemon
extract.
[0058] The therapeutic composition of the present invention can
also include a penetration enhancer. As used herein, a penetration
enhancer is any material that, when added to a formulation
including an active agent (such as the mucositis therapeutic in the
therapeutic composition) enables permeation of the active agent
across biological tissues and cells, such as epithelium, thereby
increasing the amount of therapeutic at the target site. While the
penetration enhancer may also act as a mucositis therapeutic or
bioadhesive, the primary purpose of adding the penetration enhancer
is to increase the amount or the rate of permeation of the
mucositis therapeutic into the mucosa. Exemplary penetration
enhancers include various molecular weight chitosans and chitosan
derivatives, such as N,O-carboxymethyl chitosan; fatty acids, such
as lauric acid, lipoic acid, and those extracted from cod-liver
oil, including palmitic and oleic acids; bile salts such as
deoxycholate, glycolate, cholate, taurocholate, taurodeoxycholate,
and glycodeoxycholate; polyoxyethylenesorbitan such as Tween.RTM.
20 and Tween.RTM. 80; sodium lauryl sulfate;
polyoxyethylene-9-lauryl ether (Laureth.RTM.-9); EDTA; citric acid;
salicylates; caprylic/capric glycerides; sodium caprylate; sodium
caprate; sodium laurate; sodium glycyrrhetinate; dipotassium
glycyrrhizinate; glycyrrhetinic acid hydrogen succinate, disodium
salt (carbenoxolone.RTM.); acylcarnitines such as
palmitoylcarnitine; cyclodextrin; and phospholipids, such as
lysophosphatidylcholine. Preferably, the penetration enhancer is
selected from the group consisting of chitosans, fatty acids, EDTA,
and bile salts. More preferably, the penetration enhancer is
selected from the group consisting of chitosans and fatty
acids.
[0059] When present, the amount of penetration enhancer in the
therapeutic composition of the present invention generally varies
depending on the particular penetration enhancer used. Typically,
however, the amount of penetration enhancer, when used, will be
present in the therapeutic composition in an amount from about
0.001% by weight to about 10% by weight of the therapeutic
composition, preferably from about 0.01% by weight to about 5% by
weight, and more preferably from about 0.01% by weight to about
1.0% by weight. In one particular aspect of the present invention
where chitosan is used as the penetration enhancer, the amount of
chitosan present in the composition is from about 0.01% by weight
to about 10% by weight, preferably from about 0.1% by weight to
about 1% by weight, and more preferably from about 0.1% by weight
to about 0.5% by weight.
[0060] The therapeutic composition of the present invention can
also include a bioadhesive agent that is different than and in
addition to the biocompatible polymer, to further aid in depositing
and holding the mucosal therapeutic in the vicinity of the desired
mucosal tissue for delivery. While the bioadhesive agent may also
act as an mucositis therapeutic or penetration enhancer, the
primary purpose of adding the bioadhesive agent is to increase the
duration of contact between the composition and the mucosal tissue.
Nonlimiting examples of bioadhesive materials include Pluronic.RTM.
F127, Pluronic.RTM. F68, chitosans, salivary or intestinal mucin
glycoproteins, trefoil peptides, hydroxypropylmethyl cellulose, and
polycarbophils. Improved bioadhesion of the composition onto the
mucosa lengthens the contact time of the therapeutic at its target
site. It is believed that increased contact time enables the
mucositis therapeutic to be more effective in preventing or
reducing the severity or duration of mucositis by having a longer
time of action or a longer time with which to permeate the mucosa.
When such a separate bioadhesive polymer is included in the
therapeutic composition, the therapeutic composition will include
at least two polymers, with a first polymer being the biocompatible
polymer as discussed above and the second polymer being a
bioadhesive agent that is more bioadhesive than the first
polymer.
