U.S. patent application number 10/021168 was filed with the patent office on 2002-10-31 for nitric oxide donor composition and method for treatment of anal disorders.
This patent application is currently assigned to Cellegy Pharmaceuticals, Inc.. Invention is credited to Gorfine, Stephen R..
Application Number | 20020161042 10/021168 |
Document ID | / |
Family ID | 26940977 |
Filed Date | 2002-10-31 |
United States Patent
Application |
20020161042 |
Kind Code |
A1 |
Gorfine, Stephen R. |
October 31, 2002 |
Nitric oxide donor composition and method for treatment of anal
disorders
Abstract
A pharmaceutical composition contains a nitric oxide donor and
advantageously an optional corticosteroid and/or topical
anesthetic. The composition is useful in a method for treating anal
disorders such as anal fissure, anal ulcer, hemorrhoidal disease,
levator spasm, and so forth, by topical application to or proximate
the affected area.
Inventors: |
Gorfine, Stephen R.; (New
York, NY) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Cellegy Pharmaceuticals,
Inc.
|
Family ID: |
26940977 |
Appl. No.: |
10/021168 |
Filed: |
December 11, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10021168 |
Dec 11, 2001 |
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08970447 |
Nov 14, 1997 |
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08970447 |
Nov 14, 1997 |
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08666264 |
Jun 20, 1996 |
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5693676 |
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08666264 |
Jun 20, 1996 |
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08371088 |
Jan 10, 1995 |
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08371088 |
Jan 10, 1995 |
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08250555 |
May 27, 1994 |
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5504117 |
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Current U.S.
Class: |
514/509 ;
514/742 |
Current CPC
Class: |
A61P 9/14 20180101; A61K
31/573 20130101; A61P 17/02 20180101; A61P 29/00 20180101; A61P
17/00 20180101; A61P 3/00 20180101; Y10S 514/882 20130101; A61K
31/47 20130101; A61K 31/573 20130101; A61K 33/00 20130101; A61P
1/04 20180101; A61K 31/21 20130101; A61K 31/47 20130101; A61K 31/47
20130101; A61K 31/21 20130101; A61K 31/34 20130101; A61K 31/21
20130101; A61K 2300/00 20130101; A61K 31/34 20130101; A61P 25/02
20180101; A61P 43/00 20180101; A61K 31/34 20130101; A61P 1/00
20180101; Y10S 514/929 20130101; A61K 31/573 20130101; A61K 2300/00
20130101; A61K 31/47 20130101; A61K 31/573 20130101; A61K 31/47
20130101; A61K 31/47 20130101; A61P 25/04 20180101 |
Class at
Publication: |
514/509 ;
514/742 |
International
Class: |
A61K 031/21 |
Claims
What is claimed is:
1. A pharmaceutical composition useful for topical treatment of an
anal disease, said composition comprising an organic nitric oxide
donor in combination with a carrier, in a form selected from the
group consisting of a powder, an aerosol, a liquid to include a
thickened liquid, an ointment and a suppository; wherein if the
organic nitric oxide donor is only nitroglycerin and the
composition is a soft paraffin or petroleum based ointment then the
nitroglycerin is present in an amount excluding 2.0% by weight.
2. The composition of claim 1, wherein the organic nitric oxide
donor is nitroglycerin.
3. The composition of claim 2, which is an ointment.
4. The composition of claim 1, wherein nitroglycerin is the organic
nitric oxide donor, present in an amount from about 0.25 to about
0.45 percent by weight, in an ointment.
5. The composition of claim 1, wherein nitroglycerin is the organic
nitric oxide donor, present in an amount from about 0.07 to about
0.15 percent by weight, in an ointment.
6. The composition of claim 1, which is a suppository.
7. The composition of claim 1, wherein the organic nitric oxide
donor includes at least one organic nitrate represented by the
following general formula: R(--CR'R"--O--NO.sub.2).sub.x wherein:
R, R' and R" are, independently at each occurrence, organic or
hydro moiety or covalent bond, and x is an integer from 1 to about
12.
8. The composition of claim 7, wherein R is a 2 to about 12 carbon
hydrocarbon or oxygen-substituted hydrocarbon; R' is of 2 to 6
carbons and from 0 to 2 oxygen(s), a hydra moiety or a covalent
bond; R" is a hydro moiety; and x is from 2 to 6.
9. The composition of claim 8, which excludes nitroglycerin;
ethylene glycol dinitrate; isopropyl nitrate;
glyceryl-1-mononitrate; glyceryl-1,2-dinitrate;
glyceryl-1,3-dinitrate; butane-1,2,4-triol-trinit- rate; erythrityl
tetranitrate; pentaerythrityl tetranitrate; isosorbide mononitrate;
and isosorbide dinitrate.
10. The composition of claim 1, wherein the organic nitric oxide
donor includes at least one organic nitrate selected from the group
consisting of ethylene glycol dinitrate; isopropyl nitrate;
glyceryl-1-mononitrate; glyceryl-1,2-dinitrate;
glyceryl-1,3-dinitrate; butane-1,2,4-triol-trinit- rate; erythrityl
tetranitrate; pentaerythrityl tetranitrate; isosorbide mononitrate;
and isosorbide dinitrate, in an ointment or suppository form.
11. The composition of claim 1, wherein the organic nitrate donor
is selected from the group consisting of one or more of erythrityl
tetranitrate; pentaerythrityl tetranitrate; and isosorbide
dinitrate.
12. A pharmaceutical composition useful for treating anal disease
comprising an organic nitric oxide donor in combination with a
corticosteroid and a pharmaceutically acceptable topical
carrier.
13. The composition of claim 12, wherein the organic nitric oxide
donor is nitroglycerin.
14. The composition of claim 13, wherein the corticosteroid is
hydrocortisone.
15. The composition of claim 12, wherein a topical anesthetic is
also present.
16. A pharmaceutical composition useful for treating anal disease
comprising an organic nitric oxide donor in combination with a
topical anesthetic and a carrier.
17. The composition of claim 16, wherein the organic nitric oxide
donor is nitroglycerin.
18. The composition of claim 17, wherein the topical anesthetic is
dibucaine.
19. A method for treating an anal disease comprising contacting an
appropriate anal area with an effective amount of nitric oxide.
20. The method of claim 19, wherein the nitric oxide is delivered
by release from an organic nitric oxide donor.
21. The method of claim 20, wherein the organic nitric oxide donor
is an organic nitrate represented by the following general
formula:R(--CR'R"--O--NO.sub.2).sub.x wherein: R, R' and R" are,
independently at each occurrence organic or hydro moiety or
covalent bond, and x is an integer from 1 to about 12.
22. The method of claim 21, wherein R is a 2 to about 12 carbon
hydrocarbon or oxygen-substituted hydrocarbon; R' is of 2 to 6
carbons and from 0 to 2 oxygen(s), a hydro moiety or a covalent
bond; R" is a hydro moiety; and x is from 2 to 6.
23. The method of claim 20, wherein the organic nitric oxide donor
is nitroglycerin.
24. The method of claim 20, wherein at least one agent selected
from the group consisting of a corticosteroid and a topical
anesthetic is employed in conjunction with the nitric oxide
donor.
25. The method of claim 21, wherein at least one agent selected
from the group consisting of a corticosteroid and a topical
anesthetic is employed in conjunction with the nitric oxide
donor.
26. The method of claim 25, wherein the corticosteroid is
hydrocortisone, and the topical anesthetic is dibucaine.
27. The method of claim 19, wherein anal pain is controlled
thereby.
28. The method of claim 19, wherein the anal disease is anal
fissure or ulcer.
29. The method of claim 19, wherein the anal disease is hemorrhoid
disease.
30. The method of claim 19, wherein the anal disease is levator
spasm.
31. The method of claim 28, wherein nitroglycerin is employed.
32. The method of claim 29, wherein nitroglycerin is employed.
33. The method of claim 30, wherein nitroglycerin is employed.
34. The method of claim 31, wherein anal pain is controlled
thereby.
35. The method of claim 32, wherein anal pain is controlled
thereby.
36. The method of claim 33, wherein anal pain is controlled
thereby.
Description
[0001] This is a continuation-in-part of application Ser. No.
08/250,555, filed on May 27, 1994, which is incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] This invention is directed to a composition and method for
treating anal disorders such as anal fissure, anal ulcer,
hemorrhoidal disease and levator spasm, by topical application of
the composition to or proximate the affected area.
[0003] In general, anal fissure (fissure-in-ano), anal ulcer, acute
hemorrhoidal disease, and levator spasm (proctalgia fugax) are
common, benign conditions of the anal canal which affect humans of
all ages, races and sexes. However, these conditions can be
problematical to treat and inconvenient if not painful to endure.
An anal fissure or ulcer is a tear or ulcer of the mucosa or lining
tissue of the distal anal canal. Anal fissure/ulcer can be
associated with other systemic or local diseases but is more
frequently present as an isolated finding. The typical, idiopathic
fissure or ulcer is confined to the anal mucosa, and usually lies
in the posterior midline, distal to the dentate line. The person
with an anal fissure or ulcer frequently experiences anal pain and
bleeding, the pain being more pronounced during and after bowel
movements.
[0004] Hemorrhoids are specialized vascular areas lying subjacent
the anal mucosa. Symptomatic hemorrhoidal disease is manifest by
bleeding, thrombosis and/or prolapse of the hemorrhoidal tissues.
Commonly, internal hemorrhoidal tissue bulges into the anal canal
during defecation causing bleeding and pain. As the tissue
enlarges, further bleeding and pain, prolapse and thrombosis can
ensue. The thrombosis of hemorrhoids is another cause of bleeding
and pain.
[0005] Levator spasm is a condition affecting women more frequently
than men. This syndrome is characterized by spasticity of the
levator ani muscle, a portion of the anal sphincter complex. The
patient suffering from levator spasm may experience severe,
episodic rectal pain. Physical exam may reveal spasm of the
puborectalis muscle and pain may be reproduced by direct pressure
on this muscle. Bleeding is normally not associated with this
condition.
[0006] The underlying causes of these anal disorders are poorly
understood, but all of these conditions are associated with a
relative or absolute degree of anal sphincter hypertonicity. In the
case of anal fissure/ulcer, the abnormality appears to be an
as-yet-unidentified problem of the internal anal sphincter muscle.
The internal sphincter is a specialized, involuntary muscle arising
from the inner circular muscular layer of the rectum. Intra-anal
pressure measurements obtained from people suffering from typical
anal fissure/ulcer disease show an exaggerated pressure response to
a variety of stimuli. The abnormally high intra-anal pressure is
generated by the internal sphincter muscle and is responsible for
non-healing of the fissure or ulcer and the associated pain.