[0061] When a bioadhesive agent is used, the amount of bioadhesive
agent in the therapeutic composition will vary depending on the
nature and potency of the bioadhesive agent. Typically, however,
when included in the therapeutic composition, the amount of the
bioadhesive agent is from about 0.01% by weight of the composition
to about 70% by weight of the composition, more typically from
about 0.1% by weight to about 50% by weight, and most typically
from about 0.1% by weight to about 25% by weight.
[0062] Nonlimiting examples of mucositis therapeutics that may be
used to make the therapeutic composition of the present invention
include antioxidants, antibacterials, antiinflammatories,
anesthetics, analgesics, proteins, peptides and cytokines,
including those currently available or later developed. Preferably
the mucositis therapeutic is selected from the group consisting of
antioxidants. More preferably the antioxidant is selected from the
group consisting of sulfur-containing antioxidants or vitamin
antioxidants, with sulfur-containing antioxidants generally being
more preferred. Even more preferably, the sulfur-containing
antioxidant includes sulfur in at least one constituent group
selected from thiol, thioether, thioester, thiourea, thiocarbamate,
disulfide and sulfonium, with thiol-containing antioxidants (also
referred to as sulfhydryl-containing antioxidants) being
particularly preferred. Some examples of preferred thiol-containing
antioxidants include N-acetylcysteine (NAC) and glutathione. Other
examples of preferred sulfur-containing antioxidants include
S-carboxymethylcysteine and methylmethionine sulfonium
chloride.
[0063] In an especially preferred embodiment, the sulfur-containing
antioxidants are precursors for biosynthesis of glutathione in the
host, such as by providing cysteine or a precursor for cysteine for
glutathione synthesis. In this way, the mucosal therapeutic
promotes the production of glutathione. Examples of antioxidants
that are precursors for glutathione biosynthesis include NAC,
procysteine, lipoic acid, s-allyl cysteine, and methylmethionine
sulfonium chloride. In one preferred embodiment the mucositis
therapeutic is NAC.
[0064] Examples of vitamin antioxidants include vitamin E, vitamin
E mimetics, vitamin E analogs, vitamin C, and vitamin A.
Particularly preferred in the vitamin class of antioxidants are
water soluble vitamin forms of vitamin E, including Trolox and
vitamin E TGPS (d-.alpha.-tocopherol polyethylene glycol 1000
succinate).
[0065] The action and selection of the antioxidant are not limited
by the above description as many antioxidants may have a multitude
of actions and thus fall under several classes of antioxidants or
several classes of therapeutic agents. For example, NAC may
directly scavenge free radicals extracellularly and provide
cysteine intracellularly as a precursor for intracellular
scavenging of free radicals via glutathione biosynthesis and
regulation of glutathione-dependent antioxidative enzymes. Another
example includes curcumin, which, in addition to its antioxidative
action, possesses anti-inflammatory and antiproliferative actions
that are beneficial in preventing or alleviating the clinical
course of oral mucositis. In addition to therapeutic action, the
antioxidant selected may exert other beneficial effects as a
component of the therapeutic composition including bioadhesion as
in the case of lipid soluble forms of vitamin E and penetration
enhancement as in the case of lipoic acid, curcumin, and vitamin E
TGPS.
[0066] The amount of mucosal therapeutic included in the
therapeutic composition of the present invention varies depending
on the nature and potency of the particular therapeutic. Typically,
however, the amount of mucosal therapeutic present in the
therapeutic composition is in a range having a lower limit
typically of about 0.001%, more typically about 0.01%, and even
more typically about 0.1% by weight of the therapeutic composition,
and having an upper limit of typically about 50%, more typically
about 25%, and even more typically about 10% by weight of the
therapeutic composition.
[0067] The therapeutic composition of the present invention may be
administered to a host (patient) to achieve any desired effect in
the clinical outcome of the targeted mucositis. Preferably the host
is a mammal, and more preferably a human. The therapeutic
composition can be administered in a variety of forms adapted to
the chosen route of administration.
[0068] When treating for oral mucositis, the therapeutic
composition is contacted with the oral mucosa in the oral cavity.