[0007] An abnormal pressure response in the anal canal has also
been observed in people suffering from symptomatic hemorrhoidal
disease. Elevated intra-anal pressures may be a major factor in the
development of this condition. It has been postulated that the pain
associated with acute hemorrhoidal disease is caused in part by
spasm of the internal anal sphincter muscle. Similarly, the pain
associated with levator spasm is induced by the muscle spasm
itself.
[0008] Various therapies have been devised to treat these anal
disorders. Typical, non-surgical therapy includes bulk laxatives
and sitz baths. Sitz baths are helpful because they induce
relaxation of the anal sphincter mechanism. See e.g., Shafik, "Role
of warm-water bath in anorectal conditions: The `thermosphincteric
reflex,`" J. Clin. Gastroenterol., 16:304-308, 1993.
[0009] Topical anal therapy is also used in an effort to promote
healing, relieve pain, and reduce swelling and inflammation. Many
preparations have been tried including those containing local
anesthetics, corticosteroids, astringents, and other agents.
However, none of these preparations has been shown conclusively to
reduce the healing time or to reliably ameliorate associated
pain.
[0010] In certain instances, surgery may be employed to treat anal
disorders. Cases of anal fissure/ulcer or hemorrhoids recalcitrant
to medical therapy are often referred for surgical treatment. In
keeping with the proposed etiology of anal fissure/ulcer, the
current standard surgical procedure therefor is lateral internal
anal sphincterotomy. In this procedure, the internal anal sphincter
muscle is partially cut, thereby reducing the intra-anal pressure.
The lowered pressure allows the fissure/ulcer to heal and also
relieves the associated pain. Surgical hemorrhoidectomy removes the
redundant hemorrhoidal tissue, and many surgeons will perform
concomitant limited internal anal sphincterotomy to lower anal
canal pressure. There is no successful surgical treatment for
levator spasm.
[0011] Recently, a third component of the autonomic nervous system,
known as the enteric nervous system (ENS), has been described and
elucidated. This neural network innervates the gut continuously
from esophagus to anus. It is composed of enteric neurons, and the
processes of extrinsic efferent and afferent neurons of the
traditional autonomic system. This system regulates the motor and
secretory function of the gut. A notable feature of the ENS is the
diversity of chemical messengers which enteric neurons contain and
release. In addition to acetylcholine and norepinephrine, various
peptide and non-peptide substances have been identified which
appear to function as neurotransmitters in the ENS. Inhibitory
non-adrenergic non-cholinergic (NANC) nerves are thought to be
important therein.
[0012] More recently, nitric oxide (NO) has been identified as an
inhibitory transmitter to muscle. It has been shown that NO
mediates the anorectal inhibitory reflex in animals and man. See
e.g., Rattan et al., "Nitric oxide pathway in rectoanal inhibitory
reflex of opossum internal anal sphincter," Gastroenterology,
103:43-50, 1992; Chakder et al., "Release of nitric oxide by
activation of nonadrenergic noncholinergic neurons of internal anal
sphincter," Am. J. Physiol., 264:G7-G12, 1993; O'Kelley et al.,
"Nerve mediated relaxation of the internal anal sphincter: The role
of nitric oxide," Gut, 34:689-693, 1993. See also, Gillespie et
al., "Influence of haemoglobin and erythrocytes on the effects of
EDRF, a smooth muscle inhibitory factor, and nitric oxide on
vascular and non-vascular smooth muscle," Br. J. Pharmacol.,
95:1151-1156, 1988; Ignarro et al., "Nitric oxide and cyclic GMP
formation upon electrical field stimulation cause relaxation of
corpus cavernosum smooth muscle," Biochem. Biophys. Res. Commun.,
170:843-850, 1990; Bult et al., "Nitric oxide as an inhibitory
non-adrenergic non-cholinergic neurotransmitter," Nature,
345:346-3471990. It has been proposed that NO formation, based upon
non-enzymatic NO release from various organic nitrates as catalyzed
in the presence of cysteine, causes direct or indirect activation
of the soluble guanylate cyclase, finally resulting in relaxation
of vascular smooth muscle in vivo. See, Feelisch et al. ,
"Correlation between nitric oxide formation during degradation of
organic nitrates and activation of guanylate cyclase," Eur. J.
Pharmacol., 139:19-30, 1987. See also Fung et al., "Biochemical
mechanism of organic nitrate action," Am. J. Cardiol., 70:4B-10B,
1992.
[0013] Organic nitrates such as nitroglycerin (GTN) , isosorbide
dlnitrate (ISDN), isosorbide mononitrate (ISMN), erythrityl
tetranitrate (ETN), pentaerythrityl tetranitrate (PETN) are known
to cause vasodilation and have been used for decades in the
treatment of angina pectoris. See e.g., Huff et al. (Eds.),
"Physicians' Desk Reference," 41st Edition, Medical Economics
company, Oradell, N.J., 1987, at pages 780, 1176-78, 1533 and
1984-85; Rubin, U.S. Pat. No. 5,059,603 (October 1991); Budavari et
al. (Eds.), "The Merck Index," 11th Edition, Merck & Co.,
Rahway, N.J., 1989, p. 821 (isopropyl nitrate); Fung et al.,
"Biochemical mechanism of organic nitrate action," Am. J. Cardiol.,
70:4B-10B, 1992.