Administration in this situation can include, for example, use of a
mouthwash, spray, lollipop or other product form of the
formulation. Preferably, the mode of administering the therapeutic
composition for treating oral mucositis is a mouthwash which, after
being swished in the mouth, may then be spit out or, more
preferably, swallowed in order to coat both mucosal surfaces in the
mouth and in the esophagus, as well as provide systemic effects
upon gastrointestinal absorption.
[0069] The therapeutic composition is typically prepared in water
or a saline solution. Under ordinary conditions of storage and use,
these preparations can also contain a preservative to prevent the
growth of microorganisms. For oral mucositis applications, the
therapeutic composition typically is a fluid, i.e., in a liquid
form, to the extent that it is palatable and thus, easily
tolerated, by the often nauseous cancer patient. The therapeutic
composition can be stable under the conditions of manufacture and
storage and preferably preserved against the contaminating action
of microorganisms such as bacteria and fungi. The carrier liquid
can be a solvent of dispersion medium containing, for example,
water, ethanol, polyol (e.g., glycerol, propylene glycol, and
liquid polyethylene glycol, and the like), and suitable mixtures
thereof. The proper fluidity can be maintained, for example, by
maintaining the temperature of the therapeutic composition having
reverse-thermal gelation properties below the transition
temperature. The prevention of the action of microorganisms can be
brought about by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal,
benzoic acid, alcohol, benzalkonium chloride and the like. In many
cases, it will be preferable to include isotonic agents, e.g.,
sugars, phosphate buffers, sodium benzoate, sodium chloride, or
mixtures thereof.
[0070] In many situations, it will be desirable for the therapeutic
composition to be in the form of a flowable medium when introduced
into the host for treatment of a mucosal site. This will often be
the case for example for oral mucositis applications in which the
therapeutic composition is to be administered as a refrigerated
mouthwash. In one preferred embodiment, the therapeutic composition
has a relatively low viscosity when the therapeutic composition is
at a temperature for introduction into the host for treatment. In
this embodiment, the viscosity of the therapeutic composition when
introduced into the host is no larger than 60 cP (centipoises), and
more preferably no larger than 50 cP. Because the therapeutic
composition is typically administered at a reduced temperature, in
this embodiment, the therapeutic composition will preferably have a
viscosity at 2.degree. C. of no larger than 60 cP and more
preferably no larger than 50 cP. When the therapeutic composition
exhibits reverse-thermal viscosity behavior, the viscosity of the
therapeutic composition will preferably exhibit an increase in
viscosity from a viscosity of no larger than 60 cP (and more
preferably no larger than 50 cP) to a viscosity of at least 70 cP,
or even 80 cp or more (and more preferably even larger) as the
temperature of the therapeutic composition is increased over at
least some range of temperatures between 1.degree. C. and the
physiological temperature of the host (e.g., 37.degree. C. for a
human host). When the therapeutic composition has reverse-thermal
gelation properties, the viscosity will often increase to a level
of 90 cp, or even 100 cP or more with an increase in temperature
from below to above the reverse-thermal gel transition
temperature.
[0071] In some situations when treating for oral mucositis, it will
be desirable to specifically target sublingual mucosal surfaces. In
this situation, the therapeutic composition can be sublingually
placed, such as in the form of a tablet, patch or film. In one
preferred sublingual application, the therapeutic composition is
already in the form of a gel when sublingually placed, and the gel
then dissipates as it is diluted with biological fluids. In this
situation, the administered gel can have a thick, pudding-like
texture and can be spooned or squeezed from a tube into the
sublingual location. In this situation, when administered, the
therapeutic composition will typically have a viscosity of at least
70 cP, and more typically a viscosity of at least 80 cP, at least
90 cP or even at least 100 cP.