[0014] Corticosteroids such as hydrocortisone have been used for
the treatment of various benign anal disorders for many years.
Studies of this treatment have shown some benefit thereby but not
in a reproducible nor significant fashion.
[0015] Topical anesthetics such as dibucaine, lidocaine, pramoxine,
and others have been used for treatment of anal pain. However, any
relief has been relatively short-lived.
[0016] Various other preparations are known. See e.g., Suzuki et
al., U.S. Pat. No. 4,292,299 (September 1981), note column 5 lines
18-20 & 26-28; Rubin '603, note column 7, lines 61-65 &
example 1; Greiner, U.S. Pat. No. 5,183,663 (February 1993). See
also, Williams, U.S. Pat. No. 4,118,480 (October 1978); Huff et al.
(Eds.), "The Merck Index," 11th Edition, page 198.
SUMMARY OF THE INVENTION
[0017] It is an object of the present invention to provide an
effective treatment for anal diseases such as anal fissure, anal
ulcer, hemorrhoidal disease, and levator spasm, which treatment
includes the rapid relief of pain associated with such
diseases.
[0018] It is another object of the invention to provide a
composition containing an organic nitric oxide donor compound which
can be employed in the treatment of such anal disease(s).
[0019] It is also an object of the invention to provide a method of
treating such anal disease(s) by contacting the affected area with
an effective amount of nitric oxide delivered by release from an
organic nitrate.
[0020] It is a further object of this invention to provide a
composition containing an organic nitric oxide donor compound in
combination with a corticosteroid and/or topical anesthetic which
can be employed in the treatment of such anal disease(s).
[0021] It is a still further object hereof to provide a method of
treating such anal disease(s) by contacting the affected area with
an effective amount of nitric oxide delivered by release from an
organic nitrate plus a corticosteroid and/or topical
anesthetic.
[0022] To accomplish these and other related objects of the
invention, the present invention provides, in one aspect, a
pharmaceutical composition useful for treating anal disease without
debilitating side effects comprising an organic nitric oxide donor
in combination with a carrier, optionally with a corticosteroid
and/or topical anesthetic. In one embodiment, if the organic nitric
oxide donor is only nitroglycerin and the composition is a soft
paraffin or petroleum based ointment then the nitroglycerin is
present in an amount excluding 0.5 percent by weight, and
optionally also excluding 0.2, 1 and/or 2 percent by weight. All
weight percents expressed herein are based on the total weight of
the composition. In another aspect, the invention is directed to a
method for treating an anal disease comprising contacting an
appropriate anal area with an effective amount of nitric oxide,
preferably delivered by release from an organic nitric oxide donor.
The method may also include optional application of a
corticosteroid and/or topical anesthetic to the anal area. The
present invention is useful in treatment of anal disease,
especially anal fissure, anal ulcer, hemorrhoids and levator spasm.
In many patients treatment can be obtained without debilitating
side effects. Notably, and perhaps most significantly, anal pain
can be rapidly and effectively controlled with the composition of
the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0023] All references cited in the present specification are
incorporated herein by reference.
[0024] In general herein, the term "anal" includes musculature and
vasculature tissue of or proximate the anus and/or lower gut. The
term "anal disease" means a disorder of the tissue which may
include musculature and/or vasculature of or proximate the anus
and/or lower gut. The term "organic nitric oxide donor" means an
organic compound or mixture of compounds with at least one of such
compound(s) which can release nitric oxide under physiological or
anal disease treatment conditions.
[0025] The present invention concerns treatment directed at the
underlying cause of anal diseases which include, for example, anal
fissure, anal ulcer, hemorrhoids and/or levator spasm. In general,
the cause of these diseases is believed to be an unidentified
abnormality of the anal sphincter muscles.
[0026] The compositions useful for treatment according to the
present invention can be in suitable topical, including
suppository, form. An appropriate physiologically acceptable
carrier is utilized to contain the organic nitric oxide donor,
optionally with other agent(s) such as a corticosteroid and/or a
topical anesthetic. The methods of treating anal diseases in
accordance with the present invention can employ nitric oxide from
any suitable source.
[0027] The invention may be employed in therapeutic medicine with
human patients. Preferably, the organic nitric oxide donor includes
at least one organic nitrate, which include esters of nitric acid
and may be an acyclic or cyclic compound, such as represented by
the following general formula:
R(--CR'R"--O--NO.sub.2).sub.x
[0028] wherein:
[0029] R is an organic or H (hydro) moiety or covalent bond,
preferably a 2 to about 12 carbon hydrocarbon or oxygen-substituted
hydrocarbon, especially one having 2 to 6 carbons and from 0 to 2
oxygen(s);
[0030] R' is an organic or hydro moiety or covalent bond, and
preferably methyl; lower alkyl, to include ethyl, propyl, butyl,
pentyl, and hexyl; methoxy; lower alkoxy; or hydro;
[0031] R" is an organic or hydro moiety or covalent bond,
preferably methyl, lower alkyl, methoxy, lower alkoxy, or hydro,
and especially hydro; and
[0032] x is an integer from 1 to about 12, and preferably from 2 to
6.
[0033] For instance, the organic nitrate may be ethylene glycol
dinitrate; isopropyl nitrate; glyceryl-1-mcnonitrate;
glyceryl-1,2-dinitrate; glyceryl-1,3-dinitrate; nitroglycerin
(GTN); butane-1,2,4-triol-trinitrat- e; erythrityl tetranitrate
(ETN); pentaerythrityl tetranitrate (PETN) ; isosorbide mononitrate
(ISMN) , which may include isosorbide-2-mononitrat- e (IS2N) and/or
isosorbide-5-mononitrate (IS5N) ; and/or isosorbide dinitrate
(ISDN), and so forth and the like. An advantageous organic nitrate
is GTN, and advantageous other organic nitrates include ISDN, ETN,
PETN, etc., which may have been given regulatory approval for use
in treatments in other fields of medicine on human subjects.
[0034] In general, the organic nitric oxide donor, to include the
organic nitrate, is present in any amount which is effective in the
practice of the treatment of anal disease. In typical practice of
the invention the organic nitric oxide donor can be present in a
concentration from about 0.01 to about 10 percent by weight. All
weight percentages herein are based on the total weight of the
composition. If GTN is the organic nitrate, preferred
concentrations reside in the range of from about 0.01 to about 5
percent by weight. The following table lists some more particular
general ranges for other organic nitrates in compositions of the
invention:
1 Compound Approximate Weight Percents ISDN 0.01 to 7.5, to include
0.3 to 3 ETN 0.01 to 4, to include 0.1 to 1.5 PETN 0.01 to 4, to
include 0.1 to 1.5
[0035] Optionally, a corticosteroid may be present in the
compositions of the present invention. For instance, the
corticosteroid may include hydrocortisone, i.e.,
11-17-21-trihydroxypregn-4-ene-3,20-dione or cortisol, cortisol
acetate, hydrocortisone phosphate, hydrocortisone 21-sodium
succinate, hydrocortisone tebutate, corticosterone, corticosterone
acetate, cortisone, cortisone acetate, cortisone
21B-cyclopentanepropionate, cortisone phosphate, triamcinolone
hexacetonide, dexamethasone phosphate, desonide, betamethasone
dipropionate, mometasone furate, and so forth and the like.
[0036] In general, the corticosteroid may be present in any amount
which is effective in the practice of the treatment of anal
disease. In typical practice of the invention, the corticosteroid
can be present in a concentration from about 0.001 to about 10
percent by weight and preferably from about 0.1 to about 5 percent
by weight. If cortisol is the corticosteroid, preferred
concentrations reside in the range of from about 0.5 to about 2.5
percent by weight. If hydrocortisone is the corticosteroid,
preferred concentrations reside in the range of from about 0.5 to
about 5 percent by weight. If dexamethasone phosphate is the
corticosteroid, preferred concentrations reside in the range of
from about 0.005 to about 0.03 percent by weight.
[0037] Optionally, a topical anesthetic may be present in the
composition of the invention. For instance, the topical anesthetic
may include dibucaine, lidocaine, pramoxine, benzocaine,
tetracaine, and so forth and the like. In general, the topical
anesthetic may be present in any amount which is effective in the
practice of the treatment of anal disease. In typical practice of
the invention, the topical anesthetic can be present in a
concentration from about 0.1 to about 5 percent by weight and
preferably from about 0.5 to about 4 percent by weight based on the
total weight of the composition. If dibucaine is the topical
anesthetic, preferred concentrations reside in the range of from
about 0.25 to about 2 percent by weight. If benzocaine is the
topical anesthetic, preferred concentrations reside in the range of
from about 10 to about 20 percent by weight. If tetracaine is the
topical anesthetic, preferred concentrations reside in the range of
from about 1 to about 2 percent by weight.
[0038] The corticosteroid and topical anesthetic may be employed
together in the practice of the invention.
[0039] As those skilled in the art can appreciate, the composition
of the invention may be formulated in any pharmaceutical state
suitable for topical application, examples of which include liquid,
aerosol, thickened liquid, emulsion, semisolid, powder, and a
tablet or capsule, which may be lubricated for insertion into the
anus. The method of the invention may employ any of such
formulations as may be appropriate for treatment in particular
cases. Advantageously, the composition can be formulated into
highly convenient dosage forms with thickening agents to include
thickened solutions or lotions, ointments to include creams and
gels, and so forth.
[0040] Thickened solutions or lotions and ointments may be formed
by incorporating with the active ingredients various gelling agents
or other thickeners (viscosity increasers) which permit release of
the active ingredients to the skin or tissue upon or following
application. These forms are advantageously employed to lessen the
runoff from the skin or tissue which may occur with more fluid
(less viscous) formulations. Importantly, they also permit more
sustained contact of the active ingredient(s) and any penetration
enhancer with the treated surfaces, thus permitting an enhancement
of the speed of delivery of the active ingredient(s)
subcutaneously, and providing more accurate and controllable
dosing. Accidental spilling and undesired contact with the
composition can also be minimized with such types of
formulations.
[0041] It can be advantageous to employ water-dispersible
thickening agents, i.e., agents dispersible in water to form a
homogeneous distribution or even solution, such as the polyethylene
glycols and similar agents, as they are readily compatible with
water or other diluents which may be formulated in the composition.
Alternatively, an emulsion base may be employed to impart the
desired thickening effect, together with the emollient effect of
the lipoid phase of the emulsion base.