[0072] For oral mucositis applications when the therapeutic
composition has reverse-thermal gelation properties, the
therapeutic composition can be used as a mouthwash at a temperature
below the reverse-thermal gel transition temperature, whereupon the
therapeutic composition will ordinarily become more viscous or even
gelatinous as it warms inside the mouth. Not all aspects of the
invention when treating for oral mucositis are so limited, however.
For example, in some instances the therapeutic composition may not
become more viscous or gelatinous inside the mouth of the host, but
the biocompatible polymer will still provide some protection to the
oral mucositis therapeutic and enable contact and permeation of the
mucositis therapeutic within the oral mucosa.
[0073] Solutes can be incorporated into the therapeutic composition
of the present invention to stabilize the mucositis therapeutic.
Stabilizing solutes such as those that modify the pH of the
therapeutic composition or a second antioxidant, may aid in
protecting and stabilizing the therapeutic by keeping it in a
reduced, thus active, form. Furthermore, pH modification, inclusion
of an antioxidant (in addition to the mucositis therapeutic), or
inclusion of a solute such as sucrose may not only aid in
protecting and stabilizing the therapeutic, but also allow the
biocompatible polymer to form solutions at suitable viscosities at
lower concentrations than needed in water or buffer alone and/or to
change the transition temperature at which thermal gelation occurs.
Thus, the working range of biocompatible polymer concentration can
be widened and the transition temperature modified.
[0074] It is known that in some cases a gel will not form when the
concentration of polyoxyethelene-polyoxypropylene block copolymer
in water or dilute buffer is outside a particular range, e.g.,
equal to or less than 15% by weight in water for Pluronic.TM. F127.
However, by introducing therapeutic-stabilizing solutes, or other
components, into the therapeutic composition of the present
invention, the transition temperature may be manipulated, while
also lowering the concentration of polyoxyethelene-polyoxypropylene
block copolymer that is necessary to form a gel. Also, the presence
of the mucosal therapeutic, a penetration enhancer and other
additives, tend to alter the viscosity behavior of the therapeutic
composition, often by lowering the concentration of the
reverse-thermal gelation polymer required to impart reverse-thermal
gelation properties to the therapeutic composition.
[0075] Much of the foregoing description has been primarily
directed to the treatment of oral mucositis. It should be
recognized, however, that the same principles discussed above are
also generally applicable to treatment of mucosal disorders
occurring in other regions of the body, with the product form of
the therapeutic composition being modified for administration to
the other targeted mucosal site. For example, the therapeutic
composition of the present invention is applicable for the
prevention and/or treatment of mucosal disorders of the esophagus,
vagina, bladder and the entire gastrointestinal tract (for example
including stomach, small intestine, large intestine and rectum).
These mucosal disorders include but are not limited to sinusitis,
asthma, inflammatory bowel disease, colitis, cystitis, GERD,
proctitis, stomatitis, celiac disease and Crohn's disease. Mucosal
disorders at these other locations are mechanistically similar to
oral mucositis, and particularly when the disorder is the result of
chemotherapy or radiation therapy. For example, patients undergoing
radiation therapy treatment for non-small cell lung cancer
frequently develop esophagitis as a side effect of treatment.
Esophagitis in this patient population can impede the progress of
cancer treatment. The pharmaceutical substances described above are
also applicable for treatment of mucositis disorders in other
regions of the body. The method of delivery to the affected region
may be by any convenient technique as suitably adapted for the
particular region of the body at issue.
[0076] Depending on the area of delivery the pharmaceutical
substance of the present invention can be formulated in different
product forms. Some examples of possible product forms for
administration of the therapeutic composition include an oral
solution, bladder irrigation solution, gel, slurry, mouthwash,
lozenge, tablet, film, patch, lollipop, spray, drops or
suppository. For example, a gel formulated into a suppository would
be one preferred product form for administration to treat mucosal
surfaces of either the rectum or the vagina. A tablet, patch or
film could be formulated to administer the therapeutic composition
sublingually. A slurry or oral solution could be used for treatment
of mucosal surfaces in the oral cavity, esophagus and/or
gastrointestinal tract. A bladder irrigation solution would be
administered to the bladder by catheter. A spray would be
advantageous in delivering the present invention to either the
nasal cavity or the lungs, while a droplet formulation would be
advantageous for delivery to the eye or inner ear.