[0042] Water-soluble or water-dispersible thickening bases or
substances may employ polyethylene glycols and the like of
different viscosities depending upon the desired consistency and
concentration of active ingredient(s) which may be incorporated
into the composition. Other thickening agents which may be suitable
for employment herein include but are not limited to
water-dispersible gums, carboxyvinyl polymers, methyl cellulose,
sodium carboxymethyl cellulose, and alginates.
[0043] Lotions and ointments incorporating emulsion bases may
contain the usual ingredients to provide the base, including fatty
alcohols such as acetyl alcohol, an emulsifier such as, for
example, lauryl sulfate, and water. Also, the remainder of a
topical preparation may contain one or more conventional ointment
components such as, for example, white petrolatum, lanolin,
distilled water, and mineral oil in conventional amounts. The
remainder of a suppository may contain conventional amounts of
known suppository components such as, for example, zinc oxide
and/or cocoa butter.
[0044] Pourable pharmaceutical dosages may be provided and
dispensed in graduated containers, or in containers which contain a
given volume, say, for example, 5 or 10 cc, and so forth.
Containers with greater volumes, say, for example, of 20 cc and
greater, can provide convenient multiple dosage forms. Containers
containing a typical single dose, for example, from about 0.5 g to
about 10 g of active ingredient(s), can provide convenient dosage
forms. Squeeze tubes for lotions and ointments and cotton stick
applicators may be employed for topical application of the
composition for liquids ranging from those of water-like viscosity
to the more viscous formulations of thickened compositions and for
powders and the like.
[0045] Dusts may be employed. An inert ingredient such as, for
example, starch and/or talc may be employed to dilute the active
ingredient(s) in powder form.
[0046] The composition of the invention, and the ingredient(s) in a
method, may also be administered by dusting, spraying or misting
such as from shakers, dusting devices, misting devices and aerosol
bottles. Containers of the composition may be charged with any
suitable amount and concentration of ingredient(s). As an
illustration, a container may be charged with a fluid formulation
containing at least about 10 percent by weight of a combination of
active ingredients, along with an aqueous diluent, optionally with
thickening agent(s), physiological salt(s), and so forth. Liquid
compositions, for example, may be administered as low viscosity
substances to semisolid gels or mousses, depending on any amount of
gelling agent(s) and/or surfactant(s) included therein. Such
compositions can be sufficiently fluid to permit their dispensing
by spray or mist from the container and also can meet criteria for
penetrability.
[0047] In treatment according to the invention, an amount of active
ingredient(s) or composition of the invention is contacted with or
applied to the affected anal area or proximate thereto such that an
effective amount of nitric oxide, preferably delivered by release
from an organic nitric oxide donor, is administered. The amount of
active ingredient(s) or composition which is employed should be
effective for the amelioration, control and/or healing of the anal
disease and the prompt and dramatic control or relief of pain
resulting from or associated with the disease. For example, an
ointment composition of the invention can be applied topically at
each application to the external anus and to the distal anal canal
with the finger or an applicator. As an illustrative alternative,
the medication can be delivered intra-rectally as a suppository.
The medication can be applied in this fashion, for example, three
or more times daily in the case of the ointment or once or more
times daily in the case of the suppository.
[0048] Employment of the optional corticosteroid and/or topical
anesthetic in the practice of the invention can provide decidedly
advantageous results. In cases where treatment with an organic
nitrate alone as active treating agent fails to provide relief from
pain and/or healing, most notably, the employment of the
corticosteroid and/or topical anesthetic in combination with the
organic nitrate often can provide significant if not complete
relief from pain and provide for significant if not total healing
as well.
[0049] Pain relief from the invention is rapid and often
dramatic.
[0050] The following examples further illustrate the present
invention. All parts and percentages (percent or %) therein are by
weight, unless otherwise specified.
EXAMPLE 1
[0051] An ointment was prepared by admixing 12.5 g of 2 percent
nitroglycerin in white petrolatum, lanolin, and distilled water
(nitroglycerin ointment, USP 2%; E. Fougera & Co., Melville,
N.Y.) with 37.5 g white petrolatum, USP (VASELINE;
Chesebrough-Ponds USA Co., Greenwich, Conn.) in a laboratory mixing
vessel at room temperature. The resulting mixture was 50 g of a 0.5
percent nitroglycerin ointment.
EXAMPLE 2
[0052] An ointment of 12.5 g of 2 percent nitroglycerin in white
petrolatum, lanolin, and distilled water (nitroglycerin ointment,
USP 2%; E. Fougera & Co., Melville, N.Y.) was admixed with 20 g
of 2.5 percent hydrocortisone in white petrolatum and light mineral
oil (hydrocortisone ointment, USP 2.5%; Clay-Park Labs, Inc.,
Bronx, N.Y.) and with 17.5 g of white petrolatum, USP (VASELINE;
Chesebrough-Ponds USA Co., Greenwich, Conn.) in a laboratory mixing
vessel at room temperature. The resulting mixture was 50 g of a 0.5
percent nitroglycerin and 1 percent hydrocortisone ointment.
EXAMPLE 3
[0053] An ointment of 12.5 g of 2 percent nitroglycerin in white
petrolatum, lanolin, and distilled water (nitroglycerin ointment,
USP 2%; E. Fougera & Co., Melville, N.Y.) was admixed with 25 g
of 1 percent dibucaine, USP, in white petrolatum, light mineral
oil, acetone sodium bisulfite, lanolin, and purified water
(NUPERCAINAL; Ciba Consumer Pharmaceuticals, Edison, N.J.) and with
12.5 g of white petrolatum, USP (VASELINE; Chesebrough-Ponds USA
Co., Greenwich, Conn.) in a laboratory mixing vessel at room
temperature. The resulting mixture was 50 g of a 0.5 percent
nitroglycerin and 0.5 percent dibucaine ointment.
EXAMPLE 4
[0054] An ointment of 2.5 g of 2 percent nitroglycerin in white
petrolatum, lanolin, and distilled water (nitroglycerin ointment,
USP 2%; E. Fougera & Co., Melville, N.Y.) was admixed with 20 g
of 2.5 percent hydrocortisone in white petrolatum and light mineral
oil (hydrocortisone ointment, USP 2.5%; Clay-Park Labs, Inc.,
Bronx, N.Y.) and with 25 g of 1 percent dibucaine, USP, in white
petrolatum, light mineral oil, acetone sodium bisulfite, lanolin,
and purified water (NUPERCAINAL; Ciba Consumer Pharmaceuticals,
Edison, N.J.) and with 2.5 g of white petrolatum, USP (VASELINE;
Chesebrough-Ponds USA Co., Greenwich, Conn.) in a laboratory mixing
vessel at room temperature. The resulting mixture was 50 g of a 0.5
percent nitroglycerin, 1 percent hydrocortisone, and 0.5 percent
dibucaine ointment.
EXAMPLE 5
[0055] A 29-year old female had a 7-day history of anal pain and
bleeding with bowel movements. Physical exam showed posterior
midline anal fissure. The patient rated her pre-treatment pain
{fraction (7/10)}. The patient applied approximately 500 mg of the
ointment as prepared in Example 1, three times daily and after
bowel movements. The patient reported that her pain was gone
following initial application. After two weeks of treatment, the
fissure had healed completely.
EXAMPLE 6
[0056] A 40-year old female had a 3-month history of anal pain and
bleeding with bowel movements. Physical examination showed a
superficial posterior midline anal fissure. The patient rated her
pre-treatment pain {fraction (7/10)}. The patient applied
approximately 500 mg of the ointment as prepared in Example 1,
three times daily and after bowel movements. After one week of
treatment, the patient noted persistent bleeding, but her pain was
rated {fraction (2/10)}. After three weeks of treatment, the
fissure was healed, and the pain was gone.
EXAMPLE 7
[0057] A 36-year old man had a 2-year history of anal pain and
bleeding with bowel movements. Examination showed a posterior
midline anal ulcer. Pre-treatment pain was rated {fraction (9/10)}.
The patient was treated with hydrocortisone/pramoxine cream
(ANALPRAM-HC, 2.5%; Ferndale Laboratories, Inc., Ferndale, Mich.)
three times daily and following bowel movements. After one week of
treatment, the patient rated his pain {fraction (6/10)}, and the
physical condition was essentially unchanged. The patient was then
treated with approximately 500 mg of the ointment as prepared in
Example 2, three times daily and after bowel movements. He reported
"immediate" relief of pain with each application. After one week of
such therapy, the ulcer was smaller, but not yet completely
healed.
EXAMPLE 8
[0058] A 23-year old female had a 1-month history of anal pain and
bleeding with bowel movements. Examination showed a superficial
posterior midline anal fissure. She had previously failed a course
of hydrocortisone therapy. Pre-treatment pain was rated {fraction
(9/10)}. The patient was treated with approximately 500 mg of the
preparation of Example 1, three times daily and after bowel
movements. After one week of treatment, the fissure was still
present, and pain was rated {fraction (8/10)}. The patient was then
treated with approximately 500 mg of the preparation of Example 2,
three times daily and after bowel movements. Following one week of
therapy with the ointment as of Example 2, the patient reported no
pain and no bleeding. Subsequent examination showed that the
fissure had healed.
EXAMPLE 9
[0059] A 27-year old female had a 3-day history of anal pain and
bleeding with bowel movements. Physical examination showed a
superficial anterior midline anal fissure. Pre-treatment pain was
rated {fraction (4/10)}. The patient was treated with the ointment
as of Example 2, approximately 500 mg three times daily and after
bowel movements. Following one week of therapy, the patient
reported that her pain had diminished, and it was rated {fraction
(2/10)}. Examination showed improvement. After another fifteen days
of therapy, the patient was pain free, and the fissure had
healed.
EXAMPLE 10
[0060] A 27-year old man presented with a 5-day history of anal
pain. Physical examination revealed a 1-cm thrombosed external
hemorrhoid in the left anterolateral anal quadrant. The patient was
treated with the ointment as of Example 3, approximately 500 mg
three times daily and after bowel movements. He reported a
significant reduction in anal pain and throbbing three days
later.
EXAMPLE 11
[0061] A 57-year old man was referred for treatment of documented
levator spasm which developed following lower spinal surgery two
years before. The patient was treated with the ointment as of
Example 1, approximately 500 mg intra-anally three times daily and
after bowel movements. He reported improvement of the anorectal
spasm within one day. Treatment was then switched to the
preparation of Example 3, approximately 500 mg intra-anally three
times daily and after bowel movements. Pain relief was not as
great, and so, treatment with the preparation as of Example 1 was
restarted.