[0077] When treating for esophagitis, the therapeutic composition
could be introduced into the oral cavity in the form of a flowable
medium, such as discussed above with respect to treatment for oral
mucositis, with the therapeutic composition being swallowed to coat
at least a portion of mucosal surfaces in the esophagus. The
therapeutic composition could be immediately swallowed after
introduction into the oral cavity, or could be swallowed after it
has first been swished in the oral cavity. In one preferred
embodiment, for treating esophagitis, the therapeutic composition
is introduced into the oral cavity in a highly viscous form,
typically a gel form, that may have a thick, pudding-like texture.
When this highly viscous form is swallowed it moves slowly through
the esophagus to promote good coating of esophageal mucosal
surfaces. When introduced into the oral cavity of the host, the
high viscosity form will be at a temperature where the viscosity of
the therapeutic composition has a viscosity of at least 70 cP,
often at least 80 cP, or even at least 90 cP or at least 100 cP or
more. Also, because the coating effect to the esophageal mucosal
surfaces must be accomplished with only a single pass through the
esophagus, it is highly preferred that the therapeutic composition
include a bioadhesive agent, as discussed above, with a preferred
bioadhesive agent being a carbophil polymer.
[0078] When treating for mucositis in the gastrointestinal tract,
and particularly in the stomach, the therapeutic composition will
generally be administered to the oral cavity and swallowed as
described with treatment of esophagitis. The product form of the
therapeutic composition when introduced into the oral cavity will
preferably be of a form as described with respect to treatment for
esophagitis.
[0079] When treating for mucositis at a nasal mucosal site, the
therapeutic composition is introduced into the nasal cavity to
contact mucosal surfaces in the nasal cavity. For nasal
applications, a preferred method of administration is in the form
of a nasal spray, such as is generated by a nasal nebulizer or
other spray device. Also, for nasal applications it is generally
preferred that the therapeutic composition have reverse-thermal
gelation properties, with a reverse-thermal gel transition
temperature that is no higher than the physiological temperature of
the host. When the spray is generated, the therapeutic composition
should be at a temperature at which the therapeutic composition is
in the form of a flowable medium that can be processed in the
nebulizer or other spray device to generate the desired spray.
[0080] When treating for mucositis at a pulmonary mucosal site, the
therapeutic composition is typically introduced into the host by
inhalation of the therapeutic composition in aerosol form to
introduce the therapeutic composition into at least one lung of the
host. Considerations are similar to delivery of a nasal spray for
nasal applications. For pulmonary applications, however, the
aerosol should preferably have smaller and better controlled
aerosol particle size, such as could be provided by a pulmonary
nebulizer or other inhaler. Again, when generating the aerosol, the
therapeutic composition should be at a temperature where the
therapeutic composition is in the form of a flowable medium.
[0081] When treating for mucositis at a rectal mucosal site, the
therapeutic composition will be introduced into the rectum of the
host. Preferably, for rectal applications the therapeutic
composition will be in the form of a gel at least when the
therapeutic composition is at the physiological temperature of the
host. The therapeutic composition may or may not have
reverse-thermal gelation properties, but preferably does have
reverse thermal gelation properties and is administrable as a
flowable medium below the reverse-thermal gel transition
temperature. Considerations for vaginal applications are similar to
those for rectal applications, except that the therapeutic
composition is introduced into the vagina rather than the
rectum.
[0082] When treating for mucositis at a mucosal site in the
bladder, the therapeutic composition will typically be introduced
into the bladder through a catheter. In this situation, it is
preferred that during administration, the therapeutic composition
be in the form of a flowable medium that is injectable through the
catheter. The therapeutic composition will preferably not have
reverse-thermal gelation properties.