EXAMPLE 12--GROUP STUDIES METHODS
[0062] TEH Group: Five patients (three women and two men) were
recruited to participate in a trial of topical nitroglycerin
treatment for acutely thrombosed external hemorrhoids (TEH) . Their
ages ranged from 23 to 51 years old. The duration of their symptoms
ranged from 2 to 4 days. Anorectal examination of all of these
patients revealed TEH in one anal quadrant (three patients) and in
two anal quadrants (two patients). None of these patients had
evidence of internal hemorrhoid thrombosis, fissure, abscess, or
fistula. All of these patients had used one or more topical
preparations (ANUSOL or ANUSOL-HC, Parke-Davis, Morris Plains,
N.J.; PREPARATION H, Whitehall Laboratories, Madison, N.J.;
PROCTOCREAM-HC, Reed & Carnrick, Jersey City, N.J.) without
symptomatic relief.
[0063] Fissure Group: Fifteen patients (ten women and five men)
were recruited to participate in a trial of topical nitroglycerin
treatment for anal fissure or ulcer. Their ages ranged from 23 to
61 years old. The duration of their symptoms ranged from 2 days to
2 years. Three patients had posterior midline anal ulcers; eleven
had acute, posterior midline fissures; one had an acute, anterior
midline anal fissure. Two patients had a history of Crohn's
ileitis. None of these patients had a history of recent anal
surgery.
[0064] After obtaining informed consent from each participant, a
program of therapy was begun. Treatment included psyllium seed (1-2
g daily) and sitz baths as needed. Approximately 500 to 1000 mg of
0.5 percent nitroglycerin ointment as in Example 1 was applied with
the finger to the external anus and distal anal canal four or more
times daily and after bowel movements. All patients were
interviewed and examined one week after initiating the therapy.
Patients of the fissure group were re-examined three weeks after
initiating therapy, and every one week or two weeks thereafter
until either the fissure had healed or eight weeks of the therapy
had passed.
RESULTS
[0065] TEH Group: All patients reported total or near total relief
of anal pain within 2 to 3 minutes of nitroglycerin application.
The nitroglycerin was especially useful in relieving the pain which
typically occurred following defecation. Each application of the
nitroglycerin ointment relieved anal pain from 4 to 6 hours in all
patients. All patients reported the need for fewer sitz baths. The
nitroglycerin ointment was used for an average of three days (range
two to six days). Resolution of the thrombus appeared to follow the
usual time course. Side effects were limited to transient headache
in two patients (40 percent of the group population).
[0066] Fissure Group: All patients reported dramatic relief of anal
pain within 3 to 4 minutes of application of the nitroglycerin
ointment, and the effect of pain relief was sustained from 2 to 6
hours. Most patients reported that the nitroglycerin ointment was
especially useful in relieving the pain that occurred following
defecation. Fourteen patients applied the ointment every four to
six hours while awake. One patient required application every two
to three hours to achieve satisfactory pain control. Of the twelve
with superficial anal fissures, ten (83 percent of this set) were
healed within two weeks, and this set included the two patients
with Crohn's disease. Two patients who had discontinued treatment
after complete healing at two weeks had recurrences of their
fissures. Both responded to another two weeks of therapy with no
further recurrence of symptoms. The remaining two patients with
anal fissures healed after four weeks of continuous treatment. One
patient with a posterior anal ulcer was improved but not completely
healed after two weeks of therapy. She requested sphincterotomy
which resulted in complete healing within another month. Two
patients with posterior anal ulcers were improved but not
completely healed after two months of therapy, and sphincterotomy
was refused in both cases. Side effects were limited to mild,
transient headaches in five patients (33 percent of the group
population).
[0067] The twenty patients in this study experienced dramatic pain
relief after the first dose of the topically applied nitroglycerin
ointment, and healing was significant. The nitroglycerin ointment
topically applied to the anal and rectal area was well tolerated by
most patients in this study. Seven of the twenty human subjects (35
percent of the groups population) experienced headaches after
topical application of the nitroglycerin ointment. The headaches
were generally self-limited and abated after about fifteen
minutes.
EXAMPLE 13
[0068] An ointment is prepared by admixing 8.75 g of 2 percent
nitroglycerin in white petrolatum, lanolin, and distilled water
(nitroglycerin ointment, USP 2%; E. Fougera & Co., Melville,
N.Y.) with 41.25 g white petrolatum, USP (VASELINE;
Chesebrough-Ponds USA Co., Greenwich, Conn.) in a laboratory mixing
vessel at room temperature. The resulting mixture is 50 g of a 0.35
percent nitroglycerin ointment.
[0069] The ointment is effective in the treatment of anal disease
when applied topically to or proximate the affected area.
Therewith, pain relief and healing are significant, and side
effects such as headache are few and/or mild. The ointment can be
employed with humans.
CONCLUSION
[0070] From the foregoing, it will be seen that this invention is
one well adapted to attain all the ends and objects hereinabove set
forth.
[0071] It will be understood that certain features and
subcombinations are of utility and may be employed without
reference to other features and subcombinations. This is
contemplated by and is within the scope of the claims.
[0072] Since many possible embodiments may be made of the invention
without departing from the scope thereof, it is to be understood
that all matter herein set forth is to be interpreted as
illustrative and not in a limiting sense.
* * * * *