[0083] When treating for mucositis at an ocular mucosal site, the
therapeutic composition is generally introduced into the orbita,
preferably by applying to an eye of the host at least one drop of
the therapeutic composition in the form of a flowable medium. The
therapeutic composition will preferably not have reverse-thermal
gelation properties.
[0084] When treating for mucositis at an aural mucosal site, the
therapeutic composition is generally introduced into the ear, and
preferably into the inner ear, by administration into the ear of at
least one drop of the therapeutic composition in the form of a
flowable medium. The therapeutic composition will preferably not
have reverse-thermal gelation properties.
[0085] The following example is given to illustrate the present
invention. It should be understood that the invention is not to be
limited to the specific conditions or details described in the
example.
EXAMPLE
[0086] This example describes the formulation and use of the
antioxidant, NAC, within a Pluronic.RTM. F127 delivery matrix in
the absence and presence of chitosan as a penetration enhancer, for
preventing or reducing the clinical outcome of oral mucositis in a
hamster model of radiation-induced buccal mucositis.
[0087] Preparation of stock solutions: Pluronic.RTM. F127
(poloxamer 407; BASF Corporation, Washington, N.J.) was autoclaved
and dissolved in sterile water for injection (Abbott Laboratories,
North Chicago, Ill.) at 30% (w/w). Chitosan (medium molecular
weight; Sigma-Aldrich, St. Louis, Mo.) was autoclaved and dissolved
at 3% (w/w) in sterile filtered water for injection containing 1%
(v/v) acetic acid (Fisher Scientific, Fair Lawn, N.J.). NaOH
(Fisher Scientific) was prepared in sterile water for injection at
4 M and sterile filtered.
[0088] Preparation of antioxidant formulations: The antioxidant,
N-acetyl-L-cysteine (NAC; Sigma-Aldrich), was formulated in the
various delivery matrices by weighing and mixing the desired
components under sterile conditions. The pH was determined by
litmus pH paper (Sigma-Aldrich). Examples of antioxidant-containing
formulations are described belowin Table 1.
1TABLE 1 Descriptions of formulations Antioxidant Pluronic .RTM.
Chitosan NaOH Formulation (Wt %) F127 (Wt %) (Wt %) (M) pH N-acetyl
cysteine Tube A2.01 10 16.25 0.5 0.57 4-5 Tube A2.02 10 16.25 0
0.57 4-5 Tube A2.03 10 (in WFI) 0 0 0.57 5-6 Controls Vehicle
control 0 16.25 0.5 0 5-6 Water 0 0 0 0 control (WFI) All
formulations were stored at 2-8.degree. C.
[0089] Use of Antioxidants in an Animal Model of Radiation-Induced
Oral Mucositis:
[0090] Study location and animals: The study was carried out by
Biomodels and Affiliates (Boston, Mass.) at the Massachusetts
College of Pharmacy and Health Sciences. Male Golden Syrian
hamsters (Charles River Laboratories, Wilmington, Mass.), 5 to 6
weeks of age, weighing approximately 90 g at study commencement
were used.
[0091] Radiation: The acute-radiation hamster model was developed
by Dr. Steve Sonis (Harvard School of Dental Medicine, Brigham and
Women's Hospital, Boston, Mass.). Hamsters were anesthetized with
an intraperitoneal injection of sodium pentobarbital (80 mg/kg).
The left buccal pouch was everted, fixed and isolated using a lead
shield. Oral mucositis was induced using a standardized acute
radiation protocol. A single dose of radiation (40 Gy/dose) was
administered to all animals on Day 0. Radiation was generated with
a 250 kilovolt potential (15-ma) source at a focal distance of 50
cm, hardened with a 0.35 mm Cu filtration system. Irradiation
targeted the left buccal pouch mucosa at a rate of 121.5
cGy/minute. This radiation protocol produces `peak` oral mucositis
14 to 18 days after irradiation.
[0092] Formulation application: Each animal was dosed topically 3
times per day by applying 0.25 mL of formulation into the the left
(irradiated) buccal pouch per application. Dosing was carried out
from Day-1 to Day 28.
[0093] Mucositis evaluation: Clinical mucositis was assessed every
2nd day starting on Day 6 to Day 28. Mucositis was evaluated by
visual scoring using a validated photographic scale for comparison.
Following visual scoring, a photograph of each animal's mucosa was
taken so that mucositis could be scored `blind` at the end of the
study.
[0094] Mucositis data: Data showing the results of visual scoring
of mucositis to Day 28 are shown in FIG. 1. Values are the mean
clinical mucositis scores.+-.SEM per formulation treatment group
(N=7 hamsters per group).
2TABLE 2 Description of clinical mucositis scoring: Score:
Description: 0 Pouch completely healthy. No erythema or
vasodilation 1 Light to severe erythema and vasodilation. No
erosion of mucosa 2 Severe erythema and vasodilation. Erosion of
superficial aspects of mucosa leaving denuded areas. Decreased
stippling of mucosa. 3 Formation of off-white ulcers in one or more
places. Ulcers may have a yellow/gray due to pseudomembrane.
Cumulative size of ulcers should equal about 1/4 of the pouch.
Severe erythema and vasodilation. 4 Cumulative size of ulcers
should equal about 1/2 of the pouch. Loss of pliability. Severe
erythema and vasodilation. 5 Virtually all of pouch is ulcerated.
Loss of pliability (pouch can only partially be extracted from
mouth)
[0095] A score of 1-2 is considered to represent a mild stage of
the disease, whereas a score of 3-5 is considered to indicate
moderate to severe mucositis. Following visual scoring, a
photograph was taken of each animal's mucosa using a standardized
technique. At the conclusion of the experiment, all film was
developed and the photographs randomly numbered. At least two
independent trained observers graded the photographs in blinded
fashion using the above-described scale (blinded scoring).
[0096] Clinical mucositis scores in the hamster buccal pouch
following acute radiation and application of NAC-containing
formulations. Values are the mean clinical mucositis scores.+-.SEM
per formulation treatment group (N=7 hamsters per group).
[0097] Results:
[0098] The water control treatment group exhibited the expected
clinical mucositis score (i.e., a score of 3 or 4) at the expected
peak mucositis time (i.e., 14 to 18 days post-irradiation). All
three NAC formulations reduced the mean clinical mucositis scores
relative to the vehicle and water controls, with the NAC formulated
in Pluronic.RTM. F127 (Tube A2.02) being the most effective. The
vehicle appeared to have some beneficial effect in reducing the
mean clinical mucositis score at day 14, but this effect was not
maintained throughout the peak time of mucositis induction.
[0099] The description of the invention, including the foregoing
example, has been presented for purposes of illustration and
description. Moreover, the description is not intended to limit the
variations and modifications commensurate with the above teachings,
and the skill or knowledge in the relevant art are within the scope
of the present invention. It will be apparent to those skilled in
the art that various modifications and variations can be made in
the methods and compositions of the present invention without
departing from the spirit or scope of the present invention, and
thus it is intended that the present invention cover modifications
and variations of this invention provided they come within the
scope of the appended claims and their equivalents. Also, the
preferred embodiment(s) described hereinabove are intended to
explain the best mode known of practicing the invention and to
enable others skilled in the art to utilize the invention in
various embodiments and with the various modifications required by
their particular applications or uses of the invention. Moreover,
to the extent that features are not functionally incompatible, it
is contemplated within the scope of the present invention that any
feature of any disclosed embodiment is combinable in any
combination with any feature of any other embodiment. It is
intended that the appended claims be construed to include alternate
embodiments to the extent permitted by the prior art. Use of the
terms "comprise," "include," "contain," "have" and variations of
those terms are used to indicate the presence of an attribute,
feature or component, but not to the exclusion of the presence of
other possible attributes, features or components.
* * * * *